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Sample records for autophagic flux mediates

  1. Disturbed Flow Induces Autophagy, but Impairs Autophagic Flux to Perturb Mitochondrial Homeostasis

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    Li, Rongsong; Jen, Nelson; Wu, Lan; Lee, Juhyun; Fang, Karen; Quigley, Katherine; Lee, Katherine; Wang, Sky; Zhou, Bill; Vergnes, Laurent; Chen, Yun-Ru; Li, Zhaoping; Reue, Karen; Ann, David K.

    2015-01-01

    Abstract Aim: Temporal and spatial variations in shear stress are intimately linked with vascular metabolic effects. Autophagy is tightly regulated in intracellular bulk degradation/recycling system for maintaining cellular homeostasis. We postulated that disturbed flow modulates autophagy with an implication in mitochondrial superoxide (mtO2•−) production. Results: In the disturbed flow or oscillatory shear stress (OSS)-exposed aortic arch, we observed prominent staining of p62, a reverse marker of autophagic flux, whereas in the pulsatile shear stress (PSS)-exposed descending aorta, p62 was attenuated. OSS significantly increased (i) microtubule-associated protein light chain 3 (LC3) II to I ratios in human aortic endothelial cells, (ii) autophagosome formation as quantified by green fluorescent protein (GFP)-LC3 dots per cell, and (iii) p62 protein levels, whereas manganese superoxide dismutase (MnSOD) overexpression by recombinant adenovirus, N-acetyl cysteine treatment, or c-Jun N-terminal kinase (JNK) inhibition reduced OSS-mediated LC3-II/LC3-I ratios and mitochondrial DNA damage. Introducing bafilomycin to Earle's balanced salt solution or to OSS condition incrementally increased both LC3-II/LC3-I ratios and p62 levels, implicating impaired autophagic flux. In the OSS-exposed aortic arch, both anti-phospho-JNK and anti-8-hydroxy-2′-deoxyguanosine (8-OHdG) staining for DNA damage were prominent, whereas in the PSS-exposed descending aorta, the staining was nearly absent. Knockdown of ATG5 with siRNA increased OSS-mediated mtO2•−, whereas starvation or rapamycin-induced autophagy reduced OSS-mediated mtO2•−, mitochondrial respiration, and complex II activity. Innovation: Disturbed flow-mediated oxidative stress and JNK activation induce autophagy. Conclusion: OSS impairs autophagic flux to interfere with mitochondrial homeostasis. Antioxid. Redox Signal. 23, 1207–1219. PMID:26120766

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

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    Qinghe Song

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

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

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    Hyunju Kim

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

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

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    Kim, Hyunju; Lee, Kang Il; Jang, Minsu; Namkoong, Sim; Park, Rackhyun; Ju, Hyunwoo; Choi, Inho; Oh, Won Keun

    2016-01-01

    Conessine, a steroidal alkaloid isolated from Holarrhena floribunda, has anti-malarial activity and interacts with the histamine H3 receptor. However, the cellular effects of conessine are poorly understood. Accordingly, we evaluated the involvement of conessine in the regulation of autophagy. We searched natural compounds that modulate autophagy, and conessine was identified as an inhibitor of autophagic flux. Conessine treatment induced the formation of autophagosomes, and p62, an autophagic adapter, accumulated in the autophagosomes. Reactive oxygen species such as hydrogen peroxide (H2O2) result in muscle cell death by inducing excessive autophagic flux. Treatment with conessine inhibited H2O2-induced autophagic flux in C2C12 myoblast cells and also interfered with cell death. Our results indicate that conessine has the potential effect to inhibit muscle cell death by interfering with autophagic flux. PMID:27257813

  5. Autophagic flux data in differentiated C2C12 myotubes following exposure to acetylcholine and caffeine

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    Darin Bloemberg

    2016-06-01

    Full Text Available The C2C12 line of mouse myoblasts is a useful cell culture model in which to conduct in vitro analyses related to skeletal muscle. Here we present data regarding the autophagic response induced by two chemicals known to influence calcium release and contraction in skeletal muscles and C2C12 cells: acetylcholine and caffeine. More specifically, by concurrently administering acetylcholine or caffeine along with chloroquine to differentiated myotubes for various amounts of time and assessing the protein expression of LC3 and p62, we report data on the relative level of autophagic flux induced by these two calcium- and contraction-regulating chemicals.

  6. Autophagic flux data in differentiated C2C12 myotubes following exposure to acetylcholine and caffeine.

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    Bloemberg, Darin; Quadrilatero, Joe

    2016-06-01

    The C2C12 line of mouse myoblasts is a useful cell culture model in which to conduct in vitro analyses related to skeletal muscle. Here we present data regarding the autophagic response induced by two chemicals known to influence calcium release and contraction in skeletal muscles and C2C12 cells: acetylcholine and caffeine. More specifically, by concurrently administering acetylcholine or caffeine along with chloroquine to differentiated myotubes for various amounts of time and assessing the protein expression of LC3 and p62, we report data on the relative level of autophagic flux induced by these two calcium- and contraction-regulating chemicals. PMID:27054179

  7. The Drosophila effector caspase Dcp-1 regulates mitochondrial dynamics and autophagic flux via SesB.

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    DeVorkin, Lindsay; Go, Nancy Erro; Hou, Ying-Chen Claire; Moradian, Annie; Morin, Gregg B; Gorski, Sharon M

    2014-05-26

    Increasing evidence reveals that a subset of proteins participates in both the autophagy and apoptosis pathways, and this intersection is important in normal physiological contexts and in pathological settings. In this paper, we show that the Drosophila effector caspase, Drosophila caspase 1 (Dcp-1), localizes within mitochondria and regulates mitochondrial morphology and autophagic flux. Loss of Dcp-1 led to mitochondrial elongation, increased levels of the mitochondrial adenine nucleotide translocase stress-sensitive B (SesB), increased adenosine triphosphate (ATP), and a reduction in autophagic flux. Moreover, we find that SesB suppresses autophagic flux during midoogenesis, identifying a novel negative regulator of autophagy. Reduced SesB activity or depletion of ATP by oligomycin A could rescue the autophagic defect in Dcp-1 loss-of-function flies, demonstrating that Dcp-1 promotes autophagy by negatively regulating SesB and ATP levels. Furthermore, we find that pro-Dcp-1 interacts with SesB in a nonproteolytic manner to regulate its stability. These data reveal a new mitochondrial-associated molecular link between nonapoptotic caspase function and autophagy regulation in vivo. PMID:24862573

  8. 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.

  9. The Drosophila effector caspase Dcp-1 regulates mitochondrial dynamics and autophagic flux via SesB

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    DeVorkin, Lindsay; Go, Nancy Erro; Hou, Ying-Chen Claire; Moradian, Annie; Morin, Gregg B.; Gorski, Sharon M.

    2014-01-01

    Increasing evidence reveals that a subset of proteins participates in both the autophagy and apoptosis pathways, and this intersection is important in normal physiological contexts and in pathological settings. In this paper, we show that the Drosophila effector caspase, Drosophila caspase 1 (Dcp-1), localizes within mitochondria and regulates mitochondrial morphology and autophagic flux. Loss of Dcp-1 led to mitochondrial elongation, increased levels of the mitochondrial adenine nucleotide t...

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

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

    2016-02-01

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

  11. Analysis of Relevant Parameters for Autophagic Flux Using HeLa Cells Expressing EGFP-LC3.

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    Muñoz-Braceras, Sandra; Escalante, Ricardo

    2016-01-01

    Macroautophagy (called just autophagy hereafter) is an intracellular degradation machinery essential for cell survival under stress conditions and for the maintenance of cellular homeostasis. The hallmark of autophagy is the formation of double membrane vesicles that engulf cytoplasmic material. These vesicles, called autophagosomes, mature by fusion with endosomes and lysosomes that allows the degradation of the cargo. Autophagy is a dynamic process regulated at multiple steps. Assessment of autophagy is not trivial because the number autophagosomes might not necessarily reflect the real level of autophagic degradation, the so-called autophagic flux. Here, we describe an optimized protocol for the analysis of relevant parameters of autophagic flux using HeLa cells stably expressing EGFP-LC3. These cells are a convenient tool to determine the influence of the downregulation or overexpression of specific proteins in the autophagic flux as well as the analysis of autophagy-modulating compounds. Western blot analysis of relevant parameters, such as the levels of EGFP-LC3, free EGFP generated by autophagic degradation and endogenous LC3·I-II are analyzed in the presence and absence of the autophagic inhibitor chloroquine. PMID:27613046

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

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    Highlights: •Free fatty acids exposure induces elevated autophagy. •H2O2 inhibits autophagic flux through impairing the fusion between autophagosomes and lysosomes. •Inhibition of autophagy potentiates H2O2-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 H2O2 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

  13. 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.

  14. Autophagic flux inhibition and lysosomogenesis ensuing cellular capture and retention of the cationic drug quinacrine in murine models.

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    Parks, Alexandre; Charest-Morin, Xavier; Boivin-Welch, Michael; Bouthillier, Johanne; Marceau, Francois

    2015-01-01

    uptake of micromolar quinacrine at the plasma membrane level. As shown in vitro and in vivo, V-ATPase-mediated cation sequestration is associated, above a certain threshold, to autophagic flux inhibition and feed-back lysosomogenesis. PMID:26500823

  15. Paternal mitochondrial destruction after fertilization is mediated by a common endocytic and autophagic pathway in Drosophila.

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    Politi, Yoav; Gal, Liron; Kalifa, Yossi; Ravid, Liat; Elazar, Zvulun; Arama, Eli

    2014-05-12

    Almost all animals contain mitochondria of maternal origin only, but the exact mechanisms underlying this phenomenon are still vague. We investigated the fate of Drosophila paternal mitochondria after fertilization. We demonstrate that the sperm mitochondrial derivative (MD) is rapidly eliminated in a stereotypical process dubbed paternal mitochondrial destruction (PMD). PMD is initiated by a network of vesicles resembling multivesicular bodies and displaying common features of the endocytic and autophagic pathways. These vesicles associate with the sperm tail and mediate the disintegration of its plasma membrane. Subsequently, the MD separates from the axoneme and breaks into smaller fragments, which are then sequestered by autophagosomes for degradation in lysosomes. We further provide evidence for the involvement of the ubiquitin pathway and the autophagy receptor p62 in this process. Finally, we show that the ubiquitin ligase Parkin is not involved in PMD, implying a divergence from the autophagic pathway of damaged mitochondria. PMID:24823375

  16. ESCRT-0 dysfunction compromises autophagic degradation of protein aggregates and facilitates ER stress-mediated neurodegeneration via apoptotic and necroptotic pathways

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    Oshima, Ryuji; Hasegawa, Takafumi; Tamai, Keiichi; Sugeno, Naoto; Yoshida, Shun; Kobayashi, Junpei; Kikuchi, Akio; Baba, Toru; Futatsugi, Akira; Sato, Ikuro; Satoh, Kennichi; Takeda, Atsushi; Aoki, Masashi; Tanaka, Nobuyuki

    2016-01-01

    Endosomal sorting required for transport (ESCRT) complexes orchestrate endo-lysosomal sorting of ubiquitinated proteins, multivesicular body formation and autophagic degradation. Defects in the ESCRT pathway have been implicated in many neurodegenerative diseases, but the underlying molecular mechanisms that link them to neurodegeneration remain unknown. In this study, we showed that forebrain-specific ablation of ESCRT-0/Hrs induced marked hippocampal neuronal cell loss accompanied by the accumulation of ubiquitinated proteins, including α-synuclein, TDP-43 and huntingtin as well as the autophagic substrate SQSTM1/p62. Consistent with this, silencing of Hrs in cultured cells not only led to α-synuclein and TDP-43 accumulation in addition to impaired autophagic flux but also suppressed cell viability through the induction of ER stress followed by the activation of JNK and RIPK1, a key regulator of necroptosis. Moreover, necrostatin-1, a specific inhibitor of RIPK1, and pan-caspase inhibitors partially reduced the neurotoxicity in the Hrs-silenced cells. Altogether, these findings suggest that the disruption of ESCRT-0/Hrs in the nervous system compromises autophagic/lysosomal degradation of neurodegenerative disease-related proteins, which thereby triggers ER stress-mediated apoptotic and necroptotic cell death. PMID:27112194

  17. Autophagy initiation correlates with the autophagic flux in 3D models of mesothelioma and with patient outcome.

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    Follo, Carlo; Barbone, Dario; Richards, William G; Bueno, Raphael; Broaddus, V Courtney

    2016-07-01

    Understanding the role of autophagy in cancer has been limited by the inability to measure this dynamic process in formalin-fixed tissue. We considered that 3-dimensional models including ex vivo tumor, such as we have developed for studying mesothelioma, would provide valuable insights. Using these models, in which we could use lysosomal inhibitors to measure the autophagic flux, we sought a marker of autophagy that would be valid in formalin-fixed tumor and be used to assess the role of autophagy in patient outcome. Autophagy was studied in mesothelioma cell lines, as 2-dimensional (2D) monolayers and 3-dimensional (3D) multicellular spheroids (MCS), and in tumor from 25 chemonaive patients, both as ex vivo 3D tumor fragment spheroids (TFS) and as formalin-fixed tissue. Autophagy was evaluated as autophagic flux by detection of the accumulation of LC3 after lysosomal inhibition and as autophagy initiation by detection of ATG13 puncta. We found that autophagic flux in 3D, but not in 2D, correlated with ATG13 positivity. In each TFS, ATG13 positivity was similar to that of the original tumor. When tested in tissue microarrays of 109 chemonaive patients, higher ATG13 positivity correlated with better prognosis and provided information independent of known prognostic factors. Our results show that ATG13 is a static marker of the autophagic flux in 3D models of mesothelioma and may also reflect autophagy levels in formalin-fixed tumor. If confirmed, this marker would represent a novel prognostic factor for mesothelioma, supporting the notion that autophagy plays an important role in this cancer. PMID:27097020

  18. 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. PMID:26890602

  19. Epigallocatechin-3-gallate attenuates impairment of learning and memory in chronic unpredictable mild stress-treated rats by restoring hippocampal autophagic flux.

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    Hong-Feng Gu

    Full Text Available Epigallocatechin gallate (EGCG is a major polyphenol in green tea with beneficial effects on the impairment in learning and memory. Autophagy is a cellular process that protects neurons from stressful conditions. The present study was designed to investigate whether EGCG can rescue chronic unpredictable mild stress (CUMS-induced cognitive impairment in rats and whether its protective effect involves improvement of autophagic flux. As expected, our results showed that CUMS significantly impaired memory performance and inhibited autophagic flux as indicated by elevated LC3-II and p62 protein levels. At the same time, we observed an increased neuronal loss and activated mammalian target of rapamycin (mTOR/p70 ribosomal protein S6 kinase (p70S6k signaling in the CA1 regions. Interestingly, chronic treatment with EGCG (25 mg/kg, i.p. significantly improved those behavioral alterations, attenuated histopathological abnormalities in hippocampal CA1 regions, reduced amyloid beta1-42 (Aβ1-42 levels, and restored autophagic flux. However, blocking autophagic flux with chloroquine, an inhibitor of autophagic flux, reversed these effects of EGCG. Taken together, these findings suggest that the impaired autophagy in CA1 regions of CUMS rats may contribute to learning and memory impairment. Therefore, we conclude that EGCG attenuation of CUMS-induced learning and memory impairment may be through rescuing autophagic flux.

  20. p-Cresol mediates autophagic cell death in renal proximal tubular cells.

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    Lin, Hsin-Hung; Huang, Chiu-Ching; Lin, Tze-Yi; Lin, Ching-Yuang

    2015-04-01

    Higher serum level of p-cresol (PC) in chronic kidney disease (CKD) patients has been linked with CKD progression. The toxic effect of PC on diverse cells has been reported by prior studies, except for renal tubular cells. Both autophagy and apoptosis contribute to renal tubular cell death, yet evidence of its response to PC is limited and their crosstalk is still unclear. Autophagy is an important cellular process involved in toxin-induced cell death. Renal tubular cell death in tubular injury is thought to be one of the key events causing the progression of CKD. Thus, we treated rat (NRK-52E) and human (HRPTEC) renal proximal tubular cells (RPTC) with PC and found the cell proliferation was significantly decreased. Cell apoptosis was significantly increased and accompanied with the activation of autophagy as evidenced by increases in LC3-II, beclin 1 and Atg 4. We also found an increase of p62 by c-Jun activation. p62 accumulation could mediate the activation of caspase 8-dependent cell apoptosis. Conversely, knockdown of p62 by siRNA of p62 had the opposite effect by arresting LC3-II accumulation and promoting increasing cell viability. We conclude that PC triggered autophagic RPTC death via JNK-mediated p62 accumulation and then activated caspase 8-dependent cell death pathway. PC can be considered as one of the key events causing progression of CKD, which might affect drug disposition in CKD cases. PMID:25668154

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

    International Nuclear Information System (INIS)

    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. 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.

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

    International Nuclear Information System (INIS)

    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 KM 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

  4. Autophagic Cell Death and Apoptosis Jointly Mediate Cisatracurium Besylate-Induced Cell Injury

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    Haixia Zhuang

    2016-04-01

    Full Text Available Cisatracurium besylate is an ideal non-depolarizing muscle relaxant which is widely used in clinical application. However, some studies have suggested that cisatracurium besylate can affect cell proliferation. Moreover, its specific mechanism of action remains unclear. Here, we found that the number of GFP-LC3 (green fluoresent protein-light chain 3 positive autophagosomes and the rate of mitochondria fracture both increased significantly in drug-treated GFP-LC3 and MitoDsRed stable HeLa cells. Moreover, cisatracurium promoted the co-localization of LC3 and mitochondria and induced formation of autolysosomes. Levels of mitochondrial proteins decreased, which were reversed by the lysosome inhibitor Bafinomycin A1. Similar results with evidence of dose-dependent effects were found in both HeLa and Human Umbilical Vein Endothelial Cells (HUVECs. Cisatracurium lowered HUVEC viability to 0.16 (OD490 at 100 µM and to 0.05 (OD490 after 48 h in vitro; it increased the cell death rate to 56% at 100 µM and to 60% after 24 h in a concentration- and time-dependent manner (p < 0.01. Cell proliferation decreased significantly by four fold in Atg5 WT (wildtype MEF (mouse embryonic fibroblast (p < 0.01 but was unaffected in Atg5 KO (Knockout MEF, even upon treatment with a high dose of cisatracurium. Cisatracurium induced significant increase in cell death of wild-type MEFs even in the presence of the apoptosis inhibitor zVAD. Thus, we conclude that activation of both the autophagic cell death and cell apoptosis pathways contributes to cisatracurium-mediated cell injury.

  5. Aurantiamide acetate suppresses the growth of malignant gliomas in vitro and in vivo by inhibiting autophagic flux.

    Science.gov (United States)

    Yang, Yi; Zhang, Li-hui; Yang, Bing-xian; Tian, Jin-kui; Zhang, Lin

    2015-05-01

    We aim to investigate the effect of aurantiamide acetate isolated from the aerial parts of Clematis terniflora DC against gliomas. Human malignant glioma U87 and U251 cells were incubated with different concentrations (0-100 μM) of aurantiamide acetate. Aurantiamide acetate greatly decreased the cell viability in a dose- and time-dependent manner. It induced moderate mitochondrial fragmentation and the loss of mitochondrial membrane potential. No significant difference was found in the alternation of other intracellular organelles, although F-actin structure was slightly disturbed. Apparent ultrastructure alternation with increased autophagosome and autolysosome accumulation was observed in aurantiamide acetate-treated cells. The expression of LC3-II was greatly up-regulated in cells exposed to aurantiamide acetate (P < 0.05 compared with control). The cytoplasmic accumulation of autophagosomes and autolysosomes induced by aurantiamide acetate treatment was confirmed by fluorescent reporter protein labelling. Administration of chloroquine (CQ), which inhibits the fusion step of autophagosomes, further increased the accumulation of autophagosomes in the cytoplasm of U87 cells. Autophagy inhibition by 3-methyladenine, Bafilomycin A1 or CQ had no influence on aurantiamide acetate-induced cytotoxicity, whereas autophagy stimulator rapamycin significantly suppressed aurantiamide acetate-induced cell death. The anti-tumour effects of aurantiamide acetate were further evaluated in tumour-bearing nude mice. Intratumoural injection of aurantiamide acetate obviously suppressed tumour growth, and increased number of autophagic vacuoles was observed in tumour tissues of animals receiving aurantiamide acetate. Our findings suggest that aurantiamide acetate may suppress the growth of malignant gliomas by blocking autophagic flux. PMID:25704599

  6. Fucosylation of LAMP-1 and LAMP-2 by FUT1 correlates with lysosomal positioning and autophagic flux of breast cancer cells.

    Science.gov (United States)

    Tan, Keng-Poo; Ho, Ming-Yi; Cho, Huan-Chieh; Yu, John; Hung, Jung-Tung; Yu, Alice Lin-Tsing

    2016-01-01

    Alpha1,2-fucosyltransferases, FUT1 and FUT2, which transfer fucoses onto the terminal galactose of N-acetyl-lactosamine via α1,2-linkage have been shown to be highly expressed in various types of cancers. A few studies have shown the involvement of FUT1 substrates in tumor cell proliferation and migration. Lysosome-associated membrane protein 1, LAMP-1, has been reported to carry alpha1,2-fucosylated Lewis Y (LeY) antigens in breast cancer cells, however, the biological functions of LeY on LAMP-1 remain largely unknown. Whether or not its family member, LAMP-2, displays similar modifications and functions as LAMP-1 has not yet been addressed. In this study, we have presented evidence supporting that both LAMP-1 and 2 are substrates for FUT1, but not FUT2. We have also demonstrated the presence of H2 and LeY antigens on LAMP-1 by a targeted nanoLC-MS(3) and the decreased levels of fucosylation on LAMP-2 by MALDI-TOF analysis upon FUT1 knockdown. In addition, we found that the expression of LeY was substantial in less invasive ER+/PR+/HER- breast cancer cells (MCF-7 and T47D) but negligible in highly invasive triple-negative MDA-MB-231 cells, of which LeY levels were correlated with the levels of LeY carried by LAMP-1 and 2. Intriguingly, we also observed a striking change in the subcellular localization of lysosomes upon FUT1 knockdown from peripheral distribution of LAMP-1 and 2 to a preferential perinuclear accumulation. Besides that, knockdown of FUT1 led to an increased rate of autophagic flux along with diminished activity of mammalian target of rapamycin complex 1 (mTORC1) and enhanced autophagosome-lysosome fusion. This may be associated with the predominantly perinuclear distribution of lysosomes mediated by FUT1 knockdown as lysosomal positioning has been reported to regulate mTOR activity and autophagy. Taken together, our results suggest that downregulation of FUT1, which leads to the perinuclear localization of LAMP-1 and 2, is correlated with increased

  7. A Cluster of Thin Tubular Structures Mediates Transformation of the Endoplasmic Reticulum to Autophagic Isolation Membrane

    OpenAIRE

    Uemura, Takefumi; Yamamoto, Masaya; Kametaka, Ai; Sou, Yu-shin; Yabashi, Atsuko; Yamada, Akane; Annoh, Hiromichi; Kametaka, Satoshi; Komatsu, Masaaki; Waguri, Satoshi

    2014-01-01

    Recent findings have suggested that the autophagic isolation membrane (IM) might originate from a domain of the endoplasmic reticulum (ER) called the omegasome. However, the morphological relationships between ER, omegasome, and IM remain unclear. In the present study, we found that hybrid structures composed of a double FYVE domain-containing protein 1 (DFCP1)-positive omegasome and the IM accumulated in Atg3-deficient mouse embryonic fibroblasts (MEFs). Moreover, correlative light and elect...

  8. Inhibition of autophagic flux by ROS promotes apoptosis during DTT-induced ER/oxidative stress in HeLa cells.

    Science.gov (United States)

    Xiang, Xi-Yan; Yang, Xiao-Chun; Su, Jin; Kang, Jing-Song; Wu, Yao; Xue, Ya-Nan; Dong, Yu-Tong; Sun, Lian-Kun

    2016-06-01

    As targets for cancer therapy, endoplasmic reticulum (ER) stress and autophagy are closely linked. However, the signaling pathways responsible for induction of autophagy in response to ER stress and its cellular consequences appear to vary with cell type and stimulus. In the present study, we showed that dithiothreitol (DTT) induced ER stress in HeLa cells in a time- and dose-dependent fashion. With increased ER stress, reactive oxygen species (ROS) production increased and autophagy flux, assessed by intracellular accumulation of LC3B-II and p62, was inhibited. N-acetyl-L-cysteine (NAC), a classic antioxidant, exacerbated cell death induced by 3.2 mM of DTT, but attenuated that induced by 6.4 mM DTT. Low cytotoxic doses of DTT transiently activated c-JNU N-terminal kinase (JNK) and p38, whereas high dose of DTT persistently activated JNK and p38 and simultaneously reduced extracellular signal-regulated kinase (ERK) activity. Combined treatment with DTT and U0126, an inhibitor of ERK upstream activators mitogen-activated protein kinase (MAPK) kinase 1 and 2 (MEK1/2), blocked autophagy flux in HeLa cells. This effect was similar to that caused by a combination of DTT and chloroquine (CQ). These data suggested that insufficient autophagy was accompanied by increased ROS production during DTT-induced ER stress. ROS appeared to regulate MAPK signaling, switching from a pro-survival to a pro-apoptotic signal as ER stress increased. ERK inhibition by ROS during severe ER stress blocked autophagic flux. Impaired autophagic flux, in turn, aggravated ER stress, ultimately leading to cell death. Taken together, our data provide the first reported evidence that ROS may control cell fate through regulating the MAPK pathways and autophagic flux during DTT-induced ER/oxidative stress. PMID:27035858

  9. 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

    2016-01-01

    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. PMID:27023584

  10. 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.

  11. U(1) mediation of flux supersymmetry breaking

    International Nuclear Information System (INIS)

    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.

  12. Repairing DNA damage by XRCC6/KU70 reverses TLR4-deficiency-worsened HCC development via restoring senescence and autophagic flux.

    Science.gov (United States)

    Wang, Ziyan; Lin, Heng; Hua, Fang; Hu, Zhuo-wei

    2013-06-01

    Hepatocellular carcinoma (HCC) is among the most lethal and prevalent cancers in the human population. The initiation and progression of HCC is closely associated with chronic liver inflammation. Recent research indicates that nonhomologous end joining (NHEJ), one of the DNA repair mechanisms, autophagy and senescence are all involved in the pathogenesis of HCC induced by carcinogens or oxidative stress. DNA repair proteins including XRCC6/KU70 and XRCC5/KU80 are the critical NHEJ factors that play pivotal roles in genome-maintenance issues such as DNA replication and repair, telomere maintenance and chromosomal instability. Our studies indicate that a deficiency of toll-like receptor 4 (TLR4)-mediated immune activities results in a decreased expression of XRCC5 and XRCC6 in response to insult by the carcinogen diethylnitrosamine (DEN). This effect causes a failure in DNA repair, and promotes the transformation of precancerous hepatocytes and HCC development. Ectopic expression of XRCC6 protects against HCC initiation and progression by restoring the cellular senescent response and activation of immune networks, which induces an effective autophagic degradation, removes the accumulated reactive oxygen species (ROS), decreases DNA damage, attenuates proliferation, and promotes programmed cell death in TLR4-deficient livers. Our work indicates that repairing DNA damage by XRCC6 reverses TLR4-deficiency-worsened HCC development via restoring immunity to support senescence and autophagy in liver cells. PMID:23518600

  13. The Autophagic Machinery in Enterovirus Infection

    Directory of Open Access Journals (Sweden)

    Jeffrey K. F. Lai

    2016-01-01

    Full Text Available 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.

  14. Autophagic pathways in Parkinson disease and related disorders.

    Science.gov (United States)

    Xilouri, Maria; Stefanis, Leonidas

    2011-01-01

    Macroautophagy and chaperone-mediated autophagy (CMA) are the two main mammalian lysosomal proteolytic systems. In macroautophagy, double-membrane structures engulf organelles and other intracellular constituents through a highly regulated process that involves the formation of autophagic vacuoles and their fusion with lysosomes. In CMA, selected proteins are targeted through a nonvesicular pathway to a transport complex at the lysosomal membrane, through which they are threaded into the lysosomes and degraded. Autophagy is important in development, differentiation, cellular remodelling and survival during nutrient starvation. Increasing evidence suggests that autophagic dysregulation causes accumulation of abnormal proteins or damaged organelles, which is a characteristic of chronic neurodegenerative conditions, such as Parkinson disease (PD). Evidence from post-mortem material, transgenic mice, and animal and cellular models of PD suggests that both major autophagic pathways are malfunctioning. Numerous connections exist between proteins genetically linked to autosomal dominant PD, in particular α-synuclein and LRRK2, and autophagic pathways. However, proteins involved in recessive PD, such as PINK1 and Parkin (PINK2), function in the process of mitophagy, whereby damaged mitochondria are selectively engulfed by macroautophagy. This wealth of new data suggests that both autophagic pathways are potential targets for therapeutic intervention in PD and other related neurodegenerative conditions. PMID:21418705

  15. Combined aerobic exercise and enzyme replacement therapy rejuvenates the mitochondrial-lysosomal axis and alleviates autophagic blockage in Pompe disease.

    Science.gov (United States)

    Nilsson, M I; MacNeil, L G; Kitaoka, Y; Suri, R; Young, S P; Kaczor, J J; Nates, N J; Ansari, M U; Wong, T; Ahktar, M; Brandt, L; Hettinga, B P; Tarnopolsky, M A

    2015-10-01

    A unifying feature in the pathogenesis of aging, neurodegenerative disease, and lysosomal storage disorders is the progressive deposition of macromolecular debris impervious to enzyme catalysis by cellular waste disposal mechanisms (e.g., lipofuscin). Aerobic exercise training (AET) has pleiotropic effects and stimulates mitochondrial biogenesis, antioxidant defense systems, and autophagic flux in multiple organs and tissues. Our aim was to explore the therapeutic potential of AET as an ancillary therapy to mitigate autophagic buildup and oxidative damage and rejuvenate the mitochondrial-lysosomal axis in Pompe disease (GSD II/PD). Fourteen weeks of combined recombinant acid α-glucosidase (rhGAA) and AET polytherapy attenuated mitochondrial swelling, fortified antioxidant defense systems, reduced oxidative damage, and augmented glycogen clearance and removal of autophagic debris/lipofuscin in fast-twitch skeletal muscle of GAA-KO mice. Ancillary AET potently augmented the pool of PI4KA transcripts and exerted a mild restorative effect on Syt VII and VAMP-5/myobrevin, collectively suggesting improved endosomal transport and Ca(2+)- mediated lysosomal exocytosis. Compared with traditional rhGAA monotherapy, AET and rhGAA polytherapy effectively mitigated buildup of protein carbonyls, autophagic debris/lipofuscin, and P62/SQSTM1, while enhancing MnSOD expression, nuclear translocation of Nrf-2, muscle mass, and motor function in GAA-KO mice. Combined AET and rhGAA therapy reactivates cellular clearance pathways, mitigates mitochondrial senescence, and strengthens antioxidant defense systems in GSD II/PD. Aerobic exercise training (or pharmacologic targeting of contractile-activity-induced pathways) may have therapeutic potential for mitochondrial-lysosomal axis rejuvenation in lysosomal storage disorders and related conditions (e.g., aging and neurodegenerative disease). PMID:26001726

  16. Role of phosphoinositide 3-kinase in the autophagic death of serum-deprived PC12 cells.

    Science.gov (United States)

    Guillon-Munos, A; van Bemmelen, M X P; Clarke, P G H

    2005-10-01

    The death of serum-deprived undifferentiated PC12 cells shows both autophagic and apoptotic features. Since it is still controversial whether the autophagy is instrumental in the cell death or a mere epiphenomenon, we tested the effects of inhibiting the autophagy by a variety of phosphoinositide 3-kinase inhibitors, and provided evidence that the autophagy, or a related trafficking event, is indeed instrumental in the cell death. Furthermore, by comparing the effects of PI3-K inhibition and caspase-inhibition on autophagic and apoptotic cellular events, we showed that in this case the autophagic and apoptotic mechanisms mediate cell death by parallel pathways and do not act in series. PMID:16151638

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

    Science.gov (United States)

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

    2016-01-01

    Women experience menopause later in life. Menopause is characterized by dramatically decreased circulating estrogen level secondary to loss of ovarian function and atrophic state of genital organs. However, the molecular mechanisms for this process are not fully understood. In this study, we aimed to investigate the potential molecular mechanisms that underlie menopause-induced uterine endometrial atrophy. Our data showed that autophagy was activated in the uterine epithelial cells of both ovariectomized rats and peri-menopausal females. Endoplasmic reticulum (ER) stress occurred even prior to autophagy induction. Integrated bioinformatics analysis revealed that ER stress induced downstream decreased release of arachidonic acid (AA) and downregulation of AA/prostaglandin E2 (PGE2) axis, which led to Akt/mTOR signaling pathway inactivation. Consequently, autophagosomes were recruited and LC3-dependent autophagy was induced in uterine epithelial cells. Treatment with exogenous E2, PGE2, salubrinal or RNAi-mediated silencing of key autophagy genes could effectively counteract estrogen depletion-induced autophagy. Collectively, autophagy is a critical regulator of the uterine epithelium that accounts for endometrial atrophy after menopause. PMID:27506466

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

    Science.gov (United States)

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

    2016-01-01

    Women experience menopause later in life. Menopause is characterized by dramatically decreased circulating estrogen level secondary to loss of ovarian function and atrophic state of genital organs. However, the molecular mechanisms for this process are not fully understood. In this study, we aimed to investigate the potential molecular mechanisms that underlie menopause-induced uterine endometrial atrophy. Our data showed that autophagy was activated in the uterine epithelial cells of both ovariectomized rats and peri-menopausal females. Endoplasmic reticulum (ER) stress occurred even prior to autophagy induction. Integrated bioinformatics analysis revealed that ER stress induced downstream decreased release of arachidonic acid (AA) and downregulation of AA/prostaglandin E2 (PGE2) axis, which led to Akt/mTOR signaling pathway inactivation. Consequently, autophagosomes were recruited and LC3-dependent autophagy was induced in uterine epithelial cells. Treatment with exogenous E2, PGE2, salubrinal or RNAi-mediated silencing of key autophagy genes could effectively counteract estrogen depletion-induced autophagy. Collectively, autophagy is a critical regulator of the uterine epithelium that accounts for endometrial atrophy after menopause. PMID:27506466

  19. Upper Ocean Thermal Responses to Sea Spray Mediated Turbulent Fluxes during Typhoon Passage

    OpenAIRE

    Lianxin Zhang; Changlong Guan; Chunjian Sun; Siyu Gao; Shaomei Yu

    2015-01-01

    A one-dimensional turbulent model is used to investigate the effect of sea spray mediated turbulent fluxes on upper ocean temperature during the passage of typhoon Yagi over the Kuroshio Extension area in 2006. Both a macroscopical sea spray momentum flux algorithm and a microphysical heat and moisture flux algorithm are included in this turbulent model. Numerical results show that the model can well reproduce the upper ocean temperature, which is consistent with the data from the Kuroshio Ex...

  20. 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.

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

    International Nuclear Information System (INIS)

    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

  2. Flavor and CP conserving moduli mediated SUSY breaking in flux compactification

    CERN Document Server

    Choi, Kiwoon; Okumura, Ken-Ichi

    2008-01-01

    In certain class of flux compactification, moduli mediated supersymmetry (SUSY) breaking preserves flavor and CP at leading order in the perturbative expansion controlled by the vacuum expectation value of the messenger modulus. Nevertheless there still might be dangerous flavor or CP violation induced by higher order K\\"ahler potential. We examine the constraints on such SUSY breaking scheme imposed by low energy flavor and/or CP violating observables. It is found that all phenomenological constraints can be satisfied even for generic form of higher order K\\"ahler potential and sparticle spectra in the sub-TeV range, under plausible assumptions on the size of higher order correction and flavor mixing angles. This implies for instance that mirage mediation scheme of SUSY breaking, which involves such modulus mediation together with an anomaly mediation of comparable size, and also the modulus-dominated mediation realized in flux compactification can be free from the SUSY flavor and CP problems, while giving g...

  3. The Regulation of the Autophagic Network and Its Implications for Human Disease

    NARCIS (Netherlands)

    Yang, Jing; Carra, Serena; Zhu, Wei-Guo; Kampinga, Harm H.

    2013-01-01

    Autophagy has attracted a lot of attention in recent years. More and more proteins and signaling pathways have been discovered that somehow feed into the autophagy regulatory pathways. Regulation of autophagy is complex and condition-specific, and in several diseases, autophagic fluxes are changed.

  4. Lysosomal and autophagic reactions as predictive indicators of environmental impact in aquatic animals.

    Science.gov (United States)

    Moore, Michael N; Allen, J Icarus; McVeigh, Allan; Shaw, Jenny

    2006-01-01

    The lysosomal-autophagic system appears to be a common target for many environmental pollutants as lysosomes accumulate many toxic metals and organic xenobiotics, which perturb normal function and damage the lysosomal membrane. In fact, lysosomal membrane integrity or stability appears to be an effective generic indicator of cellular well-being in eukaryotes: in bivalve molluscs and fish, stability is correlated with many toxicological responses and pathological reactions. Prognostic use of adverse lysosomal and autophagic reactions to environmental pollutants has been explored in relation to predicting cellular dysfunction and health in marine mussels, which are extensively used as sensitive bioindicators in monitoring ecosystem health. Derivation of explanatory frameworks for prediction of pollutant impact on health is a major goal; and we have developed a conceptual mechanistic model linking lysosomal damage and autophagic dysfunction with injury to cells and tissues. This model has also complemented the creation of a cell-based computational model for molluscan hepatopancreatic cells that simulates lysosomal, autophagic and other cellular reactions to pollutants. Experimental and simulated results have also indicated that nutritional deprivation-induced autophagy has a protective function against toxic effects mediated by reactive oxygen species (ROS). Finally, coupled measurement of lysosomal-autophagic reactions and modelling is proposed as a practical toolbox for predicting toxic environmental risk. PMID:16874099

  5. 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

    2009-09-01

    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±0.16s−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 of hours; sizes at which

  6. 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

  7. 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.

  8. Inhibition of HDAC6 modifies tau inclusion body formation and impairs autophagic clearance.

    Science.gov (United States)

    Leyk, Janina; Goldbaum, Olaf; Noack, Monika; Richter-Landsberg, Christiane

    2015-04-01

    of apoptotic cell death. Furthermore, the heat shock response is altered, and TST suppresses the MG-132-stimulated induction of HSP70. To test whether the alteration of protein aggregate formation is related to the influence of HDAC6 on the autophagic degradation system, an oligodendroglial cell line, i.e., OLN-93 cells stably expressing green fluorescent protein (GFP)-microtubule associated protein light chain 3 (LC3) and tau, was used. During autophagosome formation, endogenous LC3 is processed to LC3-I, which is then converted to LC3-II. An increase of LC3-II is used as a reliable marker for autophagosome formation and abundance. It is demonstrated that inhibition of HDAC6 leads to the accumulation of LC3-positive autophagosomal vacuoles and an increase in LC3-II immunoreactivity, but the autophagic flux is rather impaired. Hence, the inhibition or dysregulation of HDAC6 contributes to stress responses and pathological processes in oligodendrocytes. PMID:25434725

  9. Potential Landscape and Flux of p53-Mdm2 Oscillator Mediated by Mdm2 Degradation Rate

    Science.gov (United States)

    Bi, Yuanhong; Yang, Zhuoqin

    The dynamics of the tumor suppressor p53 can play a crucial role in deciding cell fate after DNA damage. In this paper, we explore the dynamics and stability of p53 mediated by Mdm2 degradation rate in p53-Mdm2 oscillator through bifurcation, the potential landscape and flux. Based on the investigation of the bifurcation, we find that p53 can exhibit rich dynamics including monostability, bistability of two stable steady states and oscillation behaviors as well as bistability between a stable steady state and an oscillatory state. The stability of these states are further validated by the potential landscape. In addition, oscillatory behaviors of p53 are explored by means of the negative gradient of the potential landscape and the probability flux. It is shown that the negative gradient of the potential landscape can attract the system towards the oscillatory path and the flux can drive oscillation along the path. Moreover, the quicker the flux runs, the smaller the period is. Besides, stability and sensitivity of the system are explored by the barrier height and the entropy production rate in a single cell level, and we further compare the potential landscapes at single and population cell levels. Our results may be useful for understanding the regulation of p53 signaling pathways in response to DNA damage.

  10. Upper Ocean Thermal Responses to Sea Spray Mediated Turbulent Fluxes during Typhoon Passage

    Directory of Open Access Journals (Sweden)

    Lianxin Zhang

    2015-01-01

    Full Text Available A one-dimensional turbulent model is used to investigate the effect of sea spray mediated turbulent fluxes on upper ocean temperature during the passage of typhoon Yagi over the Kuroshio Extension area in 2006. Both a macroscopical sea spray momentum flux algorithm and a microphysical heat and moisture flux algorithm are included in this turbulent model. Numerical results show that the model can well reproduce the upper ocean temperature, which is consistent with the data from the Kuroshio Extension Observatory. Besides, the sea surface temperature is decreased by about 0.5°C during the typhoon passage, which also agrees with the sea surface temperature dataset derived from Advanced Microwave Scanning Radiometer for the Earth Observing and Reynolds. Diagnostic analysis indicates that sea spray acts as an additional source of the air-sea turbulent fluxes and plays a key role in increasing the turbulent kinetic energy in the upper ocean, which enhances the temperature diffusion there. Therefore, sea spray is also an important factor in determining the upper mixed layer depth during the typhoon passage.

  11. Cationic polystyrene nanospheres induce autophagic cell death through the induction of endoplasmic reticulum stress

    Science.gov (United States)

    Chiu, Hui-Wen; Xia, Tian; Lee, Yu-Hsuan; Chen, Chun-Wan; Tsai, Jui-Chen; Wang, Ying-Jan

    2014-12-01

    Nanoparticles (NPs) have been used to produce a wide range of products that have applications in imaging and drug delivery in medicine. Due to their chemical stability, well-controlled sizes and surface charges, polystyrene (PS) NPs have been developed as biosensors and drug delivery carriers. However, the possible adverse biological effects and underlying mechanisms are still unclear. Recently, autophagy has been implicated in the regulation of cell death. In this study, we evaluated a library of PS NPs with different surface charges. We found that NH2-labeled polystyrene (NH2-PS) nanospheres were highly toxic with enhanced uptake in macrophage (RAW 264.7) and lung epithelial (BEAS-2B) cells. Furthermore, NH2-PS could induce autophagic cell death. NH2-PS increased autophagic flux due to reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress caused by misfolded protein aggregation. The inhibition of ER stress decreased cytotoxicity and autophagy in the NH2-PS-treated cells. In addition, the Akt/mTOR and AMPK signaling pathways were involved in the regulation of NH2-PS-triggered autophagic cell death. These results suggest an important role of autophagy in cationic NP-induced cell death and provide mechanistic insights into the inhibition of the toxicity and safe material design.Nanoparticles (NPs) have been used to produce a wide range of products that have applications in imaging and drug delivery in medicine. Due to their chemical stability, well-controlled sizes and surface charges, polystyrene (PS) NPs have been developed as biosensors and drug delivery carriers. However, the possible adverse biological effects and underlying mechanisms are still unclear. Recently, autophagy has been implicated in the regulation of cell death. In this study, we evaluated a library of PS NPs with different surface charges. We found that NH2-labeled polystyrene (NH2-PS) nanospheres were highly toxic with enhanced uptake in macrophage (RAW 264.7) and lung

  12. Bacterial mediation of carbon fluxes during a diatom bloom in a mesocosm

    Science.gov (United States)

    Smith, David C.; Steward, Grieg F.; Long, Richard A.; Azam, Farooq

    Bacteria-diatom interactions were studied during a diatom bloom produced in a mesocosm, in the absence of metazoan grazers, in order to examine the significance of bacterial hydrolytic ectoenzymes in mediating carbon fluxes and influencing diatom aggregation. The abundances of bacteria and protozoa, the production rates and hydrolytic ectoenzyme activities (protease, α and β glucosidase and chitobiase) of attached and free bacteria, were followed as well as the dynamics of the dissolved organic carbon (DOC) pool. An intense diatom bloom occurred with chlorophyll a (chl a) concentrations reaching 132 μg liter 1 prior to aggregation. The diatoms were colonized by bacteria early on in the bloom and remained colonized throughout the bloom, yet they grew rapidly (>1 day -1). Attached bacteria were numerically a small fraction of the total, but they also grew very rapidly (μ = 4-16 day -1) and were generally responsible for the majority of bacterial carbon demand, BCD, (46-92%) and hydrolytic enzyme activities (41-99%). BCD accounted for an estimated 40-60% of the total carbon fixed during the bloom; thus, roughly onehalf of the primary production was channeled, via the DOC pool, into bacteria. The high ectohydrolase activities of bacteria attached to the surface of diatoms suggests that the hydrolysis of diatom surface mucus could be responsible for a major flux into the DOC pool making it a significant, but previously unrecognized, mechanism of DOM production. Enzymatic hydrolysis of surface mucus may also have inhibited diatom aggregation. Addition of purified glucosidase and protease to samples from the mesocosm inhibited diatom aggregation in experiments designed to induce aggregation. It is hypothesized that the action of bacterial ectoenzyme on diatom surfaces inhibited diatom aggregation by reducing stickiness, thus prolonging the bloom and allowing the accumulation of extremely high chl a levels prior to aggregation. Future studies should consider bacterial

  13. Herbivore-mediated material fluxes in a northern deciduous forest under elevated carbon dioxide and ozone concentrations.

    Science.gov (United States)

    Meehan, Timothy D; Couture, John J; Bennett, Alison E; Lindroth, Richard L

    2014-10-01

    Anthropogenic changes in atmospheric carbon dioxide (CO2 ) and ozone (O3 ) are known to alter tree physiology and growth, but the cascading effects on herbivore communities and herbivore-mediated nutrient cycling are poorly understood. We sampled herbivore frass, herbivore-mediated greenfall, and leaf-litter deposition in temperate forest stands under elevated CO2 (c. 560 ppm) and O3 (c. 1.5× ambient), analyzed substrate chemical composition, and compared the quality and quantity of fluxes under multiple atmospheric treatments. Leaf-chewing herbivores fluxed 6.2 g m(-2)  yr(-1) of frass and greenfall from the canopy to the forest floor, with a carbon : nitrogen (C : N) ratio 32% lower than that of leaf litter. Herbivore fluxes of dry matter, C, condensed tannins, and N increased under elevated CO2 (35, 32, 63 and 39%, respectively), while fluxes of N decreased (18%) under elevated O3 . Herbivore-mediated dry matter inputs scaled across atmospheric treatments as a constant proportion of leaf-litter inputs. Increased fluxes under elevated CO2 were consistent with increased herbivore consumption and abundance, and with increased plant growth and soil respiration, previously reported for this experimental site. Results suggest that insect herbivory will reinforce other factors, such as photosynthetic rate and fine-root production, impacting C sequestration by forests in future environments. PMID:25078062

  14. Baicalein induces autophagic cell death through AMPK/ULK1 activation and downregulation of mTORC1 complex components in human cancer cells.

    Science.gov (United States)

    Aryal, Pramod; Kim, Kijoong; Park, Pil-Hoon; Ham, Seongho; Cho, Junghee; Song, Kyung

    2014-10-01

    Baicalein, a flavonoid and aglycon hydrolyzed from baicalin, has anticancer properties in several human carcinomas, but its molecular mechanisms of action remain unclear. Here, we show that baicalein leads to human cancer cell death by inducing autophagy rather than apoptosis, because cell death induced by baicalein was completely reversed by suppressing the expression levels of key molecules in autophagy such as Beclin 1, vacuolar protein sorting 34 (Vps34), autophagy-related (Atg)5 and Atg7, but not by pan-caspase inhibitor. Our data revealed that baicalein significantly increased the number of green fluorescence protein-cytosol-associated protein light chain 3 (GFP-LC3)-containing puncta and LC3B-II expression levels, which were further enhanced by chloroquine treatment. Furthermore, a luciferase-based reporter assay showed that the ratio of RLuc-LC3wt/RLuc-LC3G120A was greatly reduced. The data suggested that baicalein induced not only autophagosome formation, but also autophagic flux. Experiments using short interfering RNAs and pharmacological inhibitors revealed that Beclin 1, Vps34, Atg5, Atg7 and UNC-51 (Caenorhabditis elegans)-like kinase 1 (ULK1) play pivotal roles in mediating baicalein-induced autophagy. Moreover, baicalein activated AMP-activated protein kinase (AMPK)α, leading to ULK1 activation through phosphorylation at Ser555, whereas both protein and mRNA levels of mammalian target of rapamycin (mTOR) and Raptor, upstream inhibitors of ULK1 and autophagy, were markedly downregulated by baicalein. Our data suggest that the anticancer effects of baicalein are mainly due to autophagic cell death through activation of the AMPK/ULK1 pathway and inhibition of mTOR/Raptor complex 1 expression. These results provide new mechanistic insights into the anticancer functions of autophagy inducers, such as baicalein, which may be used as potential therapeutics for cancer treatment. PMID:25132405

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

    OpenAIRE

    Mansilla Pareja, Maria Eugenia; 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 d...

  16. Large-volume flux closure during plasmoid-mediated reconnection in coaxial helicity injection

    Science.gov (United States)

    Ebrahimi, F.; Raman, R.

    2016-04-01

    A large-volume flux closure during transient coaxial helicity injection (CHI) in NSTX-U is demonstrated through resistive magnetohydrodynamics (MHD) simulations. Several major improvements, including the improved positioning of the divertor poloidal field coils, are projected to improve the CHI start-up phase in NSTX-U. Simulations in the NSTX-U configuration with constant in time coil currents show that with strong flux shaping the injected open field lines (injector flux) rapidly reconnect and form large volume of closed flux surfaces. This is achieved by driving parallel current in the injector flux coil and oppositely directed currents in the flux shaping coils to form a narrow injector flux footprint and push the injector flux into the vessel. As the helicity and plasma are injected into the device, the oppositely directed field lines in the injector region are forced to reconnect through a local Sweet-Parker type reconnection, or to spontaneously reconnect when the elongated current sheet becomes MHD unstable to form plasmoids. In these simulations for the first time, it is found that the closed flux is over 70% of the initial injector flux used to initiate the discharge. These results could work well for the application of transient CHI in devices that employ super conducting coils to generate and sustain the plasma equilibrium.

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

    International Nuclear Information System (INIS)

    Insulin (IN) induces a rapid stimulation of Ca2+ fluxes and membrane transport in mouse kidney cortex which involves rapid polyamine synthesis. 1.3 nM (IN) induced an early (45Ca2+ 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, 45Ca2+ 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

  18. Nanoparticles modulate autophagic effect in a dispersity-dependent manner

    Science.gov (United States)

    Huang, Dengtong; Zhou, Hualu; Gao, Jinhao

    2015-09-01

    Autophagy plays a key role in human health and disease, especially in cancer and neurodegeneration. Many autophagy regulators are developed for therapy. Diverse nanomaterials have been reported to induce autophagy. However, the underlying mechanisms and universal rules remain unclear. Here, for the first time, we show a reliable and general mechanism by which nanoparticles induce autophagy and then successfully modulate autophagy via tuning their dispersity. Various well-designed univariate experiments demonstrate that nanomaterials induce autophagy in a dispersity-dependent manner. Aggregated nanoparticles induce significant autophagic effect in comparison with well-dispersed nanoparticles. As the highly stable nanoparticles may block autophagic degradation in autolysosomes, endocytosis and intracellular accumulation of nanoparticles can be responsible for this interesting phenomenon. Our results suggest dispersity-dependent autophagic effect as a common cellular response to nanoparticles, reveal the relationship between properties of nanoparticles and autophagy, and offer a new alternative way to modulate autophagy.

  19. The autophagic- lysosomal pathway determines the fate of glial cells under manganese- induced oxidative stress conditions.

    Science.gov (United States)

    Gorojod, R M; Alaimo, A; Porte Alcon, S; Pomilio, C; Saravia, F; Kotler, M L

    2015-10-01

    Manganese (Mn) overexposure is frequently associated with the development of a neurodegenerative disorder known as Manganism. The Mn-mediated generation of reactive oxygen species (ROS) promotes cellular damage, finally leading to apoptotic cell death in rat astrocytoma C6 cells. In this scenario, the autophagic pathway could play an important role in preventing cytotoxicity. In the present study, we found that Mn induced an increase in the amount and total volume of acidic vesicular organelles (AVOs), a process usually related to the activation of the autophagic pathway. Particularly, the generation of enlarged AVOs was a ROS- dependent event. In this report we demonstrated for the first time that Mn induces autophagy in glial cells. This conclusion emerged from the results obtained employing a battery of autophagy markers: a) the increase in LC3-II expression levels, b) the formation of autophagic vesicles labeled with monodansylcadaverine (MDC) or LC3 and, c) the increase in Beclin 1/ Bcl-2 and Beclin 1/ Bcl-X(L) ratio. Autophagy inhibition employing 3-MA and mAtg5(K130R) resulted in decreased cell viability indicating that this event plays a protective role in Mn- induced cell death. In addition, mitophagy was demonstrated by an increase in LC3 and TOM-20 colocalization. On the other hand, we proposed the occurrence of lysosomal membrane permeabilization (LMP) based in the fact that cathepsins B and D activities are essential for cell death. Both cathepsin B inhibitor (Ca-074 Me) or cathepsin D inhibitor (Pepstatin A) completely prevented Mn- induced cytotoxicity. In addition, low dose of Bafilomycin A1 showed a similar effect, a finding that adds evidence about the lysosomal role in Mn cytotoxicity. Finally, in vivo experiments demonstrated that Mn induces injury and alters LC3 expression levels in rat striatal astrocytes. In summary, our results demonstrated that autophagy is activated to counteract the harmful effect caused by Mn. These data is valuable to

  20. 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.

  1. AB158. Atorvastatin induces autophagic cell death in prostate cancer cells in vitro

    Science.gov (United States)

    He, Zhenhua; Wang, Zhiping

    2016-01-01

    Objective Although it is well known that apoptosis contributes to cancer cell death, the role of autophagy in cancer cell death has remained in dispute. Atorvastatin has been suggested to exhibit anti-cancer effects. The present study aimed to examine atorvastatin-induced autophagy-associated cell death and the autophagy-associated gene expression profile in the PC3 prostate carcinoma cell line. Methods The atorvastatin-induced process of autophagy in PC3 cells was determined via evaluation of the cellular expression levels of autophagosomal marker light-chain-3 (LC3)-II, using immunoblotting and counting of green fluorescent protein (GFP)-LC3-transfected autophagiccells. Apoptosis was examined by terminal deoxynucleotidyl transferase dUTP nick end labeling assay and an MTT assay was used to evaluate cell viability. Total RNA of PC3 cells was isolated for characterization of the gene expression profile following atorvastatin treatment. Results Atorvastatin treatment of PC3 cells for 24 h increased the expression of GFP-LC3-II by >25% and expression continued for >72 h, while apoptosis was not significantly induced within this time period. Four genes associated with the autophagy machinery were also significantly upregulated. Conclusions In the presence of atorvastatin, autophagy may be unable to abrogate cell damage and may therefore contribute to cellular dysfunction, leading to autophagic/type II programmed cell death. In response to atorvastatin treatment, the expression of genes involved in autophagic mediating pathways may have a role in tumor suppression.

  2. Intraneuronal aggregation of the β-CTF fragment of APP (C99) induces Aβ-independent lysosomal-autophagic pathology.

    Science.gov (United States)

    Lauritzen, Inger; Pardossi-Piquard, Raphaëlle; Bourgeois, Alexandre; Pagnotta, Sophie; Biferi, Maria-Grazia; Barkats, Martine; Lacor, Pascale; Klein, William; Bauer, Charlotte; Checler, Frederic

    2016-08-01

    Endosomal-autophagic-lysosomal (EAL) dysfunction is an early and prominent neuropathological feature of Alzheimers's disease, yet the exact molecular mechanisms contributing to this pathology remain undefined. By combined biochemical, immunohistochemical and ultrastructural approaches, we demonstrate a link between EAL pathology and the intraneuronal accumulation of the β-secretase-derived βAPP fragment (C99) in two in vivo models, 3xTgAD mice and adeno-associated viral-mediated C99-infected mice. We present a pathological loop in which the accumulation of C99 is both the effect and causality of impaired lysosomal-autophagic function. The deleterious effect of C99 was found to be linked to its aggregation within EAL-vesicle membranes leading to disrupted lysosomal proteolysis and autophagic impairment. This effect was Aβ independent and was even exacerbated when γ-secretase was pharmacologically inhibited. No effect was observed in inhibitor-treated wild-type animals suggesting that lysosomal dysfunction was indeed directly linked to C99 accumulation. In some brain areas, strong C99 expression also led to inflammatory responses and synaptic dysfunction. Taken together, this work demonstrates a toxic effect of C99 which could underlie some of the early-stage anatomical hallmarks of Alzheimer's disease pathology. Our work also proposes molecular mechanisms likely explaining some of the unfavorable side-effects associated with γ-secretase inhibitor-directed therapies. PMID:27138984

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

    Science.gov (United States)

    Chiu, Chang-Fang; Weng, Jing-Ru; Jadhav, Appaso; Wu, Chia-Yung; Sargeant, Aaron M.; Bai, Li-Yuan

    2016-01-01

    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. PMID:27537872

  4. Computer simulations of neuron-glia interactions mediated by ion flux.

    Science.gov (United States)

    Somjen, G G; Kager, H; Wadman, W J

    2008-10-01

    Extracellular potassium concentration, [K(+)](o), and intracellular calcium, [Ca(2+)](i), rise during neuron excitation, seizures and spreading depression. Astrocytes probably restrain the rise of K(+) in a way that is only partly understood. To examine the effect of glial K(+) uptake, we used a model neuron equipped with Na(+), K(+), Ca(2+) and Cl(-) conductances, ion pumps and ion exchangers, surrounded by interstitial space and glia. The glial membrane was either "passive", incorporating only leak channels and an ion exchange pump, or it had rectifying K(+) channels. We computed ion fluxes, concentration changes and osmotic volume changes. Increase of [K(+)](o) stimulated the glial uptake by the glial 3Na/2K ion pump. The [K(+)](o) flux through glial leak and rectifier channels was outward as long as the driving potential was outwardly directed, but it turned inward when rising [K(+)](o)/[K(+)](i) ratio reversed the driving potential. Adjustments of glial membrane parameters influenced the neuronal firing patterns, the length of paroxysmal afterdischarge and the ignition point of spreading depression. We conclude that voltage gated K(+) currents can boost the effectiveness of the glial "potassium buffer" and that this buffer function is important even at moderate or low levels of excitation, but especially so in pathological states. PMID:18297383

  5. Microtubule flux mediates poleward motion of acentric chromosome fragments during meiosis in insect spermatocytes.

    Science.gov (United States)

    LaFountain, J R; Oldenbourg, R; Cole, R W; Rieder, C L

    2001-12-01

    We applied a combination of laser microsurgery and quantitative polarization microscopy to study kinetochore-independent forces that act on chromosome arms during meiosis in crane fly spermatocytes. When chromosome arms located within one of the half-spindles during prometa- or metaphase were cut with the laser, the acentric fragments (lacking kinetochores) that were generated moved poleward with velocities similar to those of anaphase chromosomes (approximately 0.5 microm/min). To determine the mechanism underlying this poleward motion of detached arms, we treated spermatocytes with the microtubule-stabilizing drug taxol. Spindles in taxol-treated cells were noticeably short, yet with polarized light, the distribution and densities of microtubules in domains where fragment movement occurred were not different from those in control cells. When acentric fragments were generated in taxol-treated spermatocytes, 22 of 24 fragments failed to exhibit poleward motion, and the two that did move had velocities attenuated by 80% (to approximately 0.1 microm/min). In these cells, taxol did not inhibit the disjunction of chromosomes nor prevent their poleward segregation during anaphase, but the velocity of anaphase was also decreased 80% (approximately 0.1 microm/min) relative to untreated controls. Together, these data reveal that microtubule flux exerts pole-directed forces on chromosome arms during meiosis in crane fly spermatocytes and strongly suggest that the mechanism underlying microtubule flux also is used in the anaphase motion of kinetochores in these cells. PMID:11739800

  6. U(1)_R mediation from the flux compactification in six dimensions

    CERN Document Server

    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.

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

    International Nuclear Information System (INIS)

    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.

  8. Autophagic machinery activated by dengue virus enhances virus replication

    International Nuclear Information System (INIS)

    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

  9. Chikungunya triggers an autophagic process which promotes viral replication

    Directory of Open Access Journals (Sweden)

    Briant Laurence

    2011-09-01

    Full Text Available Abstract Background Chikungunya Virus (ChikV surprised by a massive re-emerging outbreak in Indian Ocean in 2006, reaching Europe in 2007 and exhibited exceptional severe physiopathology in infants and elderly patients. In this context, it is important to analyze the innate immune host responses triggered against ChikV. Autophagy has been shown to be an important component of the innate immune response and is involved in host defense elimination of different pathogens. However, the autophagic process was recently observed to be hijacked by virus for their own replication. Here we provide the first evidence that hallmarks of autophagy are specifically found in HEK.293 infected cells and are involved in ChikV replication. Methods To test the capacity of ChikV to mobilize the autophagic machinery, we performed fluorescence microscopy experiments on HEK.GFP.LC3 stable cells, and followed the LC3 distribution during the time course of ChikV infection. To confirm this, we performed electron microscopy on HEK.293 infected cells. To test the effect of ChikV-induced-autophagy on viral replication, we blocked the autophagic process, either by pharmacological (3-MA or genetic inhibition (siRNA against the transcript of Beclin 1, an autophagic protein, and analyzed the percentage of infected cells and the viral RNA load released in the supernatant. Moreover, the effect of induction of autophagy by Rapamycin on viral replication was tested. Results The increasing number of GFP-LC3 positive cells with a punctate staining together with the enhanced number of GFP-LC3 dots per cell showed that ChikV triggered an autophagic process in HEK.293 infected cells. Those results were confirmed by electron microscopy analysis since numerous membrane-bound vacuoles characteristic of autophagosomes were observed in infected cells. Moreover, we found that inhibition of autophagy, either by biochemical reagent and RNA interference, dramatically decreases ChikV replication

  10. Protection against neurotoxicity by an autophagic mechanism

    Directory of Open Access Journals (Sweden)

    Kangyong Liu

    2012-05-01

    Full Text Available The objective of the present study was to investigate the effects of 3-n-butylphthalide (NBP on a 1-methyl-4-phenylpyridinium (MPP+-induced cellular model of Parkinson’s disease (PD and to illustrate the potential mechanism of autophagy in this process. For this purpose, rat PC12 pheochromocytoma cells were treated with MPP+ (1 mM for 24 h following pretreatment with NBP (0.1 mM. Cell metabolic viability was determined by the MTT assay and cell ultrastructure was examined by transmission electron microscopy. The intracellular distribution and expression of α-synuclein and microtubule-associated protein light chain 3 (LC3 were detected by immunocytochemistry and Western blotting. Our results demonstrated that: 1 NBP prevented MPP+-induced cytotoxicity in PC12 cells by promoting metabolic viability. 2 NBP induced the accumulation of autophagosomes in MPP+-treated PC12 cells. 3 Further study of the molecular mechanism demonstrated that NBP enhanced the colocalization of α-synuclein and LC3 and up-regulated the protein level of LC3-II. These results demonstrate that NBP protects PC12 cells against MPP+-induced neurotoxicity by activating autophagy-mediated α-synuclein degradation, implying that it may be a potential effective therapeutic agent for the treatment of PD.

  11. The autophagic paradox in cancer therapy.

    Science.gov (United States)

    Wu, W K K; Coffelt, S B; Cho, C H; Wang, X J; Lee, C W; Chan, F K L; Yu, J; Sung, J J Y

    2012-02-23

    Autophagy, hallmarked by the formation of double-membrane bound organelles known as autophagosomes, is a lysosome-dependent pathway for protein degradation. The role of autophagy in carcinogenesis is context dependent. As a tumor-suppressing mechanism in early-stage carcinogenesis, autophagy inhibits inflammation and promotes genomic stability. Moreover, disruption of autophagy-related genes accelerates tumorigenesis in animals. However, autophagy may also act as a pro-survival mechanism to protect cancer cells from various forms of cellular stress. In cancer therapy, adaptive autophagy in cancer cells sustains tumor growth and survival in face of the toxicity of cancer therapy. To this end, inhibition of autophagy may sensitize cancer cells to chemotherapeutic agents and ionizing radiation. Nevertheless, in certain circumstances, autophagy mediates the therapeutic effects of some anticancer agents. Data from recent studies are beginning to unveil the apparently paradoxical nature of autophagy as a cell-fate decision machinery. Taken together, modulation of autophagy is a novel approach for enhancing the efficacy of existing cancer therapy, but its Janus-faced nature may complicate the clinical development of autophagy modulators as anticancer therapeutics. PMID:21765470

  12. Protection against neurotoxicity by an autophagic mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Kangyong; Huang, Jiankang; Chen, Rongfu; Zhang, Ting [Department of Neurology, Affiliated Sixth People' s Hospital, Shanghai Jiaotong University, Shanghai (China); Shen, Liwei [Department of Neurology, Fifth People' s Hospital, Fudan University, Shanghai (China); Yang, Jiajun; Sun, Xiaojiang [Department of Neurology, Affiliated Sixth People' s Hospital, Shanghai Jiaotong University, Shanghai (China)

    2012-03-23

    The objective of the present study was to investigate the effects of 3-n-butylphthalide (NBP) on a 1-methyl-4-phenylpyridinium (MPP{sup +})-induced cellular model of Parkinson's disease (PD) and to illustrate the potential mechanism of autophagy in this process. For this purpose, rat PC12 pheochromocytoma cells were treated with MPP{sup +} (1 mM) for 24 h following pretreatment with NBP (0.1 mM). Cell metabolic viability was determined by the MTT assay and cell ultrastructure was examined by transmission electron microscopy. The intracellular distribution and expression of α-synuclein and microtubule-associated protein light chain 3 (LC3) were detected by immunocytochemistry and Western blotting. Our results demonstrated that: 1) NBP prevented MPP{sup +}-induced cytotoxicity in PC12 cells by promoting metabolic viability. 2) NBP induced the accumulation of autophagosomes in MPP{sup +}-treated PC12 cells. 3) Further study of the molecular mechanism demonstrated that NBP enhanced the colocalization of α-synuclein and LC3 and up-regulated the protein level of LC3-II. These results demonstrate that NBP protects PC12 cells against MPP{sup +}-induced neurotoxicity by activating autophagy-mediated α-synuclein degradation, implying that it may be a potential effective therapeutic agent for the treatment of PD.

  13. Protection against neurotoxicity by an autophagic mechanism

    International Nuclear Information System (INIS)

    The objective of the present study was to investigate the effects of 3-n-butylphthalide (NBP) on a 1-methyl-4-phenylpyridinium (MPP+)-induced cellular model of Parkinson's disease (PD) and to illustrate the potential mechanism of autophagy in this process. For this purpose, rat PC12 pheochromocytoma cells were treated with MPP+ (1 mM) for 24 h following pretreatment with NBP (0.1 mM). Cell metabolic viability was determined by the MTT assay and cell ultrastructure was examined by transmission electron microscopy. The intracellular distribution and expression of α-synuclein and microtubule-associated protein light chain 3 (LC3) were detected by immunocytochemistry and Western blotting. Our results demonstrated that: 1) NBP prevented MPP+-induced cytotoxicity in PC12 cells by promoting metabolic viability. 2) NBP induced the accumulation of autophagosomes in MPP+-treated PC12 cells. 3) Further study of the molecular mechanism demonstrated that NBP enhanced the colocalization of α-synuclein and LC3 and up-regulated the protein level of LC3-II. These results demonstrate that NBP protects PC12 cells against MPP+-induced neurotoxicity by activating autophagy-mediated α-synuclein degradation, implying that it may be a potential effective therapeutic agent for the treatment of PD

  14. Autophagic degradation contributes to muscle wasting in cancer cachexia.

    Science.gov (United States)

    Penna, Fabio; Costamagna, Domiziana; Pin, Fabrizio; Camperi, Andrea; Fanzani, Alessandro; Chiarpotto, Elena M; Cavallini, Gabriella; Bonelli, Gabriella; Baccino, Francesco M; Costelli, Paola

    2013-04-01

    Muscle protein wasting in cancer cachexia is a critical problem. The underlying mechanisms are still unclear, although the ubiquitin-proteasome system has been involved in the degradation of bulk myofibrillar proteins. The present work has been aimed to investigate whether autophagic degradation also plays a role in the onset of muscle depletion in cancer-bearing animals and in glucocorticoid-induced atrophy and sarcopenia of aging. The results show that autophagy is induced in muscle in three different models of cancer cachexia and in glucocorticoid-treated mice. In contrast, autophagic degradation in the muscle of sarcopenic animals is impaired but can be reactivated by calorie restriction. These results further demonstrate that different mechanisms are involved in pathologic muscle wasting and that autophagy, either excessive or defective, contributes to the complicated network that leads to muscle atrophy. In this regard, particularly intriguing is the observation that in cancer hosts and tumor necrosis factor α-treated C2C12 myotubes, insulin can only partially blunt autophagy induction. This finding suggests that autophagy is triggered through mechanisms that cannot be circumvented by using classic upstream modulators, prompting us to identify more effective approaches to target this proteolytic system. PMID:23395093

  15. 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

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

    International Nuclear Information System (INIS)

    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

  17. 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.

  18. Removal of the BH4 Domain from Bcl-2 Protein Triggers an Autophagic Process that Impairs Tumor Growth12

    Science.gov (United States)

    Trisciuoglio, Daniela; De Luca, Teresa; Desideri, Marianna; Passeri, Daniela; Gabellini, Chiara; Scarpino, Stefania; Liang, Chengyu; Orlandi, Augusto; Del Bufalo, Donatella

    2013-01-01

    Here, we show that forced expression of a B-cell lymphoma 2 (bcl-2) protein lacking residues 1 to 36 at the N-terminal, including the entire Bcl-2 homology 4 (BH4) domain, determines reduction of in vitro and in vivo human melanoma growth. Noteworthy, melanoma cells in vivo exhibit markedly increased autophagy, as response to expression of bcl-2 protein deleted of its BH4 domain. This observation led to the identification of a novel gain of function for bcl-2 protein lacking the BH4 domain. In particular, upon different autophagic stimuli in vitro, overexpression of bcl-2 protein deleted of BH4 domain induces autophagosome accumulation, conversion of microtubule-associated protein 1 light chain 3B-II, reduced expression of p62/SQSTM1 protein, and thereby enhanced autophagic flux. The relevance of Beclin-1 is evidenced by the fact that 1) the autophagy-promoting and growth-inhibiting properties are partially rescued by Beclin-1 knockdown in cells expressing bcl-2 protein lacking the BH4 domain, 2) Beclin-1 only interacts with wild-type but not with deleted bcl-2, and 3) BH4 domain removal from bcl-2 protein does not influence in vitro and in vivo growth of tumor cells expressing low levels of endogenous Beclin-1. These results provide new insight into molecular mechanism of bcl-2 functions and represent a rationale for the development of agents interfering with the BH4 domain of bcl-2 protein. PMID:23479509

  19. Removal of the BH4 Domain from Bcl-2 Protein Triggers an Autophagic Process that Impairs Tumor Growth

    Directory of Open Access Journals (Sweden)

    Daniela Trisciuoglio

    2013-03-01

    Full Text Available Here, we show that forced expression of a B-cell lymphoma 2 (bcl-2 protein lacking residues 1 to 36 at the N-terminal, including the entire Bcl-2 homology 4 (BH4 domain, determines reduction of in vitro and in vivo human melanoma growth. Noteworthy, melanoma cells in vivo exhibit markedly increased autophagy, as response to expression of bcl-2 protein deleted of its BH4 domain. This observation led to the identification of a novel gain of function for bcl-2 protein lacking the BH4 domain. In particular, upon different autophagic stimuli in vitro, overexpression of bcl-2 protein deleted of BH4 domain induces autophagosome accumulation, conversion of microtubule-associated protein 1 light chain 3B-II, reduced expression of p62/SQSTM1 protein, and thereby enhanced autophagic flux. The relevance of Beclin-1 is evidenced by the fact that 1 the autophagy-promoting and growth-inhibiting properties are partially rescued by Beclin-1 knockdown in cells expressing bcl-2 protein lacking the BH4 domain, 2 Beclin-1 only interacts with wild-type but not with deleted bcl-2, and 3 BH4 domain removal from bcl-2 protein does not influence in vitro and in vivo growth of tumor cells expressing low levels of endogenous Beclin-1. These results provide new insight into molecular mechanism of bcl-2 functions and represent a rationale for the development of agents interfering with the BH4 domain of bcl-2 protein.

  20. Removal of the BH4 domain from Bcl-2 protein triggers an autophagic process that impairs tumor growth.

    Science.gov (United States)

    Trisciuoglio, Daniela; De Luca, Teresa; Desideri, Marianna; Passeri, Daniela; Gabellini, Chiara; Scarpino, Stefania; Liang, Chengyu; Orlandi, Augusto; Del Bufalo, Donatella

    2013-03-01

    Here, we show that forced expression of a B-cell lymphoma 2 (bcl-2) protein lacking residues 1 to 36 at the N-terminal, including the entire Bcl-2 homology 4 (BH4) domain, determines reduction of in vitro and in vivo human melanoma growth. Noteworthy, melanoma cells in vivo exhibit markedly increased autophagy, as response to expression of bcl-2 protein deleted of its BH4 domain. This observation led to the identification of a novel gain of function for bcl-2 protein lacking the BH4 domain. In particular, upon different autophagic stimuli in vitro, overexpression of bcl-2 protein deleted of BH4 domain induces autophagosome accumulation, conversion of microtubule-associated protein 1 light chain 3B-II, reduced expression of p62/SQSTM1 protein, and thereby enhanced autophagic flux. The relevance of Beclin-1 is evidenced by the fact that 1) the autophagy-promoting and growth-inhibiting properties are partially rescued by Beclin-1 knockdown in cells expressing bcl-2 protein lacking the BH4 domain, 2) Beclin-1 only interacts with wild-type but not with deleted bcl-2, and 3) BH4 domain removal from bcl-2 protein does not influence in vitro and in vivo growth of tumor cells expressing low levels of endogenous Beclin-1. These results provide new insight into molecular mechanism of bcl-2 functions and represent a rationale for the development of agents interfering with the BH4 domain of bcl-2 protein. PMID:23479509

  1. Autophagic response to cell culture stress in pluripotent stem cells.

    Science.gov (United States)

    Gregory, Siân; Swamy, Sushma; Hewitt, Zoe; Wood, Andrew; Weightman, Richard; Moore, Harry

    2016-05-01

    Autophagy is an important conserved cellular process, both constitutively as a recycling pathway for long lived proteins and as an upregulated stress response. Recent findings suggest a fundamental role for autophagic processes in the maintenance of pluripotent stem cell function. In human embryonic stem cells (hESCS), autophagy was investigated by transfection of LC3-GFP to visualize autophagosomes and with an antibody to LC3B protein. The presence of the primary cilium (PC) in hESCs as the site of recruitment of autophagy-related proteins was also assessed. HESCs (mShef11) in vitro displayed basal autophagy which was upregulated in response to deprivation of culture medium replacement. Significantly higher levels of autophagy were exhibited on spontaneous differentiation of hESCs in vitro. The PC was confirmed to be present in hESCs and therefore may serve to coordinate autophagy function. PMID:26385182

  2. Cocaine elicits autophagic cytotoxicity via a nitric oxide-GAPDH signaling cascade.

    Science.gov (United States)

    Guha, Prasun; Harraz, Maged M; Snyder, Solomon H

    2016-02-01

    Cocaine exerts its behavioral stimulant effects by facilitating synaptic actions of neurotransmitters such as dopamine and serotonin. It is also neurotoxic and broadly cytotoxic, leading to overdose deaths. We demonstrate that the cytotoxic actions of cocaine reflect selective enhancement of autophagy, a process that physiologically degrades metabolites and cellular organelles, and that uncontrolled autophagy can also lead to cell death. In brain cultures, cocaine markedly increases levels of LC3-II and depletes p62, both actions characteristic of autophagy. By contrast, cocaine fails to stimulate cell death processes reflecting parthanatos, monitored by cleavage of poly(ADP ribose)polymerase-1 (PARP-1), or necroptosis, assessed by levels of phosphorylated mixed lineage kinase domain-like protein. Pharmacologic inhibition of autophagy protects neurons against cocaine-induced cell death. On the other hand, inhibition of parthanatos, necroptosis, or apoptosis did not change cocaine cytotoxicity. Depletion of ATG5 or beclin-1, major mediators of autophagy, prevents cocaine-induced cell death. By contrast, depleting caspase-3, whose cleavage reflects apoptosis, fails to alter cocaine cytotoxicity, and cocaine does not alter caspase-3 cleavage. Moreover, depleting PARP-1 or RIPK1, key mediators of parthanatos and necroptosis, respectively, did not prevent cocaine-induced cell death. Autophagic actions of cocaine are mediated by the nitric oxide-glyceraldehyde-3-phosphate dehydrogenase signaling pathway. Thus, cocaine-associated autophagy is abolished by depleting GAPDH via shRNA; by the drug CGP3466B, which prevents GAPDH nitrosylation; and by mutating cysteine-150 of GAPDH, its site of nitrosylation. Treatments that selectively influence cocaine-associated autophagy may afford therapeutic benefit. PMID:26787898

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

    Directory of Open Access Journals (Sweden)

    Holger Hetschko

    2008-08-01

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

  4. Interleukin-22 Ameliorates Cerulein-Induced Pancreatitis in Mice by Inhibiting the Autophagic Pathway

    Directory of Open Access Journals (Sweden)

    Dechun Feng, Ogyi Park, Svetlana Radaeva, Hua Wang, Shi Yin, Xiaoni Kong, Mingquan Zheng, Sam Zakhari, Jay K. Kolls, Bin Gao

    2012-01-01

    Full Text Available Pancreatitis occurs when digestive enzymes are activated in the pancreas. Severe pancreatitis has a 10-30% mortality rate. No specific treatments for pancreatitis exist now. Here, we discovered that interleukin-22 (IL-22 may have therapeutic potential in treating acute and chronic pancreatitis. Wild-type and IL-22 knockout mice were equally susceptible to cerulein-induced acute and chronic pancreatitis, whereas liver-specific IL-22 transgenic mice were completely resistant to cerulein-induced elevation of serum digestive enzymes, pancreatic necrosis and apoptosis, and inflammatory cell infiltration. Treatment of wild-type mice with recombinant IL-22 or adenovirus IL-22 markedly attenuated the severity of cerulein-induced acute and chronic pancreatitis. Mechanistically, we show that the protective effect of IL-22 on pancreatitis was mediated via the induction of Bcl-2 and Bcl-XL, which bind to Beclin-1 and subsequently inhibit autophagosome formation to ameliorate pancreatitis. In conclusion, IL-22 ameliorates cerulein-induced pancreatitis by inhibiting the autophagic pathway. IL-22 could be a promising therapeutic drug to treat pancreatitis.

  5. Changes in Autophagic Response in Patients with Chronic Hepatitis C Virus Infection

    OpenAIRE

    Rautou, Pierre-Emmanuel; Cazals-Hatem, Dominique; Feldmann, Gérard; Mansouri, Abdellah; Grodet, Alain; Barge, Sandrine; Martinot-Peignoux, Michèle; Duces, Aurélie; Bièche, Ivan; Lebrec, Didier; Bedossa, Pierre; Paradis, Valérie; Marcellin, Patrick; Valla, Dominique; Asselah, Tarik

    2011-01-01

    Autophagy is a regulated process that can be involved in the elimination of intracellular microorganisms and in antigen presentation. Some in vitro studies have shown an altered autophagic response in hepatitis C virus infected hepatocytes. The present study aimed at evaluating the autophagic process in the liver of chronic hepatitis C (CHC) patients. Fifty-six CHC patients and 47 control patients (8 with nonalcoholic steatohepatitis or alcoholic liver disease, 18 with chronic heptatitis B vi...

  6. The tyrosine kinase inhibitor, sunitinib malate, induces cognitive impairment in vivo via dysregulating VEGFR signaling, apoptotic and autophagic machineries.

    Science.gov (United States)

    Abdel-Aziz, Amal Kamal; Mantawy, Eman M; Said, Riham Soliman; Helwa, Reham

    2016-09-01

    Chemobrain refers to a cluster of cognitive deficits which affects almost 4-75% of chemotherapy-treated cancer patients. Sunitinib, an FDA-approved multityrosine kinase inhibitor, is currently used in treating different types of tumors. Despite being regarded as targeted therapy which blunts sustained angiogenesis in cancer milieu through inhibiting vascular endothelial growth factor receptor 2 (VEGFR2) signaling, the latter has a cardinal role in cognition. Recent clinical reports warned that sunitinib adversely affected memory processing in cancer patients. Nevertheless, the underlying mechanisms have not been investigated yet. Hence, we explored the impact of a clinically relevant dose of sunitinib on memory processing in vivo and questioned the implication of VEGFR2 signaling, autophagy and apoptosis. Strikingly, sunitinib preferentially impaired spatial cognition as evidenced in Morris water maze, T-maze and passive avoidance task. Consistently, sunitinib degenerated cortical and hippocampal neurons as assessed by histopathological examination and toluidine blue staining. Ultrastructural examination also depicted chromatin condensation, mitochondrial damage and accumulated autophagosomes. Digging deeper, central VEGF/VEGFR2/mTOR signaling was robustly suppressed. Besides, sunitinib boosted cortical and hippocampal p53 and executioner caspase-3 and decreased nuclear factor kappa B and Bcl-2 levels promoting apoptotic cell death. It also profoundly impeded neuronal autophagic flux as shown by decreased beclin-1 and Atg5 and increased p62/SQTSM1 levels. To our knowledge, this is the first study to provide molecular insights into sunitinib-induced chemofog where impeded VEGFR2 signaling and autophagic and hyperactivated apoptotic machineries act in neurodegenerative concert. Importantly, our findings shed light on potential therapeutic strategies to be exploited in the management of sunitinib-induced chemobrain. PMID:27288242

  7. Disturbed Flow Induces Autophagy, but Impairs Autophagic Flux to Perturb Mitochondrial Homeostasis

    OpenAIRE

    Li, Rongsong; Jen, Nelson; Wu, Lan; Lee, Juhyun; Fang, Karen; Quigley, Katherine; Lee, Katherine; Wang, Sky; Zhou, Bill; Vergnes, Laurent; Chen, Yun-Ru; Li, Zhaoping; Reue, Karen; Ann, David K.; Hsiai, Tzung K.

    2015-01-01

    Aim: Temporal and spatial variations in shear stress are intimately linked with vascular metabolic effects. Autophagy is tightly regulated in intracellular bulk degradation/recycling system for maintaining cellular homeostasis. We postulated that disturbed flow modulates autophagy with an implication in mitochondrial superoxide (mtO2•−) production. Results: In the disturbed flow or oscillatory shear stress (OSS)-exposed aortic arch, we observed prominent staining of p62, a reverse marker of a...

  8. Adenovirus-mediated wild-type PTEN promoting glioma stem/progenitor cells autophagy activity

    OpenAIRE

    ZHAO Yao-dong; Zi-long WEI; Zhang, Quan-Bin; LOU Mei-qing; HUANG, QIANG

    2013-01-01

    Background PTEN is an anti-oncogene frequently inactivating in glioma. The previous study found that PTEN was closely related to cellular autophagy activity. The purpose of this paper is to study whether the inactivation of PTEN in glioma stem/progenitor cells (GSPCs) is correlative with the low autophagic activity in GSPCs. Methods Wild-type PTEN genes were transferred into GSPCs mediated by adenovirus. The autophagic activity in GSPCs before or after the introduction of wild-type PTEN was...

  9. Phospholipase Cγ2 Is Critical for Dectin-1-mediated Ca2+ Flux and Cytokine Production in Dendritic Cells*

    OpenAIRE

    Xu, Shengli; Huo, Jianxin; Lee, Koon-Guan; Kurosaki, Tomohiro; Lam, Kong-Peng

    2009-01-01

    Dectin-1 is a C-type lectin that recognizes β-glucan in the cell walls of fungi and plays an important role in anti-fungal immunity. It signals via tyrosine kinase Syk and adaptor protein Card9 to activate NF-κB leading to proinflammatory cytokine production in dendritic cells (DCs). Other than this, not much else is known of the mechanism of Dectin-1 signaling. We demonstrate here that stimulation of DCs with zymosan triggers an intracellular Ca2+ flux that can be att...

  10. Changes in autophagic response in patients with chronic hepatitis C virus infection.

    Science.gov (United States)

    Rautou, Pierre-Emmanuel; Cazals-Hatem, Dominique; Feldmann, Gérard; Mansouri, Abdellah; Grodet, Alain; Barge, Sandrine; Martinot-Peignoux, Michèle; Duces, Aurélie; Bièche, Ivan; Lebrec, Didier; Bedossa, Pierre; Paradis, Valérie; Marcellin, Patrick; Valla, Dominique; Asselah, Tarik; Moreau, Richard

    2011-06-01

    Autophagy is a regulated process that can be involved in the elimination of intracellular microorganisms and in antigen presentation. Some in vitro studies have shown an altered autophagic response in hepatitis C virus infected hepatocytes. The present study aimed at evaluating the autophagic process in the liver of chronic hepatitis C (CHC) patients. Fifty-six CHC patients and 47 control patients (8 with nonalcoholic steatohepatitis or alcoholic liver disease, 18 with chronic heptatitis B virus infection, and 21 with no or mild liver abnormalities at histological examination) were included. Autophagy was assessed by means of electron microscopy and microtubule-associated protein light chain 3 immunoblotting. Using light chain 3 immunoblotting, the form present on autophagic vesicle (light chain 3-II) was significantly higher in CHC patients than in controls (P < 0.05). Using quantitative electron microscopy analysis, the median number of autophagic vesicles observed in hepatocytes from CHC patients was sixfold higher than in overall controls (P < 0.001). In contrast, there was no difference between CHC patients and controls in the number of mature lysosomes with electron-dense contents arguing in favor of a lack of fusion between autophagosome and lysosome. Neither genotype nor viral load influenced the autophagy level. In conclusion, autophagy is altered in hepatocytes from CHC patients, likely due to a blockade of the last step of the autophagic process. PMID:21641393

  11. Marine ecosystem connectivity mediated by migrant-resident interactions and the concomitant cross-system flux of lipids.

    Science.gov (United States)

    van Deurs, Mikael; Persson, Anders; Lindegren, Martin; Jacobsen, Charlotte; Neuenfeldt, Stefan; Jørgensen, Christian; Nilsson, P Anders

    2016-06-01

    Accumulating research argues that migrants influence the functioning and productivity of local habitats and ecosystems along migration routes and potentially drive cross-system energy fluxes of considerable magnitude, yet empirical documentation of local ecological effects and descriptions of the underlying mechanisms are surprisingly rare. In this study, we discovered migrant-resident interactions and substantial cross-system lipid transportation in the transition zone between the Baltic Sea and the North Sea where a resident cod population (predators) was found to interact with a herring population (prey) on a seasonal basis. We traced the lipids, using fatty acid trophic markers (FATM), from the herring feeding grounds in the North Sea to the cod livers in the Western Baltic Sea. Time series analysis of population dynamics indicated that population-level production of cod is positively affected by the herring subsidies. However, the underlying mechanisms were more complicated than anticipated. During the herring season, large cod received most of its dietary lipids from the herring, whereas smaller cod were prevented from accessing the lipid pool due to a mismatch in predator-prey size ratio. Furthermore, while the herring were extremely rich in bulk energy, they were surprisingly poor in a specific functional fatty acid. Hence, our study was the first to illustrate how the magnitude cross-system fluxes of subsidies in migrant-resident systems are potentially constrained by the size structure of the resident predator population and the nutritional quality of the migrants. PMID:27516865

  12. Role of a mitogen-activated protein kinase cascade in ion flux-mediated turgor regulation in fungi.

    Science.gov (United States)

    Lew, Roger R; Levina, Natalia N; Shabala, Lana; Anderca, Marinela I; Shabala, Sergey N

    2006-03-01

    Fungi normally maintain a high internal hydrostatic pressure (turgor) of about 500 kPa. In response to hyperosmotic shock, there are immediate electrical changes: a transient depolarization (1 to 2 min) followed by a sustained hyperpolarization (5 to 10 min) prior to turgor recovery (10 to 60 min). Using ion-selective vibrating probes, we established that the transient depolarization is due to Ca(2+) influx and the sustained hyperpolarization is due to H(+) efflux by activation of the plasma membrane H(+)-ATPase. Protein synthesis is not required for H(+)-ATPase activation. Net K(+) and Cl(-) uptake occurs at the same time as turgor recovery. The magnitude of the ion uptake is more than sufficient to account for the osmotic gradients required for turgor to return to its original level. Two osmotic mutants, os-1 and os-2, homologs of a two-component histidine kinase sensor and the yeast high osmotic glycerol mitogen-activated protein (MAP) kinase, respectively, have lower turgor than the wild type and do not exhibit the sustained hyperpolarization after hyperosmotic treatment. The os-1 mutant does not exhibit all of the wild-type turgor-adaptive ion fluxes (Cl(-) uptake increases, but net K(+) flux barely changes and net H(+) efflux declines) (os-2 was not examined). Both os mutants are able to regulate turgor but at a lower level than the wild type. Our results demonstrate that a MAP kinase cascade regulates ion transport, activation of the H(+)-ATPase, and net K(+) and Cl(-) uptake during turgor regulation. Other pathways regulating turgor must also exist. PMID:16524903

  13. Role of a Mitogen-Activated Protein Kinase Cascade in Ion Flux-Mediated Turgor Regulation in Fungi

    Science.gov (United States)

    Lew, Roger R.; Levina, Natalia N.; Shabala, Lana; Anderca, Marinela I.; Shabala, Sergey N.

    2006-01-01

    Fungi normally maintain a high internal hydrostatic pressure (turgor) of about 500 kPa. In response to hyperosmotic shock, there are immediate electrical changes: a transient depolarization (1 to 2 min) followed by a sustained hyperpolarization (5 to 10 min) prior to turgor recovery (10 to 60 min). Using ion-selective vibrating probes, we established that the transient depolarization is due to Ca2+ influx and the sustained hyperpolarization is due to H+ efflux by activation of the plasma membrane H+-ATPase. Protein synthesis is not required for H+-ATPase activation. Net K+ and Cl− uptake occurs at the same time as turgor recovery. The magnitude of the ion uptake is more than sufficient to account for the osmotic gradients required for turgor to return to its original level. Two osmotic mutants, os-1 and os-2, homologs of a two-component histidine kinase sensor and the yeast high osmotic glycerol mitogen-activated protein (MAP) kinase, respectively, have lower turgor than the wild type and do not exhibit the sustained hyperpolarization after hyperosmotic treatment. The os-1 mutant does not exhibit all of the wild-type turgor-adaptive ion fluxes (Cl− uptake increases, but net K+ flux barely changes and net H+ efflux declines) (os-2 was not examined). Both os mutants are able to regulate turgor but at a lower level than the wild type. Our results demonstrate that a MAP kinase cascade regulates ion transport, activation of the H+-ATPase, and net K+ and Cl− uptake during turgor regulation. Other pathways regulating turgor must also exist. PMID:16524903

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

    Energy Technology Data Exchange (ETDEWEB)

    Zois, Christos E. [Department of Radiotherapy - Oncology, Democritus University of Thrace, Alexandroupolis 68100 (Greece); Giatromanolaki, Alexandra [Department of Pathology, Democritus University of Thrace, Alexandroupolis (Greece); Kainulainen, Heikki [Department of Biology of Physical Activity, University of Jyvaeskylae (Finland); Botaitis, Sotirios [Department of Experimental Surgery, Democritus University of Thrace, Alexandroupolis (Greece); Torvinen, Sira [Department of Biology of Physical Activity, University of Jyvaeskylae (Finland); Simopoulos, Constantinos [Department of Experimental Surgery, Democritus University of Thrace, Alexandroupolis (Greece); Kortsaris, Alexandros [Department of Biochemistry, Democritus University of Thrace, Alexandroupolis (Greece); Sivridis, Efthimios [Department of Pathology, Democritus University of Thrace, Alexandroupolis (Greece); Koukourakis, Michael I., E-mail: targ@her.forthnet.gr [Department of Radiotherapy - Oncology, Democritus University of Thrace, Alexandroupolis 68100 (Greece)

    2011-01-07

    Research highlights: {yields} We investigated the effect 6 Gy of WBI on the autophagic machinery of normal mouse lung. {yields} 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. {yields} The membrane bound LC3A-II protein levels increased in the cytosolic fraction (not in the pellet), contrasting the patterns noted after starvation-induced autophagy. {yields} 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 {gamma}-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

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

    International Nuclear Information System (INIS)

    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

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

    Science.gov (United States)

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

    2010-01-01

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

  17. 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

  18. pH-Sensitive Polymeric Nanoparticles Modulate Autophagic Effect via Lysosome Impairment.

    Science.gov (United States)

    Lin, Yao-Xin; Wang, Yi; Qiao, Sheng-Lin; An, Hong-Wei; Zhang, Ruo-Xin; Qiao, Zeng-Ying; Rajapaksha, R P Y J; Wang, Lei; Wang, Hao

    2016-06-01

    In drug delivery systems, pH-sensitive polymers are commonly used as drug carriers, and significant efforts have been devoted to the aspects of controlled delivery and release of drugs. However, few studies address the possible autophagic effects on cells. Here, for the first time, using a fluorescent autophagy-reporting cell line, this study evaluates the autophagy-induced capabilities of four types of pH-sensitive polymeric nanoparticles (NPs) with different physical properties, including size, surface modification, and pH-sensitivity. Based on experimental results, this study concludes that pH-sensitivity is one of the most important factors in autophagy induction. In addition, this study finds that variation of concentration of NPs could cause different autophagic effect, i.e., low concentration of NPs induces autophagy in an mTOR-dependent manner, but high dose of NPs leads to autophagic cell death. Identification of this tunable autophagic effect offers a novel strategy for enhancing therapeutic effect in cancer therapy through modulation of autophagy. PMID:27120078

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

    Directory of Open Access Journals (Sweden)

    Emeric Deruy

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

  20. Fluorescence-based visualization of autophagic activity predicts mouse embryo viability

    Science.gov (United States)

    Tsukamoto, Satoshi; Hara, Taichi; Yamamoto, Atsushi; Kito, Seiji; Minami, Naojiro; Kubota, Toshiro; Sato, Ken; Kokubo, Toshiaki

    2014-03-01

    Embryo quality is a critical parameter in assisted reproductive technologies. Although embryo quality can be evaluated morphologically, embryo morphology does not correlate perfectly with embryo viability. To improve this, it is important to understand which molecular mechanisms are involved in embryo quality control. Autophagy is an evolutionarily conserved catabolic process in which cytoplasmic materials sequestered by autophagosomes are degraded in lysosomes. We previously demonstrated that autophagy is highly activated after fertilization and is essential for further embryonic development. Here, we developed a simple fluorescence-based method for visualizing autophagic activity in live mouse embryos. Our method is based on imaging of the fluorescence intensity of GFP-LC3, a versatile marker for autophagy, which is microinjected into the embryos. Using this method, we show that embryonic autophagic activity declines with advancing maternal age, probably due to a decline in the activity of lysosomal hydrolases. We also demonstrate that embryonic autophagic activity is associated with the developmental viability of the embryo. Our results suggest that embryonic autophagic activity can be utilized as a novel indicator of embryo quality.

  1. Exogenous hydrogen peroxide, nitric oxide and calcium mediate root ion fluxes in two non-secretor mangrove species subjected to NaCl stress.

    Science.gov (United States)

    Lu, Yanjun; Li, Niya; Sun, Jian; Hou, Peichen; Jing, Xiaoshu; Zhu, Huipeng; Deng, Shurong; Han, Yansha; Huang, Xuxin; Ma, Xujun; Zhao, Nan; Zhang, Yuhong; Shen, Xin; Chen, Shaoliang

    2013-01-01

    Using 3-month-old seedlings of Bruguiera gymnorrhiza (L.) Savigny and Kandelia candel (L.) Druce, we compared species differences in ionic homeostasis control between the two non-secretor mangrove species. A high salinity (400 mM NaCl, 4 weeks) resulted in a decline of the K(+)/Na(+) ratio in root and leaf tissues, and the reduction was more pronounced in K. candel (41-66%) as compared with B. gymnorrhiza (5-36%). Salt-altered flux profiles of Na(+), K(+), H(+) and Ca(2+) in roots and effects of exogenous hydrogen peroxide (H(2)O(2)), nitric oxide (NO) and Ca(2+) on root ion fluxes were examined in seedlings that were hydroponically treated short term with 100 mM NaCl (ST, 24 h) and long term with 200 mM NaCl (LT, 7 days). Short term and LT salinity resulted in Na(+) efflux and a correspondingly increased H(+) influx in roots of both species, although a more pronounced effect was observed in B. gymnorrhiza. The salt-enhanced exchange of Na(+) with H(+) was obviously inhibited by amiloride (a Na(+)/H(+) antiporter inhibitor) or sodium orthovanadate (a plasma membrane H(+)-ATPase inhibitor), indicating that the Na(+) efflux resulted from active Na(+) exclusion across the plasma membrane. Short term and LT salinity accelerated K(+) efflux in the two species, but K. candel exhibited a higher flux rate. The salt-induced K(+) efflux was markedly restricted by the K(+) channel blocker, tetraethylammonium chloride, indicating that the K(+) efflux is mediated by depolarization-activated channels, e.g., KORCs (outward rectifying K(+) channels) and NSCCs (non-selective cation channels). Exogenous H(2)O(2) application (10 mM) markedly increased the apparent Na(+) efflux and limited K(+) efflux in ST-treated roots, although H(2)O(2) caused a higher Na(+) efflux in B. gymnorrhiza roots. CaCl(2) (10 mM) reduced the efflux of K(+) in salinized roots of the two mangroves, but its enhancement of Na(+) efflux was found only in B. gymnorrhiza. Under ST treatment, sodium nitroprusside

  2. The Autophagic Process Occurs in Human Bone Metastasis and Implicates Molecular Mechanisms Differently Affected by Rab5a in the Early and Late Stages

    Directory of Open Access Journals (Sweden)

    Paola Maroni

    2016-03-01

    Full Text Available Autophagy favours metastatic growth through fuelling energy and nutrients and resistance to anoikis, typical of disseminated-tumour cells. The autophagic process, mediated by a unique organelle, the autophagosome, which fuses with lysosomes, is divided into three steps. Several stages, especially early omegasome formation and isolation-membrane initiation, remain controversial; molecular mechanisms involve the small-GTPase Rab5a, which regulates vesicle traffic for autophagosome formation. We examined Rab5a involvement in the function of key members of ubiquitin-conjugation systems, Atg7 and LC3-lipidated, interacting with the scaffold-protein p62. Immunohistochemistry of Rab5a was performed in human specimens of bone metastasis and pair-matched breast carcinoma; the autophagic-molecular mechanisms affected by Rab5a were evaluated in human 1833 bone metastatic cells, derived from breast-carcinoma MDA-MB231 cells. To clarify the role of Rab5a, 1833 cells were transfected transiently with Rab5a-dominant negative, and/or stably with the short-hairpin RNA Atg7, were exposed to two inhibitors of autolysosome function, and LC3II and p62 expression was measured. We showed basal autophagy in bone-metastatic cells and the pivotal role of Rab5a together with Beclin 1 between the early stages, elongation of isolation membrane/closed autophagosome mediated by Atg7, and the late-degradative stages. This regulatory network might occur in bone-metastasis and in high-grade dysplastic lesions, preceding invasive-breast carcinoma and conferring phenotypic characteristics for dissemination.

  3. The Autophagic Process Occurs in Human Bone Metastasis and Implicates Molecular Mechanisms Differently Affected by Rab5a in the Early and Late Stages.

    Science.gov (United States)

    Maroni, Paola; Bendinelli, Paola; Resnati, Massimo; Matteucci, Emanuela; Milan, Enrico; Desiderio, Maria Alfonsina

    2016-01-01

    Autophagy favours metastatic growth through fuelling energy and nutrients and resistance to anoikis, typical of disseminated-tumour cells. The autophagic process, mediated by a unique organelle, the autophagosome, which fuses with lysosomes, is divided into three steps. Several stages, especially early omegasome formation and isolation-membrane initiation, remain controversial; molecular mechanisms involve the small-GTPase Rab5a, which regulates vesicle traffic for autophagosome formation. We examined Rab5a involvement in the function of key members of ubiquitin-conjugation systems, Atg7 and LC3-lipidated, interacting with the scaffold-protein p62. Immunohistochemistry of Rab5a was performed in human specimens of bone metastasis and pair-matched breast carcinoma; the autophagic-molecular mechanisms affected by Rab5a were evaluated in human 1833 bone metastatic cells, derived from breast-carcinoma MDA-MB231 cells. To clarify the role of Rab5a, 1833 cells were transfected transiently with Rab5a-dominant negative, and/or stably with the short-hairpin RNA Atg7, were exposed to two inhibitors of autolysosome function, and LC3II and p62 expression was measured. We showed basal autophagy in bone-metastatic cells and the pivotal role of Rab5a together with Beclin 1 between the early stages, elongation of isolation membrane/closed autophagosome mediated by Atg7, and the late-degradative stages. This regulatory network might occur in bone-metastasis and in high-grade dysplastic lesions, preceding invasive-breast carcinoma and conferring phenotypic characteristics for dissemination. PMID:27023526

  4. WASH is required for lysosomal recycling and efficient autophagic and phagocytic digestion

    OpenAIRE

    King, Jason S.; Gueho, Aurélie; Hagedorn, Monica; Gopaldass, Navin Andréw; Leuba, Florence; Soldati, Thierry; Insall, Robert H.

    2013-01-01

    Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) is an important regulator of vesicle trafficking. By generating actin on the surface of intracellular vesicles, WASH is able to directly regulate endosomal sorting and maturation. We report that, in Dictyostelium, WASH is also required for the lysosomal digestion of both phagocytic and autophagic cargo. Consequently, Dictyostelium cells lacking WASH are unable to grow on many bacteria or to digest their own cytoplasm to survive starva...

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

    OpenAIRE

    Kyoung Hoon Jeong; Un Ju Jung; Sang Ryong Kim

    2015-01-01

    Kainic acid (KA) is well known as a chemical compound to study epileptic seizures and neuronal excitotoxicity. KA-induced excitotoxicity causes neuronal death by induction of autophagic stress and microglia-derived neuroinflammation, suggesting that the control of KA-induced effects may be important to inhibit epileptic seizures with neuroprotection. Naringin, a flavonoid in grapefruit and citrus fruits, has anti-inflammatory and antioxidative activities, resulting in neuroprotection in anima...

  6. Spinster is required for autophagic lysosome reformation and mTOR reactivation following starvation

    OpenAIRE

    Rong, Yueguang; McPhee, Christina K; Deng, Shuangshen; Huang, Lei; Chen, Lilian; Liu, Mei; Tracy, Kirsten; Baehrecke, Eric H.; Yu, Li; Lenardo, Michael J.

    2011-01-01

    Autophagy is a conserved cellular process to degrade and recycle cytoplasmic components. During autophagy, lysosomes fuse with an autophagosome to form an autolysosome. Sequestered components are degraded by lysosomal hydrolases and presumably released into the cytosol by lysosomal efflux permeases. Following starvation-induced autophagy, lysosome homeostasis is restored by autophagic lysosome reformation (ALR) requiring activation of the “target of rapamycin” (TOR) kinase. Spinster (Spin) en...

  7. 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

  8. A proposed paradigm for solar cycle dynamics mediated via turbulent pumping of magnetic flux in Babcock-Leighton type solar dynamos

    CERN Document Server

    Hazra, Soumitra

    2016-01-01

    At present, Babcock-Leighton flux transport solar dynamo models appear as the most promising model 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 is recovered even when meridional circulation is altogether absent, however, in this case the solar surface m...

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

    Directory of Open Access Journals (Sweden)

    Feng Li

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

  10. Fumonisin B1 induces autophagic cell death via activation of ERN1-MAPK8/9/10 pathway in monkey kidney MARC-145 cells.

    Science.gov (United States)

    Yin, Shutao; Guo, Xiao; Li, Jinghua; Fan, Linghong; Hu, Hongbo

    2016-04-01

    Mycotoxins are secondary fungal metabolites that are capable of inducing a variety of toxic effects in animals and humans resulting from the consumption of the contaminated food. Understanding the mechanisms of the toxicities behind these mycotoxins is required to develop mechanism-based approach to counteract their toxic potential. Fumonisin B1 (FB1) is the most prevalent member of fumonisins that are a group of mycotoxins produced primarily by Fusarium verticillioides and Fusarium proliferatum. Kidney is one of the primary target organs for FB1 action. Using monkey kidney MARC-145 cells as an intro model, we found that FB1 induced caspase-independent programmed cell death accompanied with autophagy induction. Inhibition of autophagy by either chemical inhibitors or RNAi approach led to a significant reduction in cell death by FB1 exposure, indicating possible involvement of autophagy-mediated cell death in nephrotoxicity of FB1. Further mechanistic investigation revealed that activation of ERN1-MAPK8/9/10 axis played a critical role in autophagy induction and autophagy-mediated cell death by FB1 exposure. In addition, we demonstrated that disruption of sphingolipid metabolism was an apical event in FB1-induced ERN1-MAPK8/9/10-mediated autophagic cell death in MARC-145 cells. Lastly, we identified curcumin, a naturally occurring plant phenolic compound, as a possible anti-FB1 agent that can be used to protect kidney cells from FB1-induced cell death through inhibition of MAPK8/9/10 activation. PMID:25925693

  11. Inhibition of UCH-L1 in oligodendroglial cells results in microtubule stabilization and prevents α-synuclein aggregate formation by activating the autophagic pathway: implications for multiple system atrophy

    Directory of Open Access Journals (Sweden)

    Katharina Pukaß

    2015-05-01

    Full Text Available α-Synuclein (α-syn positive glial cytoplasmic inclusions (GCI originating in oligodendrocytes are a characteristic hallmark in multiple system atrophy. Their occurrence may be linked to a failure of the ubiquitin proteasome system (UPS or the autophagic pathway. For proteasomal degradation, proteins need to be covalently modified by ubiquitin, and deubiquitinated by deubiquitinating enzymes before proteolytic degradation is performed. The deubiquitinating enzyme UCH-L1 is a component of the UPS, it is abundantly expressed in neuronal brain cells and has been connected to Parkinson`s disease. It interacts with α-syn and tubulin. The present study was undertaken to investigate whether UCH-L1 is a constituent of oligodendrocytes, the myelin forming cells of the CNS, and is associated with GCIs in MSA. Furthermore, LDN-57444 (LDN, a specific UCH-L1 inhibitor, was used to analyze its effects on cell morphology, microtubule organization and the proteolytic degradation system. Towards this an oligodendroglial cell line (OLN cells, stably transfected with α-syn or with α-syn and GFP-LC3, to monitor the autophagic flux, was used. The data show that UCHL-1 is expressed in oligodendrocytes derived from the brains of newborn rats and colocalizes with α-syn in GCIs of MSA brain sections. LDN treatment had a direct impact on the microtubule network by affecting tubulin posttranslational modifications, i.e. acetylation and tyrosination. An increase in α-tubulin detyrosination was observed and detyrosinated microtubules were abundantly recruited to the cellular extensions. Furthermore, small α-syn aggregates, which are constitutively expressed in OLN cells overexpressing α-syn, were abolished, and LDN caused the upregulation of the autophagic pathway. Our data add to the knowledge that the UPS and the autophagy-lysosomal pathway are tightly balanced, and that UCH-L1 and its regulation may play a role in neurodegenerative diseases with oligodendroglia

  12. 17β-Estradiol mediates superior adaptation of right ventricular function to acute strenuous exercise in female rats with severe pulmonary hypertension.

    Science.gov (United States)

    Lahm, Tim; Frump, Andrea L; Albrecht, Marjorie E; Fisher, Amanda J; Cook, Todd G; Jones, Thomas J; Yakubov, Bakhtiyor; Whitson, Jordan; Fuchs, Robyn K; Liu, Aiping; Chesler, Naomi C; Brown, M Beth

    2016-08-01

    17β-Estradiol (E2) exerts protective effects on right ventricular (RV) function in pulmonary arterial hypertension (PAH). Since acute exercise-induced increases in afterload may lead to RV dysfunction in PAH, we sought to determine whether E2 allows for superior RV adaptation after an acute exercise challenge. We studied echocardiographic, hemodynamic, structural, and biochemical markers of RV function in male and female rats with sugen/hypoxia (SuHx)-induced pulmonary hypertension, as well as in ovariectomized (OVX) SuHx females, with or without concomitant E2 repletion (75 μg·kg(-1)·day(-1)) immediately after 45 min of treadmill running at 75% of individually determined maximal aerobic capacity (75% aerobic capacity reserve). Compared with males, intact female rats exhibited higher stroke volume and cardiac indexes, a strong trend for better RV compliance, and less pronounced increases in indexed total pulmonary resistance. OVX abrogated favorable RV adaptations, whereas E2 repletion after OVX markedly improved RV function. E2's effects on pulmonary vascular remodeling were complex and less robust than its RV effects. Postexercise hemodynamics in females with endogenous or exogenous E2 were similar to hemodynamics in nonexercised controls, whereas OVX rats exhibited more severely altered postexercise hemodynamics. E2 mediated inhibitory effects on RV fibrosis and attenuated increases in RV collagen I/III ratio. Proapoptotic signaling, endothelial nitric oxide synthase phosphorylation, and autophagic flux markers were affected by E2 depletion and/or repletion. Markers of impaired autophagic flux correlated with endpoints of RV structure and function. Endogenous and exogenous E2 exerts protective effects on RV function measured immediately after an acute exercise challenge. Harnessing E2's mechanisms may lead to novel RV-directed therapies. PMID:27288487

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

    International Nuclear Information System (INIS)

    Water soluble fullerenes, such as the hydroxylated fullerene, fullerenol (C60OHx), are currently under development for diagnostic and therapeutic biomedical applications in the field of nanotechnology. These molecules have been shown to undergo urinary clearance, yet there is limited data available on their renal biocompatibility. Here we examine the biological responses of renal proximal tubule cells (LLC-PK1) exposed to fullerenol. Fullerenol was found to be cytotoxic in the millimolar range, with viability assessed by the sulforhodamine B and trypan blue assays. Fullerenol-induced cell death was associated with cytoskeleton disruption and autophagic vacuole accumulation. Interaction with the autophagy pathway was evaluated in vitro by Lysotracker Red dye uptake, LC3-II marker expression and TEM. Fullerenol treatment also resulted in coincident loss of cellular mitochondrial membrane potential and ATP depletion, as measured by the Mitotracker Red dye and the luciferin-luciferase assays, respectively. Fullerenol-induced ATP depletion and loss of mitochondrial potential were partially ameliorated by co-treatment with the autophagy inhibitor, 3-methyladenine. In vitro fullerenol treatment did not result in appreciable oxidative stress, as measured by lipid peroxide and glutathione content. Based on these data, it is hypothesized that cytoskeleton disruption may be an initiating event in fullerenol cytotoxicity, leading to subsequent autophagy dysfunction and loss of mitochondrial capacity. As nanoparticle-induced cytoskeleton disruption, autophagic vacuole accumulation and mitochondrial dysfunction are commonly reported in the literature, the proposed mechanism may be relevant for a variety of nanomaterials.

  14. Autophagic sequestration of [14C]sucrose, introduced into rat hepatocytes by reversible electro-permeabilization

    International Nuclear Information System (INIS)

    Isolated rat hepatocytes could be made permeable to small molecules such as [14C]sucrose (but not to proteins) but subjecting the cells to repeated discharges in a high-voltage field. During subsequent incubation at 370C, the permeability changes were reversed within 15 min, the electron-injected [14C]sucros remaining trapped inside the re-sealed plasma membrane. Autophagic sequestration of [14C]sucrose, i.e., the transfer of radioactivity from cytosol to sedimentable vesicles (autophagosomes and lysosomes), could be followed by incubating the [14C]sucrose-loaded hepatocytes for up to 2 h at 370C. After incubation, the cells were disrupted by a single high-voltage discharge in electrolyte-free medium (sucrose), and sedimentable cell components were separated from the cytosol by centrifugation through metrizamide. By the use of these methods, which are particularly suitable for the analysis of many small cell samples, it could be shown that [14C]sucros was autophagically sequestered in the hepatocytes at a rate of 4-5%/h. The sequestration was nearly completely inhibited by the specific autophagy inhibitor 3-methyladenine

  15. Ubiquitin-independent function of optineurin in autophagic clearance of protein aggregates.

    Science.gov (United States)

    Korac, Jelena; Schaeffer, Veronique; Kovacevic, Igor; Clement, Albrecht M; Jungblut, Benno; Behl, Christian; Terzic, Janos; Dikic, Ivan

    2013-01-15

    Aggregation of misfolded proteins and the associated loss of neurons are considered a hallmark of numerous neurodegenerative diseases. Optineurin is present in protein inclusions observed in various neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), Huntington's disease, Alzheimer's disease, Parkinson's disease, Creutzfeld-Jacob disease and Pick's disease. Optineurin deletion mutations have also been described in ALS patients. However, the role of optineurin in mechanisms of protein aggregation remains unclear. In this report, we demonstrate that optineurin recognizes various protein aggregates via its C-terminal coiled-coil domain in a ubiquitin-independent manner. We also show that optineurin depletion significantly increases protein aggregation in HeLa cells and that morpholino-silencing of the optineurin ortholog in zebrafish causes the motor axonopathy phenotype similar to a zebrafish model of ALS. A more severe phenotype is observed when optineurin is depleted in zebrafish carrying ALS mutations. Furthermore, TANK1 binding kinase 1 (TBK1) is colocalized with optineurin on protein aggregates and is important in clearance of protein aggregates through the autophagy-lysosome pathway. TBK1 phosphorylates optineurin at serine 177 and regulates its ability to interact with autophagy modifiers. This study provides evidence for a ubiquitin-independent function of optineurin in autophagic clearance of protein aggregates as well as additional relevance for TBK1 as an upstream regulator of the autophagic pathway. PMID:23178947

  16. Increased autophagic activity in dorsal root ganglion attenuates neuropathic pain following peripheral nerve injury.

    Science.gov (United States)

    Guo, Jian-Shuang; Jing, Peng-Bo; Wang, Ji-An; Zhang, Rui; Jiang, Bao-Chun; Gao, Yong-Jing; Zhang, Zhi-Jun

    2015-07-10

    Autophagy is a process of cellular self-cannibalization, and provides an adaptive mechanism to protect cells against diverse pathological settings. Following peripheral nerve injury, autophagic process was changed in Schwann cells and spinal neurons and glial cells, implicating a vital role of autophagy in chronic pain. However, little is known about the role of autophagy in dorsal root ganglion (DRG) in neuropathic pain. In the present study, we investigated the autophagic process in DRG and its effect on neuropathic pain induced by L5 spinal nerve ligation (SNL). The level of microtubule associated protein 1 light chain 3 (LC3)-II, a general marker for autophagy, was increased in L5 DRG after SNL. Immunofluorescence staining showed that LC3-II puncta were observed in DRG neurons after SNL. Injection of autophagy inducer rapamycin into L5 DRG before or after SNL dose-dependently attenuated neuropathic pain. The expression of LC3 was enhanced in L5 DRG by rapamycin. These data suggest that the autophagy in L5 DRG neurons is a defensive reaction to L5 spinal nerve injury, and pharmacological enhancement of autophagy may be a potential treatment to prevent the onset and chronification of neuropathic pain. PMID:26021876

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

    International Nuclear Information System (INIS)

    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.

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

    Directory of Open Access Journals (Sweden)

    Kyoung Hoon Jeong

    2015-01-01

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

  19. 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.

  20. The role of autophagic and lysosomal pathways in ischemic brain injury******

    Institute of Scientific and Technical Information of China (English)

    Zhaohua Gu; Nan Shi; Qian Zhang; Wei Zhang; Meizhen Zhao; Xiaojiang Sun; Yinyi Sun; Kangyong Liu; Fen Wang; Ting Zhang; Qiang Li; Liwei Shen; Ling Zhou; Liang Dong

    2013-01-01

    Autophagy is involved in neural cel death after cerebral ischemia. Our previous studies showed that rapamycin-induced autophagy decreased the rate of apoptosis, but the rate of apoptosis was creased after the autophagy inhibitor, 3-methyladenine, was used. In this study, a suture-occluded method was performed to generate a rat model of brain ischemia. Under a transmission electron microscope, autophagic bodies and autophagy lysosomes were markedly accumulated in neurons at 4 hours post brain ischemic injury, with their numbers gradual y reducing over time. Western blotting demonstrated that protein levels of light chain 3-II and cathepsin B were significantly in-creased within 4 hours of ischemic injury, but these levels were not persistently upregulated over time. Confocal microscopy showed that autophagy was mainly found in neurons with positive light chain 3 signal. Injection of rapamycin via tail vein promoted the occurrence of autophagy in rat brain tissue after cerebral ischemia and elevated light chain 3 and cathepsin B expression. However, in-jection of 3-methyladenine significantly diminished light chain 3-II and cathepsin B expression. Results verified that autophagic and lysosomal activity is increased in ischemic neurons. Abnormal components in cel s can be eliminated through upregulating cel autophagy or inhibiting autophagy after ischemic brain injury, resulting in a dynamic balance of substances in cel s. Moreover, drugs that interfere with autophagy may be potential therapies for the treatment of brain injury.

  1. Autophagic down-regulation in motor neurons remarkably prolongs the survival of ALS mice.

    Science.gov (United States)

    Hsueh, Kuo-Wei; Chiou, Tzyy-Wen; Chiang, Shu-Fen; Yamashita, Toru; Abe, Koji; Borlongan, Cesar V; Sanberg, Paul R; Huang, Angela Yu Hsuan; Lin, Shinn-Zong; Harn, Horng-Jyh

    2016-09-01

    Amyotrophic lateral sclerosis (ALS) is a lethal degenerating disease, characterized by progressive muscular atrophy without any effective treatment. Here, we demonstrated the efficacy of abrograting autophagy in motor neurons (MN) by treatment with n-butylidenephthalide (n-BP) in ALS transgenic mice (SOD1(G93A)). Pre-symptomatic oral administration of 250 mg/kg/bid n-BP significantly prolonged the survival period (203.9 ± 18.3 days), improved motor function, and attenuated MN loss compared to vehicle control (126.4 ± 7.2 days). This prolonged survival of ALS mice is much more robust than that reported with riluzole (140 days), which is an approved clinical therapy for ALS. The therapeutic mechanism targeted by n-BP involved the autophagic pathway as evidenced by decreased LC3-II expression (a biomarker of autophagy), enhanced mTOR levels, and attenuated autophagic activity, altogether increasing MN survival in a dose-dependent manner. This result was also confirmed by double transgenic mice (SOD1(G93A):LC3-GFP) which showed that oral administration of n-BP reduced GFP density and decreased caspase-3 expression. In addition, electron microscopy revealed that n-BP administration not only decreased autophagosome number but also reduced morphological dysfunction of mitochondria. In summary, these results indicate that down-regulation of autophagy activation via n-BP may pose as a therapeutic regimen for ALS and relevant neurodegenerative diseases. PMID:27059126

  2. Arsenic Inhibits Autophagic Flux, Activating the Nrf2-Keap1 Pathway in a p62-Dependent Manner

    OpenAIRE

    Lau, Alexandria; Zheng, Yi; Tao, Shasha; Wang, Huihui; Whitman, Samantha A; White, Eileen; Zhang, Donna D.

    2013-01-01

    The Nrf2-Keap1 signaling pathway is a protective mechanism promoting cell survival. Activation of the Nrf2 pathway by natural compounds has been proven to be an effective strategy for chemoprevention. Interestingly, a cancer-promoting function of Nrf2 has recently been observed in many types of tumors due to deregulation of the Nrf2-Keap1 axis, which leads to constitutive activation of Nrf2. Here, we report a novel mechanism of Nrf2 activation by arsenic that is distinct from that of chemopre...

  3. AMP-Dependent Kinase and Autophagic Flux are Involved in Aldehyde Dehydrogenase 2-Offered Protection against Cardiac Toxicity of Ethanol

    OpenAIRE

    Ge, Wei; GUO Rui; Ren, Jun

    2011-01-01

    Mitochondrial aldehyde dehydrogenase-2 (ALDH2) alleviates ethanol toxicity although the precise mechanism is unclear. This study was designed to evaluate the effect of ALDH2 on ethanol-induced myocardial damage with a focus on autophagy. Wild-type FVB and transgenic mice overexpressing ALDH2 were challenged with ethanol (3 g/kg/d, i.p.) for 3 days and cardiac mechanical function was assessed using the echocardiographic and IonOptix systems. Western blot analysis was used to evaluate essential...

  4. Aurantiamide acetate suppresses the growth of malignant gliomas in vitro and in vivo by inhibiting autophagic flux

    OpenAIRE

    Yi YANG; Zhang, Li-hui; Yang, Bing-xian; Tian, Jin-kui; Zhang, Lin

    2015-01-01

    We aim to investigate the effect of aurantiamide acetate isolated from the aerial parts of Clematis terniflora DC against gliomas. Human malignant glioma U87 and U251 cells were incubated with different concentrations (0–100 μM) of aurantiamide acetate. Aurantiamide acetate greatly decreased the cell viability in a dose- and time-dependent manner. It induced moderate mitochondrial fragmentation and the loss of mitochondrial membrane potential. No significant difference was found in the altern...

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

    DEFF Research Database (Denmark)

    Christensen, S T; Chemnitz, J; Straarup, E M; Kristiansen, Karsten; Wheatley, D N; Rasmussen, L

    phosphorylation of the PKC-specific substrate, myelin basic protein fragment 4-14. Our results show that cell death in the presence of staurosporine is associated with morphological and ultrastructural changes similar to both apoptosis and autophagic degeneration, but these in turn can be postponed or prevented...

  6. 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.

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

    International Nuclear Information System (INIS)

    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.

  8. Water- and Plant-Mediated Responses of Ecosystem Carbon Fluxes to Warming and Nitrogen Addition on the Songnen Grassland in Northeast China

    Science.gov (United States)

    Jiang, Li; Guo, Rui; Zhu, Tingcheng; Niu, Xuedun; Guo, Jixun; Sun, Wei

    2012-01-01

    Background 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. Methodology/Principal Findings In-situ canopy CO2 exchange rates were measured in a meadow steppe subjected to 4-year warming and nitrogen addition treatments. Warming treatment reduced net ecosystem CO2 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. Conclusion/Significance 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. PMID:23028848

  9. The convergent point of the endocytic and autophagic pathways in leydig cells

    Institute of Scientific and Technical Information of China (English)

    YIJING; XUEMINGTANG

    1999-01-01

    Endocytic tracers and marker enzyme of lysosomes were used in the present study to analyze the processes of autophagocytosis and endocytosis,and the convergent point of these two pathways in Leydig cells.The endocytic and autophagic compartments can be easily identified in Leydig cells,which makes easier to difine the stages of two pathways than was possible before.The evidences indicated that late endosomes (dense MVBs) deliver their endocytosed gold tracers together with lysosomal enzymes to the early autophagosomes and they are the convergent point of the two pathways.During this convergent process,the early autophadosomes transform into late autophagosomes and the late endosomes transform into mature lysosomes.

  10. Mesenchymal Stromal Cells Differentiating to Adipocytes Accumulate Autophagic Vesicles Instead of Functional Lipid Droplets.

    Science.gov (United States)

    Gruia, Alexandra T; Suciu, Maria; Barbu-Tudoran, Lucian; Azghadi, Seyed Mohammad Reza; Cristea, Mirabela I; Nica, Dragos V; Vaduva, Adrian; Muntean, Danina; Mic, Ani Aurora; Mic, Felix A

    2016-04-01

    Adult bone marrow mesenchymal stromal cells (BMSCs) can easily be differentiated into a variety of cells. In vivo transplantation of BMSCs-differentiated cells has had limited success, suggesting that these cells may not be fully compatible with the cells they are intended to replace in vivo. We investigated the structural and functional features of BMSCs-derived adipocytes as compared with adipocytes from adipose tissue, and the structure and functionality of lipid vesicles formed during BMSCs differentiation to adipocytes. Gas chromatography-mass spectrometry showed fatty acid composition of BMSCs-derived adipocytes and adipocytes from the adipose tissue to be very different, as is the lipid rafts composition, caveolin-1 expression, caveolae distribution in their membranes, and the pattern of expression of fatty acid elongases. Confocal microscopy confirmed the absence from BMSCs-derived adipocytes of markers of lipid droplets. BMSCs-derived adipocytes cannot convert deuterated glucose into deuterated species of fatty acids and cannot uptake the deuterated fatty acid-bovine serum albumin complexes from the culture medium, suggesting that intra-cellular accumulation of lipids does not occur by lipogenesis. We noted that BMSCs differentiation to adipocytes is accompanied by an increase in autophagy. Autophagic vesicles accumulate in the cytoplasm of BMSCs-derived adipocytes and their size and distribution resembles that of Nile Red-stained lipid vesicles. Stimulation of autophagy in BMSCs triggers the intra-cellular accumulation of lipids, while inhibition of autophagy prevents this accumulation. In conclusion, differentiation of BMSCs-derived adipocytes leads to intra-cellular accumulation of autophagic vesicles rather than functional lipid droplets, suggesting that these cells are not authentic adipocytes. J. Cell. Physiol. 231: 863-875, 2016. © 2015 Wiley Periodicals, Inc. PMID:26332160

  11. Advantages and limitations of different p62-based assays for estimating autophagic activity in Drosophila.

    Directory of Open Access Journals (Sweden)

    Karolina Pircs

    Full Text Available Levels of the selective autophagy substrate p62 have been established in recent years as a specific readout for basal autophagic activity. Here we compared different experimental approaches for using this assay in Drosophila larvae. Similar to the more commonly used western blots, quantifying p62 dots in immunostained fat body cells of L3 stage larvae detected a strong accumulation of endogenous p62 aggregates in null mutants for Atg genes and S6K. Importantly, genes whose mutation or silencing results in early stage lethality can only be analyzed by microscopy using clonal analysis. The loss of numerous general housekeeping genes show a phenotype in large-scale screens including autophagy, and the p62 assay was potentially suitable for distinguishing bona fide autophagy regulators from silencing of a DNA polymerase subunit or a ribosomal gene that likely has a non-specific effect on autophagy. p62 accumulation upon RNAi silencing of known autophagy regulators was dependent on the duration of the knockdown effect, unlike in the case of starvation-induced autophagy. The endogenous p62 assay was more sensitive than a constitutively overexpressed p62-GFP reporter, which showed self-aggregation and large-scale accumulation even in control cells. We recommend western blots for following the conversion of overexpressed p62-GFP reporters to estimate autophagic activity if sample collection from mutant larvae or adults is possible. In addition, we also showed that overexpressed p62 or Atg8 reporters can strongly influence the phenotypes of each other, potentially giving rise to false or contradicting results. Overexpressed p62 aggregates also incorporated Atg8 reporter molecules that might lead to a wrong conclusion of strongly enhanced autophagy, whereas expression of an Atg8 reporter transgene rescued the inhibitory effect of a dominant-negative Atg4 mutant on basal and starvation-induced autophagy.

  12. Cilostazol Modulates Autophagic Degradation of β-Amyloid Peptide via SIRT1-Coupled LKB1/AMPKα Signaling in Neuronal Cells

    Science.gov (United States)

    Lee, Won Suk; Shin, Hwa Kyoung; Kim, Hye Young; Hong, Ki Whan; Kim, Chi Dae

    2016-01-01

    A neuroprotective role of autophagy mediates the degradation of β-amyloid peptide (Aβ) in Alzheimer’s disease (AD). The previous study showed cilostazol modulates autophagy by increasing beclin1, Atg5 and LC3-II expressions, and depletes intracellular Aβ accumulation. This study elucidated the mechanisms through which cilostazol modulates the autophagic degradation of Aβ in neurons. In N2a cells, cilostazol (10–30 μM), significantly increased the expression of P-AMPKα (Thr 172) and downstream P-ACC (acetyl-CoA carboxylase) (Ser 79) as did resveratrol (SIRT1 activator), or AICAR (AMPK activator), which were blocked by KT5720, compound C (AMPK inhibitor), or sirtinol. Furthermore, phosphorylated-mTOR (Ser 2448) and phosphorylated-P70S6K (Thr 389) expressions were suppressed, and LC3-II levels were elevated in association with decreased P62/Sqstm1 by cilostazol. Cilostazol increased cathepsin B activity and decreased p62/SQSTM 1, consequently decreased accumulation of Aβ1–42 in the activated N2aSwe cells, and these results were blocked by sirtinol, compound C and bafilomycin A1 (autophagosome blocker), suggesting enhanced autophagosome formation by cilostazol. In SIRT1 gene-silenced N2a cells, cilostazol failed to increase the expressions of P-LKB1 (Ser 428) and P-AMPKα, which contrasted with its effect in negative control cells transfected with scrambled siRNA duplex. Further, N2a cells transfected with expression vectors encoding pcDNA SIRT1 showed increased P-AMPKα expression, which mimicked the effect of cilostazol in N2a cells; suggesting cilostazol-stimulated expressions of P-LKB1 and P-AMPKα were SIRT1-dependent. Unlike their effects in N2a cells, in HeLa cells, which lack LKB1, cilostazol and resveratrol did not elevate SIRT1 or P-AMPKα expression, indicating cilostazol and resveratrol-stimulated expressions of SIRT1 and P-AMPKα are LKB1-dependent. In conclusion, cilostazol upregulates autophagy by activating SIRT1-coupled P-LKB1/P-AMPKα and

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

    Science.gov (United States)

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

    2013-08-30

    A mesocosm experiment was conducted to quantify the relationships between the presence and body size of two burrowing heart urchins (Brissopsis lyrifera and Echinocardium cordatum) and rates of sediment nutrient flux. Furthermore, the impact of seawater acidification on these relationships was determined during this 40-day exposure experiment. Using carbon dioxide (CO2) gas, seawater was acidified to pHNBS 7.6, 7.2 or 6.8. Control treatments were maintained in natural seawater (pH≈8.0). Under normocapnic conditions, burrowing urchins were seen to reduce the sediment uptake of nitrite or nitrate whilst enhancing the release of silicate and phosphate. In acidified (hypercapnic) treatments, the biological control of biogeochemical cycles by urchins was significantly affected, probably through the combined impacts of high CO2 on nitrifying bacteria, benthic algae and urchin behaviour. This study highlights the importance of considering biological interactions when predicting the consequences of seawater acidification on ecosystem function. PMID:23218873

  14. Increased abscisic acid levels in transgenic maize overexpressing AtLOS5 mediated root ion fluxes and leaf water status under salt stress.

    Science.gov (United States)

    Zhang, Juan; Yu, Haiyue; Zhang, Yushi; Wang, Yubing; Li, Maoying; Zhang, Jiachang; Duan, Liusheng; Zhang, Mingcai; Li, Zhaohu

    2016-03-01

    Abscisic acid (ABA) is a vital cellular signal in plants, and effective ABA signalling is pivotal for stress tolerance. AtLOS5 encoding molybdenum cofactor sulphurase is a key regulator of ABA biosynthesis. Here, transgenic AtLOS5 plants were generated to explore the role of AtLOS5 in salt tolerance in maize. AtLOS5 overexpression significantly up-regulated the expression of ZmVp14-2, ZmAO, and ZmMOCO, and increased aldehyde oxidase activities, which enhanced ABA accumulation in transgenic plants under salt stress. Concurrently, AtLOS5 overexpression induced the expression of ZmNHX1, ZmCBL4, and ZmCIPK16, and enhanced the root net Na(+) efflux and H(+) influx, but decreased net K(+) efflux, which maintained a high cytosolic K(+)/Na(+) ratio in transgenic plants under salt stress. However, amiloride or sodium orthovanadate could significantly elevate K(+) effluxes and decrease Na(+) efflux and H(+) influx in salt-treated transgenic roots, but the K(+) effluxes were inhibited by TEA, suggesting that ion fluxes regulated by AtLOS5 overexpression were possibly due to activation of Na(+)/H(+) antiport and K(+) channels across the plasma membrane. Moreover, AtLOS5 overexpression could up-regulate the transcripts of ZmPIP1:1, ZmPIP1:5, and ZmPIP2:4, and enhance root hydraulic conductivity. Thus transgenic plants had higher leaf water potential and turgor, which was correlated with greater biomass accumulation under salt stress. Thus AtLOS5 overexpression induced the expression of ABA biosynthetic genes to promote ABA accumulation, which activated ion transporter and PIP aquaporin gene expression to regulate root ion fluxes and water uptake, thus maintaining high cytosolic K(+) and Na(+) homeostasis and better water status in maize exposed to salt stress. PMID:26743432

  15. Flux Creep and Flux Jumping

    CERN Document Server

    Mints, R G

    1995-01-01

    We consider the flux jump instability of the Bean's critical state arising in the flux creep regime in type-II superconductors. We find the flux jump field, $B_j$, that determines the superconducting state stability criterion. We calculate the dependence of $B_j$ on the external magnetic field ramp rate, magnetization experiments the slope of the current-voltage curve in the flux creep regime determines the stability of the Bean's critical state, {\\it i.e.}, the value of $B_j$. We show that a flux jump can be preceded by the magneto-thermal oscillations and find the frequency of these oscillations as a function of $\\dot B_e$.

  16. Methane Flux

    Data.gov (United States)

    U.S. Geological Survey, Department of the Interior — Methane (CH4) flux is the net rate of methane exchange between an ecosystem and the atmosphere. Data of this variable were generated by the USGS LandCarbon project...

  17. 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.

  18. 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

  19. TNFα Impairs Rhabdoviral Clearance by Inhibiting the Host Autophagic Antiviral Response

    Science.gov (United States)

    Roca, Francisco J.; López-Muñoz, Azucena; Tyrkalska, Sylwia D.; Candel, Sergio; García-Moreno, Diana; Falco, Alberto; Meseguer, José

    2016-01-01

    TNFα is a pleiotropic pro-inflammatory cytokine with a key role in the activation of the immune system to fight viral infections. Despite its antiviral role, a few viruses might utilize the host produced TNFα to their benefit. Some recent reports have shown that anti-TNFα therapies could be utilized to treat certain viral infections. However, the underlying mechanisms by which TNFα can favor virus replication have not been identified. Here, a rhabdoviral infection model in zebrafish allowed us to identify the mechanism of action by which Tnfa has a deleterious role for the host to combat certain viral infections. Our results demonstrate that Tnfa signals through its receptor Tnfr2 to enhance viral replication. Mechanistically, Tnfa does not affect viral adhesion and delivery from endosomes to the cytosol. In addition, the host interferon response was also unaffected by Tnfa levels. However, Tnfa blocks the host autophagic response, which is required for viral clearance. This mechanism of action provides new therapeutic targets for the treatment of SVCV-infected fish, and advances our understanding of the previously enigmatic deleterious role of TNFα in certain viral infections. PMID:27351838

  20. Morin hydrate augments phagocytosis mechanism and inhibits LPS induced autophagic signaling in murine macrophage.

    Science.gov (United States)

    Jakhar, Rekha; Paul, Souren; Chauhan, Anil Kumar; Kang, Sun Chul

    2014-10-01

    Morin, a natural flavonoid that is the primary bioactive constituent of the family Moraceae, has been found to be associated with many therapeutic properties. In this study, we evaluated the immunomodulatory activities of increasing concentration of morin hydrate in vitro. Three different concentrations of morin hydrate (5, 10, and 15μM) were used to evaluate their effect on splenocyte proliferation, phagocytic activity of macrophages, cytokine secretion and complement inhibition. We also evaluated the role of morin hydrate on lipopolysaccharide (LPS) induced autophagy. Our study demonstrated that morin hydrate elicited a significant increase in splenocyte proliferation, phagocytic capacity and suppressed the production of cytokines and nitric oxide in activated macrophages. Humoral immunity measured by anti-complement activity showed an increase in inhibition of the complement system after the addition of morin hydrate, where morin hydrate at 15μM concentration induced a significant inhibition. Depending on our results, we can also conclude that morin hydrate protects macrophages from LPS induced autophagic cell death. Our findings suggest that morin hydrate represents a structurally diverse class of flavonoid and this structural variability can profoundly affect its cell-type specificity and its biological activities. Supplementation of immune cells with morin hydrate has an upregulating and immunoprotective effect that shows potential as a countermeasure to the immune dysfunction and suggests an interesting use in inflammation related diseases. PMID:25068824

  1. Updates from the Intestinal Front Line: Autophagic Weapons against Inflammation and Cancer

    Directory of Open Access Journals (Sweden)

    Cristiano Simone

    2012-08-01

    Full Text Available The intestine lies at the interface between the organism and its environment and responds to infection/inflammation in a multi-leveled manner, potentially leading to chronic inflammatory pathologies and cancer formation. Indeed, the immune response at the intestinal epithelium has been found to be involved in the origin and development of colorectal cancer, which is the third most commonly diagnosed neoplastic disease. Among the mechanisms induced upon inflammation, autophagy appears as a defensive strategy for the clearance of invading microbes and intracellular waste components. Autophagy has also been found to play an important role in colorectal cancer, where it seems to have a pro-survival or pro-death function depending on the stage of the neoplastic process. In this paper we discuss the dual role of autophagy in colorectal cancer and review evidence showing that modulation of autophagy affects the immune response and cancer biology. The study of key players involved in autophagy might contribute to the design of new approaches for colorectal cancer, consisting in combined therapies capable of modifying cancer-specific metabolism rather than simply evoking a generic apoptotic and/or autophagic response, thus enhancing the efficacy of currently used drugs and treatments.

  2. Autophagic myelin destruction by schwann cells during wallerian degeneration and segmental demyelination.

    Science.gov (United States)

    Jang, So Young; Shin, Yoon Kyung; Park, So Young; Park, Joo Youn; Lee, Hye Jeong; Yoo, Young Hyun; Kim, Jong Kuk; Park, Hwan Tae

    2016-05-01

    As lysosomal hydrolysis has long been suggested to be responsible for myelin clearance after peripheral nerve injury, in this study, we investigated the possible role of autophagolysosome formation in myelin phagocytosis by Schwann cells and its final contribution to nerve regeneration. We found that the canonical formation of autophagolysosomes was induced in demyelinating Schwann cells after injury, and the inhibition of autophagy via Schwann cell-specific knockout of the atg7 gene or pharmacological intervention of lysosomal function caused a significant delay in myelin clearance. However, Schwann cell dedifferentiation, as demonstrated by extracellular signal-regulated kinase activation and c-Jun induction, and redifferentiation were not significantly affected, and thus the entire repair program progressed normally in atg7 knockout mice. Finally, autophagic Schwann cells were also found during segmental demyelination in a mouse model of inflammatory peripheral neuropathy. Together, our findings suggest that autophagy is the self-myelin destruction mechanism of Schwann cells, but mechanistically, it is a process distinct from Schwann cell plasticity for nerve repair. GLIA 2016;64:730-742. PMID:26712109

  3. Modulation of deregulated chaperone-mediated autophagy by a phosphopeptide.

    Science.gov (United States)

    Macri, Christophe; Wang, Fengjuan; Tasset, Inmaculada; Schall, Nicolas; Page, Nicolas; Briand, Jean-Paul; Cuervo, Ana Maria; Muller, Sylviane

    2015-01-01

    The P140 peptide, a 21-mer linear peptide (sequence 131-151) generated from the spliceosomal SNRNP70/U1-70K protein, contains a phosphoserine residue at position 140. It significantly ameliorates clinical manifestations in autoimmune patients with systemic lupus erythematosus and enhances survival in MRL/lpr lupus-prone mice. Previous studies showed that after P140 treatment, there is an accumulation of autophagy markers sequestosome 1/p62 and MAP1LC3-II in MRL/lpr B cells, consistent with a downregulation of autophagic flux. We now identify chaperone-mediated autophagy (CMA) as a target of P140 and demonstrate that its inhibitory effect on CMA is likely tied to its ability to alter the composition of HSPA8/HSC70 heterocomplexes. As in the case of HSPA8, expression of the limiting CMA component LAMP2A, which is increased in MRL/lpr B cells, is downregulated after P140 treatment. We also show that P140, but not the unphosphorylated peptide, uses the clathrin-dependent endo-lysosomal pathway to enter into MRL/lpr B lymphocytes and accumulates in the lysosomal lumen where it may directly hamper lysosomal HSPA8 chaperoning functions, and also destabilize LAMP2A in lysosomes as a result of its effect on HSP90AA1. This dual effect may interfere with the endogenous autoantigen processing and loading to major histocompatibility complex class II molecules and as a consequence, lead to lower activation of autoreactive T cells. These results shed light on mechanisms by which P140 can modulate lupus disease and exert its tolerogenic activity in patients. The unique selective inhibitory effect of the P140 peptide on CMA may be harnessed in other pathological conditions in which reduction of CMA activity would be desired. PMID:25719862

  4. 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

    emissions. 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.......Temporal trends of N2O fluxes across the soil–atmosphere interface were determined using continuous flux chamber measurements over an entire growing season of a subsurface aerating macrophyte (Phalaris arundinacea) in a nonmanaged Danish wetland. Observed N2O fluxes were linked to changes in...

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

    Science.gov (United States)

    Schaffner, Adam; Fedick, Anastasia; Kaye, Lauren E.; Liao, Jun; Yachelevich, Naomi; Chu, Mary-Lynn; Boles, Richard G.; Moran, Ellen; Tokita, Mari; Gorman, Elizabeth; Zhang, Wei; Xia, Fan; Leduc, Magalie; Yang, Yaping; Eng, Christine; Wong, Lee-Jun; Schiffmann, Raphael; Diaz, George A.; Kornreich, Ruth; Thummel, Ryan; Wasserstein, Melissa; Yue, Zhenyu; Edelmann, Lisa

    2016-01-01

    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. PMID:27120463

  6. 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.

  7. Critical flux determination by flux-stepping

    DEFF Research Database (Denmark)

    Beier, Søren; Jonsson, Gunnar Eigil

    2010-01-01

    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...

  8. The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy

    OpenAIRE

    Burchell, Victoria S; Nelson, David E.; Sanchez-Martinez, Alvaro; Delgado-Camprubi, Marta; Ivatt, Rachael M; Pogson, Joe H.; Randle, Suzanne J.; Wray, Selina; Lewis, Patrick A.; Houlden, Henry; Abramov, Andrey Y; Hardy, John; Wood, Nicholas W; Whitworth, Alexander J.; Laman, Heike

    2013-01-01

    Compelling evidence indicates that two autosomal recessive Parkinson’s disease genes, PINK1 (PARK6) and Parkin (PARK2), co-operate to mediate the autophagic clearance of damaged mitochondria (mitophagy). Mutations in the F-box domain containing protein Fbxo7 (PARK15) also cause early onset autosomal recessive Parkinson’s disease by an unknown mechanism. Here we show that Fbxo7 participates in mitochondrial maintenance through direct interaction with PINK1 and Parkin and plays a role in Parkin...

  9. 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.

  10. Some autophagic and apoptotic features of programmed cell death in the anterior silk glands of the silkworm, Bombyx mori.

    Science.gov (United States)

    Goncu, Ebru; Parlak, Osman

    2008-11-01

    Programmed cell death has been subdivided into two major groups: apoptosis and autophagic cell death. The anterior silk gland of Bombyx mori degenerates during larval-pupal metamorphosis. Our findings indicate that two types of programmed cell death features are observed during this physiological process. During the prepupal period, pyknosis of the nucleus, cell detachment,and membrane blebbing occur and they are the first signs of programmed cell death in the anterior silk glands. According to previous studies, all of these morphological appearances are common for both cell-death types. Autophagy features are also exhibited during the prepupal period. Levels of one of the lysosomal marker enzymes-acid phosphatase-are high during this period then decrease gradually. Vacuole formation begins to appear first at the basal surface of the cell, then expands to the apical surface just before the larval pupal ecdysis. After larval-pupal ecdysis, DNA fragmentation, which is the obvious biochemical marker of apoptosis, is detected in agarose gel electrophoresis, which also shows that caspase-like enzyme activities occur during the programmed cell death process of the anterior silk glands. Apoptosis and autophagic cell death interact with each other during the degeneration process of the anterior silk gland in Bombyx mori and this interaction occurs at a late phase of cell death. We suggest that apoptotic cell death only is not enough for whole gland degeneration and that more effective degeneration occurs with this cooperation. PMID:18838861

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

    OpenAIRE

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

    2015-01-01

    Danon disease is a familial cardiomyopathy associated with impaired autophagy due to mutations in the gene encoding lysosomal-associated membrane protein type 2 (LAMP-2). Emerging evidence has highlighted the importance of autophagy in regulating cardiomyocyte bioenergetics, function, and survival. However, the mechanisms responsible for cellular dysfunction and death in cardiomyocytes with impaired autophagic flux remain unclear. To investigate the molecular mechanisms responsible for Danon ...

  12. Autophagy mediated by arginine depletion activation of the nutrient sensor GCN2 contributes to interferon-γ-induced malignant transformation of primary bovine mammary epithelial cells

    Science.gov (United States)

    Xia, X-j; Gao, Y-y; Zhang, J; Wang, L; Zhao, S; Che, Y-y; Ao, C-j; Yang, H-j; Wang, J-q; Lei, L-c

    2016-01-01

    Autophagy has been linked to the regulation of both the prevention and progression of cancer. IFN-γ has been shown to induce autophagy in multiple cell lines in vitro. However, whether IFN-γ can induce autophagy and whether autophagy promotes malignant transformation in healthy lactating bovine mammary epithelial cells (BMECs) remain unclear. Here, we provide the first evidence of the correlation between IFN-γ treatment, autophagy and malignant transformation and of the mechanism underlying IFN-γ-induced autophagy and subsequent malignant transformation in primary BMECs. IFN-γ levels were significantly increased in cattle that received normal long-term dietary corn straw (CS) roughage supplementation. In addition, an increase in autophagy was clearly observed in the BMECs from the mammary tissue of cows expressing high levels of IFN-γ. In vitro, autophagy was clearly induced in primary BMECs by IFN-γ within 24 h. This induced autophagy could subsequently promote dramatic primary BMEC transformation. Furthermore, we found that IFN-γ promoted arginine depletion, activated the general control nonderepressible-2 kinase (GCN2) signalling pathway and resulted in an increase in autophagic flux and the amount of autophagy in BMECs. Overall, our findings are the first to demonstrate that arginine depletion and kinase GCN2 expression mediate IFN-γ-induced autophagy that may promote malignant progression and that immunometabolism, autophagy and cancer are strongly correlated. These results suggest new directions and paths for preventing and treating breast cancer in relation to diet. PMID:27551491

  13. 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)

    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

  14. Lipid rafts participate in aberrant degradative autophagic-lysosomal pathway of amyloid-beta peptide in Alzheimer’s disease

    Institute of Scientific and Technical Information of China (English)

    Xin Zhou; Chun Yang; Yufeng Liu; Peng Li; Huiying Yang; Jingxing Dai; Rongmei Qu; Lin Yuan

    2014-01-01

    Amyloid-beta peptide is the main component of amyloid plaques, which are found in Alzhei-mer’s disease. The generation and deposition of amyloid-beta is one of the crucial factors for the onset and progression of Alzheimer’s disease. Lipid rafts are glycolipid-rich liquid domains of the plasma membrane, where certain types of protein tend to aggregate and intercalate. Lipid rafts are involved in the generation of amyloid-beta oligomers and the formation of amyloid-beta peptides. In this paper, we review the mechanism by which lipid rafts disturb the aberrant deg-radative autophagic-lysosomal pathway of amyloid-beta, which plays an important role in the pathological process of Alzheimer’s disease. Moreover, we describe this mechanism from the view of the Two-system Theory of fasciology and thus, suggest that lipid rafts may be a new target of Alzheimer’s disease treatment.

  15. The M2 macrophages induce autophagic vascular disorder and promote mouse sensitivity to urethane-related lung carcinogenesis.

    Science.gov (United States)

    Li, G-G; Guo, Z-Z; Ma, X-F; Cao, N; Geng, S-N; Zheng, Y-Q; Meng, M-J; Lin, H-H; Han, G; Du, G-J

    2016-06-01

    Tumor vessels are known to be abnormal, with typically aberrant, leaky and disordered vessels. Here, we investigated whether polarized macrophage phenotypes are involved in tumor abnormal angiogenesis and what is its mechanism. We found that there was no difference in chemotaxis of polarized M1 and M2 macrophages to lewis lung carcinoma (LLC) cells and that either M1 or M2 macrophage-conditioned media had no effect on LLC cell proliferation. Unexpectedly, the M2 but not M1 macrophage-conditioned media promoted the proliferation of human umbilical vein endothelial cells (HUVECs) and simultaneously increased endothelial cell permeability in vitro and angiogenic index in the chick embryo chorioallantoic membrane (CAM). The treatment with M2 but not M1 macrophage-conditioned media increased autophagosomes as well as microtubule-associated protein light chain 3B (LC3-B) expression (a robust marker of autophagosomes) but decreased p62 protein expression (a selective autophagy substrate) in HUVECs, the treatment with chloroquine that blocked autophagy abrogated the abnormal angiogenic efficacy of M2 macrophage-conditioned media. These results were confirmed in urethane-induced lung carcinogenic progression. Urethane-induced lung carcinogenesis led to more M2 macrophage phenotype and increased abnormal angiogenesis concomitant with the upregulation of LC3-B and the downregulation of p62. Clodronate liposome-induced macrophage depletion, chloroquine-induced autophagic prevention or salvianolic acid B-induced vascular protection decreased abnormal angiogenesis and lung carcinogenesis. In addition, we found that the tendency of age-related M2 macrophage polarization also promoted vascular permeability and carcinogenesis in urethane carcinogenic progression. These findings indicate that the M2 macrophages induce autophagic vascular disorder to promote lung cancer progression, and the autophagy improvement represents an efficacious strategy for abnormal angiogenesis and cancer

  16. 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.

  17. 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. PMID:27265145

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

    Science.gov (United States)

    Fernandes, Hugo J R; Hartfield, Elizabeth M; Christian, Helen C; Emmanoulidou, Evangelia; Zheng, Ying; Booth, Heather; Bogetofte, Helle; Lang, Charmaine; Ryan, Brent J; Sardi, S Pablo; Badger, Jennifer; Vowles, Jane; Evetts, Samuel; Tofaris, George K; Vekrellis, Kostas; Talbot, Kevin; Hu, Michele T; James, William; Cowley, Sally A; Wade-Martins, Richard

    2016-03-01

    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. PMID:26905200

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

    OpenAIRE

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

    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...

  20. Adenovirus-mediated wild-type PTEN promoting glioma stem/progenitor cells autophagy activity

    Directory of Open Access Journals (Sweden)

    ZHAO Yao-dong

    2013-05-01

    Full Text Available Background PTEN is an anti-oncogene frequently inactivating in glioma. The previous study found that PTEN was closely related to cellular autophagy activity. The purpose of this paper is to study whether the inactivation of PTEN in glioma stem/progenitor cells (GSPCs is correlative with the low autophagic activity in GSPCs. Methods Wild-type PTEN genes were transferred into GSPCs mediated by adenovirus. The autophagic activity in GSPCs before or after the introduction of wild-type PTEN was detected by immunocytochemistry, electron microscopy, and Western blotting assay. Results After transfection of wild-type PTEN, a large number of microtuble-associated protein 1 light chain 3 (MAP1LC3-positive granules could be found in the cytoplasm of GSPCs under a confocal microscopy, and these granules were demonstrated to be autophagosomes under an electron microscope. Moreover, the expression of autophagy-related gene Beclin-1 significantly increased after the transfection of wild-type PTEN gene. Conclusion The inactivation of PTEN in GSPCs is one reason of the low autophagic activity of GSPCs.

  1. Effects of hypoxia-inducible factor-1α on radiation-induced autophagic cell death in breast cancer cells

    International Nuclear Information System (INIS)

    Objective: To study the effects of hypoxia-inducible factor-1α (HIF-1α) on radiation-induced autophagic cell death in breast cancer cells. Methods: MCF-7 cells were divided into four groups:control (normoxia,21% Oxygen),irradiation (8 Gy X-rays), hypoxia (Cobalt chloride, CoCl2) and irradiation with hypoxia (CoCl2). 150 μmol/L CoCl2 was utilized to induce hypoxic conditions. Western blot was applied to detect the expression of HIF-1α and MAPLC3. MDC and Hoechst staining were used to detect autophagy and apoptosis. Radiosensitivity was detected by cloning formation. The short hairpin interfering RNA (shRNA) retroviral transduction particles targeting HIF-1α was transfected into MCF-7 cells to establish HIF-1α knockdown cells, then the radiosensibility, autophagy and apoptosis were detected. Results: Compared with control group and irradiation group,the protein level of HIF-1 increased obviously in the normoxia, irradiation, hypoxia and irradiation with hypoxia groups, and the values were 0, 0, 1.00, 1.89, respectively. The expression levels of MAPLC3 were markedly up-regulated in irradiation, hypoxia and irradiation with hypoxia groups as compared with control, and the ratios of LC3Ⅱ/LC3Ⅰ were 1.15, 1.73, 2.38 and 3.60, respectively. The radiosensitivity of MCF-7 cells decreased in the following order:normoxia with 3MA > normoxia > hypoxia with 3MA > hypoxia. HIF-1α knockdown cell (pSUPER-HIF-1α Ri) and vector control were constructed. After treatment with CoCl2, survival fraction of MCF-7-pSUPER was significantly higher than that of control (t=3.080, 6.946, 6.658, 6.380, P<0.05), and radiosensitivity was down-regulated after irradiation,but there was no significant difference between normoxia and hypoxia in survival fraction of MCF-7-pSUPER-HIF-1α Ri. After treatment of irradiation or hypoxia, the autophagic fractions in MCF-7-pSUPER-HIF-1α Ri significantly decreased, reduced by 21.1%, 25.5%, 15.5%, respectively (t=4.635, 4.738, 6.354, P<0.05) as

  2. Repairing DNA damage by XRCC6/KU70 reverses TLR4-deficiency-worsened HCC development via restoring senescence and autophagic flux

    OpenAIRE

    Wang, Ziyan; Lin, Heng; Hua, Fang; Hu, Zhuo-Wei

    2013-01-01

    Hepatocellular carcinoma (HCC) is among the most lethal and prevalent cancers in the human population. The initiation and progression of HCC is closely associated with chronic liver inflammation. Recent research indicates that nonhomologous end joining (NHEJ), one of the DNA repair mechanisms, autophagy and senescence are all involved in the pathogenesis of HCC induced by carcinogens or oxidative stress. DNA repair proteins including XRCC6/KU70 and XRCC5/KU80 are the critical NHEJ factors tha...

  3. Mediation Analysis

    OpenAIRE

    David P. MacKinnon; Fairchild, Amanda J.; Fritz, Matthew S.

    2007-01-01

    Mediating variables are prominent in psychological theory and research. A mediating variable transmits the effect of an independent variable on a dependent variable. Differences between mediating variables and confounders, moderators, and covariates are outlined. Statistical methods to assess mediation and modern comprehensive approaches are described. Future directions for mediation analysis are discussed.

  4. Flux-P: Automating Metabolic Flux Analysis

    Directory of Open Access Journals (Sweden)

    Birgitta E. Ebert

    2012-11-01

    Full Text Available Quantitative knowledge of intracellular fluxes in metabolic networks is invaluable for inferring metabolic system behavior and the design principles of biological systems. However, intracellular reaction rates can not often be calculated directly but have to be estimated; for instance, via 13C-based metabolic flux analysis, a model-based interpretation of stable carbon isotope patterns in intermediates of metabolism. Existing software such as FiatFlux, OpenFLUX or 13CFLUX supports experts in this complex analysis, but requires several steps that have to be carried out manually, hence restricting the use of this software for data interpretation to a rather small number of experiments. In this paper, we present Flux-P as an approach to automate and standardize 13C-based metabolic flux analysis, using the Bio-jETI workflow framework. Exemplarily based on the FiatFlux software, it demonstrates how services can be created that carry out the different analysis steps autonomously and how these can subsequently be assembled into software workflows that perform automated, high-throughput intracellular flux analysis of high quality and reproducibility. Besides significant acceleration and standardization of the data analysis, the agile workflow-based realization supports flexible changes of the analysis workflows on the user level, making it easy to perform custom analyses.

  5. Synergistic chemopreventive effects of curcumin and berberine on human breast cancer cells through induction of apoptosis and autophagic cell death.

    Science.gov (United States)

    Wang, Kai; Zhang, Chao; Bao, Jiaolin; Jia, Xuejing; Liang, Yeer; Wang, Xiaotong; Chen, Meiwan; Su, Huanxing; Li, Peng; Wan, Jian-Bo; He, Chengwei

    2016-01-01

    Curcumin (CUR) and berberine (BBR) are renowned natural compounds that exhibit potent anticancer activities through distinct molecular mechanisms. However, the anticancer capacity of either CUR or BBR is limited. This prompted us to investigate the chemopreventive potential of co-treatment of CUR and BBR against breast cancers. The results showed that CUR and BBR in combination synergistically inhibited the growth of both MCF-7 and MDA-MB-231 breast cancer cells than the compounds used alone. Further study confirmed that synergistic anti-breast cancer activities of co-treatment of these two compounds was through inducing more apoptosis and autophagic cell death (ACD). The co-treatment-induced apoptosis was caspase-dependent and through activating ERK pathways. Our data also demonstrated that co-treatment of CUR and BBR strongly up-regulated phosphorylation of JNK and Beclin1, and decreased phosphorylated Bcl-2. Inhibition of JNK by SP600125 markedly decreased LC3-II and Beclin1, restored phosphorylated Bcl-2, and reduced the cytotoxicity induced by the two compounds in combination. These results strongly suggested that JNK/Bcl-2/Beclin1 pathway played a key role in the induction of ACD in breast cancer cells by co-treatment of CUR and BBR. This study provides an insight into the potential application of curcumin and berberine in combination for the chemoprevention and treatment of breast cancers. PMID:27263652

  6. Betanin-Enriched Red Beetroot (Beta vulgaris L.) Extract Induces Apoptosis and Autophagic Cell Death in MCF-7 Cells.

    Science.gov (United States)

    Nowacki, Laëtitia; Vigneron, Pascale; Rotellini, Laura; Cazzola, Hélène; Merlier, Franck; Prost, Elise; Ralanairina, Robert; Gadonna, Jean-Pierre; Rossi, Claire; Vayssade, Muriel

    2015-12-01

    Recent studies have pointed out the preventive role of beetroot extracts against cancers and their cytotoxic activity on cancer cells. Among many different natural compounds, these extracts contained betanin and its stereoisomer isobetanin, which belongs to the betalain group of highly bioavailable antioxidants. However, a precise identification of the molecules responsible for this tumor-inhibitory effect was still required. We isolated a betanin/isobetanin concentrate from fresh beetroots, corresponding to the highest purified betanin extract used for studying anticancer activities of these molecules. The cytotoxicity of this betanin-enriched extract was then characterized on cancer and normal cells and we highlighted the death signalling pathways involved. Betanin/isobetanin concentrate significantly decreased cancer cell proliferation and viability. Particularly in MCF-7-treated cells, the expressions of apoptosis-related proteins (Bad, TRAILR4, FAS, p53) were strongly increased and the mitochondrial membrane potential was altered, demonstrating the involvement of both intrinsic and extrinsic apoptotic pathways. Autophagosome vesicles in MCF-7-treated cells were observed, also suggesting autophagic cell death upon betanin/isobetanin treatment. Importantly, the betanin-enriched extract had no obvious effect towards normal cell lines. Our data bring new insight to consider the betanin/isobetanin mix as therapeutic anticancer compound, alone or in combination with classical chemotherapeutic drugs, especially in functional p53 tumors. PMID:26463240

  7. Tribenuron-Methyl Induces Male Sterility through Anther-Specific Inhibition of Acetolactate Synthase Leading to Autophagic Cell Death.

    Science.gov (United States)

    Zhao, Lun; Jing, Xue; Chen, Li; Liu, Yingjun; Su, Yanan; Liu, Tingting; Gao, Changbin; Yi, Bin; Wen, Jing; Ma, Chaozhi; Tu, Jinxing; Zou, Jitao; Fu, Tingdong; Shen, Jinxiong

    2015-12-01

    Tribenuron-methyl (TM) is a powerful sulfonylurea herbicide that inhibits branched-chain amino acid (BCAA) biosynthesis by targeting the catalytic subunit (CSR1) of acetolactate synthase (ALS). Selective induction of male sterility by foliar spraying of TM at low doses has been widely used for hybrid seed production in rapeseed (Brassica napus); however, the underlying mechanism remains unknown. Here, we report greater TM accumulation and subsequent stronger ALS inhibition and BCAA starvation in anthers than in leaves and stems after TM application. Constitutive or anther-specific expression of csr1-1D (a CSR1 mutant) eliminated anther-selective ALS inhibition and reversed the TM-induced male sterile phenotype in both rapeseed and Arabidopsis. The results of TM daub-stem experiments, combined with the observations of little TM accumulation in anthers and reversion of TM-induced male sterility by targeted expression of the TM metabolism gene Bel in either the mesophyll or phloem, suggested that foliar-sprayed TM was polar-transported to anthers mainly through the mesophyll and phloem. Microscopy and immunoblotting revealed that autophagy, a bulk degradation process induced during cell death, was elevated in TM-induced male sterile anthers and by anther-specific knockdown of ALS. Moreover, TM-induced pollen abortion was significantly inhibited by the autophagy inhibitor 3-MA. These data suggested that TM was polar-transported to anthers, resulting in BCAA starvation via anther-specific ALS inhibition and, ultimately, autophagic cell death in anthers. PMID:26362932

  8. Ultracytochemical localization of H+—adenosine triphosphatase activity in autophagic vacuoles induced by vinblastine in rat liver

    Institute of Scientific and Technical Information of China (English)

    LUOSHENQIU; MASAHIROSAKAI; 等

    1990-01-01

    H-adenosine triphosphatase (H+-ATPase) activity was demonstrated cytochemically in autophagic vacuoles(AVs) of rat hepatocytes using a modification of the method for the demonstration of neutral p-nitrophenyl phosphatase(p-NPPase) activity[1].When an inhibitor of H+-ATPase,N-ethylmaleimide (NEM) or 4,4'-diisothiocyanostilbene-2,2'disulfonic acid,disodium salt (DIDS) was included in the incubation medium the enyzme activity was abolished indicating that p-NPPase demonstrated in this study represents H+-ATPase.Autophagy was induced by a single intraperitoneal injection of vinblastine sulfate(VBL).The number of AVs increased remarkably in hepatocytes from 40 min after VBL treatment.H+-ATPase activity was observed mainly on the membranes of lysosomes and AVs.However,early forms of AVs containing only incompletely digested material showed no H+-ATPase activity.Most AVs revealing a positive reaction seemed to be in advanced stages of development.Acid phosphatase acticity was demonstrable in mature but not in early forms of AVs.The present investigation showed that membranes of advanced stage AVs possess an H+-ATPase which may be derived from lysosomal membranes.

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

    Directory of Open Access Journals (Sweden)

    David Ramonet

    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.

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

    International Nuclear Information System (INIS)

    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.

  11. Retromer Ensures the Degradation of Autophagic Cargo by Maintaining Lysosome Function in Drosophila.

    Science.gov (United States)

    Maruzs, Tamás; Lőrincz, Péter; Szatmári, Zsuzsanna; Széplaki, Szilvia; Sándor, Zoltán; Lakatos, Zsolt; Puska, Gina; Juhász, Gábor; Sass, Miklós

    2015-10-01

    The retromer is an evolutionarily conserved coat complex that consists of Vps26, Vps29, Vps35 and a heterodimer of sorting nexin (Snx) proteins in yeast. Retromer mediates the recycling of transmembrane proteins from endosomes to the trans-Golgi network, including receptors that are essential for the delivery of hydrolytic enzymes to lysosomes. Besides its function in lysosomal enzyme receptor recycling, involvement of retromer has also been proposed in a variety of vesicular trafficking events, including early steps of autophagy and endocytosis. Here we show that the late stages of autophagy and endocytosis are impaired in Vps26 and Vps35 deficient Drosophila larval fat body cells, but formation of autophagosomes and endosomes is not compromised. Accumulation of aberrant autolysosomes and amphisomes in the absence of retromer function appears to be the consequence of decreased degradative capacity, as they contain undigested cytoplasmic material. Accordingly, we show that retromer is required for proper cathepsin L trafficking mainly independent of LERP, the Drosophila homolog of the cation-independent mannose 6-phosphate receptor. Finally, we find that Snx3 and Snx6 are also required for proper autolysosomal degradation in Drosophila larval fat body cells. PMID:26172538

  12. 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.

  13. Avian influenza A virus H5N1 causes autophagy-mediated cell death through suppression of mTOR signaling

    Institute of Scientific and Technical Information of China (English)

    Jianhui Ma; Qian Sun; Ruifang Mi; Hongbing Zhang

    2011-01-01

    Of the few avian influenza viruses that have crossed the species barrier to infect humans,the highly pathogenic influenza A (H5N1) strain has claimed the lives of more than half of the infected patients.With largely unknown mechanism of lung injury by H5N1 infection,acute respiratory distress syndrome (ARDS) is the major cause of death among the victims.Here we present the fact that H5N1 caused autophagic cell death through suppression of mTOR signaling.Inhibition of autophagy,either by depletion of autophagy gene Beclinl or by autophagy inhibitor 3-methyladenine (3-MA),significantly reduced H5N1 mediated cell death.We suggest that autophagic cell death may contribute to the development of ARDS in H5N1 influenza patients and inhibition of autophagy could therefore become a novel strategy for the treatment of H5N1 infection.

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

    International Nuclear Information System (INIS)

    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

  15. 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.

  16. 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.)

  17. Anomaly mediation in superstring theory

    International Nuclear Information System (INIS)

    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 T6 volume and the untwisted T2 volume respectively. (orig.)

  18. Video Meteor Fluxes

    Science.gov (United States)

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

    2011-01-01

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

  19. Flux pinning behaviors of a textured Gd–Ba–Cu–O superconductor mediated by the addition of BaTiO{sub 3}, TiO{sub 2} and BaO{sub 2}

    Energy Technology Data Exchange (ETDEWEB)

    Li, Beizhan, E-mail: d102029@kaiyodai.ac.jp [Laboratory of Applied Physics, Tokyo University of Marine Science and Technology (TUMSAT), Tokyo 135-8533 (Japan); Zhou, Difan [Laboratory of Applied Physics, Tokyo University of Marine Science and Technology (TUMSAT), Tokyo 135-8533 (Japan); Xu, Kun [Laboratory of Applied Physics, Tokyo University of Marine Science and Technology (TUMSAT), Tokyo 135-8533 (Japan); Department of Physics and Electronics Engineering, Qujing Normal University, Sanjiang Road, Qujing 655000 (China); Tsuzuki, Keita [Laboratory of Applied Physics, Tokyo University of Marine Science and Technology (TUMSAT), Tokyo 135-8533 (Japan); Zhang, Jincang [Department of Physics, Shanghai University, Shanghai 200444 (China); Izumi, Mitsuru [Laboratory of Applied Physics, Tokyo University of Marine Science and Technology (TUMSAT), Tokyo 135-8533 (Japan)

    2014-01-15

    Highlights: •The structural effect of the doping of BaTiO{sub 3} was studied in Gd123 superconductors. •Dilute additions are rearranged by crystal growth leading to the prominent peak effect. •The origin of the peak effect was discussed with respect to weak superconductivity, certain degree of order of defects. -- Abstract: We present a study on the investigation of the proper secondary phases for engineering magnetic flux pinning centers in textured Gd–Ba–Cu–O bulk superconductors. Compared with the joint TiO{sub 2} and BaO{sub 2} doping methods, the addition of BaTiO{sub 3} shows a relevant advantage due to its perovskite structure. Both TiO{sub 2} and BaO{sub 2} doping tends to enter the crystal lattice of the superconducting matrix by ionic substitution, which leads to the variable peak effect in the J{sub c}–B diagram. The BaTiO{sub 3} doping method shows a unique pinning behavior, which is attributed to the distinctive precipitations generated by the additions. The composition of the BaTiO{sub 3} doping-related precipitation appears to be controlled under different growth temperatures. The self-field J{sub c} improved by nearly double at 77 K in a sample grown with a low growth temperature. In addition, the second peaks caused by various types of additions are located in a narrow field range of 1.25–1.5 T in the J{sub c}–B diagram, indicating that the dilute doping follows a unique tendency, which is likely relevant to anisotropic crystal growth. The different observed peak heights suggest the existence of several average pinning potentials provided by various types of additions. BaTiO{sub 3} doping exhibited a stabilization of the unique onset superconducting transition temperature. Therefore, BaTiO{sub 3} can be classified as a useful dopant to control flux pinning behavior in Gd–Ba–Cu–O bulk superconductors.

  20. Mimulone-induced autophagy through p53-mediated AMPK/mTOR pathway increases caspase-mediated apoptotic cell death in A549 human lung cancer cells.

    Directory of Open Access Journals (Sweden)

    Hyun-Kyu An

    Full Text Available Anticancer properties and mechanisms of mimulone (MML, C-geranylflavonoid isolated from the Paulownia tomentosa fruits, were firstly elucidated in this study. MML prevented cell proliferation in a dose- and time-dependent way and triggered apoptosis through the extrinsic pathway in A549 human lung adenocarcinoma cells. Furthermore, MML-treated cells displayed autophagic features, such as the formation of autophagic vacuoles, a primary morphological feature of autophagy, and the accumulation of microtubule-associated protein 1 light chain 3 (LC3 puncta, another typical maker of autophagy, as determined by FITC-conjugated immunostaining and monodansylcadaverine (MDC staining, respectively. The expression levels of LC3-I and LC3-II, specific markers of autophagy, were also augmented by MML treatment. Autophagy inhibition by 3-methyladenine (3-MA, pharmacological autophagy inhibitor, and shRNA knockdown of Beclin-1 reduced apoptotic cell death induced by MML. Autophagic flux was not significantly affected by MML treatment and lysosomal inhibitor, chloroquine (CQ suppressed MML-induced autophagy and apoptosis. MML-induced autophagy was promoted by decreases in p53 and p-mTOR levels and increase of p-AMPK. Moreover, inhibition of p53 transactivation by pifithrin-α (PFT-α and knockdown of p53 enhanced induction of autophagy and finally promoted apoptotic cell death. Overall, the results demonstrate that autophagy contributes to the cytotoxicity of MML in cancer cells harboring wild-type p53. This study strongly suggests that MML is a potential candidate for an anticancer agent targeting both autophagy and apoptotic cell death in human lung cancer. Moreover, co-treatment of MML and p53 inhibitor would be more effective in human lung cancer therapy.

  1. Mimulone-induced autophagy through p53-mediated AMPK/mTOR pathway increases caspase-mediated apoptotic cell death in A549 human lung cancer cells.

    Science.gov (United States)

    An, Hyun-Kyu; Kim, Kyoung-Sook; Lee, Ji-Won; Park, Mi-Hyun; Moon, Hyung-In; Park, Shin-Ji; Baik, Ji-Sue; Kim, Cheorl-Ho; Lee, Young-Choon

    2014-01-01

    Anticancer properties and mechanisms of mimulone (MML), C-geranylflavonoid isolated from the Paulownia tomentosa fruits, were firstly elucidated in this study. MML prevented cell proliferation in a dose- and time-dependent way and triggered apoptosis through the extrinsic pathway in A549 human lung adenocarcinoma cells. Furthermore, MML-treated cells displayed autophagic features, such as the formation of autophagic vacuoles, a primary morphological feature of autophagy, and the accumulation of microtubule-associated protein 1 light chain 3 (LC3) puncta, another typical maker of autophagy, as determined by FITC-conjugated immunostaining and monodansylcadaverine (MDC) staining, respectively. The expression levels of LC3-I and LC3-II, specific markers of autophagy, were also augmented by MML treatment. Autophagy inhibition by 3-methyladenine (3-MA), pharmacological autophagy inhibitor, and shRNA knockdown of Beclin-1 reduced apoptotic cell death induced by MML. Autophagic flux was not significantly affected by MML treatment and lysosomal inhibitor, chloroquine (CQ) suppressed MML-induced autophagy and apoptosis. MML-induced autophagy was promoted by decreases in p53 and p-mTOR levels and increase of p-AMPK. Moreover, inhibition of p53 transactivation by pifithrin-α (PFT-α) and knockdown of p53 enhanced induction of autophagy and finally promoted apoptotic cell death. Overall, the results demonstrate that autophagy contributes to the cytotoxicity of MML in cancer cells harboring wild-type p53. This study strongly suggests that MML is a potential candidate for an anticancer agent targeting both autophagy and apoptotic cell death in human lung cancer. Moreover, co-treatment of MML and p53 inhibitor would be more effective in human lung cancer therapy. PMID:25490748

  2. 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

    2015-01-01

    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-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. PMID:26598009

  3. 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.

  4. 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.

  5. Mcl-1-dependent activation of Beclin 1 mediates autophagic cell death induced by sorafenib and SC-59 in hepatocellular carcinoma cells

    OpenAIRE

    Tai, W-T; Shiau, C-W; Chen, H-L; Liu, C-Y; Lin, C-S; Cheng, A-L; Chen, P-J; Chen, K-F

    2013-01-01

    We investigated the molecular mechanisms underlying the effect of sorafenib and SC-59, a novel sorafenib derivative, on hepatocellular carcinoma (HCC). Sorafenib activated autophagy in a dose- and time-dependent manner in the HCC cell lines PLC5, Sk-Hep1, HepG2 and Hep3B. Sorafenib downregulated phospho-STAT3 (P-STAT3) and subsequently reduced the expression of myeloid cell leukemia-1 (Mcl-1). Inhibition of Mcl-1 by sorafenib resulted in disruption of the Beclin 1-Mcl-1 complex; however, sora...

  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. Confining flux tubes in a current algebra approach

    CERN Document Server

    Benson, K M; Benson, K M; Saadi, M

    1995-01-01

    We describe flux tubes and their interactions in a low energy sigma model induced by SU(\\NF) \\goto SO(\\NF) flavor symmetry breaking in SO(N_c) QCD. Unlike standard QCD, this model allows gauge confinement to manifest itself in the low energy theory, which has unscreened spinor color sources and global Z_2 flux tubes. We construct the flux tubes and show how they mediate the confinement of spinor sources. We further examine the flux tubes' quantum stability, spectrum and interactions. We find that flux tubes are Alice strings, despite ambiguities in defining parallel transport. However, loops of flux tube cannot support skyrmion number, unlike gauged Alice strings whose loops support monopole charge. This model, while phenomenologically nonviable, thus affords a perspective on both the dynamics of confinement and on subtleties which arise for global Alice strings.

  8. Directed flux motor

    Science.gov (United States)

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

    2011-01-01

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

  9. Aeronet Solar Flux

    Data.gov (United States)

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

  10. Flux in Tallinn

    Index Scriptorium Estoniae

    2004-01-01

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

  11. Nitrous Oxide Flux

    Data.gov (United States)

    U.S. Geological Survey, Department of the Interior — Nitrous Oxide (N20) flux is the net rate of nitrous oxide exchange between an ecosystem and the atmosphere. Data of this variable were generated by the USGS...

  12. Net Ecosystem Carbon Flux

    Data.gov (United States)

    U.S. Geological Survey, Department of the Interior — Net Ecosystem Carbon Flux is defined as the year-over-year change in Total Ecosystem Carbon Stock, or the net rate of carbon exchange between an ecosystem and the...

  13. Flux Emergence (Theory)

    OpenAIRE

    Cheung, Mark C. M.; Hiroaki Isobe

    2014-01-01

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

  14. Flux Emergence (Theory

    Directory of Open Access Journals (Sweden)

    Mark C. M. Cheung

    2014-07-01

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

  15. 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 ha...

  16. Specialized Mediation.

    Science.gov (United States)

    Hammond, Carol; And Others

    1992-01-01

    Six articles discuss librarians as mediators in special circumstances. Highlights include the reference librarian and the information paraprofessional; effective reference mediation for nontraditional public library users, including mentally impaired patrons and illiterate adults; the academic librarian's role in the education process; and…

  17. PAMAM Nanoparticles Promote Acute Lung Injury by Inducing Autophagic Cell Death through the Akt-TSC2-mTOR Signaling Pathway

    Institute of Scientific and Technical Information of China (English)

    Chenggang Li; Haolin Liu; Yang Sun; Hongliang Wang; Feng Guo; Shuan Rao; Jiejie Deng; Yanli Zhang; Yufa Miao; Chenying Guo; Jie Meng; Xiping Chen; Limin Li; Dangsheng Li; Haiyan Xu; Heng Wang; Bo Li; Chengyu Jiang

    2009-01-01

    Nanotechnology is an important and emerging industry with a projected annual market of around one trillion US dollars by 2011–2015. Concerns about the toxicity of nanomaterials in humans, however, have recently been raised. Although studies of nanoparticle toxicity have focused on lung disease the molecular link between nanoparticle exposure and lung injury remained unclear. In this report, we show that cationic Starburst polyamidoamine dendrimer (PAMAM), a class of nanomaterials that are being widely developed for clinical applications can induce acute lung injury in vivo. PAMAM triggers autophagic cell death by deregulating the Akt-TSC2-mTOR signaling pathway. The autophagy inhibitor 3-methyladenine rescued PAMAM dendrimer-induced cell death and ameliorated acute lung injury caused by PAMAM in mice. Our data provide a molecular explanation for nanoparticle-induced lung injury, and suggest potential remedies to address the growing concerns of nanotechnology safety.

  18. Solar Magnetic Flux Ropes

    CERN Document Server

    Filippov, Boris; Srivastava, Abhishek K; Uddin, Wahab

    2015-01-01

    The most probable initial magnetic configuration of a CME is a flux rope consisting of twisted field lines which fill the whole volume of a dark coronal cavity. The flux ropes can be in stable equilibrium in the coronal magnetic field for weeks and even months, but suddenly they loose their stability and erupt with high speed. Their transition to the unstable phase depends on the parameters of the flux rope (i.e., total electric current, twist, mass loading etc.), as well as on the properties of the ambient coronal magnetic field. One of the major governing factors is the vertical gradient of the coronal magnetic field which is estimated as decay index (n). Cold dense prominence material can be collected in the lower parts of the helical flux tubes. Filaments are therefore good tracers of the flux ropes in the corona, which become visible long before the beginning of the eruption. The perspectives of the filament eruptions and following CMEs can be estimated by the comparison of observed filament heights with...

  19. Superradiance and flux conservation

    Science.gov (United States)

    Boonserm, Petarpa; Ngampitipan, Tritos; Visser, Matt

    2014-09-01

    The theoretical foundations of the phenomenon known as superradiance still continue to attract considerable attention. Despite many valiant attempts at pedagogically clear presentations, the effect nevertheless still continues to generate some significant confusion. Part of the confusion arises from the fact that superradiance in a quantum field theory context is not the same as superradiance (superfluorescence) in some condensed matter contexts; part of the confusion arises from traditional but sometimes awkward normalization conventions, and part is due to sometimes unnecessary confusion between fluxes and probabilities. We shall argue that the key point underlying the effect is flux conservation (and, in the presence of dissipation, a controlled amount of flux nonconservation), and that attempting to phrase things in terms of reflection and transmission probabilities only works in the absence of superradiance. To help clarify the situation we present a simple exactly solvable toy model exhibiting both superradiance and damping.

  20. Magnetic flux tube tunneling

    International Nuclear Information System (INIS)

    We present numerical simulations of the collision and subsequent interaction of orthogonal magnetic flux tubes. The simulations were carried out using a parallelized spectral algorithm for compressible magnetohydrodynamics. It is found that, under a wide range of conditions, the flux tubes can open-quotes tunnelclose quotes through each other, a behavior not previously seen in studies of either vortex tube or magnetic flux tube interactions. Two conditions must be satisfied for tunneling to occur: the magnetic field must be highly twisted with a field line pitch >1, and the Lundquist number must be somewhat large, ≥2880. An examination of magnetic field lines suggests that tunneling is due to a double-reconnection mechanism. Initially orthogonal field lines reconnect at two specific locations, exchange interacting sections, and open-quotes passclose quotes through each other. The implications of these results for solar and space plasmas are discussed. copyright 1997 The American Physical Society

  1. Solar Magnetic Flux Ropes

    Indian Academy of Sciences (India)

    Boris Filippov; Olesya Martsenyuk; Abhishek K. Srivastava; Wahab Uddin

    2015-03-01

    In the early 1990s, it was found that the strongest disturbances of the space–weather were associated with huge ejections of plasma from the solar corona, which took the form of magnetic clouds when moved from the Sun. It is the collisions of the magnetic clouds with the Earth's magnetosphere that lead to strong, sometimes catastrophic changes in space–weather. The onset of a coronal mass ejection (CME) is sudden and no reliable forerunners of CMEs have been found till date. The CME prediction methodologies are less developed compared to the methods developed for the prediction of solar flares. The most probable initial magnetic configuration of a CME is a flux rope consisting of twisted field lines which fill the whole volume of a dark coronal cavity. The flux ropes can be in stable equilibrium in the coronal magnetic field for weeks and even months, but suddenly they lose their stability and erupt with high speed. Their transition to the unstable phase depends on the parameters of the flux rope (i.e., total electric current, twist, mass loading, etc.), as well as on the properties of the ambient coronal magnetic field. One of the major governing factors is the vertical gradient of the coronal magnetic field, which is estimated as decay index (). Cold dense prominence material can be collected in the lower parts of the helical flux tubes. Filaments are, therefore, good tracers of the flux ropes in the corona, which become visible long before the beginning of the eruption. The perspectives of the filament eruptions and following CMEs can be estimated by a comparison of observed filament heights with calculated decay index distributions. The present paper reviews the formation of magnetic flux ropes, their stable and unstable phases, eruption conditions, and also discusses their physical implications in the solar corona.

  2. Radiation flux measuring device

    International Nuclear Information System (INIS)

    A radiation flux measuring device is described which employs an attenuator circuit, the output of which is maintained constant, connected to a radiation detector. Means connected to the attenuator circuit produce an output representing the log of the a-c component of the radiation detector, thereby providing a true root mean square logarithmic output

  3. Radiation flux measuring device

    International Nuclear Information System (INIS)

    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

  4. Coupled superconducting flux qubits

    NARCIS (Netherlands)

    Plantenberg, J.H.

    2007-01-01

    This thesis presents results of theoretical and experimental work on superconducting persistent-current quantum bits. These qubits offer an attractive route towards scalable solid-state quantum computing. The focus of this work is on the gradiometer flux qubit which has a special geometric design, t

  5. Disconnecting Solar Magnetic Flux

    CERN Document Server

    DeForest, C E; McComas, D J

    2011-01-01

    Disconnection of open magnetic flux by reconnection is required to balance the injection of open flux by CMEs and other eruptive events. Making use of recent advances in heliospheric background subtraction, we have imaged many abrupt disconnection events. These events produce dense plasma clouds whose distinctie shape can now be traced from the corona across the inner solar system via heliospheric imaging. The morphology of each initial event is characteristic of magnetic reconnection across a current sheet, and the newly-disconnected flux takes the form of a "U"-shaped loop that moves outward, accreting coronal and solar wind material. We analyzed one such event on 2008 December 18 as it formed and accelerated at 20 m/s^2 to 320 km/s, expanding self-similarly until it exited our field of view 1.2 AU from the Sun. From acceleration and photometric mass estimates we derive the coronal magnetic field strength to be 8uT, 6 Rs above the photosphere, and the entrained flux to be 1.6x10^11 Wb (1.6x10^19 Mx). We mod...

  6. Atmospheric lepton fluxes

    Directory of Open Access Journals (Sweden)

    Gaisser Thomas K.

    2015-01-01

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

  7. Mediatized Humanitarianism

    DEFF Research Database (Denmark)

    Vestergaard, Anne

    2014-01-01

    The article investigates the implications of mediatization for the legitimation strategies of humanitarian organizations. Based on a (full population) corpus of ~400 pages of brochure material from 1970 to 2007, the micro-textual processes involved in humanitarian organizations' efforts to...... legitimate themselves and their moral claim were examined. A time trend analysis of the prioritization of actors in the material indicates that marked shifts in legitimation loci have taken place during the past 40 years. A discourse analysis unfolds the three dominant discourses behind these shifts, namely...... legitimation by accountancy, legitimation by institutionalization, and legitimation by compensation. The analysis relates these changes to a problem of trust associated with mediatization through processes of mediation....

  8. 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....

  9. 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....

  10. 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)

    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 Aβ25–35-induced cell death in the nerve growth factor-induced differentiation of PC12 cells. Aβ25–35 (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. Aβ25–35 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. Aβ25–35 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 Aβ25–35-induced neurotoxicity, including oxidative stress, apoptosis, and autophagic cell death. In conclusion, GP-17 conferred protection against Aβ25–35-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. - Highlights:

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

    DEFF Research Database (Denmark)

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

    2010-01-01

    We propose a method to achieve coherent coupling between nitrogen-vacancy (NV) centers in diamond and superconducting (SC) flux qubits. The resulting coupling can be used to create a coherent interaction between the spin states of distant NV centers mediated by the flux qubit. Furthermore, the ma...

  12. Cocaine-Mediated Autophagy in Astrocytes Involves Sigma 1 Receptor, PI3K, mTOR, Atg5/7, Beclin-1 and Induces Type II Programed Cell Death.

    Science.gov (United States)

    Cao, Lu; Walker, Mary P; Vaidya, Naveen K; Fu, Mingui; Kumar, Santosh; Kumar, Anil

    2016-09-01

    Cocaine, a commonly used drug of abuse, has been shown to cause neuropathological dysfunction and damage in the human brain. However, the role of autophagy in this process is not defined. Autophagy, generally protective in nature, can also be destructive leading to autophagic cell death. This study was designed to investigate whether cocaine induces autophagy in the cells of CNS origin. We employed astrocyte, the most abundant cell in the CNS, to define the effects of cocaine on autophagy. We measured levels of the autophagic marker protein LC3II in SVGA astrocytes after exposure with cocaine. The results showed that cocaine caused an increase in LC3II level in a dose- and time-dependent manner, with the peak observed at 1 mM cocaine after 6-h exposure. This result was also confirmed by detecting LC3II in SVGA astrocytes using confocal microscopy and transmission electron microscopy. Next, we sought to explore the mechanism by which cocaine induces the autophagic response. We found that cocaine-induced autophagy was mediated by sigma 1 receptor, and autophagy signaling proteins p-mTOR, Atg5, Atg7, and p-Bcl-2/Beclin-1 were also involved, and this was confirmed by using selective inhibitors and small interfering RNAs (siRNAs). In addition, we found that chronic treatment with cocaine resulted in cell death, which is caspase-3 independent and can be ameliorated by autophagy inhibitor. Therefore, this study demonstrated that cocaine induces autophagy in astrocytes and is associated with autophagic cell death. PMID:26243186

  13. Nucleolin antagonist triggers autophagic cell death in human glioblastoma primary cells and decreased in vivo tumor growth in orthotopic brain tumor model.

    Science.gov (United States)

    Benedetti, Elisabetta; Antonosante, Andrea; d'Angelo, Michele; Cristiano, Loredana; Galzio, Renato; Destouches, Damien; Florio, Tiziana Marilena; Dhez, Anne Chloé; Astarita, Carlo; Cinque, Benedetta; Fidoamore, Alessia; Rosati, Floriana; Cifone, Maria Grazia; Ippoliti, Rodolfo; Giordano, Antonio; Courty, José; Cimini, Annamaria

    2015-12-01

    Nucleolin (NCL) is highly expressed in several types of cancer and represents an interesting therapeutic target. It is expressed at the plasma membrane of tumor cells, a property which is being used as a marker for several human cancer including glioblastoma. In this study we investigated targeting NCL as a new therapeutic strategy for the treatment of this pathology. To explore this possibility, we studied the effect of an antagonist of NCL, the multivalent pseudopeptide N6L using primary culture of human glioblastoma cells. In this system, N6L inhibits cell growth with different sensitivity depending to NCL localization. Cell cycle analysis indicated that N6L-induced growth reduction was due to a block of the G1/S transition with down-regulation of the expression of cyclin D1 and B2. By monitoring autophagy markers such as p62 and LC3II, we demonstrate that autophagy is enhanced after N6L treatment. In addition, N6L-treatment of mice bearing tumor decreased in vivo tumor growth in orthotopic brain tumor model and increase mice survival. The results obtained indicated an anti-proliferative and pro-autophagic effect of N6L and point towards its possible use as adjuvant agent to the standard therapeutic protocols presently utilized for glioblastoma. PMID:26540346

  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)

    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. Computing the Flux Footprint

    Science.gov (United States)

    Wilson, J. D.

    2015-07-01

    We address the flux footprint for measurement heights in the atmospheric surface layer, comparing eddy diffusion solutions with those furnished by the first-order Lagrangian stochastic (or "generalized Langevin") paradigm. The footprint given by Langevin models differs distinctly from that given by the random displacement model (i.e. zeroth-order Lagrangian stochastic model) corresponding to its "diffusion limit," which implies that a well-founded theory of the flux footprint must incorporate the turbulent velocity autocovariance. But irrespective of the choice of the eddy diffusion or Langevin class of model as basis for the footprint, tuning relative to observations is ultimately necessary. Some earlier treatments assume Monin-Obukhov profiles for the mean wind and eddy diffusivity and that the effective Schmidt number (ratio of eddy viscosity to the tracer eddy diffusivity) in the neutral limit , while others calibrate the model to the Project Prairie Grass dispersion trials. Because there remains uncertainty as to the optimal specification of (or a related parameter in alternative theories, e.g. the Kolmogorov coefficient in Langevin models) it is recommended that footprint models should be explicit in this regard.

  17. Autophagic UVRAG Promotes UV-Induced Photolesion Repair by Activation of the CRL4(DDB2) E3 Ligase.

    Science.gov (United States)

    Yang, Yongfei; He, Shanshan; Wang, Qiaoxiu; Li, Fan; Kwak, Mi-Jeong; Chen, Sally; O'Connell, Douglas; Zhang, Tian; Pirooz, Sara Dolatshahi; Jeon, YongHeui; Chimge, Nyam-Osor; Frenkel, Baruch; Choi, Younho; Aldrovandi, Grace M; Oh, Byung-Ha; Yuan, Zengqiang; Liang, Chengyu

    2016-05-19

    UV-induced DNA damage, a major risk factor for skin cancers, is primarily repaired by nucleotide excision repair (NER). UV radiation resistance-associated gene (UVRAG) is a tumor suppressor involved in autophagy. It was initially isolated as a cDNA partially complementing UV sensitivity in xeroderma pigmentosum (XP), but this was not explored further. Here we show that UVRAG plays an integral role in UV-induced DNA damage repair. It localizes to photolesions and associates with DDB1 to promote the assembly and activity of the DDB2-DDB1-Cul4A-Roc1 (CRL4(DDB2)) ubiquitin ligase complex, leading to efficient XPC recruitment and global genomic NER. UVRAG depletion decreased substrate handover to XPC and conferred UV-damage hypersensitivity. We confirmed the importance of UVRAG for UV-damage tolerance using a Drosophila model. Furthermore, increased UV-signature mutations in melanoma correlate with reduced expression of UVRAG. Our results identify UVRAG as a regulator of CRL4(DDB2)-mediated NER and suggest that its expression levels may influence melanoma predisposition. PMID:27203177

  18. Fisetin stimulates autophagic degradation of phosphorylated tau via the activation of TFEB and Nrf2 transcription factors

    Science.gov (United States)

    Kim, Sunhyo; Choi, Ki Ju; Cho, Sun-Jung; Yun, Sang-Moon; Jeon, Jae-Pil; Koh, Young Ho; Song, Jihyun; Johnson, Gail V. W.; Jo, Chulman

    2016-01-01

    The neuronal accumulation of phosphorylated tau plays a critical role in the pathogenesis of Alzheimer’s disease (AD). Here, we examined the effect of fisetin, a flavonol, on tau levels. Treatment of cortical cells or primary neurons with fisetin resulted in significant decreases in the levels of phosphorylated tau. In addition, fisetin decreased the levels of sarkosyl-insoluble tau in an active GSK-3β-induced tau aggregation model. However, there was no difference in activities of tau kinases and phosphatases such as protein phosphatase 2A, irrespective of fisetin treatment. Fisetin activated autophagy together with the activation of transcription factor EB (TFEB) and Nrf2 transcriptional factors. The activation of autophagy including TFEB is likely due to fisetin-mediated mammalian target of rapamycin complex 1 (mTORC1) inhibition, since the phosphorylation levels of p70S6 kinase and 4E-BP1 were decreased in the presence of fisetin. Indeed, fisetin-induced phosphorylated tau degradation was attenuated by chemical inhibitors of the autophagy-lysosome pathway. Together the results indicate that fisetin reduces levels of phosphorylated tau through the autophagy pathway activated by TFEB and Nrf2. Our result suggests fisetin should be evaluated further as a potential preventive and therapeutic drug candidate for AD. PMID:27112200

  19. California's Future Carbon Flux

    Science.gov (United States)

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

    2008-12-01

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

  20. Photospheric flux cancellation and associated flux rope formation and eruption

    CERN Document Server

    Green, L M; Wallace, A J; 10.1051/0004-6361/201015146

    2010-01-01

    We study an evolving bipolar active region that exhibits flux cancellation at the internal polarity inversion line, the formation of a soft X-ray sigmoid along the inversion line and a coronal mass ejection. The evolution of the photospheric magnetic field is described and used to estimate how much flux is reconnected into the flux rope. About one third of the active region flux cancels at the internal polarity inversion line in the 2.5~days leading up to the eruption. In this period, the coronal structure evolves from a weakly to a highly sheared arcade and then to a sigmoid that crosses the inversion line in the inverse direction. These properties suggest that a flux rope has formed prior to the eruption. The amount of cancellation implies that up to 60% of the active region flux could be in the body of the flux rope. We point out that only part of the cancellation contributes to the flux in the rope if the arcade is only weakly sheared, as in the first part of the evolution. This reduces the estimated flux...

  1. Quantitative Flux Ecoregions for AmeriFlux Using MODIS

    Science.gov (United States)

    Hoffman, F. M.; Hargrove, W. W.

    2004-12-01

    Multivariate Geographic Clustering was used with maps of climate, soils, and physiography and MODIS remotely sensed data products to statistically produce a series of the 90 most-different homogeneous flux-relevant ecoregions in the conterminous United States using a parallel supercomputer. Nine separate sets of flux ecoregions were produced; only two will be discussed here. Both the IB and IIIB maps were quantitatively constructed from subsets of the input data integrated during the local growing season (frost-free period) in every 1 km cell. Each map is shown two ways --- once with the 90 flux ecoregions colored randomly, and once using color combinations derived statistically from the first three Principal Component Axes. Although the underlying flux ecoregion polygons are the same in both cases, the statistically derived colors show the similarity of conditions within each flux ecoregion. Coloring the same map in this way shows the continuous gradient of changing flux environments across the US. The IB map, since it considers only abiotic environmental factors, represents flux-ecoregions based on potential vegetation. The IIIB map, since it contains remotely sensed MODIS information about existing vegetation, includes the effects of natural and anthropogenic disturbance, and represents actual or realized flux ecoregions. Thus, differences between the maps are attributable to human activity and natural disturbances. The addition of information on existing vegetation exerts a unifying effect on abiotic-only flux ecoregions. The Mississippi Valley and Corn Belt areas show large differences between the two maps. Map IIIB shows a mosaic of ``speckles'' in areas of intense human land use, ostensibly from disturbances like agriculture, irrigation, fertilization, and clearing. Such ``speckles'' are absent from areas devoid of intense human land use. Major cities are also evident in the IIIB map. We will use the quantitative similarity of the suite of flux

  2. Optimal fluxes and Reynolds stresses

    CERN Document Server

    Jimenez, Javier

    2016-01-01

    It is remarked that fluxes in conservation laws, such as the Reynolds stresses in the momentum equation of turbulent shear flows, or the spectral energy flux in isotropic turbulence, are only defined up to an arbitrary solenoidal field. While this is not usually significant for long-time averages, it becomes important when fluxes are modelled locally in large-eddy simulations, or in the analysis of intermittency and cascades. As an example, a numerical procedure is introduced to compute fluxes in scalar conservation equations in such a way that their total integrated magnitude is minimised. The result is an irrotational vector field that derives from a potential, thus minimising sterile flux `circuits'. The algorithm is generalised to tensor fluxes and applied to the transfer of momentum in a turbulent channel. The resulting instantaneous Reynolds stresses are compared with their traditional expressions, and found to be substantially different.

  3. Vorticity flux from active dimples

    Science.gov (United States)

    McKeon, Beverley; Sherwin, Spencer; Morrison, Jonathan

    2004-11-01

    The effect of surface depressions, or dimples, in reducing drag on golf balls is well-known. Here this concept is extended to using ``active" dimples to manipulate vorticity flux at the wall. Surface vorticity flux is governed by surface accelerations, pressure and shear stress gradients, and surface curvature. ``Active" (or vibrating) dimples may generate vorticity flux by each of these terms, making them an excellent candidate for a basic study of flux manipulation, by which flow control may be achieved. Flow over an active dimple in fully-developed laminar channel flow is simulated with velocity boundary conditions developed from a linearized perturbation method imposed at the wall. This simple model cannot capture flow separation, but gives insight into the most straightforward means of flux generation from the concave surface. Vorticity flux due to dimple geometry and motion is quantified, and enhancements of two to three orders of magnitude in peak vorticity over the static dimple case are observed.

  4. Heat Flux Apportionment to Heterogeneous Surfaces Using Flux Footprint Analysis

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Heat flux data collected from the Baiyangdian Heterogeneous Field Experiment were analyzed using the footprint method. High resolution (25 m) Landsat-5 satellite imaging was used to determine the land cover as one of four surface types: farmland, lake, wetland, or village. Data from two observation sites in September 2005 were used. One site (Wangjiazhai) was characterized by highly heterogeneous surfaces in the central area of the Baiyangdian: lake/wetland. The other site (Xiongxian) was on land with more uniform surface cover. An improved Eulerian analytical flux footprint model was used to determine "source areas" of the heat fluxes measured at towers located at each site from surrounding landscapes of mixed surface types.In relative terms results show that wetland and lake areas generally contributed most to the observed heat flux at Wangjiazhai, while farmland contributed most at Xiongxian. Given the areal distribution of surface type contributions, calculations were made to obtain the magnitudes of the heat flux from lake, wetland and farmland to the total observed flux and apportioned contributions of each surface type to the sensible and latent heat fluxes. Results show that on average the sensible heat flux from wetland and farmland were comparable over the diurnal cycle, while the latent heat flux from farmland was somewhat larger by about 30-50 W m-2 during daytime. The latent and sensible fluxes from the lake source in daytime were about 50 W m-2 and 100 W m-2 less, respectively, than from wetland and farmland. The results are judged reasonable and serve to demonstrate the potential for flux apportionment over heterogeneous surfaces.

  5. 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....

  6. Data Acquisition and Flux Calculations

    DEFF Research Database (Denmark)

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

    2012-01-01

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

  7. Methane flux from wetlands areas

    OpenAIRE

    BAKER-BLOCKER, ANITA; Donahue, Thomas M.; MANCY, KHALIL H.

    2011-01-01

    Ebullient gases from Michigan wetlands have been collected and analyzed to deduce in situ methane fluxes. Methane flux has been found to be a function of mean air temperature. This relationship has been utilized to extrapolate observed methane fluxes to estimates of fluxes from the Pripet marshes, Sudd, Everglades, and Ugandan swamps. These four wetlands together provide a yearly source of 6.8 × 1013 g of methane to the atmosphere.DOI: 10.1111/j.2153-3490.1977.tb00731.x

  8. Effects of interval and continuous exercise training on CD4 lymphocyte apoptotic and autophagic responses to hypoxic stress in sedentary men.

    Directory of Open Access Journals (Sweden)

    Tzu-Pin Weng

    Full Text Available Exercise is linked with the type/intensity-dependent adaptive immune responses, whereas hypoxic stress facilitates the programmed death of CD4 lymphocytes. This study investigated how high intensity-interval (HIT and moderate intensity-continuous (MCT exercise training influence hypoxia-induced apoptosis and autophagy of CD4 lymphocytes in sedentary men. Thirty healthy sedentary males were randomized to engage either HIT (3-minute intervals at 40% and 80%VO2max, n=10 or MCT (sustained 60%VO2max, n=10 for 30 minutes/day, 5 days/week for 5 weeks, or to a control group that did not received exercise intervention (CTL, n=10. CD4 lymphocyte apoptotic and autophagic responses to hypoxic exercise (HE, 100 W under 12%O2 for 30 minutes were determined before and after various regimens. The results demonstrated that HIT exhibited higher enhancements of pulmonary ventilation, cardiac output, and VO2 at ventilatory threshold and peak performance than MCT did. Before the intervention, HE significantly down-regulated autophagy by decreased beclin-1, Atg-1, LC3-II, Atg-12, and LAMP-2 expressions and acridine orange staining, and simultaneously enhanced apoptosis by increased phospho-Bcl-2 and active caspase-9/-3 levels and phosphotidylserine exposure in CD4 lymphocytes. However, five weeks of HIT and MCT, but not CTL, reduced the extents of declined autophagy and potentiated apoptosis in CD4 lymphocytes caused by HE. Furthermore, both HIT and MCT regimens manifestly lowered plasma myeloperoxidase and interleukin-4 levels and elevated the ratio of interleukin-4 to interferon-γ at rest and following HE. Therefore, we conclude that HIT is superior to MCT for enhancing aerobic fitness. Moreover, either HIT or MCT effectively depresses apoptosis and promotes autophagy in CD4 lymphocytes and is accompanied by increased interleukin-4/interferon-γ ratio and decreased peroxide production during HE.

  9. Effects of interval and continuous exercise training on CD4 lymphocyte apoptotic and autophagic responses to hypoxic stress in sedentary men.

    Science.gov (United States)

    Weng, Tzu-Pin; Huang, Shu-Chun; Chuang, Yu-Fen; Wang, Jong-Shyan

    2013-01-01

    Exercise is linked with the type/intensity-dependent adaptive immune responses, whereas hypoxic stress facilitates the programmed death of CD4 lymphocytes. This study investigated how high intensity-interval (HIT) and moderate intensity-continuous (MCT) exercise training influence hypoxia-induced apoptosis and autophagy of CD4 lymphocytes in sedentary men. Thirty healthy sedentary males were randomized to engage either HIT (3-minute intervals at 40% and 80%VO2max, n=10) or MCT (sustained 60%VO2max, n=10) for 30 minutes/day, 5 days/week for 5 weeks, or to a control group that did not received exercise intervention (CTL, n=10). CD4 lymphocyte apoptotic and autophagic responses to hypoxic exercise (HE, 100 W under 12%O2 for 30 minutes) were determined before and after various regimens. The results demonstrated that HIT exhibited higher enhancements of pulmonary ventilation, cardiac output, and VO2 at ventilatory threshold and peak performance than MCT did. Before the intervention, HE significantly down-regulated autophagy by decreased beclin-1, Atg-1, LC3-II, Atg-12, and LAMP-2 expressions and acridine orange staining, and simultaneously enhanced apoptosis by increased phospho-Bcl-2 and active caspase-9/-3 levels and phosphotidylserine exposure in CD4 lymphocytes. However, five weeks of HIT and MCT, but not CTL, reduced the extents of declined autophagy and potentiated apoptosis in CD4 lymphocytes caused by HE. Furthermore, both HIT and MCT regimens manifestly lowered plasma myeloperoxidase and interleukin-4 levels and elevated the ratio of interleukin-4 to interferon-γ at rest and following HE. Therefore, we conclude that HIT is superior to MCT for enhancing aerobic fitness. Moreover, either HIT or MCT effectively depresses apoptosis and promotes autophagy in CD4 lymphocytes and is accompanied by increased interleukin-4/interferon-γ ratio and decreased peroxide production during HE. PMID:24236174

  10. 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)

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

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

    International Nuclear Information System (INIS)

    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

  12. 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

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

    International Nuclear Information System (INIS)

    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

  14. PRACTICAL ASPECTS OF MEDIATION

    OpenAIRE

    IULIA FLOCA

    2011-01-01

    Today the Romanian state gives some advantages to those who use mediation. If the Romanian state would take further steps, mediation would work as in the countries with old tradition. The article refers to success and failure got in the two years of practice. The mediation can be seen in two aspects: The first aspect regarding the mediation itself can lead to a mediation agreement. The mediation agreement gives both winnings to the conflict parts and professional satisfactions to the mediator...

  15. Silencing of MicroRNA-21 confers the sensitivity to tamoxifen and fulvestrant by enhancing autophagic cell death through inhibition of the PI3K-AKT-mTOR pathway in breast cancer cells.

    Science.gov (United States)

    Yu, Xinfeng; Li, Ruilian; Shi, Wenna; Jiang, Tao; Wang, Yufei; Li, Cong; Qu, Xianjun

    2016-02-01

    Tamoxifen (TAM) and fulvestrant (FUL) represent the major adjuvant therapy to estrogen receptor-alpha positive (ER(+)) breast cancer patients. However, endocrine resistance to TAM and FUL is a great impediment for successful treatment. We hypothesized that miR-21 might alter the sensitivity of breast cancer cells to TAM or FUL by regulating cell autophagy. Using the ER(+) breast cancer cells, we knockdown miR-21.by transfection with miR-21 inhibitor, then the cells were exposed to TAM or FUL and the percentages of apoptosis and autophagy were determined. Knockdown of miR-21 significantly increased the TAM or FUL-induced apoptosis in ER(+) breast cancer cells. Further, silencing of miR-21 in MCF-7 cells enhanced cell autophagy at both basal and TAM or FUL-induced level. The increase of autophagy in miR-21-knockdown MCF-7 cells was also indicated by increase of beclin-1, LC3-II and increased GFP-LC3 dots. Importantly, knockdown of miR-21 contributed to autophagic cell death, which is responsible for part of TAM induced cell death in miR-21 inhibitor-transfected cells. Further analysis suggested that miR-21 inhibitor enhance autophagic cell death through inhibition of PI3K-AKT-mTOR pathway. MiR-21 coordinated the function of autophagy and apoptosis by targeting Phosphatase and tensin homolog (PTEN) through inhibition of PI3K-AKT-mTOR pathway. In conclusion, silencing of miR-21 increased the sensitivity of ER(+) breast cancer cells to TAM or FUL by increasing autophagic cell death. Targeting autophagy-related miRNAs is a potential strategy for overcoming endocrine resistance to TAM and FUL. PMID:26796263

  16. Interpreting Flux from Broadband Photometry

    CERN Document Server

    Brown, Peter J; Roming, Peter W A; Siegel, Michael

    2016-01-01

    We discuss the transformation of observed photometry into flux for the creation of spectral energy distributions and the computation of bolometric luminosities. We do this in the context of supernova studies, particularly as observed with the Swift spacecraft, but the concepts and techniques should be applicable to many other types of sources and wavelength regimes. Traditional methods of converting observed magnitudes to flux densities are not very accurate when applied to UV photometry. Common methods for extinction and the integration of pseudo-bolometric fluxes can also lead to inaccurate results. The sources of inaccuracy, though, also apply to other wavelengths. Because of the complicated nature of translating broad-band photometry into monochromatic flux densities, comparison between observed photometry and a spectroscopic model is best done by comparing in the natural units of the observations. We recommend that integrated flux measurements be made using a spectrum or spectral energy distribution whic...

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

    International Nuclear Information System (INIS)

    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.)

  18. 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.)

  19. Small helical flux compression amplifiers

    International Nuclear Information System (INIS)

    Small, explosively compressed, magnetic flux transducers with many closely spaced helical turns are investigated theoretically and experimentally. The analysis is limited to linear operation, but takes into account load influence, proximity effects, and switching delays. The latter are due to retarded breakdown in the wire insulation and to the finite decay time of the magnetic field in the wire. More than 150 experiments showed considerable data scatter. Shots which exhibited low clocking and high amplification were in good agreement with the theory. The main conclusion is that device performance is limited not only by flux loss, but by flux remaining in the generator after compression

  20. Generalised Geometry and Flux Vacua

    CERN Document Server

    Larfors, Magdalena

    2015-01-01

    This note discusses the connection between generalised geometry and flux compactifications of string theory. Firstly, we explain in a pedestrian manner how the supersymmetry constraints of type II ${\\mathcal{N}}=1$ flux compactifications can be restated as integrability constraints on certain generalised complex structures. This reformulation uses generalised complex geometry, a mathematical framework that geometrizes the B-field. Secondly, we discuss how exceptional generalised geometry may provide a similar geometrization of the RR fields. Thirdly, we examine the connection between generalised geometry and non-geometry, and finally we present recent developments where generalised geometry is used to construct explicit examples of flux compactifications to flat space.

  1. The Solar Wind Energy Flux

    OpenAIRE

    Chat, G. Le; Issautier, K.; Meyer-Vernet, N.

    2012-01-01

    The solar-wind energy flux measured near the ecliptic is known to be independent of the solar-wind speed. Using plasma data from Helios, Ulysses, and Wind covering a large range of latitudes and time, we show that the solar-wind energy flux is independent of the solar-wind speed and latitude within 10%, and that this quantity varies weakly over the solar cycle. In other words the energy flux appears as a global solar constant. We also show that the very high speed solar-wind (VSW > 700 km/s) ...

  2. 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...

  3. 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)

    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

  4. The Solar Wind Energy Flux

    CERN Document Server

    Chat, G Le; Meyer-Vernet, N

    2012-01-01

    The solar-wind energy flux measured near the ecliptic is known to be independent of the solar-wind speed. Using plasma data from Helios, Ulysses, and Wind covering a large range of latitudes and time, we show that the solar-wind energy flux is independent of the solar-wind speed and latitude within 10%, and that this quantity varies weakly over the solar cycle. In other words the energy flux appears as a global solar constant. We also show that the very high speed solar-wind (VSW > 700 km/s) has the same mean energy flux as the slower wind (VSW < 700 km/s), but with a different histogram. We use this result to deduce a relation between the solar-wind speed and density, which formalizes the anti-correlation between these quantities.

  5. 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.

  6. Measuring temperature and thermal flux

    International Nuclear Information System (INIS)

    A sensitive temperature measuring device is described for detecting small temperature differences and associated thermal fluxes. Highly-doped silicon diodes operated at constant current are used in conjunction with suitable circuitry. (U.K.)

  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. Specification of ROP flux shape

    International Nuclear Information System (INIS)

    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

  9. 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...

  10. Periodicities in photospheric magnetic flux

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Magnetic field plays an important role in solar structure and activity. In principle, the determination of magnetic flux would provide the best general-purpose index of solar activity. Currently, the periodicity studies corresponding to photospheric magnetic flux (PMF) are very few possibly due to the absence of a uniform flux sequence. In this paper, by using 383 NSO/Kitt Peak magnetic synoptic charts we reconstruct a flux sequence from February 1975 to August 2003 and perform a relatively systemic periodicity analysis with two methods of the Scargle periodogram and the Morlet wavelet transform. As a result, four periods are found at around 1050, 500, 300 and 160 days. We analyze these periods' temporal variabilities in detail and discuss their respective origins briefly.

  11. Flux networks in metabolic graphs

    International Nuclear Information System (INIS)

    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

  12. Notes on neutron flux measurement

    International Nuclear Information System (INIS)

    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

  13. 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...

  14. Flux emergence and coronal eruption

    CERN Document Server

    Archontis, V; 10.1051/0004-6361/200913502

    2010-01-01

    Our aim is to study the photospheric flux distribution of a twisted flux tube that emerges from the solar interior. We also report on the eruption of a new flux rope when the emerging tube rises into a pre-existing magnetic field in the corona. To study the evolution, we use 3D numerical simulations by solving the time-dependent and resistive MHD equations. We qualitatively compare our numerical results with MDI magnetograms of emerging flux at the solar surface. We find that the photospheric magnetic flux distribution consists of two regions of opposite polarities and elongated magnetic tails on the two sides of the polarity inversion line (PIL), depending on the azimuthal nature of the emerging field lines and the initial field strength of the rising tube. Their shape is progressively deformed due to plasma motions towards the PIL. Our results are in qualitative agreement with observational studies of magnetic flux emergence in active regions (ARs). Moreover, if the initial twist of the emerging tube is sma...

  15. Beclin-1-independent autophagy mediates programmed cancer cell death through interplays with endoplasmic reticulum and/or mitochondria in colbat chloride-induced hypoxia.

    Science.gov (United States)

    Sun, Lei; Liu, Ning; Liu, Shan-Shan; Xia, Wu-Yan; Liu, Meng-Yao; Li, Lin-Feng; Gao, Jian-Xin

    2015-01-01

    Autophagy has dual functions in cell survival and death. However, the effects of autophagy on cancer cell survival or death remain controversial. In this study, we show that Autophagy can mediate programmed cell death (PCD) of cancer cells in responding to cobalt chloride (CoCl2)-induced hypoxia in a Beclin-1-independent but autophagy protein 5 (ATG5)-dependent manner. Although ATG5 is not directly induced by CoCl2, its constitutive expression is essential for CoCl2-induced PCD. The ATG5-mediated autophagic PCD requires interplays with endoplasmic reticulum (ER) and/or mitochondria. In this process, ATG5 plays a central role in regulating ER stress protein CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) and mitochondrial protein second mitochondria derived activator of caspases (Smac). Two pathways for autophagic PCD in cancer cells responding to hypoxia have been identified: ATG5/CHOP/Smac pathway and ATG5/Smac pathway, which are probably dependent on the context of cell lines. The former is more potent than the latter for the induction of PCD at the early stage of hypoxia, although the ultimate efficiency of both pathways is comparable. In addition, both pathways may require ATG5-mediated conversion of LC3-I into LC3-II. Therefore, we have defined two autophagy-mediated pathways for the PCD of cancer cells in hypoxia, which are dependent on ATG5, interplayed with ER and mitochondria and tightly regulated by hypoxic status. The findings provide a new evidence that autophagy may inhibit tumor cell proliferation through trigger of PCD, facilitating the development of novel anti-cancer drugs. PMID:26609472

  16. Ras-Related Tumorigenesis Is Suppressed by BNIP3-Mediated Autophagy through Inhibition of Cell Proliferation

    Directory of Open Access Journals (Sweden)

    Shan-Ying Wu

    2011-12-01

    Full Text Available Autophagy plays diverse roles in Ras-related tumorigenesis. H-rasval12 induces autophagy through multiple signaling pathways including Raf-1/ERK pathway, and various ERK downstream molecules of autophagy have been reported. In this study, Bcl-2/adenovirus E1B 19-kDa–interacting protein 3 (BNIP3 is identified as a downstream transducer of the Ras/Raf/ERK signaling pathway to induce autophagy. BNIP3 was upregulated by H-rasval12 at the transcriptional level to compete with Beclin 1 for binding with Bcl-2. H-rasval12–induced autophagy suppresses cell proliferation demonstrated both in vitro and in vivo by expression of ectopic BNIP3, Atg5, or interference RNA of BNIP3 (siBNIP3 and Atg5 (shAtg5 using mouse NIH3T3 and embryo fibroblast cells. H-rasval12 induces different autophagic responses depending on the duration of Ras overexpression. After a short time (48 hours of Ras overexpression, autophagy inhibits cell proliferation. In contrast, a longer time (2 weeks of Ras overexpression, cell proliferation was enhanced by autophagy. Furthermore, overexpression of mutant Ras, BNIP3, and LC3-II was detected in bladder cancer T24 cells and the tumor parts of 75% of bladder cancer specimens indicating a positive correlation between autophagy and tumorigenesis. Taken together, our mouse model demonstrates a balance between BNIP3-mediated autophagy and H-rasval12–induced tumor formation and reveals that H-rasval12 induces autophagy in a BNIP3-dependent manner, and the threshold of autophagy plays a decisive role in H-rasval12–induced tumorigenesis. Our findings combined with others’ reports suggest a new therapeutic strategy against Ras-related tumorigenesis by negative or positive regulation of autophagic activity, which is determined by the level of autophagy and tumor progression stages.

  17. General Gaugino Mediation

    OpenAIRE

    Sudano, Matthew

    2010-01-01

    The spectrum of a class of gaugino mediation models with arbitrary hidden sector is considered. These models are defined by a diagonal breaking of the mediating gauge group, which places them outside the realm of General Gauge Mediation. While gauginos get masses as in ordinary gauge mediation, the scalar masses are screened.

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

    Science.gov (United States)

    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.

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

    International Nuclear Information System (INIS)

    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

  20. 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...

  1. Thermality of the Hawking flux

    CERN Document Server

    Visser, Matt

    2014-01-01

    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, and 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 lum...

  2. Mediated Electron Transfer at Redox Active Monolayers. Part 4: Kinetics of Redox Enzymes Coupled With Electron Mediators

    Directory of Open Access Journals (Sweden)

    Michael E.G. Lyons

    2003-01-01

    Full Text Available A detailed kinetic analysis of the pertinent physical processes underlying the operation of enzyme electrodes immobilized within alkane thiol self assembled monolayers is developed. These electrodes utilize a soluble mediator, which partitions into the monolayer, regenerates the active catalytic form of the enzyme and is re-oxidized at the underlying support electrode surface giving rise to a current which reflects kinetic events at the enzyme surface. Both the enzyme/substrate and enzyme mediator kinetics have been quantified fully in terms of a ping-pong mechanism for the former and Michaelis-Menten kinetics for the latter. The effect of substrate and mediator diffusion in solution have also been specifically considered and the latter processes have been shown to result in a complex expression for the reaction flux. Four limiting kinetic cases have been enumerated and simple expressions for the reaction flux in each of these rate limiting situations have been developed. Kinetic case diagrams have been presented as an aid to mechanistic diagnosis. The complicating effects of diffusive loss of reduced mediator from the enzyme layer have also been examined and the relation between the observed flux corresponding to reduced mediator oxidation at the support electrode and the substrate reaction flux in the enzyme layer have been quantified in terms of an efficiency factor. Results extracted from recently published practical realizations of immobilized monolayer enzyme systems have been discussed in the context of the proposed model analysis.

  3. p53 isoforms regulate astrocyte-mediated neuroprotection and neurodegeneration.

    Science.gov (United States)

    Turnquist, C; Horikawa, I; Foran, E; Major, E O; Vojtesek, B; Lane, D P; Lu, X; Harris, B T; Harris, C C

    2016-09-01

    Bidirectional interactions between astrocytes and neurons have physiological roles in the central nervous system and an altered state or dysfunction of such interactions may be associated with neurodegenerative diseases, such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Astrocytes exert structural, metabolic and functional effects on neurons, which can be either neurotoxic or neuroprotective. Their neurotoxic effect is mediated via the senescence-associated secretory phenotype (SASP) involving pro-inflammatory cytokines (e.g., IL-6), while their neuroprotective effect is attributed to neurotrophic growth factors (e.g., NGF). We here demonstrate that the p53 isoforms Δ133p53 and p53β are expressed in astrocytes and regulate their toxic and protective effects on neurons. Primary human astrocytes undergoing cellular senescence upon serial passaging in vitro showed diminished expression of Δ133p53 and increased p53β, which were attributed to the autophagic degradation and the SRSF3-mediated alternative RNA splicing, respectively. Early-passage astrocytes with Δ133p53 knockdown or p53β overexpression were induced to show SASP and to exert neurotoxicity in co-culture with neurons. Restored expression of Δ133p53 in near-senescent, otherwise neurotoxic astrocytes conferred them with neuroprotective activity through repression of SASP and induction of neurotrophic growth factors. Brain tissues from AD and ALS patients possessed increased numbers of senescent astrocytes and, like senescent astrocytes in vitro, showed decreased Δ133p53 and increased p53β expression, supporting that our in vitro findings recapitulate in vivo pathology of these neurodegenerative diseases. Our finding that Δ133p53 enhances the neuroprotective function of aged and senescent astrocytes suggests that the p53 isoforms and their regulatory mechanisms are potential targets for therapeutic intervention in neurodegenerative diseases. PMID:27104929

  4. Phase versus flux coupling between resonator and superconducting flux qubit

    Science.gov (United States)

    Birenbaum, J. S.; O'Kelley, S. R.; Anton, S. M.; Nugroho, C. D.; Orlyanchik, V.; Dove, A. H.; Yoscovits, Z. R.; Olson, G. A.; van Harlingen, D. J.; Eckstein, J.; Braje, D. A.; Johnson, R. C.; Oliver, W. D.; Clarke, John

    2013-03-01

    The dispersive coupling of qubits to microwave resonators has become widely used for qubit readout. Recent advances in coupling qubits to 3D resonators have demonstrated the importance of the nature of the qubit-resonator coupling in determining the qubit relaxation and decoherence times, T1 and T2*. We study the effect of phase versus flux coupling on flux qubits coupled to planar resonators. Using an aluminum shadow evaporation technique we fabricate a low-loss planar resonator, consisting of a meandering inductor and interdigitated capacitor, and a flux qubit, all in a single processing step. Whereas the qubit and resonator are always flux coupled via a geometric mutual inductance, a phase coupling can be added by including a shared trace between the qubit and resonator. This technique allows us to control both the magnitude and nature of the qubit-resonator coupling without significantly affecting either the qubit or resonator design. We characterize the dependence of the qubit parameters T1, T2*, and spin echo time Techo on the resonator coupling parameters to gain insight into possible sources of decoherence and loss. This work was supported by ARO, IARPA, and the US Government

  5. Flux attenuation at NREL's High-Flux Solar Furnace

    Science.gov (United States)

    Bingham, Carl E.; Scholl, Kent L.; Lewandowski, Allan A.

    1994-10-01

    The High-Flux Solar Furnace (HFSF) at the National Renewable Energy Laboratory (NREL) has a faceted primary concentrator and a long focal-length-to-diameter ratio (due to its off-axis design). Each primary facet can be aimed individually to produce different flux distributions at the target plane. Two different types of attenuators are used depending on the flux distribution. A sliding-plate attenuator is used primarily when the facets are aimed at the same target point. The alternate attenuator resembles a venetian blind. Both attenuators are located between the concentrator and the focal point. The venetian-blind attenuator is primarily used to control the levels of sunlight failing on a target when the primary concentrators are not focused to a single point. This paper will demonstrate the problem of using the sliding-plate attenuator with a faceted concentrator when the facets are not aimed at the same target point. We will show that although the alternate attenuator necessarily blocks a certain amount of incoming sunlight, even when fully open, it provides a more even attenuation of the flux for alternate aiming strategies.

  6. The flux database concerted action

    International Nuclear Information System (INIS)

    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)

  7. Flux stabilization in compact groups

    International Nuclear Information System (INIS)

    We consider the Born-Infeld action for symmetry-preserving, orientable D-branes in compact group manifolds. We find classical solutions that obey the flux quantization condition. They correspond to conformally invariant boundary conditions on the world sheet. We compute the spectrum of quadratic fluctuations and find agreement with the predictions of conformal field theory, up to a missing level-dependent truncation. Our results extend to D-branes with the geometry of twined conjugacy classes; they illustrate the mechanism of flux stabilization of D-branes. (author)

  8. Flux stabilization in compact groups

    CERN Document Server

    Bordalo, P; Schweigert, C; Bordalo, Pedro; Ribault, Sylvain; Schweigert, Christoph

    2001-01-01

    We consider the Born-Infeld action for symmetry-preserving, orientable D-branes in compact group manifolds. We find classical solutions that obey the flux quantization condition. They correspond to conformally invariant boundary conditions on the world sheet. We compute the spectrum of quadratic fluctuations and find agreement with the predictions of conformal field theory, up to a missing level-dependent truncation. Our results extend to D-branes with the geometry of twined conjugacy classes; they illustrate the mechanism of flux stabilization of D-branes.

  9. Oxaloacetate enhances neuronal cell bioenergetic fluxes and infrastructure.

    Science.gov (United States)

    Wilkins, Heather M; Koppel, Scott; Carl, Steven M; Ramanujan, Suruchi; Weidling, Ian; Michaelis, Mary L; Michaelis, Elias K; Swerdlow, Russell H

    2016-04-01

    We tested how the addition of oxaloacetate (OAA) to SH-SY5Y cells affected bioenergetic fluxes and infrastructure, and compared the effects of OAA to malate, pyruvate, and glucose deprivation. OAA displayed pro-glycolysis and pro-respiration effects. OAA pro-glycolysis effects were not a consequence of decarboxylation to pyruvate because unlike OAA, pyruvate lowered the glycolysis flux. Malate did not alter glycolysis flux and reduced mitochondrial respiration. Glucose deprivation essentially eliminated glycolysis and increased mitochondrial respiration. OAA increased, while malate decreased, the cell NAD+/NADH ratio. Cytosolic malate dehydrogenase 1 protein increased with OAA treatment, but not with malate or glucose deprivation. Glucose deprivation increased protein levels of ATP citrate lyase, an enzyme which produces cytosolic OAA, whereas OAA altered neither ATP citrate lyase mRNA nor protein levels. OAA, but not glucose deprivation, increased cytochrome oxidase subunit 2, PGC1α, PGC1β, and PGC1 related co-activator protein levels. OAA increased total and phosphorylated SIRT1 protein. We conclude that adding OAA to SH-SY5Y cells can support or enhance both glycolysis and respiration fluxes. These effects appear to depend, at least partly, on OAA causing a shift in the cell redox balance to a more oxidized state, that it is not a glycolysis pathway intermediate, and possibly its ability to act in an anaplerotic fashion. We examined how oxaloacetate (OAA) affects bioenergetic fluxes. To advance the understanding of how OAA mediates these changes, we compared the effects of OAA to malate, pyruvate, and glucose deprivation. We further examined how OAA affects levels of enzymes that facilitate its cytosolic metabolism, and found OAA increased the expression of malate dehydrogenase 1 (MDH1-cytosolic). We propose the following: OAA supports both glycolysis and respiration fluxes, shifts the cell redox balance toward a more oxidized state, and acts in an anaplerotic

  10. Initiation of CMEs by Magnetic Flux Emergence

    Indian Academy of Sciences (India)

    Govind Dubey; Bart van der Holst; Stefaan Poedts

    2006-06-01

    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 atmosphere with a background dipole magnetic field. The flux rope is in equilibrium due to an image current below the photosphere. An emerging flux triggering mechanism is used to make this equilibrium system unstable. When the magnetic flux emerges within the filament below the flux rope, this results in a catastrophic behavior similar to previous models. As a result, the flux rope rises and a current sheet forms below it. It is shown that the magnetic reconnection in the current sheet below the flux rope in combination with the outward curvature forces results in a fast ejection of the flux rope as observed for solar CMEs.We have done a parametric study of the emerging flux rate.

  11. FACTORS ON VISCOSITY STABILITY OF MOLD FLUXES

    Institute of Scientific and Technical Information of China (English)

    C.Y.Zhu; C.J.Liu; M.F.Jiang; Z.D.Yang

    2004-01-01

    Viscosity stability indexes of mold flux at high temperature and low temperature have been introduced,and the effects of flux compositions on viscosity stability indexes have been studied.Two mold fluxes have been developed by analyzing the effects of flux viscosity stability on the process and the condition of continuous casting slab of medium carbon steel.The results show that the fluxes are suitable for the process.

  12. Flux-balance modelling of plant metabolism

    OpenAIRE

    Lee James Sweetlove; R. George eRatcliffe

    2011-01-01

    Flux-balance modelling of plant metabolic networks provides an important complement to 13C-based metabolic flux analysis. Flux-balance modelling is a constraints-based approach in which steady-state fluxes in a metabolic network are predicted by using optimisation algorithms within an experimentally bounded solution space. In the last two years several flux-balance models of plant metabolism have been published including genome-scale models of Arabidopsis metabolism. In this review we conside...

  13. Causal mediation analysis with a latent mediator.

    Science.gov (United States)

    Albert, Jeffrey M; Geng, Cuiyu; Nelson, Suchitra

    2016-05-01

    Health researchers are often interested in assessing the direct effect of a treatment or exposure on an outcome variable, as well as its indirect (or mediation) effect through an intermediate variable (or mediator). For an outcome following a nonlinear model, the mediation formula may be used to estimate causally interpretable mediation effects. This method, like others, assumes that the mediator is observed. However, as is common in structural equations modeling, we may wish to consider a latent (unobserved) mediator. We follow a potential outcomes framework and assume a generalized structural equations model (GSEM). We provide maximum-likelihood estimation of GSEM parameters using an approximate Monte Carlo EM algorithm, coupled with a mediation formula approach to estimate natural direct and indirect effects. The method relies on an untestable sequential ignorability assumption; we assess robustness to this assumption by adapting a recently proposed method for sensitivity analysis. Simulation studies show good properties of the proposed estimators in plausible scenarios. Our method is applied to a study of the effect of mother education on occurrence of adolescent dental caries, in which we examine possible mediation through latent oral health behavior. PMID:26363769

  14. Flux

    DEFF Research Database (Denmark)

    Ravn, Ib

    Med udgangspunkt i kompleksistetsforskning og studiet af selvorganiserende systemer beskriver lb Ravn den fysiske og biologiske evolution og menneskets udvikling. Han fortolker begreber som kultur, sprog, frihed, værdier, mening, smerte og det ondes problem i lyset af en procesbaseret ontologi...

  15. Shared mediated workspaces

    OpenAIRE

    Greef, Tjerk de; Gullström, Charlie; Handberg, Leif; Nefs, H.T.; Parnes, Peter

    2012-01-01

    Shared mediated spaces provide viable alternatives for meetings and interactions. The development of collaborative mediated workspaces and shared negotiation spaces will have a fundamental impact on all human practices. Previous design-led research, has identified spatial design concepts, such as mediated gaze, and spatial montage, which, if unaddressed, may be said to impose friction, and thus impact negatively on the experience of mediated presence. The current paper discusses a set of conc...

  16. Mediation and Conflict Management

    OpenAIRE

    Gerald Eisenkopf

    2009-01-01

    Mediation is a popular process to manage conflicts, but there is little systematic insight into its mechanisms. This paper discusses the results from an experiment in which a mediator can induce two conflict parties to behave cooperatively. If the mediator recommends cooperative behavior and threatens to punish deviations, she achieves the efficient solution. Similar results even obtain if the mediator is biased towards one party or has no incentive to prevent the conflict. Communication betw...

  17. Confidentiality of mediation communications

    OpenAIRE

    Koo, AKC

    2011-01-01

    Discusses the common law protection afforded to mediation negotiations by the without prejudice rule, legal professional privilege and the mediation agreement signed by all parties prior to the commencement of the mediation process. Examines the inclusion of admissions within the without prejudice rule, and the exceptions to the rule. Notes two pieces of legislation offering protection, namely the US Uniform Mediation Act 2001 and Directive 2008/52. Argues that the limited protection in the U...

  18. 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...

  19. Mediation as Signal

    OpenAIRE

    Holler, M.J.; Lindner, I.

    2004-01-01

    This paper analyzes mediation as a signal. Starting from a stylized case, a game theoretical model of one-sided incomplete information, taken from Cho and Kreps (1987), is applied to discuss strategic effects of mediation. It turns out that to reject mediation can be interpreted as a ”negative signal” while the interpretation of accepting or proposing mediation is ambiguous and does not necessarily change the prior beliefs of the uninformed party. This asymmetry suggests that, in equilibrium,...

  20. Mediators as Walrasian Auctioneers

    OpenAIRE

    Dickenson, David L.

    2004-01-01

    This article opens up mediation to systematic economic analysis by considering mediators as analogous.to the Walrasian auctioneers of exchange theory. By altering trade-off rates among bargaining issues, mediators facilitate a process leading towards Pareto efficient voluntary settlements.

  1. Hybrid Gauge Mediation

    OpenAIRE

    McGarrie, Moritz

    2011-01-01

    Inspired by four dimensional (de)constructions, we use the framework of "General gauge mediation in five dimensions" to interpolate between gaugino and ordinary gauge mediation. In particular we emphasise that an intermediate hybrid regime of mediation may be obtained in these higher dimensional models as has been obtained in the quiver gauge models.

  2. Bayesian Mediation Analysis

    Science.gov (United States)

    Yuan, Ying; MacKinnon, David P.

    2009-01-01

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

  3. 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.

  4. Inhibition of stress mediated cell death by human lactate dehydrogenase B in yeast.

    Science.gov (United States)

    Sheibani, Sara; Jones, Natalie K; Eid, Rawan; Gharib, Nada; Arab, Nagla T T; Titorenko, Vladimir; Vali, Hojatollah; Young, Paul A; Greenwood, Michael T

    2015-08-01

    We report the identification of human L- lactate dehydrogenase B (LDHB) as a novel Bax suppressor. Yeast heterologously expressing LDHB is also resistant to the lethal effects of copper indicating that it is a general suppressor of stress mediated cell death. To identify potential LDHB targets, LDHB was expressed in yeast mutants defective in apoptosis, necrosis and autophagy. The absence of functional PCD regulators including MCA1, YBH3, cyclophilin (CPR3) and VMA3, as well as the absence of the pro-survival autophagic pathway (ATG1,7) did not interfere with the LDHB mediated protection against copper indicating that LDHB functions independently of known PCD regulators or by simply blocking or stimulating a common PCD promoting or inhibitory pathway. Measurements of lactate levels revealed that short-term copper stress (1.6 mM, 4 h), does not increase intracellular levels of lactate, instead a three-fold increase in extracellular lactate was observed. Thus, yeast cells resemble mammalian cells where different stresses are known to lead to increased lactate production leading to lactic acidosis. In agreement with this, we found that the addition of exogenous lactic acid to growth media was sufficient to induce cell death that could be inhibited by the expression of LDHB. Taken together our results suggest that lactate dehydrogenase is a general suppressor of PCD in yeast. PMID:26032856

  5. Autophagy and cellular senescence mediated by Sox2 suppress malignancy of cancer cells.

    Directory of Open Access Journals (Sweden)

    Yong-Yeon Cho

    Full Text Available Autophagy is a critical cellular process required for maintaining cellular homeostasis in health and disease states, but the molecular mechanisms and impact of autophagy on cancer is not fully understood. Here, we found that Sox2, a key transcription factor in the regulation of the "stemness" of embryonic stem cells and induced-pluripotent stem cells, strongly induced autophagic phenomena, including intracellular vacuole formation and lysosomal activation in colon cancer cells. The activation occurred through Sox2-mediated ATG10 gene expression and resulted in the inhibition of cell proliferation and anchorage-independent colony growth ex vivo and tumor growth in vivo. Further, we found that Sox2-induced-autophagy enhanced cellular senescence by up-regulating tumor suppressors or senescence factors, including p16(INK4a, p21 and phosphorylated p53 (Ser15. Notably, knockdown of ATG10 in Sox2-expressing colon cancer cells restored cancer cell properties. Taken together, our results demonstrated that regulation of autophagy mediated by Sox2 is a mechanism-driven novel strategy to treat human colon cancers.

  6. CCD flux measurement system Prohermes

    Energy Technology Data Exchange (ETDEWEB)

    Kroger-Vodde, A. [University of Almeria, Plataforma Solar de Almeria (Spain); Hollander, A. [German Aerospace Center, Plataforma de Almeria, Head of Engineering (Spain)

    1999-03-01

    At the Plataforma Solar de Almeria (PSA) a new, PC based, 14 bit CCD video flux measurement system, called PROHERMES, has been introduced to improve the precision of data acquisition and includes with Optimas a flexible, more user friendly, easy adaptable software environment. The hardware and software is described. Macros have been created to meet the special requirements of the tasks at the PSA. As an example for a macro, the program flow structure is given for the acquisition of the moving-bar sequence to measure the performance of receivers like in the REFOS project. The results are exported to Excel. The comparison with the former measurement system HERMES II concludes the new system as an important progress. Future efforts will focus on the further automation of flux measurements and heliostat controls. (authors)

  7. Constrained Allocation Flux Balance Analysis

    CERN Document Server

    Mori, Matteo; Martin, Olivier C; De Martino, Andrea; Marinari, Enzo

    2016-01-01

    New experimental results on bacterial growth inspire a novel top-down approach to study cell metabolism, combining mass balance and proteomic constraints to extend and complement Flux Balance Analysis. We introduce here Constrained Allocation Flux Balance Analysis, CAFBA, in which the biosynthetic costs associated to growth are accounted for in an effective way through a single additional genome-wide constraint. Its roots lie in the experimentally observed pattern of proteome allocation for metabolic functions, allowing to bridge regulation and metabolism in a transparent way under the principle of growth-rate maximization. We provide a simple method to solve CAFBA efficiently and propose an "ensemble averaging" procedure to account for unknown protein costs. Applying this approach to modeling E. coli metabolism, we find that, as the growth rate increases, CAFBA solutions cross over from respiratory, growth-yield maximizing states (preferred at slow growth) to fermentative states with carbon overflow (preferr...

  8. Comments on Heterotic Flux Compactifications

    CERN Document Server

    Kimura, T; Kimura, Tetsuji; Yi, Piljin

    2006-01-01

    In heterotic flux compactification with supersymmetry, three different connections with torsion appear naturally, all in the form $\\omega+a H$. Supersymmetry condition carries $a=-1$, the Dirac operator has $a=-1/3$, and higher order term in the effective action involves $a=1$. With a view toward the gauge sector, we explore the geometry with such torsions. After reviewing the supersymmetry constraints and finding a relation between the scalar curvature and the flux, we derive the squared form of the zero mode equations for gauge fermions. With $\\d H=0$, the operator has a positive potential term, and the mass of the unbroken gauge sector appears formally positive definite. However, this apparent contradiction is avoided by a no-go theorem that the compactification with $H\

  9. Phenomenological Implications of Deflected Mirage Mediation: Comparison with Mirage Mediation

    OpenAIRE

    Altunkaynak, Baris; Everett, Lisa L.; Kim, Ian-Woo; Nelson, Brent D.; Rao, Yongyan

    2010-01-01

    We compare the collider phenomenology of mirage mediation and deflected mirage mediation, which are two recently proposed "mixed" supersymmetry breaking scenarios motivated from string compactifications. The scenarios differ in that deflected mirage mediation includes contributions from gauge mediation in addition to the contributions from gravity mediation and anomaly mediation also present in mirage mediation. The threshold effects from gauge mediation can drastically alter the low energy s...

  10. SQUID With Integral Flux Concentrator

    Science.gov (United States)

    Peters, Palmer N.; Sisk, Robert C.

    1989-01-01

    In improved superconducting quantum interference device (SQUID), change in size and shape of superconducting ring improves coupling to external signal coil and eases coil-positioning tolerances. More rugged and easier to manufacture than conventional SQUID's with comparable electrical characteristics. Thin-film superconducting flux concentrator utilizes Meissner effect to deflect magnetic field of signal coil into central hole of SQUID. Used in magnetometers, ammeters, analog-to-digital converters, and related electronic applications in which high signal-to-noise ratios required.

  11. Flux tubes at Finite Temperature

    CERN Document Server

    Bicudo, Pedro; Cardoso, Marco

    2016-01-01

    We show the flux tubes produced by static quark-antiquark, quark-quark and quark-gluon charges at finite temperature. The sources are placed in the lattice with fundamental and adjoint Polyakov loops. We compute the square densities of the chromomagnetic and chromoelectric fields above and below the phase transition. Our results are gauge invariant and produced in pure gauge SU(3). The codes are written in CUDA and the computations are performed with GPUs.

  12. Flux footprints in different ecosystems

    Czech Academy of Sciences Publication Activity Database

    Macálková, Lenka; Havránková, Kateřina; Pavelka, Marian

    Brno : Global Change Research Centre, The Czech Academy of Sciences, v. v. i., 2015 - ( Urban , O.; Šprtová, M.; Klem, K.), s. 54-57 ISBN 978-80-87902-10-3. [Global Change: A Complex Challenge /4th/. Brno (CZ), 23.03.2015-24.03.2015] R&D Projects: GA MŠk(CZ) LO1415; GA MŠk(CZ) LM2010007 Institutional support: RVO:67179843 Keywords : eddy covariance * flux footprints * ecosystems Subject RIV: EH - Ecology, Behaviour

  13. Sparsity of the Hawking flux

    CERN Document Server

    Visser, Matt; Schuster, Sebastian; Van-Brunt, Alexander

    2015-01-01

    It is (or should be) well-known that the Hawking flux that reaches spatial infinity is extremely sparse, and extremely thin, with the Hawking quanta, one-by-one, slowly dribbling out of the black hole. The typical time between quanta reaching infinity is much larger than the timescale set by the energy of the quanta. Among other things, this means that the Hawking evaporation of a black hole should be viewed as a sequential cascade of 2-body decays.

  14. 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.

  15. Center vortices as composites of monopole fluxes

    CERN Document Server

    Deldar, Sedigheh

    2015-01-01

    We study the relation between the flux of a center vortex obtained from the center vortex model and the flux formed between monopoles obtained from the Abelian gauge fixing method. Motivated by the Monte Carlo simulations which have shown that almost all monopoles are sitting on the top of vortices, we construct the fluxes of center vortices for $SU(2)$ and $SU(3)$ gauge groups using fractional fluxes of monopoles. Then, we compute the potentials in the fundamental representation induced by center vortices and fractional fluxes of monopoles. We show that by combining the fractional fluxes of monopoles one can produce the center vortex fluxes for $SU(3)$ gauge group in a "center vortex model". Comparing the potentials, we conclude that the fractional fluxes of monopoles attract each other.

  16. JNK-dependent Atg4 upregulation mediates asperphenamate derivative BBP-induced autophagy in MCF-7 cells

    International Nuclear Information System (INIS)

    N-Benzoyl-O-(N′-(1-benzyloxycarbonyl-4-piperidiylcarbonyl) -D-phenylalanyl)-D-phenylalaninol (BBP), a novel synthesized asperphenamate derivative with the increased solubility, showed growth inhibitory effect on human breast carcinoma MCF-7 cells in a time- and concentration-dependent manner. The growth inhibitory effect of BBP was associated with induction of autophagy, which was demonstrated by the development of acidic vesicular organelles, cleavage of LC3 and upregulation of Atg4 in BBP-treated MCF-7 cells. Since the application of Atg4 siRNA totally blocked the cleavage of LC3, we demonstrated a central role of Atg4 in BBP-induced autophagy. The further studies showed that BBP increased the levels of reactive oxygen species (ROS), and pretreatment with NAC effectively blocked the accumulation of ROS, autophagy and growth inhibition triggered by BBP. Moreover, BBP induced the activation of JNK, and JNK inhibitor SP600125 reversed autophagy, the increase of Atg4 levels, conversion of LC3 and growth inhibition induced by BBP. Knockdown of JNK by siRNA efficiently inhibited ROS production and autophagy, but antioxidant NAC failed to block JNK activation induced by BBP, indicating that JNK activation may be a upstream signaling of ROS and should be a core component in BBP-induced autophagic signaling pathway. These results suggest that BBP produces its growth inhibitory effect through induction of the autophagic cell death in MCF-7 cells, which is modulated by a JNK-dependent Atg4 upregulation involving ROS production. -- Highlights: ► Asperphenamate derivative BBP with increased solubility was synthesized. ► BBP selectively inhibited the growth of human breast tumor cells. ► The growth inhibitory effect of BBP was associated with induction of autophagy. ► JNK-dependent Atg4 upregulation mediated BBP-induced autophagy.

  17. 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.

  18. Reluctance motor employing superconducting magnetic flux switches

    International Nuclear Information System (INIS)

    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

  19. Apparatus for measuring a flux of neutrons

    Science.gov (United States)

    Stringer, James L.

    1977-01-01

    A flux of neutrons is measured by disposing a detector in the flux and applying electronic correlation techniques to discriminate between the electrical signals generated by the neutron detector and the unwanted interfering electrical signals generated by the incidence of a neutron flux upon the cables connecting the detector to the electronic measuring equipment at a remote location.

  20. Flux-limited diffusion with relativistic corrections

    International Nuclear Information System (INIS)

    A recently reported flux-limited diffusion theory is extended to include relativistic terms, correct to first order in the fluid velocity. We show that this diffusion theory is fully flux limited, and yields the correct result for the radiative flux in the classical diffusion limit, namely a Fick's law component plus a v/c convective term

  1. Advanced high temperature heat flux sensors

    Science.gov (United States)

    Atkinson, W.; Hobart, H. F.; Strange, R. R.

    1983-01-01

    To fully characterize advanced high temperature heat flux sensors, calibration and testing is required at full engine temperature. This required the development of unique high temperature heat flux test facilities. These facilities were developed, are in place, and are being used for advanced heat flux sensor development.

  2. Decision making by Berry's flux

    OpenAIRE

    Sung, Benjamin O.; Lawler, Michael J

    2015-01-01

    Order by disorder is a decision making process for frustrated systems but often leads to simple answers. We study order by disorder in the kagome Kondo model known for its complexity seeking rich decision making capabilities. At half filling and large Kondo coupling to hopping ratio $J_K/t$, the full manifold of 120$^o$ kagome ground states are degenerate at second order in $t/J_K$. We show this degeneracy lifts at sixth order when a fermion can hop around a hexagon and feel the Berry flux in...

  3. Complementary neutron flux monitoring system

    International Nuclear Information System (INIS)

    The present work is an example for that, how with modern technical instruments it is possible to compensate disadvantage and to increase technical resources of the old systems, without a change of given system totally with new one. The system detail design and implementation was possible mostly, due to the international conferences and courses organized by IAEA and technical information provided by the agency. The system acts as a complementary to the existing systems for the reactor core neutron flux monitoring AKNP. The new system extends the measurement range of the original AKNP system approximately by two decades. It allows neutron flux to be monitored during refuelling. The system is permitted for use by Bulgarian Nuclear Safety Authority - CUAEPP. The system also calculates the reactivity and thus allows the operator to monitor the criticality condition very precisely. The system calculates also the period of the reactor and has adjustable setpoints at two levels for alarm and pre-alarm, both for counting rate and period. The system sends the analog signals for the counting rate and for the period as well as digital signals for the alarm and pre-alarm to the refueling machine cabin for on-line control. It also produces sound and blinks (LEDs) if any setpoint is reached. It should be mentioned that the refueling machine panel do not need additional power supply and thus high reliability is achieved. The system automatically stores the data for neutron flux, period, reactivity, alarm and prealarm state and value, reactor kinetic parameters(β,λ and source) on hard disk. The stored data can be reviewed very easy and printed. Depending on the hard disk capacity the storage period can be longer than a year. The old system for neutron flux monitoring during refuelling, which operated with 3 removable neutron fission chambers KNT-54 located next to the reactor core is now obsolete and is decommissioned. This have the significant impact on personnel dose

  4. Methane Fluxes from Subtropical Wetlands

    Science.gov (United States)

    DeLucia, N.; Gomez-Casanovas, N.; Bernacchi, C.

    2013-12-01

    It is well documented that green house gas concentrations have risen at unequivocal rates since the industrial revolution but the disparity between anthropogenic sources and natural sources is uncertain. Wetlands are one example of a natural ecosystem that can be a substantial source or sink for methane (CH4) depending on climate conditions. Due to strict anaerobic conditions required for CH4-generating microorganisms, natural wetlands are one of the main sources for biogenic CH4. Although wetlands occupy less than 5% of total land surface area, they contribute approximately 20% of total CH4 emissions to the atmosphere. The processes regulating CH4 emissions are sensitive to land use and management practices of areas surrounding wetlands. Variation in adjacent vegetation or grazing intensity by livestock can, for example, alter CH4 fluxes from wetland soils by altering nutrient balance, carbon inputs and hydrology. Therefore, understanding how these changes will affect wetland source strength is essential to understand the impact of wetland management practices on the global climate system. In this study we quantify wetland methane fluxes from subtropical wetlands on a working cattle ranch in central Florida near Okeechobee Lake (27o10'52.04'N, 81o21'8.56'W). To determine differences in CH4 fluxes associated with land use and management, a replicated (n = 4) full factorial experiment was designed for wetlands where the surrounding vegetation was (1) grazed or un-grazed and (2) composed of native vegetation or improved pasture. Net exchange of CH4 and CO2 between the land surface and the atmosphere were sampled with a LICOR Li-7700 open path CH4 analyzer and Li-7500A open path CO2/H20 analyzer mounted in a 1-m3 static gas-exchange chamber. Our results showed and verified that CH4 emissions from subtropical wetlands were larger when high soil moisture was coupled with high temperatures. The presence of cattle only amplified these results. These results help quantify

  5. Evaluation of flux synthesis algorithms

    International Nuclear Information System (INIS)

    The flux synthesis algorithm which is the best fit to the numerical solution of the multigroup diffusion equations, was determined. Three different types of synthesis were studied: 1) discontinuous synthesis 2) continuous synthesis 3) pseudo-continuous synthesis. A matrix and a differential formulation were developed for the first two types of synthesis. For pseudo-continuous synthesis only the matrix formulation was used. Some tests were performed and the results allowed us to establish the following order of efficiency for the algorithms: 1) continuous synthesis (matrix formulation) 2) continuous synthesis (differential formulation) 3) pseudo-continuous synthesis 4) discontinuous synthesis (matrix formulation) 5) discontinuous synthesis (differential formulation). (Author)

  6. Geometrical correction factors for heat flux meters

    Science.gov (United States)

    Baumeister, K. J.; Papell, S. S.

    1974-01-01

    General formulas are derived for determining gage averaging errors of strip-type heat flux meters used in the measurement of one-dimensional heat flux distributions. The local averaging error e(x) is defined as the difference between the measured value of the heat flux and the local value which occurs at the center of the gage. In terms of e(x), a correction procedure is presented which allows a better estimate for the true value of the local heat flux. For many practical problems, it is possible to use relatively large gages to obtain acceptable heat flux measurements.

  7. Calculated Electron Fluxes at Airplane Altitudes

    CERN Document Server

    Schaefer, R K; Stanev, T

    1993-01-01

    A precision measurement of atmospheric electron fluxes has been performed on a Japanese commercial airliner (Enomoto, {\\it et al.}, 1991). We have performed a monte carlo calculation of the cosmic ray secondary electron fluxes expected in this experiment. The monte carlo uses the hadronic portion of our neutrino flux cascade program combined with the electromagnetic cascade portion of the CERN library program GEANT. Our results give good agreement with the data, provided we boost the overall normalization of the primary cosmic ray flux by 12\\% over the normalization used in the neutrino flux calculation.

  8. Magnetic reconnection in plasma under inertial confinement fusion conditions driven by heat flux effects in Ohm's law

    OpenAIRE

    Joglekar, A. S.; Thomas, A. G. R.; Fox, W; Bhattacharjee, A.

    2015-01-01

    In the interaction of high-power laser beams with solid density plasma there are a number of mechanisms that generate strong magnetic fields. Such fields subsequently inhibit or redirect electron flows, but can themselves be advected by heat fluxes, resulting in complex interplay between thermal transport and magnetic fields.We show that for heating by multiple laser spots reconnection of magnetic field lines can occur, mediated by these heat fluxes, using a fully implicit 2D Vlasov-Fokker-Pl...

  9. Technology-Use Mediation

    DEFF Research Database (Denmark)

    Bansler, Jørgen P.; Havn, Erling C.

    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)....

  10. The Schizosaccharomyces pombe Mediator

    DEFF Research Database (Denmark)

    Venturi, Michela

    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, 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...

  11. 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...... 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)....... 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...

  12. Quantifying wind and pressure effects on trace gas fluxes across the soil-atmosphere interface

    Science.gov (United States)

    Redeker, K. R.; Baird, A. J.; Teh, Y. A.

    2015-12-01

    Large uncertainties persist in estimates of soil-atmosphere exchange of important trace gases. One significant source of uncertainty is the combined effect of wind and pressure on these fluxes. Wind and pressure effects are mediated by surface topography: few surfaces are uniform and over scales of tenths of a metre to tens of metres, air pressure and wind speed at the ground surface may be very variable. In this paper we consider how such spatial variability in air pressure and wind speed affects fluxes of trace gases. We used a novel nested wind tunnel design comprising a toroidial wind tunnel, in which wind speed and pressure may be controlled, set within a larger, linear wind tunnel. The effects of both wind speed and pressure differentials on fluxes of CO2 and CH4 within three different ecosystems (forest, grassland, peat bog) were quantified. We find that trace gas fluxes are positively correlated with both wind speed and pressure differential near the surface boundary. We argue that wind speed is the better proxy for trace gas fluxes because of its stronger correlation and because wind speed is more easily measured and wind speed measurement methodology more easily standardized. Trace gas fluxes, whether into or out of the soil, increase with wind speed within the toroidal tunnel (+55 % flux per m s-1), while faster, localized surface winds that are external to the toroidal wind tunnel reduce trace gas fluxes (-13 % flux per m s-1). These results are consistent for both trace gases over all ecosystem soil types studied. Our findings support the need for a revised conceptualization of soil-atmosphere gas exchange. We propose a conceptual model of the soil profile that has a "mixed layer", with fluxes controlled by wind speed, wind duration, porosity, water table, and gas production and consumption.

  13. Prospects for Mirage Mediation

    OpenAIRE

    Pierce, Aaron; Thaler, Jesse

    2006-01-01

    Mirage mediation reduces the fine-tuning in the minimal supersymmetric standard model by dynamically arranging a cancellation between anomaly-mediated and modulus-mediated supersymmetry breaking. We explore the conditions under which a mirage "messenger scale" is generated near the weak scale and the little hierarchy problem is solved. We do this by explicitly including the dynamics of the SUSY-breaking sector needed to cancel the cosmological constant. The most plausible scenario for generat...

  14. Immunologically mediated oral diseases

    OpenAIRE

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

  15. Flux focusing eddy current probe

    Science.gov (United States)

    Simpson, John W. (Inventor); Clendenin, C. Gerald (Inventor); Fulton, James P. (Inventor); Wincheski, Russell A. (Inventor); Todhunter, Ronald G. (Inventor); Namkung, Min (Inventor); Nath, Shridhar C. (Inventor)

    1997-01-01

    A flux-focusing electromagnetic sensor which uses a ferromagnetic flux-focusing lens simplifies inspections and increases detectability of fatigue cracks and material loss in high conductivity material. The unique feature of the device is the ferrous shield isolating a high-turn pick-up coil from an excitation coil. The use of the magnetic shield is shown to produce a null voltage output across the receiving coil in the presence of an unflawed sample. A redistribution of the current flow in the sample caused by the presence of flaws, however, eliminates the shielding condition and a large output voltage is produced, yielding a clear unambiguous flaw signal. The maximum sensor output is obtained when positioned symmetrically above the crack. Hence, by obtaining the position of the maximum sensor output, it is possible to track the fault and locate the area surrounding its tip. The accuracy of tip location is enhanced by two unique features of the sensor; a very high signal-to-noise ratio of the probe's output which results in an extremely smooth signal peak across the fault, and a rapidly decaying sensor output outside a small area surrounding the crack tip which enables the region for searching to be clearly defined. Under low frequency operation, material thinning due to corrosion damage causes an incomplete shielding of the pick-up coil. The low frequency output voltage of the probe is therefore a direct indicator of the thickness of the test sample.

  16. SEP flux mapping with PHOEBUS

    Energy Technology Data Exchange (ETDEWEB)

    Grimani, C [Universita di Urbino and INFN Florence, Urbino (Italy); Bagni, G [Universita di Urbino and INFN Florence, Urbino (Italy); Fabi, M [Universita di Urbino and INFN Florence, Urbino (Italy); Vicere, A [Universita di Urbino and INFN Florence, Urbino (Italy); Marconi, L [Universita di Pisa and INFN Florence, Pisa (Italy); Stanga, R [Universita and INFN, Florence (Italy); Bosi, L [Universita and INFN Perugia, Perugia (Italy); Vocca, H [Universita and INFN Perugia, Perugia (Italy); Araujo, H [Imperial College, London (United Kingdom); Shaul, D [Imperial College, London (United Kingdom); Sumner, T [Imperial College, London (United Kingdom); Wass, P [Imperial College, London (United Kingdom); Boatella, C [IEEC, Barcelona (Spain); Lobo, A [ICE/CSIC and IEEC, Barcelona (Spain); Chmeissani, M [IFAE, Barcelona (Spain); Martinez, I [IFAE, Barcelona (Spain)

    2006-03-02

    We report about PHOEBUS (PHysics Of Events BUrsted by the Sun): a proposal for solar physics and space weather investigation with LISA (Laser Interferometer Space Antenna). Galactic and solar cosmic-ray particles with energies larger than 100 MeV(/n) penetrate and charge the LISA test masses. Spurious forces occur between the test masses and the surrounding electrodes mimicking gravitational wave signals. This process constitutes one of the major sources of acceleration noise for LISA. Silicon particle detectors will be placed on board the LISA-PF and LISA missions to monitor the overall energetic incident cosmic-ray fluxes. These telescopes can be also used to carry out a map of shock accelerated Solar Energetic Particle (SEPs) fluxes associated with evolving Coronal Mass Ejections (CMEs) at different steps in longitude. We discuss the role of protons, helium nuclei, galactic heavy nuclei and solar ions. We aim to contribute to the COST724 (European CO-operation in the field of Scientific and Technical Research) action inside WG1/WP13000 developing appropriate simulations of the dynamics of CMEs by using space-based data and theoretical models.

  17. Constrained Allocation Flux Balance Analysis

    Science.gov (United States)

    Mori, Matteo; Hwa, Terence; Martin, Olivier C.

    2016-01-01

    New experimental results on bacterial growth inspire a novel top-down approach to study cell metabolism, combining mass balance and proteomic constraints to extend and complement Flux Balance Analysis. We introduce here Constrained Allocation Flux Balance Analysis, CAFBA, in which the biosynthetic costs associated to growth are accounted for in an effective way through a single additional genome-wide constraint. Its roots lie in the experimentally observed pattern of proteome allocation for metabolic functions, allowing to bridge regulation and metabolism in a transparent way under the principle of growth-rate maximization. We provide a simple method to solve CAFBA efficiently and propose an “ensemble averaging” procedure to account for unknown protein costs. Applying this approach to modeling E. coli metabolism, we find that, as the growth rate increases, CAFBA solutions cross over from respiratory, growth-yield maximizing states (preferred at slow growth) to fermentative states with carbon overflow (preferred at fast growth). In addition, CAFBA allows for quantitatively accurate predictions on the rate of acetate excretion and growth yield based on only 3 parameters determined by empirical growth laws. PMID:27355325

  18. Atmospheric discharges and particle fluxes

    Science.gov (United States)

    Chilingarian, A.; Chilingaryan, S.; Reymers, A.

    2015-07-01

    Fluxes of the electrons, gamma rays, and neutrons observed by particle detectors located on the Earth's surface during thunderstorms originate so-called Thunderstorm Ground Enhancements (TGEs). The relativistic runaway electron avalanches giving rise to TGEs originate in the thundercloud's lower dipole between the main negatively charged region in the middle of the thundercloud and transient lower positively charged region. Acceleration of electrons in the upper dipole between main negative and main positive charge regions leads to initiation of the terrestrial gamma flashes (TGFs) intensive researched during the last two decades by orbiting gamma ray observatories. TGFs are exceptionally intense, submillisecond bursts of electromagnetic radiation directed to the open space from the thunderstorm atmosphere. Unlike visible lightning, TGF beams do not create a hot plasma channel and optical flash; hence, in the literature they got name "dark lightning." We investigate the TGEs development in 1 min and 1 s time series of particle detector count rates. Synchronized time series of the near-surface electric field and lightning occurrences allows interconnecting two atmospheric phenomena. Registration of the Extensive Air Showers allows approaching problems of relation of the lightning occurrences and particle fluxes.

  19. Flux of Millimetric Space Debris

    Science.gov (United States)

    Goldstein, R. M.; Goldstein, S. J., Jr.

    1995-01-01

    In 21.4 hr of zenith radar observations on 4 days at 8510 MHz, we found 831 particles with altitudes between 177 and 1662 km. From the duration of the echoes and the angular size (0.030 deg) of the antenna beam 157 particles were identified as passing through the side lobes and not through the main beam. Our analysis is based on the 674 particles that did not broaden the beam. On the assumptions that these particles went through the main beam, their radar cross sections vary between 0.02 and 260 sq mm , and their radial velocities vary between +/- 700 m/s. If they are conducting spheres, their diameters lie between 2 and 18 mm. If not, they must be larger. The flux of these particles, that is the number per sq km day, was determined in 100 km intervals. The maximum flux, 3.3 particles per sq km day, occurs at 950 km altitude. The small and large particles are not well mixed. The largest particles occur beyond 1000 km and middle-sized particles are missing below 300 km. If the earth's atmosphere caused the smallest particles to lose energy from initial orbits identical to those of the large particles, the orbits would have lower eccentricity at low altitudes. We find a larger eccentricity for the inner particles, and conclude that two or more populations are present.

  20. Mediation in Romanian Legislation

    Directory of Open Access Journals (Sweden)

    Gianina Anemona Radu

    2012-05-01

    Full Text Available The complexity of the current social relations generates the necessity of developing and applyingnew methods of settling conflicts. Mediation can serve as an effective tool in resolving various conflictsincluding the criminal matters. This article gives a panoramic view on the application of the concept ofmediation and highlights the main features of mediation in criminal cases as they are reported to the nationallegislation and the legislation of Romania. Therefore the advantages of mediation and the opportunity toapply the latter in order to slave the conflicts caused by the commission of criminal offences are still beingdiscussed. The Romanian legislation and the Community rules establish the scope of expressly exemptedareas, the sides of freedom being the main principle, the mandatory dispositions being the exception. Fromthe contents of the Law 192/2006 result that mediation is exercisable in all areas with the condition that therights which make the subject of mediation could be used by the sides of the mediation. The mediation theoryanalyses the extrajudicial mediation and judicial mediation settlement.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-08-15

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

  2. Glucose transport carrier of human erythrocytes. Radiation target size measurement based on flux inactivation

    International Nuclear Information System (INIS)

    Intact human erythrocytes frozen in the presence of cryoprotective reagents and irradiated with an electron beam retained their diffusion barrier to L-glucose. The carrier-mediated flux of D-glucose, on the other hand, was inactivated as a simple exponential function of the radiation dose. Classical target size analysis of this data yielded a molecular size of 185,000 daltons for the carrier. This represents the first measurement of the functional size of a transport protein based directly on flux inactivation

  3. 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…

  4. Mediation and Domestic Violence

    Directory of Open Access Journals (Sweden)

    Jacques Faget

    2005-07-01

    Full Text Available This paper analyzes the potential and limits of recourse to mediation for regulating domestic violence. On the basis of an empirical study of its implementation in France and of the existing academic literature, it shows the existence of two types of practices reflecting two conceptions of mediation and more generally, two conceptions of the articulation between social and penal regulation

  5. Mediation and Domestic Violence

    OpenAIRE

    Jacques Faget

    2005-01-01

    This paper analyzes the potential and limits of recourse to mediation for regulating domestic violence. On the basis of an empirical study of its implementation in France and of the existing academic literature, it shows the existence of two types of practices reflecting two conceptions of mediation and more generally, two conceptions of the articulation between social and penal regulation

  6. Annihilation of Quantum Magnetic Fluxes

    Science.gov (United States)

    Gonzalez, W. D.

    After introducing the concepts associated with the Aharonov and Bohm effect and with the existence of a quantum of magnetic flux (QMF), we briefly discuss the Ginzburg-Landau theory that explains its origin and fundamental consequences. Also relevant observations of QMFs obtained in the laboratory using superconducting systems (vortices) are mentioned. Next, we describe processes related with the interaction of QMFs with opposite directions in terms of the gauge field geometry related to the vector potential. Then, we discuss the use of a Lagrangian density for a scalar field theory involving radiation in order to describe the annihilation of QMFs, claimed to be responsible for the emission of photons with energies corresponding to that of the annihilated magnetic fields. Finally, a possible application of these concepts to the observed variable dynamics of neutron stars is briefly mentioned.

  7. Insects, infestations and nutrient fluxes

    Science.gov (United States)

    Michalzik, B.

    2012-04-01

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

  8. Flux Variation of Cosmic Muons

    CERN Document Server

    Ramesh, Nepal; Martin, Clayton; Bachri, Abdel

    2012-01-01

    In the current paper, we analyzed the variation of cosmic radiation flux with elevation, time of the year and ambient temperature with the help of a portable cosmic muon detector, the construction of which was completed by a team from Southern Arkansas University (SAU) at Lawrence Berkeley National Laboratory (LBNL). Cosmic muons and gamma rays traverse two synchronized scintillators connected to two photomultiplier tubes (PMT) via light guides, and generate electronic pulses which we counted using a Data Acquisition Board (DAQ). Because muons are the product of collisions between high-energy cosmic rays and atmospheric nuclei, and therefore shower onto earth, the scintillators were arranged horizontally for detection. The elevation measurements were recorded at different locations, starting from 60 feet below sea-level at the Underground Radiation Counting Laboratory at Johnson Space Center, TX, to 4200 feet at Mt. Hamilton, CA. Intermediate locations included sea-level Galveston Bay, TX, and Mt. Magazine, A...

  9. 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.

  10. Measurements of neutron flux in the RA reactor

    International Nuclear Information System (INIS)

    This report includes results of the following measurements performed at the RA reactor: thermal neutron flux in the experimental channels, epithermal and fast neutron flux, neutron flux in the biological shield, neutron flux distribution in the reactor cell

  11. Music, Radio, and Mediatization

    DEFF Research Database (Denmark)

    Krogh, Mads; Michelsen, Morten

    2016-01-01

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

  12. Mimulone-Induced Autophagy through p53-Mediated AMPK/mTOR Pathway Increases Caspase-Mediated Apoptotic Cell Death in A549 Human Lung Cancer Cells

    OpenAIRE

    An, Hyun-Kyu; Kim, Kyoung-Sook; Lee, Ji-Won; Park, Mi-Hyun; Moon, Hyung-In; Park, Shin-Ji; Baik, Ji-Sue; Kim, Cheorl-Ho; Lee, Young-Choon

    2014-01-01

    Anticancer properties and mechanisms of mimulone (MML), C-geranylflavonoid isolated from the Paulownia tomentosa fruits, were firstly elucidated in this study. MML prevented cell proliferation in a dose- and time-dependent way and triggered apoptosis through the extrinsic pathway in A549 human lung adenocarcinoma cells. Furthermore, MML-treated cells displayed autophagic features, such as the formation of autophagic vacuoles, a primary morphological feature of autophagy, and the accumulation ...

  13. Metamaterial anisotropic flux concentrators and magnetic arrays

    DEFF Research Database (Denmark)

    Bjørk, Rasmus; Smith, Anders; Bahl, Christian R.H.

    2013-01-01

    A metamaterial magnetic flux concentrator is investigated in detail in combination with a Halbach cylinder of infinite length. A general analytical solution to the field is determined and the magnetic figure of merit is determined for a Halbach cylinder with a flux concentrator. It is shown that an...... ideal flux concentrator will not change the figure of merit of a given magnet design, while the non-ideal will always lower it. The geometric parameters producing maximum figure of merit, i.e., the most efficient devices, are determined. The force and torque between two concentric Halbach cylinders with...... flux concentrators is determined and the maximum torque is found. Finally, the effect of non-ideal flux concentrators and the practical use of flux concentrators, as well as demagnetization issues, is discussed. © 2013 AIP Publishing LLC....

  14. rf SQUID system as tunable flux qubit

    International Nuclear Information System (INIS)

    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. 大鼠坐骨神经再生过程中许旺氏细胞的自噬作用%The autophagic role of Schwann cell on regeneration of rat sciatic nerves

    Institute of Scientific and Technical Information of China (English)

    王万山; 朴仲贤; 王启伟; Han Ming-Hu; 朴英杰

    2004-01-01

    背景 :Wallerian变性时髓鞘溃变碎片的清除对于神经的再生至关重要 ,但溃变碎片的清除机制一直没有彻底阐明 ,关于参与清除的细胞成分类型仍有很大争议. 目的 :探讨大鼠坐骨神经再生过程中许旺氏细胞的自噬作用. 设计 :完全随机自身对照研究. 地点和对象 :本实验由第一军医大学解剖教研室、汕头大学医学院中心实验室和西南大学达拉斯医学中心精神病学部共同完成 ,研究对象为成年 Wistar大鼠 30只 ,雌雄各半 ,体质量 180- 250 g. 干预 :横切大鼠坐骨神经制作 Wallerian变性模型 ,分别于造模后 0,0.5,1,1.5,2,3,4,5,7,10,15 d取远断端组织行电镜观察. 主要观察指标 :电镜观察轴突和髓鞘的超微结构 ,Gomori染色后检查酸性磷酸酶活性. 结果 :轴突在第 0.5天时从髓鞘脱离,溃变呈空泡状.第 2天开始髓鞘皱褶、断裂形成碎片,许旺氏细胞内见大的膜结合髓鞘碎片和许多散在小碎片,并与溶酶体融合形成自噬泡,呈酸性磷酸酶 (AcPase)阳性.第 4天时内膜区偶见幼稚细胞 ,1周后见大量幼稚细胞.第 7天后许旺氏细胞内自噬泡数量开始减少.实验全程偶见巨噬细胞 ,内有吞噬泡. 结论 :大鼠坐骨神经再生过程中溃变髓鞘主要经许旺氏细胞自噬清除,许旺氏细胞脱分化为许旺氏细胞祖细胞后大量增殖分化参与神经再生过程.%BACKGROUND:The removal of degenerated debris of myelin sheath during wallerian degeneration is very important for nerve regeneration,but the mechanism by which the debris is removed has not been completely clarified and there is still considerable controversies on the types of cells involved in the clearance process.OBJECTIVE:To investigate the autophagic role of Schwann cell on regeneration of rat sciatic nerves.DESIGN: Completely randomized animal experiment conducted in March 2003. SETTING AND PARTICIPANTS:Rats were bought from the Laboratory Animal

  16. Surface Flux Modeling for Air Quality Applications

    OpenAIRE

    Limei Ran; Jonathan Pleim

    2011-01-01

    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...

  17. Surface fluxes over natural landscapes using scintillometry

    OpenAIRE

    Meijninger, W.M.L.

    2003-01-01

    Motivated by the demand for reliable area-averaged fluxes associated with natural landscapes this thesis investigates a relative new measurement technique known as the scintillation method. For homogeneous areas the surface fluxes can be derived with reasonable accuracy. However, fluxes representative for large natural landscapes (comparable to the horizontal grid box size of numerical models or the pixel size of satellite imagers) are more difficult to obtain because at these scales the surf...

  18. Flux-conserving finite element methods

    OpenAIRE

    Zhang, Shangyou; Zhang, Zhimin; Zou, Qingsong

    2012-01-01

    We analyze the flux conservation property of the finite element method. It is shown that the finite element solution does approximate the flux locally in the optimal order, i.e., the same order as that of the nodal interpolation operator. We propose two methods, post-processing the finite element solutions locally. The new solutions, remaining as optimal-order solutions, are flux-conserving elementwise. In one of our methods, the processed solution also satisfies the original finite element e...

  19. Magnetic flux generator for balanced membrane loudspeaker

    DEFF Research Database (Denmark)

    Rehder, Jörg; Rombach, Pirmin; Hansen, Ole

    2002-01-01

    This paper reports the development of a magnetic flux generator with an application in a hearing aid loudspeaker produced in microsystem technology (MST). The technology plans for two different designs for the magnetic flux generator utilizing a softmagnetic substrate or electroplated NiCoFe as c......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...

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

    Science.gov (United States)

    Taneike, Manabu; Nishida, Kazuhiko; Omiya, Shigemiki; Zarrinpashneh, Elham; Misaka, Tomofumi; Kitazume-Taneike, Rika; Austin, Ruth; Takaoka, Minoru; Yamaguchi, Osamu; Gambello, Michael J.; Shah, Ajay M.; Otsu, Kinya

    2016-01-01

    Mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cell growth, proliferation and metabolism. mTORC1 regulates protein synthesis positively and autophagy negatively. Autophagy is a major system to manage bulk degradation and recycling of cytoplasmic components and organelles. Tuberous sclerosis complex (TSC) 1 and 2 form a heterodimeric complex and inactivate Ras homolog enriched in brain, resulting in inhibition of mTORC1. Here, we investigated the effects of hyperactivation of mTORC1 on cardiac function and structure using cardiac-specific TSC2-deficient (TSC2-/-) mice. TSC2-/- mice were born normally at the expected Mendelian ratio. However, the median life span of TSC2-/- mice was approximately 10 months and significantly shorter than that of control mice. TSC2-/- mice showed cardiac dysfunction and cardiomyocyte hypertrophy without considerable fibrosis, cell infiltration or apoptotic cardiomyocyte death. Ultrastructural analysis of TSC2-/- hearts revealed misalignment, aggregation and a decrease in the size and an increase in the number of mitochondria, but the mitochondrial function was maintained. Autophagic flux was inhibited, while the phosphorylation level of S6 or eukaryotic initiation factor 4E -binding protein 1, downstream of mTORC1, was increased. The upregulation of autophagic flux by trehalose treatment attenuated the cardiac phenotypes such as cardiac dysfunction and structural abnormalities of mitochondria in TSC2-/- hearts. The results suggest that autophagy via the TSC2-mTORC1 signaling pathway plays an important role in maintenance of cardiac function and mitochondrial quantity and size in the heart and could be a therapeutic target to maintain mitochondrial homeostasis in failing hearts. PMID:27023784

  1. Axionic Mirage Mediation

    International Nuclear Information System (INIS)

    In this talk, we propose a model of mirage mediation, in which Peccei-Quinn symmetry is incorporated. In this axionic mirage mediation, it is shown that the Peccei-Quinn symmetry breaking scale is dynamically determined around 1010 GeV to 1012 GeV due to the supersymmetry breaking effects. The problems in the original mirage mediation such as the μ-problem and the moduli problem can be solved simultaneouly. Furthermore, in our model the axino, which is the superpartner of the axion, is the lightest sparticle.

  2. Axionic Mirage Mediation

    CERN Document Server

    Nakamura, Shuntaro; Yamaguchi, Masahiro

    2008-01-01

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

  3. Prospects for mirage mediation

    International Nuclear Information System (INIS)

    Mirage mediation reduces the fine-tuning in the minimal supersymmetric standard model by dynamically arranging a cancellation between anomaly-mediated and modulus-mediated supersymmetry breaking. We explore the conditions under which a mirage 'messenger scale' is generated near the weak scale and the little hierarchy problem is solved. We do this by explicitly including the dynamics of the SUSY-breaking sector needed to cancel the cosmological constant. The most plausible scenario for generating a low mirage scale does not readily admit an extra-dimensional interpretation. We also review the possibilities for solving the μ/Bμ problem in such theories, a potential hidden source of fine-tuning

  4. Axionic Mirage Mediation

    OpenAIRE

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

    2008-01-01

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

  5. 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.

  6. Gravity in gauge mediation

    International Nuclear Information System (INIS)

    We investigate O'Raifeartaigh-type models for F-term supersymmetry breaking in gauge mediation scenarios in the presence of gravity. It is pointed out that the vacuum structure of those models is such that in metastable vacua gravity mediation contribution to scalar masses is always suppressed to the level below 1 percent, almost sufficient for avoiding FCNC problem. Close to that limit, gravitino mass can be in the range 10-100 GeV, opening several interesting possibilities for gauge mediation models, including Giudice-Masiero mechanism for μ and Bμ generation. Gravity sector can include stabilized moduli.

  7. Self-organization in magnetic flux ropes

    Science.gov (United States)

    Lukin, Vyacheslav S.

    2014-06-01

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

  8. Phenomenological Implications of Deflected Mirage Mediation: Comparison with Mirage Mediation

    CERN Document Server

    Altunkaynak, Baris; Kim, Ian-Woo; Nelson, Brent D; Rao, Yongyan

    2010-01-01

    We compare the collider phenomenology of mirage mediation and deflected mirage mediation, which are two recently proposed "mixed" supersymmetry breaking scenarios motivated from string compactifications. The scenarios differ in that deflected mirage mediation includes contributions from gauge mediation in addition to the contributions from gravity mediation and anomaly mediation also present in mirage mediation. The threshold effects from gauge mediation can drastically alter the low energy spectrum from that of pure mirage mediation models, resulting in some cases in a squeezed gaugino spectrum and a gluino that is much lighter than other colored superpartners. We provide several benchmark deflected mirage mediation models and construct model lines as a function of the gauge mediation contributions, and discuss their discovery potential at the LHC.

  9. 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.

  10. 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)

    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

  11. Mediator scolar - School Mediator (Romanian version)

    OpenAIRE

    Madalina CONSTANTIN

    2011-01-01

    The present article proposes to highlight the most important concepts with regard to school mediator. In this case we intend to add into discution the folowing: 1. Planning activities 2 Teamwork 3. Professional Development 4. PC Use 5. Communication 6. Solving conflicts 7. Developing school-community partnership 8. Counseling families / social groups disadvantaged on the role and importance of schooling 9. Implementation of inclusive practices 10. Overcoming emotional and behavioral difficult...

  12. 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.

  13. Dual active surface heat flux gage probe

    Science.gov (United States)

    Liebert, Curt H.; Kolodziej, Paul

    1995-02-01

    A unique plug-type heat flux gage probe was tested in the NASA Ames Research Center 2x9 turbulent flow duct facility. The probe was fabricated by welding a miniature dual active surface heat flux gage body to the end of a hollow metal cylindrical bolt containing a metal inner tube. Cooling air flows through the inner tube, impinges onto the back of the gage body and then flows out through the annulus formed between the inner tube and the hollow bolt wall. Heat flux was generated in the duct facility with a Huels arc heater. The duct had a rectangular cross section and one wall was fabricated from 2.54 centimeter thick thermal insulation rigid surface material mounted onto an aluminum plate. To measure heat flux, the probe was inserted through the plate and insulating materials with the from of the gage located flush with the hot gas-side insulation surface. Absorbed heat fluxes measured with the probe were compared with absorbed heat fluxes measured with six water-cooled reference calorimeters. These calorimeters were located in a water-cooled metal duct wall which was located across from the probe position. Correspondence of transient and steady heat fluxes measured with the reference calorimeters and heat flux gage probe was generally within a satisfactory plus or minus 10 percent. This good correspondence was achieved even though the much cooler probe caused a large surface temperature disruption of 1000K between the metal gage and the insulation. However, this temperature disruption did not seriously effect the accuracy of the heat flux measurement. A current application for dual active surface heat flux gages is for transient and steady absorbed heat flux, surface temperature and heat transfer coefficient measurements on the surface of an oxidizer turbine inlet deflector operating in a space shuttle test bed engine.

  14. PHELIX for flux compression studies

    Energy Technology Data Exchange (ETDEWEB)

    Turchi, Peter J [Los Alamos National Laboratory; Rousculp, Christopher L [Los Alamos National Laboratory; Reinovsky, Robert E [Los Alamos National Laboratory; Reass, William A [Los Alamos National Laboratory; Griego, Jeffrey R [Los Alamos National Laboratory; Oro, David M [Los Alamos National Laboratory; Merrill, Frank E [Los Alamos National Laboratory

    2010-06-28

    PHELIX (Precision High Energy-density Liner Implosion eXperiment) is a concept for studying electromagnetic implosions using proton radiography. This approach requires a portable pulsed power and liner implosion apparatus that can be operated in conjunction with an 800 MeV proton beam at the Los Alamos Neutron Science Center. The high resolution (< 100 micron) provided by proton radiography combined with similar precision of liner implosions driven electromagnetically can permit close comparisons of multi-frame experimental data and numerical simulations within a single dynamic event. To achieve a portable implosion system for use at high energy-density in a proton laboratory area requires sub-megajoule energies applied to implosions only a few cms in radial and axial dimension. The associated inductance changes are therefore relatively modest, so a current step-up transformer arrangement is employed to avoid excessive loss to parasitic inductances that are relatively large for low-energy banks comprising only several capacitors and switches. We describe the design, construction and operation of the PHELIX system and discuss application to liner-driven, magnetic flux compression experiments. For the latter, the ability of strong magnetic fields to deflect the proton beam may offer a novel technique for measurement of field distributions near perturbed surfaces.

  15. Extraterrestrial high energy neutrino fluxes

    International Nuclear Information System (INIS)

    With the aid of using the most recent cosmic ray spectra up to 2x1020 eV, production spectra of high-energy neutrinos from cosmic ray interactions with interstellar gas and extragalactic interactions of ultrahigh-energy cosmic rays with 3K universal background photons are presented and discussed. Estimates of the fluxes from cosmic diffuse sources and the nearby quasar 3C273 are made using the generic relationship between secondary neutrinos and gammas and using recent gamma ray satellite data. These gamma ray data provide important upper limits on cosmological neutrinos. Quantitative estimates of the observability of high-energy neutrinos from the inner galaxy and 3C273 above atmospheric background for a DUMAND-type detector are discussed in the context of the Weinberg-Salam model with sin2 theta/sub ω/ = 0.2 and including the atmospheric background from the decay of charmed mesons. Constraints on cosmological high-energy neutrino production models are also discussed. It appears that important high-energy neutrino astronomy may be possible with DUMAND, but very long observing times are required

  16. Extraterrestrial high energy neutrino fluxes

    Science.gov (United States)

    Stecker, F. W.

    1979-01-01

    Using the most recent cosmic ray spectra up to 2x10 to the 20th power eV, production spectra of high energy neutrinos from cosmic ray interactions with interstellar gas and extragalactic interactions of ultrahigh energy cosmic rays with 3K universal background photons are presented and discussed. Estimates of the fluxes from cosmic diffuse sources and the nearby quasar 3C273 are made using the generic relationship between secondary neutrinos and gammas and using recent gamma ray satellite data. These gamma ray data provide important upper limits on cosmological neutrinos. Quantitative estimates of the observability of high energy neutrinos from the inner galaxy and 3C273 above atmospheric background for a DUMAND type detector are discussed in the context of the Weinberg-Salam model with sq sin theta omega = 0.2 and including the atmospheric background from the decay of charmed mesons. Constraints on cosmological high energy neutrino production models are also discussed. It appears that important high energy neutrino astronomy may be possible with DUMAND, but very long observing times are required.

  17. Extraterrestrial high energy neutrino fluxes

    Energy Technology Data Exchange (ETDEWEB)

    Stecker, F.W.

    1979-06-01

    With the aid of using the most recent cosmic ray spectra up to 2x10/sup 20/ eV, production spectra of high-energy neutrinos from cosmic ray interactions with interstellar gas and extragalactic interactions of ultrahigh-energy cosmic rays with 3K universal background photons are presented and discussed. Estimates of the fluxes from cosmic diffuse sources and the nearby quasar 3C273 are made using the generic relationship between secondary neutrinos and gammas and using recent gamma ray satellite data. These gamma ray data provide important upper limits on cosmological neutrinos. Quantitative estimates of the observability of high-energy neutrinos from the inner galaxy and 3C273 above atmospheric background for a DUMAND-type detector are discussed in the context of the Weinberg-Salam model with sin/sup 2/ theta/sub ..omega../ = 0.2 and including the atmospheric background from the decay of charmed mesons. Constraints on cosmological high-energy neutrino production models are also discussed. It appears that important high-energy neutrino astronomy may be possible with DUMAND, but very long observing times are required.

  18. Phenomenology of a Fluxed MSSM

    CERN Document Server

    Allanach, Benjamin C; Ibáñez, L E

    2005-01-01

    We analyze the phenomenology of a set of minimal supersymmetric standard model (MSSM) soft terms inspired by flux-induced supersymmetry (SUSY)-breaking in Type IIB string orientifolds. The scheme is extremely constrained with essentially only two free mass parameters: a parameter M, which sets the scale of soft terms, and the mu parameter. After imposing consistent radiative electro-weak symmetry breaking (EWSB) the model depends upon one mass parameter (say, M). In spite of being so constrained one finds consistency with EWSB conditions. We demonstrate that those conditions have two solutions for mu0. The parameter tan beta results as a prediction and is approximately 3-5 for one solution, and 25-40 for the other, depending upon M and the top mass. We examine further constraints on the model coming from b->s gamma, the muon g-2, Higgs mass limits and WMAP constraints on dark matter. The MSSM spectrum is predicted in terms of the single free parameter M. The low tan beta branch is consistent with a relatively...

  19. Energetic consequences of flux emergence

    CERN Document Server

    Tarr, Lucas A

    2013-01-01

    When magnetic field in the solar convection zone buoyantly rises to pierce the visible solar surface (photosphere), the atmosphere (corona) above this surface must respond in some way. One response of the coronal field to photospheric forcing is the creation of stress in the magnetic field, generating large currents and storing magnetic free energy. Using a topological model of the coronal magnetic field we will quantify this free energy. We find the free energy just prior to major flares in active regions to be between 30% and 50% of the potential field energy. In a second way, the coronal field may topologically restructure to form new magnetic connections with newly emerged fields. We use our topological model to quantify the rapid restructuring in the case of solar flare and coronal mass ejections, finding that between 1% and 10% of total active region flux is exchanged. Finally, we use observational data to quantify the slow, quiescent reconnection with preexisting field, and find that for small active r...

  20. Technology-Use Mediation

    DEFF Research Database (Denmark)

    Bansler, Jørgen P.; Havn, Erling C.

    2004-01-01

    deepens our understanding of how organizations appropriate new electronic communication media. The paper analyzes how a group of mediators in a large, multinational company adapted a new web-based CMC technology (a virtual workspace) to the local organizational context (and vice versa) by modifying...... features of the technology, providing ongoing support for users, and promoting appropriate conventions of use. We found that these mediators exerted considerable influence on how the technology was established and used in the organization. The mediators were not neutral facilitators of a well......Implementation of new computer-mediated communication (CMC) systems in organizations is a complex socio-technical endeavour, involving the mutual adaptation of technology and organization over time. Drawing on the analytic concept of sensemaking, this paper provides a theoretical perspective that...

  1. Technology-Use Mediation

    DEFF Research Database (Denmark)

    Bansler, Jørgen P.; Havn, Erling C.

    2004-01-01

    Implementation of new computer-mediated communication (CMC) systems in organizations is a complex socio-technical endeavour, involving the mutual adaptation of technology and organization over time. Drawing on the analytic concept of sensemaking, this paper provides a theoretical perspective that...... deepens our understanding of how organizations appropriate new electronic communication media. The paper analyzes how a group of mediators in a large, multinational company adapted a new web-based CMC technology (a virtual workspace) to the local organizational context (and vice versa) by modifying...... features of the technology, providing ongoing support for users, and promoting appropriate conventions of use. We found that these mediators exerted considerable influence on how the technology was established and used in the organization. The mediators were not neutral facilitators of a well...

  2. HST CALSPEC Flux Standards: Sirius (and Vega)

    CERN Document Server

    Bohlin, R C

    2014-01-01

    The Space Telescope Imaging Spectrograph (STIS) has measured the flux for Sirius from 0.17--1.01~$\\mu$m on the \\emph{HST} White Dwarf scale. Because of the cool debris disk around Vega, Sirius is commonly recommended as the primary IR flux standard. The measured STIS flux agrees well with predictions of a special Kurucz model atmosphere, adding confidence to the modeled IR flux predictions. The IR flux agrees to 2--3% with respect to the standard template of Cohen and to 2% with the MSX absolute flux measurements in the mid-IR. A weighted average of the independent visible and mid-IR absolute flux measures implies that the monochromatic flux at 5557.5~\\AA\\ (5556~\\AA\\ in air) for Sirius and Vega, respectively, is $1.35\\times10^{-8}$ and $3.44\\times10^{-9}$~erg cm$^{-2}$ s$^{-1}$ \\AA$^{-1}$ with formal uncertainties of 0.5%. Contrary to previously published conclusions, the Hipparcos photometry offers no support for the variability of Vega. Pulse pileup severely affects the Hp photometry for the brightest stars...

  3. Heat flux viscosity in collisional magnetized plasmas

    Science.gov (United States)

    Liu, C.; Fox, W.; Bhattacharjee, A.

    2015-05-01

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

  4. Heat flux viscosity in collisional magnetized plasmas

    International Nuclear Information System (INIS)

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

  5. EL-2 reactor: Thermal neutron flux distribution

    International Nuclear Information System (INIS)

    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.)

  6. 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...

  7. Magnetic flux generator for balanced membrane loudspeaker

    DEFF Research Database (Denmark)

    Rehder, Jörg; Rombach, Pirmin; Hansen, Ole

    This paper reports the development of a magnetic flux generator with an application in a hearing aid loudspeaker produced in microsystem technology (MST). The technology plans for two different designs for the magnetic flux generator utilizing a softmagnetic substrate or electroplated NiCoFe as...

  8. Inflammatory mediators in osteoarthritis

    OpenAIRE

    M Beekhuizen

    2014-01-01

    Osteoarthritis (OA) is a degenerative joint disorder involving cartilage destruction and joint inflammation. Despite extensive research, still much is unknown on the pathogenesis and aetiology of OA. Inflammation and inflammatory mediators (both local and systemic) are key in the pathogenesis of OA. For rheumatoid arthritis, multiple therapies are based on targeting the mediators that are associated with inflammation and joint destruction. Motivated by these findings we set off to identify wh...

  9. Interactive Mediated Reality

    OpenAIRE

    Grasset, Raphaël; Boissieux, Laurence; Gascuel, Jean-Dominique; Schmalstieg, Dieter

    2005-01-01

    International audience Mediated reality describes the concept of filtering our vision of reality, typically using a head-mounted video mixing display. We can redefine this idea in a more constructive context, applying dynamic changes to the appearance and geometry of objects in a real scene using computer graphics. In this paper, we propose new tools for interactively mediated reality. After describing a new generic framework for achieving this goal, we present a prototype system for paint...

  10. Chronic alloantibody mediated rejection

    OpenAIRE

    Smith, R. Neal; Colvin, Robert B.

    2011-01-01

    Alloantibodies clearly cause acute antibody mediated rejection, and all available evidence supports their pathogenic etiology in the development of chronic alloantibody mediated rejection (CAMR). But the slow evolution of this disease, the on-going immunosuppression, the variations in titer of alloantibodies, and variation in antigenic targets all complicate identifying which dynamic factors are most important clinically and pathologically. This review highlights the pathological factors rela...

  11. Large scale surface heat fluxes. [through oceans

    Science.gov (United States)

    Sarachik, E. S.

    1984-01-01

    The heat flux through the ocean surface, Q, is the sum of the net radiation at the surface, the latent heat flux into the atmosphere, and the sensible heat flux into the atmosphere (all fluxes positive upwards). A review is presented of the geographical distribution of Q and its constituents, and the current accuracy of measuring Q by ground based measurements (both directly and by 'bulk formulae') is assessed. The relation of Q to changes of oceanic heat content, heat flux, and SST is examined and for each of these processes, the accuracy needed for Q is discussed. The needed accuracy for Q varies from process to process, varies geographically, and varies with the time and space scale considered.

  12. High flux expansion divertor studies in NSTX

    CERN Document Server

    Soukhanovskii, V A; Bell, R E; Gates, D A; Kaita, R; Kugel, H W; LeBlanc, B P; Maqueda, R; Menard, J E; Mueller, D; Paul, S F; Raman, R; Roquemore, A L

    2009-01-01

    High flux expansion divertor studies have been carried out in the National Spherical Torus Experiment using steady-state X-point height variations from 22 to 5-6 cm. Small-ELM H-mode confinement was maintained at all X-point heights. Divertor flux expansions from 6 to 26-28 were obtained, with associated reduction in X-point connection length from 5-6 m to 2 m. Peak divertor heat flux was reduced from 7-8 MW/m$^2$ to 1-2 MW/m$^2$. In low X-point configuration, outer strike point became nearly detached. Among factors affecting deposition of parallel heat flux in the divertor, the flux expansion factor appeared to be dominant

  13. Plasma crowbars in cylindrical flux compression experiments

    International Nuclear Information System (INIS)

    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

  14. Hyperoxia-mediated LC3B activation contributes to the impaired transdifferentiation of type II alveolar epithelial cells (AECIIs) to type I cells (AECIs).

    Science.gov (United States)

    Zhang, Liang; Zhao, Shuang; Yuan, Lijie; Wu, Hongmin; Jiang, Hong; Luo, Gang

    2016-09-01

    Life-saving mechanical ventilation can also cause lung injury through the overproduction of reactive oxygen species (ROS), leading to bronchopulmonary dysplasia (BPD)-like symptoms in preterm infants. It is reported that the autophagic protein microtubule-associated protein-1 light chain (LC)-3B can confer protection against hyperoxia-induced DNA damage in lung alveolar epithelium. However, its role in the transdifferentiation of type II alveolar epithelial cells (AECIIs) to type I cells (AECIs) is unclear and requires further investigation. In this study, newborn Sprague-Dawley rats were exposed to 90% oxygen for up to 14 days to mimic BPD in human infants, with neonatal pups exposed to room air (21% oxygen) as controls. Primary rat AECIIs were cultured under hyperoxic conditions for up to 24 hours to further investigate the underlying mechanisms. This study found that hyperoxia promoted a significant and time-dependent increase of AECII marker surfactant protein (SP)-C in the lung. The increase of AECI marker T1α was repressed by hyperoxia during lung development. These results indicated an impaired AECII transdifferentiation. Pulmonary ROS concentration and expression of autophagic protein LC-3B were increased gradually in response to hyperoxia exposure. Furthermore, AECIIs produced more ROS when cultured under hyperoxic conditions in vitro. Both the LC3B expression and the conversion from LC3BI to LC3BII were enhanced in hyperoxic AECs. Interestingly, inhibition of LC3B either by ROS inhibitor N-acetyl-l-cysteine (NAC) or adenovirus-mediated LC3B shRNA could partly restore AECII transdifferentiation under hyperoxia condition. In summary, the current study reveals a novel role of activated LC3B induced by hyperoxia in AECII transdifferentiation. PMID:27187184

  15. Comparison of debris flux models

    Science.gov (United States)

    Sdunnus, H.; Beltrami, P.; Klinkrad, H.; Matney, M.; Nazarenko, A.; Wegener, P.

    The availability of models to estimate the impact risk from the man-made space debris and the natural meteoroid environment is essential for both, manned and unmanned satellite missions. Various independent tools based on different approaches have been developed in the past years. Due to an increased knowledge of the debris environment and its sources e.g. from improved measurement capabilities, these models could be updated regularly, providing more detailed and more reliable simulations. This paper addresses an in-depth, quantitative comparison of widely distributed debris flux models which were recently updated, namely ESA's MASTER 2001 model, NASA's ORDEM 2000 and the Russian SDPA 2000 model. The comparison was performed in the frame of the work of the 20t h Interagency Debris Coordination (IADC) meeting held in Surrey, UK. ORDEM 2000ORDEM 2000 uses careful empirical estimates of the orbit populations based onthree primary data sources - the US Space Command Catalog, the H ystackaRadar, and the Long Duration Exposure Facility spacecraft returned surfaces.Further data (e.g. HAX and Goldstone radars, impacts on Shuttle windows andradiators, and others) were used to adjust these populations for regions in time,size, and space not covered by the primary data sets. Some interpolation andextrapolation to regions with no data (such as projections into the future) wasprovided by the EVOLVE model. MASTER 2001The ESA MASTER model offers a full three dimensional description of theterrestrial debris distribution reaching from LEO up to the GEO region. Fluxresults relative to an orbiting target or to an inertial volume can be resolved intosource terms, impactor characteristics and orbit, as well as impact velocity anddirection. All relevant debris source terms are considered by the MASTERmodel. For each simulated source, a corresponding debris generation model interms of mass/diameter distribution, additional velocities, and directionalspreading has been developed. A

  16. Justicidin A-induced autophagy flux enhances apoptosis of human colorectal cancer cells via class III PI3K and Atg5 pathway.

    Science.gov (United States)

    Won, Shen-Jeu; Yen, Cheng-Hsin; Liu, Hsiao-Sheng; Wu, Shan-Ying; Lan, Sheng-Hui; Jiang-Shieh, Ya-Fen; Lin, Chun-Nan; Su, Chun-Li

    2015-04-01

    Our previous reports showed that justicidin A (JA), a novel and pure arylnaphthalide lignan isolated from Justicia procumbens, induces apoptosis of human colorectal cancer cells and hepatocellular carcinoma cells, leading to the suppression of both tumor cell growth in NOD-SCID mice. Here, we reveal that JA induces autophagy in human colorectal cancer HT-29 cells by conversion of autophagic marker LC3-I to LC3-II. Furthermore, LC3 puncta and autophagic vesicle formation, and SQSTM1/p62 suppression were observed. Administration of autophagy inhibitor (bafilomycin A1 and chloroquine) and transfection of a tandem fluorescent-tagged LC3 (mRFP-GFP) reporter plasmid (ptfLC3) demonstrated that JA induces autophagy flux in HT-29 cells. Expression of LC3, SQSTM1, Beclin 1, and nuclear DNA double-strand breaks (representing apoptosis) were also detected in the tumor tissue of HT-29 cells transplanted into NOD-SCID mice orally administrated with JA. In addition, the expression of autophagy signaling pathway-related molecules p-PDK1, p-mTOR, p-p70S6k/p-RPS6KB2 was decreased, whereas that of class III PI3K, Beclin 1, Atg5-Atg12, and mitochondrial BNIP3 was increased in response to JA. Pre-treatment of the cells with class III PI3K inhibitor 3-methyladenine or Atg5 shRNA attenuated JA-induced LC3-II expression and LC3 puncta formation, indicating the involvement of class III PI3K and Atg5. A novel mechanism was demonstrated in the anticancer compound JA; pre-treatment with 3-methyladenine or Atg5 shRNA blocked JA-induced suppression in cell growth and colony formation, respectively, via inhibition of apoptosis. In contrast, administration of apoptosis inhibitor Z-VAD did not affect JA-induced autophagy. Our data suggest the chemotherapeutic potential of JA for treatment of human colorectal cancer. PMID:25216025

  17. Direct Torque Control Induction Motor Drive with Improved Flux Response

    OpenAIRE

    Bhoopendra Singh; Shailendra Jain; Sanjeet Dwivedi

    2012-01-01

    Accurate flux estimation and control of stator flux by the flux control loop is the determining factor in effective implementation of DTC algorithm. In this paper a comparison of voltage-model-based flux estimation techniques for flux response improvement is carried out. The effectiveness of these methods is judged on the basis of Root Mean Square Flux Error (RMSFE), Total Harmonic Distortion (THD) of stator current, and dynamic flux response. The theoretical aspects of these methods are disc...

  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. Carbon and nitrogen fluxes between beech and their ectomycorrhizal assemblage.

    Science.gov (United States)

    Valtanen, Kerttu; Eissfeller, Verena; Beyer, Friderike; Hertel, Dietrich; Scheu, Stefan; Polle, Andrea

    2014-11-01

    To determine the exchange of nitrogen and carbon between ectomycorrhiza and host plant, young beech (Fagus sylvatica) trees from natural regeneration in intact soil cores were labelled for one growing season in a greenhouse with (13)CO2 and (15)NO3 (15)NH4. The specific enrichments of (15)N and (13)C were higher in ectomycorrhizas (EMs) than in any other tissue. The enrichments of (13)C and (15)N were also higher in the fine-root segments directly connected with the EM (mainly second-order roots) than that in bulk fine or coarse roots. A strict, positive correlation was found between the specific (15)N enrichment in EM and the attached second-order roots. This finding indicates that strong N accumulators provide more N to their host than low N accumulators. A significant correlation was also found for the specific (13)C enrichment in EM and the attached second-order roots. However, the specific enrichments for (15)N and (13)C in EM were unrelated showing that under long-term conditions, C and N exchange between host and EMs are uncoupled. These findings suggest that EM-mediated N flux to the plant is not the main control on carbon flux to the fungus, probably because EMs provide many different services to their hosts in addition to N provision in their natural assemblages. PMID:24756632

  20. Mechanism for Clofarabine Inducing Autophagic Death of Acute Myelocytic Leukemia Cell U937%氯法拉滨诱导U937细胞自噬性死亡的机制

    Institute of Scientific and Technical Information of China (English)

    李程亮; 刘海波; 张梅; 贺鹏程

    2013-01-01

    本研究旨在探讨氯法拉滨诱导急性髓系白血病(AML)细胞U937自噬性死亡的机制.不同浓度氯法拉滨作用U937细胞24、48 h后,用MTT法计算细胞生长抑制率及氯法拉滨半数抑制浓度(IC50),流式细胞术检测细胞自噬率的变化;Western blot方法检测细胞自噬相关蛋白Beclin1的表达变化.结果表明,0.01和0.15 μmol/L氯法拉滨作用U937细胞48 h,增殖抑制率分别为(46.92±4.24)%和(86.10±1.16)%,IC50为0.022 μmol/L,与对照组比较差异有统计学意义(P<0.05).0.01和0.1μmol/L氯法拉滨作用U937细胞48 h,自噬率分别为(11.0033±1.4387)%和(59.4133±3.5409)%,且呈剂量依赖性增强(r=0.99);随药物浓度的增加,Beclin 1表达逐渐上调,与对照组比较差异有统计学意义(P<0.05).结论:氯法拉滨对U937细胞有明显的增殖抑制作用,且存在剂量依赖性,其作用机制可能是通过上调Beclin 1的蛋白表达诱导U937细胞自噬性死亡.%To explore the mechanism of autophagic death of acute myelocytic leukemia cell U937 induced by clofarabine, the MTT bioassay was used to analyze the growth inhibitory effect and half inhibition concentration on U937 incubated in vitro with different concentrations of clofarabine for 24 and 48 hours, and the flow cytometry was used to detect the autophagy rate of U937. The expression of Beclin 1 in U937 treated by clofarabine for 48h was meaused by Western blot. The results indicated that when U937 cells were treated with 0. 01 μmol/L and 0.15 μmol/L clofarabine for 48 hours, the proliferation inhibition rate was 46. 92% ±4. 24% and 86. 10% ± 1. 16% , and the half inhibition concentration of clofarabine was 0.022 μmol/L. With 0.01 μmol/L and 0.1μmol/L clofarabine on U937 for 48 hours, the autophagy rate was 11.0033% ±1.4387% and 59.4133% ±3.5409% ,and increased in dose-dependent manner(r = 0.99). Meanwhile the Beclin 1 was upregulated along with increase of clofarabine concentration, as

  1. NMDA-receptor activation but not ion flux is required for amyloid-beta induced synaptic depression.

    Directory of Open Access Journals (Sweden)

    Albert Tamburri

    Full Text Available Alzheimer disease is characterized by a gradual decrease of synaptic function and, ultimately, by neuronal loss. There is considerable evidence supporting the involvement of oligomeric amyloid-beta (Aβ in the etiology of Alzheimer's disease. Historically, AD research has mainly focused on the long-term changes caused by Aβ rather than analyzing its immediate effects. Here we show that acute perfusion of hippocampal slice cultures with oligomeric Aβ depresses synaptic transmission within 20 minutes. This depression is dependent on synaptic stimulation and the activation of NMDA-receptors, but not on NMDA-receptor mediated ion flux. It, therefore, appears that Aβ dependent synaptic depression is mediated through a use-dependent metabotropic-like mechanism of the NMDA-receptor, but does not involve NMDA-receptor mediated synaptic transmission, i.e. it is independent of calcium flux through the NMDA-receptor.

  2. Methodological errors in radioisotope flux measurements

    Energy Technology Data Exchange (ETDEWEB)

    Egnor, R.W.; Vaccarezza, S.G.; Charney, A.N. (New York Univ. School of Medicine, New York (USA))

    1988-11-01

    The authors examined several sources of error in isotopic flux measurements in a commonly used experimental model: the study of {sup 22}Na and {sup 36}Cl fluxes across rat ileal tissue mounted in the Ussing flux chamber. The experiment revealed three important sources of error: the absolute counts per minute, the difference in counts per minute between serial samples, and averaging of serial samples. By computer manipulation, they then applied hypothetical changes in the experimental protocol to generalize these findings and assess the effect and interaction of the absolute counts per minute, the sampling interval, and the counting time on the magnitude of the error. They found that the error of a flux measurement will vary inversely with the counting time and the difference between the consecutive sample counts per minute used in the flux calculations and will vary directly with the absolute counts per minute of each sample. Alteration of the hot side specific activity, the surface area of the tissue across which flux is measured and the sample volume have a smaller impact on measurement error. Experimental protocols should be designed with these methodological considerations in mind to minimize the error inherent in measuring isotope flux.

  3. Calculated electron fluxes at airplane altitudes

    International Nuclear Information System (INIS)

    A precision measurement of atmospheric electron fluxes has been performed on a Japanese commercial airliner (Enomoto et al.). The bulk of these electrons are produced in pairs from the γ rays emitted when π0's decay, which in turn have been produced in cosmic-ray--air-nucleus collisions. These electron fluxes can be used to test elements of our atmospheric neutrino flux calculation, i.e., the assumed primary spectrum and the Monte Carlo shower code. Here we have modified the Monte Carlo program which has previously been used to calculate the fluxes of atmospheric neutrinos by combining it with the program GEANT to compute the electromagnetic part of the shower. This hybrid program now keeps track of the electrons produced in cosmic-ray showers as a function of energy and atmospheric depth. We compare our calculated integral fluxes above the experimental threshold energies 1, 2, and 4 GeV for a variety of atmospheric depths and cutoff rigidities. Our results are in good agreement (∼ a few %) with the data, but we found we needed to boost the normalization of the primary flux by 12% over the value we had previously used to calculate the atmospheric neutrino flux

  4. On calculating the potential vorticity flux

    Energy Technology Data Exchange (ETDEWEB)

    Hsu, Pei-Chun; Diamond, P. H. [Center for Astrophysics and Space Sciences and Department of Physics, University of California San Diego, La Jolla, California 92093-0424 (United States)

    2015-03-15

    We discuss and compare different approaches to calculating the dynamics of anisotropic flow structure formation in quasi two-dimensional turbulence based on potential vorticity (PV) transport in real space. The general structure of the PV flux in the relaxation processes is deduced non-perturbatively. The transport coefficients of the PV flux are then systematically calculated using perturbation theory. We develop two non-perturbative relaxation models: the first is a mean field theory for the dynamics of minimum enstrophy relaxation based on the requirement that the mean flux of PV dissipates total potential enstrophy but conserves total fluid kinetic energy. The results show that the structure of PV flux has the form of a sum of a positive definite hyper-viscous and a negative or positive viscous flux of PV. Turbulence spreading is shown to be related to PV mixing via the link of turbulence energy flux to PV flux. In the relaxed state, the ratio of the PV gradient to zonal flow velocity is homogenized. This homogenized quantity sets a constraint on the amplitudes of PV and zonal flow in the relaxed state. The second relaxation model is derived from symmetry principles alone. The form of PV flux contains a nonlinear convective term in addition to viscous and hyper-viscous terms. For both cases, the transport coefficients are calculated using perturbation theory. For a broad turbulence spectrum, a modulational calculation of the PV flux gives both a negative viscosity and a positive hyper-viscosity. For a narrow turbulence spectrum, the result of a parametric instability analysis shows that PV transport is also convective. In both relaxation and perturbative analyses, it is shown that turbulent PV transport is sensitive to flow structure, and the transport coefficients are nonlinear functions of flow shear.

  5. Nitrous oxide flux following tropical land clearing

    Science.gov (United States)

    Luizao, Flavio; Luizao, Regina; Matson, Pamela; Livingston, Gerald; Vitousek, Peter

    1989-01-01

    The importance of seasonal cycles of N2O flux from tropical ecosystems and the possibility that tropical deforestation could contribute to the ongoing global increase in N2O concentrations were assessed by measuring N2O flux from forest, cleared land, and pasture over an annual cycle in the central Amazon. A pasture that had been converted from tropical forest had threefold greater annual N2O flux than a paired forest site; similar results were obtained in spot measurements in other pastures. If these results are general, such tropical pastures represent a globally significant source of increased N2O.

  6. The separation velocity of emerging magnetic flux

    Science.gov (United States)

    Chou, Dean-Yi; Wang, Haimin

    1987-01-01

    The separation velocities and magnetic fluxes of 24 emerging bipoles on the sun are measured in order to provide data on the emerging mechanism. Velocities are shown to range from about 0.2-1 km/s, bipole fluxes to range over more than two orders of magnitude, and the mean field strength and the sizes to range over one order of magnitude. No correlation is noted between measured separation velocities and either the flux or the mean field strength of the bipole. Predicted separation velocities are found be about one order of magnitude greater than measured values.

  7. A time-varying magnetic flux concentrator

    Science.gov (United States)

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

    2016-08-01

    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.

  8. Anomalous cross field flux in CHS

    International Nuclear Information System (INIS)

    Anomalous quasi-linear fluxes induced by the curvature drift resonance and transit resonance are evaluated in a rotating helical plasma. The radial electric field makes the Doppler shift, but does not contribute to the anomalous fluxes. The curvature drift resonance induces the new curvature term in the quasi-linear fluxes. The effect of helical magnetic field is through this curvature of magnetic field lines, and contributes to the inward transport. The ion heat diffusivity due to the curvature drift resonance is obtained in the form modified gyro-Bohm coefficient, and is compared with experimentally observed one in CHS Heliotron. (author)

  9. M Theory, Orientifolds and G-Flux

    CERN Document Server

    Das-Gupta, K; Sethi, S K; Dasgupta, Keshav; Rajesh, Govindan; Sethi, Savdeep

    1999-01-01

    We study the properties of M and F theory compactifications to three and four dimensions with background fluxes. We provide a simple construction of supersymmetric vacua, including some with orientifold descriptions. These vacua, which have warp factors, typically have fewer moduli than conventional Calabi-Yau compactifications. The mechanism for anomaly cancellation in the orientifold models involves background RR and NS fluxes. We consider in detail an orientifold of $K3\\times T^2$ with background fluxes. After a combination of T and S-dualities, this type IIB orientifold is mapped to a compactification of the SO(32) heterotic string on a non-Kahler space with torsion.

  10. Explosive Ballooning Flux Tubes in Tokamaks

    CERN Document Server

    Ham, C J; Brochard, G; Wilson, H R

    2016-01-01

    Tokamak stability to, potentially explosive, `ballooning' displacements of elliptical magnetic flux tubes is examined in large aspect ratio equilibrium. Above a critical pressure gradient the energy stored in the plasma may be lowered by finite (but not infinitesimal) displacements of such tubes (metastability). Above a higher pressure gradient, the linear stability boundary, such tubes are linearly and nonlinearly unstable. The flux tube displacement can be of the order of the pressure gradient scale length. Plasma transport from displaced flux tubes may result in rapid loss of confinement.

  11. YAG laser welding with surface activating flux

    Institute of Scientific and Technical Information of China (English)

    樊丁; 张瑞华; 田中学; 中田一博; 牛尾诚夫

    2003-01-01

    YAG laser welding with surface activating flux has been investigated, and the influencing factors and mechanism are discussed. The results show that both surface activating flux and surface active element S have fantastic effects on the YAG laser weld shape, that is to obviously increase the weld penetration and D/W ratio in various welding conditions. The mechanism is thought to be the change of weld pool surface tension temperature coefficient, thus, the change of fluid flow pattern in weld pool due to the flux.

  12. Minkowski flux vacua of type II supergravities

    CERN Document Server

    Andriot, David; Van Riet, Thomas

    2016-01-01

    We study flux compactifications of 10d type II supergravities to 4d Minkowski space-time, supported by parallel orientifold Op-planes with 3 $\\leq$ p $\\leq$ 8. Upon few geometric restrictions, the 4d Ricci scalar can be written as a negative sum of squares involving BPS-like conditions. Setting all squares to zero provides automatically a solution to 10d equations of motion. This way, we characterise a broad class, if not the complete set, of Minkowski flux vacua. We also conjecture an extension to include non-geometric fluxes. None of our results rely on supersymmetry.

  13. [Immune-mediated neuropathies].

    Science.gov (United States)

    Stoll, G; Reiners, K

    2016-08-01

    The Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are the most common immune-mediated polyneuropathies, which can show variable clinical and electrophysiological manifestations. Rarer immune-mediated neuropathies encompass paraproteinemic neuropathies (PPN), multifocal motor neuropathy (MMN) and vasculitic neuropathies. The diagnosis usually relies on the history of symptom evolution, distribution of nerve dysfunction and particularly on characteristic features in nerve conduction studies, aided by cerebrospinal fluid (CSF) examination and nerve biopsy findings. The therapeutic toolbox encompasses corticosteroids, immunoglobulins and plasmapheresis often accompanied by long-term immunosuppression. It is important to note that immune-mediated neuropathies selectively respond to treatment and contraindications need to be considered. Despite treatment a considerable number of patients suffer from permanent neurological deficits. PMID:27474733

  14. The Strategic Mediator

    DEFF Research Database (Denmark)

    Rossignoli, Cecilia; Carugati, Andrea; Mola, Lapo

    2009-01-01

    The last 10 years have witnessed the emergence of electronic marketplaces as players that leverage new technologies to facilitate B2B internet-mediated collaborative business. Nowadays these players are augmenting their services from simple intermediation to include new inter-organizational relat......The last 10 years have witnessed the emergence of electronic marketplaces as players that leverage new technologies to facilitate B2B internet-mediated collaborative business. Nowadays these players are augmenting their services from simple intermediation to include new inter...... e-marketplace assumes the paradoxical role of strategic mediator: an agent who upholds and heightens the fences of the transactions instead of leveling them. The results have implication in shaping how we see the role of technology as strategic or commoditized....

  15. Immunologically mediated oral diseases

    Directory of Open Access Journals (Sweden)

    Sudha Jimson

    2015-01-01

    Full Text Available 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 immunoflouresence, immune precipitation and immunoblotting. Therapeutic agents should be selected after thorough evaluation of immune status through a variety of tests and after determining any aggravating or provoking factors. Early and appropriate diagnosis is important for proper treatment planning contributing to better prognosis and better quality of life of patient.

  16. Immunologically mediated oral diseases.

    Science.gov (United States)

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

    2015-04-01

    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 immunoflouresence, immune precipitation and immunoblotting. Therapeutic agents should be selected after thorough evaluation of immune status through a variety of tests and after determining any aggravating or provoking factors. Early and appropriate diagnosis is important for proper treatment planning contributing to better prognosis and better quality of life of patient. PMID:26015713

  17. Seasonal variability of turbulent heat fluxes in the tropical Atlantic Ocean based on WHOI flux product

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    The mean seasonal variability of turbulent heat fluxes in the tropical Atlantic Ocean is examined using the Woods Hole Oceanographic Institution (WHOI) flux product. The most turbulent heat fluxes occur during winter seasons in the two hemispheres, whose centers are located at 10°~20°N and 5°~15°S respectively. In climatological ITCZ, the turbulent heat fluxes are the greatest from June to August, and in equatorial cold tongue the turbulent heat fluxes are the greatest from March to May. Seasonal variability of sensible heat flux is smaller than that of latent heat flux and mainly is dominated by the variations of air-sea temperature difference. In the region with larger climatological mean wind speed (air-sea humidity difference), the variations of air-sea humidity difference (wind speed) dominate the variability of latent heat flux. The characteristics of turbulent heat flux yielded from theory analysis and WHOI dataset is consistent in physics which turns out that WHOI's flux data are pretty reliable in the tropical Atlantic Ocean.

  18. Reconciling heat-flux and salt-flux estimates at a melting ice-ocean interface

    CERN Document Server

    Keitzl, Thomas; Notz, Dirk

    2016-01-01

    The ratio of heat and salt flux is employed in ice-ocean models to represent ice-ocean interactions. In this study, this flux ratio is determined from direct numerical simulations of free convection beneath a melting, horizontal, smooth ice-ocean interface. We find that the flux ratio at the interface is three times as large as previously assessed based on turbulent-flux measurements in the field. As a consequence, interface salinities and melt rates are overestimated by up to 40\\% if they are based on the three-equation formulation. We also find that the interface flux ratio depends only very weakly on the far-field conditions of the flow. Lastly, our simulations indicate that estimates of the interface flux ratio based on direct measurements of the turbulent fluxes will be difficult because at the interface the diffusivities alone determine the mixing and the flux ratio varies with depth. As an alternative, we present a consistent evaluation of the flux ratio based on the total heat and salt fluxes across t...

  19. Exploring general gauge mediation

    International Nuclear Information System (INIS)

    We explore various aspects of General Gauge Mediation (GGM). We present a reformulation of the correlation functions used in GGM, and further elucidate their IR and UV properties. Additionally we clarify the issue of UV sensitivity in the calculation of the soft masses in the MSSM, highlighting the role of the supertrace over the messenger spectrum. Finally, we present weakly coupled messenger models which fully cover the parameter space of GGM. These examples demonstrate that the full parameter space of GGM is physical and realizable. Thus it should be considered a valid basis for future phenomenological explorations of gauge mediation.

  20. Observations on fluxes near anti-branes

    CERN Document Server

    Cohen-Maldonado, Diego; Van Riet, Thomas; Vercnocke, Bert

    2015-01-01

    We revisit necessary conditions for gluing local (anti)-D3 throats into flux throats with opposite charge. These consistency conditions typically reveal singularities in the 3-form fluxes whose meaning is being debated. In this note we prove, under well-motivated assumptions, that singularities remain even when the anti-D3 branes are puffed up into spherical NS5 branes. It does not seem possible to ascribe the singular flux to the self-energy of the 5-branes but rather to the singular clumping of the background fluxes. We furthermore comment on the gluing conditions at finite temperature and point out that one specific assumption of a recent no-go theorem can be broken if anti-branes are to polarise into spherical NS5 branes at zero temperature. Our first result, however, casts some doubt on whether this gap in the no-go theorem can be successfully employed to construct finite temperature solutions.

  1. Neutron flux measurements in PUSPATI Triga Reactor

    International Nuclear Information System (INIS)

    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/cm2 sec and 1.10E+12n/cm2 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)

  2. Rotating flux compressor for energy conversion

    International Nuclear Information System (INIS)

    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

  3. On the taxonomy of flux vacua

    International Nuclear Information System (INIS)

    We investigate several predictions about the properties of IIB flux vacua on Calabi-Yau orientifolds, by constructing and characterizing a very large set of vacua in a specific example, an orientifold of the Calabi-Yau hypersurface in WP1,1,1,1,44. We find support for the prediction of Ashok and Douglas that the density of vacua on moduli space is governed by det(-R-ω) where R and ω are curvature and Kaehler forms on the moduli space. The conifold point ψ = 1 on moduli space therefore serves as an attractor, with a significant fraction of the flux vacua contained in a small neighborhood surrounding ψ = 1. We also study the functional dependence of the number of flux vacua on the D3 charge in the fluxes, finding simple power law growth. (author)

  4. Cool and hot flux ropes, their helicity

    Science.gov (United States)

    Nindos, Alexander

    2016-07-01

    We will review recent indirect and direct evidence for the existence of magnetic flux ropes in the solar atmosphere. Magnetic flux ropes may appear as S-shaped or reverse S-shaped (sigmoidal) structures in regions that are likely to erupt, and may also show in nonlinear force-free field extrapolations that use data from photospheric vector magnetograms as boundary condition. The availability of high sensitivity data recorded with unprecedented spatial and temporal resolution in hot EUV wavelengths by the Atmospheric Imaging Assembly (AIA) onboard the Solar Dynamics Observatory (SDO) has revealed the existence of coherent structures identified as hot flux ropes. In this presentation, we will review the properties of both cool and hot flux ropes with an emphasis on the frequency of their occurrence in large flares and on their magnetic helicity content.

  5. Quantum wire network with magnetic flux

    International Nuclear Information System (INIS)

    The charge transport and the noise of a quantum wire network, made of three semi-infinite external leads attached to a ring crossed by a magnetic flux, are investigated. The system is driven away from equilibrium by connecting the external leads to heat reservoirs with different temperatures and/or chemical potentials. The properties of the exact scattering matrix of this configuration as a function of the momentum, the magnetic flux and the transmission along the ring are explored. We derive the conductance and the noise, describing in detail the role of the magnetic flux. In the case of weak coupling between the ring and the reservoirs, a resonant tunneling effect is observed. We also discover that a non-zero magnetic flux has a strong impact on the usual Johnson–Nyquist law for the pure thermal noise at small temperatures.

  6. Calculation of eigenfunction fluxes in nuclear systems

    International Nuclear Information System (INIS)

    A new Monte Carlo method is being developed to calculate eigenfunction fluxes in critical or near-critical nuclear systems. The correct estimation of fluxes is essential for radiation protection and shielding near these systems, in addition to isotope production, isotope depletion, nuclear criticality and other applications. The proposed method applies to Monte Carlo criticality eigenvalue calculations in which the fission sites in one generation are used as fission sources in subsequent generations. The usual Monte Carlo power iteration method for such problems often calculates fluxes (eigenfunctions) that are inaccurate and very different in symmetric parts of a problem geometry. The proposed method calculates flux distributions by estimating an approximate fission matrix. The way the fission matrix is estimated and used differs from other recent works. Preliminary results are promising. (authors)

  7. Flux Partitioning by Isotopic Eddy Covariance

    Science.gov (United States)

    Wehr, R.; Munger, J. W.; Nelson, D. D.; McManus, J. B.; Zahniser, M. S.; Wofsy, S. C.; Saleska, S. R.

    2011-12-01

    Net ecosystem-atmosphere exchange of CO2 is routinely measured by eddy covariance at sites around the world, but studies of ecosystem processes are more interested in the gross photosynthetic and respiratory fluxes that comprise the net flux. The standard method of partitioning the net flux into these components has been to extrapolate nighttime respiration into daytime based on a relationship between nighttime respiration, temperature, and sometimes moisture. However, such relationships generally account for only a small portion of the variation in nighttime respiration, and the assumption that they can predict respiration throughout the day is dubious. A promising alternate method, known as isotopic flux partitioning, works by identifying the stable isotopic signatures of photosynthesis and respiration in the CO2 flux. We have used this method to partition the net flux at Harvard Forest, MA, based on eddy covariance measurements of the net 12CO2 and 13CO2 fluxes (as well as measurements of the sensible and latent heat fluxes and other meteorological variables). The CO2 isotopologues were measured at 4 Hz by an Aerodyne quantum cascade laser spectrometer with a δ13C precision of 0.4 % in 0.25 sec and 0.02 % in 100 sec. In the absence of such high-frequency, high-precision isotopic measurements, past attempts at isotopic flux partitioning have combined isotopic flask measurements with high-frequency (total) CO2 measurements to estimate the isoflux (the EC/flask approach). Others have used a conditional flask sampling approach called hyperbolic relaxed eddy accumulation (HREA). We 'sampled' our data according to each of these approaches, for comparison, and found disagreement in the calculated fluxes of ~10% for the EC/flask approach, and ~30% for HREA, at midday. To our knowledge, this is the first example of flux partitioning by isotopic eddy covariance. Wider use of this method, enabled by a new generation of laser spectrometers, promises to open a new window

  8. An improved flux-step method to determine the critical flux and the critical flux for irreversibility in a membrane bioreactor

    NARCIS (Netherlands)

    Marel, van der P.; Zwijnenburg, A.; Kemperman, A.; Wessling, M.; Temmink, B.G.; Meer, van der W.

    2009-01-01

    An improved flux-step method is presented incorporating cleaning steps by relaxation to determine the critical flux and the critical flux for irreversibility. Experiments are performed with activated sludge fed with real municipal wastewater. The improved flux-step method is compared with a common f

  9. Flux-Confinement in Dilatonic Cosmic Strings

    OpenAIRE

    G.W. Gibbons; Wells, C. G.

    1993-01-01

    We study dilaton-electrodynamics in flat spacetime and exhibit a set of global cosmic string like solutions in which the magnetic flux is confined. These solutions continue to exist for a small enough dilaton mass but cease to do so above a critcal value depending on the magnetic flux. There also exist domain wall and Dirac monopole solutions. We discuss a mechanism whereby magnetic monopolesmight have been confined by dilaton cosmic strings during an epoch in the early universe during which ...

  10. Induction Machine Speed Control with Flux Optimization

    OpenAIRE

    Ouadi, Hamid; Giri, Fouad; Elfadili, Abderrahim; Dugard, Luc

    2010-01-01

    A new speed control strategy is developed, based on a machine model that accounts for the magnetic characteristic saturation. The control strategy includes a flux reference generator designed to meet optimal operational conditions, and a speed controller designed using nonlinear techniques. Both flux generation and speed control laws involve the machine state variables. The performances of the proposed control strategy are formally analysed and its supremacy with respect to standard control s...

  11. Observations on fluxes near anti-branes

    OpenAIRE

    Cohen-Maldonado, Diego; Diaz Dorronsoro, Juan; Van Riet, Thomas; Vercnocke, Bert

    2016-01-01

    We revisit necessary conditions for gluing local (anti-)D3 throats into flux throats with opposite charge. These consistency conditions typically reveal singularities in the three-form fluxes whose meaning is being debated. In this note we prove, under well-motivated assumptions, that unphysical singularities can potentially be avoided when the anti-branes polarise into spherical NS5 branes with a specific radius. If a consistent solution can then indeed be found, our analysis seems to sugges...

  12. Effective string description of confining flux tubes

    CERN Document Server

    Brandt, Bastian B

    2016-01-01

    We review the current knowledge about the theoretical foundations of the effective string theory for confining flux tubes and the comparison of the predictions to pure gauge lattice data. A concise presentation of the effective string theory is provided, incorporating recent developments. We summarize the predictions for the spectrum and the profile/width of the flux tube and their comparison to lattice data. The review closes with a short summary of open questions for future research.

  13. Controlling fluxes for microbial metabolic engineering

    OpenAIRE

    Sachdeva, Gairik

    2014-01-01

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

  14. Vertical Josephson Interferometer for Tunable Flux Qubit

    International Nuclear Information System (INIS)

    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. Auroral and photoelectron fluxes in cometary ionospheres

    International Nuclear Information System (INIS)

    The analytical yield spectrum method has been used to ascertain photoelectron and auroral electron fluxes in cometary ionospheres, with a view to determining the effects of cometocentric distances, solar zenith angle, and solar minimum and maximum conditions. Auroral electron fluxes are thus calculated for monoenergetic and observed primary electron spectra; auroral electrons are found to make a larger contribution to the observed electron spectrum than EUV-generated photoelectrons. Good agreement is established with extant theoretical works. 55 refs

  16. Effective string description of confining flux tubes

    Science.gov (United States)

    Brandt, Bastian B.; Meineri, Marco

    2016-08-01

    We review the current knowledge about the theoretical foundations of the effective string theory for confining flux tubes and the comparison of the predictions to pure gauge lattice data. A concise presentation of the effective string theory is provided, incorporating recent developments. We summarize the predictions for the spectrum and the profile/width of the flux tube and their comparison to lattice data. The review closes with a short summary of open questions for future research.

  17. Growth of zircaloy 4 under neutron flux

    International Nuclear Information System (INIS)

    Between 300 and 3850C, and under neutron fluxes between 0.5 and 2.1014n/cm2/s, the growth of zircaloy tubes is nil in the plane perpendicular to the axis, and can be represented by the equation: Δl/l=4.6610-14(phit)sup(0.49) in the axial direction. In the area investigated, neither the irradiation temperature nor the instantaneous flux has any effect on the metallurgical state (relieved or recrystallized)

  18. Flux at a point in MCNP

    International Nuclear Information System (INIS)

    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

  19. Determination flux in the Reactor JEN-1

    International Nuclear Information System (INIS)

    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

  20. Magnetic Flux and Helicity of Magnetic Clouds

    Science.gov (United States)

    Démoulin, P.; Janvier, M.; Dasso, S.

    2016-02-01

    Magnetic clouds (MCs) are formed by flux ropes (FRs) launched from the Sun as part of coronal mass ejections (CMEs). They carry away a large amount of magnetic flux and helicity. The main aim of this study is to quantify these amounts from in situ measurements of MCs at 1 AU. The fit of these data by a local FR model provides the axial magnetic field strength, the radius, the magnetic flux, and the helicity per unit length along the FR axis. We show that these quantities are statistically independent of the position along the FR axis. We then derive the generic shape and length of the FR axis from two sets of MCs. These results improve the estimation of magnetic helicity. Next, we evaluate the total magnetic flux and helicity that cross the sphere of radius of 1 AU, centred at the Sun, per year and during a solar cycle. We also include in the study two sets of small FRs that do not have all the typical characteristics of MCs. While small FRs are at least ten times more numerous than MCs, the magnetic flux and helicity are dominated by the contribution from the larger MCs. In one year they carry away the magnetic flux of about 25 large active regions and the magnetic helicity of 200 of them. MCs carry away an amount of unsigned magnetic helicity similar to the amount estimated for the solar dynamo and that measured in emerging active regions.

  1. Flux expulsion variation in SRF cavities

    CERN Document Server

    Posen, S; Romanenko, A; Melnychuk, O; Sergatskov, D A; Martinello, M; Checchin, M; Crawford, A C

    2015-01-01

    Treating a cavity with nitrogen doping significantly increases $Q_0$ at medium fields, reducing cryogenic costs for high duty factor linear accelerators such as LCLS II. N-doping also makes cavities more sensitive to increased residual resistance due to trapped magnetic flux, making it critical to either have extremely effective magnetic shielding, or to prevent flux from being trapped in the cavity during cooldown. In this paper, we report on results of a study of flux expulsion. We discuss possible ways in which flux can be pinned in the inner surface, outer surface, or bulk of a cavity, and we present experimental results studying these mechanisms. We show that grain structure appears to play a key role and that a cavity that expelled flux poorly changed to expelling flux well after a high temperature furnace treatment. We further show that after furnace treatment, this cavity exhibited a significant improvement in quality factor when cooled in an external magnetic field. We conclude with implications for ...

  2. Ecosystem fluxes of hydrogen: a comparison of flux-gradient methods

    Directory of Open Access Journals (Sweden)

    L. K. Meredith

    2014-03-01

    Full Text Available Our understanding of biosphere-atmosphere exchange has been considerably enhanced by eddy-covariance measurements, however there remain many trace gases, such as molecular hydrogen (H2, for which there are no suitable analytical methods to measure their fluxes by eddy covariance. In such cases, flux-gradient methods can be used to calculate ecosystem-scale fluxes from vertical concentration gradients. The budget of atmospheric H2 is poorly constrained by the limited available observations, thus the ability to quantify and characterize the sources and sinks of H2 by flux-gradient methods in various ecosystems is important. We developed an approach to make nonintrusive, automated measurements of ecosystem-scale H2 fluxes both above and below the forest canopy at the Harvard Forest in Petersham, MA for over a year. We used three flux-gradient methods to calculate the fluxes: two similarity methods that do not rely on a micrometeorological determination of the eddy diffusivity, K, based on (1 trace gases or (2 sensible heat and one flux-gradient method that (3 parameterizes K. We quantitatively assessed the flux-gradient methods on CO2 and H2O by comparison to their simultaneous independent flux measurements via eddy covariance and chambers. All three flux-gradient methods performed well in certain locations, seasons, and times of day, and the best methods were trace gas similarity above and K parameterization below the canopy. Sensible heat similarity required several independent measurements and the results were more variable, in part because those data were only available in the winter when heat fluxes and temperature gradients were small and difficult to measure. Biases were often observed between flux-gradient methods and the independent flux measurements, including at least a 26% difference in nocturnal eddy-derived Net Ecosystem Exchange (NEE and soil chamber measurements. All flux-gradient methods used to calculate above and below canopy H2

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

    DEFF Research Database (Denmark)

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

    2015-01-01

    -frequency contributions to vertical turbulent surface fluxes. For high flux rates (|Sensible heat flux| > 40Wm-2, |latent heat flux|> 20Wm-2 and |CO2 flux|> 100 mmolm-2 d-1/ we found that the average relative difference between fluxes estimated by ogive optimization and the conventional method was low (5–20 %) suggesting...... negligible low-frequency influence and that both methods capture the turbulent fluxes equally well. For flux rates below these thresholds, however, the average relative difference between flux estimates was found to be very high (23–98 %) suggesting non-negligible low-frequency influence...... and that the conventional method fails in separating low-frequency influences from the turbulent fluxes. Hence, the ogive optimization method is an appropriate method of flux analysis, particularly in low-flux environments....

  4. 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

  5. Axionic Mirage Mediation

    CERN Document Server

    Nakamura, Shuntaro; Yamaguchi, Masahiro

    2008-01-01

    Although the mirage mediation is one of the most plausible mediation mechanisms of supersymmetry breaking, it suffers from two crucial problems. One is the \\mu-/B \\mu-problem and the second is the cosmological one. The former stems from the fact that the B parameter tends to be comparable with the gravitino mass, which is two order of magnitude larger than the other soft masses. The latter problem is caused by the decay of the modulus whose branching ratio into the gravitino pair is sizable. In this paper, we propose a model of mirage mediation, in which Peccei-Quinn symmetry is incorporated. In this \\textit{axionic mirage mediation}, it is shown that the PQ symmetry breaking scale is dynamically determined around 10^{10-12} GeV due to the supersymmetry breaking effects, and the \\mu-problem can be solved naturally. Furthermore, in our model, the lightest supersymmetric particle (LSP) is the axino, that is the superpartner of the axion. The overabundance of the LSPs due to decays of modulus/gravitino, which is...

  6. Inflammatory mediators in osteoarthritis

    NARCIS (Netherlands)

    Beekhuizen, M.

    2014-01-01

    Osteoarthritis (OA) is a degenerative joint disorder involving cartilage destruction and joint inflammation. Despite extensive research, still much is unknown on the pathogenesis and aetiology of OA. Inflammation and inflammatory mediators (both local and systemic) are key in the pathogenesis of OA.

  7. Thermally favourable gauge mediation

    International Nuclear Information System (INIS)

    We discuss the thermal evolution of the spurion and messenger fields of ordinary gauge mediation models taking into account the Standard Model degrees of freedom. It is shown that for thermalized messengers the metastable susy breaking vacuum becomes thermally selected provided that the susy breaking sector is sufficiently weakly coupled to messengers or to any other observable field.

  8. Den sundhedsfremmende mediator

    DEFF Research Database (Denmark)

    Læssøe, Jeppe

    2009-01-01

    mediering samt mellem forskellige mediator-roller og tilhørsforhold. Det er også vigtigt at være bevidst om de centrale kvaliteter, risici og dilemmaer, som mediering indebærer i forhold til involvering af borgerne. Denne artikel rummer et bud på en sådan nuanceret begrebsliggørelse og refleksion, relateret...

  9. Bradykinin-mediated angioedema.

    Science.gov (United States)

    Obtułowicz, Krystyna

    2016-02-01

    Angioedema and urticaria often constitute a challenge in daily clinical practice. They may either co- -occur or present as independent conditions. They are characterized by a complex pathomechanism, and their symptoms may be triggered by diverse factors. These differences are crucial for developing a successful treatment regimen. Both conditions may have an allergic origin (immunoglobulin [Ig] E and non-IgE-related), usually induced by histamine, or a nonallergic one, such as bradykinin-mediated angioedema in patients with C1 inhibitor (C1-INH) deficiency or angioedema induced by certain drugs (eg, angiotensin-converting enzyme inhibitors). Currently, we distinguish 5 types of nonallergic angioedema: hereditary angioedema (HAE) due to C1-INH deficiency, acquired angioedema (AAE), and angioedema induced by the renin-angiotensin-aldosterone system, all of which are mediated by bradykinin, as well as pseudoallergic angioedema and idiopathic angioedema. Bradykinin-mediated angioedema (eg, laryngeal angioedema) may be life-threatening because of resistance to corticosteroids and antihistamine drugs. C1-INH concentrates are the drugs of choice in the treatment of HAE and AAE. In recent years, some new drugs have been introduced in the treatment of bradykinin-mediated angioedema, such as bradykinin B2-receptor antagonist, icatibant, and kallikrein inhibitor, ecallantide, which allow to improve treatment outcomes. PMID:26842379

  10. Sr flux stability against oxidation in oxide-MBE environment: flux, geometry, and pressure dependence

    OpenAIRE

    Kim, Y.S.; Bansal, Namrata; Chaparro, Carlos; Gross, Heiko; Oh, Seongshik

    2011-01-01

    Maintaining stable fluxes for multiple source elements is a challenging task when the source materials have significantly different oxygen affinities in a complex-oxide molecular-beam-epitaxy (MBE) environment. Considering that Sr is one of the most easily oxidized and widely used element in various complex oxides, we took Sr as a probe to investigate the flux stability problem in a number of different conditions. Source oxidation was less for higher flux, extended port geometry, and un-melte...

  11. Latent and sensible heat fluxes overestimated and net heat flux underestimated in Lake Victoria

    CERN Document Server

    Verburg, Piet

    2014-01-01

    Cozar et al. (2012) used remotely-sensed data to link phytoplankton growth to the net heat flux in both the northern and southern parts of Lake Victoria. However, the latent and sensible heat fluxes were overestimated by ~26% by assuming a constant air density of 1.3 kg m-3. As a result, the net heat flux was underestimated, bringing into question conclusions regarding the convective circulation.

  12. Numerical Simulations of a Flux Rope Ejection

    Indian Academy of Sciences (India)

    P. Pagano; D. H. Mackay; S. Poedts

    2015-03-01

    Coronal mass ejections (CMEs) are the most violent phenomena observed on the Sun. One of the most successful models to explain CMEs is the flux rope ejection model, where a magnetic flux rope is expelled from the solar corona after a long phase along which the flux rope stays in equilibrium while magnetic energy is being accumulated. However, still many questions are outstanding on the detailed mechanism of the ejection and observations continuously provide new data to interpret and put in the context. Currently, extreme ultraviolet (EUV) images from the Atmospheric Imaging Assembly (AIA) on board the Solar Dynamic Observatory (SDO) are providing new insights into the early phase of CME evolution. In particular, observations show the ejection of magnetic flux ropes from the solar corona and how they evolve into CMEs. However, these observations are difficult to interpret in terms of basic physical mechanisms and quantities, thus, we need to compare equivalent quantities to test and improve our models. In our work, we intend to bridge the gap between models and observations with our model of flux rope ejection where we consistently describe the full life span of a flux rope from its formation to ejection. This is done by coupling the global non-linear force-free model (GNLFFF) built to describe the slow low- formation phase, with a full MHD simulation run with the software MPI-AMRVAC, suitable to describe the fast MHD evolution of the flux rope ejection that happens in a heterogeneous regime. We also explore the parameter space to identify the conditions upon which the ejection is favoured (gravity stratification and magnetic field intensity) and we produce synthesised AIA observations (171 Å and 211 Å). To carry this out, we run 3D MHD simulation in spherical coordinates where we include the role of thermal conduction and radiative losses, both of which are important for determining the temperature distribution of the solar corona during a CME. Our model of flux

  13. Axionic mirage mediation

    International Nuclear Information System (INIS)

    Although mirage mediation is one of the most plausible mediation mechanisms of supersymmetry breaking, it suffers from two crucial problems. One is the μ/Bμ problem, and the second is the cosmological one. The former stems from the fact that the B parameter tends to be comparable with the gravitino mass, which is 2 orders of magnitude larger than the other soft masses. The latter problem is caused by the decay of the modulus whose branching ratio into the gravitino pair is sizable. In this paper, we propose a model of mirage mediation, in which Peccei-Quinn symmetry is incorporated. In this axionic mirage mediation, it is shown that the Peccei-Quinn symmetry breaking scale is dynamically determined around 1010 GeV to 1012 GeV due to the supersymmetry breaking effects, and the μ problem can be solved naturally. Furthermore, in our model, the lightest supersymmetric particle (LSP) is the axino, that is, the superpartner of the axion. The overabundance of the LSPs due to decays of the modulus/gravitino, which is the most serious cosmological difficulty in the mirage mediation, can be avoided if the axino is sufficiently light. The next-LSPs (NLSPs) produced by the gravitino decay eventually decay into the axino LSPs, yielding the dominant component of the axinos remaining today. It is shown that the axino with a mass of O(100) MeV is naturally realized, which can constitute the dark matter of the Universe, with a free-streaming length of the order of 0.1 Mpc. The saxion, the real scalar component of the axion supermultiplet, can also be cosmologically harmless due to the dilution of the modulus decay. The lifetime of the NLSP is relatively long, but much shorter than 1 sec, when the big-bang nucleosynthesis commences. The decay of the NLSP would provide intriguing collider signatures

  14. The SeaFlux Turbulent Flux Dataset Version 1.0 Documentation

    Science.gov (United States)

    Clayson, Carol Anne; Roberts, J. Brent; Bogdanoff, Alec S.

    2012-01-01

    Under the auspices of the World Climate Research Programme (WCRP) Global Energy and Water cycle EXperiment (GEWEX) Data and Assessment Panel (GDAP), the SeaFlux Project was created to investigate producing a high-resolution satellite-based dataset of surface turbulent fluxes over the global oceans. The most current release of the SeaFlux product is Version 1.0; this represents the initial release of turbulent surface heat fluxes, associated near-surface variables including a diurnally varying sea surface temperature.

  15. Flux mapping system for AHWR critical facility

    International Nuclear Information System (INIS)

    A software for flux mapping system (FMS) for AHWR critical facility has been developed. The system consists of 25 LEU based pulse detectors and associated software. The objective of the FMS is to obtain the flux profiles over the central 5 x 5 lattice locations. For development of flux mapping system it is required to compute the higher harmonics of the diffusion equation. These harmonics (also called λ-modes) are the eigen functions of multi-group diffusion equation. The fundamental mode is found by power iteration method. Apart from the fundamental mode, other higher modes are evaluated by subtraction technique. In the present paper, fundamental eigenvalue and eigenfunction are evaluated by finite difference method. The bi-orthogonality relations between the direct and adjoint eigenvectors are used for this purpose. The reference core for AHWR has been simulated by computer code FINSQR. Two group lattice cell data have been generated using transport theory code WIMSD and its associated 69-group nuclear data library. The reactor core along with the surrounding radial and axial reflector was represented using 3243 mesh points. In total 5 λ-modes and corresponding eigenvalues have been estimated. The computer code FMS has been developed specifically for AHWR/PHWR critical facility. Flux construction at 5 x 5 lattice locations of the core has been achieved by using observed fluxes at 25 detector locations and linear combinations of pre calculated eigen functions. Combining coefficients have been computed by least square method. To validate the code, we have used computer code based on Monte Carlo method for estimation of thermal fluxes at a few discrete locations. The fluxes were estimated using ENDF/B-VI point nuclear data library. (author)

  16. Stellar Coronal Response to Differential Rotation and Flux Emergence

    CERN Document Server

    Gibb, G P S; Jardine, M M; Yeates, A R

    2016-01-01

    We perform a numerical parameter study to determine what effect varying differential rotation and flux emergence has on a star's non-potential coronal magnetic field. In particular we consider the effects on the star's surface magnetic flux, open magnetic flux, mean azimuthal field strength, coronal free magnetic energy, coronal heating and flux rope eruptions. To do this, we apply a magnetic flux transport model to describe the photospheric evolution, and couple this to the non-potential coronal evolution using a magnetofrictional technique. A flux emergence model is applied to add new magnetic flux onto the photosphere and into the corona. The parameters of this flux emergence model are derived from the solar flux emergence profile, however the rate of emergence can be increased to represent higher flux emergence rates than the Sun's. Overall we find that flux emergence has a greater effect on the non-potential coronal properties compared to differential rotation, with all the aforementioned properties incr...

  17. Mediation Analysis with Principal Stratification

    OpenAIRE

    Gallop, Robert; Small, Dylan; Lin, Julia Y.; Elliot, Michael R.; Joffe, Marshall; Ten Have, Thomas R.

    2009-01-01

    In assessing the mechanism of treatment efficacy in randomized clinical trials, investigators often perform mediation analyses by analyzing if the significant intent-to-treat treatment effect on outcome occurs through or around a third intermediate or mediating variable: indirect and direct effects, respectively. Standard mediation analyses assume sequential ignorability, i.e., conditional on covariates the intermediate or mediating factor is randomly assigned, as is the treatment in a random...

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

    Science.gov (United States)

    Sievers, J.; Papakyriakou, T.; Larsen, S. E.; Jammet, M. M.; Rysgaard, S.; Sejr, M. K.; Sørensen, L. L.

    2015-02-01

    Estimating representative surface fluxes using eddy covariance leads invariably to questions concerning inclusion or exclusion of low-frequency flux contributions. For studies where fluxes are linked to local physical parameters and up-scaled through numerical modelling efforts, low-frequency contributions interfere with our ability to isolate local biogeochemical processes of interest, as represented by turbulent fluxes. No method currently exists to disentangle low-frequency contributions on flux estimates. Here, we present a novel comprehensive numerical scheme to identify and separate out low-frequency contributions to vertical turbulent surface fluxes. For high flux rates (|Sensible heat flux| > 40 Wm-2, |latent heat flux|> 20 Wm-2 and |CO2 flux|> 100 mmol m-2 d-1 we found that the average relative difference between fluxes estimated by ogive optimization and the conventional method was low (5-20%) suggesting negligible low-frequency influence and that both methods capture the turbulent fluxes equally well. For flux rates below these thresholds, however, the average relative difference between flux estimates was found to be very high (23-98%) suggesting non-negligible low-frequency influence and that the conventional method fails in separating low-frequency influences from the turbulent fluxes. Hence, the ogive optimization method is an appropriate method of flux analysis, particularly in low-flux environments.

  19. Freshwater fluxes through the Western Fram Strait

    Science.gov (United States)

    Meredith, Michael; Heywood, Karen; Dennis, Paul; Goldson, Laura; White, Rowan; Fahrbach, Eberhard; Schauer, Ursula; Østerhus, Svein

    Two hydrographic and δ18O transects across Fram Strait (Aug-Sept 1997, 1998) are used to examine freshwater contributions to the East Greenland Current (EGC). The EGC featured up to ˜16% meteoric water in both years, but was made comparatively more saline through the formation of up to ˜11 m of sea ice. We derive meteoric water fluxes of ˜3680 km³yr-1 in Aug-Sept 1997, and ˜2000 km³yr-1 in Aug-Sept 1998. The 1997 and 1998 data show a long-term mean sea ice flux through Fram Strait around half the long-term mean meteoric water flux. A 1991 δ18O section [Bauch et al., 1995] yielded a very similar ratio. Our 1998 section reveals fresh, low-δ18O water on the East Greenland shelf whose comparatively large volume constitutes a potentially significant contribution to the total freshwater flux through Fram Strait. Such fluxes are important to the regional and global thermohaline circulation; we suggest that efforts towards monitoring both the EGC and East Greenland shelf waters are thus required.

  20. Interface-flux nodal transport method

    International Nuclear Information System (INIS)

    The development of the interface-flux nodal (IFN) method is presented to determine the flux distribution in reactor cells, cores and shielding. The method offers geometric flexibility, high order of spatial expansions of the node-interior sources and the node surface quantities. The surface-integral formulation is reduced to response-matrix-like global equations through coupling coefficients which are generalized expressions for escape and transmission probabilities. The spatial distribution of the neutron flux may be represented by high order polynomials using geometric basis functions determined by a least-square minimalization technique. The angular dependency of the outgoing/incoming surface flux components is treated using a general DPn expansion and the spatial variation is handled with a boundary element technique. The scattering iterations are eliminated by using an explicit expansion of the scalar fluxes. Based on the IFN method a computer code has been developed capable of calculating fixed-source and eigenvalue problems. Test problems for 1-D and 2-d X-Y and hexagonal geometries are presented including comparison with other techniques to demonstrate the validity and accuracy of the IFN method. 15 refs., 3 figs., 5 tabs

  1. Neutron flux oscillations at German BWRs

    International Nuclear Information System (INIS)

    Neutron flux oscillations are a well known phenomenon for boiling water reactors (BWRs). The oscillations can occur in a specific region of power and core flow map. The oscillations themselves are caused by interdependencies between thermo-hydraulic parameters and the reactivity feedback. In the instability region these interdependencies can result in an insufficiently damped oscillation of the neutron flux with increasing amplitudes. It cannot be excluded that fuel rod cladding limits may be exceeded if these oscillations are not timely suppressed. During the specified normal operation a BWR should run in stable regions with adequate margins to the instability region. But, during transients the point of operation may enter the instability region. Worldwide several events occurred since the 1980ies related to neutron flux oscillations. Countermeasures have been derived from these events. In the last years, neutron flux oscillations occurred again in some BWRs, especially in Sweden and Germany. The events showed that the combination of advanced fuel assembly design with high burn-up, spectral shift operation, and low leakage core configuration could result in fast increasing neutron flux oscillations following transients. GRS has evaluated these new events under specific consideration of potential out-of-phase oscillations and derived recommendations to prevent, detect and suppress these oscillations. (orig.)

  2. Neutron flux measurement utilizing Campbell technique

    International Nuclear Information System (INIS)

    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)

  3. Evaluation of momentum flux with radar

    Science.gov (United States)

    Riggin, Dennis M.; Tsuda, Toshitaka; Shinbori, Atsuki

    2016-05-01

    The statistics of gravity wave momentum flux estimation are investigated using data from the MU radar at Shigariki, Japan (136°E, 35°N). The radar has been operating during campaign periods since 1986. The first part of the paper focuses on a multi-day campaign during October 13-31, 1986. The second part of the paper investigates data after 2006 when the radar was operated in a meteor scatter mode. Momentum fluxes are derived from both the turbulent scatter and the meteor scatter measurements, but the techniques are quite different. Probability Distribution Functions are formed using turbulent scatter data. These show that wave packets sometimes have momentum flux magnitudes in excess of 100 m2 s-2. The technique for meteor radars, introduced by Hocking (2005), has been widely adopted by the radar community in recent years. The momentum flux estimated using this technique is found to be anti-correlated with the background tidal winds. A validation investigation is carried out for periods with a high meteor echo data rate. The conclusion was that the method can be used to calculate the sign of momentum flux, but does not accurately specify the magnitude.

  4. Z p charged branes in flux compactifications

    Science.gov (United States)

    Berasaluce-González, M.; Cámara, P. G.; Marchesano, F.; Uranga, A. M.

    2013-04-01

    We consider 4d string compactifications in the presence of fluxes, and classify particles, strings and domain walls arising from wrapped branes which have charges conserved modulo an integer p, and whose annihilation is catalized by fluxes, through the Freed-Witten anomaly or its dual versions. The Z p -valued strings and particles are associated to Z p discrete gauge symmetries, which we show are realized as discrete subgroups of 4d U(1) symmetries broken by their Chern-Simons couplings to the background fluxes. We also describe examples where the discrete gauge symmetry group is actually non-Abelian. The Z p -valued domain walls separate vacua which have different flux quanta, yet are actually equivalent by an integer shift of axion fields (or further string duality symmetries). We argue that certain examples are related by T-duality to the realization of discrete gauge symmetries and Z p charges from torsion (co)homology. At a formal level, the groups classifying these discrete charges should correspond to a generalization of K-theory in the presence of general fluxes (and including fundamental strings and NS5-branes).

  5. Magnetic flux density in the heliosphere

    Science.gov (United States)

    Balogh, André; Erdös, Géza

    2013-04-01

    Recently it was shown that the evaluation of the open magnetic flux in the heliosphere is strongly affected by the fluctuations of the field. A new method of data analysis has been developed which effectively reduces the bias introduced by the fluctuations (Erdős, G., & Balogh, A., Ap. J. 753:130, 2012). As a result, the magnetic flux density has been shown to be highly uniform in the heliosphere with respect to latitude and longitude. Also, a regular R-2 form decay by heliospheric distance of the flux density was established. In the present paper these results are further investigated by analysing magnetic field measurements by spacecraft in various heliospheric locations. The main data sources are from observations by ACE, STEREO A and B, and Ulysses; these observations cover a large range of latitude and longitude in location and almost two complete solar cycles in time. Special focus is devoted to the search for any possible longitudinal variations of the magnetic flux density in the ecliptic, in particular as related to CIRs and CMEs and the way these affect the observed relationship between the open solar magnetic field and the heliospheric flux density.

  6. Microtubule Flux Mediates Poleward Motion of Acentric Chromosome Fragments during Meiosis in Insect SpermatocytesV⃞

    OpenAIRE

    LaFountain, James R.; Oldenbourg, Rudolf; Cole, Richard W.; Rieder, Conly L

    2001-01-01

    We applied a combination of laser microsurgery and quantitative polarization microscopy to study kinetochore-independent forces that act on chromosome arms during meiosis in crane fly spermatocytes. When chromosome arms located within one of the half-spindles during prometa- or metaphase were cut with the laser, the acentric fragments (lacking kinetochores) that were generated moved poleward with velocities similar to those of anaphase chromosomes (∼0.5 μm/min). To determine the mechanism und...

  7. Effects of solar radiation on the abiotic and bacterially mediated carbon flux in aquatic ecosystems

    Energy Technology Data Exchange (ETDEWEB)

    Anesio, A.M.

    2000-05-01

    In this thesis, I studied some of the current aspects of organic matter photochemistry. I analyzed abiotic photo transformations of several types of dissolved (DOM) and particulate organic matter (POM). I also evaluated the effects of photo transformation of several types of DOM on bacteria. Finally, in a field experiment, I analyzed net effects of solar radiation on organic matter decomposition. DOM undergoes several transformations due to solar irradiation. One such transformation is photooxidation of organic matter into inorganic carbon. Results of this Thesis show that photooxidation is ubiquitous to all kinds of organic matter in both dissolved and particulate forms. The intensity of this process depends on several factors, including DOM composition, radiation type and time of exposure. Besides mineralization to inorganic carbon, DOM undergoes other chemical transformations due to UV radiation, with profound consequences to DOM availability for bacteria. Bioavailability was tested by measuring bacterial growth and respiration on irradiated and nonirradiated DOM from several types of humic matter and plant leachates. Irradiation of freshly-leached DOM often produced negative effects on bacteria, whereas irradiation of humic material was followed by stimulation of bacterial growth. The degree of stimulation seems to be related to the initial bioavailability of the DOM and to the capability of the DOM to produce hydrogen peroxide upon irradiation. Other factors also accounted for differences in bacterial response to photochemical modification of DOM, including length and type of irradiation exposure. The effects of solar radiation on litter decomposition were also evaluated using experiments that more closely mimic natural conditions. I could not observe differences between dry weight loss of leaves and culms exposed to solar radiation or kept in darkness, which may be explained by the fact that abiotic decomposition under solar radiation is counterbalanced by negative effects of solar radiation on decomposers.

  8. Physiology of intracellular potassium channels: A unifying role as mediators of counterion fluxes?

    Science.gov (United States)

    Checchetto, Vanessa; Teardo, Enrico; Carraretto, Luca; Leanza, Luigi; Szabo, Ildiko

    2016-08-01

    Plasma membrane potassium channels importantly contribute to maintain ion homeostasis across the cell membrane. The view is emerging that also those residing in intracellular membranes play pivotal roles for the coordination of correct cell function. In this review we critically discuss our current understanding of the nature and physiological tasks of potassium channels in organelle membranes in both animal and plant cells, with a special emphasis on their function in the regulation of photosynthesis and mitochondrial respiration. In addition, the emerging role of potassium channels in the nuclear membranes in regulating transcription will be discussed. The possible functions of endoplasmic reticulum-, lysosome- and plant vacuolar membrane-located channels are also referred to. Altogether, experimental evidence obtained with distinct channels in different membrane systems points to a possible unifying function of most intracellular potassium channels in counterbalancing the movement of other ions including protons and calcium and modulating membrane potential, thereby fine-tuning crucial cellular processes. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-7, 2016', edited by Prof. Paolo Bernardi. PMID:26970213

  9. MACROALGAE MEDIATION OF DISSOLVED ORGANIC NITROGEN FLUXES IN A TEMPERATE COASTAL LAGOON. (U915532)

    Science.gov (United States)

    The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

  10. Cholesterol and ORP1L-mediated ER contact sites control autophagosome transport and fusion with the endocytic pathway.

    Science.gov (United States)

    Wijdeven, Ruud H; Janssen, Hans; Nahidiazar, Leila; Janssen, Lennert; Jalink, Kees; Berlin, Ilana; Neefjes, Jacques

    2016-01-01

    Autophagy is the main homeostatic pathway guiding cytosolic materials for degradation by the lysosome. Maturation of autophagosomes requires their transport towards the perinuclear region of the cell, with key factors underlying both processes still poorly understood. Here we show that transport and positioning of late autophagosomes depends on cholesterol by way of the cholesterol-sensing Rab7 effector ORP1L. ORP1L localizes to late autophagosomes and-under low-cholesterol conditions-contacts the ER protein VAP-A, forming ER-autophagosome contact sites, which prevent minus-end transport by the Rab7-RILP-dynein complex. ORP1L-mediated contact sites also inhibit localization of PLEKHM1 to Rab7. PLEKHM1, together with RILP, then recruits the homotypic fusion and vacuole protein-sorting (HOPS) complex for fusion of autophagosomes with late endosomes and lysosomes. Thus, ORP1L, via its liganding by lipids and the formation of contacts between autophagic vacuoles and the ER, governs the last steps in autophagy that lead to the lysosomal degradation of cytosolic material. PMID:27283760

  11. Coupling of HIV-1 Antigen to the Selective Autophagy Receptor SQSTM1/p62 Promotes T-Cell-Mediated Immunity

    Science.gov (United States)

    Andersen, Aram Nikolai; Landsverk, Ole Jørgen; Simonsen, Anne; Bogen, Bjarne; Corthay, Alexandre; Øynebråten, Inger

    2016-01-01

    Vaccines aiming to promote T-cell-mediated immune responses have so far showed limited efficacy, and there is a need for novel strategies. Studies indicate that autophagy plays an inherent role in antigen processing and presentation for CD4+ and CD8+ T cells. Here, we report a novel vaccine strategy based on fusion of antigen to the selective autophagy receptor sequestosome 1 (SQSTM1)/p62. We hypothesized that redirection of vaccine antigen from proteasomal degradation into the autophagy pathway would increase the generation of antigen-specific T cells. A hybrid vaccine construct was designed in which the antigen is fused to the C-terminus of p62, a signaling hub, and a receptor that naturally delivers ubiquitinated cargo for autophagic degradation. Fusion of the human immunodeficiency virus-1 antigen Gagp24 to p62 resulted in efficient antigen delivery into the autophagy pathway. Intradermal immunization of mice revealed that, in comparison to Gagp24 delivered alone, fusion to p62 enhanced the number of Gagp24-specific interferon-γ-producing T cells, including CD8+ T cells. The strategy may also have the potential to modulate the antigenic peptide repertoire. Because p62 and autophagy are highly conserved between species, we anticipate this strategy to be a candidate for the development of T-cell-based vaccines in humans.

  12. P2X7 receptor-mediated PARP1 activity regulates astroglial death in the rat hippocampus following status epilepticus

    Directory of Open Access Journals (Sweden)

    Ji Yang eKim

    2015-09-01

    Full Text Available Poly(ADP-ribose polymerase-1 (PARP1 plays a regulatory role in apoptosis, necrosis, and other cellular processes after injury. Recently, we revealed that PARP1 regulates the differential neuronal/astroglial responses to pilocarpine-induced status epilepticus (SE in the distinct brain regions. In addition, P2X7 receptor (P2X7R, an ATP-gated ion channel, activation accelerates astroglial apoptosis, while it attenuates clasmatodendrosis (lysosome-derived autophagic astroglial death. Therefore, we investigated whether P2X7R regulates regional specific astroglial PARP1 expression/activation in response to SE. In the present study, P2X7R activation exacerbates SE-induced astroglial apoptosis, while P2X7R inhibition attenuates it accompanied by increasing PARP1 activity in the molecular layer of the dentate gyrus following SE. In the CA1 region, however, P2X7R inhibition deteriorates SE-induced clasmatodendrosis via PARP1 activation following SE. Taken together, our findings suggest that P2X7R function may affect SE-induced astroglial death by regulating PARP1 activation/expression in regional-specific manner. Therefore, the selective modulation of P2X7R-mediated PARP1 functions may be a considerable strategy for controls in various types of cell deaths.

  13. Presenilin 1 Maintains Lysosomal Ca2+ Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification

    Directory of Open Access Journals (Sweden)

    Ju-Hyun Lee

    2015-09-01

    Full Text Available Presenilin 1 (PS1 deletion or Alzheimer’s disease (AD-linked mutations disrupt lysosomal acidification and proteolysis, which inhibits autophagy. Here, we establish that this phenotype stems from impaired glycosylation and instability of vATPase V0a1 subunit, causing deficient lysosomal vATPase assembly and function. We further demonstrate that elevated lysosomal pH in Presenilin 1 knockout (PS1KO cells induces abnormal Ca2+ efflux from lysosomes mediated by TRPML1 and elevates cytosolic Ca2+. In WT cells, blocking vATPase activity or knockdown of either PS1 or the V0a1 subunit of vATPase reproduces all of these abnormalities. Normalizing lysosomal pH in PS1KO cells using acidic nanoparticles restores normal lysosomal proteolysis, autophagy, and Ca2+ homeostasis, but correcting lysosomal Ca2+ deficits alone neither re-acidifies lysosomes nor reverses proteolytic and autophagic deficits. Our results indicate that vATPase deficiency in PS1 loss-of-function states causes lysosomal/autophagy deficits and contributes to abnormal cellular Ca2+ homeostasis, thus linking two AD-related pathogenic processes through a common molecular mechanism.

  14. Models as Mediators

    DEFF Research Database (Denmark)

    Sommerlund, Julie

    from laboratory studies, (Latour 1979; Lynch 1985; Sommerlund 2004 (2007); Sommerlund 2006) and is complemented by the attention paid to the "mediator" by Hennion (1989; 1997; 2005). The empirical focus will be on a central - but overlooked - actor of branding and advertising; the model. The model has...... solely been theorized within cultural studies (Craik 1994) as feminine spectacle, but has been neglected as mediator and actor. This paper will argue that models are co-producers of brands, and vice versa. Empirically, the paper will present interviews with models, model-scouts, agents, and advertisers...... using models in branding-campaigns. The paper will contribute to the field of cultural economy by extending the productive methodology of STS into the fields of branding and marketing, and to the understanding of branding and marketing by focusing on an understudied phenomena - the model - and by...

  15. Fashion, Mediations & Method Assemblages

    DEFF Research Database (Denmark)

    Sommerlund, Julie; Jespersen, Astrid Pernille

    , it is an important ambition of this paper to go into a methodological discussion of how "that which effectively happens" can be approached. To this end, the paper will combine Hennion's term of the "mediator" with John Laws methodological term of "method assemblages". Method assemblages is a suggested as a way...... relations between individuals and social contexts, aesthetics and production, distribution and consumption, as well as relations between fluidity and stability. By addressing the field of fashion, the paper proposes to shed light on an empirical setting which has so far been studied either as a purely...... - Domestication of the Scallops and Fishermen of St. Brieuc Bay. Power, Action, and Belief - A New Sociology of Knowledge. J. Law. London, Routledge and Keagan Paul: 196-233. Hennion, A. (1997). "Baroque and rock: Music, mediators and musical taste." Poetics 24: 414 - 435. Latour, B. (1993). We Have Never Been...

  16. Direct Gaugino Mediation

    International Nuclear Information System (INIS)

    We describe renormalizable supersymmetric four-dimensional theories which lead to gaugino mediation and various generalizations thereof. Even though these models are strongly coupled, we can demonstrate the parametric suppression of soft scalar masses via Seiberg duality. We show that our models have a parameter which continuously interpolates between suppressed soft scalar masses and their conventional gauge mediated contribution. The main physical effect which we utilize is the general relation between massive deformations in one frame and the Higgs mechanism in the dual frame. Some compelling and relatively unexplored phenomenological scenarios arise naturally in this framework. We offer preliminary comments on various aspects of the phenomenology and outline several of the outstanding open problems.

  17. Minimal gaugino mediation

    International Nuclear Information System (INIS)

    We propose minimal gaugino mediation as the simplest known solution to the supersymmetric flavor and CP problems. The framework predicts a very minimal structure for the soft parameters at ultrahigh energies: gaugino masses are unified and non-vanishing whereas all other soft supersymmetry breaking parameters vanish. We show that this boundary condition naturally arises from a small extra dimension and present a complete model which includes a new extra-dimensional solution to the μ problem. We briefly discuss the predicted superpartner spectrum as a function of the two parameters of the model. The commonly ignored renormalization group evolution above the GUT scale is crucial to the viability of minimal gaugino mediation but does not introduce new model dependence

  18. Minimal Gaugino Mediation

    International Nuclear Information System (INIS)

    The authors propose Minimal Gaugino Mediation as the simplest known solution to the supersymmetric flavor and CP problems. The framework predicts a very minimal structure for the soft parameters at ultra-high energies: gaugino masses are unified and non-vanishing whereas all other soft supersymmetry breaking parameters vanish. The authors show that this boundary condition naturally arises from a small extra dimension and present a complete model which includes a new extra-dimensional solution to the mu problem. The authors briefly discuss the predicted superpartner spectrum as a function of the two parameters of the model. The commonly ignored renormalization group evolution above the GUT scale is crucial to the viability of Minimal Gaugino Mediation but does not introduce new model dependence

  19. OPAL REACTOR: Calculation/Experiment comparison of Neutron Flux Mapping in Flux Coolant Channels

    Energy Technology Data Exchange (ETDEWEB)

    Barbot, L.; Domergue, C.; Villard, J. F.; Destouches, C. [CEA, Paris (France); Braoudakis, G.; Wassink, D.; Sinclair, B.; Osborn, J. C.; Huayou, Wu [ANSTO, Syeney (Australia)

    2013-07-01

    The measurement and calculation of the neutron flux mapping of the OPAL research reactor are presented. Following an investigation of fuel coolant channels using sub-miniature fission chambers to measure thermal neutron flux profiles, neutronic calculations were performed. Comparison between calculation and measurement shows very good agreement.

  20. Development of a High Flux Research Reactor with Assembly- Integral Flux Traps

    International Nuclear Information System (INIS)

    In recent years, the demand for irradiation services has increased as research reactors face a number of challenges. These challenges include reduction in enrichment, the need for economical use of fuel, and the medical isotope crisis brought about by the temporary shutdowns of the NRU and HFR. These challenges have inspired the design of a revolutionary research reactor assembly concept making use of the new U-Mo monolithic fuel form. Each assembly consists of a trapezoidal plate-fueled region and integral triangular flux trap. When placed in a hexagonal core, this structure permits multiple orientations of the flux trap with respect to those surrounding it. As a result, multiple orientations, sizes and shapes of the flux trap are possible. These flux trap parameters can be adjusted to provide the spectra needed to meet ever-changing experimental needs. This assembly concept was applied to the development of a 5 MWth research reactor core, and optimized for peak thermal flux. During the design process, attention was given to making the design economical, manufacturable, and maintainable. The design was able to produce a maximum unperturbed thermal flux of 1.2 x 1014 neutrons/cm2 s, 70% higher than existing research reactors of the same power rating. Despite this optimization for thermal flux, the reactor is still capable of producing fast fluxes in excess of 1 x 1014 neutrons/cm2 s in other regions of the core. The response of the resulting core to thermal hydraulic transients was also analyzed. (author)

  1. 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...

  2. Effect of including corner point fluxes on the pin power reconstruction using nodal point flux scheme

    International Nuclear Information System (INIS)

    Highlights: • Including corner fluxes improve pin power reconstruction. • The maximum errors in pin power reconstruction occur in the peripheral water region. • The errors are significantly less in the fuel region. • MSS predictions for corner pin flux are preferable. - Abstract: Although there have been well established transport based codes for core neutronics analysis, it is yet impractical to implement them in the real core treatment because their performance is not so great on ordinary server computers. For this reason, most of neutronics codes for core calculation are subject to two steps calculation procedure which consists of homogenized group constant generation and flux distribution generation which is the main concern of this work. This paper brings out a 2 dimensional nodal code based on point flux algorithm and implements two schemes for pin power reconstruction. In the first scheme, pin power reconstruction is obtained without considering corner point fluxes in the fuel assemblies but in the second method corner fluxes are included to assess their effect on pin power reconstruction. To obtain corner point fluxes, Smith’s procedure and the method of successive smoothing are used. Improvement in pin power reconstruction by including fuel assembly corner fluxes is illustrated in this paper and assessed by Monte Carlo simulation

  3. 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.

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

    International Nuclear Information System (INIS)

    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

  5. Amplitude mediated chimera states

    OpenAIRE

    Sethia, Gautam C.; Sen, Abhijit; Johnston, George L.

    2013-01-01

    We investigate the possibility of obtaining chimera state solutions of the non-local Complex Ginzburg-Landau Equation (NLCGLE) in the strong coupling limit when it is important to retain amplitude variations. Our numerical studies reveal the existence of a variety of amplitude mediated chimera states (including stationary and non-stationary two cluster chimera states), that display intermittent emergence and decay of amplitude dips in their phase incoherent regions. The existence regions of t...

  6. Teachers as mediators

    DEFF Research Database (Denmark)

    Dorf, Hans; Kelly, Peter; Hohmann, Ulrike;

    2012-01-01

    Within the context of lower secondary English teaching in South West England, this study identifies in broad terms the competing goals between which English teachers mediate and the explicit and hidden tensions that result. To understand the interactions of competing goals, teachers’ goal...... cultural influences on practice. Yet the teachers observed moved smoothly between goal-oriented behaviours in a continuous and comfortable style, easily and without reflecting any tensions between them. Thus, this article elaborates an account of situated English teaching....

  7. Strongly magnetized accretion discs require poloidal flux

    Science.gov (United States)

    Salvesen, Greg; Armitage, Philip J.; Simon, Jacob B.; Begelman, Mitchell C.

    2016-05-01

    Motivated by indirect observational evidence for strongly magnetized accretion discs around black holes, and the novel theoretical properties of such solutions, we investigate how a strong magnetization state can develop and persist. To this end, we perform local simulations of accretion discs with an initially purely toroidal magnetic field of equipartition strength. We demonstrate that discs with zero net vertical magnetic flux and realistic boundary conditions cannot sustain a strong toroidal field. However, a magnetic pressure-dominated disc can form from an initial configuration with a sufficient amount of net vertical flux and realistic boundary conditions. Our results suggest that poloidal flux is a necessary prerequisite for the sustainability of strongly magnetized accretion discs.

  8. Intrinsic Thickness of QCD Flux-Tubes

    CERN Document Server

    Vyas, Vikram

    2010-01-01

    The effects of finite intrinsic thickness of QCD flux-tubes are explored using gauge/gravity duality under the assumptions that the position of the string in the fifth dimension is related to the intrinsic thickness of the QCD flux-tube, and the action of the five-dimensional fundamental string is the Nambu-Goto action. Under these assumptions the static quark-antiquark potential is calculated in the large d approximation, where d is the number of transverse direction in the flat space where the gauge theory lives. The potential is found to be given by Arvis's formula corrected by an exponentially suppressed term, which can be thought of as arising from the fluctuations of the intrinsic thickness of the QCD flux-tube. This result suggests that when the effects of intrinsic thickness can be ignored, then the four-dimensional effective string theory is just the Nambu-Goto string with no additional marginal or irrelevant terms.

  9. Internal analysis of a transverse flux sensor

    Energy Technology Data Exchange (ETDEWEB)

    Voyant, J.-Yves [Laboratoire d' Electrotechnique de Grenoble-UMR 5529 INPG/UJF-CNRS-ENSIEG, BP 46, 38402 Saint-Martin-d' Heres Cedex (France)]. E-mail: jean-yves.voyant@leg.ensieg.inpg.fr; Yonnet, J.-Paul [Laboratoire d' Electrotechnique de Grenoble-UMR 5529 INPG/UJF-CNRS-ENSIEG, BP 46, 38402 Saint-Martin-d' Heres Cedex (France); Jay, Guillaume [Precilec, 41, 47 rue Guynemer, B.P. 239, 89002 AUXERRE Cedex (France); Foucher, Christian [Precilec, 41, 47 rue Guynemer, B.P. 239, 89002 AUXERRE Cedex (France)

    2005-04-15

    Rotary variable differential transformer (RVDT) sensors are used for industrial applications and are appreciated for their frictionless operation, reliability, linearity and sensitivity. The sensor shown here derives from a classic RVDT and is based on a differential rotating transformer. The functioning principle is explained and experimental measurements are shown. The originality of the studied sensor lies in the transverse flux design which gives a linearity error less than 0.1% of the stroke. However, this transverse flux circulation has uncommon features for an electrotechnical system due to flux paths which are not enclosed in radial planes. Finite element and experimental analysis are used for the magnetic study. This study aims to enhance sensor performances and manufacturing easiness.

  10. Comic ray flux anisotropies caused by astrospheres

    CERN Document Server

    Scherer, K; Ferreira, S E S; Fichtner, H

    2016-01-01

    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 $r_{0}$, to the outer boundary. It turns out that such small-scale sinks can influence the cosmic ray flux at the observer's location by a few permille (i.e\\ a few 0.1\\%), which is in the range of the observations by IceCube, Milagro and other large area telescopes.

  11. Super-radiance and flux conservation

    CERN Document Server

    Boonserm, Petarpa; Visser, Matt

    2014-01-01

    The theoretical foundations of the phenomenon known as super-radiance still continues to attract considerable attention. Despite many valiant attempts at pedagogically clear presentations, the effect nevertheless still continues to generate some significant confusion. Part of the confusion arises from the fact that super-radiance in a quantum field theory [QFT] context is not the same as super-radiance (super-fluorescence) in some condensed matter contexts; part of the confusion arises from traditional but sometimes awkward normalization conventions, and part is due to sometimes unnecessary confusion between fluxes and probabilities. We shall argue that the key point underlying the effect is flux conservation, (and, in the presence of dissipation, a controlled amount of flux non-conservation), and that attempting to phrase things in terms of reflection and transmission probabilities only works in the absence of super-radiance. To help clarify the situation we present a simple exactly solvable toy model exhibi...

  12. Strongly magnetized accretion discs require poloidal flux

    CERN Document Server

    Salvesen, Greg; Simon, Jacob B; Begelman, Mitchell C

    2016-01-01

    Motivated by indirect observational evidence for strongly magnetized accretion discs around black holes, and the novel theoretical properties of such solutions, we investigate how a strong magnetization state can develop and persist. To this end, we perform local simulations of accretion discs with an initially purely toroidal magnetic field of equipartition strength. We demonstrate that discs with zero net vertical magnetic flux and realistic boundary conditions cannot sustain a strong toroidal field. However, a magnetic pressure-dominated disc can form from an initial configuration with a sufficient amount of net vertical flux and realistic boundary conditions. Our results suggest that poloidal flux is a necessary prerequisite for the sustainability of strongly magnetized accretion discs.

  13. Heat-Flux Gage thermophosphor system

    Energy Technology Data Exchange (ETDEWEB)

    Tobin, K.W.

    1991-08-01

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

  14. Magnetic Flux Quantization of the Landau Problem

    Science.gov (United States)

    Wang, Jianhua; Li, Kang; Long, Shuming; Yuan, Yi

    2014-08-01

    Landau problem has a very important application in modern physics, in which two-dimensional electron gas system and quantum Hall effect are outstanding. In this paper, first we review the solution of the Pauli equation, then using the single electron wave function, we calculate moving area expectations of the ideal 2-dimensional electron gas system and the per unit area's degeneracy of the electron gas system. As a result, how to calculate the magnetic flux of the electron gas system is given. It shows that the magnetic flux of 2-dimensional electron gas system in magnetic field is quantized, and magnetic flux quantization results from the quantization of the moving area expectations of electron gas system.

  15. 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.

  16. One-sided flux of fermions

    International Nuclear Information System (INIS)

    In the one-body window-friction pricture for inelastic heavy-ion collisions the one-sided flux of nucleons passing the window in the mean potential plays the role of the frictional form factor. In this paper a quantum mechanical operator for the one-sided flux is defined. Its expectation value calculated with any given many-body wave function yields the number of particles crossing an area element dA vector per unit time in one direction. The quantum one-sided flux is compared to the classical one calculated with a uniform momentum distribution up to the Fermi momentum. The wave function was taken from a model calculation for a fermion gas in a one-dimensional box. 1 figure

  17. Strongly magnetized accretion discs require poloidal flux

    Science.gov (United States)

    Salvesen, Greg; Armitage, Philip J.; Simon, Jacob B.; Begelman, Mitchell C.

    2016-08-01

    Motivated by indirect observational evidence for strongly magnetized accretion discs around black holes, and the novel theoretical properties of such solutions, we investigate how a strong magnetization state can develop and persist. To this end, we perform local simulations of accretion discs with an initially purely toroidal magnetic field of equipartition strength. We demonstrate that discs with zero net vertical magnetic flux and realistic boundary conditions cannot sustain a strong toroidal field. However, a magnetic pressure-dominated disc can form from an initial configuration with a sufficient amount of net vertical flux and realistic boundary conditions. Our results suggest that poloidal flux is a necessary prerequisite for the sustainability of strongly magnetized accretion discs.

  18. Real Time Flux Control in PM Motors

    Energy Technology Data Exchange (ETDEWEB)

    Otaduy, P.J.

    2005-09-27

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

  19. U-dual fluxes and Generalized Geometry

    CERN Document Server

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

    2010-01-01

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

  20. Open string wavefunctions in flux compactifications

    CERN Document Server

    Cámara, Pablo G

    2009-01-01

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

  1. More Dual Fluxes and Moduli Fixing

    CERN Document Server

    Aldazabal, G; Font, A; Ibáñez, L E

    2006-01-01

    We generalize the recent proposal that invariance under T-duality leads to additional non-geometric fluxes required so that superpotentials in type IIA and type IIB orientifolds match. We show that invariance under type IIB S-duality requires the introduction of a new set of fluxes leading to further superpotential terms. We find new classes of N=1 supersymmetric Minkowski vacua based on type IIB toroidal orientifolds in which not only dilaton and complex moduli but also Kahler moduli are fixed. The chains of dualities relating type II orientifolds to heterotic and M-theory compactifications suggests the existence of yet further flux degrees of freedom. Restricting to a particular type IIA/IIB or heterotic compactification only some of these degrees of freedom have a simple perturbative and/or geometric interpretation.

  2. From Hubble's NGSL to Absolute Fluxes

    Science.gov (United States)

    Heap, Sara R.; Lindler, Don

    2012-01-01

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

  3. Footprint prediction of scalar fluxes - Reliability and implications for airborne flux measurements over the FIFE site

    Science.gov (United States)

    Schuepp, P. H.; Desjardins, R. L.; Macpherson, J. I.; Leclerc, M. Y.

    1990-01-01

    Estimates of the location and extension of the upwind ground area that affects flux observations most directly are examined to determine the reliability of airborne versus near-ground flux measurements. The theoretical issues regarding the 'footprint' are examined, and specific observations are analyzed by studying the data over a grid regarding sensible heat, latent heat, CO2, and greenness. The grid is footprint-corrected to correlate better with independently observed surface characteristics, and an optimized footprint is developed that satisfies the relationships between the observed variables. Optimized mapping of the surface flux is given which demonstrates the importance of considering local advection to correlate airborne and ground-based flux observations. The technique is particularly applicable to situations in which significant variations in the surface flux density exist.

  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. CURRENT BUILDUP IN EMERGING SERPENTINE FLUX TUBES

    International Nuclear Information System (INIS)

    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.

  6. 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. PMID:23131418

  7. Superpotentials in IIA compactifications with general fluxes

    International Nuclear Information System (INIS)

    We derive the effective N=1, D=4 supergravity for the seven main moduli of type IIA orientifolds with D6-branes, compactified on T6/(Z2xZ2) in the presence of general fluxes. We illustrate and apply a general method that relates the N=1 effective Kahler potential and superpotential to a consistent truncation of gauged N=4 supergravity. We identify the correspondence between various admissible fluxes, N=4 gaugings and N=1 superpotential terms. We construct explicit examples with different features: in particular, new IIA no-scale models and a model which admits a supersymmetric AdS4 vacuum with all seven main moduli stabilized

  8. High flux source of cold rubidium atoms

    International Nuclear Information System (INIS)

    We report on the production of a continuous, slow, and cold beam of 87Rb atoms with an extremely high flux of 3.2x1012 atoms/s, a transverse temperature of 3 mK, and a longitudinal temperature of 90 mK. We describe the apparatus created to generate the atom beam. Hot atoms are emitted from a rubidium candlestick atomic beam source and transversely cooled and collimated by a 20 cm long atomic collimator section, boosting overall beam flux by a factor of 50. The Rb atomic beam is then decelerated and longitudinally cooled by a 1 m long Zeeman slower

  9. High flux source of cold rubidium atoms

    Science.gov (United States)

    Slowe, Christopher; Vernac, Laurent; Hau, Lene Vestergaard

    2005-10-01

    We report on the production of a continuous, slow, and cold beam of Rb87 atoms with an extremely high flux of 3.2×1012atoms/s, a transverse temperature of 3mK, and a longitudinal temperature of 90mK. We describe the apparatus created to generate the atom beam. Hot atoms are emitted from a rubidium candlestick atomic beam source and transversely cooled and collimated by a 20cm long atomic collimator section, boosting overall beam flux by a factor of 50. The Rb atomic beam is then decelerated and longitudinally cooled by a 1m long Zeeman slower.

  10. A High Flux Source of Cold Rubidium

    CERN Document Server

    Slowe, C; Hau, L V; Slowe, Christopher; Vernac, Laurent; Hau, Lene Vestergaard

    2004-01-01

    We report the production of a continuous, slow, and cold beam of 87-Rb atoms with an unprecedented flux of 3.2 x 10^12 atoms/s and a temperature of a few milliKelvin. Hot atoms are emitted from a Rb candlestick atomic beam source and transversely cooled and collimated by a 20 cm long atomic collimator section, augmenting overall beam flux by a factor of 50. The atomic beam is then decelerated and longitudinally cooled by Zeeman slowing.

  11. Interplanetary magnetic flux - Measurement and balance

    Science.gov (United States)

    Mccomas, D. J.; Gosling, J. T.; Phillips, J. L.

    1992-01-01

    A new method for determining the approximate amount of magnetic flux in various solar wind structures in the ecliptic (and solar rotation) plane is developed using single-spacecraft measurements in interplanetary space and making certain simplifying assumptions. The method removes the effect of solar wind velocity variations and can be applied to specific, limited-extent solar wind structures as well as to long-term variations. Over the 18-month interval studied, the ecliptic plane flux of coronal mass ejections was determined to be about 4 times greater than that of HFDs.

  12. Statistical analysis of radon flux measurements

    International Nuclear Information System (INIS)

    The radon emerging from the earth's surface can be used in classifying lands for development purposes. Radon flux is subject to diurnal variation, weather variables, seasonal fluctuations. Statistical sampling procedures are applied to this problem to ascertain the proper spacing of sampling points, the number of samples taken at each point per day, and the number of days in the sampling program to establish the exhalation rate at a known precision. Results from small and large pieces of land showed that reliable radon flux measurements require extensive sampling programs

  13. Atmospheric electron flux at airplane altitude

    International Nuclear Information System (INIS)

    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. On LBNE neutrino flux systematic uncertainties

    Science.gov (United States)

    Lebrun, Paul L. G.; Hylen, James; Marchionni, Alberto; Fields, Laura; Bashyal, Amit; Park, Seongtae; Watson, Blake

    2015-10-01

    The systematic uncertainties in the neutrino flux of the Long-Baseline Neutrino Experiment, due to alignment uncertanties and tolerances of the neutrino beamline components, are estimated. In particular residual systematics are evaluated in the determination of the neutrino flux at the far detector, assuming that the experiment will be equipped with a near detector with the same target material of the far detector, thereby canceling most of the uncertainties from hadroproduction and neutrino cross sections. This calculation is based on a detailed Geant4-based model of the neutrino beam line that includes the target, two focusing horns, the decay pipe and ancillary items, such as shielding.

  15. 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)

    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 PB80In20 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 Pb60In40 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 Pb60In40 after cold working are also discussed

  16. 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.

  17. An Alternative Framework for Defining Mediation.

    Science.gov (United States)

    Collins, Linda M.; Graham, John W.; Flaherty, Brian P.

    1998-01-01

    Presents an alternative framework for evaluating mediated relationships. The distinguishing feature of mediation is that mediation involves a chain reaction. The definition presented emphasizes the intra-individual, time-ordered nature of mediation. (SLD)

  18. The C-shunt Flux Qubit: A New Generation of Superconducting Flux Qubit

    Science.gov (United States)

    Birenbaum, Jeffrey Scott

    While quantum computation has the potential to revolutionize the scientific community, to date no architecture has been developed which offers the necessary combination of high coherence times and massive scalability. Superconducting flux qubits satisfy the second requirement well but to date useful devices are limited to coherence times of typically only a few mus. In this dissertation we examine the possibilities of improving the coherence performance of the flux qubit to the levels required for fault-tolerant quantum computation. We find that coherence times for many devices are limited by photon-induced quasiparticles and mitigation of these quasiparticles increases coherence times by more than a factor of two. Beyond this, however, we find little improvement in flux qubit performance compared to prior results. Despite improved fabrication techniques and varied device designs we find flux qubit coherence times are still typically below 5 mus. Furthermore, wide device-to-device variations are observed which prevent effective scaling of the flux qubit to quantum information circuits. Based on the proposal by You, et al. we develop of a capacitively-shunted version of the flux qubit called the C-shunt flux qubit. With the addition of a capacitive shunt across the small junction of the flux qubit we are able to reduce the amplitude sensitivity to both charge and flux noise by more than a factor of three. The result is a predicted ten-fold enhancement in the coherence times compared to the unshunted flux qubit. At the same time we preserve much of the anharmonicity of the flux qubit resulting in a device with coherence times comparable to modern transmons but with a factor of four better anharmonicity and more flexible coupling configurations. By using a high-quality MBE aluminum shunt process on an annealed sapphire substrate coupled with a more conventional electron-beam-evaporated aluminum Josephson junction process we fabricate hybrid C-shunt flux qubits. We

  19. Atmospheric neutrino flux at INO, South Pole and Pyhaesalmi

    Energy Technology Data Exchange (ETDEWEB)

    Sajjad Athar, M., E-mail: sajathar@gmail.com [Department of Physics, Aligarh Muslim University, Aligarh-202002 (India); Honda, M., E-mail: mhonda@icrr.u-tokyo.ac.jp [Institute for Cosmic Ray Research, the University of Tokyo, 5-1-5 Kashiwa-no-ha, Kashiwa, Chiba 277-8582 (Japan); Kajita, T., E-mail: kajita@icrr.u-tokyo.ac.jp [Kavli Institute for the Physics and the Mathematics of the Universe, the University of Tokyo, 5-1-5 Kashiwa-no-ha, Kashiwa, Chiba 277-8582 (Japan); Institute for Cosmic Ray Research, the University of Tokyo, 5-1-5 Kashiwa-no-ha, Kashiwa, Chiba 277-8582 (Japan); Kasahara, K., E-mail: kasahara@icrc.u-tokyo.ac.jp [Research Institute for Science and Engineering, Waseda University, 3-4-1 Okubo Shinjuku-ku, Tokyo, 169-8555 (Japan); Midorikawa, S., E-mail: midori@aomori-u.ac.jp [Faculty of Software and Information Technology, Aomori University, Aomori, 030-0943 (Japan)

    2013-01-29

    We present the calculation of the atmospheric neutrino fluxes for the neutrino experiments proposed at INO, South Pole and Pyhaesalmi. Neutrino fluxes have been obtained using ATMNC, a simulation code for cosmic ray in the atmosphere. Even using the same primary flux model and the interaction model, the calculated atmospheric neutrino fluxes are different for the different sites due to the geomagnetic field. The prediction of these fluxes in the present Letter would be quite useful in the experimental analysis.

  20. Autophagic degradation of peroxisomes in mammals

    Science.gov (United States)

    Katarzyna, Zientara-Rytter; Suresh, Subramani

    2016-01-01

    Peroxisomes are essential organelles required for proper cell function in all eukaryotic organisms. They participate in a wide range of cellular processes including the metabolism of lipids and generation, as well as detoxification, of hydrogen peroxide. Therefore, peroxisome homeostasis, manifested by the precise and efficient control of peroxisome number and functionality, must be tightly regulated in response to environmental changes. Due to the existence of many physiological disorders and diseases associated with peroxisome homeostasis imbalance, the dynamics of peroxisomes have been widely examined. The increasing volume of reports demonstrating significant involvement of the autophagy machinery in peroxisome removal leads us to summarize current knowledge of peroxisome degradation in mammalian cells. In this review we present current models of peroxisome degradation. We particularly focus on pexophagy - the selective clearance of peroxisomes through autophagy. We also critically discuss concepts of peroxisome recognition for pexophagy, including signaling and selectivity factors. Finally, we present examples of the pathological effects of pexophagy dysfunction and suggest promising future directions. PMID:27068951