WorldWideScience

Sample records for autophagic flux mediates

  1. Why should autophagic flux be assessed?

    Institute of Scientific and Technical Information of China (English)

    Xiao-jie ZHANG; Sheng CHEN; Kai-xing HUANG; Wei-dong LE

    2013-01-01

    As autophagy is involved in cell growth,survival,development and death,impaired autophagic flux has been linked to a variety of human pathophysiological processes,including neurodegeneration,cancer,myopathy,cardiovascular and immune-mediated disorders.There is a growing need to identify and quantify the status of autophagic flux in different pathological conditions.Given that autophagy is a highly dynamic and complex process that is regulated at multiple steps,it is often assessed accurately.This perspective review article will focus on the autophagic flux defects in different human disorders and update the current methods of monitoring autophagic flux.This knowledge is essential for developing autophagy-related therapeutics for treating the diseases.

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

    Directory of Open Access Journals (Sweden)

    Qinghe Song

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

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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.

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

    OpenAIRE

    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...

  7. Exaggerated arsenic nephrotoxicity in female mice through estrogen-dependent impairments in the autophagic flux.

    Science.gov (United States)

    Kimura, Akihiko; Ishida, Yuko; Nosaka, Mizuho; Kuninaka, Yumi; Hama, Mizuki; Kawaguchi, Takashi; Sakamoto, Shoichi; Shinozaki, Kohei; Iwahashi, Yumi; Takayasu, Tatsunori; Kondo, Toshikazu

    2016-01-01

    Gender is one of the essential factors in the development of various diseases and poisoning. Therefore, we herein examined gender differences in sodium arsenite (NaAsO2)-induced acute renal dysfunction. When male and female BALB/c mice were subcutaneously injected with NaAsO2 (12.5mg/kg), serum and urinary markers for proximal tubular injury were significantly higher in female mice than in male ones. NaAsO2-induced histopathological alterations were consistently more evident in females than in males. Ovariectomy, but not orchiectomy significantly attenuated NaAsO2-induced renal injury. These results imply that the hypersusceptibility of female mice is attributed to estrogen signals. NaAsO2 suppressed the autophagic flux in tubular cells through the activation of ERK. Enhancements in the activation of ERK were significantly greater in females than in males, with the eventual accumulation of LC3-II and P62 in the kidneys, implying that the autophagic flux is impaired in females. The IL-6/STAT3 signaling pathway had protective roles in NaAsO2-induced nephrotoxicity through the suppression of ERK activation. Despite the absence of differences in intrarenal IL-6 expression between male and female mice, STAT3 was less activated with enhanced SOCS3 expression in females than in males. An in vitro study using mProx24 cells revealed that the estrogen treatment induced SOCS3 expression, and eventually suppressed the autophagic flux, as evidenced by greater increases in the accumulation of LC3-II and p62 with ERK activation, which was canceled by the knockdown of Socs3. Collectively, these results indicate that estrogen has a negative impact on the development of NaAsO2 nephrotoxicity through its suppression of the autophagic flux.

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

    Science.gov (United States)

    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

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  10. Monitoring autophagic flux using Ref(2)P, the Drosophila p62 ortholog.

    Science.gov (United States)

    DeVorkin, Lindsay; Gorski, Sharon M

    2014-09-02

    Human p62, also known as Sequestome-1 (SQSTM1), is a multifunctional scaffold protein that contains many domains, including a Phox/Bem1P (PB1) multimerization domain, an ubiquitin-associated (UBA) domain, and a light chain 3 (LC3) recognition sequence. p62 binds ubiquitinated proteins and targets them for degradation by the proteasome. In addition, p62 directly binds LC3; this may serve as a mechanism to deliver ubiquitinated proteins for degradation by autophagy. During this process, p62 itself is degraded. The inhibition of autophagy leads to the accumulation of p62, indicating that it can be used as a marker of autophagic flux. Ref(2)P (refractory to sigma P), the Drosophila ortholog of p62, is also required for the formation of ubiquitinated protein aggregates. Ref(2)P contains a putative LC3-interacting region, and genetic inhibition of autophagy in Drosophila leads to the accumulation of Ref(2)P protein levels. Thus, like p62, Ref(2)P may serve as a marker of autophagic flux. Here we provide two procedures to examine Ref(2)P protein levels in Drosophila ovaries.

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

    Science.gov (United States)

    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

  12. Blocking autophagic flux enhances matrine-induced apoptosis in human hepatoma cells.

    Science.gov (United States)

    Wang, Li; Gao, Chun; Yao, Shukun; Xie, Bushan

    2013-11-25

    Autophagy, a self-defense mechanism, has been found to be associated with drug resistance in hepatocellular carcinoma (HCC). Our study was designed to investigate the role and related mechanisms of autophagy in matrine-induced apoptosis in hepatoma cells of HepG2 and Bel7402. Cell apoptosis was detected by flow cytometry analysis (Annexin V-FITC/PI double-staining assay), the activity and activating cleavages of caspase-3, -8, and -9. MTT assay and colony forming assay were used to assess the effect of matrine on growth and proliferation of HCC cells. Autophagic flux in HCC cells was analyzed using the expression of LC3BI/II and p62/SQSTM1, GFP-LC3 transfection, and transmission electron microscopy. Moreover, regarding to the associated mechanisms, the effects of matrine on the phosphoinositide 3-kinase/AKT/mTOR pathway and beclin-1 were studied. Our results showed that: (1) both autophagy and apoptosis could be induced by treatment with matrine; (2) using the autophagic inhibitor chloroquine and beclin-1 small-interfering RNA, cell apoptosis induced by matrine could be enhanced in a caspase-dependent manner; and (3) autophagy was induced via inhibition of PI3K/AKT/mTOR pathway and up-regulation of beclin-1. In conclusion, inhibition of autophagy could enhance matrine-induced apoptosis in human hepatoma cells.

  13. Blocking Autophagic Flux Enhances Matrine-Induced Apoptosis in Human Hepatoma Cells

    Directory of Open Access Journals (Sweden)

    Li Wang

    2013-11-01

    Full Text Available Autophagy, a self-defense mechanism, has been found to be associated with drug resistance in hepatocellular carcinoma (HCC. Our study was designed to investigate the role and related mechanisms of autophagy in matrine-induced apoptosis in hepatoma cells of HepG2 and Bel7402. Cell apoptosis was detected by flow cytometry analysis (Annexin V–FITC/PI double-staining assay, the activity and activating cleavages of caspase-3, -8, and -9. MTT assay and colony forming assay were used to assess the effect of matrine on growth and proliferation of HCC cells. Autophagic flux in HCC cells was analyzed using the expression of LC3BI/II and p62/SQSTM1, GFP-LC3 transfection, and transmission electron microscopy. Moreover, regarding to the associated mechanisms, the effects of matrine on the phosphoinositide 3-kinase/AKT/mTOR pathway and beclin-1 were studied. Our results showed that: (1 both autophagy and apoptosis could be induced by treatment with matrine; (2 using the autophagic inhibitor chloroquine and beclin-1 small-interfering RNA, cell apoptosis induced by matrine could be enhanced in a caspase-dependent manner; and (3 autophagy was induced via inhibition of PI3K/AKT/mTOR pathway and up-regulation of beclin-1. In conclusion, inhibition of autophagy could enhance matrine-induced apoptosis in human hepatoma cells.

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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

  16. 5-ALA mediated photodynamic therapy induces autophagic cell death via AMP-activated protein kinase

    Directory of Open Access Journals (Sweden)

    Lin Yu-Hsin

    2010-04-01

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

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

    Directory of Open Access Journals (Sweden)

    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.

  18. ASSAYING OF AUTOPHAGIC PROTEIN DEGRADATION

    NARCIS (Netherlands)

    C. Bauvy; A.J. Meijer; P. Codogno

    2009-01-01

    Macroautophagy is a three-step process: (1) autophagosomes form and mature, (2) the autophagosomes fuse with lysosomes, and (3) the autophagic cargo is degraded in the lysosomes. It is this lysosomal degradation of the autophagic cargo that constitutes the autophagic flux. As in the case of metaboli

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

    Science.gov (United States)

    Almeida, Luciana O; Goto, Renata N; Neto, Marinaldo P C; Sousa, Lucas O; Curti, Carlos; Leopoldino, Andréia M

    2015-03-01

    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.

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

    Science.gov (United States)

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

    Science.gov (United States)

    Parks, Alexandre; Marceau, François

    2016-08-15

    Cation trapping in acidic cell compartments determines an antiproliferative effect that has a potential interest in oncology, as shown by clinical data and trials involving chloroquine and hydroxychloroquine. To further characterize the mechanism of this effect, we studied a series of 6 substituted triethylamine (s-Et3N) drugs that encompasses a wide range of liposolubility (amiodarone, quinacrine, chloroquine, hydroxychloroquine, lidocaine, and procainamide). Three tumor cell lines and primary human endothelial cells were exploited in proliferation assays (48h, cell counts). Accumulation of the autophagic effector LC3 II and the apoptotic marker cleaved PARP1 (immunoblots), cytotoxicity, cell cycle analysis and endocytic function were further tested in the p53-null histiocytic lymphoma U937 line. A profound and desynchronized antiproliferative effect was observed in response to all s-Et3Ns with essentially no cell type specificity. Predictors of s-Et3N potency were liposolubility and the acute accumulation of the autophagic effector LC3 II (6h-treatments). For each s-Et3N, there was an antiproliferative concentration range where cytotoxicity and apoptosis were not triggered in U937 cells (24-48h-treatments). Quinacrine was the most potent cytostatic drug (1-5μM). Co-treatment of cells with inhibitors of cholesterol, β-cyclodextrin or lovastatin, partially reversed the antiproliferative effect of each s-Et3N. The cytopathology induced by cationic drug accumulation includes a cytostatic effect. Its intensity is cell type- and p53-independent, but predicted by the inhibition of autophagic flux and by the liposolubility of individual drugs and alleviated by cholesterol ablation. The superiority of quinacrine, biomarker value of LC3 II and antagonism by a statin may be clinically relevant. PMID:27288732

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

    Directory of Open Access Journals (Sweden)

    Kyung Min eChung

    2016-05-01

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

  3. 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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-03-06

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

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

    Directory of Open Access Journals (Sweden)

    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.

  6. 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

  7. 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

  8. 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

  9. Toll-like receptor 8 ligands activate a vitamin D mediated autophagic response that inhibits human immunodeficiency virus type 1.

    Directory of Open Access Journals (Sweden)

    Grant R Campbell

    Full Text Available Toll-like receptors (TLR are important in recognizing microbial pathogens and triggering host innate immune responses, including autophagy, and in the mediation of immune activation during human immunodeficiency virus type-1 (HIV infection. We report here that TLR8 activation in human macrophages induces the expression of the human cathelicidin microbial peptide (CAMP, the vitamin D receptor (VDR and cytochrome P450, family 27, subfamily B, polypeptide 1 (CYP27B1, which 1α-hydroxylates the inactive form of vitamin D, 25-hydroxycholecalciferol, into its biologically active metabolite. Moreover, we demonstrate using RNA interference, chemical inhibitors and vitamin D deficient media that TLR8 agonists inhibit HIV through a vitamin D and CAMP dependent autophagic mechanism. These data support an important role for vitamin D in the control of HIV infection, and provide a biological explanation for the benefits of vitamin D. These findings also provide new insights into potential novel targets to prevent and treat HIV infection.

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

    Science.gov (United States)

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

    2016-03-01

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

  11. 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. NAC1 modulates sensitivity of ovarian cancer cells to cisplatin by altering the HMGB1-mediated autophagic response.

    Science.gov (United States)

    Zhang, Y; Cheng, Y; Ren, X; Zhang, L; Yap, K L; Wu, H; Patel, R; Liu, D; Qin, Z-H; Shih, I-M; Yang, J-M

    2012-02-23

    Nucleus accumbens-1 (NAC1), a nuclear factor belonging to the BTB/POZ gene family, is known to have important roles in proliferation and growth of tumor cells and in chemotherapy resistance. Yet, the mechanisms underlying how NAC1 contributes to drug resistance remain largely unclear. We report here that autophagy was involved in NAC1-mediated resistance to cisplatin, a commonly used chemotherapeutic drug in the treatment of ovarian cancer. We found that treatment with cisplatin caused an activation of autophagy in ovarian cancer cell lines, A2780, OVCAR3 and SKOV3. We further demonstrated that knockdown of NAC1 by RNA interference or inactivation of NAC1 by inducing the expression of a NAC1 deletion mutant that contains only the BTB/POZ domain significantly inhibited the cisplatin-induced autophagy, resulting in increased cisplatin cytotoxicity. Moreover, inhibition of autophagy and sensitization to cisplatin by NAC1 knockdown or inactivation were accompanied by induction of apoptosis. To confirm that the sensitizing effect of NAC1 inhibition on the cytotoxicity of cisplatin was attributed to suppression of autophagy, we assessed the effects of the autophagy inhibitors 3-methyladenosine and chloroquine, and small interfering RNAs (siRNAs) targeting beclin 1 or Atg5 on the cytotoxicity of cisplatin. Treatment with 3-methyladenosine, chloroquine or beclin 1 and Atg5-targeted siRNA also enhanced the sensitivity of SKOV3, A2780 and OVCAR3 cells to cisplatin, indicating that suppression of autophagy indeed renders tumor cells more sensitive to cisplatin. Regulation of autophagy by NAC1 was mediated by the high-mobility group box 1 (HMGB1), as the functional status of NAC1 was associated with the expression, translocation and release of HMGB1. The results of our study not only revealed a new mechanism determining cisplatin sensitivity but also identified NAC1 as a novel regulator of autophagy. Thus, the NAC1-mediated autophagy may be exploited as a new target for

  14. A novel herbal medicine, KIOM-C, induces autophagic and apoptotic cell death mediated by activation of JNK and reactive oxygen species in HT1080 human fibrosarcoma cells.

    Directory of Open Access Journals (Sweden)

    Aeyung Kim

    Full Text Available KIOM-C was recently demonstrated to have anti-metastatic activity in highly malignant cancer cells via suppression of NF-κB-mediated MMP-9 activity. In addition, it was reported to be effective for clearance of the influenza virus by increasing production of anti-viral cytokines, such as TNF-α and IFN-γ, and efficacious in the treatment of pigs suffering from porcine circovirus-associated disease (PCVAD. In this study, we investigated whether KIOM-C induces cancer cell death and elucidated the underlying anti-cancer mechanisms. In addition, we examined whether KIOM-C oral administration suppresses in vivo tumor growth of HT1080 cells in athymic nude mice. We initially found that KIOM-C at concentrations of 500 and 1000 µg/ml caused dose- and time-dependent cell death in cancer cells, but not normal hepatocytes, to approximately 50% of control levels. At the early stage of KIOM-C treatment (12 h, cells were arrested in G1 phase, which was accompanied by up-regulation of p21 and p27, down-regulation of cyclin D1, and subsequent increases in apoptotic and autophagic cells. Following KIOM-C treatment, the extent of caspase-3 activation, PARP cleavage, Beclin-1 expression, and LC3-II conversion was remarkably up-regulated, but p62 expression was down-regulated. Phosphorylation of AMPK, ULK, JNK, c-jun, and p53 was increased significantly in response to KIOM-C treatment. The levels of intracellular ROS and CHOP expression were also increased. In particular, the JNK-specific inhibitor SP600125 blocked KIOM-C-induced ROS generation and CHOP expression almost completely, which consequently almost completely rescued cell death, indicating that JNK activation plays a critical role in KIOM-C-induced cell death. Furthermore, daily oral administration of 85 and 170 mg/kg KIOM-C efficiently suppressed the tumorigenic growth of HT1080 cells, without systemic toxicity. These results collectively suggest that KIOM-C efficiently induces cancer cell death by

  15. Targeting autophagic pathways for cancer drug discovery

    Institute of Scientific and Technical Information of China (English)

    Bo Liu; Jin-Ku Bao; Jin-Ming Yang; Yan Cheng

    2013-01-01

    Autophagy,an evolutionarily conserved lysosomal degradation process,has drawn an increasing amount of attention in recent years for its role in a variety of human diseases,such as cancer.Notably,autophagy plays an important role in regulating several survival and death signaling pathways that determine cell fate in cancer.To date,substantial evidence has demonstrated that some key autophagic mediators,such as autophagy-related genes (ATGs),PI3K,mTOR,p53,and Beclin-1,may play crucial roles in modulating autophagic activity in cancer initiation and progression.Because autophagy-modulating agents such as rapamycin and chloroquine have already been used clinically to treat cancer,it is conceivable that targeting autophagic pathways may provide a new opportunity for discovery and development of more novel cancer therapeutics.With a deeper understanding of the regulatory mechanisms governing autophagy,we will have a better opportunity to facilitate the exploitation of autophagy as a target for therapeutic intervention in cancer.This review discusses the current status of targeting autophagic pathways as a potential cancer therapy.

  16. 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

  17. Autophagic components contribute to hypersensitive cell death in Arabidopsis

    DEFF Research Database (Denmark)

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

    2009-01-01

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

  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. 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

  20. 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

  1. 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.

  2. 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.

  3. 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

  4. 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

  5. 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.

  6. Export stoichiometry and migrant-mediated flux of phosphorus in the North Pacific Subtropical Gyre

    Science.gov (United States)

    Hannides, Cecelia C. S.; Landry, Michael R.; Benitez-Nelson, Claudia R.; Styles, Renée M.; Montoya, Joseph P.; Karl, David M.

    2009-01-01

    Export processes play a major role in regulating global marine primary production by reducing the efficiency of nutrient cycling and turnover in surface waters. Most studies of euphotic zone export focus on passive fluxes, that is, sinking particles. However, active transport, the vertical transfer of material by migrating zooplankton, can also be an important component of carbon (C) and nitrogen (N) removal from the surface ocean. Here we demonstrate that active transport is an especially important mechanism for phosphorus (P) removal from the euphotic zone at Station ALOHA (Hawaii Ocean Time-series program; 22°45'N, 158°W), a P-stressed site in the North Pacific Subtropical Gyre. Migrant excretions in this region are P-rich (C 51:N 12:P 1) relative to sinking particles (C 250:N 31:P 1), and migrant-mediated P fluxes are almost equal in magnitude (82%) to P fluxes from sediment traps. Migrant zooplankton biomass and therefore the importance of this P removal pathway relative to sinking fluxes has increased significantly over the past 12 years, suggesting that active transport may be a major driving force for enhanced P-limitation of biological production in the NPSG. We further assess the C:N:P composition of zooplankton size fractions at Station ALOHA (C 88:N 18:P 1, on average) and discuss migrant-mediated P export in light of the balance between zooplankton and suspended particle stoichiometries. We conclude that, because active transport is such a large component of the total P flux and significantly impacts ecosystem stoichiometry, export processes involving migrant zooplankton must be included in large-scale efforts to understand biogeochemical cycles.

  7. 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.

  8. 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.

  9. 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

  10. Autophagic regulation of smooth muscle cell biology

    Science.gov (United States)

    Salabei, Joshua K.; Hill, Bradford G.

    2014-01-01

    Autophagy regulates the metabolism, survival, and function of numerous cell types, including those comprising the cardiovascular system. In the vasculature, changes in autophagy have been documented in atherosclerotic and restenotic lesions and in hypertensive vessels. The biology of vascular smooth muscle cells appears particularly sensitive to changes in the autophagic program. Recent evidence indicates that stimuli or stressors evoked during the course of vascular disease can regulate autophagic activity, resulting in modulation of VSMC phenotype and viability. In particular, certain growth factors and cytokines, oxygen tension, and pharmacological drugs have been shown to trigger autophagy in smooth muscle cells. Importantly, each of these stimuli has a redox component, typically associated with changes in the abundance of reactive oxygen, nitrogen, or lipid species. Collective findings support the hypothesis that autophagy plays a critical role in vascular remodeling by regulating smooth muscle cell phenotype transitions and by influencing the cellular response to stress. In this graphical review, we summarize current knowledge on the role of autophagy in the biology of the smooth muscle cell in (patho)physiology. PMID:25544597

  11. Autophagic regulation of smooth muscle cell biology

    Directory of Open Access Journals (Sweden)

    Joshua K. Salabei

    2015-04-01

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

  12. Cotyledon cells of Vigna mungo seedlings use at least two distinct autophagic machineries for degradation of starch granules and cellular components.

    Science.gov (United States)

    Toyooka, K; Okamoto, T; Minamikawa, T

    2001-09-01

    alpha-Amylase is expressed in cotyledons of germinated Vigna mungo seeds and is responsible for the degradation of starch that is stored in the starch granule (SG). Immunocytochemical analysis of the cotyledon cells with anti-alpha-amylase antibody showed that alpha-amylase is transported to protein storage vacuole (PSV) and lytic vacuole (LV), which is converted from PSV by hydrolysis of storage proteins. To observe the insertion/degradation processes of SG into/in the inside of vacuoles, ultrastructural analyses of the cotyledon cells were conducted. The results revealed that SG is inserted into LV through autophagic function of LV and subsequently degraded by vacuolar alpha-amylase. The autophagy for SG was structurally similar to micropexophagy detected in yeast cells. In addition to the autophagic process for SG, autophagosome-mediated autophagy for cytoplasm and mitochondria was detected in the cotyledon cells. When the embryo axes were removed from seeds and the detached cotyledons were incubated, the autophagosome-mediated autophagy was observed, but the autophagic process for the degradation of SG was not detected, suggesting that these two autophagic processes were mediated by different cellular mechanisms. The two distinct autophagic processes were thought to be involved in the breakdown of SG and cell components in the cells of germinated cotyledon.

  13. Pro-apoptotic and pro-autophagic effects of the Aurora kinase A inhibitor alisertib (MLN8237 on human osteosarcoma U-2 OS and MG-63 cells through the activation of mitochondria-mediated pathway and inhibition of p38 MAPK/PI3K/Akt/mTOR signaling pathway

    Directory of Open Access Journals (Sweden)

    Niu NK

    2015-03-01

    mesenchymal transition (EMT and the underlying mechanisms in two human OS cell lines U-2 OS and MG-63. The results showed that ALS had potent growth inhibitory, pro-apoptotic, pro-autophagic, and EMT inhibitory effects on U-2 OS and MG-63 cells. ALS remarkably induced G2/M arrest and down-regulated the expression levels of cyclin-dependent kinases 1 and 2 and cyclin B1 in both U-2 OS and MG-63 cells. ALS markedly induced mitochondria-mediated apoptosis with a significant increase in the expression of key pro-apoptotic proteins and a decrease in main anti-apoptotic proteins. Furthermore, ALS promoted autophagic cell death via the inhibition of phosphatidylinositol 3-kinase (PI3K/protein kinase B (Akt/mammalian target of rapamycin (mTOR and p38 mitogen-activated protein kinase (p38 MAPK signaling pathways, and activation of 5'-AMP-dependent kinase (AMPK signaling pathway. Inducers or inhibitors of apoptosis or autophagy simultaneously altered ALS-induced apoptotic and autophagic death in both U-2 OS and MG-63 cells, suggesting a crosstalk between these two primary modes of programmed cell death. Moreover, ALS suppressed EMT-like phenotypes with a marked increase in the expression of E-cadherin but a decrease in N-cadherin in U-2 OS and MG-63 cells. ALS treatment also induced reactive oxygen species (ROS generation but inhibited the expression levels of sirtuin 1 and nuclear factor-erythroid-2-related factor 2 (Nrf2 in both cell lines. Taken together, these findings show that ALS promotes apoptosis and autophagy but inhibits EMT via PI3K/Akt/mTOR, p38 MAPK, and AMPK signaling pathways with involvement of ROS- and sirtuin 1-associated pathways in U-2 OS and MG-63 cells. ALS is a promising anticancer agent in OS treatment and further studies are needed to confirm its efficacy and safety in OS chemotherapy. Keywords: ALS, autophagy, apoptosis, osteosarcoma, PI3K/Akt/mTOR pathway, EMT

  14. Reversal of intramyocellular lipid accumulation by lipophagy and a p62-mediated pathway.

    Science.gov (United States)

    Lam, T; Harmancey, R; Vasquez, H; Gilbert, B; Patel, N; Hariharan, V; Lee, A; Covey, M; Taegtmeyer, H

    2016-01-01

    We have previously observed the reversal of lipid droplet deposition in skeletal muscle of morbidly obese patients following bariatric surgery. We now investigated whether activation of autophagy is the mechanism underlying this observation. For this purpose, we incubated rat L6 myocytes over a period of 6 days with long-chain fatty acids (an equimolar, 1.0 mM, mixture of oleate and palmitate in the incubation medium). At day 6, the autophagic inhibitor (bafilomycin A1, 200 nM) and the autophagic activator (rapamycin, 1 μM) were added separately or in combination for 48 h. Intracellular triglyceride (TG) accumulation was visualized and quantified colorimetrically. Protein markers of autophagic flux (LC3 and p62) and cell death (caspase-3 cleavage) were measured by immunoblotting. Inhibition of autophagy by bafilomycin increased TG accumulation and also increased lipid-mediated cell death. Conversely, activation of autophagy by rapamycin reduced both intracellular lipid accumulation and cell death. Unexpectedly, treatment with both drugs added simultaneously resulted in decreased lipid accumulation. In this treatment group, immunoblotting revealed p62 degradation (autophagic flux), immunofluorescence revealed the colocalization of p62 with lipid droplets, and co-immunoprecipitation confirmed the interaction of p62 with ADRP (adipose differentiation-related protein), a lipid droplet membrane protein. Thus the association of p62 with lipid droplet turnover suggests a novel pathway for the breakdown of lipid droplets in muscle cells. In addition, treatment with rapamycin and bafilomycin together also suggested the export of TG into the extracellular space. We conclude that lipophagy promotes the clearance of lipids from myocytes and switches to an alternative, p62-mediated, lysosomal-independent pathway in the context of chronic lipid overload (*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001). PMID:27625792

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

    DEFF Research Database (Denmark)

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

    2014-01-01

    Vigabatrin is an anti-epileptic drug substance. The oral bioavailability of vigabatrin is high (60-70%), however, little is known about the mechanism(s) mediating the intestinal absorption. The aim of the present study was to identify which solute carrier(s) are involved in the absorption...... of vigabatrin in Caco-2 cells, a cell culture model of the small intestinal epithelium. The uptake and transepithelial flux of vigabatrin was measured using an LC-MS method for quantification. Transepithelial transport of vigabatrin was shown to be proton-dependent and polarized in the apical-to-basolateral (A...

  16. 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.

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

    Directory of Open Access Journals (Sweden)

    Atte Penttilä

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

  18. 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.

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

    Science.gov (United States)

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

    2016-10-01

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

  20. 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

  1. 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

  2. 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.

  3. 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

  4. Crystalloids in apparent autophagic plastids: remnants of plastids or peroxisomes?

    Science.gov (United States)

    Papini, Alessio; van Doorn, Wouter G

    2015-02-01

    Plant macroautophagy is carried out by autophagosome-type organelles. Recent evidence suggests that plastids also can carry out macroautophagy. The double membrane at the surface of plastids apparently invaginates, forming an intraplastidial space. This space contains a portion of cytoplasm that apparently becomes degraded. Here we report, in Tillandsia sp. and Aechmaea sp., the presence of almost square or diamond-shaped crystalloids inside what seems the intraplastidial space of autophagous plastids. The same type of crystalloids were observed in chloroplasts and other plastids, but were not found in the cytoplasm or the vacuole. Peroxisomes contained smaller and more irregularly shaped crystalloids compared to the ones observed in 'autophagous' plastids. It is hypothesized that plastids are able to sequester chloroplasts and other plastids. PMID:25462964

  5. 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

  6. 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.

  7. 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.

  8. 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

  9. 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

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

    Directory of Open Access Journals (Sweden)

    Kae Harada-Hada

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

  11. 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

  12. 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.

  13. 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

  14. 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

  15. Emerging role of autophagy in mediating widespread actions of ADIPOQ/adiponectin.

    Science.gov (United States)

    Xu, Aimin; Sweeney, Gary

    2015-04-01

    Autophagy can dictate changes in cell metabolism via numerous mechanisms. ADIPOQ/adiponectin has been extensively characterized to have beneficial metabolic effects, both via INS/insulin-sensitizing and INS-independent actions. Our recent work examined the regulation of skeletal muscle autophagy by ADIPOQ and the functional significance. We showed that ADIPOQ directly stimulates autophagic flux in cultured skeletal muscle cells via an AMPK-dependent signaling pathway leading to phosphorylation of ULK1 (Ser555). Pharmacological inhibition of autophagy or overexpressing an inactive mutant of ATG5 to create an autophagy-deficient cell model reduces INS sensitivity. A high-fat diet (HFD) does not induce skeletal muscle autophagy in Adipoq knockout (Ad-KO) mice, whereas it does in wild-type (WT) mice, although ADIPOQ replenishment in Ad-KO mice stimulates autophagy. Changes in skeletal muscle autophagy correlate well with peripheral INS sensitivity and glucose metabolism. Thus, ADIPOQ stimulates autophagic flux in skeletal muscle, which likely represents one important mechanism mediating multiple favorable metabolic effects.

  16. Cellular metabolic and autophagic pathways: traffic control by redox signaling.

    Science.gov (United States)

    Dodson, Matthew; Darley-Usmar, Victor; Zhang, Jianhua

    2013-10-01

    It has been established that the key metabolic pathways of glycolysis and oxidative phosphorylation are intimately related to redox biology through control of cell signaling. Under physiological conditions glucose metabolism is linked to control of the NADH/NAD redox couple, as well as providing the major reductant, NADPH, for thiol-dependent antioxidant defenses. Retrograde signaling from the mitochondrion to the nucleus or cytosol controls cell growth and differentiation. Under pathological conditions mitochondria are targets for reactive oxygen and nitrogen species and are critical in controlling apoptotic cell death. At the interface of these metabolic pathways, the autophagy-lysosomal pathway functions to maintain mitochondrial quality and generally serves an important cytoprotective function. In this review we will discuss the autophagic response to reactive oxygen and nitrogen species that are generated from perturbations of cellular glucose metabolism and bioenergetic function.

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

    Science.gov (United States)

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

    2009-03-01

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

  18. 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

  19. 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.

  20. 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...

  1. 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

  2. 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...

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

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

    Science.gov (United States)

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

    2016-01-01

    Autophagy is activated in cancer cells in response to multiple stresses and has been demonstrated to promote tumor cell survival and drug resistance in neuroblastoma (NB). This study was conducted to analyze the ultrastructural features of peripheral neuroblastic tumors (pNTs) and identify the relation of the types of NTs, the proliferation rate, and MYCN gene amplification with a number of autophagic vacuoles. Our results indicate that aggressive human NBs show a massive increase in the number of autophagic vacuoles associated with proliferation rate and that alteration of the mitochondria might be an important factor for the induction of autophagy in NTs. PMID:27669398

  9. 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.

  10. 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.

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

    Science.gov (United States)

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

    2015-01-01

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

  12. Glutathione-S-transferase omega 1 (GSTO1-1) acts as mediator of signaling pathways involved in aflatoxin B1-induced apoptosis-autophagy crosstalk in macrophages.

    Science.gov (United States)

    Paul, Souren; Jakhar, Rekha; Bhardwaj, Monika; Kang, Sun Chul

    2015-12-01

    Aflatoxin B1 (AFB1) is the most toxic aflatoxin species and has been shown to be associated with specific as well as non-specific immune responses. In the present study, using murine macrophage Raw 264.7 cells as a model, we report that short exposure (6h) to AFB1 caused an increase in the cellular calcium pool in mitochondria, which in turn elevated reactive oxygen species (ROS)-mediated oxidative stress and led to loss of mitochondrial membrane potential and ultimately c-Jun N-terminal kinases (JNK)-mediated caspase-dependent cell death. On the contrary, longer exposure (12h) to AFB1 reduced JNK phosphorylation and cell death in macrophages. Measurement of autophagic flux demonstrated that autophagy induction through the canonical pathway was responsible for suppressing AFB1-induced apoptosis after 12h. As a detailed molecular mechanism, we found that the unfolded protein response (UPR) machinery was active at 12h post-exposure to AFB1 and induced cytoprotective autophagy as confirmed by determination of major autophagic markers. Inhibition of autophagy by Beclin-1 siRNA also resulted in JNK-mediated cell death. We further established that glutathione S transferase omega1-1 (GSTO1-1), a specific class of GST, was the responsible factor between apoptosis and autophagy crosstalk. Targeting of GSTO1-1 increased JNK-mediated apoptosis by 2-fold compared to the control, whereas autophagy rate was reduced. Thus, increased expression of GSTO1-1 was associated with increased protein glutathionylation, an important protein modification in response to cellular redox status.

  13. 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.

  14. 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

  15. 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

  16. 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...

  17. 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...

  18. 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...

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

    Directory of Open Access Journals (Sweden)

    Dingding Li

    2016-01-01

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

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

    Science.gov (United States)

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

    2016-01-01

    Methylprednisolone pulse therapy (MPPT), as a public recognized therapy of spinal cord injury (SCI), is doubted recently, and the exact mechanism of MP on SCI is unclear. This study sought to investigate the exact effect of MP on SCI. We examined the effect of MP in a model of SCI in vivo and an LPS induced model in vitro. We found that administration of MP produced an increase in the Basso, Beattie, and Bresnahan scores and motor neurons counts of injured rats. Besides the number of activated microglia was apparently reduced by MP in vivo, and Beclin-1 dependent autophagic cell death of microglia was induced by MP in LPS induced model. At the same time, MP increases cellular zinc concentration and level of ZIP8, and TPEN could revert effect of MP on autophagic cell death of microglia. Finally, we have found that MP could inhibit NF-κβ in LPS induced model. These results show that the MP could result in autophagic cell death of microglia, which mainly depends on increasing cellular labile zinc, and may be associated with inhibition of NF-κβ, and that MP can produce neuroprotective effect in SCI. PMID:27057544

  1. 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

  2. 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...

  3. Differential autophagic responses to nano-sized materials.

    Science.gov (United States)

    Popp, Lauren; Segatori, Laura

    2015-12-01

    Autophagy is a complex catabolic pathway that mediates degradation of excess or unwanted cytoplasmic components through the lysosome. Activated by environmental factors, such as nutrient depletion, and intracellular stimuli, such as proteotoxic stress, it provides a highly dynamic quality control mechanism to recycle cellular components, eliminate aberrant materials, and, ultimately, maintain cellular homeostasis. A growing body of evidence suggests that autophagy is also activated upon internalization of engineered nanomaterials, most likely as a protective response to what is perceived as foreign or toxic. This review describes the mechanisms of autophagy activation in response to naturally occurring and engineered nanomaterials. We provide a comprehensive analysis of the impact of nanomaterials on the lysosome-autophagy system, with particular emphasis on cellular markers associated with biocompatible and bioadverse outcomes of autophagy activation, such as clearance of toxic material and autophagy-associated cell death. Potential applications of the next-generation nanomaterials designed to interface with cellular clearance mechanisms with precisely tunable properties are also discussed.

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

    Directory of Open Access Journals (Sweden)

    Feng Li

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

  5. 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

    . 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...... on coupled nitrification/denitrification. Therefore, P. arundinacea played an important role in facilitating N2O transport from the root zone to the atmosphere, and exclusion of the aboveground biomass in flux chamber measurements may lead to significant underestimations on net ecosystem N2O emissions......–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....

  6. Developmental changes in polyamines and autophagic marker levels in normal and growth-restricted fetal pigs.

    Science.gov (United States)

    Zhu, Y H; Lin, G; Dai, Z L; Zhou, T J; Yuan, T L; Feng, C P; Chen, F; Wu, G Y; Wang, J J

    2015-07-01

    Polyamines are essential for embryonic and fetal survival, growth, and development. Additionally, polyamines may induce autophagy in mammalian cells. However, little is known about the availability of polyamines or autophagy in the porcine conceptus with intrauterine growth restriction (IUGR). The present study was performed to evaluate the developmental changes of polyamine concentrations in IUGR and normal porcine fetuses as well as autophagic marker levels in the fetal intestinal mucosa during the second half of gestation when most fetal growth occurs. Allantoic fluid (ALF), amniotic fluid (AMF), umbilical vein, and the small-intestinal mucosa were obtained from both IUGR and normal fetal pigs at d 60, 90, and 110 of gestation. Concentrations of polyamines in fetal fluids as well as protein abundances of microtubule-associated protein light chain 3B (LC3B), an autophagic marker, in the fetal small-intestinal mucosa were determined. Concentrations of polyamines varied greatly in different fetal compartments and changed substantially with advancing gestation. Concentrations of polyamines in IUGR fetal fluids and the small-intestinal mucosa were markedly different from those in their normal counterparts at d 60 and 90 of gestation, whereas most of the differences were not detected by late (d 110) gestation. Specifically, polyamine levels were lower in the umbilical vein plasma but higher in ALF and AMF from IUGR fetuses. Furthermore, enhanced levels of an autophagic marker were observed in the small-intestinal mucosa of IUGR fetuses throughout mid and late gestation in association with abnormal spermidine levels in fetal plasma. These findings support the notion that enhanced autophagy may be an important survival mechanism in IUGR fetuses. Collectively, our findings provide a new framework for future studies to define the roles for polyamines in the prevention and treatment of IUGR in both human medicine and animal production.

  7. 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 ePukaß

    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

  8. 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

  9. 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.

  10. 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.

  11. 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.

  12. 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.

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

    Science.gov (United States)

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

    2009-07-01

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

  14. 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...

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

    Directory of Open Access Journals (Sweden)

    Li Jiang

    Full Text Available 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 CO(2 exchange rates were measured in a meadow steppe subjected to 4-year warming and nitrogen addition treatments. Warming treatment reduced net ecosystem CO(2 exchange (NEE and increased ecosystem respiration (ER; but had no significant impacts on gross ecosystem productivity (GEP. N addition increased NEE, ER and GEP. However, there were no significant interactions between N addition and warming. The variation of NEE during the four experimental years was correlated with soil water content, particularly during early spring, suggesting that water availability is a primary driver of carbon fluxes in the studied semi-arid grassland. 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.

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

    Directory of Open Access Journals (Sweden)

    Claire M. Payne

    2009-01-01

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

  17. Isogambogenic acid induces apoptosis-independent autophagic cell death in human non-small-cell lung carcinoma cells.

    Science.gov (United States)

    Yang, Jianhong; Zhou, Yongzhao; Cheng, Xia; Fan, Yi; He, Shichao; Li, Shucai; Ye, Haoyu; Xie, Caifeng; Wu, Wenshuang; Li, Chunyan; Pei, Heying; Li, Luyuan; Wei, Zhe; Peng, Aihua; Wei, Yuquan; Li, Weimin; Chen, Lijuan

    2015-01-09

    To overcome drug resistance caused by apoptosis deficiency in patients with non-small cell lung carcinoma (NSCLC), there is a need to identify other means of triggering apoptosis-independent cancer cell death. We are the first to report that isogambogenic acid (iso-GNA) can induce apoptosis-independent autophagic cell death in human NSCLC cells. Several features of the iso-GNA-treated NSCLC cells indicated that iso-GNA induced autophagic cell death. First, there was no evidence of apoptosis or cleaved caspase 3 accumulation and activation. Second, iso-GNA treatment induced the formation of autophagic vacuoles, increased LC3 conversion, caused the appearance of autophagosomes and increased the expression of autophagy-related proteins. These findings provide evidence that iso-GNA induces autophagy in NSCLC cells. Third, iso-GNA-induced cell death was inhibited by autophagic inhibitors or by selective ablation of Atg7 and Beclin 1 genes. Furthermore, the mTOR inhibitor rapamycin increased iso-GNA-induced cell death by enhancing autophagy. Finally, a xenograft model provided additional evidence that iso-GNA exhibited anticancer effect through inducing autophagy-dependent cell death in NSCLC cells. Taken together, our results demonstrated that iso-GNA exhibited an anticancer effect by inducing autophagy-dependent cell death in NSCLC cells, which may be an effective chemotherapeutic agent that can be used against NSCLC in a clinical setting.

  18. 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.

  19. 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 $\\dot B_e$.

  20. 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

  1. 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.

  2. 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

  3. 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...

  4. 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

  5. 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

  6. 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

  7. 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.

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

    Directory of Open Access Journals (Sweden)

    Yu-Chun Yin

    2015-02-01

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

  9. Involvement of Autophagic Pathway in the Progression of Retinal Degeneration in a Mouse Model of Diabetes.

    Science.gov (United States)

    Piano, Ilaria; Novelli, Elena; Della Santina, Luca; Strettoi, Enrica; Cervetto, Luigi; Gargini, Claudia

    2016-01-01

    The notion that diabetic retinopathy (DR) is essentially a micro-vascular disease has been recently challenged by studies reporting that vascular changes are preceded by signs of damage and loss of retinal neurons. As to the mode by which neuronal death occurs, the evidence that apoptosis is the main cause of neuronal loss is far from compelling. The objective of this study was to investigate these controversies in a mouse model of streptozotocin (STZ) induced diabetes. Starting from 8 weeks after diabetes induction there was loss of rod but not of cone photoreceptors, together with reduced thickness of the outer and inner synaptic layers. Correspondingly, rhodopsin expression was downregulated and the scotopic electroretinogram (ERG) is suppressed. In contrast, cone opsin expression and photopic ERG response were not affected. Suppression of the scotopic ERG preceded morphological changes as well as any detectable sign of vascular alteration. Only sparse apoptotic figures were detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and glia was not activated. The physiological autophagy flow was altered instead, as seen by increased LC3 immunostaining at the level of outer plexiform layer (OPL) and upregulation of the autophagic proteins Beclin-1 and Atg5. Collectively, our results show that the streptozotocin induced DR in mouse initiates with a functional loss of the rod visual pathway. The pathogenic pathways leading to cell death develop with the initial dysregulation of autophagy well before the appearance of signs of vascular damage and without strong involvement of apoptosis.

  10. Endothelial cells are damaged by autophagic induction before hepatocytes in Con A-induced acute hepatitis.

    Science.gov (United States)

    Yang, Ming-Chen; Chang, Chih-Peng; Lei, Huan-Yao

    2010-08-01

    We have reported both T-cell-dependent and -independent hepatitis in immunocompetent and immunodeficiency mice, respectively, after intravenous injection of Con A in mice. The mode of hepatocyte cell death is different: autophagy for T-cell-independent hepatitis in contrast to apoptosis for T-cell-dependent one. In this study, we further demonstrate that liver blood vessels are the first target in both modes. The infused Con A bond to the hepatic vascular endothelial cells and cause its damage with autophagy. Before the elevation of the serum alanine aminotransferase at 6 h post-injection, the plasma leakage and hemorrhage occur at 1-3 h without inflammation. Con A induces autophagy of endothelial cells and hemorrhage that is enhanced by IFN-gamma. Using the endothelial cell line HMEC-1, a dose- and time-dependent cell death with autophagic LC3-II (microtubule-associated protein light chain 3) conversion was induced by Con A and was enhanced by IFN-gamma. In conclusion, Con A induced autophagy on hepatic endothelial cells; the damage of liver blood vessel occurs before the induction of T-cell-dependent hepatitis via apoptosis or T-cell-independent hepatitis via autophagy.

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

    Science.gov (United States)

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

    2015-12-17

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

  12. 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

  13. 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.

  14. 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.

    Science.gov (United States)

    Pukaß, Katharina; Richter-Landsberg, Christiane

    2015-01-01

    α-Synuclein (α-syn) positive glial cytoplasmic inclusions (GCI) originating in oligodendrocytes (ODC) are a characteristic hallmark in multiple system atrophy (MSA). 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 (DUBs) before proteolytic degradation is performed. The DUB ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is a component of the UPS, it is abundantly expressed in neuronal brain cells and has been connected to Parkinson's disease (PD). It interacts with α-syn and tubulin. The present study was undertaken to investigate whether UCH-L1 is a constituent of ODC, 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 (MT) 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 UCH-L1 is expressed in ODC 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 MT network by affecting tubulin posttranslational modifications, i.e., acetylation and tyrosination. An increase in α-tubulin detyrosination was observed and detyrosinated MT 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

  15. 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...

  16. HDAC1 inactivation induces mitotic defect and caspase-independent autophagic cell death in liver cancer.

    Directory of Open Access Journals (Sweden)

    Hong Jian Xie

    Full Text Available Histone deacetylases (HDACs are known to play a central role in the regulation of several cellular properties interlinked with the development and progression of cancer. Recently, HDAC1 has been reported to be overexpressed in hepatocellular carcinoma (HCC, but its biological roles in hepatocarcinogenesis remain to be elucidated. In this study, we demonstrated overexpression of HDAC1 in a subset of human HCCs and liver cancer cell lines. HDAC1 inactivation resulted in regression of tumor cell growth and activation of caspase-independent autophagic cell death, via LC3B-II activation pathway in Hep3B cells. In cell cycle regulation, HDAC1 inactivation selectively induced both p21(WAF1/Cip1 and p27(Kip1 expressions, and simultaneously suppressed the expression of cyclin D1 and CDK2. Consequently, HDAC1 inactivation led to the hypophosphorylation of pRb in G1/S transition, and thereby inactivated E2F/DP1 transcription activity. In addition, we demonstrated that HDAC1 suppresses p21(WAF1/Cip1 transcriptional activity through Sp1-binding sites in the p21(WAF1/Cip1 promoter. Furthermore, sustained suppression of HDAC1 attenuated in vitro colony formation and in vivo tumor growth in a mouse xenograft model. Taken together, we suggest the aberrant regulation of HDAC1 in HCC and its epigenetic regulation of gene transcription of autophagy and cell cycle components. Overexpression of HDAC1 may play a pivotal role through the systemic regulation of mitotic effectors in the development of HCC, providing a particularly relevant potential target in cancer therapy.

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

    Directory of Open Access Journals (Sweden)

    Jinglan Zhang

    2016-04-01

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

  18. Synthesis, stereochemical analysis, and derivatization of myricanol provide new probes that promote autophagic tau clearance.

    Science.gov (United States)

    Martin, Mackenzie D; Calcul, Laurent; Smith, Courtney; Jinwal, Umesh K; Fontaine, Sarah N; Darling, April; Seeley, Kent; Wojtas, Lukasz; Narayan, Malathi; Gestwicki, Jason E; Smith, Garry R; Reitz, Allen B; Baker, Bill J; Dickey, Chad A

    2015-04-17

    We previously discovered that one specific scalemic preparation of myricanol (1), a constituent of Myrica cerifera (bayberry/southern wax myrtle) root bark, could lower the levels of the microtubule-associated protein tau (MAPT). The significance is that tau accumulates in a number of neurodegenerative diseases, the most common being Alzheimer's disease (AD). Herein, a new synthetic route to prepare myricanol using a suitable boronic acid pinacol ester intermediate is reported. An X-ray crystal structure of the isolated myricanol (1) was obtained and showed a co-crystal consisting of (+)-aR,11S-myricanol (2) and (-)-aS,11R-myricanol (3) coformers. Surprisingly, 3, obtained from chiral separation from 1, reduced tau levels in both cultured cells and ex vivo brain slices from a mouse model of tauopathy at reasonable mid-to-low micromolar potency, whereas 2 did not. SILAC proteomics and cell assays revealed that 3 promoted tau degradation through an autophagic mechanism, which was in contrast to that of other tau-lowering compounds previously identified by our group. During the course of structure-activity relationship (SAR) development, we prepared compound 13 by acid-catalyzed dehydration of 1. 13 had undergone an unexpected structural rearrangement through the isomyricanol substitution pattern (e.g., 16), as verified by X-ray structural analysis. Compound 13 displayed robust tau-lowering activity, and, importantly, its enantiomers reduced tau levels similarly. Therefore, the semisynthetic analogue 13 provides a foundation for further development as a tau-lowering agent without its SAR being based on chirality.

  19. 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.

  20. Thymoquinone induces caspase-independent, autophagic cell death in CPT-11-resistant lovo colon cancer via mitochondrial dysfunction and activation of JNK and p38.

    Science.gov (United States)

    Chen, Ming-Cheng; Lee, Nien-Hung; Hsu, Hsi-Hsien; Ho, Tsung-Jung; Tu, Chuan-Chou; Hsieh, Dennis Jine-Yuan; Lin, Yueh-Min; Chen, Li-Mien; Kuo, Wei-Wen; Huang, Chih-Yang

    2015-02-11

    Chemotherapy causes unwanted side effects and chemoresistance, limiting its effectiveness. Therefore, phytochemicals are now used as alternative treatments. Thymoquinone (TQ) is used to treat different cancers, including colon cancer. The irinotecan-resistant (CPT-11-R) LoVo colon cancer cell line was previously constructed by stepwise CPT-11 challenges to untreated parental LoVo cells. TQ dose-dependently increased the total cell death index and activated apoptosis at 2 μM, which then diminished at increasing doses. The possibility of autophagic cell death was then investigated. TQ caused mitochondrial outer membrane permeability (MOMP) and activated autophagic cell death. JNK and p38 inhibitors (SP600125 and SB203580, respectively) reversed TQ autophagic cell death. TQ was also found to activate apoptosis before autophagy, and the direction of cell death was switched toward autophagic cell death at initiation of autophagosome formation. Therefore, TQ resulted in caspase-independent, autophagic cell death via MOMP and activation of JNK and p38 in CPT-11-R LoVo colon cancer cells.

  1. 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.

  2. UCP2 inhibition triggers ROS-dependent nuclear translocation of GAPDH and autophagic cell death in pancreatic adenocarcinoma cells.

    Science.gov (United States)

    Dando, Ilaria; Fiorini, Claudia; Pozza, Elisa Dalla; Padroni, Chiara; Costanzo, Chiara; Palmieri, Marta; Donadelli, Massimo

    2013-03-01

    Mitochondrial uncoupling protein 2 (UCP2) can moderate oxidative stress by favoring the influx of protons into the mitochondrial matrix, thus reducing electron leakage from respiratory chain and mitochondrial superoxide production. Here, we demonstrate that UCP2 inhibition by genipin or UCP2 siRNA strongly increases reactive oxygen species (ROS) production inhibiting pancreatic adenocarcinoma cell growth. We also show that UCP2 inhibition triggers ROS-dependent nuclear translocation of the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH), formation of autophagosomes, and the expression of the autophagy marker LC3-II. Consistently, UCP2 over-expression significantly reduces basal autophagy confirming the anti-autophagic role of UCP2. Furthermore, we demonstrate that autophagy induced by UCP2 inhibition determines a ROS-dependent cell death, as indicated by the apoptosis decrease in the presence of the autophagy inhibitors chloroquine (CQ) or 3-methyladenine (3-MA), or the radical scavenger NAC. Intriguingly, the autophagy induced by genipin is able to potentiate the autophagic cell death triggered by gemcitabine, the standard chemotherapeutic drug for pancreatic adenocarcinoma, supporting the development of an anti-cancer therapy based on UCP2 inhibition associated to standard chemotherapy. Our results demonstrate for the first time that UCP2 plays a role in autophagy regulation bringing new insights into mitochondrial uncoupling protein field.

  3. 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...

  4. 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 ...

  5. Effect of the pituitary adenylate cyclase-activating polypeptide on the autophagic activation observed in in vitro and in vivo models of Parkinson's disease.

    Science.gov (United States)

    Lamine-Ajili, Asma; Fahmy, Ahmed M; Létourneau, Myriam; Chatenet, David; Labonté, Patrick; Vaudry, David; Fournier, Alain

    2016-04-01

    Parkinson's disease (PD) is a neurodegenerative disorder that leads to destruction of the midbrain dopaminergic (DA) neurons. This phenomenon is related to apoptosis and its activation can be blocked by the pituitary adenylate cyclase-activating polypeptide (PACAP). Growing evidence indicates that autophagy, a self-degradation activity that cleans up the cell, is induced during the course of neurodegenerative diseases. However, the role of autophagy in the pathogenesis of neuronal disorders is yet poorly understood and the potential ability of PACAP to modulate the related autophagic activation has never been significantly investigated. Hence, we explored the putative autophagy-modulating properties of PACAP in in vitro and in vivo models of PD, using the neurotoxic agents 1-methyl-4-phenylpyridinium (MPP(+)) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), respectively, to trigger alterations of DA neurons. In both models, following the toxin exposure, PACAP reduced the autophagic activity as evaluated by the production of LC3 II, the modulation of the p62 protein levels, and the formation of autophagic vacuoles. The ability of PACAP to inhibit autophagy was also observed in an in vitro cell assay by the blocking of the p62-sequestration activity produced with the autophagy inducer rapamycin. Thus, the results demonstrated that autophagy is induced in PD experimental models and that PACAP exhibits not only anti-apoptotic but also anti-autophagic properties.

  6. Clinical utility of LC3 and p62 immunohistochemistry in diagnosis of drug-induced autophagic vacuolar myopathies: a case-control study.

    Directory of Open Access Journals (Sweden)

    Han S Lee

    Full Text Available BACKGROUND: Some patients treated with chloroquine, hydroxychloroquine, or colchicine develop autophagic vacuolar myopathy, the diagnosis of which currently requires electron microscopy. The goal of the current study was to develop an immunohistochemical diagnostic marker for this pathologic entity. METHODOLOGY: Microtubule-associated protein light chain 3 (LC3 has emerged as a robust marker of autophagosomes. LC3 binds p62/SQSTM1, an adapter protein that is selectively degraded via autophagy. In this study, we evaluated the utility of immunohistochemical stains for LC3 and p62 as diagnostic markers of drug-induced autophagic vacuolar myopathy. The staining was performed on archival muscle biopsy material, with subject assignment to normal control, drug-treated control, and autophagic myopathy groups based on history of drug use and morphologic criteria. PRINCIPAL FINDINGS: In all drug-treated subjects, but not in normal controls, LC3 and p62 showed punctate staining characteristic of autophagosome buildup. In the autophagic myopathy subjects, puncta were coarser and tended to coalesce into linear structures aligned with the longitudinal axis of the fiber, often in the vicinity of vacuoles. The percentage of LC3- and p62-positive fibers was significantly higher in the autophagic myopathy group compared to either the normal control (p<0.001 or the drug-treated control group (p<0.05. With the diagnostic threshold set between 8% and 15% positive fibers (depending on the desired level of sensitivity and specificity, immunohistochemical staining for either LC3 or p62 could be used to identify subjects with autophagic vacuolar myopathy within the drug-treated subject group (p ≤ 0.001. SIGNIFICANCE: Immunohistochemistry for LC3 and p62 can facilitate tissue-based diagnosis of drug-induced autophagic vacuolar myopathies. By limiting the need for electron microscopy (a time consuming and costly technique with high specificity, but low sensitivity

  7. 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

  8. The autophagic tumor stroma model of cancer or "battery-operated tumor growth": A simple solution to the autophagy paradox.

    Science.gov (United States)

    Martinez-Outschoorn, Ubaldo E; Whitaker-Menezes, Diana; Pavlides, Stephanos; Chiavarina, Barbara; Bonuccelli, Gloria; Casey, Trimmer; Tsirigos, Aristotelis; Migneco, Gemma; Witkiewicz, Agnieszka; Balliet, Renee; Mercier, Isabelle; Wang, Chengwang; Flomenberg, Neal; Howell, Anthony; Lin, Zhao; Caro, Jaime; Pestell, Richard G; Sotgia, Federica; Lisanti, Michael P

    2010-11-01

    The role of autophagy in tumorigenesis is controversial. Both autophagy inhibitors (chloroquine) and autophagy promoters (rapamycin) block tumorigenesis by unknown mechanism(s). This is called the "Autophagy Paradox". We have recently reported a simple solution to this paradox. We demonstrated that epithelial cancer cells use oxidative stress to induce autophagy in the tumor microenvironment. As a consequence, the autophagic tumor stroma generates recycled nutrients that can then be used as chemical building blocks by anabolic epithelial cancer cells. This model results in a net energy transfer from the tumor stroma to epithelial cancer cells (an energy imbalance), thereby promoting tumor growth. This net energy transfer is both unilateral and vectorial, from the tumor stroma to the epithelial cancer cells, representing a true host-parasite relationship. We have termed this new paradigm "The Autophagic Tumor Stroma Model of Cancer Cell Metabolism" or "Battery-Operated Tumor Growth". In this sense, autophagy in the tumor stroma serves as a "battery" to fuel tumor growth, progression and metastasis, independently of angiogenesis. Using this model, the systemic induction of autophagy will prevent epithelial cancer cells from using recycled nutrients, while the systemic inhibiton of autophagy will prevent stromal cells from producing recycled nutrients-both effectively "starving" cancer cells. We discuss the idea that tumor cells could become resistant to the systemic induction of autophagy, by the upregulation of natural endogenous autophagy inhibitors in cancer cells. Alternatively, tumor cells could also become resistant to the systemic induction of autophagy, by the genetic silencing/deletion of pro-autophagic molecules, such as Beclin1. If autophagy resistance develops in cancer cells, then the systemic inhibition of autophagy would provide a therapeutic solution to this type of drug resistance, as it would still target autophagy in the tumor stroma. As such, an

  9. 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.

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

    DEFF Research Database (Denmark)

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

    1998-01-01

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

  11. 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.

  12. 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

  13. 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.

  14. 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...

  15. 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

  16. 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...

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

    Science.gov (United States)

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

    2012-12-01

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

  18. Graveoline isolated from ethanolic extract of Ruta graveolens triggers apoptosis and autophagy in skin melanoma cells: a novel apoptosis-independent autophagic signaling pathway.

    Science.gov (United States)

    Ghosh, Samrat; Bishayee, Kausik; Khuda-Bukhsh, Anisur Rahman

    2014-08-01

    Anti-cancer drugs generally kill cancer cells by apoptosis but fail to do so when they become resistant and escape apoptosis signals. But these resistant cells can still be killed by autophagy. Therefore, drugs having both apoptotic and autophagic abilities are solicited in effective cancer management. In search of such a drug, we examined the efficacy of graveoline, a bioactive compound isolated from Ruta graveolens on skin melanoma A375 cells through the use of specific signaling cascades and their inhibitors. Cytotoxicity of graveoline was tested by conducting MTT assay. Induction of autophagy and apoptosis was checked. Expression of related proteins and their localization were studied by conducting immunoblot assay and through confocal microscopy, respectively. We found graveoline-induced Beclin-1 associated autophagy in A375 cells and 3-methyladenine, an inhibitor of autophagy did not affect apoptosis. Conversely, caspase inhibitor that blocked apoptosis did not affect autophagic cell death, suggesting thereby that these two were independent events. Use of reactive oxygen species (ROS) scavengers inhibited cell death, but blocking autophagy did not affect graveoline-induced ROS generation, suggesting that ROS generation ensued autophagy. Thus, graveoline-induced both apoptotic and autophagic cell death in skin melanoma cells, a desirable quality in effective anti-cancer drug design.

  19. 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.

  20. 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

  1. 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

  2. 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.

  3. Patterns of Flux Emergence

    Science.gov (United States)

    Title, A.; Cheung, M.

    2008-05-01

    The high spatial resolution and high cadence of the Solar Optical Telescope on the JAXA Hinode spacecraft have allowed capturing many examples of magnetic flux emergence from the scale of granulation to active regions. The observed patterns of emergence are quite similar. Flux emerges as a array of small bipoles on scales from 1 to 5 arc seconds throughout the region that the flux eventually condenses. Because the fields emerging from the underlying flux rope my appear many in small segments and the total flux (absolute sum) is not a conserved quantity the amount of total flux on the surface may vary significantly during the emergence process. Numerical simulations of flux emergence exhibit patterns similar to observations. Movies of both observations and numerical simulations will be presented.

  4. 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.

  5. The novel pterostilbene derivative ANK-199 induces autophagic cell death through regulating PI3 kinase class III/beclin 1/Atg‑related proteins in cisplatin‑resistant CAR human oral cancer cells.

    Science.gov (United States)

    Hsieh, Min-Tsang; Chen, Hao-Ping; Lu, Chi-Cheng; Chiang, Jo-Hua; Wu, Tian-Shung; Kuo, Daih-Huang; Huang, Li-Jiau; Kuo, Sheng-Chu; Yang, Jai-Sing

    2014-08-01

    Pterostilbene is an effective chemopreventive agent against multiple types of cancer cells. A novel pterostilbene derivative, ANK-199, was designed and synthesized by our group. Its antitumor activity and mechanism in cisplatin-resistant CAR human oral cancer cells were investigated in this study. Our results show that ANK-199 has an extremely low toxicity in normal oral cell lines. The formation of autophagic vacuoles and acidic vesicular organelles (AVOs) was observed in the ANK-199-treated CAR cells by monodansylcadaverine (MDC) and acridine orange (AO) staining, suggesting that ANK-199 is able to induce autophagic cell death in CAR cells. Neither DNA fragmentation nor DNA condensation was observed, which means that ANK-199-induced cell death is not triggered by apoptosis. In accordance with morphological observation, 3-MA, a specific inhibitor of PI3K kinase class III, can inhibit the autophagic vesicle formation induced by ANK-199. In addition, ANK-199 is also able to enhance the protein levels of autophagic proteins, Atg complex, beclin 1, PI3K class III and LC3-II, and mRNA expression of autophagic genes Atg7, Atg12, beclin 1 and LC3-II in the ANK-199-treated CAR cells. A molecular signaling pathway induced by ANK-199 was therefore summarized. Results presented in this study show that ANK-199 may become a novel therapeutic reagent for the treatment of oral cancer in the near future (patent pending).

  6. 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

  7. 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

  8. 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.

  9. 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.

  10. Early activation of MyD88-mediated autophagy sustains HSV-1 replication in human monocytic THP-1 cells

    Science.gov (United States)

    Siracusano, Gabriel; Venuti, Assunta; Lombardo, Daniele; Mastino, Antonio; Esclatine, Audrey; Sciortino, Maria Teresa

    2016-01-01

    Autophagy is a cellular degradation pathway that exerts numerous functions in vital biological processes. Among these, it contributes to both innate and adaptive immunity. On the other hand, pathogens have evolved strategies to manipulate autophagy for their own advantage. By monitoring autophagic markers, we showed that HSV-1 transiently induced autophagosome formation during early times of the infection of monocytic THP-1 cells and human monocytes. Autophagy is induced in THP-1 cells by a mechanism independent of viral gene expression or viral DNA accumulation. We found that the MyD88 signaling pathway is required for HSV-1-mediated autophagy, and it is linked to the toll-like receptor 2 (TLR2). Interestingly, autophagy inhibition by pharmacological modulators or siRNA knockdown impaired viral replication in both THP-1 cells and human monocytes, suggest that the virus exploits the autophagic machinery to its own benefit in these cells. Taken together, these findings indicate that the early autophagic response induced by HSV-1 exerts a proviral role, improving viral production in a semi-permissive model such as THP-1 cells and human monocytes. PMID:27509841

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

    Directory of Open Access Journals (Sweden)

    Feng Xu

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

  12. Aqueous Extract of Solanum nigrum Leaf Activates Autophagic Cell Death and Enhances Docetaxel-Induced Cytotoxicity in Human Endometrial Carcinoma Cells

    Directory of Open Access Journals (Sweden)

    Cheng-Jeng Tai

    2012-01-01

    Full Text Available Chemotherapy is the main approach in dealing with advanced and recurrent endometrial cancer. An effective complementary ingredient can be helpful in improving the clinical outcome. Aqueous extract of Solanum nigrum leaf (AE-SN is a principal ingredient for treating cancer patients in traditional Chinese medicinal practice but lacks sufficient evidence to verify its tumor suppression efficacy. This study evaluated the antitumor effects of AE-SN and also assessed the synergistic effects of AE-SN with docetaxel On the human endometrial cancer cell lines, HEC1A, HEC1B, and KLE. The activation of apoptotic markers, caspase-3 and poly-ADP-ribose polymerase, and autophagic marker, microtubule-associated protein 1 light chain 3 A/B, wAS determined to clarify the cell death pathways responsible for AE-SN induced tumor cell death. Results indicated that AE-SN-treatment has significant cytotoxicity on the tested endometrial cancer cells with accumulation of LC3 A/B II and demonstrated a synergistic effect of AE-SN and docetaxel in HEC1A and HEC1B cells, but not KLE cells. In conclusion, AE-SN treatment was effective in suppressing endometrial cancer cells via the autophagic pathway and was also capable of enhancing the cytotoxicity of docetaxel in human endometrial cancer cells. Our results provide meaningful evidence for integrative cancer therapy in the future.

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

    Directory of Open Access Journals (Sweden)

    Hugo J.R. Fernandes

    2016-03-01

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

  14. 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.

  15. Autophagic induction of amyotrophic lateral sclerosis-linked Cu/Zn superoxide dismutase 1 G93A mutant in NSC34 cells

    Institute of Scientific and Technical Information of China (English)

    Yanming Wei

    2014-01-01

    Previous studies have conifrmed that the beclin 1 complex plays a key role in the initial stage of autophagy and deregulated autophagy might involve in amyotrophic lateral sclerosis. However, the mechanism underlying altered autophagy associated with the beclin 1 complex remains un-clear. In this study, we transfected the Cu/Zn superoxide dismutase 1 G93A mutant protein into the motor neuron-like cell line NSC34 cultured in vitro. Western blotting and co-immunopre-cipitation showed that the Cu/Zn superoxide dismutase 1 G93A mutant enhanced the turnover of autophagic marker microtubule-associated protein light chain 3II (LC3II) and stimulated the conversion of EGFP-LC3I to EGFP-LC3II, but had little inlfuence on the binding capacity of the autophagy modulators ATG14L, rubicon, UVRAG, and hVps34 to beclin 1 during auto-phagosome formation. These results suggest that the amyotrophic lateral sclerosis-linked Cu/Zn superoxide dismutase 1 G93A mutant can upregulate autophagic activity in NSC34 cells, but that this does not markedly affect beclin 1 complex components.

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

    Science.gov (United States)

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

    2015-12-16

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

  17. 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

    2016-01-01

    Summary 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

  18. 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

  19. 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.

  20. 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.)

  1. 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.)

  2. 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...

  3. 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...

  4. 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...

  5. 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

  6. 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.

  7. 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

  8. 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.

  9. Flux Pinning in Superconductors

    CERN Document Server

    Matsushita, Teruo

    2007-01-01

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

  10. Flux pinning in superconductors

    CERN Document Server

    Matsushita, Teruo

    2014-01-01

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

  11. 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.

  12. Flux amplification in SSPX

    Science.gov (United States)

    Lodestro, Lynda; Hooper, E. B.; Jayakumar, R. J.; Pearlstein, L. D.; Wood, R. D.; McLean, H. S.

    2007-11-01

    Flux amplification---the ratio of poloidal flux enclosed between the magnetic and geometric axes to that between the separatrix and the geometric axis---is a key measure of efficiency for edge-current-driven spheromaks. With the new, modular capacitor bank, permitting flexible programming of the gun current, studies of flux amplification under various drive scenarios can be performed. Analysis of recent results of pulsed operation with the new bank finds an efficiency ˜ 0.2, in selected shots, of the conversion of gun energy to confined magnetic energy during the pulses, and suggests a route toward sustained efficiency at 0.2. Results of experiments, a model calculation of field build-up, and NIMROD simulations exploring this newly suggested scenario will be presented.

  13. 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.

  14. 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

  15. 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.

  16. 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...

  17. 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

  18. 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...

  19. 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…

  20. 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.

  1. 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...

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

    Science.gov (United States)

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

    2011-12-01

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

  3. 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.

  4. Critical heat flux thermodynamics

    Energy Technology Data Exchange (ETDEWEB)

    Collado, F.J. E-mail: fjk@posta.unizar.es

    2002-11-01

    Convective boiling in subcooled water flowing through a heated channel is essential in many engineering applications where high heat flux need to be accommodated, such as in the divertor plates of fusion reactors. There are many available correlations for predicting heat transfer in the individual regimes of the empirical Nukiyama boiling curve, although unfortunately there is no physical fundamentals of such curve. Recently, the author has shown that the classical entropy balance could contain key information about boiling heat transfer. So, it was found that the average thermal gap in the heated channel (the wall temperature minus the average temperature of the coolant fluid) was strongly correlated with the efficiency of a theoretical reversible engine placed in this thermal gap. In this work and from the new proposed correlation, a new expression of the wall temperature in function of the average fluid temperature is derived and successfully checked against experimental data from General Electric. This expression suggests a new and simple definition of the critical heat flux (CHF), a key parameter of the thermal-hydraulic design of fusion reactors. Finally, based on the new definition, the CHF trends are commented.

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

    Science.gov (United States)

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

    2014-09-01

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

  6. 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

  7. 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...

  8. 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

  9. 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.

  10. 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....

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. 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....

  16. 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....

  17. 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

  18. New Examples of Flux Vacua

    CERN Document Server

    Maxfield, Travis; Robbins, Daniel; Sethi, Savdeep

    2013-01-01

    Type IIB toroidal orientifolds are among the earliest examples of flux vacua. By applying T-duality, we construct the first examples of massive IIA flux vacua with Minkowski space-times, along with new examples of type IIA flux vacua. The backgrounds are surprisingly simple with no four-form flux at all. They serve as illustrations of the ingredients needed to build type IIA and massive IIA solutions with scale separation. To check that these backgrounds are actually solutions, we formulate the complete set of type II supergravity equations of motion in a very useful form that treats the R-R fields democratically.

  19. 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...

  20. 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

  1. Gauge - Mediated Supersymmetry Breaking in String Compactifications

    Energy Technology Data Exchange (ETDEWEB)

    Diaconescu, Duiliu-Emanuel; /Rutgers U., Piscataway; Florea, Bogdan; Kachru, Shamit; Svrcek, Peter; /Stanford U., Phys. Dept. /SLAC

    2006-01-04

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

  2. Carbon Dioxide Flux Measurement Systems (CO2Flux) Handbook

    Energy Technology Data Exchange (ETDEWEB)

    Fischer, M

    2005-01-01

    The Southern Great Plains (SGP) carbon dioxide flux (CO2 flux) measurement systems provide half-hour average fluxes of CO2, H2O (latent heat), and sensible heat. The fluxes are obtained by the eddy covariance technique, which computes the flux as the mean product of the vertical wind component with CO2 and H2O densities, or estimated virtual temperature. A three-dimensional sonic anemometer is used to obtain the orthogonal wind components and the virtual (sonic) temperature. An infrared gas analyzer is used to obtain the CO2 and H2O densities. A separate sub-system also collects half-hour average measures of meteorological and soil variables from separate 4-m towers.

  3. 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

  4. Earth's surface heat flux

    Directory of Open Access Journals (Sweden)

    J. H. Davies

    2009-11-01

    Full Text Available We present a revised estimate of Earth's surface heat flux that is based upon a heat flow data-set with 38 347 measurements, which is 55% more than used in previous estimates. Our methodology, like others, accounts for hydrothermal circulation in young oceanic crust by utilising a half-space cooling approximation. For the rest of Earth's surface, we estimate the average heat flow for different geologic domains as defined by global digital geology maps; and then produce the global estimate by multiplying it by the total global area of that geologic domain. The averaging is done on a polygon set which results from an intersection of a 1 degree equal area grid with the original geology polygons; this minimises the adverse influence of clustering. These operations and estimates are derived accurately using methodologies from Geographical Information Science. We consider the virtually un-sampled Antarctica separately and also make a small correction for hot-spots in young oceanic lithosphere. A range of analyses is presented. These, combined with statistical estimates of the error, provide a measure of robustness. Our final preferred estimate is 47±2 TW, which is greater than previous estimates.

  5. Errors in airborne flux measurements

    Science.gov (United States)

    Mann, Jakob; Lenschow, Donald H.

    1994-07-01

    We present a general approach for estimating systematic and random errors in eddy correlation fluxes and flux gradients measured by aircraft in the convective boundary layer as a function of the length of the flight leg, or of the cutoff wavelength of a highpass filter. The estimates are obtained from empirical expressions for various length scales in the convective boundary layer and they are experimentally verified using data from the First ISLSCP (International Satellite Land Surface Climatology Experiment) Field Experiment (FIFE), the Air Mass Transformation Experiment (AMTEX), and the Electra Radome Experiment (ELDOME). We show that the systematic flux and flux gradient errors can be important if fluxes are calculated from a set of several short flight legs or if the vertical velocity and scalar time series are high-pass filtered. While the systematic error of the flux is usually negative, that of the flux gradient can change sign. For example, for temperature flux divergence the systematic error changes from negative to positive about a quarter of the way up in the convective boundary layer.

  6. 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...

  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 legiti......The article investigates the implications of mediatization for the legitimation strategies of humanitarian organizations. Based on a (full population) corpus of ~400 pages of brochure material from 1970 to 2007, the micro-textual processes involved in humanitarian organizations' efforts...... 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...

  8. 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

  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. 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.

  11. 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.)

  12. Interpreting Flux from Broadband Photometry

    Science.gov (United States)

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

    2016-10-01

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

  13. 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

  14. 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) ...

  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.

  16. 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

  17. 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.)

  18. 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.

  19. Periodicities in photospheric magnetic flux

    Institute of Scientific and Technical Information of China (English)

    SONG; Wenbin; WANG; Jingxiu

    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.

  20. Flux Emergence at the Photosphere

    Science.gov (United States)

    Cheung, M. C. M.; Schüssler, M.; Moreno-Insertis, F.

    2006-12-01

    To model the emergence of magnetic fields at the photosphere, we carried out 3D magneto-hydrodynamics (MHD) simulations using the MURaM code. Our simulations take into account the effects of compressibility, energy exchange via radiative transfer and partial ionization in the equation of state. All these physical ingredients are essential for a proper treatment of the problem. In the simulations, an initially buoyant magnetic flux tube is embedded in the upper layers of the convection zone. We find that the interaction between the flux tube and the external flow field has an important influence on the emergent morphology of the magnetic field. Depending on the initial properties of the flux tube (e.g. field strength, twist, entropy etc.), the emergence process can also modify the local granulation pattern. The inclusion of radiative transfer allows us to directly compare the simulation results with real observations of emerging flux.

  1. 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.

  2. 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...

  3. $P$ fluxes and exotic branes

    CERN Document Server

    Lombardo, Davide M; Risoli, Stefano

    2016-01-01

    We consider the ${\\cal N}=1$ superpotential generated in type-II orientifold models by non-geometric fluxes. In particular, we focus on the family of $P$ fluxes, that are related by T-duality transformations to the S-dual of the $Q$ flux. We determine the general rule that transforms a given flux in this family under a single T-duality transformation. This rule allows to derive a complete expression for the superpotential for both the IIA and the IIB theory for the particular case of a $T^6/[\\mathbb{Z}_2 \\times \\mathbb{Z}_2 ]$ orientifold. We then consider how these fluxes modify the generalised Bianchi identities. In particular, we derive a fully consistent set of quadratic constraints coming from the NS-NS Bianchi identities. On the other hand, the $P$ flux Bianchi identities induce tadpoles, and we determine a set of exotic branes that can be consistently included in order to cancel them. This is achieved by determining a universal transformation rule under T-duality satisfied by all the branes in string t...

  4. 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...

  5. Producing and Distinguishing x-Type Four-Qubit States in Flux Qubits

    Institute of Scientific and Technical Information of China (English)

    GAO Gui-Long; SONG Fu-Quan; HUANG Shou-Sheng; WANG Yan-Wei; FAN Zhi-Qiang; YUAN Xian-Zhang; JIANG Nian-Quan

    2012-01-01

    We propose an effective method to produce four-qubit x~type entangled states by using flux qubits coupled to an LC circuit which acts as a quantum data bus (QDB). In our scheme, the interaction is mediated by the exchange of virtual rather than real photons because of the large detuning between flux qubits and QDB, and then QDB-induced loss can be effectively avoided. The experimental feasibility of the scheme is also presented.%We propose an effective method to produce four-qubit x-type entangled states by using flux qubits coupled to an LC circuit which acts as a quantum data bus (QDB).In our scheme,the interaction is mediated by the exchange of virtual rather than real photons because of the large detuning between flux qubits and QDB,and then QDB-induced loss can be effectively avoided.The experimental feasibility of the scheme is also presented.

  6. 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...

  7. 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...

  8. 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...

  9. Ideal flux field dielectric concentrators.

    Science.gov (United States)

    García-Botella, Angel

    2011-10-01

    The concept of the vector flux field was first introduced as a photometrical theory and later developed in the field of nonimaging optics; it has provided new perspectives in the design of concentrators, overcoming standard ray tracing techniques. The flux field method has shown that reflective concentrators with the geometry of the field lines achieve the theoretical limit of concentration. In this paper we study the role of surfaces orthogonal to the field vector J. For rotationally symmetric systems J is orthogonal to its curl, and then a family of surfaces orthogonal to the lines of J exists, which can be called the family of surfaces of constant pseudopotential. Using the concept of the flux tube, it is possible to demonstrate that refractive concentrators with the shape of these pseudopotential surfaces achieve the theoretical limit of concentration. PMID:22016201

  10. BVOC fluxes above mountain grassland

    Directory of Open Access Journals (Sweden)

    I. Bamberger

    2010-05-01

    Full Text Available Grasslands comprise natural tropical savannah over managed temperate fields to tundra and cover one quarter of the Earth's land surface. Plant growth, maintenance and decay result in volatile organic compound (VOCs emissions to the atmosphere. Furthermore, biogenic VOCs (BVOCs are emitted as a consequence of various environmental stresses including cutting and drying during harvesting. Fluxes of BVOCs were measured with a proton-transfer-reaction-mass-spectrometer (PTR-MS over temperate mountain grassland in Stubai Valley (Tyrol, Austria over one growing season (2008. VOC fluxes were calculated from the disjunct PTR-MS data using the virtual disjunct eddy covariance method and the gap filling method. Methanol fluxes obtained with the two independent flux calculation methods were highly correlated (y = 0.95×−0.12, R2 = 0.92. Methanol showed strong daytime emissions throughout the growing season – with maximal values of 9.7 nmol m−2 s−1, methanol fluxes from the growing grassland were considerably higher at the beginning of the growing season in June compared to those measured during October (2.5 nmol m−2 s−1. Methanol was the only component that exhibited consistent fluxes during the entire growing periods of the grass. The cutting and drying of the grass increased the emissions of methanol to up to 78.4 nmol m−2 s−1. In addition, emissions of acetaldehyde (up to 11.0 nmol m−2 s−1, and hexenal (leaf aldehyde, up to 8.6 nmol m−2 s−1 were detected during/after harvesting.

  11. 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.

  12. 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.

  13. 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...

  14. 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.

  15. 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...

  16. A Push-Pull Test to Measure Volatilization Fluxes of Organic Pollutants without Flux Chambers

    Science.gov (United States)

    Reid, M. C.; Jaffe, P. R.

    2011-12-01

    Volatilization of organic contaminants is a potentially significant removal mechanism from wetlands, but field measurements are scarce and the physiochemical controls on volatilization from wetland soils remain poorly understood. It has been established that volatilization rates of certain pollutants are enhanced by vegetation and are strongly correlated with evapotranspiration (ET). These observations rely on flux chambers measurements, which are characterized by significant uncertainty due the chamber's effects on the meteorological variables around the plant and consequent impact on the biophysical processes governing ET and plant uptake of soil contaminants. Here we present data from a mesocosm study using a modified single-well push-pull test to measure in-situ volatilization rates from inundated soils vegetated with the wetland macrophytes Scirpus acutus and Typha latifolia, as well as from unplanted soil. This new method uses a test solution containing the volatile tracers sulfur hexafluoride (SF6), helium (He), and dichlorodifluoromethane (CFC-12) to estimate first-order volatilization rates and examine the relationship between physiochemical properties and volatilization rates. The test also yields an estimate for the volume of subsurface gas bubbles, which is used to derive a retardation factor for the effect of interphase partitioning on the estimation of kinetic parameters. We evaluate models to partition observed fluxes into different pathways for plant-mediated volatilization: transpirational uptake and consequent volatilization, and gas-phase diffusion through porous root aerenchyma. Those models are then used to scale tracer-derived volatilization fluxes to priority organic pollutants including benzene, trichloroethylene, and vinyl chloride. We also discuss the implementation of this method at field scales to estimate volatilization as a component of phytoremediation applications.

  17. Mass fluxes for hot stars

    CERN Document Server

    Lucy, L B

    2009-01-01

    In an attempt to understand the extraordinarily small mass-loss rates of late-type O dwarfs, mass fluxes in the relevant part of (Teff, g)-space are derived from first principles using a previously-described code for constructing moving reversing layers. From these mass fluxes, a weak-wind domain is identified within which a star's rate of mass loss by a radiatively-driven wind is less than that due to nuclear burning. The five weak-wind stars recently analysed by Marcolino et al. (2009) fall within or at the edge of this domain. But although the theoretical mass fluxes for these stars are approximately 1.4 dex lower than those derived with the formula of Vink et al. (2000), the observed rates are still not matched, a failure that may reflect our poor understanding of low-density supersonic outflows. Mass fluxes are also computed for two strong-wind O4 stars analysed by Bouret et al. (2005). The predictions agree with the sharply reduced mass loss rates found when wind clumping is taken into account.

  18. Mass fluxes for hot stars

    Science.gov (United States)

    Lucy, L. B.

    2010-03-01

    In an attempt to understand the extraordinarily small mass-loss rates of late-type O dwarfs, mass fluxes in the relevant part of (Teff, g)-space are derived from first principles using a previously-described code for constructing moving reversing layers. From these mass fluxes, a weak-wind domain is identified within which a star's rate of mass loss by a radiatively-driven wind is less than that due to nuclear burning. The five weak-wind stars recently analysed by Marcolino et al. (2009, A&A, 498, 837) fall within or at the edge of this domain. But although the theoretical mass fluxes for these stars are ≈1.4 dex lower than those derived with the formula of Vink et al. (2000), the observed rates are still not matched, a failure that may reflect our poor understanding of low-density supersonic outflows. Mass fluxes are also computed for two strong-wind O4 stars analysed by Bouret et al. (2005, A&A, 438, 301). The predictions agree with the sharply reduced mass loss rates found when Bouret et al. take wind clumping into account.

  19. 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

  20. 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.

  1. 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.

  2. Determination of Energy Fluxes Over Agricultural Surfaces

    OpenAIRE

    Josefina Argete

    1994-01-01

    An energy budget was conducted over two kinds if surfaces: grass and corn canopy. The net radiative flux and the soil heat flux were directly measured while the latent and sensible heat flux were calculated from the vertical profiles if wet and dry-bulb temperature and wind speed. The crop storage flux was also estimated. Using the gradient or aerodynamic equations, the calculated fluxes when compared to the measured fluxes in the context of an energy budget gave an SEE = 63 Wm-2 over grass a...

  3. 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.

  4. 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\

  5. 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...

  6. 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.

  7. Classical Transitions for Flux Vacua

    CERN Document Server

    Deskins, J Tate; Yang, I-Sheng

    2012-01-01

    We present the simplest model for classical transitions in flux vacua. A complex field with a spontaneously broken U(1) symmetry is embedded in $M_2\\times S_1$. We numerically construct different winding number vacua, the vortices interpolating between them, and simulate the collisions of these vortices. We show that classical transitions are generic at large boosts, independent of whether or not vortices miss each other in the compact $S_1$.

  8. 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.

  9. 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.

  10. Flux Tracking Control of Induction Motors

    Institute of Scientific and Technical Information of China (English)

    LanLin; XiaowuMu; ChunxiaBu

    2004-01-01

    This paper deals with flux tracking control of induction motors. Firstly,we analyze convergency of non-homogeneous linear time-varying systems and a sufficient condition is given. Finally, the flux regulator of induction motors is discussed.

  11. Determination of Energy Fluxes Over Agricultural Surfaces

    Directory of Open Access Journals (Sweden)

    Josefina Argete

    1994-12-01

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

  12. The Significance of Common Molecular Biomarkers of Autophay Pathway in Reflecting Autophagic Activity%自噬途径常用分子生物学指标在反映自噬活性上的意义

    Institute of Scientific and Technical Information of China (English)

    潘明娇; 王小丹(综述); 喻陆(审校)

    2015-01-01

    As a self-degradative cell pathway in eukaryotic cells,autophagy is evolutionarily conserved and mainly responsible for the degradation of long-lived proteins and damaged organelles.Autophagy is alsoconducive to maintaining the normal cellular homeostasis.The past decades have witnessed a remarkable progressof research on autophagy.A great number of studies obtain their conclusions through observing thechange of autophagic activity,therefore it is important to correctly explain the results from the autophagy activity test.Among the test methods,the molecular biological methods are widely used,and through clarifying the molecular mechanisms of autophagy and the relationship between autophagy and ubiquitin proteasome system,we could make better use of the common molecular biomarkers to reflect the change of autophagic activity.%自噬是一种真核细胞自我降解、维持自稳态的细胞途径,在进化过程中高度保守,主要负责降解长寿蛋白和损伤细胞器。近年来,关于自噬的研究较多,其中许多研究需要通过观察自噬活性的变化来得出结论,因此准确解释自噬活性检测结果十分重要。在众多自噬活性检测方法中,分子生物学检测技术应用较为广泛,通过了解自噬的分子机制及其与泛素蛋白酶体系的关系,可以更好地利用自噬途径常用分子生物学指标来反映自噬活性变化。

  13. 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

  14. Intermittently Flowing Rivers of Quantized Magnetic Flux

    OpenAIRE

    Nori, Franco

    1997-01-01

    Recent experiments and realistic flux-gradient-driven computer simulations provide evidence of plastic flow of flux lines in a superconductor. The striking videos of the onset of vortex motion vividly illustrate the existence of flowing "rivers" of quantized magnetic flux that intermittently form, freeze, and reappear at different locations in the sample. These rivers flow around "islands" (or domains) of flux lines which are temporarily trapped by the pinning sites. The shape and size of the...

  15. Hypermoduli Stabilization, Flux Attractors, and Generating Functions

    CERN Document Server

    Larsen, Finn; Robbins, Daniel

    2009-01-01

    We study stabilization of hypermoduli with emphasis on the effects of generalized fluxes. We find a class of no-scale vacua described by ISD conditions even in the presence of geometric flux. The associated flux attractor equations can be integrated by a generating function with the property that the hypermoduli are determined by a simple extremization principle. We work out several orbifold examples where all vector moduli and many hypermoduli are stabilized, with VEVs given explicitly in terms of fluxes.

  16. 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.

  17. Flux balance analysis accounting for metabolite dilution.

    Science.gov (United States)

    Benyamini, Tomer; Folger, Ori; Ruppin, Eytan; Shlomi, Tomer

    2010-01-01

    Flux balance analysis is a common method for predicting steady-state flux distributions within metabolic networks, accounting for the growth demand for the synthesis of a predefined set of essential biomass precursors. Ignoring the growth demand for the synthesis of intermediate metabolites required for balancing their dilution leads flux balance analysis to false predictions in some cases. Here, we present metabolite dilution flux balance analysis, which addresses this problem, resulting in improved metabolic phenotype predictions.

  18. 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.

  19. Surface fluxes over natural landscapes using scintillometry

    NARCIS (Netherlands)

    Meijninger, W.M.L.

    2003-01-01

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

  20. 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.

  1. 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

  2. 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

  3. 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)

  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. 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.

  6. 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.

  7. 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

  8. 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...

  9. 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...

  10. 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...

  11. 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,...

  12. 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.

  13. 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…

  14. Mediation as Signal

    NARCIS (Netherlands)

    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 signa

  15. 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.

  16. 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.

  17. 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

  18. A quantitative method for silica flux evaluation

    Science.gov (United States)

    Schonewille, R. H.; O'Connell, G. J.; Toguri, J. M.

    1993-02-01

    In the smelting of copper and copper/nickel concentrates, the role of silica flux is to aid in the removal of iron by forming a slag phase. Alternatively, the role of flux may be regarded as a means of controlling the formation of magnetite, which can severely hinder the operation of a furnace. To adequately control the magnetite level, the flux must react rapidly with all of the FeO within the bath. In the present study, a rapid method for silica flux evaluation that can be used directly in the smelter has been developed. Samples of flux are mixed with iron sulfide and magnetite and then smelted at a temperature of 1250 °C. Argon was swept over the reaction mixture and analyzed continuously for sulfur dioxide. The sulfur dioxide concentration with time was found to contain two peaks, the first one being independent of the flux content of the sample. A flux quality parameter has been defined as the height-to-time ratio of the second peak. The value of this parameter for pure silica is 5100 ppm/min. The effects of silica content, silica particle size, and silicate mineralogy were investigated. It was found that a limiting flux quality is achieved for particle sizes less than 0.1 mm in diameter and that fluxes containing feldspar are generally of a poorer quality. The relative importance of free silica and melting point was also studied using synthetic flux mixtures, with free silica displaying the strongest effect.

  19. Partitioning evapotranspiration fluxes using atmometer

    Science.gov (United States)

    Orsag, Matej; Fischer, Milan; Trnka, Miroslav; Kucera, Jiri; Zalud, Zdenek

    2013-04-01

    This effort is aimed to derive a simple tool for separating soil evaporation and transpiration from evapotranspiration, measured by Bowen ration energy balance method (BREB) in short rotation coppice (SRC). The main idea is to utilize daily data of actual evapotranspiration (ETa) measured above bare soil (spring 2010 - first year following harvest), reference evapotranspiration (ETo) measured by atmometer ETgage and precipitation data, in order to create an algorithm for estimation evaporation from bare soil. This approach is based on the following assumption: evaporation of wetted bare soil same as the ETo from atmometer is assumed to be identical in days with rain. In first and further days with no rain (and e.g. high evaporative demand) the easily evaporable soil water depletes and ETa so as crop coefficient of bare soil (Kcb) decreases in a way similar to decreasing power function. The algorithm represents a parameterized function of daily cumulated ETo (ETc) measured by atmometer in days elapsed from last rain event (Kcb = a*ETc^b). After each rain event the accumulation of ETo starts again till next rain event (e. g. only days with no rain are cumulated). The function provides decreasing Kcb for each day without rain. The bare soil evaporation can be estimated when the atmometer-recorded value is multiplied by Kcb for particular day without rain. In days with rain Kcb is assumed to be back at 1. This method was successfully tested for estimating evaporation from bare soil under closed canopy of poplar-based SRC. When subtracting the estimated soil evaporation from total ETa flux, measured above the canopy using BREB method, it is possible to obtain transpiration flux of the canopy. There is also possibility to test this approach on the contrary - subtracting transpiration derived from sap-flow measurement from total ETa flux is possible to get soil evaporation as well. Acknowledgements: The present experiment is made within the frame of project Inter

  20. 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...

  1. 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

  2. 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...

  3. Warped branches of flux compactifications

    CERN Document Server

    Lim, Yen-Kheng

    2012-01-01

    We consider Freund-Rubin-type compactifications which are described by (p+q)-dimensional Einstein gravity with a positive cosmological constant and a q-form flux. Using perturbative expansions of Kinoshita's ansatz for warped dS_pxS^q and AdS_pxS^q spacetimes, we obtain analytical solutions describing the warped branches and their respective phase spaces. These equations are given by inhomogeneous Gegenbauer differential equations which can be solved by the Green's function method. The requirement that the Green's functions are regular provides constraints which determine the structure of the phase space of the warped branches. We apply the perturbation results to calculate the thermodynamic variables for the warped dS_pxS^q branch. In particular, the first law of thermodynamics can be reproduced using this method.

  4. Energy release and seismic flux

    Directory of Open Access Journals (Sweden)

    J. M. Munuera

    1965-06-01

    Full Text Available From the basic data and tlie previous results of priorpapers, we have made evaluations of the energy released and studied itsvariation. Its pulsative form is confirmed, which suggests several superposedperiods, perhaps of simple multiples of tlie undecenal of solar activity.For steps of a whole unity of m, the total approximated energy is computed.EN and Et may be compared, it being possible to replace one by the other,indifferently, from m = 5 up to m = 7.5. The compared variation of logEN with N demostrates they are not proportional.The tectonic flux is evaluated and we have the graphs for 5 and 15year lapses, from 1901 to I960, as well as another graph which correspondsto the representative average of these 60 years. A reduction of the mapof seismic activity attained through log (2 Eli2-. 60 x 2.5 is attached, whichrefers the annual flux for every 1000 sq km. This map is analyzed and thecomparative results with the zones of the first seismotectonic sketch publishedby Rey Pastor (1927 are considered. The conformity is checked andthe differences are shown.With Benioff's curve, expressed by 10u (ergV2, we show the accumulationand release of the total elastic strain, S60 (S Exh and (S JB1/2 for everyyear of the instrumental period (1901-1960. The cumulative interval (halfa Century coincides with the return period of the destructive earthquakes,which was estimated through other considerations.We have made a comparative sketch between seismic activity andthe admitted drawing of the Alpine Geosyncline on the Western Mediterreaneanand we suggest a possible rough-draft of the Oval regression at itsWestern end. The alignments of the intermediate shocks, in the AlboranSea and the Betican region, indicate active faults which might associated,perhaps, in a half-close as another oval connected to the Guadalquivir Faultand Southwards.

  5. 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

  6. 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....

  7. 硫链丝菌素诱导非小细胞肺癌细胞自噬性死亡%Thiostrepton induces autophagic cell death in non-small-cell lung cancer cells

    Institute of Scientific and Technical Information of China (English)

    邹争志; 聂培培; 倪艺榕; 周小明

    2014-01-01

    Autophagy is a fundamental cellular process that controls cells in a normal homeostatic state by recycling nu-trients to maintain cellular energy levels for cell survival through the turnover of proteins and damaged organelles.Where-as,persistent activation of autophagy can cause excessive depletion of cellular organelles and essential proteins,leading to caspase-independent autophagic cell death.Therefore,inducing cell death via this autophagic pathway might be an al-ternative approach for cancer therapy.Here,we show that the thiazole antibiotic thiostrepton decreased cell viability and induced cell apoptosis in non-small-cell lung cancer (NSCLC)PC-9 cells.Additionally,we found thiostrepton induced cell autophagy in PC-9 cells.Moreover,the cell apoptosis induced by thiostrepton could be blocked by 3-Methyladenine (3-MA),a autophagy inhibitor.These findings suggested that thiostrepton can promote the autophagic death of human NSCLC cells.Moreover,this study provided evidence that administration of thiostrepton combined with autophagy induc-er may be an effective therapeutic strategy for targeting human non-small-cell lung cancers.%自噬在细胞的生命过程中起了非常重要的作用,它能通过清除受损的细胞器和过多的蛋白质以维持细胞内环境稳定基本能量代谢的稳定。然而,自噬的持续激活可导致细胞器以及必需的蛋白质的过度消耗,导致不依赖caspase的自噬性细胞死亡。因此,通过这种自噬途径诱导细胞死亡可能是癌症治疗的一种新方法。在本研究我们发现,硫链丝菌素能够减少非小细胞肺癌PC-9细胞的细胞活力和诱导细胞凋亡。另外,我们发现硫链丝菌素诱导了PC-9细胞自噬。此外,我们也发现硫链丝菌素诱导的细胞凋亡可以被自噬抑制剂3-甲基腺嘌呤(3-MA)阻止。这些结果表明,硫链丝菌素促进人体非小细胞肺癌细胞的自噬性死亡。在本研究我们的发现也提示硫

  8. Turmeric toxicity in A431 epidermoid cancer cells associates with autophagy degradation of anti-apoptotic and anti-autophagic p53 mutant.

    Science.gov (United States)

    Thongrakard, Visa; Titone, Rossella; Follo, Carlo; Morani, Federica; Suksamrarn, Apichart; Tencomnao, Tewin; Isidoro, Ciro

    2014-12-01

    The keratinocyte-derived A431 Squamous Cell Carcinoma cells express the p53R273H mutant, which has been reported to inhibit apoptosis and autophagy. Here, we show that the crude extract of turmeric (Curcuma longa), similarly to its bioactive component Curcumin, could induce both apoptosis and autophagy in A431 cells, and these effects were concomitant with degradation of p53. Turmeric and curcumin also stimulated the activity of mTOR, which notoriously promotes cell growth and acts negatively on basal autophagy. Rapamycin-mediated inhibition of mTOR synergized with turmeric and curcumin in causing p53 degradation, increased the production of autophagosomes and exacerbated cell toxicity leading to cell necrosis. Small-interference mediated silencing of the autophagy proteins BECLIN 1 or ATG7 abrogated the induction of autophagy and largely rescued p53 stability in Turmeric-treated or Curcumin-treated cells, indicating that macroautophagy was mainly responsible for mutant p53 degradation. These data uncover a novel mechanism of turmeric and curcumin toxicity in chemoresistant cancer cells bearing mutant p53.

  9. Atmospheric neutrino flux and muon data

    OpenAIRE

    G. FiorentiniU & INFN, Ferrara; Naumov, V A.; Villante, F. L.

    2015-01-01

    We present a new one-dimensional calculation of low and intermediate energy atmospheric muon and neutrino fluxes, using up-to-date data on primary cosmic rays and hadronic interactions. The existing agreement between calculated muon fluxes and the data of the CAPRICE 94 muon experiment provides an evidence in favor of the validity of our description of hadronic interactions and shower development. This also supports our neutrino fluxes which are essentially lower than those used for the stand...

  10. 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...

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

    Energy Technology Data Exchange (ETDEWEB)

    Li, Yanchun; Luo, Qiyu [Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016 (China); Yuan, Lei [School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016 (China); Miao, Caixia; Mu, Xiaoshuo [Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016 (China); Xiao, Wei [Jiangsu Kanion Pharmaceutical Co., Ltd., Nanjing 222001 (China); Li, Jianchun [Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016 (China); Sun, Tiemin, E-mail: suntiemin@126.com [School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016 (China); Ma, Enlong, E-mail: maenlong@hotmail.com [Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016 (China); Jiangsu Kanion Pharmaceutical Co., Ltd., Nanjing 222001 (China)

    2012-08-15

    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.

  12. Ebb-and-flow of macroautophagy and chaperone-mediated autophagy in Raji cells induced by starvation and arsenic trioxide.

    Science.gov (United States)

    Li, Cai-Li; Wei, Hu-Lai; Chen, Jing; Wang, Bei; Xie, Bei; Fan, Lin-Lan; Li, Lin-Jing

    2014-01-01

    Autophagy is crucial in the maintenance of homeostasis and regenerated energy of mammalian cells. Macroautophagy and chaperone-mediated autophagy(CMA) are the two best-identified pathways. Recent research has found that in normal cells, decline of macroautophagy is appropriately parallel with activation of CMA. However, whether it is also true in cancer cells has been poorly studied. Here we focused on cross-talk and conversion between macroautophagy and CMA in cultured Burkitt lymphoma Raji cells when facing serum deprivation and exposure to a toxic compound, arsenic trioxide. The results showed that both macroautophagy and CMA were activated sequentially instead of simultaneously in starvation-induced Raji cells, and macroautophagy was quickly activated and peaked during the first hours of nutrition deprivation, and then gradually decreased to near baseline. With nutrient deprivation persisted, CMA progressively increased along with the decline of macroautophagy. On the other hand, in arsenic trioxide-treated Raji cells, macroautophagy activity was also significantly increased, but CMA activity was not rapidly enhanced until macroautophagy was inhibited by 3-methyladenine, an inhibitor. Together, we conclude that cancer cells exhibit differential responses to diverse stressor-induced damage by autophagy. The sequential switch of the first-aider macroautophagy to the homeostasis-stabilizer CMA, whether active or passive, might be conducive to the adaption of cancer cells to miscellaneous intracellular or extracellular stressors. These findings must be helpful to understand the characteristics, compensatory mechanisms and answer modes of different autophagic pathways in cancer cells, which might be very important and promising to the development of potential targeting interventions for cancer therapies via regulation of autophagic pathways. PMID:25081691

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-08-15

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

  14. 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

  15. 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.

  16. Surface Flux Modeling for Air Quality Applications

    Directory of Open Access Journals (Sweden)

    Limei Ran

    2011-08-01

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

  17. 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...

  18. 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...

  19. 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...

  20. 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...

  1. 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.

  2. 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

  3. Magnetic Flux Emergence in the Solar Photosphere

    Science.gov (United States)

    Cheung, M. C. M.; Schüssler, M.; Moreno-Insertis, F.

    2008-04-01

    The most prominent magnetic structures on the surface of the Sun are bipolar active regions. These magnetic complexes are comprised of a hierarchy of magnetic structures of different sizes, the largest of which are sunspots. Observations indicate that the appearance of active regions on the solar surface result from the emergence of bundles of magnetic flux from the underlying convection zone. We study the emergence process by means of 3D radiation MHD simulations. In the simulations, an initially buoyant magnetic flux tube is introduced into the near-surface layers of the convection zone. Subject to the buoyancy force, the flux tube rises towards the photosphere. Our simulations highlight the importance of magneto-convection on the evolution of the magnetic flux tube. The external convective flow field has an important influence on the emergence morphology of the emerging magnetic field. Depending on the initial properties of the magnetic flux tube (e.g. field strength, twist, entropy etc.), flux emergence may lead to a disturbance of the local granulation pattern. The observational signatures associated with emerging magnetic flux in our simulations are in qualitative and quantitative agreement with observational studies of emerging flux regions on the Sun.

  4. 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.

  5. 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.

  6. Magnetic balltracking: Tracking the photospheric magnetic flux

    CERN Document Server

    Attie, R

    2014-01-01

    Context: One aspect of understanding the dynamics of the quiet Sun is to quantify the evolution of the flux within small-scale magnetic features. These features are routinely observed in the quiet photosphere and were given various names, such as pores, knots, magnetic patches. Aims: This work presents a new algorithm for tracking the evolution of the broad variety of small-scale magnetic features in the photosphere, with a precision equal to the instrumental resolution. Methods: We have developed a new technique to track the evolution of the individual magnetic features from magnetograms, called "magnetic balltracking". It quantifies the flux of the tracked features, and it can track the footpoints of magnetic field lines inferred from magnetic field extrapolation. The algorithm can detect and quantify flux emergence, as well as flux cancellation. Results: The capabilities of magnetic balltracking are demonstrated with the detection and the tracking of two cases of magnetic flux emergence that lead to the br...

  7. Corrected Wavemaker Theory, Momentum Flux and Vorticity

    CERN Document Server

    Chafin, Clifford

    2014-01-01

    The usual wavemaker theory hides an unjustified integration constant assumption that renders it invalid. We discuss some surprising subtleties of momentum flux in infinite waves, packets and some counterintuitive examples where "hidden" flux contributions can arise. From here, we construct an ideal wavemaker that builds Airy waves from a series of microjets that allows an exact calculation of the forces on boundaries. This allows us to also compute the fluxes of all conserved quantities directly and rule out some of these hidden contributions to momentum flux. We then discuss some realistic flapper wavemakers and the trouble vorticity sources can create in the resulting fluid motion. Along the way we present a completely local derivation of the group velocity using fluxes.

  8. 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

  9. 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

  10. 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

  11. 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

  12. Nutrient fluxes from insect herbivory increase during ecosystem retrogression in boreal forest.

    Science.gov (United States)

    Metcalfe, Daniel B; Crutsinger, Gregory M; Kumordzi, Bright B; Wardle, David A

    2016-01-01

    Ecological theory, developed largely from ungulates and grassland systems, predicts that herbivory accelerates nutrient cycling more in productive than unproductive systems. This prediction may be important for understanding patterns of ecosystem change over time and space, but its applicability to other ecosystems and types of herbivore remain uncertain. We estimated fluxes of nitrogen (N) and phosphorus (P) from herbivory of a common tree species (Betula pubescens) by a common species of herbivorous insect along a -5000-yr boreal chronosequence. Contrary to established theory, fluxes of N and P via herbivory increased along the chronosequence despite a decline in plant productivity. The herbivore-mediated N and P fluxes to the soil are comparable to the main alternative pathway for these nutrients via tree leaf litterfall. We conclude that insect herbivores can make large contributions to nutrient cycling even in unproductive systems, and influence the rate and pattern of ecosystem development, particularly in systems with low external nutrient inputs.

  13. 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.

  14. 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

  15. 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

  16. 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…

  17. Dynamic public service mediation

    NARCIS (Netherlands)

    Hofman, W.; Staalduinen, M. van

    2010-01-01

    This paper presents an approach to dynamic public service mediation. It is based on a conceptual model and the use of search and ranking algorithms. The conceptual model is based on Abstract State Machine theory. Requirements for dynamic service mediation were derived from a real-world case. The con

  18. 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

  19. What Is Mediation?

    Science.gov (United States)

    Consortium for Appropriate Dispute Resolution in Special Education (CADRE), Eugene, OR.

    This brief paper discusses the use of mediation as a method for resolving disagreements between schools or early intervention programs and parents of children with disabilities. It identifies benefits of mediation such as maintenance of an ongoing and positive relationship between the school and family, simple resolution of conflicts arising out…

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

    Science.gov (United States)

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

    1993-01-01

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

  1. Global estimates of boreal forest carbon stocks and flux

    Science.gov (United States)

    Bradshaw, Corey J. A.; Warkentin, Ian G.

    2015-05-01

    The boreal ecosystem is an important global reservoir of stored carbon and a haven for diverse biological communities. The natural disturbance dynamics there have historically been driven by fire and insects, with human-mediated disturbances increasing faster than in other biomes globally. Previous research on the total boreal carbon stock and predictions of its future flux reveal high uncertainty in regional patterns. We reviewed and standardised this extensive body of quantitative literature to provide the most up-to-date and comprehensive estimates of the global carbon balance in the boreal forest. We also compiled century-scale predictions of the carbon budget flux. Our review and standardisation confirmed high uncertainty in the available data, but there is evidence that the region's total carbon stock has been underestimated. We found a total carbon store of 367.3 to 1715.8 Pg (1015 g), the mid-point of which (1095 Pg) is between 1.3 and 3.8 times larger than any previous mean estimates. Most boreal carbon resides in its soils and peatlands, although estimates are highly uncertain. We found evidence that the region might become a net carbon source following a reduction in carbon uptake rate from at least the 1980s. Given that the boreal potentially constitutes the largest terrestrial carbon source in the world, in one of the most rapidly warming parts of the globe (Walsh, 2014), how we manage these stocks will be influential on future climate dynamics.

  2. Music, radio and mediatization

    DEFF Research Database (Denmark)

    Michelsen, Morten; Krogh, Mads

    2016-01-01

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

  3. Magnetic Flux Controllers for Induction Heating Applications

    Institute of Scientific and Technical Information of China (English)

    Valentin Nemkov; Robert Goldstein; Robert Ruffini

    2004-01-01

    Application of magnetic flux controllers/concentrators to induction heating coils can drastically improve the process efficiency and heat pattern control. Presentation includes: benefits provided by flux controllers, materials available for controllers, application techniques, computer assisted design of induction coils with concentrators, examples of applications. Depending on induction system design, magnetic flux controllers can concentrate heating in a specified area,change heat source distribution and shield a particular part zone or external area preventing unintended eddy current heating.Besides of the coil efficiency improvement and optimal power distribution, magnetic flux controllers reduce the coil current demand from a supplying circuitry thus strongly reducing losses in busswork, cables, transformers and inverter components.Improvement that can be achieved due to magnetic flux controllers is case dependable. 2D and 3D computer simulation allows the designer to predict accurately effect of controllers on the coil parameters and temperature distribution and optimize the whole electromagnetic system. Special attention in presentation is paid to new magnetodielectric materials optimized for induction heating conditions. These materials have high magnetic permeability and saturation flux density,excellent machinability, good chemical and temperature resistance. Concentrators from these materials can work in a wide range of frequencies and specific powers. Examples of magnetic flux controller application include surface hardening of shafts and gears, induction surface hardfacing and brazing.

  4. 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.

  5. Magnetic balltracking: Tracking the photospheric magnetic flux

    Science.gov (United States)

    Attie, R.; Innes, D. E.

    2015-02-01

    Context. One aspect of understanding the dynamics of the quiet Sun is to quantify the evolution of the flux within small-scale magnetic features. These features are routinely observed in the quiet photosphere and were given various names, such as pores, knots, magnetic patches. Aims: This work presents a new algorithm for tracking the evolution of the broad variety of small-scale magnetic features in the photosphere, with a precision equal to the instrumental resolution. Methods: We have developed a new technique to track the evolution of the individual magnetic features from magnetograms, called "magnetic balltracking". It quantifies the flux of the tracked features, and it can track the footpoints of magnetic field lines inferred from magnetic field extrapolation. The algorithm can detect and quantify flux emergence, as well as flux cancellation. Results: The capabilities of magnetic balltracking are demonstrated with the detection and the tracking of two cases of magnetic flux emergence that lead to the brightening of X-ray loops. The maximum emerged flux ranges from 1018 Mx to 1019 Mx (unsigned flux) when the X-ray loops are observed. Movies associated to Figs. 6 and 18 are available in electronic form at http://www.aanda.org

  6. 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 ...

  7. Atmospheric neutrino flux and muon data

    CERN Document Server

    Fiorentini, G; Villante, F L

    2001-01-01

    We present a new one-dimensional calculation of low and intermediate energy atmospheric muon and neutrino fluxes, using up-to-date data on primary cosmic rays and hadronic interactions. The existing agreement between calculated muon fluxes and the data of the CAPRICE 94 muon experiment provides an evidence in favor of the validity of our description of hadronic interactions and shower development. This also supports our neutrino fluxes which are essentially lower than those used for the standard analyses of the sub-GeV and multi-GeV neutrino induced events in underground detectors.

  8. Open flux in Saturn’s magnetosphere

    Science.gov (United States)

    Badman, Sarah V.; Jackman, Caitriona M.; Nichols, Jonathan D.; Clarke, John T.; Gérard, Jean-Claude

    2014-03-01

    We characterise the interaction between the solar wind and Saturn’s magnetosphere by evaluating the amount of ‘open’ magnetic flux connected to the solar wind. This is deduced from a large set of Hubble Space Telescope images of the ultraviolet aurora, using the poleward boundary of the main aurora as a proxy for the open-closed field line boundary in the ionosphere. The amount of open flux is found to be 10-50 GWb, with a mean of 35 GWb. The typical change in open flux between consecutive observations separated by 10-60 h is -5 or +7 GWb. These changes are a result of imbalance between open flux creation at the dayside magnetopause and its closure in the magnetotail. The 5 GWb typical decrease in open flux is consistent with in situ measurements of the flux transported following a reconnection event. Estimates of average, net reconnection rates are found to be typically a few tens of kV, with some extreme examples of unbalanced magnetopause or tail reconnection occurring at ∼300 kV. The range of values determined suggest that Saturn’s magnetosphere does not generally achieve a steady state between flux opening at the magnetopause and flux closure in the magnetotail. The percentage of magnetic flux which is open in Saturn’s magnetosphere is similar to that measured at the Earth (2-11%), but the typical percentage that is closed between observations is significantly lower (13% compared to 40-70%). Therefore, open flux is usually closed in smaller (few GWb) events in Saturn’s magnetosphere. The exception to this behaviour is large, rapid flux closure events which are associated with solar wind compressions. While the rates of flux opening and closure should be equal over long timescales, they are evidently different on shorter (up to tens of hours) timescales. The relative independence of the magnetopause and tail reconnection rates can be attributed to the long loading timescales required to transport open field lines into the tail.

  9. 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.

  10. 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.

  11. Controlled decoherence of floating flux qubits

    Institute of Scientific and Technical Information of China (English)

    Ji Ying-Hua; Xu Lin

    2010-01-01

    In Born-Markov approximation, this paper calculates the energy relaxation time T1 and the decoherence time T2 of a floating flux qubit by solving the set of Bloch-Redfield equations. It shows that there are two main factors influencing the floating flux qubits: coupling capacitor in the circuit and the environment resistor. It also discusses how to improvethe quantum coherence time of a qubit. Through shunt connecting/series connecting inductive elements, an inductive environment resistor is obtained and further the reactance component of the environment resistor is improved, which is beneficial to the enhancement of decoherence time of floating flux qubits.

  12. Warped K\\"ahler potentials and fluxes

    CERN Document Server

    Martucci, Luca

    2016-01-01

    The four-dimensional effective theory for type IIB warped flux compactifications proposed in [1] is completed by taking into account the backreaction of the K\\"ahler moduli on the three-form fluxes. The only required modification consists in a flux-dependent contribution to the chiral fields parametrising the K\\"ahler moduli. The resulting supersymmetric effective theory satisfies the no-scale condition and consistently combines previous partial results present in the literature. Similar results hold for M-theory warped compactifications on Calabi-Yau fourfolds, whose effective field theory and K\\"ahler potential are also discussed.

  13. Exponentially tapered Josephson flux-flow oscillator

    DEFF Research Database (Denmark)

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

    1996-01-01

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

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  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. 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.

  20. 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

  1. Muon Fluxes From Dark Matter Annihilation

    CERN Document Server

    Erkoca, Arif Emre; Sarcevic, Ina

    2009-01-01

    We calculate the muon flux from annihilation of the dark matter in the core of the Sun, in the core of the Earth and from cosmic diffuse neutrinos produced in dark matter annihilation in the halos. We consider model-independent direct neutrino production and secondary neutrino production from the decay of taus produced in the annihilation of dark matter. We illustrate how muon energy distribution from dark matter annihilation has a very different shape than muon flux from atmospheric neutrinos. We consider both the upward muon flux, when muons are created in the rock below the detector, and the contained flux when muons are created in the (ice) detector. We contrast our results to the ones previously obtained in the literature, illustrating the importance of properly treating muon propagation and energy loss. We comment on neutrino flavor dependence and their detection.

  2. 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.

  3. A Brazilian network of carbon flux stations

    Science.gov (United States)

    Roberti, Débora R.; Acevedo, Otávio C.; Moraes, Osvaldo L. L.

    2012-05-01

    First Brasflux Workshop; Santa Maria, Rio Grande do Sul, Brazil, 14-15 November 2011 Last November, 33 researchers participated in a workshop to establish Brasflux, the Brazilian network of carbon flux stations, with the objective of integrating previous efforts and planning for the future. Among the participants were those leading ongoing flux observation projects and others planning to establish flux stations in the near future. International scientists also participated to share the experiences gained with other networks. The need to properly characterize terrestrial ecosystems for their roles in the global carbon, water, and energy budgets has motivated the implementation of hundreds of micrometeorological research sites throughout the world in recent years. The eddy covariance (EC) technique for turbulent flux determination is the preferred method to provide integral information on ecosystematmosphere exchanges. Integrating the observations regionally and globally has proven to be an effective approach to maximizing the usefulness of this technique for carbon cycle studies at multiple scales.

  4. 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

  5. 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.

  6. 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.

  7. 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

  8. 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...

  9. Anisotropic flux pinning in high Tc superconductors

    Science.gov (United States)

    Koleśnik, S.; Igalson, J.; Skośkiewicz, T.; Szymczak, R.; Baran, M.; Pytel, K.; Pytel, B.

    1995-02-01

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

  10. 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.

  11. Magnetic flux generator for balanced membrane loudspeaker

    DEFF Research Database (Denmark)

    Rehder, Jörg; Rombach, Pirmin; Hansen, Ole

    2002-01-01

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

  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. 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

  14. 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)

  15. Magnetic Flux Emergence on Different Scales

    Science.gov (United States)

    Hagenaar, M.; Cheung, M.

    2009-12-01

    Magnetic flux emerges on the Sun on many different scales, from weak intranetwork to network concentrations and (ephemeral) active regions. Methods previously developed to recognize regions of magnetic emergence on MDI Full Disk magnetograms fail when applied to Hinode/SOT Stokes maps: the resolution is so much higher that simple bipoles on MDI are observed as collections of fragments. We present a new method for the automatic detection and characterization of flux emergence on a range of scales.

  16. 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

  17. Factors controlling vertical fluxes of prrticles in the Arabian Sea

    Digital Repository Service at National Institute of Oceanography (India)

    Nair, T.M.B.; Ramaswamy, V.; Parthiban, G.; Shankar, R.

    whereas organic carbon percentages decreased. Particle flux patterns show a strong seasonality with peak fluxes during the southwest (SW) monsoon (June to September). Relatively high fluxes were also observed during the northeast (NE) monsoon (December...

  18. 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

  19. Quantitation of cellular metabolic fluxes of methionine.

    Science.gov (United States)

    Shlomi, Tomer; Fan, Jing; Tang, Baiqing; Kruger, Warren D; Rabinowitz, Joshua D

    2014-02-01

    Methionine is an essential proteogenic amino acid. In addition, it is a methyl donor for DNA and protein methylation and a propylamine donor for polyamine biosynthesis. Both the methyl and propylamine donation pathways involve metabolic cycles, and methods are needed to quantitate these cycles. Here, we describe an analytical approach for quantifying methionine metabolic fluxes that accounts for the mixing of intracellular and extracellular methionine pools. We observe that such mixing prevents isotope tracing experiments from reaching the steady state due to the large size of the media pools and hence precludes the use of standard stationary metabolic flux analysis. Our approach is based on feeding cells with (13)C methionine and measuring the isotope-labeling kinetics of both intracellular and extracellular methionine by liquid chromatography-mass spectrometry (LC-MS). We apply this method to quantify methionine metabolism in a human fibrosarcoma cell line and study how methionine salvage pathway enzyme methylthioadenosine phosphorylase (MTAP), frequently deleted in cancer, affects methionine metabolism. We find that both transmethylation and propylamine transfer fluxes amount to roughly 15% of the net methionine uptake, with no major changes due to MTAP deletion. Our method further enables the quantification of flux through the pro-tumorigenic enzyme ornithine decarboxylase, and this flux increases 2-fold following MTAP deletion. The analytical approach used to quantify methionine metabolic fluxes is applicable for other metabolic systems affected by mixing of intracellular and extracellular metabolite pools.

  20. Vertical eddy heat fluxes from model simulations

    Science.gov (United States)

    Stone, Peter H.; Yao, Mao-Sung

    1991-01-01

    Vertical eddy fluxes of heat are calculated from simulations with a variety of climate models, ranging from three-dimensional GCMs to a one-dimensional radiative-convective model. The models' total eddy flux in the lower troposphere is found to agree well with Hantel's analysis from observations, but in the mid and upper troposphere the models' values are systematically 30 percent to 50 percent smaller than Hantel's. The models nevertheless give very good results for the global temperature profile, and the reason for the discrepancy is unclear. The model results show that the manner in which the vertical eddy flux is carried is very sensitive to the parameterization of moist convection. When a moist adiabatic adjustment scheme with a critical value for the relative humidity of 100 percent is used, the vertical transports by large-scale eddies and small-scale convection on a global basis are equal: but when a penetrative convection scheme is used, the large-scale flux on a global basis is only about one-fifth to one-fourth the small-scale flux. Comparison of the model results with observations indicates that the results with the latter scheme are more realistic. However, even in this case, in mid and high latitudes the large and small-scale vertical eddy fluxes of heat are comparable in magnitude above the planetary boundary layer.

  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. 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

  3. Crystalline Nickel Sulfide Induced Malignant Transformation of 16HBE Cells through Autophagic Pathway%结晶型硫化镍通过自噬途径诱导16HBE细胞恶性转化癌变

    Institute of Scientific and Technical Information of China (English)

    张岚; 杨磊; 吕嘉春

    2012-01-01

    Nickel compounds, which widely exist in the environment of human occupation, are the major risk factor for human lung cancer. Our previous studies had confirmed that exposure to toxic,metallic crystalline nickel sulfide (NiS) was an important cause of lung cancer, but the concrete carcinogenic mechanism is still unclear. In this study, we used the previouslyestablished human bronchial epithelial (16HBE-T) cells malignant transformation model, which was induced by crystalline NiS. For the first time, fluorescence intensity and position of the GFP-LC3 protein in malignant transformed (16HBE-T) cells and normal cell (16HBE-N), were real-time monitored with the technique of confocal laser scanning microscopy imaging without damaging the condition. Moreover, we used Western Blotting to detect the intracellular autophagic signal which is expressed by key effective molecule pathway. Confocal experimental results showed that: Compared with that of 16HBE-N-cells, the GFP-LC3 protein punctate aggregation of 16HBE-T cells significantly reduced to the merely 1/3 amount of 16HBE-N-cells, suggesting that autophagy levels declined. At the same time, it was found that the mTOR kinase activity increased, and that Beclin 1 expression decreased. The above research result demonstrated that the mechanism of crystalline NiS induced 16HBE cell malignant transformation was through multiple autophagic pathway and it will provide an important message in the prevention and treatment of lung cancer.%镍化合物广泛存在于人类职业环境中,是人类发生肺癌的主要危险因素.我们前期研究已证实金属毒物结晶型硫化镍(NiS)的暴露是发生肺癌的重要病因,但具体的致癌机制仍未明了.本研究利用前期建立的结晶型NiS恶性转化人支气管上皮细胞的细胞模型,首次采用激光共聚焦扫描显微镜成像技术,在无损伤状态下,实时观测恶性转化细胞(16HBE-T)和正常细胞(16HBE-N)中自噬体标记蛋白GFP-LC3

  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. Technology-Use Mediation

    DEFF Research Database (Denmark)

    Bansler, Jørgen P.; Havn, Erling C.

    2004-01-01

    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......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...... 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...

  6. Natural generalized mirage mediation

    CERN Document Server

    Baer, Howard; Serce, Hasan; Tata, Xerxes

    2016-01-01

    In the supersymmetric scenario known as mirage mediation (MM), the soft SUSY breaking terms receive comparable anomaly-mediation and moduli-mediation contributions leading to the phenomenon of mirage unification. The simplest MM SUSY breaking models which are consistent with the measured Higgs mass and sparticle mass constraints are strongly disfavoured by fine-tuning considerations. However, while MM makes robust predictions for gaugino masses, the scalar sector is quite sensitive to specific mechanisms for moduli stabilization and potential uplifting. We suggest here a broader setup of generalized mirage mediation (GMM), where heretofore discrete parameters are allowed as continuous to better parametrize these other schemes. We find that natural SUSY spectra consistent with both the measured value of m(h). as well as LHC lower bounds on superpartner masses are then possible. We explicitly show that models generated from natural GMM may be beyond the reach of even high-luminosity LHC searches. In such a case...

  7. 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...

  8. 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.

  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. 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...

  11. 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...

  12. ENVIRONMENTAL CONFLICT MEDIATION

    Directory of Open Access Journals (Sweden)

    GABRIELA G. MIHUT

    2011-04-01

    Full Text Available At a time of global economic crisis followed by resource crisis, a period in which the world seeks alternative resources through eco-investment, environmental conflicts are inevitable. Romania is among the few countries that do not pay enough attention to environmental conflicts and to the advantages to of solving them through mediation procedure. The present paper deals with areas in which conflicts can be applied in environmental mediation and its benefits.

  13. ENVIRONMENTAL CONFLICT MEDIATION

    OpenAIRE

    GABRIELA G. MIHUT

    2011-01-01

    At a time of global economic crisis followed by resource crisis, a period in which the world seeks alternative resources through eco-investment, environmental conflicts are inevitable. Romania is among the few countries that do not pay enough attention to environmental conflicts and to the advantages to of solving them through mediation procedure. The present paper deals with areas in which conflicts can be applied in environmental mediation and its benefits.

  14. 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

  15. Flux pinning in superconductors. 2. ed.

    Energy Technology Data Exchange (ETDEWEB)

    Matsushita, Teruo [Kyushu Institute of Technology, Iizuka, Fukuoka (Japan). Dept. of Computer Science and Electronics

    2014-04-01

    Ideal for graduate students studying superconductivity and experts alike. Written by a researcher with more than 30 years experience in the field. All chapters are completely revised. The book covers the flux pinning mechanisms and properties and the electromagnetic phenomena caused by the flux pinning common for metallic, high-Tc and MgB2 superconductors. The condensation energy interaction known for normal precipitates or grain boundaries and the kinetic energy interaction proposed for artificial Nb pins in Nb-Ti, etc., are introduced for the pinning mechanism. Summation theories to derive the critical current density are discussed in detail. Irreversible magnetization and AC loss caused by the flux pinning are also discussed. The loss originally stems from the ohmic dissipation of normal electrons in the normal core driven by the electric field induced by the flux motion. The readers will learn why the resultant loss is of hysteresis type in spite of such mechanism. The influence of the flux pinning on the vortex phase diagram in high Tc superconductors is discussed, and the dependencies of the irreversibility field are also described on other quantities such as anisotropy of superconductor, specimen size and electric field strength. Recent developments of critical current properties in various high-Tc superconductors and MgB2 are introduced. Other topics are: singularity in the case of transport current in a parallel magnetic field such as deviation from the Josephson relation, reversible flux motion inside pinning potentials which causes deviation from the critical state model prediction, the concept of the minimization of energy dissipation in the flux pinning phenomena which gives the basis for the critical state model, etc. Significant reduction in the AC loss in AC wires with very fine filaments originates from the reversible flux motion which is dominant in the two-dimensional pinning. The concept of minimum energy dissipation explains also the behavior

  16. 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.

  17. 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

  18. 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...

  19. 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.

  20. 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.

  1. 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)

  2. 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).

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

    NARCIS (Netherlands)

    Velthof, G.L.; Oenema, O.

    1995-01-01

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

  5. 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

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

    Directory of Open Access Journals (Sweden)

    Basheer N. Al-Duwairi

    2014-07-01

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

  7. 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.

  8. 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...

  9. 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.

  10. Study on Potassium Fluoaluminate Eutectic Flux

    Institute of Scientific and Technical Information of China (English)

    张韻慧; 尹淑梅; 肖莉; 李宁; 张则甡

    2004-01-01

    In this study, Nocolok eutectic flux,used widely in the process of the brazing of aluminum and its alloy, was prepared by the reaction between Al(OH)3/KOH resolution and HF. A series of KF-AlF3 eutectic productions at various reaction temperatures were prepared. The melting points of the products were measured by differential thermal analysis (DTA), and the composites were characterized by X-ray diffraction (XRD). The results suggest that the temperature control is important to produce an ideal flux consisting of K2AlF5, H2O and KAlF4, with a low melting point of 560 ℃,which is suitable for the brazing of aluminum and its alloy as the aluminum fluxes.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. CO2 fluxes near a forest edge

    DEFF Research Database (Denmark)

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

    2008-01-01

    as a function of both sources/sinks distribution and the vertical structure of the canopy. Results suggest that the ground source plays a major role in the formation of wave-like vertical CO2 flux behavior downwind of a forest edge, despite the fact that the contribution of foliage sources/sinks changes......In contrast with recent advances on the dynamics of the flow at a forest edge, few studies have considered its role on scalar transport and, in particular, on CO2 transfer. The present study addresses the influence of the abrupt roughness change on forest atmosphere CO2 exchange and contrasts...... the concentration and flux fields against those of a uniform forested surface. We use an atmospheric boundary layer two-equation closure model that accounts for the flow dynamics and vertical divergence of CO2 sources/sinks within a plant canopy. This paper characterizes the spatial variation of CO2 fluxes...

  17. 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

  18. 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.

  19. 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

  20. 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.

  1. 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.

  2. 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

  3. 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.

  4. 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.

  5. High heat flux loop heat pipes

    Science.gov (United States)

    North, Mark T.; Sarraf, David B.; Rosenfeld, John H.; Maidanik, Yuri F.; Vershinin, Sergey

    1997-01-01

    Loop heat pipes (LHPs) can transport very large thermal power loads over long distances, through flexible, small diameter tubes against gravitational heads. In order to overcome the evaporator limit of LHPs, which is of about 0.07 MW/sq m, work was carried out to improve the efficiency by threefold to tenfold. The vapor passage geometry for the high heat flux conditions is shown. A bidisperse wick material within the circumferential vapor passages was used. Along with heat flux enhancement, several underlying issues were demonstrated, including the fabrication of bidisperse powder with controlled properties and the fabrication of a device geometry capable of replacing vapor passages with bidisperse powder.

  6. 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.

  7. Bubbles of Nothing in Flux Compactifications

    CERN Document Server

    Blanco-Pillado, Jose J

    2010-01-01

    We construct a simple $5d$ flux compactification stabilized by a complex scalar field winding the extra dimension and demonstrate an instability via nucleation of a bubble of nothing. This occurs when the Kaluza -- Klein dimension degenerates to a point, defining the bubble surface. Because the extra dimension is stabilized by a flux, the bubble surface must be charged, in this case under the axionic part of the complex scalar. This smooth geometry can be seen as a de Sitter topological defect with asymptotic behavior identical to the pure compactification. We discuss how a similar construction can be implemented in more general Freund -- Rubin compactifications.

  8. Plasma momentum meter for momentum flux measurements

    Science.gov (United States)

    Zonca, Fulvio; Cohen, Samuel A.; Bennett, Timothy; Timberlake, John R.

    1993-01-01

    Invention comprises an instrument in which momentum flux onto a biasable target plate is transferred via a suspended quartz tube onto a sensitive force transducer--a capacitance-type pressure gauge. The transducer is protected from thermal damage, arcing and sputtering, and materials used in the target and pendulum are electrically insulating, rigid even at elevated temperatures, and have low thermal conductivity. The instrument enables measurement of small forces (10.sup.-5 to 10.sup.3 N) accompanied by high heat fluxes which are transmitted by energetic particles with 10's of eV of kinetic energy in a intense magnetic field and pulsed plasma environment.

  9. 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

  10. 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.

  11. [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

  12. Autophagy as a Survival Mechanism for Squamous Cell Carcinoma Cells in Endonuclease G-Mediated Apoptosis

    Science.gov (United States)

    Masui, Atsushi; Hamada, Masakazu; Kameyama, Hiroyasu; Wakabayashi, Ken; Takasu, Ayako; Imai, Tomoaki; Iwai, Soichi; Yura, Yoshiaki

    2016-01-01

    Safingol, L- threo-dihydrosphingosine, induces cell death in human oral squamous cell carcinoma (SCC) cells through an endonuclease G (endoG) -mediated pathway. We herein determined whether safingol induced apoptosis and autophagy in oral SCC cells. Safingol induced apoptotic cell death in oral SCC cells in a dose-dependent manner. In safingol-treated cells, microtubule-associated protein 1 light chain 3 (LC3)-I was changed to LC3-II and the cytoplasmic expression of LC3, amount of acidic vesicular organelles (AVOs) stained by acridine orange and autophagic vacuoles were increased, indicating the occurrence of autophagy. An inhibitor of autophagy, 3-methyladenine (3-MA), enhanced the suppressive effects of safingol on cell viability, and this was accompanied by an increase in the number of apoptotic cells and extent of nuclear fragmentation. The nuclear translocation of endoG was minimal at a low concentration of safingol, but markedly increased when combined with 3-MA. The suppressive effects of safingol and 3-MA on cell viability were reduced in endoG siRNA- transfected cells. The scavenging of reactive oxygen species (ROS) prevented cell death induced by the combinational treatment, whereas a pretreatment with a pan-caspase inhibitor z-VAD-fmk did not. These results indicated that safingol induced apoptosis and autophagy in SCC cells and that the suppression of autophagy by 3-MA enhanced apoptosis. Autophagy supports cell survival, but not cell death in the SCC cell system in which apoptosis occurs in an endoG-mediated manner. PMID:27658240

  13. Cocaine-mediated microglial activation involves the ER stress-autophagy axis.

    Science.gov (United States)

    Guo, Ming-Lei; Liao, Ke; Periyasamy, Palsamy; Yang, Lu; Cai, Yu; Callen, Shannon E; Buch, Shilpa

    2015-01-01

    Cocaine abuse leads to neuroinflammation, which, in turn, contributes to the pathogenesis of neurodegeneration associated with advanced HIV-1 infection. Autophagy plays important roles in both innate and adaptive immune responses. However, the possible functional link between cocaine and autophagy has not been explored before. Herein, we demonstrate that cocaine exposure induced autophagy in both BV-2 and primary rat microglial cells as demonstrated by a dose- and time-dependent induction of autophagy-signature proteins such as BECN1/Beclin 1, ATG5, and MAP1LC3B. These findings were validated wherein cocaine treatment of BV-2 cells resulted in increased formation of puncta in cells expressing either endogenous MAP1LC3B or overexpressing GFP-MAP1LC3B. Specificity of cocaine-induced autophagy was confirmed by treating cells with inhibitors of autophagy (3-MA and wortmannin). Intriguingly, cocaine-mediated induction of autophagy involved upstream activation of 2 ER stress pathways (EIF2AK3- and ERN1-dependent), as evidenced by the ability of the ER stress inhibitor salubrinal to ameliorate cocaine-induced autophagy. In vivo validation of these findings demonstrated increased expression of BECN1, ATG5, and MAP1LC3B-II proteins in cocaine-treated mouse brains compared to untreated animals. Increased autophagy contributes to cocaine-mediated activation of microglia since pretreatment of cells with wortmannin resulted in decreased expression and release of inflammatory factors (TNF, IL1B, IL6, and CCL2) in microglial cells. Taken together, our findings suggest that cocaine exposure results in induction of autophagy that is closely linked with neuroinflammation. Targeting autophagic proteins could thus be considered as a therapeutic strategy for the treatment of cocaine-related neuroinflammation diseases.

  14. Cocaine-mediated microglial activation involves the ER stress-autophagy axis.

    Science.gov (United States)

    Guo, Ming-Lei; Liao, Ke; Periyasamy, Palsamy; Yang, Lu; Cai, Yu; Callen, Shannon E; Buch, Shilpa

    2015-01-01

    Cocaine abuse leads to neuroinflammation, which, in turn, contributes to the pathogenesis of neurodegeneration associated with advanced HIV-1 infection. Autophagy plays important roles in both innate and adaptive immune responses. However, the possible functional link between cocaine and autophagy has not been explored before. Herein, we demonstrate that cocaine exposure induced autophagy in both BV-2 and primary rat microglial cells as demonstrated by a dose- and time-dependent induction of autophagy-signature proteins such as BECN1/Beclin 1, ATG5, and MAP1LC3B. These findings were validated wherein cocaine treatment of BV-2 cells resulted in increased formation of puncta in cells expressing either endogenous MAP1LC3B or overexpressing GFP-MAP1LC3B. Specificity of cocaine-induced autophagy was confirmed by treating cells with inhibitors of autophagy (3-MA and wortmannin). Intriguingly, cocaine-mediated induction of autophagy involved upstream activation of 2 ER stress pathways (EIF2AK3- and ERN1-dependent), as evidenced by the ability of the ER stress inhibitor salubrinal to ameliorate cocaine-induced autophagy. In vivo validation of these findings demonstrated increased expression of BECN1, ATG5, and MAP1LC3B-II proteins in cocaine-treated mouse brains compared to untreated animals. Increased autophagy contributes to cocaine-mediated activation of microglia since pretreatment of cells with wortmannin resulted in decreased expression and release of inflammatory factors (TNF, IL1B, IL6, and CCL2) in microglial cells. Taken together, our findings suggest that cocaine exposure results in induction of autophagy that is closely linked with neuroinflammation. Targeting autophagic proteins could thus be considered as a therapeutic strategy for the treatment of cocaine-related neuroinflammation diseases. PMID:26043790

  15. 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.

  16. 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

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

    DEFF Research Database (Denmark)

    Lu, Kaiyuan; Wu, Weimin

    2015-01-01

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

  18. Estimation of sensible heat, water vapor, and CO2 fluxes using the flux-variance method.

    Science.gov (United States)

    Hsieh, Cheng-I; Lai, Mei-Chun; Hsia, Yue-Joe; Chang, Tsang-Jung

    2008-07-01

    This study investigated the flux-variance relationships of temperature, humidity, and CO(2), and examined the performance of using this method for predicting sensible heat (H), water vapor (LE), and CO(2) fluxes (F(CO2)) with eddy-covariance measured flux data at three different ecosystems: grassland, paddy rice field, and forest. The H and LE estimations were found to be in good agreement with the measurements over the three fields. The prediction accuracy of LE could be improved by around 15% if the predictions were obtained by the flux-variance method in conjunction with measured sensible heat fluxes. Moreover, the paddy rice field was found to be a special case where water vapor follows flux-variance relation better than heat does. However, the CO(2) flux predictions were found to vary from poor to fair among the three sites. This is attributed to the complicated CO(2) sources and sinks distribution. Our results also showed that heat and water vapor were transported with the same efficiency above the grassland and rice paddy. For the forest, heat was transported 20% more efficiently than evapotranspiration.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-10-20

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

  20. 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

  1. 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.

  2. 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...

  3. Carbon fluxes to Antarctic top predators

    NARCIS (Netherlands)

    Franeker, van J.A.; Bathmann, U.V.; Mathot, S.

    1997-01-01

    The role of birds, seals and whales in the overall biological carbon fluxes of the Southern Ocean has been estimated based on census counts of top predator individuals in the region. Using standard routines for conversion to food consumption and respiration rates we demonstrate that at most 0.3-0.6%

  4. Propagation of nuclear particle fluxes in atmosphere

    International Nuclear Information System (INIS)

    The Monte Carlo model of propagation of nuclear-active particle shower initiated in the atmosphere by cosmic rays or by any other radiation source is developed. The model permits to calculate spatial distributions and energy spectra of charged and neutral particle fluxes in the air and inside the blocks

  5. Fusion Neutron Flux Monitor for ITER

    Institute of Scientific and Technical Information of China (English)

    YANG Jinwei; YANG Qingwei; XIAO Gongshan; ZHANG Wei; SONG Xianying; LI Xu

    2008-01-01

    Neutron flux monitor (NFM) as an important diagnostic sub-system in ITER (international thermonuclear experimental reactor) provides a global neutron source intensity, fusion power and neutron flux in real time. Three types of neutron flux monitor assemblies with different sensitivities and shielding materials have been designed. Through MCNP (Mante-Carlo neutral particle transport code) calculations, this extended system of NFM can detect the neutron flux in a range of 104 n/(cm2·s) to 1014 n/(cm2·s). It is capable of providing accurate neutron yield measurements for all operational modes encountered in the ITER experiments including the in-situ calibration. Combining both the counting mode and Campbelling (MSV; Mean Square Voltage) mode in the signal processing units, the requirement of the dynamic range (107) for these NFMs and time resolution (1 ms) can be met. Based on a uncertainty analysis, the estimated absolute measurement accuracies of the total fusion neutron yield can reach the required 10% level in both the early stage of the DD-phase and the full power DT operation mode. In the advanced DD-phase, the absolute measurement accuracy would be better than 20%.

  6. Probabilistic Forecasting of the Wave Energy Flux

    DEFF Research Database (Denmark)

    Pinson, Pierre; Reikard, G.; Bidlot, J.-R.

    2012-01-01

    markets. A methodology for the probabilistic forecasting of the wave energy flux is introduced, based on a log-Normal assumption for the shape of predictive densities. It uses meteorological forecasts (from the European Centre for Medium-range Weather Forecasts – ECMWF) and local wave measurements...

  7. Helioseismic Detection of Emerging Magnetic Flux

    CERN Document Server

    Ilonidis, Stathis; Kosovichev, Alexander G

    2012-01-01

    Investigating the properties of magnetic flux emergence is one of the most important problems of solar physics. In this study we present a newly developed deep-focus time-distance measurement scheme which is able to detect strong emerging flux events in the deep solar interior, before the flux becomes visible on the surface. We discuss in detail the differences between our method and previous methods, and demonstrate step-by-step how the signal-to-noise (S/N) ratio is increased. The method is based on detection of perturbations in acoustic phase travel times determined from cross-covariances of solar oscillations observed on the surface. We detect strong acoustic travel-time reductions of an order of 12 - 16 seconds at a depth of 42 - 75 Mm. These acoustic anomalies are detected 1 - 2 days before high peaks in the photospheric magnetic flux rate implying that the average emerging speed is 0.3 - 0.6 km/s. The results of this work contribute to our understanding of solar magnetism and benefit space weather fore...

  8. Optimal flux patterns in cellular metabolic networks

    Energy Technology Data Exchange (ETDEWEB)

    Almaas, E

    2007-01-20

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

  9. Radiation linewidth of flux-flow oscillators

    DEFF Research Database (Denmark)

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

    2001-01-01

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

  10. Calcium flux assay in Xenopus oocytes.

    Science.gov (United States)

    Murphy, P M

    2001-05-01

    Many G protein-coupled receptors of interest to neuroscientists induce transient increases in [Ca(2+)](i), which can be used as a convenient measure of receptor activation in a variety of applications. This unit describes a simple calcium flux assay applied to Xenopus oocytes. PMID:18428482

  11. Predicting flux decline of reverse osmosis membranes

    NARCIS (Netherlands)

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

    1981-01-01

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

  12. Reactor antineutrino fluxes - status and challenges

    CERN Document Server

    Huber, Patrick

    2016-01-01

    In this contribution we describe the current understanding of reactor antineutrino fluxes and point out some recent developments. This is not intended to be a complete review of this vast topic but merely a selection of observations and remarks, which despite their incompleteness, will highlight the status and the challenges of this field.

  13. Flux agreement above a Scots pine plantation

    Science.gov (United States)

    Gay, L. W.; Vogt, R.; Bernhofer, Ch.; Blanford, J. H.

    1996-03-01

    The surface energy exchange of 12m high Scots pine plantation at Hartheim, Germany, was measured with a variety of methods during a 11-day period of fine weather in mid-May 1992. Net radiation and rate of thermal storage were measured with conventional net radiometers, soil heat flux discs and temperature-based storage models. The turbulent fluxes discussed in this report were obtained with an interchanging Bowen ratio energy budget system (BREB, at 14 m), two one-propeller eddy correlation systems (OPEC systems 1 and 2 at 17m), a 1-dimensional sonic eddy correlation system (SEC system 3) at 15 m, all on one “low” tower, and a 3-dimensional sonic eddy correlation system (SEC system 22) at 22 m on the “high” tower that was about 46 m distant. All systems measured sensible and latent heat (H and LE) directly, except for OPEC systems 1 and 2 which estimated LE as a residual term in the surface energy balance. Closure of turbulent fluxes from the two SEC systems was around 80% for daytime and 30% for night, with closure of 1-dimensional SEC system 3 exceeding that of 3-dimensional SEC system 22. The night measurements of turbulent fluxes contained considerable uncertainty, especially with the BREB system where measured gradients often yielded erroneous fluxes due to problems inherent in the method (i.e., computational instability as Bowen's ratio approaches -1). Also, both eddy correlation system designs (OPEC and SEC) appeared to underestimate |H| during stable conditions at night. In addition, both sonic systems (1- and 3-dimensional) underestimated |LE| during stable conditions. The underestimate of |H| at night generated residual estimates of OPEC LE containing a “phantom dew” error that erroneously decreased daily LE totals by about 10 percent. These special night problems are circumvented here by comparing results for daytime periods only, rather than for full days. To summarize, turbulent fluxes on the low tower from OPEC system 2 and the adjacent

  14. Optical sampling of the flux tower footprint

    Directory of Open Access Journals (Sweden)

    J. A. Gamon

    2015-03-01

    Full Text Available The purpose of this review is to address the reasons and methods for conducting optical remote sensing within the flux tower footprint. Fundamental principles and conclusions gleaned from over two decades of proximal remote sensing at flux tower sites are reviewed. An organizing framework is the light-use efficiency (LUE model, both because it is widely used, and because it provides a useful theoretical construct for integrating optical remote sensing with flux measurements. Multiple ways of driving this model, ranging from meteorological measurements to remote sensing, have emerged in recent years, making it a convenient conceptual framework for comparative experimental studies. New interpretations of established optical sampling methods, including the Photochemical Reflectance Index (PRI and Solar-Induced Fluorescence (SIF, are discussed within the context of the LUE model. Multi-scale analysis across temporal and spatial axes is a central theme, because such scaling can provide links between ecophysiological mechanisms detectable at the level of individual organisms and broad patterns emerging at larger scales, enabling evaluation of emergent properties and extrapolation to the flux footprint and beyond. Proper analysis of sampling scale requires an awareness of sampling context that is often essential to the proper interpretation of optical signals. Additionally, the concept of optical types, vegetation exhibiting contrasting optical behavior in time and space, is explored as a way to frame our understanding of the controls on surface–atmosphere fluxes. Complementary NDVI and PRI patterns across ecosystems are offered as an example of this hypothesis, with the LUE model and light-response curve providing an integrating framework. We conclude that experimental approaches allowing systematic exploration of plant optical behavior in the context of the flux tower network provides a unique way to improve our understanding of environmental

  15. Optical sampling of the flux tower footprint

    Science.gov (United States)

    Gamon, J. A.

    2015-03-01

    The purpose of this review is to address the reasons and methods for conducting optical remote sensing within the flux tower footprint. Fundamental principles and conclusions gleaned from over two decades of proximal remote sensing at flux tower sites are reviewed. An organizing framework is the light-use efficiency (LUE) model, both because it is widely used, and because it provides a useful theoretical construct for integrating optical remote sensing with flux measurements. Multiple ways of driving this model, ranging from meteorological measurements to remote sensing, have emerged in recent years, making it a convenient conceptual framework for comparative experimental studies. New interpretations of established optical sampling methods, including the Photochemical Reflectance Index (PRI) and Solar-Induced Fluorescence (SIF), are discussed within the context of the LUE model. Multi-scale analysis across temporal and spatial axes is a central theme, because such scaling can provide links between ecophysiological mechanisms detectable at the level of individual organisms and broad patterns emerging at larger scales, enabling evaluation of emergent properties and extrapolation to the flux footprint and beyond. Proper analysis of sampling scale requires an awareness of sampling context that is often essential to the proper interpretation of optical signals. Additionally, the concept of optical types, vegetation exhibiting contrasting optical behavior in time and space, is explored as a way to frame our understanding of the controls on surface-atmosphere fluxes. Complementary NDVI and PRI patterns across ecosystems are offered as an example of this hypothesis, with the LUE model and light-response curve providing an integrating framework. We conclude that experimental approaches allowing systematic exploration of plant optical behavior in the context of the flux tower network provides a unique way to improve our understanding of environmental constraints and

  16. Mediated Cultural Memories

    DEFF Research Database (Denmark)

    Frølunde, Lisbeth; Bjerregaard, Mette

    2013-01-01

    culture as convergent with evolving genres. From a socio-cultural linguistic perspective, a standardization of meaning-making (Machin and van Leeuwen) affects our reading, viewing, sense of identity within families, culture, nation-states, and notions of enemy. In the discussion, we consider how mediated...

  17. Mediated intimacy in families

    DEFF Research Database (Denmark)

    Stougaard, Malthe Kirkhoff

    2006-01-01

    with other types of intimate relations such as strong-tie intimacy (couples cohabiting). However, we also identified several issues of intimacy unique to the special relation between children and their parents. These unique acts of intimacy propose challenges when designing technologies for mediated intimacy...

  18. 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.

  19. Expanding mediation theory

    NARCIS (Netherlands)

    Verbeek, P.P.C.C.

    2012-01-01

    In his article In Between Us, Yoni van den Eede expands existing theories of mediation into the realm of the social and the political, focusing on the notions of opacity and transparency. His approach is rich and promising, but two pitfalls should be avoided. First, his concept of ‘in-between’ runs

  20. 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.

  1. 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...

  2. 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...

  3. Regional airborne flux measurements in Europe

    Science.gov (United States)

    Gioli, B.; Miglietta, F.; Vaccari, F. P.; Zaldei, A.; Hutjes, R. W. A.

    2003-04-01

    The problem of identifying the spatial and temporal distribution of sources and sinks of atmospheric CO2 is the subject of considerable scientific and political debate. Even if it is now possible to estimate within reasonable accuracy the sink strength of European forests at the local scale, difficulties still exist in determining the partitioning of the sinks at the global and regional scales. The aim of the EU-project RECAB (Regional Assessment of the Carbon Balance in Europe) that is coordinated by Alterra, Wageningen (NL), is to bridge the gap between local scale flux measurements and continental scale inversion models by a generic modelling effort and measurement program, focussing on a limited number of selected regions in Europe for which previous measurements exists. This required the establishment of a European facility for airborne measurement of surface fluxes of CO2 at very low altitude, and a research aircraft capable of performing airborne eddy covariance measurements has been acquired by this project and used on several occasions at the different RECAB sites. The aircraft is the italian Sky Arrows ERA (Environmental Research Aircraft) equipped with the NOAA/ARA Mobile Flux Platform (MFP), and a commercial open-path infrared gas analyser. Airborne eddy covariance measurements were made from June 2001 onwards in Southern Spain near Valencia (June and December 2001), in Central Germany near Jena (July 2001), in Sweden near Uppsala (August 2001), in The Netherlands near Wageningen (January and July 2002) and in Italy near Rome (June 2002). Flux towers were present at each site to provide a validation of airborne eddy covariance measurements. This contribution reports some validation results based on the comparison between airborne and ground based flux measurements and some regional scale results for different locations and different seasons, in a wide range of meteorological and ecological settings.

  4. Flux trapping and shielding in irreversible superconductors

    International Nuclear Information System (INIS)

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

  5. STRATIFIED COMPOSITION EFFECTS ON PLANETARY NEUTRON FLUX

    Energy Technology Data Exchange (ETDEWEB)

    O. GASNAULT; ET AL

    2001-01-01

    All the bodies of the solar system that are directly irradiated by the galactic cosmic rays, emit enough neutrons to allow a measurement from space. These leakage neutron fluxes are indexes of the surface composition, depending on the energy of the neutrons [1]. Recent work propose geochemical interpretations of these fluxes: the thermal energy range is sensitive to iron, titanium, rare earth elements and thorium [2, 3], the epithermal energy range is sensitive to hydrogen, samarium and gadolinium [2] and the fast energy range is representative of the average soil atomic mass [4]. Nevertheless these studies make the hypothesis of a composition uniform within the footprint of the spectrometer and independent of depth. We show in this abstract that a stratified composition could change significantly the flux intensity and complicate the interpretation of the measurements. The neutron leakage flux is a competition between production effects (sensitive at high energy) and diffusion-capture effects (mostly sensitive at low energy). On one hand, it happens to be that the elements which produce the higher number of neutrons in typical lunar compositions are iron and titanium, which have also large cross section of absorption with the neutrons. On the other hand, the maximum of neutron intensity does not occur at the surface but at about 180 g cm{sup {minus}2} in depth. Therefore, if we have an iron- and/or titanium-rich soil (important production of neutrons) with a top layer having less iron and/or titanium (i.e. more transparent to the neutrons), we can expect an enhancement of the flux compared to a uniform composition.

  6. Autophagic effect on tumor and its potential applicationsin non-small cell lung cancer molecular targeted therapy%肿瘤自噬效应及其在非小细胞肺癌分子靶向治疗中的潜在应用

    Institute of Scientific and Technical Information of China (English)

    陈美娟; 詹瑧; 张旭

    2012-01-01

    目前针对非小细胞肺癌(NSCLC)的手术、放化疗等治疗手段临床疗效仍很不足,相应的分子靶向治疗药物随着临床抗药性的产生疗效也明显下降.自噬对肿瘤进展具有双重影响作用.在NSCLC临床治疗的各个阶段都应充分考虑自噬效应所起的作用,对其进行合理调节和利用,从而提高各种治疗手段的临床疗效.%Now clinical treatments for non-small cell lung cancer ( NSCLC ) such as surgery, radiotherapy, and chemotherapy are still insufficient, and the efficacy of some molecular targeted therapy is also limited because of natural and acquired resistance in clinics. Autophagy exhibited the effects of a double-blade sword on tumor progression. On the one hand, autophagic can induce the death of tumor cells, and on the other hand, it alsoprotects the tumor in stress such as nutritional deficiency. Clinical treatment of NSCLC at various stages should take full account of autophagic effect on its progression, which can improve the clinical efficacy of various treatments by reasonable combination.

  7. Ischemia/reperfusion mediated oxygen free radical production in rat brain endothelium

    Energy Technology Data Exchange (ETDEWEB)

    Grammas, P.; Wood, K. (Univ. of Oklahoma, Oklahoma City (United States)); Liu, G.J.; Floyd, R.A. (Oklahoma Medical Research Foundation, Oklahoma City (United States)); Wood, K. (Univ. of Oklahoma Health Sciences Center, Oklahoma City (United States) Oklahoma Medical Research Foundation, Oklahoma City (United States))

    1991-03-11

    Oxygen free radicals have been increasingly implicated in ischemia/reperfusion mediated injury to tissue. Recent methods of assessing tissue oxygen free radical flux including spin trapping, salicylate hydroxylation, protein oxidation and specific enzymatic activity loss have clearly shown that ischemia/reperfusion mediates oxidative damage in brain. Vascular endothelia cells are increasingly implicated in inactivating oxidative damage. The authors have used salicylate to assess hydroxyl free radical flux during an anoxia-reoxygenation insult in isolated brain microvessels. Brain microvessels that were subjected to a 20 min anoxia period and then reoxygenated for 20 min hydroxylated salicylate to form tissue localized 2,3-dihydroxybenzoic acid (2,3-DHBA) whereas microvessels that remained oxygenated throughout contained very little 2,3-DHBA. The data suggest that anoxia/reoxygenation of microvessels produces tissue localized hydroxyl free radical flux.

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

    KAUST Repository

    Ordoñez, Natalia Maria

    2013-09-03

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

  9. Design of a Modular E-Core Flux Concentrating Axial Flux Machine

    Energy Technology Data Exchange (ETDEWEB)

    Husain, Tausif; Sozer, Yilmaz; Husain, Iqbal; Muljadi, Eduard

    2015-09-02

    In this paper a novel E-Core axial flux machine is proposed. The machine has a double stator-single rotor configuration with flux concentrating ferrite magnets, and pole windings across each leg of an E-Core stator. E-Core stators with the proposed flux-concentrating rotor arrangement result in better magnet utilization and higher torque density. The machine also has a modular structure facilitating simpler construction. This paper presents a single phase and a three-phase version of the E-Core machine. Case study for a 1.1 kW, 400 rpm machine for both the single phase and three-phase axial flux machine is presented. The results are verified through 3D finite element analysis.

  10. Response of actinides to flux changes in high-flux systems

    International Nuclear Information System (INIS)

    When discussing the transmutation of actinides in accelerator-based transmutation of waste (ATW) systems, there has been some concern about the dynamics of the actinides under high transient fluxes. For a pure neptunium feed, it has been estimated that the 238Np/237Np ratio increase due to an increasing flux may lead to an unstable, positive reactivity growth. In this analysis, a perturbation method is used to calculate the response of the entire set of actinides in a general way that allows for more species than just neptunium. The time response of the system can be calculated; i.e., a plot of fuel composition and reactivity versus time after a change in flux can be made. The effects of fission products can also be included. The procedure is extremely accurate on short time scales (∼ 1000 s) for the flux levels we contemplate. Calculational results indicate that the reactivity insertions are always smaller than previously estimated

  11. Flux Creep and Giant Flux Creep in High Tc Hg,Pb-based Superconductors

    Science.gov (United States)

    Kirven, Douglas; Owens, Frank; Iqbal, Z.; Bleiweiss, M.; Lungu, A.; Datta, T.

    1996-03-01

    Dynamic behavior of the trapped flux in fields of up to 17.5 T was studied in a set of Hg-Pb based superconductors with a Tc in excess of 130 K. Depending on the experimental conditions, both creep and giant flux creep dynamics were observed. Results were analyzed using to standard models such as Anderson-Kim and giant-flux creep models (GFC). The plots of relaxation rate of remnant magnetization versus temperature show a peak below Tc. These results were compared with other Cu-O compounds. A distribution of activation energies was found from the magnetization rate. The activation energy distribution shows a peak around 50 K. The peak determines the temperature where the flux flow rate is a maximum. A universal relation of the resistive behavior was also found as a function of temperature and field. The zero-field/field-cooled results gave a reversibility curve that also obeyed a universal power relation.

  12. 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

  13. Effects of Benthic Flux on Dissolved-Mercury Distributions in Camp Far West Reservoir, California

    Science.gov (United States)

    Kuwabara, J. S.; Alpers, C. N.; Marvin-Dipasquale, M.; Topping, B. R.; Carter, J. L.; Stewart, A. R.; Fend, S. V.; Parchaso, F.; Moon, G. E.; Krabbenhoft, D. P.; Agee, J. L.; Kieu, L. H.

    2003-12-01

    shallower, up-gradient sites to 0.48 +/- 0.03 pM (n=3) at the deepest sampling site in November 2002. Dissolved MeHg concentrations in the bottom waters were significantly lower under the low-flow conditions of November 2002 relative to high flow in April 2002, but spatial trends were not temporally consistent. The reservoir was highly phosphate-limited with molar N:P ratios in water column samples ranging from 136 to >5,000 (compared to the Redfield N:P molar ratio of 16). Sulfide benthic fluxes were highest (1,180 +/- 50 nmoles-m-2-h-1) at the deepest site in November 2002 following at least 2 weeks of hypolimnetic anoxia (based on prior water-column monitoring), and lowest at the same site in April 2002 (290 +/- 30 nmoles-m-2-h-1) under oxic, high-flow conditions. Sparse benthic macroinvertebrate distributions, mirrored by low benthic-chlorophyll concentrations, were considered to be inconsequential factors mediating benthic flux. Despite their seasonal variability, the magnitude of benthic flux estimates for HgT were consistently comparable to or greater than riverine sources during a relatively dry year. Diffusive transport of dissolved, bioavailable mercury species between the reservoir bed and water column may therefore be an important process regulating the concentration of mercury species in the reservoir water column.

  14. Regional nitrous oxide flux in Amazon basin

    International Nuclear Information System (INIS)

    Nitrous oxide (N2O) is the third most important anthropogenic greenhouse gas. Globally, the main sources of N2O are nitrification and denitrification in soils. About two thirds of the soil emissions occur in the tropics and approximately 20% originate in wet rain forest ecosystems, like the Amazon forest. The work presented here involves aircraft vertical profiles of N2O from the surface to 4 km over two sites in the Eastern and Central Amazon: Tapajos National Forest (2000-2009) and Cuieiras Biologic Reserve (2004-2007), and the estimation of N2O fluxes for regions upwind of these sites using two methods: Column Integration Technique and Inversion Model - FLEXPART. To our knowledge, these regional scale N2O measurements in Amazonia are unique and represent a new approach to looking regional scale emissions. For the both methods, the fluxes upwind of Cuieiras Biologic Reserve exhibited little seasonality, and the annual mean was 1.9 ±1.6 mgN2Om-2day-1 for the Column Integration Technique and 2.3±0.9 mgN2Om-2day-1 for Inversion Model - FLEXPART. For fluxes upwind of Tapajos Nacional Forest, the Inversion Model - FLEXPART presented about half (0.9±1.7 mgN2Om-2day-1) of the Column Integration Technique (2.0±1.1 mgN2Om-2day-1) for the same period (2004-2008). One reason could be because the inversion model does not consider anthropic activities, once it had a good representation for less impacted area. Both regions presented similar emission during wet season. By Column Integration Technique, fluxes upwind Tapajos Nacional Forest were similar for dry and wet seasons. The dry season N2O fluxes exhibit significant correlations with CO fluxes, indicating a larger than expected source of N2O from biomass burning. The average CO:N2O ratio for all 38 profiles sampled during the dry season was 82±69 mol CO:molN2O and suggests a larger biomass burning contribution to the global N2O budget than previously reported. (author)

  15. Topological Membranes, Current Algebras and H-flux - R-flux Duality based on Courant Algebroids

    CERN Document Server

    Bessho, Taiki; Ikeda, Noriaki; Watamura, Satoshi

    2015-01-01

    We construct a topological sigma model and a current algebra based on a Courant algebroid structure on a Poisson manifold. In order to construct models, we reformulate the Poisson Courant algebroid by supergeometric construction on a QP-manifold. A new duality of Courant algebroids which transforms H-flux and R-flux is proposed, where the transformation is interpreted as a canonical transformation of a graded symplectic manifold.

  16. Flux frequency analysis of seasonally dry ecosystem fluxes in two unique biomes of Sonora Mexico

    Science.gov (United States)

    Verduzco, V. S.; Yepez, E. A.; Robles-Morua, A.; Garatuza, J.; Rodriguez, J. C.; Watts, C.

    2013-05-01

    Complex dynamics from the interactions of ecosystems processes makes difficult to model the behavior of ecosystems fluxes of carbon and water in response to the variation of environmental and biological drivers. Although process oriented ecosystem models are critical tools for studying land-atmosphere fluxes, its validity depends on the appropriate parameterization of equations describing temporal and spatial changes of model state variables and their interactions. This constraint often leads to discrepancies between model simulations and observed data that reduce models reliability especially in arid and semiarid ecosystems. In the semiarid north western Mexico, ecosystem processes are fundamentally controlled by the seasonality of water and the intermittence of rain pulses which are conditions that require calibration of specific fitting functions to describe the response of ecosystem variables (i.e. NEE, GPP, ET, respiration) to these wetting and drying periods. The goal is to find functions that describe the magnitude of ecosystem fluxes during individual rain pulses and the seasonality of the ecosystem. Relaying on five years of eddy covariance flux data of a tropical dry forest and a subtropical shrubland we present a flux frequency analysis that describe the variation of net ecosystem exchange (NEE) of CO2 to highlight the relevance of pulse driven dynamics controlling this flux. Preliminary results of flux frequency analysis of NEE indicate that these ecosystems are strongly controlled by the frequency distribution of rain. Also, the output of fitting functions for NEE, GPP, ET and respiration using semi-empirical functions applied at specific rain pulses compared with season-long statistically generated simulations do not agree. Seasonality and the intrinsic nature of individual pulses have different effects on ecosystem flux responses. This suggests that relationships between the nature of seasonality and individual pulses can help improve the

  17. Poynting flux dominated jets challenged by their photospheric emission

    CERN Document Server

    Bégué, D

    2014-01-01

    One of the key open question in the study of jets in general, and jets in gamma-ray bursts (GRBs) in particular, is the magnetization of the outflow. Here we consider the photospheric emission of Poynting flux dominated outflows, when the dynamics is mediated by magnetic reconnection. We show that thermal three-particle processes, responsible for the thermalization of the plasma, become inefficient at a radius $r_{\\rm sup} \\sim 10^{9.5}$~cm, far below the photosphere, at $\\sim 10^{11.5}$~cm. Conservation of the total photon number above $r_{\\rm sup}$ combined with Compton scattering below the photosphere enforces kinetic equilibrium between electrons and photons. This, in turn, leads to an increase in the observed photon temperature, which reaches $\\gtrsim 8$~MeV (observed energy) when decoupling the plasma at the photosphere. This result is weakly dependent on the free model parameters. We show that in this case, the expected thermal luminosity is a few \\% of the total luminosity, and could therefore be dete...

  18. Contribution of Oceanic Circulation to the Poleward Heat Flux

    Institute of Scientific and Technical Information of China (English)

    HUANG Ruixin

    2005-01-01

    Oceanic contribution to the poleward heat flux in the climate system includes two components: the sensible heat flux and the latent heat flux. Although the latent heat flux has been classified as atmospheric heat flux exclusively, it is argued that oceanic control over this component of poleward heat flux should play a critically important role. The so-called swamp ocean model practice is analyzed in detail, and the critical role of oceanic circulation in the establishment of the meridional moisture transport is emphasized.

  19. Atmosphere–Surface Fluxes of CO2 using Spectral Techniques

    DEFF Research Database (Denmark)

    Sørensen, Lise Lotte; Larsen, Søren Ejling

    2010-01-01

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

  20. An HTS flux pump operated by directly driving a superconductor into flux flow region in the E– J curve

    Science.gov (United States)

    Geng, Jianzhao; Coombs, T. A.

    2016-09-01

    High-T c superconducting (HTS) flux pumps are capable of compensating the persistent current decay in HTS magnets without electrical contact. In this paper, following work on a low-T c superconducting self-switching flux pump, we propose a new HTS flux pump by directly driving a high-T c superconductor into the flux flow region in the E– J curve. The flux pump consists of a transformer which has a superconducting secondary winding shorted by an YBCO-coated conductor bridge. A high alternating current with a much higher positive peak value than the negative peak value is induced in the secondary winding. The current always drives the bridge superconductor into the flux flow region only at around its positive peak value, thus resulting in flux pumping. The proposed flux pump is much simpler than existing HTS flux pumps.

  1. 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...... as an exclusive club, the belonging to which provides a strategic advantage. The technology brought forth by the marketplace participates in shaping the strategic demands of the participants which in turn request the marketplace to redesign its own strategy. Profiting from this unintended demand, the e...

  2. 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....... Jacobs, Nancy Weiss. Oxford, Blackwell Publishing. Latour, B. W., Steve (1979). Laboratory Life. London, New Delhi, Sage. Lynch, M. (1985). Art and artifact in laboratory science. London, Boston, Melbourne and Henley, Routledge & Kegan Paul. Sommerlund, J. (2004 (2007)). "Beauty and Bacteria...

  3. 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.

  4. 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

  5. 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

  6. 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...

  7. Helium cosmic ray flux measurements at Mars

    International Nuclear Information System (INIS)

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

  8. Helium cosmic ray flux measurements at Mars

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Kerry [University of Houston, 4800 Calhoun Rd. Houston, TX 77204 (United States)]. E-mail: ktlee@ems.jsc.nasa.gov; Pinsky, Lawrence [University of Houston, 4800 Calhoun Rd. Houston, TX 77204 (United States); Andersen, Vic [University of Houston, 4800 Calhoun Rd. Houston, TX 77204 (United States); Zeitlin, Cary [National Space Biomedical Research Institute, Baylor College of Medicine, Houston, TX (United States); Cleghorn, Tim [NASA Johnson Space Center, 2101 NASA Road 1, Houston, TX 77058 (United States); Cucinotta, Frank [NASA Johnson Space Center, 2101 NASA Road 1, Houston, TX 77058 (United States); Saganti, Premkumar [Prairie View A and M University, P.O. Box 519, Prairie View, TX 77446-0519 (United States); Atwell, William [The Boeing Company, Houston, TX (United States); Turner, Ron [Advancing National Strategies and Enabling Results (ANSER), Arlington, Virginia (United States)

    2006-10-15

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

  9. Metabolic flux rewiring in mammalian cell cultures.

    Science.gov (United States)

    Young, Jamey D

    2013-12-01

    Continuous cell lines (CCLs) engage in 'wasteful' glucose and glutamine metabolism that leads to accumulation of inhibitory byproducts, primarily lactate and ammonium. Advances in techniques for mapping intracellular carbon fluxes and profiling global changes in enzyme expression have led to a deeper understanding of the molecular drivers underlying these metabolic alterations. However, recent studies have revealed that CCLs are not necessarily entrenched in a glycolytic or glutaminolytic phenotype, but instead can shift their metabolism toward increased oxidative metabolism as nutrients become depleted and/or growth rate slows. Progress to understand dynamic flux regulation in CCLs has enabled the development of novel strategies to force cultures into desirable metabolic phenotypes, by combining fed-batch feeding strategies with direct metabolic engineering of host cells. PMID:23726154

  10. Optical Manipulation of Single Flux Quanta

    CERN Document Server

    Veshchunov, I S; Mironov, S V; Godin, A G; Trebbia, J -B; Buzdin, A I; Tamarat, Ph; Lounis, B

    2016-01-01

    Magnetic field can penetrate into type-II superconductors in the form of Abrikosov vortices, which are magnetic flux tubes surrounded by circulating supercurrents often trapped at defects referred to as pinning sites. Although the average properties of the vortex matter can be tuned with magnetic fields, temperature or electric currents, handling of individual vortices remains challenging and has been demonstrated only with sophisticated magnetic force, superconducting quantum interference device or strain-induced scanning local probe microscopies. Here, we introduce a far-field optical method based on local heating of the superconductor with a focused laser beam to realize a fast, precise and non-invasive manipulation of individual Abrikosov vortices, in the same way as with optical tweezers. This simple approach provides the perfect basis for sculpting the magnetic flux profile in superconducting devices like a vortex lens or a vortex cleaner, without resorting to static pinning or ratchet effects. Since a ...

  11. Observational biases in flux magnification measurements

    CERN Document Server

    Hildebrandt, Hendrik

    2015-01-01

    Flux magnification is an interesting complement to shear-based lensing measurements, especially at high redshift where sources are harder to resolve. One measures either changes in the source density (magnification bias) or in the shape of the flux distribution (e.g. magnitude-shift). The interpretation of these measurements relies on theoretical estimates of how the observables change under magnification. Here we present simulations to create multi-band photometric mock catalogues of Lyman-break galaxies in a CFHTLenS-like survey that include several observational effects that can change these relations, making simple theoretical estimates unusable. In particular, we show how the magnification bias can be affected by photometric noise, colour selection, and dust extinction. We find that a simple measurement of the slope of the number-counts is not sufficient for the precise interpretation of virtually all observations of magnification bias. We also explore how sensitive the shift in the mean magnitude of a s...

  12. Computation of 7Be solar neutrino flux

    Institute of Scientific and Technical Information of China (English)

    YE Zipiao; SHENG Xiangdong; DAI Changjiang

    2003-01-01

    Within the target range from 0 to 0.1217 times the solar radius, the probability of 7Be existing as an ion with one or two bound electrons is calculated, which is turned out to be about 4.69 %, and about 95.3 1 % 7Be nucleus is completely ionized. After considering the influence of that portion of incompletely ionized 7Be, the renewly calculative result shows that the solar neutrino flux of 7Be will decrease from 45 000 m-2.s-1 to 43 000 m-2.s-1, and the predicted value of the 8B solar neutrino flux will increase from 51 5 m-2.s-1 to 535 m-2.s-1.

  13. Magnetopause reconnection and interlinked flux tubes

    Directory of Open Access Journals (Sweden)

    F. R. Cardoso

    2013-10-01

    Full Text Available Magnetic reconnection can be a continuous or a transient process. Global magnetohydrodynamics (MHD simulations are important tools to understand the relevant magnetic reconnection mechanisms and the resulting magnetic structures. We have studied magnetopause reconnection using a global 3-D MHD simulation in which the interplanetary magnetic field (IMF has been set to large positive By and large negative Bz components, i.e., a south-duskward direction. Flux tubes have been observed even during these constant solar wind conditions. We have focused on the interlinked flux tubes event resulting from time-dependent, patchy and multiple reconnection. At the event onset, two reconnection modes seem to occur simultaneously: a time-dependent, patchy and multiple reconnection for the subsolar region; and, a steady and large-scale reconnection for the regions far from the subsolar site.

  14. Ion fluxes through nanopores and transmembrane channels

    Science.gov (United States)

    Bordin, J. R.; Diehl, A.; Barbosa, M. C.; Levin, Y.

    2012-03-01

    We introduce an implicit solvent Molecular Dynamics approach for calculating ionic fluxes through narrow nanopores and transmembrane channels. The method relies on a dual-control-volume grand-canonical molecular dynamics (DCV-GCMD) simulation and the analytical solution for the electrostatic potential inside a cylindrical nanopore recently obtained by Levin [Europhys. Lett.EULEEJ0295-507510.1209/epl/i2006-10240-4 76, 163 (2006)]. The theory is used to calculate the ionic fluxes through an artificial transmembrane channel which mimics the antibacterial gramicidin A channel. Both current-voltage and current-concentration relations are calculated under various experimental conditions. We show that our results are comparable to the characteristics associated to the gramicidin A pore, especially the existence of two binding sites inside the pore and the observed saturation in the current-concentration profiles.

  15. Flux Limiter Lattice Boltzmann for Compressible Flows

    Institute of Scientific and Technical Information of China (English)

    陈峰; 许爱国; 张广财; 李英骏

    2011-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Dieuaide-Noubhani Martine

    2011-06-01

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

  17. Relation of middle molecules levels and oxidative stress to erythropoietin requirements in high-flux versus low-flux hemodialysis

    Directory of Open Access Journals (Sweden)

    Hala S El-Wakil

    2013-01-01

    Full Text Available The objective of this study is to investigate the serum beta-2-microglobulin (B2MG and advanced oxidation protein products (AOPP as middle molecule uremic toxins and protein carbonyl (PCO as oxidative stress marker in uremic patients undergoing high-flux versus low-flux hemodialysis (HD and to correlate their levels to the erythropoietin requirements for those patients. Twenty patients on chronic low-flux HD were recruited in the study. At the start of the study, all patients underwent high-flux HD for eight weeks, followed by low-flux HD for two weeks as a washout period. The patients were then subjected to another eight weeks of low-flux HD. Blood samples were obtained at the beginning and at the end of the high-flux period and the low-flux period. The mean erythropoietin dose for patients using high-flux HD was significantly lower than that for low-flux HD (P = 0.0062. Post-high flux, the B2MG and PCO levels were significantly lower than the pre-high-flux levels (P = 0.026 and 0.0005, respectively, but no significant change was observed in AOPP (P = 0.68. Post-low flux, the B2MG, AOPP and PCO were significantly higher than the pre-low-flux levels (P = 0.0002, 0.021 and <0.0001, respectively. Post-low flux, the B2MG and PCO were significantly higher than the post-high-flux levels (P <0.0001, but no significant difference was observed in AOPP (P = 0.11. High-flux HD results in reduction of some of the middle molecule toxins and PCO levels better than low-flux HD, and is associated with a better response to erythropoietin.

  18. 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.

  19. Models of Flux Tubes from Constrained Relaxation

    Indian Academy of Sciences (India)

    Α. Mangalam; V. Krishan

    2000-09-01

    We study the relaxation of a compressible plasma to an equilibrium with flow. The constraints of conservation of mass, energy, angular momentum, cross-helicity and relative magnetic helicity are imposed. Equilibria corresponding to the energy extrema while conserving these invariants for parallel flows yield three classes of solutions and one of them with an increasing radial density profile, relevant to solar flux tubes is presented.

  20. High heat flux loop heat pipes

    Science.gov (United States)

    North, Mark T.; Sarraf, David B.; Rosenfeld, John H.; Maidanik, Yuri F.; Vershinin, Sergey

    1997-01-01

    Loop Heat Pipes (LHPs) can transport very large thermal power loads, over long distances, through flexible, small diameter tubes and against high gravitational heads. While recent LHPs have transported as much as 1500 W, the peak heat flux through a LHP's evaporator has been limited to about 0.07 MW/m2. This limitation is due to the arrangement of vapor passages next to the heat load which is one of the conditions necessary to ensure self priming of the device. This paper describes work aimed at raising this limit by threefold to tenfold. Two approaches were pursued. One optimized the vapor passage geometry for the high heat flux conditions. The geometry improved the heat flow into the wick and working fluid. This approach also employed a finer pored wick to support higher vapor flow losses. The second approach used a bidisperse wick material within the circumferential vapor passages. The bidisperse material increased the thermal conductivity and the evaporative surface area in the region of highest heat flux, while providing a flow path for the vapor. Proof-of-concept devices were fabricated and tested for each approach. Both devices operated as designed and both demonstrated operation at a heat flux of 0.70 MW/m2. This performance exceeded the known state of the art by a factor of more than six for both conventional heat pipes and for loop heat pipes using ammonia. In addition, the bidisperse-wick device demonstrated boiling heat transfer coefficients up to 100,000 W/m2.K, and the fine pored device demonstrated an orientation independence with its performance essentially unaffected by whether its evaporator was positioned above, below or level with the condenser.