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Sample records for cd95 death-inducing signaling

  1. Yes and PI3K bind CD95 to signal invasion of glioblastoma.

    PubMed

    Kleber, Susanne; Sancho-Martinez, Ignacio; Wiestler, Benedict; Beisel, Alexandra; Gieffers, Christian; Hill, Oliver; Thiemann, Meinolf; Mueller, Wolf; Sykora, Jaromir; Kuhn, Andreas; Schreglmann, Nina; Letellier, Elisabeth; Zuliani, Cecilia; Klussmann, Stefan; Teodorczyk, Marcin; Gröne, Hermann-Josef; Ganten, Tom M; Sültmann, Holger; Tüttenberg, Jochen; von Deimling, Andreas; Regnier-Vigouroux, Anne; Herold-Mende, Christel; Martin-Villalba, Ana

    2008-03-01

    Invasion of surrounding brain tissue by isolated tumor cells represents one of the main obstacles to a curative therapy of glioblastoma multiforme. Here we unravel a mechanism regulating glioma infiltration. Tumor interaction with the surrounding brain tissue induces CD95 Ligand expression. Binding of CD95 Ligand to CD95 on glioblastoma cells recruits the Src family member Yes and the p85 subunit of phosphatidylinositol 3-kinase to CD95, which signal invasion via the glycogen synthase kinase 3-beta pathway and subsequent expression of matrix metalloproteinases. In a murine syngeneic model of intracranial GBM, neutralization of CD95 activity dramatically reduced the number of invading cells. Our results uncover CD95 as an activator of PI3K and, most importantly, as a crucial trigger of basal invasion of glioblastoma in vivo. PMID:18328427

  2. CD95 co-stimulation blocks activation of naive T cells by inhibiting T cell receptor signaling

    PubMed Central

    Lindquist, Jonathan A.; Arhel, Nathalie; Felder, Edward; Karl, Sabine; Haas, Tobias L.; Fulda, Simone; Walczak, Henning; Kirchhoff, Frank; Debatin, Klaus-Michael

    2009-01-01

    CD95 is a multifunctional receptor that induces cell death or proliferation depending on the signal, cell type, and cellular context. Here, we describe a thus far unknown function of CD95 as a silencer of T cell activation. Naive human T cells triggered by antigen-presenting cells expressing a membrane-bound form of CD95 ligand (CD95L) or stimulated by anti-CD3 and -CD28 antibodies in the presence of recombinant CD95L had reduced activation and proliferation, whereas preactivated, CD95-sensitive T cells underwent apoptosis. Triggering of CD95 during T cell priming interfered with proximal T cell receptor signaling by inhibiting the recruitment of ζ-chain–associated protein of 70 kD, phospholipase-γ, and protein kinase C-θ into lipid rafts, thereby preventing their mutual tyrosine protein phosphorylation. Subsequently, Ca2+ mobilization and nuclear translocation of transcription factors NFAT, AP1, and NF-κB were strongly reduced, leading to impaired cytokine secretion. CD95-mediated inhibition of proliferation in naive T cells could not be reverted by the addition of exogenous interleukin-2 and T cells primed by CD95 co-stimulation remained partially unresponsive upon secondary T cell stimulation. HIV infection induced CD95L expression in primary human antigeen-presenting cells, and thereby suppressed T cell activation, suggesting that CD95/CD95L-mediated silencing of T cell activation represents a novel mechanism of immune evasion. PMID:19487421

  3. Physalis peruviana extract induces apoptosis in human Hep G2 cells through CD95/CD95L system and the mitochondrial signaling transduction pathway.

    PubMed

    Wu, Shu-Jing; Ng, Lean-Teik; Lin, Doung-Liang; Huang, Shan-Ney; Wang, Shyh-Shyan; Lin, Chun-Ching

    2004-11-25

    Physalis species is a popular folk medicine used for treating cancer, leukemia, hepatitis and other diseases. Studies have shown that the ethanol extract of Physalis peruviana (EEPP) inhibits growth and induces apoptotic death of human Hep G2 cells in culture, whereas proliferation of the mouse BALB/C normal liver cells was not affected. In this study, we performed detailed studies to define the molecular mechanism of EEPP-induced apoptosis in Hep G2 cells. The results further confirmed that EEPP inhibited cell proliferation in a dose- and time-dependent manner. At 50 microg/ml, EEPP significantly increased the accumulation of the sub-G1 peak (hypoploid) and the portion of apoptotic annexin V positive cells. EEPP was found to trigger apoptosis through the release of cytochrome c, Smac/DIABLO and Omi/HtrA2 from mitochondria to cytosol and consequently resulted in caspase-3 activation. Pre-treatment with a general caspase inhibitor (z-VAD-fmk) prevented cytochrome c release. After 48 h of EEPP treatment, the apoptosis of Hep G2 cells was found to associate with an elevated p53, and CD95 and CD95L proteins expression. Furthermore, a marked down-regulation of the expression of the Bcl-2, Bcl-XL and XIAP, and up-regulation of the Bax and Bad proteins were noted. Taken together, the present results suggest that EEPP-induced Hep G2 cell apoptosis was possibly mediated through the CD95/CD95L system and the mitochondrial signaling transduction pathway. PMID:15488639

  4. Liposomal ET-18-OCH(3) induces cytochrome c-mediated apoptosis independently of CD95 (APO-1/Fas) signaling.

    PubMed

    Cuvillier, O; Mayhew, E; Janoff, A S; Spiegel, S

    1999-11-15

    ELL-12, a liposome formulation of the ether-lipid 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (ET-18-OCH(3)), is a nonmyelosuppressive antiproliferative agent that is more effective and less toxic than the ether lipid itself in tumor model systems. We found that ELL-12 induced apoptosis in Jurkat, H9, and U-937 cells that was preceded by activation of executioner caspases. In addition, ELL-12 triggered release of cytochrome c from mitochondria to the cytoplasm before caspase-9 activation. Apoptosis, activation of caspases, and cytochrome c release were blocked by Bcl-x(L) overexpression in Jurkat T cells, suggesting a critical role for mitochondria in ELL-12-triggered cell death. Furthermore, ELL-12 had no effect on expression of CD95 ligand, and inhibition of the Fas signaling pathway with antagonistic anti-CD95 antibody did not affect apoptosis induced by ELL-12. Hence, ELL-12 could be a promising adjunct for the treatment of tumors in addition to myelosuppressive chemotherapeutic drugs and/or those that use the CD95-ligand/receptor system to trigger apoptosis. PMID:10552970

  5. Ligand stimulation of CD95 induces activation of Plk3 followed by phosphorylation of caspase-8

    PubMed Central

    Helmke, Christina; Raab, Monika; Rödel, Franz; Matthess, Yves; Oellerich, Thomas; Mandal, Ranadip; Sanhaji, Mourad; Urlaub, Henning; Rödel, Claus; Becker, Sven; Strebhardt, Klaus

    2016-01-01

    Upon interaction of the CD95 receptor with its ligand, sequential association of the adaptor molecule FADD (MORT1), pro-forms of caspases-8/10, and the caspase-8/10 regulator c-FLIP leads to the formation of a death-inducing signaling complex. Here, we identify polo-like kinase (Plk) 3 as a new interaction partner of the death receptor CD95. The enzymatic activity of Plk3 increases following interaction of the CD95 receptor with its ligand. Knockout (KO) or knockdown of caspase-8, CD95 or FADD prevents activation of Plk3 upon CD95 stimulation, suggesting a requirement of a functional DISC for Plk3 activation. Furthermore, we identify caspase-8 as a new substrate for Plk3. Phosphorylation occurs on T273 and results in stimulation of caspase-8 proapoptotic function. Stimulation of CD95 in cells expressing a non-phosphorylatable caspase-8-T273A mutant in a rescue experiment or in Plk3-KO cells generated by CRISPR/Cas9 reduces the processing of caspase-8 prominently. Low T273 phosphorylation correlates significantly with low Plk3 expression in a cohort of 95 anal tumor patients. Our data suggest a novel mechanism of kinase activation within the Plk family and propose a new model for the stimulation of the extrinsic death pathway in tumors with high Plk3 expression. PMID:27325299

  6. Ligand stimulation of CD95 induces activation of Plk3 followed by phosphorylation of caspase-8.

    PubMed

    Helmke, Christina; Raab, Monika; Rödel, Franz; Matthess, Yves; Oellerich, Thomas; Mandal, Ranadip; Sanhaji, Mourad; Urlaub, Henning; Rödel, Claus; Becker, Sven; Strebhardt, Klaus

    2016-08-01

    Upon interaction of the CD95 receptor with its ligand, sequential association of the adaptor molecule FADD (MORT1), pro-forms of caspases-8/10, and the caspase-8/10 regulator c-FLIP leads to the formation of a death-inducing signaling complex. Here, we identify polo-like kinase (Plk) 3 as a new interaction partner of the death receptor CD95. The enzymatic activity of Plk3 increases following interaction of the CD95 receptor with its ligand. Knockout (KO) or knockdown of caspase-8, CD95 or FADD prevents activation of Plk3 upon CD95 stimulation, suggesting a requirement of a functional DISC for Plk3 activation. Furthermore, we identify caspase-8 as a new substrate for Plk3. Phosphorylation occurs on T273 and results in stimulation of caspase-8 proapoptotic function. Stimulation of CD95 in cells expressing a non-phosphorylatable caspase-8-T273A mutant in a rescue experiment or in Plk3-KO cells generated by CRISPR/Cas9 reduces the processing of caspase-8 prominently. Low T273 phosphorylation correlates significantly with low Plk3 expression in a cohort of 95 anal tumor patients. Our data suggest a novel mechanism of kinase activation within the Plk family and propose a new model for the stimulation of the extrinsic death pathway in tumors with high Plk3 expression. PMID:27325299

  7. The 55-kD tumor necrosis factor receptor and CD95 independently signal murine hepatocyte apoptosis and subsequent liver failure.

    PubMed Central

    Leist, M.; Gantner, F.; Künstle, G.; Bohlinger, I.; Tiegs, G.; Bluethmann, H.; Wendel, A.

    1996-01-01

    BACKGROUND: Activation of either the 55-kD tumor necrosis factor receptor (TNF-R1) or CD95 (Fas/Apo-1) causes apoptosis of cells and liver failure in mice, and has been associated with human liver disorders. The aim of this study was first to clarify the association between CD95 activation, hepatocyte apoptosis, and fulminant liver failure. Next, we investigated whether TNF-R1 and CD95 operate independently of each other in the induction of hepatocyte apoptosis. MATERIALS AND METHODS: Using both mice and primary liver cell cultures deficient in either TNF-R1 or functional CD95, the induction of apoptosis and hepatocyte death following activation of TNF-R1 or CD95 were studied in vitro and in various in vivo models of acute liver failure. RESULTS: In vivo or in vitro stimulation of CD95 caused apoptosis of wild-type (wt) murine hepatocytes which had not been sensitized by blocking transcription. Time course studies showed that DNA fragmentation and chromatin condensation preceded, respectively, membrane lysis in vitro and necrosis in vivo. Similar results were obtained after CD95 activation in hepatocytes or livers lacking TNF-R1. Conversely, hepatocytotoxicity due to endogenous or exogenous TNF was not affected in animals or liver cell cultures lacking the expression of functional CD95. CONCLUSIONS: TNF-R1 and CD95 are independent and differentially regulated triggers of murine apoptotic liver failure. Images FIG. 3 FIG. 6 FIG. 7 FIG. 9 PMID:8900539

  8. Glutathione peroxidase-1 protects from CD95-induced apoptosis.

    PubMed

    Gouaze, Valerie; Andrieu-Abadie, Nathalie; Cuvillier, Olivier; Malagarie-Cazenave, Sophie; Frisach, Marie-Francoise; Mirault, Marc-Edouard; Levade, Thierry

    2002-11-01

    Through the induction of apoptosis, CD95 plays a crucial role in the immune response and the elimination of cancer cells. Ligation of CD95 receptor activates a complex signaling network that appears to implicate the generation of reactive oxygen species (ROS). This study investigated the place of ROS production in CD95-mediated apoptosis and the role of the antioxidant enzyme glutathione peroxidase-1 (GPx1). Anti-CD95 antibodies triggered an early generation of ROS in human breast cancer T47D cells that was blocked by overexpression of GPx1 and inhibition of initiator caspase activation. Enforced expression of GPx1 also resulted in inhibition of CD95-induced effector caspase activation, DNA fragmentation, and apoptotic cell death. Resistance to CD95-mediated apoptosis was not due to an increased expression of anti-apoptotic molecules and could be reversed by glutathione-depleting agents. In addition, whereas the anti-apoptotic protein Bcl-xL prevented CD95-induced apoptosis in MCF-7 cells, it did not inhibit the early ROS production. Moreover, Bcl-xL but not GPx1 overexpression could suppress the staurosporine-induced late generation of ROS and subsequent cell death. Altogether, these findings suggest that GPx1 functions upstream of the mitochondrial events to inhibit the early ROS production and apoptosis induced by CD95 ligation. Finally, transgenic mice overexpressing GPx1 were partially protected from the lethal effect of anti-CD95, underlying the importance of peroxide formation (and GPx1) in CD95-triggered apoptosis. PMID:12221075

  9. The role of CD95 and CD95 ligand in cancer

    PubMed Central

    Peter, M E; Hadji, A; Murmann, A E; Brockway, S; Putzbach, W; Pattanayak, A; Ceppi, P

    2015-01-01

    CD95 (Fas/APO-1) and its ligand, CD95L, have long been viewed as a death receptor/death ligand system that mediates apoptosis induction to maintain immune homeostasis. In addition, these molecules are important in the immune elimination of virus-infected cells and cancer cells. CD95L was, therefore, considered to be useful for cancer therapy. However, major side effects have precluded its systemic use. During the last 10 years, it has been recognized that CD95 and CD95L have multiple cancer-relevant nonapoptotic and tumor-promoting activities. CD95 and CD95L were discovered to be critical survival factors for cancer cells, and were found to protect and promote cancer stem cells. We now discuss five different ways in which inhibiting or eliminating CD95L, rather than augmenting, may be beneficial for cancer therapy alone or in combination with standard chemotherapy or immune therapy. PMID:25656654

  10. Cucurbitacin E Induces G(2)/M Phase Arrest through STAT3/p53/p21 Signaling and Provokes Apoptosis via Fas/CD95 and Mitochondria-Dependent Pathways in Human Bladder Cancer T24 Cells.

    PubMed

    Huang, Wen-Wen; Yang, Jai-Sing; Lin, Meng-Wei; Chen, Po-Yuan; Chiou, Shang-Ming; Chueh, Fu-Shin; Lan, Yu-Hsuan; Pai, Shu-Jen; Tsuzuki, Minoru; Ho, Wai-Jane; Chung, Jing-Gung

    2012-01-01

    Cucurbitacin E, a tetracyclic triterpenes compound extracted from cucurbitaceous plants, has been shown to exhibit anticancer and anti-inflammatory activities. The purpose of this study was to elucidate whether cucurbitacin E promotes cell cycle arrest and induces apoptosis in T24 cells and further to explore the underlying molecular mechanisms. The effects of cucurbitacin E on T24 cell's growth and accompanied morphological changes were examined by MTT assay and a phase-contrast microscope. DNA content, mitochondrial membrane potential (ΔΨ(m)) and annexin V/PI staining were determined by flow cytometry. The protein levels were measured by Western blotting. Our results demonstrated that cucurbitacin E-induced G(2)/M arrest was associated with a marked increase in the levels of p53, p21 and a decrease in phospho-signal transducer and activator of transcription 3 (STAT3), cyclin-dependent kinase 1 (CDK1) and cyclin B. Cucurbitacin E-triggered apoptosis was accompanied with up-regulation of Fas/CD95, truncated BID (t-BID) and a loss of ΔΨ(m), resulting in the releases of cytochrome c, apoptotic protease activating factor 1 (Apaf-1) and apoptosis-inducing factor (AIF), and sequential activation of caspase-8, caspase-9, and caspase-3. Our findings provided the first evidence that STAT3/p53/p21 signaling, Fas/CD95 and mitochondria-dependent pathways play critical roles in cucurbitacin E-induced G(2)/M phase arrest and apoptosis of T24 cells. PMID:22272214

  11. Cucurbitacin E Induces G2/M Phase Arrest through STAT3/p53/p21 Signaling and Provokes Apoptosis via Fas/CD95 and Mitochondria-Dependent Pathways in Human Bladder Cancer T24 Cells

    PubMed Central

    Huang, Wen-Wen; Yang, Jai-Sing; Lin, Meng-Wei; Chen, Po-Yuan; Chiou, Shang-Ming; Chueh, Fu-Shin; Lan, Yu-Hsuan; Pai, Shu-Jen; Tsuzuki, Minoru; Ho, Wai-Jane; Chung, Jing-Gung

    2012-01-01

    Cucurbitacin E, a tetracyclic triterpenes compound extracted from cucurbitaceous plants, has been shown to exhibit anticancer and anti-inflammatory activities. The purpose of this study was to elucidate whether cucurbitacin E promotes cell cycle arrest and induces apoptosis in T24 cells and further to explore the underlying molecular mechanisms. The effects of cucurbitacin E on T24 cell's growth and accompanied morphological changes were examined by MTT assay and a phase-contrast microscope. DNA content, mitochondrial membrane potential (ΔΨm) and annexin V/PI staining were determined by flow cytometry. The protein levels were measured by Western blotting. Our results demonstrated that cucurbitacin E-induced G2/M arrest was associated with a marked increase in the levels of p53, p21 and a decrease in phospho-signal transducer and activator of transcription 3 (STAT3), cyclin-dependent kinase 1 (CDK1) and cyclin B. Cucurbitacin E-triggered apoptosis was accompanied with up-regulation of Fas/CD95, truncated BID (t-BID) and a loss of ΔΨm, resulting in the releases of cytochrome c, apoptotic protease activating factor 1 (Apaf-1) and apoptosis-inducing factor (AIF), and sequential activation of caspase-8, caspase-9, and caspase-3. Our findings provided the first evidence that STAT3/p53/p21 signaling, Fas/CD95 and mitochondria-dependent pathways play critical roles in cucurbitacin E-induced G2/M phase arrest and apoptosis of T24 cells. PMID:22272214

  12. Increased serum concentrations of soluble CD95/Fas and caspase 1/ICE in patients with acute angina

    PubMed Central

    Ankersmit, H J; Weber, T; Auer, J; Roth, G; Brunner, M; Kvas, E; Moser, B; Spreitzer, S; Lassnig, E; Maurer, E; Hartl, P; Wolner, E; Boltz-Nitulescu, G; Eber, B

    2004-01-01

    Objectives: To investigate the expression of death inducing receptors in the sera of patients with stable and unstable angina. Design: 80 consecutive patients with stable (n  =  40) or unstable (n  =  40) angina pectoris were studied. Serum concentrations of soluble CD95 (sCD95), soluble CD95 ligand (sCD95L; CD178), tumour necrosis factor (TNF) α, soluble TNFα receptor type 1 (sTNFR1), and interleukin 1β converting enzyme (ICE; caspase 1) were measured by enzyme linked immunosorbent assay (ELISA). Results: Significant increases in the concentrations of sCD95 and ICE (p < 0.001 and p < 0.023, respectively) were found in the serum from patients with unstable angina relative to those with stable angina. There were no significant differences in the concentrations of sCD95L, TNF α, and sTNFR1 between the groups. Conclusions: These data provide the first evidence that sCD95 and ICE are important serological markers that may help to discriminate between stable and unstable angina. This observation may warrant further clinical study to elucidate the clinical impact of sCD95 and ICE in acute coronary syndromes. PMID:14729783

  13. Differential CD95 expression and function in T and B lineage acute lymphoblastic leukemia cells.

    PubMed

    Karawajew, L; Wuchter, C; Ruppert, V; Drexler, H; Gruss, H J; Dörken, B; Ludwig, W D

    1997-08-01

    CD95 (Fas/APO-1) is a cell surface receptor able to trigger apoptosis in a variety of cell types. The expression and function of the CD95 antigen on leukemic blasts from 42 patients with B lineage and 53 patients with T lineage acute lymphoblastic leukemia (ALL) were investigated using immunofluorescence staining and apoptosis assays. The CD95 surface antigen was expressed in most ALL cases, with the T lineage ALL usually showing a higher intensity of surface CD95 expression as compared with the B lineage ALL cells (relative fluorescence intensity, RFI: 4.8 +/- 0.47 vs 2.2 +/- 0.23, respectively, P < 0.01). Functional studies disclosed that upon oligomerization by anti-CD95 monoclonal antibodies the CD95 protein was either not able to initiate apoptosis of leukemic cells (75% of cases) or induced low rates of apoptosis (20% of cases). Only in 5% of cases did the apoptosis rate exceed the 20% level of the CD95-specific apoptosis. Most of the CD95-sensitive cases were found among T lineage ALLs (38% of T lineage vs 10% of B lineage ALLs). Overall, the extent of CD95-induced apoptosis did not correlate with the expression level of CD95. Similarly, no significant correlation between expression level and functionality of CD95 in human leukemia cell lines of B and T cell origin could be observed. Bcl-2 protein has been associated with prolonged cell survival and has been shown to block partially CD95-mediated apoptosis, but for ALL cells no correlation between bcl-2 expression and spontaneous or CD95-mediated apoptosis could be found. The results obtained in this study indicate that, despite constitutive expression of CD95, the ALL cells are mainly resistant to CD95-triggering. More detailed investigations of the molecular mechanisms involved in the intracellular apoptotic signal transduction, such as interactions of the bcl-2 and the other members of the bcl-2 family, and functionality of the interleukin-1beta converting enzyme (ICE) like-proteases, may give new

  14. Precise Mapping of the CD95 Pre-Ligand Assembly Domain

    PubMed Central

    Penna, Aubin; Taupin, Jean-Luc; Daburon, Sophie; Moreau, Jean-François; Legembre, Patrick

    2012-01-01

    Pre-association of CD95 at the plasma membrane is mandatory for efficient death receptor signaling. This homotrimerization occurs through self-association of an extracellular domain called the pre-ligand assembly domain (PLAD). Using novel molecular and cellular tools, we confirmed that CD95-PLAD is necessary to promote CD95 multimerization and plays a pivotal role in the transmission of apoptotic signals. However, while a human CD95 mutant deleted of the previously described PLAD domain (amino acids 1 to 66) fails to interact with its wild-type counterpart and trigger autonomous cell death, deletion of amino acids 1 to 42 does not prevent homo- or hetero (human/mouse)-oligomerization of CD95, and thus does not alter transmission of the apoptotic signal. Overall, these findings indicate that the region between amino acids 43 to 66 corresponds to the minimal motif involved in CD95 homotypic interaction and is necessary to convey an efficient apoptotic signal. Interfering with this PLAD may represent a new therapeutic strategy for altering CD95-induced apoptotic and non-apoptotic signals. PMID:23049989

  15. Intravital imaging reveals p53-dependent cancer cell death induced by phototherapy via calcium signaling

    PubMed Central

    Missiroli, Sonia; Poletti, Federica; Ramirez, Fabian Galindo; Morciano, Giampaolo; Morganti, Claudia; Pandolfi, Pier Paolo; Mammano, Fabio; Pinton, Paolo

    2015-01-01

    One challenge in biology is signal transduction monitoring in a physiological context. Intravital imaging techniques are revolutionizing our understanding of tumor and host cell behaviors in the tumor environment. However, these deep tissue imaging techniques have not yet been adopted to investigate the second messenger calcium (Ca2+). In the present study, we established conditions that allow the in vivo detection of Ca2+ signaling in three-dimensional tumor masses in mouse models. By combining intravital imaging and a skinfold chamber technique, we determined the ability of photodynamic cancer therapy to induce an increase in intracellular Ca2+ concentrations and, consequently, an increase in cell death in a p53-dependent pathway. PMID:25544762

  16. Inorganic mercury dissociates preassembled Fas/CD95 receptor oligomers in T lymphocytes

    SciTech Connect

    Ziemba, Stamatina E.; McCabe, Michael J.; Rosenspire, Allen J. . E-mail: arosensp@sun.science.wayne.edu

    2005-08-15

    Genetically susceptible rodents exposed to low burdens of inorganic mercury (Hg{sup 2+}) develop autoimmune disease. Previous studies have shown that low, noncytotoxic levels of Hg{sup 2+} inhibit Fas-mediated apoptosis in T cells. These results suggest that inhibition of the Fas death receptor pathway potentially contributes to autoimmune disease after Hg{sup 2+} exposure, as a consequence of disruption of peripheral tolerance. The formation of active death inducing signaling complexes (DISC) following CD95/Fas receptor oligomerization is a primary step in the Fas-mediated apoptotic pathway. Other recent studies have shown that Hg{sup 2+} at concentrations that inhibit apoptosis also inhibit formation of active DISC, suggesting that inhibition of DISC is the mechanism responsible for Hg{sup 2+}-mediated inhibition of apotosis. Preassociated Fas receptors have been implicated as key elements necessary for the production of functional DISC. We present evidence in this study showing that low and nontoxic concentrations of Hg{sup 2+} induce the dissociation of preassembled Fas receptor complexes in Jurkat T cells. Thus, this Hg{sup 2+}-induced event should subsequently decrease the amount of preassembled Fas available for DISC formation, potentially resulting in the attenuation of Fas-mediated apoptosis in T lymphocytes.

  17. Regulation of hippocampal Fas receptor and death-inducing signaling complex after kainic acid treatment in mice.

    PubMed

    Keller, Benjamin; García-Sevilla, Jesús A

    2015-12-01

    Kainic acid (KA)-induced brain neuronal cell death (especially in the hippocampus) was shown to be mainly mediated by the intrinsic (mitochondrial) apoptotic pathway. This study investigated the regulation of the extrinsic apoptotic pathway mediated by Fas ligand/Fas receptor and components of the indispensable death-inducing signaling complex (DISC) in the hippocampus (marked changes) and cerebral cortex (modest changes) of KA-treated mice. KA (45mg/kg) induced a severe behavioral syndrome with recurrent motor seizures (scores; maximal at 60-90min; minimal at 72h) with activation of hippocampal pro-apoptotic JNK (+2.5 fold) and increased GFAP (+57%) and nuclear PARP-1 fragmentation (+114%) 72h post-treatment (delayed neurotoxicity). In the extrinsic apoptotic pathway (hippocampus), KA (72h) reduced Fas ligand (-92%) and Fas receptor aggregates (-24%). KA (72h) also altered the contents of major DISC components: decreased FADD adaptor (-44%), reduced activation of initiator caspase-8 (-47%) and increased survival FLIP-S (+220%). Notably, KA (72h) upregulated the content of anti-apoptotic p-Ser191 FADD (+41%) and consequently the expression of p-FADD/FADD ratio (+1.9-fold), a neuroplastic index. Moreover, the p-FADD dependent transcription factor NF-κB was also increased (+61%) in the hippocampus after KA (72h). The convergent adaptation of the extrinsic apoptotic machinery 72h after KA in mice (with otherwise normal gross behavior) is a novel finding which suggests the induction of survival mechanisms to partly counteract the delayed neuronal death in the hippocampus. PMID:26044520

  18. Docosahexaenoic acid counteracts attenuation of CD95-induced cell death by inorganic mercury

    SciTech Connect

    Gill, Randall; Lanni, Lydia; Jen, K.-L. Catherine; McCabe, Michael J.; Rosenspire, Allen

    2015-01-01

    In the United States the principal environmental exposure to mercury is through dietary consumption of sea food. Although the mechanism by which low levels of mercury affect the nervous system is not well established, epidemiological studies suggest that low level exposure of pregnant women to dietary mercury can adversely impact cognitive development in their children, but that Docosahexaenoic acid (DHA), the most prominent n-polyunsaturated fatty acid (n-PUFA) present in fish may counteract negative effects of mercury on the nervous system. Aside from effects on the nervous system, epidemiological and animal studies have also suggested that low level mercury exposure may be a risk factor for autoimmune disease. However unlike the nervous system where a mechanism linking mercury to impaired cognitive development remains elusive, we have previously suggested a potential mechanism linking low level mercury exposures to immune system dysfunction and autoimmunity. In the immune system it is well established that disruption of CD95 mediated apoptosis leads to autoimmune disease. We have previously shown in vitro as well as in vivo that in lymphocytes burdened with low levels of mercury, CD95 mediated cell death is impaired. In this report we now show that DHA counteracts the negative effect of mercury on CD95 signaling in T lymphocytes. T cells which have been pre-exposed to DHA are able to cleave pro-caspase 3 and efficiently signal programmed cell death through the CD95 signaling pathway, whether or not they are burdened with low levels of mercury. Thus DHA may lower the risk of autoimmune disease after low level mercury exposures. - Highlights: • Inorganic mercury (Hg{sup 2+}) interferes with CD95 mediated cell death in Jurkat T cells • DHA restores the ability of CD95 to signal cell death in Hg{sup 2+} intoxicated T cells • The restoration of CD95 mediated cell death by DHA is correlated with increased activation of Caspase 3.

  19. Parameter identification using stochastic simulations reveals a robustness in CD95 apoptotic response.

    PubMed

    Zimmer, Christoph; Schleich, Kolja; Lavrik, Inna

    2016-04-26

    A number of mathematical models of apoptosis generated recently allowed us to understand intrinsic mechanisms of life/death decisions in a cell. Nevertheless, the parameters for the mathematical models are often experimentally difficult to obtain and there is an emerging need for the development of efficient approaches for parameter estimation. In this study we suggest a new method for parameter estimation, which is based on stochastic simulations and can be used when the number of molecules in the system is small. Our approach comprised the following steps: we start from the selection of parameters that lead to a good ordinary differential equation (ODE) fit. We continued by carrying out stochastic simulations for each of these parameters. Comparing the correlation structure of these simulations with the data, we finally could identify the best parameter set. The method was applied for a model of CD95-induced apoptosis, the new best identified parameters fit well to the experimental data. The best parameter set allowed us to get new insights into CD95 apoptosis regulation and can be applied for the comprehensive analysis of other signaling networks. The modeling approach allowed us to get new insights into network regulation, in particular, to identify robustness in CD95 apoptotic response. Taken together, this new method provides valuable predictions and can be applied for the analysis of other signaling networks. PMID:27004466

  20. Infiltration of circulating myeloid cells through CD95L contributes to neurodegeneration in mice

    PubMed Central

    Gao, Liang; Brenner, David; Llorens-Bobadilla, Enric; Saiz-Castro, Gonzalo; Frank, Tobias; Wieghofer, Peter; Hill, Oliver; Thiemann, Meinolf; Karray, Saoussen; Prinz, Marco; Weishaupt, Jochen H.

    2015-01-01

    Neuroinflammation is increasingly recognized as a hallmark of neurodegeneration. Activated central nervous system–resident microglia and infiltrating immune cells contribute to the degeneration of dopaminergic neurons (DNs). However, how the inflammatory process leads to neuron loss and whether blocking this response would be beneficial to disease progression remains largely unknown. CD95 is a mediator of inflammation that has also been proposed as an apoptosis inducer in DNs, but previous studies using ubiquitous deletion of CD95 or CD95L in mouse models of neurodegeneration have generated conflicting results. Here we examine the role of CD95 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP)–induced neurodegeneration using tissue-specific deletion of CD95 or CD95L. We show that DN death is not mediated by CD95-induced apoptosis because deletion of CD95 in DNs does not influence MPTP-induced neurodegeneration. In contrast, deletion of CD95L in peripheral myeloid cells significantly protects against MPTP neurotoxicity and preserves striatal dopamine levels. Systemic pharmacological inhibition of CD95L dampens the peripheral innate response, reduces the accumulation of infiltrating myeloid cells, and efficiently prevents MPTP-induced DN death. Altogether, this study emphasizes the role of the peripheral innate immune response in neurodegeneration and identifies CD95 as potential pharmacological target for neurodegenerative disease. PMID:25779632

  1. Ex vivo pediatric brain tumors express Fas (CD95) and FasL (CD95L) and are resistant to apoptosis induction.

    PubMed Central

    Riffkin, C. D.; Gray, A. Z.; Hawkins, C. J.; Chow, C. W.; Ashley, D. M.

    2001-01-01

    Fas (APO-1/CD95/TNFRSF6) is a member of the tumor necrosis/nerve growth factor receptor family that signals apoptotic cell death in sensitive cells.Expression of Fas and its agonistic ligand (FasL/TNFSF6) was investigated in ex vivo pediatric brain tumor specimens of various histologic types. Fas expression was identified in all of the 18 tumors analyzed by flow cytometry and immunohistochemistry. FasL expression was identified in most of the 13 tumors analyzed by both Western analysis and immunohistochemistry. Nine of these tumor specimens were treated with either the agonistic anti-Fas antibody (APO-1) in combination with protein A or FasL in short-term cytotoxicity assays. Sensitivity to apoptosis induced by the topoisomerase II inhibitor, etoposide, was also assessed. Despite the presence of Fas, all the specimens analyzed demonstrated a high degree of resistance to Fas-mediated apoptosis. These 9 specimens also showed a high degree of resistance to etoposide. Only 2 of the 9 specimens were susceptible to etoposide-induced cell death, whereas only 3 were sensitive to Fas-mediated apoptosis. One brain tumor was sensitive to both Fas ligation and etoposide treatment. This contrasted with the high degree of susceptibility to both etoposide- and Fas-induced apoptosis observed in the reference Jurkat cell line. The results suggest that Fas expression may be a general feature of tumors of the CNS and that a significant degree of resistance to Fas-mediated apoptosis may exist in ex vivo pediatric brain tumor specimens. PMID:11584892

  2. CD95 promotes metastatic spread via Sck in pancreatic ductal adenocarcinoma.

    PubMed

    Teodorczyk, M; Kleber, S; Wollny, D; Sefrin, J P; Aykut, B; Mateos, A; Herhaus, P; Sancho-Martinez, I; Hill, O; Gieffers, C; Sykora, J; Weichert, W; Eisen, C; Trumpp, A; Sprick, M R; Bergmann, F; Welsch, T; Martin-Villalba, A

    2015-07-01

    Cancer stem cells (CSCs) have been implicated in the initiation and maintenance of tumour growth as well as metastasis. Recent reports link stemness to epithelial-mesenchymal transition (EMT) in cancer. However, there is still little knowledge about the molecular markers of those events. In silico analysis of RNA profiles of 36 pancreatic ductal adenocarcinomas (PDAC) reveals an association of the expression of CD95 with EMT and stemness that was validated in CSCs isolated from PDAC surgical specimens. CD95 expression was also higher in metastatic pancreatic cells than in primary PDAC. Pharmacological inhibition of CD95 activity reduced PDAC growth and metastasis in CSC-derived xenografts and in a murine syngeneic model. On the mechanistic level, Sck was identified as a novel molecule indispensable for CD95's induction of cell cycle progression. This study uncovers CD95 as a marker of EMT and stemness in PDAC. It also addresses the molecular mechanism by which CD95 drives tumour growth and opens tantalizing therapeutic possibilities in PDAC. PMID:25613377

  3. CD95/CD95L-mediated apoptosis of the hepatic stellate cell. A mechanism terminating uncontrolled hepatic stellate cell proliferation during hepatic tissue repair.

    PubMed Central

    Saile, B.; Knittel, T.; Matthes, N.; Schott, P.; Ramadori, G.

    1997-01-01

    During liver tissue repair, hepatic stellate cells (HSC), a pericyte-like mesenchymal liver cell population, transform from a "quiescent" status ("resting" HSC) into myofibroblast-like cells ("activated" HSC) with the latter representing the principle matrix synthesizing cell of the liver. Presently, the mechanisms that terminate HSC cell proliferation when tissue repair is concluded are poorly understood. Controlled cell death known as apoptosis could be a mechanism underlying this phenomenon. Therefore, apoptosis and its regulation were studied in HSC using an in vitro and in vivo approach. Spontaneous apoptosis became detectable in parallel with HSC activation because resting cells (2 days after isolation) displayed no sign of apoptosis, whereas apoptosis was present in 8% (+/- 5%) of "transitional" cells (day 4) and in 18% (+/- 8%) of fully activated cells (day 7). Both CD95 (APO-1/Fas) and CD95L (APO-1-/Fas-ligand) became increasingly expressed during the course of activation. Apoptosis could be fully blocked by CD95-blocking antibodies in normal cells and HSC already entering the apoptotic cycle. Using CD95-activating antibodies, transition of more than 95% cells into apoptosis was evident at each activation step. The apoptosis-regulating proteins Bcl-2 and p53 could not be detected in resting cells but were found in increasing amounts at days 4 and 7 of cultivation. Whereas p53 expression was induced by the CD95-activating antibody, no change was inducible in Bcl-2 expression. The Bcl-2-related protein bax could be found at days 2 and 4 in similar expression, was considerably up-regulated at day 7, but was not regulated by CD95-agonistic antibodies. In vivo, acute tissue damage was first accompanied by activation and proliferation of HSC displaying no sign of apoptosis. In the recovery phase, apoptotic HSC were detectable in parallel to a reduction in the total number of HSC present in the liver tissue. The data demonstrate that apoptosis becomes detectable

  4. TLR9-ERK-mTOR signaling is critical for autophagic cell death induced by CpG oligodeoxynucleotide 107 combined with irradiation in glioma cells

    PubMed Central

    Li, Xiaoli; Cen, Yanyan; Cai, Yongqing; Liu, Tao; Liu, Huan; Cao, Guanqun; Liu, Dan; Li, Bin; Peng, Wei; Zou, Jintao; Pang, Xueli; Zheng, Jiang; Zhou, Hong

    2016-01-01

    Synthetic oligodeoxynucleotides containing unmethylated CpG dinucleotides (CpG ODN) function as potential radiosensitizers for glioma treatment, although the underlying mechanism is unclear. It was observed that CpG ODN107, when combined with irradiation, did not induce apoptosis. Herein, the effect of CpG ODN107 + irradiation on autophagy and the related signaling pathways was investigated. In vitro, CpG ODN107 + irradiation induced autophagosome formation, increased the ratio of LC3 II/LC3 I, beclin 1 and decreased p62 expression in U87 cells. Meanwhile, CpG ODN107 also increased LC3 II/LC3 I expression in U251 and CHG-5 cells. In vivo, CpG ODN107 combined with local radiotherapy induced autophagosome formation in orthotopic transplantation tumor. Investigation of the molecular mechanisms demonstrated that CpG ODN107 + irradiation increased the levels of TLR9 and p-ERK, and decreased the level of p-mTOR in glioma cells. Further, TLR9-specific siRNA could affect the expressions of p-ERK and autophagy-related proteins in glioma cells. Taken together, CpG ODN107 combined with irradiation could induce autophagic cell death, and this effect was closely related to the TLR9-ERK-mTOR signaling pathway in glioma cells, providing new insights into the investigation mechanism of CpG ODN. PMID:27251306

  5. TLR9-ERK-mTOR signaling is critical for autophagic cell death induced by CpG oligodeoxynucleotide 107 combined with irradiation in glioma cells.

    PubMed

    Li, Xiaoli; Cen, Yanyan; Cai, Yongqing; Liu, Tao; Liu, Huan; Cao, Guanqun; Liu, Dan; Li, Bin; Peng, Wei; Zou, Jintao; Pang, Xueli; Zheng, Jiang; Zhou, Hong

    2016-01-01

    Synthetic oligodeoxynucleotides containing unmethylated CpG dinucleotides (CpG ODN) function as potential radiosensitizers for glioma treatment, although the underlying mechanism is unclear. It was observed that CpG ODN107, when combined with irradiation, did not induce apoptosis. Herein, the effect of CpG ODN107 + irradiation on autophagy and the related signaling pathways was investigated. In vitro, CpG ODN107 + irradiation induced autophagosome formation, increased the ratio of LC3 II/LC3 I, beclin 1 and decreased p62 expression in U87 cells. Meanwhile, CpG ODN107 also increased LC3 II/LC3 I expression in U251 and CHG-5 cells. In vivo, CpG ODN107 combined with local radiotherapy induced autophagosome formation in orthotopic transplantation tumor. Investigation of the molecular mechanisms demonstrated that CpG ODN107 + irradiation increased the levels of TLR9 and p-ERK, and decreased the level of p-mTOR in glioma cells. Further, TLR9-specific siRNA could affect the expressions of p-ERK and autophagy-related proteins in glioma cells. Taken together, CpG ODN107 combined with irradiation could induce autophagic cell death, and this effect was closely related to the TLR9-ERK-mTOR signaling pathway in glioma cells, providing new insights into the investigation mechanism of CpG ODN. PMID:27251306

  6. A paraptosis-like cell death induced by δ-tocotrienol in human colon carcinoma SW620 cells is associated with the suppression of the Wnt signaling pathway.

    PubMed

    Zhang, Jing-Shu; Li, Da-Ming; He, Ning; Liu, Ying-Hua; Wang, Chun-Hua; Jiang, Shu-Qing; Chen, Bing-Qing; Liu, Jia-Ren

    2011-07-11

    Tocotrienol is considered a beneficial effect agent on inhibition of tumor development. In this study, we focused on the effects of δ-tocotrienol and its possible mechanism on induction of death in human colon cancer SW620 cells. δ-Tocotrienol inhibited proliferation of SW620 cell in a dose-dependent manner. Our findings showed that δ-tocotrienol effectively induced paraptosis-like death in SW620 cells, correlated with the vacuolation that may be from welling and fusion of mitochondria and/or the endoplasmic reticulum (ER) as well as caspase-3 nonactivated. However, there were no changes in apoptosis based on flow cytometry analysis. Of being noted, δ-tocotrienol reduced the expression of β-catenin and wnt-1 proteins by about 50% at the highest dose (20μmol/L). δ-Tocotrienol also decreased cyclin D1, c-jun and MMP-7 protein levels in SW620 cells. Altogether, these data indicate that δ-tocotrienol induces paraptosis-like cell death, which is associated with the suppression of the Wnt signaling pathway. Thus, our findings may provide a novel application in treatment of human colon carcinoma. PMID:21453743

  7. Interferon-{beta}-induced activation of c-Jun NH{sub 2}-terminal kinase mediates apoptosis through up-regulation of CD95 in CH31 B lymphoma cells

    SciTech Connect

    Takada, Eiko; Shimo, Kuniaki; Hata, Kikumi; Abiake, Maira; Mukai, Yasuo; Moriyama, Masami; Heasley, Lynn; Mizuguchi, Junichiro . E-mail: mizu@tokyo-med.ac.jp

    2005-04-01

    Type I interferon (IFN)-induced antitumor action is due in part to apoptosis, but the molecular mechanisms underlying IFN-induced apoptosis remain largely unresolved. In the present study, we demonstrate that IFN-{beta} induced apoptosis and the loss of mitochondrial membrane potential ({delta}{psi}m) in the murine CH31 B lymphoma cell line, and this was accompanied by the up-regulation of CD95, but not CD95-ligand (CD95-L), tumor necrosis factor (TNF), or TNF-related apoptosis-inducing ligand (TRAIL). Pretreatment with anti-CD95-L mAb partially prevented the IFN-{beta}-induced loss of {delta}{psi}m, suggesting that the interaction of IFN-{beta}-up-regulated CD95 with CD95-L plays a crucial role in the induction of fratricide. IFN-{beta} induced a sustained activation of c-Jun NH{sub 2}-terminal kinase 1 (JNK1), but not extracellular signal-regulated kinases (ERKs). The IFN-{beta}-induced apoptosis and loss of {delta}{psi}m were substantially compromised in cells overexpressing a dominant-negative form of JNK1 (dnJNK1), and it was slightly enhanced in cells carrying a constitutively active JNK construct, MKK7-JNK1 fusion protein. The IFN-{beta}-induced up-regulation of CD95 together with caspase-8 activation was also abrogated in the dnJNK1 cells while it was further enhanced in the MKK7-JNK1 cells. The levels of cellular FLIP (c-FLIP), competitively interacting with caspase-8, were down-regulated by stimulation with IFN-{beta} but were reversed by the proteasome inhibitor lactacystin. Collectively, the IFN-{beta}-induced sustained activation of JNK mediates apoptosis, at least in part, through up-regulation of CD95 protein in combination with down-regulation of c-FLIP protein.

  8. Structural Insight for Roles of DR5 Death Domain Mutations on Oligomerization of DR5 Death Domain-FADD Complex in the Death-Inducing Signaling Complex Formation: A Computational Study.

    PubMed

    Yang, Hongyi; Song, Yuhua

    2016-04-01

    Death receptor 5 (DR5)-induced apoptosis that prioritizes the death of tumor cells has been proposed as one of the promising cancer therapies. In this process, oligomerized DR5 death domain (DD) binding to Fas-associated death domain (FADD) leads to FADD activating caspase-8, which marks the formation of the death-inducing signaling complex (DISC) that initiates apoptosis. DR5 DD mutations found in cancer cells have been suggested to play an important pathological role, the mechanism through which those mutants prevent the DR5-activated DISC formation is not clear yet. This study sought to provide structural and molecular insight for the roles of four selected DR5 DD mutations (E355K, E367K, K415N, and L363F) in the oligomerization of DR5 DD-FADD complex during the DISC formation. Results from the molecular dynamics simulations show that the simulated mutants induce conformational, dynamical motions and interactions changes in the DR5 DD-FADD tetramer complex, including changes in a protein's backbone flexibility, less exposure of FADD DED's caspase-8 binding site, reduced H-bonding and hydrophobic contacts at the DR5 DD-FADD DD binding, altered distribution of the electrostatic potentials and correlated motions of residues, and reduced binding affinity of DR5 DD binding to FADD. This study provides structural and molecular insight for the influence of DR5 DD mutations on oligomerization of DR5 DD-FADD complex, which is expected to foster understanding of the DR5 DD mutants' resistance mechanism against DR5-activated DISC formation. PMID:26995783

  9. Sildenafil (Viagra) sensitizes prostate cancer cells to doxorubicin-mediated apoptosis through CD95

    PubMed Central

    Das, Anindita; Durrant, David; Mitchell, Clint; Dent, Paul; Batra, Surinder K.; Kukreja, Rakesh C.

    2016-01-01

    We previously reported that Sildenafil enhances apoptosis and antitumor efficacy of doxorubicin (DOX) while attenuating its cardiotoxic effect in prostate cancer. In the present study, we investigated the mechanism by which sildenafil sensitizes DOX in killing of prostate cancer (PCa) cells, DU145. The death receptor Fas (APO-1 or CD95) induces apoptosis in many carcinoma cells, which is negatively regulated by anti-apoptotic molecules such as FLIP (Fas-associated death domain (FADD) interleukin-1-converting enzyme (FLICE)-like inhibitory protein). Co-treatment of PCa cells with sildenafil and DOX for 48 hours showed reduced expression of both long and short forms of FLIP (FLIP-L and -S) as compared to individual drug treatment. Over-expression of FLIP-s with an adenoviral vector attentuated the enhanced cell-killing effect of DOX and sildenafil. Colony formation assays also confirmed that FLIP-S over-expression inhibited the DOX and sildenafil-induced synergistic killing effect as compared to the cells infected with an empty vector. Moreover, siRNA knock-down of CD95 abolished the effect of sildenafil in enhancing DOX lethality in cells, but had no effect on cell killing after treatment with a single agent. Sildenafil co-treatment with DOX inhibited DOX-induced NF-κB activity by reducing phosphorylation of IκB and nuclear translocation of the p65 subunit, in addition to down regulation of FAP-1 (Fas associated phosphatase-1, a known inhibitor of CD95-mediated apoptosis) expression. This data provides evidence that the CD95 is a key regulator of sildenafil and DOX mediated enhanced cell death in prostate cancer. PMID:26716643

  10. Impairment of Na(+),K(+)-ATPase in CD95(APO-1)-induced human T-cell leukemia cell apoptosis mediated by glutathione depletion and generation of hydrogen peroxide.

    PubMed

    Yin, W; Cheng, W; Shen, W; Shu, L; Zhao, J; Zhang, J; Hua, Z-C

    2007-08-01

    Human T-cell leukemia is a malignant disease that needs various regimens of cytotoxic chemotherapy to overcome drug resistance. Recently, Na(+),K(+)-ATPase has emerged as a potential target for cancer therapy. However, its exact signaling pathway in human T-cell leukemia cell death has not been well defined. In the current study, we found CD95(APO-1) was able to trigger the internalization of plasma membrane Na(+),K(+)-ATPase in Jurkat cells or primary T cells as a mechanism to suppress its activity. This internalization was closely relevant to intracellular glutathione (GSH) depletion in Jurkat cells downstream of Fas-associated death domain protein (FADD) and caspase 8. GSH depletion in Fas L-treated Jurkat cells induced the generation of hydrogen peroxide (H(2)O(2)), which subsequently increased the serine phosphorylation of Na(+),K(+)-ATPase alpha1 subunit. Exogenous H(2)O(2) even mimicked the effect of Fas L to upregulate the serine phosphorylation of Na(+),K(+)-ATPase alpha1 subunit and suppress Na(+),K(+)-ATPase activity. Overall, our results indicate that CD95(APO-1) induces the FADD- and caspase 8-dependent internalization of Na(+),K(+)-ATPase through intracellular GSH loss, and the subsequent generation of H(2)O(2)-mediated serine phosphorylation of Na(+),K(+)-ATPase alpha1 subunit. Taken together, this study presents a novel regulatory mechanism of Na(+),K(+)-ATPase in CD95(APO-1)-mediated human T-leukemia cell apoptosis. PMID:17554377

  11. IL-7 Promotes CD95-Induced Apoptosis in B Cells via the IFN-γ/STAT1 Pathway

    PubMed Central

    Sammicheli, Stefano; Dang Vu Phuong, Linh; Ruffin, Nicolas; Pham Hong, Thang; Lantto, Rebecka; Vivar, Nancy; Chiodi, Francesca; Rethi, Bence

    2011-01-01

    Interleukin-7 (IL-7) concentrations are increased in the blood of CD4+ T cell depleted individuals, including HIV-1 infected patients. High IL-7 levels might stimulate T cell activation and, as we have shown earlier, IL-7 can prime resting T cell to CD95 induced apoptosis as well. HIV-1 infection leads to B cell abnormalities including increased apoptosis via the CD95 (Fas) death receptor pathway and loss of memory B cells. Peripheral B cells are not sensitive for IL-7, due to the lack of IL-7Ra expression on their surface; however, here we demonstrate that high IL-7 concentration can prime resting B cells to CD95-mediated apoptosis via an indirect mechanism. T cells cultured with IL-7 induced high CD95 expression on resting B cells together with an increased sensitivity to CD95 mediated apoptosis. As the mediator molecule responsible for B cell priming to CD95 mediated apoptosis we identified the cytokine IFN-γ that T cells secreted in high amounts in response to IL-7. These results suggest that the lymphopenia induced cytokine IL-7 can contribute to the increased B cell apoptosis observed in HIV-1 infected individuals. PMID:22194871

  12. CD95 maintains stem cell-like and non-classical EMT programs in primary human glioblastoma cells

    PubMed Central

    Drachsler, M; Kleber, S; Mateos, A; Volk, K; Mohr, N; Chen, S; Cirovic, B; Tüttenberg, J; Gieffers, C; Sykora, J; Wirtz, C R; Mueller, W; Synowitz, M; Martin-Villalba, A

    2016-01-01

    Glioblastoma (GBM) is one of the most aggressive types of cancer with limited therapeutic options and unfavorable prognosis. Stemness and non-classical epithelial-to-mesenchymal transition (ncEMT) features underlie the switch from normal to neoplastic states as well as resistance of tumor clones to current therapies. Therefore, identification of ligand/receptor systems maintaining this privileged state is needed to devise efficient cancer therapies. In this study, we show that the expression of CD95 associates with stemness and EMT features in GBM tumors and cells and serves as a prognostic biomarker. CD95 expression increases in tumors and with tumor relapse as compared with non-tumor tissue. Recruitment of the activating PI3K subunit, p85, to CD95 death domain is required for maintenance of EMT-related transcripts. A combination of the current GBM therapy, temozolomide, with a CD95 inhibitor dramatically abrogates tumor sphere formation. This study molecularly dissects the role of CD95 in GBM cells and contributes the rational for CD95 inhibition as a GBM therapy. PMID:27124583

  13. CD95 maintains stem cell-like and non-classical EMT programs in primary human glioblastoma cells.

    PubMed

    Drachsler, M; Kleber, S; Mateos, A; Volk, K; Mohr, N; Chen, S; Cirovic, B; Tüttenberg, J; Gieffers, C; Sykora, J; Wirtz, C R; Mueller, W; Synowitz, M; Martin-Villalba, A

    2016-01-01

    Glioblastoma (GBM) is one of the most aggressive types of cancer with limited therapeutic options and unfavorable prognosis. Stemness and non-classical epithelial-to-mesenchymal transition (ncEMT) features underlie the switch from normal to neoplastic states as well as resistance of tumor clones to current therapies. Therefore, identification of ligand/receptor systems maintaining this privileged state is needed to devise efficient cancer therapies. In this study, we show that the expression of CD95 associates with stemness and EMT features in GBM tumors and cells and serves as a prognostic biomarker. CD95 expression increases in tumors and with tumor relapse as compared with non-tumor tissue. Recruitment of the activating PI3K subunit, p85, to CD95 death domain is required for maintenance of EMT-related transcripts. A combination of the current GBM therapy, temozolomide, with a CD95 inhibitor dramatically abrogates tumor sphere formation. This study molecularly dissects the role of CD95 in GBM cells and contributes the rational for CD95 inhibition as a GBM therapy. PMID:27124583

  14. Constitutive expression levels of CD95 and Bcl-2 as well as CD95 function and spontaneous apoptosis in vitro do not predict the response to induction chemotherapy and relapse rate in childhood acute lymphoblastic leukaemia.

    PubMed

    Wuchter, C; Karawajew, L; Ruppert, V; Schrappe, M; Harbott, J; Ratei, R; Dörken, B; Ludwig, W D

    2000-07-01

    CD95 (Fas/APO-1) expression and function and Bcl-2 expression, as well as spontaneous apoptosis in vitro, have been shown to be predictive markers for the in vivo response to chemotherapy in acute myeloid leukaemia (AML). To determine the clinical significance of apoptosis-regulating factors in acute lymphoblastic leukaemia (ALL), we investigated cell samples of children with ALL who had been included in the German ALL Berlin-Frankfurt-Münster (BFM) study using flow cytometry for constitutive expression levels of CD95 (n = 110) and Bcl-2 (n = 110). Furthermore, we determined the extent of spontaneous apoptosis in vitro (n = 102) and susceptibility to anti-CD95-induced apoptosis (CD95-sensitivity) (n = 97). We correlated these findings with the functional activity of the multidrug resistance (MDR)-associated P-glycoprotein (P-gp), as detected by the rhodamine123 efflux test, immunophenotype, cytogenetics and clinical data of the patients examined. Good responders to initial prednisone therapy ('prednisone response') revealed significantly higher Bcl-2 expression levels [5.4 +/- 3.4 relative fluorescence intensity (RFI), n = 68] than poor responders (3.7 +/- 2.6 RFI, n = 42; P = 0.002). There was no significant correlation between the other investigated parameters and prednisone response. Moreover, neither the CD95 and Bcl-2 expression levels nor the extent of spontaneous apoptosis in vitro, CD95 sensitivity or P-gp function were correlated with the response to induction chemotherapy or relapse rate, either for B-cell precursor ALL or T-cell ALL. No consistent pattern of change in CD95 (n = 10) and Bcl-2 expression (n = 9) was noted in cases studied at both initial diagnosis and relapse. In conclusion, our findings underline the different cell biological features of primary AML and ALL cells. PMID:10930993

  15. Antiinflammatory Effects of CD95 Ligand (FasL)-induced Apoptosis

    PubMed Central

    Gao, Yakun; Herndon, John M.; Zhang, Hui; Griffith, Thomas S.; Ferguson, Thomas A.

    1998-01-01

    Apoptosis is critical to homeostasis of multicellular organisms. In immune privileged sites such as the eye, CD95 ligand (FasL)-induced apoptosis controls dangerous inflammatory reactions that can cause blindness. Recently, we demonstrated that apoptotic cell death of inflammatory cells was a prerequisite for the induction of immune deviation after antigen presentation in the eye. In this report, we examine the mechanism by which this takes place. Our results show that Fas- mediated apoptosis of lymphoid cells leads to rapid production of interleukin (IL)-10 in these cells. The apoptotic cells containing IL-10 are responsible for the activation of immune deviation through interaction with antigen-presenting cells (APC). In support of this, we found that apoptotic cells from IL-10+/+ animals fed to APC in vitro promote Th2 cell differentiation, whereas apoptotic IL-10−/− cells, as well as nonapoptotic cells, favor Th1 induction. Thus, apoptotic cell death and tolerance are linked through the production of an antiinflammatory cytokine to prevent dangerous and unwanted immune responses that might compromise organ integrity. PMID:9730890

  16. Dexamethasone -induced apoptosis of human monocytes exposed to immune complexes. Intervention of CD95- and XIAP-dependent pathways.

    PubMed

    Ottonello, L; Bertolotto, M; Montecucco, F; Dapino, P; Dallegri, F

    2005-01-01

    Monocytes and macrophages play a key role in the initiation and persistence of inflammatory reactions. The possibility to interfere with the survival of these cells, once recruited and activated at sites of inflammation, is an attractive therapeutic option. Although resting monocytes are susceptible to pharmacologically induced apoptosis, no data are available about the possibility to modulate the survival of activated monocytes. The present work was planned to investigate if dexamethasone is able to promote apoptosis of human monocytes activated by immune complexes. When monocytes were cultured with immune complexes, a dose-dependent inhibition of apoptosis was observed. Dexamethasone stimulated apoptosis of resting and activated monocytes in a dose-dependent manner. Both the immune complex inhibitory activity and dexamethasone stimulatory properties depend on NF-kappaB/XIAP and Ras/MEK/ERK/CD95 pathways. In fact, the exposure of monocytes to immune complexes increased NF-kB activation and XIAP expression, which in turn were inhibited by dexamethasone. On the other hand, immune complex-stimulated monocytes displayed a reduced expression of CD95, which is prevented by dexamethasone, as well as by MEK inhibitor U0126. Furthermore, anti-CD95 ZB4 mAb prevented dexamethasone-induced apoptosis in immune complex stimulated monocytes. Similarly, ZB4 inhibited dexamethasone-mediated augmentation of caspase 3 activity. The present findings suggest that Fc triggering by insoluble immune complexes result in the activation of two intracellular pathways crucial for the survival of monocytes: 1. Ras/MEK/ERK pathway responsible for the down-regulation of CD95 expression; 2. NF-kappaB pathway governing the expression of XIAP. Both the pathways are susceptible to inhibition by monocyte treatment with pharmacologic concentrations of dexamethasone. PMID:16164824

  17. A Recombinant Bispecific CD20×CD95 Antibody With Superior Activity Against Normal and Malignant B-cells.

    PubMed

    Nalivaiko, Kristina; Hofmann, Martin; Kober, Karina; Teichweyde, Nadine; Krammer, Peter H; Rammensee, Hans-Georg; Grosse-Hovest, Ludger; Jung, Gundram

    2016-02-01

    Monoclonal antibodies directed to the B-cell-specific CD20-antigen are successfully used for the treatment of lymphomas and autoimmune diseases. Here, we compare the anti-B-cell activity of three different antibodies directed to CD20: (i) a chimeric, monospecific antibody, (ii) an Fc-optimized variant thereof, and (iii) a bispecific CD20×CD95-antibody in a newly developed recombinant format, termed Fabsc. The bispecific antibody specifically triggers the CD95 death receptor on malignant, as well as activated, normal B-cells. We found that the capability of this antibody to suppress the growth of malignant B-cells in vitro and in vivo and to specifically deplete normal, activated B-cells from peripheral blood mononuclear cell (PBMC) cultures was superior to that of the Fc-optimized monospecific antibody. This antibody in turn was more effective than its nonoptimized variant. Moreover, the bispecific antibody was the only reagent capable of significantly suppressing antibody production in vitro. Our findings imply that the bispecific CD20×CD95-antibody might become a new, prototypical reagent for the treatment of B-cell-mediated autoimmune disease. PMID:26581163

  18. Relation of oxidative stress and glutathione synthesis to CD95(Fas/APO-1)-mediated apoptosis of adult T cell leukemia cells.

    PubMed

    Kohno, T; Yamada, Y; Hata, T; Mori, H; Yamamura, M; Tomonaga, M; Urata, Y; Goto, S; Kondo, T

    1996-06-15

    An IL-2 dependent adult T cell leukemia cell line (SO4) has been established that is sensitive to CD95-mediated apoptosis as well as a subline (R-SO4) that is resistant. Incubating SO4 cells with anti-CD95 IgM mAb caused concentration-dependent cell death. On the contrary, R-SO4 cells did not die even at 1000 ng/ml of anti-CD95 IgM mAb. The levels of CD95 expression on R-SO4 cells were one-third of those on SO4 cells. However a blocking Ab, anti-CD95 IgG mAb, did not induce complete resistance of SO4 cells to anti-CD95 IgM mAb as R-SO4 cells. As CD95 and TNF receptor are similar, and TNF/TNF receptor binding induces oxygen radicals, the involvement of oxidant and antioxidant systems in CD95-mediated apoptosis has been examined. The addition of anti-CD95 IgM mAb resulted in formation of intracellular oxygen radical species in the SO4 cells as measured using 2',5',-dichlorofluorescein as substrate. The oxygen radical production induced DNA damage as determined by formation of 8-hydroxydeoxyguanosine. No increase in the formation of oxygen radicals was observed in R-SO4 cells. Concentrations of the intracellular antioxidant, glutathione, and the key enzyme for its synthesis, gamma-glutamylcysteine synthetase, were 150% increased in R-SO4 cells in comparison with that of SO4 cells. Moreover, glutathione ester decreased the formation of 8-hydroxydeoxyguanosine. These results suggested that apoptosis mediated by CD95 in ATL cells is related to the production of oxygen radical species and cellular antioxidant systems, especially, glutathione synthesis. PMID:8648118

  19. [TLR9 expression is positively correlated with the levels of CD38, HLA-DR and CD95 on peripheral blood mononuclear cells in chronic HBV infected patients].

    PubMed

    Mao, Xuefeng; Peng, Lishan; Liu, Xian; Yang, Yang; Wang, Qihui; Wang, Dengrong; Xiao, Jian; Leng, Jing

    2016-05-01

    Objective To explore the relationship between the expression of TLR9 and the levels of CD38, HLA-DR and CD95 on peripheral blood mononuclear cells (PBMCs) of chronic hepatitis B virus (HBV) infected patients. Methods70 chronic HBV infected patients and 12 healthy donors were enrolled in this study, and density gradient centrifugation was used to isolate PBMCs from peripheral blood with EDTA for anticoagulation. Flow cytometry was used to detect the levels of TLR9, CD38, HLA-DR and CD95 on PBMCs. Results Compared to the healthy donors, chronic HBV infected patients with low viral load or high viral load had significantly higher levels of TLR9, HLA-DR and CD95 on PMBCs. Furthermore, the co-expression rates of TLR9 and CD38, HLA-DR, CD95 on PBMCs were obviously higher than those of the healthy donors. Correlation analysis showed that the expression of TLR9 was positively correlated with CD38 (r=0.345), HLA-DR (r=0.334), CD95 (r=0.227) on PBMCs in the patients with chronic HBV infection. Conclusion The expression of TLR9 increased and was positively associated with CD38, HLA-DR and CD95 on PBMCs during chronic HBV infection. PMID:27126946

  20. Inhibition of Fas receptor (CD95)-induced hepatic caspase activation and apoptosis by acetaminophen in mice.

    PubMed

    Lawson, J A; Fisher, M A; Simmons, C A; Farhood, A; Jaeschke, H

    1999-05-01

    The mechanism of liver cell injury induced by an overdose of the analgesic acetaminophen (AAP) remains controversial. Recently, it was hypothesized that a significant number of hepatocytes die by apoptosis. Since caspases have been implicated as critical signal and effector proteases in apoptosis, we investigated their potential role in the pathophysiology of AAP-induced liver injury. Male C3Heb/FeJ mice were fasted overnight and then treated with 500 mg/kg AAP. Liver injury became apparent at 4 h and was more severe at 6 h (plasma ALT activities: 4110 +/- 320 U/liter; centrilobular necrosis). DNA fragmentation increased parallel to the increase of plasma ALT values. At 6 h there was a 420% increase of DNA fragmentation and a 74-fold increase of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells located predominantly around central veins. However, the activity of the proapoptotic caspase-3 was not increased at any time after AAP. In contrast, injection of the anti-Fas antibody Jo-2 (positive control) caused a 28-fold increase of caspase-3 activity and severe DNA fragmentation before significant ALT release. Treatment with the caspase inhibitor ZVAD-CHF2 had no effect on AAP toxicity but completely prevented Jo-mediated apoptosis. In contrast, Jo-induced caspase activation and apoptosis could be inhibited by AAP treatment in a time- and dose-dependent manner. We conclude that AAP-induced DNA fragmentation does not involve caspases, suggesting a direct activation of endonucleases through elevated Ca2+ levels. In addition, electrophilic metabolites of AAP may inactivate caspases or their activation pathway. This indicates that AAP metabolism has the potential to inhibit signal transduction mechanisms of receptor-mediated apoptosis. PMID:10222310

  1. α-Galactosylceramide suppresses murine eosinophil production through interferon-γ-dependent induction of NO synthase and CD95

    PubMed Central

    Gaspar-Elsas, Maria Ignez; Queto, Túlio; Masid-de-Brito, Daniela; Vieira, Bruno Marques; de Luca, Bianca; Cunha, Fernando Queiroz; Xavier-Elsas, Pedro

    2015-01-01

    Background and Purpose α-Galactosylceramide (α-GalCer), a pleiotropic immunomodulator with therapeutic potential in neoplastic, autoimmune and allergic diseases, activates invariant natural killer T-cells throughCD1-restricted receptors for α-GalCer on antigen-presenting cells, inducing cytokine secretion. However the haemopoietic effects of α-GalCer remain little explored. Experimental Approach α-GalCer-induced modulation of eosinophil production in IL-5-stimulated bone marrow cultures was examined in wild-type (BALB/c, C57BL/6) mice and their mutants lacking CD1, inducible NOS (iNOS), CD95 and IFN-γ, along with the effects of lymphocytes; IFN-γ; caspase and iNOS inhibitors; non-steroidal anti-inflammatory drugs (NSAIDs) and LTD4; and dexamethasone. Key Results α-GalCer (10−6–10−8M) suppressed IL-5-stimulated eosinopoiesis by inducing apoptosis. α-GalCer pretreatment in vivo (100 μg·kg−1, i.v.) suppressed colony formation by GM-CSF-stimulated bone marrow progenitors in semi-solid cultures. α-GalCer and dexamethasone synergistically promoted eosinophil maturation. Suppression of eosinophil production by α-GalCer was prevented by aminoguanidine and was undetectable in bone marrow lacking iNOS, CD95, CD28; or CD1d. Separation on Percoll gradients and depletion of CD3+ cells made bone marrow precursors unresponsive to α-GalCer. Responsiveness was restored with splenic lymphocytes. Experiments with (i) IFN-γ-deficient bone marrow, alone or co-cultured with spleen T-cells from wild-type, but not from CD1d-deficient, donors; (ii) IFN-γ neutralization; and (iii) recombinant IFN-γ, showed that these effects of α-GalCer were mediated by IFN-γ. Effects of α-GalCer on eosinophil production were blocked by LTD4 and NSAIDs. Conclusions and Implications α-GalCer activation of IFN-γ-secreting, CD1d-restricted lymphocytes induced iNOS-CD95-dependent apoptosis in developing eosinophils. This pathway is initiated by endogenous regulatory lymphocytes

  2. Fas (CD95) Induces Macrophage Pro-Inflammatory Chemokine Production via a MyD88-dependent, Caspase-independent Pathway

    PubMed Central

    Altemeier, William A.; Zhu, Xiaodong; Berrington, William R.; Harlan, John M.; Liles, W. Conrad

    2015-01-01

    Activation of the prototypical death receptor, Fas (CD95), can induce both caspase-dependent cell death and production of pro-inflammatory chemokines, leading to neutrophil recruitment and end-organ injury. The precise mechanism(s), by which Fas upregulates chemokine production and release, is currently unclear. We hypothesized that Fas-induced chemokine release by macrophages is dependent on the MyD88 adapter molecule and independent of caspase activity. To test this hypothesis, we measured chemokine response to Fas activation both in RAW 264.7 cells with RNAi-attenuated MyD88 expression and in MyD88-deficient primary macrophages. We found that Fas-induced chemokine release was abrogated in the absence of MyD88. In vivo, MyD88−/− mice had impaired CXCL1/KC release and polymorphonuclear cell recruitment in response to intratracheal treatment with the Fas-activating monoclonal antibody, Jo-2. Furthermore, Fas-induced chemokine release was not dependent on either IL-1 receptor signaling or on caspase activity. We conclude that MyD88 plays an integral role in Fas-induced macrophage-mediated inflammation. PMID:17576821

  3. Cysteine cathepsins are not critical for TRAIL- and CD95-induced apoptosis in several human cancer cell lines.

    PubMed

    Špes, Aleš; Sobotic, Barbara; Turk, Vito; Turk, Boris

    2012-12-01

    The potential role of cysteine cathepsins in tumor necrosis factor-related apoptosis-inducing ligand(TRAIL/Apo2L)- and CD95 (Fas/APO-1)-induced apoptosis was investigated using four different cell lines (HeLa, HuH-7, Jurkat, and U-937). All four cell lines exhibited different levels of cathepsins and responded differently to apoptosis triggering, with Jurkat cells being the most sensitive and the only ones that were sensitive to the agonistic anti-APO-1 antibody. Apoptosis was accompanied by caspase activation, loss of the mitochondria and lysosome integrity, and the release of cysteine cathepsins into the cytosol, as judged based on the hydrolysis of the cysteine cathepsin substrate benzyloxycarbonyl-Phe-Arg-7-amino-4-methylcoumarin and by the immunological detection of cathepsin B. The inhibition of caspases by the broad-spectrum inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone prevented apoptosis,including the mitochondrial and lysosomal membrane permeabilization, as well as cathepsin release into the cytosol, consistent with caspases playing a crucial role in the process. Conversely, however, although the broad-spectrum cysteine cathepsin inhibitor (2 S ,3 S )-trans -epoxysuccinyl-leucyl amido-3-methyl-butane ethyl ester and the more cathepsin B-selective inhibitor[(2 S ,3 S )-3-propylcarbamoyloxirane-2-carbonyl]-l-isoleucyl-l-proline methyl ester completely blocked cathepsin activity, these inhibitors neither prevented apoptosis including the mitochondrial and lysosomal membrane permeabilization, as well as cathepsin release into the cytosol, consistent with caspases playing a crucial role in the process. Conversely, however, although the broad-spectrum cysteine cathepsin inhibitor (2 S ,3 S )-trans -epoxysuccinyl-leucylamido-3-methyl-butane ethyl ester and the more cathepsin B-selective inhibitor[(2 S ,3 S )-3-propylcarbamoyloxirane-2-carbonyl]-l-isoleucyl-l-proline methyl ester completely blocked cathepsin activity, these inhibitors neither

  4. Up-regulation of Fas (CD95) and induction of apoptosis in intestinal epithelial cells by nematode-derived molecules.

    PubMed

    Kuroda, Akio; Uchikawa, Ryuichi; Matsuda, Shinji; Yamada, Minoru; Tegoshi, Tatsuya; Arizono, Naoki

    2002-08-01

    Infection by the intestinal nematode Nippostrongylus brasiliensis induces acceleration of apoptosis in the small intestinal villus epithelial cells in vivo. In the present study, we examined whether worm extract or excretory-secretory product induces apoptosis in the rat intestinal epithelial cell line IEC-6 in vitro. In the presence of worm extract or excretory-secretory product (> or =6 microg/ml), IEC-6 cell growth was significantly suppressed, and there was a concomitant increase in the number of detached cells in culture dishes. Detached cells showed nuclear fragmentation, activation of caspase-3, and specific cleavage of poly(ADP-ribose) polymerase, suggesting that apoptosis was induced in these cells. Semiquantitative reverse transcription-PCR showed that expression of Fas (CD95) mRNA was up-regulated as early as 6 h after addition of excretory-secretory product, while Fas ligand expression and p53 expression were not up-regulated. Fluorescence-activated cell sorter analyses revealed a significant increase in Fas expression and a slight increase in FasL expression in IEC-6 cells cultured in the presence of excretory-secretory product, while control IEC-6 cells expressed neither Fas or FasL. These results indicated that N. brasiliensis worms produce and secrete biologically active molecules that trigger apoptosis in intestinal epithelial cells together with up-regulation of Fas expression, although the mechanism of induction of apoptosis remains to be elucidated. PMID:12117905

  5. Conversion of membrane-bound Fas(CD95) ligand to its soluble form is associated with downregulation of its proapoptotic activity and loss of liver toxicity.

    PubMed

    Schneider, P; Holler, N; Bodmer, J L; Hahne, M; Frei, K; Fontana, A; Tschopp, J

    1998-04-20

    Human Fas ligand (L) (CD95L) and tumor necrosis factor (TNF)-alpha undergo metalloproteinase-mediated proteolytic processing in their extracellular domains resulting in the release of soluble trimeric ligands (soluble [s]FasL, sTNF-alpha) which, in the case of sFasL, is thought to be implicated in diseases such as hepatitis and AIDS. Here we show that the processing of sFasL occurs between Ser126 and Leu127. The apoptotic-inducing capacity of naturally processed sFasL was reduced by >1,000-fold compared with membrane-bound FasL, and injection of high doses of recombinant sFasL in mice did not induce liver failure. However, soluble FasL retained its capacity to interact with Fas, and restoration of its cytotoxic activity was achieved both in vitro and in vivo with the addition of cross-linking antibodies. Similarly, the marginal apoptotic activity of recombinant soluble TNF-related apoptosis-inducing ligand (sTRAIL), another member of the TNF ligand family, was greatly increased upon cross-linking. These results indicate that the mere trimerization of the Fas and TRAIL receptors may not be sufficient to trigger death signals. Thus, the observation that sFasL is less cytotoxic than membrane-bound FasL may explain why in certain types of cancer, systemic tissue damage is not detected, even though the levels of circulating sFasL are high. PMID:9547332

  6. CD95/Fas-induced ceramide formation proceeds with slow kinetics and is not blocked by caspase-3/CPP32 inhibition.

    PubMed

    Tepper, A D; Cock, J G; de Vries, E; Borst, J; van Blitterswijk, W J

    1997-09-26

    The current confusion regarding the relevance of endogenous ceramide in mediating CD95/Fas-induced apoptosis is based mainly on (i) discrepancies in kinetics of the ceramide response between different studies using the same apoptotic stimulus and (ii) the observation that late ceramide formation (hours) often parallels apoptosis onset. We investigated CD95-induced ceramide formation in Jurkat cells, using two methods (radiolabeling/thin layer chromatography and benzoylation/high performance liquid chromatography), which, unlike the commonly used diglyceride kinase assay, discriminate between ceramide species and de novo formed dihydroceramide. We demonstrate that ceramide accumulates after several hours, reaching a 7-fold increase after 8 h, kinetics closely paralleling apoptosis induction. No fast response was observed, not even in the presence of inhibitors of ceramide metabolism. The majority ( approximately 70%) of the ceramide response remained unaffected when apoptosis was completely inhibited at the level of caspase-3/CPP32 processing by the inhibitor peptide DEVD-CHO. Exogenous cell-permeable C2-ceramide induced the proteolytic processing of caspase-3, albeit with somewhat slower kinetics than with CD95. DEVD-CHO dose-dependently inhibited C2-ceramide- or exogenous sphingomyelinase-induced apoptosis. The results support the idea that ceramide acts in conjunction with the caspase cascade in CD95-induced apoptosis. PMID:9305886

  7. CD31 signals confer immune privilege to the vascular endothelium

    PubMed Central

    Cheung, Kenneth; Ma, Liang; Wang, Guosu; Coe, David; Ferro, Riccardo; Falasca, Marco; Buckley, Christopher D.; Mauro, Claudio; Marelli-Berg, Federica M.

    2015-01-01

    Constitutive resistance to cell death induced by inflammatory stimuli activating the extrinsic pathway of apoptosis is a key feature of vascular endothelial cells (ECs). Although this property is central to the maintenance of the endothelial barrier during inflammation, the molecular mechanisms of EC protection from cell-extrinsic, proapoptotic stimuli have not been investigated. We show that the Ig-family member CD31, which is expressed by endothelial but not epithelial cells, is necessary to prevent EC death induced by TNF-α and cytotoxic T lymphocytes in vitro. Combined quantitative RT-PCR array and biochemical analysis show that, upon the engagement of the TNF receptor with TNF-α on ECs, CD31 becomes activated and, in turn, counteracts the proapoptotic transcriptional program induced by TNF-α via activation of the Erk/Akt pathway. Specifically, Akt activation by CD31 signals prevents the localization of the forkhead transcription factor FoxO3 to the nucleus, thus inhibiting transcription of the proapoptotic genes CD95/Fas and caspase 7 and de-repressing the expression of the antiapoptotic gene cFlar. Both CD31 intracellular immunoreceptor tyrosine-based inhibition motifs are required for its prosurvival function. In vivo, CD31 gene transfer is sufficient to recapitulate the cytoprotective mechanisms in CD31− pancreatic β cells, which become resistant to immune-mediated rejection when grafted in fully allogeneic recipients. PMID:26392551

  8. Five Xanthomonas type III effectors suppress cell death induced by components of immunity-associated MAP kinase cascades

    PubMed Central

    Teper, Doron; Sunitha, Sukumaran; Martin, Gregory B; Sessa, Guido

    2015-01-01

    Mitogen-activated protein kinase (MAPK) cascades play a fundamental role in signaling of plant immunity and mediate elicitation of cell death. Xanthomonas spp. manipulate plant signaling by using a type III secretion system to deliver effector proteins into host cells. We examined the ability of 33 Xanthomonas effectors to inhibit cell death induced by overexpression of components of MAPK cascades in Nicotiana benthamiana plants. Five effectors inhibited cell death induced by overexpression of MAPKKKα and MEK2, but not of MAP3Kϵ. In addition, expression of AvrBs1 in yeast suppressed activation of the high osmolarity glycerol MAPK pathway, suggesting that the target of this effector is conserved in eukaryotic organisms. These results indicate that Xanthomonas employs several type III effectors to suppress immunity-associated cell death mediated by MAPK cascades. PMID:26237448

  9. Induction of death receptor CD95 and co-stimulatory molecules CD80 and CD86 by meningococcal capsular polysaccharide-loaded vaccine nanoparticles.

    PubMed

    Ubale, Ruhi V; Gala, Rikhav P; Zughaier, Susu M; D'Souza, Martin J

    2014-09-01

    Neisseria meningitidis is a leading cause of bacterial meningitis and sepsis, and its capsular polysaccharides (CPS) are a major virulence factor in meningococcal infections and form the basis for serogroup designation and protective vaccines. We formulated a novel nanovaccine containing meningococcal CPS as an antigen encapsulated in albumin-based nanoparticles (NPs) that does not require chemical conjugation to a protein carrier. These nanoparticles are taken up by antigen-presenting cells and act as antigen depot by slowly releasing the antigen. In this study, we determined the ability of CPS-loaded vaccine nanoparticles to induce co-stimulatory molecules, namely CD80, CD86, and CD95 that impact effective antigen presentation. Co-stimulatory molecule gene induction and surface expression on macrophages and dendritic cells pulsed with meningococcal CPS-loaded nanoparticles were investigated using gene array and flow cytometry methods. Meningococcal CPS-loaded NP significantly induced the surface protein expression of CD80 and CD86, markers of dendritic cell maturation, in human THP-1 macrophages and in murine dendritic cells DC2.4 in a dose-dependent manner. The massive upregulation was also observed at the gene expression. However, high dose of CPS-loaded NP, but not empty NP, induced the expression of death receptor CD95 (Fas) leading to reduced TNF-α release and reduction in cell viability. The data suggest that high expression of CD95 may lead to death of antigen-presenting cells and consequently suboptimal immune responses to vaccine. The CPS-loaded NP induces the expression of co-stimulatory molecules and acts as antigen depot and can spare antigen dose, highly desirable criteria for vaccine formulations. PMID:24981893

  10. Functional Consequences for Apoptosis by Transcription Elongation Regulator 1 (TCERG1)-Mediated Bcl-x and Fas/CD95 Alternative Splicing

    PubMed Central

    Montes, Marta; Coiras, Mayte; Becerra, Soraya; Moreno-Castro, Cristina; Mateos, Elena; Majuelos, Jara; Oliver, F. Javier; Hernández-Munain, Cristina; Alcamí, José; Suñé, Carlos

    2015-01-01

    Here, we present evidence for a specific role of the splicing-related factor TCERG1 in regulating apoptosis in live cells by modulating the alternative splicing of the apoptotic genes Bcl-x and Fas. We show that TCERG1 modulates Bcl-x alternative splicing during apoptosis and its activity in Bcl-x alternative splicing correlates with the induction of apoptosis, as determined by assessing dead cells, sub-G1-phase cells, annexin-V binding, cell viability, and cleavage of caspase-3 and PARP-1. Furthermore, the effect of TCERG1 on apoptosis involved changes in mitochondrial membrane permeabilization. We also found that depletion of TCERG1 reduces the expression of the activated form of the pro-apoptotic mitochondrial membrane protein Bak, which remains inactive by heterodimerizing with Bcl-xL, preventing the initial step of cytochrome c release in Bak-mediated mitochondrial apoptosis. In addition, we provide evidence that TCERG1 also participates in the death receptor-mediated apoptosis pathway. Interestingly, TCERG1 also modulates Fas/CD95 alternative splicing. We propose that TCERG1 sensitizes a cell to apoptotic agents, thus promoting apoptosis by regulating the alternative splicing of both the Bcl-x and Fas/CD95 genes. Our findings may provide a new link between the control of alternative splicing and the molecular events leading to apoptosis. PMID:26462236

  11. [Research of modulation of CD95-mediated apoptosis in lymphoblastic MP-1 and BJAB cells infected by adenovirus and Epstein-Barr virus].

    PubMed

    Nesterova, N V; Diachenko, N S; Zahorodnia, S D; Nosach, L M; Povnytsia, O Iu; Baranova, H V; Zhovnovata, V L

    2006-01-01

    Model systems of infecting limphoblastic MP-1 and BJAB cells by Epstein-Barr virus, 5 serotype adenovirus and double infection are developed. A rather high level of accumulation of DNA of these viruses in the cells in dynamics at monoinfection and inhibition interference at multi-infection was shown by PCR method. The influence of virus infection on proliferative activity was studied. The stimulation of cells growth in the system BJAB + EBV was detected, and double infecting inhibited the process by 50%. The 25% difference in development of apoptosis process between cells infected by adenovirus and EBV was established when defining CD95-mediated apoptosis in infected MP-1 cells. The infecting of BJAB cells by viruses had a scarce effect on the processes of spontaneous apoptosis, but the data on CD95-mediated apoptosis at EBV infection testify to inhibition of this process both at a monoinfection, and at a double infection. The work was performed in the framework of the fundamental agreement of Ministry of Education and Science of Ukraine F7/366-2001, and grant INTAS N011-2382. PMID:16786631

  12. Modulation of hippocampal neuroplasticity by Fas/CD95 regulatory protein 2 (Faim2) in the course of bacterial meningitis.

    PubMed

    Tauber, Simone C; Harms, Kristian; Falkenburger, Björn; Weis, Joachim; Sellhaus, Bernd; Nau, Roland; Schulz, Jörg B; Reich, Arno

    2014-01-01

    Fas-apoptotic inhibitory molecule 2 (Faim2) is a neuron-specific membrane protein and a member of the evolutionary conserved lifeguard apoptosis regulatory gene family. Its neuroprotective effect in acute neurological diseases has been demonstrated in an in vivo model of focal cerebral ischemia. Here we show that Faim2 is physiologically expressed in the human brain with a changing pattern in cases of infectious meningoencephalitis.In Faim2-deficient mice, there was increased caspase-associated hippocampal apoptotic cell death and an increased extracellular signal-regulated kinase pattern during acute bacterial meningitis induced by subarachnoid infection with Streptococcus pneumoniae type 3 strain. However, after rescuing the animals by antibiotic treatment, Faim2 deficiency led to increased hippocampal neurogenesis at 7 weeks after infection. This was associated with improved performance of Faim2-deficient mice compared to wild-type littermates in the Morris water maze, a paradigm for hippocampal spatial learning and memory. Thus, Faim2 deficiency aggravated degenerative processes in the acute phase but induced regenerative processes in the repair phase of a mouse model of pneumococcal meningitis. Hence, time-dependent modulation of neuroplasticity by Faim2 may offer a new therapeutic approach for reducing hippocampal neuronal cell death and improving cognitive deficits after bacterial meningitis. PMID:24335530

  13. New bichalcone analogs as NF-κB inhibitors and as cytotoxic agents inducing Fas/CD95-dependent apoptosis

    PubMed Central

    Vijaya Bhaskar Reddy, M.; Shen, Yuh-Chiang; Hwang, Tsong-Long; Bastow, Kenneth F.; Qian, Keduo; Lee, Kuo-Hsiung; Wu, Tian-Shung

    2011-01-01

    A series of novel bichalcone analogs were synthesized and evaluated in lipopolysaccharide (LPS)-activated microglial cells as inhibitors of nitric oxide (NO) and for in vitro anticancer activity using a limited panel of four human cancer cell lines. All analogs inhibited NO production. Compounds 4 and 11 exhibited optimal activity with IC50 values of 0.3 and 0.5 µM, respectively, and were at least 38-fold better than the positive control. A mechanism of action study showed that both compounds significantly blocked the nuclear translocation of NF-κB p65 and up-regulation of iNOS at 1.0 µM. Compound 4 and three other analogs (3, 20, and 23) exerted significant in vitro anticancer activity GI50 values ranging from 0.70~13.10 µM. A mode of action study using HT-29 colon cancer cells showed that 23 acts by inducing apoptosis signaling. PMID:21377368

  14. Identification and Characterization of Plant Cell Death-Inducing Secreted Proteins From Ustilaginoidea virens.

    PubMed

    Fang, Anfei; Han, Yanqing; Zhang, Nan; Zhang, Min; Liu, Lijuan; Li, Shuai; Lu, Fen; Sun, Wenxian

    2016-05-01

    Ustilaginoidea virens (Cooke) Takah (telemorph Villosiclava virens) is an ascomycetous fungus that causes rice false smut, one of the most important rice diseases. Fungal effectors often play essential roles in host-pathogen coevolutionary interactions. However, little is known about the functions of U. virens effectors. Here, we performed functional studies on putative effectors in U. virens and demonstrated that 13 of 119 putative effectors caused necrosis or necrosis-like phenotypes in Nicotiana benthamiana. Among them, 11 proteins were confirmed to be secreted, using a yeast secretion system, and the corresponding genes are all highly induced during infection, except UV_44 and UV_4753. Eight secreted proteins were proven to trigger cell death or defenses in rice protoplasts and the secretion signal of these proteins is essential for their cell death-inducing activity. The ability of UV_44 and UV_1423 to trigger cell death is dependent on the predicted serine peptidase and ribonuclease catalytic active sites, respectively. We demonstrated that UV_1423 and UV_6205 are N-glycosylated proteins, which glycosylation has different impacts on their abilities to induce cell death. Collectively, the study identified multiple secreted proteins in U. virens with specific structural motifs that induce cell death or defense machinery in nonhost and host plants. PMID:26927000

  15. A blast without power - cell death induced by the tuberculosis-necrotizing toxin fails to elicit adequate immune responses.

    PubMed

    Maueröder, C; Chaurio, R A; Dumych, T; Podolska, M; Lootsik, M D; Culemann, S; Friedrich, R P; Bilyy, R; Alexiou, C; Schett, G; Berens, C; Herrmann, M; Munoz, L E

    2016-06-01

    In this study, we deploy a doxycycline-dependent suicide switch integrated in a tumor challenge model. With this experimental setup, we characterized the immunological consequences of cells dying by four distinct cell death stimuli in vivo. We observed that apoptotic cell death induced by expression of the truncated form of BH3 interacting-domain death agonist (tBid) and a constitutively active form of caspase 3 (revC3), respectively, showed higher immunogenicity than cell death induced by expression of the tuberculosis-necrotizing toxin (TNT). Our data indicate that the early release of ATP induces the silent clearance of dying cells, whereas the simultaneous presence of 'find me' signals and danger-associated molecular patterns (DAMPs) promotes inflammatory reactions and increased immunogenicity. This proposed model is supported by findings showing that the production and release of high concentrations of IL-27 by bone-marrow-derived macrophages (BMDM) is limited to BMDM exposed to those forms of death that simultaneously released ATP and the DAMPs heat-shock protein 90 (HSP90) and high-mobility group box-1 protein (HMGB1). These results demonstrate that the tissue microenvironment generated by dying cells may determine the subsequent immune response. PMID:26943324

  16. Primary Effusion Lymphoma Cell Death Induced by Bortezomib and AG 490 Activates Dendritic Cells through CD91

    PubMed Central

    Cirone, Mara; Di Renzo, Livia; Lotti, Lavinia Vittoria; Conte, Valeria; Trivedi, Pankaj; Santarelli, Roberta; Gonnella, Roberta; Frati, Luigi; Faggioni, Alberto

    2012-01-01

    To understand how cytotoxic agent-induced cancer cell death affects the immune system is of fundamental importance to stimulate immune response to counteract the high mortality due to cancer. Here we compared the immunogenicity of Primary Effusion Lymphoma (PEL) cell death induced by anticancer drug Bortezomib (Velcade) and Tyrphostin AG 490, a Janus Activated Kinase 2/signal trasducer and activator of transcription-3 (JAK2/STAT3) inhibitor. We show that both treatments were able to induce PEL apoptosis with similar kinetics and promote dendritic cells (DC) maturation. The surface expression of molecules involved in immune activation, namely calreticulin (CRT), heat shock proteins (HSP) 90 and 70 increased in dying cells. This was correlated with DC activation. We found that PEL cell death induced by Bortezomib was more effective in inducing uptake by DC compared to AG 490 or combination of both drugs. However the DC activation induced by all treatments was completely inhibited when these cells were pretreated with a neutralizing antiboby directed against the HSP90/70 and CRT common receptor, CD91. The activation of DC by Bortezomib and AG 490 treated PEL cells, as seen in the present study, might have important implications for a combined chemo and immunotherapy in such patients. PMID:22412839

  17. Endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls B-cell immunity through degradation of the death receptor CD95/Fas.

    PubMed

    Kong, Sinyi; Yang, Yi; Xu, Yuanming; Wang, Yajun; Zhang, Yusi; Melo-Cardenas, Johanna; Xu, Xiangping; Gao, Beixue; Thorp, Edward B; Zhang, Donna D; Zhang, Bin; Song, Jianxun; Zhang, Kezhong; Zhang, Jianning; Zhang, Jinping; Li, Huabin; Fang, Deyu

    2016-09-13

    Humoral immunity involves multiple checkpoints during B-cell development, maturation, and activation. The cell death receptor CD95/Fas-mediated apoptosis plays a critical role in eliminating the unwanted activation of B cells by self-reactive antigens and in maintaining B-cell homeostasis through activation-induced B-cell death (AICD). The molecular mechanisms controlling AICD remain largely undefined. Herein, we show that the E3 ubiquitin ligase Hrd1 protected B cells from activation-induced cell death by degrading the death receptor Fas. Hrd1-null B cells exhibited high Fas expression during activation and rapidly underwent Fas-mediated apoptosis, which could be largely inhibited by FasL neutralization. Fas mutation in Hrd1 KO mice abrogated the increase in B-cell AICD. We identified Hrd1 as the first E3 ubiquitin ligase of the death receptor Fas and Hrd1-mediated Fas destruction as a molecular mechanism in regulating B-cell immunity. PMID:27573825

  18. Differential immunomodulatory activity of tumor cell death induced by cancer therapeutic toll-like receptor ligands.

    PubMed

    Klein, Johanna C; Wild, Clarissa A; Lang, Stephan; Brandau, Sven

    2016-06-01

    Synthetic toll-like receptor (TLR) ligands stimulate defined immune cell subsets and are currently tested as novel immunotherapeutic agents against cancer with, however, varying clinical efficacy. Recent data showed the expression of TLR receptors also on tumor cells. In this study we investigated immunological events associated with the induction of tumor cell death by poly(I:C) and imiquimod. A human head and neck squamous cell carcinoma (HNSCC) cell line was exposed to poly(I:C) and imiquimod, which were delivered exogenously via culture medium or via electroporation. Cell death and cell biological consequences thereof were analyzed. For in vivo analyses, a human xenograft and a syngeneic immunocompetent mouse model were used. Poly(I:C) induced cell death only if delivered by electroporation into the cytosol. Cell death induced by poly(I:C) resulted in cytokine release and activation of monocytes in vitro. Monocytes activated by the supernatant of cancer cells previously exposed to poly(I:C) recruited significantly more Th1 cells than monocytes exposed to control supernatants. If delivered exogenously, imiquimod also induced tumor cell death and some release of interleukin-6, but cell death was not associated with release of Th1 cytokines, interferons, monocyte activation and Th1 recruitment. Interestingly, intratumoral injection of poly(I:C) triggered tumor cell death in tumor-bearing mice and reduced tumor growth independent of TLR signaling on host cells. Imiquimod did not affect tumor size. Our data suggest that common cancer therapeutic RNA compounds can induce functionally diverse types of cell death in tumor cells with implications for the use of TLR ligands in cancer immunotherapy. PMID:27034235

  19. The Expression of TLR-9, CD86, and CD95 Phenotypes in Circulating B Cells of Patients with Chronic Viral Hepatitis B or C before and after Antiviral Therapy

    PubMed Central

    Zhao, Ping-wei; Ma, Liang; Ji, Hui-fan; Yu, Lei; Feng, Jun-yan; Liu, Ming-yuan; Jiang, Yan-fang

    2015-01-01

    Aims. This study aimed to assess the differential expression of specific B cell subtypes in patients with chronic viral hepatitis. Methods. The frequencies of differential expression of specific B cell subtypes in patients with chronic viral hepatitis and healthy controls were assessed by flow cytometry using monoclonal antibodies specific for CD38, CD27, CD86, CD95, TLR-9, and IgD. The effect of adefovir treatment on B cell subsets in HBV patients was determined. The values of clinical parameters in the patients were also measured. Results. The frequency of CD86+ B cells was not significantly different in chronic HBV patients but was higher in HCV patients compared with that in healthy controls. CD95 and IgD levels were lower in HBV and HCV patients than in healthy controls. A significant negative correlation occurred between the proportion of CD95+ B cells and HBV DNA viral load. The frequency of TLR-9 on the B cells in HBV and HCV patients was higher compared with that of healthy controls. After treatment with adefovir, the frequency of CD95 and IgD expressed on B cells was increased in HBV patients. Conclusions. Activated B cells and exhausted B cells homeostasis were commonly disturbed in HBV and HCV patients. PMID:25892855

  20. Turkish propolis supresses MCF-7 cell death induced by homocysteine.

    PubMed

    Tartik, Musa; Darendelioglu, Ekrem; Aykutoglu, Gurkan; Baydas, Giyasettin

    2016-08-01

    Elevated plasma homocysteine (Hcy) level is a most important risk factor for various vascular diseases including coronary, cerebral and peripheral arterial and venous thrombosis. Propolis is produced by honeybee from various oils, pollens and wax materials. Therefore, it has various biological properties including antioxidant, antitumor and antimicrobial activities. This study investigated the effects of propolis and Hcy on apoptosis in cancer cells. According to our findings, Hcy induced apoptosis in human breast adenocarcinoma (MCF-7) cells by regulating numerous genes and proteins involved in the apoptotic signal transduction pathway. In contrast, treatment with propolis inhibited caspase- 3 and -9 induced by Hcy in MCF-7 cells. It can be concluded that Hcy may augment the activity of anticancer agents that induce excessive reactive oxygen species (ROS) generation and apoptosis in their target cells. In contrast to the previous studies herein we found that propolis in low doses protected cancer cells inhibiting cellular apoptosis mediated by intracellular ROS-dependent mitochondrial pathway. PMID:27470414

  1. Levetiracetam Differentially Alters CD95 Expression of Neuronal Cells and the Mitochondrial Membrane Potential of Immune and Neuronal Cells in vitro.

    PubMed

    Rogers, Susannah K; Shapiro, Lee A; Tobin, Richard P; Tow, Benjamin; Zuzek, Aleksej; Mukherjee, Sanjib; Newell-Rogers, M Karen

    2014-01-01

    Epilepsy is a neurological seizure disorder that affects over 100 million people worldwide. Levetiracetam, either alone, as monotherapy, or as adjunctive treatment, is widely used to control certain types of seizures. Despite its increasing popularity as a relatively safe and effective anti-convulsive treatment option, its mechanism(s) of action are poorly understood. Studies have suggested neuronal, glial, and immune mechanisms of action. Understanding the precise mechanisms of action of levetiracetam would be extremely beneficial in helping to understand the processes involved in seizure generation and epilepsy. Moreover, a full understanding of these mechanisms would help to create more efficacious treatments while minimizing side-effects. The current study examined the effects of levetiracetam on the mitochondrial membrane potential of neuronal and non-neuronal cells, in vitro, in order to determine if levetiracetam influences metabolic processes in these cell types. In addition, this study sought to address possible immune-mediated mechanisms by determining if levetiracetam alters the expression of immune receptor-ligand pairs. The results show that levetiracetam induces expression of CD95 and CD178 on NGF-treated C17.2 neuronal cells. The results also show that levetiracetam increases mitochondrial membrane potential on C17.2 neuronal cells in the presence of nerve growth factor. In contrast, levetiracetam decreases the mitochondrial membrane potential of splenocytes and this effect was dependent on intact invariant chain, thus implicating immune cell interactions. These results suggest that both neuronal and non-neuronal anti-epileptic activities of levetiracetam involve control over energy metabolism, more specifically, mΔΨ. Future studies are needed to further investigate this potential mechanism of action. PMID:24600432

  2. Age-Dependent Changes in FasL (CD95L) Modulate Macrophage Function in a Model of Age-Related Macular Degeneration

    PubMed Central

    Zhao, Hui; Roychoudhury, Jayeeta; Doggett, Teresa A.; Apte, Rajendra S.; Ferguson, Thomas A.

    2013-01-01

    Purpose. We examined the effect of aging on Fas ligand (FasL) function in a mouse model of choroidal neovascularization (CNV). Methods. Young and aged mice were laser treated to induce CNV. Bone marrow chimeras were performed between young and aged mice. FasL protein expression was examined in the eye and soluble FasL (sFasL) was measured in the blood. Young and aged mice were treated with a matrix metalloprotease (MMP) inhibitor and systemic sFasL was neutralized by antibody treatment. Macrophages from young and aged mice were tested for sFasL-mediated cytokine production and migration. Results. The elevated CNV response observed with aging was dependent on bone marrow–derived cells. FasL expression in the eye was increased with age, but decreased following laser treatment. Aged mice had higher levels of sFasL in the blood compared to young mice. Systemic treatment with an MMP inhibitor decreased bloodborne sFasL, and reduced CNV in young and aged mice. Systemic neutralization of sFasL reduced CNV only in aged mice. sFasL increased cytokine production in aged macrophages and proangiogenic M2 macrophages. Aged M2 macrophages had elevated Fas (CD95) expression and displayed increased migration in response to sFasL compared to M1 macrophages derived from young animals. Conclusions. Age modulates FasL function where increased MMP cleavage leads to a loss of function in the eye. The released form of FasL (sFasL) preferentially induces the migration of proangiogenic M2 macrophages into the laser lesions and increases proangiogenic cytokines promoting CNV. FasL may be a viable target for therapeutic intervention in aged-related neovascular disease. PMID:23821188

  3. The hnRNP-Htt axis regulates necrotic cell death induced by transcriptional repression through impaired RNA splicing

    PubMed Central

    Mao, Y; Tamura, T; Yuki, Y; Abe, D; Tamada, Y; Imoto, S; Tanaka, H; Homma, H; Tagawa, K; Miyano, S; Okazawa, H

    2016-01-01

    In this study, we identify signaling network of necrotic cell death induced by transcriptional repression (TRIAD) by α-amanitin (AMA), the selective RNA polymerase II inhibitor, as a model of neurodegenerative cell death. We performed genetic screen of a knockdown (KD) fly library by measuring the ratio of transformation from pupa to larva (PL ratio) under TRIAD, and selected the cell death-promoting genes. Systems biology analysis of the positive genes mapped on protein–protein interaction databases predicted the signaling network of TRIAD and the core pathway including heterogeneous nuclear ribonucleoproteins (hnRNPs) and huntingtin (Htt). RNA sequencing revealed that AMA impaired transcription and RNA splicing of Htt, which is known as an endoplasmic reticulum (ER)-stabilizing molecule. The impairment in RNA splicing and PL ratio was rescued by overexpresion of hnRNP that had been also affected by transcriptional repression. Fly genetics with suppressor or expresser of Htt and hnRNP worsened or ameliorated the decreased PL ratio by AMA, respectively. Collectively, these results suggested involvement of RNA splicing and a regulatory role of the hnRNP-Htt axis in the process of the transcriptional repression-induced necrosis. PMID:27124581

  4. The hnRNP-Htt axis regulates necrotic cell death induced by transcriptional repression through impaired RNA splicing.

    PubMed

    Mao, Y; Tamura, T; Yuki, Y; Abe, D; Tamada, Y; Imoto, S; Tanaka, H; Homma, H; Tagawa, K; Miyano, S; Okazawa, H

    2016-01-01

    In this study, we identify signaling network of necrotic cell death induced by transcriptional repression (TRIAD) by α-amanitin (AMA), the selective RNA polymerase II inhibitor, as a model of neurodegenerative cell death. We performed genetic screen of a knockdown (KD) fly library by measuring the ratio of transformation from pupa to larva (PL ratio) under TRIAD, and selected the cell death-promoting genes. Systems biology analysis of the positive genes mapped on protein-protein interaction databases predicted the signaling network of TRIAD and the core pathway including heterogeneous nuclear ribonucleoproteins (hnRNPs) and huntingtin (Htt). RNA sequencing revealed that AMA impaired transcription and RNA splicing of Htt, which is known as an endoplasmic reticulum (ER)-stabilizing molecule. The impairment in RNA splicing and PL ratio was rescued by overexpresion of hnRNP that had been also affected by transcriptional repression. Fly genetics with suppressor or expresser of Htt and hnRNP worsened or ameliorated the decreased PL ratio by AMA, respectively. Collectively, these results suggested involvement of RNA splicing and a regulatory role of the hnRNP-Htt axis in the process of the transcriptional repression-induced necrosis. PMID:27124581

  5. Characterization of a novel epigenetic effect of ionizing radiation: the death-inducing effect

    NASA Technical Reports Server (NTRS)

    Nagar, Shruti; Smith, Leslie E.; Morgan, William F.

    2003-01-01

    The detrimental effects associated with exposure to ionizing radiation have long been thought to result from the direct targeting of the nucleus leading to DNA damage; however, the emergence of concepts such as radiation-induced genomic instability and bystander effects have challenged this dogma. After cellular exposure to ionizing radiation, we have isolated a number of clones of Chinese hamster-human hybrid GM10115 cells that demonstrate genomic instability as measured by chromosomal destabilization. These clones show dynamic and persistent generation of chromosomal rearrangements multiple generations after the original insult. We hypothesize that these unstable clones maintain this delayed instability phenotype by secreting factors into the culture medium. To test this hypothesis we transferred filtered medium from unstable cells to unirradiated GM10115 cells. No GM10115 cells were able to survive this medium. This phenomenon by which GM10115 cells die when cultured in medium from chromosomally unstable GM10115 clones is the death-inducing effect. Medium transfer experiments indicate that a factor or factors is/are secreted by unstable cells within 8 h of growth in fresh medium and result in cell killing within 24 h. These factors are stable at ambient temperature but do not survive heating or freezing, and are biologically active when diluted with fresh medium. We present the initial description and characterization of the death-inducing effect. This novel epigenetic effect of radiation has implications for radiation risk assessment and for health risks associated with radiation exposure.

  6. Increase of p25 associated with cortical neuronal death induced by hypoxia.

    PubMed

    Huang, Tianwen; Fang, Lijun; Lin, Zhiying; Huang, En; Ye, Qinyong

    2016-09-01

    The mechanisms of neuronal damage in hypoxic cerebral cortex are complicated. Recent studies indicated that deregulation of Cdk5 was involved in neuronal death induced by hypoxia (1% O2). However, the pathological effect of Cdk5 is not fully elucidated. Therefore, in order to decipher the effect of Cdk5 on cellular death in hypoxic condition, the Cdk5 and its activator p35/p25 were investigated in cortical neurons at 10 DIV (Days In Vitro). Upon exposure to hypoxia, the cortical neurons showed a time-dependent increase of neuronal death compared to normoxia-treated control neurons. In correlation to the increase of neuronal death under hypoxia, the level of p25, a truncated form of p35, also increased in a time-dependent manner. Importantly, inhibition of Cdk5 kinase activity by roscovitine protected neurons from death under hypoxic stress. In contrast, ectopic upregulation of Cdk5 kinase activity in neurons expressing p25 led to an increase of neuronal death in comparison to control neurons expressing GFP. It suggests that ectopic increase of Cdk5 kinase activity through conversion of p35 to p25 is involved in the process of neuronal death induced by hypoxia. PMID:27402274

  7. Molecular mechanism of cell death induced by king cobra (Ophiophagus hannah) venom l-amino acid oxidase.

    PubMed

    Fung, Shin Yee; Lee, Mui Li; Tan, Nget Hong

    2015-03-01

    Snake venom LAAOs have been reported to exhibit a wide range of pharmacological activities, including cytotoxic, edema-inducing, platelet aggregation-inducing/platelet aggregation-inhibiting, bactericidal and antiviral activities. A heat-stable form of l-amino acid oxidase isolated from king cobra (Ophiophagus hannah) venom (OH-LAAO) has been shown to exhibit very potent cytotoxicity against human tumorigenic cells but not in their non-tumorigenic counterparts, and the cytotoxicity was due to the apoptosis-inducing effect of the enzyme. In this work, the molecular mechanism of cell death induced by OH-LAAO was investigated. The enzyme exerts its apoptosis-inducing effect presumably via both intrinsic and extrinsic pathways as suggested by the increase in caspase-8 and -9 activities. Oligonucleotide microarray analysis showed that the expression of a total of 178 genes was significantly altered as a result of oxidative stress induced by the hydrogen peroxide generated by the enzyme. Of the 178 genes, at least 27 genes are involved in apoptosis and cell death. These alterations of gene expression was presumably caused by the direct cytotoxic effect of H2O2 generated during the enzymatic reaction, as well as the non-specific oxidative modifications of signaling molecules that eventually lead to apoptosis and cell death. The very substantial up-regulation of cytochrome P450 genes may also contribute to the potent cytotoxic action of OH-LAAO by producing excessive reactive oxygen species (ROS). In conclusion, the potent apoptosis inducing activity of OH-LAAO was likely due to the direct cytotoxic effect of H2O2 generated during the enzymatic reaction, as well as the non-specific oxidation of signalling molecules. PMID:25615711

  8. Nerve cell death induced in vivo by kainic acid and quinolinic acid does not involve apoptosis.

    PubMed

    Ignatowicz, E; Vezzani, A M; Rizzi, M; D'Incalci, M

    1991-11-01

    We investigated whether in vivo excitotoxicity was mediated by a mechanism of programmed cell death called apoptosis. Neurotoxic doses of kainic acid (1.2 nmol) and quinolinic acid (120 nmol) were unilaterally injected in the dorsal hippocampus of anesthetized rats. Eight or 16 h later the animals were killed and DNA was extracted from the injected hippocampi. DNA from mouse thymocytes exposed to methylprednisolone (10(-5) M for 6 h at 37 degrees C) was used as a positive control of apoptotic cells. No typical 'ladder' of DNA fragments (multimers of approximately 200 Kb) which characterizes apoptosis was seen in hippocampal cells after toxic doses of kainic or quinolinic acid, as assessed by agarose gel electrophoresis. This suggests that hippocampal nerve cell death induced in vivo by the excitotoxins is not mediated by apoptosis. PMID:1839770

  9. Iron prochelator BSIH protects retinal pigment epithelial cells against cell death induced by hydrogen peroxide.

    PubMed

    Charkoudian, Louise K; Dentchev, Tzvete; Lukinova, Nina; Wolkow, Natalie; Dunaief, Joshua L; Franz, Katherine J

    2008-12-01

    Dysregulation of localized iron homeostasis is implicated in several degenerative diseases, including Parkinson's, Alzheimer's, and age-related macular degeneration, wherein iron-mediated oxidative stress is hypothesized to contribute to cell death. Inhibiting toxic iron without altering normal metal-dependent processes presents significant challenges for standard small molecule chelating agents. We previously introduced BSIH (isonicotinic acid [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzylidene]-hydrazide) prochelators that are converted by hydrogen peroxide into SIH (salicylaldehyde isonicotinoyl hydrazone) chelating agents that inhibit iron-catalyzed hydroxyl radical generation. Here, we show that BSIH protects a cultured cell model for retinal pigment epithelium against cell death induced by hydrogen peroxide. BSIH is more stable than SIH in cell culture medium and is more protective during long-term experiments. Repetitive exposure of cells to BSIH is nontoxic, whereas SIH and desferrioxamine induce cell death after repeated exposure. Combined, our results indicate that cell protection by BSIH involves iron sequestration that occurs only when the cells are stressed by hydrogen peroxide. These findings suggest that prochelators discriminate toxic iron from healthy iron and are promising candidates for neuro- and retinal protection. PMID:18835041

  10. Induction of morphological changes in death-induced cancer cells monitored by holographic microscopy.

    PubMed

    El-Schich, Zahra; Mölder, Anna; Tassidis, Helena; Härkönen, Pirkko; Falck Miniotis, Maria; Gjörloff Wingren, Anette

    2015-03-01

    We are using the label-free technique of holographic microscopy to analyze cellular parameters including cell number, confluence, cellular volume and area directly in the cell culture environment. We show that death-induced cells can be distinguished from untreated counterparts by the use of holographic microscopy, and we demonstrate its capability for cell death assessment. Morphological analysis of two representative cell lines (L929 and DU145) was performed in the culture flasks without any prior cell detachment. The two cell lines were treated with the anti-tumour agent etoposide for 1-3days. Measurements by holographic microscopy showed significant differences in average cell number, confluence, volume and area when comparing etoposide-treated with untreated cells. The cell volume of the treated cell lines was initially increased at early time-points. By time, cells decreased in volume, especially when treated with high doses of etoposide. In conclusion, we have shown that holographic microscopy allows label-free and completely non-invasive morphological measurements of cell growth, viability and death. Future applications could include real-time monitoring of these holographic microscopy parameters in cells in response to clinically relevant compounds. PMID:25637284

  11. Impedance-Based Monitoring of Ongoing Cardiomyocyte Death Induced by Tumor Necrosis Factor-α

    PubMed Central

    Qiu, Yiling; Liao, Ronglih; Zhang, Xin

    2009-01-01

    Deregulated cardiomyocyte death is a critical risk factor in a variety of cardiovascular diseases. Although various assays have been developed to detect cell responses during cell death, the capability of monitoring cell detachment will enhance the understanding of death processes by providing instant information at its early phase. In this work, we developed an impedance-sensing assay for real-time monitoring of cardiomyocyte death induced by tumor necrosis factor-α based on recording the change in cardiomyocyte adhesion to extracellular matrix. Electrochemical impedance spectroscopy was employed in impedance data processing, followed by calibration with the electrical cell-substrate impedance-sensing technique. The adhesion profile of cardiomyocytes undergoing cell death processes was recorded as the time course of equivalent cell-substrate distance. The cell detachment was detected with our assay and proved related to cell death in the following experiments, indicating its advantage against the conventional assays, such as Trypan blue exclusion. An optimal concentration of tumor necrosis factor-α (20 ng/mL) was determined to induce cardiomyocyte apoptosis rather than the combinative cell death of necrosis and apoptosis by comparing the concentration-related adhesion profiles. The cardiomyocytes undergoing apoptosis experienced an increase of cell-substrate distance from 59.1 to 89.2 nm within 24 h. The early change of cell adhesion was proved related to cardiomyocyte apoptosis in the following TUNEL test at t = 24 h, which suggested the possibility of early and noninvasive detection of cardiomyocyte apoptosis. PMID:19254558

  12. The expression of Death Inducer-Obliterator (DIDO) variants in Myeloproliferative Neoplasms.

    PubMed

    Berzoti-Coelho, Maria Gabriela; Ferreira, Aline Fernanda; de Souza Nunes, Natalia; Pinto, Mariana Tomazini; Júnior, Maurício Cristiano Rocha; Simões, Belinda Pinto; Martínez-A, Carlos; Souto, Elizabeth Xisto; Panepucci, Rodrigo Alexandre; Covas, Dimas Tadeu; Kashima, Simone; Castro, Fabíola Attié

    2016-07-01

    Chronic Myeloid Leukemia (CML), Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF) are Myeloproliferative Neoplasms (MPN) characterized by clonal myeloproliferation without cell maturation impairment. CML pathogenesis is associated with the Ph chromosome leading to BCR-ABL tyrosine-kinase constitutive expression. The Ph negative MPN (PV, ET and PMF) are characterized by the mutation JAK2(V617F) of the JAK2 protein in the auto-inhibitory JH2 domain, which is found in most PV patients and in approximately half of ET and PMF patients. Considerable effort is being made to understand the role of JAK2(V617F) at the MPN initiation and to clarify the pathogenesis and apoptosis resistance in CML, PV, ET and PMF patients. In the present investigation, we evaluated the Death Inducer-Obliterator (DIDO) (variants DIDO 1, 2 and 3) levels in CML, PV, ET and PMF patients. Our data reported the DIDO 1, 2 and 3 differential expressions in Myeloproliferative Neoplasms. PMID:27282563

  13. Cell death induced by mechanical compression on engineered muscle results from a gradual physiological mechanism.

    PubMed

    Wu, Yabin; van der Schaft, Daisy W J; Baaijens, Frank P; Oomens, Cees W J

    2016-05-01

    Deep tissue injury (DTI), a type of pressure ulcer, arises in the muscle layers adjacent to bony prominences due to sustained mechanical loading. DTI presents a serious problem in the clinic, as it is often not visible until reaching an advanced stage. One of the causes can be direct mechanical deformation of the muscle tissue and cell. The mechanism of cell death induced by mechanical compression was studied using bio-artificial skeletal muscle tissues. Compression was applied by placing weights on top of the constructs. The morphological changes of the cytoskeleton and the phosphorylation of mitogen-activated protein kinases (MAPK) under compression were investigated. Moreover, inhibitors for each of the three major MAPK groups, p38, ERK, and JNK, were applied separately to look at their roles in the compression caused apoptosis and necrosis. The present study for the first time showed that direct mechanical compression activates MAPK phosphorylation. Compression also leads to a gradual destruction of the cytoskeleton. The percentage apoptosis is strongly reduced by p38 and JNK inhibitors down to the level of the unloaded group. This phenomenon could be observed up to 24h after initiation of compression. Therefore, cell death in bio-artificial muscle tissue caused by mechanical compression is primarily caused by a physiological mechanism, rather than through a physical mechanism which kills the cell directly. These findings reveal insight of muscle cell death under mechanical compression. Moreover, the result indicates a potential clinical solution to prevent DTI by pre-treating with p38 or/and JNK inhibitors. PMID:26961799

  14. High expression of CD38, CD69, CD95 and CD154 biomarkers in cultured peripheral T lymphocytes correlates with an increased risk of acute rejection in liver allograft recipients.

    PubMed

    Boix, Francisco; Millan, Olga; Segundo, David San; Mancebo, Esther; Rimola, Antoni; Fabrega, Emilio; Fortuna, Virginia; Mrowiec, Anna; Castro-Panete, Maria J; Peña, Jesus de la; Llorente, Santiago; Minguela, Alfredo; Bolarin, Jose M; Paz-Artal, Estela; Lopez-Hoyos, Marcos; Brunet, Mercé; Muro, Manuel

    2016-05-01

    The mayor goal still outstanding into the solid organ transplantation field involves the search of surrogate biomarkers able to predict several clinical events, such as acute rejection (AR) or opportunistic infection. In the present multicenter study, a series of interesting surface antigens with important activator or inhibitory immune functions on cultured peripheral T cells were monitored in liver transplant recipients drawn at baseline and up to one year after transplantation. Sixty-four patients were included in the multicenter study during 3 years. Pre- and post-transplantation surface antigens levels displayed significant differences between AR and non acute rejection (NAR) groups, and also this differential expression was used to construct a risk predictive model based on a composite panel of outcome biomarkers (CD38, CD69, CD95 and CD154). The model was able to stratify these patients at high risk of AR. These preliminary results could provide basic information to improve the immunosuppressive treatment and it might better help to predict AR episodes. PMID:26850323

  15. Mitochondrial complex I inhibition is not required for dopaminergic neuron death induced by rotenone, MPP+, or paraquat

    PubMed Central

    Choi, Won-Seok; Kruse, Shane E.; Palmiter, Richard D.; Xia, Zhengui

    2008-01-01

    Inhibition of mitochondrial complex I is one of the leading hypotheses for dopaminergic neuron death associated with Parkinson's disease (PD). To test this hypothesis genetically, we used a mouse strain lacking functional Ndufs4, a gene encoding a subunit required for complete assembly and function of complex I. Deletion of the Ndufs4 gene abolished complex I activity in midbrain mesencephalic neurons cultured from embryonic day (E) 14 mice, but did not affect the survival of dopaminergic neurons in culture. Although dopaminergic neurons were more sensitive than other neurons in these cultures to cell death induced by rotenone, MPP+, or paraquat treatments, the absence of complex I activity did not protect the dopaminergic neurons, as would be expected if these compounds act by inhibiting complex 1. In fact, the dopaminergic neurons were more sensitive to rotenone. These data suggest that dopaminergic neuron death induced by treatment with rotenone, MPP+, or paraquat is independent of complex I inhibition. PMID:18812510

  16. Protective effect of aqueous extract from Spirulina platensis against cell death induced by free radicals

    PubMed Central

    2010-01-01

    Background Spirulina is a commercial alga well known to contain various antioxidants, especially phycocyanin. Apart from being sold as a nutraceutical, Spirulina is incorporated as a functional ingredient in food products and beverages. Most of the previous reports on antioxidant activity of Spirulina were based on chemical rather than cell-based assays. The primary objective of this study was to assess the antioxidant activity of aqueous extract from Spirulina based on its protective effect against cell death induced by free radicals. Methods The antioxidant activity of the cold water extract from food-grade Spirulina platensis was assessed using both chemical and cell-based assays. In the cell-based assay, mouse fibroblast cells (3T3) cells were incubated for 1 h in medium containing aqueous extract of Spirulina or vitamin C (positive control) at 25, 125 and 250 μg/mL before the addition of 50 μM 1,1-diphenyl-2-picrylhydrazyl (DPPH) or 3-ethylbenzothiazoline-6-sulfonic acid (ABTS). The cells were incubated for another 24 h before being assessed for cell death due to apoptosis using the Cell Death Detection ELISA Kit. Spectrophotometric assays based on DPPH and ABTS were also used to assess the antioxidant activity of the extract compared to vitamin C and vitamin E (positive controls). Results Spirulina extract did not cause cytotoxic effect on 3T3 cells within the range of concentrations tested (0 - 250 μg/mL). The extract reduced significantly (p < 0.05) apoptotic cell death due to DPPH and ABTS by 4 to 5-fold although the activity was less than vitamin C. Based on the DPPH assay, the radical scavenging activity of the extract was higher than phycocyanin and was at least 50% of vitamin C and vitamin E. Based on the ABTS assay, the antioxidant activity of the extract at 50 μmug/mL was as good as vitamin C and vitamin E. Conclusions The results showed that aqueous extract of Spirulina has a protective effect against apoptotic cell death due to free radicals

  17. Mitotic catastrophe and cell death induced by depletion of centrosomal proteins

    PubMed Central

    Kimura, M; Yoshioka, T; Saio, M; Banno, Y; Nagaoka, H; Okano, Y

    2013-01-01

    Mitotic catastrophe, which refers to cell death or its prologue triggered by aberrant mitosis, can be induced by a heterogeneous group of stimuli, including chromosome damage or perturbation of the mitotic apparatus. We investigated the mechanism of mitotic catastrophe and cell death induced by depletion of centrosomal proteins that perturbs microtubule organization. We transfected cells harboring wild-type or mutated p53 with siRNAs targeting Aurora A, ninein, TOG, TACC3, γ-tubulin, or pericentriolar material-1, and monitored the effects on cell death. Knockdown of Aurora A, ninein, TOG, and TACC3 led to cell death, regardless of p53 status. Knockdown of Aurora A, ninein, and TOG, led to aberrant spindle formation and subsequent cell death, which was accompanied by several features of apoptosis, including nuclear condensation and Annexin V binding in HeLa cells. During this process, cleavage of poly(ADP-ribose) polymerase-1, caspase-3, and caspase-9 was detected, but cleavage of caspase-8 was not. Cell death, monitored by time-lapse imaging, occurred during both interphase and M phase. In cells depleted of a centrosomal protein (Aurora A, ninein, or TOG), the rate of cell death was higher if the cells were cotransfected with siRNA against BubR1 or Mad2 than if they were transfected with siRNA against Bub1 or a control siRNA. These results suggest that metaphase arrest is necessary for the mitotic catastrophe and cell death caused by depletion of centrosomal proteins. Knockdown of centrosomal proteins led to increased phosphorylation of Chk2. Enhanced p-Chk2 localization was also observed at the centrosome in cells arrested in M phase, as well as in the nuclei of dying cells. Cotransfection of siRNAs against Chk2, in combination with depletion of a centrosomal protein, decreased the amount of cell death. Thus, Chk2 activity is indispensable for apoptosis after mitotic catastrophe induced by depletion of centrosomal proteins that perturbs microtubule organization

  18. T-cell factor (TCF/LEF1) binding elements (TBEs) of FasL (Fas ligand or CD95 ligand) bind and cluster Fas (CD95) and form complexes with the TCF-4 and b-catenin transcription factors in vitro and in vivo which result in triggering cell death and/or cell activation.

    PubMed

    Liu, Xia; Huang, Yuwei; Zhang, Yuanyuan; Li, Xiaohong; Liu, Chun; Huang, Shen; Xu, Dezhi; Wu, Yang; Liu, Xiaojuan

    2016-08-01

    T-cell factor 4 (TCF4) is an important transcription factor of the Wnt signaling system. β-catenin, an upstream protein of TCF4, accumulates in the cytoplasm, then translocates to the nucleus to activate the β-catenin/T-cell factor/lymphoid enhancer factor (TCF/LEF) transcriptional machinery and regulates target genes. Previous studies showed that TCF4 was involved in cell proliferation and apoptosis. However, its expression and function in central nervous system injury are unclear. We performed a traumatic brain injury (TBI) model in adult rats. The expression of TCF4 in the brain cortex detected by Western blot increased after TBI. Double immunofluorescence staining revealed that TCF4 was expressed by neurons and microglia. In addition, co-localization of TCF4 with active caspase-3 or proliferating cell nuclear antigen was observed in neurons and microglia, respectively, suggesting that TCF4 might participate in neuronal apoptosis and microglial proliferation after TBI. To further investigate the functions of TCF4, PC12 and HAPI cells were employed to establish a neuronal apoptosis and microglial proliferation model in vitro, respectively. Knocking down TCF4 with siRNA proved the pro-apoptotic and pro-proliferation effect of TCF4 in PC12 and HAPI cells, respectively. Taken together, TCF4 might promote neuronal apoptosis and microglial proliferation after TBI. PMID:27090258

  19. Evaluation of the Contribution of Multiple DAMPs and DAMP Receptors in Cell Death-Induced Sterile Inflammatory Responses

    PubMed Central

    Patel, Zubin; Rock, Kenneth L.

    2014-01-01

    When cells die by necrosis in vivo they stimulate an inflammatory response. It is thought that this response is triggered when the injured cells expose proinflammatory molecules, collectively referred to as damage associated molecular patterns (DAMPs), which are recognized by cells or soluble molecules of the innate or adaptive immune system. Several putative DAMPs and/or their receptors have been identified, but whether and how much they participate in responses in vivo is incompletely understood, and they have not previously been compared side-by-side in the same models. This study focuses on evaluating the contribution of multiple mechanisms that have been proposed to or potentially could participate in cell death-induced inflammation: The third component of complement (C3), ATP (and its receptor P2X7), antibodies, the C-type lectin receptor Mincle (Clec4e), and protease-activated receptor 2 (PAR2). We investigate the role of these factors in cell death-induced inflammation to dead cells in the peritoneum and acetaminophen-induced liver damage. We find that mice deficient in antibody, C3 or PAR2 have impaired inflammatory responses to dying cells. In contrast there was no reduction in inflammation to cell death in the peritoneum or liver of mice that genetically lack Mincle, the P2X7 receptor or that were treated with apyrase to deplete ATP. These results indicate that antibody, complement and PAR2 contribute to cell death-induced inflammation but that Mincle and ATP- P2X7 receptor are not required for this response in at least 2 different in vivo models. PMID:25127469

  20. The Differential DRP1 Phosphorylation and Mitochondrial Dynamics in the Regional Specific Astroglial Death Induced by Status Epilepticus

    PubMed Central

    Ko, Ah-Reum; Hyun, Hye-Won; Min, Su-Ji; Kim, Ji-Eun

    2016-01-01

    The response and susceptibility to astroglial degenerations are relevant to the distinctive properties of astrocytes in a hemodynamic-independent manner following status epilepticus (SE). Since impaired mitochondrial fission plays an important role in mitosis, apoptosis and programmed necrosis, we investigated whether the unique pattern of mitochondrial dynamics is involved in the characteristics of astroglial death induced by SE. In the present study, SE induced astroglial apoptosis in the molecular layer of the dentate gyrus, accompanied by decreased mitochondrial length. In contrast, clasmatodendritic (autophagic) astrocytes in the CA1 region showed mitochondrial elongation induced by SE. Mdivi-1 (an inhibitor of mitochondrial fission) effectively attenuated astroglial apoptosis, but WY14643 (an enhancer of mitochondrial fission) aggravated it. In addition, Mdivi-1 accelerated clasmatodendritic changes in astrocytes. These regional specific mitochondrial dynamics in astrocytes were closely correlated with dynamin-related protein 1 (DRP1; a mitochondrial fission protein) phosphorylation, not optic atrophy 1 (OPA1; a mitochondrial fusion protein) expression. To the best of our knowledge, the present data demonstrate for the first time the novel role of DRP1-mediated mitochondrial fission in astroglial loss. Thus, the present findings suggest that the differential astroglial mitochondrial dynamics may participate in the distinct characteristics of astroglial death induced by SE. PMID:27242436

  1. Cell-Centric View of Apoptosis and Apoptotic Cell Death-Inducing Antitumoral Strategies

    PubMed Central

    Apraiz, Aintzane; Boyano, Maria Dolores; Asumendi, Aintzane

    2011-01-01

    Programmed cell death and especially apoptotic cell death, occurs under physiological conditions and is also desirable under pathological circumstances. However, the more we learn about cellular signaling cascades, the less plausible it becomes to find restricted and well-limited signaling pathways. In this context, an extensive description of pathway-connections is necessary in order to point out the main regulatory molecules as well as to select the most appropriate therapeutic targets. On the other hand, irregularities in programmed cell death pathways often lead to tumor development and cancer-related mortality is projected to continue increasing despite the effort to develop more active and selective antitumoral compounds. In fact, tumor cell plasticity represents a major challenge in chemotherapy and improvement on anticancer therapies seems to rely on appropriate drug combinations. An overview of the current status regarding apoptotic pathways as well as available chemotherapeutic compounds provides a new perspective of possible future anticancer strategies. PMID:24212653

  2. Site Specific Activation of AKT Protects Cells from Death Induced by Glucose Deprivation

    PubMed Central

    Gao, Meng; Liang, Jiyong; Lu, Yiling; Guo, Huifang; German, Peter; Bai, Shanshan; Jonasch, Eric; Yang, Xingsheng; Mills, Gordon B.; Ding, Zhiyong

    2013-01-01

    The serine/threonine kinase AKT is a key mediator of cancer cell survival. We demonstrate that transient glucose deprivation modestly induces AKT phosphorylation at both Thr308 and Ser473. In contrast, prolonged glucose deprivation induces selective AKTThr308 phosphorylation and phosphorylation of a distinct subset of AKT downstream targets leading to cell survival under metabolic stress. Glucose deprivation-induced AKTThr308 phosphorylation is dependent on PDK1 and PI3K but not EGFR or IGF1R. Prolonged glucose deprivation induces the formation of a complex of AKT, PDK1, and the GRP78 chaperone protein, directing phosphorylation of AKTThr308 but AKTSer473. Our results reveal a novel mechanism of AKT activation under prolonged glucose deprivation that protects cells from metabolic stress. The selective activation of AKTThr308 phosphorylation that occurs during prolonged nutrient deprivation may provide an unexpected opportunity for the development and implementation of drugs targeting cell metabolism and aberrant AKT signaling. PMID:23396361

  3. Cell death induced by ozone and various non-thermal plasmas: therapeutic perspectives and limitations

    PubMed Central

    Lunov, Oleg; Zablotskii, Vitalii; Churpita, Olexander; Chánová, Eliška; Syková, Eva; Dejneka, Alexandr; Kubinová, Šárka

    2014-01-01

    Non-thermal plasma has been recognized as a promising tool across a vast variety of biomedical applications, with the potential to create novel therapeutic methods. However, the understanding of the molecular mechanisms behind non-thermal plasma cellular effects remains a significant challenge. In this study, we show how two types of different non-thermal plasmas induce cell death in mammalian cell cultures via the formation of multiple intracellular reactive oxygen/nitrogen species. Our results showed a discrepancy in the superoxide accumulation and lysosomal activity in response to air and helium plasma, suggesting that triggered signalling cascades might be grossly different between different plasmas. In addition, the effects of ozone, a considerable component of non-thermal plasma, have been simultaneously evaluated and have revealed much faster and higher cytotoxic effects. Our findings offer novel insight into plasma-induced cellular responses, and provide a basis for better controlled biomedical applications. PMID:25410636

  4. Cell death induced by ozone and various non-thermal plasmas: therapeutic perspectives and limitations

    NASA Astrophysics Data System (ADS)

    Lunov, Oleg; Zablotskii, Vitalii; Churpita, Olexander; Chánová, Eliška; Syková, Eva; Dejneka, Alexandr; Kubinová, Šárka

    2014-11-01

    Non-thermal plasma has been recognized as a promising tool across a vast variety of biomedical applications, with the potential to create novel therapeutic methods. However, the understanding of the molecular mechanisms behind non-thermal plasma cellular effects remains a significant challenge. In this study, we show how two types of different non-thermal plasmas induce cell death in mammalian cell cultures via the formation of multiple intracellular reactive oxygen/nitrogen species. Our results showed a discrepancy in the superoxide accumulation and lysosomal activity in response to air and helium plasma, suggesting that triggered signalling cascades might be grossly different between different plasmas. In addition, the effects of ozone, a considerable component of non-thermal plasma, have been simultaneously evaluated and have revealed much faster and higher cytotoxic effects. Our findings offer novel insight into plasma-induced cellular responses, and provide a basis for better controlled biomedical applications.

  5. p53-induced Gene 3 Mediates Cell Death Induced by Glutathione Peroxidase 3*

    PubMed Central

    Wang, Hui; Luo, Katherine; Tan, Lang-Zhu; Ren, Bao-Guo; Gu, Li-Qun; Michalopoulos, George; Luo, Jian-Hua; Yu, Yan P.

    2012-01-01

    Expression of glutathione peroxidase 3 (GPx3) is down-regulated in a variety of human malignancies. Both methylation and deletion of GPx3 gene underlie the alterations of GPx3 expression in prostate cancer. A strong correlation between the down-regulation of GPx3 expression and progression of prostate cancer and the suppression of prostate cancer xenografts in SCID mice by forced expression of GPx3 suggests a tumor suppression role of GPx3 in prostate cancer. However, the mechanism of GPx3-mediated tumor suppression remains unclear. In this report, GPx3 was found to interact directly with p53-induced gene 3 (PIG3). Forced overexpression of GPx3 in prostate cancer cell lines DU145 and PC3 as well as immortalized prostate epithelial cells RWPE-1 increased apoptotic cell death. Expression of GPx3x73c, a peroxidase-negative OPAL codon mutant, in DU145 and PC3 cells also increased cell death. The induced expression of GPx3 in DU145 and PC3 cells resulted in an increase in reactive oxygen species and caspase-3 activity. These activities were abrogated by either knocking down PIG3 or mutating the PIG3 binding motif in GPx3 or binding interference from a peptide corresponding to PIG3 binding motif in GPx3. In addition, UV-treated RWPE-1 cells underwent apoptotic death, which was partially prevented by knocking down GPx3 or PIG3, suggesting that GPx3-PIG3 signaling is critical for UV-induced apoptosis. Taken together, these results reveal a novel signaling pathway of GPx3-PIG3 in the regulation of cell death in prostate cancer. PMID:22461624

  6. Nitric oxide activates superoxide dismutase and ascorbate peroxidase to repress the cell death induced by wounding.

    PubMed

    Lin, Chih-Ching; Jih, Pei-Ju; Lin, Hsin-Hung; Lin, Jeng-Shane; Chang, Ling-Lan; Shen, Yu-Hsing; Jeng, Shih-Tong

    2011-10-01

    Wounding caused by rain, wind, and pathogen may lead plants to onset defense response. Previous studies indicated that mechanical wounding stimulates plants to generate nitric oxide (NO) and hydrogen peroxide (H(2)O(2)). In this study, the functions of NO and H(2)O(2) after wounding in sweet potato (Ipomoea batatas cv. Tainung 57) was further analyzed. Mechanical wounding damaged cells and resulted in necrosis, but the presence of NO donors or NO scavenger might reduce or enhance the cell death caused by wounding, respectively. The amount of H(2)O(2) induced by wounding was also decreased or increased when plants were incubated with NO donors or NO scavenger, individually. These results indicate that NO may regulate H(2)O(2) generation to affect cell death. NO-induced proteins isolated from two-dimensional electrophoresis were identified to be Copper/Zinc superoxide dismutases (CuZnSODs). The activities of CuZnSODs and ascorbate peroxidase (APX) could be enhanced by NO. In addition, the expression of CuZnSOD and APX was induced by wounding via NO, and their expression was further stimulated by NO through the generation of cGMP. The influx of calcium ions and the activity of NADPH oxidase were also involved in the NO signal transduction pathway inducing APX expression. Collectively, the generation of H(2)O(2) in wounded plants might trigger cell death. Meanwhile, the production of NO induced by wounding stimulated signal transducers including cGMP, calcium ions, and H(2)O(2) to activate CuZnSOD and APX, which further decreased H(2)O(2) level and reduced the cell death caused by wounding. PMID:21833542

  7. Microglial cell death induced by glycated bovine serum albumin: nitric oxide involvement.

    PubMed

    Khazaei, Mohammad R; Habibi-Rezaei, Mehran; Karimzadeh, Fereshteh; Moosavi-Movahedi, Ali Akbar; Sarrafnejhad, Abdo Alfattah; Sabouni, Farzaneh; Bakhti, Mostafa

    2008-08-01

    Nonenzymatic glycation results in the formation of advanced glycation end products (AGEs) through a nonenzymatic multistep reaction of reducing sugars with proteins. AGEs have been suspected to be involved in the pathogenesis of several chronic clinical neurodegenerative complications including Alzheimer's disease, which is characterized with the activation of microglial cells in neuritic plaques. To find out the consequence of this activation on microglial cells, we treated the cultured microglial cells with different glycation levels of Bovine Serum Albumin (BSA) which were prepared in vitro. Extent of glycation of protein has been characterized during 16 weeks of incubation with glucose. Treatment of microglial cells with various levels of glycated albumin induced nitric oxide (NO) production and consequently cell death. We also tried to find out the mode of death in AGE-activated microglial cells. Altogether, our results suggest that AGE treatment causes microglia to undergo NO-mediated apoptotic and necrotic cell death in short term and long term, respectively. NO production is a consequence of iNOS expression in a JNK dependent RAGE signalling after activation of RAGE by AGE-BSA. PMID:18463114

  8. Characterization of cell death induced by vinflunine, the most recent Vinca alkaloid in clinical development

    PubMed Central

    Kruczynski, A; Etiévant, C; Perrin, D; Chansard, N; Duflos, A; Hill, B T

    2002-01-01

    Vinflunine, the most recent Vinca alkaloid in clinical development, demonstrated superior antitumour activity to other Vincas in preclinical tumour models. This study aimed to define its molecular mechanisms of cell killing in both parental sensitive and vinflunine-resistant P388 leukaemia cells. Vinflunine treatment of these cells resulted in apoptosis characterized by DNA fragmentation and proteolytic cleavage of poly-(ADP-ribose) polymerase. Apoptosis-inducing concentrations of vinflunine caused c-Jun N-terminal kinase 1 stimulation, as well as caspases-3/7 activation. This activation of caspases and the induction of apoptosis could be inhibited by the caspase inhibitor acetyl-Asp-Glu-Val-Asp-aldehyde. Interestingly, the apoptosis signal triggered by vinflunine in these P388 cells was not mediated through Bcl-2 phosphorylation. In addition, when vinflunine resistance was developed in P388 cells, it was associated with resistance to vinflunine-induced apoptosis, as reflected by a loss of capacity to induce DNA fragmentation and PARP degradation, and characterized by increased levels of Bcl-2 and Bfl-1/A1. Therefore, these data indirectly implicate Bcl-2 and Bfl-1/A1 in vinflunine-induced cell death mechanisms. British Journal of Cancer (2002) 86, 143–150. DOI: 10.1038/sj/bjc/6600025 www.bjcancer.com © 2002 The Cancer Research Campaign PMID:11857026

  9. Sam68 is cleaved by caspases under apoptotic cell death induced by ionizing radiation.

    PubMed

    Cho, Seong-Jun; Choi, Moo Hyun; Nam, Seon Young; Kim, Ji Young; Kim, Cha Soon; Pyo, Suhkneung; Yang, Kwang Hee

    2015-03-01

    The RNA-binding protein Sam68, a mitotic substrate of tyrosine kinases, has been reported to participate in the cell cycle, apoptosis, and signaling. In particular, overexpression of Sam68 protein is known to suppress cell growth and cell cycle progression in NIH3T3 cells. Although Sam68 is involved in many cellular activities, the function of Sam68, especially in response to apoptotic stimulation, is not well understood. In this study, we found that Sam68 protein is cleaved in immune cells undergoing apoptosis induced by γ-radiation. Moreover, we found that Sam68 cleavage was induced by apoptotic stimuli containing γ-radiation in a caspase-dependent manner. In particular, we showed that activated casepase-3, 7, 8 and 9 can directly cleave Sam68 protein through in vitro protease cleavage assay. Finally, we found that the knockdown of Sam68 attenuated γ-radiation-induced cell death and growth suppression. Conclusively, the cleavage of Sam68 is a new indicator for the cell damaging effects of ionizing radiation. PMID:25666188

  10. CNOT3 suppression promotes necroptosis by stabilizing mRNAs for cell death-inducing proteins

    PubMed Central

    Suzuki, Toru; Kikuguchi, Chisato; Sharma, Sahil; Sasaki, Toshio; Tokumasu, Miho; Adachi, Shungo; Natsume, Tohru; Kanegae, Yumi; Yamamoto, Tadashi

    2015-01-01

    The CCR4-NOT complex is conserved in eukaryotes and is involved in mRNA metabolism, though its molecular physiological roles remain to be established. We show here that CNOT3-depleted mouse embryonic fibroblasts (MEFs) undergo cell death. Levels of other complex subunits are decreased in CNOT3-depleted MEFs. The death phenotype is rescued by introduction of wild-type (WT), but not mutated CNOT3, and is not suppressed by the pan-caspase inhibitor, zVAD-fluoromethylketone. Gene expression profiling reveals that mRNAs encoding cell death-related proteins, including receptor-interacting protein kinase 1 (RIPK1) and RIPK3, are stabilized in CNOT3-depleted MEFs. Some of these mRNAs bind to CNOT3, and in the absence of CNOT3 their poly(A) tails are elongated. Inhibition of RIPK1-RIPK3 signaling by a short-hairpin RNA or a necroptosis inhibitor, necrostatin-1, confers viability upon CNOT3-depleted MEFs. Therefore, we conclude that CNOT3 targets specific mRNAs to prevent cells from being disposed to necroptotic death. PMID:26437789

  11. Characterization of cell death inducing Phytophthora capsici CRN effectors suggests diverse activities in the host nucleus

    PubMed Central

    Stam, Remco; Howden, Andrew J. M.; Delgado-Cerezo, Magdalena; M. M. Amaro, Tiago M.; Motion, Graham B.; Pham, Jasmine; Huitema, Edgar

    2013-01-01

    Plant-Microbe interactions are complex associations that feature recognition of Pathogen Associated Molecular Patterns by the plant immune system and dampening of subsequent responses by pathogen encoded secreted effectors. With large effector repertoires now identified in a range of sequenced microbial genomes, much attention centers on understanding their roles in immunity or disease. These studies not only allow identification of pathogen virulence factors and strategies, they also provide an important molecular toolset suited for studying immunity in plants. The Phytophthora intracellular effector repertoire encodes a large class of proteins that translocate into host cells and exclusively target the host nucleus. Recent functional studies have implicated the CRN protein family as an important class of diverse effectors that target distinct subnuclear compartments and modify host cell signaling. Here, we characterized three necrosis inducing CRNs and show that there are differences in the levels of cell death. We show that only expression of CRN20_624 has an additive effect on PAMP induced cell death but not AVR3a induced ETI. Given their distinctive phenotypes, we assessed localization of each CRN with a set of nuclear markers and found clear differences in CRN subnuclear distribution patterns. These assays also revealed that expression of CRN83_152 leads to a distinct change in nuclear chromatin organization, suggesting a distinct series of events that leads to cell death upon over-expression. Taken together, our results suggest diverse functions carried by CRN C-termini, which can be exploited to identify novel processes that take place in the host nucleus and are required for immunity or susceptibility. PMID:24155749

  12. Preventing cell death induced by carbonyl stress, oxidative stress or mitochondrial toxins with vitamin B anti-AGE agents.

    PubMed

    Mehta, Rhea; Shangari, Nandita; O'Brien, Peter J

    2008-03-01

    Carbonyls generated by autoxidation of carbohydrates or lipid peroxidation have been implicated in advanced glycation end product (AGE) formation in tissues adversely affected by diabetes complications. Tissue AGE and associated pathology have been decreased by vitamin B(1)/B(6) in trials involving diabetic animal models. To understand the molecular cytoprotective mechanisms involved, the effects of B(1)/B(6) vitamers against cytotoxicity induced by AGE/advanced lipid end product (ALE) carbonyl precursors (glyoxal/acrolein) have been compared to cytotoxicity induced by oxidative stress (hydroperoxide) or mitochondrial toxins (cyanide/copper). Thiamin was found to be best at preventing cell death induced by carbonyl stress and mitochondrial toxins but not oxidative stress cell death suggesting that thiamin pyrophosphate restored pyruvate and alpha-ketoglutarate dehydrogenases inhibited by mitochondrial toxicity. However, B(6) vitamers were most effective at preventing oxidative stress or lipid peroxidation cytotoxicity suggesting that pyridoxal or pyridoxal phosphate were antioxidants and/or Fe/Cu chelators. A therapeutic vitamin cocktail could provide maximal prevention against carbonyl stress toxicity associated with diabetic complications. PMID:17918169

  13. Cell death-inducing stresses are required for defense activation in DS1-phosphatidic acid phosphatase-silenced Nicotiana benthamiana.

    PubMed

    Nakano, Masahito; Yoshioka, Hirofumi; Ohnishi, Kouhei; Hikichi, Yasufumi; Kiba, Akinori

    2015-07-20

    We previously identified DS1 plants that showed resistance to compatible Ralstonia solanacearum with accelerated defense responses. Here, we describe activation mechanisms of defense responses in DS1 plants. After inoculation with incompatible R. solanacearum 8107, DS1 plants showed hyperinduction of hypersensitive response (HR) and reactive oxygen species (ROS) generation. Transient expression of PopP1 and AvrA induced hyperinduction of HR and ROS generation. Furthermore, Pseudomonas cichorii (Pc) and a type III secretion system (TTSS)-deficient mutant of P. cichorii showed accelerated induction of HR and ROS generation. Chitin and flg22 did not induce either HR or ROS hyperaccumulation; however, INF1 accelerated HR and ROS in DS1 plants. Activation of these defense responses was closely associated with increased phosphatidic acid (PA) content. Our results show that DS1 plants exhibit PA-mediated sensitization of plant defenses and that cell death-inducing stress is required to achieve full activation of defense responses. PMID:26188395

  14. Cell Death Induced on Cell Cultures and Nude Mouse Skin by Non-Thermal, Nanosecond-Pulsed Generated Plasma

    PubMed Central

    Bousquet, Guilhem; Gapihan, Guillaume; Starikovskaia, Svetlana M.; Rousseau, Antoine; Janin, Anne

    2013-01-01

    Non-thermal plasmas are gaseous mixtures of molecules, radicals, and excited species with a small proportion of ions and energetic electrons. Non-thermal plasmas can be generated with any high electro-magnetic field. We studied here the pathological effects, and in particular cell death, induced by nanosecond-pulsed high voltage generated plasmas homogeneously applied on cell cultures and nude mouse skin. In vitro, Jurkat cells and HMEC exhibited apoptosis and necrosis, in dose-dependent manner. In vivo, on nude mouse skin, cell death occurred for doses above 113 J/cm2 for the epidermis, 281 J/cm2 for the dermis, and 394 J/cm2 for the hypodermis. Using electron microscopy, we characterized apoptosis for low doses and necrosis for high doses. We demonstrated that these effects were not related to thermal, photonic or pH variations, and were due to the production of free radicals. The ability of cold plasmas to generate apoptosis on cells in suspension and, without any sensitizer, on precise skin areas, opens new fields of application in dermatology for extracorporeal blood cell treatment and the eradication of superficial skin lesions. PMID:24358244

  15. Cell Death-Inducing DFFA-Like Effector b Is Required for Hepatitis C Virus Entry into Hepatocytes

    PubMed Central

    Wu, Xianfang; Lee, Emily M.; Hammack, Christy; Robotham, Jason M.; Basu, Mausumi; Lang, Jianshe; Brinton, Margo A.

    2014-01-01

    ABSTRACT The molecular mechanism of the hepatic tropism of hepatitis C virus (HCV) remains incompletely defined. In vitro hepatic differentiation of pluripotent stem cells produces hepatocyte-like cells (HLCs) permissive for HCV infection, providing an opportunity for studying liver development and host determinants of HCV susceptibility. We previously identified the transition stage of HCV permissiveness and now investigate whether a host protein whose expression is induced during this transition stage is important for HCV infection. We suppressed the expression of a liver-specific protein, cell death-inducing DFFA-like effector b (CIDEB), and performed hepatocyte function and HCV infection assays. We also used a variety of cell-based assays to dissect the specific step of the HCV life cycle that potentially requires CIDEB function. We found CIDEB to be an essential cofactor for HCV entry into hepatocytes. Genetic interference with CIDEB in stem cells followed by hepatic differentiation leads to HLCs that are refractory to HCV infection, and infection time course experiments revealed that CIDEB functions in a late step of HCV entry, possibly to facilitate membrane fusion. The role of CIDEB in mediating HCV entry is distinct from those of the well-established receptors, as it is not required for HCV pseudoparticle entry. Finally, HCV infection effectively downregulates CIDEB protein through a posttranscriptional mechanism. IMPORTANCE This study identifies a hepatitis C virus (HCV) entry cofactor that is required for HCV infection of hepatocytes and potentially facilitates membrane fusion between viral and host membranes. CIDEB and its interaction with HCV may open up new avenues of investigation of lipid droplets and viral entry. PMID:24829338

  16. Acid-sensing ion channel 1a is involved in retinal ganglion cell death induced by hypoxia

    PubMed Central

    Tan, Jian; Xu, Yipin; Wang, Hao; Sheng, Minjie; Wang, Fang

    2011-01-01

    Purpose Loss of retinal ganglion cells (RGCs) during retinal ischemia is the potentially blinding mechanism that underlies several sight-threatening disorders. Fluctuations in extracellular pH are associated with such pathological conditions. It has been demonstrated that the retina is a functionally distinct region of central neurons that are known to contain acid-sensing ion channels (ASICs), which are depolarizing conductance channels directly activated by protons. This study was conducted to determine whether ASIC1a channels in RGCs are essential for ischemia-induced cell death. Methods Expression of ASIC1a channels was detected in primary cultures of rat RGCs and in retinal sections. The patch-clamp technique in the conventional whole-cell configuration was used to examine the currents evoked by acid in the cultured RGCs. Intracellular Ca2+ ([Ca2+]i) elevation was detected by Ca2+ imaging. Furthermore, hypoxia-induced cell death in RGC cultures was measured by methyl thiazolyl tetrazolium assay. Results RGCs expressed a high density of ASIC1a channels. The expression and function of ASIC1a channels were upregulated after hypoxia in cultured RGCs. Ratiometric Ca2+ imaging showed that RGCs responding to a drop in pH presented an increase in the concentration of (Ca2+)i. Acute blockade of ASIC1a channels with the specific inhibitor amiloride or psalmotoxin 1 reduced RGC death in vitro. Conclusions Based on these novel findings, we conclude that ASIC1a plays a role in RGC death induced by hypoxia. Therefore, neuroprotective strategies in glaucoma could include tools to improve the ability of these neurons to survive the cytotoxic consequences of ASIC1a activation. PMID:22194656

  17. Identification of a novel cell death-inducing domain reveals that fungal amyloid-controlled programmed cell death is related to necroptosis.

    PubMed

    Daskalov, Asen; Habenstein, Birgit; Sabaté, Raimon; Berbon, Mélanie; Martinez, Denis; Chaignepain, Stéphane; Coulary-Salin, Bénédicte; Hofmann, Kay; Loquet, Antoine; Saupe, Sven J

    2016-03-01

    Recent findings have revealed the role of prion-like mechanisms in the control of host defense and programmed cell death cascades. In fungi, HET-S, a cell death-inducing protein containing a HeLo pore-forming domain, is activated through amyloid templating by a Nod-like receptor (NLR). Here we characterize the HELLP protein behaving analogously to HET-S and bearing a new type of N-terminal cell death-inducing domain termed HeLo-like (HELL) and a C-terminal regulatory amyloid motif known as PP. The gene encoding HELLP is part of a three-gene cluster also encoding a lipase (SBP) and a Nod-like receptor, both of which display the PP motif. The PP motif is similar to the RHIM amyloid motif directing formation of the RIP1/RIP3 necrosome in humans. The C-terminal region of HELLP, HELLP(215-278), encompassing the motif, allows prion propagation and assembles into amyloid fibrils, as demonstrated by X-ray diffraction and FTIR analyses. Solid-state NMR studies reveal a well-ordered local structure of the amyloid core residues and a primary sequence that is almost entirely arranged in a rigid conformation, and confirm a β-sheet structure in an assigned stretch of three amino acids. HELLP is activated by amyloid templating and displays membrane-targeting and cell death-inducing activity. HELLP targets the SBP lipase to the membrane, suggesting a synergy between HELLP and SBP in membrane dismantling. Remarkably, the HeLo-like domain of HELLP is homologous to the pore-forming domain of MLKL, the cell death-execution protein in necroptosis, revealing a transkingdom evolutionary relationship between amyloid-controlled fungal programmed cell death and mammalian necroptosis. PMID:26903619

  18. Susceptibility to oral cancers with CD95 and CD95L promoter SNPs may vary with the site and gender.

    PubMed

    Daripally, Sarika; Nallapalle, Sateesh Reddy; Katta, Saritha; Prasad, Vidudala V T S

    2015-09-01

    We investigated risk association of oral cancers (tongue and buccal mucosa cancers) with FAS (-1377G > A and FAS -670 A > G) and FASL (-844 T > C) SNPs, in males and females. A case-control study of 535 oral cancer and 525 control subjects was performed. SNPs were detected in the genomic DNA isolated from peripheral blood using PCR-RFLP. We report FASL -844 T > C SNPs increased risk for buccal mucosa cancer in females but not in males. On the other hand, FAS genotypes did not alter the risk of the cancers in both females and males. However, co-occurrence of FAS -1377 GA and -670 GG, FAS -1377 AA and -670 GG genotypes, and combined genotypes of FAS and FASL (FAS -1377 AA + FAS -670 GG + FASL -844 CC) alter male susceptibility towards tongue cancer. In females, combined genotypes of FAS (-1377GA and -670 AA) were found to be a risk factor of buccal mucosa cancer (OR = 3.27, CI = 1.28-8.36; P ≤ 0.01). FASL variants (GA and AA) increased tongue cancer risk in females who were tobacco users compared to non-tobacco users. In conclusion, SNPs of the FAS and FASL might alter risk of tongue and buccal mucosa cancers differentially, in a gender-dependent manner. PMID:25944167

  19. Apoptotic death induced by the cyclophosphamide analogue mafosfamide in human lymphoblastoid cells: Contribution of DNA replication, transcription inhibition and Chk/p53 signaling

    SciTech Connect

    Goldstein, Michael; Roos, Wynand P. Kaina, Bernd

    2008-05-15

    Cyclophosphamide is one of the most often used anticancer drugs. Although DNA interstrand cross-links are considered responsible for its cytotoxicity, the mechanism of initiation and execution of cell death is largely unknown. Using the cyclophosphamide analogue mafosfamide, which does not need metabolic activation, we show that mafosfamide induces apoptosis dose and time dependently in lymphoblastoid cells, with clearly more apoptosis in p53{sup wt} cells. We identified two upstream processes that initiate apoptosis, DNA replication blockage and transcriptional inhibition. In lymphoblastoid cells, wherein DNA replication can be switched off by tetracycline, proliferation is required for inducing apoptosis at low dose mafosfamide. At high dose, transcriptional inhibition also contributes to cell death. The RNA synthesis inhibitor {alpha}-amanitin induced similar to mafosfamide more apoptosis in p53{sup wt} than in p53{sup mt} cells. In combination with mafosfamide, however, {alpha}-amanitin had no additive effect. Mafosfamide caused p53 stabilization by phosphorylation of Ser15, 20 and 37, and activation of ATM/ATR and Chk1/Chk2. Inhibition of ATM/ATR, PI3-kinase and Chk1/Chk2 by CGK733, wortmannin and DBH, respectively, attenuated the apoptotic response in p53{sup wt} but not p53{sup mt} cells. Mafosfamide induced caspase dependent apoptosis and, for low dose treated cells, caspases were preferentially activated in the S-phase, whereas at high dose caspases were activated in all cell cycle stages. These data support the conclusion that at low dose level of mafosfamide, DNA replication blockage is the dominant apoptosis-inducing event, while at high dose, transcriptional inhibition comes into play. The data provide a mechanistic explanation of why cyclophosphamide applied at therapeutic doses preferentially kills replicating tumor cells.

  20. Advanced age protects microvascular endothelium from aberrant Ca2+ influx and cell death induced by hydrogen peroxide

    PubMed Central

    Socha, Matthew J; Boerman, Erika M; Behringer, Erik J; Shaw, Rebecca L; Domeier, Timothy L; Segal, Steven S

    2015-01-01

    Abstract Endothelial cell Ca2+ signalling is integral to blood flow control in the resistance vasculature yet little is known of how its regulation may be affected by advancing age. We tested the hypothesis that advanced age protects microvascular endothelium by attenuating aberrant Ca2+ signalling during oxidative stress. Intact endothelial tubes (width, ∼60 μm; length, ∼1000 μm) were isolated from superior epigastric arteries of Young (3–4 months) and Old (24–26 months) male C57BL/6 mice and loaded with Fura-2 dye to monitor [Ca2+]i. At rest there was no difference in [Ca2+]i between age groups. Compared to Young, the [Ca2+]i response to maximal stimulation with acetylcholine (3 μm, 2 min) was ∼25% greater in Old, confirming signalling integrity with advanced age. Basal H2O2 availability was ∼33% greater in Old while vascular catalase activity was reduced by half. Transient exposure to elevated H2O2 (200 μm, 20 min) progressively increased [Ca2+]i to ∼4-fold greater levels in endothelium of Young versus Old. With no difference between age groups at rest, Mn2+ quench of Fura-2 fluorescence revealed 2-fold greater Ca2+ influx in Young during elevated H2O2; this effect was attenuated by ∼75% using ruthenium red (5 μm) as a broad-spectrum inhibitor of transient receptor potential channels. Prolonged exposure to H2O2 (200 μm, 60 min) induced ∼7-fold greater cell death in endothelium of Young versus Old. Thus, microvascular endothelium can adapt to advanced age by reducing Ca2+ influx during elevated oxidative stress. Protection from cell death during oxidative stress will sustain endothelial integrity during ageing. Key points Calcium signalling in endothelial cells of resistance arteries is integral to blood flow regulation. Oxidative stress and endothelial dysfunction can prevail during advanced age and we questioned how calcium signalling may be affected. Intact endothelium was freshly isolated from superior epigastric arteries of

  1. Fructose Protects Murine Hepatocytes from Tumor Necrosis Factor-induced Apoptosis by Modulating JNK Signaling*

    PubMed Central

    Speicher, Tobias; Köhler, Ulrike A.; Choukèr, Alexander; Werner, Sabine; Weiland, Timo; Wendel, Albrecht

    2012-01-01

    Fructose-induced hepatic ATP depletion prevents TNF-induced apoptosis, whereas it contrarily enhances CD95-induced hepatocyte apoptosis in vitro and in vivo. By contrast, transformed liver cells are not protected against TNF due to metabolic alterations, allowing selective tumor targeting. We analyzed the molecular mechanisms by which fructose modulates cytokine-induced apoptosis. A release of adenosine after fructose-induced ATP depletion, followed by a cAMP response, was demonstrated. Likewise, cAMP and adenosine mimicked per se the modulation by fructose of CD95- and TNF-induced apoptosis. The effects of fructose on cytokine-induced apoptosis were sensitive to inhibition of protein kinase A. Fructose prevented the pro-apoptotic, sustained phase of TNF-induced JNK signaling and thereby blocked bid-mediated activation of the intrinsic mitochondrial apoptosis pathway in a PKA-dependent manner. We explain the dichotomal effects of fructose on CD95- and TNF-induced cell death by the selective requirement of JNK signaling for the latter. These findings provide a mechanistic rationale for the protection of hepatocytes from TNF-induced cell death by pharmacological doses of fructose. PMID:22086922

  2. Calcium signaling and cytotoxicity.

    PubMed Central

    Kass, G E; Orrenius, S

    1999-01-01

    The divalent calcium cation Ca(2+) is used as a major signaling molecule during cell signal transduction to regulate energy output, cellular metabolism, and phenotype. The basis to the signaling role of Ca(2+) is an intricate network of cellular channels and transporters that allow a low resting concentration of Ca(2+) in the cytosol of the cell ([Ca(2+)]i) but that are also coupled to major dynamic and rapidly exchanging stores. This enables extracellular signals from hormones and growth factors to be transduced as [Ca(2+)]i spikes that are amplitude and frequency encoded. There is considerable evidence that a number of toxic environmental chemicals target these Ca(2+) signaling processes, alter them, and induce cell death by apoptosis. Two major pathways for apoptosis will be considered. The first one involves Ca(2+)-mediated expression of ligands that bind to and activate death receptors such as CD95 (Fas, APO-1). In the second pathway, Ca(2+) has a direct toxic effect and its primary targets include the mitochondria and the endoplasmic reticulum (ER). Mitochondria may respond to an apoptotic Ca(2+) signal by the selective release of cytochrome c or through enhanced production of reactive oxygen species and opening of an inner mitochondrial membrane pore. Toxic agents such as the environmental pollutant tributyltin or the natural plant product thapsigargin, which deplete the ER Ca(2+) stores, will induce as a direct result of this effect the opening of plasma membrane Ca(2+) channels and an ER stress response. In contrast, under some conditions, Ca(2+) signals may be cytoprotective and antagonize the apoptotic machinery. Images Figure 1 Figure 2 Figure 3 PMID:10229704

  3. Tat-NOL3 protects against hippocampal neuronal cell death induced by oxidative stress through the regulation of apoptotic pathways.

    PubMed

    Sohn, Eun Jeong; Shin, Min Jea; Eum, Won Sik; Kim, Dae Won; Yong, Ji In; Ryu, Eun Ji; Park, Jung Hwan; Cho, Su Bin; Cha, Hyun Ju; Kim, Sang Jin; Yeo, Hyeon Ji; Yeo, Eun Ji; Choi, Yeon Joo; Im, Seung Kwon; Kweon, Hae Young; Kim, Duk-Soo; Yu, Yeon Hee; Cho, Sung-Woo; Park, Meeyoung; Park, Jinseu; Cho, Yong-Jun; Choi, Soo Young

    2016-07-01

    Oxidative stress-induced apoptosis is associated with neuronal cell death and ischemia. The NOL3 [nucleolar protein 3 (apoptosis repressor with CARD domain)] protein protects against oxidative stress-induced cell death. However, the protective mechanism responsible for this effect as well as the effects of NOL3 against oxidative stress in ischemia remain unclear. Thus, we examined the protective effects of NOL3 protein on hydrogen peroxide (H2O2)-induced oxidative stress and the mechanism responsible for these effects in hippocampal neuronal HT22 cells and in an animal model of forebrain ischemia using Tat-fused NOL3 protein (Tat-NOL3). Purified Tat-NOL3 protein transduced into the H2O2-exposed HT22 cells and inhibited the production of reactive oxygen species (ROS), DNA fragmentation and reduced mitochondrial membrane potential (ΔΨm). In addition, Tat-NOL3 prevented neuronal cell death through the regulation of apoptotic signaling pathways including Bax, Bcl-2, caspase-2, -3 and -8, PARP and p53. In addition, Tat-NOL3 protein transduced into the animal brains and significantly protected against neuronal cell death in the CA1 region of the hippocampus by regulating the activation of microglia and astrocytes. Taken together, these findings demonstrate that Tat-NOL3 protein protects against oxidative stress-induced neuronal cell death by regulating oxidative stress and by acting as an anti-apoptotic protein. Thus, we suggest that Tat-NOL3 represents a potential therapeutic agent for protection against ischemic brain injury. PMID:27221790

  4. Novel Insights into the Molecular Events Linking to Cell Death Induced by Tetracycline in the Amitochondriate Protozoan Trichomonas vaginalis

    PubMed Central

    Huang, Kuo-Yang; Ku, Fu-Man; Cheng, Wei-Hung; Lee, Chi-Ching; Huang, Po-Jung; Chu, Lichieh Julie; Cheng, Chih-Chieh; Fang, Yi-Kai; Wu, Hsueh-Hsia

    2015-01-01

    Trichomonas vaginalis colonizes the human urogenital tract and causes trichomoniasis, the most common nonviral sexually transmitted disease. Currently, 5-nitroimidazoles are the only recommended drugs for treating trichomoniasis. However, increased resistance of the parasite to 5-nitroimidazoles has emerged as a highly problematic public health issue. Hence, it is essential to identify alternative chemotherapeutic agents against refractory trichomoniasis. Tetracycline (TET) is a broad-spectrum antibiotic with activity against several protozoan parasites, but the mode of action of TET in parasites remains poorly understood. The in vitro effect of TET on the growth of T. vaginalis was examined, and the mode of cell death was verified by various apoptosis-related assays. Next-generation sequencing-based RNA sequencing (RNA-seq) was employed to elucidate the transcriptome of T. vaginalis in response to TET. We show that TET has a cytotoxic effect on both metronidazole (MTZ)-sensitive and -resistant T. vaginalis isolates, inducing some features resembling apoptosis. RNA-seq data reveal that TET significantly alters the transcriptome via activation of specific pathways, such as aminoacyl-tRNA synthetases and carbohydrate metabolism. Functional analyses demonstrate that TET disrupts the hydrogenosomal membrane potential and antioxidant system, which concomitantly elicits a metabolic shift toward glycolysis, suggesting that the hydrogenosomal function is impaired and triggers cell death. Collectively, we provide in vitro evidence that TET is a potential alternative therapeutic choice for treating MTZ-resistant T. vaginalis. The in-depth transcriptomic signatures in T. vaginalis upon TET treatment presented here will shed light on the signaling pathways linking to cell death in amitochondriate organisms. PMID:26303799

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

    PubMed

    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. PMID:26303508

  6. Cell-death-inducing DFFA-like Effector B Contributes to the Assembly of Hepatitis C Virus (HCV) Particles and Interacts with HCV NS5A

    PubMed Central

    Cai, Hua; Yao, Wenxia; Li, Leike; Li, Xinlei; Hu, Longbo; Mai, Runming; Peng, Tao

    2016-01-01

    Hepatitis C virus (HCV) uses components of the very-low-density lipoprotein (VLDL) pathway for assembly/release. We previously reported that hepatocyte nuclear factor 4α (HNF4α) participates in HCV assembly/release through downstream factors those participate in VLDL assembly/secretion. Cell-death-inducing DFFA-like effector B (CIDEB) is an important regulator of the VLDL pathway. CIDEB is required for entry of HCV particles from cell culture (HCVcc), but the effects of CIDEB on the post-entry steps of the HCV lifecycle are unclear. In the present study, we determined that CIDEB is required for HCV assembly in addition to HCVcc entry. Furthermore, CIDEB interacts with the HCV NS5A protein, and the N terminus of CIDEB and the domain I of NS5A are involved in this interaction. Moreover, CIDEB silencing impairs the association of apolipoprotein E (ApoE) with HCV particles. Interestingly, CIDEB is also required for the post-entry stages of the dengue virus (DENV) life cycle. Collectively, these results indicate that CIDEB is a new host factor that is involved in HCV assembly, presumably by interacting with viral protein, providing new insight into the exploitation of the VLDL regulator CIDEB by HCV. PMID:27282740

  7. Differential Roles of Cell Death-inducing DNA Fragmentation Factor-α-like Effector (CIDE) Proteins in Promoting Lipid Droplet Fusion and Growth in Subpopulations of Hepatocytes.

    PubMed

    Xu, Wenyi; Wu, Lizhen; Yu, Miao; Chen, Feng-Jung; Arshad, Muhammad; Xia, Xiayu; Ren, Hao; Yu, Jinhai; Xu, Li; Xu, Dijin; Li, John Zhong; Li, Peng; Zhou, Linkang

    2016-02-26

    Lipid droplets (LDs) are dynamic subcellular organelles whose growth is closely linked to obesity and hepatic steatosis. Cell death-inducing DNA fragmentation factor-α-like effector (CIDE) proteins, including Cidea, Cideb, and Cidec (also called Fsp27), play important roles in lipid metabolism. Cidea and Cidec are LD-associated proteins that promote atypical LD fusion in adipocytes. Here, we find that CIDE proteins are all localized to LD-LD contact sites (LDCSs) and promote lipid transfer, LD fusion, and growth in hepatocytes. We have identified two types of hepatocytes, one with small LDs (small LD-containing hepatocytes, SLHs) and one with large LDs (large LD-containing hepatocytes, LLHs) in the liver. Cideb is localized to LDCSs and promotes lipid exchange and LD fusion in both SLHs and LLHs, whereas Cidea and Cidec are specifically localized to the LDCSs and promote lipid exchange and LD fusion in LLHs. Cideb-deficient SLHs have reduced LD sizes and lower lipid exchange activities. Fasting dramatically induces the expression of Cidea/Cidec and increases the percentage of LLHs in the liver. The majority of the hepatocytes from the liver of obese mice are Cidea/Cidec-positive LLHs. Knocking down Cidea or Cidec significantly reduced lipid storage in the livers of obese animals. Our data reveal that CIDE proteins play differential roles in promoting LD fusion and lipid storage; Cideb promotes lipid storage under normal diet conditions, whereas Cidea and Cidec are responsible for liver steatosis under fasting and obese conditions. PMID:26733203

  8. Quinazoline-based tricyclic compounds that regulate programmed cell death, induce neuronal differentiation, and are curative in animal models for excitotoxicity and hereditary brain disease

    PubMed Central

    Vainshtein, A; Veenman, L; Shterenberg, A; Singh, S; Masarwa, A; Dutta, B; Island, B; Tsoglin, E; Levin, E; Leschiner, S; Maniv, I; Pe’er, L; Otradnov, I; Zubedat, S; Aga-Mizrachi, S; Weizman, A; Avital, A; Marek, I; Gavish, M

    2015-01-01

    Expanding on a quinazoline scaffold, we developed tricyclic compounds with biological activity. These compounds bind to the 18 kDa translocator protein (TSPO) and protect U118MG (glioblastoma cell line of glial origin) cells from glutamate-induced cell death. Fascinating, they can induce neuronal differentiation of PC12 cells (cell line of pheochromocytoma origin with neuronal characteristics) known to display neuronal characteristics, including outgrowth of neurites, tubulin expression, and NeuN (antigen known as ‘neuronal nuclei’, also known as Rbfox3) expression. As part of the neurodifferentiation process, they can amplify cell death induced by glutamate. Interestingly, the compound 2-phenylquinazolin-4-yl dimethylcarbamate (MGV-1) can induce expansive neurite sprouting on its own and also in synergy with nerve growth factor and with glutamate. Glycine is not required, indicating that N-methyl-D-aspartate receptors are not involved in this activity. These diverse effects on cells of glial origin and on cells with neuronal characteristics induced in culture by this one compound, MGV-1, as reported in this article, mimic the diverse events that take place during embryonic development of the brain (maintenance of glial integrity, differentiation of progenitor cells to mature neurons, and weeding out of non-differentiating progenitor cells). Such mechanisms are also important for protective, curative, and restorative processes that occur during and after brain injury and brain disease. Indeed, we found in a rat model of systemic kainic acid injection that MGV-1 can prevent seizures, counteract the process of ongoing brain damage, including edema, and restore behavior defects to normal patterns. Furthermore, in the R6-2 (transgenic mouse model for Huntington disease; Strain name: B6CBA-Tg(HDexon1)62Gpb/3J) transgenic mouse model for Huntington disease, derivatives of MGV-1 can increase lifespan by >20% and reduce incidence of abnormal movements. Also in vitro

  9. The phospholipase A2 activity of peroxiredoxin 6 promotes cancer cell death induced by tumor necrosis factor alpha in hepatocellular carcinoma.

    PubMed

    Xu, Xiao; Lu, Di; Zhuang, Runzhou; Wei, Xuyong; Xie, Haiyang; Wang, Chao; Zhu, Yangbo; Wang, Jianguo; Zhong, Cheng; Zhang, Xuanyu; Wei, Qiang; He, Zenglei; Zhou, Lin; Zheng, Shusen

    2016-09-01

    In this study, we used proteomic profiling to compare hepatocellular carcinoma (HCC) and peri-tumoral tissues to identify potential tumor markers of HCC. We identified eight differentially expressed proteins (>3-fold), including Peroxiredoxin 6 (PRDX6). PRDX6 is a bifunctional enzyme with both peroxidase and calcium-independent phospholipase A2 (iPLA2) activity. We found that peri-tumoral tissues expressed higher levels of PRDX6 mRNA (n = 59, P = 0.018) and protein (n = 265, P < 0.001) than HCC tissues, and that decreased expression of PRDX6 in HCC tissues was an independent risk factor indicating a poor prognosis (n = 145, P = 0.007). Combining the examination of serum PRDX6 with α-fetoprotein improved the diagnostic sensitivity of tests for HCC compared to α-fetoprotein alone (85.0% vs 50.0%, n = 40). We found that PRDX6 induced S phase arrest in HCC cells and inhibited HCC tumorigenicity in mice injected with cancer cells. When treated with H2 O2 , PRDX6 inhibited apoptosis. When treated with tumor necrosis factor alpha (TNF-α), PRDX6 promoted apoptosis. Inhibition of iPLA2 activity of PRDX6 decreased the apoptosis induced by TNF-α. In conclusion, PRDX6 inhibited the carcinogenesis of HCC, and the iPLA2 activity of PRDX6 promoted cancer cell death induced by TNF-α. © 2015 Wiley Periodicals, Inc. PMID:26293541

  10. Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia.

    PubMed

    Chen, Yongqiang; Henson, Elizabeth S; Xiao, Wenyan; Huang, Daniel; McMillan-Ward, Eileen M; Israels, Sara J; Gibson, Spencer B

    2016-06-01

    Autophagy is an intracellular lysosomal degradation pathway where its primary function is to allow cells to survive under stressful conditions. Autophagy is, however, a double-edge sword that can either promote cell survival or cell death. In cancer, hypoxic regions contribute to poor prognosis due to the ability of cancer cells to adapt to hypoxia in part through autophagy. In contrast, autophagy could contribute to hypoxia induced cell death in cancer cells. In this study, we showed that autophagy increased during hypoxia. At 4 h of hypoxia, autophagy promoted cell survival whereas, after 48 h of hypoxia, autophagy increased cell death. Furthermore, we found that the tyrosine phosphorylation of EGFR (epidermal growth factor receptor) decreased after 16 h in hypoxia. Furthermore, EGFR binding to BECN1 in hypoxia was significantly higher at 4 h compared to 72 h. Knocking down or inhibiting EGFR resulted in an increase in autophagy contributing to increased cell death under hypoxia. In contrast, when EGFR was reactivated by the addition of EGF, the level of autophagy was reduced which led to decreased cell death. Hypoxia led to autophagic degradation of the lipid raft protein CAV1 (caveolin 1) that is known to bind and activate EGFR in a ligand-independent manner during hypoxia. By knocking down CAV1, the amount of EGFR phosphorylation was decreased in hypoxia and amount of autophagy and cell death increased. This indicates that the activation of EGFR plays a critical role in the switch between cell survival and cell death induced by autophagy in hypoxia. PMID:27166522

  11. NAMPT inhibition sensitizes pancreatic adenocarcinoma cells to tumor-selective, PAR-independent metabolic catastrophe and cell death induced by β-lapachone

    PubMed Central

    Moore, Z; Chakrabarti, G; Luo, X; Ali, A; Hu, Z; Fattah, F J; Vemireddy, R; DeBerardinis, R J; Brekken, R A; Boothman, D A

    2015-01-01

    Nicotinamide phosphoribosyltransferase (NAMPT) inhibitors (e.g., FK866) target the most active pathway of NAD+ synthesis in tumor cells, but lack tumor-selectivity for use as a single agent. Reducing NAD+ pools by inhibiting NAMPT primed pancreatic ductal adenocarcinoma (PDA) cells for poly(ADP ribose) polymerase (PARP1)-dependent cell death induced by the targeted cancer therapeutic, β-lapachone (β-lap, ARQ761), independent of poly(ADP ribose) (PAR) accumulation. β-Lap is bioactivated by NADPH:quinone oxidoreductase 1 (NQO1) in a futile redox cycle that consumes oxygen and generates high levels of reactive oxygen species (ROS) that cause extensive DNA damage and rapid PARP1-mediated NAD+ consumption. Synergy with FK866+β-lap was tumor-selective, only occurring in NQO1-overexpressing cancer cells, which is noted in a majority (∼85%) of PDA cases. This treatment strategy simultaneously decreases NAD+ synthesis while increasing NAD+ consumption, reducing required doses and treatment times for both drugs and increasing potency. These complementary mechanisms caused profound NAD(P)+ depletion and inhibited glycolysis, driving down adenosine triphosphate levels and preventing recovery normally observed with either agent alone. Cancer cells died through an ROS-induced, μ-calpain-mediated programmed cell death process that kills independent of caspase activation and is not driven by PAR accumulation, which we call NAD+-Keresis. Non-overlapping specificities of FK866 for PDA tumors that rely heavily on NAMPT-catalyzed NAD+ synthesis and β-lap for cancer cells with elevated NQO1 levels affords high tumor-selectivity. The concept of reducing NAD+ pools in cancer cells to sensitize them to ROS-mediated cell death by β-lap is a novel strategy with potential application for pancreatic and other types of NQO1+ solid tumors. PMID:25590809

  12. Overexpression of alpha-synuclein at non-toxic levels increases dopaminergic cell death induced by copper exposure via modulation of protein degradation pathways.

    PubMed

    Anandhan, Annadurai; Rodriguez-Rocha, Humberto; Bohovych, Iryna; Griggs, Amy M; Zavala-Flores, Laura; Reyes-Reyes, Elsa M; Seravalli, Javier; Stanciu, Lia A; Lee, Jaekwon; Rochet, Jean-Christophe; Khalimonchuk, Oleh; Franco, Rodrigo

    2015-09-01

    Gene multiplications or point mutations in alpha (α)-synuclein are associated with familial and sporadic Parkinson's disease (PD). An increase in copper (Cu) levels has been reported in the cerebrospinal fluid and blood of PD patients, while occupational exposure to Cu has been suggested to augment the risk to develop PD. We aimed to elucidate the mechanisms by which α-synuclein and Cu regulate dopaminergic cell death. Short-term overexpression of wild type (WT) or mutant A53T α-synuclein had no toxic effect in human dopaminergic cells and primary midbrain cultures, but it exerted a synergistic effect on Cu-induced cell death. Cell death induced by Cu was potentiated by overexpression of the Cu transporter protein 1 (Ctr1) and depletion of intracellular glutathione (GSH) indicating that the toxic effects of Cu are linked to alterations in its intracellular homeostasis. Using the redox sensor roGFP, we demonstrated that Cu-induced oxidative stress was primarily localized in the cytosol and not in the mitochondria. However, α-synuclein overexpression had no effect on Cu-induced oxidative stress. WT or A53T α-synuclein overexpression exacerbated Cu toxicity in dopaminergic and yeast cells in the absence of α-synuclein aggregation. Cu increased autophagic flux and protein ubiquitination. Impairment of autophagy by overexpression of a dominant negative Atg5 form or inhibition of the ubiquitin/proteasome system (UPS) with MG132 enhanced Cu-induced cell death. However, only inhibition of the UPS stimulated the synergistic toxic effects of Cu and α-synuclein overexpression. Our results demonstrate that α-synuclein stimulates Cu toxicity in dopaminergic cells independent from its aggregation via modulation of protein degradation pathways. PMID:25497688

  13. Cancer Cell Death-Inducing Radiotherapy: Impact on Local Tumour Control, Tumour Cell Proliferation and Induction of Systemic Anti-tumour Immunity.

    PubMed

    Frey, Benjamin; Derer, Anja; Scheithauer, Heike; Wunderlich, Roland; Fietkau, Rainer; Gaipl, Udo S

    2016-01-01

    Radiotherapy (RT) predominantly is aimed to induce DNA damage in tumour cells that results in reduction of their clonogenicity and finally in tumour cell death. Adaptation of RT with higher single doses has become necessary and led to a more detailed view on what kind of tumour cell death is induced and which immunological consequences result from it. RT is capable of rendering tumour cells immunogenic by modifying the tumour cell phenotype and the microenvironment. Danger signals are released as well as the senescence-associated secretory phenotype. This results in maturation of dendritic cells and priming of cytotoxic T cells as well as in activation of natural killer cells. However, RT on the other hand can also result in immune suppressive events including apoptosis induction and foster tumour cell proliferation. That's why RT is nowadays increasingly combined with selected immunotherapies. PMID:27558821

  14. CHIP, a carboxy terminus HSP-70 interacting protein, prevents cell death induced by endoplasmic reticulum stress in the central nervous system

    PubMed Central

    Cabral Miranda, Felipe; Adão-Novaes, Juliana; Hauswirth, William W.; Linden, Rafael; Petrs-Silva, Hilda; Chiarini, Luciana B.

    2015-01-01

    Endoplasmic reticulum (ER) stress and protein misfolding are associated with various neurodegenerative diseases. ER stress activates unfolded protein response (UPR), an adaptative response. However, severe ER stress can induce cell death. Here we show that the E3 ubiquitin ligase and co-chaperone Carboxyl Terminus HSP70/90 Interacting Protein (CHIP) prevents neuron death in the hippocampus induced by severe ER stress. Organotypic hippocampal slice cultures (OHSCs) were exposed to Tunicamycin, a pharmacological ER stress inducer, to trigger cell death. Overexpression of CHIP was achieved with a recombinant adeno-associated viral vector (rAAV) and significantly diminished ER stress-induced cell death, as shown by analysis of propidium iodide (PI) uptake, condensed chromatin, TUNEL and cleaved caspase 3 in the CA1 region of OHSCs. In addition, overexpression of CHIP prevented upregulation of both CHOP and p53 both pro-apoptotic pathways induced by ER stress. We also detected an attenuation of eIF2a phosphorylation promoted by ER stress. However, CHIP did not prevent upregulation of BiP/GRP78 induced by UPR. These data indicate that overexpression of CHIP attenuates ER-stress death response while maintain ER stress adaptative response in the central nervous system. These results indicate a neuroprotective role for CHIP upon UPR signaling. CHIP emerge as a candidate for clinical intervention in neurodegenerative diseases associated with ER stress. PMID:25620910

  15. CHIP, a carboxy terminus HSP-70 interacting protein, prevents cell death induced by endoplasmic reticulum stress in the central nervous system.

    PubMed

    Cabral Miranda, Felipe; Adão-Novaes, Juliana; Hauswirth, William W; Linden, Rafael; Petrs-Silva, Hilda; Chiarini, Luciana B

    2014-01-01

    Endoplasmic reticulum (ER) stress and protein misfolding are associated with various neurodegenerative diseases. ER stress activates unfolded protein response (UPR), an adaptative response. However, severe ER stress can induce cell death. Here we show that the E3 ubiquitin ligase and co-chaperone Carboxyl Terminus HSP70/90 Interacting Protein (CHIP) prevents neuron death in the hippocampus induced by severe ER stress. Organotypic hippocampal slice cultures (OHSCs) were exposed to Tunicamycin, a pharmacological ER stress inducer, to trigger cell death. Overexpression of CHIP was achieved with a recombinant adeno-associated viral vector (rAAV) and significantly diminished ER stress-induced cell death, as shown by analysis of propidium iodide (PI) uptake, condensed chromatin, TUNEL and cleaved caspase 3 in the CA1 region of OHSCs. In addition, overexpression of CHIP prevented upregulation of both CHOP and p53 both pro-apoptotic pathways induced by ER stress. We also detected an attenuation of eIF2a phosphorylation promoted by ER stress. However, CHIP did not prevent upregulation of BiP/GRP78 induced by UPR. These data indicate that overexpression of CHIP attenuates ER-stress death response while maintain ER stress adaptative response in the central nervous system. These results indicate a neuroprotective role for CHIP upon UPR signaling. CHIP emerge as a candidate for clinical intervention in neurodegenerative diseases associated with ER stress. PMID:25620910

  16. Okadaic acid, a protein phosphatase inhibitor, blocks calcium changes, gene expression, and cell death induced by gibberellin in wheat aleurone cells.

    PubMed Central

    Kuo, A; Cappelluti, S; Cervantes-Cervantes, M; Rodriguez, M; Bush, D S

    1996-01-01

    The cereal aleurone functions during germination by secreting hydrolases, mainly alpha-amylase, into the starchy endosperm. Multiple signal transduction pathways exist in cereal aleurone cells that enable them to modulate hydrolase production in response to both hormonal and environmental stimuli. Gibberellic acid (GA) promotes hydrolase production, whereas abscisic acid (ABA), hypoxia, and osmotic stress reduce amylase production. In an effort to identify the components of transduction pathways in aleurone cells, we have investigated the effect of okadaic acid (OA), a protein phosphatase inhibitor, on stimulus-response coupling for GA, ABA, and hypoxia. We found that OA (100 nM) completely inhibited all the GA responses that we measured, from rapid changes in cytosolic Ca2+ through changes in gene expression and accelerated cell death. OA (100 nM) partially inhibited ABA responses, as measured by changes in the level of PHAV1, a cDNA for an ABA-induced mRNA in barley. In contrast, OA had no effect on the response to hypoxia, as measured by changes in cytosolic Ca2+ and by changes in enzyme activity and RNA levels of alcohol dehydrogenase. Our data indicate that OA-sensitive protein phosphatases act early in the transduction pathway of GA but are not involved in the response to hypoxia. These data provide a basis for a model of multiple transduction pathways in which the level of cytosolic Ca2+ is a key point of convergence controlling changes in stimulus-response coupling. PMID:8742711

  17. Antiproliferative Activity of Cinnamomum cassia Constituents and Effects of Pifithrin-Alpha on Their Apoptotic Signaling Pathways in Hep G2 Cells

    PubMed Central

    Ng, Lean-Teik; Wu, Shu-Jing

    2011-01-01

    Cinnamaldehyde (Cin), cinnamic acid (Ca) and cinnamyl alcohol (Cal), major constituents of Cinnamomum cassia, have been shown to possess antioxidant, anti-inflammatory, anticancer and other activities. In this study, our aim was to evaluate the antiproliferative activity of these compounds in human hepatoma Hep G2 cells and examine the effects of pifithrin-alpha (PFTα; a specific p53 inhibitor) on their apoptotic signaling transduction mechanism. The antiproliferative activity was measured by XTT assay. Expression of apoptosis-related proteins was detected by western blotting. Results showed that at a concentration of 30 μM, the order of antiproliferative activity in Hep G2 cells was Cin > Ca > Cal. Cin (IC50 9.76 ± 0.67 μM) demonstrated an antiproliferative potency as good as 5-fluorouracil (an anti-cancer drug; IC50 9.57 ± 0.61 μM). Further studies on apoptotic mechanisms of Cin showed that it downregulated the expression of Bcl-XL, upregulated CD95 (APO-1), p53 and Bax proteins, as well as cleaving the poly (ADP-ribose) polymerase (PARP) in a time-dependent pattern. PFTα pre-incubation significantly diminished the effect of Cin-induced apoptosis. It markedly upregulated the anti-apoptotic (Bcl-XL) expression and downregulated the pro-apoptotic (Bax) expression, as well as effectively blocking the CD95 (APO-1) and p53 expression, and PARP cleavage in Cin-treated cells. This study indicates that Cin was the most potent antiproliferative constituent of C. cassia, and its apoptotic mechanism in Hep G2 cells could be mediated through the p53 induction and CD95 (APO-1) signaling pathways. PMID:20038571

  18. Analysis of cell death inducing compounds.

    PubMed

    Spicker, Jeppe S; Pedersen, Henrik Toft; Nielsen, Henrik Bjørn; Brunak, Søren

    2007-11-01

    Biomarkers for early detection of toxicity hold the promise of improving the failure rates in drug development. In the present study, gene expression levels were measured using full-genome RAE230 version 2 Affymetrix GeneChips on rat liver tissue 48 h after administration of six different compounds, three toxins (ANIT, DMN and NMF) and three non-toxins (Caeruelein, Dinitrophenol and Rosiglitazone). We identified three gene transcripts with exceptional predictive performance towards liver toxicity and/or changes in histopathology. The three genes were: glucokinase regulatory protein (GCKR), ornithine aminotransferase (OAT) and Cytochrome P450, subfamily IIC (mephenytoin 4-hydroxylase) (Cyp2C29). RT-PCR for these three genes was performed and four additional compounds were included for validation. The quantitative RT-PCR analysis confirmed the findings based on the microarray data and using the three genes a classification rate of 55 of 57 samples was achieved for the classification of not toxic versus toxic. The single most promising biomarker (OAT) alone resulted in a surprisingly 100% correctly classified samples. OAT has not previously been linked to toxicity and cell death in the literature and the novel finding represents a putative hepatotoxicity biomarker. PMID:17503021

  19. How Kidney Cell Death Induces Renal Necroinflammation.

    PubMed

    Mulay, Shrikant R; Kumar, Santhosh V; Lech, Maciej; Desai, Jyaysi; Anders, Hans-Joachim

    2016-05-01

    The nephrons of the kidney are independent functional units harboring cells of a low turnover during homeostasis. As such, physiological renal cell death is a rather rare event and dead cells are flushed away rapidly with the urinary flow. Renal cell necrosis occurs in acute kidney injuries such as thrombotic microangiopathies, necrotizing glomerulonephritis, or tubular necrosis. All of these are associated with intense intrarenal inflammation, which contributes to further renal cell loss, an autoamplifying process referred to as necroinflammation. But how does renal cell necrosis trigger inflammation? Here, we discuss the role of danger-associated molecular patterns (DAMPs), mitochondrial (mito)-DAMPs, and alarmins, as well as their respective pattern recognition receptors. The capacity of DAMPs and alarmins to trigger cytokine and chemokine release initiates the recruitment of leukocytes into the kidney that further amplify necroinflammation. Infiltrating neutrophils often undergo neutrophil extracellular trap formation associated with neutrophil death or necroptosis, which implies a release of histones, which act not only as DAMPs but also elicit direct cytotoxic effects on renal cells, namely endothelial cells. Proinflammatory macrophages and eventually cytotoxic T cells further drive kidney cell death and inflammation. Dissecting the molecular mechanisms of necroinflammation may help to identify the best therapeutic targets to limit nephron loss in kidney injury. PMID:27339382

  20. Apoptotic cell death induced by intracellular proteolysis.

    PubMed

    Williams, M S; Henkart, P A

    1994-11-01

    To mimic the injection of granzymes into target cells by cytotoxic lymphocytes or the activation of endogenous proteases in programmed cell death, the proteases chymotrypsin, proteinase K, or trypsin were loaded into the cytoplasm of several different cell types using the osmotic lysis of pinosomes technique. Internalization of these proteases caused cell lysis within several hours, accompanied by extensive nuclear damage in most but not all combinations of target cells and proteases. This nuclear damage, quantitated by DNA release from nuclei, was associated with apoptotic features including DNA fragmentation into nucleosomal ladders, chromatin condensation, nuclear fragmentation, and membrane blebbing. Agents reported to block programmed cell death, including aurintricarboxylic acid, inhibitors of energy metabolism, and protein or RNA synthesis, failed to block this protease-induced death, although some inhibited nuclear damage. In separate experiments, introduction of staphylococcal nuclease into cells led to near complete (at least 75% of total) nucleosomal DNA fragmentation within 6 to 8 h. Condensation of chromatin did not accompany this fragmentation to the same extent, and there was approximately a 10-h lag between half-maximal DNA fragmentation and 50% loss of membrane integrity. The results suggest that activation of intracellular proteases during cell death by any molecular pathway could give rise to apoptotic morphology and DNA fragmentation. PMID:7930626

  1. Signal voter

    DOEpatents

    Goodwin, Roy L.

    1981-01-01

    A voter for providing a single accurate output signal that is derived from the closest two signal levels of three input signals, each of which signals represents a measurement of the same phenomena. By means of the voting circuit, the signals are first sorted by level of amplitude and then ranked as highest, middle or lowest. The highest or lowest signal that is furthest from the middle signal is rejected, while the other highest or lowest signal is selected for processing. The selected high or low signal is then averaged with the middle signal to provide the output signal.

  2. Signal Words

    MedlinePlus

    ... Signal Words? Signal words are found on pesticide product labels, and they describe the acute (short-term) toxicity ... red letters on the front panel of the product label. 2,4 Acute Oral LD 50 Inhalation LC ...

  3. Fas ligand based immunotherapy: A potent and effective neoadjuvant with checkpoint inhibitor properties, or a systemically toxic promoter of tumor growth?

    PubMed

    Modiano, Jaime F; Bellgrau, Donald

    2016-02-01

    Fas ligand (FasL, CD95L) is a 40-kDa type II transmembrane protein that binds to Fas (CD95) receptors and promotes programmed cell death. Fas receptors are expressed at higher levels in many tumors than in normal cells; however, systemic administration of FasL or agonistic anti-Fas antibodies to mice with tumors caused lethal hepatitis. Somewhat paradoxically, elimination of Fas or FasL from tumors also leads to death induced by CD95 receptor/ligand elimination (DICE). At face value, this suggests that Fas signaling not only kills normal cells, but that it also is essential for tumor cell survival. Targeting this pathway may not only fail to kill tumors, but instead may even enhance their growth, leading some to report the demise of Fas ligand in cancer immunotherapy. But, to paraphrase Mark Twain, is this death an exaggeration? Here, we provide a careful examination of the literature exploring the merits of FasL as a novel form of cancer immunotherapy. With local administration using delivery vectors that achieve high levels of expression in the tumor environment, our results indicate that the potential for systemic toxicity is eliminated in higher mammals, and that a systemic anti-tumor response ensues, which delays or prevents progression and simultaneously attacks distant metastases. PMID:27011046

  4. Uncouplers of Oxidative Phosphorylation Can Enhance a Fas Death Signal

    PubMed Central

    Linsinger, Georg; Wilhelm, Sabine; Wagner, Hermann; Häcker, Georg

    1999-01-01

    Recent work suggests a participation of mitochondria in apoptotic cell death. This role includes the release of apoptogenic molecules into the cytosol preceding or after a loss of mitochondrial membrane potential ΔΨm. The two uncouplers of oxidative phosphorylation carbonyl cyanide m-chlorophenylhydrazone (CCCP) and 2,4-dinitrophenol (DNP) reduce ΔΨm by direct attack of the proton gradient across the inner mitochondrial membrane. Here we show that both compounds enhance the apoptosis-inducing capacity of Fas/APO-1/CD95 signaling in Jurkat and CEM cells without causing apoptotic changes on their own account. This amplification occurred upstream or at the level of caspases and was not inhibited by Bcl-2. The effect could be blocked by the cowpox protein CrmA and is thus likely to require caspase 8 activity. Apoptosis induction by staurosporine in Jurkat cells as well as by Fas in SKW6 cells was unaffected by CCCP and DNP. The role of cytochrome c during Fas-DNP signaling was investigated. No early cytochrome c release from mitochondria was detected by Western blotting. Functional assays with cytoplasmic preparations from Fas-DNP-treated cells also indicated that there was no major contribution by cytochrome c or caspase 9 to the activation of effector caspases. Furthermore, an increase of rhodamine-123 uptake into intact cells, which has been explained by mitochondrial swelling, occurred considerably later than the caspase activation and was blocked by Z-VAD-fmk. These data show that uncouplers of oxidative phosphorylation can presensitize some but not all cells for a Fas death signal and provide information about the existence of separate pathways in the induction of apoptosis. PMID:10207055

  5. Uncouplers of oxidative phosphorylation can enhance a Fas death signal.

    PubMed

    Linsinger, G; Wilhelm, S; Wagner, H; Häcker, G

    1999-05-01

    Recent work suggests a participation of mitochondria in apoptotic cell death. This role includes the release of apoptogenic molecules into the cytosol preceding or after a loss of mitochondrial membrane potential DeltaPsim. The two uncouplers of oxidative phosphorylation carbonyl cyanide m-chlorophenylhydrazone (CCCP) and 2, 4-dinitrophenol (DNP) reduce DeltaPsim by direct attack of the proton gradient across the inner mitochondrial membrane. Here we show that both compounds enhance the apoptosis-inducing capacity of Fas/APO-1/CD95 signaling in Jurkat and CEM cells without causing apoptotic changes on their own account. This amplification occurred upstream or at the level of caspases and was not inhibited by Bcl-2. The effect could be blocked by the cowpox protein CrmA and is thus likely to require caspase 8 activity. Apoptosis induction by staurosporine in Jurkat cells as well as by Fas in SKW6 cells was unaffected by CCCP and DNP. The role of cytochrome c during Fas-DNP signaling was investigated. No early cytochrome c release from mitochondria was detected by Western blotting. Functional assays with cytoplasmic preparations from Fas-DNP-treated cells also indicated that there was no major contribution by cytochrome c or caspase 9 to the activation of effector caspases. Furthermore, an increase of rhodamine-123 uptake into intact cells, which has been explained by mitochondrial swelling, occurred considerably later than the caspase activation and was blocked by Z-VAD-fmk. These data show that uncouplers of oxidative phosphorylation can presensitize some but not all cells for a Fas death signal and provide information about the existence of separate pathways in the induction of apoptosis. PMID:10207055

  6. Phosphoinositide signaling.

    PubMed

    Boss, Wendy F; Im, Yang Ju

    2012-01-01

    "All things flow and change…even in the stillest matter there is unseen flux and movement." Attributed to Heraclitus (530-470 BC), from The Story of Philosophy by Will Durant. Heraclitus, a Greek philosopher, was thinking on a much larger scale than molecular signaling; however, his visionary comments are an important reminder for those studying signaling today. Even in unstimulated cells, signaling pathways are in constant metabolic flux and provide basal signals that travel throughout the organism. In addition, negatively charged phospholipids, such as the polyphosphorylated inositol phospholipids, provide a circuit board of on/off switches for attracting or repelling proteins that define the membranes of the cell. This template of charged phospholipids is sensitive to discrete changes and metabolic fluxes-e.g., in pH and cations-which contribute to the oscillating signals in the cell. The inherent complexities of a constantly fluctuating system make understanding how plants integrate and process signals challenging. In this review we discuss one aspect of lipid signaling: the inositol family of negatively charged phospholipids and their functions as molecular sensors and regulators of metabolic flux in plants. PMID:22404474

  7. Hedgehog signalling.

    PubMed

    Lee, Raymond Teck Ho; Zhao, Zhonghua; Ingham, Philip W

    2016-02-01

    The Hedgehog (Hh) signalling pathway is one of the key regulators of metazoan development. Hh proteins have been shown to play roles in many developmental processes and have become paradigms for classical morphogens. Dysfunction of the Hh pathway underlies a number of human developmental abnormalities and diseases, making it an important therapeutic target. Interest in Hh signalling thus extends across many fields, from evo-devo to cancer research and regenerative medicine. Here, and in the accompanying poster, we provide an outline of the current understanding of Hh signalling mechanisms, highlighting the similarities and differences between species. PMID:26839340

  8. Identifying Fragilities in Biochemical Networks: Robust Performance Analysis of Fas Signaling-Induced Apoptosis

    PubMed Central

    Shoemaker, Jason E.; Doyle, Francis J.

    2008-01-01

    Proper control of apoptotic signaling is critical to immune response and development in multicellular organisms. Two tools from control engineering are applied to a mathematical model of Fas ligand signaling-induced apoptosis. Structured singular value analysis determines the volume in parameter space within which the system parameters may exist and still maintain efficacious signaling, but is limited to linear behaviors. Sensitivity analysis can be applied to nonlinear systems but is difficult to relate to performance criteria. Thus, structured singular value analysis is used to quantify performance during apoptosis rejection, ensuring that the system remains sensitive but not overly so to apoptotic stimuli. Sensitivity analysis is applied when the system has switched to the death-inducing, apoptotic steady state to determine parameters significant to maintaining the bistability. The analyses reveal that the magnitude of the death signal is fragile to perturbations in degradation parameters (failures in the ubiquitin/proteasome mechanism) while the timing of signal expression can be tuned by manipulating local parameters. Simultaneous parameter uncertainty highlights apoptotic fragility to disturbances in the ubiquitin/proteasome system. Sensitivity analysis reveals that the robust signaling characteristics of the apoptotic network is due to network architecture, and the apoptotic signaling threshold is best manipulated by interactions upstream of the apoptosome. PMID:18539637

  9. Hyperactivated Wnt signaling induces synthetic lethal interaction with Rb inactivation by elevating TORC1 activities.

    PubMed

    Zhang, Tianyi; Liao, Yang; Hsu, Fu-Ning; Zhang, Robin; Searle, Jennifer S; Pei, Xun; Li, Xuan; Ryoo, Hyung Don; Ji, Jun-Yuan; Du, Wei

    2014-05-01

    Inactivation of the Rb tumor suppressor can lead to increased cell proliferation or cell death depending on specific cellular context. Therefore, identification of the interacting pathways that modulate the effect of Rb loss will provide novel insights into the roles of Rb in cancer development and promote new therapeutic strategies. Here, we identify a novel synthetic lethal interaction between Rb inactivation and deregulated Wg/Wnt signaling through unbiased genetic screens. We show that a weak allele of axin, which deregulates Wg signaling and increases cell proliferation without obvious effects on cell fate specification, significantly alters metabolic gene expression, causes hypersensitivity to metabolic stress induced by fasting, and induces synergistic apoptosis with mutation of fly Rb ortholog, rbf. Furthermore, hyperactivation of Wg signaling by other components of the Wg pathway also induces synergistic apoptosis with rbf. We show that hyperactivated Wg signaling significantly increases TORC1 activity and induces excessive energy stress with rbf mutation. Inhibition of TORC1 activity significantly suppressed synergistic cell death induced by hyperactivated Wg signaling and rbf inactivation, which is correlated with decreased energy stress and decreased induction of apoptotic regulator expression. Finally the synthetic lethality between Rb and deregulated Wnt signaling is conserved in mammalian cells and that inactivation of Rb and APC induces synergistic cell death through a similar mechanism. These results suggest that elevated TORC1 activity and metabolic stress underpin the evolutionarily conserved synthetic lethal interaction between hyperactivated Wnt signaling and inactivated Rb tumor suppressor. PMID:24809668

  10. Gibberellin signaling.

    PubMed

    Hartweck, Lynn M

    2008-12-01

    This review covers recent advances in gibberellin (GA) signaling. GA signaling is now understood to hinge on DELLA proteins. DELLAs negatively regulate GA response by activating the promoters of several genes including Xerico, which upregulates the abscisic acid pathway which is antagonistic to GA. DELLAs also promote transcription of the GA receptor, GIBBERELLIN INSENSITIVE DWARF 1 (GID1) and indirectly regulate GA biosynthesis genes enhancing GA responsiveness and feedback control. A structural analysis of GID1 provides a model for understanding GA signaling. GA binds within a pocket of GID1, changes GID1 conformation and increases the affinity of GID1 for DELLA proteins. GA/GID1/DELLA has increased affinity for an F-Box protein and DELLAs are subsequently degraded via the proteasome. Therefore, GA induces growth through degradation of the DELLAs. The binding of DELLA proteins to three of the PHYTOCHROME INTERACTING FACTOR (PIF) proteins integrates light and GA signaling pathways. This binding prevents PIFs 3, 4, and 5 from functioning as positive transcriptional regulators of growth in the dark. Since PIFs are degraded in light, these PIFs can only function in the combined absence of light and presence of GA. New analyses suggest that GA signaling evolved at the same time or just after the plant vascular system and before plants acquired the capacity for seed reproduction. An analysis of sequences cloned from Physcomitrella suggests that GID1 and DELLAs were the first to evolve but did not initially interact. The more recently diverging spike moss Selaginella has all the genes required for GA biosynthesis and signaling, but the role of GA response in Selaginella physiology remains a mystery. PMID:18936962

  11. Activin Signaling in the Pathogenesis and Therapy of Neuropsychiatric Diseases

    PubMed Central

    Link, Andrea S.; Zheng, Fang; Alzheimer, Christian

    2016-01-01

    Activins are members of the transforming growth factor β (TGFβ) family and serve as multifunctional regulatory proteins in many tissues and organs. In the brain, activin A, which is formed by two disulfide-linked βA subunits, is recognized as the predominant player in activin signaling. Over the last years, considerable progress has been made in elucidating novel and unexpected functions of activin in the normal and diseased brain and in deciphering the underlying molecular mechanisms. Initially identified as a neurotrophic and protective factor during development and in several forms of acute injury, the scope of effects of activin A in the adult central nervous system (CNS) has been considerably broadened by now. Here, we will highlight recent findings that bear significance for a better understanding of the pathogenesis of various neuropsychiatric diseases and might hold promise for novel therapeutic strategies. While the basal level of activin A in the adult brain is low, significant short-term up-regulation occurs in response to increased neuronal activity. In fact, brief exposure to an enriched environment (EE) is already sufficient to considerably strengthen activin signaling. Enhancement of this pathway tunes the performance of glutamatergic and GABAergic synapses in a fashion that impacts on cognitive functions and affective behavior, counteracts death-inducing signals through extrasynaptic NMDA receptors (NMDARs), and stimulates adult neurogenesis in the hippocampus. We will discuss how impaired activin signaling is involved in anxiety disorders, depression, drug dependence, and neurodegenerative diseases such as Alzheimer’s and Parkinson’s, and how reinforcement of activin signaling might be exploited for therapeutic interventions. PMID:27242425

  12. Mitochondria-dependent reactive oxygen species-mediated programmed cell death induced by 3,3'-diindolylmethane through inhibition of F0F1-ATP synthase in unicellular protozoan parasite Leishmania donovani.

    PubMed

    Roy, Amit; Ganguly, Agneyo; BoseDasgupta, Somdeb; Das, Benu Brata; Pal, Churala; Jaisankar, Parasuraman; Majumder, Hemanta K

    2008-11-01

    Mitochondria are the principal site for the generation of cellular ATP by oxidative phosphorylation. F0F1-ATP synthase, a complex V of the electron transport chain, is an important constituent of mitochondria-dependent signaling pathways involved in apoptosis. In the present study, we have shown for the first time that 3,3'-diindolylmethane (DIM), a DNA topoisomerase I poison, inhibits mitochondrial F0F1-ATP synthase of Leishmania donovani and induces programmed cell death (PCD), which is a novel insight into the mechanism in protozoan parasites. DIM-induced inhibition of F0F1-ATP synthase activity causes depletion of mitochondrial ATP levels and significant stimulation of mitochondrial reactive oxygen species (ROS) production, followed by depolarization of mitochondrial membrane potential (DeltaPsi(m)). Because DeltaPsi(m) is the driving force for mitochondrial ATP synthesis, loss of DeltaPsi(m) results in depletion of cellular ATP level. The loss of DeltaPsi(m) causes the cellular ROS generation and in turn leads to the oxidative DNA lesions followed by DNA fragmentation. In contrast, loss of DeltaPsi(m) leads to release of cytochrome c into the cytosol and subsequently activates the caspase-like proteases, which lead to oligonucleosomal DNA cleavage. We have also shown that mitochondrial DNA-depleted cells are insensitive to DIM to induce PCD. Therefore, mitochondria are necessary for cytotoxicity of DIM in kinetoplastid parasites. Taken together, our study indicates for the first time that DIM-induced mitochondrial dysfunction by inhibition of F0F1-ATP synthase activity leads to PCD in Leishmania spp. parasites, which could be exploited to develop newer potential therapeutic targets. PMID:18703668

  13. The root hair assay facilitates the use of genetic and pharmacological tools in order to dissect multiple signalling pathways that lead to programmed cell death.

    PubMed

    Kacprzyk, Joanna; Devine, Aoife; McCabe, Paul F

    2014-01-01

    The activation of programmed cell death (PCD) is often a result of complex signalling pathways whose relationship and intersection are not well understood. We recently described a PCD root hair assay and proposed that it could be used to rapidly screen genetic or pharmacological modulators of PCD. To further assess the applicability of the root hair assay for studying multiple signalling pathways leading to PCD activation we have investigated the crosstalk between salicylic acid, autophagy and apoptosis-like PCD (AL-PCD) in Arabidopsis thaliana. The root hair assay was used to determine rates of AL-PCD induced by a panel of cell death inducing treatments in wild type plants treated with chemical modulators of salicylic acid synthesis or autophagy, and in genetic lines defective in autophagy or salicylic acid signalling. The assay demonstrated that PCD induced by exogenous salicylic acid or fumonisin B1 displayed a requirement for salicylic acid signalling and was partially dependent on the salicylic acid signal transducer NPR1. Autophagy deficiency resulted in an increase in the rates of AL-PCD induced by salicylic acid and fumonisin B1, but not by gibberellic acid or abiotic stress. The phenylalanine ammonia lyase-dependent salicylic acid synthesis pathway contributed only to death induced by salicylic acid and fumonisin B1. 3-Methyladenine, which is commonly used as an inhibitor of autophagy, appeared to influence PCD induction in all treatments suggesting a possible secondary, non-autophagic, effect on a core component of the plant PCD pathway. The results suggest that salicylic acid signalling is negatively regulated by autophagy during salicylic acid and mycotoxin-induced AL-PCD. However, this crosstalk does not appear to be directly involved in PCD induced by gibberellic acid or abiotic stress. This study demonstrates that the root hair assay is an effective tool for relatively rapid investigation of complex signalling pathways leading to the activation of

  14. The Root Hair Assay Facilitates the Use of Genetic and Pharmacological Tools in Order to Dissect Multiple Signalling Pathways That Lead to Programmed Cell Death

    PubMed Central

    Kacprzyk, Joanna; Devine, Aoife; McCabe, Paul F.

    2014-01-01

    The activation of programmed cell death (PCD) is often a result of complex signalling pathways whose relationship and intersection are not well understood. We recently described a PCD root hair assay and proposed that it could be used to rapidly screen genetic or pharmacological modulators of PCD. To further assess the applicability of the root hair assay for studying multiple signalling pathways leading to PCD activation we have investigated the crosstalk between salicylic acid, autophagy and apoptosis-like PCD (AL-PCD) in Arabidopsis thaliana. The root hair assay was used to determine rates of AL-PCD induced by a panel of cell death inducing treatments in wild type plants treated with chemical modulators of salicylic acid synthesis or autophagy, and in genetic lines defective in autophagy or salicylic acid signalling. The assay demonstrated that PCD induced by exogenous salicylic acid or fumonisin B1 displayed a requirement for salicylic acid signalling and was partially dependent on the salicylic acid signal transducer NPR1. Autophagy deficiency resulted in an increase in the rates of AL-PCD induced by salicylic acid and fumonisin B1, but not by gibberellic acid or abiotic stress. The phenylalanine ammonia lyase-dependent salicylic acid synthesis pathway contributed only to death induced by salicylic acid and fumonisin B1. 3-Methyladenine, which is commonly used as an inhibitor of autophagy, appeared to influence PCD induction in all treatments suggesting a possible secondary, non-autophagic, effect on a core component of the plant PCD pathway. The results suggest that salicylic acid signalling is negatively regulated by autophagy during salicylic acid and mycotoxin-induced AL-PCD. However, this crosstalk does not appear to be directly involved in PCD induced by gibberellic acid or abiotic stress. This study demonstrates that the root hair assay is an effective tool for relatively rapid investigation of complex signalling pathways leading to the activation of

  15. DICE

    PubMed Central

    Peter, Marcus E

    2014-01-01

    The conventional view of CD95 (Fas/APO-1) is that it is a dedicated apoptosis-inducing receptor with important functions in immune cell homeostasis and in viral and tumor defense. There is an emerging recognition, however, that CD95 also has multiple non-apoptotic activities. In the context of cancer, CD95 was shown to have tumor-promoting activities, and the concept of this new function of CD95 in cancer is gaining traction. Recently, we showed that not only is CD95 a growth promoter for cancer cells, but, paradoxically, when either CD95 or CD95 ligand (CD95L) is removed, that virtually all cancer cells die through a process we have named DICE (death induced by CD95R/L elimination). In this perspective, I outline a hypothesis regarding the physiological function of DICE, and why it may be possible to use induction of DICE to treat many, if not most, cancers. PMID:24690893

  16. Concurrent MEK and autophagy inhibition is required to restore cell death associated danger-signalling in Vemurafenib-resistant melanoma cells.

    PubMed

    Martin, S; Dudek-Perić, A M; Maes, H; Garg, A D; Gabrysiak, M; Demirsoy, S; Swinnen, J V; Agostinis, P

    2015-02-01

    Vemurafenib (PLX4032), an inhibitor of BRAF(V600E), has demonstrated significant clinical anti-melanoma effects. However, the majority of treated patients develop resistance, due to a variety of molecular mechanisms including MAPK reactivation through MEK. The induction of a cancer cell death modality associated with danger-signalling resulting in surface mobilization of crucial damage-associated-molecular-patterns (DAMPs), e.g. calreticulin (CRT) and heat shock protein-90 (HSP90), from dying cells, is emerging to be crucial for therapeutic success. Both cell death and danger-signalling are modulated by autophagy, a key adaptation mechanism stimulated during melanoma progression. However, whether melanoma cell death induced by MAPK inhibition is associated with danger-signalling, and the reliance of these mechanisms on autophagy, has not yet been scrutinized. Using a panel of isogenic PLX4032-sensitive and resistant melanoma cell lines we show that PLX4032-induced caspase-dependent cell death and DAMPs exposure in the drug-sensitive cells, but failed to do so in the drug-resistant cells, displaying heightened MEK activation. MEK inhibitor, U0126, treatment sensitized PLX4032-resistant cells to death and re-established their danger-signalling capacity. Only melanoma cells exposing death-induced danger-signals were phagocytosed and induced DC maturation. Although the PLX4032-resistant melanoma cells displayed higher basal and drug-induced autophagy, compromising autophagy, pharmacologically or by ATG5 knockdown, was insufficient to re-establish their PLX4032 sensitivity. Interestingly, autophagy abrogation was particularly efficacious in boosting cell death and ecto-CRT/ecto-HSP90 in PLX4032-resistant cells upon blockage of MEK hyper-activation by U0126. Thus combination of MEK inhibitors with autophagy blockers may represent a novel treatment regime to increase both cell death and danger-signalling in Vemurafenib-resistant metastatic melanoma. PMID:25529535

  17. Systemic silencing signal(s).

    PubMed

    Fagard, M; Vaucheret, H

    2000-06-01

    Grafting experiments have revealed that transgenic plants that undergo co-suppression of homologous transgenes and endogenous genes or PTGS of exogenous transgenes produce a sequence-specific systemic silencing signal that is able to propagate from cell to cell and at long distance. Similarly, infection of transgenic plants by viruses that carry (part of) a transgene sequence results in global silencing (VIGS) of the integrated transgenes although viral infection is localized. Systemic PTGS and VIGS strongly resemble recovery from virus infection in non-transgenic plants, leading to protection against secondary infection in newly emerging leaves and PTGS of transiently expressed homologous transgenes. The sequence-specific PTGS signal is probably a transgene product (for example, aberrant RNA) or a secondary product (for example, RNA molecules produced by an RNA-dependent RNA polymerase with transgene RNA as a matrix) that mimics the type of viral RNA that is targeted for degradation by cellular defence. Whether some particular cases of transgene TGS could also rely on the production of such a mobile molecule is discussed. PMID:10999411

  18. Niche signaling promotes stem cell survival in the Drosophila testis via the Jak-STAT target DIAP1

    PubMed Central

    Hasan, Salman; Hétié, Phylis; Matunis, Erika L.

    2015-01-01

    Tissue-specific stem cells are thought to resist environmental insults better than their differentiating progeny, but this resistance varies from one tissue to another, and the underlying mechanisms are not well-understood. Here, we use the Drosophila testis as a model system to study the regulation of cell death within an intact niche. This niche contains sperm-producing germline stem cells (GSCs) and accompanying somatic cyst stem cells (or CySCs). Although many signals are known to promote stem cell self-renewal in this tissue, including the highly conserved JAK-STAT pathway, the response of these stem cells to potential death-inducing signals, and factors promoting stem cell survival, have not been characterized. Here we find that both GSCs and CySCs resist cell death better than their differentiating progeny, under normal laboratory conditions and in response to potential death-inducing stimuli such as irradiation or starvation. To ask what might be promoting stem cell survival, we characterized the role of the anti-apoptotic gene Drosophila inhibitor of apoptosis 1 (diap1) in testis stem cells. DIAP1 protein is enriched in the GSCs and CySCs and is a Jak-STAT target. diap1 is necessary for survival of both GSCs and CySCs, and ectopic up-regulation of DIAP1 in somatic cyst cells is sufficient to non-autonomously rescue stress-induced cell death in adjacent differentiating germ cells (spermatogonia). Altogether, our results show that niche signals can promote stem cell survival by up-regulation of highly conserved anti-apoptotic proteins, and suggest that this strategy may underlie the ability of stem cells to resist death more generally. PMID:25941003

  19. Acquisition signal transmitter

    NASA Technical Reports Server (NTRS)

    Friedman, Morton L. (Inventor)

    1989-01-01

    An encoded information transmitter which transmits a radio frequency carrier that is amplitude modulated by a constant frequency waveform and thereafter amplitude modulated by a predetermined encoded waveform, the constant frequency waveform modulated carrier constituting an acquisition signal and the encoded waveform modulated carrier constituting an information bearing signal, the acquisition signal providing enhanced signal acquisition and interference rejection favoring the information bearing signal. One specific application for this transmitter is as a distress transmitter where a conventional, legislated audio tone modulated signal is transmitted followed first by the acquisition signal and then the information bearing signal, the information bearing signal being encoded with, among other things, vehicle identification data. The acquistion signal enables a receiver to acquire the information bearing signal where the received signal is low and/or where the received signal has a low signal-to-noise ratio in an environment where there are multiple signals in the same frequency band as the information bearing signal.

  20. Paraptosis-like cell death induced by yessotoxin.

    PubMed

    Korsnes, Mónica Suárez; Espenes, Arild; Hetland, Dyveke Lem; Hermansen, Lene C

    2011-12-01

    This study shows that BC3H1 myoblast cell lines exposed to 100 nM yessotoxin (YTX) undergo a form of programmed cell death distinct from apoptosis and with features resembling paraptosis. Morphologically, cells treated with YTX reveal extensive cytoplasmic vacuolation, mitochondrial and endoplasmic reticulum swelling, uncondensed chromatin and cytoskeletal alterations. DNA electrophoresis evidences lack of DNA fragmentation and Western blotting analysis demonstrates activation of the mitogen-activated protein kinase JNK/SAPK1. Further characterisation of this form of programmed cell death may have interest within medicine and cancer therapy. PMID:21945047

  1. Trial Watch: Immunogenic cell death inducers for anticancer chemotherapy

    PubMed Central

    Pol, Jonathan; Vacchelli, Erika; Aranda, Fernando; Castoldi, Francesca; Eggermont, Alexander; Cremer, Isabelle; Sautès-Fridman, Catherine; Fucikova, Jitka; Galon, Jérôme; Spisek, Radek; Tartour, Eric; Zitvogel, Laurence; Kroemer, Guido; Galluzzi, Lorenzo

    2015-01-01

    The term “immunogenic cell death” (ICD) is now employed to indicate a functionally peculiar form of apoptosis that is sufficient for immunocompetent hosts to mount an adaptive immune response against dead cell-associated antigens. Several drugs have been ascribed with the ability to provoke ICD when employed as standalone therapeutic interventions. These include various chemotherapeutics routinely employed in the clinic (e.g., doxorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, bortezomib, cyclophosphamide and oxaliplatin) as well as some anticancer agents that are still under preclinical or clinical development (e.g., some microtubular inhibitors of the epothilone family). In addition, a few drugs are able to convert otherwise non-immunogenic instances of cell death into bona fide ICD, and may therefore be employed as chemotherapeutic adjuvants within combinatorial regimens. This is the case of cardiac glycosides, like digoxin and digitoxin, and zoledronic acid. Here, we discuss recent developments on anticancer chemotherapy based on ICD inducers. PMID:26137404

  2. Unraveling the mechanism of cell death induced by chemical fibrils

    PubMed Central

    Julien, Olivier; Kampmann, Martin; Bassik, Michael C.; Zorn, Julie A.; Venditto, Vincent J.; Shimbo, Kazutaka; Agard, Nicholas J.; Shimada, Kenichi; Rheingold, Arnold L.; Stockwell, Brent R.; Weissman, Jonathan S.

    2014-01-01

    We previously discovered a small-molecule inducer of cell death, named 1541, that non-covalently self-assembles into chemical fibrils (“chemi-fibrils”) and activates procaspase-3 in vitro. We report here that 1541-induced cell death is caused by the fibrillar, rather than the soluble form of the drug. An shRNA screen reveals that knockdown of genes involved in endocytosis, vesicle trafficking, and lysosomal acidification causes partial 1541 resistance. We confirm the role of these pathways using pharmacological inhibitors. Microscopy shows that the fluorescent chemi-fibrils accumulate in punctae inside cells that partially co-localize with lysosomes. Notably, the chemi-fibrils bind and induce liposome leakage in vitro, suggesting they may do the same in cells. The chemi-fibrils induce extensive proteolysis including caspase substrates, yet modulatory profiling reveals that chemi-fibrils form a distinct class from existing inducers of cell death. The chemi-fibrils share similarities to proteinaceous fibrils and may provide insight into their mechanism of cellular toxicity. PMID:25262416

  3. Lung epithelial cell death induced by oil-dispersant mixtures.

    PubMed

    Wang, He; Shi, Yongli; Major, Danielle; Yang, Zhanjun

    2012-08-01

    The dispersants used in oil spill disasters are claimed to be safe, but increased solubility of high-molecular-weight components in crude oil is of public health concern. The water-accommodated fractions (WAF) of crude oil mixed with dispersants may become airborne and cause lung epithelial damage when inhaled. This study was designed to examine the cell death and related death pathways of lung epithelial cells in response to WAF. Cultured A549 cells were treated for 2 or 24h with different concentrations of WAF. The WAF was prepared by mixing each of the dispersants (Corexit EC9527A, Corexit EC9500A and Corexit EC9580A) with crude oil for extraction with PBS. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide MTT assay, lactate dehydrogenase assay, morphology and cleaved caspase 9 protein, and microtubule-associated protein 1 light chain 3 were all used to measure cell viability, necrosis, apoptosis and autophagy quantitation, respectively. Results showed that the WAF of oil-dispersant mixtures caused cell death in the lung epithelial cells, in a dose-dependent manner, with the major cellular pathways of necrosis and apoptosis involved. Autophagy also occurred in cells exposed to WAF mixtures at lower concentrations before any detectable cell death, indicating greater sensitivity to WAF exposure. The three types of cell behavior, namely necrosis, apoptosis and autophagy, may play different roles in oil spill-related respiratory disorders. PMID:22504303

  4. An Evolution-Guided Analysis Reveals a Multi-Signaling Regulation of Fas by Tyrosine Phosphorylation and its Implication in Human Cancers

    PubMed Central

    Chakrabandhu, Krittalak; Huault, Sébastien; Durivault, Jérôme; Lang, Kévin; Ta Ngoc, Ly; Bole, Angelique; Doma, Eszter; Dérijard, Benoit; Gérard, Jean-Pierre; Pierres, Michel; Hueber, Anne-Odile

    2016-01-01

    Demonstrations of both pro-apoptotic and pro-survival abilities of Fas (TNFRSF6/CD95/APO-1) have led to a shift from the exclusive “Fas apoptosis” to “Fas multisignals” paradigm and the acceptance that Fas-related therapies face a major challenge, as it remains unclear what determines the mode of Fas signaling. Through protein evolution analysis, which reveals unconventional substitutions of Fas tyrosine during divergent evolution, evolution-guided tyrosine-phosphorylated Fas proxy, and site-specific phosphorylation detection, we show that the Fas signaling outcome is determined by the tyrosine phosphorylation status of its death domain. The phosphorylation dominantly turns off the Fas-mediated apoptotic signal, while turning on the pro-survival signal. We show that while phosphorylations at Y232 and Y291 share some common functions, their contributions to Fas signaling differ at several levels. The findings that Fas tyrosine phosphorylation is regulated by Src family kinases (SFKs) and the phosphatase SHP-1 and that Y291 phosphorylation primes clathrin-dependent Fas endocytosis, which contributes to Fas pro-survival signaling, reveals for the first time the mechanistic link between SFK/SHP-1-dependent Fas tyrosine phosphorylation, internalization route, and signaling choice. We also demonstrate that levels of phosphorylated Y232 and Y291 differ among human cancer types and differentially respond to anticancer therapy, suggesting context-dependent involvement of Fas phosphorylation in cancer. This report provides a new insight into the control of TNF receptor multisignaling by receptor phosphorylation and its implication in cancer biology, which brings us a step closer to overcoming the challenge in handling Fas signaling in treatments of cancer as well as other pathologies such as autoimmune and degenerative diseases. PMID:26942442

  5. Protection of Momordica charantia polysaccharide against intracerebral hemorrhage-induced brain injury through JNK3 signaling pathway.

    PubMed

    Duan, Zhen-Zhen; Zhou, Xiao-Ling; Li, Yi-Hang; Zhang, Feng; Li, Feng-Ying; Su-Hua, Qi

    2015-01-01

    It has been well documented that Momordica charantia polysaccharide (MCP) has multiple biological effects such as immune enhancement, anti-oxidation and anti-cancer. However, the potential protective effects of MCP on stroke damage and its relative mechanisms remain unclear. Our present study demonstrated that MCP could scavenge reactive oxygen species (ROS) in intra-cerebral hemorrhage damage, significantly attenuating the neuronal death induced by thrombin in primary hippocampal neurons. Furthermore, we found that MCP prevented the activation of the c-Jun N-terminal protein kinase (JNK3), c-Jun and caspase-3, which was caused by the intra-cerebral hemorrhage injury. Taken together, our study demonstrated that MCP had a neuroprotective effect in response to intra-cerebral hemorrhage and its mechanisms involved the inhibition of JNK3 signaling pathway. PMID:25264226

  6. Cadmium overkill: autophagy, apoptosis and necrosis signalling in endothelial cells exposed to cadmium.

    PubMed

    Messner, Barbara; Türkcan, Adrian; Ploner, Christian; Laufer, Günther; Bernhard, David

    2016-04-01

    Apoptosis, necrosis, or autophagy-it is the mode of cell demise that defines the response of surrounding cells and organs. In case of one of the most toxic substances known to date, cadmium (Cd), and despite a large number of studies, the mode of cell death induced is still unclear. As there exists conflicting data as to which cell death mode is induced by Cd both across various cell types and within a single one, we chose to analyse Cd-induced cell death in primary human endothelial cells by investigating all possibilities that a cell faces in undergoing cell death. Our results indicate that Cd-induced death signalling starts with the causation of DNA damage and a cytosolic calcium flux. These two events lead to an apoptosis signalling-related mitochondrial membrane depolarisation and a classical DNA damage response. Simultaneously, autophagy signalling such as ER stress and phagosome formation is initiated. Importantly, we also observed lysosomal membrane permeabilization. It is the integration of all signals that results in DNA degradation and a disruption of the plasma membrane. Our data thus suggest that Cd causes the activation of multiple death signals in parallel. The genotype (for example, p53 positive or negative) as well as other factors may determine the initiation and rate of individual death signals. Differences in the signal mix and speed may explain the differing results recorded as to the Cd-induced mode of cell death thus far. In human endothelial cells it is the sum of most if not all of these signals that determine the mode of Cd-induced cell death: programmed necrosis. PMID:26588916

  7. The Fas-FADD Death Domain Complex Structure Unravels Signalling by Receptor Clustering

    SciTech Connect

    Scott, F.; Stec, B; Pop, C; Dobaczewska, M; Lee, J; Monosov, E; Robinson, H; Salvesen, G; Schwarzenbacher, R; Riedl, S

    2009-01-01

    The death inducing signalling complex (DISC) formed by Fas receptor, FADD (Fas-associated death domain protein) and caspase 8 is a pivotal trigger of apoptosis1, 2, 3. The Fas-FADD DISC represents a receptor platform, which once assembled initiates the induction of programmed cell death. A highly oligomeric network of homotypic protein interactions comprised of the death domains of Fas and FADD is at the centre of DISC formation4, 5. Thus, characterizing the mechanistic basis for the Fas-FADD interaction is crucial for understanding DISC signalling but has remained unclear largely because of a lack of structural data. We have successfully formed and isolated the human Fas-FADD death domain complex and report the 2.7 A crystal structure. The complex shows a tetrameric arrangement of four FADD death domains bound to four Fas death domains. We show that an opening of the Fas death domain exposes the FADD binding site and simultaneously generates a Fas-Fas bridge. The result is a regulatory Fas-FADD complex bridge governed by weak protein-protein interactions revealing a model where the complex itself functions as a mechanistic switch. This switch prevents accidental DISC assembly, yet allows for highly processive DISC formation and clustering upon a sufficient stimulus. In addition to depicting a previously unknown mode of death domain interactions, these results further uncover a mechanism for receptor signalling solely by oligomerization and clustering events.

  8. Flotillin-2 Modulates Fas Signaling Mediated Apoptosis after Hyperoxia in Lung Epithelial Cells

    PubMed Central

    Wei, Shuquan; Moon, Hyung-Geun; Zheng, Yijie; Liang, Xiaoliang; An, Chang Hyeok; Jin, Yang

    2013-01-01

    Lipid rafts are subdomains of the cell membrane with distinct protein composition and high concentrations of cholesterol and glycosphingolipids. Raft proteins are thought to mediate diverse cellular processes including signal transduction. However, its cellular mechanisms remain unclear. Caveolin-1 (cav-1, marker protein of caveolae) has been thought as a switchboard between extracellular matrix (ECM) stimuli and intracellular signals. Flotillin-2/reggie-1(Flot-2) is another ubiquitously expressed raft protein which defines non-caveolar raft microdomains (planar raft). Its cellular function is largely uncharacterized. Our novel studies demonstrated that Flot-2, in conjunction with cav-1, played important functions on controlling cell death via regulating Fas pathways. Using Beas2B epithelial cells, we found that in contrast to cav-1, Flot-2 conferred cytoprotection via preventing Fas mediated death-inducing signaling complex (DISC) formation, subsequently suppressed caspase-8 mediated extrinsic apoptosis. Moreover, Flot-2 reduced the mitochondria mediated intrinsic apoptosis by regulating the Bcl-2 family and suppressing cytochrome C release from mitochondria to cytosol. Flot-2 further modulated the common apoptosis pathway and inhibited caspase-3 activation via up-regulating the members in the inhibitor of apoptosis (IAP) family. Last, Flot-2 interacted with cav-1 and limited its expression. Taken together, we found that Flot-2 protected cells from Fas induced apoptosis and counterbalanced the pro-apoptotic effects of cav-1. Thus, Flot-2 played crucial functions in cellular homeostasis and cell survival, suggesting a differential role of individual raft proteins. PMID:24204853

  9. Signal processor for processing ultrasonic receiver signals

    DOEpatents

    Fasching, George E.

    1980-01-01

    A signal processor is provided which uses an analog integrating circuit in conjunction with a set of digital counters controlled by a precision clock for sampling timing to provide an improved presentation of an ultrasonic transmitter/receiver signal. The signal is sampled relative to the transmitter trigger signal timing at precise times, the selected number of samples are integrated and the integrated samples are transferred and held for recording on a strip chart recorder or converted to digital form for storage. By integrating multiple samples taken at precisely the same time with respect to the trigger for the ultrasonic transmitter, random noise, which is contained in the ultrasonic receiver signal, is reduced relative to the desired useful signal.

  10. Structural insights of homotypic interaction domains in the ligand-receptor signal transduction of tumor necrosis factor (TNF)

    PubMed Central

    Park, Young-Hoon; Jeong, Mi Suk; Jang, Se Bok

    2016-01-01

    Several members of tumor necrosis factor receptor (TNFR) superfamily that these members activate caspase-8 from death-inducing signaling complex (DISC) in TNF ligand-receptor signal transduction have been identified. In the extrinsic pathway, apoptotic signal transduction is induced in death domain (DD) superfamily; it consists of a hexahelical bundle that contains 80 amino acids. The DD superfamily includes about 100 members that belong to four subfamilies: death domain (DD), caspase recruitment domain (CARD), pyrin domain (PYD), and death effector domain (DED). This superfamily contains key building blocks: with these blocks, multimeric complexes are formed through homotypic interactions. Furthermore, each DD-binding event occurs exclusively. The DD superfamily regulates the balance between death and survival of cells. In this study, the structures, functions, and unique features of DD superfamily members are compared with their complexes. By elucidating structural insights of DD superfamily members, we investigate the interaction mechanisms of DD domains; these domains are involved in TNF ligand-receptor signaling. These DD superfamily members play a pivotal role in the development of more specific treatments of cancer. [BMB Reports 2016; 49(3): 159-166] PMID:26615973

  11. Signal verification can promote reliable signalling.

    PubMed

    Broom, Mark; Ruxton, Graeme D; Schaefer, H Martin

    2013-11-22

    The central question in communication theory is whether communication is reliable, and if so, which mechanisms select for reliability. The primary approach in the past has been to attribute reliability to strategic costs associated with signalling as predicted by the handicap principle. Yet, reliability can arise through other mechanisms, such as signal verification; but the theoretical understanding of such mechanisms has received relatively little attention. Here, we model whether verification can lead to reliability in repeated interactions that typically characterize mutualisms. Specifically, we model whether fruit consumers that discriminate among poor- and good-quality fruits within a population can select for reliable fruit signals. In our model, plants either signal or they do not; costs associated with signalling are fixed and independent of plant quality. We find parameter combinations where discriminating fruit consumers can select for signal reliability by abandoning unprofitable plants more quickly. This self-serving behaviour imposes costs upon plants as a by-product, rendering it unprofitable for unrewarding plants to signal. Thus, strategic costs to signalling are not a prerequisite for reliable communication. We expect verification to more generally explain signal reliability in repeated consumer-resource interactions that typify mutualisms but also in antagonistic interactions such as mimicry and aposematism. PMID:24068354

  12. Signal verification can promote reliable signalling

    PubMed Central

    Broom, Mark; Ruxton, Graeme D.; Schaefer, H. Martin

    2013-01-01

    The central question in communication theory is whether communication is reliable, and if so, which mechanisms select for reliability. The primary approach in the past has been to attribute reliability to strategic costs associated with signalling as predicted by the handicap principle. Yet, reliability can arise through other mechanisms, such as signal verification; but the theoretical understanding of such mechanisms has received relatively little attention. Here, we model whether verification can lead to reliability in repeated interactions that typically characterize mutualisms. Specifically, we model whether fruit consumers that discriminate among poor- and good-quality fruits within a population can select for reliable fruit signals. In our model, plants either signal or they do not; costs associated with signalling are fixed and independent of plant quality. We find parameter combinations where discriminating fruit consumers can select for signal reliability by abandoning unprofitable plants more quickly. This self-serving behaviour imposes costs upon plants as a by-product, rendering it unprofitable for unrewarding plants to signal. Thus, strategic costs to signalling are not a prerequisite for reliable communication. We expect verification to more generally explain signal reliability in repeated consumer–resource interactions that typify mutualisms but also in antagonistic interactions such as mimicry and aposematism. PMID:24068354

  13. Retroactive Signaling in Short Signaling Pathways

    PubMed Central

    Sepulchre, Jacques-Alexandre; Merajver, Sofía D.; Ventura, Alejandra C.

    2012-01-01

    In biochemical signaling pathways without explicit feedback connections, the core signal transduction is usually described as a one-way communication, going from upstream to downstream in a feedforward chain or network of covalent modification cycles. In this paper we explore the possibility of a new type of signaling called retroactive signaling, offered by the recently demonstrated property of retroactivity in signaling cascades. The possibility of retroactive signaling is analysed in the simplest case of the stationary states of a bicyclic cascade of signaling cycles. In this case, we work out the conditions for which variables of the upstream cycle are affected by a change of the total amount of protein in the downstream cycle, or by a variation of the phosphatase deactivating the same protein. Particularly, we predict the characteristic ranges of the downstream protein, or of the downstream phosphatase, for which a retroactive effect can be observed on the upstream cycle variables. Next, we extend the possibility of retroactive signaling in short but nonlinear signaling pathways involving a few covalent modification cycles. PMID:22848403

  14. Multiplexing oscillatory biochemical signals.

    PubMed

    de Ronde, Wiet; ten Wolde, Pieter Rein

    2014-04-01

    In recent years it has been increasingly recognized that biochemical signals are not necessarily constant in time and that the temporal dynamics of a signal can be the information carrier. Moreover, it is now well established that the protein signaling network of living cells has a bow-tie structure and that components are often shared between different signaling pathways. Here we show by mathematical modeling that living cells can multiplex a constant and an oscillatory signal: they can transmit these two signals simultaneously through a common signaling pathway, and yet respond to them specifically and reliably. We find that information transmission is reduced not only by noise arising from the intrinsic stochasticity of biochemical reactions, but also by crosstalk between the different channels. Yet, under biologically relevant conditions more than 2 bits of information can be transmitted per channel, even when the two signals are transmitted simultaneously. These observations suggest that oscillatory signals are ideal for multiplexing signals. PMID:24685537

  15. Scrophularia orientalis extract induces calcium signaling and apoptosis in neuroblastoma cells.

    PubMed

    Lange, Ingo; Moschny, Julia; Tamanyan, Kamilla; Khutsishvili, Manana; Atha, Daniel; Borris, Robert P; Koomoa, Dana-Lynn

    2016-04-01

    Effective neuroblastoma (NB) treatments are still limited despite treatment options available today. Therefore, this study attempted to identify novel plant extracts that have anticancer effects. Cytotoxicity and increased intracellular calcium levels were determined using the Sulforhodamine B (SRB) assay and Fluo4-AM (acetoxymethyl) staining and fluorescence microscopy in NB cells in order to screen a library of plant extracts. The current study examined the anticancer effects of a dichloromethane extract from Scrophularia orientalis L. (Scrophulariaceae), a plant that has been used in Traditional Chinese Medicine. This extract contained highly potent agents that significantly reduced cell survival and increased calcium levels in NB cells. Further analysis revealed that cell death induced by this extract was associated with intracellular calcium release, opening of the MPTP, caspase 3- and PARP-cleavage suggesting that this extract induced aberrant calcium signaling that resulted in apoptosis via the mitochondrial pathway. Therefore, agents from Scrophularia orientalis may have the potential to lead to new chemo-therapeutic anticancer drugs. Furthermore, targeting intracellular calcium signaling may be a novel strategy to develop more effective treatments for NB. PMID:26848085

  16. Scrophularia orientalis extract induces calcium signaling and apoptosis in neuroblastoma cells

    PubMed Central

    LANGE, INGO; MOSCHNY, JULIA; TAMANYAN, KAMILLA; KHUTSISHVILI, MANANA; ATHA, DANIEL; BORRIS, ROBERT P.; KOOMOA, DANA-LYNN

    2016-01-01

    Effective neuroblastoma (NB) treatments are still limited despite treatment options available today. Therefore, this study attempted to identify novel plant extracts that have anticancer effects. Cytotoxicity and increased intracellular calcium levels were determined using the Sulforhodamine B (SRB) assay and Fluo4-AM (acetoxymethyl) staining and fluorescence microscopy in NB cells in order to screen a library of plant extracts. The current study examined the anticancer effects of a dichloromethane extract from Scrophularia orientalis L. (Scrophulariaceae), a plant that has been used in Traditional Chinese Medicine. This extract contained highly potent agents that significantly reduced cell survival and increased calcium levels in NB cells. Further analysis revealed that cell death induced by this extract was associated with intracellular calcium release, opening of the MPTP, caspase 3- and PARP-cleavage suggesting that this extract induced aberrant calcium signaling that resulted in apoptosis via the mitochondrial pathway. Therefore, agents from Scrophularia orientalis may have the potential to lead to new chemo therapeutic anticancer drugs. Furthermore, targeting intracellular calcium signaling may be a novel strategy to develop more effective treatments for NB. PMID:26848085

  17. ERK Signals: Scaffolding Scaffolds?

    PubMed Central

    Casar, Berta; Crespo, Piero

    2016-01-01

    ERK1/2 MAP Kinases become activated in response to multiple intra- and extra-cellular stimuli through a signaling module composed of sequential tiers of cytoplasmic kinases. Scaffold proteins regulate ERK signals by connecting the different components of the module into a multi-enzymatic complex by which signal amplitude and duration are fine-tuned, and also provide signal fidelity by isolating this complex from external interferences. In addition, scaffold proteins play a central role as spatial regulators of ERKs signals. In this respect, depending on the subcellular localization from which the activating signals emanate, defined scaffolds specify which substrates are amenable to be phosphorylated. Recent evidence has unveiled direct interactions among different scaffold protein species. These scaffold-scaffold macro-complexes could constitute an additional level of regulation for ERK signals and may serve as nodes for the integration of incoming signals and the subsequent diversification of the outgoing signals with respect to substrate engagement. PMID:27303664

  18. Sending Signals Dynamically

    PubMed Central

    Smock, Robert G.; Gierasch, Lila M.

    2010-01-01

    Proteins mediate transmission of signals along intercellular and intracellular pathways and between the exterior and the interior of a cell. The dynamic properties of signaling proteins are crucial to their functions. We discuss emerging paradigms for the role of protein dynamics in signaling. A central tenet is that proteins fluctuate among many states on evolutionarily selected energy landscapes. Upstream signals remodel this landscape, causing signaling proteins to transmit information to downstream partners. New methods provide insight into the dynamic properties of signaling proteins at the atomic scale. The next stages in the signaling hierarchy—how multiple signals are integrated and how cellular signaling pathways are organized in space and time—present exciting challenges for the future, requiring bold multidisciplinary approaches. PMID:19359576

  19. Signal sciences workshop proceedings

    SciTech Connect

    Candy, J.V.

    1997-05-01

    This meeting is aimed primarily at signal processing and controls. The technical program for the 1997 Workshop includes a variety of efforts in the Signal Sciences with applications in the Microtechnology Area a new program at LLNL and a future area of application for both Signal/Image Sciences. Special sessions organized by various individuals in Seismic and Optical Signal Processing as well as Micro-Impulse Radar Processing highlight the program, while the speakers at the Signal Processing Applications session discuss various applications of signal processing/control to real world problems. For the more theoretical, a session on Signal Processing Algorithms was organized as well as for the more pragmatic, featuring a session on Real-Time Signal Processing.

  20. Signal Processing, Analysis, & Display

    SciTech Connect

    Lager, Darrell; Azevado, Stephen

    1986-06-01

    SIG is a general-purpose signal processing, analysis, and display program. Its main purpose is to perform manipulations on time- and frequency-domain signals. However, it has been designed to ultimately accommodate other representations for data such as multiplexed signals and complex matrices. Two user interfaces are provided in SIG - a menu mode for the unfamiliar user and a command mode for more experienced users. In both modes errors are detected as early as possible and are indicated by friendly, meaningful messages. An on-line HELP package is also included. A variety of operations can be performed on time- and frequency-domain signals including operations on the samples of a signal, operations on the entire signal, and operations on two or more signals. Signal processing operations that can be performed are digital filtering (median, Bessel, Butterworth, and Chebychev), ensemble average, resample, auto and cross spectral density, transfer function and impulse response, trend removal, convolution, Fourier transform and inverse window functions (Hamming, Kaiser-Bessel), simulation (ramp, sine, pulsetrain, random), and read/write signals. User definable signal processing algorithms are also featured. SIG has many options including multiple commands per line, command files with arguments,commenting lines, defining commands, and automatic execution for each item in a repeat sequence. Graphical operations on signals and spectra include: x-y plots of time signals; real, imaginary, magnitude, and phase plots of spectra; scaling of spectra for continuous or discrete domain; cursor zoom; families of curves; and multiple viewports.

  1. Reliable Signal Transduction

    NASA Astrophysics Data System (ADS)

    Wollman, Roy

    Stochasticity inherent to biochemical reactions (intrinsic noise) and variability in cellular states (extrinsic noise) degrade information transmitted through signaling networks. We analyzed the ability of temporal signal modulation - that is dynamics - to reduce noise-induced information loss. In the extracellular signal-regulated kinase (ERK), calcium (Ca(2 +)) , and nuclear factor kappa-B (NF- κB) pathways, response dynamics resulted in significantly greater information transmission capacities compared to nondynamic responses. Theoretical analysis demonstrated that signaling dynamics has a key role in overcoming extrinsic noise. Experimental measurements of information transmission in the ERK network under varying signal-to-noise levels confirmed our predictions and showed that signaling dynamics mitigate, and can potentially eliminate, extrinsic noise-induced information loss. By curbing the information-degrading effects of cell-to-cell variability, dynamic responses substantially increase the accuracy of biochemical signaling networks.

  2. Mitochondria and cell signalling

    PubMed Central

    Tait, Stephen W. G.; Green, Douglas R.

    2012-01-01

    Mitochondria have long been considered as crucial organelles, primarily for their roles in biosynthetic reactions such as ATP synthesis. However, it is becoming increasingly apparent that mitochondria are intimately involved in cell signalling pathways. Mitochondria perform various signalling functions, serving as platforms to initiate cell signalling, as well as acting as transducers and effectors in multiple processes. Here, we discuss the active roles that mitochondria have in cell death signalling, innate immunity and autophagy. Common themes of mitochondrial regulation emerge from these diverse but interconnected processes. These include: the outer mitochondrial membrane serving as a major signalling platform, and regulation of cell signalling through mitochondrial dynamics and by mitochondrial metabolites, including ATP and reactive oxygen species. Importantly, defects in mitochondrial control of cell signalling and in the regulation of mitochondrial homeostasis might underpin many diseases, in particular age-related pathologies. PMID:22448037

  3. Telephone multiline signaling using common signal pair

    NASA Technical Reports Server (NTRS)

    Goodloe, R. R.; Toole, P. C.; Belt, J. L.; Leininger, D. B. (Inventor)

    1979-01-01

    An operator can rapidly and automatically produce coded electrical signals by manipulating mechanical thumb wheel switches so as to instruct a service center to connect any number of telephone lines to the console thus enabling the operator to listen and/or talk over several lines simultaneously. The system includes an on-site console having several mechanically operated thumb wheel switches to which the desired lines to be connected can be dialed in. Electrical coded signals are fed to a number of banks of line AND gates representing units, tens and hundreds, a group of channel gates, and a command gate. These signals are gated out in a controlled manner to an encoder which generates tones that are transmitted over a single line to a communication service center.

  4. Measurand transient signal suppressor

    NASA Technical Reports Server (NTRS)

    Bozeman, Richard J., Jr. (Inventor)

    1994-01-01

    A transient signal suppressor for use in a controls system which is adapted to respond to a change in a physical parameter whenever it crosses a predetermined threshold value in a selected direction of increasing or decreasing values with respect to the threshold value and is sustained for a selected discrete time interval is presented. The suppressor includes a sensor transducer for sensing the physical parameter and generating an electrical input signal whenever the sensed physical parameter crosses the threshold level in the selected direction. A manually operated switch is provided for adapting the suppressor to produce an output drive signal whenever the physical parameter crosses the threshold value in the selected direction of increasing or decreasing values. A time delay circuit is selectively adjustable for suppressing the transducer input signal for a preselected one of a plurality of available discrete suppression time and producing an output signal only if the input signal is sustained for a time greater than the selected suppression time. An electronic gate is coupled to receive the transducer input signal and the timer output signal and produce an output drive signal for energizing a control relay whenever the transducer input is a non-transient signal which is sustained beyond the selected time interval.

  5. The cleaved FAS ligand activates the Na+/H+ exchanger NHE1 through Akt/ROCK1 to stimulate cell motility

    PubMed Central

    Monet, Michael; Poët, Mallorie; Tauzin, Sébastien; Fouqué, Amélie; Cophignon, Auréa; Lagadic-Gossmann, Dominique; Vacher, Pierre; Legembre, Patrick; Counillon, Laurent

    2016-01-01

    Transmembrane CD95L (Fas ligand) can be cleaved to release a promigratory soluble ligand, cl-CD95L, which can contribute to chronic inflammation and cancer cell dissemination. The motility signaling pathway elicited by cl-CD95L remains poorly defined. Here, we show that in the presence of cl-CD95L, CD95 activates the Akt and RhoA signaling pathways, which together orchestrate an allosteric activation of the Na+/H+ exchanger NHE1. Pharmacologic inhibition of Akt or ROCK1 independently blocks the cl-CD95L-induced migration. Confirming these pharmacologic data, disruption of the Akt and ROCK1 phosphorylation sites on NHE1 decreases cell migration in cells exposed to cl-CD95L. Together, these findings demonstrate that NHE1 is a novel molecular actor in the CD95 signaling pathway that drives the cl-CD95L-induced cell migration through both the Akt and RhoA signaling pathways. PMID:27302366

  6. Requirements for security signalling

    SciTech Connect

    Pierson, L.G.; Tarman, T.D.

    1995-02-05

    There has been some interest lately in the need for ``authenticated signalling``, and the development of signalling specifications by the ATM Forum that support this need. The purpose of this contribution is to show that if authenticated signalling is required, then supporting signalling facilities for directory services (i.e. key management) are also required. Furthermore, this contribution identifies other security related mechanisms that may also benefit from ATM-level signalling accommodations. For each of these mechanisms outlined here, an overview of the signalling issues and a rough cut at the required fields for supporting Information Elements are provided. Finally, since each of these security mechanisms are specified by a number of different standards, issues pertaining to the selection of a particular security mechanism at connection setup time (i.e. specification of a required ``Security Quality of Service``) are also discussed.

  7. Semaphorin 3A and neurotrophins: a balance between apoptosis and survival signaling in embryonic DRG neurons.

    PubMed

    Ben-Zvi, Ayal; Yagil, Zohar; Hagalili, Yamit; Klein, Hagit; Lerman, Omer; Behar, Oded

    2006-01-01

    Large numbers of neurons are eliminated by apoptosis during nervous system development. For instance, in the mouse dorsal root ganglion (DRG), the highest incidence of cell death occurs between embryonic days 12 and 14 (E12-E14). While the cause of cell death and its biological significance in the nervous system is not entirely understood, it is generally believed that limiting quantities of neurotrophins are responsible for neuronal death. Between E12 and E14, developing DRG neurons pass through tissues expressing high levels of axonal guidance molecules such as Semaphorin 3A (Sema3A) while navigating to their targets. Here, we demonstrate that Sema3A acts as a death-inducing molecule in neurotrophin-3 (NT-3)-, brain-derived neurotrophic factor (BDNF)- and nerve growth factor (NGF)-dependent E12 and E13 cultured DRG neurons. We show that Sema3A most probably induces cell death through activation of the c-Jun N-terminal kinase (JNK)/c-Jun signaling pathway, and that this cell death is blocked by a moderate increase in NGF concentration. Interestingly, increasing concentrations of other neurotrophic factors, such as NT-3 or BDNF, do not elicit similar effects. Our data suggest that the number of DRG neurons is determined by a fine balance between neurotrophins and Semaphorin 3A, and not only by neurotrophin levels. PMID:16336628

  8. Signal Processing, Analysis, & Display

    Energy Science and Technology Software Center (ESTSC)

    1986-06-01

    SIG is a general-purpose signal processing, analysis, and display program. Its main purpose is to perform manipulations on time- and frequency-domain signals. However, it has been designed to ultimately accommodate other representations for data such as multiplexed signals and complex matrices. Two user interfaces are provided in SIG - a menu mode for the unfamiliar user and a command mode for more experienced users. In both modes errors are detected as early as possible andmore » are indicated by friendly, meaningful messages. An on-line HELP package is also included. A variety of operations can be performed on time- and frequency-domain signals including operations on the samples of a signal, operations on the entire signal, and operations on two or more signals. Signal processing operations that can be performed are digital filtering (median, Bessel, Butterworth, and Chebychev), ensemble average, resample, auto and cross spectral density, transfer function and impulse response, trend removal, convolution, Fourier transform and inverse window functions (Hamming, Kaiser-Bessel), simulation (ramp, sine, pulsetrain, random), and read/write signals. User definable signal processing algorithms are also featured. SIG has many options including multiple commands per line, command files with arguments,commenting lines, defining commands, and automatic execution for each item in a repeat sequence. Graphical operations on signals and spectra include: x-y plots of time signals; real, imaginary, magnitude, and phase plots of spectra; scaling of spectra for continuous or discrete domain; cursor zoom; families of curves; and multiple viewports.« less

  9. Digital signal processing the Tevatron BPM signals

    SciTech Connect

    Cancelo, G.; James, E.; Wolbers, S.; /Fermilab

    2005-05-01

    The Beam Position Monitor (TeV BPM) readout system at Fermilab's Tevatron has been updated and is currently being commissioned. The new BPMs use new analog and digital hardware to achieve better beam position measurement resolution. The new system reads signals from both ends of the existing directional stripline pickups to provide simultaneous proton and antiproton measurements. The signals provided by the two ends of the BPM pickups are processed by analog band-pass filters and sampled by 14-bit ADCs at 74.3MHz. A crucial part of this work has been the design of digital filters that process the signal. This paper describes the digital processing and estimation techniques used to optimize the beam position measurement. The BPM electronics must operate in narrow-band and wide-band modes to enable measurements of closed-orbit and turn-by-turn positions. The filtering and timing conditions of the signals are tuned accordingly for the operational modes. The analysis and the optimized result for each mode are presented.

  10. Precision signal power measurement

    NASA Technical Reports Server (NTRS)

    Winkelstein, R.

    1972-01-01

    Accurate estimation of signal power is an important Deep Space Network (DSN) consideration. Ultimately, spacecraft power and weight is saved if no reserve transmitter power is needed to compensate for inaccurate measurements. Spectral measurement of the received signal has proved to be an effective method of estimating signal power over a wide dynamic range. Furthermore, on-line spectral measurements provide an important diagnostic tool for examining spacecraft anomalies. Prototype equipment installed at a 64-m-diameter antenna site has been successfully used to make measurements of carrier power and sideband symmetry of telemetry signals received from the Mariner Mars 1971 spacecraft.

  11. Slit-Robo signaling.

    PubMed

    Blockus, Heike; Chédotal, Alain

    2016-09-01

    Slits are secreted proteins that bind to Roundabout (Robo) receptors. Slit-Robo signaling is best known for mediating axon repulsion in the developing nervous system. However, in recent years the functional repertoire of Slits and Robo has expanded tremendously and Slit-Robo signaling has been linked to roles in neurogenesis, angiogenesis and cancer progression among other processes. Likewise, our mechanistic understanding of Slit-Robo signaling has progressed enormously. Here, we summarize new insights into Slit-Robo evolutionary and system-dependent diversity, receptor-ligand interactions, signaling crosstalk and receptor activation. PMID:27578174

  12. Overexpression of membrane-bound fas ligand (CD95L) exacerbates autoimmune disease and renal pathology in pristane-induced lupus.

    PubMed

    Bossaller, Lukas; Rathinam, Vijay A K; Bonegio, Ramon; Chiang, Ping-I; Busto, Patricia; Wespiser, Adam R; Caffrey, Daniel R; Li, Quan-Zhen; Mohan, Chandra; Fitzgerald, Katherine A; Latz, Eicke; Marshak-Rothstein, Ann

    2013-09-01

    Loss-of-function mutations in the Fas death receptor or its ligand result in a lymphoproliferative syndrome and exacerbate clinical disease in most lupus-prone strains of mice. One exception is mice injected with 2,6,10,14-tetramethylpentadecane (TMPD), a hydrocarbon oil commonly known as pristane, which induces systemic lupus erythematosus-like disease. Although Fas/Fas ligand (FasL) interactions have been strongly implicated in the activation-induced cell death of both lymphocytes and other APCs, FasL can also trigger the production of proinflammatory cytokines. FasL is a transmembrane protein with a matrix metalloproteinase cleavage site in the ectodomain. Matrix metalloproteinase cleavage inactivates membrane-bound FasL and releases a soluble form reported to have both antagonist and agonist activity. To better understand the impact of FasL cleavage on both the proapoptotic and proinflammatory activity of FasL, its cleavage site was deleted through targeted mutation to produce the deleted cleavage site (ΔCS) mouse line. ΔCS mice express higher levels of membrane-bound FasL than do wild-type mice and fail to release soluble FasL. To determine to what extent FasL promotes inflammation in lupus mice, TMPD-injected FasL-deficient and ΔCS BALB/c mice were compared with control TMPD-injected BALB/c mice. We found that FasL deficiency significantly reduced the early inflammatory exudate induced by TMPD injection. In contrast, ΔCS mice developed a markedly exacerbated disease profile associated with a higher frequency of splenic neutrophils and macrophages, a profound change in anti-nuclear Ab specificity, and markedly increased proteinuria and kidney pathology compared with controls. These results demonstrate that FasL promotes inflammation in TMPD-induced autoimmunity, and its cleavage limits FasL proinflammatory activity. PMID:23918976

  13. Cytosolic DNA triggers mitochondrial apoptosis via DNA damage signaling proteins independently of AIM2 and RNA polymerase III.

    PubMed

    Wenzel, Michael; Wunderlich, Michael; Besch, Robert; Poeck, Hendrik; Willms, Simone; Schwantes, Astrid; Kremer, Melanie; Sutter, Gerd; Endres, Stefan; Schmidt, Andreas; Rothenfusser, Simon

    2012-01-01

    A key host response to limit microbial spread is the induction of cell death when foreign nucleic acids are sensed within infected cells. In mouse macrophages, transfected DNA or infection with modified vaccinia virus Ankara (MVA) can trigger cell death via the absent in melanoma 2 (AIM2) inflammasome. In this article, we show that nonmyeloid human cell types lacking a functional AIM2 inflammasome still die in response to cytosolic delivery of different DNAs or infection with MVA. This cell death induced by foreign DNA is independent of caspase-8 and carries features of mitochondrial apoptosis: dependence on BAX, APAF-1, and caspase-9. Although it does not require the IFN pathway known to be triggered by infection with MVA or transfected DNA via polymerase III and retinoid acid-induced gene I-like helicases, it shows a strong dependence on components of the DNA damage signaling pathway: cytosolic delivery of DNA or infection with MVA leads to phosphorylation of p53 (serines 15 and 46) and autophosphorylation of ataxia telangiectasia mutated (ATM); depleting p53 or ATM with small interfering RNA or inhibiting the ATM/ATM-related kinase family by caffeine strongly reduces apoptosis. Taken together, our findings suggest that a pathway activating DNA damage signaling plays an important independent role in detecting intracellular foreign DNA, thereby complementing the induction of IFN and activation of the AIM2 inflammasome. PMID:22140256

  14. Signaling by Gasotransmitters

    PubMed Central

    Mustafa, Asif K.; Gadalla, Moataz M.; Snyder, Solomon H.

    2009-01-01

    Nitric oxide is well established as a major signaling molecule. Evidence is accumulating that carbon monoxide and hydrogen sulfide also are physiologic mediators in the cardiovascular, immune, and nervous systems. This Review focuses on mechanisms whereby they signal by binding to metal centers in metalloproteins, such as in guanylyl cyclase, or modifying sulfhydryl groups in protein targets. PMID:19401594

  15. Seismic signal of avalanches

    NASA Astrophysics Data System (ADS)

    Pesaresi, Damiano; Ravanat, Xavier; Thibert, Emmanuel

    2010-05-01

    The characterization of avalanches with seismic signals is an important task. For risk mitigation, estimating remotely avalanche activity by means of seismic signals is a good alternative to direct observations that are often limited by visual conditions and observer's availability. In seismology, the main challenge is to discriminate avalanche signals within the natural earth seismic activity and background noise. Some anthropogenic low frequency (infra-sound) sources like helicopters also generate seismic signals. In order to characterize an avalanche seismic signal, a 3-axis broad band seismometer (Guralp 3T) has been set-up on a real scale avalanche test site in Lautaret (France). The sensor is located in proximity of 2 avalanche paths where avalanches can be artificially released. Preliminary results of seismic records are presented, correlated with avalanche physical parameters (volume released, velocity, energy).

  16. Bioelectric Signal Measuring System

    NASA Astrophysics Data System (ADS)

    Guadarrama-Santana, A.; Pólo-Parada, L.; García-Valenzuela, A.

    2015-01-01

    We describe a low noise measuring system based on interdigitated electrodes for sensing bioelectrical signals. The system registers differential voltage measurements in order of microvolts. The base noise during measurements was in nanovolts and thus, the sensing signals presented a very good signal to noise ratio. An excitation voltage of 1Vrms with 10 KHz frequency was applied to an interdigitated capacitive sensor without a material under test and to a mirror device simultaneously. The output signals of both devices was then subtracted in order to obtain an initial reference value near cero volts and reduce parasitic capacitances due to the electronics, wiring and system hardware as well. The response of the measuring system was characterized by monitoring temporal bioelectrical signals in real time of biological materials such as embryo chicken heart cells and bovine suprarenal gland cells.

  17. Exosomes in developmental signalling.

    PubMed

    McGough, Ian John; Vincent, Jean-Paul

    2016-07-15

    In order to achieve coordinated growth and patterning during development, cells must communicate with one another, sending and receiving signals that regulate their activities. Such developmental signals can be soluble, bound to the extracellular matrix, or tethered to the surface of adjacent cells. Cells can also signal by releasing exosomes - extracellular vesicles containing bioactive molecules such as RNA, DNA and enzymes. Recent work has suggested that exosomes can also carry signalling proteins, including ligands of the Notch receptor and secreted proteins of the Hedgehog and WNT families. Here, we describe the various types of exosomes and their biogenesis. We then survey the experimental strategies used so far to interfere with exosome formation and critically assess the role of exosomes in developmental signalling. PMID:27436038

  18. Biological signals as handicaps.

    PubMed

    Grafen, A

    1990-06-21

    An ESS model of Zahavi's handicap principle is constructed. This allows a formal exposition of how the handicap principle works, and shows that its essential elements are strategic. The handicap model is about signalling, and it is proved under fairly general conditions that if the handicap principle's conditions are met, then an evolutionarily stable signalling equilibrium exists in a biological signalling system, and that any signalling equilibrium satisfies the conditions of the handicap principle. Zahavi's major claims for the handicap principle are thus vindicated. The place of cheating is discussed in view of the honesty that follows from the handicap principle. Parallel signalling models in economics are discussed. Interpretations of the handicap principle are compared. The models are not fully explicit about how females use information about male quality, and, less seriously, have no genetics. A companion paper remedies both defects in a model of the handicap principle at work in sexual selection. PMID:2402153

  19. Mitochondrial emitted electromagnetic signals mediate retrograde signaling.

    PubMed

    Bagkos, Georgios; Koufopoulos, Kostas; Piperi, Christina

    2015-12-01

    Recent evidence shows that mitochondria regulate nuclear transcriptional activity both in normal and cell stress conditions, known as retrograde signaling. Under normal mitochondrial function, retrograde signaling is associated with mitochondrial biogenesis, normal cell phenotype and metabolic profile. In contrast, mitochondrial dysfunction leads to abnormal (oncogenic) cell phenotype and altered bio-energetic profile (nucleus reprogramming). Despite intense research efforts, a concrete mechanism through which mitochondria determine the group of genes expressed by the nucleus is still missing. The present paper proposes a novel hypothesis regarding retrograde signaling. More specifically, it reveals the mitochondrial membrane potential (MMP) and the accompanied strong electromagnetic field (EF) as key regulatory factors of nuclear activity. Mitochondrial emitted EFs extend in long distance and affect the function of nuclear membrane receptors. Depending on their frequencies, EFs can directly activate or deactivate different groups of nuclear receptors and so determine nuclear gene expression. One of the key features of the above hypothesis is that nuclear membrane receptors, besides their own endogenous or chemical ligands (hormones, lipids, etc.), can also be activated by electromagnetic signals. Moreover, normal MMP values (about -140 mV) are associated with the production of high ATP quantities and small levels of reactive oxygen species (ROS) while the hyperpolarization observed in all cancer cell types leads to a dramatic fall in ATP production and an analogous increase in ROS. The diminished ATP and increased ROS production negatively affect the function of all cellular systems including nucleus. Restoration of mitochondrial function, which is characterized by the fluctuation of MMP and EF values within a certain (normal) range, is proposed as a necessary condition for normal nuclear function and cancer therapy. PMID:26474928

  20. Hedgehog signaling and steroidogenesis.

    PubMed

    Finco, Isabella; LaPensee, Christopher R; Krill, Kenneth T; Hammer, Gary D

    2015-01-01

    Since its discovery nearly 30 years ago, the Hedgehog (Hh) signaling pathway has been shown to be pivotal in many developmental and pathophysiological processes in several steroidogenic tissues, including the testis, ovary, adrenal cortex, and placenta. New evidence links the evolutionarily conserved Hh pathway to the steroidogenic organs, demonstrating how Hh signaling can influence their development and homeostasis and can act in concert with steroids to mediate physiological functions. In this review, we highlight the role of the components of the Hh signaling pathway in steroidogenesis of endocrine tissues. PMID:25668018

  1. Plant Cyclic Nucleotide Signalling

    PubMed Central

    Martinez-Atienza, Juliana; Van Ingelgem, Carl; Roef, Luc

    2007-01-01

    The presence of the cyclic nucleotides 3′,5′-cyclic adenyl monophosphate (cAMP) and 3′,5′-cyclic guanyl monophosphate (cGMP) in plants is now generally accepted. In addition, cAMP and cGMP have been implicated in the regulation of important plant processes such as stomatal functioning, monovalent and divalent cation fluxes, chloroplast development, gibberellic acid signalling, pathogen response and gene transcription. However, very little is known regarding the components of cyclic nucleotide signalling in plants. In this addendum, the evidence for specific mechanisms of plant cyclic nucleotide signalling is evaluated and discussed. PMID:19704553

  2. Signal processing for microcalorimeters

    NASA Astrophysics Data System (ADS)

    Szymkowiak, A. E.; Kelley, R. L.; Moseley, S. H.; Stahle, C. K.

    1993-11-01

    Most of the power in the signals from microcalorimeters occurs at relatively low frequencies. At these frequencies, typical amplifiers will have significant amounts of 1/f noise. Our laboratory systems can also suffer from pickup at several harmonics of the AC power line, and from microphonic pickup at frequencies that vary with the configuration of the apparatus. We have developed some optimal signal processing techniques in order to construct the best possible estimates of our pulse heights in the presence of these non-ideal effects. In addition to a discussion of our laboratory systems, we present our plans for providing this kind of signal processing in flight experiments.

  3. Signal processing in SETI

    NASA Technical Reports Server (NTRS)

    Cullers, D. K.; Linscott, I. R.; Oliver, B. M.

    1985-01-01

    It is believed that the Galaxy might contain ten billion potential life sites. In view of the physical inaccessibility of extraterrestrial life on account of the vast distances involved, a logical first step in a search for extraterrestrial intelligence (SETI) appears to be an attempt to detect signals already being radiated. The characteristics of the signals to be expected are discussed together with the search strategy of a NASA program. It is pointed out that all presently planned searches will use existing radio-astronomy antennas. If no extraterrestrial intelligence signals are discovered, society will have to decide whether SETI justifies a dedicated facility of much greater collecting area. Attention is given to a multichannel spectrum analyzer, CW signal detection, pulse detection, the pattern detector, and details of SETI system operation.

  4. GNSS Ocean Reflected Signals

    NASA Astrophysics Data System (ADS)

    Hoeg, P.

    2012-12-01

    Ocean reflected signals from the GNSS satellites (received at low-Earth orbiting satellites, airplanes and fixed mountain locations) describe the ocean surface mean height, waves, roughness, spectral reflectivity and emissivity. The estimated accuracy of the average surface height is of the order of 10 cm for smooth conditions. Thus global observations could be an important new contribution to long-term variations of the ocean mean height as well as the monitoring of ocean mesoscale eddies, which result in sea-height changes much larger than the accuracy of the GNSS technique for reflected signals. The ocean reflected signals can be divided into two set of measurements, 1) high elevation measurements (equal to low incidence angles) and 2) low elevation grazing angle measurements. For the first type the ocean reflection cross-section has a limited extent. The reflected signal is coherent with smaller errors due to ocean waves, sampling rate and the internal processing method of the receiver. For low elevations, the signal reveals the incoherent scatter process at the reflection zone. To quantify the potential of the GNSS signals for determining spectral reflectivity at low elevations, we present ocean reflection GPS measurements from the Haleakala Summit on Maui, Hawaii, revealing the spectral characteristics of both the direct satellite signal and the ocean reflected signal for low elevation angles. The characteristics of the reflected signal depend on the scattering properties of the sea surface and the footprint of the reflection zone. While the footprint size and shape in turn depends on the signal incidence angle, the ocean mean tilt, and the relative velocities of transmitter and receiver to the reflection point. Thus the scattering properties of the sea surface are related to the sea surface roughness. We present the spectral properties of the signals as received by a high precision GPS instrument, simultaneously in both phase-locked mode and open-loop raw

  5. Signals and Receptors.

    PubMed

    Heldin, Carl-Henrik; Lu, Benson; Evans, Ron; Gutkind, J Silvio

    2016-04-01

    Communication between cells in a multicellular organism occurs by the production of ligands (proteins, peptides, fatty acids, steroids, gases, and other low-molecular-weight compounds) that are either secreted by cells or presented on their surface, and act on receptors on, or in, other target cells. Such signals control cell growth, migration, survival, and differentiation. Signaling receptors can be single-span plasma membrane receptors associated with tyrosine or serine/threonine kinase activities, proteins with seven transmembrane domains, or intracellular receptors. Ligand-activated receptors convey signals into the cell by activating signaling pathways that ultimately affect cytosolic machineries or nuclear transcriptional programs or by directly translocating to the nucleus to regulate transcription. PMID:27037414

  6. Audio signal processor

    NASA Technical Reports Server (NTRS)

    Hymer, R. L.

    1970-01-01

    System provides automatic volume control for an audio amplifier or a voice communication system without introducing noise surges during pauses in the input, and without losing the initial signal when the input resumes.

  7. Signals from the Cosmos.

    ERIC Educational Resources Information Center

    Lichtman, Jeffrey M.

    1991-01-01

    Introduces the basics of radio astronomy and describes how to assemble several simple systems for receiving radio signals from the cosmos. Includes schematics, parts lists, working drawings, and contact information for radio astronomy suppliers. (11 references) (Author/JJK)

  8. IRAK signalling in cancer.

    PubMed

    Rhyasen, G W; Starczynowski, D T

    2015-01-20

    Innate immune signalling has an essential role in inflammation, and the dysregulation of signalling components of this pathway is increasingly being recognised as an important mediator in cancer initiation and progression. In some malignancies, dysregulation of inflammatory toll-like receptor (TLR) and interleukin-1 receptor (IL1R) signalling is typified by increased NF-κB activity, and it occurs through somatic mutations, chromosomal deletions, and/or transcriptional deregulation. Interleukin-1 receptor-associated kinase (IRAK) family members are mediators of TLR/IL1R superfamily signalling, and mounting evidence implicates these kinases as viable cancer targets. Although there have been previous efforts aimed at the development of IRAK kinase inhibitors, this is currently an area of renewed interest for cancer drug development. PMID:25290089

  9. Quantifying Ubiquitin Signaling

    PubMed Central

    Ordureau, Alban; Münch, Christian; Harper, J. Wade

    2015-01-01

    Ubiquitin (UB)-driven signaling systems permeate biology, and are often integrated with other types of post-translational modifications (PTMs), most notably phosphorylation. Flux through such pathways is typically dictated by the fractional stoichiometry of distinct regulatory modifications and protein assemblies as well as the spatial organization of pathway components. Yet, we rarely understand the dynamics and stoichiometry of rate-limiting intermediates along a reaction trajectory. Here, we review how quantitative proteomic tools and enrichment strategies are being used to quantify UB-dependent signaling systems, and to integrate UB signaling with regulatory phosphorylation events. A key regulatory feature of ubiquitylation is that the identity of UB chain linkage types can control downstream processes. We also describe how proteomic and enzymological tools can be used to identify and quantify UB chain synthesis and linkage preferences. The emergence of sophisticated quantitative proteomic approaches will set a new standard for elucidating biochemical mechanisms of UB-driven signaling systems. PMID:26000850

  10. Advanced signal processing

    NASA Astrophysics Data System (ADS)

    Creasey, D. J.

    1985-12-01

    A collection of papers on advanced signal processing in radar, sonar, and communications is presented. The topics addressed include: transmitter aerials, high-power amplifier design for active sonar, radar transmitters, receiver array technology for sonar, new underwater acoustic detectors, diversity techniques in communications receivers, GaAs IC amplifiers for radar and communication receivers, integrated optical techniques for acoustooptic receivers, logarithmic receivers, CCD processors for sonar, acoustooptic correlators, designing in silicon, very high performance integrated circuits, and digital filters. Also discussed are: display types, scan converters in sonar, display ergonomics, simulators, high throughput sonar processors, optical fiber systems for signal processing, satellite communications, VLSI array processor for image and signal processing, ADA, future of cryogenic devices for signal processing applications, advanced image understanding, and VLSI architectures for real-time image processing.

  11. Modularity in signaling systems

    NASA Astrophysics Data System (ADS)

    Del Vecchio, Domitilla

    2012-08-01

    Modularity is a property by which the behavior of a system does not change upon interconnection. It is crucial for understanding the behavior of a complex system from the behavior of the composing subsystems. Whether modularity holds in biology is an intriguing and largely debated question. In this paper, we discuss this question taking a control system theory view and focusing on signaling systems. In particular, we argue that, despite signaling systems being constituted of structural modules, such as covalent modification cycles, modularity does not hold in general. As in any engineering system, impedance-like effects, called retroactivity, appear at interconnections and alter the behavior of connected modules. We further argue that while signaling systems have evolved sophisticated ways to counter-act retroactivity and enforce modularity, retroactivity may also be exploited to finely control the information processing of signaling pathways. Testable predictions and experimental evidence are discussed with their implications.

  12. Error-prone signalling.

    PubMed

    Johnstone, R A; Grafen, A

    1992-06-22

    The handicap principle of Zahavi is potentially of great importance to the study of biological communication. Existing models of the handicap principle, however, make the unrealistic assumption that communication is error free. It seems possible, therefore, that Zahavi's arguments do not apply to real signalling systems, in which some degree of error is inevitable. Here, we present a general evolutionarily stable strategy (ESS) model of the handicap principle which incorporates perceptual error. We show that, for a wide range of error functions, error-prone signalling systems must be honest at equilibrium. Perceptual error is thus unlikely to threaten the validity of the handicap principle. Our model represents a step towards greater realism, and also opens up new possibilities for biological signalling theory. Concurrent displays, direct perception of quality, and the evolution of 'amplifiers' and 'attenuators' are all probable features of real signalling systems, yet handicap models based on the assumption of error-free communication cannot accommodate these possibilities. PMID:1354361

  13. Signal-light nomogram

    NASA Technical Reports Server (NTRS)

    Gordon, J. I.; Edgerton, C. F.; Duntley, S. Q.

    1975-01-01

    A nomogram is presented for predicting the sighting range for white, steady-burning signal lights. The theoretical and experimental bases are explained and instructions are provided for its use for a variety of practical problems concerning the visibility of signal lights. The nomogram is appropriate for slant path as well as horizontal sightings, and the gain of range achieved by utilizing binoculars can be predicted by use of it.

  14. Wnt Signaling in Bone

    PubMed Central

    Kubota, Takuo; Michigami, Toshimi; Ozono, Keiichi

    2010-01-01

    Wnt signaling is involved not only in embryonic development but also in maintenance of homeostasis in postnatal tissues. Multiple lines of evidence have increased understanding of the roles of Wnt signaling in bone since mutations in the LRP5 gene were identified in human bone diseases. Canonical Wnt signaling promotes mesenchymal progenitor cells to differentiate into osteoblasts. The canonical Wnt/β-catenin pathway possibly through Lrp6, a co-receptor for Wnts as well as Lrp5, in osteoblasts regulates bone resorption by increasing the OPG/RANKL ratio. However, endogenous inhibitors of Wnt signaling including sclerostin block bone formation. Regulation of sclerostin appears to be one of the mechanisms of PTH anabolic actions on bone. Since sclerostin is almost exclusively expressed in osteocytes, inhibition of sclerostin is the most promising design. Surprisingly, Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum, but not by directly promoting bone formation. Pharmacological intervention may be considered in many components of the canonical Wnt signaling pathway, although adverse effects and tumorigenicity to other tissues are important. More studies will be needed to fully understand how the Wnt signaling pathway actually influences bone metabolism and to assure the safety of new interventions. PMID:23926379

  15. Sucrose signaling in plants

    PubMed Central

    Tognetti, Jorge A.; Pontis, Horacio G.; Martínez-Noël, Giselle M.A.

    2013-01-01

    The role of sucrose as a signaling molecule in plants was originally proposed several decades ago. However, recognition of sucrose as a true signal has been largely debated and only recently this role has been fully accepted. The best-studied cases of sucrose signaling involve metabolic processes, such as the induction of fructan or anthocyanin synthesis, but a large volume of scattered information suggests that sucrose signals may control a vast array of developmental processes along the whole life cycle of the plant. Also, wide gaps exist in our current understanding of the intracellular steps that mediate sucrose action. Sucrose concentration in plant tissues tends to be directly related to light intensity, and inversely related to temperature, and accordingly, exogenous sucrose supply often mimics the effect of high light and cold. However, many exceptions to this rule seem to occur due to interactions with other signaling pathways. In conclusion, the sucrose role as a signal molecule in plants is starting to be unveiled and much research is still needed to have a complete map of its significance in plant function. PMID:23333971

  16. Semaphorin signaling in bone.

    PubMed

    Verlinden, Lieve; Vanderschueren, Dirk; Verstuyf, Annemieke

    2016-09-01

    Semaphorin molecules regulate cell adhesion and motility in a wide variety of cell types and are therefore involved in numerous processes including axon guidance, angiogenesis, cardiogenesis, tumor growth, and immune response. Increasing evidence points to a role of transmembrane, membrane-associated and soluble semaphorins during bone development as well as in the control of normal bone homeostasis. Within bone, semaphorins are implicated in the communication between different cell types by relaying signals in an autocrine or paracrine way. Semaphorins are not only involved in bone resorption but also in bone formation. Therefore, targeting semaphorin-induced signaling in bone may constitute an interesting new therapeutic strategy in osteoporosis. However, all the pioneering research on semaphorins is performed in mice and it remains to be established to what extent semaphorin signaling pathways are conserved between mice and men. In addition, knowledge of semaphorin signaling in bone mostly arises from loss/gain of function studies of one single semaphorin and/or receptor. However, different semaphorin molecules are co-expressed in bone and their signaling pathways are likely to interact in a complex and coherent way that needs proper understanding before targeting semaphorin signaling can be therapeutically exploited. PMID:26365296

  17. Vibrio vulnificus VvhA induces autophagy-related cell death through the lipid raft-dependent c-Src/NOX signaling pathway.

    PubMed

    Song, Eun Ju; Lee, Sei-Jung; Lim, Hyeon Su; Kim, Jun Sung; Jang, Kyung Ku; Choi, Sang Ho; Han, Ho Jae

    2016-01-01

    VvhA, a virulent factor of Vibrio (V.) vulnificus, induces acute cell death in a destructive manner. Autophagy plays an important role in cell death, but the functional role of VvhA in autophagy-related cell death has not been elucidated yet. We found that rVvhA significantly increased LC3 puncta formation and autophagic flux in promoting the cell death of human intestinal epithelial Caco-2 cells. The cell death induced by rVvhA was independent of lysosomal permeabilizaton and caspase activation. rVvhA induced rapid phosphorylation of c-Src in the membrane lipid raft, which resulted in an increased interaction between lipid raft molecule caveolin-1 and NADPH oxidase (NOX) complex Rac1 for ROS production. NOX-mediated ROS signaling induced by rVvhA increased the phosphorylation of extracellular signal-regulated kinase (ERK) and eukaryotic translation initiation factor 2α (eIF2α) which are required for mRNA expression of Atg5 and Atg16L1 involved in autophagosome formation. In an in vivo model, VvhA increased autophagy activation and paracellular permeabilization in intestinal epithelium. Collectively, the results here show that VvhA plays a pivotal role in the pathogenesis and dissemination of V. vulnificus by autophagy upregulation, through the lipid raft-mediated c-Src/NOX signaling pathway and ERK/eIF2α activation. PMID:27250250

  18. Vibrio vulnificus VvhA induces autophagy-related cell death through the lipid raft-dependent c-Src/NOX signaling pathway

    PubMed Central

    Song, Eun Ju; Lee, Sei-Jung; Lim, Hyeon Su; Kim, Jun Sung; Jang, Kyung Ku; Choi, Sang Ho; Han, Ho Jae

    2016-01-01

    VvhA, a virulent factor of Vibrio (V.) vulnificus, induces acute cell death in a destructive manner. Autophagy plays an important role in cell death, but the functional role of VvhA in autophagy-related cell death has not been elucidated yet. We found that rVvhA significantly increased LC3 puncta formation and autophagic flux in promoting the cell death of human intestinal epithelial Caco-2 cells. The cell death induced by rVvhA was independent of lysosomal permeabilizaton and caspase activation. rVvhA induced rapid phosphorylation of c-Src in the membrane lipid raft, which resulted in an increased interaction between lipid raft molecule caveolin-1 and NADPH oxidase (NOX) complex Rac1 for ROS production. NOX-mediated ROS signaling induced by rVvhA increased the phosphorylation of extracellular signal-regulated kinase (ERK) and eukaryotic translation initiation factor 2α (eIF2α) which are required for mRNA expression of Atg5 and Atg16L1 involved in autophagosome formation. In an in vivo model, VvhA increased autophagy activation and paracellular permeabilization in intestinal epithelium. Collectively, the results here show that VvhA plays a pivotal role in the pathogenesis and dissemination of V. vulnificus by autophagy upregulation, through the lipid raft-mediated c-Src/NOX signaling pathway and ERK/eIF2α activation. PMID:27250250

  19. Pulse code modulated signal synchronizer

    NASA Technical Reports Server (NTRS)

    Kobayashi, H. S. (Inventor)

    1974-01-01

    A bit synchronizer for a split phase PCM transmission is reported that includes three loop circuits which receive incoming phase coded PCM signals. In the first loop, called a Q-loop, a generated, phase coded, PCM signal is multiplied with the incoming signals, and the frequency and phase of the generated signal are nulled to that of the incoming subcarrier signal. In the second loop, called a B-loop, a circuit multiplies a generated signal with incoming signals to null the phase of the generated signal in a bit phase locked relationship to the incoming signal. In a third loop, called the I-loop, a phase coded PCM signal is multiplied with the incoming signals for decoding the bit information from the PCM signal. A counter means is used for timing of the generated signals and timing of sample intervals for each bit period.

  20. Analysis of porcine granulosa cell death signaling pathways induced by vinclozolin.

    PubMed

    Knet, Malgorzata; Wartalski, Kamil; Hoja-Lukowicz, Dorota; Tabarowski, Zbigniew; Slomczynska, Maria; Duda, Malgorzata

    2015-10-01

    Recent studies suggest that disturbing androgen-signaling pathways in porcine ovarian follicles may cause granulosa cell (GC) death. For this reason, we investigated which apoptotic pathway is initiated after GC exposure to an environmental antiandrogen, vinclozolin (Vnz), in vitro. Immunocytochemistry, Western blots, and fluorometric assays were used to quantify caspase-3 and -9 expression and activity. To elucidate the specific mechanism of Vnz action and toxicity, GCs were assessed for viability, cytotoxicity, and apoptotic activity using the ApoTox-Glo Triplex Assay. To further determine the mechanism of GC death induced by Vnz, we used the Apoptosis Antibody Array Kit. In response to Vnz stimulus, we found an increased level of caspase-3 protein expression (P ≤ 0.001) and an increase in caspase-3 proteolytic activity (P ≤ 0.001), confirming that Vnz is a potent proapoptotic factor. The strong immunoreaction of caspase-9 after Vnz treatment (P ≤ 0.001) suggests that intrinsic mitochondrial apoptosis pathway was activated during GC death. On the other hand, caspase-8, being a part of the extrinsic receptor pathway, was also activated (P ≤ 0.001). Therefore, it is possible that Vnz induces porcine granulosal apoptosis also through a parallel pathway. Activation of these two pathways was confirmed by the Apoptosis Antibody Array Kit. In conclusion, it is possible that the intrinsic signaling pathway may not act as an initial trigger for GC apoptosis but might contribute to the amplification and propagation of apoptotic cell death in the granulosa layer after treatment with this antiandrogen. Moreover, Vnz disturbs the physiological process of programmed cell death. Consequently, this could explain why atretic follicles are rapidly removed and suggests that normal function of the ovarian follicle may be destroyed. PMID:26141531

  1. Fusaric acid induction of programmed cell death modulated through nitric oxide signalling in tobacco suspension cells.

    PubMed

    Jiao, Jiao; Zhou, Benguo; Zhu, Xiaoping; Gao, Zhengliang; Liang, Yuancun

    2013-10-01

    Fusaric acid (FA) is a nonhost-selective toxin mainly produced by Fusarium oxysporum, the causal agent of plant wilt diseases. We demonstrate that FA can induce programmed cell death (PCD) in tobacco suspension cells and the FA-induced PCD is modulated by nitric oxide (NO) signalling. Cells undergoing cell death induced by FA treatment exhibited typical characteristics of PCD including cytoplasmic shrinkage, chromatin condensation, DNA fragmentation, membrane plasmolysis, and formation of small cytoplasmic vacuoles. In addition, caspase-3-like activity was activated upon the FA treatment. The process of FA-induced PCD was accompanied by a rapid accumulation of NO in a FA dose-dependent manner. Pre-treatment of cells with NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO) or NO synthase inhibitor N(G)-monomethyl-arginine monoacetate (L-NMMA) significantly reduced the rate of FA-induced cell death. Furthermore, the caspase-3-like activity and the expression of PAL and Hsr203J genes were alleviated by application of cPTIO or L-NMMA to FA-treated tobacco cells. This indicates that NO is an important factor involved in the FA-induced PCD. Our results also show that pre-treatment of tobacco cells with a caspase-3-specific inhibitor, Ac-DEVD-CHO, can reduce the rate of FA-induced cell death. These results demonstrate that the FA-induced cell death is a PCD and is modulated by NO signalling through caspase-3-like activation. PMID:23838885

  2. Respiration signals from photoplethysmography.

    PubMed

    Nilsson, Lena M

    2013-10-01

    Pulse oximetry is based on the technique of photoplethysmography (PPG) wherein light transmitted through tissues is modulated by the pulse. In addition to variations in light modulation by the cardiac cycle, the PPG signal contains a respiratory modulation and variations associated with changing tissue blood volume of other origins. Cardiovascular, respiratory, and neural fluctuations in the PPG signal are of different frequencies and can all be characterized according to their sinusoidal components. PPG was described in 1937 to measure blood volume changes. The technique is today increasingly used, in part because of developments in semiconductor technology during recent decades that have resulted in considerable advances in PPG probe design. Artificial neural networks help to detect complex nonlinear relationships and are extensively used in electronic signal analysis, including PPG. Patient and/or probe-tissue movement artifacts are sources of signal interference. Physiologic variations such as vasoconstriction, a deep gasp, or yawn also affect the signal. Monitoring respiratory rates from PPG are often based on respiratory-induced intensity variations (RIIVs) contained in the baseline of the PPG signal. Qualitative RIIV signals may be used for monitoring purposes regardless of age, gender, anesthesia, and mode of ventilation. Detection of breaths in adult volunteers had a maximal error of 8%, and in infants the rates of overdetected and missed breaths using PPG were 1.5% and 2.7%, respectively. During central apnea, the rhythmic RIIV signals caused by variations in intrathoracic pressure disappear. PPG has been evaluated for detecting airway obstruction with a sensitivity of 75% and a specificity of 85%. The RIIV and the pulse synchronous PPG waveform are sensitive for detecting hypovolemia. The respiratory synchronous variation of the PPG pulse amplitude is an accurate predictor of fluid responsiveness. Pleth variability index is a continuous measure of the

  3. Sphingosine 1-phosphate signalling.

    PubMed

    Mendelson, Karen; Evans, Todd; Hla, Timothy

    2014-01-01

    Sphingosine 1-phosphate (S1P) is a lipid mediator formed by the metabolism of sphingomyelin. In vertebrates, S1P is secreted into the extracellular environment and signals via G protein-coupled S1P receptors to regulate cell-cell and cell-matrix adhesion, and thereby influence cell migration, differentiation and survival. The expression and localization of S1P receptors is dynamically regulated and controls vascular development, vessel stability and immune cell trafficking. In addition, crucial events during embryogenesis, such as angiogenesis, cardiogenesis, limb development and neurogenesis, are regulated by S1P signalling. Here, and in the accompanying poster, we provide an overview of S1P signalling in development and in disease. PMID:24346695

  4. Signal peptide of cellulase.

    PubMed

    Yan, Shaomin; Wu, Guang

    2014-06-01

    Cellulase is an enzyme playing a crucial role in biotechnology industries ranging from textile to biofuel because of tremendous amount of cellulose produced in plant. In order to improve cellulase productivity, huge resource has been spent in search for good cellulases from microorganism in remote areas and in creation of ideal cellulase by engineering. However, not much attention is given to the secretion of cellulases from cell into extracellular space, where a cellulase plays its enzymatic role. In this minireview, the signal peptides, which lead secreted proteins to specific secretion systems and scatter in literature, are reviewed. The patterns of signal peptides are checked against 4,101 cellulases documented in UniProtKB, the largest protein database in the world, to determine how these cellulases are secreted. Simultaneous review on both literature and cellulases from the database not only provides updated knowledge on signal peptides but also indicates the gap in our research. PMID:24743986

  5. Telemetry Ranging: Signal Processing

    NASA Astrophysics Data System (ADS)

    Hamkins, J.; Kinman, P.; Xie, H.; Vilnrotter, V.; Dolinar, S.

    2016-02-01

    This article describes the details of the signal processing used in a telemetry ranging system in which timing information is extracted from the downlink telemetry signal in order to compute spacecraft range. A previous article describes telemetry ranging concepts and architecture, which are a slight variation of a scheme published earlier. As in that earlier work, the telemetry ranging concept eliminates the need for a dedicated downlink ranging signal to communicate the necessary timing information. The present article describes the operation and performance of the major receiver functions on the spacecraft and the ground --- many of which are standard tracking loops already in use in JPL's flight and ground radios --- and how they can be used to provide the relevant information for making a range measurement. It also describes the implementation of these functions in software, and performance of an end-to-end software simulation of the telemetry ranging system.

  6. Endocytosis, Signaling, and Beyond

    PubMed Central

    Di Fiore, Pier Paolo; von Zastrow, Mark

    2014-01-01

    The endocytic network comprises a vast and intricate system of membrane-delimited cell entry and cargo sorting routes running between biochemically and functionally distinct intracellular compartments. The endocytic network caters to the organization and redistribution of diverse subcellular components, and mediates appropriate shuttling and processing of materials acquired from neighboring cells or the extracellular milieu. Such trafficking logistics, despite their importance, represent only one facet of endocytic function. The endocytic network also plays a key role in organizing, mediating, and regulating cellular signal transduction events. Conversely, cellular signaling processes tightly control the endocytic pathway at different steps. The present article provides a perspective on the intimate relationships that exist between particular endocytic and cellular signaling processes in mammalian cells, within the context of understanding the impact of this nexus on integrated physiology. PMID:25085911

  7. Separation of Climate Signals

    SciTech Connect

    Kamath, C; Fodor, I

    2002-11-13

    Understanding changes in global climate is a challenging scientific problem. Simulated and observed data include signals from many sources, and untangling their respective effects is difficult. In order to make meaningful comparisons between different models, and to understand human effects on global climate, we need to isolate the effects of different sources. Recent eruptions of the El Chichon and Mt. Pinatubo volcanoes coincided with large El Nino and Southern Oscillation (ENSO) events, which complicates the separation of their contributions on global temperatures. Current approaches for separating volcano and ENSO signals in global mean data involve parametric models and iterative techniques [3]. We investigate alternative methods based on principal component analysis (PCA) [2] and independent component analysis (ICA) [1]. Our goal is to determine if such techniques can automatically identify the signals corresponding to the different sources, without relying on parametric models.

  8. Honest signalling with costly gambles

    PubMed Central

    Meacham, Frazer; Perlmutter, Aaron; Bergstrom, Carl T.

    2013-01-01

    Costly signalling theory is commonly invoked as an explanation for how honest communication can be stable when interests conflict. However, the signal costs predicted by costly signalling models often turn out to be unrealistically high. These models generally assume that signal cost is determinate. Here, we consider the case where signal cost is instead stochastic. We examine both discrete and continuous signalling games and show that, under reasonable assumptions, stochasticity in signal costs can decrease the average cost at equilibrium for all individuals. This effect of stochasticity for decreasing signal costs is a fundamental mechanism that probably acts in a wide variety of circumstances. PMID:23904587

  9. PKD signaling and pancreatitis

    PubMed Central

    Yuan, Jingzhen; Pandol, Stephen J.

    2016-01-01

    Background Acute pancreatitis is a serious medical disorder with no current therapies directed to the molecular pathogenesis of the disorder. Inflammation, inappropriate intracellular activation of digestive enzymes, and parenchymal acinar cell death by necrosis are the critical pathophysiologic processes of acute pancreatitis. Thus, it is necessary to elucidate the key molecular signals that mediate these pathobiologic processes and develop new therapeutic strategies to attenuate the appropriate signaling pathways in order to improve outcomes for this disease. A novel serine/threonine protein kinase D (PKD) family has emerged as key participants in signal transduction, and this family is increasingly being implicated in the regulation of multiple cellular functions and diseases. Methods This review summarizes recent findings of our group and others regarding the signaling pathway and the biological roles of the PKD family in pancreatic acinar cells. In particular, we highlight our studies of the functions of PKD in several key pathobiologic processes associated with acute pancreatitis in experimental models. Results Our findings reveal that PKD signaling is required for NF-κB activation/inflammation, intracellular zymogen activation, and acinar cell necrosis in rodent experimental pancreatitis. Novel small-molecule PKD inhibitors attenuate the severity of pancreatitis in both in vitro and in vivo experimental models. Further, this review emphasizes our latest advances in the therapeutic application of PKD inhibitors to experimental pancreatitis after the initiation of pancreatitis. Conclusions These novel findings suggest that PKD signaling is a necessary modulator in key initiating pathobiologic processes of pancreatitis, and that it constitutes a novel therapeutic target for treatments of this disorder. PMID:26879861

  10. Packaging signals in alphaviruses.

    PubMed

    Frolova, E; Frolov, I; Schlesinger, S

    1997-01-01

    Alphaviruses synthesize large amounts of both genomic and subgenomic RNA in infected cells, but usually only the genomic RNA is packaged. This implies the existence of an encapsidation or packaging signal which would be responsible for selectivity. Previously, we had identified a region of the Sindbis virus genome that interacts specifically with the viral capsid protein. This 132-nucleotide (nt) fragment lies within the coding region of the nsP1 gene (nt 945 to 1076). We proposed that the 132-mer is important for capsid recognition and initiates the formation of the viral nucleocapsid. To study the encapsidation of Sindbis virus RNAs in infected cells, we designed a new assay that uses the self-replicating Sindbis virus genomes (replicons) which lack the viral structural protein genes and contain heterologous sequences under the control of the subgenomic RNA promoter. These replicons can be packaged into viral particles by using defective helper RNAs that contain the structural protein genes (P. Bredenbeek, I. Frolov, C. M. Rice, and S. Schlesinger, J. Virol. 67:6439-6446, 1993). Insertion of the 132-mer into the subgenomic RNA significantly increased the packaging of this RNA into viral particles. We have used this assay and defective helpers that contain the structural protein genes of Ross River virus (RRV) to investigate the location of the encapsidation signal in the RRV genome. Our results show that there are several fragments that could act as packaging signals. They are all located in a different region of the genome than the signal for the Sindbis virus genome. For RRV, the strongest packaging signal lies between nt 2761 and 3062 in the nsP2 gene. This is the same region that was proposed to contain the packaging signal for Semliki Forest virus genomic RNA. PMID:8985344

  11. Multichannel signal enhancement

    DOEpatents

    Lewis, Paul S.

    1990-01-01

    A mixed adaptive filter is formulated for the signal processing problem where desired a priori signal information is not available. The formulation generates a least squares problem which enables the filter output to be calculated directly from an input data matrix. In one embodiment, a folded processor array enables bidirectional data flow to solve the recursive problem by back substitution without global communications. In another embodiment, a balanced processor array solves the recursive problem by forward elimination through the array. In a particular application to magnetoencephalography, the mixed adaptive filter enables an evoked response to an auditory stimulus to be identified from only a single trial.

  12. Mechanisms of auxin signaling.

    PubMed

    Lavy, Meirav; Estelle, Mark

    2016-09-15

    The plant hormone auxin triggers complex growth and developmental processes. Its underlying molecular mechanism of action facilitates rapid switching between transcriptional repression and gene activation through the auxin-dependent degradation of transcriptional repressors. The nuclear auxin signaling pathway consists of a small number of core components. However, in most plants each component is represented by a large gene family. The modular construction of the pathway can thus produce diverse transcriptional outputs depending on the cellular and environmental context. Here, and in the accompanying poster, we outline the current model for TIR1/AFB-dependent auxin signaling with an emphasis on recent studies. PMID:27624827

  13. Array signal processing

    SciTech Connect

    Haykin, S.; Justice, J.H.; Owsley, N.L.; Yen, J.L.; Kak, A.C.

    1985-01-01

    This is the first book to be devoted completely to array signal processing, a subject that has become increasingly important in recent years. The book consists of six chapters. Chapter 1, which is introductory, reviews some basic concepts in wave propagation. The remaining five chapters deal with the theory and applications of array signal processing in (a) exploration seismology, (b) passive sonar, (c) radar, (d) radio astronomy, and (e) tomographic imaging. The various chapters of the book are self-contained. The book is written by a team of five active researchers, who are specialists in the individual fields covered by the pertinent chapters.

  14. JNK Signaling in Apoptosis

    PubMed Central

    Dhanasekaran, Danny N.; Reddy, E. Premkumar

    2011-01-01

    Jun N-terminal kinases or JNKs play a critical role in death receptor-initiated extrinsic as well as mitochondrial intrinsic apoptotic pathways. JNKs activate apoptotic signaling by the upregulation pro-apoptotic genes via the transactivation of specific transcription factors or by directly modulating the activities of mitochondrial pro- and anti-apoptotic proteins through distinct phosphorylation events. This review analyzes our present understanding of the role of JNK in apoptotic signaling and the various mechanisms by which JNK promotes apoptosis PMID:18931691

  15. Noninvasive vital signal monitoring

    NASA Astrophysics Data System (ADS)

    Wang, Zenan; Chee, Jonny; Chua, Kok Poo; Chen, ZhouDe

    2010-05-01

    Vital signals of patients, such as heart rate, temperature and movement are crucial to monitor patients in hospital. Current heart rate measurement is obtained by using Electrocardiograph, which normally applies electrodes to the patient's body. As electrodes are extremely uncomfortable to ware and hinder patient's movement, a non-invasive vital signal-monitoring device will be a better solution. Similar to Electrocardiograph, the device detects the voltage difference across the heart by using concept of capacitance, which can be obtained by two conductive fiber sewing on the bed sheet. Simultaneous temperature reading can also be detected by using surface mounted temperature sensor. This paper will mainly focus on the heart rate monitoring.

  16. Universal signal conditioning amplifier

    NASA Technical Reports Server (NTRS)

    Larson, William E.; Hallberg, Carl; Medelius, Pedro J.

    1994-01-01

    Engineers at NASA's Kennedy Space Center have designed a signal conditioning amplifier which automatically matches itself to almost any kind of transducer. The product, called Universal Signal Conditioning Amplifier (USCA), uses state-of-the-art technologies to deliver high accuracy measurements. USCA's features which can be either programmable or automated include: voltage, current, or pulsed excitation, unlimited resolution gain, digital filtering and both analog and digital output. USCA will be used at Kennedy Space Center's launch pads for environmental measurements such as vibrations, strains, temperatures and overpressures. USCA is presently being commercialized through a co-funded agreement between NASA, the State of Florida, and Loral Test and Information Systems, Inc.

  17. 29 CFR 1926.1422 - Signals-hand signal chart.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 8 2011-07-01 2011-07-01 false Signals-hand signal chart. 1926.1422 Section 1926.1422 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION... Construction § 1926.1422 Signals—hand signal chart. Hand signal charts must be either posted on the...

  18. 29 CFR 1926.1422 - Signals-hand signal chart.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 29 Labor 8 2013-07-01 2013-07-01 false Signals-hand signal chart. 1926.1422 Section 1926.1422 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION... Construction § 1926.1422 Signals—hand signal chart. Hand signal charts must be either posted on the...

  19. 29 CFR 1926.1422 - Signals-hand signal chart.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 29 Labor 8 2012-07-01 2012-07-01 false Signals-hand signal chart. 1926.1422 Section 1926.1422 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION... Construction § 1926.1422 Signals—hand signal chart. Hand signal charts must be either posted on the...

  20. 29 CFR 1926.1422 - Signals-hand signal chart.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 29 Labor 8 2014-07-01 2014-07-01 false Signals-hand signal chart. 1926.1422 Section 1926.1422 Labor Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION... Construction § 1926.1422 Signals—hand signal chart. Hand signal charts must be either posted on the...

  1. Hybrid ECG signal conditioner

    NASA Technical Reports Server (NTRS)

    Rinard, G. A.; Steffen, D. A.; Sturm, R. E.

    1979-01-01

    Circuit with high common-mode rejection has ability to filter and amplify accepted analog electrocardiogram (ECG) signals of varying amplitude, shape, and polarity. In addition, low power circuit develops standardized pulses that can be counted and averaged by heart/breath rate processor.

  2. Pulsed Terahertz Signal Reconstruction

    NASA Astrophysics Data System (ADS)

    Fletcher, J. R.; Swift, G. P.; Dai, DeChang; Chamberlain, J. M.; Upadhya, P. C.

    2007-12-01

    A procedure is outlined which can be used to determine the response of an experimental sample to a single, simple broadband frequency pulse in terahertz frequency time domain spectroscopy (TDS). The advantage that accrues from this approach is that oscillations and spurious signals (arising from a variety of sources in the TDS system or from ambient water vapor) can be suppressed. In consequence, small signals (arising from the interaction of the radiation with the sample) can be more readily observed in the presence of noise. Procedures for choosing key parameters and methods for eliminating further artifacts are described. In particular, the use of input functions which are based on the binomial distribution is described. These binomial functions are used to unscramble the sample response to a simple pulse: they have sufficient flexibility to allow for variations in the spectra of different terahertz sources, some of which have low frequency as well as high frequency cutoffs. The signal processing procedure is validated by simple reflection and transmission experiments using a gap between polytetrafluoroethylene (PTFE) plates to mimic a void within a larger material. It is shown that a resolution of 100μm is easily achievable in reflection geometry after signal processing.

  3. Signaling by Sensory Receptors

    PubMed Central

    Julius, David; Nathans, Jeremy

    2012-01-01

    Sensory systems detect small molecules, mechanical perturbations, or radiation via the activation of receptor proteins and downstream signaling cascades in specialized sensory cells. In vertebrates, the two principal categories of sensory receptors are ion channels, which mediate mechanosensation, thermosensation, and acid and salt taste; and G-protein-coupled receptors (GPCRs), which mediate vision, olfaction, and sweet, bitter, and umami tastes. GPCR-based signaling in rods and cones illustrates the fundamental principles of rapid activation and inactivation, signal amplification, and gain control. Channel-based sensory systems illustrate the integration of diverse modulatory signals at the receptor, as seen in the thermosensory/pain system, and the rapid response kinetics that are possible with direct mechanical gating of a channel. Comparisons of sensory receptor gene sequences reveal numerous examples in which gene duplication and sequence divergence have created novel sensory specificities. This is the evolutionary basis for the observed diversity in temperature- and ligand-dependent gating among thermosensory channels, spectral tuning among visual pigments, and odorant binding among olfactory receptors. The coding of complex external stimuli by a limited number of sensory receptor types has led to the evolution of modality-specific and species-specific patterns of retention or loss of sensory information, a filtering operation that selectively emphasizes features in the stimulus that enhance survival in a particular ecological niche. The many specialized anatomic structures, such as the eye and ear, that house primary sensory neurons further enhance the detection of relevant stimuli. PMID:22110046

  4. Intersection auxiliary signal system

    NASA Astrophysics Data System (ADS)

    Zhang, Jian

    1995-12-01

    Many intersection accidents are related to drivers' inappropriate responses to an amber signal light, due to their misjudgment on the traffic situation and/or their aggressive behavior. To reduce intersection accidents of this nature, this paper proposes the Intersection Auxiliary Signal System (IAS). IAS can be installed at selected intersections, where information regarding signal phasing, intersection geometry and speed limit is transmitted from an ultrasonic/infra-red transmitter. An on-vehicle device receivers and processes the information, the provides the driver with explicit suggestions on the correct action to take (continue to pass or decelerate to stop), or warnings against on-going incorrect actions. IAS is expected to be more effective in suburban intersections, which are usually characterized by greater dimension, longer amber phases, and higher vehicle speeds. Both the intersection transmitters and the on-vehicle processors are expected to have simple structures and low costs. Simulation results show that IAS has a significant effect on reducing red signal violation, especially when there is no significant dilemma zones.

  5. Communication Signals in Lizards.

    ERIC Educational Resources Information Center

    Carpenter, Charles C.

    1983-01-01

    Discusses mechanisms and functional intent of visual communication signals in iguanid/agamid lizards. Demonstrated that lizards communicate with each other by using pushups and head nods and that each species does this in its own way, conveying different types of information. (JN)

  6. Signal processing in SETI.

    PubMed

    Cullers, D K; Linscott, I R; Oliver, B M

    1985-11-01

    The development of a multi-channel spectrum analyzer (MCSA) for the SETI program is described. The spectrum analyzer is designed for both all-sky surveys and targeted searches. The mechanisms of the MCSA are explained and a diagram is provided. Detection of continuous wave signals, pulses, and patterns is examined. PMID:11542023

  7. Hedgehog signaling update.

    PubMed

    Cohen, M Michael

    2010-08-01

    In vertebrate hedgehog signaling, hedgehog ligands are processed to become bilipidated and then multimerize, which allows them to leave the signaling cell via Dispatched 1 and become transported via glypicans and megalin to the responding cells. Hedgehog then interacts with a complex of Patched 1 and Cdo/Boc, which activates endocytic Smoothened to the cilium. Patched 1 regulates the activity of Smoothened (1) via Vitamin D3, which inhibits Smoothened in the absence of hedgehog ligand or (2) via oxysterols, which activate Smoothened in the presence of hedgehog ligand. Hedgehog ligands also interact with Hip1, Patched 2, and Gas1, which regulate the range as well as the level of hedgehog signaling. In vertebrates, Smoothened is shortened at its C-terminal end and lacks most of the phosphorylation sites of importance in Drosophila. Cos2, also of importance in Drosophila, plays no role in mammalian transduction, nor do its homologs Kif7 and Kif27. The cilium may provide a function analogous to that of Cos2 by linking Smoothened to the modulation of Gli transcription factors. Disorders associated with the hedgehog signaling network follow, including nevoid basal cell carcinoma syndrome, holoprosencephaly, Smith-Lemli-Opitz syndrome, Greig cephalopolysyndactyly syndrome, Pallister-Hall syndrome, Carpenter syndrome, and Rubinstein-Taybi syndrome. PMID:20635334

  8. Signals: Applying Academic Analytics

    ERIC Educational Resources Information Center

    Arnold, Kimberly E.

    2010-01-01

    Academic analytics helps address the public's desire for institutional accountability with regard to student success, given the widespread concern over the cost of higher education and the difficult economic and budgetary conditions prevailing worldwide. Purdue University's Signals project applies the principles of analytics widely used in…

  9. Wnt signaling in osteosarcoma.

    PubMed

    Lin, Carol H; Ji, Tao; Chen, Cheng-Fong; Hoang, Bang H

    2014-01-01

    Osteosarcoma (OS) is the most common primary bone malignancy diagnosed in children and adolescents with a high propensity for local invasion and distant metastasis. Despite current multidisciplinary treatments, there has not been a drastic change in overall prognosis within the last two decades. With current treatments, 60-70 % of patients with localized disease survive. Given a propensity of Wnt signaling to control multiple cellular processes, including proliferation, cell fate determination, and differentiation, it is a critical pathway in OS disease progression. At the same time, this pathway is extremely complex with vast arrays of cross-talk. Even though decades of research have linked the role of Wnt to tumorigenesis, there are still outstanding areas that remain poorly understood and even controversial. The canonical Wnt pathway functions to regulate the levels of the transcriptional co-activator β-catenin, which ultimately controls key developmental gene expressions. Given the central role of this mediator, inhibition of Wnt/β-catenin signaling has been investigated as a potential strategy for cancer control. In OS, several secreted protein families modulate the Wnt/β-catenin signaling, including secreted Frizzled-related proteins (sFRPs), Wnt inhibitory protein (WIF), Dickkopf proteins (DKK-1,2,3), sclerostin, and small molecules. This chapter focuses on our current understanding of Wnt/β-catenin signaling in OS, based on recent in vitro and in vivo data. Wnt activates noncanonical signaling pathways as well that are independent of β-catenin which will be discussed. In addition, stem cells and their association with Wnt/β-catenin are important factors to consider. Ultimately, the multiple canonical and noncanonical Wnt/β-catenin agonists and antagonists need to be further explored for potential targeted therapies. PMID:24924167

  10. Electronic signal generators: A compilation

    NASA Technical Reports Server (NTRS)

    1971-01-01

    Electronic signal generator data based on solid state concepts were simplified or refined to meet requirements, such as reliability, simplicity, fail-safe characteristics, and the capability of withstanding environmental extremes. Pulse generators, high voltage pulse generators, oscillators, analog signal generators, square wave signal generators, and special function signal generators are described.

  11. Analog and digital signal processing

    NASA Astrophysics Data System (ADS)

    Baher, H.

    The techniques of signal processing in both the analog and digital domains are addressed in a fashion suitable for undergraduate courses in modern electrical engineering. The topics considered include: spectral analysis of continuous and discrete signals, analysis of continuous and discrete systems and networks using transform methods, design of analog and digital filters, digitization of analog signals, power spectrum estimation of stochastic signals, FFT algorithms, finite word-length effects in digital signal processes, linear estimation, and adaptive filtering.

  12. Microglia Ontology and Signaling

    PubMed Central

    ElAli, Ayman; Rivest, Serge

    2016-01-01

    Microglia constitute the powerhouse of the innate immune system in the brain. It is now widely accepted that they are monocytic-derived cells that infiltrate the developing brain at the early embryonic stages, and acquire a resting phenotype characterized by the presence of dense branching processes, called ramifications. Microglia use these dynamic ramifications as sentinels to sense and detect any occurring alteration in brain homeostasis. Once a danger signal is detected, such as molecular factors associated to brain damage or infection, they get activated by acquiring a less ramified phenotype, and mount adequate responses that range from phagocyting cell debris to secreting inflammatory and trophic factors. Here, we review the origin of microglia and we summarize the main molecular signals involved in controlling their function under physiological conditions. In addition, their implication in the pathogenesis of multiple sclerosis and stress is discussed. PMID:27446922

  13. General stress response signaling

    PubMed Central

    Huo, Yi-Xin; Rosenthal, Adam Z.; Gralla, Jay D.

    2008-01-01

    E. coli responds to stress by a combination of specific and general transcription signaling pathways. The general pathways typically require the master stress regulator sigma38 (rpoS). Here we show that the signaling from multiple stresses that relax DNA is processed by a non-conserved 8 amino acid tail of the sigma 38 C-terminal domain (CTD). By contrast, responses to stresses that accumulate potassium glutamate do not rely on this short tail, but still require the overall CTD. In vitro transcription and footprinting studies suggest that multiple stresses can target a poised RNA polymerase and activate it by unwrapping DNA from a nucleosome-like state, allowing the RNA polymerase to escape into productive mode. This transition can be accomplished by either the DNA relaxation or potassium glutamate accumulation that characterizes many stresses. PMID:18761624

  14. Digital signal processing

    NASA Astrophysics Data System (ADS)

    Meyer, G.

    The theory, realization techniques, and applications of digital filtering are surveyed, with an emphasis on the development of software, in a handbook for advanced students of electrical and electronic engineering and practicing development engineers. The foundations of the theory of discrete signals and systems are introduced. The design of one-dimensional linear systems is discussed, and the techniques are expanded to the treatment of two-dimensional discrete and multidimensional analog systems. Numerical systems, quantification and limitation, and the characteristics of particular signal-processing devices are considered in a section on design realization. An appendix contains definitions of the basic mathematical concepts, derivations and proofs, and tables of integration and differentiation formulas.

  15. Tailpulse signal generator

    DOEpatents

    Baker, John; Archer, Daniel E.; Luke, Stanley John; Decman, Daniel J.; White, Gregory K.

    2009-06-23

    A tailpulse signal generating/simulating apparatus, system, and method designed to produce electronic pulses which simulate tailpulses produced by a gamma radiation detector, including the pileup effect caused by the characteristic exponential decay of the detector pulses, and the random Poisson distribution pulse timing for radioactive materials. A digital signal process (DSP) is programmed and configured to produce digital values corresponding to pseudo-randomly selected pulse amplitudes and pseudo-randomly selected Poisson timing intervals of the tailpulses. Pulse amplitude values are exponentially decayed while outputting the digital value to a digital to analog converter (DAC). And pulse amplitudes of new pulses are added to decaying pulses to simulate the pileup effect for enhanced realism in the simulation.

  16. Regulation of inflammasome signaling

    PubMed Central

    Rathinam, Vijay A K; Vanaja, Sivapriya Kailasan; Fitzgerald, Katherine A

    2012-01-01

    Innate immune responses have the ability to both combat infectious microbes and drive pathological inflammation. Inflammasome complexes are a central component of these processes through their regulation of interleukin 1β (IL-1β), IL-18 and pyroptosis. Inflammasomes recognize microbial products or endogenous molecules released from damaged or dying cells both through direct binding of ligands and indirect mechanisms. The potential of the IL-1 family of cytokines to cause tissue damage and chronic inflammation emphasizes the importance of regulating inflammasomes. Many regulatory mechanisms have been identified that act as checkpoints for attenuating inflammasome signaling at multiple steps. Here we discuss the various regulatory mechanisms that have evolved to keep inflammasome signaling in check to maintain immunological balance. PMID:22430786

  17. RASSP signal processing architectures

    NASA Astrophysics Data System (ADS)

    Shirley, Fred; Bassett, Bob; Letellier, J. P.

    1995-06-01

    The rapid prototyping of application specific signal processors (RASSP) program is an ARPA/tri-service effort to dramatically improve the process by which complex digital systems, particularly embedded signal processors, are specified, designed, documented, manufactured, and supported. The domain of embedded signal processing was chosen because it is important to a variety of military and commercial applications as well as for the challenge it presents in terms of complexity and performance demands. The principal effort is being performed by two major contractors, Lockheed Sanders (Nashua, NH) and Martin Marietta (Camden, NJ). For both, improvements in methodology are to be exercised and refined through the performance of individual 'Demonstration' efforts. The Lockheed Sanders' Demonstration effort is to develop an infrared search and track (IRST) processor. In addition, both contractors' results are being measured by a series of externally administered (by Lincoln Labs) six-month Benchmark programs that measure process improvement as a function of time. The first two Benchmark programs are designing and implementing a synthetic aperture radar (SAR) processor. Our demonstration team is using commercially available VME modules from Mercury Computer to assemble a multiprocessor system scalable from one to hundreds of Intel i860 microprocessors. Custom modules for the sensor interface and display driver are also being developed. This system implements either proprietary or Navy owned algorithms to perform the compute-intensive IRST function in real time in an avionics environment. Our Benchmark team is designing custom modules using commercially available processor ship sets, communication submodules, and reconfigurable logic devices. One of the modules contains multiple vector processors optimized for fast Fourier transform processing. Another module is a fiberoptic interface that accepts high-rate input data from the sensors and provides video-rate output data to a

  18. Digital signal processing

    NASA Astrophysics Data System (ADS)

    Morgera, Salvatore D.; Krishna, Hari

    Computationally efficient digital signal-processing algorithms over finite fields are developed analytically, and the relationship of these algorithms to algebraic error-correcting codes is explored. A multidisciplinary approach is employed, in an effort to make the results accessible to engineers, mathematicians, and computer scientists. Chapters are devoted to systems of bilinear forms, efficient finite-field algorithms, multidimensional methods, a new class of linear codes, and a new error-control scheme.

  19. Plant peptide hormone signalling.

    PubMed

    Motomitsu, Ayane; Sawa, Shinichiro; Ishida, Takashi

    2015-01-01

    The ligand-receptor-based cell-to-cell communication system is one of the most important molecular bases for the establishment of complex multicellular organisms. Plants have evolved highly complex intercellular communication systems. Historical studies have identified several molecules, designated phytohormones, that function in these processes. Recent advances in molecular biological analyses have identified phytohormone receptors and signalling mediators, and have led to the discovery of numerous peptide-based signalling molecules. Subsequent analyses have revealed the involvement in and contribution of these peptides to multiple aspects of the plant life cycle, including development and environmental responses, similar to the functions of canonical phytohormones. On the basis of this knowledge, the view that these peptide hormones are pivotal regulators in plants is becoming increasingly accepted. Peptide hormones are transcribed from the genome and translated into peptides. However, these peptides generally undergo further post-translational modifications to enable them to exert their function. Peptide hormones are expressed in and secreted from specific cells or tissues. Apoplastic peptides are perceived by specialized receptors that are located at the surface of target cells. Peptide hormone-receptor complexes activate intracellular signalling through downstream molecules, including kinases and transcription factors, which then trigger cellular events. In this chapter we provide a comprehensive summary of the biological functions of peptide hormones, focusing on how they mature and the ways in which they modulate plant functions. PMID:26374891

  20. Phytosulfokine peptide signalling.

    PubMed

    Sauter, Margret

    2015-08-01

    Phytosulfokine (PSK) belongs to the group of plant peptide growth factors. It is a disulfated pentapeptide encoded by precursor genes that are ubiquitously present in higher plants, suggestive of universal functions. Processing of the preproprotein involves sulfonylation by a tyrosylprotein sulfotransferase in the trans-golgi and proteolytic cleavage in the apoplast. The secreted peptide is perceived at the cell surface by a membrane-bound receptor kinase of the leucine-rich repeat family. The PSK receptor PSKR1 from Arabidopsis thaliana is an active kinase and has guanylate cyclase activity resulting in dual-signal outputs. Receptor activity is regulated by calmodulin. While PSK may be an autocrine growth factor, it also acts non-cell autonomously by promoting growth of cells that are receptor-deficient. In planta, PSK has multiple functions. It promotes cell growth, acts in the quiescent centre cells of the root apical meristem, contributes to funicular pollen tube guidance, and differentially alters immune responses depending on the pathogen. It has been suggested that PSK integrates growth and defence signals to balance the competing metabolic costs of these responses. This review summarizes our current understanding of PSK synthesis, signalling, and activity. PMID:25754406

  1. Integrin endosomal signalling suppresses anoikis.

    PubMed

    Alanko, Jonna; Mai, Anja; Jacquemet, Guillaume; Schauer, Kristine; Kaukonen, Riina; Saari, Markku; Goud, Bruno; Ivaska, Johanna

    2015-11-01

    Integrin-containing focal adhesions transmit extracellular signals across the plasma membrane to modulate cell adhesion, signalling and survival. Although integrins are known to undergo continuous endo/exocytic traffic, the potential impact of endocytic traffic on integrin-induced signals is unknown. Here, we demonstrate that integrin signalling is not restricted to cell-ECM adhesions and identify an endosomal signalling platform that supports integrin signalling away from the plasma membrane. We show that active focal adhesion kinase (FAK), an established marker of integrin-ECM downstream signalling, localizes with active integrins on endosomes. Integrin endocytosis positively regulates adhesion-induced FAK activation, which is early endosome antigen-1 and small GTPase Rab21 dependent. FAK binds directly to purified endosomes and becomes activated on them, suggesting a role for endocytosis in enhancing distinct integrin downstream signalling events. Finally, endosomal integrin signalling contributes to cancer-related processes such as anoikis resistance, anchorage independence and metastasis. PMID:26436690

  2. TRAIL receptor signalling and modulation: Are we on the right TRAIL?

    PubMed

    Mahalingam, Devalingam; Szegezdi, Eva; Keane, Maccon; de Jong, Steven; Samali, Afshin

    2009-05-01

    Tumour necrosis factor-related apoptosis-inducing ligand or Apo2 ligand (TRAIL/Apo2L) is a member of the tumour necrosis factor (TNF) superfamily of cytokines that induces apoptosis upon binding to its death domain-containing transmembrane receptors, death receptors 4 and 5 (DR4, DR5). Importantly, TRAIL preferentially induces apoptosis in cancer cells while exhibiting little or no toxicity in normal cells. To date, research has focused on the mechanism of apoptosis induced by TRAIL and the processes involved in the development of TRAIL resistance. TRAIL-resistant tumours can be re-sensitized to TRAIL by a combination of TRAIL with chemotherapeutics or irradiation. Studies suggest that in many cancer cells only one of the two death-inducing TRAIL receptors is functional. These findings as well as the aim to avoid decoy receptor-mediated neutralization of TRAIL led to the development of receptor-specific TRAIL variants and agonistic antibodies. These molecules are predicted to be more potent than native TRAIL in vivo and may be suitable for targeted treatment of particular tumours. This review focuses on the current status of TRAIL receptor-targeting for cancer therapy, the apoptotic signalling pathway induced by TRAIL receptors, the prognostic implications of TRAIL receptor expression and modulation of TRAIL sensitivity of tumour cells by combination therapies. The mechanisms of TRAIL resistance and the potential measures that can be taken to overcome them are also addressed. Finally, the status of clinical trials of recombinant TRAIL and DR4-/DR5-specific agonistic antibodies as well as the pre-clinical studies of receptor-selective TRAIL variants is discussed including the obstacles facing the use of these molecules as anti-cancer therapeutics. PMID:19117685

  3. SIRT1 is involved in oncogenic signaling mediated by GPER in breast cancer

    PubMed Central

    Santolla, M F; Avino, S; Pellegrino, M; De Francesco, E M; De Marco, P; Lappano, R; Vivacqua, A; Cirillo, F; Rigiracciolo, D C; Scarpelli, A; Abonante, S; Maggiolini, M

    2015-01-01

    A number of tumors exhibit an altered expression of sirtuins, including NAD+-dependent histone deacetylase silent information regulator 1 (SIRT1) that may act as a tumor suppressor or tumor promoter mainly depending on the tumor types. For instance, in breast cancer cells SIRT1 was shown to exert an essential role toward the oncogenic signaling mediated by the estrogen receptor-α (ERα). In accordance with these findings, the suppression of SIRT1 led to the inhibition of the transduction pathway triggered by ERα. As the regulation of SIRT1 has not been investigated in cancer cells lacking ER, in the present study we ascertained the expression and function of SIRT1 by estrogens in ER-negative breast cancer cells and cancer-associated fibroblasts obtained from breast cancer patients. Our results show that 17β-estradiol (E2) and the selective ligand of GPER, namely G-1, induce the expression of SIRT1 through GPER and the subsequent activation of the EGFR/ERK/c-fos/AP-1 transduction pathway. Moreover, we demonstrate that SIRT1 is involved in the pro-survival effects elicited by E2 through GPER, like the prevention of cell cycle arrest and cell death induced by the DNA damaging agent etoposide. Interestingly, the aforementioned actions of estrogens were abolished silencing GPER or SIRT1, as well as using the SIRT1 inhibitor Sirtinol. In addition, we provide evidence regarding the involvement of SIRT1 in tumor growth stimulated by GPER ligands in breast cancer cells and xenograft models. Altogether, our data suggest that SIRT1 may be included in the transduction network activated by estrogens through GPER toward the breast cancer progression. PMID:26225773

  4. Interplant signalling through hyphal networks.

    PubMed

    Johnson, David; Gilbert, Lucy

    2015-03-01

    Mycorrhizal fungi can form common mycelial networks (CMNs) that interconnect plants. Here, we provide an insight into recent findings demonstrating that CMNs can be conduits for interplant signalling, influencing defence against insect herbivores and foliar necrotrophic fungi. A likely mechanism is direct transfer of signalling molecules within hyphae. However, electrical signals, which can be induced by wounding, may also enable signalling over relatively long distances, because the biophysical constraints imposed by liquid transport in hyphae and interaction with soil are relieved. We do not yet understand the ecological, evolutionary and agronomic implications of interplant signalling via CMNs. Identifying the mechanism of interplant signalling will help to address these gaps. PMID:25421970

  5. Digital processing of bandpass signals

    NASA Astrophysics Data System (ADS)

    Jackson, M. C.; Matthewson, P.

    Modern radar and radio systems rely on digital signal processing to enhance the quality of received signals. Prior to such processing, these signals must be converted to digital form. The historical development of signal digitization is briefly discussed in this paper and leads to a description of some current work on digital mixing. A method of directly sampling a band-limited intermediate frequency (i.f.) signal is presented, using a pair of digital mixer channels to produce complex low-pass samples of the signal envelope. The method is found to produce well matched channel outputs. Finally, the applicability of the method to radar is discussed.

  6. Notch Signaling Components

    PubMed Central

    Liu, Zhi-Yan; Wu, Tao; Li, Qing; Wang, Min-Cong; Jing, Li; Ruan, Zhi-Ping; Yao, Yu; Nan, Ke-Jun; Guo, Hui

    2016-01-01

    Abstract Non-small-cell lung cancer (NSCLC) is a lethal and aggressive malignancy. Currently, the identities of prognostic and predictive makers of NSCLC have not been fully established. Dysregulated Notch signaling has been implicated in many human malignancies, including NSCLC. However, the prognostic value of measuring Notch signaling and the utility of developing Notch-targeted therapies in NSCLC remain inconclusive. The present study investigated the association of individual Notch receptor and ligand levels with lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) prognosis using the Kaplan-Meier plotte database. This online database encompasses 2437 lung cancer samples. Hazard ratios with 95% confidence intervals were calculated. The results showed that higher Notch1, Notch2, JAG1, and DLL1 mRNA expression predicted better overall survival (OS) in lung ADC, but showed no significance in SCC patients. Elevated Notch3, JAG2, and DLL3 mRNA expression was associated with poor OS of ADC patients, but not in SCC patients. There was no association between Notch4 and OS in either lung ADC or SCC patients. In conclusion, the set of Notch1, Notch2, JAG1, DLL1 and that of Notch3, JAG2, DLL3 played opposing prognostic roles in lung ADC patients. Neither set of Notch receptors and ligands was indicative of lung SCC prognosis. Notch signaling could serve as promising marker to predict outcomes in lung ADC patients. The distinct features of lung cancer subtypes and Notch components should be considered when developing future Notch-targeted therapies. PMID:27196489

  7. Biphonation in voice signals

    SciTech Connect

    Herzel, H.; Reuter, R.

    1996-06-01

    Irregularities in voiced speech are often observed as a consequence of vocal fold lesions, paralyses, and other pathological conditions. Many of these instabilities are related to the intrinsic nonlinearities in the vibrations of the vocal folds. In this paper, a specific nonlinear phenomenon is discussed: The appearance of two independent fundamental frequencies termed biphonation. Several narrow-band spectrograms are presented showing biphonation in signals from voice patients, a newborn cry, a singer, and excised larynx experiments. Finally, possible physiological mechanisms of instabilities of the voice source are discussed. {copyright} {ital 1996 American Institute of Physics.}

  8. Neural Membrane Signaling Platforms

    PubMed Central

    Wallace, Ron

    2010-01-01

    Throughout much of the history of biology, the cell membrane was functionally defined as a semi-permeable barrier separating aqueous compartments, and an anchoring site for proteins. Little attention was devoted to its possible regulatory role in intracellular molecular processes and neuron electrical signaling. This article reviews the history of membrane studies and the current state of the art. Emphasis is placed on natural and artificial membrane studies of electric field effects on molecular organization, especially as these may relate to impulse propagation in neurons. Implications of these studies for new designs in artificial intelligence are briefly examined. PMID:20640161

  9. Growth hormone signaling pathways.

    PubMed

    Carter-Su, Christin; Schwartz, Jessica; Argetsinger, Lawrence S

    2016-06-01

    Over 20years ago, our laboratory showed that growth hormone (GH) signals through the GH receptor-associated tyrosine kinase JAK2. We showed that GH binding to its membrane-bound receptor enhances binding of JAK2 to the GHR, activates JAK2, and stimulates tyrosyl phosphorylation of both JAK2 and GHR. The activated JAK2/GHR complex recruits a variety of signaling proteins, thereby initiating multiple signaling pathways and cellular responses. These proteins and pathways include: 1) Stat transcription factors implicated in the expression of multiple genes, including the gene encoding insulin-like growth factor 1; 2) Shc adapter proteins that lead to activation of the grb2-SOS-Ras-Raf-MEK-ERK1,2 pathway; 3) insulin receptor substrate proteins implicated in the phosphatidylinositol-3-kinase and Akt pathway; 4) signal regulatory protein α, a transmembrane scaffold protein that recruits proteins including the tyrosine phosphatase SHP2; and 5) SH2B1, a scaffold protein that can activate JAK2 and enhance GH regulation of the actin cytoskeleton. Our recent work has focused on the function of SH2B1. We have shown that SH2B1β is recruited to and phosphorylated by JAK2 in response to GH. SH2B1 localizes to the plasma membrane, cytoplasm and focal adhesions; it also cycles through the nucleus. SH2B1 regulates the actin cytoskeleton and promotes GH-dependent motility of RAW264.7 macrophages. Mutations in SH2B1 have been found in humans exhibiting severe early-onset childhood obesity and insulin resistance. These mutations impair SH2B1 enhancement of GH-induced macrophage motility. As SH2B1 is expressed ubiquitously and is also recruited to a variety of receptor tyrosine kinases, our results raise the possibility that effects of SH2B1 on the actin cytoskeleton in various cell types, including neurons, may play a role in regulating body weight. PMID:26421979

  10. Sphingosine in apoptosis signaling.

    PubMed

    Cuvillier, Olivier

    2002-12-30

    The sphingolipid metabolites ceramide, sphingosine, and sphingosine 1-phosphate contribute to controlling cell proliferation and apoptosis. Ceramide and its catabolite sphingosine act as negative regulators of cell proliferation and promote apoptosis. Conversely, sphingosine 1-phosphate, formed by phosphorylation of sphingosine by a sphingosine kinase, has been involved in stimulating cell growth and inhibiting apoptosis. As the phosphorylation of sphingosine diminishes apoptosis, while dephosphorylation of sphingosine 1-phosphate potentiates it, the role of sphingosine as a messenger of apoptosis is of importance. Herein, the effects of sphingosine on diverse signaling pathways implicated in the apoptotic process are reviewed. PMID:12531549

  11. Signal quality of endovascular electroencephalography

    NASA Astrophysics Data System (ADS)

    He, Bryan D.; Ebrahimi, Mosalam; Palafox, Leon; Srinivasan, Lakshminarayan

    2016-02-01

    Objective, Approach. A growing number of prototypes for diagnosing and treating neurological and psychiatric diseases are predicated on access to high-quality brain signals, which typically requires surgically opening the skull. Where endovascular navigation previously transformed the treatment of cerebral vascular malformations, we now show that it can provide access to brain signals with substantially higher signal quality than scalp recordings. Main results. While endovascular signals were known to be larger in amplitude than scalp signals, our analysis in rabbits borrows a standard technique from communication theory to show endovascular signals also have up to 100× better signal-to-noise ratio. Significance. With a viable minimally-invasive path to high-quality brain signals, patients with brain diseases could one day receive potent electroceuticals through the bloodstream, in the course of a brief outpatient procedure.

  12. Recurrent Infections May Signal Immunodeficiencies

    MedlinePlus

    ... Search AAAAI Breadcrumb navigation Home ▸ Conditions & Treatments ▸ Library ▸ Primary Immunodeficiency Disease Library ▸ Recurrent Infections May Signal Immunodeficiencies Share | Recurrent Infections May Signal Immunodeficiencies This article has been reviewed by Thanai Pongdee, MD, FAAAAI ...

  13. Calcium Signaling in the Liver

    PubMed Central

    Amaya, Maria Jimena; Nathanson, Michael H.

    2014-01-01

    Intracellular free Ca2+ ([Ca2+]i) is a highly versatile second messenger that regulates a wide range of functions in every type of cell and tissue. To achieve this versatility, the Ca2+ signaling system operates in a variety of ways to regulate cellular processes that function over a wide dynamic range. This is particularly well exemplified for Ca2+ signals in the liver, which modulate diverse and specialized functions such as bile secretion, glucose metabolism, cell proliferation, and apoptosis. These Ca2+ signals are organized to control distinct cellular processes through tight spatial and temporal coordination of [Ca2+]i signals, both within and between cells. This article will review the machinery responsible for the formation of Ca2+ signals in the liver, the types of subcellular, cellular, and intercellular signals that occur, the physiological role of Ca2+ signaling in the liver, and the role of Ca2+ signaling in liver disease. PMID:23720295

  14. [Signal systems of plant immunity].

    PubMed

    Dmitriev, A P

    2002-01-01

    Plants can recognise the penetrating pathogen and respond to the attack with an array of defense reactions. Signal transduction from receptor in plasma membrane to genome is necessary to activate these reactions. Plant cell signaling systems which take part in signal transduction were discovered and identified recently. The obtained results suggest that plant cells have complex and well coordinated signal network which regulates their immune potential. PMID:12187855

  15. Signal processing in magnetoencephalography.

    PubMed

    Vrba, J; Robinson, S E

    2001-10-01

    The subject of this article is detection of brain magnetic fields, or magnetoencephalography (MEG). The brain fields are many orders of magnitude smaller than the environmental magnetic noise and their measurement represent a significant metrological challenge. The only detectors capable of resolving such small fields and at the same time handling the large dynamic range of the environmental noise are superconducting quantum interference devices (or SQUIDs). The SQUIDs are coupled to the brain magnetic fields using combinations of superconducting coils called flux transformers (primary sensors). The environmental noise is attenuated by a combination of shielding, primary sensor geometry, and synthetic methods. One of the most successful synthetic methods for noise elimination is synthetic higher-order gradiometers. How the gradiometers can be synthesized is shown and examples of their noise cancellation effectiveness are given. The MEG signals measured on the scalp surface must be interpreted and converted into information about the distribution of currents within the brain. This task is complicated by the fact that such inversion is nonunique. Additional mathematical simplifications, constraints, or assumptions must be employed to obtain useful source images. Methods for the interpretation of the MEG signals include the popular point current dipole, minimum norm methods, spatial filtering, beamformers, MUSIC, and Bayesian techniques. The use of synthetic aperture magnetometry (a class of beamformers) is illustrated in examples of interictal epileptic spiking and voluntary hand-motor activity. PMID:11812209

  16. TGIF inhibits retinoid signaling.

    PubMed

    Bartholin, Laurent; Powers, Shannon E; Melhuish, Tiffany A; Lasse, Samuel; Weinstein, Michael; Wotton, David

    2006-02-01

    TGIF (TG-interacting factor) represses transforming growth factor beta (TGF-beta)-activated gene expression and can repress transcription via a specific retinoid response element. Mutations in human TGIF are associated with holoprosencephaly, a severe defect of craniofacial development with both genetic and environmental causes. Both TGF-beta and retinoic acid signaling are implicated in craniofacial development. Here, we analyze the role of TGIF in regulating retinoid responsive gene expression. We demonstrate that TGIF interacts with the ligand binding domain of the RXRalpha retinoid receptor and represses transcription from retinoid response elements. TGIF recruits the general corepressor, CtBP, to RXRalpha, and this recruitment is required for full repression by TGIF. Interaction between TGIF and RXRalpha is reduced by the addition of retinoic acid, consistent with a role for TGIF as an RXRalpha transcriptional corepressor. We created a Tgif null mutation in mice and tested the sensitivity of mutant mice to increased levels of retinoic acid. Tgif mutant embryos are more sensitive to retinoic acid-induced teratogenesis, and retinoid target genes are expressed at a higher level in tissues from Tgif null mice. These results demonstrate an important role for TGIF as a transcriptional corepressor, which regulates developmental signaling by retinoic acid, and raises the possibility that TGIF may repress other RXR-dependent transcriptional responses. PMID:16428452

  17. Endocannabinoid Signaling in Autism.

    PubMed

    Chakrabarti, Bhismadev; Persico, Antonio; Battista, Natalia; Maccarrone, Mauro

    2015-10-01

    Autism spectrum disorder (ASD) is a complex behavioral condition with onset during early childhood and a lifelong course in the vast majority of cases. To date, no behavioral, genetic, brain imaging, or electrophysiological test can specifically validate a clinical diagnosis of ASD. However, these medical procedures are often implemented in order to screen for syndromic forms of the disorder (i.e., autism comorbid with known medical conditions). In the last 25 years a good deal of information has been accumulated on the main components of the "endocannabinoid (eCB) system", a rather complex ensemble of lipid signals ("endocannabinoids"), their target receptors, purported transporters, and metabolic enzymes. It has been clearly documented that eCB signaling plays a key role in many human health and disease conditions of the central nervous system, thus opening the avenue to the therapeutic exploitation of eCB-oriented drugs for the treatment of psychiatric, neurodegenerative, and neuroinflammatory disorders. Here we present a modern view of the eCB system, and alterations of its main components in human patients and animal models relevant to ASD. This review will thus provide a critical perspective necessary to explore the potential exploitation of distinct elements of eCB system as targets of innovative therapeutics against ASD. PMID:26216231

  18. Universal signal conditioning amplifier

    NASA Technical Reports Server (NTRS)

    Medelius, Pedro J.; Hallberg, Carl; Cecil, Jim

    1994-01-01

    A state-of-the-art instrumentation amplifier capable of being used with most types of transducers has been developed at the Kennedy Space Center. This Universal Signal Conditioning Amplifier (USCA) can eliminate costly measurement setup item and troubleshooting, improve system reliability and provide more accurate data than conventional amplifiers. The USCA can configure itself for maximum resolution and accuracy based on information read from a RAM chip attached to each transducer. Excitation voltages or current are also automatically configured. The amplifier uses both analog and digital state-of-the-art technology with analog-to-digital conversion performed in the early stages in order to minimize errors introduced by offset and gain drifts in the analog components. A dynamic temperature compensation scheme has been designed to achieve and maintain 12-bit accuracy of the amplifier from 0 to 70 C. The digital signal processing section allows the implementation of digital filters up to 511th order. The amplifier can also perform real-time linearizations up to fourth order while processing data at a rate of 23.438 kS/s. Both digital and analog outputs are available from the amplifier.

  19. TLR-signaling Networks

    PubMed Central

    Brown, J.; Wang, H.; Hajishengallis, G.N.; Martin, M.

    2011-01-01

    Toll-like receptors play a critical role in innate immunity by detecting invading pathogens. The ability of TLRs to engage different intracellular signaling molecules and cross-talk with other regulatory pathways is an important factor in shaping the type, magnitude, and duration of the inflammatory response. The present review will cover the fundamental signaling pathways utilized by TLRs and how these pathways regulate the innate immune response to pathogens. Abbreviations: TLR, Toll-like receptor; PRR, pattern recognition receptor; PAMP, pathogen-associated molecular pattern; LPS, lipopolysaccharide; APC, antigen-presenting cell; IL, interleukin; TIR, Toll/IL-1R homology; MyD88, myeloid differentiation factor 88; IFN, interferon; TRIF, TIR-domain-containing adapter-inducing interferon-β; IRAK, IL-1R-associated kinase; TAK1, TGF-β-activated kinase; TAB1, TAK1-binding protein; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B-cells; MAPK, mitogen-activated protein kinase; NLR, NOD-like receptors; LRR, leucine-rich repeats; DC, dendritic cell; PI3K, phosphoinositide 3-kinases; GSK3, glycogen synthase kinase-3; mTOR, mammalian target of rapamycin; DAF, decay-accelerating factor; IKK, IκB kinase; IRF, interferon regulatory factors; TBK1, TANK-binding kinase 1; CARD, caspase activation and recruitment domain; PYD, pyrin N-terminal homology domain; ATF, activating transcription factor; and PTEN, phosphatase and tensin homolog. PMID:20940366

  20. Salicylic acid signaling inhibits apoplastic reactive oxygen species signaling

    PubMed Central

    2014-01-01

    Background Reactive oxygen species (ROS) are used by plants as signaling molecules during stress and development. Given the amount of possible challenges a plant face from their environment, plants need to activate and prioritize between potentially conflicting defense signaling pathways. Until recently, most studies on signal interactions have focused on phytohormone interaction, such as the antagonistic relationship between salicylic acid (SA)-jasmonic acid and cytokinin-auxin. Results In this study, we report an antagonistic interaction between SA signaling and apoplastic ROS signaling. Treatment with ozone (O3) leads to a ROS burst in the apoplast and induces extensive changes in gene expression and elevation of defense hormones. However, Arabidopsis thaliana dnd1 (defense no death1) exhibited an attenuated response to O3. In addition, the dnd1 mutant displayed constitutive expression of defense genes and spontaneous cell death. To determine the exact process which blocks the apoplastic ROS signaling, double and triple mutants involved in various signaling pathway were generated in dnd1 background. Simultaneous elimination of SA-dependent and SA-independent signaling components from dnd1 restored its responsiveness to O3. Conversely, pre-treatment of plants with SA or using mutants that constitutively activate SA signaling led to an attenuation of changes in gene expression elicited by O3. Conclusions Based upon these findings, we conclude that plants are able to prioritize the response between ROS and SA via an antagonistic action of SA and SA signaling on apoplastic ROS signaling. PMID:24898702

  1. Signal and Image Processing Operations

    Energy Science and Technology Software Center (ESTSC)

    1995-05-10

    VIEW is a software system for processing arbitrary multidimensional signals. It provides facilities for numerical operations, signal displays, and signal databasing. The major emphasis of the system is on the processing of time-sequences and multidimensional images. The system is designed to be both portable and extensible. It runs currently on UNIX systems, primarily SUN workstations.

  2. Isolated transfer of analog signals

    NASA Technical Reports Server (NTRS)

    Bezdek, T.

    1974-01-01

    Technique transfers analog signal levels across high isolation boundary without circuit performance being affected by magnetizing reactance or leakage inductance. Transfers of analog information across isolated boundary are made by interrupting signal flow, with switch, in such a manner as to produce alternating signal which is applied to transformer.

  3. Multiple source navigation signal generator

    NASA Astrophysics Data System (ADS)

    Bojda, Petr

    2010-09-01

    The paper presents a FPGA based digital VOR/LOC signal generator. It provides the composite signal, which consists of the particular signals of several predefined navigation sources - VOR beacons. Design of the generator is implemented into the two different FPGA DSP platforms.

  4. SIG. Signal Processing, Analysis, & Display

    SciTech Connect

    Hernandez, J.; Lager, D.; Azevedo, S.

    1992-01-22

    SIG is a general-purpose signal processing, analysis, and display program. Its main purpose is to perform manipulations on time- and frequency-domain signals. However, it has been designed to ultimately accommodate other representations for data such as multiplexed signals and complex matrices. Two user interfaces are provided in SIG - a menu mode for the unfamiliar user and a command mode for more experienced users. In both modes errors are detected as early as possible and are indicated by friendly, meaningful messages. An on-line HELP package is also included. A variety of operations can be performed on time- and frequency-domain signals including operations on the samples of a signal, operations on the entire signal, and operations on two or more signals. Signal processing operations that can be performed are digital filtering (median, Bessel, Butterworth, and Chebychev), ensemble average, resample, auto and cross spectral density, transfer function and impulse response, trend removal, convolution, Fourier transform and inverse window functions (Hamming, Kaiser-Bessel), simulation (ramp, sine, pulsetrain, random), and read/write signals. User definable signal processing algorithms are also featured. SIG has many options including multiple commands per line, command files with arguments,commenting lines, defining commands, and automatic execution for each item in a repeat sequence. Graphical operations on signals and spectra include: x-y plots of time signals; real, imaginary, magnitude, and phase plots of spectra; scaling of spectra for continuous or discrete domain; cursor zoom; families of curves; and multiple viewports.

  5. SIG. Signal Processing, Analysis, & Display

    SciTech Connect

    Hernandez, J.; Lager, D.; Azevedo, S.

    1992-01-22

    SIG is a general-purpose signal processing, analysis, and display program. Its main purpose is to perform manipulations on time and frequency-domain signals. However, it has been designed to ultimately accommodate other representations for data such as multiplexed signals and complex matrices. Two user interfaces are provided in SIG; a menu mode for the unfamiliar user and a command mode for more experienced users. In both modes errors are detected as early as possible and are indicated by friendly, meaningful messages. An on-line HELP package is also included. A variety of operations can be performed on time and frequency-domain signals including operations on the samples of a signal, operations on the entire signal, and operations on two or more signals. Signal processing operations that can be performed are digital filtering (median, Bessel, Butterworth, and Chebychev), ensemble average, resample, auto and cross spectral density, transfer function and impulse response, trend removal, convolution, Fourier transform and inverse window functions (Hamming, Kaiser-Bessel), simulation (ramp, sine, pulsetrain, random), and read/write signals. User definable signal processing algorithms are also featured. SIG has many options including multiple commands per line, command files with arguments, commenting lines, defining commands, and automatic execution for each item in a `repeat` sequence. Graphical operations on signals and spectra include: x-y plots of time signals; real, imaginary, magnitude, and phase plots of spectra; scaling of spectra for continuous or discrete domain; cursor zoom; families of curves; and multiple viewports.

  6. SIG. Signal Processing, Analysis, & Display

    SciTech Connect

    Hernandez, J.; Lager, D.; Azevedo, S.

    1992-01-22

    SIG is a general-purpose signal processing, analysis, and display program. Its main purpose is to perform manipulations on time-and frequency-domain signals. However, it has been designed to ultimately accommodate other representations for data such as multiplexed signals and complex matrices. Two user interfaces are provided in SIG - a menu mode for the unfamiliar user and a command mode for more experienced users. In both modes errors are detected as early as possible and are indicated by friendly, meaningful messages. An on-line HELP package is also included. A variety of operations can be performed on time and frequency-domain signals including operations on the samples of a signal, operations on the entire signal, and operations on two or more signals. Signal processing operations that can be performed are digital filtering (median, Bessel, Butterworth, and Chebychev), ensemble average, resample, auto and cross spectral density, transfer function and impulse response, trend removal, convolution, Fourier transform and inverse window functions (Hamming, Kaiser-Bessel), simulation (ramp, sine, pulsetrain, random), and read/write signals. User definable signal processing algorithms are also featured. SIG has many options including multiple commands per line, command files with arguments, commenting lines, defining commands, and automatic execution for each item in a repeat sequence. Graphical operations on signals and spectra include: x-y plots of time signals; real, imaginary, magnitude, and phase plots of spectra; scaling of spectra for continuous or discrete domain; cursor zoom; families of curves; and multiple viewports.

  7. Asymmetry In Biphase Data Signals

    NASA Technical Reports Server (NTRS)

    Nguyen, Tien M.

    1992-01-01

    Report presents analysis of some effects of asymmetry in Manchester (biphase) binary data signal transmitted by phase modulation of sinusoidal carrier signal. Report extends analysis described in article, "Effects of Asymmetry of NRZ Data Signals on Performance" (NPO-18261), to include case where data biphase-modulated directly on residual carrier.

  8. Fangchinoline induces autophagic cell death via p53/sestrin2/AMPK signalling in human hepatocellular carcinoma cells

    PubMed Central

    Wang, Ning; Pan, Weidong; Zhu, Meifen; Zhang, Maosheng; Hao, Xiaojian; Liang, Guangyi; Feng, Yibin

    2011-01-01

    BACKGROUND AND PURPOSE Fangchinoline is a novel anti-tumour agent with little known of its cellular and molecular mechanisms of action. Here we have investigated the mode of cell death induced by fangchinoline and its underlying mechanism in two human hepatocellular carcinoma cell lines, HepG2 and PLC/PRF/5. EXPERIMENTAL APPROACH Apoptosis and autophagy were monitored in fangchinoline-treated HepG2 and PLC/PRF/5 cells by histological methods. The signal transduction pathways involved in activation of autophagy were examined, using immunoblotting, real-time PCR and siRNA techniques. KEY RESULTS Fangchinoline did not induce apoptosis in HepG2 and PLC/PRF/5 cells but triggered, dose-dependently, autophagy, an alternative mode of cell death which may contribute to fangchinoline's anti-tumour action. Nuclear translocation of p53 was involved in induction of autophagy by fangchinoline, followed by selective transactivation of the autophagy-related gene sestrin2 and initiation of the autophagic process. Signalling by the AMP-activated protein kinase was also involved as a downstream target of sestrin2 and induced mTOR-independent autophagic cell death in both cell lines. siRNA for Atg 5 or pharmacological block of p53 abolished fangchinoline-induced autophagy and inhibition of autophagy switched cell death to apoptosis in these cells, suggesting that cell death is irreversible once autophagy is induced by fangchinoline. CONCLUSIONS AND IMPLICATIONS Fangchinoline is a highly specific agent inducing autophagic cell death in hepatocellular carcinoma cells with a novel mechanism, which elucidates the potential of fangchinoline to potentiate programmed cell death in cancer cells. PMID:21418191

  9. Binary-Signal Recovery

    NASA Technical Reports Server (NTRS)

    Griebeler, Elmer L.

    2011-01-01

    Binary communication through long cables, opto-isolators, isolating transformers, or repeaters can become distorted in characteristic ways. The usual solution is to slow the communication rate, change to a different method, or improve the communication media. It would help if the characteristic distortions could be accommodated at the receiving end to ease the communication problem. The distortions come from loss of the high-frequency content, which adds slopes to the transitions from ones to zeroes and zeroes to ones. This weakens the definition of the ones and zeroes in the time domain. The other major distortion is the reduction of low frequency, which causes the voltage that defines the ones or zeroes to drift out of recognizable range. This development describes a method for recovering a binary data stream from a signal that has been subjected to a loss of both higher-frequency content and low-frequency content that is essential to define the difference between ones and zeroes. The method makes use of the frequency structure of the waveform created by the data stream, and then enhances the characteristics related to the data to reconstruct the binary switching pattern. A major issue is simplicity. The approach taken here is to take the first derivative of the signal and then feed it to a hysteresis switch. This is equivalent in practice to using a non-resonant band pass filter feeding a Schmitt trigger. Obviously, the derivative signal needs to be offset to halfway between the thresholds of the hysteresis switch, and amplified so that the derivatives reliably exceed the thresholds. A transition from a zero to a one is the most substantial, fastest plus movement of voltage, and therefore will create the largest plus first derivative pulse. Since the quiet state of the derivative is sitting between the hysteresis thresholds, the plus pulse exceeds the plus threshold, switching the hysteresis switch plus, which re-establishes the data zero to one transition

  10. Signaling Pathways in Osteoclast Differentiation.

    PubMed

    Kim, Jung Ha; Kim, Nacksung

    2016-01-01

    Osteoclasts are multinucleated cells of hematopoietic origin that are responsible for the degradation of old bone matrix. Osteoclast differentiation and activity are controlled by two essential cytokines, macrophage colony-stimulating factor (M-CSF) and the receptor activator of nuclear factor-κB ligand (RANKL). M-CSF and RANKL bind to their respective receptors c-Fms and RANK to stimulate osteoclast differentiation through regulation of delicate signaling systems. Here, we summarize the critical or essential signaling pathways for osteoclast differentiation including M-CSF-c-Fms signaling, RANKL-RANK signaling, and costimulatory signaling for RANK. PMID:26865996

  11. Emerging Trends in Retrograde Signaling.

    PubMed

    Suvarna, Yashasvi; Maity, Nivedita; Shivamurthy, M C

    2016-05-01

    Retrograde signaling is defined as the signaling events leading from the plastids to the nucleus in plants and across the chemical synapse, from the postsynaptic neuron to the presynaptic neuron in animals. The discovery of various retrograde messengers has opened many avenues and clouds of thoughts as to the role of retrograde signaling. They have been implicated particularly in long-term potentiation (LTP) and synaptic plasticity. But the basic assumptions about retrograde signaling have not been studied upon for many years. This review focuses on established facts and hypothesis put forward in retrograde signaling. PMID:26081150

  12. Notch Signaling in Pancreatic Development

    PubMed Central

    Li, Xu-Yan; Zhai, Wen-Jun; Teng, Chun-Bo

    2015-01-01

    The Notch signaling pathway plays a significant role in embryonic cell fate determination and adult tissue homeostasis. Various studies have demonstrated the deep involvement of Notch signaling in the development of the pancreas and the lateral inhibition of Notch signaling in pancreatic progenitor differentiation and maintenance. The targeted inactivation of the Notch pathway components promotes premature differentiation of the endocrine pancreas. However, there is still the contrary opinion that Notch signaling specifies the endocrine lineage. Here, we review the current knowledge of the Notch signaling pathway in pancreatic development and its crosstalk with the Wingless and INT-1 (Wnt) and fibroblast growth factor (FGF) pathways. PMID:26729103

  13. Eph/ephrin signaling: networks

    PubMed Central

    Arvanitis, Dina; Davy, Alice

    2008-01-01

    Bidirectional signaling has emerged as an important signature by which Ephs and ephrins control biological functions. Eph/ephrin signaling participates in a wide spectrum of developmental processes, and cross-regulation with other communication pathways lies at the heart of the complexity underlying their function in vivo. Here, we review in vitro and in vivo data describing molecular, functional, and genetic interactions between Eph/ephrin and other cell surface signaling pathways. The complexity of Eph/ephrin function is discussed in terms of the pathways that regulate Eph/ephrin signaling and also the pathways that are regulated by Eph/ephrin signaling. PMID:18281458

  14. Interactive digital signal processor

    NASA Technical Reports Server (NTRS)

    Mish, W. H.; Wenger, R. M.; Behannon, K. W.; Byrnes, J. B.

    1982-01-01

    The Interactive Digital Signal Processor (IDSP) is examined. It consists of a set of time series analysis Operators each of which operates on an input file to produce an output file. The operators can be executed in any order that makes sense and recursively, if desired. The operators are the various algorithms used in digital time series analysis work. User written operators can be easily interfaced to the sysatem. The system can be operated both interactively and in batch mode. In IDSP a file can consist of up to n (currently n=8) simultaneous time series. IDSP currently includes over thirty standard operators that range from Fourier transform operations, design and application of digital filters, eigenvalue analysis, to operators that provide graphical output, allow batch operation, editing and display information.

  15. [Signal Processing Suite Design

    NASA Technical Reports Server (NTRS)

    Sahr, John D.; Mir, Hasan; Morabito, Andrew; Grossman, Matthew

    2003-01-01

    Our role in this project was to participate in the design of the signal processing suite to analyze plasma density measurements on board a small constellation (3 or 4) satellites in Low Earth Orbit. As we are new to space craft experiments, one of the challenges was to simply gain understanding of the quantity of data which would flow from the satellites, and possibly to interact with the design teams in generating optimal sampling patterns. For example, as the fleet of satellites were intended to fly through the same volume of space (displaced slightly in time and space), the bulk plasma structure should be common among the spacecraft. Therefore, an optimal, limited bandwidth data downlink would take advantage of this commonality. Also, motivated by techniques in ionospheric radar, we hoped to investigate the possibility of employing aperiodic sampling in order to gain access to a wider spatial spectrum without suffering aliasing in k-space.

  16. Collider Signal I :. Resonance

    NASA Astrophysics Data System (ADS)

    Tait, Tim M. P.

    2010-08-01

    These TASI lectures were part of the summer school in 2008 and cover the collider signal associated with resonances in models of physics beyond the Standard Model. I begin with a review of the Z boson, one of the best-studied resonances in particle physics, and review how the Breit-Wigner form of the propagator emerges in perturbation theory and discuss the narrow width approximation. I review how the LEP and SLAC experiments could use the kinematics of Z events to learn about fermion couplings to the Z. I then make a brief survey of models of physics beyond the Standard Model which predict resonances, and discuss some of the LHC observables which we can use to discover and identify the nature of the BSM physics. I finish up with a discussion of the linear moose that one can use for an effective theory description of a massive color octet vector particle.

  17. Signalling by tips.

    PubMed

    Feijó, José A; Costa, Sílvia S; Prado, Ana Margarida; Becker, Jörg D; Certal, Ana Catarina

    2004-10-01

    New molecules, including protein kinases, lipids and molecules that have neurotransmitter activities in animals have emerged as important players in tip-growing cells. Transcriptomics analysis reveals that the largest single class of genes expressed in pollen tubes encode signal transducers, reflecting the necessity to decode complex and diverse pathways that are associated with tip growth. Many of these pathways may use common intracellular second messengers, with ions and reactive oxygen species emerging as two major common denominators in many of the processes involved in tip growth. These second messengers might influence the actin cytoskeleton through known interactions with actin-binding proteins. In turn, changes in the dynamic properties of the cytoskeleton would define the basic polarity events needed to shape and modify tip-growing cells. PMID:15337103

  18. Olfactory receptor signaling.

    PubMed

    Antunes, Gabriela; Simoes de Souza, Fabio Marques

    2016-01-01

    The guanine nucleotide protein (G protein)-coupled receptors (GPCRs) superfamily represents the largest class of membrane protein in the human genome. More than a half of all GPCRs are dedicated to interact with odorants and are termed odorant-receptors (ORs). Linda Buck and Richard Axel, the Nobel Prize laureates in physiology or medicine in 2004, first cloned and characterized the gene family that encode ORs, establishing the foundations to the understanding of the molecular basis for odor recognition. In the last decades, a lot of progress has been done to unravel the functioning of the sense of smell. This chapter gives a general overview of the topic of olfactory receptor signaling and reviews recent advances in this field. PMID:26928542

  19. Signal conditioning system

    NASA Technical Reports Server (NTRS)

    Zahzah, Mohamad (Inventor); Korkosz, Gregory J. (Inventor); Bohr, Gerald (Inventor)

    2000-01-01

    A current-driven signal conditioning system comprising a first terminal, a second terminal, a strain gauge, and an instrumentation amplifier is disclosed. The strain gauge is adapted to measure a deformation of a structure and to generate a resistance which corresponds to the measured deformation. The instrumentation amplifier is adapted to be connected between the first terminal and the second terminal. The instrumentation amplifier is further adapted to be connected to the strain gauge and to place an output current on the second terminal. The output current is proportional to the resistance generated by the strain gauge. An output resister is coupled between the strain gauge and the second terminal, and a capacitor is coupled between the resister and the first terminal. A zenor diode is coupled between the first terminal and the strain gauge, and a diode is also coupled between the first terminal and the strain gauge.

  20. Elementary signals in ptychography.

    PubMed

    da Silva, Julio Cesar; Menzel, Andreas

    2015-12-28

    Ptychographic imaging has gained popularity for its high resolving power and sensitivity as well as for its ability to map simultaneously the sample's complex-valued refractive index and the illumination. Yet, despite significant progress that allows for reliable practical implementation, some of the technique's fundamentals remain poorly understood, and oftentimes successful data acquisition is either overly conservative or relies more on experimenters experience than on rational data acquisition strategies. Here, we propose a theoretical framework of ptychography, which is based on Gabor's notion of decomposition into elementary signals and the concept of frames. We demonstrate how this framework can straightforwardly be used to derive sampling requirements or to provide arguments on how to optimize the ptychographic scan. More generally, our theoretical framework can serve as a bridge between the experimental technique and the rich and well established mathematical disciplines of wavelets decomposition and spectrogram analysis. PMID:26832042

  1. Epigenetic signaling in schizophrenia.

    PubMed

    Ibi, Daisuke; González-Maeso, Javier

    2015-10-01

    Histone modifications and DNA methylation represent central dynamic and reversible processes that regulate gene expression and contribute to cellular phenotypes. These epigenetic marks have been shown to play fundamental roles in a diverse set of signaling and behavioral outcomes. Psychiatric disorders such as schizophrenia and depression are complex and heterogeneous diseases with multiple and independent factors that may contribute to their pathophysiology, making challenging to find a link between specific elements and the underlying mechanisms responsible for the disorder and its treatment. Growing evidences suggest that epigenetic modifications in certain brain regions and neural circuits represent a key mechanism through which environmental factors interact with individual's genetic constitution to affect risk of psychiatric conditions throughout life. This review focuses on recent advances that directly implicate epigenetic modifications in schizophrenia and antipsychotic drug action. PMID:26120009

  2. Quantitative measures for redox signaling.

    PubMed

    Pillay, Ché S; Eagling, Beatrice D; Driscoll, Scott R E; Rohwer, Johann M

    2016-07-01

    Redox signaling is now recognized as an important regulatory mechanism for a number of cellular processes including the antioxidant response, phosphokinase signal transduction and redox metabolism. While there has been considerable progress in identifying the cellular machinery involved in redox signaling, quantitative measures of redox signals have been lacking, limiting efforts aimed at understanding and comparing redox signaling under normoxic and pathogenic conditions. Here we have outlined some of the accepted principles for redox signaling, including the description of hydrogen peroxide as a signaling molecule and the role of kinetics in conferring specificity to these signaling events. Based on these principles, we then develop a working definition for redox signaling and review a number of quantitative methods that have been employed to describe signaling in other systems. Using computational modeling and published data, we show how time- and concentration- dependent analyses, in particular, could be used to quantitatively describe redox signaling and therefore provide important insights into the functional organization of redox networks. Finally, we consider some of the key challenges with implementing these methods. PMID:27151506

  3. Signaling on the endocytic pathway.

    PubMed

    McPherson, P S; Kay, B K; Hussain, N K

    2001-06-01

    Ligand binding to receptor tyrosine kinases and G-protein-coupled receptors initiates signal transduction events and induces receptor endocytosis via clathrin-coated pits and vesicles. While receptor-mediated endocytosis has been traditionally considered an effective mechanism to attenuate ligand-activated responses, more recent studies demonstrate that signaling continues on the endocytic pathway. In fact, certain signaling events, such as the activation of the extracellular signal-regulated kinases, appear to require endocytosis. Protein components of signal transduction cascades can assemble at clathrin coated pits and remain associated with endocytic vesicles following their dynamin-dependent release from the plasma membrane. Thus, endocytic vesicles can function as a signaling compartment distinct from the plasma membrane. These observations demonstrate that endocytosis plays an important role in the activation and propagation of signaling pathways. PMID:11389765

  4. EEG signal analysis: a survey.

    PubMed

    Subha, D Puthankattil; Joseph, Paul K; Acharya U, Rajendra; Lim, Choo Min

    2010-04-01

    The EEG (Electroencephalogram) signal indicates the electrical activity of the brain. They are highly random in nature and may contain useful information about the brain state. However, it is very difficult to get useful information from these signals directly in the time domain just by observing them. They are basically non-linear and nonstationary in nature. Hence, important features can be extracted for the diagnosis of different diseases using advanced signal processing techniques. In this paper the effect of different events on the EEG signal, and different signal processing methods used to extract the hidden information from the signal are discussed in detail. Linear, Frequency domain, time - frequency and non-linear techniques like correlation dimension (CD), largest Lyapunov exponent (LLE), Hurst exponent (H), different entropies, fractal dimension(FD), Higher Order Spectra (HOS), phase space plots and recurrence plots are discussed in detail using a typical normal EEG signal. PMID:20433058

  5. Integrin endosomal signalling suppresses anoikis

    PubMed Central

    Alanko, Jonna; Mai, Anja; Jacquemet, Guillaume; Schauer, Kristine; Kaukonen, Riina; Saari, Markku; Goud, Bruno; Ivaska, Johanna

    2016-01-01

    Integrin containing focal adhesions (FAs) transmit extracellular signals across the plasma membrane to modulate cell adhesion, signalling and survival. Although integrins are known to undergo continuous endo/exocytic traffic, potential impact of endocytic traffic on integrin-induced signals is unknown. Here, we demonstrate that integrin signalling is not restricted to cell-ECM adhesions and identify an endosomal signalling platform that supports integrin signalling away from the plasma membrane. We show that active focal adhesion kinase (FAK), an established marker of integrin-ECM downstream signalling, localises with active integrins on endosomes. Integrin endocytosis positively regulates adhesion-induced FAK activation, which is early endosome antigen-1 (EEA1) and small GTPase Rab21 dependent. FAK binds directly to purified endosomes and becomes activated on them, suggesting a role for endocytosis in enhancing distinct integrin downstream signalling events. Finally, endosomal integrin signalling contributes to cancer-related processes such as anoikis resistance, anchorage-independence and metastasis. Integrins are heterodimeric cell surface adhesion receptors functioning as integrators of the extra-cellular matrix (ECM) driven cues, the cellular cytoskeleton and the cellular signalling apparatus 1.Upon adhesion, integrins trigger the formation of plasma-membrane proximal large mechanosensing and signal-transmitting protein clusters depicted as “adhesomes” 2, 3. In addition, integrins undergo constant endocytic traffic to facilitate focal adhesion turnover, cell migration, invasion and cytokinesis 4. For other receptor systems it is well established that endocytic membrane traffic regulates bioavailability of cell-surface molecules and therefore the intensity and/or specificity of receptor-initiated signals 5, 6. Although active integrins and their ligands have been detected in endosomes 7–9 and increased integrin recycling to the plasma membrane contributes

  6. Efficient signal transmission by synchronization through compound chaotic signal

    NASA Astrophysics Data System (ADS)

    Murali, K.; Lakshmanan, M.

    1997-07-01

    The idea of synchronization of chaotic systems is further extended to the case where all the drive system variables are combined suitably to obtain a compound chaotic signal. An appropriate feedback loop is constructed in the response system to achieve synchronization among the variables of the drive and response systems. We apply this approach to transmit both analog and digital data signals in which the quality of the recovered signal is higher and the encoding is more secure.

  7. The principle of conformational signaling.

    PubMed

    Tompa, Peter

    2016-07-25

    Signal transduction is the primary process by which cells respond to changes in their physical and chemical environments. Cellular response is initiated through a signaling protein (a receptor), which interacts with the "signal", most often a novel molecule outside or inside the cell. The mechanism of activation of the receptor is a conformational change and/or covalent modification, which then sets in motion a signaling pathway, i.e. a cascade of modification and binding events that relay and amplify the message to eventually alter the state of the cell. In reflection of this general perception, concepts such as the "second messenger" and the "phosphorylation cascade" dominate our views of signal transduction. The idea I advocate here is that the non-covalent change in protein conformation itself might serve as the initial or intermittent "signal" in the cascade, and it is often the primary event being recognized and interpreted by downstream receptor(s). This signaling principle is intertwined with many other cellular regulatory concepts, such as (pathway) allostery, conformational spread, induced folding/unfolding, conformational memory, the hierarchical assembly of complexes, and the action of regulatory chaperones and prions. By elaborating on many examples and also recent advances in experimental methodology, I show that conformational signaling, although thus far underappreciated, is a general and robust signaling principle that most of the time operates in close interplay with covalent signals in the cell. PMID:27242242

  8. Regulation of Hippo signalling by p38 signalling.

    PubMed

    Huang, Dashun; Li, Xiaojiao; Sun, Li; Huang, Ping; Ying, Hao; Wang, Hui; Wu, Jiarui; Song, Haiyun

    2016-08-01

    The Hippo signalling pathway has a crucial role in growth control during development, and its dysregulation contributes to tumorigenesis. Recent studies uncover multiple upstream regulatory inputs into Hippo signalling, which affects phosphorylation of the transcriptional coactivator Yki/YAP/TAZ by Wts/Lats. Here we identify the p38 mitogen-activated protein kinase (MAPK) pathway as a new upstream branch of the Hippo pathway. In Drosophila, overexpression of MAPKK gene licorne (lic), or MAPKKK gene Mekk1, promotes Yki activity and induces Hippo target gene expression. Loss-of-function studies show that lic regulates Hippo signalling in ovary follicle cells and in the wing disc. Epistasis analysis indicates that Mekk1 and lic affect Hippo signalling via p38b and wts We further demonstrate that the Mekk1-Lic-p38b cascade inhibits Hippo signalling by promoting F-actin accumulation and Jub phosphorylation. In addition, p38 signalling modulates actin filaments and Hippo signalling in parallel to small GTPases Ras, Rac1, and Rho1. Lastly, we show that p38 signalling regulates Hippo signalling in mammalian cell lines. The Lic homologue MKK3 promotes nuclear localization of YAP via the actin cytoskeleton. Upregulation or downregulation of the p38 pathway regulates YAP-mediated transcription. Our work thus reveals a conserved crosstalk between the p38 MAPK pathway and the Hippo pathway in growth regulation. PMID:27402810

  9. Signaling during Kidney Development.

    PubMed

    Krause, Mirja; Rak-Raszewska, Aleksandra; Pietilä, Ilkka; Quaggin, Susan E; Vainio, Seppo

    2015-01-01

    The kidney plays an essential role during excretion of metabolic waste products, maintenance of key homeostasis components such as ion concentrations and hormone levels. It influences the blood pressure, composition and volume. The kidney tubule system is composed of two distinct cell populations: the nephrons forming the filtering units and the collecting duct system derived from the ureteric bud. Nephrons are composed of glomeruli that filter the blood to the Bowman's capsule and tubular structures that reabsorb and concentrate primary urine. The collecting duct is a Wolffian duct-derived epithelial tube that concentrates and collects urine and transfers it via the renal pelvis into the bladder. The mammalian kidney function depends on the coordinated development of specific cell types within a precise architectural framework. Due to the availability of modern analysis techniques, the kidney has become a model organ defining the paradigm to study organogenesis. As kidney diseases are a problem worldwide, the understanding of mammalian kidney cells is of crucial importance to develop diagnostic tools and novel therapies. This review focuses on how the pattern of renal development is generated, how the inductive signals are regulated and what are their effects on proliferation, differentiation and morphogenesis. PMID:25867084

  10. Angular signal radiography.

    PubMed

    Li, Panyun; Zhang, Kai; Bao, Yuan; Ren, Yuqi; Ju, Zaiqiang; Wang, Yan; He, Qili; Zhu, Zhongzhu; Huang, Wanxia; Yuan, Qingxi; Zhu, Peiping

    2016-03-21

    Microscopy techniques using visible photons, x-rays, neutrons, and electrons have made remarkable impact in many scientific disciplines. The microscopic data can often be expressed as the convolution of the spatial distribution of certain properties of the specimens and the inherent response function of the imaging system. The x-ray grating interferometer (XGI), which is sensitive to the deviation angle of the incoming x-rays, has attracted significant attention in the past years due to its capability in achieving x-ray phase contrast imaging with low brilliance source. However, the comprehensive and analytical theoretical framework is yet to be presented. Herein, we propose a theoretical framework termed angular signal radiography (ASR) to describe the imaging process of the XGI system in a classical, comprehensive and analytical manner. We demonstrated, by means of theoretical deduction and synchrotron based experiments, that the spatial distribution of specimens' physical properties, including absorption, refraction and scattering, can be extracted by ASR in XGI. Implementation of ASR in XGI offers advantages such as simplified phase retrieval algorithm, reduced overall radiation dose, and improved image acquisition speed. These advantages, as well as the limitations of the proposed method, are systematically investigated in this paper. PMID:27136780

  11. Purinergic signaling in epilepsy.

    PubMed

    Rassendren, François; Audinat, Etienne

    2016-09-01

    Until recently, analysis of the mechanisms underlying epilepsy was centered on neuron dysfunctions. Accordingly, most of the available pharmacological treatments aim at reducing neuronal excitation or at potentiating neuronal inhibition. These therapeutic options can lead to obvious secondary effects, and, moreover, seizures cannot be controlled by any known medication in one-third of the patients. A purely neurocentric view of brain functions and dysfunctions has been seriously questioned during the past 2 decades because of the accumulation of experimental data showing the functional importance of reciprocal interactions between glial cells and neurons. In the case of epilepsy, our current knowledge of the human disease and analysis of animal models clearly favor the involvement of astrocytes and microglial cells during the progression of the disease, including at very early stages, opening the way to the identification of new therapeutic targets. Purinergic signaling is a fundamental feature of neuron-glia interactions, and increasing evidence indicates that modifications of this pathway contribute to the functional remodeling of the epileptic brain. This Review discusses the recent experimental results indicating the roles of astrocytic and microglial P2X and P2Y receptors in epilepsy. © 2016 Wiley Periodicals, Inc. PMID:27302739

  12. Signaling during Kidney Development

    PubMed Central

    Krause, Mirja; Rak-Raszewska, Aleksandra; Pietilä, Ilkka; Quaggin, Susan E.; Vainio, Seppo

    2015-01-01

    The kidney plays an essential role during excretion of metabolic waste products, maintenance of key homeostasis components such as ion concentrations and hormone levels. It influences the blood pressure, composition and volume. The kidney tubule system is composed of two distinct cell populations: the nephrons forming the filtering units and the collecting duct system derived from the ureteric bud. Nephrons are composed of glomeruli that filter the blood to the Bowman’s capsule and tubular structures that reabsorb and concentrate primary urine. The collecting duct is a Wolffian duct-derived epithelial tube that concentrates and collects urine and transfers it via the renal pelvis into the bladder. The mammalian kidney function depends on the coordinated development of specific cell types within a precise architectural framework. Due to the availability of modern analysis techniques, the kidney has become a model organ defining the paradigm to study organogenesis. As kidney diseases are a problem worldwide, the understanding of mammalian kidney cells is of crucial importance to develop diagnostic tools and novel therapies. This review focuses on how the pattern of renal development is generated, how the inductive signals are regulated and what are their effects on proliferation, differentiation and morphogenesis. PMID:25867084

  13. SUMO chains: polymeric signals.

    PubMed

    Vertegaal, Alfred C O

    2010-02-01

    Ubiquitin and ubiquitin-like proteins are conjugated to a wide variety of target proteins that play roles in all biological processes. Target proteins are conjugated to ubiquitin monomers or to ubiquitin polymers that form via all seven internal lysine residues of ubiquitin. The fate of these target proteins is controlled in a chain architecture-dependent manner. SUMO (small ubiquitin-related modifier) shares the ability of ubiquitin to form chains via internal SUMOylation sites. Interestingly, a SUMO-binding site in Ubc9 is important for SUMO chain synthesis. Similar to ubiquitin-polymer cleavage by USPs (ubiquitin-specific proteases), SUMO chain formation is reversible. SUMO polymers are cleaved by the SUMO proteases SENP6 [SUMO/sentrin/SMT3 (suppressor of mif two 3)-specific peptidase 6], SENP7 and Ulp2 (ubiquitin-like protease 2). SUMO chain-binding proteins including ZIP1, SLX5/8 (synthetic lethal of unknown function 5/8), RNF4 (RING finger protein 4) and CENP-E (centromere-associated protein E) have been identified that interact non-covalently with SUMO chains, thereby regulating target proteins that are conjugated to SUMO multimers. SUMO chains play roles in replication, in the turnover of SUMO targets by the proteasome and during mitosis and meiosis. Thus signalling via polymers is an exciting feature of the SUMO family. PMID:20074033

  14. Steganography in arrhythmic electrocardiogram signal.

    PubMed

    Edward Jero, S; Ramu, Palaniappan; Ramakrishnan, S

    2015-08-01

    Security and privacy of patient data is a vital requirement during exchange/storage of medical information over communication network. Steganography method hides patient data into a cover signal to prevent unauthenticated accesses during data transfer. This study evaluates the performance of ECG steganography to ensure secured transmission of patient data where an abnormal ECG signal is used as cover signal. The novelty of this work is to hide patient data into two dimensional matrix of an abnormal ECG signal using Discrete Wavelet Transform and Singular Value Decomposition based steganography method. A 2D ECG is constructed according to Tompkins QRS detection algorithm. The missed R peaks are computed using RR interval during 2D conversion. The abnormal ECG signals are obtained from the MIT-BIH arrhythmia database. Metrics such as Peak Signal to Noise Ratio, Percentage Residual Difference, Kullback-Leibler distance and Bit Error Rate are used to evaluate the performance of the proposed approach. PMID:26736533

  15. Requirements for signaling channel authentication

    SciTech Connect

    Tarman, T.D.

    1995-12-11

    This contribution addresses requirements for ATM signaling channel authentication. Signaling channel authentication is an ATM security service that binds an ATM signaling message to its source. By creating this binding, the message recipient, and even a third party, can confidently verify that the message originated from its claimed source. This provides a useful mechanism to mitigate a number of threats. For example, a denial of service attack which attempts to tear-down an active connection by surreptitiously injecting RELEASE or DROP PARTY messages could be easily thwarted when authenticity assurances are in place for the signaling channel. Signaling channel authentication could also be used to provide the required auditing information for accurate billing which is impervious to repudiation. Finally, depending on the signaling channel authentication mechanism, end-to-end integrity of the message (or at least part of it) can be provided. None of these capabilities exist in the current specifications.

  16. Hedgehog signaling in skin cancers

    PubMed Central

    Li, Chengxin; Chi, Sumin; Xie, Jingwu

    2011-01-01

    An increasing progress on the role of Hedgehog (Hh) signaling for carcinogenesis has been achieved since the link of Hh pathway to human cancer was firstly established. In particular, the critical role of Hh signaling in the development of Basal cell carcinoma (BCC) has been convincingly demonstrated by genetic mutation analyses, mouse models of BCCs, and successful clinical trials of BCCs using Hh signaling inhibitors. In addition, the Hh pathway activity is also reported to be involved in the pathogenesis of Squamous Cell Carcinoma (SCC), melanoma and Merkel Cell Carcinoma. These findings have significant new paradigm on Hh signaling transduction, its mechanisms in skin cancer and even therapeutic approaches for BCC. In this review, we will summarize the major advances in the understanding of Hh signaling transduction, the roles of Hh signaling in skin cancer development, and the current implications of “mechanism-based” therapeutic strategies. PMID:21397013

  17. Algorithm evolution for signal understanding

    SciTech Connect

    Teller, A.

    1996-12-31

    Automated program evolution has existed in some form for over thirty years. Signal understanding (e.g., signal classification) has been a scientific concern for even longer than that. Interest in generating, through machine learning techniques, a general signal understanding system is a newer topic, but has recently attracted considerable attention. First, I have proposed to define and create a machine learning mechanism for generating signal understanding systems independent of the signal`s type and size. Second, I have proposed to do this through an evolutionary strategy that is an extension of genetic programming. Third, I have proposed to introduce a suite of sub-mechanisms that not only contribute to the power of the thesis mechanism, but are also contributions to the understanding of the learning technique developed.

  18. Calcium signalling remodelling and disease.

    PubMed

    Berridge, Michael J

    2012-04-01

    A wide range of Ca2+ signalling systems deliver the spatial and temporal Ca2+ signals necessary to control the specific functions of different cell types. Release of Ca2+ by InsP3 (inositol 1,4,5-trisphosphate) plays a central role in many of these signalling systems. Ongoing transcriptional processes maintain the integrity and stability of these cell-specific signalling systems. However, these homoeostatic systems are highly plastic and can undergo a process of phenotypic remodelling, resulting in the Ca2+ signals being set either too high or too low. Such subtle dysregulation of Ca2+ signals have been linked to some of the major diseases in humans such as cardiac disease, schizophrenia, bipolar disorder and Alzheimer's disease. PMID:22435804

  19. The autophagy pathway maintained signaling crosstalk with the Keap1-Nrf2 system through p62 in auditory cells under oxidative stress.

    PubMed

    Hayashi, Ken; Dan, Katsuaki; Goto, Fumiyuki; Tshuchihashi, Nana; Nomura, Yasuyuki; Fujioka, Masato; Kanzaki, Sho; Ogawa, Kaoru

    2015-02-01

    The main purposes of our study were to consider the effect of autophagy on auditory cells under oxidative stress, and the function of possible crosstalk among p62, Keap1 and Nrf2 in autophagy-deficient auditory cells. First, we described how cell death was induced in auditory cell line (HEI-OC1) exposed to H2O2. We found that the decision for the cell death of auditory cells under oxidative stress depends on the balance between autophagy and necrosis due to ATP depletion, and autophagy plays a cytoprotective function in oxidative stress-induced necrosis. Our data clearly suggested that autophagy was a cell survival mechanism in H2O2-induced cell death, based on the observation that suppression of autophagy by knockdown of Atg7 sensitized, whereas activation of autophagy by rapamycin protected against H2O2-induced cell death. Next, our results regarding the relationship among p62, Nrf2 and Keap1 by siRNA paradoxically showed that p62 creates a positive feedback loop in the Keap1/Nrf2 pathway. Autophagy impaired by Atg7 knockdown degrades Keap1 in a p62-dependent manner, whereas Nrf2 is activated. As a result, the cell death induced by H2O2 was promoted in auditory cells. Taken together, these results suggested that the autophagy pathway maintained signaling crosstalk with the Keap1-Nrf2 system through p62 in auditory cells under oxidative stress. PMID:25435427

  20. Synchronous Photodiode-Signal Sampler

    NASA Technical Reports Server (NTRS)

    Primus, Howard K.

    1988-01-01

    Synchronous sampling circuit increases signal-to-noise ratio of measurements of chopped signal of known phase and frequency in presence of low-frequency or dc background noise. Used with linear array of photoelectric sensors for locating edge of metal plate. Multiplexing circuit cycles through 16 light-emitting-diode/photodiode pairs, under computer control. Synchronized with multiplexer so edge detector makes one background-subtracted signal measurement per emitter/detector pair in turn.

  1. The TIR-domain-containing adapter inducing interferon-β-dependent signaling cascade plays a crucial role in ischemia–reperfusion-induced retinal injury, whereas the contribution of the myeloid differentiation primary response 88-dependent signaling cascade is not as pivotal

    PubMed Central

    Dvoriantchikova, Galina; Santos, Andrea Rachelle C; Danek, Dagmara; Dvoriantchikova, Xenia; Ivanov, Dmitry

    2014-01-01

    Toll-like receptor 4 (Tlr4) plays an important role in ischemia–reperfusion (IR)-induced retinal inflammation and damage. However, the role of two Tlr4-dependent signaling cascades, myeloid differentiation primary response 88 (Myd88) and TIR-domain-containing adapter inducing interferon-β (Trif), in retinal IR injury is poorly understood. In this study, we investigated the contribution of the Myd88-dependent and Trif-dependent signaling cascades in retinal damage and inflammation triggered by IR, by using Myd88 knockout (Myd88KO) and Trif knockout (TrifKO) mice. Retinal IR injury was induced by unilateral elevation of intraocular pressure for 45 min by direct corneal cannulation. To study IR-induced retinal ganglion cell (RGC) death in vitro, we used an oxygen and glucose deprivation (OGD) model. Our data suggested that Myd88 was present in many retinal layers of sham-operated and ischemic mice, whereas Trif was mainly present in the ganglion cell layer (GCL). The level of Myd88 was increased in the retina after IR. We found that retinas of TrifKO mice had a significantly reduced neurotoxic pro-inflammatory response and significantly increased survival of the GCL neurons after IR. Although Myd88KO mice had relatively low levels of inflammation in ischemic retinas, their levels of IR-induced retinal damage were notably higher than those of TrifKO mice. We also found that Trif-deficient RGCs were more resistant to death induced by OGD than were RGCs isolated from Myd88KO mice. These data suggested that, as compared with the Myd88-dependent signaling cascade, Trif signaling contributes significantly to retinal damage after IR. PMID:24754835

  2. Protein modules and signalling networks

    NASA Astrophysics Data System (ADS)

    Pawson, Tony

    1995-02-01

    Communication between cells assumes particular importance in multicellular organisms. The growth, migration and differentiation of cells in the embryo, and their organization into specific tissues, depend on signals transmitted from one cell to another. In the adult, cell signalling orchestrates normal cellular behaviour and responses to wounding and infection. The consequences of breakdowns in this signalling underlie cancer, diabetes and disorders of the immune and cardiovascular systems. Conserved protein domains that act as key regulatory participants in many of these different signalling pathways are highlighted.

  3. Chirp signal generator feasibility study

    NASA Astrophysics Data System (ADS)

    Chomiki, M.; Genauzeau, F.

    1983-03-01

    The feasibility of a signal generator with 100 microsec temporal dispersion, and 330 MHz frequency dispersion, for the ERS-1 (ESA satellite) radar altimeter, with a solid state transmitter, is demonstrated. Two surface wave dispersive filters (20 and 80 microsec dispersion) are cascaded with a frequency multiplier to give a 900 MHz output signal. The first filter receives an impulse which ensures an output signal to noise ratio 20 dB. The chirp signal output level is 0 dBm; amplitude fluctuation 2 dBcc, phase error compared with theory 10 deg rms; short term jitter 100 psec. The generator model occupies 0.5 l, and consumes 7 W.

  4. Recognition of a signal peptide by the signal recognition particle

    PubMed Central

    Janda, Claudia Y.; Li, Jade; Oubridge, Chris; Hernández, Helena; Robinson, Carol V.; Nagai, Kiyoshi

    2010-01-01

    Targeting of proteins to appropriate sub-cellular compartments is a crucial process in all living cells. Secretory and membrane proteins usually contain an N-terminal signal peptide, which is recognised by the signal recognition particle (SRP) when nascent polypeptide chains emerge from the ribosome. The SRP-ribosome nascent chain complex is then targeted through its GTP-dependent interaction with SRP-receptor to the protein-conducting channel on endoplasmic reticulum membrane in eukaryotes or plasma membrane in bacteria. A universally conserved component of SRP1, 2, SRP54 or its bacterial homolog, fifty-four homolog (Ffh), binds the signal peptides which have a highly divergent sequence divisible into a positively charged n-region, an h-region commonly containing 8-20 hydrophobic residues and a polar c-region 3-5. No structure has been reported that exemplified SRP54 binding of any signal sequence. We have produced a fusion protein between Sulfolobus solfataricus SRP54 and a signal peptide connected via a flexible linker. This fusion protein oligomerises in solution, through interaction between the SRP54 and signal peptide moieties belonging to different chains, and it is functional, able to bind SRP RNA and SRP-receptor FtsY. Here we present the crystal structure at 3.5 Å resolution of an SRP54-signal peptide complex in the dimer, which reveals how a signal sequence is recognised by SRP54. PMID:20364120

  5. Correlation theory-based signal processing method for CMF signals

    NASA Astrophysics Data System (ADS)

    Shen, Yan-lin; Tu, Ya-qing

    2016-06-01

    Signal processing precision of Coriolis mass flowmeter (CMF) signals affects measurement accuracy of Coriolis mass flowmeters directly. To improve the measurement accuracy of CMFs, a correlation theory-based signal processing method for CMF signals is proposed, which is comprised of the correlation theory-based frequency estimation method and phase difference estimation method. Theoretical analysis shows that the proposed method eliminates the effect of non-integral period sampling signals on frequency and phase difference estimation. The results of simulations and field experiments demonstrate that the proposed method improves the anti-interference performance of frequency and phase difference estimation and has better estimation performance than the adaptive notch filter, discrete Fourier transform and autocorrelation methods in terms of frequency estimation and the data extension-based correlation, Hilbert transform, quadrature delay estimator and discrete Fourier transform methods in terms of phase difference estimation, which contributes to improving the measurement accuracy of Coriolis mass flowmeters.

  6. Ramentaceone, a Naphthoquinone Derived from Drosera sp., Induces Apoptosis by Suppressing PI3K/Akt Signaling in Breast Cancer Cells.

    PubMed

    Kawiak, Anna; Lojkowska, Ewa

    2016-01-01

    The phosphoinositide 3-kinase (PI3K) signaling pathway plays an important role in processes critical for breast cancer progression and its upregulation confers increased resistance of cancer cells to chemotherapy and radiation. The present study aimed at determining the activity of ramentaceone, a constituent of species in the plant genera Drosera, toward breast cancer cells and defining the involvement of PI3K/Akt inhibition in ramentaceone-mediated cell death induction. The results showed that ramentaceone exhibited high antiproliferative activity toward breast cancer cells, in particular HER2-overexpressing breast cancer cells. The mode of cell death induced by ramentaceone was through apoptosis as determined by cytometric analysis of caspase activity and Annexin V staining. Apoptosis induction was found to be mediated by inhibition of PI3K/Akt signaling and through targeting its downstream anti-apoptotic effectors. Ramentaceone inhibited PI3-kinase activity, reduced the expression of the PI3K protein and inhibited the phosphorylation of the Akt protein in breast cancer cells. The expression of the anti-apoptotic Bcl-2 protein was decreased and the levels of the pro-apoptotic proteins, Bax and Bak, were elevated. Moreover, inhibition of PI3K and silencing of Akt expression increased the sensitivity of cells to ramentaceone-induced apoptosis. In conclusion, our results indicate that ramentaceone induces apoptosis in breast cancer cells through PI3K/Akt signaling inhibition. These findings suggest further investigation of ramentaceone as a potential therapeutic agent in breast cancer therapy, in particular HER2-positive breast cancer. PMID:26840401

  7. Ramentaceone, a Naphthoquinone Derived from Drosera sp., Induces Apoptosis by Suppressing PI3K/Akt Signaling in Breast Cancer Cells

    PubMed Central

    Kawiak, Anna; Lojkowska, Ewa

    2016-01-01

    The phosphoinositide 3-kinase (PI3K) signaling pathway plays an important role in processes critical for breast cancer progression and its upregulation confers increased resistance of cancer cells to chemotherapy and radiation. The present study aimed at determining the activity of ramentaceone, a constituent of species in the plant genera Drosera, toward breast cancer cells and defining the involvement of PI3K/Akt inhibition in ramentaceone-mediated cell death induction. The results showed that ramentaceone exhibited high antiproliferative activity toward breast cancer cells, in particular HER2-overexpressing breast cancer cells. The mode of cell death induced by ramentaceone was through apoptosis as determined by cytometric analysis of caspase activity and Annexin V staining. Apoptosis induction was found to be mediated by inhibition of PI3K/Akt signaling and through targeting its downstream anti-apoptotic effectors. Ramentaceone inhibited PI3-kinase activity, reduced the expression of the PI3K protein and inhibited the phosphorylation of the Akt protein in breast cancer cells. The expression of the anti-apoptotic Bcl-2 protein was decreased and the levels of the pro-apoptotic proteins, Bax and Bak, were elevated. Moreover, inhibition of PI3K and silencing of Akt expression increased the sensitivity of cells to ramentaceone-induced apoptosis. In conclusion, our results indicate that ramentaceone induces apoptosis in breast cancer cells through PI3K/Akt signaling inhibition. These findings suggest further investigation of ramentaceone as a potential therapeutic agent in breast cancer therapy, in particular HER2-positive breast cancer. PMID:26840401

  8. Intracellular Signal Modulation by Nanomaterials

    PubMed Central

    Hussain, Salik; Garantziotis, Stavros; Rodrigues-Lima, Fernando; Dupret, Jean-Marie; Baeza-Squiban, Armelle; Boland, Sonja

    2016-01-01

    A thorough understanding of the interactions of nanomaterials with biological systems and the resulting activation of signal transduction pathways is essential for the development of safe and consumer friendly nanotechnology. Here we present an overview of signaling pathways induced by nanomaterial exposures and describe the possible correlation of their physicochemical characteristics with biological outcomes. In addition to the hierarchical oxidative stress model and a review of the intrinsic and cell-mediated mechanisms of reactive Oxygen species (ROS) generating capacities of nanomaterials, we also discuss other oxidative stress dependent and independent cellular signaling pathways. Induction of the inflammasome, calcium signaling, and endoplasmic reticulum stress are reviewed. Furthermore, the uptake mechanisms can crucially affect the cytotoxicity of nanomaterials and membrane-dependent signaling pathways can be responsible for cellular effects of nanomaterials. Epigenetic regulation by nanomaterials effects of nanoparticle-protein interactions on cell signaling pathways, and the induction of various cell death modalities by nanomaterials are described. We describe the common trigger mechanisms shared by various nanomaterials to induce cell death pathways and describe the interplay of different modalities in orchestrating the final outcome after nanomaterial exposures. A better understanding of signal modulations induced by nanomaterials is not only essential for the synthesis and design of safer nanomaterials but will also help to discover potential nanomedical applications of these materials. Several biomedical applications based on the different signaling pathways induced by nanomaterials are already proposed and will certainly gain a great deal of attraction in the near future. PMID:24683030

  9. Noise Reduction by Signal Accumulation

    ERIC Educational Resources Information Center

    Kraftmakher, Yaakov

    2006-01-01

    The aim of this paper is to show how the noise reduction by signal accumulation can be accomplished with a data acquisition system. This topic can be used for student projects. In many cases, the noise reduction is an unavoidable part of experimentation. Several techniques are known for this purpose, and among them the signal accumulation is the…

  10. Echolocation signals of wild dolphins

    NASA Astrophysics Data System (ADS)

    Au, W. W. L.

    2004-07-01

    Most of our understanding of dolphin echolocation has come from studies of captive dolphins performing various echolocation tasks. Recently, measurements of echolocation signals in the wild have expanded our understanding of the characteristics of these signals in a natural setting. Measuring undistorted dolphin echolocation signals with free swimming dolphins in the field can be a challenging task. A four hydrophone array arranged in a symmetrical star pattern was used to measure the echolocation signals of four species of dolphins in the wild. Echolocation signals of the following dolphins have been measured with the symmetrical star array: white-beaked dolphins in Iceland, Atlantic spotted dolphins in the Bahamas, killer whales in British Columbia, and dusky dolphins in New Zealand. There are many common features in the echolocation signals of the different species. Most of the signals had spectra that were bimodal: two peaks, one at low frequencies and another about an octave higher in frequency. The source level of the sonar transmission varies as a function of 20log R, suggesting a form of time-varying gain but on the transmitting end of the sonar process rather than the receiving end. The results of the field work call into question the issue of whether the signals used by captive dolphins may be shaped by the task they are required to perform rather than what they would do more naturally.

  11. Thermocouple-Signal-Conditioning Circuit

    NASA Technical Reports Server (NTRS)

    Simon, Richard A.

    1991-01-01

    Thermocouple-signal-conditioning circuit acting in conjunction with thermocouple, exhibits electrical behavior of voltage in series with resistance. Combination part of input bridge circuit of controller. Circuit configured for either of two specific applications by selection of alternative resistances and supply voltages. Includes alarm circuit detecting open circuit in thermocouple and provides off-scale output to signal malfunctions.

  12. Hybrid respiration-signal conditioner

    NASA Technical Reports Server (NTRS)

    Rinard, G. A.; Steffen, D. A.; Sturm, R. E.

    1979-01-01

    Hybrid impedance-pneumograph and respiration-rate signal conditioner element of hand-held vital signs monitor measures changes in impedance of chest during breathing cycle and generates analog respiration signal as output along with synchronous square wave that can be monitored by breath-rate processor.

  13. Retrograde signaling: Organelles go networking.

    PubMed

    Kleine, Tatjana; Leister, Dario

    2016-08-01

    The term retrograde signaling refers to the fact that chloroplasts and mitochondria utilize specific signaling molecules to convey information on their developmental and physiological states to the nucleus and modulate the expression of nuclear genes accordingly. Signals emanating from plastids have been associated with two main networks: 'Biogenic control' is active during early stages of chloroplast development, while 'operational' control functions in response to environmental fluctuations. Early work focused on the former and its major players, the GUN proteins. However, our view of retrograde signaling has since been extended and revised. Elements of several 'operational' signaling circuits have come to light, including metabolites, signaling cascades in the cytosol and transcription factors. Here, we review recent advances in the identification and characterization of retrograde signaling components. We place particular emphasis on the strategies employed to define signaling components, spanning the entire spectrum of genetic screens, metabolite profiling and bioinformatics. This article is part of a Special Issue entitled 'EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2-6, 2016', edited by Prof. Paolo Bernardi. PMID:26997501

  14. Bioelectric signal analysis and measurement

    NASA Technical Reports Server (NTRS)

    Lai, D. C.

    1975-01-01

    Nonstationary time series techniques are used to analyze EEG signals for the estimation of alertness. A time varying order is extracted in sequential time series measurement of these data and strategies are devised for obtaining optimal representation of the EEG signal.

  15. Signaling equilibria in sensorimotor interactions.

    PubMed

    Leibfried, Felix; Grau-Moya, Jordi; Braun, Daniel A

    2015-08-01

    Although complex forms of communication like human language are often assumed to have evolved out of more simple forms of sensorimotor signaling, less attention has been devoted to investigate the latter. Here, we study communicative sensorimotor behavior of humans in a two-person joint motor task where each player controls one dimension of a planar motion. We designed this joint task as a game where one player (the sender) possesses private information about a hidden target the other player (the receiver) wants to know about, and where the sender's actions are costly signals that influence the receiver's control strategy. We developed a game-theoretic model within the framework of signaling games to investigate whether subjects' behavior could be adequately described by the corresponding equilibrium solutions. The model predicts both separating and pooling equilibria, in which signaling does and does not occur respectively. We observed both kinds of equilibria in subjects and found that, in line with model predictions, the propensity of signaling decreased with increasing signaling costs and decreasing uncertainty on the part of the receiver. Our study demonstrates that signaling games, which have previously been applied to economic decision-making and animal communication, provide a framework for human signaling behavior arising during sensorimotor interactions in continuous and dynamic environments. PMID:25935748

  16. Signals in Communication Engineering History

    ERIC Educational Resources Information Center

    Consonni, Denise; Silva, Magno T. M.

    2010-01-01

    This paper is a study of various electric signals, which have been employed throughout the history of communication engineering in its two main landmarks: the telegraph and the telephone. The signals are presented in their time and frequency domain representations. The historical order has been followed in the presentation: wired systems, spark…

  17. Perception and Signaling of Strigolactones

    PubMed Central

    Marzec, Marek

    2016-01-01

    Strigolactones (SLs), a recently discovered class of phytohormones, are important regulators of plant growth and development. While the biosynthetic pathway of these molecules is well documented, until recently there was not much known about the molecular mechanisms underlying SL perception and signal transduction in plants. Certain aspects of their perception and signaling, including the hormone-mediated interaction between receptor and F-box protein, degradation of suppressor proteins and activation of transcription factors, are also found in other phytohormones. However, some of SL signaling features seem to be specific for the SL signaling pathway. These include the enzymatic activity of the SL receptor and its destabilization caused by SLs. This review summarizes the current knowledge about SL signaling pathway in plants. PMID:27602041

  18. Signal focusing through active transport

    NASA Astrophysics Data System (ADS)

    Godec, Aljaž; Metzler, Ralf

    2015-07-01

    The accuracy of molecular signaling in biological cells and novel diagnostic devices is ultimately limited by the counting noise floor imposed by the thermal diffusion. Motivated by the fact that messenger RNA and vesicle-engulfed signaling molecules transiently bind to molecular motors and are actively transported in biological cells, we show here that the random active delivery of signaling particles to within a typical diffusion distance to the receptor generically reduces the correlation time of the counting noise. Considering a variety of signaling particle sizes from mRNA to vesicles and cell sizes from prokaryotic to eukaryotic cells, we show that the conditions for active focusing—faster and more precise signaling—are indeed compatible with observations in living cells. Our results improve the understanding of molecular cellular signaling and novel diagnostic devices.

  19. Protein Regulation in Signal Transduction.

    PubMed

    Lee, Michael J; Yaffe, Michael B

    2016-01-01

    SUMMARYCells must respond to a diverse, complex, and ever-changing mix of signals, using a fairly limited set of parts. Changes in protein level, protein localization, protein activity, and protein-protein interactions are critical aspects of signal transduction, allowing cells to respond highly specifically to a nearly limitless set of cues and also to vary the sensitivity, duration, and dynamics of the response. Signal-dependent changes in levels of gene expression and protein synthesis play an important role in regulation of protein levels, whereas posttranslational modifications of proteins regulate their degradation, localization, and functional interactions. Protein ubiquitylation, for example, can direct proteins to the proteasome for degradation or provide a signal that regulates their interactions and/or location within the cell. Similarly, protein phosphorylation by specific kinases is a key mechanism for augmenting protein activity and relaying signals to other proteins that possess domains that recognize the phosphorylated residues. PMID:27252361

  20. Optimal investment in social signals.

    PubMed

    Dessalles, Jean-Louis

    2014-06-01

    This study is an attempt to determine how much individuals should invest in social communication, depending on the type of relationships they may form. Two simple models of social relationships are considered. In both models, individuals emit costly signals to advertise their "quality" as potential friends. Relationships are asymmetrical or symmetrical. In the asymmetrical condition (first model), we observe that low-quality individuals are discouraged from signaling. In the symmetrical condition (second model), all individuals invest in communication. In both models, high-quality individuals (elite) do not compete and signal uniformly. The level of this uniform signal and the size of the "elite" turn out to be controlled by the accuracy of signals. The two models may be relevant to several aspects of animal and human social communication. PMID:24495174

  1. A highly parallel signal processor

    NASA Astrophysics Data System (ADS)

    Bigham, Jackson D., Jr.

    There is an increasing need for signal processors functional across a broad range of problems, from radar systems to E-O and ESM applications. To meet this challenge, a signal processing system capable of efficiently meeting the processing requirements over a broad range of avionics sensor systems has been developed. The CDC Parallel Modular Signal Processor (PMSP) is a complete MIL/E-5400-qualified digital signal processing system capable of computation rates greater than 600 MOPS (million operations per second). The signal processing element of the PMSP is the Micro-AFP. It is an all-VLSI processor capable of executing multiple simultaneous operations. Up to five Micro-AFPs and 12 MB of main store memory (MSM), along with associated control and I/O functions, are contained in the PMSP's standard ATR enclosure.

  2. Perception and Signaling of Strigolactones.

    PubMed

    Marzec, Marek

    2016-01-01

    Strigolactones (SLs), a recently discovered class of phytohormones, are important regulators of plant growth and development. While the biosynthetic pathway of these molecules is well documented, until recently there was not much known about the molecular mechanisms underlying SL perception and signal transduction in plants. Certain aspects of their perception and signaling, including the hormone-mediated interaction between receptor and F-box protein, degradation of suppressor proteins and activation of transcription factors, are also found in other phytohormones. However, some of SL signaling features seem to be specific for the SL signaling pathway. These include the enzymatic activity of the SL receptor and its destabilization caused by SLs. This review summarizes the current knowledge about SL signaling pathway in plants. PMID:27602041

  3. Spatiotemporal signalling in plant development

    PubMed Central

    Sparks, Erin; Wachsman, Guy; Benfey, Philip N.

    2013-01-01

    Plants, being sessile organisms, need to respond to changing environments, and as a result they have evolved unique signalling mechanisms that allow rapid communication between different parts of the plant. The signalling mechanisms that direct plant development include long-range effectors, such as phytohormones, and molecules with a local intra-organ range, such as peptides, transcription factors and some small RNAs. In this Review, we highlight recent advances in understanding plant signalling mechanisms and discuss how different classes of signalling networks can integrate with gene regulatory networks and contribute to plant development. In some cases, we also address the evolutionary context of mechanisms and discuss possible links between the lifestyle of plants and selection for different signalling mechanisms. PMID:23949543

  4. Evolution of Cytokine Receptor Signaling.

    PubMed

    Liongue, Clifford; Sertori, Robert; Ward, Alister C

    2016-07-01

    Cytokines represent essential mediators of cell-cell communication with particularly important roles within the immune system. These secreted factors are produced in response to developmental and/or environmental cues and act via cognate cytokine receptors on target cells, stimulating specific intracellular signaling pathways to facilitate appropriate cellular responses. This review describes the evolution of cytokine receptor signaling, focusing on the class I and class II receptor families and the downstream JAK-STAT pathway along with its key negative regulators. Individual components generated over a long evolutionary time frame coalesced to form an archetypal signaling pathway in bilateria that was expanded extensively during early vertebrate evolution to establish a substantial "core" signaling network, which has subsequently undergone limited diversification within discrete lineages. The evolution of cytokine receptor signaling parallels that of the immune system, particularly the emergence of adaptive immunity, which has likely been a major evolutionary driver. PMID:27317733

  5. Cell death induced by direct laser activation of singlet oxygen at 1270 nm

    NASA Astrophysics Data System (ADS)

    Anquez, F.; El Yazidi Belkoura, I.; Suret, P.; Randoux, S.; Courtade, E.

    2013-02-01

    Singlet oxygen plays a major role in many chemical and biological photo-oxidation processes. It has a high chemical reactivity, which is commonly harnessed for therapeutic issues. Indeed, singlet oxygen is recognized as the major cytotoxic agent in photodynamic therapy. In this treatment of cancer, singlet oxygen is created, among other reactive species, by an indirect transfer of energy from light to molecular oxygen via excitation of a photosensitizer. In this paper, we show that the conventional singlet oxygen production scheme can be simplified. Production of singlet oxygen is achieved in living cells from photosensitizer-free 1270 nm laser excitation of the electronic ground state of molecular oxygen. The quantity of singlet oxygen produced in this way is sufficient to induce an oxidative stress leading to cell death. Other effects such as thermal stress are discriminated, and we conclude that cell death is only due to singlet oxygen creation. This new simplified scheme of singlet oxygen activation can be seen as a breakthrough for phototherapies of malignant diseases and/or as a non-invasive possibility to generate reactive oxygen species in a tightly controlled manner.

  6. Apoptosis and cell proliferation in the mouse model of embryonic death induced by Tritrichomonas foetus infection.

    PubMed

    Woudwyk, Mariana A; Zanuzzi, Carolina N; Nishida, Fabián; Gimeno, Eduardo J; Soto, Pedro; Monteavaro, Cristina E; Barbeito, Claudio G

    2015-09-01

    Bovine tritrichomonosis is a sexually transmitted disease caused by the protozoon Tritrichomonas foetus and characterised by embryonic-death and abortion. During pregnancy, the processes of cell proliferation and death play a crucial role for blastocyst implantation and the subsequent maintenance of early pregnancy, and their misbalance may lead to the abortion. In this study, we aimed to investigate whether cell proliferation and death may be altered during tritrichomonosis. For this purpose, we used pregnant BALB/c mice as an alternative experimental animal model that has successfully reproduced the infection. We analysed the immunohistochemical expression of active caspase-3 and proliferating cell nuclear (PCNA) antigens in the endometrium of infected mice. We found an increase in the number of caspase-3 positive cells in infected mice that were not pregnant at the necropsy. Besides, the number of positive proliferating cells increased in the uterine luminal epithelium of infected animals killed at 5-7 days post coitum (dpc). Pregnant infected mice killed at 8-11 dpc showed higher proliferation than control animals. We suggest that the cytopathic effect induced by T. foetus in the uteri of infected mice may induce the apoptosis of the epithelial cells and, as a result, promote a compensatory proliferative response. The information described here will be helpful to further study the pathogenesis of the bovine tritrichomonosis. PMID:26028409

  7. Delayed luminescence to monitor programmed cell death induced by berberine on thyroid cancer cells.

    PubMed

    Scordino, Agata; Campisi, Agata; Grasso, Rosaria; Bonfanti, Roberta; Gulino, Marisa; Iauk, Liliana; Parenti, Rosalba; Musumeci, Francesco

    2014-01-01

    Correlation between apoptosis and UVA-induced ultraweak photon emission delayed luminescence (DL) from tumor thyroid cell lines was investigated. In particular, the effects of berberine, an alkaloid that has been reported to have anticancer activities, on two cancer cell lines were studied. The FTC-133 and 8305C cell lines, as representative of follicular and anaplastic thyroid human cancer, respectively, were chosen. The results show that berberine is able to arrest cell cycle and activate apoptotic pathway as shown in both cell lines by deoxyribonucleic acid fragmentation, caspase-3 cleavage, p53 and p27 protein overexpression. In parallel, changes in DL spectral components after berberine treatment support the hypothesis that DL from human cells originates mainly from mitochondria, since berberine acts especially at the mitochondrial level. The decrease of DL blue component for both cell lines could be related to the decrease of intra-mitochondrial nicotinamide adenine dinucleotide and may be a hallmark of induced apoptosis. In contrast, the response in the red spectral range is different for the two cell lines and may be ascribed to a different iron homeostasis. PMID:25393968

  8. Apoptotic and autophagic cell death induced by glucolaxogenin in cervical cancer cells.

    PubMed

    Sánchez-Sánchez, L; Escobar, M L; Sandoval-Ramírez, J; López-Muñoz, H; Fernández-Herrera, M A; Hernández-Vázquez, J M V; Hilario-Martínez, C; Zenteno, E

    2015-12-01

    The antiproliferative and cytotoxic activity of glucolaxogenin and its ability to induce apoptosis and autophagy in cervical cancer cells are reported. We ascertained that glucolaxogenin exerts an inhibitory effect on the proliferation of HeLa, CaSki and ViBo cells in a dose-dependent manner. Analysis of DNA distribution in the cell-cycle phase of tumor cells treated with glucolaxogenin suggests that the anti-proliferative activity of this steroid is not always dependent on the cell cycle. Cytotoxic activity was evaluated by detection of the lactate dehydrogenase enzyme in supernatants from tumor cell cultures treated with the steroid. Glucolaxogenin exhibited null cytotoxic activity. With respect to the apoptotic activity, the generation of apoptotic bodies, the presence of active caspase-3 and annexin-V, as well as the DNA fragmentation observed in all tumor lines after treatment with glucolaxogenin suggests that this compound does indeed induce cell death by apoptosis. Also, a significantly increased presence of the LC3-II, LC3 and Lamp-1 proteins was evidenced with the ultrastructural existence of autophagic vacuoles in cells treated with this steroidal glycoside, indicating that glucolaxogenin also induces autophagic cell death. It is important to note that this compound showed no cytotoxic effect and did not affect the proliferative capacity of mononuclear cells obtained from normal human peripheral blood activated by phytohaemagglutinin. Thus, glucolaxogenin is a compound with anti-proliferative properties that induces programmed cell death in cancer cell lines, though it is selective with respect to normal lymphocytic cells. These findings indicate that this glycoside could have a selective action on tumor cells and, therefore, be worthy of consideration as a therapeutic candidate with anti-tumor potential. PMID:26437916

  9. Cell Death Inducing Microbial Protein Phosphatase Inhibitors--Mechanisms of Action.

    PubMed

    Kleppe, Rune; Herfindal, Lars; Døskeland, Stein Ove

    2015-10-01

    Okadaic acid (OA) and microcystin (MC) as well as several other microbial toxins like nodularin and calyculinA are known as tumor promoters as well as inducers of apoptotic cell death. Their intracellular targets are the major serine/threonine protein phosphatases. This review summarizes mechanisms believed to be responsible for the death induction and tumor promotion with focus on the interdependent production of reactive oxygen species (ROS) and activation of Ca(2+)/calmodulin kinase II (CaM-KII). New data are presented using inhibitors of specific ROS producing enzymes to curb nodularin/MC-induced liver cell (hepatocyte) death. They indicate that enzymes of the arachidonic acid pathway, notably phospholipase A2, 5-lipoxygenase, and cyclooxygenases, may be required for nodularin/MC-induced (and presumably OA-induced) cell death, suggesting new ways to overcome at least some aspects of OA and MC toxicity. PMID:26506362

  10. Cell death induced by Bothrops asper snake venom metalloproteinase on endothelial and other cell lines.

    PubMed

    Brenes, Oscar; Muñóz, Eduardo; Roldán-Rodríguez, Raquel; Díaz, Cecilia

    2010-06-01

    Two adherent cell lines, BAEC and HeLa, and non-adherent Jurkat, were treated with snake venom metalloproteinase BaP1 to determine whether cytotoxicity, previously reported for this toxin, could be mediated by the process of anoikis. It was observed that there was no correlation between the ability of this toxin to induce loss of adherence, and the cytotoxic effect, since concentrations that do not induce loss of adherence (3-6 microg/mL), were able to trigger 50% of cytotoxicity in BAEC. In the case of HeLa, where toxicity was very low (less than 20% at maximun concentrations and times of exposure), significant detachment and no toxicity was observed at concentrations of 1.5 microg/mL, showing also no correlation between both events. We also observed differences between BAEC toxicity measured by XTT reduction and DNA fragmentation determined by flow cytometry (as an indicator of apoptosis), since concentrations that induce 100% of cytotoxicity barely showed any DNA fragmentation (12% at 24h), suggesting that if apoptosis was involved, DNA damage is still not present, although chromatin condensation, another indicator of apoptosis, is observed in 40% of the cells. Inhibition of BAEC cytotoxicity by caspase inhibitors indicate that apoptosis is playing a role in this process, but other mechanisms of cell death could be participating also. Another way to determine whether the mechanism of cell death was related to anoikis was using a non-adherent cell line, which should show substrate independence. We determined by TUNEL that at 50 microg/ml BaP1 triggered 50% of apoptosis at 96 h, an effect that was seen earlier, suggesting also that if this toxin was inducing apoptosis in a non-adherent cell line, the mechanism could not be related to loss of attachment. Cell cycle arrest in S phase was also observed in Jurkat cells, an effect that could be leading to apoptosis. In conclusion, since there was no correlation between cell detachment and cytotoxicity (and apoptosis) in adherent cell lines and due to the ability of BaP1 to induce apoptosis in a non-adherent cell line, we suggest that this enzyme is toxic by a mechanism not related to anoikis, and that in the case of Jurkat cells, it is likely to be related to its ability to induce cell cycle arrest. Processes other than apoptosis could be also involved in the cell death mechanism mediated by BaP1 on BAEC. PMID:20219457

  11. Coronatine inhibits stomatal closure and delays hypersensitive response cell death induced by nonhost bacterial pathogens

    PubMed Central

    Lee, Seonghee; Ishiga, Yasuhiro; Clermont, Kristen

    2013-01-01

    Pseudomonas syringae is the most widespread bacterial pathogen in plants. Several strains of P. syringae produce a phytotoxin, coronatine (COR), which acts as a jasmonic acid mimic and inhibits plant defense responses and contributes to disease symptom development. In this study, we found that COR inhibits early defense responses during nonhost disease resistance. Stomatal closure induced by a nonhost pathogen, P. syringae pv. tabaci, was disrupted by COR in tomato epidermal peels. In addition, nonhost HR cell death triggered by P. syringae pv. tabaci on tomato was remarkably delayed when COR was supplemented along with P. syringae pv. tabaci inoculation. Using isochorismate synthase (ICS)-silenced tomato plants and transcript profiles of genes in SA- and JA-related defense pathways, we show that COR suppresses SA-mediated defense during nonhost resistance. PMID:23638370

  12. Cell Death Inducing Microbial Protein Phosphatase Inhibitors—Mechanisms of Action

    PubMed Central

    Kleppe, Rune; Herfindal, Lars; Døskeland, Stein Ove

    2015-01-01

    Okadaic acid (OA) and microcystin (MC) as well as several other microbial toxins like nodularin and calyculinA are known as tumor promoters as well as inducers of apoptotic cell death. Their intracellular targets are the major serine/threonine protein phosphatases. This review summarizes mechanisms believed to be responsible for the death induction and tumor promotion with focus on the interdependent production of reactive oxygen species (ROS) and activation of Ca2+/calmodulin kinase II (CaM-KII). New data are presented using inhibitors of specific ROS producing enzymes to curb nodularin/MC-induced liver cell (hepatocyte) death. They indicate that enzymes of the arachidonic acid pathway, notably phospholipase A2, 5-lipoxygenase, and cyclooxygenases, may be required for nodularin/MC-induced (and presumably OA-induced) cell death, suggesting new ways to overcome at least some aspects of OA and MC toxicity. PMID:26506362

  13. GENERAL: Entanglement sudden death induced by the Dzialoshinskii-Moriya interaction

    NASA Astrophysics Data System (ADS)

    Zeng, Hong-Fang; Shao, Bin; Yang, Lin-Guang; Li, Jian; Zou, Jian

    2009-08-01

    In this paper, we study the entanglement dynamics of two-spin Heisenberg XYZ model with the Dzialoshinskii-Moriya (DM) interaction. The system is initially prepared in the Werner state. The effects of purity of the initial state and DM coupling parameter on the evolution of entanglement are investigated. The necessary and sufficient condition for the appearance of the entanglement sudden death (ESD) phenomenon has been deduced. The result shows that the ESD always occurs if the initial state is sufficiently impure for the given coupling parameter or the DM interaction is sufficiently strong for the given initial state. Moreover, the critical values of them are calculated.

  14. Hydrogen Peroxide Contributes to the Epithelial Cell Death Induced by the Oral Mitis Group of Streptococci

    PubMed Central

    Okahashi, Nobuo; Sumitomo, Tomoko; Nakata, Masanobu; Sakurai, Atsuo; Kuwata, Hirotaka; Kawabata, Shigetada

    2014-01-01

    Members of the mitis group of streptococci are normal inhabitants of the commensal flora of the oral cavity and upper respiratory tract of humans. Some mitis group species, such as Streptococcus oralis and Streptococcus sanguinis, are primary colonizers of the human oral cavity. Recently, we found that hydrogen peroxide (H2O2) produced by S. oralis is cytotoxic to human macrophages, suggesting that streptococcus-derived H2O2 may act as a cytotoxin. Since epithelial cells provide a physical barrier against pathogenic microbes, we investigated their susceptibility to infection by H2O2-producing streptococci in this study. Infection by S. oralis and S. sanguinis was found to stimulate cell death of Detroit 562, Calu-3 and HeLa epithelial cell lines at a multiplicity of infection greater than 100. Catalase, an enzyme that catalyzes the decomposition of H2O2, inhibited S. oralis cytotoxicity, and H2O2 alone was capable of eliciting epithelial cell death. Moreover, S. oralis mutants lacking the spxB gene encoding pyruvate oxidase, which are deficient in H2O2 production, exhibited reduced cytotoxicity toward Detroit 562 epithelial cells. In addition, enzyme-linked immunosorbent assays revealed that both S. oralis and H2O2 induced interleukin-6 production in Detroit 562 epithelial cells. These results suggest that streptococcal H2O2 is cytotoxic to epithelial cells, and promotes bacterial evasion of the host defense systems in the oral cavity and upper respiratory tracts. PMID:24498253

  15. p53 regulates a non-apoptotic death induced by ROS

    PubMed Central

    Montero, J; Dutta, C; van Bodegom, D; Weinstock, D; Letai, A

    2013-01-01

    DNA damage induced by reactive oxygen species and several chemotherapeutic agents promotes both p53 and poly (ADP-ribose) polymerase (PARP) activation. p53 activation is well known to regulate apoptotic cell death, whereas robust activation of PARP-1 has been shown to promote a necrotic cell death associated with energetic collapse. Here we identify a novel role for p53 in modulating PARP enzymatic activity to regulate necrotic cell death. In mouse embryonic fibroblasts, human colorectal and human breast cancer cell lines, loss of p53 function promotes resistance to necrotic, PARP-mediated cell death. We therefore demonstrate that p53 can regulate both necrotic and apoptotic cell death, mutations or deletions in this tumor-suppressor protein may be selected by cancer cells to provide not only their resistance to apoptosis but also to necrosis, and explain resistance to chemotherapy and radiation even when it kills via non-apoptotic mechanisms. PMID:23703322

  16. Delayed luminescence to monitor programmed cell death induced by berberine on thyroid cancer cells

    NASA Astrophysics Data System (ADS)

    Scordino, Agata; Campisi, Agata; Grasso, Rosaria; Bonfanti, Roberta; Gulino, Marisa; Iauk, Liliana; Parenti, Rosalba; Musumeci, Francesco

    2014-11-01

    Correlation between apoptosis and UVA-induced ultraweak photon emission delayed luminescence (DL) from tumor thyroid cell lines was investigated. In particular, the effects of berberine, an alkaloid that has been reported to have anticancer activities, on two cancer cell lines were studied. The FTC-133 and 8305C cell lines, as representative of follicular and anaplastic thyroid human cancer, respectively, were chosen. The results show that berberine is able to arrest cell cycle and activate apoptotic pathway as shown in both cell lines by deoxyribonucleic acid fragmentation, caspase-3 cleavage, p53 and p27 protein overexpression. In parallel, changes in DL spectral components after berberine treatment support the hypothesis that DL from human cells originates mainly from mitochondria, since berberine acts especially at the mitochondrial level. The decrease of DL blue component for both cell lines could be related to the decrease of intra-mitochondrial nicotinamide adenine dinucleotide and may be a hallmark of induced apoptosis. In contrast, the response in the red spectral range is different for the two cell lines and may be ascribed to a different iron homeostasis.

  17. Tumor cell death induced by the inhibition of mitochondrial electron transport: The effect of 3-hydroxybakuchiol

    SciTech Connect

    Jaña, Fabián; Faini, Francesca; Lapier, Michel; Pavani, Mario; Kemmerling, Ulrike; Morello, Antonio; Maya, Juan Diego; Jara, José; Parra, Eduardo; Ferreira, Jorge

    2013-10-15

    Changes in mitochondrial ATP synthesis can affect the function of tumor cells due to the dependence of the first step of glycolysis on mitochondrial ATP. The oxidative phosphorylation (OXPHOS) system is responsible for the synthesis of approximately 90% of the ATP in normal cells and up to 50% in most glycolytic cancers; therefore, inhibition of the electron transport chain (ETC) emerges as an attractive therapeutic target. We studied the effect of a lipophilic isoprenylated catechol, 3-hydroxybakuchiol (3-OHbk), a putative ETC inhibitor isolated from Psoralea glandulosa. 3-OHbk exerted cytotoxic and anti-proliferative effects on the TA3/Ha mouse mammary adenocarcinoma cell line and induced a decrease in the mitochondrial transmembrane potential, the activation of caspase-3, the opening of the mitochondrial permeability transport pore (MPTP) and nuclear DNA fragmentation. Additionally, 3-OHbk inhibited oxygen consumption, an effect that was completely reversed by succinate (an electron donor for Complex II) and duroquinol (electron donor for Complex III), suggesting that 3-OHbk disrupted the electron flow at the level of Complex I. The inhibition of OXPHOS did not increase the level of reactive oxygen species (ROS) but caused a large decrease in the intracellular ATP level. ETC inhibitors have been shown to induce cell death through necrosis and apoptosis by increasing ROS generation. Nevertheless, we demonstrated that 3-OHbk inhibited the ETC and induced apoptosis through an interaction with Complex I. By delivering electrons directly to Complex III with duroquinol, cell death was almost completely abrogated. These results suggest that 3-OHbk has antitumor activity resulting from interactions with the ETC, a system that is already deficient in cancer cells. - Highlights: • We studied the anticancer activity of a natural compound, 3-OHbk, on TA3/Ha cells. • 3-OHbk inhibited mitochondrial electron flow by interacting with Complex I. • Complex I inhibition did not induce ROS generation. • 3-OHbk induced apoptosis in tumor cells with no effect on mammary epithelial cells. • Mitochondrial bioenergetics is implicated in anticancer action of 3-OHbk.

  18. Blocking autophagy enhanced leukemia cell death induced by recombinant human arginase.

    PubMed

    Li, Yubin; Zeng, Xian; Wang, Shaofei; Fan, Jiajun; Wang, Ziyu; Song, Ping; Mei, Xiaobin; Ju, Dianwen

    2016-05-01

    Recombinant human arginase (rhArg) is an arginine-degrading enzyme that has been evaluated as effective therapeutics for varieties of malignant tumors and is in clinical trials for hepatocellular carcinoma (HCC) treatment nowadays. Our previous studies have reported that rhArg could induce autophagy and apoptosis in lymphoma cells and inhibiting autophagy could enhance the efficacy of rhArg on lymphoma. However, whether rhArg could induce autophagy and what roles autophagy plays in leukemia cells are unclear. In this study, we demonstrated that rhArg treatment could lead to the formation of autophagosomes and the upregulation of microtubule-associated protein light chain 3 II (LC3-II) in human promyelocytic leukemia HL-60 cells and human acute T cell leukemia Jurkat cells. Furthermore, inhibiting autophagy using 3-methyladenine (3-MA) or chloroquine (CQ) could significantly enhance rhArg-induced cell growth inhibition and apoptosis. Taken together, these findings indicated that rhArg induced autophagy in leukemia cells and inhibiting autophagy enhanced anti-leukemia effect of rhArg, which might encourage the treatment of leukemia by targeting arginine depletion and autophagy in clinics. PMID:26643895

  19. Proinflammatory caspase-2-mediated macrophage cell death induced by a rough attenuated Brucella suis strain.

    PubMed

    Chen, Fang; Ding, Xicheng; Ding, Ying; Xiang, Zuoshuang; Li, Xinna; Ghosh, Debashis; Schurig, Gerhardt G; Sriranganathan, Nammalwar; Boyle, Stephen M; He, Yongqun

    2011-06-01

    Brucella spp. are intracellular bacteria that cause an infectious disease called brucellosis in humans and many domestic and wildlife animals. B. suis primarily infects pigs and is pathogenic to humans. The macrophage-Brucella interaction is critical for the establishment of a chronic Brucella infection. Our studies showed that smooth virulent B. suis strain 1330 (S1330) prevented programmed cell death of infected macrophages and rough attenuated B. suis strain VTRS1 (a vaccine candidate) induced strong macrophage cell death. To further investigate the mechanism of VTRS1-induced macrophage cell death, microarrays were used to analyze temporal transcriptional responses of murine macrophage-like J774.A1 cells infected with S1330 or VTRS1. In total 17,685 probe sets were significantly regulated based on the effects of strain, time and their interactions. A miniTUBA dynamic Bayesian network analysis predicted that VTRS1-induced macrophage cell death was mediated by a proinflammatory gene (the tumor necrosis factor alpha [TNF-α] gene), an NF-κB pathway gene (the IκB-α gene), the caspase-2 gene, and several other genes. VTRS1 induced significantly higher levels of transcription of 40 proinflammatory genes than S1330. A Mann-Whitney U test confirmed the proinflammatory response in VTRS1-infected macrophages. Increased production of TNF-α and interleukin 1β (IL-1β) were also detected in the supernatants in VTRS1-infected macrophage cell culture. Hyperphosphorylation of IκB-α was observed in macrophages infected with VTRS1 but not S1330. The important roles of TNF-α and IκB-α in VTRS1-induced macrophage cell death were further confirmed by individual inhibition studies. VTRS1-induced macrophage cell death was significantly inhibited by a caspase-2 inhibitor but not a caspase-1 inhibitor. The role of caspase-2 in regulating the programmed cell death of VTRS1-infected macrophages was confirmed in another study using caspase-2-knockout mice. In summary, VTRS1 induces a proinflammatory, caspase-2- and NF-κB-mediated macrophage cell death. This unique cell death differs from apoptosis, which is not proinflammatory. It is also different from classical pyroptosis, which is caspase-1 mediated. PMID:21464087

  20. ATG7 deficiency suppresses apoptosis and cell death induced by lysosomal photodamage

    PubMed Central

    Kessel, David H.; Price, Michael; Reiners, Jr., John J.

    2012-01-01

    Photodynamic therapy (PDT) involves photosensitizing agents that, in the presence of oxygen and light, initiate formation of cytotoxic reactive oxygen species (ROS). PDT commonly induces both apoptosis and autophagy. Previous studies with murine hepatoma 1c1c7 cells indicated that loss of autophagy-related protein 7 (ATG7) inhibited autophagy and enhanced the cytotoxicity of photosensitizers that mediate photodamage to mitochondria or the endoplasmic reticulum. In this study, we examined two photosensitizing agents that target lysosomes: the chlorin NPe6 and the palladium bacteriopheophorbide WST11. Irradiation of wild-type 1c1c7 cultures loaded with either photosensitizer induced apoptosis and autophagy, with a blockage of autophagic flux. An ATG7- or ATG5-deficiency suppressed the induction of autophagy in PDT protocols using either photosensitizer. Whereas ATG5-deficient cells were quantitatively similar to wild-type cultures in their response to NPe6 and WST11 PDT, an ATG7-deficiency suppressed the apoptotic response (as monitored by analyses of chromatin condensation and procaspase-3/7 activation) and increased the LD50 light dose by > 5-fold (as monitored by colony-forming assays). An ATG7-deficiency did not prevent immediate lysosomal photodamage, as indicated by loss of the lysosomal pH gradient. However, unlike wild-type and ATG5-deficient cells, the lysosomes of ATG7-deficient cells recovered this gradient within 4 h of irradiation, and never underwent permeabilization (monitored as release of endocytosed 10-kDa dextran polymers). We propose that the efficacy of lysosomal photosensitizers is in part due to both promotion of autophagic stress and suppression of autophagic prosurvival functions. In addition, an effect of ATG7 unrelated to autophagy appears to modulate lysosomal photodamage. PMID:22889762

  1. Oxidative damage and cell-programmed death induced in Zea mays L. by allelochemical stress.

    PubMed

    Ciniglia, Claudia; Mastrobuoni, Francesco; Scortichini, Marco; Petriccione, Milena

    2015-05-01

    The allelochemical stress on Zea mays was analyzed by using walnut husk washing waters (WHWW), a by-product of Juglans regia post-harvest process, which possesses strong allelopathic potential and phytotoxic effects. Oxidative damage and cell-programmed death were induced by WHWW in roots of maize seedlings. Treatment induced ROS burst, with excess of H2O2 content. Enzymatic activities of catalase were strongly increased during the first hours of exposure. The excess in malonildialdehyde following exposure to WHWW confirmed that oxidative stress severely damaged maize roots. Membrane alteration caused a decrease in NADPH oxidase activity along with DNA damage as confirmed by DNA laddering. The DNA instability was also assessed through sequence-related amplified polymorphism assay, thus suggesting the danger of walnut processing by-product and focusing the attention on the necessity of an efficient treatment of WHWW. PMID:25736610

  2. Oscillator death induced by amplitude-dependent coupling in repulsively coupled oscillators.

    PubMed

    Liu, Weiqing; Xiao, Guibao; Zhu, Yun; Zhan, Meng; Xiao, Jinghua; Kurths, Jürgen

    2015-05-01

    The effects of amplitude-dependent coupling on oscillator death (OD) are investigated for two repulsively coupled Lorenz oscillators. Based on numerical simulations, it is shown that as constraint strengths on the amplitude-dependent coupling change, an oscillatory state may undergo a transition to an OD state. The parameter regimes of the OD domain are theoretically determined, which coincide well with the numerical results. An electronic circuit is set up to exhibit the transition process to the OD state with an amplitude-dependent coupling. These findings may have practical importance on chaos control and oscillation depression. PMID:26066224

  3. Effect of platinum nanoparticles on cell death induced by ultrasound in human lymphoma U937 cells.

    PubMed

    Jawaid, Paras; Rehman, Mati Ur; Hassan, Mariame Ali; Zhao, Qing Li; Li, Peng; Miyamoto, Yusei; Misawa, Masaki; Ogawa, Ryohei; Shimizu, Tadamichi; Kondo, Takashi

    2016-07-01

    In this study, we report on the potential use of platinum nanoparticles (Pt-NPs), a superoxide dismutase (SOD)/catalase mimetic antioxidant, in combination with 1MHz ultrasound (US) at an intensity of 0.4 W/cm(2), 10% duty factor, 100 Hz PRF, for 2 min. Apoptosis induction was assessed by DNA fragmentation assay, cell cycle analysis and Annexin V-FITC/PI staining. Cell killing was confirmed by cell counting and microscopic examination. The mitochondrial and Ca(2+)-dependent pathways were investigated. Caspase-8 expression and autophagy-related proteins were detected by spectrophotometry and western blot analysis, respectively. Intracellular reactive oxygen species (ROS) elevation was detected by flow cytometry, while extracellular free radical formation was assessed by electron paramagnetic resonance spin trapping spectrometry. The results showed that Pt-NPs exerted differential effects depending on their internalization. Pt-NPs functioned as potent free radical scavengers when added immediately before sonication while pre-treatment with Pt-NPs suppressed the induction of apoptosis as well as autophagy (AP), and resulted in enhanced cell killing. Dead cells displayed the features of pyknosis. The exact mode of cell death is still unclear. In conclusion, the results indicate that US-induced AP may contribute to cell survival post sonication. To our knowledge this is the first study to discuss autophagy as a pro-survival pathway in the context of US. The combination of Pt-NPs and US might be effective in cancer eradication. PMID:26964942

  4. p53 Dependent Apoptotic Cell Death Induces Embryonic Malformation in Carassius auratus under Chronic Hypoxia

    PubMed Central

    Dasgupta, Subrata; Sawant, Bhawesh T.; Chadha, Narinder K.; Pal, Asim K.

    2014-01-01

    Hypoxia is a global phenomenon affecting recruitment as well as the embryonic development of aquatic fauna. The present study depicts hypoxia induced disruption of the intrinsic pathway of programmed cell death (PCD), leading to embryonic malformation in the goldfish, Carrasius auratus. Constant hypoxia induced the early expression of pro-apoptotic/tumor suppressor p53 and concomitant expression of the cell death molecule, caspase-3, leading to high level of DNA damage and cell death in hypoxic embryos, as compared to normoxic ones. As a result, the former showed delayed 4 and 64 celled stages and a delay in appearance of epiboly stage. Expression of p53 efficiently switched off expression of the anti-apoptotic Bcl-2 during the initial 12 hours post fertilization (hpf) and caused embryonic cell death. However, after 12 hours, simultaneous downregulation of p53 and Caspase-3 and exponential increase of Bcl-2, caused uncontrolled cell proliferation and prevented essential programmed cell death (PCD), ultimately resulting in significant (p<0.05) embryonic malformation up to 144 hpf. Evidences suggest that uncontrolled cell proliferation after 12 hpf may have been due to downregulation of p53 abundance, which in turn has an influence on upregulation of anti-apoptotic Bcl-2. Therefore, we have been able to show for the first time and propose that hypoxia induced downregulation of p53 beyond 12 hpf, disrupts PCD and leads to failure in normal differentiation, causing malformation in gold fish embryos. PMID:25068954

  5. Evaluation of Cytotoxicity and Cell Death Induced In Vitro by Saxitoxin in Mammalian Cells.

    PubMed

    Melegari, Silvia P; de Carvalho Pinto, Cátia R S; Moukha, Serge; Creppy, Edmond E; Matias, William G

    2015-01-01

    Since the cyanotoxin saxitoxin (STX) is a neurotoxin and induces ecological changes in aquatic environments, a potential risk to public and environmental health exists. However, data on STX-mediated cytotoxic and genotoxic effects are still scare. In order to gain a better understanding of the effects of this toxin, the cytotoxic and genotoxic potential of STX was examined in two mammalian cell lines. Neuro 2A (N2A), a neuroblastoma mouse cell line, and Vero cell line, derived from Vero green monkey kidney cells, were exposed to several concentrations of STX ranging from 0.5 to 64 nM to determine cell viability, induction of apoptosis (DNA fragmentation assay), and formation of micronuclei (MN) (cytokinesis-block micronucleus assay; CBMN) following 24 h of incubation. The half maximal effective concentration (EC50) values for STX calculated in cell viability tests were 1.01 nM for N2A and 0.82 nM for Vero cells. With increasing STX concentration there was evidence of DNA fragmentation indicating apoptosis induction in Vero cells with a 50% increase in DNA fragmentation compared to control at the highest STX concentration tested (3 nM). The results demonstrated no significant changes in the frequency of micronucleated binucleated cells in N2A and Vero cells exposed to STX, indicating the absence of genotoxicity under these test conditions. There was no apparent cellular necrosis as evidenced by a lack of formation of multinucleated cells. In conclusion, data reported herein demonstrate that STX produced death of both cell types tested through an apoptotic process. PMID:26436995

  6. Cell death induced by 2-phenylethynesulfonamide uncovers a pro-survival function of BAX.

    PubMed

    Mattiolo, Paolo; Barbero-Farran, Ares; Amigó, Josep; Ripamonti, Marta; Ribas, Judit; Boix, Jacint

    2014-11-01

    PES (2-phenylethynesulfonamide) was initially identified as an inhibitor of p53 translocation to mitochondria and named Pifithrin-µ. Further studies showed that PES selectively killed tumour cells and was thus a promising anticancer agent. PES-induced cell death was characterised by a non-apoptotic, autophagosome-rich phenotype. We observed this phenotype via electron microscopy in wild type (wt) and double Bax-/- Bak-/- (DKO) mouse embryonic fibroblasts (MEFs) treated with PES. We excluded the involvement of effector caspases, BAX and BAK, in causing PES-triggered cell death. Therefore, apoptosis was ruled out as the lethal mode of action of PES. Surprisingly, MEFs containing BAX were significantly protected from PES treatments. BAX overexpression in Bax-/- MEFs confirmed this pro-survival effect. Moreover, this protective effect required the ability of BAX to localise to mitochondrial membranes. Conversely, mitochondrial fusion induced by treatment with Mdivi-1 conferred increased resistance to MEFs subjected to PES treatment. The involvement of BAX in the regulation of mitochondrial dynamics has been reported. We propose the promotion of mitochondrial fusion by BAX to be the pro-survival function attributed to BAX. PMID:25111896

  7. Necromechanics: Death-induced changes in the mechanical properties of human tissues.

    PubMed

    Martins, Pedro A L S; Ferreira, Francisca; Natal Jorge, Renato; Parente, Marco; Santos, Agostinho

    2015-05-01

    After the death phenomenon, the rigor mortis development, characterized by body stiffening, is one of the most evident changes that occur in the body. In this work, the development of rigor mortis was assessed using a skinfold caliper in human cadavers and in live people to measure the deformation in the biceps brachii muscle in response to the force applied by the device. Additionally, to simulate the measurements with the finite element method, a two-dimensional model of an arm section was used. As a result of the experimental procedure, a decrease in deformation with increasing postmortem time was observed, which corresponds to an increase in rigidity. As expected, the deformations for the live subjects were higher. The finite element method analysis showed a correlation between the c1 parameter of the neo-Hookean model in the 4- to 8-h postmortem interval. This was accomplished by adjusting the c1 material parameter in order to simulate the measured experimental displacement. Despite being a preliminary study, the obtained results show that combining the proposed experimental procedure with a numerical technique can be very useful in the study of the postmortem mechanical modifications of human tissues. Moreover, the use of data from living subjects allows us to estimate the time of death paving the way to establish this process as an alternative to the existing techniques. This solution constitutes a portable, non-invasive method of estimating the postmortem interval with direct quantitative measurements using a skinfold caliper. The tools and methods described can be used to investigate the subject and to gain epidemiologic knowledge on rigor mortis phenomenon. PMID:25991713

  8. Phenylpropenoic Acid Glucoside from Rooibos Protects Pancreatic Beta Cells against Cell Death Induced by Acute Injury

    PubMed Central

    Himpe, Eddy; Cunha, Daniel A.; Song, Imane; Bugliani, Marco; Marchetti, Piero; Cnop, Miriam; Bouwens, Luc

    2016-01-01

    Objective Previous studies demonstrated that a phenylpropenoic acid glucoside (PPAG) from rooibos (Aspalathus linearis) extract had anti-hyperglycemic activity and significant protective effects on the pancreatic beta cell mass in a chronic diet-induced diabetes model. The present study evaluated the cytoprotective effect of the phytochemical on beta cells exposed to acute cell stress. Methods Synthetically prepared PPAG was administered orally in mice treated with a single dose of streptozotocin to acutely induce beta cell death and hyperglycemia. Its effect was assessed on beta cell mass, proliferation and apoptotic cell death. Its cytoprotective effect was also studied in vitro on INS-1E beta cells and on human pancreatic islet cells. Results Treatment with the phytochemical PPAG protected beta cells during the first days after the insult against apoptotic cell death, as evidenced by TUNEL staining, and prevented loss of expression of anti-apoptotic protein BCL2 in vivo. In vitro, PPAG protected INS-1E beta cells from streptozotocin-induced apoptosis and necrosis in a BCL2-dependent and independent way, respectively, depending on glucose concentration. PPAG also protected human pancreatic islet cells against the cytotoxic action of the fatty acid palmitate. Conclusions These findings show the potential use of PPAG as phytomedicine which protects the beta cell mass exposed to acute diabetogenic stress. PMID:27299564

  9. Exendin-4 attenuates brain death-induced liver damage in the rat.

    PubMed

    Carlessi, Rodrigo; Lemos, Natalia E; Dias, Ana L; Brondani, Leticia A; Oliveira, Jarbas R; Bauer, Andrea C; Leitão, Cristiane B; Crispim, Daisy

    2015-11-01

    The majority of liver grafts destined for transplantation originate from brain dead donors. However, significantly better posttransplantation outcomes are achieved when organs from living donors are used, suggesting that brain death (BD) causes irreversible damage to the liver tissue. Recently, glucagon-like peptide-1 (GLP1) analogues were shown to possess interesting hepatic protection effects in different liver disease models. We hypothesized that donor treatment with the GLP1 analogue exendin-4 (Ex-4) could alleviate BD-induced liver damage. A rat model of BD was employed in order to estimate BD-induced liver damage and Ex-4's potential protective effects. Liver damage was assessed by biochemical determination of circulating hepatic markers. Apoptosis in the hepatic tissue was assessed by immunoblot and immunohistochemistry using an antibody that only recognizes the active form of caspase-3. Gene expression changes in inflammation and stress response genes were monitored by quantitative real-time polymerase chain reaction. Here, we show that Ex-4 administration to the brain dead liver donors significantly reduces levels of circulating aspartate aminotransferase and lactate dehydrogenase. This was accompanied by a remarkable reduction in hepatocyte apoptosis. In this model, BD caused up-regulation of tumor necrosis factor and stress-related genes, confirming previous findings in clinical and animal studies. In conclusion, treatment of brain dead rats with Ex-4 reduced BD-induced liver damage. Further investigation is needed to determine the molecular basis of the observed liver protection. After testing in a randomized clinical trial, the inclusion of GLP1 analogues in organ donor management might help to improve organ quality, maximize organ donation, and possibly increase liver transplantation success rates. PMID:26334443

  10. Apoptosis-like cell death induced by Salmonella in Acanthamoeba rhysodes.

    PubMed

    Feng, Ye; Hsiao, Yi-Hsing; Chen, Hsiu-Ling; Chu, Chishih; Tang, Petrus; Chiu, Cheng-Hsun

    2009-08-01

    Free-living amoebae act as environmental hosts of several intracellular pathogens. We examined the interaction between Acanthamoeba rhysodes and Salmonella, a human intracellular pathogen. There was no difference among three different serovars of Salmonella in terms of their growth within A. rhysodes over time. The number of intracellular bacteria increased at 6 h post-infection, and the viability of A. rhysodes was significantly reduced at 24 h post-infection. Amoebic cell death was characterized by TUNEL and Annexin V assay, without DNA ladder identified, indicating an apoptosis-like cell death in Salmonella-infected A. rhysodes. Global gene expression screening between intracellular and extracellular Salmonella by microarray and quantitative PCR showed that genes from Salmonella pathogenicity islands and virulence plasmid were up-regulated within A. rhysodes. The phase-dependent expression pattern suggests their distinct roles in the pathogenesis. A. rhysodes and Salmonella provide a model to study transient symbiosis between bacterial pathogens and protozoa in an aquatic ecosystem. PMID:19446019

  11. The class I histone deacetylase inhibitor MS-275 prevents pancreatic beta cell death induced by palmitate.

    PubMed

    Plaisance, Valérie; Rolland, Laure; Gmyr, Valéry; Annicotte, Jean-Sébastien; Kerr-Conte, Julie; Pattou, François; Abderrahmani, Amar

    2014-01-01

    Elevation of the dietary saturated fatty acid palmitate contributes to the reduction of functional beta cell mass in the pathogenesis of type 2 diabetes. The diabetogenic effect of palmitate is achieved by increasing beta cell death through induction of the endoplasmic reticulum (ER) stress markers including activating transcription factor 3 (Atf3) and CAAT/enhancer-binding protein homologous protein-10 (Chop). In this study, we investigated whether treatment of beta cells with the MS-275, a HDAC1 and HDAC3 activity inhibitor which prevents beta cell death elicited by cytokines, is beneficial for combating beta cell dysfunction caused by palmitate. We show that culture of isolated human islets and MIN6 cells with MS-275 reduced apoptosis evoked by palmitate. The protective effect of MS-275 was associated with the attenuation of the expression of Atf3 and Chop. Silencing of HDAC3, but not of HDAC1, mimicked the effects of MS-275 on the expression of the two ER stress markers and apoptosis. These data point to HDAC3 as a potential drug target for preserving beta cells against lipotoxicity in diabetes. PMID:25610877

  12. The Class I Histone Deacetylase Inhibitor MS-275 Prevents Pancreatic Beta Cell Death Induced by Palmitate

    PubMed Central

    Plaisance, Valérie; Rolland, Laure; Gmyr, Valéry; Annicotte, Jean-Sébastien; Kerr-Conte, Julie; Pattou, François; Abderrahmani, Amar

    2014-01-01

    Elevation of the dietary saturated fatty acid palmitate contributes to the reduction of functional beta cell mass in the pathogenesis of type 2 diabetes. The diabetogenic effect of palmitate is achieved by increasing beta cell death through induction of the endoplasmic reticulum (ER) stress markers including activating transcription factor 3 (Atf3) and CAAT/enhancer-binding protein homologous protein-10 (Chop). In this study, we investigated whether treatment of beta cells with the MS-275, a HDAC1 and HDAC3 activity inhibitor which prevents beta cell death elicited by cytokines, is beneficial for combating beta cell dysfunction caused by palmitate. We show that culture of isolated human islets and MIN6 cells with MS-275 reduced apoptosis evoked by palmitate. The protective effect of MS-275 was associated with the attenuation of the expression of Atf3 and Chop. Silencing of HDAC3, but not of HDAC1, mimicked the effects of MS-275 on the expression of the two ER stress markers and apoptosis. These data point to HDAC3 as a potential drug target for preserving beta cells against lipotoxicity in diabetes. PMID:25610877

  13. Quorum Quenching Revisited—From Signal Decays to Signalling Confusion

    PubMed Central

    Hong, Kar-Wai; Koh, Chong-Lek; Sam, Choon-Kook; Yin, Wai-Fong; Chan, Kok-Gan

    2012-01-01

    In a polymicrobial community, while some bacteria are communicating with neighboring cells (quorum sensing), others are interrupting the communication (quorum quenching), thus creating a constant arms race between intercellular communication. In the past decade, numerous quorum quenching enzymes have been found and initially thought to inactivate the signalling molecules. Though this is widely accepted, the actual roles of these quorum quenching enzymes are now being uncovered. Recent evidence extends the role of quorum quenching to detoxification or metabolism of signalling molecules as food and energy source; this includes “signalling confusion”, a term coined in this paper to refer to the phenomenon of non-destructive modification of signalling molecules. While quorum quenching has been explored as a novel anti-infective therapy targeting, quorum sensing evidence begins to show the development of resistance against quorum quenching. PMID:22666051

  14. Some dynamics of signaling games

    PubMed Central

    Huttegger, Simon; Skyrms, Brian; Tarrès, Pierre; Wagner, Elliott

    2014-01-01

    Information transfer is a basic feature of life that includes signaling within and between organisms. Owing to its interactive nature, signaling can be investigated by using game theory. Game theoretic models of signaling have a long tradition in biology, economics, and philosophy. For a long time the analyses of these games has mostly relied on using static equilibrium concepts such as Pareto optimal Nash equilibria or evolutionarily stable strategies. More recently signaling games of various types have been investigated with the help of game dynamics, which includes dynamical models of evolution and individual learning. A dynamical analysis leads to more nuanced conclusions as to the outcomes of signaling interactions. Here we explore different kinds of signaling games that range from interactions without conflicts of interest between the players to interactions where their interests are seriously misaligned. We consider these games within the context of evolutionary dynamics (both infinite and finite population models) and learning dynamics (reinforcement learning). Some results are specific features of a particular dynamical model, whereas others turn out to be quite robust across different models. This suggests that there are certain qualitative aspects that are common to many real-world signaling interactions. PMID:25024209

  15. Baird's beaked whale echolocation signals.

    PubMed

    Baumann-Pickering, Simone; Yack, Tina M; Barlow, Jay; Wiggins, Sean M; Hildebrand, John A

    2013-06-01

    Echolocation signals from Baird's beaked whales were recorded during visual and acoustic shipboard surveys of cetaceans in the California Current ecosystem and with autonomous, long-term recorders in the Southern California Bight. The preliminary measurement of the visually validated Baird's beaked whale echolocation signals from towed array data were used as a basis for identifying Baird's signals in the autonomous recorder data. Two distinct signal types were found, one being a beaked whale-like frequency modulated (FM) pulse, the other being a dolphin-like broadband click. The median FM inter-pulse interval was 230 ms. Both signal types showed a consistent multi-peak structure in their spectra with peaks at ~9, 16, 25, and 40 kHz. Depending on signal type, as well as recording aspect and distance to the hydrophone, these peaks varied in relative amplitude. The description of Baird's echolocation signals will allow for studies of their distribution and abundance using towed array data without associated visual sightings and from autonomous seafloor hydrophones. PMID:23742381

  16. Some dynamics of signaling games.

    PubMed

    Huttegger, Simon; Skyrms, Brian; Tarrès, Pierre; Wagner, Elliott

    2014-07-22

    Information transfer is a basic feature of life that includes signaling within and between organisms. Owing to its interactive nature, signaling can be investigated by using game theory. Game theoretic models of signaling have a long tradition in biology, economics, and philosophy. For a long time the analyses of these games has mostly relied on using static equilibrium concepts such as Pareto optimal Nash equilibria or evolutionarily stable strategies. More recently signaling games of various types have been investigated with the help of game dynamics, which includes dynamical models of evolution and individual learning. A dynamical analysis leads to more nuanced conclusions as to the outcomes of signaling interactions. Here we explore different kinds of signaling games that range from interactions without conflicts of interest between the players to interactions where their interests are seriously misaligned. We consider these games within the context of evolutionary dynamics (both infinite and finite population models) and learning dynamics (reinforcement learning). Some results are specific features of a particular dynamical model, whereas others turn out to be quite robust across different models. This suggests that there are certain qualitative aspects that are common to many real-world signaling interactions. PMID:25024209

  17. VLSI systems design for digital signal processing. Volume 1 - Signal processing and signal processors

    NASA Astrophysics Data System (ADS)

    Bowen, B. A.; Brown, W. R.

    This book is concerned with the design of digital signal processing systems which utilize VLSI (Very Large Scale Integration) components. The presented material is intended for use by electrical engineers at the senior undergraduate or introductory graduate level. It is the purpose of this volume to present an overview of the important elements of background theory, processing techniques, and hardware evolution. Digital signals are considered along with linear systems and digital filters, taking into account the transform analysis of deterministic signals, a statistical signal model, time domain representations of discrete-time linear systems, and digital filter design techniques and implementation issues. Attention is given to aspects of detection and estimation, digital signal processing algorithms and techniques, issues which must be resolved in a processor design methodology, the fundamental concepts of high performance processing in terms of two early super computers, and the extension of these concepts to more recent processors.

  18. Signal conditioning, the next generation

    NASA Astrophysics Data System (ADS)

    Penharlow, David

    This paper describes recent advances in signal conditioning techiques used on flight test programs, which were achieved due to the availability to the electronic designer of new or improved analog and digital monolithic devices. These changes were driven by the design of new sensors, the architecture of the data acquisition systems, and by the vehicle type and design. The paper considers how each of these factors influenced the signal conditioning equipment and discusses new technology introduced, such as hybridized signal conditioners, amplifier-filter products, the self-balancing amplifier, and automatic gain ranging amplifiers.

  19. Lysophosphatidic acid signalling in development.

    PubMed

    Sheng, Xiaoyan; Yung, Yun C; Chen, Allison; Chun, Jerold

    2015-04-15

    Lysophosphatidic acid (LPA) is a bioactive phospholipid that is present in all tissues examined to date. LPA signals extracellularly via cognate G protein-coupled receptors to mediate cellular processes such as survival, proliferation, differentiation, migration, adhesion and morphology. These LPA-influenced processes impact many aspects of organismal development. In particular, LPA signalling has been shown to affect fertility and reproduction, formation of the nervous system, and development of the vasculature. Here and in the accompanying poster, we review the developmentally related features of LPA signalling. PMID:25852197

  20. GA signalling and cross-talk with other signalling pathways.

    PubMed

    Lor, Vai S; Olszewski, Neil E

    2015-01-01

    Gibberellins (GAs) are phytohormones that regulate growth and development. DELLA proteins repress GA responses. GA binding to its receptor triggers a series of events that culminate in the destruction of DELLA proteins by the 26S proteasome, which removes the repression of GA signalling. DELLA proteins are transcription co-activators that induce the expression of genes which encode products that inhibit GA responses. In addition to repressing GA responses, DELLA proteins influence the activity of other signalling pathways and serve as a central hub from which other pathways influence GA signalling. In this role, DELLA proteins bind to and inhibit proteins, including transcription factors that act in the signalling pathways of other hormones and light. The binding of these proteins to DELLA proteins also inhibits DELLA activity. GA signalling is subject to homoeostatic regulation through GA-induced repression of GA biosynthesis gene expression, and increased production of the GA receptor and enzymes that catabolize bioactive GAs. This review also discusses the nature of mutant DELLA alleles that are used to produce high-yielding 'Green Revolution' cereal varieties, and highlights important gaps in our knowledge of GA signalling. PMID:26374886

  1. BMP signaling in vascular diseases.

    PubMed

    Cai, Jie; Pardali, Evangelia; Sánchez-Duffhues, Gonzalo; ten Dijke, Peter

    2012-07-01

    Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β (TGF-β) family that signal via type I and type II serine/threonine kinase receptors and intracellular Smad transcription factors. BMPs are multifunctional regulators of development and tissue homeostasis and they were initially characterized as inducers of bone regeneration. Genetic studies in humans and mice showed that perturbations in BMP signaling lead to various diseases, such as skeletal diseases, vascular diseases and cancer. Mutations in BMP type II receptor and BMP type I receptor/activin receptor-like kinase 1 have been linked to pulmonary arterial hypertension and hereditary hemorrhagic telangiectasia, respectively. BMPs have also been implicated in promoting vascular calcification and tumor angiogenesis. In this review we discuss the role of BMP signaling in vascular diseases and the value of BMP signaling as a vascular disease marker or a therapeutic target. PMID:22710160

  2. Systolic processor for signal processing

    SciTech Connect

    Frank, G.A.; Greenawalt, E.M.; Kulkarni, A.V.

    1982-01-01

    A systolic array is a natural architecture for a high-performance signal processor, in part because of the extensive use of inner-product operations in signal processing. The modularity and simple interconnection of systolic arrays promise to simplify the development of cost-effective, high-performance, special-purpose processors. ESL incorporated has built a proof of concept model of a systolic processor. It is flexible enough to permit experimentation with a variety of algorithms and applications. ESL is exploring the application of systolic processors to image- and signal-processing problems. This paper describes this experimental system and some of its applications to signal processing. ESL is also pursuing new types of systolic architectures, including the VLSI implementation of systolic cells for solving systems of linear equations. These new systolic architectures allow the real-time design of adaptive filters. 14 references.

  3. Invariants of DNA genomic signals

    NASA Astrophysics Data System (ADS)

    Cristea, Paul Dan A.

    2005-02-01

    For large scale analysis purposes, the conversion of genomic sequences into digital signals opens the possibility to use powerful signal processing methods for handling genomic information. The study of complex genomic signals reveals large scale features, maintained over the scale of whole chromosomes, that would be difficult to find by using only the symbolic representation. Based on genomic signal methods and on statistical techniques, the paper defines parameters of DNA sequences which are invariant to transformations induced by SNPs, splicing or crossover. Re-orienting concatenated coding regions in the same direction, regularities shared by the genomic material in all exons are revealed, pointing towards the hypothesis of a regular ancestral structure from which the current chromosome structures have evolved. This property is not found in non-nuclear genomic material, e.g., plasmids.

  4. Mechanical Signaling in Reproductive Tissues

    PubMed Central

    Jorge, Soledad; Chang, Sydney; Barzilai, Joshua J.; Leppert, Phyllis

    2014-01-01

    The organs of the female reproductive system are among the most dynamic tissues in the human body, undergoing repeated cycles of growth and involution from puberty through menopause. To achieve such impressive plasticity, reproductive tissues must respond not only to soluble signals (hormones, growth factors, and cytokines) but also to physical cues (mechanical forces and osmotic stress) as well. Here, we review the mechanisms underlying the process of mechanotransduction—how signals are conveyed from the extracellular matrix that surrounds the cells of reproductive tissues to the downstream molecules and signaling pathways that coordinate the cellular adaptive response to external forces. Our objective was to examine how mechanical forces contribute significantly to physiological functions and pathogenesis in reproductive tissues. We highlight how widespread diseases of the reproductive tract, from preterm labor to tumors of the uterus and breast, result from an impairment in mechanical signaling. PMID:25001021

  5. INTRACELLULAR SIGNALING AND DEVELOPMENTAL NEUROTOXICITY.

    EPA Science Inventory

    A book chapter in ?Molecular Toxicology: Transcriptional Targets? reviewed the role of intracellular signaling in the developmental neurotoxicity of environmental chemicals. This chapter covered a number of aspects including the development of the nervous system, role of intrace...

  6. Stem Cells and Calcium Signaling

    PubMed Central

    Tonelli, Fernanda M.P.; Santos, Anderson K.; Gomes, Dawidson A.; da Silva, Saulo L.; Gomes, Katia N.; Ladeira, Luiz O.

    2014-01-01

    The increasing interest in stem cell research is linked to the promise of developing treatments for many lifethreatening, debilitating diseases, and for cell replacement therapies. However, performing these therapeutic innovations with safety will only be possible when an accurate knowledge about the molecular signals that promote the desired cell fate is reached. Among these signals are transient changes in intracellular Ca2+ concentration [Ca2+]i. Acting as an intracellular messenger, Ca2+ has a key role in cell signaling pathways in various differentiation stages of stem cells. The aim of this chapter is to present a broad overview of various moments in which Ca2+-mediated signaling is essential for the maintenance of stem cells and for promoting their development and differentiation, also focusing on their therapeutic potential. PMID:22453975

  7. SIGNALING NETWORKS IN PALATE DEVELOPMENT

    PubMed Central

    Lane, Jamie; Kaartinen, Vesa

    2014-01-01

    Palatogenesis, the formation of the palate, is a dynamic process that is regulated by a complex series of context-dependent morphogenetic signaling events. Many genes involved in palatogenesis have been discovered through the use of genetically-manipulated mouse models as well as from human genetic studies, but the roles of these genes and their products in signaling networks regulating palatogenesis are still poorly known. In this review, we give a brief overview on palatogenesis and introduce key signaling cascades leading to formation of the intact palate. Moreover, we review conceptual differences between pathway biology and network biology and discuss how some of the recent technological advances in conjunction with mouse genetic models have contributed to our understanding of signaling networks regulating palate growth and fusion. PMID:24644145

  8. Extracellular modulators of Wnt signalling.

    PubMed

    Malinauskas, Tomas; Jones, E Yvonne

    2014-12-01

    Wnt morphogens are secreted signalling proteins that play leading roles in embryogenesis and tissue homeostasis throughout life. Wnt signalling is controlled by multiple mechanisms, including posttranslational modification of Wnts, antagonist binding (to Wnts or their receptors), and regulation of the availability of Wnt receptors. Recent crystallographic, structure-guided biophysical and cell-based studies have advanced our understanding of how Wnt signalling is regulated at the cell surface. Structures include Wnt in complex with the cysteine-rich domain (CRD) of Frizzled, extracellular fragments of Wnt co-receptor LRP6, LRP6-binding antagonists Dickkopf and Sclerostin, antagonists 5T4/WAIF1 and Wnt inhibitory factor 1 (WIF-1), as well as Frizzled-ubiquitin ligases ZNRF3/RNF43 (in isolation and in complexes with Wnt signalling promoters R-spondins and LGR5). We review recent discoveries and remaining questions. PMID:25460271

  9. Acoustic emission and signal analysis

    NASA Astrophysics Data System (ADS)

    Rao, A. K.

    1990-01-01

    A review is given of the acoustic emission (AE) phenomenon and its applications in NDE and geological rock mechanics. Typical instrumentation used in AE signal detection, data acquisition, processing, and analysis is discussed. The parameters used in AE signal analysis are outlined, and current methods of AE signal analysis procedures are discussed. A literature review is presented on the pattern classification of AE signals. A discussion then follows on the application of AE in aircraft component monitoring, with an experiment described which focuses on in-flight AE monitoring during fatigue crack growth in an aero engine mount. A pattern recognition approach is detailed for the classification of the experimental data. The approach subjects each of the data files to a cluster analysis by the threshold-k-means scheme. The technique is shown to classify the data successfully.

  10. 49 CFR 236.310 - Signal governing approach to home signal.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Signal governing approach to home signal. 236.310... Standards § 236.310 Signal governing approach to home signal. A signal shall be provided on main track to govern the approach with the current of traffic to any home signal except where the home signal is...

  11. 49 CFR 236.310 - Signal governing approach to home signal.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Signal governing approach to home signal. 236.310... Standards § 236.310 Signal governing approach to home signal. A signal shall be provided on main track to govern the approach with the current of traffic to any home signal except where the home signal is...

  12. 49 CFR 236.310 - Signal governing approach to home signal.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Signal governing approach to home signal. 236.310... Standards § 236.310 Signal governing approach to home signal. A signal shall be provided on main track to govern the approach with the current of traffic to any home signal except where the home signal is...

  13. 49 CFR 236.310 - Signal governing approach to home signal.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Signal governing approach to home signal. 236.310... Standards § 236.310 Signal governing approach to home signal. A signal shall be provided on main track to govern the approach with the current of traffic to any home signal except where the home signal is...

  14. 49 CFR 236.310 - Signal governing approach to home signal.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Signal governing approach to home signal. 236.310... Standards § 236.310 Signal governing approach to home signal. A signal shall be provided on main track to govern the approach with the current of traffic to any home signal except where the home signal is...

  15. Striation effect on HF signals

    NASA Astrophysics Data System (ADS)

    Price, G. H.

    1985-06-01

    Methods are described for calculating the effects of forward scatter by ionospheric irregularities on high-frequency sky-wave radio signals. The approach combines the forward-scatter theory (developed to treat refracted-ray paths in the context of acoustic propagation in oceans) with the model of ionospheric irregularities developed by the Defense Nuclear Agency. Expressions are given for calculating signal decorrelation in time, space and frequency.

  16. Identification techniques for SARSAT signals

    NASA Astrophysics Data System (ADS)

    El-Naga, S.; Carter, C. R.

    1987-03-01

    A process for the identification of emergency locator transmitter (ELT) signals related to search and rescue satellite-aided tracking (SARSAT) is presented. The ELT identification process is particularly important in order to increase the probability of detection and eliminate sources of interference from the data set. A set of ELT signal parameters is introduced and methods for estimating these parameters are developed. A theoretical analysis and performance evaluation of these methods is provided.

  17. Aberrant Wnt Signaling in Leukemia.

    PubMed

    Staal, Frank J T; Famili, Farbod; Garcia Perez, Laura; Pike-Overzet, Karin

    2016-01-01

    The Wnt signaling pathway is essential in the development and homeostasis of blood and immune cells, but its exact role is still controversial and is the subject of intense research. The malignant counterpart of normal hematopoietic cells, leukemic (stem) cells, have hijacked the Wnt pathway for their self-renewal and proliferation. Here we review the multiple ways dysregulated Wnt signaling can contribute to leukemogenesis, both cell autonomously as well as by changes in the microenvironment. PMID:27571104

  18. Insulin Signaling and Heart Failure.

    PubMed

    Riehle, Christian; Abel, E Dale

    2016-04-01

    Heart failure is associated with generalized insulin resistance. Moreover, insulin-resistant states such as type 2 diabetes mellitus and obesity increases the risk of heart failure even after adjusting for traditional risk factors. Insulin resistance or type 2 diabetes mellitus alters the systemic and neurohumoral milieu, leading to changes in metabolism and signaling pathways in the heart that may contribute to myocardial dysfunction. In addition, changes in insulin signaling within cardiomyocytes develop in the failing heart. The changes range from activation of proximal insulin signaling pathways that may contribute to adverse left ventricular remodeling and mitochondrial dysfunction to repression of distal elements of insulin signaling pathways such as forkhead box O transcriptional signaling or glucose transport, which may also impair cardiac metabolism, structure, and function. This article will review the complexities of insulin signaling within the myocardium and ways in which these pathways are altered in heart failure or in conditions associated with generalized insulin resistance. The implications of these changes for therapeutic approaches to treating or preventing heart failure will be discussed. PMID:27034277

  19. Digital Filter Separates Signal From Noise

    NASA Technical Reports Server (NTRS)

    Lear, W. M.

    1986-01-01

    Variance of signal-estimation error minimized. Mathematical technique extracts best estimates of signal component from periodic digital samples of signal plus noise. Technique combines Kalman- and smoothingfilter algorithms to minimize mean-square estimation error based on past, present, and predicted samples of signal plus noise. Technique useful in image analysis and other applications involving processing of noisy signals.

  20. 46 CFR 109.503 - Emergency signals.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 4 2010-10-01 2010-10-01 false Emergency signals. 109.503 Section 109.503 Shipping... Emergency Signals § 109.503 Emergency signals. (a) Emergency stations signals are established as follows: (1) The signal to man emergency stations is a rapid succession of short soundings of both the...

  1. SignalPlant: an open signal processing software platform.

    PubMed

    Plesinger, F; Jurco, J; Halamek, J; Jurak, P

    2016-07-01

    The growing technical standard of acquisition systems allows the acquisition of large records, often reaching gigabytes or more in size as is the case with whole-day electroencephalograph (EEG) recordings, for example. Although current 64-bit software for signal processing is able to process (e.g. filter, analyze, etc) such data, visual inspection and labeling will probably suffer from rather long latency during the rendering of large portions of recorded signals. For this reason, we have developed SignalPlant-a stand-alone application for signal inspection, labeling and processing. The main motivation was to supply investigators with a tool allowing fast and interactive work with large multichannel records produced by EEG, electrocardiograph and similar devices. The rendering latency was compared with EEGLAB and proves significantly faster when displaying an image from a large number of samples (e.g. 163-times faster for 75  ×  10(6) samples). The presented SignalPlant software is available free and does not depend on any other computation software. Furthermore, it can be extended with plugins by third parties ensuring its adaptability to future research tasks and new data formats. PMID:27243208

  2. Chemotactic signal integration in bacteria.

    PubMed Central

    Khan, S; Spudich, J L; McCray, J A; Trentham, D R

    1995-01-01

    Chemotactic signaling in Escherichia coli involves transmission of both negative and positive signals. In order to examine mechanisms of signal processing, behavioral responses to dual inputs have been measured by using photoactivable "caged" compounds, computer video analysis, and chemoreceptor deletion mutants. Signaling from Tar and Tsr, two receptors that sense amino acids and pH, was studied. In a Tar deletion mutant the photoactivated release of protons, a Tsr repellent, and of serine, a Tsr attractant, in separate experiments at pH 7.0 resulted in tumbling (negative) or smooth-swimming (positive) responses in ca. 50 and 140 ms, respectively. Simultaneous photorelease of protons and serine resulted in a single tumbling or smooth-swimming response, depending on the relative amounts of the two effectors. In contrast, in wild-type E. coli, proton release at pH 7.0 resulted in a biphasic response that was attributed to Tsr-mediated tumbling followed by Tar-mediated smooth-swimming. In wild-type E. coli at more alkaline pH values the Tar-mediated signal was stronger than the Tsr signal, resulting in a strong smooth-swimming response preceded by a diminished tumbling response. These observations imply that (i) a single receptor time-averages the binding of different chemotactic ligands generating a single response; (ii) ligand binding to different receptors can result in a nonintegrated response with the tumbling response preceding the smooth-swimming response; (iii) however, chemotactic signals of different intensities derived from different receptors can also result in an apparently integrated response; and (iv) the different chemotactic responses to protons at neutral and alkaline pH may contribute to E. coli migration toward neutrality. Images Fig. 6 PMID:7568212

  3. Differential phase shift keyed signal resolver

    NASA Technical Reports Server (NTRS)

    Hopkins, P. M.; Wallingford, W. M. (Inventor)

    1974-01-01

    A differential phase shift keyed signal resolver resolves the differential phase shift in the incoming signal to determine the data content thereof overcoming phase uncertainty without requiring a transmitted reference signal.

  4. Microcontrollers Generate Timing Signals For CCD Arrays

    NASA Technical Reports Server (NTRS)

    Hostetter, Marilyn K.; Mccloskey, John C.; Reed, Kenneth V.

    1992-01-01

    Microcontrollers generate timing signals for charge-coupled-device array detectors in electronic system developed to test such detectors. With microcontroller, one changes timing signals via software, without changes in wiring. Approach more flexible, timing signals changed easier and quicker.

  5. EGFR Signaling in Liver Diseases

    PubMed Central

    Komposch, Karin; Sibilia, Maria

    2015-01-01

    The epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase that is activated by several ligands leading to the activation of diverse signaling pathways controlling mainly proliferation, differentiation, and survival. The EGFR signaling axis has been shown to play a key role during liver regeneration following acute and chronic liver damage, as well as in cirrhosis and hepatocellular carcinoma (HCC) highlighting the importance of the EGFR in the development of liver diseases. Despite the frequent overexpression of EGFR in human HCC, clinical studies with EGFR inhibitors have so far shown only modest results. Interestingly, a recent study has shown that in human HCC and in mouse HCC models the EGFR is upregulated in liver macrophages where it plays a tumor-promoting function. Thus, the role of EGFR in liver diseases appears to be more complex than what anticipated. Further studies are needed to improve the molecular understanding of the cell-specific signaling pathways that control disease development and progression to be able to develop better therapies targeting major components of the EGFR signaling network in selected cell types. In this review, we compiled the current knowledge of EGFR signaling in different models of liver damage and diseases, mainly derived from the analysis of HCC cell lines and genetically engineered mouse models (GEMMs). PMID:26729094

  6. Polarization signals in mantis shrimps

    NASA Astrophysics Data System (ADS)

    Cronin, Thomas W.; Chiou, Tsyr-Huei; Caldwell, Roy L.; Roberts, Nicholas; Marshall, Justin

    2009-08-01

    While color signals are well known as a form of animal communication, a number of animals communicate using signals based on patterns of polarized light reflected from specialized body parts or structures. Mantis shrimps, a group of marine crustaceans, have evolved a great diversity of such signals, several of which are based on photonic structures. These include resonant scattering devices, structures based on layered dichroic molecules, and structures that use birefringent layers to produce circular polarization. Such biological polarizers operate in different spectral regions ranging from the near-UV to medium wavelengths of visible light. In addition to the structures that are specialized for signal production, the eyes of many species of mantis shrimp are adapted to detect linearly polarized light in the ultraviolet and in the green, using specialized sets of photoreceptors with oriented, dichroic visual pigments. Finally, a few mantis shrimp species produce biophotonic retarders within their photoreceptors that permit the detection of circularly polarized light and are thus the only animals known to sense this form of polarization. Mantis shrimps use polarized light in species-specific signals related to mating and territorial defense, and their means of manipulating light's polarization can inspire designs for artificial polarizers and achromatic retarders.

  7. Signalling drought in guard cells.

    PubMed

    Luan, S.

    2002-02-01

    A number of environmental conditions including drought, low humidity, cold and salinity subject plants to osmotic stress. A rapid plant response to such stress conditions is stomatal closure to reduce water loss from plants. From an external stress signal to stomatal closure, many molecular components constitute a signal transduction network that couples the stimulus to the response. Numerous studies have been directed to resolving the framework and molecular details of stress signalling pathways in plants. In guard cells, studies focus on the regulation of ion channels by abscisic acid (ABA), a chemical messenger for osmotic stress. Calcium, protein kinases and phosphatases, and membrane trafficking components have been shown to play a role in ABA signalling process in guard cells. Studies also implicate ABA-independent regulation of ion channels by osmotic stress. In particular, a direct osmosensing pathway for ion channel regulation in guard cells has been identified. These pathways form a complex signalling web that monitors water status in the environment and initiates responses in stomatal movements. PMID:11841666

  8. Notch Signaling and the Skeleton.

    PubMed

    Zanotti, Stefano; Canalis, Ernesto

    2016-06-01

    Notch 1 to 4 receptors are important determinants of cell fate and function, and Notch signaling plays an important role in skeletal development and bone remodeling. After direct interactions with ligands of the Jagged and Delta-like families, a series of cleavages release the Notch intracellular domain (NICD), which translocates to the nucleus where it induces transcription of Notch target genes. Classic gene targets of Notch are hairy and enhancer of split (Hes) and Hes-related with YRPW motif (Hey). In cells of the osteoblastic lineage, Notch activation inhibits cell differentiation and causes cancellous bone osteopenia because of impaired bone formation. In osteocytes, Notch1 has distinct effects that result in an inhibition of bone resorption secondary to an induction of osteoprotegerin and suppression of sclerostin with a consequent enhancement of Wnt signaling. Notch1 inhibits, whereas Notch2 enhances, osteoclastogenesis and bone resorption. Congenital disorders of loss- and gain-of-Notch function present with severe clinical manifestations, often affecting the skeleton. Enhanced Notch signaling is associated with osteosarcoma, and Notch can influence the invasive potential of carcinoma of the breast and prostate. Notch signaling can be controlled by the use of inhibitors of Notch activation, small peptides that interfere with the formation of a transcriptional complex, or antibodies to the extracellular domain of specific Notch receptors or to Notch ligands. In conclusion, Notch plays a critical role in skeletal development and homeostasis, and serious skeletal disorders can be attributed to alterations in Notch signaling. PMID:27074349

  9. Cancer stem cell signaling pathways.

    PubMed

    Matsui, William H

    2016-09-01

    Tissue development and homeostasis are governed by the actions of stem cells. Multipotent cells are capable of self-renewal during the course of one's lifetime. The accurate and appropriate regulation of stem cell functions is absolutely critical for normal biological activity. Several key developmental or signaling pathways have been shown to play essential roles in this regulatory capacity. Specifically, the Janus-activated kinase/signal transducer and activator of transcription, Hedgehog, Wnt, Notch, phosphatidylinositol 3-kinase/phosphatase and tensin homolog, and nuclear factor-κB signaling pathways have all been shown experimentally to mediate various stem cell properties, such as self-renewal, cell fate decisions, survival, proliferation, and differentiation. Unsurprisingly, many of these crucial signaling pathways are dysregulated in cancer. Growing evidence suggests that overactive or abnormal signaling within and among these pathways may contribute to the survival of cancer stem cells (CSCs). CSCs are a relatively rare population of cancer cells capable of self-renewal, differentiation, and generation of serially transplantable heterogeneous tumors of several types of cancer. PMID:27611937

  10. Dialkylresorcinols as bacterial signaling molecules

    PubMed Central

    Brameyer, Sophie; Kresovic, Darko; Bode, Helge B.; Heermann, Ralf

    2015-01-01

    It is well recognized that bacteria communicate via small diffusible molecules, a process termed quorum sensing. The best understood quorum sensing systems are those that use acylated homoserine lactones (AHLs) for communication. The prototype of those systems consists of a LuxI-like AHL synthase and a cognate LuxR receptor that detects the signal. However, many proteobacteria possess LuxR receptors, yet lack any LuxI-type synthase, and thus these receptors are referred to as LuxR orphans or solos. In addition to the well-known AHLs, little is known about the signaling molecules that are sensed by LuxR solos. Here, we describe a novel cell–cell communication system in the insect and human pathogen Photorhabdus asymbiotica. We identified the LuxR homolog PauR to sense dialkylresorcinols (DARs) and cyclohexanediones (CHDs) instead of AHLs as signals. The DarABC synthesis pathway produces the molecules, and the entire system emerged as important for virulence. Moreover, we have analyzed more than 90 different Photorhabdus strains by HPLC/MS and showed that these DARs and CHDs are specific to the human pathogen P. asymbiotica. On the basis of genomic evidence, 116 other bacterial species are putative DAR producers, among them many human pathogens. Therefore, we discuss the possibility of DARs as novel and widespread bacterial signaling molecules and show that bacterial cell–cell communication goes far beyond AHL signaling in nature. PMID:25550519

  11. Intracellular signalling during neutrophil recruitment.

    PubMed

    Mócsai, Attila; Walzog, Barbara; Lowell, Clifford A

    2015-08-01

    Recruitment of leucocytes such as neutrophils to the extravascular space is a critical step of the inflammation process and plays a major role in the development of various diseases including several cardiovascular diseases. Neutrophils themselves play a very active role in that process by sensing their environment and responding to the extracellular cues by adhesion and de-adhesion, cellular shape changes, chemotactic migration, and other effector functions of cell activation. Those responses are co-ordinated by a number of cell surface receptors and their complex intracellular signal transduction pathways. Here, we review neutrophil signal transduction processes critical for recruitment to the site of inflammation. The two key requirements for neutrophil recruitment are the establishment of appropriate chemoattractant gradients and the intrinsic ability of the cells to migrate along those gradients. We will first discuss signalling steps required for sensing extracellular chemoattractants such as chemokines and lipid mediators and the processes (e.g. PI3-kinase pathways) leading to the translation of extracellular chemoattractant gradients to polarized cellular responses. We will then discuss signal transduction by leucocyte adhesion receptors (e.g. tyrosine kinase pathways) which are critical for adhesion to, and migration through the vessel wall. Finally, additional neutrophil signalling pathways with an indirect effect on the neutrophil recruitment process, e.g. through modulation of the inflammatory environment, will be discussed. Mechanistic understanding of these pathways provide better understanding of the inflammation process and may point to novel therapeutic strategies for controlling excessive inflammation during infection or tissue damage. PMID:25998986

  12. Mathematical model for classification of EEG signals

    NASA Astrophysics Data System (ADS)

    Ortiz, Victor H.; Tapia, Juan J.

    2015-09-01

    A mathematical model to filter and classify brain signals from a brain machine interface is developed. The mathematical model classifies the signals from the different lobes of the brain to differentiate the signals: alpha, beta, gamma and theta, besides the signals from vision, speech, and orientation. The model to develop further eliminates noise signals that occur in the process of signal acquisition. This mathematical model can be used on different platforms interfaces for rehabilitation of physically handicapped persons.

  13. TGFβ signaling and cardiovascular diseases.

    PubMed

    Pardali, Evangelia; Ten Dijke, Peter

    2012-01-01

    Transforming growth factor β (TGFβ) family members are involved in a wide range of diverse functions and play key roles in embryogenesis, development and tissue homeostasis. Perturbation of TGFβ signaling may lead to vascular and other diseases. In vitro studies have provided evidence that TGFβ family members have a wide range of diverse effects on vascular cells, which are highly dependent on cellular context. Consistent with these observations genetic studies in mice and humans showed that TGFβ family members have ambiguous effects on the function of the cardiovascular system. In this review we discuss the recent advances on TGFβ signaling in (cardio)vascular diseases, and describe the value of TGFβ signaling as both a disease marker and therapeutic target for (cardio)vascular diseases. PMID:22253564

  14. Intelligent signal analysis and recognition

    NASA Technical Reports Server (NTRS)

    Levinson, Robert; Helman, Daniel; Oswalt, Edward

    1987-01-01

    Progress in the research and development of self-organizing database system that can support the identification and characterization of signals in an RF environment is described. As the radio frequency spectrum becomes more crowded, there are a number of situations that require a characterization of the RF environment. This database system is designed to be practical in applications where communications and other instruments encounter a time varying and complex RF environment. The primary application of this system is the guidance and control of NASA's SETI Microwave Observing Project. Other possible applications include selection of telemety bands for communication with spacecraft, and the scheduling of antenna for radio astronomy are two examples where characterization of the RF environment is required. In these applications, the RF environment is constantly changing, and even experienced operators cannot quickly identify the multitude of signals that can be encountered. Some of these signals are repetitive, others appear to occur sporadically.

  15. Multiscale Representation of Genomic Signals

    PubMed Central

    Knijnenburg, Theo A.; Ramsey, Stephen A.; Berman, Benjamin P.; Kennedy, Kathleen A.; Smit, Arian F.A.; Wessels, Lodewyk F.A.; Laird, Peter W.; Aderem, Alan; Shmulevich, Ilya

    2014-01-01

    Genomic information is encoded on a wide range of distance scales, ranging from tens of base pairs to megabases. We developed a multiscale framework to analyze and visualize the information content of genomic signals. Different types of signals, such as GC content or DNA methylation, are characterized by distinct patterns of signal enrichment or depletion across scales spanning several orders of magnitude. These patterns are associated with a variety of genomic annotations, including genes, nuclear lamina associated domains, and repeat elements. By integrating the information across all scales, as compared to using any single scale, we demonstrate improved prediction of gene expression from Polymerase II chromatin immunoprecipitation sequencing (ChIP-seq) measurements and we observed that gene expression differences in colorectal cancer are not most strongly related to gene body methylation, but rather to methylation patterns that extend beyond the single-gene scale. PMID:24727652

  16. Hedgehog Signaling in the Liver

    PubMed Central

    Omenetti, Alessia; Choi, Steve; Michelotti, Gregory; Diehl, Anna Mae

    2010-01-01

    Reactivation of Hedgehog (Hh), a morphogenic signaling pathway that controls progenitor cell fate and tissue construction during embryogenesis occurs during many types of liver injury in adult. The net effects of activating the Hedgehog pathway include expansion of liver progenitor populations to promote liver regeneration, but also hepatic accumulation of inflammatory cells, liver fibrogenesis, and vascular remodeling. All of these latter responses are known to be involved in the pathogenesis of cirrhosis. In addition, Hh signaling may play a role in primary liver cancers, such as cholangiocarcinoma and hepatocellular carcinoma. Study of Hedgehog signaling in liver cells is in its infancy. Additional research in this area is justified given growing experimental and clinical data supporting a role for the pathway in regulating outcomes of liver injury. PMID:21093090

  17. Multichannel Coding of Applause Signals

    NASA Astrophysics Data System (ADS)

    Hotho, Gerard; van de Par, Steven; Breebaart, Jeroen

    2007-12-01

    We develop a parametric multichannel audio codec dedicated to coding signals consisting of a dense series of transient-type events. These signals of which applause is a typical example are known to be problematic for such audio codecs. The codec design is based on preservation of both timbre and transient-type event density. It combines a very low complexity and a low parameter bit rate (0.2 kbps). In a formal listening test, we compared the proposed codec to the recently standardised MPEG Surround multichannel codec, with an associated parameter bit rate of 9 kbps. We found the new codec to have a significantly higher audio quality than the MPEG Surround codec for the two multichannel applause signals under test. Though this seems promising, the technique presented is not fully mature, for example, because issues related to integration of the proposed codec in the MPEG Surround codec were not addressed.

  18. Signaling lansdscape of prostate cancer.

    PubMed

    Lin, X; Aslam, A; Attar, R; Yaylim, I; Qureshi, M Z; Hasnain, S; Qadir, M I; Farooqi, A A

    2016-01-01

    Research over the decades has gradually and sequentially shown that both intratumor heterogeneity and multifocality make prostate cancer difficult to target. Different challenges associated with generation of risk-stratification tools that correlate genomic landscape with clinical outcomes severely influence clinical efficacy of therapeutic strategies. Androgen receptor mediated signaling has gained great appreciation and rewiring of AR induced signaling cascade in absence of androgen, structural variants of AR have provided near complete resolution of genomic landscape and underlying mechanisms of prostate cancer. In this review we have attempted to provide an overview of most recent advancements in our knowledge related to different signaling cascades including TGF, SHH, Notch, JAK-STAT in prostate cancer progression and development. PMID:26828986

  19. Signaling pathways mediating alcohol effects.

    PubMed

    Ron, Dorit; Messing, Robert O

    2013-01-01

    Ethanol's effects on intracellular signaling pathways contribute to acute effects of ethanol as well as to neuroadaptive responses to repeated ethanol exposure. In this chapter we review recent discoveries that demonstrate how ethanol alters signaling pathways involving several receptor tyrosine kinases and intracellular tyrosine and serine-threonine kinases, with consequences for regulation of cell surface receptor function, gene expression, protein translation, neuronal excitability and animal behavior. We also describe recent work that demonstrates a key role for ethanol in regulating the function of scaffolding proteins that organize signaling complexes into functional units. Finally, we review recent exciting studies demonstrating ethanol modulation of DNA and histone modification and the expression of microRNAs, indicating epigenetic mechanisms by which ethanol regulates neuronal gene expression and addictive behaviors. PMID:21877259

  20. The Yeast Sphingolipid Signaling Landscape

    PubMed Central

    Montefusco, David J.; Matmati, Nabil

    2014-01-01

    Sphingolipids are recognized as signaling mediators in a growing number of pathways, and represent potential targets to address many diseases. The study of sphingolipid signaling in yeast has created a number of breakthroughs in the field, and has the potential to lead future advances. The aim of this article is to provide an inclusive view of two major frontiers in yeast sphingolipid signaling. In the first section, several key studies in the field of sphingolipidomics are consolidated to create a yeast sphingolipidome that ranks nearly all known sphingolipid species by their level in a resting yeast cell. The second section presents an overview of most known phenotypes identified for sphingolipid gene mutants, presented with the intention of illuminating not yet discovered connections outside and inside of the field. PMID:24220500

  1. Epigenetic Mechanisms of Serotonin Signaling.

    PubMed

    Holloway, Terrell; González-Maeso, Javier

    2015-07-15

    Histone modifications and DNA methylation represent central dynamic and reversible processes that regulate gene expression and contribute to cellular phenotypes. These epigenetic marks have been shown to play fundamental roles in a diverse set of signaling and behavioral outcomes. Serotonin is a monoamine that regulates numerous physiological responses including those in the central nervous system. The cardinal signal transduction mechanisms via serotonin and its receptors are well established, but fundamental questions regarding complex interactions between the serotonin system and heritable epigenetic modifications that exert control on gene function remain a topic of intense research and debate. This review focuses on recent advances and contributions to our understanding of epigenetic mechanisms of serotonin receptor-dependent signaling, with focus on psychiatric disorders such as schizophrenia and depression. PMID:25734378

  2. Signaling from axon guidance receptors.

    PubMed

    Bashaw, Greg J; Klein, Rüdiger

    2010-05-01

    Determining how axon guidance receptors transmit signals to allow precise pathfinding decisions is fundamental to our understanding of nervous system development and may suggest new strategies to promote axon regeneration after injury or disease. Signaling mechanisms that act downstream of four prominent families of axon guidance cues--netrins, semaphorins, ephrins, and slits--have been extensively studied in both invertebrate and vertebrate model systems. Although details of these signaling mechanisms are still fragmentary and there appears to be considerable diversity in how different guidance receptors regulate the motility of the axonal growth cone, a number of common themes have emerged. Here, we review recent insights into how specific receptors for each of these guidance cues engage downstream regulators of the growth cone cytoskeleton to control axon guidance. PMID:20452961

  3. Smoke signals and seed dormancy

    PubMed Central

    Waters, Mark T; Nelson, David C

    2011-01-01

    The Arabidopsis thaliana F-box protein MAX2 has been discovered in four separate genetic screens, indicating that it has roles in leaf senescence, seedling photosensitivity, shoot outgrowth and seed germination. Both strigolactones and karrikins can regulate A. thaliana seed germination and seedling photomorphogenesis in a MAX2-dependent manner, but only strigolactones inhibit shoot branching. How MAX2 mediates specific responses to both classes of structurally-related signals, and the origin of its dual role remains unknown. The moss Physcomitrella patens utilizes strigolactones and MAX2 orthologs are present across the land plants, suggesting that this signaling system could have an ancient origin. The seed of parasitic Orobanchaceae species germinate preferentially in response to strigolactones over karrikins, and putative Orobanchaceae MAX2 orthologs form a sub-clade distinct from those of other dicots. These observations suggest that lineage-specific evolution of MAX2 may have given rise to specialized responses to these signaling molecules. PMID:22019642

  4. Sortilins in neurotrophic factor signaling.

    PubMed

    Glerup, S; Nykjaer, A; Vaegter, C B

    2014-01-01

    The sortilin family of Vps10p-domain receptors includes sortilin, SorLA, and SorCS1-3. These type-I transmembrane receptors predominate in distinct neuronal tissues, but expression is also present in certain specialized non-neuronal cell populations including hepatocytes and cells of the immune system. The biology of sortilins is complex as they participate in both cell signaling and in intracellular protein sorting. Sortilins function physiologically in signaling by pro- and mature neurotrophins in neuronal viability and functionality. Recent genome-wide association studies have linked members to neurological disorders such as Alzheimer's disease and bipolar disorder and outside the nervous system to development of coronary artery disease and type-2 diabetes. Particularly well described are the receptor functions in neuronal signaling by pro- (proNT) and mature (NT) neurotrophins and in the processing/metabolism of amyloid precursor protein (APP). PMID:24668473

  5. The ins and outs of adrenergic signaling.

    PubMed

    Lohse, Martin J

    2015-09-01

    Adrenergic signaling, in particular signaling in the sympathetic nervous system, is a prime example of the control of an essential physiological system. It has served as a model system both for the control of mediator release and for receptor signaling and regulation. This review covers the historical development of the field and then addresses issues that represent key fields of ongoing research: the mechanisms and kinetics of receptor activation, temporal patterns of downstream signaling and signal bias, receptor mobility and aggregation, and signal compartmentation and specificity. The available evidence suggests that adrenergic signaling may involve complex spatiotemporal patterns, which give texture to the signaling process and may contain additional biological information. PMID:26199112

  6. Digital signal processor and programming system for parallel signal processing

    SciTech Connect

    Van den Bout, D.E.

    1987-01-01

    This thesis describes an integrated assault upon the problem of designing high-throughput, low-cost digital signal-processing systems. The dual prongs of this assault consist of: (1) the design of a digital signal processor (DSP) which efficiently executes signal-processing algorithms in either a uniprocessor or multiprocessor configuration, (2) the PaLS programming system which accepts an arbitrary algorithm, partitions it across a group of DSPs, synthesizes an optimal communication link topology for the DSPs, and schedules the partitioned algorithm upon the DSPs. The results of applying a new quasi-dynamic analysis technique to a set of high-level signal-processing algorithms were used to determine the uniprocessor features of the DSP design. For multiprocessing applications, the DSP contains an interprocessor communications port (IPC) which supports simple, flexible, dataflow communications while allowing the total communication bandwidth to be incrementally allocated to achieve the best link utilization. The net result is a DSP with a simple architecture that is easy to program for both uniprocessor and multi-processor modes of operation. The PaLS programming system simplifies the task of parallelizing an algorithm for execution upon a multiprocessor built with the DSP.

  7. Expected geoneutrino signal at JUNO

    NASA Astrophysics Data System (ADS)

    Strati, Virginia; Baldoncini, Marica; Callegari, Ivan; Mantovani, Fabio; McDonough, William F.; Ricci, Barbara; Xhixha, Gerti

    2015-12-01

    Constraints on the Earth's composition and on its radiogenic energy budget come from the detection of geoneutrinos. The Kamioka Liquid scintillator Antineutrino Detector (KamLAND) and Borexino experiments recently reported the geoneutrino flux, which reflects the amount and distribution of U and Th inside the Earth. The Jiangmen Underground Neutrino Observatory (JUNO) neutrino experiment, designed as a 20 kton liquid scintillator detector, will be built in an underground laboratory in South China about 53 km from the Yangjiang and Taishan nuclear power plants, each one having a planned thermal power of approximately 18 GW. Given the large detector mass and the intense reactor antineutrino flux, JUNO aims not only to collect high statistics antineutrino signals from reactors but also to address the challenge of discriminating the geoneutrino signal from the reactor background. The predicted geoneutrino signal at JUNO is terrestrial neutrino unit (TNU), based on the existing reference Earth model, with the dominant source of uncertainty coming from the modeling of the compositional variability in the local upper crust that surrounds (out to approximately 500 km) the detector. A special focus is dedicated to the 6° × 4° local crust surrounding the detector which is estimated to contribute for the 44% of the signal. On the basis of a worldwide reference model for reactor antineutrinos, the ratio between reactor antineutrino and geoneutrino signals in the geoneutrino energy window is estimated to be 0.7 considering reactors operating in year 2013 and reaches a value of 8.9 by adding the contribution of the future nuclear power plants. In order to extract useful information about the mantle's composition, a refinement of the abundance and distribution of U and Th in the local crust is required, with particular attention to the geochemical characterization of the accessible upper crust where 47% of the expected geoneutrino signal originates and this region contributes

  8. Acoustically-Induced Electrical Signals

    NASA Astrophysics Data System (ADS)

    Brown, S. R.

    2014-12-01

    We have observed electrical signals excited by and moving along with an acoustic pulse propagating in a sandstone sample. Using resonance we are now studying the characteristics of this acousto-electric signal and determining its origin and the controlling physical parameters. Four rock samples with a range of porosities, permeabilities, and mineralogies were chosen: Berea, Boise, and Colton sandstones and Austin Chalk. Pore water salinity was varied from deionized water to sea water. Ag-AgCl electrodes were attached to the sample and were interfaced to a 4-wire electrical resistivity system. Under computer control, the acoustic signals were excited and the electrical response was recorded. We see strong acoustically-induced electrical signals in all samples, with the magnitude of the effect for each rock getting stronger as we move from the 1st to the 3rd harmonics in resonance. Given a particular fluid salinity, each rock has its own distinct sensitivity in the induced electrical effect. For example at the 2nd harmonic, Berea Sandstone produces the largest electrical signal per acoustic power input even though Austin Chalk and Boise Sandstone tend to resonate with much larger amplitudes at the same harmonic. Two effects are potentially responsible for this acoustically-induced electrical response: one the co-seismic seismo-electric effect and the other a strain-induced resistivity change known as the acousto-electric effect. We have designed experimental tests to separate these mechanisms. The tests show that the seismo-electric effect is dominant in our studies. We note that these experiments are in a fluid viscosity dominated seismo-electric regime, leading to a simple interpretation of the signals where the electric potential developed is proportional to the local acceleration of the rock. Toward a test of this theory we have measured the local time-varying acoustic strain in our samples using a laser vibrometer.

  9. Lipid signals and insulin resistance.

    PubMed

    Zhang, Chongben; Klett, Eric L; Coleman, Rosalind A

    2013-12-01

    The metabolic syndrome, a cluster of metabolic derangements that include obesity, glucose intolerance, dyslipidemia and hypertension, is a major risk factor for cardiovascular disease. Insulin resistance has been proposed to be the common feature that links obesity to the metabolic syndrome, but the mechanism remains obscure. Although the excess content of triacylglycerol in muscle and liver is highly associated with insulin resistance in these tissues, triacylglycerol itself is not causal but merely a marker. Thus, attention has turned to the accumulation of cellular lipids known to have signaling roles. This review will discuss recent progress in understanding how glycerolipids and related lipid intermediates may impair insulin signaling. PMID:24533033

  10. Phosphoinositide signaling in somatosensory neurons.

    PubMed

    Rohacs, Tibor

    2016-05-01

    Somatosensory neurons of the dorsal root ganglia (DRG) and trigeminal ganglia (TG) are responsible for detecting thermal and tactile stimuli. They are also the primary neurons mediating pain and itch. A large number of cell surface receptors in these neurons couple to phospholipase C (PLC) enzymes leading to the hydrolysis of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and the generation of downstream signaling molecules. These neurons also express many different ion channels, several of which are regulated by phosphoinositides. This review will summarize the knowledge on phosphoinositide signaling in DRG neurons, with special focus on effects on sensory and other ion channels. PMID:26724974

  11. Pharmacology of intracellular signalling pathways

    PubMed Central

    Nahorski, Stefan R

    2006-01-01

    This article provides a brief and somewhat personalized review of the dramatic developments that have occurred over the last 45 years in our understanding of intracellular signalling pathways associated with G-protein-coupled receptor activation. Signalling via cyclic AMP, the phosphoinositides and Ca2+ is emphasized and these systems have already been revealed as new pharmacological targets. The therapeutic benefits of most of such targets are, however, yet to be realized, but it is certain that the discipline of pharmacology needs to widen its boundaries to meet these challenges in the future. PMID:16402119

  12. Genomic Signals of Reoriented ORFs

    NASA Astrophysics Data System (ADS)

    Dan Cristea, Paul

    2004-12-01

    Complex representation of nucleotides is used to convert DNA sequences into complex digital genomic signals. The analysis of the cumulated phase and unwrapped phase of DNA genomic signals reveals large-scale features of eukaryote and prokaryote chromosomes that result from statistical regularities of base and base-pair distributions along DNA strands. By reorienting the chromosome coding regions, a "hidden" linear variation of the cumulated phase has been revealed, along with the conspicuous almost linear variation of the unwrapped phase. A model of chromosome longitudinal structure is inferred on these bases.

  13. Ubiquitin signaling in immune responses

    PubMed Central

    Hu, Hongbo; Sun, Shao-Cong

    2016-01-01

    Ubiquitination has emerged as a crucial mechanism that regulates signal transduction in diverse biological processes, including different aspects of immune functions. Ubiquitination regulates pattern-recognition receptor signaling that mediates both innate immune responses and dendritic cell maturation required for initiation of adaptive immune responses. Ubiquitination also regulates the development, activation, and differentiation of T cells, thereby maintaining efficient adaptive immune responses to pathogens and immunological tolerance to self-tissues. Like phosphorylation, ubiquitination is a reversible reaction tightly controlled by the opposing actions of ubiquitin ligases and deubiquitinases. Deregulated ubiquitination events are associated with immunological disorders, including autoimmune and inflammatory diseases. PMID:27012466

  14. Tyrosine Phosphorylation in Brassinosteroid Signaling

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Brassinosteroids (BRs) regulate plant growth and development through a complex signal transduction pathway involving BRASSINOSTEROID INSENSITIVE 1 (BRI1), which is the BR receptor, and its co-receptor BRI1-ASSOCIATED KINASE 1 (BAK1). Both proteins are classified as Ser/Thr protein kinases. Recently,...

  15. VLSI mixed signal processing system

    NASA Technical Reports Server (NTRS)

    Alvarez, A.; Premkumar, A. B.

    1993-01-01

    An economical and efficient VLSI implementation of a mixed signal processing system (MSP) is presented in this paper. The MSP concept is investigated and the functional blocks of the proposed MSP are described. The requirements of each of the blocks are discussed in detail. A sample application using active acoustic cancellation technique is described to demonstrate the power of the MSP approach.

  16. Velocimetry signal synthesis with fringen.

    SciTech Connect

    Dolan, Daniel H., III

    2011-02-01

    An important part of velocimetry analysis is the recovery of a known velocity history from simulated data signals. The fringen program synthesizes VISAR and PDV signals, given a specified velocity history, using exact formulations for the optical signal. Time-dependent light conditions, non-ideal measurement conditions, and various diagnostic limitations (noise, etc.) may be incorporated into the simulated signals. This report describes the fringen program, which performs forward VISAR (Velocity Interferometer System for Any Reflector) and PDV (Photonic Doppler Velocimetry, also known as heterodyne velocimetry) analysis. Nearly all effects that might occur in VISAR/PDV measurement of a single velocity can be modeled by fringen. The program operates in MATLAB, either within a graphical interface or as a user-callable function. The current stable version of fringen is 0.3, which was released in October 2010. The following sections describe the operation and use of fringen. Section 2 gives a brief overview of VISAR and PDV synthesis. Section 3 illustrates the graphical and console interface of fringen. Section 4 presents several example uses of the program. Section 5 summarizes program capabilities and discusses potential future work.

  17. Focus issue: signaling across membranes.

    PubMed

    Gough, Nancy R

    2005-12-01

    This week's issues of Science and Science's STKE focus on movement of molecules and information across cellular membranes. Science highlights the mechanisms by which proteins, ions, and DNA cross the membranes of eukaryotic and prokaryotic cells. STKE addresses how information is transmitted across cell membranes to allow cells to communicate with each other and to respond to signals in their environments. PMID:16333016

  18. Multipactor theory for multicarrier signals

    SciTech Connect

    Anza, S.; Vicente, C.; Gil, J.; Raboso, D.; Boria, V. E.

    2011-03-15

    This work presents a new theory of multipactor under multicarrier signals for parallel-plate geometries, assuming a homogeneous electric field and one-dimensional electron motion. It is the generalization of the nonstationary multipactor theory for single-carrier signals [S. Anza et al.,Phys. Plasmas 17, 062110 (2010)]. It is valid for multicarrier signals with an arbitrary number of carriers with different amplitude, arbitrary frequency, and phase conditions and for any material coating. This new theory is able to model the real dynamics of the electrons during the multipactor discharge for both single and double surface interactions. Among other parameters of the discharge, it calculates the evolution in time of the charge growth, electron absorption, and creation rates as well as the instantaneous secondary emission yield and order. An extensive set of numerical tests with particle-in-cell software has been carried out in order to validate the theory under many different conditions. This theoretical development constitutes the first multipactor theory which completely characterizes the multipactor discharge for arbitrary multicarrier signals, setting the first step for further investigations in the field.

  19. Signal Prediction With Input Identification

    NASA Technical Reports Server (NTRS)

    Juang, Jer-Nan; Chen, Ya-Chin

    1999-01-01

    A novel coding technique is presented for signal prediction with applications including speech coding, system identification, and estimation of input excitation. The approach is based on the blind equalization method for speech signal processing in conjunction with the geometric subspace projection theory to formulate the basic prediction equation. The speech-coding problem is often divided into two parts, a linear prediction model and excitation input. The parameter coefficients of the linear predictor and the input excitation are solved simultaneously and recursively by a conventional recursive least-squares algorithm. The excitation input is computed by coding all possible outcomes into a binary codebook. The coefficients of the linear predictor and excitation, and the index of the codebook can then be used to represent the signal. In addition, a variable-frame concept is proposed to block the same excitation signal in sequence in order to reduce the storage size and increase the transmission rate. The results of this work can be easily extended to the problem of disturbance identification. The basic principles are outlined in this report and differences from other existing methods are discussed. Simulations are included to demonstrate the proposed method.

  20. Text Signals Influence Team Artifacts

    ERIC Educational Resources Information Center

    Clariana, Roy B.; Rysavy, Monica D.; Taricani, Ellen

    2015-01-01

    This exploratory quasi-experimental investigation describes the influence of text signals on team visual map artifacts. In two course sections, four-member teams were given one of two print-based text passage versions on the course-related topic "Social influence in groups" downloaded from Wikipedia; this text had two paragraphs, each…

  1. Receiving signals of any polarization

    NASA Technical Reports Server (NTRS)

    Ohlson, J. E.; Seidel, B. L.; Stelzried, C. H.

    1981-01-01

    Two-channel detection accomodates linear, circular, and elliptical polarization in one receiving unit. Receiver employs orthomode transducer which breaks any type signal into one left and one right circular component. These are processed in separate receiver channels with equal time-delay, and then recombined for data extraction. System eliminates losses due to polarization mismatch.

  2. Decomposition of indwelling EMG signals

    PubMed Central

    Nawab, S. Hamid; Wotiz, Robert P.; De Luca, Carlo J.

    2008-01-01

    Decomposition of indwelling electromyographic (EMG) signals is challenging in view of the complex and often unpredictable behaviors and interactions of the action potential trains of different motor units that constitute the indwelling EMG signal. These phenomena create a myriad of problem situations that a decomposition technique needs to address to attain completeness and accuracy levels required for various scientific and clinical applications. Starting with the maximum a posteriori probability classifier adapted from the original precision decomposition system (PD I) of LeFever and De Luca (25, 26), an artificial intelligence approach has been used to develop a multiclassifier system (PD II) for addressing some of the experimentally identified problem situations. On a database of indwelling EMG signals reflecting such conditions, the fully automatic PD II system is found to achieve a decomposition accuracy of 86.0% despite the fact that its results include low-amplitude action potential trains that are not decomposable at all via systems such as PD I. Accuracy was established by comparing the decompositions of indwelling EMG signals obtained from two sensors. At the end of the automatic PD II decomposition procedure, the accuracy may be enhanced to nearly 100% via an interactive editor, a particularly significant fact for the previously indecomposable trains. PMID:18483170

  3. Meeting Report: Teaching Signal Transduction

    ERIC Educational Resources Information Center

    Kramer, IJsbrand; Thomas, Geraint

    2006-01-01

    In July, 2005, the European Institute of Chemistry and Biology at the campus of the University of Bordeaux, France, hosted a focused week of seminars, workshops, and discussions around the theme of "teaching signal transduction." The purpose of the summer school was to offer both junior and senior university instructors a chance to reflect on the…

  4. Calcium signalling and Alzheimer's disease.

    PubMed

    Berridge, Michael J

    2011-07-01

    New insights into how Ca(2+) regulates learning and memory have begun to provide clues as to how the amyloid-dependent remodelling of neuronal Ca(2+) signalling pathways can disrupt the mechanisms of learning and memory in Alzheimer's disease (AD). The calcium hypothesis of AD proposes that activation of the amyloidogenic pathway remodels the neuronal Ca(2+) signalling pathways responsible for cognition by enhancing the entry of Ca(2+) and/or the release of internal Ca(2+) by ryanodine receptors or InsP(3) receptors. The specific proposal is that Ca(2+) signalling remodelling results in a persistent elevation in the level of Ca(2+) that constantly erases newly acquired memories by enhancing the mechanism of long-term depression (LTD). Neurons can still form memories through the process of LTP, but this stored information is rapidly removed by the persistent activation of LTD. Further dysregulation in Ca(2+) signalling will then go on to induce the neurodegeneration that characterizes the later stages of dementia. PMID:21184278

  5. Deconstructing Signaling in Three Dimensions

    PubMed Central

    2015-01-01

    Cells in vivo exist within the context of a multicellular tissue, where their behavior is governed by homo- and heterotypic cell–cell interactions, the material properties of the extracellular matrix, and the distribution of various soluble and physical factors. Most methods currently used to study and manipulate cellular behavior in vitro, however, sacrifice physiological relevance for experimental expediency. The fallacy of such approaches has been highlighted by the recent development and application of three-dimensional culture models to cell biology, which has revealed striking phenotypic differences in cell survival, migration, and differentiation in genetically identical cells simply by varying culture conditions. These perplexing findings beg the question of what constitutes a three-dimensional culture and why cells behave so differently in two- and three-dimensional culture formats. In the following review, we dissect the fundamental differences between two- and three-dimensional culture conditions. We begin by establishing a basic definition of what “three dimensions” means at different biological scales and discuss how dimensionality influences cell signaling across different length scales. We identify which three-dimensional features most potently influence intracellular signaling and distinguish between conserved biological principles that are maintained across culture conditions and cellular behaviors that are sensitive to microenvironmental context. Finally, we highlight state-of-the-art molecular tools amenable to the study of signaling in three dimensions under conditions that facilitate deconstruction of signaling in a more physiologically relevant manner. PMID:24649923

  6. Decoding Gαq signaling.

    PubMed

    Litosch, Irene

    2016-05-01

    Gαq signals with phospholipase C-β (PLC-β) to modify behavior in response to an agonist-bound GPCR. While the fundamental steps which prime Gαq to interact with PLC-β have been identified, questions remain concerning signal strength with PLC-β and other effectors. Gαq is generally viewed to function as a simple ON and OFF switch for its effector, dependent on the binding of GTP or GDP. However, Gαq does not have a single effector, Gαq has many different effectors. Furthermore, select effectors also regulate Gαq activity. PLC-β is a lipase and a GTPase activating protein (GAP) selective for Gαq. The contribution of G protein regulating activity to signal amplitude remains unclear. The unique PLC-β coiled-coil domain is essential for maximum Gαq response, both lipase and GAP. Nonetheless, coiled-coil domain associations necessary to maximum response have not been revealed by the structural approach. This review discusses progress towards understanding the basis for signal strength with PLC-β and other effectors. Shared and effector-specific interactions have been identified. Finally, the evidence for allosteric regulation of lipase stimulation by protein kinase C, the membrane, phosphatidic acid, phosphatidylinositol-4, 5-bisphosphate and GPCR is explored. Endogenous allosteric regulators can suppress or enhance maximum lipase stimulation dependent on the PLC-β coiled-coil domain. A better understanding of allosteric modulation may therefore identify a wealth of new targets to regulate signal strength and behavior. PMID:27012764

  7. Phosphorylation in halobacterial signal transduction.

    PubMed Central

    Rudolph, J; Tolliday, N; Schmitt, C; Schuster, S C; Oesterhelt, D

    1995-01-01

    Regulated phosphorylation of proteins has been shown to be a hallmark of signal transduction mechanisms in both Eubacteria and Eukarya. Here we demonstrate that phosphorylation and dephosphorylation are also the underlying mechanism of chemo- and phototactic signal transduction in Archaea, the third branch of the living world. Cloning and sequencing of the region upstream of the cheA gene, known to be required for chemo- and phototaxis in Halobacterium salinarium, has identified cheY and cheB analogs which appear to form part of an operon which also includes cheA and the following open reading frame of 585 nucleotides. The CheY and CheB proteins have 31.3 and 37.5% sequence identity compared with the known signal transduction proteins CheY and CheB from Escherichia coli, respectively. The biochemical activities of both CheA and CheY were investigated following their expression in E.coli, isolation and renaturation. Wild-type CheA could be phosphorylated in a time-dependent manner in the presence of [gamma-32P]ATP and Mg2+, whereas the mutant CheA(H44Q) remained unlabeled. Phosphorylated CheA was dephosphorylated rapidly by the addition of wild-type CheY. The mutant CheY(D53A) had no effect on phosphorylated CheA. The mechanism of chemo- and phototactic signal transduction in the Archaeon H.salinarium, therefore, is similar to the two-component signaling system known from chemotaxis in the eubacterium E.coli. Images PMID:7556066

  8. BPSK Demodulation Using Digital Signal Processing

    NASA Technical Reports Server (NTRS)

    Garcia, Thomas R.

    1996-01-01

    A digital communications signal is a sinusoidal waveform that is modified by a binary (digital) information signal. The sinusoidal waveform is called the carrier. The carrier may be modified in amplitude, frequency, phase, or a combination of these. In this project a binary phase shift keyed (BPSK) signal is the communication signal. In a BPSK signal the phase of the carrier is set to one of two states, 180 degrees apart, by a binary (i.e., 1 or 0) information signal. A digital signal is a sampled version of a "real world" time continuous signal. The digital signal is generated by sampling the continuous signal at discrete points in time. The rate at which the signal is sampled is called the sampling rate (f(s)). The device that performs this operation is called an analog-to-digital (A/D) converter or a digitizer. The digital signal is composed of the sequence of individual values of the sampled BPSK signal. Digital signal processing (DSP) is the modification of the digital signal by mathematical operations. A device that performs this processing is called a digital signal processor. After processing, the digital signal may then be converted back to an analog signal using a digital-to-analog (D/A) converter. The goal of this project is to develop a system that will recover the digital information from a BPSK signal using DSP techniques. The project is broken down into the following steps: (1) Development of the algorithms required to demodulate the BPSK signal; (2) Simulation of the system; and (3) Implementation a BPSK receiver using digital signal processing hardware.

  9. Blood pressure reprogramming adapter assists signal recording

    NASA Technical Reports Server (NTRS)

    Vick, H. A.

    1967-01-01

    Blood pressure reprogramming adapter separates the two components of a blood pressure signal, a dc pressure signal and an ac Korotkoff sounds signal, so that the Korotkoff sounds are recorded on one channel as received while the dc pressure signal is converted to FM and recorded on a second channel.

  10. 33 CFR 117.15 - Signals.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... used to request the opening of the draw and to acknowledge that request shall be sound signals, visual... described in this subpart sufficient to alert the party being signaled may be used. (b) Sound signals. (1) Sound signals shall be made by whistle, horn, megaphone, hailer, or other device capable of...

  11. Multifractal nature of unvoiced speech signals

    SciTech Connect

    Adeyemi, O.A.; Hartt, K.; Boudreaux-Bartels, G.F.

    1996-06-01

    A refinement is made in the nonlinear dynamic modeling of speech signals. Previous research successfully characterized speech signals as chaotic. Here, we analyze fricative speech signals using multifractal measures to determine various fractal regimes present in their chaotic attractors. Results support the hypothesis that speech signals have multifractal measures. {copyright} {ital 1996 American Institute of Physics.}

  12. On the Spectrum of Periodic Signals

    ERIC Educational Resources Information Center

    Al-Smadi, Adnan

    2004-01-01

    In theory, there are many methods for the representation of signals. In practice, however, Fourier analysis involving the resolution of signals into sinusoidal components is used widely. There are several methods for Fourier analysis available for representation of signals. If the signal is periodic, then the Fourier series is used to represent…

  13. Science Signaling Podcast for 7 June 2016: Modeling signal integration.

    PubMed

    Janes, Kevin A; VanHook, Annalisa M

    2016-01-01

    This Podcast features an interview with Kevin Janes, senior author of a Research Article that appears in the 7 June 2016 issue of Science Signaling, about a statistical modeling method that can extract useful information from complex data sets. Cells exist in very complex environments. They are constantly exposed to growth factors, hormones, nutrients, and many other factors that influence cellular behavior. When cells integrate information from multiple stimuli, the resulting output does not necessarily reflect a simple additive effect of the responses to each individual stimulus. Chitforoushzadeh et al employed a statistical modeling approach that maintained the multidimensional nature of the data to analyze the responses of colonic epithelial cells to various combinations of the proinflammatory cytokine TNF, the growth factor EGF, and insulin. As the model predicted, experiments confirmed that insulin suppressed TNF-induced proinflammatory signaling through a mechanism that involved the transcription factor GATA6.Listen to Podcast. PMID:27273095

  14. The Fog signaling pathway: insights into signaling in morphogenesis.

    PubMed

    Manning, Alyssa J; Rogers, Stephen L

    2014-10-01

    Epithelia form the building blocks of many tissue and organ types. Epithelial cells often form a contiguous 2-dimensional sheet that is held together by strong adhesions. The mechanical properties conferred by these adhesions allow the cells to undergo dramatic three-dimensional morphogenetic movements while maintaining cell-cell contacts during embryogenesis and post-embryonic development. The Drosophila Folded gastrulation pathway triggers epithelial cell shape changes that drive gastrulation and tissue folding and is one of the most extensively studied examples of epithelial morphogenesis. This pathway has yielded key insights into the signaling mechanisms and cellular machinery involved in epithelial remodeling. In this review, we discuss principles of morphogenesis and signaling that have been discovered through genetic and cell biological examination of this pathway. We also consider various regulatory mechanisms and the system׳s relevance to mammalian development. We propose future directions that will continue to broaden our knowledge of morphogenesis across taxa. PMID:25127992

  15. Dynamic range control of audio signals by digital signal processing

    NASA Astrophysics Data System (ADS)

    Gilchrist, N. H. C.

    It is often necessary to reduce the dynamic range of musical programs, particularly those comprising orchestral and choral music, for them to be received satisfactorily by listeners to conventional FM and AM broadcasts. With the arrival of DAB (Digital Audio Broadcasting) a much wider dynamic range will become available for radio broadcasting, although some listeners may prefer to have a signal with a reduced dynamic range. This report describes a digital processor developed by the BBC to control the dynamic range of musical programs in a manner similar to that of a trained Studio Manager. It may be used prior to transmission in conventional broadcasting, replacing limiters or other compression equipment. In DAB, it offers the possibility of providing a dynamic range control signal to be sent to the receiver via an ancillary data channel, simultaneously with the uncompressed audio, giving the listener the option of the full dynamic range or a reduced dynamic range.

  16. The Fog signaling pathway: Insights into signaling in morphogenesis

    PubMed Central

    Manning, Alyssa J.; Rogers, Stephen L.

    2014-01-01

    Epithelia form the building blocks of many tissue and organ types. Epithelial cells often form a contiguous 2-dimensional sheet that is held together by strong adhesions. The mechanical properties conferred by these adhesions allow the cells to undergo dramatic three-dimensional morphogenetic movements while maintaining cell–cell contacts during embryogenesis and post-embryonic development. The Drosophila Folded gastrulation pathway triggers epithelial cell shape changes that drive gastrulation and tissue folding and is one of the most extensively studied examples of epithelial morphogenesis. This pathway has yielded key insights into the signaling mechanisms and cellular machinery involved in epithelial remodeling. In this review, we discuss principles of morphogenesis and signaling that have been discovered through genetic and cell biological examination of this pathway. We also consider various regulatory mechanisms and the system's relevance to mammalian development. We propose future directions that will continue to broaden our knowledge of morphogenesis across taxa. PMID:25127992

  17. Optically isolated signal coupler with linear response

    DOEpatents

    Kronberg, James W.

    1994-01-01

    An optocoupler for isolating electrical signals that translates an electrical input signal linearly to an electrical output signal. The optocoupler comprises a light emitter, a light receiver, and a light transmitting medium. The light emitter, preferably a blue, silicon carbide LED, is of the type that provides linear, electro-optical conversion of electrical signals within a narrow wavelength range. Correspondingly, the light receiver, which converts light signals to electrical signals and is preferably a cadmium sulfide photoconductor, is linearly responsive to light signals within substantially the same wavelength range as the blue LED.

  18. Timing in Cellular Ca2+ signaling

    PubMed Central

    Boulware, Michael J.; Marchant, Jonathan S.

    2011-01-01

    Calcium (Ca2+) signals are generated across a broad time range. Kinetic considerations impact how information is processed to encode and decode Ca2+ signals, the choreography of responses that ensure specific and efficient signaling and the overall temporal gearing such that ephemeral Ca2+ signals have lasting physiological value. The reciprocal importance of timing for Ca2+ signaling, and Ca2+ signaling for timing is exemplified by the altered kinetic profiles of Ca2+ signals in certain diseases and the likely role of basal Ca2+ fluctuations in the perception of time itself. PMID:18786382

  19. Empirical mode decomposition for analyzing acoustical signals

    NASA Technical Reports Server (NTRS)

    Huang, Norden E. (Inventor)

    2005-01-01

    The present invention discloses a computer implemented signal analysis method through the Hilbert-Huang Transformation (HHT) for analyzing acoustical signals, which are assumed to be nonlinear and nonstationary. The Empirical Decomposition Method (EMD) and the Hilbert Spectral Analysis (HSA) are used to obtain the HHT. Essentially, the acoustical signal will be decomposed into the Intrinsic Mode Function Components (IMFs). Once the invention decomposes the acoustic signal into its constituting components, all operations such as analyzing, identifying, and removing unwanted signals can be performed on these components. Upon transforming the IMFs into Hilbert spectrum, the acoustical signal may be compared with other acoustical signals.

  20. Cleavage of Signal Regulatory Protein α (SIRPα) Enhances Inflammatory Signaling.

    PubMed

    Londino, James D; Gulick, Dexter; Isenberg, Jeffrey S; Mallampalli, Rama K

    2015-12-25

    Signal regulatory protein α (SIRPα) is a membrane glycoprotein immunoreceptor abundant in cells of monocyte lineage. SIRPα ligation by a broadly expressed transmembrane protein, CD47, results in phosphorylation of the cytoplasmic immunoreceptor tyrosine-based inhibitory motifs, resulting in the inhibition of NF-κB signaling in macrophages. Here we observed that proteolysis of SIRPα during inflammation is regulated by a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), resulting in the generation of a membrane-associated cleavage fragment in both THP-1 monocytes and human lung epithelia. We mapped a charge-dependent putative cleavage site near the membrane-proximal domain necessary for ADAM10-mediated cleavage. In addition, a secondary proteolytic cleavage within the membrane-associated SIRPα fragment by γ-secretase was identified. Ectopic expression of a SIRPα mutant plasmid encoding a proteolytically resistant form in HeLa cells inhibited activation of the NF-κB pathway and suppressed STAT1 phosphorylation in response to TNFα to a greater extent than expression of wild-type SIRPα. Conversely, overexpression of plasmids encoding the proteolytically cleaved SIRPα fragments in cells resulted in enhanced STAT-1 and NF-κB pathway activation. Thus, the data suggest that combinatorial actions of ADAM10 and γ-secretase on SIRPα cleavage promote inflammatory signaling. PMID:26534964

  1. CHM-1 Suppresses Formation of Cell Surface-associated GRP78-p85α Complexes, Inhibiting PI3K-AKT Signaling and Inducing Apoptosis of Human Nasopharyngeal Carcinoma Cells.

    PubMed

    Lin, Meng-Liang; Chen, Shih-Shun; Ng, Sue-Hwee

    2015-10-01

    The endoplasmic reticulum chaperone glucose-regulated protein 78 (GRP78) is selectively expressed on the surface of cancer cells, and contributes to the survival of cancer cells by forming complexes with p85α and promoting phosphatidylinositol 3-kinase-protein kinase B (PI3K-AKT) signaling. Hereιin we report that 2'-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone (CHM-1) induces apoptosis of human nasopharyngeal carcinoma (NPC) cells, as characterized by morphological changes, DNA fragmentation, caspase-3 activation, and cleavage of poly (ADP-ribose) polymerase. Using cell surface biotinylation, flow cytometric analysis, co-immunoprecipitation, and ectopic expression of GRP78, we demonstrated that the attenuation of the cell surface localization and complex formation with p85α of GRP78 by CHM-1 was involved in the inhibition of PI3K-AKT signaling and the induction of apoptosis. CHM-1 treatment induced phosphorylation on Thr 69 of B cell lymphoma 2 and inhibited phosphorylation of Ser 136 on Bcl-2-associated death promoter, that were reversed by overexpression of GRP78. We further observed that loss of mitochondrial membrane potential and increase in reactive oxygen species content, release of mitochondrial cytochrome c, caspase-9 activation, and apoptotic cell death induced by CHM-1, were suppressed by treatment with cyclosporine A, and by the overexpression of constitutively active AKT1 or GRP78. These results indicate that CHM-1 induces NPC cell apoptosis by suppressing the formation of the cell surface-associated GRP78-PI3K-AKT signaling complex, likely through inhibition of the formation of cell surface-associated GRP78-p85α complexes. PMID:26408697

  2. Nuclear sensor signal processing circuit

    DOEpatents

    Kallenbach, Gene A.; Noda, Frank T.; Mitchell, Dean J.; Etzkin, Joshua L.

    2007-02-20

    An apparatus and method are disclosed for a compact and temperature-insensitive nuclear sensor that can be calibrated with a non-hazardous radioactive sample. The nuclear sensor includes a gamma ray sensor that generates tail pulses from radioactive samples. An analog conditioning circuit conditions the tail-pulse signals from the gamma ray sensor, and a tail-pulse simulator circuit generates a plurality of simulated tail-pulse signals. A computer system processes the tail pulses from the gamma ray sensor and the simulated tail pulses from the tail-pulse simulator circuit. The nuclear sensor is calibrated under the control of the computer. The offset is adjusted using the simulated tail pulses. Since the offset is set to zero or near zero, the sensor gain can be adjusted with a non-hazardous radioactive source such as, for example, naturally occurring radiation and potassium chloride.

  3. Calcium Signaling in Lacrimal Glands

    PubMed Central

    Putney, James W.; Bird, Gary S.

    2014-01-01

    Lacrimal glands provide the important function of lubricating and protecting the ocular surface. Failure of proper lacrimal gland function results in a number of debilitating dry eye diseases. Lacrimal glands secrete lipids, mucins, proteins, salts and water and these secretions are at least partially regulated by neurotransmitter-mediated cell signaling. The predominant signaling mechanism for lacrimal secretion involves activation of phospholipase C, generation of the Ca2+-mobilizing messenger, IP3, and release of Ca2+ stored in the endoplasmic reticulum. The loss of Ca2+ from the endoplasmic reticulum then triggers a process known as store-operated Ca2+ entry, involving a Ca2+ sensor in the endoplasmic reticulum, STIM1, which activates plasma membrane store-operated channels comprised of Orai subunits. Recent studies with deletions of the channel subunit, Orai1, confirm the important role of SOCE in both fluid and protein secretion in lacrimal glands, both in vivo and in vitro. PMID:24507443

  4. A signal model for GPS

    NASA Technical Reports Server (NTRS)

    Braasch, Michael S.

    1991-01-01

    As the development of GPS continues, there will be an increasing need for a software-centered signal model. This model must accurately generate the observed pseudorange that would typically be encountered. The observed pseudorange varies from the true geometric range because of range measurement errors, which stem from a variety of hardware and environmental factors. In this paper, these errors are classified as either deterministic or random, and, where appropriate, their models are summarized. Of particular interest is the model for Selective Availability, which was derived from actual GPS data. The procedure for determination of this model, known as system identification theory, is briefly outlined. The synthesis of these error sources into the final signal model is given, along with simulation results.

  5. Glycopolymer probes of signal transduction†

    PubMed Central

    Kiessling, Laura L.; Grim, Joseph C.

    2013-01-01

    Glycans are key participants in biological processes ranging from reproduction to cellular communication to infection. Revealing glycan roles and the underlying molecular mechanisms by which glycans manifest their function requires access to glycan derivatives that vary systematically. To this end, glycopolymers (polymers bearing pendant carbohydrates) have emerged as valuable glycan analogs. Because glycopolymers can readily be synthesized, their overall shape can be varied, and they can be altered systematically to dissect the structural features that underpin their activities. This review provides examples in which glycopolymers have been used to effect carbohydrate-mediated signal transduction. Our objective is to illustrate how these powerful tools can reveal the molecular mechanisms that underlie carbohydrate-mediated signal transduction. PMID:23595539

  6. Useful signals from motor cortex

    PubMed Central

    Schwartz, Andrew B

    2007-01-01

    Historically, the motor cortical function has been explained as a funnel to muscle activation. This invokes the idea that motor cortical neurons, or ‘upper motoneurons’, directly cause muscle contraction just like spinal motoneurons. Thus, the motor cortex and muscle activity are inextricably entwined like a puppet master and his marionette. Recently, this concept has been challenged by current experimentation showing that many behavioural aspects of action are represented in motor cortical activity. Although this activity may still be related to muscle activation, the relation between the two is likely to be indirect and complex, whereas the relation between cortical activity and kinematic parameters is simple and robust. These findings show how to extract useful signals that help explain the underlying process that generates behaviour and to harness these signals for potentially therapeutic applications. PMID:17255162

  7. Signal processing of anthropometric data

    NASA Astrophysics Data System (ADS)

    Zimmermann, W. J.

    1983-09-01

    The Anthropometric Measurements Laboratory has accumulated a large body of data from a number of previous experiments. The data is very noisy, therefore it requires the application of some signal processing schemes. Moreover, it was not regarded as time series measurements but as positional information; hence, the data is stored as coordinate points as defined by the motion of the human body. The accumulated data defines two groups or classes. Some of the data was collected from an experiment designed to measure the flexibility of the limbs, referred to as radial movement. The remaining data was collected from experiments designed to determine the surface of the reach envelope. An interactive signal processing package was designed and implemented. Since the data does not include time this package does not include a time series element. Presently the results is restricted to processing data obtained from those experiments designed to measure flexibility.

  8. DNA signals at isoform promoters

    PubMed Central

    Dai, Zhiming; Xiong, Yuanyan; Dai, Xianhua

    2016-01-01

    Transcriptional heterogeneity is extensive in the genome, and most genes express variable transcript isoforms. However, whether variable transcript isoforms of one gene are regulated by common promoter elements remain to be elucidated. Here, we investigated whether isoform promoters of one gene have separated DNA signals for transcription and translation initiation. We found that TATA box and nucleosome-disfavored DNA sequences are prevalent in distinct transcript isoform promoters of one gene. These DNA signals are conserved among species. Transcript isoform has a RNA-determined unstructured region around its start site. We found that these DNA/RNA features facilitate isoform transcription and translation. These results suggest a DNA-encoded mechanism by which transcript isoform is generated. PMID:27353836

  9. Acoustic Localization with Infrasonic Signals

    NASA Astrophysics Data System (ADS)

    Threatt, Arnesha; Elbing, Brian

    2015-11-01

    Numerous geophysical and anthropogenic events emit infrasonic frequencies (<20 Hz), including volcanoes, hurricanes, wind turbines and tornadoes. These sounds, which cannot be heard by the human ear, can be detected from large distances (in excess of 100 miles) due to low frequency acoustic signals having a very low decay rate in the atmosphere. Thus infrasound could be used for long-range, passive monitoring and detection of these events. An array of microphones separated by known distances can be used to locate a given source, which is known as acoustic localization. However, acoustic localization with infrasound is particularly challenging due to contamination from other signals, sensitivity to wind noise and producing a trusted source for system development. The objective of the current work is to create an infrasonic source using a propane torch wand or a subwoofer and locate the source using multiple infrasonic microphones. This presentation will present preliminary results from various microphone configurations used to locate the source.

  10. Wnt signaling in skin organogenesis.

    PubMed

    Widelitz, Randall B

    2008-04-01

    While serving as the interface between an organism and its environment, the skin also can elaborate a wide range of skin appendages to service specific purposes in a region-specific fashion. As in other organs, Wnt signaling plays a key role in regulating the proliferation, differentiation and motility of skin cells during their morphogenesis. Here I will review some of the recent work that has been done on skin organogenesis. I will cover dermis formation, the development of skin appendages, cycling of appendages in the adult, stem cell regulation, patterning, orientation, regional specificity and modulation by sex hormone nuclear receptors. I will also cover their roles in wound healing, hair regeneration and skin related diseases. It appears that Wnt signaling plays essential but distinct roles in different hierarchical levels of morphogenesis and organogenesis. Many of these areas have not yet been fully explored but are certainly promising areas of future research. PMID:19279724

  11. Wnt signaling in skin organogenesis

    PubMed Central

    2008-01-01

    While serving as the interface between an organism and its environment, the skin also can elaborate a wide range of skin appendages to service specific purposes in a region-specific fashion. As in other organs, Wnt signaling plays a key role in regulating the proliferation, differentiation and motility of skin cells during their morphogenesis. Here I will review some of the recent work that has been done on skin organogenesis. I will cover dermis formation, the development of skin appendages, cycling of appendages in the adult, stem cell regulation, patterning, orientation, regional specificity and modulation by sex hormone nuclear receptors. I will also cover their roles in wound healing, hair regeneration and skin related diseases. It appears that Wnt signaling plays essential but distinct roles in different hierarchical levels of morphogenesis and organogenesis. Many of these areas have not yet been fully explored but are certainly promising areas of future research. PMID:19279724

  12. Automatic communication signal monitoring system

    NASA Technical Reports Server (NTRS)

    Bernstein, A. J. (Inventor)

    1978-01-01

    A system is presented for automatic monitoring of a communication signal in the RF or IF spectrum utilizing a superheterodyne receiver technique with a VCO to select and sweep the frequency band of interest. A first memory is used to store one band sweep as a reference for continual comparison with subsequent band sweeps. Any deviation of a subsequent band sweep by more than a predetermined tolerance level produces an alarm signal which causes the band sweep data temporarily stored in one of two buffer memories to be transferred to long-term store while the other buffer memory is switched to its store mode to assume the task of temporarily storing subsequent band sweeps.

  13. DNA signals at isoform promoters.

    PubMed

    Dai, Zhiming; Xiong, Yuanyan; Dai, Xianhua

    2016-01-01

    Transcriptional heterogeneity is extensive in the genome, and most genes express variable transcript isoforms. However, whether variable transcript isoforms of one gene are regulated by common promoter elements remain to be elucidated. Here, we investigated whether isoform promoters of one gene have separated DNA signals for transcription and translation initiation. We found that TATA box and nucleosome-disfavored DNA sequences are prevalent in distinct transcript isoform promoters of one gene. These DNA signals are conserved among species. Transcript isoform has a RNA-determined unstructured region around its start site. We found that these DNA/RNA features facilitate isoform transcription and translation. These results suggest a DNA-encoded mechanism by which transcript isoform is generated. PMID:27353836

  14. Early signaling in actinorhizal symbioses

    PubMed Central

    Alloisio, Nicole; Bogusz, Didier; Normand, Philippe

    2011-01-01

    Nitrogen-fixing root nodulation, confined to four plant orders, encompasses more than 14,000 Leguminosae species, and approximately 200 actinorhizal species forming symbioses with rhizobia (Rhizobium, Bradyrhizobium, etc.,) and Frankia bacterial species, respectively. While several genetic components of the host-symbiont interaction have been identified in legumes, little is known about the genetic bases of actinorhizal symbiosis. However, we recently demonstrated the existence of common symbiotic signaling pathways in actinorhizals and legumes. Moreover, important data on the identification of flavonoids as plant signaling compounds and the role for auxins during Frankia infection process and nodule organogenesis have been acquired. All together these results lead us to propose a unified model for symbiotic exchange and genetic control of actinorhizal symbiosis. PMID:21847030

  15. Signaling Pathways in Cartilage Repair

    PubMed Central

    Mariani, Erminia; Pulsatelli, Lia; Facchini, Andrea

    2014-01-01

    In adult healthy cartilage, chondrocytes are in a quiescent phase characterized by a fine balance between anabolic and catabolic activities. In ageing, degenerative joint diseases and traumatic injuries of cartilage, a loss of homeostatic conditions and an up-regulation of catabolic pathways occur. Since cartilage differentiation and maintenance of homeostasis are finely tuned by a complex network of signaling molecules and biophysical factors, shedding light on these mechanisms appears to be extremely relevant for both the identification of pathogenic key factors, as specific therapeutic targets, and the development of biological approaches for cartilage regeneration. This review will focus on the main signaling pathways that can activate cellular and molecular processes, regulating the functional behavior of cartilage in both physiological and pathological conditions. These networks may be relevant in the crosstalk among joint compartments and increased knowledge in this field may lead to the development of more effective strategies for inducing cartilage repair. PMID:24837833

  16. Signal processing of anthropometric data

    NASA Technical Reports Server (NTRS)

    Zimmermann, W. J.

    1983-01-01

    The Anthropometric Measurements Laboratory has accumulated a large body of data from a number of previous experiments. The data is very noisy, therefore it requires the application of some signal processing schemes. Moreover, it was not regarded as time series measurements but as positional information; hence, the data is stored as coordinate points as defined by the motion of the human body. The accumulated data defines two groups or classes. Some of the data was collected from an experiment designed to measure the flexibility of the limbs, referred to as radial movement. The remaining data was collected from experiments designed to determine the surface of the reach envelope. An interactive signal processing package was designed and implemented. Since the data does not include time this package does not include a time series element. Presently the results is restricted to processing data obtained from those experiments designed to measure flexibility.

  17. Endocannabinoid signalling in Alzheimer's disease.

    PubMed

    Maroof, Nazia; Pardon, Marie Christine; Kendall, David A

    2013-12-01

    The ECs (endocannabinoids) AEA (anandamide) and 2-AG (2-arachidonoylglycerol) and their lipid congeners OEA (N-oleoylethanolamide) and PEA (N-palmitoylethanolamide) are multifunctional lipophilic signalling molecules. The ECs, OEA and PEA have multiple physiological roles including involvement in learning and memory, neuroinflammation, oxidative stress, neuroprotection and neurogenesis. They have also been implicated in the pathology of, or perhaps protective responses to, neurodegenerative diseases. This is particularly the case with Alzheimer's disease, the most common age-related dementia associated with impairments in learning and memory accompanied by neuroinflammation, oxidative stress and neurodegeneration. The present mini-review examines the evidence supporting the roles that ECs appear to play in Alzheimer's disease and the potential for beneficial therapeutic manipulation of the EC signalling system. PMID:24256258

  18. Notch Signaling in Neuroendocrine Tumors

    PubMed Central

    Crabtree, Judy S.; Singleton, Ciera S.; Miele, Lucio

    2016-01-01

    Carcinoids and neuroendocrine tumors (NETs) are a heterogeneous group of tumors that arise from the neuroendocrine cells of the GI tract, endocrine pancreas, and the respiratory system. NETs remain significantly understudied with respect to molecular mechanisms of pathogenesis, particularly the role of cell fate signaling systems such as Notch. The abundance of literature on the Notch pathway is a testament to its complexity in different cellular environments. Notch receptors can function as oncogenes in some contexts and tumor suppressors in others. The genetic heterogeneity of NETs suggests that to fully understand the roles and the potential therapeutic implications of Notch signaling in NETs, a comprehensive analysis of Notch expression patterns and potential roles across all NET subtypes is required. PMID:27148486

  19. Noncoherent detection of periodic signals

    NASA Technical Reports Server (NTRS)

    Gagliardi, R. M.

    1974-01-01

    The optimal Bayes detector for a general periodic waveform having uniform delay and additive white Gaussian noise is examined. It is shown that the detector is much more complex than that for the well known cases of pure sine waves (i.e. classical noncoherent detection) and narrowband signals. An interpretation of the optimal processing is presented, and several implementations are discussed. The results have application to the noncoherent detection of optical square waves.

  20. Wind profiler signal detection improvements

    NASA Technical Reports Server (NTRS)

    Hart, G. F.; Divis, Dale H.

    1992-01-01

    Research is described on potential improvements to the software used with the NASA 49.25 MHz wind profiler located at Kennedy Space Center. In particular, the analysis and results are provided of a study to (1) identify preferred mathematical techniques for the detection of atmospheric signals that provide wind velocities which are obscured by natural and man-made sources, and (2) to analyze one or more preferred techniques to demonstrate proof of the capability to improve the detection of wind velocities.

  1. Cell signalling and phospholipid metabolism

    SciTech Connect

    Boss, W.F.

    1990-01-01

    These studies explored whether phosphoinositide (PI) has a role in plants analogous to its role in animal cells. Although no parallel activity of PI in signal transduction was found in plant cells, activity of inositol phospholipid kinase was found to be modulated by light and by cell wall degrading enzymes. These studies indicate a major role for inositol phospholipids in plant growth and development as membrane effectors but not as a source of second messengers.

  2. Purinergic signaling in glioma progression.

    PubMed

    Braganhol, Elizandra; Wink, Márcia Rosângela; Lenz, Guido; Battastini, Ana Maria Oliveira

    2013-01-01

    Among the pathological alterations that give tumor cells invasive potential, purinergic signaling is emerging as an important component. Studies performed in in vitro, in vivo and ex vivo glioma models indicate that alterations in the purinergic signaling are involved in the progression of these tumors. Gliomas have low expression of all E-NTPDases, when compared to astrocytes in culture. Nucleotides induce glioma proliferation and ATP, although potentially neurotoxic, does not evoke cytotoxic action on the majority of glioma cells in culture. The importance of extracellular ATP for glioma pathobiology was confirmed by the reduction in glioma tumor size by apyrase, which degrades extracellular ATP to AMP, and the striking increase in tumor size by over-expression of an ecto-enzyme that degrades ATP to ADP, suggesting the effect of extracellular ATP on the tumor growth depends on the nucleotide produced by its degradation. The participation of purinergic receptors on glioma progression, particularly P2X(7), is involved in the resistance to ATP-induced cell death. Although more studies are necessary, the purinergic signaling, including ectonucleotidases and receptors, may be considered as future target for glioma pharmacological or gene therapy. PMID:22879065

  3. FGFR signalling in women's cancers.

    PubMed

    Fearon, Abbie E; Gould, Charlotte R; Grose, Richard P

    2013-12-01

    FGFs, in a complex with their receptors (FGFRs) and heparan sulfate (HS), are responsible for a range of cellular functions, from embryogenesis to metabolism. Both germ line and somatic FGFR mutations are known to play a role in a range of diseases, most notably craniosynestosis dysplasias, dwarfism and cancer. Because of the ability of FGFR signalling to induce cell proliferation, migration and survival, FGFRs are readily co-opted by cancer cells. Mutations in, and amplifications of, these receptors are found in a range of cancers with some of the most striking clinical findings relating to their contribution to pathogenesis and progression of female cancers. Here, we outline the molecular mechanisms of FGFR signalling and discuss the role of this pathway in women's cancers, focusing on breast, endometrial, ovarian and cervical carcinomas, and their associated preclinical and clinical data. We also address the rationale for therapeutic intervention and the need for FGFR-targeted therapy to selectively target cancer cells in view of the fundamental roles of FGF signalling in normal physiology. PMID:24148254

  4. Calcium signaling in trypanosomatid parasites.

    PubMed

    Docampo, Roberto; Huang, Guozhong

    2015-03-01

    Calcium ion (Ca(2+)) is an important second messenger in trypanosomatids and essential for their survival although prolonged high intracellular Ca(2+) levels lead to cell death. As other eukaryotic cells, trypanosomes use two sources of Ca(2+) for generating signals: Ca(2+) release from intracellular stores and Ca(2+) entry across the plasma membrane. Ca(2+) release from intracellular stores is controlled by the inositol 1,4,5-trisphosphate receptor (IP3R) that is located in acidocalcisomes, acidic organelles that are the primary Ca(2+) reservoir in these cells. A plasma membrane Ca(2+)-ATPase controls the cytosolic Ca(2+) levels and a number of pumps and exchangers are responsible for Ca(2+) uptake and release from intracellular compartments. The trypanosomatid genomes contain a wide variety of signaling and regulatory proteins that bind Ca(2+) as well as many Ca(2+)-binding proteins that await further characterization. The mitochondrial Ca(2+) transporters of trypanosomatids have an important role in the regulation of cell bioenergetics and flagellar Ca(2+) appears to have roles in sensing the environment. In trypanosomatids in which an intracellular life cycle is present, Ca(2+) signaling is important for host cell invasion. PMID:25468729

  5. Eph Receptor Signaling and Ephrins

    PubMed Central

    Lisabeth, Erika M.; Falivelli, Giulia; Pasquale, Elena B.

    2013-01-01

    The Eph receptors are the largest of the RTK families. Like other RTKs, they transduce signals from the cell exterior to the interior through ligand-induced activation of their kinase domain. However, the Eph receptors also have distinctive features. Instead of binding soluble ligands, they generally mediate contact-dependent cell–cell communication by interacting with surface-associated ligands—the ephrins—on neighboring cells. Eph receptor–ephrin complexes emanate bidirectional signals that affect both receptor- and ephrin-expressing cells. Intriguingly, ephrins can also attenuate signaling by Eph receptors coexpressed in the same cell. Additionally, Eph receptors can modulate cell behavior independently of ephrin binding and kinase activity. The Eph/ephrin system regulates many developmental processes and adult tissue homeostasis. Its abnormal function has been implicated in various diseases, including cancer. Thus, Eph receptors represent promising therapeutic targets. However, more research is needed to better understand the many aspects of their complex biology that remain mysterious. PMID:24003208

  6. Cell Signaling Underlying Epileptic Behavior

    PubMed Central

    Bozzi, Yuri; Dunleavy, Mark; Henshall, David C.

    2011-01-01

    Epilepsy is a complex disease, characterized by the repeated occurrence of bursts of electrical activity (seizures) in specific brain areas. The behavioral outcome of seizure events strongly depends on the brain regions that are affected by overactivity. Here we review the intracellular signaling pathways involved in the generation of seizures in epileptogenic areas. Pathways activated by modulatory neurotransmitters (dopamine, norepinephrine, and serotonin), involving the activation of extracellular-regulated kinases and the induction of immediate early genes (IEGs) will be first discussed in relation to the occurrence of acute seizure events. Activation of IEGs has been proposed to lead to long-term molecular and behavioral responses induced by acute seizures. We also review deleterious consequences of seizure activity, focusing on the contribution of apoptosis-associated signaling pathways to the progression of the disease. A deep understanding of signaling pathways involved in both acute- and long-term responses to seizures continues to be crucial to unravel the origins of epileptic behaviors and ultimately identify novel therapeutic targets for the cure of epilepsy. PMID:21852968

  7. Diabetes: Models, Signals and control

    NASA Astrophysics Data System (ADS)

    Cobelli, C.

    2010-07-01

    Diabetes and its complications impose significant economic consequences on individuals, families, health systems, and countries. The control of diabetes is an interdisciplinary endeavor, which includes significant components of modeling, signal processing and control. Models: first, I will discuss the minimal (coarse) models which describe the key components of the system functionality and are capable of measuring crucial processes of glucose metabolism and insulin control in health and diabetes; then, the maximal (fine-grain) models which include comprehensively all available knowledge about system functionality and are capable to simulate the glucose-insulin system in diabetes, thus making it possible to create simulation scenarios whereby cost effective experiments can be conducted in silico to assess the efficacy of various treatment strategies - in particular I will focus on the first in silico simulation model accepted by FDA as a substitute to animal trials in the quest for optimal diabetes control. Signals: I will review metabolic monitoring, with a particular emphasis on the new continuous glucose sensors, on the crucial role of models to enhance the interpretation of their time-series signals, and on the opportunities that they present for automation of diabetes control. Control: I will review control strategies that have been successfully employed in vivo or in silico, presenting a promise for the development of a future artificial pancreas and, in particular, I will discuss a modular architecture for building closed-loop control systems, including insulin delivery and patient safety supervision layers.

  8. Calcium Signals from the Vacuole

    PubMed Central

    Schönknecht, Gerald

    2013-01-01

    The vacuole is by far the largest intracellular Ca2+ store in most plant cells. Here, the current knowledge about the molecular mechanisms of vacuolar Ca2+ release and Ca2+ uptake is summarized, and how different vacuolar Ca2+ channels and Ca2+ pumps may contribute to Ca2+ signaling in plant cells is discussed. To provide a phylogenetic perspective, the distribution of potential vacuolar Ca2+ transporters is compared for different clades of photosynthetic eukaryotes. There are several candidates for vacuolar Ca2+ channels that could elicit cytosolic [Ca2+] transients. Typical second messengers, such as InsP3 and cADPR, seem to trigger vacuolar Ca2+ release, but the molecular mechanism of this Ca2+ release still awaits elucidation. Some vacuolar Ca2+ channels have been identified on a molecular level, the voltage-dependent SV/TPC1 channel, and recently two cyclic-nucleotide-gated cation channels. However, their function in Ca2+ signaling still has to be demonstrated. Ca2+ pumps in addition to establishing long-term Ca2+ homeostasis can shape cytosolic [Ca2+] transients by limiting their amplitude and duration, and may thus affect Ca2+ signaling. PMID:27137394

  9. Nanotubes for noisy signal processing

    NASA Astrophysics Data System (ADS)

    Lee, Ian Yenyin

    Nanotubes can process noisy signals. We present two central results in support of this general thesis and make an informed extrapolation that uses nanotubes to improve body armor. The first result is that noise can help nanotubes detect weak signals. The finding confirmed a stochastic-resonance theoretical prediction that noise can enhance detection at the nano-level. Laboratory experiments with nanotubes showed that three types of noise improved three measures of detection. Small amounts of Gaussian, uniform, and Cauchy additive white noise increased mutual-information, cross-correlation, and bit-error-rate measures before degrading them with further increases in noise. Nanotubes can apply this noise-enhancement and nanotube electrical and mechanical properties to improve signal processing. Similar noise enhancement may benefit a proposed nanotube-array cochlear-model spectral processing. The second result is that nanotube antennas can directly detect narrowband electromagnetic (EM) signals. The finding showed that nanotube and thin-wire dipoles are similar: They are resonant and narrowband and can implement linear-array designs if the EM waves in the nanotubes propagate at or near the free-space velocity of light. The nanotube-antenna prediction is based on a Fresnel-zone or near-zone analysis of antenna impedance using a quantum-conductor model. The analysis also predicts a failure to resonate if the nanotube EM-wave propagation is much slower than free-space light propagation. We extrapolate based on applied and theoretical analysis of body armor. Field experiments used a baseball comparison and statistical and other techniques to model body-armor bruising effects. A baseball comparison showed that a large caliber handgun bullet can hit an armored chest as hard as a fast baseball can hit a bare chest. Adaptive fuzzy systems learned to predict a bruise profile directly from the experimental data and also from statistical analysis of the data. Nanotube signal

  10. Wave-based signal processing

    NASA Astrophysics Data System (ADS)

    McClure, Mark Richard

    The efficacy of imbedding knowledge of wave-scattering phenomenology into the processing of remote-sensing data is examined. In particular, the processing of radar and sonar phase history and synthetic-aperture imagery is considered. Algorithms are developed for effecting signal denoising, feature extraction (for use in target identification/classification) and detection. Three classes of algorithms are presented: (1) superresolution, (2) adaptive-signal decomposition, and (3) template matching. A superresolution signal-processing algorithm is used for the identification of wavefronts from the fields scattered from several canonical targets. Particular wave objects that are examined are single and multiple edge diffraction, scattering from flat and curved surfaces, cone diffraction, and creeping waves. General properties of superresolution processing of such data--independent of the particular algorithm used--are assessed through examination of the Cramer-Rao bounds. The method of matching pursuits is used to effect data-adaptive signal decomposition. This algorithm utilizes a nonlinear iterative procedure to project a given waveform onto a particular dictionary. For scattering problems, the most appropriate dictionary is composed of waveobjects consistent with the underlying wave phenomenology. A signal scattered from most targets of interest can be decomposed in terms of wavefronts, resonances, and chirps--and each of these subclasses can be further subdivided based on characteristic wave physics. Here the efficacy of applying the method of matching pursuits with a wave-based dictionary is examined, for the processing of scattering data. Detection test statistics are derived based on matching-pursuits results from each dictionary separately as well as with the cumulative results from multiple dictionaries. Examples are presented using measured data, for wideband, time-domain acoustic scattering from a submerged elastic shell. Finally, a full-wave electromagnetic

  11. Blurring in bar code signals

    NASA Astrophysics Data System (ADS)

    Tang, Hong

    1997-10-01

    When a bar code symbol is passed over a scanner, it is struck across by a fast moving laser beam. The laser light is scattered by the bar code. The total scattered power is modulated by the reflectivity of the bars and spaces in the symbol. A fraction of the scattered light is collected and focused onto a photodetector that converts the light variation into an electronic signal. The electronic signal is then digitized for analysis by a computer. The scanning and detection process can be modeled by a convolution of the laser beam profile and the bar code reflectivity function. The switching between states in the digitized bar code signal, which represents transitions from a space to a bar or vice versa, is determined by a zero-crossing point in the second derivative of the analog signal. The laser profile acts like a smoothing function. It blurs the analog electronic signal. If the width of the laser profile is less than the minimum width of bars and spaces in the bar code reflectivity function, the transition point is not affected by the location of its neighboring edges. If the laser profile is wider than the minimum width in the bar code, the transition point can be shifted due to the locations of its neighboring edges. The behavior of the shift of transition is analyzed here for all cases in a UPC symbol. It is found that the amount of shift in the transition point is almost the same for several different cases within the depth of field of the scanner. The knowledge of the behavior of transition point shift can be used to accurately compensate printing errors in an over-printed bar code. The modulation transfer function (MTF) of bar code scanning is the Fourier transform of the marginal function of the scanning laser beam. The MTF through focus for a scanning system is presented. By using an aperture with central obscuration in the laser focusing system, the high frequency resolution of bar code scanning can be enhanced and the depth of field of the scanner can

  12. DETECTOR FOR MODULATED AND UNMODULATED SIGNALS

    DOEpatents

    Patterson, H.H.; Webber, G.H.

    1959-08-25

    An r-f signal-detecting device is described, which is embodied in a compact coaxial circuit principally comprising a detecting crystal diode and a modulating crystal diode connected in parallel. Incoming modulated r-f signals are demodulated by the detecting crystal diode to furnish an audio input to an audio amplifier. The detecting diode will not, however, produce an audio signal from an unmodulated r-f signal. In order that unmodulated signals may be detected, such incoming signals have a locally produced audio signal superimposed on them at the modulating crystal diode and then the"induced or artificially modulated" signal is reflected toward the detecting diode which in the process of demodulation produces an audio signal for the audio amplifier.

  13. Multiband signal reconstruction for random equivalent sampling

    NASA Astrophysics Data System (ADS)

    Zhao, Y. J.; Liu, C. J.

    2014-10-01

    The random equivalent sampling (RES) is a sampling approach that can be applied to capture high speed repetitive signals with a sampling rate that is much lower than the Nyquist rate. However, the uneven random distribution of the time interval between the excitation pulse and the signal degrades the signal reconstruction performance. For sparse multiband signal sampling, the compressed sensing (CS) based signal reconstruction algorithm can tease out the band supports with overwhelming probability and reduce the impact of uneven random distribution in RES. In this paper, the mathematical model of RES behavior is constructed in the frequency domain. Based on the constructed mathematical model, the band supports of signal can be determined. Experimental results demonstrate that, for a signal with unknown sparse multiband, the proposed CS-based signal reconstruction algorithm is feasible, and the CS reconstruction algorithm outperforms the traditional RES signal reconstruction method.

  14. Multiband signal reconstruction for random equivalent sampling.

    PubMed

    Zhao, Y J; Liu, C J

    2014-10-01

    The random equivalent sampling (RES) is a sampling approach that can be applied to capture high speed repetitive signals with a sampling rate that is much lower than the Nyquist rate. However, the uneven random distribution of the time interval between the excitation pulse and the signal degrades the signal reconstruction performance. For sparse multiband signal sampling, the compressed sensing (CS) based signal reconstruction algorithm can tease out the band supports with overwhelming probability and reduce the impact of uneven random distribution in RES. In this paper, the mathematical model of RES behavior is constructed in the frequency domain. Based on the constructed mathematical model, the band supports of signal can be determined. Experimental results demonstrate that, for a signal with unknown sparse multiband, the proposed CS-based signal reconstruction algorithm is feasible, and the CS reconstruction algorithm outperforms the traditional RES signal reconstruction method. PMID:25362458

  15. Do earthquakes generate EM signals?

    NASA Astrophysics Data System (ADS)

    Walter, Christina; Onacha, Stephen; Malin, Peter; Shalev, Eylon; Lucas, Alan

    2010-05-01

    In recent years there has been significant interest in the seismoelectric effect which is the conversion of acoustic energy into electromagnetic energy. At the onset of the earthquake and at layer interfaces, it is postulated that the seismoelectric signal propagates at the speed of light and thus travels much faster than the acoustic wave. The focus has mainly been to use this method as a tool of predicting earthquakes. Our main objective is to study the possibility of using the seismoelectric effect to determine the origin time of an earthquake, establish an accurate velocity model and accurately locate microearthquakes. Another aspect of this research is to evaluate the possibility of detecting porous zones where seismic activity is postulated to generate fluid movement through porous medium. The displacement of pore fluid relative to the porous medium solid grains generates electromagnetic signals. The Institute of Earth Science and Engineering (IESE) has installed electromagnetic coils in 3 different areas to investigate the seismoelectric effect. Two of the research areas (Krafla in Iceland and Wairakei in New Zealand) are in active geothermal fields where high microearthquake activity has been recorded. The other area of research is at the site of the San Andreas Fault Observatory at Depth (SAFOD) at Parkfield area on the active San Andreas Fault which is associated with repeating earthquakes. In the Wairakei and Parkfield cases a single borehole electromagnetic coil close to borehole seismometers has been used whereas in the Krafla study area, 3 borehole electromagnetic coils coupled to borehole seismometers have been used. The technical difficulties of working in the borehole environment mean that some of these deployments had a short life span. Nevertheless in all cases data was gathered and is being analysed. At the SAFOD site, the electromagnetic coil recorded seismoelectric signals very close to a magnitude 2 earthquake. In the Wairakei and Krafla

  16. 6-Shogaol Inhibits Breast Cancer Cells and Stem Cell-Like Spheroids by Modulation of Notch Signaling Pathway and Induction of Autophagic Cell Death.

    PubMed

    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

  17. 6-Shogaol Inhibits Breast Cancer Cells and Stem Cell-Like Spheroids by Modulation of Notch Signaling Pathway and Induction of Autophagic Cell Death

    PubMed Central

    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

  18. Regulation of Calcium signaling through spatial Organization

    NASA Astrophysics Data System (ADS)

    Ullah, Aman; Ullah, Ghanim; Machaca, Khalid; Jung, Peter

    2010-03-01

    Calcium waves and signals in oocytes are produced and sustained by the release of Ca^2+ from the Endoplasmic Reticulum (ER) through clustered release channels. Changes in the spatial organization of calcium signaling effectors regulate the spatiotemporal features of the calcium signal as is e.g. observed during oocyte maturation. We report here how specific changes in the clustering of the calcium release channels in conjunction with physiologic alterations of other signaling effectors can affect a) the sensitivity of the signaling machinery to external factors, b) the time course of global intracellular signals and c), the speed and propagation range of intracellular calcium waves.

  19. Signalling crosstalk in plants: emerging issues.

    PubMed

    Taylor, Jane E; McAinsh, Martin R

    2004-01-01

    The Oxford English Dictionary defines crosstalk as 'unwanted transfer of signals between communication channels'. How does this definition relate to the way in which we view the organization and function of signalling pathways? Recent advances in the field of plant signalling have challenged the traditional view of a signalling transduction cascade as isolated linear pathways. Instead the picture emerging of the mechanisms by which plants transduce environmental signals is of the interaction between transduction chains. The manner in which these interactions occur (and indeed whether the transfer of these signals is 'unwanted' or beneficial) is currently the topic of intense research. PMID:14673021

  20. Leptin signalling pathways in hypothalamic neurons.

    PubMed

    Kwon, Obin; Kim, Ki Woo; Kim, Min-Seon

    2016-04-01

    Leptin is the most critical hormone in the homeostatic regulation of energy balance among those so far discovered. Leptin primarily acts on the neurons of the mediobasal part of hypothalamus to regulate food intake, thermogenesis, and the blood glucose level. In the hypothalamic neurons, leptin binding to the long form leptin receptors on the plasma membrane initiates multiple signaling cascades. The signaling pathways known to mediate the actions of leptin include JAK-STAT signaling, PI3K-Akt-FoxO1 signaling, SHP2-ERK signaling, AMPK signaling, and mTOR-S6K signaling. Recent evidence suggests that leptin signaling in hypothalamic neurons is also linked to primary cilia function. On the other hand, signaling molecules/pathways mitigating leptin actions in hypothalamic neurons have been extensively investigated in an effort to treat leptin resistance observed in obesity. These include SOCS3, tyrosine phosphatase PTP1B, and inflammatory signaling pathways such as IKK-NFκB and JNK signaling, and ER stress-mitochondrial signaling. In this review, we discuss leptin signaling pathways in the hypothalamus, with a particular focus on the most recently discovered pathways. PMID:26786898

  1. Molecular Signaling in Muscle Plasticity

    NASA Technical Reports Server (NTRS)

    Epstein, Henry F.

    1999-01-01

    Extended spaceflight under microgravity conditions leads to significant atrophy of weight-bearing muscles. Atrophy and hypertrophy are the extreme outcomes of the high degree of plasticity exhibited by skeletal muscle. Stimuli which control muscle plasticity include neuronal, hormonal, nutritional, and mechanical inputs. The mechanical stimulus for muscle is directly related to the work or exercise against a load performed. Little or no work is performed by weight-bearing muscles under microgravity conditions. A major hypothesis is that focal adhesion kinase (FAK) which is associated with integrin at the adherens junctions and costa meres of all skeletal muscles is an integral part of the major mechanism for molecular signaling upon mechanical stimulation in all muscle fibers. Additionally, we propose that myotonic protein kinase (DMPK) and dystrophin (DYSTR) also participate in distinct mechanically stimulated molecular signaling pathways that are most critical in type I and type II muscle fibers, respectively. To test these hypotheses, we will use the paradigms of hindlimb unloading and overloading in mice as models for microgravity conditions and a potential exercise countermeasure, respectively, in mice. We expect that FAK loss-of-function will impair hypertrophy and enhance atrophy in all skeletal muscle fibers whereas DYSTR and DMPK loss-of-function will have similar but more selective effects on Type IT and Type I fibers, respectively. Gene expression will be monitored by muscle-specific creatine kinase M promoter-reporter construct activity and specific MRNA and protein accumulation in the soleus (type I primarily) and plantaris (type 11 primarily) muscles. With these paradigms and assays, the following Specific Project Aims will be tested in genetically altered mice: 1) identify the roles of DYSTR and its pathway; 2) evaluate the roles of the DMPK and its pathway; 3) characterize the roles of FAK and its pathway and 4) genetically analyze the mechanisms

  2. Vertical jumping and signaled avoidance

    PubMed Central

    Cándido, Antonio; Maldonado, Antonio; Vila, Jaime

    1988-01-01

    This paper reports an experiment intended to demonstrate that the vertical jumping response can be learned using a signaled-avoidance technique. A photoelectric cell system was used to record the response. Twenty female rats, divided equally into two groups, were exposed to intertrial intervals of either 15 or 40 s. Subjects had to achieve three successive criteria of acquisition: 3, 5, and 10 consecutive avoidance responses. Results showed that both groups learned the avoidance response, requiring increasingly larger numbers of trials as the acquisition criteria increased. No significant effect of intertrial interval was observed. PMID:16812559

  3. Lagrange wavelets for signal processing.

    PubMed

    Shi, Z; Wei, G W; Kouri, D J; Hoffman, D K; Bao, Z

    2001-01-01

    This paper deals with the design of interpolating wavelets based on a variety of Lagrange functions, combined with novel signal processing techniques for digital imaging. Halfband Lagrange wavelets, B-spline Lagrange wavelets and Gaussian Lagrange (Lagrange distributed approximating functional (DAF)) wavelets are presented as specific examples of the generalized Lagrange wavelets. Our approach combines the perceptually dependent visual group normalization (VGN) technique and a softer logic masking (SLM) method. These are utilized to rescale the wavelet coefficients, remove perceptual redundancy and obtain good visual performance for digital image processing. PMID:18255493

  4. NASA's Software Bank (Signal Group)

    NASA Technical Reports Server (NTRS)

    1992-01-01

    A COSMIC program helped the Signal Group to provide a communications system linking a desert area without communications facilities to civilization. The system was developed for a hunting party of wealthy Middle Eastern men. The latest in two-way radio technology was incorporated into a portable system with a small inflatable tethered blimp, which served as a solar-powered relay station. The program, Transverse Mercator Map Projection of the Spheroid Using Transformation of the Elliptic Integral, enabled the company to develop the system without the aid of accurate satellite derived terrain data.

  5. Allied-Signal site overview

    SciTech Connect

    Douglas, D.S.

    1990-11-01

    This paper reports on the applications of robotics at Allied-Signal Aerospace Company. This paper describes applications in rivet shaving and insert installation, solenoid torque and hi-pot testing, diode pull testing, solid film lubricant burnishing, plastic preform fabrication, paint spraying, deburring, polyimide spray coating, dual inline package (DIP) handling, DIP lead wrapping, electrical component tinning, part handling in cable marking, PWB component insertion, heating and die forming, titration, and axial lead tinning and forming; systems under development include surface mount transistor trimming and tinning, diode pull testing, part handling within a matching cell, automated welding, and desiccant molding.

  6. Advanced detectors and signal processing

    NASA Technical Reports Server (NTRS)

    Greve, D. W.; Rasky, P. H. L.; Kryder, M. H.

    1986-01-01

    Continued progress is reported toward development of a silicon on garnet technology which would allow fabrication of advanced detection and signal processing circuits on bubble memories. The first integrated detectors and propagation patterns have been designed and incorporated on a new mask set. In addition, annealing studies on spacer layers are performed. Based on those studies, a new double layer spacer is proposed which should reduce contamination of the silicon originating in the substrate. Finally, the magnetic sensitivity of uncontaminated detectors from the last lot of wafers is measured. The measured sensitivity is lower than anticipated but still higher than present magnetoresistive detectors.

  7. Optical stereo video signal processor

    NASA Astrophysics Data System (ADS)

    Craig, G. D.

    1985-12-01

    An otpical video signal processor is described which produces a two-dimensional cross-correlation in real time of images received by a stereo camera system. The optical image of each camera is projected on respective liquid crystal light valves. The images on the liquid crystal valves modulate light produced by an extended light source. This modulated light output becomes the two-dimensional cross-correlation when focused onto a video detector and is a function of the range of a target with respect to the stereo camera. Alternate embodiments utilize the two-dimensional cross-correlation to determine target movement and target identification.

  8. Signal Processing Expert Code (SPEC)

    SciTech Connect

    Ames, H.S.

    1985-12-01

    The purpose of this paper is to describe a prototype expert system called SPEC which was developed to demonstrate the utility of providing an intelligent interface for users of SIG, a general purpose signal processing code. The expert system is written in NIL, runs on a VAX 11/750 and consists of a backward chaining inference engine and an English-like parser. The inference engine uses knowledge encoded as rules about the formats of SIG commands and about how to perform frequency analyses using SIG. The system demonstrated that expert system can be used to control existing codes.

  9. Signalling pathways: jack of all cascades.

    PubMed

    Cahill, M A; Janknecht, R; Nordheim, A

    1996-01-01

    The transcription factors that bind the c-fos promoter element SRE are targeted by multiple, independent signalling cascades; the identities of these signalling pathways and their modes of activation are being elucidated. PMID:8805215

  10. Digital Signal Processing Based Biotelemetry Receivers

    NASA Technical Reports Server (NTRS)

    Singh, Avtar; Hines, John; Somps, Chris

    1997-01-01

    This is an attempt to develop a biotelemetry receiver using digital signal processing technology and techniques. The receiver developed in this work is based on recovering signals that have been encoded using either Pulse Position Modulation (PPM) or Pulse Code Modulation (PCM) technique. A prototype has been developed using state-of-the-art digital signal processing technology. A Printed Circuit Board (PCB) is being developed based on the technique and technology described here. This board is intended to be used in the UCSF Fetal Monitoring system developed at NASA. The board is capable of handling a variety of PPM and PCM signals encoding signals such as ECG, temperature, and pressure. A signal processing program has also been developed to analyze the received ECG signal to determine heart rate. This system provides a base for using digital signal processing in biotelemetry receivers and other similar applications.

  11. Signal Frequency Spectra with Audacity®

    NASA Astrophysics Data System (ADS)

    Gailey, Alycia

    2015-04-01

    The primary objective of the activity presented here is to allow students to explore the frequency components of various simple signals, with the ultimate goal of teaching them how to remove unwanted noise from a voice signal. Analysis of the frequency components of a signal allows students to design filters that remove unwanted components of a signal while conserving the shape and magnitude of the relevant portion of a signal. For example, signal noise is often contained in higher frequency (fast-changing) components whereas signal drift is contained in lower frequency (slow-changing) components of the signal. A low-pass filter allows lower frequency components below a cutoff frequency to pass through, whereas a high-pass filter allows higher frequency components above a cutoff frequency to pass through. With activities such as the one presented here, students are introduced to real-world problem-solving applications of physics concepts that go beyond simple theory and equations.

  12. Ghost signals in Allison emittance scanners

    SciTech Connect

    Stockli, Martin P.; Leitner, M.; Moehs, D.P.; Keller, R.; Welton, R.F.; /SNS Project, Oak Ridge /Tennessee U.

    2004-12-01

    For over 20 years, Allison scanners have been used to measure emittances of low-energy ion beams. We show that scanning large trajectory angles produces ghost signals caused by the sampled beamlet impacting on an electric deflection plate. The ghost signal strength is proportional to the amount of beam entering the scanner. Depending on the ions, and their velocity, the ghost signals can have the opposite or the same polarity as the main beam signals. The ghost signals cause significant errors in the emittance estimates because they appear at large trajectory angles. These ghost signals often go undetected because they partly overlap with the real signals, are mostly below the 1% level, and often hide in the noise. A simple deflection plate modification is shown to reduce the ghost signal strength by over 99%.

  13. Ghost Signals In Allison Emittance Scanners

    SciTech Connect

    Stockli, Martin P.; Leitner, M.; Keller, R.; Moehs, D.P.; Welton, R. F.

    2005-03-15

    For over 20 years, Allison scanners have been used to measure emittances of low-energy ion beams. We show that scanning large trajectory angles produces ghost signals caused by the sampled beamlet impacting on an electric deflection plate. The ghost signal strength is proportional to the amount of beam entering the scanner. Depending on the ions, and their velocity, the ghost signals can have the opposite or the same polarity as the main beam signals. The ghost signals cause significant errors in the emittance estimates because they appear at large trajectory angles. These ghost signals often go undetected because they partly overlap with the real signals, are mostly below the 1% level, and often hide in the noise. A simple deflection plate modification is shown to reduce the ghost signal strength by over 99%.

  14. 46 CFR 151.45-9 - Signals.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... HAZARDOUS MATERIAL CARGOES Operations § 151.45-9 Signals. While fast to a dock, a vessel during transfer of bulk cargo shall display a red flag by day or a red light by night, which signal shall be so...

  15. 46 CFR 151.45-9 - Signals.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... HAZARDOUS MATERIAL CARGOES Operations § 151.45-9 Signals. While fast to a dock, a vessel during transfer of bulk cargo shall display a red flag by day or a red light by night, which signal shall be so...

  16. Tracking a phase-shift-keyed signal

    NASA Technical Reports Server (NTRS)

    Villarreal, S.; Lenett, S. D.; Kobayashi, H. S.; Pawlowski, J. F.

    1977-01-01

    In detector, phase shifter is used to generate negative phase shift opposing detected phase angle. This produces converted series sideband and component carrier, with residual carrier signal and converted series sideband and component carrier added together to produce tracking signal.

  17. Determining Aliasing in Isolated Signal Conditioning Modules

    NASA Technical Reports Server (NTRS)

    2009-01-01

    The basic concept of aliasing is this: Converting analog data into digital data requires sampling the signal at a specific rate, known as the sampling frequency. The result of this conversion process is a new function, which is a sequence of digital samples. This new function has a frequency spectrum, which contains all the frequency components of the original signal. The Fourier transform mathematics of this process show that the frequency spectrum of the sequence of digital samples consists of the original signal s frequency spectrum plus the spectrum shifted by all the harmonics of the sampling frequency. If the original analog signal is sampled in the conversion process at a minimum of twice the highest frequency component contained in the analog signal, and if the reconstruction process is limited to the highest frequency of the original signal, then the reconstructed signal accurately duplicates the original analog signal. It is this process that can give birth to aliasing.

  18. Are aposematic signals honest? A review.

    PubMed

    Summers, K; Speed, M P; Blount, J D; Stuckert, A M M

    2015-09-01

    We explore the relevance of honest signalling theory to the evolution of aposematism. We begin with a general consideration of models of signal stability, with a focus on the Zahavian costly signalling framework. Next, we review early models of signalling in the context of aposematism (some that are consistent and some inconsistent with costly honest signalling). We focus on controversies surrounding the idea that aposematic signals are handicaps in a Zahavian framework. Then, we discuss how the alignment of interests between signaller and predator influences the evolution of aposematism, highlight the distinction between qualitative and quantitative honesty and review theory and research relevant to these categories. We also review recent theoretical treatments of the evolution of aposematism that have focused on honest signalling as well as empirical research on a variety of organisms, including invertebrates and frogs. Finally, we discuss future directions for empirical and theoretical research in this area. PMID:26079980

  19. Membrane estradiol signaling in the brain

    PubMed Central

    Micevych, Paul; Dominguez, Reymundo

    2009-01-01

    While the physiology of membrane-initiated estradiol signaling in the nervous system has remained elusive, a great deal of progress has been made toward understanding the activation of cell signaling. Membrane-initiated estradiol signaling activates G proteins and their downstream cascades, but the identity of membrane receptors and the proximal signaling mechanism(s) have been more difficult to elucidate. Mounting evidence suggests that classical intracellular estrogen receptor-α (ERα) and ERβ are trafficked to the membrane to mediate estradiol cell signaling. Moreover, an interaction of membrane ERα and ERβ with metabotropic glutamate receptors has been identified that explains the pleomorphic actions of membrane-initiated estradiol signaling. This review focuses on the mechanism of actions initiated by membrane estradiol receptors and discusses the role of scaffold proteins and signaling cascades involved in the regulation of nociception, sexual receptivity and the synthesis of neuroprogesterone, an important component in the central nervous system signaling. PMID:19416735

  20. Optimal Prediction by Cellular Signaling Networks

    NASA Astrophysics Data System (ADS)

    Becker, Nils B.; Mugler, Andrew; ten Wolde, Pieter Rein

    2015-12-01

    Living cells can enhance their fitness by anticipating environmental change. We study how accurately linear signaling networks in cells can predict future signals. We find that maximal predictive power results from a combination of input-noise suppression, linear extrapolation, and selective readout of correlated past signal values. Single-layer networks generate exponential response kernels, which suffice to predict Markovian signals optimally. Multilayer networks allow oscillatory kernels that can optimally predict non-Markovian signals. At low noise, these kernels exploit the signal derivative for extrapolation, while at high noise, they capitalize on signal values in the past that are strongly correlated with the future signal. We show how the common motifs of negative feedback and incoherent feed-forward can implement these optimal response functions. Simulations reveal that E. coli can reliably predict concentration changes for chemotaxis, and that the integration time of its response kernel arises from a trade-off between rapid response and noise suppression.