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Sample records for autophagic flux mediates

  1. Autophagic flux promotes cisplatin resistance in human ovarian carcinoma cells through ATP-mediated lysosomal function.

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    Ma, Liwei; Xu, Ye; Su, Jing; Yu, Huimei; Kang, Jinsong; Li, Hongyan; Li, Xiaoning; Xie, Qi; Yu, Chunyan; Sun, Liankun; Li, Yang

    2015-11-01

    Lysosomes are involved in promoting resistance of cancer cells to chemotherapeutic agents. However, the mechanisms underlying lysosomal influence of cisplatin resistance in ovarian cancer remain incompletely understood. We report that, compared with cisplatin-sensitive SKOV3 cells, autophagy increases in cisplatin-resistant SKOV3/DDP cells treated with cisplatin. Inhibition of early-stage autophagy enhanced cisplatin-mediated cytotoxicity in SKOV3/DDP cells, but autophagy inhibition at a later stage by disturbing autophagosome-lysosome fusion is more effective. Notably, SKOV3/DDP cells contained more lysosomes than cisplatin-sensitive SKOV3 cells. Abundant lysosomes and lysosomal cathepsin D activity were required for continued autolysosomal degradation and maintenance of autophagic flux in SKOV3/DDP cells. Furthermore, SKOV3/DDP cells contain abundant lysosomal ATP required for lysosomal function, and inhibition of lysosomal ATP accumulation impaired lysosomal function and blocked autophagic flux. Therefore, our findings suggest that lysosomes at least partially contribute to cisplatin resistance in ovarian cancer cells through their role in cisplatin-induced autophagic processes, and provide insight into the mechanism of cisplatin resistance in tumors.

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

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

    2015-01-01

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

  3. Glucagon-like Peptide-1 Protects Pancreatic Beta-cells from Death by Increasing Autophagic Flux and Restoring Lysosomal Function.

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    Zummo, Francesco P; Cullen, Kirsty S; Honkanen-Scott, Minna; Shaw, James Am; Lovat, Penny E; Arden, Catherine

    2017-02-23

    Studies in animal models of type 2 diabetes have shown that glucagon-like peptide-1 (GLP-1) receptor agonists prevent β-cell loss. Whether GLP-1 mediates β-cell survival via the key lysosomal-mediated process of autophagy is unknown.Here we report that treatment of INS-1E β-cells and primary islets with glucolipotoxicity (0.5mmol/l palmitate, 25mmol/l glucose) increases LC3 II, a marker of autophagy. Further analysis indicates a blockage in autophagic flux associated with lysosomal dysfunction. Accumulation of defective lysosomes leads to lysosomal membrane permeabilisation (LMP) and release of Cathepsin D, which contributes to cell death. Our data further demonstrated defects in autophagic flux and lysosomal staining in human samples of type 2 diabetes. Co-treatment with the GLP-1 receptor agonist exendin-4 reversed the lysosomal dysfunction, relieving the impairment in autophagic flux and further stimulated autophagy. siRNA knockdown showed the restoration of autophagic flux is also essential for the protective effects of exendin-4.Collectively, our data highlights lysosomal dysfunction as a critical mediator of β-cell loss and shows that exendin-4 improves cell survival via restoration of lysosomal function and autophagic flux. Modulation of autophagy / lysosomal homeostasis may thus define a novel therapeutic strategy for type 2 diabetes, with the GLP-1 signalling pathway as a potential focus.

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

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

    2016-01-01

    Mitosis is a fast process that involves dramatic cellular remodeling and has a high energy demand. Whether autophagy is active or inactive during the early stages of mitosis in a naturally dividing cell is still debated. Here we aimed to use multiple assays to resolve this apparent discrepancy. Although the LC3 puncta number was reduced in mitosis, the four different cell lines we tested all have active autophagic flux in both interphase and mitosis. In addition, the autophagic flux was highl...

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

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    Qinghe Song

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

  6. Autophagic flux regulates microglial phenotype according to the time of oxygen-glucose deprivation/reperfusion.

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    Xia, Cong-Yuan; Zhang, Shuai; Chu, Shi-Feng; Wang, Zhen-Zhen; Song, Xiu-Yun; Zuo, Wei; Gao, Yan; Yang, Peng-Fei; Chen, Nai-Hong

    2016-10-01

    Microglial phenotype alternation is a potential novel pathogenic mechanism for cerebral ischemia. Cerebral ischemia induced autophagy aggravates inflammation and neural injury. However, the effect of autophagy in the modulation of microglial phenotype is still unknown. In this study, we investigated the role of autophagic flux in the alternation of microglial phenotype following oxygen glucose deprivation/reperfusion (OGD/R) in BV-2 cells. Inhibition of autophagic flux by NH4Cl exposure significantly increased the level of microtubule-associated protein 1 light chain 3 (LC3)-II and p62 in control and OGD/R (12h, 24h and 48h) groups, but did not change their expression in OGD/R 72h group, indicating that autophagic flux was inhibited at OGD/R 72h. Once autophagic flux was inhibited at OGD/R 72h or at OGD/R 24h (with NH4Cl), BV-2 cells mainly showed M1 phenotype with increased tumor necrosis factor alpha (TNF-α), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and decreased M2 markers including interleukin-10 (IL-10), Arginase 1 (Arg-1), and brain derived neurotrophic factor (BDNF). Further study indicated that inhibition of autophagic flux activated NF-κB pathway and decreased the activity of cAMP-response element binding protein (CREB), which contributed to the alternation of microglial phenotype. Therefore, inhibition of autophagic flux regulated the alternation of microglial phenotype by modulating the balance between NF-κB and CREB.

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

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    Hyunju Kim

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

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

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

    2016-01-01

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

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

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

    2014-05-26

    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.

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

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

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

    2013-04-19

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

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

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    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

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    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. Enhancing lysosomal biogenesis and autophagic flux by activating the transcription factor EB protects against cadmium-induced neurotoxicity

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    Pi, Huifeng; Li, Min; Tian, Li; Yang, Zhiqi; Yu, Zhengping; Zhou, Zhou

    2017-01-01

    Cadmium (Cd), a highly ubiquitous heavy metal, is a well-known inducer of neurotoxicity. However, the mechanism underlying cadmium-induced neurotoxicity remains unclear. In this study, we found that Cd inhibits autophagosome-lysosome fusion and impairs lysosomal function by reducing the levels of lysosomal-associated membrane proteins, inhibiting lysosomal proteolysis and altering lysosomal pH, contributing to defects in autophagic clearance and subsequently leading to nerve cell death. In addition, Cd decreases transcription factor EB (TFEB) expression at both the mRNA and protein levels. Furthermore, Cd induces the nuclear translocation of TFEB and TFEB target-gene expression, associated with compromised lysosomal function or a compensatory effect after the impairment of the autophagic flux. Notably, restoration of the levels of lysosomal-associated membrane protein, lysosomal proteolysis, lysosomal pH and autophagic flux through Tfeb overexpression protects against Cd-induced neurotoxicity, and this protective effect is incompletely dependent on TFEB nuclear translocation. Moreover, gene transfer of the master autophagy regulator TFEB results in the clearance of toxic proteins and the correction of Cd-induced neurotoxicity in vivo. Our study is the first to demonstrate that Cd disrupts lysosomal function and autophagic flux and manipulation of TFEB signalling may be a therapeutic approach for antagonizing Cd-induced neurotoxicity. PMID:28240313

  15. 5-ALA mediated photodynamic therapy induces autophagic cell death via AMP-activated protein kinase

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    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.

  16. ASSAYING OF AUTOPHAGIC PROTEIN DEGRADATION

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    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

  17. Carbazole alkaloids from Murraya koenigii trigger apoptosis and autophagic flux inhibition in human oral squamous cell carcinoma cells.

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    Utaipan, Tanyarath; Athipornchai, Anan; Suksamrarn, Apichart; Jirachotikoon, Canussanun; Yuan, Xiaohong; Lertcanawanichakul, Monthon; Chunglok, Warangkana

    2017-01-01

    Carbazole alkaloids, a major constituent of Murraya koenigii (L.) Sprengel (Rutaceae), exhibit biological effects such as anticancer activity via the induction of apoptosis, and they represent candidate chemotherapeutic agents. Oral squamous cell carcinoma (OSCC) is the most prevalent cancer of the oral cavity and a growing and serious health problem worldwide. In this study, we investigated the anticancer properties and mechanisms of action of two carbazole alkaloids derived from M. koenigii leaves, mahanine and isomahanine, in the OSCC cell line CLS-354. At 15 μM, mahanine and isomahanine were cytotoxic to CLS-354 cells, triggering apoptosis via caspase-dependent and -independent mechanisms. Autophagosomes, visualised using monodansylcadaverine (MDC) labelling, were numerous in carbazole alkaloid-treated cells. Mahanine and isomahanine markedly induced the expression of the autophagosome marker microtubule-associated protein 1 light chain 3, type II (LC3B-II). Genetic and chemical inhibition of autophagy via silencing of the Autophagy protein 5 gene and exposure to bafilomycin A1 (BafA1), respectively, did not arrest carbazole alkaloid-induced apoptosis, indicating that it occurs independently of autophagic activation. Surprisingly, both carbazole alkaloids caused increased accumulation of p62/sequestosome1 (p62/SQSTM1), with coordinated expression of LC3B-II and cleaved caspase-3, suggesting inhibition of autophagic flux. Our results suggest that inhibition of autophagic flux is associated with carbazole alkaloid-induced apoptosis. Our findings provide evidence of a novel cytotoxic action of natural carbazole alkaloids and support their use as candidate chemotherapeutic agents for the treatment of OSCC.

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

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    Almeida, Luciana O; Goto, Renata N; 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.

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

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    Kyung Min eChung

    2016-05-01

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

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

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

    2015-03-06

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

  1. Inhibition of autophagic flux by salinomycin results in anti-cancer effect in hepatocellular carcinoma cells.

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    Johannes Klose

    Full Text Available Salinomycin raised hope to be effective in anti-cancer therapies due to its capability to overcome apoptosis-resistance in several types of cancer cells. Recently, its effectiveness against human hepatocellular carcinoma (HCC cells both in vitro and in vivo was demonstrated. However, the mechanism of action remained unclear. Latest studies implicated interference with the degradation pathway of autophagy. This study aimed to determine the impact of Salinomycin on HCC-autophagy and whether primary human hepatocytes (PHH likewise are affected. Following exposure of HCC cell lines HepG2 and Huh7 to varying concentrations of Salinomycin (0-10 µM, comprehensive analysis of autophagic activity using western-blotting and flow-cytometry was performed. Drug effects were analyzed in the settings of autophagy stimulation by starvation or PP242-treatment and correlated with cell viability, proliferation, apoptosis induction, mitochondrial mass accumulation and reactive oxygen species (ROS formation. Impact on apoptosis induction and cell function of PHH was analyzed. Constitutive and stimulated autophagic activities both were effectively suppressed in HCC by Salinomycin. This inhibition was associated with dysfunctional mitochondria accumulation, increased apoptosis and decreased proliferation and cell viability. Effects of Salinomycin were dose and time dependent and could readily be replicated by pharmacological and genetic inhibition of HCC-autophagy alone. Salinomycin exposure to PHH resulted in transient impairment of synthesis function and cell viability without apoptosis induction. In conclusion, our data suggest that Salinomycin suppresses late stages of HCC-autophagy, leading to impaired recycling and accumulation of dysfunctional mitochondria with increased ROS-production all of which are associated with induction of apoptosis.

  2. Inhibition of autophagic flux by salinomycin results in anti-cancer effect in hepatocellular carcinoma cells.

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    Klose, Johannes; Stankov, Metodi V; Kleine, Moritz; Ramackers, Wolf; Panayotova-Dimitrova, Diana; Jäger, Mark D; Klempnauer, Jürgen; Winkler, Michael; Bektas, Hüseyin; Behrens, Georg M N; Vondran, Florian W R

    2014-01-01

    Salinomycin raised hope to be effective in anti-cancer therapies due to its capability to overcome apoptosis-resistance in several types of cancer cells. Recently, its effectiveness against human hepatocellular carcinoma (HCC) cells both in vitro and in vivo was demonstrated. However, the mechanism of action remained unclear. Latest studies implicated interference with the degradation pathway of autophagy. This study aimed to determine the impact of Salinomycin on HCC-autophagy and whether primary human hepatocytes (PHH) likewise are affected. Following exposure of HCC cell lines HepG2 and Huh7 to varying concentrations of Salinomycin (0-10 µM), comprehensive analysis of autophagic activity using western-blotting and flow-cytometry was performed. Drug effects were analyzed in the settings of autophagy stimulation by starvation or PP242-treatment and correlated with cell viability, proliferation, apoptosis induction, mitochondrial mass accumulation and reactive oxygen species (ROS) formation. Impact on apoptosis induction and cell function of PHH was analyzed. Constitutive and stimulated autophagic activities both were effectively suppressed in HCC by Salinomycin. This inhibition was associated with dysfunctional mitochondria accumulation, increased apoptosis and decreased proliferation and cell viability. Effects of Salinomycin were dose and time dependent and could readily be replicated by pharmacological and genetic inhibition of HCC-autophagy alone. Salinomycin exposure to PHH resulted in transient impairment of synthesis function and cell viability without apoptosis induction. In conclusion, our data suggest that Salinomycin suppresses late stages of HCC-autophagy, leading to impaired recycling and accumulation of dysfunctional mitochondria with increased ROS-production all of which are associated with induction of apoptosis.

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

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    Chih-Yang Huang

    2016-05-01

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

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

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    Haixia Zhuang

    2016-04-01

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

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

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    Dong Xiao

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

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

    Science.gov (United States)

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

    2016-08-25

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

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

    Science.gov (United States)

    Campbell, Grant R; Spector, Stephen A

    2012-01-01

    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.

  8. 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.

  9. Impairment of Atg5-dependent autophagic flux promotes paraquat- and MPP⁺-induced apoptosis but not rotenone or 6-hydroxydopamine toxicity.

    Science.gov (United States)

    Garcia-Garcia, Aracely; Anandhan, Annandurai; Burns, Michaela; Chen, Han; Zhou, You; Franco, Rodrigo

    2013-11-01

    Controversial reports on the role of autophagy as a survival or cell death mechanism in dopaminergic cell death induced by parkinsonian toxins exist. We investigated the alterations in autophagic flux and the role of autophagy protein 5 (Atg5)-dependent autophagy in dopaminergic cell death induced by parkinsonian toxins. Dopaminergic cell death induced by the mitochondrial complex I inhibitors 1-methyl-4-phenylpyridinium (MPP⁺) and rotenone, the pesticide paraquat, and the dopamine analog 6-hydroxydopamine (6-OHDA) was paralleled by increased autophagosome accumulation. However, when compared with basal autophagy levels using chloroquine, autophagosome accumulation was a result of impaired autophagic flux. Only 6-OHDA induced an increase in autophagosome formation. Overexpression of a dominant negative form of Atg5 increased paraquat- and MPP⁺-induced cell death. Stimulation of mammalian target of rapamycin (mTOR)-dependent signaling protected against cell death induced by paraquat, whereas MPP⁺-induced toxicity was enhanced by wortmannin, a phosphoinositide 3-kinase class III inhibitor, rapamycin, and trehalose, an mTOR-independent autophagy activator. Modulation of autophagy by either pharmacological or genetic approaches had no effect on rotenone or 6-OHDA toxicity. Cell death induced by parkinsonian neurotoxins was inhibited by the pan caspase inhibitor (Z-VAD), but only caspase-3 inhibition was able to decrease MPP⁺-induced cell death. Finally, inhibition of the lysosomal hydrolases, cathepsins, increased the toxicity by paraquat and MPP⁺, supporting a protective role of Atg5-dependent autophagy and lysosomes degradation pathways on dopaminegic cell death. These results demonstrate that in dopaminergic cells, Atg5-dependent autophagy acts as a protective mechanism during apoptotic cell death induced by paraquat and MPP⁺ but not during rotenone or 6-OHDA toxicity.

  10. 腹主动脉缩窄20周大鼠心肌细胞的自噬通量%Autophagic flux of cardiomyocytes from 20-week transverse abdominal aortic constriction rats

    Institute of Scientific and Technical Information of China (English)

    崔龙彪; 圣娟娟; 王云英; 余志斌

    2013-01-01

    Cardiac autophagy dramatically increases in heart failure induced by sustained pressure overload.However,it has not yet been addressed if enhanced autophagy plays a role in protecting myocardium or mediating progression from compensative hypertrophy to heart failure.The aim of the present study was to detect autophagic flux of cardiomyocytes from 20-week transverse abdominal aortic constriction (TAC) rats.Fasting rats were used as the positive control for detecting cardiac autophagy.Echocardiography was applied to find the changes of cardiac structure and function.Immunofluorescent histochemistry and Western blot were used to analyze the related biomolecular indexes reflecting cardiac autophagic flux.After the previous methods for detecting cardiac autophagy were confirmed,the autophagic flux in cardiomyocytes of rats subjected to 20-week TAC was examined.The results showed that fasting had no obvious influence on parameters of cardiac structure in rats,including interventricular septal wall thickness and left ventricle posterior wall thickness,but heart rate,diastolic left ventricle internal dimension,fractional shortening of left ventricle dimension,ejection fraction and mitral inflow velocity decreased in rats after fasting for 3 d.Meanwhile,positively stained particles of LC3 and cathepsin D,but not ubiquitin and complement 9,distributed within cardiomyocytes of 3-day fasting rats,indicating augmented autophagic flux.Compared with sham rats,20-week TAC rats did not show any changes ofLC3,cathepsin D,ubiquitin and complement 9 in myocardium detected by immunofluorescent histochemistry.In addition,protein levels of LC3,cathepsin D and p62 in myocardium of TAC rats did not changed.These results reveal the unchanged autophagic flux in cardiomyocytes at middle or late phase of cardiac hypertrophy in TAC rats,implying a balance between inhibition of hypertrophy and activation of pressure load stress on autophagy.%长期心脏压力超负荷致心衰心肌的自噬

  11. 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

  12. 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.

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    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

  13. 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.

  14. The Autophagic Machinery in Enterovirus Infection

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    Jeffrey K. F. Lai

    2016-01-01

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

  15. Hall Effect–Mediated Magnetic Flux Transport in Protoplanetary Disks

    Science.gov (United States)

    Bai, Xue-Ning; Stone, James M.

    2017-02-01

    The global evolution of protoplanetary disks (PPDs) has recently been shown to be largely controlled by the amount of poloidal magnetic flux threading the disk. The amount of magnetic flux must also coevolve with the disk, as a result of magnetic flux transport, a process that is poorly understood. In weakly ionized gas as in PPDs, magnetic flux is largely frozen in the electron fluid, except when resistivity is large. When the disk is largely laminar, we show that the relative drift between the electrons and ions (the Hall drift), and the ions and neutral fluids (ambipolar drift) can play a dominant role on the transport of magnetic flux. Using two-dimensional simulations that incorporate the Hall effect and ambipolar diffusion (AD) with prescribed diffusivities, we show that when large-scale poloidal field is aligned with disk rotation, the Hall effect rapidly drags magnetic flux inward at the midplane region, while it slowly pushes flux outward above/below the midplane. This leads to a highly radially elongated field configuration as a global manifestation of the Hall-shear instability. This field configuration further promotes rapid outward flux transport by AD at the midplane, leading to instability saturation. In quasi-steady state, magnetic flux is transported outward at approximately the same rate at all heights, and the rate is comparable to the Hall-free case. For anti-aligned field polarity, the Hall effect consistently transports magnetic flux outward, leading to a largely vertical field configuration in the midplane region. The field lines in the upper layer first bend radially inward and then outward to launch a disk wind. Overall, the net rate of outward flux transport is about twice as fast as that of the aligned case. In addition, the rate of flux transport increases with increasing disk magnetization. The absolute rate of transport is sensitive to disk microphysics, which remains to be explored in future studies.

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

    Science.gov (United States)

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

    2015-10-01

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

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

    OpenAIRE

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

    2015-01-01

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

  18. 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.

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

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    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

  20. 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.

  1. 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.

  2. 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.

  3. 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.

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

    Science.gov (United States)

    Pareja, Maria Eugenia Mansilla; Colombo, Maria I

    2013-01-01

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

  5. 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

  6. 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.

  7. 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 the human proton-coupled amino acid transporter (hPAT1) to the apical solution. The present study indicates that the transepithelial A-B flux of vigabatrin is mainly mediated by hPAT1 in Caco-2 cells at dose-relevant concentrations....

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

    Science.gov (United States)

    Ebrahimi, F.; Raman, R.

    2016-04-01

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

  9. 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.

  10. Glucocorticoids Suppress CCR9-Mediated Chemotaxis, Calcium Flux, and Adhesion to MAdCAM-1 in Human T Cells.

    Science.gov (United States)

    Wendt, Emily; White, Gemma E; Ferry, Helen; Huhn, Michael; Greaves, David R; Keshav, Satish

    2016-05-01

    CCR9 expressed on T lymphocytes mediates migration to the small intestine in response to a gradient of CCL25. CCL25-stimulated activation of α4β7 integrin promotes cell adherence to mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed by vascular endothelial cells of the intestine, further mediating gut-specific homing. Inflammatory bowel disease is a chronic inflammatory condition that primarily affects the gastrointestinal tract and is characterized by leukocyte infiltration. Glucocorticoids (GCs) are widely used to treat inflammatory bowel disease but their effect on intestinal leukocyte homing is not well understood. We investigated the effect of GCs on the gut-specific chemokine receptor pair, CCR9 and CCL25. Using human peripheral blood-derived T lymphocytes enriched for CCR9 by cell sorting or culturing with all-trans retinoic acid, we measured chemotaxis, intracellular calcium flux, and α4β7-mediated cell adhesion to plate-bound MAdCAM-1. Dexamethasone (DEX), a specific GC receptor agonist, significantly reduced CCR9-mediated chemotaxis and adhesion to MAdCAM-1 without affecting CCR9 surface expression. In contrast, in the same cells, DEX increased CXCR4 surface expression and CXCL12-mediated signaling and downstream functions. The effects of DEX on human primary T cells were reversed by the GC receptor antagonist mifepristone. These results demonstrate that GCs suppress CCR9-mediated chemotaxis, intracellular calcium flux, and α4β7-mediated cell adhesion in vitro, and these effects could contribute to the efficacy of GCs in treating intestinal inflammation in vivo.

  11. Methods for assessing autophagy and autophagic cell death.

    Science.gov (United States)

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

    2008-01-01

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

  12. Gaseous mercury flux from salt marshes is mediated by solar radiation and temperature

    Science.gov (United States)

    Sizmur, Tom; McArthur, Gordon; Risk, David; Tordon, Robert; O'Driscoll, Nelson J.

    2017-03-01

    Salt marshes are ecologically sensitive ecosystems where mercury (Hg) methylation and biomagnification can occur. Understanding the mechanisms controlling gaseous Hg flux from salt marshes is important to predict the retention of Hg in coastal wetlands and project the impact of environmental change on the global Hg cycle. We monitored Hg flux from a remote salt marsh over 9 days which included three cloudless days and a 4 mm rainfall event. We observed a cyclical diel relationship between Hg flux and solar radiation. When measurements at the same irradiance intensity are considered, Hg flux was greater in the evening when the sediment was warm than in the morning when the sediment was cool. This is evidence to suggest that both solar radiation and sediment temperature directly influence the rate of Hg(II) photoreduction in salt marshes. Hg flux could be predicted from solar radiation and sediment temperature in sub-datasets collected during cloudless days (R2 = 0.99), and before (R2 = 0.97) and after (R2 = 0.95) the rainfall event, but the combined dataset could not account for the lower Hg flux after the rainfall event that is in contrast to greater Hg flux observed from soils after rainfall events.

  13. 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.

  14. Dismantling the autophagic arsenal when it is time to die: concerted AMBRA1 degradation by caspases and calpains.

    Science.gov (United States)

    Corazzari, Marco; Fimia, Gian Maria; Piacentini, Mauro

    2012-08-01

    Under stress conditions cells activate different response pathways which result in cell survival or apoptosis depending on: (1) the nature of the insults, (2) the type, if acute or chronic stress, and (3) how long the stress persists. Generally, autophagy is induced early to sustain cell survival and inhibit cell death. However, adverse conditions are able to overcome autophagy to promote cell death. Increasing evidence suggests that the inhibition of autophagy by the apoptotic machinery has been proposed as one of the crucial events responsible for the irreversible switch from survival to death. The mechanism seems to be related to the selective apoptotic protease-mediated degradation of key autophagic proteins. We recently found that AMBRA1, an important regulator of the autophagic process mediating the initial steps of autophagosome formation, is also irreversibly degraded by the combined activity of caspases and calpains. This phenomenon is not merely a consequence of apoptosis execution but represents a key step required to efficiently promote the autophagic vs apoptosis switch.

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

    Science.gov (United States)

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

    2015-01-01

    Spinal and bulbar muscular atrophy (SBMA) is characterized by loss of motoneurons and sensory neurons, accompanied by atrophy of muscle cells. SBMA is due to an androgen receptor containing a polyglutamine tract (ARpolyQ) that misfolds and aggregates, thereby perturbing the protein quality control (PQC) system. Using SBMA AR113Q mice we analyzed proteotoxic stress-induced alterations of HSPB8-mediated PQC machinery promoting clearance of misfolded proteins by autophagy. In muscle of symptomatic AR113Q male mice, we found expression upregulation of Pax-7, myogenin, E2-ubiquitin ligase UBE2Q1 and acetylcholine receptor (AchR), but not of MyoD, and of two E3-ligases (MuRF-1 and Cullin3). TGFβ1 and PGC-1α were also robustly upregulated. We also found a dramatic perturbation of the autophagic response, with upregulation of most autophagic markers (Beclin-1, ATG10, p62/SQSTM1, LC3) and of the HSPB8-mediated PQC response. Both HSPB8 and its co-chaperone BAG3 were robustly upregulated together with other specific HSPB8 interactors (HSPB2 and HSPB3). Notably, the BAG3:BAG1 ratio increased in muscle suggesting preferential misfolded proteins routing to autophagy rather than to proteasome. Thus, mutant ARpolyQ induces a potent autophagic response in muscle cells. Alteration in HSPB8-based PQC machinery may represent muscle-specific biomarkers useful to assess SBMA progression in mice and patients in response to pharmacological treatments. PMID:26490709

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

    Science.gov (United States)

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

    2015-10-01

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

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

    Directory of Open Access Journals (Sweden)

    Hua Chen

    2015-04-01

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

  18. 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. 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.

  20. Apigenin induces autophagic cell death in human papillary thyroid carcinoma BCPAP cells.

    Science.gov (United States)

    Zhang, Li; Cheng, Xian; Gao, Yanyan; Zheng, Jie; Xu, Qiang; Sun, Yang; Guan, Haixia; Yu, Huixin; Sun, Zhen

    2015-11-01

    Apigenin, abundantly present in fruits and vegetables, is recognized as a flavonoid with anti-inflammatory, antioxidant and anticancer properties. In this study, we first investigated the anti-neoplastic effects of apigenin on papillary thyroid carcinoma (PTC) cell line BCPAP cells. Our results show that apigenin inhibited the viability of BCPAP cells in a dose-dependent manner. A large body of evidence demonstrates that autophagy contributes to cell death in certain contexts. In the present study, autophagy was induced by apigenin treatment in BCPAP cells, as evidenced by Beclin-1 accumulation, conversion of LC3 protein, p62 degradation as well as the significantly increased formation of acidic vesicular organelles (AVOs) compared to the control group. 3-MA, an autophagy inhibitor, rescued the cells from apigenin-induced cell death. Notably, apigenin enhanced production of reactive oxygen species (ROS), and subsequent induction of significant DNA damage as monitored by the TUNEL assay. In addition, apigenin treatment caused a significant accumulation of cells in the G2/M phase via down-regulation of Cdc25C expression. Our findings reveal that apigenin inhibits papillary thyroid cancer cell viability by the stimulation of reactive oxygen species (ROS) production, induction of DNA damage, leading to G2/M cell cycle arrest followed by autophagic cell death. Thus, our results provide new insights into the molecular mechanisms underlying apigenin-mediated autophagic cell death and suggest apigenin as a potential chemotherapeutic agent which is able to fight against papillary thyroid cancer.

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

    Directory of Open Access Journals (Sweden)

    Clare M Florence

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

  2. BH3 mimetics activate multiple pro-autophagic pathways.

    Science.gov (United States)

    Malik, S A; Orhon, I; Morselli, E; Criollo, A; Shen, S; Mariño, G; BenYounes, A; Bénit, P; Rustin, P; Maiuri, M C; Kroemer, G

    2011-09-15

    The BH3 mimetic ABT737 induces autophagy by competitively disrupting the inhibitory interaction between the BH3 domain of Beclin 1 and the anti-apoptotic proteins Bcl-2 and Bcl-X(L), thereby stimulating the Beclin 1-dependent allosteric activation of the pro-autophagic lipid kinase VPS34. Here, we examined whether ABT737 stimulates other pro-autophagic signal-transduction pathways. ABT737 caused the activating phosphorylation of AMP-dependent kinase (AMPK) and of the AMPK substrate acetyl CoA carboxylase, the activating phosphorylation of several subunits of the inhibitor of NF-κB (IκB) kinase (IKK) and the hyperphosphorylation of the IKK substrate IκB, inhibition of the activity of mammalian target of rapamycin (mTOR) and consequent dephosphorylation of the mTOR substrate S6 kinase. In addition, ABT737 treatment dephosphorylates (and hence likewise inhibits) p53, glycogen synthase kinase-3 and Akt. All these effects were shared by ABT737 and another structurally unrelated BH3 mimetic, HA14-1. Functional experiments revealed that pharmacological or genetic inhibition of IKK, Sirtuin and the p53-depleting ubiquitin ligase MDM2 prevented ABT737-induced autophagy. These results point to unexpected and pleiotropic pro-autophagic effects of BH3 mimetics involving the modulation of multiple signalling pathways.

  3. 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

  4. 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.

  5. 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.

  6. The autophagic paradox in cancer therapy.

    Science.gov (United States)

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

    2012-02-23

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

  7. Histone deacetylases 1 and 2 regulate autophagy flux and skeletal muscle homeostasis in mice

    Science.gov (United States)

    Moresi, Viviana; Carrer, Michele; Grueter, Chad E.; Rifki, Oktay F.; Shelton, John M.; Richardson, James A.; Bassel-Duby, Rhonda; Olson, Eric N.

    2012-01-01

    Maintenance of skeletal muscle structure and function requires efficient and precise metabolic control. Autophagy plays a key role in metabolic homeostasis of diverse tissues by recycling cellular constituents, particularly under conditions of caloric restriction, thereby normalizing cellular metabolism. Here we show that histone deacetylases (HDACs) 1 and 2 control skeletal muscle homeostasis and autophagy flux in mice. Skeletal muscle-specific deletion of both HDAC1 and HDAC2 results in perinatal lethality of a subset of mice, accompanied by mitochondrial abnormalities and sarcomere degeneration. Mutant mice that survive the first day of life develop a progressive myopathy characterized by muscle degeneration and regeneration, and abnormal metabolism resulting from a blockade to autophagy. HDAC1 and HDAC2 regulate skeletal muscle autophagy by mediating the induction of autophagic gene expression and the formation of autophagosomes, such that myofibers of mice lacking these HDACs accumulate toxic autophagic intermediates. Strikingly, feeding HDAC1/2 mutant mice a high-fat diet from the weaning age releases the block in autophagy and prevents myopathy in adult mice. These findings reveal an unprecedented and essential role for HDAC1 and HDAC2 in maintenance of skeletal muscle structure and function and show that, at least in some pathological conditions, myopathy may be mitigated by dietary modifications. PMID:22307625

  8. 6-Shogaol Inhibits Breast Cancer Cells and Stem Cell-Like Spheroids by Modulation of Notch Signaling Pathway and Induction of Autophagic Cell Death.

    Science.gov (United States)

    Ray, Anasuya; Vasudevan, Smreti; Sengupta, Suparna

    2015-01-01

    Cancer stem cells (CSCs) pose a serious obstacle to cancer therapy as they can be responsible for poor prognosis and tumour relapse. In this study, we have investigated inhibitory activity of the ginger-derived compound 6-shogaol against breast cancer cells both in monolayer and in cancer-stem cell-like spheroid culture. The spheroids were generated from adherent breast cancer cells. 6-shogaol was effective in killing both breast cancer monolayer cells and spheroids at doses that were not toxic to noncancerous cells. The percentages of CD44+CD24-/low cells and the secondary sphere content were reduced drastically upon treatment with 6-shogaol confirming its action on CSCs. Treatment with 6-shogaol caused cytoplasmic vacuole formation and cleavage of microtubule associated protein Light Chain3 (LC3) in both monolayer and spheroid culture indicating that it induced autophagy. Kinetic analysis of the LC3 expression and a combination treatment with chloroquine revealed that the autophagic flux instigated cell death in 6-shogaol treated breast cancer cells in contrast to the autophagy inhibitor chloroquine. Furthermore, 6-shogaol-induced cell death got suppressed in the presence of chloroquine and a very low level of apoptosis was exhibited even after prolonged treatment of the compound, suggesting that autophagy is the major mode of cell death induced by 6-shogaol in breast cancer cells. 6-shogaol reduced the expression levels of Cleaved Notch1 and its target proteins Hes1 and Cyclin D1 in spheroids, and the reduction was further pronounced in the presence of a γ-secretase inhibitor. Secondary sphere formation in the presence of the inhibitor was also further reduced by 6-shogaol. Together, these results indicate that the inhibitory action of 6-shogaol on spheroid growth and sustainability is conferred through γ-secretase mediated down-regulation of Notch signaling. The efficacy of 6-shogaol in monolayer and cancer stem cell-like spheroids raise hope for its

  9. 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.

  10. Focal Adhesion Kinase-mediated Phosphorylation of Beclin1 Protein Suppresses Cardiomyocyte Autophagy and Initiates Hypertrophic Growth*♦

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    Cheng, Zhaokang; Zhu, Qiang; Dee, Rachel; Opheim, Zachary; Mack, Christopher P.; Cyr, Douglas M.; Taylor, Joan M.

    2017-01-01

    Autophagy is an evolutionarily conserved intracellular degradation/recycling system that is essential for cellular homeostasis but is dysregulated in a number of diseases, including myocardial hypertrophy. Although it is clear that limiting or accelerating autophagic flux can result in pathological cardiac remodeling, the physiological signaling pathways that fine-tune cardiac autophagy are poorly understood. Herein, we demonstrated that stimulation of cardiomyocytes with phenylephrine (PE), a well known hypertrophic agonist, suppresses autophagy and that activation of focal adhesion kinase (FAK) is necessary for PE-stimulated autophagy suppression and subsequent initiation of hypertrophic growth. Mechanistically, we showed that FAK phosphorylates Beclin1, a core autophagy protein, on Tyr-233 and that this post-translational modification limits Beclin1 association with Atg14L and reduces Beclin1-dependent autophagosome formation. Remarkably, although ectopic expression of wild-type Beclin1 promoted cardiomyocyte atrophy, expression of a Y233E phosphomimetic variant of Beclin1 failed to affect cardiomyocyte size. Moreover, genetic depletion of Beclin1 attenuated PE-mediated/FAK-dependent initiation of myocyte hypertrophy in vivo. Collectively, these findings identify FAK as a novel negative regulator of Beclin1-mediated autophagy and indicate that this pathway can facilitate the promotion of compensatory hypertrophic growth. This novel mechanism to limit Beclin1 activity has important implications for treating a variety of pathologies associated with altered autophagic flux. PMID:27994061

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-12-15

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

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. Dealcoholated red wine induces autophagic and apoptotic cell death in an osteosarcoma cell line.

    Science.gov (United States)

    Tedesco, I; Russo, M; Bilotto, S; Spagnuolo, C; Scognamiglio, A; Palumbo, R; Nappo, A; Iacomino, G; Moio, L; Russo, G L

    2013-10-01

    Until recently, the supposed preventive effects of red wine against cardiovascular diseases, the so-called "French Paradox", has been associated to its antioxidant properties. The interest in the anticancer capacity of polyphenols present in red wine strongly increased consequently to the enormous number of studies on resveratrol. In this study, using lyophilized red wine, we present evidence that its anticancer effect in a cellular model is mediated by apoptotic and autophagic cell death. Using a human osteosarcoma cell line, U2Os, we found that the lyophilized red wine was cytotoxic in a dose-dependent manner with a maximum effect in the range of 100-200 μg/ml equivalents of gallic acid. A mixed phenotype of types I/II cell death was evidenced by means of specific assays following treatment of U2Os with lyophilized red wine, e.g., autophagy and apoptosis. We found that cell death induced by lyophilized red wine proceeded through a mechanism independent from its anti-oxidant activity and involving the inhibition of PI3K/Akt kinase signaling. Considering the relative low concentration of each single bioactive compound in lyophilized red wine, our study suggests the activation of synergistic mechanism able to inhibit growth in malignant cells.

  17. The Temporal Pattern, Flux, and Function of Autophagy in Spinal Cord Injury

    Science.gov (United States)

    Zhou, Kailiang; Sansur, Charles A.; Xu, Huazi; Jia, Xiaofeng

    2017-01-01

    Previous studies have indicated that autophagy plays a critical role in spinal cord injury (SCI), including traumatic spinal cord injury (TSCI) and ischemia-reperfusion spinal cord injury (IRSCI). However, while the understanding of mechanisms underlying autophagy in SCI has progressed, there remain several controversial points: (1) temporal pattern results of autophagic activation after SCI are not consistent across studies; (2) effect of accumulation of autophagosomes due to the blockade or enhancement of autophagic flux is uncertain; (3) overall effect of enhanced autophagy remains undefined, with both beneficial and detrimental outcomes reported in SCI literature. In this review, the temporal pattern of autophagic activation, autophagic flux, autophagic cell death, relationship between autophagy and apoptosis, and pharmacological intervention of autophagy in TSCI (contusion injury, compression injury and hemisection injury) and IRSCI are discussed. Types of SCI and severity appear to contribute to differences in outcomes regarding temporal pattern, flux, and function of autophagy. With future development of specific strategies on autophagy intervention, autophagy may play an important role in improving functional recovery in patients with SCI. PMID:28230791

  18. Bortezomib induces autophagic death in proliferating human endothelial cells

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

    2010-04-01

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

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

    Science.gov (United States)

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

    2014-10-01

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

  20. Phospholipase Cgamma2 is critical for Dectin-1-mediated Ca2+ flux and cytokine production in dendritic cells.

    Science.gov (United States)

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

    2009-03-13

    Dectin-1 is a C-type lectin that recognizes beta-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-kappaB 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 attenuated by a blocking anti-Dectin-1 antibody or by pre-treatment of cells with the phospholipase C (PLC) gamma-inhibitor U73122, suggesting that Dectin-1 signals via a PLCgamma pathway to induce Ca2+ flux in DCs. Interestingly, treatment of DCs with particulate curdlan, which specifically engages Dectin-1, results in the phosphorylation of both PLCgamma1 and PLCgamma2. However, we show that PLCgamma2 is the critical enzyme for Dectin-1 signaling in DCs. PLCgamma2-deficient DCs have drastic impairment of Ca2+ signaling and are defective in their secretion of interleukin 2 (IL-2), IL-6, IL-10, IL-12, IL-23, and tumor necrosis factor alpha. PLCgamma2-deficient DCs also exhibit impaired activation of ERK and JNK MAPKs and AP-1 and NFAT transcription factors in response to Dectin-1 stimulation. In addition, PLCgamma2-deficient DCs are also impaired in their activation of NF-kappaB upon Dectin-1 engagement due to defective assembly of the Card9-Bcl10-Malt1 complex and impaired IKKalpha/beta activation and IkappaBalpha degradation. Thus, our data indicate that pattern recognition receptors such as Dectin-1 could elicit Ca2+ signaling and that PLCgamma2 is a critical player in the Dectin-1 signal transduction pathway.

  1. Rapid screening of potential autophagic inductor agents using mammalian cell lines.

    Science.gov (United States)

    Martins, Waleska K; Severino, Divinomar; Souza, Cleidiane; Stolf, Beatriz S; Baptista, Maurício S

    2013-06-01

    Recent progress in understanding the molecular basis of autophagy has demonstrated its importance in several areas of human health. Affordable screening techniques with higher sensitivity and specificity to identify autophagy are, however, needed to move the field forward. In fact, only laborious and/or expensive methodologies such as electron microscopy, dye-staining of autophagic vesicles, and LC3-II immunoblotting or immunoassaying are available for autophagy identification. Aiming to fulfill this technical gap, we describe here the association of three widely used assays to determine cell viability - Crystal Violet staining (CVS), 3-[4, 5-dimethylthiaolyl]-2, 5-diphenyl-tetrazolium bromide (MTT) reduction, and neutral red uptake (NRU) - to predict autophagic cell death in vitro. The conceptual framework of the method is the superior uptake of NR in cells engaging in autophagy. NRU was then weighted by the average of MTT reduction and CVS allowing the calculation of autophagic arbitrary units (AAU), a numeric variable that correlated specifically with the autophagic cell death. The proposed strategy is very useful for drug discovery, allowing the investigation of potential autophagic inductor agents through a rapid screening using mammalian cell lines B16-F10, HaCaT, HeLa, MES-SA, and MES-SA/Dx5 in a unique single microplate.

  2. Autophagy prevents autophagic cell death in Tetrahymena in response to oxidative stress.

    Science.gov (United States)

    Zhang, Si-Wei; Feng, Jiang-Nan; Cao, Yi; Meng, Li-Ping; Wang, Shu-Lin

    2015-05-18

    Autophagy is a major cellular pathway used to degrade long-lived proteins or organelles that may be damaged due to increased reactive oxygen species (ROS) generated by cellular stress. Autophagy typically enhances cell survival, but it may also act to promote cell death under certain conditions. The mechanism underlying this paradox, however, remains unclear. We showed that Tetrahymena cells exerted increased membrane-bound vacuoles characteristic of autophagy followed by autophagic cell death (referred to as cell death with autophagy) after exposure to hydrogen peroxide. Inhibition of autophagy by chloroquine or 3-methyladenine significantly augmented autophagic cell death induced by hydrogen peroxide. Blockage of the mitochondrial electron transport chain or starvation triggered activation of autophagy followed by cell death by inducing the production of ROS due to the loss of mitochondrial membrane potential. This indicated a regulatory role of mitochondrial ROS in programming autophagy and autophagic cell death in Tetrahymena. Importantly, suppression of autophagy enhanced autophagic cell death in Tetrahymena in response to elevated ROS production from starvation, and this was reversed by antioxidants. Therefore, our results suggest that autophagy was activated upon oxidative stress to prevent the initiation of autophagic cell death in Tetrahymena until the accumulation of ROS passed the point of no return, leading to delayed cell death in Tetrahymena.

  3. 6-Shogaol Inhibits Breast Cancer Cells and Stem Cell-Like Spheroids by Modulation of Notch Signaling Pathway and Induction of Autophagic Cell Death.

    Directory of Open Access Journals (Sweden)

    Anasuya Ray

    Full Text Available Cancer stem cells (CSCs pose a serious obstacle to cancer therapy as they can be responsible for poor prognosis and tumour relapse. In this study, we have investigated inhibitory activity of the ginger-derived compound 6-shogaol against breast cancer cells both in monolayer and in cancer-stem cell-like spheroid culture. The spheroids were generated from adherent breast cancer cells. 6-shogaol was effective in killing both breast cancer monolayer cells and spheroids at doses that were not toxic to noncancerous cells. The percentages of CD44+CD24-/low cells and the secondary sphere content were reduced drastically upon treatment with 6-shogaol confirming its action on CSCs. Treatment with 6-shogaol caused cytoplasmic vacuole formation and cleavage of microtubule associated protein Light Chain3 (LC3 in both monolayer and spheroid culture indicating that it induced autophagy. Kinetic analysis of the LC3 expression and a combination treatment with chloroquine revealed that the autophagic flux instigated cell death in 6-shogaol treated breast cancer cells in contrast to the autophagy inhibitor chloroquine. Furthermore, 6-shogaol-induced cell death got suppressed in the presence of chloroquine and a very low level of apoptosis was exhibited even after prolonged treatment of the compound, suggesting that autophagy is the major mode of cell death induced by 6-shogaol in breast cancer cells. 6-shogaol reduced the expression levels of Cleaved Notch1 and its target proteins Hes1 and Cyclin D1 in spheroids, and the reduction was further pronounced in the presence of a γ-secretase inhibitor. Secondary sphere formation in the presence of the inhibitor was also further reduced by 6-shogaol. Together, these results indicate that the inhibitory action of 6-shogaol on spheroid growth and sustainability is conferred through γ-secretase mediated down-regulation of Notch signaling. The efficacy of 6-shogaol in monolayer and cancer stem cell-like spheroids raise

  4. [EFfect of quinazolone-alkyl-carboxylic acid derivatives on the transmembrane Ca2+ ion flux mediated by AMPA receptors].

    Science.gov (United States)

    Szárics, Eva; LaszTóczi, Bálint; Nyikos, Lajos; Barabás, Péter; Kovács, Ilona; Skuban, Nina; Nagy, Péter I; Kökösi, József; Takácsné, Novák Krisztina; Kardos, Julianna

    2002-01-01

    The excitatory neurotransmitter, Glu, plays a crucial role in many sensory and motor functions as well as in brain development, learning and memory and it is also involved in the pathogenesis of a number of neurological disorders, including epilepsy, Alzheimer's and Parkinson's diseases. Therefore, the study of Glu receptors (GluRs) is of therapeutical importance. We showed here by fluorescence monitoring of transmembrane Ca2+ ion fluxes in response to (S)-alpha-amino-3-hidroxi-5-metil-4-izoxazol propionic acid ((S)-AMPA) on the time scale of 0.00004-10 s that Ca2+ ion influx proceeds through faster and slower desensitizing receptors. Pharmacological isolation of the slower and faster desensitizing AMPA receptor was possible by fluorescence monitoring of Ca2+ ion translocation in response to (S)-AMPA in the presence and absence of various 2-methyl-4-oxo-3H-quinazoline-3-alkyl-carboxilic acid derivatives (Qxs): the acetic acid Q1 inhibits the slower desensitizing receptor response specifically, while the acetyl-piperidine Q5 is a more potent inhibitor of the faster desensitizing receptor response. In addition, spontaneous interictal activity, as induced by high [K+] conditions in hippocampal slices, was reduced significantly by Q5, suggesting a possible anticonvulsant property of Q5. Substitutions of Qxs into the GluR2 S1S2 binding core were consistent with their effect by causing variable degree of S1S2 bridging interaction as one of the main determinants of AMPA receptor agonist activity. The exploitation of differences between similar receptors will be important in the development and use of drugs with high pharmacological specificity.

  5. Acute NMDA toxicity in cultured rat cerebellar granule neurons is accompanied by autophagy induction and late onset autophagic cell death phenotype

    Directory of Open Access Journals (Sweden)

    Kobeissy Firas H

    2010-02-01

    Full Text Available Abstract Background Autophagy, an intracellular response to stress, is characterized by double membrane cytosolic vesicles called autophagosomes. Prolonged autophagy is known to result in autophagic (Type II cell death. This study examined the potential role of an autophagic response in cultured cerebellar granule neurons challenged with excitotoxin N-methyl-D-aspartate (NMDA. Results NMDA exposure induced light chain-3 (LC-3-immunopositive and monodansylcadaverine (MDC fluorescent dye-labeled autophagosome formation in both cell bodies and neurites as early as 3 hours post-treatment. Elevated levels of Beclin-1 and the autophagosome-targeting LC3-II were also observed following NMDA exposure. Prolonged exposure of the cultures to NMDA (8-24 h generated MDC-, LC3-positive autophagosomal bodies, concomitant with the neurodegenerative phase of NMDA challenge. Lysosomal inhibition studies also suggest that NMDA-treatment diverted the autophagosome-associated LC3-II from the normal lysosomal degradation pathway. Autophagy inhibitor 3-methyladenine significantly reduced NMDA-induced LC3-II/LC3-I ratio increase, accumulation of autophagosomes, and suppressed NMDA-mediated neuronal death. ATG7 siRNA studies also showed neuroprotective effects following NMDA treatment. Conclusions Collectively, this study shows that autophagy machinery is robustly induced in cultured neurons subjected to prolonged exposure to excitotoxin, while autophagosome clearance by lysosomal pathway might be impaired. Our data further show that prolonged autophagy contributes to cell death in NMDA-mediated excitotoxicity.

  6. Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins.

    Science.gov (United States)

    Matsumoto, Gen; Wada, Koji; Okuno, Misako; Kurosawa, Masaru; Nukina, Nobuyuki

    2011-10-21

    Selective macroautophagy (autophagy) of ubiquitinated protein is implicated as a compensatory mechanism of the ubiquitin-proteasome system. p62/SQSTM1 is a key molecule managing autophagic clearance of polyubiquitinated proteins. However, little is known about mechanisms controlling autophagic degradation of polyubiquitinated proteins. Here, we show that the specific phosphorylation of p62 at serine 403 (S403) in its ubiquitin-associated (UBA) domain increases the affinity between UBA and polyubiquitin chain, resulting in efficiently targeting polyubiquitinated proteins in "sequestosomes" and stabilizing sequestosome structure as a cargo of ubiquitinated proteins for autophagosome entry. Casein kinase 2 (CK2) phosphorylates S403 of p62 directly. Furthermore, CK2 overexpression or phosphatase inhibition reduces the formation of inclusion bodies of the polyglutamine-expanded huntingtin exon1 fragment in a p62-dependent manner. We propose that phosphorylation of p62 at S403 regulates autophagic clearance of ubiquitinated proteins and protein aggregates that are poorly degraded by proteasomes.

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

    Directory of Open Access Journals (Sweden)

    Derong Cui

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

  9. Xenoestrogens at picomolar to nanomolar concentrations trigger membrane estrogen receptor-alpha-mediated Ca2+ fluxes and prolactin release in GH3/B6 pituitary tumor cells.

    Science.gov (United States)

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

    2005-04-01

    Xenoestrogens (XEs) are widespread in our environment and are known to have deleterious effects in animal (and perhaps human) populations. Acting as inappropriate estrogens, XEs are thought to interfere with endogenous estrogens such as estradiol (E2) to disrupt normal estrogenic signaling. We investigated the effects of E2 versus several XEs representing organochlorine pesticides (dieldrin, endosulfan, o',p'-dichlorodiphenylethylene), plastics manufacturing by-products/detergents (nonylphenol, bisphenol A), a phytoestrogen (coumestrol), and a synthetic estrogen (diethylstilbestrol) on the pituitary tumor cell subline GH3/B6/F10, previously selected for expression of high levels of membrane estrogen receptor-alpha. Picomolar to nanomolar concentrations of both E2 and XEs caused intracellular Ca2+ changes within 30 sec of administration. Each XE produced a unique temporal pattern of Ca2+ elevation. Removing Ca2+ from the extracellular solution abolished both spontaneous and XE-induced intracellular Ca2+ changes, as did 10 microM nifedipine. This suggests that XEs mediate their actions via voltage-dependent L-type Ca2+ channels in the plasma membrane. None of the Ca2+ fluxes came from intracellular Ca2+ stores. E2 and each XE also caused unique time- and concentration-dependent patterns of prolactin (PRL) secretion that were largely complete within 3 min of administration. PRL secretion was also blocked by nifedipine, demonstrating a correlation between Ca2+ influx and PRL secretion. These data indicate that at very low concentrations, XEs mediate membrane-initiated intracellular CCa2+ increases resulting in PRL secretion via a mechanism similar to that for E2, but with distinct patterns and potencies that could explain their abilities to disrupt endocrine functions.

  10. A new method to measure autophagy flux in the nervous system.

    Science.gov (United States)

    Matus, Soledad; Valenzuela, Vicente; Hetz, Claudio

    2014-04-01

    A current need in the neuroscience field is a simple method to monitor autophagic activity in vivo in neurons. Until very recently, most reports have been based on correlative and static determinations of the expression levels of autophagy markers in the brain, generating conflicting interpretations. Autophagy is a fundamental process mediating the degradation of diverse cellular components, including organelles and protein aggregates at basal levels, whereas alterations in the process (i.e., autophagy impairment) operate as a pathological mechanism driving neurodegeneration in most prevalent diseases. We have recently described a new simple method to deliver and express an autophagy flux reporter through the peripheral and central nervous system of mice by the intracerebroventricular delivery of adeno-associated viruses (AAV) into newborn mice. We obtained a wide expression of a monomeric tandem mCherry-GFP-LC3 construct in neurons through the nervous system and demonstrated efficient and accurate measurements of LC3 flux after pharmacological stimulation of the pathway or in disease settings of axonal damage. Here we discuss the possible applications of this new method to assess autophagy activity in neurons in vivo.

  11. Autophagic vesicles on mature human reticulocytes explain phosphatidylserine-positive red cells in sickle cell disease.

    Science.gov (United States)

    Mankelow, Tosti J; Griffiths, Rebecca E; Trompeter, Sara; Flatt, Joanna F; Cogan, Nicola M; Massey, Edwin J; Anstee, David J

    2015-10-08

    During maturation to an erythrocyte, a reticulocyte must eliminate any residual organelles and reduce its surface area and volume. Here we show this involves a novel process whereby large, intact, inside-out phosphatidylserine (PS)-exposed autophagic vesicles are extruded. Cell surface PS is a well-characterized apoptotic signal initiating phagocytosis. In peripheral blood from patients after splenectomy or in patients with sickle cell disease (SCD), the number of circulating red cells exposing PS on their surface is elevated. We show that in these patients PS is present on the cell surface of red cells in large (∼1.4 µm) discrete areas corresponding to autophagic vesicles. The autophagic vesicles found on reticulocytes are identical to those observed on red cells from splenectomized individuals and patients with SCD. Our data suggest the increased thrombotic risk associated with splenectomy, and patients with hemoglobinopathies is a possible consequence of increased levels of circulating mature reticulocytes expressing inside-out PS-exposed autophagic vesicles because of asplenia.

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

    DEFF Research Database (Denmark)

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

    2012-01-01

    in subsurface N2O and O2 concentrations, water level (WL), light intensity as well as mineral-N availability. Weekly concentration profiles showed that seasonal variations in N2O concentrations were directly linked to the position of the WL and O2 availability at the capillary fringe above the WL. N2O flux....... Complex interactions between seasonal changes in O2 and mineral-N availability following near-surface WL fluctuations in combination with plant-mediated gas transport by P. arundinacea controlled the subsurface N2O concentrations and gas transport mechanisms responsible for N2O fluxes across the soil...

  13. 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.

  14. Lysine suppresses protein degradation through autophagic-lysosomal system in C2C12 myotubes.

    Science.gov (United States)

    Sato, Tomonori; Ito, Yoshiaki; Nedachi, Taku; Nagasawa, Takashi

    2014-06-01

    Muscle mass is determined between protein synthesis and protein degradation. Reduction of muscle mass leads to bedridden condition and attenuation of resistance to diseases. Moreover, bedridden condition leads to additional muscle loss due to disuse muscle atrophy. In our previous study (Sato et al. 2013), we showed that administered lysine (Lys), one of essential amino acid, suppressed protein degradation in skeletal muscle. In this study, we investigated that the mechanism of the suppressive effects of Lys on skeletal muscle proteolysis in C2C12 cell line. C2C12 myotubes were incubated in the serum-free medium containing 10 mM Lys or 20 mM Lys, and myofibrillar protein degradation was determined by the rates of 3-methylhistidine (MeHis) release from the cells. The mammalian target of rapamycin (mTOR) activity from the phosphorylation levels of p70-ribosormal protein S6 kinase 1 and eIF4E-binding protein 1 and the autophagic-lysosomal system activity from the ratio of LC3-II/I in C2C12 myotubes stimulated by 10 mM Lys for 0-3 h were measured. The rates of MeHis release were markedly reduced by addition of Lys. The autophagic-lysosomal system activity was inhibited upon 30 min of Lys supplementation. The activity of mTOR was significantly increased upon 30 min of Lys supplementation. The suppressive effect of Lys on the proteolysis by the autophagic-lysosomal system was maintained partially when mTOR activity was inhibited by 100 nM rapamycin, suggesting that some regulator other than mTOR signaling, for example, Akt, might also suppress the autophagic-lysosomal system. From these results, we suggested that Lys suppressed the activity of the autophagic-lysosomal system in part through activation of mTOR and reduced myofibrillar protein degradation in C2C12 myotubes.

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

    Science.gov (United States)

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

    2016-10-01

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

  16. p53-mediated autophagic regulation: A prospective strategy for cancer therapy.

    Science.gov (United States)

    Tang, Juanjuan; Di, Jiehui; Cao, Huan; Bai, Jin; Zheng, Junnian

    2015-07-28

    Autophagy is a major catabolic process that degrades and recycles cytosolic components in autophagosomes, which fuse with lysosomes. This process enables starving cells to sustain their energy requirements and metabolic states, thus facilitating their survival, especially in cancer pathogenesis. The regulation of autophagy is quite intricate. It involves a series of signaling cascades including p53, known as the best-characterized tumor suppressor protein. Recent reports have indicated that p53 plays dual roles in regulating autophagy depending on its subcellular localization. Nuclear p53 facilitates autophagy by transactivating its target genes, whereas cytoplasmic p53 mainly inhibits autophagy through extranuclear, transcription-independent mechanisms. The relationship between autophagy and neoplasia is complicated. It may be intrinsically associated with the functional status of p53, but this is not clearly elucidated. This review focuses on the role of p53 as a master regulator of autophagy. We conclude that the contextual role of autophagy in cancer, which could be switched by p53 status, is expected to be developed into a new anticancer therapeutic approach.

  17. Protective effect of N-acetylcysteine against nicardipine hydrochloride-induced autophagic cell death of human vascular endothelial cells.

    Science.gov (United States)

    Ochi, Masanori; Tanaka, Yoshiyuki; Toyoda, Hiromu

    2015-01-01

    Nicardipine hydrochloride (NIC) injection has been widely used for emergency treatment of abnormally high blood pressure. However, NIC injection often causes severe peripheral vascular injury. The purpose of the present study was to reduce the NIC-induced cell injury in human vascular endothelial cells by use of clinical agents. The mechanism of NIC-induced cell injury was evaluated by time-lapse microscopic imaging, autophagosome staining with monodansylcadaverine, immunostaining of light chain 3 isoform B (LC-3B) and assessment of cell viability after exposure to NIC with or without an inhibitor of autophagosome formation (3-methyladenine, 3-MA). Results from autophagosome labeling and immunostaining of LC-3B revealed an increase of autophagosomes and LC-3B in NIC-treated cells. NIC-mediated reduction of cell viability was inhibited by 3-methyladenine. Moreover, we found that N-acetylcysteine (NAC) reduced NIC-induced cell injury in human vascular endothelial cells. These findings suggest that NIC causes severe peripheral venous irritation via induction of autophagic cell death and that inhibition of autophagy with NAC could contribute to the reduction of NIC-induced vascular injury.

  18. 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...

  19. 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.

  20. 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.

  1. 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

  2. Autophagic deficiency is related to steroidogenic decline in aged rat Leydig cells

    Institute of Scientific and Technical Information of China (English)

    Wei-Ren Li; Zhe-Zhu Gao; Zhong-Cheng Xin; Liang Chen; Zhi-Jie Chang; Hua Xin; Tao Liu; Yan-Quan Zhang; Guang-Yong Li; Feng Zhou; Yan-Qing Gong

    2011-01-01

    Late-onset hypogonadism (LOH) is closely related to secondary androgen deficiency in aged males,but the mechanism remains unclear.In this study,we found that reduced testosterone production in aged rat Leydig cells is associated with decreased autophagic activity.Primary rat Leydig cells and the TM3 mouse Leydig cell line were used to study the effect of autophagic deficiency on Leydig cell testosterone production.In Leydig cells from young and aged rats,treatment with wortmannin,an autophagy inhibitor,inhibited luteinising hormone (LH)-stimulated steroidogenic acute regulatory (StAR) protein expression and decreased testosterone production.In contrast,treatment with rapamycin,an autophagy activator,enhanced LH-stimulated steroidogenesis in Leydig cells from aged,but not young,rats.Intracellular reactive oxygen species (ROS) levels were increased in both young and aged Leydig cells treated with wortmannin but decreased only in aged Leydig cells treated with rapamycin.Furthermore,an increased level of ROS,induced by H2O2,resulted in LH-stimulated steroidogenic inhibition.Finally,knockdown of Beclin 1 decreased LH-stimulated StAR expression and testosterone production in TM3 mouse Leydig cells,which were associated with increased intracellular ROS level.These results suggested that autophagic deficiency is related to steroidogenic decline in aged rat Leydig cells,which might be influenced by intracellular ROS levels.

  3. 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.

  4. HTLV-1 Tax deregulates autophagy by recruiting autophagic molecules into lipid raft microdomains.

    Science.gov (United States)

    Ren, T; Takahashi, Y; Liu, X; Loughran, T P; Sun, S-C; Wang, H-G; Cheng, H

    2015-01-15

    The retroviral oncoprotein Tax from human T-cell leukemia virus type 1 (HTLV-1), an etiological factor that causes adult T-cell leukemia and lymphoma, has a crucial role in initiating T-lymphocyte transformation by inducing oncogenic signaling activation. We here report that Tax is a determining factor for dysregulation of autophagy in HTLV-1-transformed T cells and Tax-immortalized CD4 memory T cells. Tax facilitated autophagic process by activating inhibitor of κB (IκB) kinase (IKK) complex, which subsequently recruited an autophagy molecular complex containing Beclin1 and Bif-1 to the lipid raft microdomains. Tax engaged a crosstalk between IKK complex and autophagic molecule complex by directly interacting with both complexes, promoting assembly of LC3+ autophagosomes. Moreover, expression of lipid raft-targeted Bif-1 or Beclin1 was sufficient to induce formation of LC3+ autophagosomes, suggesting that Tax recruitment of autophagic molecules to lipid rafts is a dominant strategy to deregulate autophagy in the context of HTLV-1 transformation of T cells. Furthermore, depletion of autophagy molecules such as Beclin1 and PI3 kinase class III resulted in impaired growth of HTLV-1-transformed T cells, indicating a critical role of Tax-deregulated autophagy in promoting survival and transformation of virally infected T cells.

  5. 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.

  6. Interactions between autophagic and endo-lysosomal markers in endothelial cells.

    Science.gov (United States)

    Oeste, Clara L; Seco, Esther; Patton, Wayne F; Boya, Patricia; Pérez-Sala, Dolores

    2013-05-01

    Autophagic and endo-lysosomal degradative pathways are essential for cell homeostasis. Availability of reliable tools to interrogate these pathways is critical to unveil their involvement in physiology and pathophysiology. Although several probes have been recently developed to monitor autophagic or lysosomal compartments, their specificity has not been validated through co-localization studies with well-known markers. Here, we evaluate the selectivity and interactions between one lysosomal (Lyso-ID) and one autophagosomal (Cyto-ID) probe under conditions modulating autophagy and/or endo-lysosomal function in live cells. The probe for acidic compartments Lyso-ID was fully localized inside vesicles positive for markers of late endosome-lysosomes, including Lamp1-GFP and GFP-CINCCKVL. Induction of autophagy by amino acid deprivation in bovine aortic endothelial cells caused an early and potent increase in the fluorescence of the proposed autophagy dye Cyto-ID. Cyto-ID-positive compartments extensively co-localized with the autophagosomal fluorescent reporter RFP-LC3, although the time and/or threshold for organelle detection was different for each probe. Interestingly, use of Cyto-ID in combination with Lysotracker Red or Lyso-ID allowed the observation of structures labeled with either one or both probes, the extent of co-localization increasing upon treatment with protease inhibitors. Inhibition of the endo-lysosomal pathway with chloroquine or U18666A resulted in the formation of large Cyto-ID and Lyso-ID-positive compartments. These results constitute the first assessment of the selectivity of Cyto-ID and Lyso-ID as probes for the autophagic and lysosomal pathways, respectively. Our observations show that these probes can be used in combination with protein-based markers for monitoring the interactions of both pathways in live cells.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. Staphylococcal lipoteichoic acid promotes osteogenic differentiation of mouse mesenchymal stem cells by increasing autophagic activity.

    Science.gov (United States)

    Liu, Xin; Wang, Yuan; Cao, Zhen; Dou, Ce; Bai, Yun; Liu, Chuan; Dong, Shiwu; Fei, Jun

    2017-02-16

    This study sought to explore the effect of staphylococcal lipoteichoic acid (LTA) on autophagy in mouse mesenchymal stem cells (MSCs), and then influence osteogenesis through the change of autophagy. C3H10T1/2 cells were induced by osteogenic medium with the treatment of LTA at different concentrations (1, 5, 10 μg/mL); 3-methyladenine (3-MA) were used as the autophagy inhibitor, and rapamycin (rapamycin, Rap) were used to activate autophagy; the effects on osteogenesis were detected by alkaline phosphatase staining, alizarin red staining, real-time quantitative PCR, and western blotting; autophagic activity was investigated by the expression of LC3-Ⅱand p62 proteins. Compared with control group, the expression of osteogenesis markers was significantly up-regulated with the LTA treatment on the mRNA and protein level; the positive rate of alkaline phosphatase was enhanced in the LTA groups; and the formation of calcium nodules was increased simultaneously. The expression of LC3-Ⅱ protein was increased in LTA groups, while the expression of p62 protein was decreased. Inhibition of autophagy significantly reduced the effect of LTA on osteogenesis of MSCs; the promotion of LTA on osteogenic differentiation was further enhanced when adding rapamycin to activate autophagic activity. It provides new insight of prevention and treatment for bone infection.

  12. Features of autophagic cell death in Plasmodium liver-stage parasites.

    Science.gov (United States)

    Eickel, Nina; Kaiser, Gesine; Prado, Monica; Burda, Paul-Christian; Roelli, Matthias; Stanway, Rebecca R; Heussler, Volker T

    2013-04-01

    Analyzing molecular determinants of Plasmodium parasite cell death is a promising approach for exploring new avenues in the fight against malaria. Three major forms of cell death (apoptosis, necrosis and autophagic cell death) have been described in multicellular organisms but which cell death processes exist in protozoa is still a matter of debate. Here we suggest that all three types of cell death occur in Plasmodium liver-stage parasites. Whereas typical molecular markers for apoptosis and necrosis have not been found in the genome of Plasmodium parasites, we identified genes coding for putative autophagy-marker proteins and thus concentrated on autophagic cell death. We characterized the Plasmodium berghei homolog of the prominent autophagy marker protein Atg8/LC3 and found that it localized to the apicoplast. A relocalization of PbAtg8 to autophagosome-like vesicles or vacuoles that appear in dying parasites was not, however, observed. This strongly suggests that the function of this protein in liver-stage parasites is restricted to apicoplast biology.

  13. 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...

  14. 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.

  15. 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.

  16. Cargo binding to Atg19 unmasks additional Atg8 binding sites to mediate membrane-cargo apposition during selective autophagy.

    Science.gov (United States)

    Sawa-Makarska, Justyna; Abert, Christine; Romanov, Julia; Zens, Bettina; Ibiricu, Iosune; Martens, Sascha

    2014-05-01

    Autophagy protects cells from harmful substances such as protein aggregates, damaged mitochondria and intracellular pathogens, and has been implicated in a variety of diseases. Selectivity of autophagic processes is mediated by cargo receptors that link cargo to Atg8 family proteins on the developing autophagosomal membrane. To avoid collateral degradation during constitutive autophagic pathways, the autophagic machinery must not only select cargo but also exclude non-cargo material. Here we show that cargo directly activates the cargo receptor Atg19 by exposing multiple Atg8 binding sites. Furthermore, Atg19 mediates tight apposition of the cargo and Atg8-coated membranes in a fully reconstituted system. These properties are essential for the function of Atg19 during selective autophagy in vivo. Our results suggest that cargo receptors contribute to tight membrane bending of the isolation membrane around the cargo.

  17. Oxidative stress-mediated NFκB phosphorylation upregulates p62/SQSTM1 and promotes retinal pigmented epithelial cell survival through increased autophagy

    Science.gov (United States)

    Qi, Xiaoping; Beli, Eleni; Rao, Haripriya V.; Ding, Jindong; Ip, Colin S.; Gu, Hongmei; Akin, Debra; Dunn, William A.; Bowes Rickman, Catherine; Lewin, Alfred S.; Grant, Maria B.; Boulton, Michael E.

    2017-01-01

    p62 is a scaffolding adaptor implicated in the clearance of protein aggregates by autophagy. Reactive oxygen species (ROS) can either stimulate or inhibit NFκB-mediated gene expression influencing cellular fate. We studied the effect of hydrogen peroxide (H2O2)-mediated oxidative stress and NFκB signaling on p62 expression in the retinal pigment epithelium (RPE) and investigated its role in regulation of autophagy and RPE survival against oxidative damage. Cultured human RPE cell line ARPE-19 and primary human adult and fetal RPE cells were exposed to H2O2-induced oxidative stress. The human apolipoprotein E4 targeted-replacement (APOE4) mouse model of AMD was used to study expression of p62 and other autophagy proteins in the retina. p62, NFκB p65 (total, phosphorylated, nuclear and cytoplasmic) and ATG10 expression was assessed by mRNA and protein analyses. Cellular ROS and mitochondrial superoxide were measured by CM-H2DCFDA and MitoSOX staining respectively. Mitochondrial viability was determined using MTT activity. qPCR-array system was used to investigate autophagic genes affected by p62. Nuclear and cytoplasmic levels of NFκB p65 were evaluated after cellular fractionation by Western blotting. We report that p62 is up-regulated in RPE cells under H2O2-induced oxidative stress and promotes autophagic activity. Depletion of endogenous p62 reduces autophagy by downregulation of ATG10 rendering RPE more susceptible to oxidative damage. NFκB p65 phosphorylation at Ser-536 was found to be critical for p62 upregulation in response to oxidative stress. Proteasome inhibition by H2O2 causes p62-NFκB signaling as antioxidant pre-treatment reversed p62 expression and p65 phosphorylation when RPE was challenged by H2O2 but not when by Lactacystin. p62 protein but not RNA levels are elevated in APOE4-HFC AMD mouse model, suggesting reduction of autophagic flux in disease conditions. Our findings suggest that p62 is necessary for RPE cytoprotection under oxidative

  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. The tricyclic antidepressant imipramine induces autophagic cell death in U-87MG glioma cells.

    Science.gov (United States)

    Jeon, Seung-Hyun; Kim, Se Hyun; Kim, Yeni; Kim, Yong Sik; Lim, Yoongho; Lee, Young Han; Shin, Soon Young

    2011-09-23

    In this study, we investigated the antitumor effects of the tricyclic antidepressant 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine (imipramine) on glioma cells. We found that exposure of U-87MG cells to imipramine resulted in the inhibition of PI3K/Akt/mTOR signaling, reduction of clonogenicity, and induction of cell death. Imipramine stimulated the formation of acidic vesicular organelles, the conversion of LC3-I to LC3-II, and the redistribution of LC3 to autophagosomes, suggesting that it stimulates the progression of autophagy. It did not, however, induce apoptosis. We further showed that knockdown of Beclin-1 using siRNA abrogated imipramine-induced cell death. These results suggest that imipramine exerts antitumor effects on PTEN-null U-87MG human glioma cells by inhibiting PI3K/Akt/mTOR signaling and by inducing autophagic cell death.

  20. A Reconnecting Flux Rope Dynamo

    OpenAIRE

    Baggaley, Andrew W.; Barenghi, Carlo F.; Shukurov, Anvar; Subramanian, Kandaswamy

    2009-01-01

    We develop a new model of the fluctuation dynamo in which the magnetic field is confined in thin flux ropes advected by a multi-scale flow modeling turbulence. Magnetic dissipation occurs only via reconnection of the flux ropes. We investigate the kinetic energy release into heat, mediated by the dynamo action, both in our model and by solving the induction equation with the same flow. We find that a flux rope dynamo is an order of magnitude more efficient at converting mechanical energy into...

  1. Protective Effect of Sevoflurane Postconditioning against Cardiac Ischemia/Reperfusion Injury via Ameliorating Mitochondrial Impairment, Oxidative Stress and Rescuing Autophagic Clearance.

    Directory of Open Access Journals (Sweden)

    Peng Yu

    Full Text Available Myocardial infarction leads to heart failure. Autophagy is excessively activated in myocardial ischemia/reperfusion (I/R in rats. The aim of this study is to investigate whether the protection of sevoflurane postconditioning (SPC in myocardial I/R is through restored impaired autophagic flux.Except for the sham control (SHAM group, each rat underwent 30 min occlusion of the left anterior descending coronary (LAD followed by 2 h reperfusion. Cardiac infarction was determined by 2,3,5-triphenyltetrazolium chloride triazole (TTC staining. Cardiac function was examined by hemodynamics and echocardiography. The activation of autophagy was evaluated by autophagosome accumulation, LC3 conversion and p62 degradation. Potential molecular mechanisms were investigated by immunoblotting, real-time PCR and immunofluorescence staining.SPC improved the hemodynamic parameters, cardiac dysfunction, histopathological and ultrastructural damages, and decreased myocardial infarction size after myocardial I/R injury (P < 0.05 vs. I/R group. Compared with the cases in I/R group, myocardial ATP and NAD+ content, mitochondrial function related genes and proteins, and the expressions of SOD2 and HO-1 were increased, while the expressions of ROS and Vimentin were decreased in the SPC group (P < 0.05 vs. I/R group. SPC significantly activated Akt/mTOR signaling, and inhibited the formation of Vps34/Beclin1 complex via increasing expression of Bcl2 protein (P < 0.05 vs. I/R group. SPC suppressed elevated expressions of LC3 II/I ratio, Beclin1, Atg5 and Atg7 in I/R rat, which indicated that SPC inhibited over-activation of autophagy, and promoted autophagosome clearance. Meanwhile, SPC significantly suppressed the decline of Opa1 and increases of Drp1 and Parkin induced by I/R injury (P < 0.05 vs. I/R group. Moreover, SPC maintained the contents of ATP by reducing impaired mitochondria.SPC protects rat hearts against I/R injury via ameliorating mitochondrial impairment

  2. 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

  3. Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria

    Science.gov (United States)

    Cenni, V.; Capanni, C.; Columbaro, M.; Ortolani, M.; D'Apice, M.R.; Novelli, G.; Fini, M.; Marmiroli, S.; Scarano, E.; Maraldi, N.M.; Squarzoni, S.; Prencipe, S.; Lattanzi, G.

    2011-01-01

    Farnesylated prelamin A is a processing intermediate produced in the lamin A maturation pathway. Accumulation of a truncated farnesylated prelamin A form, called progerin, is a hallmark of the severe premature ageing syndrome, Hutchinson-Gilford progeria. Progerin elicits toxic effects in cells, leading to chromatin damage and cellular senescence and ultimately causes skin and endothelial defects, bone resorption, lipodystrophy and accelerated ageing. Knowledge of the mechanism underlying prelamin A turnover is critical for the development of clinically effective protein inhibitors that can avoid accumulation to toxic levels without impairing lamin A/C expression, which is essential for normal biological functions. Little is known about specific molecules that may target farnesylated prelamin A to elicit protein degradation. Here, we report the discovery of rapamycin as a novel inhibitor of progerin, which dramatically and selectively decreases protein levels through a mechanism involving autophagic degradation. Rapamycin treatment of progeria cells lowers progerin, as well as wild-type prelamin A levels, and rescues the chromatin phenotype of cultured fibroblasts, including histone methylation status and BAF and LAP2α distribution patterns. Importantly, rapamycin treatment does not affect lamin C protein levels, but increases the relative expression of the prelamin A endoprotease ZMPSTE24. Thus, rapamycin, an antibiotic belonging to the class of macrolides, previously found to increase longevity in mouse models, can serve as a therapeutic tool, to eliminate progerin, avoid farnesylated prelamin A accumulation, and restore chromatin dynamics in progeroid laminopathies. PMID:22297442

  4. 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.

  5. 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.

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

    Science.gov (United States)

    Espín-Palazón, Raquel; Martínez-López, Alicia; Roca, Francisco J; López-Muñoz, Azucena; Tyrkalska, Sylwia D; Candel, Sergio; García-Moreno, Diana; Falco, Alberto; Meseguer, José; Estepa, Amparo; Mulero, Victoriano

    2016-06-01

    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.

  7. Reserve autophagic capacity in alveolar epithelia provides a replicative niche for influenza A virus.

    Science.gov (United States)

    Hahn, David R; Na, Cheng-Lun; Weaver, Timothy E

    2014-09-01

    Autophagy contributes to cellular homeostasis through metabolite recycling and degradation of cytotoxic protein aggregates and damaged organelles. Although recent studies have established that the requirement for basal autophagy is largely tissue specific, the importance of autophagy for alveolar epithelial cell homeostasis remains an important knowledge gap. In the present study we generated two mouse models, with > 90% or > 50% recombination at the Atg5 locus in the distal respiratory epithelium, to assess the effect of dose-dependent decreases in autophagy on alveolar homeostasis. A 90% decrease in autophagy was well tolerated in young adult mice but resulted in alveolar septal thickening and altered lung mechanics in aged animals, consistent with accumulation of damage over time. By comparison, a 50% decrease in autophagy had no effect on alveolar structure or function throughout the murine life span, indicating that basal autophagy in this compartment exceeds that required for homeostasis. A 50% decrease in autophagy in the bronchoalveolar epithelium significantly attenuated influenza A/H3N2 viral replication, leading to improved lung structure and function and reduced morbidity and mortality after infection. The reserve of autophagic capacity in the alveolar epithelium may provide a niche for replication of influenza A virus.

  8. 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.

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

    Science.gov (United States)

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

    2016-01-21

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

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

    Directory of Open Access Journals (Sweden)

    Raquel Espín-Palazón

    2016-06-01

    Full Text Available 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.

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

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    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.

  12. Autophagic degradation of farnesylated prelamin A as a therapeutic approach to lamin-linked progeria

    Directory of Open Access Journals (Sweden)

    V. Cenni

    2011-10-01

    Full Text Available Farnesylated prelamin A is a processing intermediate produced in the lamin A maturation pathway. Accumulation of a truncated farnesylated prelamin A form, called progerin, is a hallmark of the severe premature ageing syndrome, Hutchinson-Gilford progeria. Progerin elicits toxic effects in cells, leading to chromatin damage and cellular senescence and ultimately causes skin and endothelial defects, bone resorption, lipodystrophy and accelerated ageing. Knowledge of the mechanism underlying prelamin A turnover is critical for the development of clinically effective protein inhibitors that can avoid accumulation to toxic levels without impairing lamin A/C expression, which is essential for normal biological functions. Little is known about specific molecules that may target farnesylated prelamin A to elicit protein degradation. Here, we report the discovery of rapamycin as a novel inhibitor of progerin, which dramatically and selectively decreases protein levels through a mechanism involving autophagic degradation. Rapamycin treatment of progeria cells lowers progerin, as well as wild-type prelamin A levels, and rescues the chromatin phenotype of cultured fibroblasts, including histone methylation status and BAF and LAP2alpha distribution patterns. Importantly, rapamycin treatment does not affect lamin C protein levels, but increases the relative expression of the prelamin A endoprotease ZMPSTE24. Thus, rapamycin, an antibiotic belonging to the class of macrolides, previously found to increase longevity in mouse models, can serve as a therapeutic tool, to eliminate progerin, avoid farnesylated prelamin A accumulation, and restore chromatin dynamics in progeroid laminopathies.

  13. Critical flux determination by flux-stepping

    DEFF Research Database (Denmark)

    Beier, Søren; Jonsson, Gunnar Eigil

    2010-01-01

    In membrane filtration related scientific literature, often step-by-step determined critical fluxes are reported. Using a dynamic microfiltration device, it is shown that critical fluxes determined from two different flux-stepping methods are dependent upon operational parameters such as step...... length, step height, and.flux start level. Filtrating 8 kg/m(3) yeast cell suspensions by a vibrating 0.45 x 10(-6) m pore size microfiltration hollow fiber module, critical fluxes from 5.6 x 10(-6) to 1.2 x 10(-5) m/s have been measured using various step lengths from 300 to 1200 seconds. Thus......, such values are more or less useless in itself as critical flux predictors, and constant flux verification experiments have to be conducted to check if the determined critical fluxes call predict sustainable flux regimes. However, it is shown that using the step-by-step predicted critical fluxes as start...

  14. Apelin-13 impedes foam cell formation by activating Class III PI3K/Beclin-1-mediated autophagic pathway.

    Science.gov (United States)

    Yao, Feng; Lv, Yun-Cheng; Zhang, Min; Xie, Wei; Tan, Yu-Lin; Gong, Duo; Cheng, Hai-Peng; Liu, Dan; Li, Liang; Liu, Xiao-Yan; Zheng, Xi-Long; Tang, Chao-Ke

    2015-10-30

    Apelin-13, an adipokine, promotes cholesterol efflux in macrophages with antiatherosclerotic effect. Autophagy, an evolutionarily ancient response to cellular stress, has been involved in atherosclerosis. Therefore, the purpose of this study was to investigate whether apelin-13 regulates macrophage foam cell cholesterol metabolism through autophagy, and also explore the underlying mechanisms. Here, we revealed that apelin-13 decreased lipid accumulation in THP-1 derived macrophages through markedly enhancing cholesterol efflux. Our study further demonstrated that apelin-13 induced autophagy via activation of Class III phosphoinositide 3-kinase (PI3K) and Beclin-1. Inhibition of Class III PI3K and Beclin-1 suppressed the stimulatory effects of apelin-13 on autophagy activity. The present study concluded that apelin-13 reduces lipid accumulation of foam cells by activating autophagy via Class III PI3K/Beclin-1 pathway. Therefore, our results provide brand new insight about apelin-13 inhibiting foam cell formation and highlight autophagy as a promising therapeutic target in atherosclerosis.

  15. Formation and excretion of autophagic plastids (plastolysomes in Brassica napus embryogenic microspores

    Directory of Open Access Journals (Sweden)

    Veronica eParra-Vega

    2015-02-01

    Full Text Available The change in developmental fate of microspores reprogrammed towards embryogenesis is a complex but fascinating experimental system where microspores undergo dramatic changes derived from the developmental switch. After 40 years of study of the ultrastructural changes undergone by the induced microspores, many questions are still open. In this work, we analyzed the architecture of DNA-containing organelles such as plastids and mitochondria in samples of B. napus isolated microspore cultures covering the different stages before, during and after the developmental switch. Mitochondria presented a conventional oval or sausage-like morphology for all cell types studied, similar to that found in vivo in other cell types from vegetative parts. Similarly, plastids of microspores before induction and of non-induced cells showed conventional architectures. However, approximately 40% of the plastids of embryogenic microspores presented atypical features such as curved profiles, protrusions, and internal compartments filled with cytoplasm. Three-dimensional reconstructions confirmed that these plastids actually engulf cytoplasm regions, isolating them from the rest of the cell. Acid phosphatase activity was found in them, confirming the lytic activity of these organelles. In addition, digested plastid-like structures were found excreted to the apoplast. All these phenomena seemed transient, since microspore-derived embryos showed conventional plastids. Together, these results strongly suggested that under special circumstances, such as those of the androgenic switch, plastids of embryogenic microspores behave as autophagic plastids (plastolysomes, engulfing cytoplasm for digestion, and then are excreted out of the cytoplasm as part of a cleaning program necessary for microspores to become embryos.

  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.

    Science.gov (United States)

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

    2016-04-01

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

  18. 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.

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

    Science.gov (United States)

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

    2016-01-01

    Genetic leukoencephalopathies (gLEs) are a group of heterogeneous disorders with white matter abnormalities affecting the central nervous system (CNS). The causative mutation in ~50% of gLEs is unknown. Using whole exome sequencing (WES), we identified homozygosity for a missense variant, VPS11: c.2536T>G (p.C846G), as the genetic cause of a leukoencephalopathy syndrome in five individuals from three unrelated Ashkenazi Jewish (AJ) families. All five patients exhibited highly concordant disease progression characterized by infantile onset leukoencephalopathy with brain white matter abnormalities, severe motor impairment, cortical blindness, intellectual disability, and seizures. The carrier frequency of the VPS11: c.2536T>G variant is 1:250 in the AJ population (n = 2,026). VPS11 protein is a core component of HOPS (homotypic fusion and protein sorting) and CORVET (class C core vacuole/endosome tethering) protein complexes involved in membrane trafficking and fusion of the lysosomes and endosomes. The cysteine 846 resides in an evolutionarily conserved cysteine-rich RING-H2 domain in carboxyl terminal regions of VPS11 proteins. Our data shows that the C846G mutation causes aberrant ubiquitination and accelerated turnover of VPS11 protein as well as compromised VPS11-VPS18 complex assembly, suggesting a loss of function in the mutant protein. Reduced VPS11 expression leads to an impaired autophagic activity in human cells. Importantly, zebrafish harboring a vps11 mutation with truncated RING-H2 domain demonstrated a significant reduction in CNS myelination following extensive neuronal death in the hindbrain and midbrain. Thus, our study reveals a defect in VPS11 as the underlying etiology for an autosomal recessive leukoencephalopathy disorder associated with a dysfunctional autophagy-lysosome trafficking pathway. PMID:27120463

  20. 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.

  1. 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.

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

    Science.gov (United States)

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

    2015-02-01

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

  3. Ceria nanoparticles stabilized by organic surface coatings activate the lysosome-autophagy system and enhance autophagic clearance.

    Science.gov (United States)

    Song, Wensi; Soo Lee, Seung; Savini, Marzia; Popp, Lauren; Colvin, Vicki L; Segatori, Laura

    2014-10-28

    Cerium oxide nanoparticles (nanoceria) are widely used in a variety of industrial applications including UV filters and catalysts. The expanding commercial scale production and use of ceria nanoparticles have inevitably increased the risk of release of nanoceria into the environment as well as the risk of human exposure. The use of nanoceria in biomedical applications is also being currently investigated because of its recently characterized antioxidative properties. In this study, we investigated the impact of ceria nanoparticles on the lysosome-autophagy system, the main catabolic pathway that is activated in mammalian cells upon internalization of exogenous material. We tested a battery of ceria nanoparticles functionalized with different types of biocompatible coatings (N-acetylglucosamine, polyethylene glycol and polyvinylpyrrolidone) expected to have minimal effect on lysosomal integrity and function. We found that ceria nanoparticles promote activation of the transcription factor EB, a master regulator of lysosomal function and autophagy, and induce upregulation of genes of the lysosome-autophagy system. We further show that the array of differently functionalized ceria nanoparticles tested in this study enhance autophagic clearance of proteolipid aggregates that accumulate as a result of inefficient function of the lysosome-autophagy system. This study provides a mechanistic understanding of the interaction of ceria nanoparticles with the lysosome-autophagy system and demonstrates that ceria nanoparticles are activators of autophagy and promote clearance of autophagic cargo. These results provide insights for the use of nanoceria in biomedical applications, including drug delivery. These findings will also inform the design of engineered nanoparticles with safe and precisely controlled impact on the environment and the design of nanotherapeutics for the treatment of diseases with defective autophagic function and accumulation of lysosomal storage material.

  4. 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.

  5. Reconnecting flux-rope dynamo.

    Science.gov (United States)

    Baggaley, Andrew W; Barenghi, Carlo F; Shukurov, Anvar; Subramanian, Kandaswamy

    2009-11-01

    We develop a model of the fluctuation dynamo in which the magnetic field is confined to thin flux ropes advected by a multiscale model of turbulence. Magnetic dissipation occurs only via reconnection of the flux ropes. This model can be viewed as an implementation of the asymptotic limit R_{m}-->infinity for a continuous magnetic field, where magnetic dissipation is strongly localized to small regions of strong-field gradients. We investigate the kinetic-energy release into heat mediated by the dynamo action, both in our model and by solving the induction equation with the same flow. We find that a flux-rope dynamo is an order of magnitude more efficient at converting mechanical energy into heat. The probability density of the magnetic energy release in reconnections has a power-law form with the slope -3 , consistent with the solar corona heating by nanoflares.

  6. A Reconnecting Flux Rope Dynamo

    CERN Document Server

    Baggaley, Andrew W; Shukurov, Anvar; Subramanian, Kandaswamy

    2009-01-01

    We develop a new model of the fluctuation dynamo in which the magnetic field is confined in thin flux ropes advected by a multi-scale flow modeling turbulence. Magnetic dissipation occurs only via reconnection of the flux ropes. We investigate the kinetic energy release into heat, mediated by the dynamo action, both in our model and by solving the induction equation with the same flow. We find that a flux rope dynamo is an order of magnitude more efficient at converting mechanical energy into heat. The probability density of the magnetic energy release in reconnections has a power-law form with the slope -3, consistent with the Solar corona heating by nanoflares.

  7. Reconnecting flux-rope dynamo

    Science.gov (United States)

    Baggaley, Andrew W.; Barenghi, Carlo F.; Shukurov, Anvar; Subramanian, Kandaswamy

    2009-11-01

    We develop a model of the fluctuation dynamo in which the magnetic field is confined to thin flux ropes advected by a multiscale model of turbulence. Magnetic dissipation occurs only via reconnection of the flux ropes. This model can be viewed as an implementation of the asymptotic limit Rm→∞ for a continuous magnetic field, where magnetic dissipation is strongly localized to small regions of strong-field gradients. We investigate the kinetic-energy release into heat mediated by the dynamo action, both in our model and by solving the induction equation with the same flow. We find that a flux-rope dynamo is an order of magnitude more efficient at converting mechanical energy into heat. The probability density of the magnetic energy release in reconnections has a power-law form with the slope -3 , consistent with the solar corona heating by nanoflares.

  8. Genetic screen in Drosophila muscle identifies autophagy-mediated T-tubule remodeling and a Rab2 role in autophagy

    Science.gov (United States)

    Fujita, Naonobu; Huang, Wilson; Lin, Tzu-han; Groulx, Jean-Francois; Jean, Steve; Nguyen, Jen; Kuchitsu, Yoshihiko; Koyama-Honda, Ikuko; Mizushima, Noboru; Fukuda, Mitsunori; Kiger, Amy A

    2017-01-01

    Transverse (T)-tubules make-up a specialized network of tubulated muscle cell membranes involved in excitation-contraction coupling for power of contraction. Little is known about how T-tubules maintain highly organized structures and contacts throughout the contractile system despite the ongoing muscle remodeling that occurs with muscle atrophy, damage and aging. We uncovered an essential role for autophagy in T-tubule remodeling with genetic screens of a developmentally regulated remodeling program in Drosophila abdominal muscles. Here, we show that autophagy is both upregulated with and required for progression through T-tubule disassembly stages. Along with known mediators of autophagosome-lysosome fusion, our screens uncovered an unexpected shared role for Rab2 with a broadly conserved function in autophagic clearance. Rab2 localizes to autophagosomes and binds to HOPS complex members, suggesting a direct role in autophagosome tethering/fusion. Together, the high membrane flux with muscle remodeling permits unprecedented analysis both of T-tubule dynamics and fundamental trafficking mechanisms. DOI: http://dx.doi.org/10.7554/eLife.23367.001 PMID:28063257

  9. Flux-P: Automating Metabolic Flux Analysis

    OpenAIRE

    Ebert, Birgitta E.; Anna-Lena Lamprecht; Bernhard Steffen; Blank, Lars M.

    2012-01-01

    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 ...

  10. Effects of contaminant exposure and food restriction on hepatic autophagic lysosomal parameters in Herring Gull (Larus argentatus) chicks.

    Science.gov (United States)

    Hegseth, Marit Nøst; Gorbi, Stephania; Bocchetti, Raffaella; Camus, Lionel; Gabrielsen, Geir Wing; Regoli, Francesco

    2014-08-01

    Lysosomal autophagic responses, such as lysosomal membrane stability, neutral lipids (NL), lipofuscin (LF), and malondialdehyde (MDA) levels, are valuable measures of cellular early-onset effects induced by environmental stress factors, such as contaminant exposure and fasting. In this study, these parameters were analysed and related to levels of halogenated organic contaminants (HOCs) in 40 Herring Gull (Larus argentatus) chicks. Chicks were experimentally exposed to HOCs through diet and went through a period of nutrient deprivation at the end of the experiment. HOC exposure and fasting were conducted separately and in combination. NL storages were depleted, and lysosomal membranes were destabilised after HOC exposure and nutrient deprivation. These responses were not related specifically to one type of stress or the extent of the treatment. No synergistic or additive effects from the combination of HOC exposure and fasting were observed. LF accumulated, and MDA levels increased as a result of fasting, but were unaffected by HOC exposure. LF accumulation was strongly associated with the percent weight change in the chicks. Large weight loss was associated with high LF levels, and slight weight gain was associated with low LF levels. Hence, food deprivation affected all the measured parameters, and HOC exposure decreased NL levels and lysosomal membrane stability in HG chick liver. Furthermore, autophagic lysosomal parameters have frequently been applied as biomarkers of cellular health status in previous studies of marine and terrestrial invertebrates, and this study suggests that these parameters may be good candidates for biomarkers of cellular health status in seabirds as well.

  11. 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.

  12. 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.

  13. A Drosophila Model of Neuronopathic Gaucher Disease Demonstrates Lysosomal-Autophagic Defects and Altered mTOR Signalling and Is Functionally Rescued by Rapamycin

    Science.gov (United States)

    Grönke, Sebastian; Castillo-Quan, Jorge Iván; Woodling, Nathaniel S.; Li, Li; Sirka, Ernestas; Gegg, Matthew; Mills, Kevin; Hardy, John; Bjedov, Ivana

    2016-01-01

    Glucocerebrosidase (GBA1) mutations are associated with Gaucher disease (GD), an autosomal recessive disorder caused by functional deficiency of glucocerebrosidase (GBA), a lysosomal enzyme that hydrolyzes glucosylceramide to ceramide and glucose. Neuronopathic forms of GD can be associated with rapid neurological decline (Type II) or manifest as a chronic form (Type III) with a wide spectrum of neurological signs. Furthermore, there is now a well-established link between GBA1 mutations and Parkinson's disease (PD), with heterozygote mutations in GBA1 considered the commonest genetic defect in PD. Here we describe a novel Drosophila model of GD that lacks the two fly GBA1 orthologs. This knock-out model recapitulates the main features of GD at the cellular level with severe lysosomal defects and accumulation of glucosylceramide in the fly brain. We also demonstrate a block in autophagy flux in association with reduced lifespan, age-dependent locomotor deficits and accumulation of autophagy substrates in dGBA-deficient fly brains. Furthermore, mechanistic target of rapamycin (mTOR) signaling is downregulated in dGBA knock-out flies, with a concomitant upregulation of Mitf gene expression, the fly ortholog of mammalian TFEB, likely as a compensatory response to the autophagy block. Moreover, the mTOR inhibitor rapamycin is able to partially ameliorate the lifespan, locomotor, and oxidative stress phenotypes. Together, our results demonstrate that this dGBA1-deficient fly model is a useful platform for the further study of the role of lysosomal-autophagic impairment and the potential therapeutic benefits of rapamycin in neuronopathic GD. These results also have important implications for the role of autophagy and mTOR signaling in GBA1-associated PD. SIGNIFICANCE STATEMENT We developed a Drosophila model of neuronopathic GD by knocking-out the fly orthologs of the GBA1 gene, demonstrating abnormal lysosomal pathology in the fly brain. Functioning lysosomes are

  14. The antimalarial amodiaquine causes autophagic-lysosomal and proliferative blockade sensitizing human melanoma cells to starvation- and chemotherapy-induced cell death.

    Science.gov (United States)

    Qiao, Shuxi; Tao, Shasha; Rojo de la Vega, Montserrat; Park, Sophia L; Vonderfecht, Amanda A; Jacobs, Suesan L; Zhang, Donna D; Wondrak, Georg T

    2013-12-01

    Pharmacological inhibition of autophagic-lysosomal function has recently emerged as a promising strategy for chemotherapeutic intervention targeting cancer cells. Repurposing approved and abandoned non-oncological drugs is an alternative approach to the identification and development of anticancer therapeutics, and antimalarials that target autophagic-lysosomal functions have recently attracted considerable attention as candidates for oncological repurposing. Since cumulative research suggests that dependence on autophagy represents a specific vulnerability of malignant melanoma cells, we screened a focused compound library of antimalarials for antimelanoma activity. Here we report for the first time that amodiaquine (AQ), a clinical 4-aminoquinoline antimalarial with unexplored cancer-directed chemotherapeutic potential, causes autophagic-lysosomal and proliferative blockade in melanoma cells that surpasses that of its parent compound chloroquine. Monitoring an established set of protein markers (LAMP1, LC3-II, SQSTM1) and cell ultrastructural changes detected by electron microscopy, we observed that AQ treatment caused autophagic-lysosomal blockade in malignant A375 melanoma cells, a finding substantiated by detection of rapid inactivation of lysosomal cathepsins (CTSB, CTSL, CTSD). AQ-treatment was associated with early induction of energy crisis (ATP depletion) and sensitized melanoma cells to either starvation- or chemotherapeutic agent-induced cell death. AQ displayed potent antiproliferative effects, and gene expression array analysis revealed changes at the mRNA (CDKN1A, E2F1) and protein level (TP53, CDKN1A, CCND1, phospho-RB1 [Ser 780]/[Ser 807/811], E2F1) consistent with the observed proliferative blockade in S-phase. Taken together, our data suggest that the clinical antimalarial AQ is a promising candidate for repurposing efforts that aim at targeting autophagic-lysosomal function and proliferative control in malignant melanoma cells.

  15. Sulindac sulfide induces autophagic death in gastric epithelial cells via survivin down-regulation: a mechanism of NSAIDs-induced gastric injury.

    Science.gov (United States)

    Chiou, Shiun-Kwei; Hoa, Neil; Hodges, Amy

    2011-06-01

    Sulindac sulfide, a nonsteroidal anti-inflammatory drug (NSAID), has anti-tumorigenic and anti-inflammatory activities, but causes gastric mucosal damage. NSAIDs cause gastric injury in part by down-regulation of Survivin, an apoptosis inhibitor, resulting in apoptosis induction. Autophagy is a process that promotes cellular health by destroying unwanted cellular materials. Excessive autophagy induction could lead to a non-apoptotic cell death (autophagic cell death). The present study showed that sulindac sulfide at a physiological concentration also induces autophagic death in human gastric epithelial AGS and rat gastric epithelial RGM-1 cells, and that Survivin down-regulation is a mechanism involved: Sulindac sulfide treatment increased LC3b-II and APG7 levels and cytosolic vacuole formation, indications of autophagy induction, in AGS and RGM-1 cells. Sulindac sulfide treatment induced AGS and RGM-1 cell death, which was significantly reduced by pretreatment with the autophagy inhibitors 3-methyladenine and chloroquine, indicating that sulindac sulfide induced autophagic cell death. Stable overexpression of Survivin in RGM-1 cells did not inhibit the induction of LC3b-II levels or vacuole formation by sulindac sulfide, but significantly reduced the resulting cell death, suggesting that Survivin may inhibit autophagic cell death downstream of LC3b-II induction and vacuole formation. Indeed, siRNA depletion of LC3b in AGS cells inhibited the down-regulation of Survivin levels and the induction of cell death by sulindac sulfide, confirming that down-regulation of Survivin occurs in the autophagy pathway downstream of LC3b-II induction by sulindac sulfide. Induction of Survivin-dependent autophagic cell death is a novel mechanism by which sulindac sulfide induces gastric mucosal injury.

  16. 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

  17. 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....

  18. 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.

  19. 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.

  20. 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.

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

    Science.gov (United States)

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

    2015-08-01

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

  2. 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.

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

    Science.gov (United States)

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

    2015-01-01

    Hereditary spastic paraplegia (HSP) is characterized by a dying back degeneration of corticospinal axons which leads to progressive weakness and spasticity of the legs. SPG11 is the most common autosomal-recessive form of HSPs and is caused by mutations in SPG11. A recent in vitro study suggested that Spatacsin, the respective gene product, is needed for the recycling of lysosomes from autolysosomes, a process known as autophagic lysosome reformation. The relevance of this observation for hereditary spastic paraplegia, however, has remained unclear. Here, we report that disruption of Spatacsin in mice indeed causes hereditary spastic paraplegia-like phenotypes with loss of cortical neurons and Purkinje cells. Degenerating neurons accumulate autofluorescent material, which stains for the lysosomal protein Lamp1 and for p62, a marker of substrate destined to be degraded by autophagy, and hence appears to be related to autolysosomes. Supporting a more generalized defect of autophagy, levels of lipidated LC3 are increased in Spatacsin knockout mouse embryonic fibrobasts (MEFs). Though distinct parameters of lysosomal function like processing of cathepsin D and lysosomal pH are preserved, lysosome numbers are reduced in knockout MEFs and the recovery of lysosomes during sustained starvation impaired consistent with a defect of autophagic lysosome reformation. Because lysosomes are reduced in cortical neurons and Purkinje cells in vivo, we propose that the decreased number of lysosomes available for fusion with autophagosomes impairs autolysosomal clearance, results in the accumulation of undegraded material and finally causes death of particularly sensitive neurons like cortical motoneurons and Purkinje cells in knockout mice. PMID:26284655

  4. FLUXES FOR MECHANIZED ELECTRIC WELDING,

    Science.gov (United States)

    WELDING FLUXES, WELDING ), (* WELDING , WELDING FLUXES), ARC WELDING , WELDS, STABILITY, POROSITY, WELDING RODS, STEEL, CERAMIC MATERIALS, FLUXES(FUSION), TITANIUM ALLOYS, ALUMINUM ALLOYS, COPPER ALLOYS, ELECTRODEPOSITION

  5. 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.

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

    Science.gov (United States)

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

    2013-07-01

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

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

    Science.gov (United States)

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

    2017-02-01

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

  8. 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.

  9. 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.

  10. Autophagic Turnover of Inactive 26S Proteasomes in Yeast Is Directed by the Ubiquitin Receptor Cue5 and the Hsp42 Chaperone

    Directory of Open Access Journals (Sweden)

    Richard S. Marshall

    2016-08-01

    Full Text Available The autophagic clearance of 26S proteasomes (proteaphagy is an important homeostatic mechanism within the ubiquitin system that modulates proteolytic capacity and eliminates damaged particles. Here, we define two proteaphagy routes in yeast that respond to either nitrogen starvation or particle inactivation. Whereas the core autophagic machineries required for Atg8 lipidation and vesiculation are essential for both routes, the upstream Atg1 kinase participates only in starvation-induced proteaphagy. Following inactivation, 26S proteasomes become extensively modified with ubiquitin. Although prior studies with Arabidopsis implicated RPN10 in tethering ubiquitylated proteasomes to ATG8 lining the autophagic membranes, yeast proteaphagy employs the evolutionarily distinct receptor Cue5, which simultaneously binds ubiquitin and Atg8. Proteaphagy of inactivated proteasomes also requires the oligomeric Hsp42 chaperone, suggesting that ubiquitylated proteasomes are directed by Hsp42 to insoluble protein deposit (IPOD-type structures before encapsulation. Together, Cue5 and Hsp42 provide a quality control checkpoint in yeast directed at recycling dysfunctional 26S proteasomes.

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

    Science.gov (United States)

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

    2011-01-01

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

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

    Science.gov (United States)

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

    2015-02-01

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

  13. 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.

  14. 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

  15. Electron heat flux instability

    Science.gov (United States)

    Saeed, Sundas; Sarfraz, M.; Yoon, P. H.; Lazar, M.; Qureshi, M. N. S.

    2017-02-01

    The heat flux instability is an electromagnetic mode excited by a relative drift between the protons and two-component core-halo electrons. The most prominent application may be in association with the solar wind where drifting electron velocity distributions are observed. The heat flux instability is somewhat analogous to the electrostatic Buneman or ion-acoustic instability driven by the net drift between the protons and bulk electrons, except that the heat flux instability operates in magnetized plasmas and possesses transverse electromagnetic polarization. The heat flux instability is also distinct from the electrostatic counterpart in that it requires two electron species with relative drifts with each other. In the literature, the heat flux instability is often called the 'whistler' heat flux instability, but it is actually polarized in the opposite sense to the whistler wave. This paper elucidates all of these fundamental plasma physical properties associated with the heat flux instability starting from a simple model, and gradually building up more complexity towards a solar wind-like distribution functions. It is found that the essential properties of the instability are already present in the cold counter-streaming electron model, and that the instability is absent if the protons are ignored. These instability characteristics are highly reminiscent of the electron firehose instability driven by excessive parallel temperature anisotropy, propagating in parallel direction with respect to the ambient magnetic field, except that the free energy source for the heat flux instability resides in the effective parallel pressure provided by the counter-streaming electrons.

  16. Autophagy-mediated Regulation of BACE1 Protein Trafficking and Degradation.

    Science.gov (United States)

    Feng, Tuancheng; Tammineni, Prasad; Agrawal, Chanchal; Jeong, Yu Young; Cai, Qian

    2017-02-03

    β-Site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the major neuronal β-secretase for amyloid-β generation and is degraded in lysosomes. The autophagy-lysosomal system plays a key role in the maintenance of cellular homeostasis in neurons. Recent studies established that nascent autophagosomes in distal axons move predominantly in the retrograde direction toward the soma, where mature lysosomes are mainly located. However, it remains unknown whether autophagy plays a critical role in regulation of BACE1 trafficking and degradation. Here, we report that induction of neuronal autophagy enhances BACE1 turnover, which is suppressed by lysosomal inhibition. A significant portion of BACE1 is recruited to the autophagy pathway and co-migrates robustly with autophagic vacuoles along axons. Moreover, we reveal that autophagic vacuole-associated BACE1 is accumulated in the distal axon of Alzheimer's disease-related mutant human APP transgenic neurons and mouse brains. Inducing autophagy in mutant human APP neurons augments autophagic retention of BACE1 in distal axons, leading to enhanced β-cleavage of APP. This phenotype can be reversed by Snapin-enhanced retrograde transport, which facilitates BACE1 trafficking to lysosomes for degradation. Therefore, our study provides new insights into autophagy-mediated regulation of BACE1 turnover and APP processing, thus building a foundation for future development of potential Alzheimer's disease therapeutic strategies.

  17. Inhibition of autophagy via p53-mediated disruption of ULK1 in a SCA7 polyglutamine disease model.

    Science.gov (United States)

    Yu, Xin; Muñoz-Alarcón, Andrés; Ajayi, Abiodun; Webling, Kristin E; Steinhof, Anne; Langel, Ülo; Ström, Anna-Lena

    2013-07-01

    Spinocerebellar ataxia type 7 (SCA7) is one of nine neurodegenerative disorders caused by expanded polyglutamine domains. These so-called polyglutamine (polyQ) diseases are all characterized by aggregation. Reducing the level of aggregating polyQ proteins via pharmacological activation of autophagy has been suggested as a therapeutic approach. However, recently, evidence implicating autophagic dysfunction in these disorders has also been reported. In this study, we show that the SCA7 polyglutamine protein ataxin-7 (ATXN7) reduces the autophagic activity via a previously unreported mechanism involving p53-mediated disruption of two key proteins involved in autophagy initiation. We show that in mutant ATXN7 cells, an increased p53-FIP200 interaction and co-aggregation of p53-FIP200 into ATXN7 aggregates result in decreased soluble FIP200 levels and subsequent destabilization of ULK1. Together, this leads to a decreased capacity for autophagy induction via the ULK1-FIP200-Atg13-Atg101 complex. We also show that treatment with a p53 inhibitor, or a blocker of ATXN7 aggregation, can restore the soluble levels of FIP200 and ULK1, as well as increase the autophagic activity and reduce ATXN7 toxicity. Understanding the mechanism behind polyQ-mediated inhibition of autophagy is of importance if therapeutic approaches based on autophagy stimulation should be developed for these disorders.

  18. Enhanced nitric oxide-mediated autophagy contributes to the hepatoprotective effects of ischemic preconditioning during ischemia and reperfusion.

    Science.gov (United States)

    Shin, Jun-Kyu; Kang, Jung-Woo; Lee, Sun-Mee

    2016-08-31

    Ischemic preconditioning (IPC) protects against liver ischemia/reperfusion (I/R) injury. Autophagy is an essential cytoprotective system that is rapidly activated by multiple stressors. Nitric oxide (NO) acts as an inducer of IPC. We examined the impact of autophagy in liver IPC and its regulation by NO. Male C57BL/6 mice were subjected to 60 min of hepatic ischemia followed by 6 h of reperfusion. IPC was achieved for 10 min of ischemia followed by 10 min of reperfusion prior to sustained ischemia. N(ω)-Nitro-l-arginine methyl ester (L-NAME, 15 mg/kg, i.v., all NOS inhibitor) and aminoguanidine (AG, 10 mg/kg, i.v., iNOS inhibitor) were injected 10 min before IPC. SB203580 (10 mg/kg, i.p., p38 inhibitor) was injected 30 min before IPC. I/R increased serum alanine aminotransferase activity. IPC attenuated this increase, which was abolished by L-NAME, but not AG. Microtubule-associated protein-1 light chain 3-II levels increased and p62 protein levels decreased after I/R; these changes were augmented by IPC and abolished by L-NAME. I/R increased liver protein expression of autophagy-related protein (Atg)12-Atg5 complex and lysosome-associated membrane protein-2. IPC augmented the expression of these proteins, which were abolished by L-NAME, but not AG. IPC also augmented the level of phosphorylated p38 MAPK induced by I/R and this phosphorylation was abolished by L-NAME. Our findings suggest that IPC-mediated NO protects against I/R-induced liver injury by enhancing autophagic flux.

  19. 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

  20. 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...

  1. 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...

  2. 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...

  3. 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).

  4. Intercultural Mediation

    OpenAIRE

    Dragos Marian Radulescu; Denisa Mitrut

    2012-01-01

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

  5. Theoretical magnetic flux emergence

    OpenAIRE

    MacTaggart, David

    2011-01-01

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

  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. Flux Emergence (Theory)

    Science.gov (United States)

    Cheung, Mark C. M.; Isobe, Hiroaki

    2014-12-01

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

  8. Carbon Dioxide Flux Measurement Systems

    Data.gov (United States)

    Oak Ridge National Laboratory — 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...

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

    Science.gov (United States)

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

    2017-02-01

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

  10. 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.

  11. 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...

  12. 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...

  13. The Flux-Flux Correlation Function for Anharmonic Barriers

    CERN Document Server

    Goussev, Arseni; Waalkens, Holger; Wiggins, Stephen

    2010-01-01

    The flux-flux correlation function formalism is a standard and widely used approach for the computation of reaction rates. In this paper we introduce a method to compute the classical and quantum flux-flux correlation functions for anharmonic barriers essentially analytically through the use of the classical and quantum normal forms. In the quantum case we show that the quantum normal form reduces the computation of the flux-flux correlation function to that of an effective one dimensional anharmonic barrier. The example of the computation of the quantum flux-flux correlation function for a fourth order anharmonic barrier is worked out in detail, and we present an analytical expression for the quantum mechanical microcanonical flux-flux correlation function. We then give a discussion of the short-time and harmonic limits.

  14. Protected Flux Pairing Qubit

    Science.gov (United States)

    Bell, Matthew; Zhang, Wenyuan; Ioffe, Lev; Gershenson, Michael

    2014-03-01

    We have studied the coherent flux tunneling in a qubit containing two submicron Josephson junctions shunted by a superinductor (a dissipationless inductor with an impedance much greater than the resistance quantum). The two low energy quantum states of this device, " open="|"> 0 and " open="|"> 1, are represented by even and odd number of fluxes in the loop, respectively. This device is dual to the charge pairing Josephson rhombi qubit. The spectrum of the device, studied by microwave spectroscopy, reflects the interference between coherent quantum phase slips in the two junctions (the Aharonov-Casher effect). The time domain measurements demonstrate the suppression of the qubit's energy relaxation in the protected regime, which illustrates the potential of this flux pairing device as a protected quantum circuit. Templeton Foundation, NSF, and ARO.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. Anomaly mediation in superstring theory

    Energy Technology Data Exchange (ETDEWEB)

    Conlon, J.P. [Rudolf Peierls Center for Theoretical Physics, 1 Keble Road, Oxford, OX1 3NP (United Kingdom); Balliol College, Oxford, OX1 3BJ (United Kingdom); Kavli Institute of Theoretical Physics, Kohn Hall, University of California, Santa Barbara CA 93106-4030 (United States); Goodsell, M. [Deutsches Elektronen-Synchrotron DESY, Notkestrasse 85, 22603 Hamburg (Germany); Palti, E. [Centre de Physique Theorique, Ecole Polytechnique, CNRS, 91128 Palaiseau (France)

    2011-01-15

    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. (Copyright copyright 2011 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

  2. 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.)

  3. 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

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

    Directory of Open Access Journals (Sweden)

    Feng Xu

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

  5. Folate deprivation modulates the expression of autophagy- and circadian-related genes in HT-22 hippocampal neuron cells through GR-mediated pathway.

    Science.gov (United States)

    Sun, Qinwei; Yang, Yang; Li, Xi; He, Bin; Jia, Yimin; Zhang, Nana; Zhao, Ruqian

    2016-08-01

    Folic acid (FA) is an extremely important nutrient for brain formation and development. FA deficiency is highly linked to brain degeneration and age-related diseases, which are also associated with autophagic activities and circadian rhythm in hippocampal neurons. However, little is known how autophagy- and circadian-related genes in hippocampal neurons are regulated under FA deficiency. Here, hippocampal neuroncells (HT-22) were employed to determine the effect of FA deprivation (FD) on the expression of relevant genes and to reveal the potential role of glucocorticoid receptor (GR). FD increased autophagic activities in HT-22 cells, associated with significantly (PGR activation indicated by higher ratio of GR phosphorylation. Out of 17 autophagy-related genes determined, 8 was significantly (PGR binding to the promoter sequence of ATG3 and Per2. Moreover, MeDIP analysis demonstrated significant (PGR-mediated pathway. Our results provide a basis for future investigations into the intracellular regulatory network in response to folate deficiency.

  6. 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.

  7. Muon and neutrino fluxes

    Science.gov (United States)

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

    1985-01-01

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

  8. Generic flux coupling analysis

    NARCIS (Netherlands)

    Reimers, A.C.; Goldstein, Y.; Bockmayr, A.

    2015-01-01

    Flux coupling analysis (FCA) has become a useful tool for aiding metabolic reconstructions and guiding genetic manipulations. Originally, it was introduced for constraint-based models of metabolic networks that are based on the steady-state assumption. Recently, we have shown that the steady-state a

  9. 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...

  10. 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

  11. 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)

    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

  12. 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.

  13. 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.

  14. Triples, Fluxes, and Strings

    CERN Document Server

    De Boer, J; Hori, K; Keurentjes, A; Morgan, J; Morrison, Douglas Robert Ogston; Sethi, S K; Boer, Jan de; Dijkgraaf, Robbert; Hori, Kentaro; Keurentjes, Arjan; Morgan, John; Morrison, David R.; Sethi, Savdeep

    2002-01-01

    We study string compactifications with sixteen supersymmetries. The moduli space for these compactifications becomes quite intricate in lower dimensions, partly because there are many different irreducible components. We focus primarily, but not exclusively, on compactifications to seven or more dimensions. These vacua can be realized in a number ways: the perturbative constructions we study include toroidal compactifications of the heterotic/type I strings, asymmetric orbifolds, and orientifolds. In addition, we describe less conventional M and F theory compactifications on smooth spaces. The last class of vacua considered are compactifications on singular spaces with non-trivial discrete fluxes. We find a number of new components in the string moduli space. Contained in some of these components are M theory compactifications with novel kinds of ``frozen'' singularities. We are naturally led to conjecture the existence of new dualities relating spaces with different singular geometries and fluxes. As our stu...

  15. High Flux Calorimetry.

    Science.gov (United States)

    1984-05-05

    These approaches are based on proven principles which have served the thermal test community well for years. Other concepts hold promise of being able to...8217. --......- - ... .... - - The thermal test community has developed instrumentation which is quite suitable for the moderate, and relatively constant, flux...on the maximum phase II system fluence of 400 cal/cm2 . Second, the present thermal test community will have confidence in the performance of an

  16. Eddy Correlation Flux Measurement System

    Data.gov (United States)

    Oak Ridge National Laboratory — The eddy correlation (ECOR) flux measurement system provides in situ, half-hour measurements of the surface turbulent fluxes of momentum, sensible heat, latent heat,...

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

    Institute of Scientific and Technical Information of China (English)

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

    2009-01-01

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

  18. 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...

  19. Mediatized Humanitarianism

    DEFF Research Database (Denmark)

    Vestergaard, Anne

    2014-01-01

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

  20. 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.

  1. 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.

  2. Are quasar jets dominated by Poynting flux?

    CERN Document Server

    Sikora, M; Madejski, G M; Lasota, J P; Sikora, Marek; Begelman, Mitchell C.; Madejski, Greg M.; Lasota, Jean-Pierre

    2005-01-01

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

  3. Complex Mediation

    DEFF Research Database (Denmark)

    Bødker, Susanne; Andersen, Peter Bøgh

    2005-01-01

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

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

    Science.gov (United States)

    Groom, Nelson J. (Inventor)

    1991-01-01

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

  5. Braneworld Flux Inflation

    CERN Document Server

    Kanno, S; Wands, D; Kanno, Sugumi; Soda, Jiro; Wands, David

    2005-01-01

    We propose a geometrical model of brane inflation where inflation is driven by the flux generated by opposing brane charges and terminated by the collision of the branes, with charge annihilation. We assume the collision process is completely inelastic and the kinetic energy is transformed into the thermal energy after collision. Thereafter the two branes coalesce together and behave as a single brane universe with zero effective cosmological constant. In the Einstein frame, the 4-dimensional effective theory changes abruptly at the collision point. Therefore, our inflationary model is necessarily 5-dimensional in nature. As the collision process has no singularity in 5-dimensional gravity, we can follow the evolution of fluctuations during the whole history of the universe. It turns out that the radion field fluctuations have a steeply tilted, red spectrum, while the primordial gravitational waves have a flat spectrum. Instead, primordial density perturbations could be generated by a curvaton mechanism.

  6. 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.

  7. 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.

  8. 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.

  9. 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....

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

    DEFF Research Database (Denmark)

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

    2012-01-01

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

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

    Science.gov (United States)

    Klamt, Steffen; Regensburger, Georg; Gerstl, Matthias P; Jungreuthmayer, Christian; Schuster, Stefan; Mahadevan, Radhakrishnan; Zanghellini, Jürgen; Müller, Stefan

    2017-04-01

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

  12. 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.

  13. 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.

  14. Data Acquisition and Flux Calculations

    DEFF Research Database (Denmark)

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

    2012-01-01

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

  15. Phytoplankton size impact on export flux in the global ocean

    Science.gov (United States)

    Mouw, Colleen B.; Barnett, Audrey; McKinley, Galen A.; Gloege, Lucas; Pilcher, Darren

    2016-10-01

    Efficiency of the biological pump of carbon to the deep ocean depends largely on biologically mediated export of carbon from the surface ocean and its remineralization with depth. Global satellite studies have primarily focused on chlorophyll concentration and net primary production (NPP) to understand the role of phytoplankton in these processes. Recent satellite retrievals of phytoplankton composition now allow for the size of phytoplankton cells to be considered. Here we improve understanding of phytoplankton size structure impacts on particle export, remineralization, and transfer. A global compilation of particulate organic carbon (POC) flux estimated from sediment traps and 234Th are utilized. Annual climatologies of NPP, percent microplankton, and POC flux at four time series locations and within biogeochemical provinces are constructed. Parameters that characterize POC flux versus depth (export flux ratio, labile fraction, and remineralization length scale) are fit for time series locations, biogeochemical provinces, and times of the year dominated by small and large phytoplankton cells where phytoplankton cell size show enough dynamic range over the annual cycle. Considering all data together, our findings support the idea of high export flux but low transfer efficiency in productive regions and vice versa for oligotrophic regions. However, when parsing by dominant size class, we find periods dominated by small cells to have both greater export flux efficiency and lower transfer efficiency than periods when large cells comprise a greater proportion of the phytoplankton community.

  16. Interpreting Flux from Broadband Photometry

    CERN Document Server

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

    2016-01-01

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

  17. Superconducting wires and fractional flux

    Science.gov (United States)

    Sá de Melo, C. A. R.

    1996-05-01

    The quantization of flux quanta in superconductors is revisited and analyzed in a new geometry. The system analyzed is a superconducting wire. The geometry is such that the superconducting wire winds N times around an insulating cylinder and that the wire has its end connected back to its beginning, thus producing an N-loop short circuited solenoid. The winding number N acts as a topological index that controls flux quantization. In this case, fractional flux quanta can be measured through the center of the insulating cylinder, provided that the cylinder radius is small enough. The Little-Parks experiment for an identical geometry is discussed. The period of oscillation of the transition temperature of the wire is found to vary as 1/N in units of flux Φ relative to the flux quantum Φ0. When a SQUID is made in such a geometry the maximal current through the SQUID varies with period Φ0/N.

  18. 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.

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

    Directory of Open Access Journals (Sweden)

    Hyojung Kwon

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

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

    Science.gov (United States)

    Kwon, Hyojung; Bang, Kyeongrin; Cho, Saeyoull

    2014-01-01

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

  1. Axion Mediation

    CERN Document Server

    Baryakhtar, Masha; March-Russell, John

    2013-01-01

    We explore the possibility that supersymmetry breaking is mediated to the Standard Model sector through the interactions of a generalized axion multiplet that gains a F-term expectation value. Using an effective field theory framework we enumerate the most general possible set of axion couplings and compute the Standard Model sector soft-supersymmetry-breaking terms. Unusual, non-minimal spectra, such as those of both natural and split supersymmetry are easily implemented. We discuss example models and low-energy spectra, as well as implications of the particularly minimal case of mediation via the QCD axion multiplet. We argue that if the Peccei-Quinn solution to the strong-CP problem is realized in string theory then such axion-mediation is generic, while in a field theory model it is a natural possibility in both DFSZ- and KSVZ-like regimes. Axion mediation can parametrically dominate gravity-mediation and is also cosmologically beneficial as the constraints arising from axino and gravitino overproduction ...

  2. 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.

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

    Science.gov (United States)

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

    2016-04-26

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

  4. Mediatized Parenthood

    DEFF Research Database (Denmark)

    Sonne Damkjær, Maja

    2017-01-01

    to parenthood? The dissertation explores this question on the basis of a synchronous study within an overall mediatization perspective. The first part of the dissertation focuses on a conceptualization of the relationship between digital media and parenting as well as an exploration of theoretical perspectives...... and methods that make it possible to study the interactions between the two. Concretely, the dissertation builds on a number of key studies within audience research, which have contributed knowledge about the media’s role in the family and the home. This is done by including three approaches to mediatization......) a family-oriented, b) a peer-oriented, c) an oppositional, and d) non-use. Secondary contribution: Based on qualitative audience research and mediatization theory, the dissertation contributes a conceptualization of the relationship between media and parenthood. This is carried out in a study design...

  5. Generalised Geometry and Flux Vacua

    CERN Document Server

    Larfors, Magdalena

    2015-01-01

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

  6. 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....

  7. Mediatized play

    DEFF Research Database (Denmark)

    Johansen, Stine Liv

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

  8. 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.)

  9. What is flux balance analysis?

    OpenAIRE

    Orth, Jeffrey D.; Thiele, Ines; Palsson, Bernhard Ø

    2010-01-01

    Flux balance analysis is a mathematical approach for analyzing the flow of metabolites through a metabolic network. This primer covers the theoretical basis of the approach, several practical examples and a software toolbox for performing the calculations.

  10. 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...

  11. Conical electromagnetic radiation flux concentrator

    Science.gov (United States)

    Miller, E. R.

    1972-01-01

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

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. P fluxes and exotic branes

    Science.gov (United States)

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

    2016-12-01

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

  17. $P$ 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...

  18. 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.

  19. The ATG autophagic conjugation system in maize: ATG transcripts and abundance of the ATG8-lipid adduct are regulated by development and nutrient availability.

    Science.gov (United States)

    Chung, Taijoon; Suttangkakul, Anongpat; Vierstra, Richard D

    2009-01-01

    Plants employ sophisticated mechanisms to recycle intracellular constituents needed for growth, development, and survival under nutrient-limiting conditions. Autophagy is one important route in which cytoplasm and organelles are sequestered in bulk into vesicles and subsequently delivered to the vacuole for breakdown by resident hydrolases. The formation and trafficking of autophagic vesicles are directed in part by associated conjugation cascades that couple the AUTOPHAGY-RELATED8 (ATG8) and ATG12 proteins to their respective targets, phosphatidylethanolamine and the ATG5 protein. To help understand the importance of autophagy to nutrient remobilization in cereals, we describe here the ATG8/12 conjugation cascades in maize (Zea mays) and examine their dynamics during development, leaf senescence, and nitrogen and fixed-carbon starvation. From searches of the maize genomic sequence using Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa) counterparts as queries, we identified orthologous loci encoding all components necessary for ATG8/12 conjugation, including a five-member gene family expressing ATG8. Alternative splicing was evident for almost all Atg transcripts, which could have important regulatory consequences. In addition to free ATG8, its membrane-associated, lipidated form was detected in many maize tissues, suggesting that its conjugation cascade is active throughout the plant at most, if not all, developmental stages. Levels of Atg transcripts and/or the ATG8-phosphatidylethanolamine adduct increase during leaf senescence and nitrogen and fixed-carbon limitations, indicating that autophagy plays a key role in nutrient remobilization. The description of the maize ATG system now provides a battery of molecular and biochemical tools to study autophagy in this crop under field conditions.

  20. 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.

  1. 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...

  2. 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.

  3. 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.

  4. 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.

  5. Charm production in flux tubes

    CERN Document Server

    Aguiar, C E; Nazareth, R A M S; Pech, G

    1996-01-01

    We argue that the non-perturbative Schwinger mechanism may play an important role in the hadronic production of charm. We present a flux tube model which assumes that the colliding hadrons become color charged because of gluon exchange, and that a single non-elementary flux tube is built up as they recede. The strong chromoelectric field inside this tube creates quark pairs (including charmed ones) and the ensuing color screening breaks the tube into excited hadronic clusters. On their turn these clusters, or `fireballs', decay statistically into the final hadrons. The model is able to account for the soft production of charmed, strange and lighter hadrons within a unified framework.

  6. Charm production in flux tubes

    Science.gov (United States)

    Aguiar, C. E.; Kodama, T.; Nazareth, R. A. M. S.; Pech, G.

    1996-01-01

    We argue that the nonperturbative Schwinger mechanism may play an important role in the hadronic production of charm. We present a flux tube model which assumes that the colliding hadrons become color charged because of gluon exchange, and that a single nonelementary flux tube is built up as they recede. The strong chromoelectric field inside this tube creates quark pairs (including charmed ones) and the ensuing color screening breaks the tube into excited hadronic clusters. In their turn these clusters, or ``fireballs,'' decay statistically into the final hadrons. The model is able to account for the soft production of charmed, strange, and lighter hadrons within a unified framework.

  7. 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.

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

    Science.gov (United States)

    Marcos, D; Wubs, M; Taylor, J M; Aguado, R; Lukin, M D; Sørensen, A S

    2010-11-19

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

  9. Giant Leaps and Monkey Branes in Multi-Dimensional Flux Landscapes

    CERN Document Server

    Brown, Adam R

    2010-01-01

    There is a standard story about decay in multi-dimensional flux landscapes: that from any state, the fastest decay is to take a small step, discharging one flux unit at a time; that fluxes with the same coupling constant are interchangeable; and that states with N units of a given flux have the same decay rate as those with -N. We show that this standard story is false. The fastest decay is a giant leap that discharges many different fluxes in unison; this decay is mediated by a 'monkey brane' that wraps the internal manifold and exhibits behavior not visible in the effective theory. The implications for the Bousso-Polchinski landscape are discussed.

  10. Black branes in flux compactifications

    Energy Technology Data Exchange (ETDEWEB)

    Torroba, Gonzalo; Wang, Huajia

    2013-10-01

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

  11. 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.

  12. 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.

  13. 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...

  14. 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...

  15. 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.

  16. 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 $S_1$.

  17. 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.

  18. 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.

  19. 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.

  20. Novel Switched Flux Permanent Magnet Machine Topologies

    Institute of Scientific and Technical Information of China (English)

    诸自强

    2012-01-01

    This paper overviews various switched flux permanent magnet machines and their design and performance features,with particular emphasis on machine topologies with reduced magnet usage or without using magnet,as well as with variable flux capability.

  1. Flux-dependent graphs for metabolic networks

    OpenAIRE

    Beguerisse-Díaz, Mariano; Bosque, Gabriel; Oyarzún, Diego; Picó, Jesús; Barahona, Mauricio

    2016-01-01

    Cells adapt their metabolic fluxes in response to changes in the environment. We present a systematic flux-based framework for the construction of graphs to represent organism-wide metabolic networks. Our graphs encode the directionality of metabolic fluxes via links that represent the flow of metabolites from source to target reactions. The methodology can be applied in the absence of a specific biological context by modelling fluxes as probabilities, or tailored to different environmental c...

  2. 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.

  3. 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.

  4. 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.

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

    Directory of Open Access Journals (Sweden)

    Vanz Ana Leticia

    2012-08-01

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

  6. 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

  7. Calculated Electron Fluxes at Airplane Altitudes

    CERN Document Server

    Schaefer, R K; Stanev, T

    1993-01-01

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

  8. 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.

  9. Flux Sampling Errors for Aircraft and Towers

    Science.gov (United States)

    Mahrt, Larry

    1998-01-01

    Various errors and influences leading to differences between tower- and aircraft-measured fluxes are surveyed. This survey is motivated by reports in the literature that aircraft fluxes are sometimes smaller than tower-measured fluxes. Both tower and aircraft flux errors are larger with surface heterogeneity due to several independent effects. Surface heterogeneity may cause tower flux errors to increase with decreasing wind speed. Techniques to assess flux sampling error are reviewed. Such error estimates suffer various degrees of inapplicability in real geophysical time series due to nonstationarity of tower time series (or inhomogeneity of aircraft data). A new measure for nonstationarity is developed that eliminates assumptions on the form of the nonstationarity inherent in previous methods. When this nonstationarity measure becomes large, the surface energy imbalance increases sharply. Finally, strategies for obtaining adequate flux sampling using repeated aircraft passes and grid patterns are outlined.

  10. 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

  11. SEP flux mapping with PHOEBUS

    Energy Technology Data Exchange (ETDEWEB)

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

    2006-03-02

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

  12. SEP flux mapping with PHOEBUS

    Science.gov (United States)

    Grimani, C.; Bagni, G.; Fabi, M.; Vicerè, A.; Marconi, L.; Stanga, R.; Bosi, L.; Vocca, H.; Araújo, H.; Shaul, D.; Sumner, T.; Wass, P.; Boatella, C.; Lobo, A.; Chmeissani, M.; Martinez, I.

    2006-03-01

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

  13. Assessing benthic oxygen fluxes in oligotrophic deep sea sediments (HAUSGARTEN observatory)

    Science.gov (United States)

    Donis, Daphne; McGinnis, Daniel F.; Holtappels, Moritz; Felden, Janine; Wenzhoefer, Frank

    2016-05-01

    Benthic oxygen fluxes, an established proxy for total organic carbon mineralization, were investigated in oligotrophic deep sea sediments. We used three different in situ technologies to estimate the benthic oxygen fluxes at an Arctic deep sea site (2500 m depth, HAUSGARTEN observatory) with limiting conditions of low oxygen gradients and fluxes, low turbulence and low particle content in the benthic boundary layer. The resolved eddy covariance turbulent oxygen flux (-0.9±0.2 (SD) mmol O2 m-2 d-1) compared well with simultaneous dissolved oxygen flux measurements carried out with a microprofiler (-1.02±0.3 (SD) mmol O2 m-2 d-1) and total oxygen uptake obtained by benthic chamber incubations (-1.1±0.1 (SD) mmol O2 m-2 d-1). The agreement between these different techniques revealed that microbial-mediated oxygen consumption was dominant at this site. The average benthic flux equals a carbon mineralization rate of 4.3 g C m-2 yr-1, which exceeds the annual sedimentation of particulate organic matter measured by sediment traps. The present study represents a detailed comparison of different in situ technologies for benthic flux measurements at different spatial scales in oligotrophic deep sea sediments. The use of eddy covariance, so far rarely used for deep sea investigations, is presented in detail.

  14. 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。

  15. Regulation of the interplanetary magnetic flux

    Energy Technology Data Exchange (ETDEWEB)

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

    1991-01-01

    In this study we use a recently developed technique for measuring the 2-D magnetic flux in the ecliptic plane to examine (1) the long term variation of the magnetic flux in interplanetary space and (2) the apparent rate at which coronal mass ejections (CMEs) may be opening new flux from the Sun. Since there is a substantial variation ({approximately}50%) of the flux in the ecliptic plane over the solar cycle, we conclude that there must be some means whereby new flux can be opened from the Sun and previously open magnetic flux can be closed off. We briefly describe recently discovered coronal disconnections events which could serve to close off previously open magnetic flux. CMEs appear to retain at least partial magnetic connection to the Sun and hence open new flux, while disconnections appear to be likely signatures of the process that returns closed flux to the Sun; the combination of these processes could regulate the amount of open magnetic flux in interplanetary space. 6 refs., 3 figs.

  16. 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.

  17. 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

  18. 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

  19. 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.

  20. Metamaterial anisotropic flux concentrators and magnetic arrays

    CERN Document Server

    Bjørk, R; Bahl, C R H

    2014-01-01

    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.

  1. Mast cells mediate neutrophil recruitment during atherosclerotic plaque progression

    NARCIS (Netherlands)

    Wezel, Anouk; Lagraauw, H Maxime; van der Velden, Daniël; de Jager, Saskia C A; Quax, Paul H A; Kuiper, Johan; Bot, Ilze

    2015-01-01

    AIMS: Activated mast cells have been identified in the intima and perivascular tissue of human atherosclerotic plaques. As mast cells have been described to release a number of chemokines that mediate leukocyte fluxes, we propose that activated mast cells may play a pivotal role in leukocyte recruit

  2. Investigating the Dynamics of Canonical Flux Tubes

    Science.gov (United States)

    von der Linden, Jens; Sears, Jason; Intrator, Thomas; You, Setthivoine

    2016-10-01

    Canonical flux tubes are flux tubes of the circulation of a species' canonical momentum. They provide a convenient generalization of magnetic flux tubes to regimes beyond magnetohydrodynamics (MHD). We hypothesize that hierarchies of instabilities which couple disparate scales could transfer magnetic pitch into helical flows and vice versa while conserving the total canonical helicity. This work first explores the possibility of a sausage instability existing on top of a kink as mechanism for coupling scales, then presents the evolution of canonical helicity in a gyrating kinked flux rope. Analytical and numerical stability spaces derived for magnetic flux tubes with core and skin currents indicate that, as a flux tube lengthens and collimates, it may become kink unstable with a sausage instability developing on top of the kink. A new analysis of 3D magnetic field and ion flow data on gyrating kinked magnetic flux ropes from the Reconnection Scaling Experiment tracks the evolution of canonical flux tubes and their helicity. These results and methodology are being developed as part of the Mochi experiment specifically designed to observe the dynamics of canonical flux tubes. This work is supported by DOE Grant DE-SC0010340 and the DOE Office of Science Graduate Student Research Program and prepared in part by LLNL under Contract DE-AC52-07NA27344. LLNL-ABS-697161.

  3. 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

  4. Magnetic Flux Compression in Plasmas

    Science.gov (United States)

    Velikovich, A. L.

    2012-10-01

    Magnetic flux compression (MFC) as a method for producing ultra-high pulsed magnetic fields had been originated in the 1950s by Sakharov et al. at Arzamas in the USSR (now VNIIEF, Russia) and by Fowler et al. at Los Alamos in the US. The highest magnetic field produced by explosively driven MFC generator, 28 MG, was reported by Boyko et al. of VNIIEF. The idea of using MFC to increase the magnetic field in a magnetically confined plasma to 3-10 MG, relaxing the strict requirements on the plasma density and Lawson time, gave rise to the research area known as MTF in the US and MAGO in Russia. To make a difference in ICF, a magnetic field of ˜100 MG should be generated via MFC by a plasma liner as a part of the capsule compression scenario on a laser or pulsed power facility. This approach was first suggested in mid-1980s by Liberman and Velikovich in the USSR and Felber in the US. It has not been obvious from the start that it could work at all, given that so many mechanisms exist for anomalously fast penetration of magnetic field through plasma. And yet, many experiments stimulated by this proposal since 1986, mostly using pulsed-power drivers, demonstrated reasonably good flux compression up to ˜42 MG, although diagnostics of magnetic fields of such magnitude in HED plasmas is still problematic. The new interest of MFC in plasmas emerged with the advancement of new drivers, diagnostic methods and simulation tools. Experiments on MFC in a deuterium plasma filling a cylindrical plastic liner imploded by OMEGA laser beam led by Knauer, Betti et al. at LLE produced peak fields of 36 MG. The novel MagLIF approach to low-cost, high-efficiency ICF pursued by Herrmann, Slutz, Vesey et al. at Sandia involves pulsed-power-driven MFC to a peak field of ˜130 MG in a DT plasma. A review of the progress, current status and future prospects of MFC in plasmas is presented.

  5. 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.

  6. 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.

  7. Magnetic flux generator for balanced membrane loudspeaker

    DEFF Research Database (Denmark)

    Rehder, Jörg; Rombach, Pirmin; Hansen, Ole

    2002-01-01

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

  8. Flux Modulation in the Electrodynamic Loudspeaker

    DEFF Research Database (Denmark)

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

    2015-01-01

    . Measurements of the generated AC flux modulation shows, that eddy currents are the main source to magnetic losses in form of phase lag and amplitude changes. Use of a copper cap shows a decrease in flux modulation amplitude at the expense of increased power losses. Finally, simulations show...

  9. Anthropogenic heat flux estimation from space

    NARCIS (Netherlands)

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

    2016-01-01

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

  10. 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...

  11. 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.

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

    Directory of Open Access Journals (Sweden)

    Nielsen Lars K

    2009-05-01

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

  16. 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. 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.

  18. Microbial imprint on soil-atmosphere H2, COS, and CO2 fluxes

    Science.gov (United States)

    Meredith, L. K.; Commane, R.; Munger, J. W.; Wofsy, S. C.; Prinn, R. G.

    2013-12-01

    Microorganisms drive large trace gas fluxes between soil and atmosphere, but the signal can be difficult to detect and quantify in the presence of stronger exchange processes in an ecosystem. Partitioning methods are often needed to estimate trace gas budgets and to develop process-based models to explore the sensitivity of microbe-mediated fluxes. In this study, we test the performance of trace gases with predominantly microbe-mediated soil fluxes as a metric of the soil microbial uptake activity of other trace gases. Using simultaneous, collocated measurements at Harvard Forest, we consider three trace gases with microbe-mediated soil fluxes of various importance relative to their other (mainly plant-mediated) ecosystem fluxes: molecular hydrogen (H2), carbonyl sulfide (COS), and carbon dioxide (CO2). These gases probe different aspects of the soil trace-gas microbiology. Soil H2 uptake is a redox reaction driving the energy metabolism of a portion of the microbial community, while soil CO2 respiration is a partial proxy for the overall soil microbial metabolism. In comparison, very little is understood about the microbiological and environmental drivers of soil COS uptake and emissions. In this study, we find that H2, COS, and CO2 soil uptake rates are often correlated, but the relative soil uptake between gases is not constant, and is influenced by seasonality and local environmental conditions. We also consider how differences in the microbial communities and pathways involved in the soil fluxes may explain differences in the observations. Our results are important for informing previous studies using tracer approaches. For example, H2 has been used to estimate COS soil uptake, which must be accounted for to use COS as a carbon cycle tracer. Furthermore, the global distribution of H2 deposition velocity has been inferred from net primary productivity (CO2). Given that insufficient measurement frequency and spatial distribution exists to partition global net

  19. 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.

  20. Poynting flux dominated jets challenged by their photospheric emission

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-12-17

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

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-08-15

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

  2. 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.

  3. Flux qubits in a planar circuit quantum electrodynamics architecture: Quantum control and decoherence

    Science.gov (United States)

    Orgiazzi, J.-L.; Deng, C.; Layden, D.; Marchildon, R.; Kitapli, F.; Shen, F.; Bal, M.; Ong, F. R.; Lupascu, A.

    2016-03-01

    We report experiments on superconducting flux qubits in a circuit quantum electrodynamics (cQED) setup. Two qubits, independently biased and controlled, are coupled to a coplanar waveguide resonator. Dispersive qubit state readout reaches a maximum contrast of 72%. We measure energy relaxation times at the symmetry point of 5 and 10 μ s , corresponding to 7 and 20 μ s when relaxation through the resonator due to Purcell effect is subtracted out, and levels of flux noise of 2.6 and 2.7 μ Φ0/√{Hz} at 1 Hz for the two qubits. We discuss the origin of decoherence in the measured devices. The strong coupling between the qubits and the cavity leads to a large, cavity-mediated, qubit-qubit coupling. This coupling, which is characterized spectroscopically, reaches 38 MHz. These results demonstrate the potential of cQED as a platform for fundamental investigations of decoherence and quantum dynamics of flux qubits.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. Wave heating in magnetic flux tubes

    Science.gov (United States)

    Kalkofen, Wolfgang

    1990-01-01

    The bright chromosphere in the quiet sun is confined to magnetic elements (flux tubes), which are located in the interior of the supergranulation cells and within the network that surrounds the cells. The paper discusses the heating of the gas in the magnetic elements of the cell interior. These intranetwork flux tubes are closely associated with bright points, which are heated by large-amplitude compressive waves with periods near the acoustic cutoff that travel outward from the photosphere and dissipate their energy in the chromosphere. The energy flux of these long-period waves appears to be sufficient for the heating of the low and middle chromosphere in the bright points.

  9. Eddy Correlation Flux Measurement System (ECOR) Handbook

    Energy Technology Data Exchange (ETDEWEB)

    Cook, DR

    2011-01-31

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

  10. Flux compactifications, gauge algebras and De Sitter

    Energy Technology Data Exchange (ETDEWEB)

    Dibitetto, Giuseppe, E-mail: g.dibitetto@rug.n [Centre for Theoretical Physics, University of Groningen, Nijenborgh 4, 9747 AG Groningen (Netherlands); Linares, Roman, E-mail: lirr@xanum.uam.m [Departamento de Fisica, Universidad Autonoma Metropolitana Iztapalapa, San Rafael Atlixco 186, C.P. 09340, Mexico D.F. (Mexico); Roest, Diederik, E-mail: d.roest@rug.n [Centre for Theoretical Physics, University of Groningen, Nijenborgh 4, 9747 AG Groningen (Netherlands)

    2010-04-26

    The introduction of (non-)geometric fluxes allows for N=1 moduli stabilisation in a De Sitter vacuum. The aim of this Letter is to assess to what extent this is true in N=4 compactifications. First we identify the correct gauge algebra in terms of gauge and (non-)geometric fluxes. We then show that this algebra does not lead to any of the known gaugings with De Sitter solutions. In particular, the gaugings that one obtains from flux compactifications involve non-semi-simple algebras, while the known gaugings with De Sitter solutions consist of direct products of (semi-)simple algebras.

  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. 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.

  13. 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.

  14. 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.

  15. 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...

  16. 400 Area/Fast Flux Test Facility

    Data.gov (United States)

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

  17. 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.

  18. Fractional flux quanta in superconducting solenoids

    Science.gov (United States)

    Sá de Melo, C. A. R.

    1996-03-01

    The quantization of flux quanta in superconductors is revisited and analyzed in a new topology. The topology is that of a superconducting wire that winds N times around a fixed axis and has its end connected back to its beginning, thus producing an N-loop short circuited solenoid. In this case, fractional flux quanta can be measured through the center of the solenoid, provided that its cross-section radius is small enough. The Little-Parks experiment for an identical topology is discussed. The period of oscillation of the transition temperature of the wire is found to vary as 1/N in units of flux Φ relative to the flux quantum Φ0.

  19. 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.

  20. Observations on fluxes near anti-branes

    CERN Document Server

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

    2015-01-01

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

  1. 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.

  2. Recurrence Analysis of Eddy Covariance Fluxes

    Science.gov (United States)

    Lange, Holger; Flach, Milan; Foken, Thomas; Hauhs, Michael

    2015-04-01

    The eddy covariance (EC) method is one key method to quantify fluxes in biogeochemical cycles in general, and carbon and energy transport across the vegetation-atmosphere boundary layer in particular. EC data from the worldwide net of flux towers (Fluxnet) have also been used to validate biogeochemical models. The high resolution data are usually obtained at 20 Hz sampling rate but are affected by missing values and other restrictions. In this contribution, we investigate the nonlinear dynamics of EC fluxes using Recurrence Analysis (RA). High resolution data from the site DE-Bay (Waldstein-Weidenbrunnen) and fluxes calculated at half-hourly resolution from eight locations (part of the La Thuile dataset) provide a set of very long time series to analyze. After careful quality assessment and Fluxnet standard gapfilling pretreatment, we calculate properties and indicators of the recurrent structure based both on Recurrence Plots as well as Recurrence Networks. Time series of RA measures obtained from windows moving along the time axis are presented. Their interpretation is guided by three different questions: (1) Is RA able to discern periods where the (atmospheric) conditions are particularly suitable to obtain reliable EC fluxes? (2) Is RA capable to detect dynamical transitions (different behavior) beyond those obvious from visual inspection? (3) Does RA contribute to an understanding of the nonlinear synchronization between EC fluxes and atmospheric parameters, which is crucial for both improving carbon flux models as well for reliable interpolation of gaps? (4) Is RA able to recommend an optimal time resolution for measuring EC data and for analyzing EC fluxes? (5) Is it possible to detect non-trivial periodicities with a global RA? We will demonstrate that the answers to all five questions is affirmative, and that RA provides insights into EC dynamics not easily obtained otherwise.

  3. 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.

  4. 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.

  5. ASTRA Spectrophotometer: Reduction and Flux Calibrations

    CERN Document Server

    Smalley, B; Adelman, S J; Smalley, Barry; Gulliver, Austin F.; Adelman, Saul J.

    2006-01-01

    The ASTRA Cassegrain Spectrophotometer and its automated 0.5-m telescope at Fairborn Observatory in Arizona will produce a large quantity of high precision stellar flux distributions. A separate paper (Adelman et al. 2007) presented a review of the design criteria for the system and an overview of its operation. This paper discusses the techniques used in the data reduction to final flux calibrations.

  6. 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...

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

    Science.gov (United States)

    Stokes, Vijay Kumar; Ramkrishna, Doraiswami

    1982-01-01

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

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

    Digital Repository Service at National Institute of Oceanography (India)

    Pankajakshan, T.; Sugimori, Y.

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

  9. Overexpression of smooth muscle myosin heavy chain leads to activation of the unfolded protein response and autophagic turnover of thick filament-associated proteins in vascular smooth muscle cells.

    Science.gov (United States)

    Kwartler, Callie S; Chen, Jiyuan; Thakur, Dhananjay; Li, Shumin; Baskin, Kedryn; Wang, Shanzhi; Wang, Zhao V; Walker, Lori; Hill, Joseph A; Epstein, Henry F; Taegtmeyer, Heinrich; Milewicz, Dianna M

    2014-05-16

    Duplications spanning nine genes at the genomic locus 16p13.1 predispose individuals to acute aortic dissections. The most likely candidate gene in this region leading to the predisposition for dissection is MYH11, which encodes smooth muscle myosin heavy chain (SM-MHC). The effects of increased expression of MYH11 on smooth muscle cell (SMC) phenotypes were explored using mouse aortic SMCs with transgenic overexpression of one isoform of SM-MHC. We found that these cells show increased expression of Myh11 and myosin filament-associated contractile genes at the message level when compared with control SMCs, but not at the protein level due to increased protein degradation. Increased expression of Myh11 resulted in endoplasmic reticulum (ER) stress in SMCs, which led to a paradoxical decrease of protein levels through increased autophagic degradation. An additional consequence of ER stress in SMCs was increased intracellular calcium ion concentration, resulting in increased contractile signaling and contraction. The increased signals for contraction further promote transcription of contractile genes, leading to a feedback loop of metabolic abnormalities in these SMCs. We suggest that overexpression of MYH11 can lead to increased ER stress and autophagy, findings that may be globally implicated in disease processes associated with genomic duplications.

  10. Overexpression of Smooth Muscle Myosin Heavy Chain Leads to Activation of the Unfolded Protein Response and Autophagic Turnover of Thick Filament-associated Proteins in Vascular Smooth Muscle Cells*

    Science.gov (United States)

    Kwartler, Callie S.; Chen, Jiyuan; Thakur, Dhananjay; Li, Shumin; Baskin, Kedryn; Wang, Shanzhi; Wang, Zhao V.; Walker, Lori; Hill, Joseph A.; Epstein, Henry F.; Taegtmeyer, Heinrich; Milewicz, Dianna M.

    2014-01-01

    Duplications spanning nine genes at the genomic locus 16p13.1 predispose individuals to acute aortic dissections. The most likely candidate gene in this region leading to the predisposition for dissection is MYH11, which encodes smooth muscle myosin heavy chain (SM-MHC). The effects of increased expression of MYH11 on smooth muscle cell (SMC) phenotypes were explored using mouse aortic SMCs with transgenic overexpression of one isoform of SM-MHC. We found that these cells show increased expression of Myh11 and myosin filament-associated contractile genes at the message level when compared with control SMCs, but not at the protein level due to increased protein degradation. Increased expression of Myh11 resulted in endoplasmic reticulum (ER) stress in SMCs, which led to a paradoxical decrease of protein levels through increased autophagic degradation. An additional consequence of ER stress in SMCs was increased intracellular calcium ion concentration, resulting in increased contractile signaling and contraction. The increased signals for contraction further promote transcription of contractile genes, leading to a feedback loop of metabolic abnormalities in these SMCs. We suggest that overexpression of MYH11 can lead to increased ER stress and autophagy, findings that may be globally implicated in disease processes associated with genomic duplications. PMID:24711452

  11. 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

  12. Metabolic flux analysis on arachidonic acid fermentation

    Institute of Scientific and Technical Information of China (English)

    JIN Mingjie; HUANG He; ZHANG Kun; YAN Jie; GAO Zhen

    2007-01-01

    The analysis of flux distributions in metabolic networks has become an important approach for understanding the fermentation characteristics of the process.A model of metabolic flux analysis of arachidonic acid (AA) synthesis in Mortierella alpina ME-1 was established and carbon flux distributions were estimated in different fermentation phases with different concentrations of N-source.During the exponential,decelerating and stationary phase,carbon fluxes to AA were 3.28%,8.80% and 6.97%,respectively,with sufficient N-source broth based on the flux of glucose uptake,and those were increased to 3.95%,19.21% and 39.29%,respectively,by regulating the shifts of carbon fluxes via fermentation with limited N-source broth and adding 0.05%NaNO3 at 96 h.Eventually AA yield was increased from 1.3 to 3.5 g.L-1.These results suggest a way to improve AA fermentation,that is,fermentation with limited N-source broth and adding low concentration N-source during the stationary phase.

  13. 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.

  14. 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...... of technology-use mediation is more complex and indeterminate than earlier literature suggests. In particular, we want to draw attention to the fact that advanced computer-mediated communication technologies are equivocal and that technology-use mediation consequently requires ongoing sensemaking (Weick 1995)....... appropriate conventions of use. Our findings corroborate earlier research on technology-use mediation, which suggests that such mediators can exert considerable influence on how a particular technology will be established and used in an organization. However, this study also indicates that the process...

  15. 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

  16. Characterizing In Situ Uranium and Groundwater Flux

    Science.gov (United States)

    Cho, J.; Newman, M. A.; Stucker, V.; Peacock, A.; Ranville, J.; Cabaniss, S.; Hatfield, K.; Annable, M. D.; Klammler, H.; Perminova, I. V.

    2010-12-01

    The goal of this project is to develop a new sensor that incorporates the field-tested concepts of the passive flux meter to provide direct in situ measures of uranium and groundwater fluxes. The sensor uses two sorbents and resident tracers to measure uranium flux and specific discharge directly; but, sensor principles and design should also apply to fluxes of other radionuclides. Flux measurements will assist with obtaining field-scale quantification of subsurface processes affecting uranium transport (e.g., advection) and transformation (e.g., uranium attenuation) and further advance conceptual and computational models for field scale simulations. Project efforts will expand our current understanding of how field-scale spatial variations in uranium fluxes and those for salient electron donor/acceptors, and groundwater are coupled to spatial variations in measured microbial biomass/community composition, effective field-scale uranium mass balances, attenuation, and stability. The new sensor uses an anion exchange resin to measure uranium fluxes and activated carbon with resident tracers to measure water fluxes. Several anion-exchange resins including Dowex 21K and 21K XLT, Purolite A500, and Lewatit S6328 were tested as sorbents for capturing uranium on the sensor and Lewatit S6328 was determined to be the most effective over the widest pH range. Four branched alcohols proved useful as resident tracers for measuring groundwater flows using activated carbon for both laboratory and field conditions. The flux sensor was redesigned to prevent the discharge of tracers to the environment, and the new design was tested in laboratory box aquifers and the field. Geochemical modeling of equilibrium speciation using Visual Minteq and an up-to-date thermodynamic data base suggested Ca-tricarbonato-uranyl complexes predominate under field conditions, while calculated uranyl ion activities were sensitive to changes in pH, dissolved inorganic carbon (DIC) and alkaline earth

  17. A Double-Ring Algorithm for Modeling Solar Active Regions: Unifying Kinematic Dynamo Models and Surface Flux-Transport Simulations

    CERN Document Server

    Muñoz-Jaramillo, Andrés; Martens, Petrus C H; Yeates, Anthony R

    2010-01-01

    The emergence of tilted bipolar active regions and the dispersal of their flux, mediated via processes such as diffusion, differential rotation and meridional circulation is believed to be responsible for the reversal of the Sun's polar field. This process (commonly known as the Babcock-Leighton mechanism) is usually modeled as a near-surface, spatially distributed $\\alpha$-effect in kinematic mean-field dynamo models. However, this formulation leads to a relationship between polar field strength and meridional flow speed which is opposite to that suggested by physical insight and predicted by surface flux-transport simulations. With this in mind, we present an improved double-ring algorithm for modeling the Babcock-Leighton mechanism based on active region eruption, within the framework of an axisymmetric dynamo model. Using surface flux-transport simulations we first show that an axisymmetric formulation -- which is usually invoked in kinematic dynamo models -- can reasonably approximate the surface flux dy...

  18. 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.

  19. 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

  20. 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

  1. An introduction to the Australian and New Zealand flux tower network – OzFlux

    OpenAIRE

    2016-01-01

    OzFlux is the regional Australian and New Zealand flux tower network that aims to provide a continental-scale national research facility to monitor and assess trends, and improve predictions, of Australia’s terrestrial biosphere and climate. This paper describes the evolution, design and current status of OzFlux as well as an overview of data processing. We analyse measurements from the Australian portion of the OzFlux network and found that the response of Australian biomes to climate was ...

  2. An introduction to the Australian and New Zealand flux tower network – OzFlux

    OpenAIRE

    2016-01-01

    OzFlux is the regional Australian and New Zealand flux tower network that aims to provide a continental-scale national research facility to monitor and assess trends, and improve predictions, of Australia's terrestrial biosphere and climate. This paper describes the evolution, design, and current status of OzFlux as well as provides an overview of data processing. We analyse measurements from all sites within the Australian portion of the OzFlux network and two sites from New Zealand. The res...

  3. 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.

  4. An automatic flux chamber for investigating gas flux at water - air interfaces

    Science.gov (United States)

    Duc, N. T.; Silverstein, S.; Lundmark, L.; Reyier, H.; Crill, P. M.; Bastviken, D.

    2011-12-01

    Aquatic ecosystems are major sources of greenhouse gases (GHG) and representative measurements of GHG fluxes from aquatic ecosystems to the atmosphere are vital in climate related biogeochemistry. One of the most important fluxes, ebullition (bubble flux) of methane (CH4) is episodic, with large fluxes during short time periods. To properly capture such fluxes long term measurement approaches are necessary which is labor intensive for manual flux chamber based methods, or require expensive equipment with e.g. eddy correlation methods. An inexpensive and easily mobile automatic flux chamber for long-term measurements has been designed to approach these drawbacks. This device includes a flux chamber, with a controller/datalogger, valves, a pump, a 12 V battery and a solar cell. Sensors used so far record CH4 concentration in the chamber headspace, temperature in water and air, barometric pressure. Other sensors for e.g. CO2 and weather variables can be attached. The unit can be programmed to measure in situ accumulation of gas in the chamber and also to collect gas samples in an array of sample bottles for subsequent analysis in the laboratory. Simultaneous deployment of many such units represent a cost efficient and easily managed solution for local long term flux monitoring.

  5. Modeling of microscale variations in methane fluxes

    Energy Technology Data Exchange (ETDEWEB)

    Kettunen, A.

    2002-07-01

    The current study analyzes the different modes of variation in methane fluxes from different microsites of a boreal mire. The results emphasize the importance of microsite characteristics, water table and vegetation cover for methane fluxes. Water level affects the moisture and oxygen profiles in peat matrix which are reflected to methane production and oxidation rates and the corresponding microbial populations. Vascular plants promote methane production by providing substrates in the form of root exudates and fine root litter, enhance methane oxidation by transporting oxygen to water saturated peat layers and accelerate methane transport by liberating methane from peat to the atmosphere via the aerenchymous tissue. The model presented in this study connects the methane fluxes to the seasonal photosynthetic cycle of plants at the microsite level while the thermal and hydrological conditions in peat are used as an operational framework. Overall, the model dynamically combines the microbial processes in peat to changing environmental factors in the level of peatland ecosystem. Sensitivity analysis of the model reveals the importance of substrate supply to methane fluxes. Furthermore, the model outcome is sensitive to increased capability of the vascular plants to transport oxygen downwards. Lack of oxygen and partly methane keep methane oxidation at a very low level. Any changes in model parameters or environmental conditions that compensate for these lacks have a remarkable decreasing effect on simulated flux. Simulated methane flux decreases considerably if the duration of simulated dry period increases, threshold for a dramatic change lying between 4 and 6 weeks of drought. Increase in air temperature enhances methane flux especially if the effect of increased temperature on gross primary production is taken into account. (orig.)

  6. 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...

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

    Science.gov (United States)

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

    2016-01-01

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

  8. 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

  9. 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…

  10. Ruimte voor mediation

    NARCIS (Netherlands)

    Combrink-Kuiters, L.; Niemeijer, E.; Voert, M. ter

    2003-01-01

    Dit onderzoek is samen met ADR en mediation Rechterlijke macht gepubliceerd. Het doel was enerzijds na te gaan of, en onder welke condities, mediation in de Nederlandse context een effectief en efficiënt alternatief is voor de gerechtelijke geschillenbeslechting. Anderzijds inzicht te verwerven in d

  11. Metabolic fluxes in an illuminated Arabidopsis rosette.

    Science.gov (United States)

    Szecowka, Marek; Heise, Robert; Tohge, Takayuki; Nunes-Nesi, Adriano; Vosloh, Daniel; Huege, Jan; Feil, Regina; Lunn, John; Nikoloski, Zoran; Stitt, Mark; Fernie, Alisdair R; Arrivault, Stéphanie

    2013-02-01

    Photosynthesis is the basis for life, and its optimization is a key biotechnological aim given the problems of population explosion and environmental deterioration. We describe a method to resolve intracellular fluxes in intact Arabidopsis thaliana rosettes based on time-dependent labeling patterns in the metabolome. Plants photosynthesizing under limiting irradiance and ambient CO2 in a custom-built chamber were transferred into a (13)CO2-enriched environment. The isotope labeling patterns of 40 metabolites were obtained using liquid or gas chromatography coupled to mass spectrometry. Labeling kinetics revealed striking differences between metabolites. At a qualitative level, they matched expectations in terms of pathway topology and stoichiometry, but some unexpected features point to the complexity of subcellular and cellular compartmentation. To achieve quantitative insights, the data set was used for estimating fluxes in the framework of kinetic flux profiling. We benchmarked flux estimates to four classically determined flux signatures of photosynthesis and assessed the robustness of the estimates with respect to different features of the underlying metabolic model and the time-resolved data set.

  12. Music, Radio, and Mediatization

    DEFF Research Database (Denmark)

    Krogh, Mads; Michelsen, Morten

    2016-01-01

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

  13. 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......+ is a nonessential gene, while deletion of med11+ resulted in unviable cells. These results are in line with those obtained in S. cerevisiae. Isolation of S. pombe Mediator by the tandem affinity purification method and Co-IP experiments lead to the conclusion that Med9 and Med11 might not belong to the Mediator...... complex, but our results did not exclude it completely either. Our attempts to demonstrate the presence of these two subunits in the Mediator complex remain inconclusive primarily due to the lack of proper expression of the tagged versions of the proteins. However, we have paved a way to further...

  14. Flux-coupled genes and their use in metabolic flux analysis.

    Science.gov (United States)

    Kim, Hyun Uk; Kim, Won Jun; Lee, Sang Yup

    2013-09-01

    As large volumes of omics data have become available, systems biology is playing increasingly important roles in elucidating new biological phenomena, especially through genome-scale metabolic network modeling and simulation. Much effort has been exerted on integrating omics data with metabolic flux simulation, but further development is necessary for more accurate flux estimation. To move one step forward, we adopted the concept of flux-coupled genes (FCGs), which show that their expression transition patterns upon perturbations are correlated with their corresponding flux values, as additional constraints in metabolic flux analysis. It was found that gnd, pfkB, rpe, sdhB, sdhD, sucA, and zwf genes, mostly associated with pentose phosphate pathway and TCA cycle, were the most consistent FCGs in Escherichia coli based on its transcriptome and (13) C-flux data obtained from the chemostat cultivation at five different dilution rates. Consequently, constraints-based flux analyses with FCGs as additional constraints were conducted for the seven single-gene knockout mutants, compared with those obtained without using FCGs. This strategy of constraining the metabolic flux analysis with FCGs is expected to be useful due to the relative ease in obtaining transcriptional information in the functional genomics era.

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

    NARCIS (Netherlands)

    Velthof, G.L.; Oenema, O.

    1995-01-01

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

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

    Digital Repository Service at National Institute of Oceanography (India)

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

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

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

    Science.gov (United States)

    Al-Duwairi, Basheer N; Al-Hammouri, Ahmad T

    2014-07-01

    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.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2013-07-01

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

  19. A preliminary study for spatial representiveness of flux observation at ChinaFLUX sites

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    <正>The results of eddy covariance observation system could represent the physical process at certain area of the surface. Thus point-to-area representativeness was of primary interest in flux observation. This research presents a preliminary study for flux observation at ChinaFLUX sites by the use of observation data and Flux Source Area Model (FSAM). Results show that the footprint expands and is further away from flux tower when atmosphere becomes more stable, the observation height increases, or the surfaces become smoother. This suggests that the area represented by the flux observation becomes larger. The distances from the reference point to the maximum point Smax and the minimum point x1 of source weight function (Dmax and Dmin, respectively) can be influenced by atmosphere stability which becomes longer when atmosphere is more stable. For more rough surfaces and lower observation point Dmax and Dmin become shorter. This research gives the footprint at level P=90% at ChinaFLUX sites at different atmosphere stability. The preliminary results of spatial representiveness at ChinaFLUX sites were given based on the dominant wind direction and footprint response to various factors. The study also provides some theoretical basis for data quality control and evaluating data uncertainty.

  20. 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.

  1. From Hubble's NGSL to Absolute Fluxes

    Science.gov (United States)

    Heap, Sara R.; Lindler, Don

    2012-01-01

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

  2. The transient transpiration heat flux meter

    Energy Technology Data Exchange (ETDEWEB)

    Martins, N. [Dept. de Engenharia Mecanica-DEM, Universidade de Aveiro, Campus Universitario de Santiago, 3810-193 Aveiro (Portugal)]. E-mail: nmartins@mec.ua.pt; Calisto, H. [Dept. de Engenharia Mecanica-DEM, Universidade de Aveiro, Campus Universitario de Santiago, 3810-193 Aveiro (Portugal); Afgan, N. [Instituto Superior Tecnico, Av. Rovisco Pais, 1049-001 Lisbon (Portugal); Leontiev, A.I. [Moscow State Technical University, 2nd Baumanskaya Str. 5, Moscow 107005 (Russian Federation)

    2006-10-15

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

  3. 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.

  4. Evaluating Energy Flux in Vibrofluidized Granular Bed

    Directory of Open Access Journals (Sweden)

    N. A. Sheikh

    2013-01-01

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

  5. A helically distorted MHD flux rope model

    Science.gov (United States)

    Theobald, Michael L.; Montgomery, David

    1990-01-01

    A flux rope model is proposed which has a variable degree of helical distortion from axisymmetry. The basis for this suggestion is a series of numerical and analytical investigations of magnetohydrodynamic states which result when an axial electric current is directed down on dc magnetic field. The helically distorted states involve a flow velocity and seem to be favored because of their lower rate of energy dissipation. Emphasis is on the magnetometer and particle energy analyzer traces that might be characteristic of such flux ropes. It is shown that even a fractionally small helical distortion may considerably alter the traces in minimum-variance coordinates. In short, what may be fairly common MHD processes can render a flux rope almost unrecognizable under standard diagnostics, even if the departures from axisymmetry are not great.

  6. Flux-Feedback Magnetic-Suspension Actuator

    Science.gov (United States)

    Groom, Nelson J.

    1990-01-01

    Flux-feedback magnetic-suspension actuator provides magnetic suspension and control forces having linear transfer characteristics between force command and force output over large range of gaps. Hall-effect devices used as sensors for electronic feedback circuit controlling currents flowing in electromagnetic windings to maintain flux linking suspended element at substantially constant value independent of changes in length of gap. Technique provides effective method for maintenance of constant flux density in gap and simpler than previous methods. Applications include magnetic actuators for control of shapes and figures of antennas and of precise segmented reflectors, magnetic suspensions in devices for storage of angular momentum and/or kinetic energy, and systems for control, pointing, and isolation of instruments.

  7. 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.

  8. 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.

  9. 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.

  10. Freezing E3-brane instantons with fluxes

    Energy Technology Data Exchange (ETDEWEB)

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

    2012-07-15

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

  11. 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.

  12. Flux Analysis in Process Models via Causality

    CERN Document Server

    Kahramanoğullari, Ozan

    2010-01-01

    We present an approach for flux analysis in process algebra models of biological systems. We perceive flux as the flow of resources in stochastic simulations. We resort to an established correspondence between event structures, a broadly recognised model of concurrency, and state transitions of process models, seen as Petri nets. We show that we can this way extract the causal resource dependencies in simulations between individual state transitions as partial orders of events. We propose transformations on the partial orders that provide means for further analysis, and introduce a software tool, which implements these ideas. By means of an example of a published model of the Rho GTP-binding proteins, we argue that this approach can provide the substitute for flux analysis techniques on ordinary differential equation models within the stochastic setting of process algebras.

  13. 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

  14. Non-geometric fluxes and mixed-symmetry potentials

    NARCIS (Netherlands)

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

    2015-01-01

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

  15. 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.

  16. 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.

  17. Gamma-ray signal from Dark Matter Annihilation mediated by mixing scalar mediators

    CERN Document Server

    Teng, Fei

    2016-01-01

    We present here a study of the direct and indirect detection prospects of a generic dark matter simplified model, in which the Majorana dark matter interacts only with a Standard Model lepton and a pair of uncolored mixing scalar mediators. We first show that the mixing angle significantly changes the feature of internal bremsstrahlung, as well as the flux ratio of $\\gamma\\gamma$ and $\\gamma Z$ line signals. The $CP$-violation phase will introduce an polarization asymmetry in the $\\gamma\\gamma$ final state. Then we study the direct detection prospect and discuss the complimentarity of these two search strategies.

  18. Threshold corrections in heterotic flux compactifications

    CERN Document Server

    Angelantonj, Carlo; Sarkis, Matthieu

    2016-01-01

    We compute the one-loop threshold corrections to the gauge and gravitational couplings for a large class of N=2 non-K\\"ahler heterotic compactifications with three-form flux, consisting in principal two-torus bundles over K3 surfaces. We obtain the results as sums of BPS-states contributions, depending on the topological data of the bundle. We analyse also the worldsheet non-perturbative corrections coming from instantons wrapping the torus fiber, that are mapped under S-duality to D-instanton corrections in type I flux compactifications.

  19. Forward flux sampling for rare event simulations.

    Science.gov (United States)

    Allen, Rosalind J; Valeriani, Chantal; Rein Ten Wolde, Pieter

    2009-11-18

    Rare events are ubiquitous in many different fields, yet they are notoriously difficult to simulate because few, if any, events are observed in a conventional simulation run. Over the past several decades, specialized simulation methods have been developed to overcome this problem. We review one recently developed class of such methods, known as forward flux sampling. Forward flux sampling uses a series of interfaces between the initial and final states to calculate rate constants and generate transition paths for rare events in equilibrium or nonequilibrium systems with stochastic dynamics. This review draws together a number of recent advances, summarizes several applications of the method and highlights challenges that remain to be overcome.

  20. Constructing Hybrid Baryons with Flux Tubes

    CERN Document Server

    Capstick, Simon; Capstick, Simon; Page, Philip R.

    1999-01-01

    Hybrid baryon states are described in quark potential models as having explicit excitation of the gluon degrees of freedom. Such states are described in a model motivated by the strong coupling limit of Hamiltonian lattice gauge theory, where three flux tubes meeting at a junction play the role of the glue. The adiabatic approximation for the quark motion is used, and the flux tubes and junction are modeled by beads which are attracted to each other and the quarks by a linear potential, and vibrate in various string modes. Quantum numbers and estimates of the energies of the lightest hybrid baryons are provided.

  1. A Grid of Synthetic Stellar UV Fluxes

    CERN Document Server

    Rodríguez-Merino, L H; Buzzoni, A; Bertone, E; Rodriguez-Merino, Lino H.; Chavez, Miguel; Buzzoni, Alberto; Bertone, Emanuele

    2001-01-01

    We present preliminary results of a large project aimed at creating an extended theoretical and observational database of stellar spectra in the ultraviolet wavelength range. This library will consist of IUE spectra at low and high resolution, and a set of LTE and NLTE theoretical fluxes. A first grid of 50 model fluxes with solar metallicity, in the wavelength interval 1000 - 4400 AA, is reported here. Calculations are based on the Kurucz (1993) SYNTHE code. The models span effective temperatures between 10,000 K and 50,000 K, and a surface gravity in the range 2.5 <= log g <= 5.0 dex.

  2. 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.

  3. Energy Flux Positivity and Unitarity in CFTs

    CERN Document Server

    Kulaxizi, Manuela

    2010-01-01

    We show that in most conformal field theories the condition of the energy flux positivity, proposed by Hofman and Maldacena, is equivalent to the absence of ghosts. At finite temperature and large energy and momenta, the two-point functions of the stress energy tensor develop lightlike poles. The residues of the poles can be computed, as long as the only spin two conserved current, which appears in the stress energy tensor OPE and acquires nonvanishing expectation value at finite temperature, is the stress energy tensor. The condition for the residues to stay positive and the theory to remain ghost free is equivalent to the condition of positivity of energy flux.

  4. 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

  5. Measuring the Magnetic Flux Density with Flux Loops and Hall Probes in the CMS Magnet Flux Return Yoke

    CERN Document Server

    Curé, B; Ball, A; Gaddi, A; Gerwig, H; Hervé, A; Klyukhin, V I; Loveless, R; Mulders, M

    2016-01-01

    The Compact Muon Solenoid (CMS) is a general purpose detector, designed to run at the highest luminosity at the CERN Large Hadron Collider (LHC). Its distinctive features include a 4 T superconducting solenoid with 6-m-diameter by 12.5-m-length free bore, enclosed inside a 10,000-ton return yoke made of construction steel. The flux return yoke consists of five dodecagonal three-layered barrel wheels and four end-cap disks at each end comprised of steel blocks up to 620 mm thick, which serve as the absorber plates of the muon detection system. To measure the field in and around the steel, a system of 22 flux loops and 82 3-D Hall sensors is installed on the return yoke blocks. A TOSCA 3-D model of the CMS magnet is developed to describe the magnetic field everywhere outside the tracking volume that was measured with the field-mapping machine. The voltages induced in the flux loops by the magnetic flux changing during the CMS magnet standard ramps down are measured with six 16-bit DAQ modules. The off-line inte...

  6. Metal contaminant fluxes across the sediment water interface.

    Science.gov (United States)

    Frogner-Kockum, Paul; Göransson, Peter; Åslund, Henrik; Ländell, Märta; Stevens, Rodney; Tengberg, Anders; Göransson, Gunnel; Ohlsson, Yvonne

    2016-10-15

    To date, most estimates of contaminant fluxes across the sediment/water interface in risk assessments have been done using diffusive flux models. However, the reliability of these is limited as the overall flux from the sediment may have contributions caused by advection and bioturbation. We found through a comparison of modelled fluxes versus measured fluxes, that the methods Benthic Flux Chamber and surface leaching tests in a risk assessment context showed similar magnitude while calculated fluxes deviated at least by a factor of 100 from measured fluxes. This may be explained by the flux contribution in connection with bioturbation. The chamber-measured fluxes of copper were low compared to those of zinc and cobalt, but this is consistent with leaching tests that indicated copper to be more strongly bound. Risk assessments based on total concentrations may be misleading.

  7. Aflatoxin B1 Induces Reactive Oxygen Species-Mediated Autophagy and Extracellular Trap Formation in Macrophages

    Science.gov (United States)

    An, Yanan; Shi, Xiaochen; Tang, Xudong; Wang, Yang; Shen, Fengge; Zhang, Qiaoli; Wang, Chao; Jiang, Mingguo; Liu, Mingyuan; Yu, Lu

    2017-01-01

    Aflatoxins are a group of highly toxic mycotoxins with high carcinogenicity that are commonly found in foods. Aflatoxin B1 (AFB1) is the most toxic member of the aflatoxin family. A recent study reported that AFB1 can induce autophagy, but whether AFB1 can induce extracellular traps (ETs) and the relationships among innate immune responses, reactive oxygen species (ROS), and autophagy and the ETs induced by AFB1 remain unknown. Here, we demonstrated that AFB1 induced a complete autophagic process in macrophages (MΦ) (THP-1 cells and RAW264.7 cells). In addition, AFB1 induced the generation of MΦ ETs (METs) in a dose-dependent manner. In particular, the formation of METs significantly reduced the AFB1 content. Further analysis using specific inhibitors showed that the inhibition of either autophagy or ROS prevented MET formation caused by AFB1, indicating that autophagy and ROS were required for AFB1-induced MET formation. The inhibition of ROS prevented autophagy, indicating that ROS generation occurred upstream of AFB1-induced autophagy. Taken together, these data suggest that AFB1 induces ROS-mediated autophagy and ETs formation and an M1 phenotype in MΦ. PMID:28280716

  8. Presenilin 1 maintains lysosomal Ca2+ homeostasis by regulating vATPase-mediated lysosome acidification

    Science.gov (United States)

    Lee, Ju-Hyun; McBrayer, Mary Kate; Wolfe, Devin M.; Haslett, Luke J.; Kumar, Asok; Sato, Yutaka; Lie, Pearl P. Y.; Mohan, Panaiyur; Coffey, Erin E.; Kompella, Uday; Mitchell, Claire H.; Lloyd-Evans, Emyr; Nixon, Ralph A.

    2015-01-01

    Summary Presenilin-1 (PS1) deletion or Alzheimer’s Disease (AD)-linked mutations disrupt lysosomal acidification and proteolysis, which inhibits autophagy. Here, we establish that this phenotype stems from impaired glycosylation and instability of vATPase V0a1 subunit causing deficient lysosomal vATPase assembly and function. We further demonstrate that elevated lysosomal pH in PS1KO cells induces abnormal Ca2+ efflux from lysosomes mediated by TRPML1 and elevates cytosolic Ca2+. In WT cells, blocking vATPase activity or knockdown of either PS1 or the V0a1 subunit of vATPase reproduces all of these abnormalities. Normalizing lysosomal pH in PS1KO cells using acidic nanoparticles restores normal lysosomal proteolysis, autophagy, and Ca2+ homeostasis, but correcting lysosomal Ca2+ deficits alone neither re-acidifies lysosomes nor reverses proteolytic and autophagic deficits. Our results indicate that vATPase deficiency in PS1 loss of function states causes lysosomal/autophagy deficits and contributes to abnormal cellular Ca2+ homeostasis, thus linking two AD-related pathogenic processes through a common molecular mechanism. PMID:26299959

  9. [Mediation in health].

    Science.gov (United States)

    Decastello, Alice

    2008-02-10

    The author presents mediation as an alternative dispute resolution method. Mediation is a process where the parties are ready to settle their dispute out of court, by way of negotiation and with the involvement of an independent third person as mediator. In the mediation process the mediator shall not decide the dispute, nor examine the default or give legal advice or express his/her opinion - the mediator's duty is to help the parties bring their positions closer and come to a settlement agreement within a short time (120 days). The author gives a summary of the applications of the Hungarian Act on Mediation in Public Health and draws conclusions from the practical experience since entry into force of the legislation and illustrates the advantages of mediation over the court procedure (which may drag on for years). The primary advantages of mediation are that both the mediators and the parties are bound by the obligation of secrecy, the procedure is cheaper than the court proceedings, and the parties can "save their faces" because in mediation the winner-winner formula asserts itself - against lawsuits where the winner-loser positions are confronted. The author also analyses the specific data and information available so far. As for the future, the legislation needs to be amended at several points. It is particularly expedient to regulate the legal relationship between the insurance companies and the health service providers because the liability insurance may not cover the damages the courts adjudicate. And so some of the service providers may go bankrupt as the difference in excess of the upper limit of coverage - it might as well be up to HUF 5 million per case - shall be paid from own budget, to the charge of the upkeep costs. It is also required to review and amend the regulations on expert activities, just as it is inevitable to make data supply compulsory - otherwise it will be impossible to monitor the number of mediation procedures in health. At present

  10. 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.

  11. Fluxes of CH4 and N2O from soil under a tropical seasonal rain forest in Xishuangbanna, Southwest China

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    CH4 and N2O fluxes from soil under a tropical seasonal rain forest in Xishuangbanna, Southwest China were measured for one year using closed static chamber technique and gas chromatography method. Three treatments were set in the studied field: (A) litter-free,(B) with litter, and (C) with litter and seedling. The results showed that the soil in our study was a sink of atmospheric CH4 and source of atmospheric N2O. The observed mean CH4 fluxes from treatments A, B, and C were -50.0±4.0, -35.9±2.8,-31.6±2.8 μgC/(m2·h),respectively,and calculated annual fluxes in2003 were -4.1,-3.1,and -2.9kgC/hm2,respectively.The observed mean N2O fluxes from treatments A,B,and C were 30.9±3.1,28.2±3.5,50.2±3.7μgN/(m2·h),respectively,and calculated annual fluxes in 2003 were 2.8, 2.6, and 3.7 kgN/hm2, respectively. Seasonal variations in CH4 and N2O fluxes were significant among all the three treatments. The presence of litter decreased CH4 uptake during wet season (P < 0.05), but not during dry season. There was a similar increase in seedlings-mediated N2O emissions during wet and dry seasons, indicating that seedlings increased N2O emission in both seasons. A strong positive relationship existed between CH4 fluxes and soil moisture for all the three treatments, and weak relationship between CH4 fluxes and soil temperature for treatment B and treatment C. The N2O fluxes correlated with soil temperature for all the three treatments.

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

    DEFF Research Database (Denmark)

    Lu, Kaiyuan; Wu, Weimin

    2015-01-01

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

  13. 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.

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

    Science.gov (United States)

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

    2013-01-01

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

  15. 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%.

  16. Primary Metabolic Pathways and Metabolic Flux Analysis

    DEFF Research Database (Denmark)

    2015-01-01

    his chapter introduces the metabolic flux analysis (MFA) or stoichiometry-based MFA, and describes the quantitative basis for MFA. It discusses the catabolic pathways in which free energy is produced to drive the cell-building anabolic pathways. An overview of these primary pathways provides...

  17. 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...

  18. 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 flu......, and (iv) better impedance matching to a load....

  19. 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...

  20. 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%

  1. Statistics of Flux Vacua for Particle Physics

    CERN Document Server

    Watari, Taizan

    2015-01-01

    Supersymmetric flux compactification of F-theory in the geometric phase yields numerous vacua, and provides an ensemble of low-energy effective theories with different symmetry, matter multiplicity and Lagrangian parameters. Theoretical tools have already been developed so that we can study how the statistics of flux vacua depend on the choice of symmetry and some of Lagrangian parameters. In this article, we estimate the fraction of i) vacua that have a U(1) symmetry for spontaneous R-parity violation, and ii) those that realise ideas which achieve hierarchical eigenvalues of the Yukawa matrices. We also learn a lesson that the number of flux vacua is reduced very much when the unbroken $U(1)_Y$ symmetry is obtained from a non-trivial Mordell--Weil group, while it is not when $U(1)_Y$ is in SU(5) unification. It also turns out that vacua with an approximate U(1) symmetry forms a locus of accumulation points of the flux vacua distribution.

  2. 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.

  3. Reactor antineutrino fluxes – Status and challenges

    Energy Technology Data Exchange (ETDEWEB)

    Huber, Patrick, E-mail: pahuber@vt.edu

    2016-07-15

    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.

  4. Moduli Stabilization Using Open String Fluxes

    Science.gov (United States)

    Kumar, Alok

    2007-04-01

    In this talk we discuss how by turning on gauge fluxes which couple to the end-points of open strings one can obtain stabilization of closed string moduli. This is done by analyzing supersymmetry constraints and RR tadpole conditions. Stabilization of complex and Kahler moduli is studied in a T6/Z2 orientifold. REFID="9789812770523_0020FN001">.

  5. 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.

  6. Axion stabilization in type IIB flux compactifications

    NARCIS (Netherlands)

    Hristov, K.

    2009-01-01

    A scenario for stabilization of axionic moduli fields in the context of type IIB Calabi-Yau flux compactifications is discussed in detail. We consider the case of a Calabi-Yau orientifold with h1,1−≠0 which allows for the presence of B2 and C2-moduli. In an attempt to generalize the KKLT and the Lar

  7. Flip-Flopping Fractional Flux Quanta

    NARCIS (Netherlands)

    Ortlepp, T.; Ariando,; Mielke, O.; Verwijs, C.J.M.; Foo, K.F.K.; Rogalla, H.; Uhlmann, F.H.; Hilgenkamp, H.

    2006-01-01

    The d-wave pairing symmetry in high–critical temperature superconductors makes it possible to realize superconducting rings with built-in phase shifts. Such rings have a twofold degenerate ground state that is characterized by the spontaneous generation of fractional magnetic flux quanta with eithe

  8. 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

  9. 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

  10. 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

  11. What controls sediment flux in dryland channels?

    Science.gov (United States)

    Michaelides, K.; Singer, M. B.

    2010-12-01

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

  12. Technology-Use Mediation

    DEFF Research Database (Denmark)

    Bansler, Jørgen P.; Havn, Erling C.

    2004-01-01

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

  13. 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...

  14. Controlling flux flow dissipation by changing flux pinning in superconducting films

    Energy Technology Data Exchange (ETDEWEB)

    Grimaldi, G.; Leo, A.; Nigro, A.; Pace, S. [CNR SPIN Salerno and Dipartimento di Fisica ' ' E. R. Caianiello' ' , Universita degli Studi di Salerno, via Ponte Don Melillo, 84084 Fisciano (Italy); Silhanek, A. V. [Department de Physique, Universite de Liege, B-4000 Sart Tilman (Belgium); INPAC-Institute for Nanoscale Physics and Chemistry, Nanoscale Superconductivity and Magnetism Group, K. U. Leuven, Celestijnenlaan 200D, B-3001 Leuven (Belgium); Verellen, N.; Moshchalkov, V. V. [INPAC-Institute for Nanoscale Physics and Chemistry, Nanoscale Superconductivity and Magnetism Group, K. U. Leuven, Celestijnenlaan 200D, B-3001 Leuven (Belgium); Milosevic, M. V. [Departement Fysica, Universiteit Antwerpen, Groenenborgerlaan 171, B-2020 Antwerpen (Belgium); Casaburi, A.; Cristiano, R. [Istituto di Cibernetica ' ' E. Caianiello' ' , CNR, 80078 Pozzuoli (Italy)

    2012-05-14

    We study the flux flow state in superconducting materials characterized by rather strong intrinsic pinning, such as Nb, NbN, and nanostructured Al thin films, in which we drag the superconducting dissipative state into the normal state by current biasing. We modify the vortex pinning strength either by ion irradiation, by tuning the measuring temperature or by including artificial pinning centers. We measure critical flux flow voltages for all materials and the same effect is observed: switching to low flux flow dissipations at low fields for an intermediate pinning regime. This mechanism offers a way to additionally promote the stability of the superconducting state.

  15. ISEE-3 ULEWAT: flux tape description and heavy ion fluxes 1978-1984. [Plasma diagnostics

    Energy Technology Data Exchange (ETDEWEB)

    Mason, G.M.; Klecker, B.

    1985-12-01

    The ISEE ULEWAT FLUX tapes contain ULEWAT and ISEE pool tape data summarized over relatively long time intervals (1hr) in order to compact the data set into an easily usable size. (Roughly 3 years of data fit onto one 1600 BPI 9-track magnetic tape). In making the tapes, corrections were made to the ULEWAT basic data tapes in order to, remove rate spikes and account for changes in instrument response so that to a large extent instrument fluxes can be calculated easily from the FLUX tapes without further consideration of instrument performance.

  16. The ISEE-3 ULEWAT: Flux tape description and heavy ion fluxes 1978-1984. [plasma diagnostics

    Science.gov (United States)

    Mason, G. M.; Klecker, B.

    1985-01-01

    The ISEE ULEWAT FLUX tapes contain ULEWAT and ISEE pool tape data summarized over relatively long time intervals (1hr) in order to compact the data set into an easily usable size. (Roughly 3 years of data fit onto one 1600 BPI 9-track magnetic tape). In making the tapes, corrections were made to the ULEWAT basic data tapes in order to, remove rate spikes and account for changes in instrument response so that to a large extent instrument fluxes can be calculated easily from the FLUX tapes without further consideration of instrument performance.

  17. DREDed Anomaly Mediation

    CERN Document Server

    Boyda, E; Pierce, A T; Boyda, Ed; Murayama, Hitoshi; Pierce, Aaron

    2002-01-01

    We offer a guide to dimensional reduction (DRED) in theories with anomaly mediated supersymmetry breaking. Evanescent operators proportional to epsilon arise in the bare Lagrangian when it is reduced from d=4 to d= (4-2 epsilon) dimensions. In the course of a detailed diagrammatic calculation, we show that inclusion of these operators is crucial. The evanescent operators conspire to drive the supersymmetry-breaking parameters along anomaly-mediation trajectories across heavy particle thresholds, guaranteeing the ultraviolet insensitivity.

  18. Mesoscopic fluctuations in biharmonically driven flux qubits

    Science.gov (United States)

    Ferrón, Alejandro; Domínguez, Daniel; Sánchez, María José

    2017-01-01

    We investigate flux qubits driven by a biharmonic magnetic signal, with a phase lag that acts as an effective time reversal broken parameter. The driving induced transition rate between the ground and the excited state of the flux qubit can be thought of as an effective transmittance, profiting from a direct analogy between interference effects at avoided level crossings and scattering events in disordered electronic systems. For time scales prior to full relaxation, but large compared to the decoherence time, this characteristic rate has been accessed experimentally by Gustavsson et al. [Phys. Rev. Lett. 110, 016603 (2013)], 10.1103/PhysRevLett.110.016603 and its sensitivity with both the phase lag and the dc flux detuning explored. In this way, signatures of universal conductance fluctuationslike effects have been analyzed and compared with predictions from a phenomenological model that only accounts for decoherence, as a classical noise. Here we go beyond the classical noise model and solve the full dynamics of the driven flux qubit in contact with a quantum bath employing the Floquet-Born-Markov master equation. Within this formalism, the computed relaxation and decoherence rates turn out to be strongly dependent on both the phase lag and the dc flux detuning. Consequently, the associated pattern of fluctuations in the characteristic rates display important differences with those obtained within the mentioned phenomenological model. In particular, we demonstrate the weak localizationlike effect in the average values of the relaxation rate. Our predictions can be tested for accessible but longer time scales than the current experimental times.

  19. Parametrization of turbulent fluxes over inhomogeneous landscapes

    Science.gov (United States)

    Panin, G. N.; Bernhofer, Ch.

    2008-12-01

    Reasons for the nonclosure of the heat balance in the atmospheric boundary layers over natural land surfaces are analyzed. Results of measuring the heat-balance components over different land surfaces are used. The Cabauw (Netherlands) data (obtained throughout 1996 over a grass surface with intermittent shrubs and single trees) and the data from the Anchor station in Germany (measured over coniferous forest in 2000-2001) are analyzed. In all, the analysis involves about fifty thousand independent values of the heat-balance components measured in the experiments, which should be indicative of the reliability of the results obtained in the paper. The data have shown that the heat balance is not closed and the imbalance is 50-250 W/m2. The sum of the latent and sensible heat fluxes λ E + H = STF is found to be systematically smaller than the difference between the net radiation and the heat flux into the ground R n - G. It is shown that the main cause of a systematic heat imbalance in the atmospheric boundary layers over inhomogeneous land surfaces is that the methods of surface-flux measurement and estimation are based on the theory that requires the hypothesis of stationarity and horizontal homogeneity. Direct data analysis has shown that the heat imbalance increases with landscape inhomogeneity. In the paper, a parametrization of the heat imbalance is carried out and the coefficient k f ( z {0/ ef }/ L ef ) is introduced as a measure of inhomogeneity. For this, data from the experiments FIFE, KUREX, TARTEX, SADE, etc., are also used. Empirical formulas are presented to refine the results of direct measurements and calculations of surface fluxes over natural (inhomogeneous) land surfaces from profile and standard (using bulk parametrizations) data. These formulas can also be used to determine surface fluxes over inhomogeneous underlying land surfaces in order to take into account so-called subgrid-scale effects in constructing prediction models.

  20. Modern Estimates of Global Water Cycle Fluxes

    Science.gov (United States)

    Rodell, M.; Beaudoing, H. K.; L'Ecuyer, T. S.; Olson, W. S.

    2014-12-01

    The goal of the first phase of the NASA Energy and Water Cycle Study (NEWS) Water and Energy Cycle Climatology project was to develop "state of the global water cycle" and "state of the global energy cycle" assessments based on data from modern ground and space based observing systems and data integrating models. Here we describe results of the water cycle assessment, including mean annual and monthly fluxes over continents and ocean basins during the first decade of the millennium. To the extent possible, the water flux estimates are based on (1) satellite measurements and (2) data-integrating models. A careful accounting of uncertainty in each flux was applied within a routine that enforced multiple water and energy budget constraints simultaneously in a variational framework, in order to produce objectively-determined, optimized estimates. Simultaneous closure of the water and energy budgets caused the ocean evaporation and precipitation terms to increase by about 10% and 5% relative to the original estimates, mainly because the energy budget required turbulent heat fluxes to be substantially larger in order to balance net radiation. In the majority of cases, the observed annual, surface and atmospheric water budgets over the continents and oceans close with much less than 10% residual. Observed residuals and optimized uncertainty estimates are considerably larger for monthly surface and atmospheric water budget closure, often nearing or exceeding 20% in North America, Eurasia, Australia and neighboring islands, and the Arctic and South Atlantic Oceans. The residuals in South America and Africa tend to be smaller, possibly because cold land processes are a non-issue. Fluxes are poorly observed over the Arctic Ocean, certain seas, Antarctica, and the Australasian and Indonesian Islands, leading to reliance on atmospheric analysis estimates. Other details of the study and future directions will be discussed.

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

    Science.gov (United States)

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

    2015-01-31

    The Lysosomal Associated Membrane Protein type-2 (LAMP-2) is an abundant lysosomal membrane protein with an important role in immunity, macroautophagy (MA) and chaperone-mediated autophagy (CMA). Mutations within the Lamp2 gene cause Danon disease, an X-linked lysosomal storage disorder characterized by (cardio)myopathy and intellectual dysfunction. The pathological hallmark of this disease is an accumulation of glycogen and autophagic vacuoles in cardiac and skeletal muscle that, along with the myopathy, is also present in LAMP-2-deficient mice. Intellectual dysfunction observed in the human disease suggests a pivotal role of LAMP-2 within brain. LAMP-2A, one specific LAMP-2 isoform, was proposed to be important for the lysosomal degradation of selective proteins involved in neurodegenerative diseases such as Huntington's and Parkinson's disease. To elucidate the neuronal function of LAMP-2 we analyzed knockout mice for neuropathological changes, MA and steady-state levels of CMA substrates. The absence of LAMP-2 in murine brain led to inflammation and abnormal behavior, including motor deficits and impaired learning. The latter abnormality points to hippocampal dysfunction caused by altered lysosomal activity, distinct accumulation of p62-positive aggregates, autophagic vacuoles and lipid storage within hippocampal neurons and their presynaptic terminals. The absence of LAMP-2 did not apparently affect MA or steady-state levels of selected CMA substrates in brain or neuroblastoma cells under physiological and prolonged starvation conditions. Our data contribute to the understanding of intellectual dysfunction observed in Danon disease patients and highlight the role of LAMP-2 within the central nervous system, particularly the hippocampus.

  2. Dominance of ENSO-Like Variability in Controlling Tropical Ocean Surface Energy Fluxes in the Satellite Era

    Science.gov (United States)

    Robertson, F. R.; Miller, T. L.; Bosilovich, M. G.

    2008-01-01

    Ocean surface turbulent and radiative fluxes are critical links in the climate system since they mediate energy exchange between the two fluid systems (ocean and atmosphere) whose combined heat transport determines the basic character of Earth's climate. Moreover, interannual to decadal climate variability depends crucially on the nature of these exchange processes. For example, addressing the question of the degree to which the global hydrologic cycle is changing depends on our ability to observe and model these fluxes accurately. In this work we investigate the interannual to decadal variation of fluxes over the global tropics, especially the tropical oceans. Recent versions of satellite-derived fresh water flux estimates as well as some reanalyses (e.g. products from Remote Sensing Systems, the Woods Hole Oceanographic Institute, and Global Precipitation Climatology Project) suggest that increases in evaporation and precipitation over the past 20 years exceed those expected on the basis of climate model projected responses to greenhouse gas forcing. At the same time, it is well known that E1 Nino / Southern Oscillation behavior in the Pacific exhibits significant variability at scales longer than interannual. We examine here the degree to which surface fluxes attending these interannual to decadal fluctuations are related to ENSO. We examine consistency between these data sets and explore relationships between SST variations, flux changes and modulation of tropical Walker and Hadley circulations.

  3. Flux calculations in an inhomogeneous Universe: weighting a flux-limited galaxy sample

    CERN Document Server

    Koers, Hylke B J

    2009-01-01

    Many astrophysical problems arising within the context of ultra-high energy cosmic rays, very-high energy gamma rays or neutrinos, require calculation of the flux produced by sources tracing the distribution of galaxies in the Universe. We discuss a simple weighting scheme, an application of the method introduced by Lynden-Bell in 1971, that allows the calculation of the flux sky map directly from a flux-limited galaxy catalog without cutting a volume-limited subsample. Using this scheme, the galaxy distribution can be modeled up to large scales while representing the distribution in the nearby Universe with maximum accuracy. We consider fluctuations in the flux map arising from the finiteness of the galaxy sample. We show how these fluctuations are reduced by the weighting scheme and discuss how the remaining fluctuations limit the applicability of the method.

  4. Flux pileup in collisionless magnetic reconnection: bursty interaction of large flux ropes.

    Science.gov (United States)

    Karimabadi, H; Dorelli, J; Roytershteyn, V; Daughton, W; Chacón, L

    2011-07-08

    Using fully kinetic simulations of the island coalescence problem for a range of system sizes greatly exceeding kinetic scales, the phenomenon of flux pileup in the collisionless regime is demonstrated. While small islands on the scale of λ ≤ 5 ion inertial length (d(i)) coalesce rapidly and do not support significant flux pileup, coalescence of larger islands is characterized by large flux pileup and a weaker time averaged reconnection rate that scales as √(d(i)/λ) while the peak rate remains nearly independent of island size. For the largest islands (λ = 100d(i)), reconnection is bursty and nearly shuts off after the first bounce, reconnecting ~20% of the available flux.

  5. Estimating biological elementary flux modes that decompose a flux distribution by the minimal branching property

    DEFF Research Database (Denmark)

    Chan, Siu Hung Joshua; Solem, Christian; Jensen, Peter Ruhdal;

    2014-01-01

    MOTIVATION: Elementary flux mode (EFM) is a useful tool in constraint-based modeling of metabolic networks. The property that every flux distribution can be decomposed as a weighted sum of EFMs allows certain applications of EFMs to studying flux distributions. The existence of biologically...... infeasible EFMs and the non-uniqueness of the decomposition, however, undermine the applicability of such methods. Efforts have been made to find biologically feasible EFMs by incorporating information from transcriptional regulation and thermodynamics. Yet, no attempt has been made to distinguish...... reduced the solution space in which the decomposition is often unique. An experimental flux distribution from a previous study on mouse cardiomyocyte was decomposed using MBD. Comparison with decomposition by a minimum number of EFMs showed that MBD found EFMs more consistent with established biological...

  6. Regulation of bacterial sulfate reduction and hydrogen sulfide fluxes in the central Namibian coastal upwelling zone

    DEFF Research Database (Denmark)

    Bruchert, V.; Jørgensen, BB; Neumann, K.;

    2003-01-01

    and the low capacity to oxidize and trap sulfide. The inner shelf break marks the seaward border of sulfidic bottom waters, and separates two different regimes of bacterial sulfate reduction. In the sulfidic bottom waters on the shelf, up to 55% of sulfide oxidation is mediated by the large nitrate...... to the sediment-water interface and reduce the hydrogen sulfide flux to the water column. Modeling of pore water sulfide concentration profiles indicates that sulfide produced by bacterial sulfate reduction in the uppermost 16 cm of sediment is sufficient to account for the total flux of hydrogen sulfide...... to the water column. However, the total pool of hydrogen sulfide in the water column is too large to be explained by steady state diffusion across the sediment-water interface. Episodic advection of hydrogen sulfide, possibly triggered by methane eruptions, may contribute to hydrogen sulfide in the water...

  7. Exo-MFA - A 13C metabolic flux analysis framework to dissect tumor microenvironment-secreted exosome contributions towards cancer cell metabolism.

    Science.gov (United States)

    Achreja, Abhinav; Zhao, Hongyun; Yang, Lifeng; Yun, Tae Hyun; Marini, Juan; Nagrath, Deepak

    2017-01-11

    Dissecting the pleiotropic roles of tumor micro-environment (TME) on cancer progression has been brought to the foreground of research on cancer pathology. Extracellular vesicles such as exosomes, transport proteins, lipids, and nucleic acids, to mediate intercellular communication between TME components and have emerged as candidates for anti-cancer therapy. We previously reported that cancer-associated fibroblast (CAF) derived exosomes (CDEs) contain metabolites in their cargo that are utilized by cancer cells for central carbon metabolism and promote cancer growth. However, the metabolic fluxes involved in donor cells towards packaging of metabolites in extracellular vesicles and exosome-mediated metabolite flux upregulation in recipient cells are still not known. Here, we have developed a novel empirical and computational technique, exosome-mediated metabolic flux analysis (Exo-MFA) to quantify flow of cargo from source cells to recipient cells via vesicular transport. Our algorithm, which is based on (13)C metabolic flux analysis, successfully predicts packaging fluxes to metabolite cargo in CAFs, dynamic changes in rate of exosome internalization by cancer cells, and flux of cargo release over time. We find that cancer cells internalize exosomes rapidly leading to depletion of extracellular exosomes within 24h. However, metabolite cargo significantly alters intracellular metabolism over the course of 24h by regulating glycolysis pathway fluxes via lactate supply. Furthermore, it can supply up to 35% of the TCA cycle fluxes by providing TCA intermediates and glutamine. Our algorithm will help gain insight into (i) metabolic interactions in multicellular systems (ii) biogenesis of extracellular vesicles and their differential packaging of cargo under changing environments, and (iii) regulation of cancer cell metabolism by its microenvironment.

  8. Flux variability scanning based on enforced objective flux for identifying gene amplification targets

    Directory of Open Access Journals (Sweden)

    Park Jong

    2012-08-01

    Full Text Available Abstract Background In order to reduce time and efforts to develop microbial strains with better capability of producing desired bioproducts, genome-scale metabolic simulations have proven useful in identifying gene knockout and amplification targets. Constraints-based flux analysis has successfully been employed for such simulation, but is limited in its ability to properly describe the complex nature of biological systems. Gene knockout simulations are relatively straightforward to implement, simply by constraining the flux values of the target reaction to zero, but the identification of reliable gene amplification targets is rather difficult. Here, we report a new algorithm which incorporates physiological data into a model to improve the model’s prediction capabilities and to capitalize on the relationships between genes and metabolic fluxes. Results We developed an algorithm, flux variability scanning based on enforced objective flux (FVSEOF with grouping reaction (GR constraints, in an effort to identify gene amplification targets by considering reactions that co-carry flux values based on physiological omics data via “GR constraints”. This method scans changes in the variabilities of metabolic fluxes in response to an artificially enforced objective flux of product formation. The gene amplification targets predicted using this method were validated by comparing the predicted effects with the previous experimental results obtained for the production of shikimic acid and putrescine in Escherichia coli. Moreover, new gene amplification targets for further enhancing putrescine production were validated through experiments involving the overexpression of each identified targeted gene under condition-controlled batch cultivation. Conclusions FVSEOF with GR constraints allows identification of gene amplification targets for metabolic engineering of microbial strains in order to enhance the production of desired bioproducts. The algorithm

  9. An introduction to the Australian and New Zealand flux tower network - OzFlux

    Science.gov (United States)

    Beringer, Jason; Hutley, Lindsay B.; McHugh, Ian; Arndt, Stefan K.; Campbell, David; Cleugh, Helen A.; Cleverly, James; Resco de Dios, Víctor; Eamus, Derek; Evans, Bradley; Ewenz, Cacilia; Grace, Peter; Griebel, Anne; Haverd, Vanessa; Hinko-Najera, Nina; Huete, Alfredo; Isaac, Peter; Kanniah, Kasturi; Leuning, Ray; Liddell, Michael J.; Macfarlane, Craig; Meyer, Wayne; Moore, Caitlin; Pendall, Elise; Phillips, Alison; Phillips, Rebecca L.; Prober, Suzanne M.; Restrepo-Coupe, Natalia; Rutledge, Susanna; Schroder, Ivan; Silberstein, Richard; Southall, Patricia; Yee, Mei Sun; Tapper, Nigel J.; van Gorsel, Eva; Vote, Camilla; Walker, Jeff; Wardlaw, Tim

    2016-10-01

    OzFlux is the regional Australian and New Zealand flux tower network that aims to provide a continental-scale national research facility to monitor and assess trends, and improve predictions, of Australia's terrestrial biosphere and climate. This paper describes the evolution, design, and current status of OzFlux as well as provides an overview of data processing. We analyse measurements from all sites within the Australian portion of the OzFlux network and two sites from New Zealand. The response of the Australian biomes to climate was largely consistent with global studies except that Australian systems had a lower ecosystem water-use efficiency. Australian semi-arid/arid ecosystems are important because of their huge extent (70 %) and they have evolved with common moisture limitations. We also found that Australian ecosystems had a similar radiation-use efficiency per unit leaf area compared to global values that indicates a convergence toward a similar biochemical efficiency. The two New Zealand sites represented extremes in productivity for a moist temperate climate zone, with the grazed dairy farm site having the highest GPP of any OzFlux site (2620 gC m-2 yr-1) and the natural raised peat bog site having a very low GPP (820 gC m-2 yr-1). The paper discusses the utility of the flux data and the synergies between flux, remote sensing, and modelling. Lastly, the paper looks ahead at the future direction of the network and concludes that there has been a substantial contribution by OzFlux, and considerable opportunities remain to further advance our understanding of ecosystem response to disturbances, including drought, fire, land-use and land-cover change, land management, and climate change, which are relevant both nationally and internationally. It is suggested that a synergistic approach is required to address all of the spatial, ecological, human, and cultural challenges of managing the delicately balanced ecosystems in Australasia.

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

    OpenAIRE

    Nielsen Lars K; Wittmann Christoph; Quek Lake-Ee; Krömer Jens O

    2009-01-01

    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 ...

  11. 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

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

    Science.gov (United States)

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

    2011-12-01

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

  13. 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.

  14. 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...

  15. Killing activity of neutrophils is mediated through activation of proteases by K+ flux

    NARCIS (Netherlands)

    Reeves, EP; Lu, H; Lortat-Jacob, H; Messina, CGM; Bolsover, S; Gabella, G; Potma, EO; Warley, A; Roes, J; Segal, AW

    2002-01-01

    According to the hitherto accepted view, neutrophils kill ingested microorganisms by subjecting them to high concentrations of highly toxic reactive oxygen species (ROS) and bringing about myeloperoxidase-catalysed halogenation. We show here that this simple scheme, which for many years has served a

  16. 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.

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

    NARCIS (Netherlands)

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

    2008-01-01

    Extracellular potassium concentration, [K(+)](o), and intracellular calcium, [Ca(2+)](i), rise during neuron excitation, seizures and spreading depression. Astrocytes probably restrain the rise of K(+) in a way that is only partly understood. To examine the effect of glial K(+) uptake, we used a mod

  18. 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...

  19. First-order chemistry in the surface-flux layer

    DEFF Research Database (Denmark)

    Kristensen, L.; Andersen, C.E.; Ejsing Jørgensen, Hans

    1997-01-01

    We have discussed the behavior of a non-conserved scalar in the stationary, horizontally homogeneous, neutral surface-flux layer and, on the basis of conventional second-order closure, derived analytic expressions for flux and for mean concentration of a gas, subjected to a first-order removal...... process, The analytic flux solution showed a clear deviation from the constant flux, characterizing a conserved scalar in the surface-flux layer. It decreases with height and is reduced by an order of magnitude of the surface flux at a height equal to about the typical mean distance a molecule can travel...

  20. 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.

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

    DEFF Research Database (Denmark)

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

    2015-01-01

    Estimating representative surface fluxes using eddy covariance leads invariably to questions concerning inclusion or exclusion of low-frequency flux contributions. For studies where fluxes are linked to local physical parameters and up-scaled through numerical modelling efforts, low-frequency con......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...

  2. FluxPro: Real time monitoring and simulation system for eddy covariance flux measurement

    Science.gov (United States)

    Kim, W.; Seo, H.; Mano, M.; Ono, K.; Miyata, A.; Yokozawa, M.

    2010-12-01

    To cope with unusual weather changes on crop cultivation in a field level, prompt and precise monitoring of photosynthesis and evapotranspiration, and those fast and reliable forecasting are indispensable. So we have developed FluxPro which is simultaneous operating system of the monitoring and the forecasting. The monitoring subsystem provides vapor and CO2 fluxes with uncertainty to understand the live condition of photosynthesis and evapotranspiration by open-path eddy covariance flux measurement (EC) system and self-developed EC tolerance analysis scheme. The forecasting subsystem serves the predicted fluxes with anomaly based on model parameter assimilation to estimate the hourly or daily water consumption and carbon assimilation during a week by multi-simulation package consisting of various models from simple to complicate. FluxPro is helpful not only to detect a critical condition of growing crop in terms of photosynthesis and evapotranspiration but also to decide time and amount of launching control for keeping those optimization condition when an unusual weather event is arisen. In our presentation, we will demonstrate the FluxPro operated at tangerine orchard in Jeju, Korea.

  3. The effect of magnetic activity saturation in chromospheric flux-flux relationships

    CERN Document Server

    Martínez-Arnáiz, R M; Crespo-Chacón, I; Montes, D

    2011-01-01

    We present a homogeneous study of chromospheric and coronal flux-flux relationships using a sample of 298 late-type dwarf active stars with spectral types F to M. The chromospheric lines were observed simultaneously in each star to avoid spread due to long term variability. Unlike other works, we subtract the basal chromospheric contribution in all the spectral lines studied. For the first time, we quantify the departure of dMe stars from the general relations. We show that dK and dKe stars also deviate from the general trend. Studying the flux-colour diagrams we demonstrate that the stars deviating from the general relations are those with saturated X-ray emission and that those stars also present saturation in the H$\\alpha$ line. Using several age spectral indicators, we show that they are younger stars than those following the general relationships. The non-universality of flux-flux relationships found in this work should be taken into account when converting between fluxes in different chromospheric activ...

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

    Science.gov (United States)

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

    1999-05-01

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

  5. 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.

  6. IIB Soliton Spectra with All Fluxes Activated

    CERN Document Server

    Evslin, J

    2003-01-01

    Building upon an earlier proposal for the classification of fluxes, a sequence is proposed which generalizes the AHSS by computing type IIB string theory's group of conserved RR and also NS charges, which is conjectured to be a K-theory of dual pairs. As a test, the formalism of Maldacena, Moore and Seiberg (hep-th/0108100) is applied to classify D-branes, NS5-branes, F-strings and their dielectric counterparts in IIB compactified on a 3-sphere with both NS and RR background fluxes. The soliton spectra on the 3-sphere are then compared with the output of the sequence, as is the baryon spectrum in Witten's non-spin^c example, AdS^5xRP^5. The group of conserved charges is seen to change during Brown-Teitelboim-like phase transitions which change the effective cosmological constant.

  7. Pentaquark in the flux tube model

    Science.gov (United States)

    Iwasaki, M.; Takagi, F.

    2008-03-01

    We propose a model for pentaquarks in an excited state in the flux tube picture. The pentaquark is assumed to be composed of two diquarks and an antiquark connected by a color flux tube with a junction. If the pentaquark is rotating rapidly, it is polarized into two clusters: one is a diquark and the other is an antiquark plus another diquark. Excited energy of this quasilinear system is calculated with the use of the WKB approximation. It is predicted that there exist quasistable excited pentaquarks: 1690MeV(3/2+), 2000MeV(5/2-), 2250MeV(7/2+) etc., which decay mainly through three-body modes.

  8. Demystifying electric flux and Gauss's law

    Science.gov (United States)

    McManus, Jeff

    2017-04-01

    Many physics students have experienced the difficulty of internalizing concepts in electrostatics. After studying concrete, measurable details in mechanics, they are challenged by abstract ideas such as electric fields, flux, Gauss's law, and electric potential. There are a few well-known hands-on activities that help students get experience with these ideas. Perhaps the most popular are field-mapping activities in many forms ranging from metal electrodes in a shallow dish of water to metal pens and conductive paper. My experience of teaching with these activities in my AP Physics course left me disappointed and my students still mystified. Over the last several years, I have developed some hands-on activities that have helped my students better understand and apply these concepts. In this column, I will describe one such activity, a flux calculation that presents an opportunity to apply Gauss's law.

  9. 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 ...

  10. Synchronized flux limiting for gas dynamics variables

    Science.gov (United States)

    Lohmann, Christoph; Kuzmin, Dmitri

    2016-12-01

    This work addresses the design of failsafe flux limiters for systems of conserved quantities and derived variables in numerical schemes for the equations of gas dynamics. Building on Zalesak's multidimensional flux-corrected transport (FCT) algorithm, we construct a new positivity-preserving limiter for the density, total energy, and pressure. The bounds for the underlying inequality constraints are designed to enforce local maximum principles in regions of strong density variations and become less restrictive in smooth regions. The proposed approach leads to closed-form expressions for the synchronized correction factors without the need to solve inequality-constrained optimization problems. A numerical study is performed for the compressible Euler equations discretized using a finite element based FCT scheme.

  11. Flux qubit to a transmission line

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-07-01

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

  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. 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.

  14. Global Gluing and G-flux

    CERN Document Server

    Marsano, Joseph; Schafer-Nameki, Sakura

    2012-01-01

    Local models that capture the 7-brane physics of F-theory compactifications for supersymmetric GUTs are conveniently described in terms of an E_8 gauge theory in the presence of a Higgs bundle. Though the Higgs bundle data is usually determined by the local geometry and G-flux, additional gluing data must be specified whenever the Higgs bundle spectral cover is not smooth. In this paper, we argue that this additional information is determined by data of the M-theory 3-form that is not necessarily captured by the cohomology class of the G-flux. More specifically, we show that when the 3-form is specified in terms of a line bundle on a spectral divisor, which is a global extension of the Higgs bundle spectral cover, the gluing data of the local model is uniquely determined in a way that ensures agreement with Heterotic results whenever a Heterotic dual exists.

  15. Global gluing and G-flux

    Science.gov (United States)

    Marsano, Joseph; Saulina, Natalia; Schäfer-Nameki, Sakura

    2013-08-01

    Local models that capture the 7-brane physics of F-theory compactifications for supersymmetric GUTs are conveniently described in terms of an E 8 gauge theory in the presence of a Higgs bundle. Though the Higgs bundle data is usually determined by the local geometry and G-flux, additional gluing data must be specified whenever the Higgs bundle spectral cover is not smooth. In this paper, we argue that this additional information is determined by data of the M-theory 3-form that is not necessarily captured by the cohomology class of the G-flux. More specifically, we show that when the 3-form is specified in terms of a line bundle on a spectral divisor, which is a global extension of the Higgs bundle spectral cover, the gluing data of the local model is uniquely determined in a way that ensures agreement with Heterotic results whenever a Heterotic dual exists.

  16. Metadata based mediator generation

    Energy Technology Data Exchange (ETDEWEB)

    Critchlow, T

    1998-03-01

    Mediators are a critical component of any data warehouse, particularly one utilizing partially materialized views; they transform data from its source format to the warehouse representation while resolving semantic and syntactic conflicts. The close relationship between mediators and databases, requires a mediator to be updated whenever an associated schema is modified. This maintenance may be a significant undertaking if a warehouse integrates several dynamic data sources. However, failure to quickly perform these updates significantly reduces the reliability of the warehouse because queries do not have access to the m current data. This may result in incorrect or misleading responses, and reduce user confidence in the warehouse. This paper describes a metadata framework, and associated software designed to automate a significant portion of the mediator generation task and thereby reduce the effort involved in adapting the schema changes. By allowing the DBA to concentrate on identifying the modifications at a high level, instead of reprogramming the mediator, turnaround time is reduced and warehouse reliability is improved.

  17. Global ocean particulate organic carbon flux merged with satellite parameters

    Science.gov (United States)

    Mouw, Colleen B.; Barnett, Audrey; McKinley, Galen A.; Gloege, Lucas; Pilcher, Darren

    2016-10-01

    Particulate organic carbon (POC) flux estimated from POC concentration observations from sediment traps and 234Th are compiled across the global ocean. The compilation includes six time series locations: CARIACO, K2, OSP, BATS, OFP, and HOT. Efficiency of the biological pump of carbon to the deep ocean depends largely on biologically mediated export of carbon from the surface ocean and its remineralization with depth; thus biologically related parameters able to be estimated from satellite observations were merged at the POC observation sites. Satellite parameters include net primary production, percent microplankton, sea surface temperature, photosynthetically active radiation, diffuse attenuation coefficient at 490 nm, euphotic zone depth, and climatological mixed layer depth. Of the observations across the globe, 85 % are concentrated in the Northern Hemisphere with 44 % of the data record overlapping the satellite record. Time series sites accounted for 36 % of the data, while 71 % of the data are measured at ≥ 500 m with the most common deployment depths between 1000 and 1500 m. This data set is valuable for investigations of CO2 drawdown, carbon export, remineralization, and sequestration. The compiled data can be freely accessed at doi:10.1594/PANGAEA.855600.

  18. 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.

  19. 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.

  20. A Gap Junction Protein, Inx2, Modulates Calcium Flux to Specify Border Cell Fate during Drosophila oogenesis

    Science.gov (United States)

    Ghosh, Ritabrata; Deshpande, Girish

    2017-01-01

    Intercellular communication mediated by gap junction (GJ) proteins is indispensable during embryogenesis, tissue regeneration and wound healing. Here we report functional analysis of a gap junction protein, Innexin 2 (Inx2), in cell type specification during Drosophila oogenesis. Our data reveal a novel involvement of Inx2 in the specification of Border Cells (BCs), a migratory cell type, whose identity is determined by the cell autonomous STAT activity. We show that Inx2 influences BC fate specification by modulating STAT activity via Domeless receptor endocytosis. Furthermore, detailed experimental analysis has uncovered that Inx2 also regulates a calcium flux that transmits across the follicle cells. We propose that Inx2 mediated calcium flux in the follicle cells stimulates endocytosis by altering Dynamin (Shibire) distribution which is in turn critical for careful calibration of STAT activation and, thus for BC specification. Together our data provide unprecedented molecular insights into how gap junction proteins can regulate cell-type specification. PMID:28114410

  1. Long term BVOC fluxes above mountain grassland

    Directory of Open Access Journals (Sweden)

    I. Bamberger

    2010-01-01

    Full Text Available Grasslands comprise natural tropical savannah over managed temperate fields to tundra and cover over a 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 due to 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. The two independent methods obtained methanol fluxes following a regression line of y=0.94x−0.06 (correlation factor: R2=0.94. Methanol showed strong daytime emissions throughout the growing season. With maximal values of 9.7 nmol m−2 s−1 the methanol fluxes from 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. During the growth only methanol emissions were observed. The cutting and drying of the grass increased the emissions of methanol, up to 30 nmol m−2 s−2. In addition, emissions of acetaldehyde, up to 10 nmol m−2 s−1, and hexenal (leaf aldehyde were detected during harvesting.

  2. Freshwater flux to Sermilik Fjord, SE Greenland

    Directory of Open Access Journals (Sweden)

    S. H. Mernild

    2010-07-01

    Full Text Available Fluctuations in terrestrial surface freshwater flux to Sermilik Fjord, SE Greenland, were simulated and analyzed. SnowModel, a state-of-the-art snow-evolution, snow and ice melt, and runoff modeling system, was used to simulate the temporal and spatial terrestrial runoff distribution to the fjord based on observed meteorological data (1999–2008 from stations located on and around the Greenland Ice Sheet (GrIS. Simulated runoff was compared and verified against independent glacier catchment runoff observations (1999–2005. Modeled runoff to Sermilik Fjord was highly variable, ranging from 2.9×109 m3 y−1 in 1999 to 5.9×109 m3 y−1 in 2005. The uneven spatial runoff distribution produced an areally-averaged annual maximum runoff at the Helheim glacier terminus of more than 3.8 m w.eq. The sub-catchment runoff of the Helheim glacier region accounted for 25% of the total runoff to Sermilik Fjord. The runoff distribution from the different sub-catchments suggested a strong influence from the spatial variation in glacier coverage. To assess the Sermilik Fjord freshwater flux, simulated terrestrial runoff and net precipitation (precipitation minus evaporation and sublimation for the fjord area were combined with satellite-derived ice discharge and subglacial geothermal and frictional melting due to basal ice motion. A terrestrial freshwater flux of ~40.4×109 m3 y−1 was found for Sermilik Fjord, with an 11% contribution originated from surface runoff. For the Helheim glacier sub-catchment only 4% of the flux originated from terrestrial surface runoff.

  3. Proton Flux Anisotropy in Low Earth Orbit

    Science.gov (United States)

    2007-12-03

    by incident particles, that that the integral flux for energy > ET calculated by inte- grating the response function with an estimated isotropic powerA...incident protons was extensively modeled using the Monte procedure as described below. Carlo MCNPX computer code which simulates the passage of 3...degrees in longitude ferent calculations is very good. and latitude and 50 km in altitude over the range 400-1650 km. For this study three specific CEASE

  4. Magnetic flux reconstruction methods for shaped tokamaks

    Energy Technology Data Exchange (ETDEWEB)

    Tsui, Chi-Wa

    1993-12-01

    The use of a variational method permits the Grad-Shafranov (GS) equation to be solved by reducing the problem of solving the 2D non-linear partial differential equation to the problem of minimizing a function of several variables. This high speed algorithm approximately solves the GS equation given a parameterization of the plasma boundary and the current profile (p` and FF` functions). The author treats the current profile parameters as unknowns. The goal is to reconstruct the internal magnetic flux surfaces of a tokamak plasma and the toroidal current density profile from the external magnetic measurements. This is a classic problem of inverse equilibrium determination. The current profile parameters can be evaluated by several different matching procedures. Matching of magnetic flux and field at the probe locations using the Biot-Savart law and magnetic Green`s function provides a robust method of magnetic reconstruction. The matching of poloidal magnetic field on the plasma surface provides a unique method of identifying the plasma current profile. However, the power of this method is greatly compromised by the experimental errors of the magnetic signals. The Casing Principle provides a very fast way to evaluate the plasma contribution to the magnetic signals. It has the potential of being a fast matching method. The performance of this method is hindered by the accuracy of the poloidal magnetic field computed from the equilibrium solver. A flux reconstruction package has been implemented which integrates a vacuum field solver using a filament model for the plasma, a multi-layer perception neural network as an interface, and the volume integration of plasma current density using Green`s functions as a matching method for the current profile parameters. The flux reconstruction package is applied to compare with the ASEQ and EFIT data. The results are promising.

  5. Axial flux permanent magnet brushless machines

    CERN Document Server

    Gieras, Jacek F; Kamper, Maarten J

    2008-01-01

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

  6. 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.

  7. 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.

  8. FAST FLUX TEST FACILITY DRIVER FUEL MEETING

    Energy Technology Data Exchange (ETDEWEB)

    None,

    1966-06-01

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

  9. Heat flux modulation in domino dynamo model

    CERN Document Server

    Reshetnyak, Maxim

    2012-01-01

    Using domino dynamo model we show how variations of the heat flux at the core-mantle boundary change frequency of geomagnetic field reversals. In fact, we are able to demonstrate effect known from the modern 3D planetary dynamo models using ensemble of the interacting spins, which obey equations of the Langevin-type with a random force. We also consider applications to the giant- planets and offer explanations of some specific episodes of the geomagnetic field in the past.

  10. Periods of High Intensity Solar Proton Flux

    Science.gov (United States)

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

    2012-01-01

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

  11. Reduction of Decoherence in the Flux Qubit

    Science.gov (United States)

    2014-12-08

    110.147002 J. Aumentado, K. W. Murch, L. Friedland, I. Siddiqi, R. Vijay, I. Barth, O. Naaman. Quantum fluctuations in the chirped pendulum , Nature...from the reversal of spins on the upper and lower surfaces of the superconducting films. Flux noise has a spectral density that scales as 1/f...fα noise via spin reversals with a broad range of time constants. The temperature dependent exponent α(T) approaches unity as the temperature is

  12. Transformation thermodynamics: cloaking and concentrating heat flux.

    Science.gov (United States)

    Guenneau, Sebastien; Amra, Claude; Veynante, Denis

    2012-03-26

    We adapt tools of transformation optics, governed by a (elliptic) wave equation, to thermodynamics, governed by the (parabolic) heat equation. We apply this new concept to an invibility cloak in order to thermally protect a region (a dead core) and to a concentrator to focus heat flux in a small region. We finally propose a multilayered cloak consisting of 20 homogeneous concentric layers with a piecewise constant isotropic diffusivity working over a finite time interval (homogenization approach).

  13. MAGNETIC FLUX SUPPLEMENT TO CORONAL BRIGHT POINTS

    Energy Technology Data Exchange (ETDEWEB)

    Mou, Chaozhou; Huang, Zhenghua; Xia, Lidong; Li, Bo; Fu, Hui; Jiao, Fangran; Hou, Zhenyong [Shandong Provincial Key Laboratory of Optical Astronomy and Solar-Terrestrial Environment, Institute of Space Sciences, Shandong University, Weihai, 264209 Shandong (China); Madjarska, Maria S., E-mail: z.huang@sdu.edu.cn [Armagh Observatory, College Hill, Armagh BT61 9DG (United Kingdom)

    2016-02-10

    Coronal bright points (BPs) are associated with magnetic bipolar features (MBFs) and magnetic cancellation. Here we investigate how BP-associated MBFs form and how the consequent magnetic cancellation occurs. We analyze longitudinal magnetograms from the Helioseismic and Magnetic Imager to investigate the photospheric magnetic flux evolution of 70 BPs. From images taken in the 193 Å passband of the Atmospheric Imaging Assembly (AIA) we dermine that the BPs’ lifetimes vary from 2.7 to 58.8 hr. The formation of the BP MBFs is found to involve three processes, namely, emergence, convergence, and local coalescence of the magnetic fluxes. The formation of an MBF can involve more than one of these processes. Out of the 70 cases, flux emergence is the main process of an MBF buildup of 52 BPs, mainly convergence is seen in 28, and 14 cases are associated with local coalescence. For MBFs formed by bipolar emergence, the time difference between the flux emergence and the BP appearance in the AIA 193 Å passband varies from 0.1 to 3.2 hr with an average of 1.3 hr. While magnetic cancellation is found in all 70 BPs, it can occur in three different ways: (I) between an MBF and small weak magnetic features (in 33 BPs); (II) within an MBF with the two polarities moving toward each other from a large distance (34 BPs); (III) within an MBF whose two main polarities emerge in the same place simultaneously (3 BPs). While an MBF builds up the skeleton of a BP, we find that the magnetic activities responsible for the BP heating may involve small weak fields.

  14. Quantifying nutrient fluxes with a new hyporheic passive flux meter (HPFM)

    Science.gov (United States)

    Kunz, Julia Vanessa; Annable, Michael D.; Cho, Jaehyun; von Tümpling, Wolf; Hatfield, Kirk; Rao, Suresh; Borchardt, Dietrich; Rode, Michael

    2017-02-01

    The hyporheic zone is a hotspot of biogeochemical turnover and nutrient removal in running waters. However, nutrient fluxes through the hyporheic zone are highly variable in time and locally heterogeneous. Resulting from the lack of adequate methodologies to obtain representative long-term measurements, our quantitative knowledge on transport and turnover in this important transition zone is still limited.In groundwater systems passive flux meters, devices which simultaneously detect horizontal water and solute flow through a screen well in the subsurface, are valuable tools for measuring fluxes of target solutes and water through those ecosystems. Their functioning is based on accumulation of target substances on a sorbent and concurrent displacement of a resident tracer which is previously loaded on the sorbent.Here we evaluate the applicability of this methodology for investigating water and nutrient fluxes in hyporheic zones. Based on laboratory experiments we developed hyporheic passive flux meters (HPFMs) with a length of 50 cm which were separated in 5-7 segments allowing for vertical resolution of horizontal nutrient and water transport. The HPFMs were tested in a 7 day field campaign including simultaneous measurements of oxygen and temperature profiles and manual sampling of pore water. The results highlighted the advantages of the novel method: with HPFMs, cumulative values for the average N and P flux during the complete deployment time could be captured. Thereby the two major deficits of existing methods are overcome: first, flux rates are measured within one device instead of being calculated from separate measurements of water flow and pore-water concentrations; second, time-integrated measurements are insensitive to short-term fluctuations and therefore deliver more representable values for overall hyporheic nutrient fluxes at the sampling site than snapshots from grab sampling. A remaining limitation to the HPFM is the potential susceptibility to

  15. Greenhouse gas flux dynamics in wetlands

    Energy Technology Data Exchange (ETDEWEB)

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

    1996-12-31

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

  16. Ion flux profiles observed at Mars

    Science.gov (United States)

    Fowler, C. M.; Andersson, L.; Lundin, R. N.; Frahm, R. A.

    2012-12-01

    How Mars lost it's water and atmosphere is still an important question. Many studies have investigated high-energy ion fluxes (>10 eV) surrounding the planet and derived ion outflow rates in order to determine atmospheric loss. These rates suggest that the outflow from high-energy ions is not the dominant escape path for atmospheric loss. Over the years increasing evidence has indicated that the loss of low-energy ions are more important than the high-energy ion loss. In this presentation ion observations (down to the spacecraft potential) from the Mars Express (MEX) mission (2010/11), are used to describe the ion altitude distribution at Mars. The focus of this study is below the altitude of ~1000 km. Within the Mars environment, using the MEX electron observations different plasma regions was identified. Supported by electron identification, different altitude profiles of ion fluxes have been analyzed from the different plasma regions. One of the results from this study is that the altitude profile of the ion flux observed below the photoelectron boundary is different when comparing the northern and the southern hemispheres. The ion distributions, resulting altitude profile, the influence of the crustal magnetic field at Mars, and the implications relating to plasma outflow will be discussed in this presentation.

  17. Galactic dynamos supported by magnetic helicity fluxes

    CERN Document Server

    Sur, S; Subramanian, K; Sur, Sharanya; Shukurov, Anvar; Subramanian, Kandaswamy

    2006-01-01

    We present a simple semi-analytical model of nonlinear, mean-field galactic dynamos and use it to study the effects of various magnetic helicity fluxes. The dynamo equations are reduced using the `no-$z$' approximation to a nonlinear system of ordinary differential equations in time; we demonstrate that the model reproduces accurately earlier results, including those where nonlinear behaviour is driven by a magnetic helicity flux. We discuss the implications and interplay of two types of magnetic helicity flux, one produced by advection (e.g., due to the galactic fountain or wind) and the other, arising from anisotropy of turbulence as suggested by Vishniac & Cho(2001). We argue that the latter is significant if the galactic differential rotation is strong enough: in our model, for $\\Rw\\la-10$ in terms of the corresponding turbulent magnetic Reynolds number. We confirm that the intensity of gas outflow from the galactic disc optimal for the dynamo action is close to that expected for normal spiral galaxie...

  18. Astronomical Flux Standards: Getting to 1%

    Science.gov (United States)

    Deustua, Susana; Cikota, Aleksandar; Hines, Dean C.; Bohlin, Ralph; Gordon, Karl

    2015-08-01

    The objective for pursuing sub-1% absolute photometric accuracies, and, establishing the Absolute Physical Flux of ever fainter standard stars, is motivated by the requirements of Dark Energy science with JWST and other facilities. Even with the best data available, the current determination of absolute physical flux is is plagued by the reliance on the Vega photometric system, which is known to be problematic primarily due to the fact that Vega is a pole-on rapid rotator with an infrared excess from its circumstellar disk! which makes it difficult to model. Vega is also far too bright for large aperture telescopes. In an effort to remedy these difficulties, teams from e.g. the National Institute of Standards (NIST), University of New Mexico, Johns Hopkins University and STScI have begun to develop a catalog of stars that have spectral energy distributions that are tied directly to SI (diode) standards with very precisely determined physical characteristics. A key element in this pursuit has been the efforts at STScI to measure the spectra of many of these objects with STIS. We discuss our program to extend this effort into the near-IR which is crucial to reliably extend the SEDs to longer wavelengths, including the mid IR. We describe results from our effort towards 1% absolute color calibration in the UV-VIS-NIR with Hubble Space Telescope's WFC3/IR observations of 15 carefully selected stars with the immediate objective of establishing their absolute flux.

  19. Stochastic flux freezing and magnetic dynamo.

    Science.gov (United States)

    Eyink, Gregory L

    2011-05-01

    Magnetic flux conservation in turbulent plasmas at high magnetic Reynolds numbers is argued neither to hold in the conventional sense nor to be entirely broken, but instead to be valid in a statistical sense associated to the "spontaneous stochasticity" of Lagrangian particle trajectories. The latter phenomenon is due to the explosive separation of particles undergoing turbulent Richardson diffusion, which leads to a breakdown of Laplacian determinism for classical dynamics. Empirical evidence is presented for spontaneous stochasticity, including numerical results. A Lagrangian path-integral approach is then exploited to establish stochastic flux freezing for resistive hydromagnetic equations and to argue, based on the properties of Richardson diffusion, that flux conservation must remain stochastic at infinite magnetic Reynolds number. An important application of these results is the kinematic, fluctuation dynamo in nonhelical, incompressible turbulence at magnetic Prandtl number (Pr(m)) equal to unity. Numerical results on the Lagrangian dynamo mechanisms by a stochastic particle method demonstrate a strong similarity between the Pr(m)=1 and 0 dynamos. Stochasticity of field-line motion is an essential ingredient of both. Finally, some consequences for nonlinear magnetohydrodynamic turbulence, dynamo, and reconnection are briefly considered.

  20. Flux-gate magnetometer for Mars exploration

    Science.gov (United States)

    Zhao, Hua; Zhu, G. W.; Yu, P.; Wang, J. D.; Yu, M. F.; Li, L.; Sun, Y. Q.; Chen, S. W.; Liao, H. Z.; Zhou, B.; Feng, Y. Y.

    2008-10-01

    A micro-satellite, Yinghuo-1, would be launched with Russian spacecraft, Phobos-Grunt in October, 2009 to investigate the space environment around Mars. YH-1 and Phobos-Grunt forms a two-point measurement configuration in the Martian space environment. YH-1 and Phobos-Grunt are equipped with similar magnetic field and plasma detecting payload on two spacecraft would give some coordinated exploration around Mars. YH-1 would orbit Mars with periapsis of 800 km above the Martian surface, and apoapsis about 80000km to the center of Mars. The orbit inclination is in the range of 0~7° to the Martian equator. A flux-gate type magnetometer, with two tri-axial sensors, is developed for YH-1 spacecraft. Two sensors are mounted on one-side of the deployable solar panel with a radial separation about 45cm to function as a gradiometer to minimize the affects of platform remanence. The dynamic range of the magnetometer is +/-256nT with a 16-bit ADC converter, and the noise level is better than 0.01nT/√Hz, to measure three-component magnetic field from DC to 10Hz. Flux-gate magnetometer would work together with the Plasma Package onboard of YH-1 to investigate the Martian bow shock, magnetosheath, magnetic pileup region (MPR). A detail description of the flux-gate magnetometer is presented in this paper, with test and calibration results.