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Sample records for enhanced death signaling

  1. Sub-lethal irradiation of human colorectal tumor cells imparts enhanced and sustained susceptibility to multiple death receptor signaling pathways.

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    Victoria Ifeadi

    Full Text Available BACKGROUND: Death receptors (DR of the TNF family function as anti-tumor immune effector molecules. Tumor cells, however, often exhibit DR-signaling resistance. Previous studies indicate that radiation can modify gene expression within tumor cells and increase tumor cell sensitivity to immune attack. The aim of this study is to investigate the synergistic effect of sub-lethal doses of ionizing radiation in sensitizing colorectal carcinoma cells to death receptor-mediated apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: The ability of radiation to modulate the expression of multiple death receptors (Fas/CD95, TRAILR1/DR4, TRAILR2/DR5, TNF-R1 and LTβR was examined in colorectal tumor cells. The functional significance of sub-lethal doses of radiation in enhancing tumor cell susceptibility to DR-induced apoptosis was determined by in vitro functional sensitivity assays. The longevity of these changes and the underlying molecular mechanism of irradiation in sensitizing diverse colorectal carcinoma cells to death receptor-mediated apoptosis were also examined. We found that radiation increased surface expression of Fas, DR4 and DR5 but not LTβR or TNF-R1 in these cells. Increased expression of DRs was observed 2 days post-irradiation and remained elevated 7-days post irradiation. Sub-lethal tumor cell irradiation alone exhibited minimal cell death, but effectively sensitized three of three colorectal carcinoma cells to both TRAIL and Fas-induced apoptosis, but not LTβR-induced death. Furthermore, radiation-enhanced Fas and TRAIL-induced cell death lasted as long as 5-days post-irradiation. Specific analysis of intracellular sensitizers to apoptosis indicated that while radiation did reduce Bcl-X(L and c-FLIP protein expression, this reduction did not correlate with the radiation-enhanced sensitivity to Fas and/or TRAIL mediated apoptosis among the three cell types. CONCLUSIONS/SIGNIFICANCE: Irradiation of tumor cells can overcome Fas and TRAIL

  2. Death signals by environmental pollutants

    International Nuclear Information System (INIS)

    Krug, H.F.

    2002-01-01

    Life and death are directly involved in the normal development of all multicellular organisms. Defects in the regulation of the mechanism of programmed cell death (apoptosis) contribute to many diseases as well as in the toxic effects of xenobiotics. Here it is described which elements of the apoptotic machinery are possible targets of hydrocarbons and metal compounds, prominent environmental pollutants. Moreover, it is shown that cytotoxic rather than cytostatic therapies might be most effective in treatment of cancer. (orig.)

  3. The Janus face of death receptor signalling during tumour immunoediting.

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    Eimear O' Reilly

    2016-10-01

    Full Text Available Cancer immune-surveillance is essential for the inhibition of carcinogenesis. Malignantly transformed cells can be recognised by both the innate and adaptive immune systems through different mechanisms. Immune effector cells induce extrinsic cell death in the identified tumour cells by expressing death ligand cytokines of the tumour necrosis factor ligand family. However, some tumour cells can escape immune elimination and progress. Acquisition of resistance to the death-ligand induced apoptotic pathway can be obtained through cleavage of effector-cell expressed death-ligands into a poorly active form, mutations or silencing of the death receptors or overexpression of decoy receptors and pro-survival proteins. Although the immune system is highly effective in the elimination of malignantly transformed cells, abnormal/ dysfunctional death-ligand signalling curbs its cytotoxicity. Moreover, death receptors can also transmit pro-survival and pro-migratory signals. Consequently, dysfunctional death receptor-mediated apoptosis/necroptosis signalling does not only give a passive resistance against cell death, but actively drives tumour cell motility, invasion and contributes to consequent metastasis. This dual contribution of the death ligand-death receptor signalling in both the early, elimination phase and then in the late, escape phase of the tumour immunoediting process is discussed in this review. Death receptor agonists still hold potential for cancer therapy since they can execute the tumour-eliminating immune-effector function even in the absence of activation of the immune system against the tumour. The opportunities and challenges of developing death receptor agonists into effective cancer therapeutics are also discussed.

  4. Membrane Trafficking of Death Receptors: Implications on Signalling

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    Wulf Schneider-Brachert

    2013-07-01

    Full Text Available Death receptors were initially recognised as potent inducers of apoptotic cell death and soon ambitious attempts were made to exploit selective ignition of controlled cellular suicide as therapeutic strategy in malignant diseases. However, the complexity of death receptor signalling has increased substantially during recent years. Beyond activation of the apoptotic cascade, involvement in a variety of cellular processes including inflammation, proliferation and immune response was recognised. Mechanistically, these findings raised the question how multipurpose receptors can ensure selective activation of a particular pathway. A growing body of evidence points to an elegant spatiotemporal regulation of composition and assembly of the receptor-associated signalling complex. Upon ligand binding, receptor recruitment in specialized membrane compartments, formation of receptor-ligand clusters and internalisation processes constitute key regulatory elements. In this review, we will summarise the current concepts of death receptor trafficking and its implications on receptor-associated signalling events.

  5. Jasmonic acid signaling modulates ozone-induced hypersensitive cell death.

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    Rao, M V; Lee, H; Creelman, R A; Mullet, J E; Davis, K R

    2000-09-01

    Recent studies suggest that cross-talk between salicylic acid (SA)-, jasmonic acid (JA)-, and ethylene-dependent signaling pathways regulates plant responses to both abiotic and biotic stress factors. Earlier studies demonstrated that ozone (O(3)) exposure activates a hypersensitive response (HR)-like cell death pathway in the Arabidopsis ecotype Cvi-0. We now have confirmed the role of SA and JA signaling in influencing O(3)-induced cell death. Expression of salicylate hydroxylase (NahG) in Cvi-0 reduced O(3)-induced cell death. Methyl jasmonate (Me-JA) pretreatment of Cvi-0 decreased O(3)-induced H(2)O(2) content and SA concentrations and completely abolished O(3)-induced cell death. Cvi-0 synthesized as much JA as did Col-0 in response to O(3) exposure but exhibited much less sensitivity to exogenous Me-JA. Analyses of the responses to O(3) of the JA-signaling mutants jar1 and fad3/7/8 also demonstrated an antagonistic relationship between JA- and SA-signaling pathways in controlling the magnitude of O(3)-induced HR-like cell death.

  6. The convergence of radiation and immunogenic cell death signaling pathways

    International Nuclear Information System (INIS)

    Golden, Encouse B.; Pellicciotta, Ilenia; Demaria, Sandra; Barcellos-Hoff, Mary H.; Formenti, Silvia C.

    2012-01-01

    Ionizing radiation (IR) triggers programmed cell death in tumor cells through a variety of highly regulated processes. Radiation-induced tumor cell death has been studied extensively in vitro and is widely attributed to multiple distinct mechanisms, including apoptosis, necrosis, mitotic catastrophe (MC), autophagy, and senescence, which may occur concurrently. When considering tumor cell death in the context of an organism, an emerging body of evidence suggests there is a reciprocal relationship in which radiation stimulates the immune system, which in turn contributes to tumor cell kill. As a result, traditional measurements of radiation-induced tumor cell death, in vitro, fail to represent the extent of clinically observed responses, including reductions in loco-regional failure rates and improvements in metastases free and overall survival. Hence, understanding the immunological responses to the type of radiation-induced cell death is critical. In this review, the mechanisms of radiation-induced tumor cell death are described, with particular focus on immunogenic cell death (ICD). Strategies combining radiotherapy with specific chemotherapies or immunotherapies capable of inducing a repertoire of cancer specific immunogens might potentiate tumor control not only by enhancing cell kill but also through the induction of a successful anti-tumor vaccination that improves patient survival.

  7. Lysosomal cysteine peptidases - Molecules signaling tumor cell death and survival.

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    Pišlar, Anja; Perišić Nanut, Milica; Kos, Janko

    2015-12-01

    Lysosomal cysteine peptidases - cysteine cathepsins - are general intracellular protein-degrading enzymes that control also a variety of specific physiological processes. They can trigger irreversible events leading to signal transduction and activation of signaling pathways, resulting in cell survival and proliferation or cell death. In cancer cells, lysosomal cysteine peptidases are involved in multiple processes during malignant progression. Their translocation from the endosomal/lysosomal pathway to nucleus, cytoplasm, plasma membrane and extracellular space enables the activation and remodeling of a variety of tumor promoting proteins. Thus, lysosomal cysteine peptidases interfere with cytokine/chemokine signaling, regulate cell adhesion and migration and endocytosis, are involved in the antitumor immune response and apoptosis, and promote cell invasion, angiogenesis and metastasis. Further, lysosomal cysteine peptidases modify growth factors and receptors involved in tyrosine kinase dependent pathways such as MAPK, Akt and JNK, thus representing key signaling tools for the activation of tumor cell growth and proliferation. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Oxidative Stress, Redox Signaling, and Autophagy: Cell Death Versus Survival

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    Navarro-Yepes, Juliana; Burns, Michaela; Anandhan, Annadurai; Khalimonchuk, Oleh; del Razo, Luz Maria; Quintanilla-Vega, Betzabet; Pappa, Aglaia; Panayiotidis, Mihalis I.

    2014-01-01

    Abstract Significance: The molecular machinery regulating autophagy has started becoming elucidated, and a number of studies have undertaken the task to determine the role of autophagy in cell fate determination within the context of human disease progression. Oxidative stress and redox signaling are also largely involved in the etiology of human diseases, where both survival and cell death signaling cascades have been reported to be modulated by reactive oxygen species (ROS) and reactive nitrogen species (RNS). Recent Advances: To date, there is a good understanding of the signaling events regulating autophagy, as well as the signaling processes by which alterations in redox homeostasis are transduced to the activation/regulation of signaling cascades. However, very little is known about the molecular events linking them to the regulation of autophagy. This lack of information has hampered the understanding of the role of oxidative stress and autophagy in human disease progression. Critical Issues: In this review, we will focus on (i) the molecular mechanism by which ROS/RNS generation, redox signaling, and/or oxidative stress/damage alter autophagic flux rates; (ii) the role of autophagy as a cell death process or survival mechanism in response to oxidative stress; and (iii) alternative mechanisms by which autophagy-related signaling regulate mitochondrial function and antioxidant response. Future Directions: Our research efforts should now focus on understanding the molecular basis of events by which autophagy is fine tuned by oxidation/reduction events. This knowledge will enable us to understand the mechanisms by which oxidative stress and autophagy regulate human diseases such as cancer and neurodegenerative disorders. Antioxid. Redox Signal. 21, 66–85. PMID:24483238

  9. Assembly of Oligomeric Death Domain Complexes during Toll Receptor Signaling*

    OpenAIRE

    Moncrieffe, Martin C.; Grossmann, J. Günter; Gay, Nicholas J.

    2008-01-01

    The Drosophila Toll receptor is activated by the endogenous protein ligand Spätzle in response to microbial stimuli in immunity and spatial cues during embryonic development. Downstream signaling is mediated by the adaptor proteins Tube, the kinase Pelle, and the Drosophila homologue of myeloid differentiation primary response protein (dMyD88). Here we have characterized heterodimeric (dMyD88-Tube) and heterotrimeric (dMyD88-Tube-Pelle) death domain complexes. We show ...

  10. Assembly of Oligomeric Death Domain Complexes during Toll Receptor Signaling*

    Science.gov (United States)

    Moncrieffe, Martin C.; Grossmann, J. Günter; Gay, Nicholas J.

    2008-01-01

    The Drosophila Toll receptor is activated by the endogenous protein ligand Spätzle in response to microbial stimuli in immunity and spatial cues during embryonic development. Downstream signaling is mediated by the adaptor proteins Tube, the kinase Pelle, and the Drosophila homologue of myeloid differentiation primary response protein (dMyD88). Here we have characterized heterodimeric (dMyD88-Tube) and heterotrimeric (dMyD88-Tube-Pelle) death domain complexes. We show that both the heterodimeric and heterotrimeric complexes form kidney-shaped structures and that Tube is bivalent and has separate high affinity binding sites for dMyD88 and Pelle. Additionally we found no interaction between the isolated death domains of Pelle and dMyD88. These results indicate that the mode of assembly of the heterotrimeric dMyD88-Tube-Pelle complex downstream of the activated Toll receptor is unique. The measured dissociation constants for the interaction between the death domains of dMyD88 and Tube and of Pelle and a preformed dMyD88-Tube complex are used to propose a model of the early postreceptor events in Drosophila Toll receptor signaling. PMID:18829464

  11. Assembly of oligomeric death domain complexes during Toll receptor signaling.

    Science.gov (United States)

    Moncrieffe, Martin C; Grossmann, J Günter; Gay, Nicholas J

    2008-11-28

    The Drosophila Toll receptor is activated by the endogenous protein ligand Spätzle in response to microbial stimuli in immunity and spatial cues during embryonic development. Downstream signaling is mediated by the adaptor proteins Tube, the kinase Pelle, and the Drosophila homologue of myeloid differentiation primary response protein (dMyD88). Here we have characterized heterodimeric (dMyD88-Tube) and heterotrimeric (dMyD88-Tube-Pelle) death domain complexes. We show that both the heterodimeric and heterotrimeric complexes form kidney-shaped structures and that Tube is bivalent and has separate high affinity binding sites for dMyD88 and Pelle. Additionally we found no interaction between the isolated death domains of Pelle and dMyD88. These results indicate that the mode of assembly of the heterotrimeric dMyD88-Tube-Pelle complex downstream of the activated Toll receptor is unique. The measured dissociation constants for the interaction between the death domains of dMyD88 and Tube and of Pelle and a preformed dMyD88-Tube complex are used to propose a model of the early postreceptor events in Drosophila Toll receptor signaling.

  12. A platycoside-rich fraction from the root of Platycodon grandiflorum enhances cell death in A549 human lung carcinoma cells via mainly AMPK/mTOR/AKT signal-mediated autophagy induction.

    Science.gov (United States)

    Yim, Nam-Hui; Hwang, Youn-Hwan; Liang, Chun; Ma, Jin Yeul

    2016-12-24

    The root of Platycodon grandiflorum (PG), commonly known as Kilkyong in Korea, Jiegeng in China, and Kikyo in Japan, has been extensively used as a traditional anti-inflammatory medicine in Asia for the treatment of respiratory conditions, such as bronchitis, asthma, and tonsillitis. Platycosides isolated from PG are especially well-known for their anti-cancer effects. We investigated the involvement of autophagic cell death and other potential molecular mechanisms induced by the platycoside-containing butanol fraction of PG (PGB) in human lung carcinoma cells. PGB-induced growth inhibition and cell death were measured using a 5-diphenyl-tetrazolium bromide (MTT) assay. The effects of PGB on autophagy were determined by observing microtubule-associated protein 1 light chain 3 (LC3) redistribution with confocal microscopy. The PGB-mediated regulation of autophagy-associated proteins was investigated using Western blotting analysis. Furthermore, the anti-cancer mechanism of PGB was confirmed using chemical inhibitors. A high-performance liquid chromatography (HPLC)-DAD system was used to analyze the platycosides in PGB. In A549 cells, PGB induced significant autophagic cell death. Specifically, PGB upregulated LC3-II in a time- and dose-dependent manner, and it redistributed LC3 via autophagosome formation in the cytoplasm. PGB treatment increased the phosphorylation of AMP-activated protein kinase (AMPK) and subsequently suppressed the AKT/mammalian target of the rapamycin (mTOR) pathway. Furthermore, PGB inhibited cell proliferation by regulating the mitogen-activated protein kinase (MAPK) pathways. In this study, six types of platycosides were identified in the PGB using HPLC. PGB efficiently induced cancer cell death via autophagy and the modulation of the AMPK/mTOR/AKT and MAPK signaling pathways in A549 cells. Therefore, PGB may be an efficacious herbal anti-cancer therapy. Copyright © 2016. Published by Elsevier Ireland Ltd.

  13. Ras and Rheb Signaling in Survival and Cell Death

    International Nuclear Information System (INIS)

    Ehrkamp, Anja; Herrmann, Christian; Stoll, Raphael; Heumann, Rolf

    2013-01-01

    One of the most obvious hallmarks of cancer is uncontrolled proliferation of cells partly due to independence of growth factor supply. A major component of mitogenic signaling is Ras, a small GTPase. It was the first identified human protooncogene and is known since more than three decades to promote cellular proliferation and growth. Ras was shown to support growth factor-independent survival during development and to protect from chemical or mechanical lesion-induced neuronal degeneration in postmitotic neurons. In contrast, for specific patho-physiological cases and cellular systems it has been shown that Ras may also promote cell death. Proteins from the Ras association family (Rassf, especially Rassf1 and Rassf5) are tumor suppressors that are activated by Ras-GTP, triggering apoptosis via e.g., activation of mammalian sterile 20-like (MST1) kinase. In contrast to Ras, their expression is suppressed in many types of tumours, which makes Rassf proteins an exciting model for understanding the divergent effects of Ras activity. It seems likely that the outcome of Ras signaling depends on the balance between the activation of its various downstream effectors, thus determining cellular fate towards either proliferation or apoptosis. Ras homologue enriched in brain (Rheb) is a protein from the Ras superfamily that is also known to promote proliferation, growth, and regeneration through the mammalian target of rapamycin (mTor) pathway. However, recent evidences indicate that the Rheb-mTor pathway may switch its function from a pro-growth into a cell death pathway, depending on the cellular situation. In contrast to Ras signaling, for Rheb, the cellular context is likely to modulate the whole Rheb-mTor pathway towards cellular death or survival, respectively

  14. Ras and Rheb Signaling in Survival and Cell Death

    Energy Technology Data Exchange (ETDEWEB)

    Ehrkamp, Anja [Molecular Neurobiochemistry, Ruhr University of Bochum, 44780 Bochum (Germany); Herrmann, Christian [Department of Physical Chemistry1, Protein Interaction, Ruhr University of Bochum, 44780 Bochum (Germany); Stoll, Raphael [Biomolecular NMR, Ruhr University of Bochum, 44780 Bochum (Germany); Heumann, Rolf, E-mail: rolf.heumann@rub.de [Molecular Neurobiochemistry, Ruhr University of Bochum, 44780 Bochum (Germany)

    2013-05-28

    One of the most obvious hallmarks of cancer is uncontrolled proliferation of cells partly due to independence of growth factor supply. A major component of mitogenic signaling is Ras, a small GTPase. It was the first identified human protooncogene and is known since more than three decades to promote cellular proliferation and growth. Ras was shown to support growth factor-independent survival during development and to protect from chemical or mechanical lesion-induced neuronal degeneration in postmitotic neurons. In contrast, for specific patho-physiological cases and cellular systems it has been shown that Ras may also promote cell death. Proteins from the Ras association family (Rassf, especially Rassf1 and Rassf5) are tumor suppressors that are activated by Ras-GTP, triggering apoptosis via e.g., activation of mammalian sterile 20-like (MST1) kinase. In contrast to Ras, their expression is suppressed in many types of tumours, which makes Rassf proteins an exciting model for understanding the divergent effects of Ras activity. It seems likely that the outcome of Ras signaling depends on the balance between the activation of its various downstream effectors, thus determining cellular fate towards either proliferation or apoptosis. Ras homologue enriched in brain (Rheb) is a protein from the Ras superfamily that is also known to promote proliferation, growth, and regeneration through the mammalian target of rapamycin (mTor) pathway. However, recent evidences indicate that the Rheb-mTor pathway may switch its function from a pro-growth into a cell death pathway, depending on the cellular situation. In contrast to Ras signaling, for Rheb, the cellular context is likely to modulate the whole Rheb-mTor pathway towards cellular death or survival, respectively.

  15. Hepatocyte growth factor enhances death receptor-induced apoptosis by up-regulating DR5

    International Nuclear Information System (INIS)

    Li, Yang; Fan, Xing; Goodwin, C Rory; Laterra, John; Xia, Shuli

    2008-01-01

    Hepatocyte growth factor (HGF) and its receptor c-MET are commonly expressed in malignant gliomas and embryonic neuroectodermal tumors including medulloblastoma and appear to play an important role in the growth and dissemination of these malignancies. Dependent on cell context and the involvement of specific downstream effectors, both pro- and anti-apoptotic effects of HGF have been reported. Human medulloblastoma cells were treated with HGF for 24–72 hours followed by death receptor ligand TRAIL (Tumor necrosis factor-related apoptosis-inducing ligand) for 24 hours. Cell death was measured by MTT and Annexin-V/PI flow cytometric analysis. Changes in expression levels of targets of interest were measured by Northern blot analysis, quantitative reverse transcription-PCR, Western blot analysis as well as immunoprecipitation. In this study, we show that HGF promotes medulloblastoma cell death induced by TRAIL. TRAIL alone triggered apoptosis in DAOY cells and death was enhanced by pre-treating the cells with HGF for 24–72 h prior to the addition of TRAIL. HGF (100 ng/ml) enhanced TRAIL (10 ng/ml) induced cell death by 36% (P < 0.001). No cell death was associated with HGF alone. Treating cells with PHA-665752, a specific c-Met receptor tyrosine kinase inhibitor, significantly abrogated the enhancement of TRAIL-induced cell death by HGF, indicating that its death promoting effect requires activation of its canonical receptor tyrosine kinase. Cell death induced by TRAIL+HGF was predominately apoptotic involving both extrinsic and intrinsic pathways as evidenced by the increased activation of caspase-3, 8, 9. Promotion of apoptosis by HGF occurred via the increased expression of the death receptor DR5 and enhanced formation of death-inducing signal complexes (DISC). Taken together, these and previous findings indicate that HGF:c-Met pathway either promotes or inhibits medulloblastoma cell death via pathway and context specific mechanisms

  16. Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed

    Science.gov (United States)

    Hsu, Li-Jin; Hong, Qunying; Chen, Shur-Tzu; Kuo, Hsiang-Lin; Schultz, Lori; Heath, John; Lin, Sing-Ru; Lee, Ming-Hui; Li, Dong-Zhang; Li, Zih-Ling; Cheng, Hui-Ching; Armand, Gerard; Chang, Nan-Shan

    2017-01-01

    Malignant cancer cells frequently secrete significant amounts of transforming growth factor beta (TGF-β), hyaluronan (HA) and hyaluronidases to facilitate metastasizing to target organs. In a non-canonical signaling, TGF-β binds membrane hyaluronidase Hyal-2 for recruiting tumor suppressors WWOX and Smad4, and the resulting Hyal-2/WWOX/Smad4 complex is accumulated in the nucleus to enhance SMAD-promoter dependent transcriptional activity. Yeast two-hybrid analysis showed that WWOX acts as a bridge to bind both Hyal-2 and Smad4. When WWOX-expressing cells were stimulated with high molecular weight HA, an increased formation of endogenous Hyal-2/WWOX/Smad4 complex occurred rapidly, followed by relocating to the nuclei in 20-40 min. In WWOX-deficient cells, HA failed to induce Smad2/3/4 relocation to the nucleus. To prove the signaling event, we designed a real time tri-molecular FRET analysis and revealed that HA induces the signaling pathway from ectopic Smad4 to WWOX and finally to p53, as well as from Smad4 to Hyal-2 and then to WWOX. An increased binding of the Smad4/Hyal-2/WWOX complex occurs with time in the nucleus that leads to bubbling cell death. In contrast, HA increases the binding of Smad4/WWOX/p53, which causes membrane blebbing but without cell death. In traumatic brain injury-induced neuronal death, the Hyal-2/WWOX complex was accumulated in the apoptotic nuclei of neurons in the rat brains in 24 hr post injury, as determined by immunoelectron microscopy. Together, HA activates the Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed. PMID:27845895

  17. Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed.

    Science.gov (United States)

    Hsu, Li-Jin; Hong, Qunying; Chen, Shur-Tzu; Kuo, Hsiang-Lin; Schultz, Lori; Heath, John; Lin, Sing-Ru; Lee, Ming-Hui; Li, Dong-Zhang; Li, Zih-Ling; Cheng, Hui-Ching; Armand, Gerard; Chang, Nan-Shan

    2017-03-21

    Malignant cancer cells frequently secrete significant amounts of transforming growth factor beta (TGF-β), hyaluronan (HA) and hyaluronidases to facilitate metastasizing to target organs. In a non-canonical signaling, TGF-β binds membrane hyaluronidase Hyal-2 for recruiting tumor suppressors WWOX and Smad4, and the resulting Hyal-2/WWOX/Smad4 complex is accumulated in the nucleus to enhance SMAD-promoter dependent transcriptional activity. Yeast two-hybrid analysis showed that WWOX acts as a bridge to bind both Hyal-2 and Smad4. When WWOX-expressing cells were stimulated with high molecular weight HA, an increased formation of endogenous Hyal-2/WWOX/Smad4 complex occurred rapidly, followed by relocating to the nuclei in 20-40 min. In WWOX-deficient cells, HA failed to induce Smad2/3/4 relocation to the nucleus. To prove the signaling event, we designed a real time tri-molecular FRET analysis and revealed that HA induces the signaling pathway from ectopic Smad4 to WWOX and finally to p53, as well as from Smad4 to Hyal-2 and then to WWOX. An increased binding of the Smad4/Hyal-2/WWOX complex occurs with time in the nucleus that leads to bubbling cell death. In contrast, HA increases the binding of Smad4/WWOX/p53, which causes membrane blebbing but without cell death. In traumatic brain injury-induced neuronal death, the Hyal-2/WWOX complex was accumulated in the apoptotic nuclei of neurons in the rat brains in 24 hr post injury, as determined by immunoelectron microscopy. Together, HA activates the Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed.

  18. The genetic algorithm for a signal enhancement

    International Nuclear Information System (INIS)

    Karimova, L.; Kuadykov, E.; Makarenko, N.

    2004-01-01

    The paper is devoted to the problem of time series enhancement, which is based on the analysis of local regularity. The model construction using this analysis does not require any a priori assumption on the structure of the noise and the functional relationship between original signal and noise. The signal itself may be nowhere differentiable with rapidly varying local regularity, what is overcome with the help of the new technique of increasing the local Hoelder regularity of the signal under research. A new signal with prescribed regularity is constructed using the genetic algorithm. This approach is applied to enhancement of time series in the paleoclimatology, solar physics, dendrochronology, meteorology and hydrology

  19. The genetic algorithm for a signal enhancement

    Energy Technology Data Exchange (ETDEWEB)

    Karimova, L. [Laboratory of Computer Modelling, Institute of Mathematics, Pushkin Street 125, 480100 Almaty (Kazakhstan)]. E-mail: karimova@math.kz; Kuadykov, E. [Laboratory of Computer Modelling, Institute of Mathematics, Pushkin Street 125, 480100 Almaty (Kazakhstan); Makarenko, N. [Laboratory of Computer Modelling, Institute of Mathematics, Pushkin Street 125, 480100 Almaty (Kazakhstan)

    2004-11-21

    The paper is devoted to the problem of time series enhancement, which is based on the analysis of local regularity. The model construction using this analysis does not require any a priori assumption on the structure of the noise and the functional relationship between original signal and noise. The signal itself may be nowhere differentiable with rapidly varying local regularity, what is overcome with the help of the new technique of increasing the local Hoelder regularity of the signal under research. A new signal with prescribed regularity is constructed using the genetic algorithm. This approach is applied to enhancement of time series in the paleoclimatology, solar physics, dendrochronology, meteorology and hydrology.

  20. Nitrosothiol signaling and protein nitrosation in cell death.

    Science.gov (United States)

    Iyer, Anand Krishnan V; Rojanasakul, Yon; Azad, Neelam

    2014-11-15

    Nitric oxide, a reactive free radical, is an important signaling molecule that can lead to a plethora of cellular effects affecting homeostasis. A well-established mechanism by which NO manifests its effect on cellular functions is the post-translational chemical modification of cysteine thiols in substrate proteins by a process known as S-nitrosation. Studies that investigate regulation of cellular functions through NO have increasingly established S-nitrosation as the primary modulatory mechanism in their respective systems. There has been a substantial increase in the number of reports citing various candidate proteins undergoing S-nitrosation, which affects cell-death and -survival pathways in a number of tissues including heart, lung, brain and blood. With an exponentially growing list of proteins being identified as substrates for S-nitrosation, it is important to assimilate this information in different cell/tissue systems in order to gain an overall view of protein regulation of both individual proteins and a class of protein substrates. This will allow for broad mapping of proteins as a function of S-nitrosation, and help delineate their global effects on pathophysiological responses including cell death and survival. This information will not only provide a much better understanding of overall functional relevance of NO in the context of various disease states, it will also facilitate the generation of novel therapeutics to combat specific diseases that are driven by NO-mediated S-nitrosation. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Autonomous rexinoid death signaling is suppressed by converging signaling pathways in immature leukemia cells.

    Science.gov (United States)

    Benoit, G R; Flexor, M; Besançon, F; Altucci, L; Rossin, A; Hillion, J; Balajthy, Z; Legres, L; Ségal-Bendirdjian, E; Gronemeyer, H; Lanotte, M

    2001-07-01

    On their own, retinoid X receptor (RXR)-selective ligands (rexinoids) are silent in retinoic acid receptor (RAR)-RXR heterodimers, and no selective rexinoid program has been described as yet in cellular systems. We report here on the rexinoid signaling capacity that triggers apoptosis of immature promyelocytic NB4 cells as a default pathway in the absence of survival factors. Rexinoid-induced apoptosis displays all features of bona fide programmed cell death and is inhibited by RXR, but not RAR antagonists. Several types of survival signals block rexinoid-induced apoptosis. RARalpha agonists switch the cellular response toward differentiation and induce the expression of antiapoptosis factors. Activation of the protein kinase A pathway in the presence of rexinoid agonists induces maturation and blocks immature cell apoptosis. Addition of nonretinoid serum factors also blocks cell death but does not induce cell differentiation. Rexinoid-induced apoptosis is linked to neither the presence nor stability of the promyelocytic leukemia-RARalpha fusion protein and operates also in non-acute promyelocytic leukemia cells. Together our results support a model according to which rexinoids activate in certain leukemia cells a default death pathway onto which several other signaling paradigms converge. This pathway is entirely distinct from that triggered by RAR agonists, which control cell maturation and postmaturation apoptosis.

  2. Acquirement and enhancement of remote speech signals

    Science.gov (United States)

    Lü, Tao; Guo, Jin; Zhang, He-yong; Yan, Chun-hui; Wang, Can-jin

    2017-07-01

    To address the challenges of non-cooperative and remote acoustic detection, an all-fiber laser Doppler vibrometer (LDV) is established. The all-fiber LDV system can offer the advantages of smaller size, lightweight design and robust structure, hence it is a better fit for remote speech detection. In order to improve the performance and the efficiency of LDV for long-range hearing, the speech enhancement technology based on optimally modified log-spectral amplitude (OM-LSA) algorithm is used. The experimental results show that the comprehensible speech signals within the range of 150 m can be obtained by the proposed LDV. The signal-to-noise ratio ( SNR) and mean opinion score ( MOS) of the LDV speech signal can be increased by 100% and 27%, respectively, by using the speech enhancement technology. This all-fiber LDV, which combines the speech enhancement technology, can meet the practical demand in engineering.

  3. Signal enhancement with variable span linear filters

    CERN Document Server

    Benesty, Jacob; Jensen, Jesper R

    2016-01-01

    This book introduces readers to the novel concept of variable span speech enhancement filters, and demonstrates how it can be used for effective noise reduction in various ways. Further, the book provides the accompanying Matlab code, allowing readers to easily implement the main ideas discussed. Variable span filters combine the ideas of optimal linear filters with those of subspace methods, as they involve the joint diagonalization of the correlation matrices of the desired signal and the noise. The book shows how some well-known filter designs, e.g. the minimum distortion, maximum signal-to-noise ratio, Wiener, and tradeoff filters (including their new generalizations) can be obtained using the variable span filter framework. It then illustrates how the variable span filters can be applied in various contexts, namely in single-channel STFT-based enhancement, in multichannel enhancement in both the time and STFT domains, and, lastly, in time-domain binaural enhancement. In these contexts, the properties of ...

  4. Signal Enhancement with Variable Span Linear Filters

    DEFF Research Database (Denmark)

    Benesty, Jacob; Christensen, Mads Græsbøll; Jensen, Jesper Rindom

    . Variable span filters combine the ideas of optimal linear filters with those of subspace methods, as they involve the joint diagonalization of the correlation matrices of the desired signal and the noise. The book shows how some well-known filter designs, e.g. the minimum distortion, maximum signal...... the time and STFT domains, and, lastly, in time-domain binaural enhancement. In these contexts, the properties of these filters are analyzed in terms of their noise reduction capabilities and desired signal distortion, and the analyses are validated and further explored in simulations....

  5. Signal Enhancement with Variable Span Linear Filters

    DEFF Research Database (Denmark)

    Benesty, Jacob; Christensen, Mads Græsbøll; Jensen, Jesper Rindom

    This book introduces readers to the novel concept of variable span speech enhancement filters, and demonstrates how it can be used for effective noise reduction in various ways. Further, the book provides the accompanying Matlab code, allowing readers to easily implement the main ideas discussed....... Variable span filters combine the ideas of optimal linear filters with those of subspace methods, as they involve the joint diagonalization of the correlation matrices of the desired signal and the noise. The book shows how some well-known filter designs, e.g. the minimum distortion, maximum signal......-to-noise ratio, Wiener, and tradeoff filters (including their new generalizations) can be obtained using the variable span filter framework. It then illustrates how the variable span filters can be applied in various contexts, namely in single-channel STFT-based enhancement, in multichannel enhancement in both...

  6. 8-aminoadenosine enhances radiation-induced cell death in human lung carcinoma A549 cells

    International Nuclear Information System (INIS)

    Meike, Shunsuke; Yamamori, Tohru; Yasui, Hironobu; Eitaki, Masato; Inanami, Osamu; Matsuda, Akira

    2011-01-01

    The combination of a chemotherapeutic agent and radiation is widely applied to enhance cell death in solid tumor cells in cancer treatment. The purine analogue 8-aminoadenosine (8-NH 2 -Ado) is known to be a transcription inhibitor that has proved very effective in multiple myeloma cell lines and primary indolent leukemia cells. In this report, to examine whether 8-NH 2 -Ado had the ability to enhance the radiation-induced cell killing in solid tumor cells, human lung adenocarcinoma A549 cells were irradiated in the presence and absence of 8-NH 2 -Ado. 8-NH 2 -Ado significantly increased reproductive cell death and apoptosis in A549 cells exposed to X-rays. When peptide inhibitors against caspase-3, -8, and -9 were utilized to evaluate the involvement of caspases, all inhibitors suppressed the enhancement of radiation-induced apoptosis, suggesting that not only mitochondria-mediated apoptotic signal transduction pathways but also death receptor-mediated pathways were involved in this enhancement of apoptosis. In addition, in the cells exposed to the treatment combining X-irradiation and 8-NH 2 -Ado, reduction of the intracellular ATP concentration was essential for survival, and down-regulation of the expression of antiapoptotic proteins such as survivin and X-linked inhibitor of apoptosis protein (XIAP) was observed. These results indicate that 8-NH 2 -Ado has potential not only as an anti-tumor drug for leukemia and lymphoma but also as a radiosensitizing agent for solid tumors. (author)

  7. Plasmalogens rescue neuronal cell death through an activation of AKT and ERK survival signaling.

    Directory of Open Access Journals (Sweden)

    Md Shamim Hossain

    Full Text Available Neuronal cells are susceptible to many stresses, which will cause the apoptosis and neurodegenerative diseases. The precise molecular mechanism behind the neuronal protection against these apoptotic stimuli is necessary for drug discovery. In the present study, we have found that plasmalogens (Pls, which are glycerophospholipids containing vinyl ether linkage at sn-1 position, can protect the neuronal cell death upon serum deprivation. Interestingly, caspse-9, but not caspase-8 and caspase-12, was cleaved upon the serum starvation in Neuro-2A cells. Pls treatments effectively reduced the activation of caspase-9. Furthermore, cellular signaling experiments showed that Pls enhanced phosphorylation of the phosphoinositide 3-kinase (PI3K-dependent serine/threonine-specific protein kinase AKT and extracellular-signal-regulated kinases ERK1/2. PI3K/AKT inhibitor LY294002 and MAPK/ERK kinase (MEK inhibitor U0126 treatments study clearly indicated that Pls-mediated cell survival was dependent on the activation of these kinases. In addition, Pls also inhibited primary mouse hippocampal neuronal cell death induced by nutrient deprivation, which was associated with the inhibition of caspase-9 and caspase-3 cleavages. It was reported that Pls content decreased in the brain of the Alzheimer's patients, which indicated that the reduction of Pls content could endanger neurons. The present findings, taken together, suggest that Pls have an anti-apoptotic action in the brain. Further studies on precise mechanisms of Pls-mediated protection against cell death may lead us to establish a novel therapeutic approach to cure neurodegenerative disorders.

  8. alpha-Toxin is a mediator of Staphylococcus aureus-induced cell death and activates caspases via the intrinsic death pathway independently of death receptor signaling

    NARCIS (Netherlands)

    Bantel, H; Sinha, B; Domschke, W; Peters, Georg; Schulze-Osthoff, K; Jänicke, R U

    2001-01-01

    Infections with Staphylococcus aureus, a common inducer of septic and toxic shock, often result in tissue damage and death of various cell types. Although S. aureus was suggested to induce apoptosis, the underlying signal transduction pathways remained elusive. We show that caspase activation and

  9. Signal transduction events in aluminum-induced cell death in tomato suspension cells

    NARCIS (Netherlands)

    Iakimova, E.T.; Kapchina-Toteva, V.M.; Woltering, E.J.

    2007-01-01

    In this study, some of the signal transduction events involved in AlCl3-induced cell death in tomato (Lycopersicon esculentum Mill.) suspension cells were elucidated. Cells treated with 100 ¿M AlCl3 showed typical features of programmed cell death (PCD) such as nuclear and cytoplasmic condensation.

  10. TRAIL enhances paracetamol-induced liver sinusoidal endothelial cell death in a Bim- and Bid-dependent manner

    Science.gov (United States)

    Badmann, A; Langsch, S; Keogh, A; Brunner, T; Kaufmann, T; Corazza, N

    2012-01-01

    Paracetamol (acetaminophen, APAP) is a universally used analgesic and antipyretic agent. Considered safe at therapeutic doses, overdoses cause acute liver damage characterized by centrilobular hepatic necrosis. One of the major clinical problems of paracetamol-induced liver disease is the development of hemorrhagic alterations. Although hepatocytes represent the main target of the cytotoxic effect of paracetamol overdose, perturbations within the endothelium involving morphological changes of liver sinusoidal endothelial cells (LSECs) have also been described in paracetamol-induced liver disease. Recently, we have shown that paracetamol-induced liver damage is synergistically enhanced by the TRAIL signaling pathway. As LSECs are constantly exposed to activated immune cells expressing death ligands, including TRAIL, we investigated the effect of TRAIL on paracetamol-induced LSEC death. We here demonstrate for the first time that TRAIL strongly enhances paracetamol-mediated LSEC death with typical features of apoptosis. Inhibition of caspases using specific inhibitors resulted in a strong reduction of cell death. TRAIL appears to enhance paracetamol-induced LSEC death via the activation of the pro-apoptotic BH3-only proteins Bid and Bim, which initiate the mitochondrial apoptotic pathway. Taken together this study shows that the liver endothelial layer, mainly LSECs, represent a direct target of the cytotoxic effect of paracetamol and that activation of TRAIL receptor synergistically enhances paracetamol-induced LSEC death via the mitochondrial apoptotic pathway. TRAIL-mediated acceleration of paracetamol-induced cell death may thus contribute to the pathogenesis of paracetamol-induced liver damage. PMID:23254290

  11. Kaempferol induces hepatocellular carcinoma cell death via endoplasmic reticulum stress-CHOP-autophagy signaling pathway.

    Science.gov (United States)

    Guo, Haiqing; Lin, Wei; Zhang, Xiangying; Zhang, Xiaohui; Hu, Zhongjie; Li, Liying; Duan, Zhongping; Zhang, Jing; Ren, Feng

    2017-10-10

    Kaempferol is a flavonoid compound that has gained widespread attention due to its antitumor functions. However, the underlying mechanisms are still not clear. The present study investigated the effect of kaempferol on hepatocellular carcinoma and its underlying mechanisms. Kaempferol induced autophagy in a concentration- and time-dependent manner in HepG2 or Huh7 cells, which was evidenced by the significant increase of autophagy-related genes. Inhibition of autophagy pathway, through 3-methyladenine or Atg7 siRNA, strongly diminished kaempferol-induced apoptosis. We further hypothesized that kaempferol can induce autophagy via endoplasmic reticulum (ER) stress pathway. Indeed, blocking ER stress by 4-phenyl butyric acid (4-PBA) or knockdown of CCAAT/enhancer-binding protein homologous protein (CHOP) with siRNA alleviated kaempferol-induced HepG2 or Huh7 cells autophagy; while transfection with plasmid overexpressing CHOP reversed the effect of 4-PBA on kaempferol-induced autophagy. Our results demonstrated that kaempferol induced hepatocarcinoma cell death via ER stress and CHOP-autophagy signaling pathway; kaempferol may be used as a potential chemopreventive agent for patients with hepatocellular carcinoma.

  12. Beacon signal in transcranial color coded ultrasound: A sign for brain death

    Directory of Open Access Journals (Sweden)

    Mehmet Akif Topçuoğlu

    2014-04-01

    Full Text Available A widely under-recognized brain-death confirming transcranial ultrasonography pattern resembling the red-blue beacon signal was demonstrated. Familiarity to this distinct and characteristic ultrasonic pattern seems to be important in the perspective of point-of-care neurological ultrasound use and knobology.

  13. Caffeine Induces Cell Death via Activation of Apoptotic Signal and Inactivation of Survival Signal in Human Osteoblasts

    Directory of Open Access Journals (Sweden)

    Wen-Hsiung Chan

    2008-05-01

    Full Text Available Caffeine consumption is a risk factor for osteoporosis, but the precise regulatory mechanisms are currently unknown. Here, we show that cell viability decreases in osteoblasts treated with caffeine in a dose-dependent manner. This cell death is attributed primarily to apoptosis and to a smaller extent, necrosis. Moreover, caffeine directly stimulates intracellular oxidative stress. Our data support caffeine-induced apoptosis in osteoblasts via a mitochondria-dependent pathway. The apoptotic biochemical changes were effectively prevented upon pretreatment with ROS scavengers, indicating that ROS plays a critical role as an upstream controller in the caffeine-induced apoptotic cascade. Additionally, p21-activated protein kinase 2 (PAK2 and c-Jun N-terminal kinase (JNK were activated in caffeine-treated osteoblasts. Experiments further found that PAK2 activity is required for caffeine-induced JNK activation and apoptosis. Importantly, our data also show that caffeine triggers cell death via inactivation of the survival signal, including the ERK- and Akt-mediated anti-apoptotic pathways. Finally, exposure of rats to dietary water containing 10~20 μM caffeine led to bone mineral density loss. These results demonstrate for the first time that caffeine triggers apoptosis in osteoblasts via activation of mitochondria-dependent cell death signaling and inactivation of the survival signal, and causes bone mineral density loss in vivo.

  14. Chloroplasts activity and PAP-signaling regulate programmed cell death in Arabidopsis

    KAUST Repository

    Bruggeman, Quentin

    2016-01-09

    Programmed cell death (PCD) is a crucial process both for plant development and responses to biotic and abiotic stress. There is accumulating evidence that chloroplasts may play a central role during plant PCD as for mitochondria in animal cells, but it is still unclear whether they participate in PCD onset, execution, or both. To tackle this question, we have analyzed the contribution of chloroplast function to the cell death phenotype of the myoinositol phosphate synthase1 (mips1) mutant that forms spontaneous lesions in a light-dependent manner. We show that photosynthetically active chloroplasts are required for PCD to occur in mips1, but this process is independent of the redox state of the chloroplast. Systematic genetic analyses with retrograde signaling mutants reveal that 3’-phosphoadenosine 5’-phosphate, a chloroplast retrograde signal that modulates nuclear gene expression in response to stress, can inhibit cell death and compromises plant innate immunity via inhibition of the RNA-processing 5’-3’ exoribonucleases. Our results provide evidence for the role of chloroplast-derived signal and RNA metabolism in the control of cell death and biotic stress response. © 2016 American Society of Plant Biologists. All Rights Reserved.

  15. Experimental assessment of fluorescence microscopy signal enhancement by stimulated emission

    Science.gov (United States)

    Dake, Fumihiro; Yazawa, Hiroki

    2017-10-01

    The quantity of photons generated during fluorescence microscopy is principally determined by the quantum yield of the fluorescence dyes and the optical power of the excitation beam. However, even though low quantum yields can produce poor images, it is challenging to tune this parameter, while increasing the power of the excitation beam often results in photodamage. Here, we propose the use of stimulated emission (SE) as a means of enhancing both the signal intensity and signal-to-noise ratio during confocal fluorescence microscopy. This work experimentally confirmed that both these factors can be enhanced by SE radiation, through generating a greater number of photons than are associated with the standard fluorescence signal. We also propose the concept of stimulated emission enhancing fluorescence (SEEF) microscopy, which employs both the SE and fluorescence signals, and demonstrate that the intensity of an SEEF signal is greater than those of the individual SE and fluorescence signals.

  16. Death receptor Fas (CD95) signaling in the central nervous system: tuning neuroplasticity?

    Science.gov (United States)

    Reich, Arno; Spering, Christopher; Schulz, Jörg B

    2008-09-01

    For over a decade, neuroscientific research has focused on processes of apoptosis and its contribution to the pathophysiology of neurological diseases. In the central nervous system, the degree of intrinsic mitochondrial-mediated apoptotic signaling expresses a cell's individual metabolic stress, whereas activation of the extrinsic death receptor-induced cascade is regarded as a sign of imbalanced cellular networks. Under physiological conditions, most neurons possess death receptors without being sensitive to receptor-mediated apoptosis. This paradox raises two questions: what is the evolutionary advantage of expressing potentially harmful proteins? How is their signaling controlled? This review summarizes the functional relevance of FasL-Fas signaling--a quintessential death ligand/receptor system--in different neurological disease models ranging from traumatic, inflammatory and ischemic to neurodegenerative processes. Furthermore, it outlines alternative non-apoptotic Fas signaling, shedding new light on its neuroplastic capacity. Finally, receptor-proximal regulatory proteins are introduced and identified as potential protagonists of disease-modifying neurological therapies.

  17. PDE2A2 regulates mitochondria morphology and apoptotic cell death via local modulation of cAMP/PKA signalling.

    Science.gov (United States)

    Monterisi, Stefania; Lobo, Miguel J; Livie, Craig; Castle, John C; Weinberger, Michael; Baillie, George; Surdo, Nicoletta C; Musheshe, Nshunge; Stangherlin, Alessandra; Gottlieb, Eyal; Maizels, Rory; Bortolozzi, Mario; Micaroni, Massimo; Zaccolo, Manuela

    2017-05-02

    cAMP/PKA signalling is compartmentalised with tight spatial and temporal control of signal propagation underpinning specificity of response. The cAMP-degrading enzymes, phosphodiesterases (PDEs), localise to specific subcellular domains within which they control local cAMP levels and are key regulators of signal compartmentalisation. Several components of the cAMP/PKA cascade are located to different mitochondrial sub-compartments, suggesting the presence of multiple cAMP/PKA signalling domains within the organelle. The function and regulation of these domains remain largely unknown. Here, we describe a novel cAMP/PKA signalling domain localised at mitochondrial membranes and regulated by PDE2A2. Using pharmacological and genetic approaches combined with real-time FRET imaging and high resolution microscopy, we demonstrate that in rat cardiac myocytes and other cell types mitochondrial PDE2A2 regulates local cAMP levels and PKA-dependent phosphorylation of Drp1. We further demonstrate that inhibition of PDE2A, by enhancing the hormone-dependent cAMP response locally, affects mitochondria dynamics and protects from apoptotic cell death.

  18. Signaling mechanisms of apoptosis-like programmed cell death in unicellular eukaryotes.

    Science.gov (United States)

    Shemarova, Irina V

    2010-04-01

    In unicellular eukaryotes, apoptosis-like cell death occurs during development, aging and reproduction, and can be induced by environmental stresses and exposure to toxic agents. The essence of the apoptotic machinery in unicellular organisms is similar to that in mammals, but the apoptotic signal network is less complex and of more ancient origin. The review summarizes current data about key apoptotic proteins and mechanisms of the transduction of apoptotic signals by caspase-like proteases and mitochondrial apoptogenic proteins in unicellular eukaryotes. The roles of receptor-dependent and receptor-independent caspase cascades are reviewed. 2010 Elsevier Inc. All rights reserved.

  19. Signal-enhancement reflective pulse oximeter with Fresnel lens

    Science.gov (United States)

    Chung, Shuang-Chao; Sun, Ching-Cherng

    2016-09-01

    In this paper, a new reflective pulse oximeter is proposed and demonstrated with implanting a Fresnel lens, which enhances the reflected signal. An optical simulation model incorporated with human skin characteristics is presented to evaluate the capability of the Fresnel lens. In addition, the distance between the light emitting diode and the photodiode is optimized. Compared with the other reflective oximeters, the reflected signal light detected by the photodiode is enhanced to more than 140%.

  20. Multichannel signal enhancement using a remote wireless microphone

    NARCIS (Netherlands)

    Bloemendal, Brian; Van De Laar, Jakob; Sommen, Piet

    2012-01-01

    A novel approach to multichannel signal enhancement is presented that exploits data from a remote wireless microphone (RWM). This RWM is placed near an interfering source and transmits only autocorrelation data of its observations to a host, i.e., not the entire signal. The host has access to the

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

    Science.gov (United States)

    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. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Glucose Metabolism and AMPK Signaling Regulate Dopaminergic Cell Death Induced by Gene (α-Synuclein)-Environment (Paraquat) Interactions.

    Science.gov (United States)

    Anandhan, Annadurai; Lei, Shulei; Levytskyy, Roman; Pappa, Aglaia; Panayiotidis, Mihalis I; Cerny, Ronald L; Khalimonchuk, Oleh; Powers, Robert; Franco, Rodrigo

    2017-07-01

    While environmental exposures are not the single cause of Parkinson's disease (PD), their interaction with genetic alterations is thought to contribute to neuronal dopaminergic degeneration. However, the mechanisms involved in dopaminergic cell death induced by gene-environment interactions remain unclear. In this work, we have revealed for the first time the role of central carbon metabolism and metabolic dysfunction in dopaminergic cell death induced by the paraquat (PQ)-α-synuclein interaction. The toxicity of PQ in dopaminergic N27 cells was significantly reduced by glucose deprivation, inhibition of hexokinase with 2-deoxy-D-glucose (2-DG), or equimolar substitution of glucose with galactose, which evidenced the contribution of glucose metabolism to PQ-induced cell death. PQ also stimulated an increase in glucose uptake, and in the levels of glucose transporter type 4 (GLUT4) and Na + -glucose transporters isoform 1 (SGLT1) proteins, but only inhibition of GLUT-like transport with STF-31 or ascorbic acid reduced PQ-induced cell death. Importantly, while autophagy protein 5 (ATG5)/unc-51 like autophagy activating kinase 1 (ULK1)-dependent autophagy protected against PQ toxicity, the inhibitory effect of glucose deprivation on cell death progression was largely independent of autophagy or mammalian target of rapamycin (mTOR) signaling. PQ selectively induced metabolomic alterations and adenosine monophosphate-activated protein kinase (AMPK) activation in the midbrain and striatum of mice chronically treated with PQ. Inhibition of AMPK signaling led to metabolic dysfunction and an enhanced sensitivity of dopaminergic cells to PQ. In addition, activation of AMPK by PQ was prevented by inhibition of the inducible nitric oxide syntase (iNOS) with 1400W, but PQ had no effect on iNOS levels. Overexpression of wild type or A53T mutant α-synuclein stimulated glucose accumulation and PQ toxicity, and this toxic synergism was reduced by inhibition of glucose metabolism

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

    Science.gov (United States)

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

    2014-02-01

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

  4. The use of contrast-enhanced post Mortem CT in the detection of cardiovascular deaths.

    Directory of Open Access Journals (Sweden)

    Jonas Christoph Apitzsch

    Full Text Available OBJECTIVES: To evaluate the diagnostic value of contrast enhanced post mortem computed tomography (PMCT in comparison to non-enhanced post mortem CT in the detection of cardiovascular causes of death (COD. BACKGROUND: As autopsy rates decline, new methods to determine CODs are necessary. So contrast enhanced PMCT shall be evaluated in comparison to established non-enhanced PMCT in order to further improve the method. METHODS: In a prospective study, 20 corpses were examined using a 64-row multisclice CT (MSCT before and after intraarterial perfusion with a newly developed, barium-bearing contrast agent and ventilation of the lungs. The cause of death was determined in enhanced and unenhanced scans and a level of confidence (LOC was given by three experienced radiologists on a scale between 0 and 4. Results were compared to autopsy results as gold standard. Autopsy was performed blinded to PMCT-findings. RESULTS: The method allowed visualization of different types of cause of death. There was a significant improvement in LOC in enhanced scans compared to unenhanced scans as well as an improvement in the detection of COD. The cause of death could be determined in 19 out of 20 patients. CONCLUSIONS: PMCT is feasible and appears to be robust for diagnosing cardiovascular causes of death. When compared with unenhanced post-mortem CT intraarterial perfusion and pulmonary ventilation significantly improve visualization and diagnostic accuracy. These promising results warrant further studies.

  5. Signal enhancement by spectral equalization of high frequency broadband signals transmitted through optical fibers

    International Nuclear Information System (INIS)

    Lyons, P.B.; Ogle, J.W.; Holzman, M.A.

    1980-01-01

    A new technique is discussed for enhancing the bandwidth and intensity of high frequency (> 1 GHz) analog, spectrally broad (40 nm) signals transmitted through one kilometer of optical fiber. The existing method for bandwidth enhancement of such a signal uses a very narrow (approx. 1 nm) filter between the fiber and detector to limit bandwidth degradation due to material dispersion. Using this method, most of the available optical intensity is rejected and lost. This new technique replaces the narrow-band filter with a spectral equalizer device which uses a reflection grating to disperse the input signal spectrum and direct it onto a linear array of fibers

  6. Searching for early-warning signals of impending dieback and death in Mediterranean oaks

    Science.gov (United States)

    Colangelo, Michele; Ripullone, Francesco; Julio Camarero, Jesus; De Micco, Veronica; Gazol, Antonio; Gentilesca, Tiziana; Borghetti, Marco

    2017-04-01

    In recent decades, forest dieback episodes have been recorded worldwide affecting different tree species. In particular, several cases of widespread dieback and increased mortality rates have been described for Mediterranean oak (Quercus spp.) species. These dieback cases are revealing the high vulnerability of Mediterranean oaks, manifested as a loss in tree vigour (leaf shedding, canopy and shoot dieback), growth decline and sometimes tree death, as a consequence of temperatures rising at unprecedented rates and drying trends. However, in the wake of the so-called 'oak decline phenomenon', the attention on these species has generally been limited, perhaps because they are often regarded as well-adapted to the dry conditions typical of Mediterranean areas. Indeed, according to recent studies, the reduced size, the ability to sprout and the anisohydric behavior of Mediterranean oak species (reduced control of water loss and high stomatal conductance rates) would make them better adapted to withstand heat and drought stress then taller and non-sprouting isohydric species (e.g. conifer, with strict control of water loss by closing stomata). Here, we investigated the vulnerability of Mediterranean oaks by comparing neighboring living and recently dead trees in species with low (Q. pubescens), intermediate (Q. cerris, Q. frainetto) and high (Q. robur) sensitivity to water shortage. We analysed changes in tree vigour using tree-ring width and functional wood anatomical traits as proxies to search for early-warning signals of dieback, in connection with the main proposed dieback mechanisms (hydraulic failure and/or carbon starvation). We also modeled the probability of tree death as a function of tree size (diameter, height) by quantifying recent changes in growth and wood anatomy along tree-ring series. Contrary to the general concept that trees tend to experience increasing cavitation risk with increasing height, our studies show that smaller oaks are more prone to die

  7. Analysis of Enhanced Velocity Signals Observed during Solar Flares ...

    Indian Academy of Sciences (India)

    2003-10-28

    Oct 28, 2003 ... close to the vicinity of the hard X-ray source regions as observed with. RHESSI. The power maps of the active region show enhancement in the frequency regime 5–6.5mHz, while there is feeble or no enhancement of these signals in 2–4 mHz frequency band. High energy particles with sufficient momentum ...

  8. Involvement of mitochondrial proteins in calcium signaling and cell death induced by staurosporine in Neurospora crassa.

    Science.gov (United States)

    Gonçalves, A Pedro; Cordeiro, J Miguel; Monteiro, João; Lucchi, Chiara; Correia-de-Sá, Paulo; Videira, Arnaldo

    2015-10-01

    Staurosporine-induced cell death in Neurospora crassa includes a well defined sequence of alterations in cytosolic calcium levels, comprising extracellular Ca(2+) influx and mobilization of Ca(2+) from internal stores. Here, we show that cells undergoing respiratory stress due to the lack of certain components of the mitochondrial complex I (like the 51kDa and 14kDa subunits) or the Ca(2+)-binding alternative NADPH dehydrogenase NDE-1 are hypersensitive to staurosporine and incapable of setting up a proper intracellular Ca(2+) response. Cells expressing mutant forms of NUO51 that mimic human metabolic diseases also presented Ca(2+) signaling deficiencies. Accumulation of reactive oxygen species is increased in cells lacking NDE-1 and seems to be required for Ca(2+) oscillations in response to staurosporine. Measurement of the mitochondrial levels of Ca(2+) further supported the involvement of these organelles in staurosporine-induced Ca(2+) signaling. In summary, our data indicate that staurosporine-induced fungal cell death involves a sophisticated response linking Ca(2+) dynamics and bioenergetics. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Glycosylation as a Main Regulator of Growth and Death Factor Receptors Signaling

    Directory of Open Access Journals (Sweden)

    Inês Gomes Ferreira

    2018-02-01

    Full Text Available Glycosylation is a very frequent and functionally important post-translational protein modification that undergoes profound changes in cancer. Growth and death factor receptors and plasma membrane glycoproteins, which upon activation by extracellular ligands trigger a signal transduction cascade, are targets of several molecular anti-cancer drugs. In this review, we provide a thorough picture of the mechanisms bywhich glycosylation affects the activity of growth and death factor receptors in normal and pathological conditions. Glycosylation affects receptor activity through three non-mutually exclusive basic mechanisms: (1 by directly regulating intracellular transport, ligand binding, oligomerization and signaling of receptors; (2 through the binding of receptor carbohydrate structures to galectins, forming a lattice thatregulates receptor turnover on the plasma membrane; and (3 by receptor interaction with gangliosides inside membrane microdomains. Some carbohydrate chains, for example core fucose and β1,6-branching, exert a stimulatory effect on all receptors, while other structures exert opposite effects on different receptors or in different cellular contexts. In light of the crucial role played by glycosylation in the regulation of receptor activity, the development of next-generation drugs targeting glyco-epitopes of growth factor receptors should be considered a therapeutically interesting goal.

  10. Pepper pathogenesis-related protein 4c is a plasma membrane-localized cysteine protease inhibitor that is required for plant cell death and defense signaling.

    Science.gov (United States)

    Kim, Nak Hyun; Hwang, Byung Kook

    2015-01-01

    Xanthomonas campestris pv. vesicatoria (Xcv) type III effector AvrBsT triggers programmed cell death (PCD) and activates the hypersensitive response (HR) in plants. Here, we isolated and identified the plasma membrane localized pathogenesis-related (PR) protein 4c gene (CaPR4c) from pepper (Capsicum annuum) leaves undergoing AvrBsT-triggered HR cell death. CaPR4c encodes a protein with a signal peptide and a Barwin domain. Recombinant CaPR4c protein expressed in Escherichia coli exhibited cysteine protease-inhibitor activity and ribonuclease (RNase) activity. Subcellular localization analyses revealed that CaPR4c localized to the plasma membrane in plant cells. CaPR4c expression was rapidly and specifically induced by avirulent Xcv (avrBsT) infection. Transient expression of CaPR4c caused HR cell death in pepper leaves, which was accompanied by enhanced accumulation of H2 O2 and significant induction of some defense-response genes. Deletion of the signal peptide from CaPR4c abolished the induction of HR cell death, indicating a requirement for plasma membrane localization of CaPR4c for HR cell death. CaPR4c silencing in pepper disrupted both basal and AvrBsT-triggered resistance responses, and enabled Xcv proliferation in infected leaves. H2 O2 accumulation, cell-death induction, and defense-response gene expression were distinctly reduced in CaPR4c-silenced pepper. CaPR4c overexpression in transgenic Arabidopsis plants conferred greater resistance against infection by Pseudomonas syringae pv. tomato and Hyaloperonospora arabidopsidis. These results collectively suggest that CaPR4c plays an important role in plant cell death and defense signaling. © 2014 The Authors The Plant Journal © 2014 John Wiley & Sons Ltd.

  11. Phenolic excipients of insulin formulations induce cell death, pro-inflammatory signaling and MCP-1 release

    Directory of Open Access Journals (Sweden)

    Claudia Weber

    2015-01-01

    Insulin solutions displayed cytotoxic and pro-inflammatory potential caused by phenol or m-cresol. We speculate that during insulin pump therapy phenol and m-cresol might induce cell death and inflammatory reactions at the infusion site in vivo. Inflammation is perpetuated by release of MCP-1 by activated monocytic cells leading to enhanced recruitment of inflammatory cells. To minimize acute skin complications caused by phenol/m-cresol accumulation, a frequent change of infusion sets and rotation of the infusion site is recommended.

  12. Ganglioside GD2 in reception and transduction of cell death signal in tumor cells

    International Nuclear Information System (INIS)

    Doronin, Igor I; Vishnyakova, Polina A; Kholodenko, Irina V; Ponomarev, Eugene D; Ryazantsev, Dmitry Y; Molotkovskaya, Irina M; Kholodenko, Roman V

    2014-01-01

    susceptibility of tumor cell lines to cytotoxic effect of anti-GD2 antibodies. Results of this study demonstrate that anti-GD2 antibodies not only passively bind to the surface of tumor cells but also directly induce rapid cell death after the incubation with GD2-positive tumor cells. These results suggest a new role of GD2 as a receptor that actively transduces death signal in malignant cells

  13. Composite mathematical modeling of calcium signaling behind neuronal cell death in Alzheimer's disease.

    Science.gov (United States)

    Ranjan, Bobby; Chong, Ket Hing; Zheng, Jie

    2018-04-11

    Alzheimer's disease (AD) is a progressive neurological disorder, recognized as the most common cause of dementia affecting people aged 65 and above. AD is characterized by an increase in amyloid metabolism, and by the misfolding and deposition of β-amyloid oligomers in and around neurons in the brain. These processes remodel the calcium signaling mechanism in neurons, leading to cell death via apoptosis. Despite accumulating knowledge about the biological processes underlying AD, mathematical models to date are restricted to depicting only a small portion of the pathology. Here, we integrated multiple mathematical models to analyze and understand the relationship among amyloid depositions, calcium signaling and mitochondrial permeability transition pore (PTP) related cell apoptosis in AD. The model was used to simulate calcium dynamics in the absence and presence of AD. In the absence of AD, i.e. without β-amyloid deposition, mitochondrial and cytosolic calcium level remains in the low resting concentration. However, our in silico simulation of the presence of AD with the β-amyloid deposition, shows an increase in the entry of calcium ions into the cell and dysregulation of Ca 2+ channel receptors on the Endoplasmic Reticulum. This composite model enabled us to make simulation that is not possible to measure experimentally. Our mathematical model depicting the mechanisms affecting calcium signaling in neurons can help understand AD at the systems level and has potential for diagnostic and therapeutic applications.

  14. BAG3 protects bovine papillomavirus type 1-transformed equine fibroblasts against pro-death signals.

    Science.gov (United States)

    Cotugno, Roberta; Gallotta, Dario; d'Avenia, Morena; Corteggio, Annunziata; Altamura, Gennaro; Roperto, Franco; Belisario, Maria Antonietta; Borzacchiello, Giuseppe

    2013-07-22

    In human cancer cells, BAG3 protein is known to sustain cell survival. Here, for the first time, we demonstrate the expression of BAG3 protein both in equine sarcoids in vivo and in EqS04b cells, a sarcoid-derived fully transformed cell line harbouring bovine papilloma virus (BPV)-1 genome. Evidence of a possible involvement of BAG3 in equine sarcoid carcinogenesis was obtained by immunohistochemistry analysis of tumour samples. We found that most tumour samples stained positive for BAG3, even though to a different grade, while normal dermal fibroblasts from healthy horses displayed very weak staining pattern for BAG3 expression. By siRNA technology, we demonstrate in EqS04b the role of BAG3 in counteracting basal as well as chemical-triggered pro-death signals. BAG3 down-modulation was indeed shown to promote cell death and cell cycle arrest in G0/G1. In addition, we found that BAG3 silencing sensitized EqS04b cells to phenethylisothiocyanate (PEITC), a promising cancer chemopreventive/chemotherapeutic agent present in edible cruciferous vegetables. Notably, such a pro-survival role of BAG3 was less marked in E. Derm cells, an equine BPV-negative fibroblast cell line taken as a normal counterpart. Altogether our findings might suggest a mutual cooperation between BAG3 and viral oncoproteins to sustain cell survival.

  15. Enhancing Raman signals with an interferometrically controlled AFM tip

    International Nuclear Information System (INIS)

    Oron-Carl, Matti; Krupke, Ralph

    2013-01-01

    We demonstrate the upgrade of a commercial confocal Raman microscope into a tip-enhanced Raman microscope/spectroscopy system (TERS) by integrating an interferometrically controlled atomic force microscope into the base of an existing upright microscope to provide near-field detection and thus signal enhancement. The feasibility of the system is demonstrated by measuring the Raman near-field enhancement on thin PEDOT:PSS films and on carbon nanotubes within a device geometry. An enhancement factor of 2–3 and of 5–6 is observed, respectively. Moreover, on a nanotube device we show local conductivity measurement and its correlation to Raman and topography recordings. Upgrading an existing upright confocal Raman microscope in the demonstrated way is significantly cheaper than purchasing a complete commercial TERS system. (paper)

  16. Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity

    International Nuclear Information System (INIS)

    Vilela, Luciano R.; Gobira, Pedro H.; Viana, Thercia G.; Medeiros, Daniel C.; Ferreira-Vieira, Talita H.; Doria, Juliana G.; Rodrigues, Flávia; Aguiar, Daniele C.; Pereira, Grace S.; Massessini, André R.; Ribeiro, Fabíola M.; Oliveira, Antonio Carlos P. de; Moraes, Marcio F.D.; Moreira, Fabricio A.

    2015-01-01

    Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited. Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication. Male Swiss mice received injections of endocannabinoid-related compounds followed by the lowest dose of cocaine that induces seizures, electroencephalographic activity and cell death in the hippocampus. The molecular mechanisms were studied in primary cell culture of this structure. The FAAH inhibitor, URB597, reduced cocaine-induced seizures and epileptiform electroencephalographic activity. The cannabinoid CB 1 receptor selective agonist, ACEA, mimicked these effects, whereas the antagonist, AM251, prevented them. URB597 also inhibited cocaine-induced activation and death of hippocampal neurons, both in animals and in primary cell culture. Finally, we investigated if the PI3K/Akt/ERK intracellular pathway, a cell surviving mechanism coupled to CB 1 receptor, mediated these neuroprotective effects. Accordingly, URB597 injection increased ERK and Akt phosphorylation in the hippocampus. Moreover, the neuroprotective effect of this compound was reversed by the PI3K inhibitor, LY294002. In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity. - Highlights: • Cocaine toxicity is characterized by seizures and hippocampal cell death. • The endocannabinoid anandamide acts as a brain protective mechanism. • Inhibition of anandamide hydrolysis attenuates

  17. Enhancement of endocannabinoid signaling protects against cocaine-induced neurotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Vilela, Luciano R. [Graduate Program in Neuroscience, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Gobira, Pedro H.; Viana, Thercia G. [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Medeiros, Daniel C.; Ferreira-Vieira, Talita H. [Department of Physiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Doria, Juliana G. [Graduate Program in Neuroscience, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Rodrigues, Flávia [Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Aguiar, Daniele C. [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Pereira, Grace S.; Massessini, André R. [Department of Physiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Ribeiro, Fabíola M. [Department of Biochemistry and Immunology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Oliveira, Antonio Carlos P. de [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Moraes, Marcio F.D., E-mail: mfdm@icb.ufmg.br [Department of Physiology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Moreira, Fabricio A., E-mail: fabriciomoreira@icb.ufmg.br [Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil)

    2015-08-01

    Cocaine is an addictive substance with a potential to cause deleterious effects in the brain. The strategies for treating its neurotoxicity, however, are limited. Evidence suggests that the endocannabinoid system exerts neuroprotective functions against various stimuli. Thus, we hypothesized that inhibition of fatty acid amide hydrolase (FAAH), the main enzyme responsible for terminating the actions of the endocannabinoid anandamide, reduces seizures and cell death in the hippocampus in a model of cocaine intoxication. Male Swiss mice received injections of endocannabinoid-related compounds followed by the lowest dose of cocaine that induces seizures, electroencephalographic activity and cell death in the hippocampus. The molecular mechanisms were studied in primary cell culture of this structure. The FAAH inhibitor, URB597, reduced cocaine-induced seizures and epileptiform electroencephalographic activity. The cannabinoid CB{sub 1} receptor selective agonist, ACEA, mimicked these effects, whereas the antagonist, AM251, prevented them. URB597 also inhibited cocaine-induced activation and death of hippocampal neurons, both in animals and in primary cell culture. Finally, we investigated if the PI3K/Akt/ERK intracellular pathway, a cell surviving mechanism coupled to CB{sub 1} receptor, mediated these neuroprotective effects. Accordingly, URB597 injection increased ERK and Akt phosphorylation in the hippocampus. Moreover, the neuroprotective effect of this compound was reversed by the PI3K inhibitor, LY294002. In conclusion, the pharmacological facilitation of the anandamide/CB1/PI3K signaling protects the brain against cocaine intoxication in experimental models. This strategy may be further explored in the development of treatments for drug-induced neurotoxicity. - Highlights: • Cocaine toxicity is characterized by seizures and hippocampal cell death. • The endocannabinoid anandamide acts as a brain protective mechanism. • Inhibition of anandamide hydrolysis

  18. Signal Enhancement as Minimization of Relevant Information Loss

    OpenAIRE

    Geiger, Bernhard C.; Kubin, Gernot

    2012-01-01

    We introduce the notion of relevant information loss for the purpose of casting the signal enhancement problem in information-theoretic terms. We show that many algorithms from machine learning can be reformulated using relevant information loss, which allows their application to the aforementioned problem. As a particular example we analyze principle component analysis for dimensionality reduction, discuss its optimality, and show that the relevant information loss can indeed vanish if the r...

  19. Protein sensing by nanofluidic crystal and its signal enhancement

    Science.gov (United States)

    Sang, Jianming; Du, Hongtan; Wang, Wei; Chu, Ming; Wang, Yuedan; Li, Haichao; Alice Zhang, Haixia; Wu, Wengang; Li, Zhihong

    2013-01-01

    Nanofluidics has a unique property that ionic conductance across a nanometer-sized confined space is strongly affected by the space surface charge density, which can be utilized to construct electrical read-out biosensor. Based on this principle, this work demonstrated a novel protein sensor along with a sandwich signal enhancement approach. Nanoparticles with designed aptamer onside are assembled in a suspended micropore to form a 3-dimensional network of nanometer-sized interstices, named as nanofluidic crystal hereafter, as the basic sensing unit. Proteins captured by aptamers will change the surface charge density of nanoparticles and thereby can be detected by monitoring the ionic conductance across this nanofluidic crystal. Another aptamer can further enlarge the variations of the surface charge density by forming a sandwich structure (capturing aptamer/protein/signal enhancement aptamer) and the read-out conductance as well. The preliminary experimental results indicated that human α-thrombin was successfully detected by the corresponding aptamer modified nanofluidic crystal with the limit of detection of 5 nM (0.18 μg/ml) and the read-out signal was enhanced up to 3 folds by using another thrombin aptamer. Being easy to graft probe, facile and low-cost to prepare the nano-device, and having an electrical read-out, the present nanofluidic crystal scheme is a promising and universal strategy for protein sensing. PMID:24404017

  20. Rapid Nanoprobe Signal Enhancement by In Situ Gold Nanoparticle Synthesis.

    Science.gov (United States)

    Dias, Jorge T; Svedberg, Gustav; Nystrand, Mats; Andersson-Svahn, Helene; Gantelius, Jesper

    2018-03-07

    The use of nanoprobes such as gold, silver, silica or iron-oxide nanoparticles as detection reagents in bioanalytical assays can enable high sensitivity and convenient colorimetric readout. However, high densities of nanoparticles are typically needed for detection. The available synthesis-based enhancement protocols are either limited to gold and silver nanoparticles or rely on precise enzymatic control and optimization. Here, we present a protocol to enhance the colorimetric readout of gold, silver, silica, and iron oxide nanoprobes. It was observed that the colorimetric signal can be improved by up to a 10000-fold factor. The basis for such signal enhancement strategies is the chemical reduction of Au 3+ to Au 0 . There are several chemical reactions that enable the reduction of Au 3+ to Au 0 . In the protocol, Good's buffers and H2O2 are used and it is possible to favor the deposition of Au 0 onto the surface of existing nanoprobes, in detriment of the formation of new gold nanoparticles. The protocol consists of the incubation of the microarray with a solution consisting of chloroauric acid and H2O2 in 2-(N-morpholino)ethanesulfonic acid pH 6 buffer following the nanoprobe-based detection assay. The enhancement solution can be applied to paper and glass-based sensors. Moreover, it can be used in commercially available immunoassays as demonstrated by the application of the method to a commercial allergen microarray. The signal development requires less than 5 min of incubation with the enhancement solution and the readout can be assessed by naked eye or low-end image acquisition devices such as a table-top scanner or a digital camera.

  1. Optimal Noise Enhanced Signal Detection in a Unified Framework

    Directory of Open Access Journals (Sweden)

    Ting Yang

    2016-06-01

    Full Text Available In this paper, a new framework for variable detectors is formulated in order to solve different noise enhanced signal detection optimal problems, where six different disjoint sets of detector and discrete vector pairs are defined according to the two inequality-constraints on detection and false-alarm probabilities. Then theorems and algorithms constructed based on the new framework are presented to search the optimal noise enhanced solutions to maximize the relative improvements of the detection and the false-alarm probabilities, respectively. Further, the optimal noise enhanced solution of the maximum overall improvement is obtained based on the new framework and the relationship among the three maximums is presented. In addition, the sufficient conditions for improvability or non-improvability under the two certain constraints are given. Finally, numerous examples are presented to illustrate the theoretical results and the proofs of the main theorems are given in the Appendix.

  2. Cystine addiction of triple-negative breast cancer associated with EMT augmented death signaling.

    Science.gov (United States)

    Tang, X; Ding, C-K; Wu, J; Sjol, J; Wardell, S; Spasojevic, I; George, D; McDonnell, D P; Hsu, D S; Chang, J T; Chi, J-T

    2017-07-27

    Despite the advances in the diagnosis and treatment of breast cancer, breast cancers still cause significant mortality. For some patients, especially those with triple-negative breast cancer, current treatments continue to be limited and ineffective. Therefore, there remains an unmet need for a novel therapeutic approach. One potential strategy is to target the altered metabolic state that is rewired by oncogenic transformation. Specifically, this rewiring may render certain outside nutrients indispensable. To identify such a nutrient, we performed a nutrigenetic screen by removing individual amino acids to identify possible addictions across a panel of breast cancer cells. This screen revealed that cystine deprivation triggered rapid programmed necrosis, but not apoptosis, in the basal-type breast cancer cells mostly seen in TNBC tumors. In contrast, luminal-type breast cancer cells are cystine-independent and exhibit little death during cystine deprivation. The cystine addiction phenotype is associated with a higher level of cystine-deprivation signatures noted in the basal type breast cancer cells and tumors. We found that the cystine-addicted breast cancer cells and tumors have strong activation of TNFα and MEKK4-p38-Noxa pathways that render them susceptible to cystine deprivation-induced necrosis. Consistent with this model, silencing of TNFα and MEKK4 dramatically reduces cystine-deprived death. In addition, the cystine addiction phenotype can be abrogated in the cystine-addictive cells by miR-200c, which converts the mesenchymal-like cells to adopt epithelial features. Conversely, the introduction of inducers of epithelial-mesenchymal transition (EMT) in cystine-independent breast cancer cells conferred the cystine-addiction phenotype by modulating the signaling components of cystine addiction. Together, our data reveal that cystine-addiction is associated with EMT in breast cancer during tumor progression. These findings provide the genetic and

  3. Par3L enhances colorectal cancer cell survival by inhibiting Lkb1/AMPK signaling pathway

    International Nuclear Information System (INIS)

    Li, Taiyuan; Liu, Dongning; Lei, Xiong; Jiang, Qunguang

    2017-01-01

    Partitioning defective 3-like protein (Par3L) is a recently identified cell polarity protein that plays an important role in mammary stem cell maintenance. Previously, we showed that high expression of Par3L is associated with poor survival in malignant colorectal cancer (CRC), but the underlying mechanism remained unknown. To this end, we established a Par3L knockout colorectal cancer cell line using the CRISPR/Cas system. Interestingly, reduced proliferation, enhanced cell death and caspase-3 activation were observed in Par3L knockout (KO) cells as compared with wildtype (WT) cells. Consistent with previous studies, we showed that Par3L interacts with a tumor suppressor protein liver kinase B1 (Lkb1). Moreover, Par3L depletion resulted in abnormal activation of Lkb1/AMPK signaling cascade. Knockdown of Lkb1 in these cells could significantly reduce AMPK activity and partially rescue cell death caused by Par3L knockdown. Furthermore, we showed that Par3L KO cells were more sensitive to chemotherapies and irradiation. Together, these results suggest that Par3L is essential for colorectal cancer cell survival by inhibiting Lkb1/AMPK signaling pathway, and is a putative therapeutic target for CRC. - Highlights: • Par3L knockout using the CRISPR/Cas system induces apoptosis in colorectal cancer cells. • Par3L interacts with Lkb1 and regulates the activity of AMPK signaling cascade. • Par3L knockout cells are more sensitive to treatment of different chemotherapy drugs and irradiation.

  4. Engineering signal peptides for enhanced protein secretion from Lactococcus lactis.

    Science.gov (United States)

    Ng, Daphne T W; Sarkar, Casim A

    2013-01-01

    Lactococcus lactis is an attractive vehicle for biotechnological production of proteins and clinical delivery of therapeutics. In many such applications using this host, it is desirable to maximize secretion of recombinant proteins into the extracellular space, which is typically achieved by using the native signal peptide from a major secreted lactococcal protein, Usp45. In order to further increase protein secretion from L. lactis, inherent limitations of the Usp45 signal peptide (Usp45sp) must be elucidated. Here, we performed extensive mutagenesis on Usp45sp to probe the effects of both the mRNA sequence (silent mutations) and the peptide sequence (amino acid substitutions) on secretion. We screened signal peptides based on their resulting secretion levels of Staphylococcus aureus nuclease and further evaluated them for secretion of Bacillus subtilis α-amylase. Silent mutations alone gave an increase of up to 16% in the secretion of α-amylase through a mechanism consistent with relaxed mRNA folding around the ribosome binding site and enhanced translation. Targeted amino acid mutagenesis in Usp45sp, combined with additional silent mutations from the best clone in the initial screen, yielded an increase of up to 51% in maximum secretion of α-amylase while maintaining secretion at lower induction levels. The best sequence from our screen preserves the tripartite structure of the native signal peptide but increases the positive charge of the n-region. Our study presents the first example of an engineered L. lactis signal peptide with a higher secretion yield than Usp45sp and, more generally, provides strategies for further enhancing protein secretion in bacterial hosts.

  5. Algorithms for enhancing public health utility of national causes-of-death data

    Directory of Open Access Journals (Sweden)

    Pourmalek Farshad

    2010-05-01

    Full Text Available Abstract Background Coverage and quality of cause-of-death (CoD data varies across countries and time. Valid, reliable, and comparable assessments of trends in causes of death from even the best systems are limited by three problems: a changes in the International Statistical Classification of Diseases and Related Health Problems (ICD over time; b the use of tabulation lists where substantial detail on causes of death is lost; and c many deaths assigned to causes that cannot or should not be considered underlying causes of death, often called garbage codes (GCs. The Global Burden of Disease Study and the World Health Organization have developed various methods to enhance comparability of CoD data. In this study, we attempt to build on these approaches to enhance the utility of national cause-of-death data for public health analysis. Methods Based on careful consideration of 4,434 country-years of CoD data from 145 countries from 1901 to 2008, encompassing 743 million deaths in ICD versions 1 to 10 as well as country-specific cause lists, we have developed a public health-oriented cause-of-death list. These 56 causes are organized hierarchically and encompass all deaths. Each cause has been mapped from ICD-6 to ICD-10 and, where possible, they have also been mapped to the International List of Causes of Death 1-5. We developed a typology of different classes of GCs. In each ICD revision, GCs have been identified. Target causes to which these GCs should be redistributed have been identified based on certification practice and/or pathophysiology. Proportionate redistribution, statistical models, and expert algorithms have been developed to redistribute GCs to target codes for each age-sex group. Results The fraction of all deaths assigned to GCs varies tremendously across countries and revisions of the ICD. In general, across all country-years of data available, GCs have declined from more than 43% in ICD-7 to 24% in ICD-10. In some regions, such

  6. Mind Bomb Regulates Cell Death during TNF Signaling by Suppressing RIPK1’s Cytotoxic Potential

    Directory of Open Access Journals (Sweden)

    Rebecca Feltham

    2018-04-01

    Full Text Available Summary: Tumor necrosis factor (TNF is an inflammatory cytokine that can signal cell survival or cell death. The mechanisms that switch between these distinct outcomes remain poorly defined. Here, we show that the E3 ubiquitin ligase Mind Bomb-2 (MIB2 regulates TNF-induced cell death by inactivating RIPK1 via inhibitory ubiquitylation. Although depletion of MIB2 has little effect on NF-κB activation, it sensitizes cells to RIPK1- and caspase-8-dependent cell death. We find that MIB2 represses the cytotoxic potential of RIPK1 by ubiquitylating lysine residues in the C-terminal portion of RIPK1. Our data suggest that ubiquitin conjugation of RIPK1 interferes with RIPK1 oligomerization and RIPK1-FADD association. Disruption of MIB2-mediated ubiquitylation, either by mutation of MIB2’s E3 activity or RIPK1’s ubiquitin-acceptor lysines, sensitizes cells to RIPK1-mediated cell death. Together, our findings demonstrate that Mind Bomb E3 ubiquitin ligases can function as additional checkpoint of cytokine-induced cell death, selectively protecting cells from the cytotoxic effects of TNF. : Feltham et al. show that MIB2 directly ubiquitylates RIPK1 upon TNF stimulation, suppressing the cytotoxic potential of RIPK1 and acting as a checkpoint within the TNF signaling pathway. Keywords: MIB2, RIPK1, TNF, cell death, caspase-8, IAPs, ubiquitin

  7. The TIR domain of TIR-NB-LRR resistance proteins is a signaling domain involved in cell death induction.

    Science.gov (United States)

    Swiderski, Michal R; Birker, Doris; Jones, Jonathan D G

    2009-02-01

    In plants, the TIR (toll interleukin 1 receptor) domain is found almost exclusively in nucleotide-binding (NB) leucine-rich repeat resistance proteins and their truncated homologs, and has been proposed to play a signaling role during resistance responses mediated by TIR containing R proteins. Transient expression in Nicotiana benthamiana leaves of "TIR + 80", the RPS4 truncation without the NB-ARC domain, leads to EDS1-, SGT1-, and HSP90-dependent cell death. Transgenic Arabidopsis plants expressing the RPS4 TIR+80 from either dexamethasone or estradiol-inducible promoters display inducer-dependent cell death. Cell death is also elicited by transient expression of similarly truncated constructs from two other R proteins, RPP1A and At4g19530, but is not elicited by similar constructs representing RPP2A and RPP2B proteins. Site-directed mutagenesis of the RPS4 TIR domain identified many loss-of-function mutations but also revealed several gain-of function substitutions. Lack of cell death induction by the E160A substitution suggests that amino acids outside of the TIR domain contribute to cell death signaling in addition to the TIR domain itself. This is consistent with previous observations that the TIR domain itself is insufficient to induce cell death upon transient expression.

  8. Valproic acid inhibits neural progenitor cell death by activation of NF-κB signaling pathway and up-regulation of Bcl-XL

    Directory of Open Access Journals (Sweden)

    Han Seol

    2011-07-01

    Full Text Available Abstract Background At the beginning of neurogenesis, massive brain cell death occurs and more than 50% of cells are eliminated by apoptosis along with neuronal differentiation. However, few studies were conducted so far regarding the regulation of neural progenitor cells (NPCs death during development. Because of the physiological role of cell death during development, aberration of normal apoptotic cell death is detrimental to normal organogenesis. Apoptosis occurs in not only neuron but also in NPCs and neuroblast. When growth and survival signals such as EGF or LIF are removed, apoptosis is activated as well as the induction of differentiation. To investigate the regulation of cell death during developmental stage, it is essential to investigate the regulation of apoptosis of NPCs. Methods Neural progenitor cells were cultured from E14 embryonic brains of Sprague-Dawley rats. For in vivo VPA animal model, pregnant rats were treated with VPA (400 mg/kg S.C. diluted with normal saline at E12. To analyze the cell death, we performed PI staining and PARP and caspase-3 cleavage assay. Expression level of proteins was investigated by Western blot and immunocytochemical assays. The level of mRNA expression was investigated by RT-PCR. Interaction of Bcl-XL gene promoter and NF-κB p65 was investigated by ChIP assay. Results In this study, FACS analysis, PI staining and PARP and caspase-3 cleavage assay showed that VPA protects cultured NPCs from cell death after growth factor withdrawal both in basal and staurosporine- or hydrogen peroxide-stimulated conditions. The protective effect of prenatally injected VPA was also observed in E16 embryonic brain. Treatment of VPA decreased the level of IκBα and increased the nuclear translocation of NF-κB, which subsequently enhanced expression of anti-apoptotic protein Bcl-XL. Conclusion To the best of our knowledge, this is the first report to indicate the reduced death of NPCs by VPA at developmentally

  9. Security Enhancement of Wireless Sensor Networks Using Signal Intervals

    Directory of Open Access Journals (Sweden)

    Jaegeun Moon

    2017-04-01

    Full Text Available Various wireless technologies, such as RF, Bluetooth, and Zigbee, have been applied to sensor communications. However, the applications of Bluetooth-based wireless sensor networks (WSN have a security issue. In one pairing process during Bluetooth communication, which is known as simple secure pairing (SSP, the devices are required to specify I/O capability or user interference to prevent man-in-the-middle (MITM attacks. This study proposes an enhanced SSP in which a nonce to be transferred is converted to a corresponding signal interval. The quantization level, which is used to interpret physical signal intervals, is renewed at every connection by the transferred nonce and applied to the next nonce exchange so that the same signal intervals can represent different numbers. Even if attackers eavesdrop on the signals, they cannot understand what is being transferred because they cannot determine the quantization level. Furthermore, the proposed model does not require exchanging passkeys as data, and the devices are secure in the case of using a fixed PIN. Subsequently, the new quantization level is calculated automatically whenever the same devices attempt to connect with each other. Therefore, the pairing process can be protected from MITM attacks and be convenient for users.

  10. Security Enhancement of Wireless Sensor Networks Using Signal Intervals.

    Science.gov (United States)

    Moon, Jaegeun; Jung, Im Y; Yoo, Jaesoo

    2017-04-02

    Various wireless technologies, such as RF, Bluetooth, and Zigbee, have been applied to sensor communications. However, the applications of Bluetooth-based wireless sensor networks (WSN) have a security issue. In one pairing process during Bluetooth communication, which is known as simple secure pairing (SSP), the devices are required to specify I/O capability or user interference to prevent man-in-the-middle (MITM) attacks. This study proposes an enhanced SSP in which a nonce to be transferred is converted to a corresponding signal interval. The quantization level, which is used to interpret physical signal intervals, is renewed at every connection by the transferred nonce and applied to the next nonce exchange so that the same signal intervals can represent different numbers. Even if attackers eavesdrop on the signals, they cannot understand what is being transferred because they cannot determine the quantization level. Furthermore, the proposed model does not require exchanging passkeys as data, and the devices are secure in the case of using a fixed PIN. Subsequently, the new quantization level is calculated automatically whenever the same devices attempt to connect with each other. Therefore, the pairing process can be protected from MITM attacks and be convenient for users.

  11. Ultrasonic correlator versus signal averager as a signal to noise enhancement instrument

    Science.gov (United States)

    Kishoni, Doron; Pietsch, Benjamin E.

    1989-01-01

    Ultrasonic inspection of thick and attenuating materials is hampered by the reduced amplitudes of the propagated waves to a degree that the noise is too high to enable meaningful interpretation of the data. In order to overcome the low Signal to Noise (S/N) ratio, a correlation technique has been developed. In this method, a continuous pseudo-random pattern generated digitally is transmitted and detected by piezoelectric transducers. A correlation is performed in the instrument between the received signal and a variable delayed image of the transmitted one. The result is shown to be proportional to the impulse response of the investigated material, analogous to a signal received from a pulsed system, with an improved S/N ratio. The degree of S/N enhancement depends on the sweep rate. This paper describes the correlator, and compares it to the method of enhancing S/N ratio by averaging the signals. The similarities and differences between the two are highlighted and the potential advantage of the correlator system is explained.

  12. Chloroethylating nitrosoureas in cancer therapy: DNA damage, repair and cell death signaling.

    Science.gov (United States)

    Nikolova, Teodora; Roos, Wynand P; Krämer, Oliver H; Strik, Herwig M; Kaina, Bernd

    2017-08-01

    Chloroethylating nitrosoureas (CNU), such as lomustine, nimustine, semustine, carmustine and fotemustine are used for the treatment of malignant gliomas, brain metastases of different origin, melanomas and Hodgkin disease. They alkylate the DNA bases and give rise to the formation of monoadducts and subsequently interstrand crosslinks (ICL). ICL are critical cytotoxic DNA lesions that link the DNA strands covalently and block DNA replication and transcription. As a result, S phase progression is inhibited and cells are triggered to undergo apoptosis and necrosis, which both contribute to the effectiveness of CNU-based cancer therapy. However, tumor cells resist chemotherapy through the repair of CNU-induced DNA damage. The suicide enzyme O 6 -methylguanine-DNA methyltransferase (MGMT) removes the precursor DNA lesion O 6 -chloroethylguanine prior to its conversion into ICL. In cells lacking MGMT, the formed ICL evoke complex enzymatic networks to accomplish their removal. Here we discuss the mechanism of ICL repair as a survival strategy of healthy and cancer cells and DNA damage signaling as a mechanism contributing to CNU-induced cell death. We also discuss therapeutic implications and strategies based on sequential and simultaneous treatment with CNU and the methylating drug temozolomide. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Excessive L-cysteine induces vacuole-like cell death by activating endoplasmic reticulum stress and mitogen-activated protein kinase signaling in intestinal porcine epithelial cells.

    Science.gov (United States)

    Ji, Yun; Wu, Zhenlong; Dai, Zhaolai; Sun, Kaiji; Zhang, Qing; Wu, Guoyao

    2016-01-01

    High intake of dietary cysteine is extremely toxic to animals and the underlying mechanism remains largely unknown. This study was conducted to test the hypothesis that excessive L-cysteine induces cell death by activating endoplasmic reticulum (ER) stress and mitogen-activated protein kinase (MAPK) signaling in intestinal porcine epithelial cells. Jejunal enterocytes were cultured in the presence of 0-10 mmol/L L-cysteine. Cell viability, morphologic alterations, mRNA levels for genes involved in ER stress, protein abundances for glucose-regulated protein 78, C/EBP homologous protein (CHOP), alpha subunit of eukaryotic initiation factor-2 (eIF2α), extracellular signal-regulated kinase (ERK1/2), p38 MAPK, and c-Jun N-terminal protein kinase (JNK1/2) were determined. The results showed that L-cysteine (5-10 mmol/L) reduced cell viability (P L-cysteine were not affected by the autophagy inhibitor 3-methyladenine. The protein abundances for CHOP, phosphorylated (p)-eIF2α, p-JNK1/2, p-p38 MAPK, and the spliced form of XBP-1 mRNA were enhanced (P L-cysteine induces vacuole-like cell death via the activation of ER stress and MAPK signaling in small intestinal epithelial cells. These signaling pathways may be potential targets for developing effective strategies to prevent the toxicity of dietary cysteine.

  14. Bcl-xL acts downstream of caspase-8 activation by the CD95 death-inducing signaling complex

    NARCIS (Netherlands)

    Medema, J. P.; Scaffidi, C.; Krammer, P. H.; Peter, M. E.

    1998-01-01

    The Bcl-2 family member Bcl-xL has often been correlated with apoptosis resistance. We have shown recently that in peripheral human T cells resistance to CD95-mediated apoptosis is characterized by a lack of caspase-8 recruitment to the CD95 death-inducing signaling complex (DISC) and by increased

  15. Signal quality enhancement using higher order wavelets for ultrasonic TOFD signals from austenitic stainless steel welds.

    Science.gov (United States)

    Praveen, Angam; Vijayarekha, K; Abraham, Saju T; Venkatraman, B

    2013-09-01

    Time of flight diffraction (TOFD) technique is a well-developed ultrasonic non-destructive testing (NDT) method and has been applied successfully for accurate sizing of defects in metallic materials. This technique was developed in early 1970s as a means for accurate sizing and positioning of cracks in nuclear components became very popular in the late 1990s and is today being widely used in various industries for weld inspection. One of the main advantages of TOFD is that, apart from fast technique, it provides higher probability of detection for linear defects. Since TOFD is based on diffraction of sound waves from the extremities of the defect compared to reflection from planar faces as in pulse echo and phased array, the resultant signal would be quite weak and signal to noise ratio (SNR) low. In many cases the defect signal is submerged in this noise making it difficult for detection, positioning and sizing. Several signal processing methods such as digital filtering, Split Spectrum Processing (SSP), Hilbert Transform and Correlation techniques have been developed in order to suppress unwanted noise and enhance the quality of the defect signal which can thus be used for characterization of defects and the material. Wavelet Transform based thresholding techniques have been applied largely for de-noising of ultrasonic signals. However in this paper, higher order wavelets are used for analyzing the de-noising performance for TOFD signals obtained from Austenitic Stainless Steel welds. It is observed that higher order wavelets give greater SNR improvement compared to the lower order wavelets. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. Enhancement of new physics signal sensitivity with mistagged charm quarks

    Directory of Open Access Journals (Sweden)

    Doojin Kim

    2016-07-01

    Full Text Available We investigate the potential for enhancing search sensitivity for signals having charm quarks in the final state, using the sizable bottom-mistagging rate for charm quarks at the LHC. Provided that the relevant background processes contain light quarks instead of charm quarks, the application of b-tagging on charm quark-initiated jets enables us to reject more background events than signal ones due to the relatively small mistagging rate for light quarks. The basic idea is tested with two rare top decay processes: i t→ch→cbb¯ and ii t→bH+→bb¯c where h and H+ denote the Standard Model-like higgs boson and a charged higgs boson, respectively. The major background source is a hadronic top quark decay such as t→bW+→bs¯c. We test our method with Monte Carlo simulation at the LHC 14 TeV, and find that the signal-over-background ratio can be increased by a factor of O(6–7 with a suitably designed (heavy flavor tagging algorithm and scheme.

  17. AMRI-59 has a role of radiosensitizer via enhancement of γ-ionizing radiation-induced apoptotic cell death

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Wan Gi; Cho, Jeong Hyun; Kim, Ju Yeon; Hwang, Sang Gu; Um, Hong Duck; Park, Jong Kuk [KAERI, Daejeon (Korea, Republic of)

    2016-05-15

    Recent in vitro studies have suggested that may increase the invasiveness of some cancer cells (e.g., glioma, hepatocellular carcinoma, and pancreatic cancer cells) by stimulating several intracellular signaling pathways and in vivo studies have found that radiotherapy of primary tumor sites may promote metastasis. Thus, in addition to having therapeutic effects, IR might promote the malignant traits of surviving cancer cells. The existing efforts to develop radiosensitizing agents have focused on overcoming radioresistance and reducing damage to normal tissues. Recently, concepts of personalized- or precision medicine are developed due to advancement of mega data technique, which provide new targets to develop new anti-cancer drugs. In this study, we sought to identify the radiosensitizer effect of AMRI-59 in vitro and in vivo., which is recently developed specific inhibitor of peroxiredoxin (Prx) I. AMRI-59 enhanced radiation-induced cell death and its mean calculated dose enhancement ratio was 1.26. We also found combination of AMRI-59 and IR In a xenograft assay, the combined PHCM and radiation group showed 14.3 days of growth delay versus the control in terms of tumor growth. The enhancement factor of this combined treatment was determined to be 2.03.

  18. Signal Transduction Pathways Involved in Brain Death-Induced Renal Injury

    NARCIS (Netherlands)

    Bouma, H. R.; Ploeg, R. J.; Schuurs, T. A.

    Kidneys derived from brain death organ donors show an inferior survival when compared to kidneys derived from living donors. Brain death is known to induce organ injury by evoking an inflammatory response in the donor. Neuronal injury triggers an inflammatory response in the brain, leading to

  19. Enhancement of Single-Channel Periodic Signals in the Time-Domain

    DEFF Research Database (Denmark)

    Jensen, Jesper Rindom; Benesty, Jacob; Christensen, Mads Græsbøll

    2012-01-01

    speech. That is, signal-dependent methods based on the signal statistics will introduce undesired distortion for some parts of speech compared to signal-independent methods based on the noise statistics. Since both the signal-independent and signal-dependent approaches to speech enhancement have...

  20. Enhanced chondrogenesis and Wnt signaling in PTH-treated fractures.

    Science.gov (United States)

    Kakar, Sanjeev; Einhorn, Thomas A; Vora, Siddharth; Miara, Lincoln J; Hon, Gregory; Wigner, Nathan A; Toben, Daniel; Jacobsen, Kimberly A; Al-Sebaei, Maisa O; Song, Michael; Trackman, Philip C; Morgan, Elise F; Gerstenfeld, Louis C; Barnes, George L

    2007-12-01

    Studies have shown that systemic PTH treatment enhanced the rate of bone repair in rodent models. However, the mechanisms through which PTH affects bone repair have not been elucidated. In these studies we show that PTH primarily enhanced the earliest stages of endochondral bone repair by increasing chondrocyte recruitment and rate of differentiation. In coordination with these cellular events, we observed an increased level of canonical Wnt-signaling in PTH-treated bones at multiple time-points across the time-course of fracture repair, supporting the conclusion that PTH responses are at least in part mediated through Wnt signaling. Since FDA approval of PTH [PTH(1-34); Forteo] as a treatment for osteoporosis, there has been interest in its use in other musculoskeletal conditions. Fracture repair is one area in which PTH may have a significant clinical impact. Multiple animal studies have shown that systemic PTH treatment of healing fractures increased both callus volume and return of mechanical competence in models of fracture healing. Whereas the potential for PTH has been established, the mechanism(s) by which PTH produces these effects remain elusive. Closed femoral fractures were generated in 8-wk-old male C57Bl/6 mice followed by daily systemic injections of either saline (control) or 30 microg/kg PTH(1-34) for 14 days after fracture. Bones were harvested at days 2, 3, 5, 7, 10, 14, 21, and 28 after fracture and analyzed at the tissue level by radiography and histomorphometry and at the molecular and biochemical levels level by RNase protection assay (RPA), real-time PCR, and Western blot analysis. Quantitative muCT analysis showed that PTH treatment induced a larger callus cross-sectional area, length, and total volume compared with controls. Molecular analysis of the expression of extracellular matrix genes associated with chondrogenesis and osteogenesis showed that PTH treated fractures displayed a 3-fold greater increase in chondrogenesis relative to

  1. Absence of Doppler signal in transcranial color-coded ultrasonography may be confirmatory for brain death: A case report

    Directory of Open Access Journals (Sweden)

    Mehmet Akif Topçuoğlu

    2015-08-01

    Full Text Available Transcranial Doppler ultrasonography (TCD is a valuable tool for demonstrating cerebral circulatory arrest (CCA in the setting of brain death. Complete reversal of diastolic flow (to-and-fro flow and systolic spikes in bilateral terminal internal carotid arteries and vertebrobasilar circulation are considered as specific sonogram configurations supporting the diagnosis of CCA. Because of the possibility of sonic bone window impermeability, absence of any waveform in TCD is not confirmatory for CCA unless there is documentation of disappearance of a previously well detected signal by the same recording settings. Transcranial color-coded sonography (TCCS with B-mode imaging can reliably detect adequacy of bone windows with clarity contralateral skull and ipsilateral planum temporale visualization. Therefore, absence of detectable intracranial Doppler signal along with available ultrasound window in TCCS can confirm clinical diagnosis of brain death. We herein discuss this entity from the frame of a representative case.

  2. The combination of MLN2238 (ixazomib) with interferon-alpha results in enhanced cell death in melanoma.

    Science.gov (United States)

    Suarez-Kelly, Lorena P; Kemper, Gregory M; Duggan, Megan C; Stiff, Andrew; Noel, Tiffany C; Markowitz, Joseph; Luedke, Eric A; Yildiz, Vedat O; Yu, Lianbo; Jaime-Ramirez, Alena Cristina; Karpa, Volodymyr; Zhang, Xiaoli; Carson, William E

    2016-12-06

    The ubiquitin-proteasome signaling pathway is critical for cell cycle regulation and neoplastic growth. Proteasome inhibition can activate apoptotic pathways. Bortezomib, a selective proteasome inhibitor, has anti-melanoma activity. MLN2238 (ixazomib), an oral proteasome inhibitor, has improved pharmacotherapeutic parameters compared to bortezomib. Interferon-alpha (IFN-α), an immune boosting agent, is FDA-approved for treatment of melanoma. In this study in vitro and in vivo evaluation of the antitumor potential of ixazomib and combination treatments with ixazomib and IFN-α were performed. Apoptosis induced by ixazomib was first observed at 12 hours and was maximal at 48 hours with similar levels of cell death compared to bortezomib. IFN-α alone had little effect on cell viability in vitro. However, the combination of ixazomib with IFN-α significantly enhanced ixazomib's ability to induce apoptotic cell death in BRAF V600E mutant and BRAF wild-type human melanoma tumor cells. The combination of ixazomib and IFN-α also enhanced inhibition of cell proliferation in BRAF V600E mutant melanoma tumor cells; however, this was not seen in BRAF wild-type cells. Ixazomib-induced apoptosis was associated with processing of the pro-apoptotic proteins procaspase-3, -7, -8, and -9, and cleavage of poly-ADP-ribose polymerase (PARP). In an in vivo xenograft model of human melanoma, combination treatment with IFN-α-2b and ixazomib demonstrated a significant reduction in tumor volume when compared to vehicle (p = 0.005) and single therapy ixazomib (p = 0.017) and IFN-α-2b (p = 0.036). These pre-clinical results support further evaluation of combination treatment with ixazomib and IFN-α for the treatment of advanced BRAF V600E mutant melanoma.

  3. ERK controls epithelial cell death receptor signalling and cellular FLICE-like inhibitory protein (c-FLIP) in ulcerative colitis

    DEFF Research Database (Denmark)

    Seidelin, Jakob Benedict; Coskun, Mehmet; Vainer, Ben

    2013-01-01

    Intestinal epithelial cell (IEC) death signalling through the Fas receptor is impaired in active ulcerative colitis (UC). This is possibly due to the activation of cytoprotective pathways resulting in limitation of the tissue injury secondary to inflammation. We hypothesized that inflammatory...... the resistance to receptor mediated epithelial apoptosis in active UC. Oncogenic c-FLIP could promote propagation of DNA-damaged IECs and contribute to cancer development in UC....

  4. Chloroplasts activity and PAP-signaling regulate programmed cell death in Arabidopsis

    KAUST Repository

    Bruggeman, Quentin; Mazubert, Christelle; Prunier, Florence; Lugan, Raphael; Chan, Kai Xun; Phua, Su Yin; Pogson, Barry J.; Krieger-Liszkay, Anja; Delarue, Marianne; Benhamed, Moussa; Bergounioux, Catherine; Raynaud, Cé cile

    2016-01-01

    Programmed cell death (PCD) is a crucial process both for plant development and responses to biotic and abiotic stress. There is accumulating evidence that chloroplasts may play a central role during plant PCD as for mitochondria in animal cells

  5. Quorum Sensing Extracellular Death Peptides Enhance the Endoribonucleolytic Activities of Mycobacterium tuberculosis MazF Toxins

    Science.gov (United States)

    Nigam, Akanksha; Kumar, Sathish

    2018-01-01

    ABSTRACT mazEF is a toxin-antitoxin module located on chromosomes of most bacteria. MazF toxins are endoribonucleases antagonized by MazE antitoxins. Previously, we characterized several quorum sensing peptides called "extracellular death factors" (EDFs). When secreted from bacterial cultures, EDFs induce interspecies cell death. EDFs also enhance the endoribonucleolytic activity of Escherichia coli MazF. Mycobacterium tuberculosis carries several mazEF modules. Among them, the endoribonucleolytic activities of MazF proteins mt-1, mt-3, and mt-6 were identified. MazF-mt6 and MazF-mt-3 cleave M. tuberculosis rRNAs. Here we report the in vitro effects of EDFs on the endoribonucleolytic activities of M. tuberculosis MazFs. Escherichia coli EDF (EcEDF) and the three Pseudomonas aeruginosa EDFs (PaEDFs) individually enhance the endoribonucleolytic activities of MazF-mt6 and MazF-mt3 and overcome the inhibitory effect of MazE-mt3 or MazE-mt6 on the endoribonucleolytic activities of the respective toxins. We propose that these EDFs can serve as a basis for a novel class of antibiotics against M. tuberculosis. PMID:29717013

  6. Niclosamide enhances ROS-mediated cell death through c-Jun activation.

    Science.gov (United States)

    Lee, Sae-lo-oom; Son, A-Rang; Ahn, Jiyeon; Song, Jie-Young

    2014-06-01

    Radiotherapy is an effective treatment modality in the clinical treatment of cancers, and has been combined with chemotherapy in order to improve therapeutic efficacy. Therefore, we aimed to develop small molecules that enhance the cytotoxic effects of radiotherapy. In this study, we provide evidence that niclosamide is an effective radiosensitizer in non-small cell lung cancer cells. Using a cell-based high-throughput viability screen of 1040 compounds in combination with γ-ionizing radiation (IR), we found niclosamide, an FDA-approved antihelminthic agent, had a radiosensitizing effect on H1299 human lung cancer cells. Pretreatment with niclosamide enhanced IR- induced cell death of H1299 in a dose-dependent manner via apoptosis compared with IR or niclosamide alone. The combined treatment induced significantly more phosphorylation of p38 MAPK and c-Jun in H1299 cells than IR or niclosamide alone. Since IR induces apoptosis through generation of reactive oxygen species (ROS), hydrogen peroxide (H2O2) was employed as another ROS generator and we found that niclosamide also sensitized cells to H2O2. Niclosamide pretreatment also induced c-Jun and its phosphorylation in the presence of H2O2, thereby enhancing apoptosis. N-acetyl-L-cysteine (NAC) treatment abolished both cell death and c-Jun activation induced by the combination treatments. Knockdown of c-Jun also decreased PARP cleavage and clonogenic cell survival in niclosamide- and IR-treated H1299 cells. Our findings suggest that niclosamide could be a promising radiosensitizer in lung cancer patients through activation of the p38 MAPK-c-Jun axis. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  7. Local readout enhancement for detuned signal-recycling interferometers

    International Nuclear Information System (INIS)

    Rehbein, Henning; Mueller-Ebhardt, Helge; Schnabel, Roman; Danzmann, Karsten; Somiya, Kentaro; Chen Yanbei; Li Chao

    2007-01-01

    High power detuned signal-recycling interferometers currently planned for second-generation interferometric gravitational-wave detectors (for example Advanced LIGO) are characterized by two resonances in the detection band, an optical resonance and an optomechanical resonance which is upshifted from the suspension pendulum frequency due to the so-called optical-spring effect. The detector's sensitivity is enhanced around these two resonances. However, at frequencies below the optomechanical resonance frequency, the sensitivity of such interferometers is significantly lower than non-optical-spring configurations with comparable circulating power; such a drawback can also compromise high-frequency sensitivity, when an optimization is performed on the overall sensitivity of the interferometer to a class of sources. In this paper, we clarify the reason for such a low sensitivity, and propose a way to fix this problem. Motivated by the optical-bar scheme of Braginsky, Gorodetsky, and Khalili, we propose to add a local readout scheme which measures the motion of the arm-cavity front mirror, which at low frequencies moves together with the arm-cavity end mirror, under the influence of gravitational waves. This scheme improves the low-frequency quantum-noise-limited sensitivity of optical-spring interferometers significantly and can be considered as an incorporation of the optical-bar scheme into currently planned second-generation interferometers. On the other hand it can be regarded as an extension of the optical-bar scheme. Taking compact binary inspiral signals as an example, we illustrate how this scheme can be used to improve the sensitivity of the planned Advanced LIGO interferometer, in various scenarios, using a realistic classical-noise budget. We also discuss how this scheme can be implemented in Advanced LIGO with relative ease

  8. The Fas-associated death domain protein/caspase-8/c-FLIP signaling pathway is involved in TNF-induced activation of ERK

    International Nuclear Information System (INIS)

    Lueschen, Silke; Falk, Markus; Scherer, Gudrun; Ussat, Sandra; Paulsen, Maren; Adam-Klages, Sabine

    2005-01-01

    The cytokine TNF activates multiple signaling pathways leading to cellular responses ranging from proliferation and survival to apoptosis. While most of these pathways have been elucidated in detail over the past few years, the molecular mechanism leading to the activation of the MAP kinases ERK remains ill defined and is controversially discussed. Therefore, we have analyzed TNF-induced ERK activation in various human and murine cell lines and show that it occurs in a cell-type-specific manner. In addition, we provide evidence for the involvement of the signaling components Fas-associated death domain protein (FADD), caspase-8, and c-FLIP in the pathway activating ERK in response to TNF. This conclusion is based on the following observations: (I) Overexpression of FADD, caspase-8, or a c-FLIP protein containing the death effector domains only leads to enhanced and prolonged ERK activation after TNF treatment. (II) TNF-induced ERK activation is strongly diminished in the absence of FADD. Interestingly, the enzymatic function of caspase-8 is not required for TNF-induced ERK activation. Additional evidence suggests a role for this pathway in the proliferative response of murine fibroblasts to TNF

  9. Cell surface-bound TIMP3 induces apoptosis in mesenchymal Cal78 cells through ligand-independent activation of death receptor signaling and blockade of survival pathways.

    Directory of Open Access Journals (Sweden)

    Christina Koers-Wunrau

    Full Text Available BACKGROUND: The matrix metalloproteinases (MMPs and their endogenous regulators, the tissue inhibitor of metalloproteinases (TIMPs 1-4 are responsible for the physiological remodeling of the extracellular matrix (ECM. Among all TIMPs, TIMP3 appears to play a unique role since TIMP3 is a secreted protein and, unlike the other TIMP family members, is tightly bound to the ECM. Moreover TIMP3 has been shown to be able to induce apoptotic cell death. As little is known about the underlying mechanisms, we set out to investigate the pro-apoptotic effect of TIMP3 in human mesenchymal cells. METHODOLOGY/PRINCIPAL FINDINGS: Lentiviral overexpression of TIMP3 in mesenchymal cells led to a strong dose-dependent induction of ligand-independent apoptosis as reflected by a five-fold increase in caspase 3 and 7 activity compared to control (pLenti6/V5-GW/lacZ or uninfected cells, whereas exogenous TIMP3 failed to induce apoptosis. Concordantly, increased cleavage of death substrate PARP and the caspases 3 and 7 was observed in TIMP3 overexpressing cultures. Notably, activation of caspase-8 but not caspase-9 was observed in TIMP3-overexpressing cells, indicating a death receptor-dependent mechanism. Moreover, overexpression of TIMP3 led to a further induction of apoptosis after stimulation with TNF-alpha, FasL and TRAIL. Most interestingly, TIMP3-overexpression was associated with a decrease in phosphorylation of cRaf, extracellular signal-regulated protein kinase (Erk1/2, ribosomal S6 kinase (RSK1 and Akt and serum deprivation of TIMP3-overexpressing cells resulted in a distinct enhancement of apoptosis, pointing to an impaired signaling of serum-derived survival factors. Finally, heparinase treatment of heparan sulfate proteoglycans led to the release of TIMP3 from the surface of overexpressing cells and to a significant decrease in apoptosis indicating that the binding of TIMP3 is necessary for apoptosis induction. CONCLUSION: The results demonstrate that

  10. Quantitative ultrasound characterization of tumor cell death: ultrasound-stimulated microbubbles for radiation enhancement.

    Directory of Open Access Journals (Sweden)

    Hyunjung Christina Kim

    Full Text Available The aim of this study was to assess the efficacy of quantitative ultrasound imaging in characterizing cancer cell death caused by enhanced radiation treatments. This investigation focused on developing this ultrasound modality as an imaging-based non-invasive method that can be used to monitor therapeutic ultrasound and radiation effects. High-frequency (25 MHz ultrasound was used to image tumor responses caused by ultrasound-stimulated microbubbles in combination with radiation. Human prostate xenografts grown in severe combined immunodeficiency (SCID mice were treated using 8, 80, or 1000 µL/kg of microbubbles stimulated with ultrasound at 250, 570, or 750 kPa, and exposed to 0, 2, or 8 Gy of radiation. Tumors were imaged prior to treatment and 24 hours after treatment. Spectral analysis of images acquired from treated tumors revealed overall increases in ultrasound backscatter intensity and the spectral intercept parameter. The increase in backscatter intensity compared to the control ranged from 1.9±1.6 dB for the clinical imaging dose of microbubbles (8 µL/kg, 250 kPa, 2 Gy to 7.0±4.1 dB for the most extreme treatment condition (1000 µL/kg, 750 kPa, 8 Gy. In parallel, in situ end-labelling (ISEL staining, ceramide, and cyclophilin A staining demonstrated increases in cell death due to DNA fragmentation, ceramide-mediated apoptosis, and release of cyclophilin A as a result of cell membrane permeabilization, respectively. Quantitative ultrasound results indicated changes that paralleled increases in cell death observed from histology analyses supporting its use for non-invasive monitoring of cancer treatment outcomes.

  11. A mutation in a coproporphyrinogen III oxidase gene confers growth inhibition, enhanced powdery mildew resistance and powdery mildew-induced cell death in Arabidopsis.

    Science.gov (United States)

    Guo, Chuan-yu; Wu, Guang-heng; Xing, Jin; Li, Wen-qi; Tang, Ding-zhong; Cui, Bai-ming

    2013-05-01

    A gene encoding a coproporphyrinogen III oxidase mediates disease resistance in plants by the salicylic acid pathway. A number of genes that regulate powdery mildew resistance have been identified in Arabidopsis, such as ENHANCED DISEASE RESISTANCE 1 to 3 (EDR1 to 3). To further study the molecular interactions between the powdery mildew pathogen and Arabidopsis, we isolated and characterized a mutant that exhibited enhanced resistance to powdery mildew. The mutant also showed dramatic powdery mildew-induced cell death as well as growth defects and early senescence in the absence of pathogens. We identified the affected gene by map-based cloning and found that the gene encodes a coproporphyrinogen III oxidase, a key enzyme in the tetrapyrrole biosynthesis pathway, previously known as LESION INITIATION 2 (LIN2). Therefore, we designated the mutant lin2-2. Further studies revealed that the lin2-2 mutant also displayed enhanced resistance to Hyaloperonospora arabidopsidis (H.a.) Noco2. Genetic analysis showed that the lin2-2-mediated disease resistance and spontaneous cell death were dependent on PHYTOALEXIN DEFICIENT 4 (PAD4), SALICYLIC ACID INDUCTION-DEFICIENT 2 (SID2), and NONEXPRESSOR OF PATHOGENESIS-RELATED GENES 1 (NPR1), which are all involved in salicylic acid signaling. Furthermore, the relative expression levels of defense-related genes were induced after powdery mildew infection in the lin2-2 mutant. These data indicated that LIN2 plays an important role in cell death control and defense responses in plants.

  12. E4orf1 Enhances Glucose Uptake Independent of Proximal Insulin Signaling

    OpenAIRE

    Na, Ha-Na; Hegde, Vijay; Dubuisson, Olga; Dhurandhar, Nikhil V.

    2016-01-01

    Impaired proximal insulin signaling is often present in diabetes. Hence, approaches to enhance glucose disposal independent of proximal insulin signaling are desirable. Evidence indicates that Adenovirus-derived E4orf1 protein may offer such an approach. This study determined if E4orf1 improves insulin sensitivity and downregulates proximal insulin signaling in vivo and enhances cellular glucose uptake independent of proximal insulin signaling in vitro. High fat fed mice were injected with a ...

  13. Hyperthermia enhances radiosensitivity of colorectal cancer cells through ROS inducing autophagic cell death.

    Science.gov (United States)

    Ba, Ming-Chen; Long, Hui; Wang, Shuai; Wu, Yin-Bing; Zhang, Bo-Huo; Yan, Zhao-Fei; Yu, Fei-Hong; Cui, Shu-Zhong

    2018-04-01

    Hyperthermia (HT) enhances the anti-cancer effects of radiotherapy (RT), but the precise biochemical mechanisms involved are unclear. This study was aim to investigate if mild HT sensitizes colorectal cancer cells to RT through reactive oxygen species (ROS)-inducing autophagic cell death in a mice model of HCT116 human colorectal cancer. HCT116 mice model were randomly divided into five groups: mock group, hyperthermia group (HT), radiotherapy group (RT), HT + RT group, and HT + RT +N-acetyl L-cysteine (NAC) group (HT + CT + NAC). After four weeks of treatment, cancer growth inhibition, rate and mitochondrial membrane potential were measured with MTT and JC-1 assays, respectively, while ROS were estimated fluorimetrically. The relationship of these parameters to expressions of autophagy-related genes Beclin1, LC3B, and mTOR was analyzed. Gene expression was measured by Real-Time polymerase chain reaction (RT-PCR). There were significant increases in ROS levels and mitochondrial membrane potential in the HT + RT group. ROS levels in the HT + RT group increased more significantly than in any other group. In contrast, ROS levels in the HT + RT + NAC group were significantly decreased relative to the HT + RT group. The number of autophagic bodies in HT + RT group was higher than that of mock group. There were significant increases in the expression of Beclin1 and LC3B genes, while mTOR expression was significantly decreased in the HT + CT group. Treatment with NAC reversed the pattern of these changes. These results indicate that HT enhances the radiosensitivity of colorectal cancer cells to RT through ROS inducing autophagic cell death. © 2017 Wiley Periodicals, Inc.

  14. Programmed cell death-10 enhances proliferation and protects malignant T cells from apoptosis

    DEFF Research Database (Denmark)

    Lauenborg, Britt; Kopp, Katharina; Krejsgaard, Thorbjørn

    2010-01-01

    is associated with serine/threonine kinases and phosphatases and modulates the extracellular signal-regulated kinase pathway suggesting a role in the regulation of cellular growth. Here we provide evidence of a constitutive expression of PDCD10 in malignant T cells and cell lines from peripheral blood......, whereas an activator of Jak3 and NF-¿B, interleukin-2 (IL-2), enhances PDCD10 expression. Functional data show that PDCD10 depletion by small interfering RNA induces apoptosis and decreases proliferation of the sensitive cells. To our knowledge, these data provide the first functional link between PDCD10...

  15. Exosomal lipids impact notch signaling and induce death of human pancreatic tumoral SOJ-6 cells.

    Directory of Open Access Journals (Sweden)

    Sadia Beloribi

    Full Text Available Exosomes are of increasing interest as alternative mode of cell-to-cell communication. We previously reported that exosomes secreted by human SOJ-6 pancreatic tumor cells induce (glycoprotein ligand-independent cell death and inhibit Notch-1 pathway, this latter being particularly active during carcinogenesis and in cancer stem cells. Therefore, we asked whether exosomal lipids were key-elements for cell death and hypothesized that cholesterol-rich membrane microdomains were privileged sites of exosome interactions with tumor cells. To address these questions and based on the lipid composition of exosomes from SOJ-6 cells (Ristorcelli et al. (2008 FASEB J. 22; 3358-3369 enriched in cholesterol and sphingomyelin (lipids forming liquid-ordered phase, Lo and depleted in phospholipids (lipids forming liquid-disordered phase, Ld, we designed Synthetic Exosome-Like Nanoparticles (SELN with ratios Lo/Ld from 3.0 to 6.0 framing that of SOJ-6 cell exosomes. SELN decreased tumor cell survival, the higher the Lo/Ld ratio, the lower the cell survival. This decreased survival was due to activation of cell death with inhibition of Notch pathway. FRET analyses indicated fusions/exchanges of SELN with cell membranes. Fluorescent SELN co-localized with the ganglioside GM1 then with Rab5A, markers of lipid microdomains and of early endosomes, respectively. These interactions occurred at lipid microdomains of plasma and/or endosome membranes where the Notch-1 pathway matures. We thus demonstrated a major role for lipids in interactions between SELN and tumor cells, and in the ensued cell death. To our knowledge this is the first report on such effects of lipidic nanoparticles on tumor cell behavior. This may have implications in tumor progression.

  16. Improved stochastic resonance algorithm for enhancement of signal-to-noise ratio of high-performance liquid chromatographic signal

    International Nuclear Information System (INIS)

    Xie Shaofei; Xiang Bingren; Deng Haishan; Xiang Suyun; Lu Jun

    2007-01-01

    Based on the theory of stochastic resonance, an improved stochastic resonance algorithm with a new criterion for optimizing system parameters to enhance signal-to-noise ratio (SNR) of HPLC/UV chromatographic signal for trace analysis was presented in this study. Compared with the conventional criterion in stochastic resonance, the proposed one can ensure satisfactory SNR as well as good peak shape of chromatographic peak in output signal. Application of the criterion to experimental weak signals of HPLC/UV was investigated and the results showed an excellent quantitative relationship between different concentrations and responses

  17. Death and Survival in Streptococcus mutans: Differing Outcomes of a Quorum-Sensing Signalling Peptide

    Directory of Open Access Journals (Sweden)

    Vincent eLeung

    2015-10-01

    Full Text Available Bacteria are considered ‘social’ organisms able to communicate with one another using small hormone-like molecules (pheromones in a process called quorum-sensing. These signalling molecules increase in concentration as a function of bacterial cell density. For most human pathogens, quorum-sensing is critical for virulence and biofilm formation, and the opportunity to interfere with bacterial quorum-sensing could provide a sophisticated means for manipulating the composition of pathogenic biofilms, and possibly eradicating the infection. Streptococcus mutans is a well-characterized resident of the dental plaque biofilm, and is the major pathogen of dental caries (tooth decay. In S. mutans, its CSP quorum-sensing signalling peptide does not act as a classical quorum-sensing signal by accumulating passively in proportion to cell density. In fact, particular stresses such as those encountered in the oral cavity, induces the production of the CSP pheromone, suggesting that the pheromone most probably functions as a stress-inducible alarmone by triggering the signalling to the bacterial population to initiate an adaptive response that results in different phenotypic outcomes. This mini-review discusses two different CSP-induced phenotypes, bacterial ‘suicide’ and dormancy, and the underlying mechanisms by which S. mutans utilizes the same quorum-sensing signalling peptide to regulate two opposite phenotypes.

  18. Blockade of PD-1 Signaling Enhances Th2 Cell Responses and Aggravates Liver Immunopathology in Mice with Schistosomiasis japonica.

    Directory of Open Access Journals (Sweden)

    Sha Zhou

    2016-10-01

    Full Text Available More than 220 million people worldwide are chronically infected with schistosomes, causing severe disease or even death. The major pathological damage occurring in schistosomiasis is attributable to the granulomatous inflammatory response and liver fibrosis induced by schistosome eggs. The inflammatory response is tightly controlled and parallels immunosuppressive regulation, constantly maintaining immune homeostasis and limiting excessive immunopathologic damage in important host organs. It is well known that the activation of programmed death 1 (PD-1 signaling causes a significant suppression of T cell function. However, the roles of PD-1 signaling in modulating CD4+ T cell responses and immunopathology during schistosome infection, have yet to be defined.Here, we show that PD-1 is upregulated in CD4+ T cells in Schistosoma japonicum (S. japonicum-infected patients. We also show the upregulation of PD-1 expression in CD4+ T cells in the spleens, mesenteric lymph nodes, and livers of mice with S. japonicum infection. Finally, we found that the blockade of PD-1 signaling enhanced CD4+ T helper 2 (Th2 cell responses and led to more severe liver immunopathology in mice with S. japonicum infection, without a reduction of egg production or deposition in the host liver.Overall, our study suggests that PD-1 signaling is specifically induced to control Th2-associated inflammatory responses during schistosome infection and is beneficial to the development of PD-1-based control of liver immunopathology.

  19. A novel Arabidopsis CHITIN ELICITOR RECEPTOR KINASE 1 (CERK1) mutant with enhanced pathogen-induced cell death and altered receptor processing.

    Science.gov (United States)

    Petutschnig, Elena K; Stolze, Marnie; Lipka, Ulrike; Kopischke, Michaela; Horlacher, Juliane; Valerius, Oliver; Rozhon, Wilfried; Gust, Andrea A; Kemmerling, Birgit; Poppenberger, Brigitte; Braus, Gerhard H; Nürnberger, Thorsten; Lipka, Volker

    2014-12-01

    Plants detect pathogens by sensing microbe-associated molecular patterns (MAMPs) through pattern recognition receptors. Pattern recognition receptor complexes also have roles in cell death control, but the underlying mechanisms are poorly understood. Here, we report isolation of cerk1-4, a novel mutant allele of the Arabidopsis chitin receptor CERK1 with enhanced defense responses. We identified cerk1-4 in a forward genetic screen with barley powdery mildew and consequently characterized it by pathogen assays, mutant crosses and analysis of defense pathways. CERK1 and CERK1-4 proteins were analyzed biochemically. The cerk1-4 mutation causes an amino acid exchange in the CERK1 ectodomain. Mutant plants maintain chitin signaling capacity but exhibit hyper-inducible salicylic acid concentrations and deregulated cell death upon pathogen challenge. In contrast to chitin signaling, the cerk1-4 phenotype does not require kinase activity and is conferred by the N-terminal part of the receptor. CERK1 undergoes ectodomain shedding, a well-known process in animal cell surface proteins. Wild-type plants contain the full-length CERK1 receptor protein as well as a soluble form of the CERK1 ectodomain, whereas cerk1-4 plants lack the N-terminal shedding product. Our work suggests that CERK1 may have a chitin-independent role in cell death control and is the first report of ectodomain shedding in plants. © 2014 The Authors. New Phytologist © 2014 New Phytologist Trust.

  20. Cytotoxic Vibrio T3SS1 Rewires Host Gene Expression to Subvert Cell Death Signaling and Activate Cell Survival Networks

    Science.gov (United States)

    De Nisco, Nicole J.; Kanchwala, Mohammed; Li, Peng; Fernandez, Jessie; Xing, Chao; Orth, Kim

    2017-01-01

    Bacterial effectors are potent manipulators of host signaling pathways. The marine bacterium Vibrio parahaemolyticus (V. para), delivers effectors into host cells through two type three secretion systems (T3SS). The ubiquitous T3SS1 is vital for V. para survival in the environment, whereas T3SS2 causes acute gastroenteritis in human hosts. Although the natural host is undefined, T3SS1 effectors attack highly conserved cellular processes and pathways to orchestrate non-apoptotic cell death. Much is known about how T3SS1 effectors function in isolation, but we wanted to understand how their concerted action globally affects host cell signaling. To assess the host response to T3SS1, we compared gene expression changes over time in primary fibroblasts infected with V. para that have a functional T3SS1 (T3SS1+) to those in cells infected with V. para lacking T3SS1 (T3SS1−). Overall, the host transcriptional response to both T3SS1+ and T3SS1− V. para was rapid, robust, and temporally dynamic. T3SS1 re-wired host gene expression by specifically altering the expression of 398 genes. Although T3SS1 effectors target host cells at the posttranslational level to cause cytotoxicity, network analysis indicated that V. para T3SS1 also precipitates a host transcriptional response that initially activates cell survival and represses cell death networks. The increased expression of several key pro-survival transcripts mediated by T3SS1 was dependent on a host signaling pathway that is silenced later in infection by the posttranslational action of T3SS1. Taken together, our analysis reveals a complex interplay between roles of T3SS1 as both a transcriptional and posttranslational manipulator of host cell signaling. PMID:28512145

  1. Death-associated protein kinase (DAPK) and signal transduction: regulation in cancer.

    Science.gov (United States)

    Michie, Alison M; McCaig, Alison M; Nakagawa, Rinako; Vukovic, Milica

    2010-01-01

    Death-associated protein kinase (DAPK) is a pro-apoptotic serine/threonine protein kinase that is dysregulated in a wide variety of cancers. The mechanism by which this occurs has largely been attributed to promoter hypermethylation, which results in gene silencing. However, recent studies indicate that DAPK expression can be detected in some cancers, but its function is still repressed, suggesting that DAPK activity can be subverted at a post-translational level in cancer cells. This review will focus on recent data describing potential mechanisms that may alter the expression, regulation or function of DAPK.

  2. Cyclic programmed cell death stimulates hormone signaling and root development in Arabidopsis

    NARCIS (Netherlands)

    Xuan, Wei; Band, Leah R.; Kumpf, Robert P.; Rybel, De Bert

    2016-01-01

    The plant root cap, surrounding the very tip of the growing root, perceives and transmits environmental signals to the inner root tissues. In Arabidopsis thaliana, auxin released by the root cap contributes to the regular spacing of lateral organs along the primary root axis. Here, we show that

  3. Mutation in Rice Abscisic Acid2 Results in Cell Death, Enhanced Disease-Resistance, Altered Seed Dormancy and Development

    Directory of Open Access Journals (Sweden)

    Yongxiang Liao

    2018-03-01

    Full Text Available Lesion mimic mutants display spontaneous cell death, and thus are valuable for understanding the molecular mechanism of cell death and disease resistance. Although a lot of such mutants have been characterized in rice, the relationship between lesion formation and abscisic acid (ABA synthesis pathway is not reported. In the present study, we identified a rice mutant, lesion mimic mutant 9150 (lmm9150, exhibiting spontaneous cell death, pre-harvest sprouting, enhanced growth, and resistance to rice bacterial and blast diseases. Cell death in the mutant was accompanied with excessive accumulation of H2O2. Enhanced disease resistance was associated with cell death and upregulation of defense-related genes. Map-based cloning identified a G-to-A point mutation resulting in a D-to-N substitution at the amino acid position 110 of OsABA2 (LOC_Os03g59610 in lmm9150. Knock-out of OsABA2 through CRISPR/Cas9 led to phenotypes similar to those of lmm9150. Consistent with the function of OsABA2 in ABA biosynthesis, ABA level in the lmm9150 mutant was significantly reduced. Moreover, exogenous application of ABA could rescue all the mutant phenotypes of lmm9150. Taken together, our data linked ABA deficiency to cell death and provided insight into the role of ABA in rice disease resistance.

  4. Mutation in Rice Abscisic Acid2 Results in Cell Death, Enhanced Disease-Resistance, Altered Seed Dormancy and Development.

    Science.gov (United States)

    Liao, Yongxiang; Bai, Que; Xu, Peizhou; Wu, Tingkai; Guo, Daiming; Peng, Yongbin; Zhang, Hongyu; Deng, Xiaoshu; Chen, Xiaoqiong; Luo, Ming; Ali, Asif; Wang, Wenming; Wu, Xianjun

    2018-01-01

    Lesion mimic mutants display spontaneous cell death, and thus are valuable for understanding the molecular mechanism of cell death and disease resistance. Although a lot of such mutants have been characterized in rice, the relationship between lesion formation and abscisic acid (ABA) synthesis pathway is not reported. In the present study, we identified a rice mutant, lesion mimic mutant 9150 ( lmm9150 ), exhibiting spontaneous cell death, pre-harvest sprouting, enhanced growth, and resistance to rice bacterial and blast diseases. Cell death in the mutant was accompanied with excessive accumulation of H 2 O 2 . Enhanced disease resistance was associated with cell death and upregulation of defense-related genes. Map-based cloning identified a G-to-A point mutation resulting in a D-to-N substitution at the amino acid position 110 of OsABA2 (LOC_Os03g59610) in lmm9150 . Knock-out of OsABA2 through CRISPR/Cas9 led to phenotypes similar to those of lmm9150 . Consistent with the function of OsABA2 in ABA biosynthesis, ABA level in the lmm9150 mutant was significantly reduced. Moreover, exogenous application of ABA could rescue all the mutant phenotypes of lmm9150 . Taken together, our data linked ABA deficiency to cell death and provided insight into the role of ABA in rice disease resistance.

  5. Enhanced Phosphoproteomic Profiling Workflow For Growth Factor Signaling Analysis

    DEFF Research Database (Denmark)

    Sylvester, Marc; Burbridge, Mike; Leclerc, Gregory

    2010-01-01

    Background Our understanding of complex signaling networks is still fragmentary. Isolated processes have been studied extensively but cross-talk is omnipresent and precludes intuitive predictions of signaling outcomes. The need for quantitative data on dynamic systems is apparent especially for our...... understanding of pathological processes. In our study we create and integrate data on phosphorylations that are initiated by several growth factor receptors. We present an approach for quantitative, time-resolved phosphoproteomic profiling that integrates the important contributions by phosphotyrosines. Methods...

  6. Kaempferol induces autophagic cell death of hepatocellular carcinoma cells via activating AMPK signaling.

    Science.gov (United States)

    Han, Bing; Yu, Yi-Qun; Yang, Qi-Lian; Shen, Chun-Ying; Wang, Xiao-Juan

    2017-10-17

    In the present study, we demonstrate that Kaempferol inhibited survival and proliferation of established human hepatocellular carcinoma (HCC) cell lines (HepG2, Huh-7, BEL7402, and SMMC) and primary human HCC cells. Kaempferol treatment in HCC cells induced profound AMP-activated protein kinase (AMPK) activation, which led to Ulk1 phosphorylation, mTOR complex 1 inhibition and cell autophagy. Autophagy induction was reflected by Beclin-1/autophagy gene 5 upregulation and p62 degradation as well as light chain 3B (LC3B)-I to LC3B-II conversion and LC3B puncta formation. Inhibition of AMPK, via AMPKα1 shRNA or dominant negative mutation, reversed above signaling changes. AMPK inhibition also largely inhibited Kaempferol-induced cytotoxicity in HCC cells. Autophagy inhibition, by 3-methyaldenine or Beclin-1 shRNA, also protected HCC cells from Kaempferol. Kaempferol downregulated melanoma antigen 6, the AMPK ubiquitin ligase, causing AMPKα1 stabilization and accumulation. We conclude that Kaempferol inhibits human HCC cells via activating AMPK signaling.

  7. The Inhibition of microRNA-128 on IGF-1-Activating mTOR Signaling Involves in Temozolomide-Induced Glioma Cell Apoptotic Death.

    Directory of Open Access Journals (Sweden)

    Peng-Hsu Chen

    Full Text Available Temozolomide (TMZ, an alkylating agent of the imidazotetrazine series, is a first-line chemotherapeutic drug used in the clinical therapy of glioblastoma multiforme, the most common and high-grade primary glioma in adults. Micro (miRNAs, which are small noncoding RNAs, post-transcriptionally regulate gene expressions and are involved in gliomagenesis. However, no studies have reported relationships between TMZ and miRNA gene regulation. We investigated TMZ-mediated miRNA profiles and its molecular mechanisms underlying the induction of glioma cell death. By performing miRNA microarray and bioinformatics analyses, we observed that expression of 248 miRNAs was altered, including five significantly upregulated and 17 significantly downregulated miRNAs, in TMZ-treated U87MG cells. miR-128 expression levels were lower in different glioma cells and strongly associated with poor survival. TMZ treatment significantly upregulated miR-128 expression. TMZ significantly enhanced miR-128-1 promoter activity and transcriptionally regulated miR-128 levels through c-Jun N-terminal kinase 2/c-Jun pathways. The overexpression and knockdown of miR-128 expression significantly affected TMZ-mediated cell viability and apoptosis-related protein expression. Furthermore, the overexpression of miR-128 alone enhanced apoptotic death of glioma cells through caspase-3/9 activation, poly(ADP ribose polymerase degradation, reactive oxygen species generation, mitochondrial membrane potential loss, and non-protective autophagy formation. Finally, we identified that key members in mammalian target of rapamycin (mTOR signaling including mTOR, rapamycin-insensitive companion of mTOR, insulin-like growth factor 1, and PIK3R1, but not PDK1, were direct target genes of miR-128. TMZ inhibited mTOR signaling through miR-128 regulation. These results indicate that miR-128-inhibited mTOR signaling is involved in TMZ-mediated cytotoxicity. Our findings may provide a better understanding

  8. Signal intensity enhancement of laser ablated volume holograms

    Science.gov (United States)

    Versnel, J. M.; Williams, C.; Davidson, C. A. B.; Wilkinson, T. D.; Lowe, C. R.

    2017-11-01

    Conventional volume holographic gratings (VHGs) fabricated in photosensitive emulsions such as gelatin containing silver salts enable the facile visualization of the holographic image in ambient lighting. However, for the fabrication of holographic sensors, which require more defined and chemically-functionalised polymer matrices, laser ablation has been introduced to create the VHGs and thereby broaden their applications, although the replay signal can be challenging to detect in ambient lighting. When traditional photochemical bleaching solutions used to reduce light scattering and modulate refractive index within the VHG are applied to laser ablated volume holographic gratings, these procedures decrease the holographic peak intensity. This is postulated to occur because both light and dark fringes contain a proportion of metal particles, which upon solubilisation are converted immediately to silver iodide, yielding no net refractive index modulation. This research advances a hypothesis that the reduced intensity of holographic replay signals is linked to a gradient of different sized metal particles within the emulsion, which reduces the holographic signal and may explain why traditional bleaching processes result in a reduction in intensity. In this report, a novel experimental protocol is provided, along with simulations based on an effective medium periodic 1D stack, that offers a solution to increase peak signal intensity of holographic sensors by greater than 200%. Nitric acid is used to etch the silver nanoparticles within the polymer matrix and is thought to remove the smaller particles to generate more defined metal fringes containing a soluble metal salt. Once the grating efficiency has been increased, this salt can be converted to a silver halide, to modulate the refractive index and increase the intensity of the holographic signal. This new protocol has been tested in a range of polymer chemistries; those containing functional groups that help to

  9. E4orf1 Enhances Glucose Uptake Independent of Proximal Insulin Signaling.

    Science.gov (United States)

    Na, Ha-Na; Hegde, Vijay; Dubuisson, Olga; Dhurandhar, Nikhil V

    2016-01-01

    Impaired proximal insulin signaling is often present in diabetes. Hence, approaches to enhance glucose disposal independent of proximal insulin signaling are desirable. Evidence indicates that Adenovirus-derived E4orf1 protein may offer such an approach. This study determined if E4orf1 improves insulin sensitivity and downregulates proximal insulin signaling in vivo and enhances cellular glucose uptake independent of proximal insulin signaling in vitro. High fat fed mice were injected with a retrovirus plasmid expressing E4orf1, or a null vector. E4orf1 significantly improved insulin sensitivity in response to a glucose load. Yet, their proximal insulin signaling in fat depots was impaired, as indicated by reduced tyrosine phosphorylation of insulin receptor (IR), and significantly increased abundance of ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1). In 3T3-L1 pre-adipocytes E4orf1 expression impaired proximal insulin signaling. Whereas, treatment with rosiglitazone reduced ENPP1 abundance. Unaffected by IR-KD (insulin receptor knockdown) with siRNA, E4orf1 significantly up-regulated distal insulin signaling pathway and enhanced cellular glucose uptake. In vivo, E4orf1 impairs proximal insulin signaling in fat depots yet improves glycemic control. This is probably explained by the ability of E4orf1 to promote cellular glucose uptake independent of proximal insulin signaling. E4orf1 may provide a therapeutic template to enhance glucose disposal in the presence of impaired proximal insulin signaling.

  10. E4orf1 Enhances Glucose Uptake Independent of Proximal Insulin Signaling.

    Directory of Open Access Journals (Sweden)

    Ha-Na Na

    Full Text Available Impaired proximal insulin signaling is often present in diabetes. Hence, approaches to enhance glucose disposal independent of proximal insulin signaling are desirable. Evidence indicates that Adenovirus-derived E4orf1 protein may offer such an approach. This study determined if E4orf1 improves insulin sensitivity and downregulates proximal insulin signaling in vivo and enhances cellular glucose uptake independent of proximal insulin signaling in vitro. High fat fed mice were injected with a retrovirus plasmid expressing E4orf1, or a null vector. E4orf1 significantly improved insulin sensitivity in response to a glucose load. Yet, their proximal insulin signaling in fat depots was impaired, as indicated by reduced tyrosine phosphorylation of insulin receptor (IR, and significantly increased abundance of ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1. In 3T3-L1 pre-adipocytes E4orf1 expression impaired proximal insulin signaling. Whereas, treatment with rosiglitazone reduced ENPP1 abundance. Unaffected by IR-KD (insulin receptor knockdown with siRNA, E4orf1 significantly up-regulated distal insulin signaling pathway and enhanced cellular glucose uptake. In vivo, E4orf1 impairs proximal insulin signaling in fat depots yet improves glycemic control. This is probably explained by the ability of E4orf1 to promote cellular glucose uptake independent of proximal insulin signaling. E4orf1 may provide a therapeutic template to enhance glucose disposal in the presence of impaired proximal insulin signaling.

  11. Growth-hormone-induced signal transducer and activator of transcription 5 signaling causes gigantism, inflammation, and premature death but protects mice from aggressive liver cancer.

    Science.gov (United States)

    Friedbichler, Katrin; Themanns, Madeleine; Mueller, Kristina M; Schlederer, Michaela; Kornfeld, Jan-Wilhelm; Terracciano, Luigi M; Kozlov, Andrey V; Haindl, Susanne; Kenner, Lukas; Kolbe, Thomas; Mueller, Mathias; Snibson, Kenneth J; Heim, Markus H; Moriggl, Richard

    2012-03-01

    Persistently high levels of growth hormone (GH) can cause liver cancer. GH activates multiple signal-transduction pathways, among them janus kinase (JAK) 2-signal transducer and activator of transcription (STAT) 5 (signal transducer and activator of transcription 5). Both hyperactivation and deletion of STAT5 in hepatocytes have been implicated in the development of hepatocellular carcinoma (HCC); nevertheless, the role of STAT5 in the development of HCC as a result of high GH levels remains enigmatic. Thus, we crossed a mouse model of gigantism and inflammatory liver cancer caused by hyperactivated GH signaling (GH(tg) ) to mice with hepatic deletion of STAT5 (STAT5(Δhep) ). Unlike GH(tg) mice, GH(tg) STAT5(Δhep) animals did not display gigantism. Moreover, the premature mortality, which was associated with chronic inflammation, as well as the pathologic alterations of hepatocytes observed in GH(tg) mice, were not observed in GH(tg) animals lacking STAT5. Strikingly, loss of hepatic STAT5 proteins led to enhanced HCC development in GH(tg) mice. Despite reduced chronic inflammation, GH(tg) STAT5(Δhep) mice displayed earlier and more advanced HCC than GH(tg) animals. This may be attributed to the combination of increased peripheral lipolysis, hepatic lipid synthesis, loss of hepatoprotective mediators accompanied by aberrant activation of tumor-promoting c-JUN and STAT3 signaling cascades, and accumulation of DNA damage secondary to loss of cell-cycle control. Thus, HCC was never observed in STAT5(Δhep) mice. As a result of their hepatoprotective functions, STAT5 proteins prevent progressive fatty liver disease and the formation of aggressive HCC in the setting of hyperactivated GH signaling. At the same time, they play a key role in controlling systemic inflammation and regulating organ and body size. Copyright © 2011 American Association for the Study of Liver Diseases.

  12. Higgs Pair Production as a Signal of Enhanced Yukawa Couplings

    Energy Technology Data Exchange (ETDEWEB)

    Bauer, Martin [Heidelberg U.; Carena, Marcela [Chicago U., KICP; Carmona, Adrián [U. Mainz, PRISMA

    2017-12-31

    We present a non-trivial correlation between the enhancement of the Higgs-fermion couplings and the Higgs pair production cross section in two Higgs doublet models with a flavour symmetry. This symmetry suppresses flavour-changing neutral couplings of the Higgs boson and allows for a partial explanation of the hierarchy in the Yukawa sector. After taking into account the constraints from electroweak precision measurements, Higgs coupling strength measurements, and unitarity and perturbativity bounds, we identify an interesting region of parameter space leading to enhanced Yukawa couplings as well as enhanced di-Higgs gluon fusion production at the LHC reach. This effect is visible in both the resonant and non-resonant contributions to the Higgs pair production cross section. We encourage dedicated searches based on differential distributions as a novel way to indirectly probe enhanced Higgs couplings to light fermions.

  13. Multinuclear giant cell formation is enhanced by down-regulation of Wnt signaling in gastric cancer cell line, AGS

    International Nuclear Information System (INIS)

    Kim, Shi-Mun; Kim, Rockki; Ryu, Jae-Hyun; Jho, Eek-Hoon; Song, Ki-Joon; Jang, Shyh-Ing; Kee, Sun-Ho

    2005-01-01

    AGS cells, which were derived from malignant gastric adenocarcinoma tissue, lack E-cadherin-mediated cell adhesion but have a high level of nuclear β-catenin, which suggests altered Wnt signal. In addition, approximately 5% of AGS cells form multinuclear giant cells in the routine culture conditions, while taxol treatment causes most AGS cells to become giant cells. The observation of reduced nuclear β-catenin levels in giant cells induced by taxol treatment prompted us to investigate the relationship between Wnt signaling and giant cell formation. After overnight serum starvation, the shape of AGS cells became flattened, and this morphological change was accompanied by decrease in Myc expression and an increase in the giant cell population. Lithium chloride treatment, which inhibits GSK3β activity, reversed these serum starvation effects, which suggests an inverse relationship between Wnt signaling and giant cell formation. Furthermore, the down-regulation of Wnt signaling caused by the over-expression of ICAT, E-cadherin, and Axin enhanced giant cell formation. Therefore, down-regulation of Wnt signaling may be related to giant cell formation, which is considered to be a survival mechanism against induced cell death

  14. Sortilin Associates with Trk Receptors to Enhance Anterograde Transport and Signaling by Neurotrophins

    DEFF Research Database (Denmark)

    Vægter, Christian Bjerggaard

      Neurotrophins (NT) are neuronal growth factors essential for development and maintenance of the nervous system. They are released in two forms with opposing biological functions. The proforms induce apoptosis by engaging a death signaling complex comprising the p75NTR neurotrophin receptor...

  15. Arctigenin enhances chemosensitivity of cancer cells to cisplatin through inhibition of the STAT3 signaling pathway.

    Science.gov (United States)

    Yao, Xiangyang; Zhu, Fenfen; Zhao, Zhihui; Liu, Chang; Luo, Lan; Yin, Zhimin

    2011-10-01

    Arctigenin is a dibenzylbutyrolactone lignan isolated from Bardanae fructus, Arctium lappa L, Saussureamedusa, Torreya nucifera, and Ipomea cairica. It has been reported to exhibit anti-inflammatory activities, which is mainly mediated through its inhibitory effect on nuclear transcription factor-kappaB (NF-κB). But the role of arctigenin in JAK-STAT3 signaling pathways is still unclear. In present study, we investigated the effect of arctigenin on signal transducer and activator of transcription 3 (STAT3) pathway and evaluated whether suppression of STAT3 activity by arctigenin could sensitize cancer cells to a chemotherapeutic drug cisplatin. Our results show that arctigenin significantly suppressed both constitutively activated and IL-6-induced STAT3 phosphorylation and subsequent nuclear translocation in cancer cells. Inhibition of STAT3 tyrosine phosphorylation was found to be achieved through suppression of Src, JAK1, and JAK2, while suppression of STAT3 serine phosphorylation was mediated by inhibition of ERK activation. Pervanadate reversed the arctigenin-induced downregulation of STAT3 activation, suggesting the involvement of a protein tyrosine phosphatase. Indeed, arctigenin can obviously induce the expression of the PTP SHP-2. Furthermore, the constitutive activation level of STAT3 was found to be correlated to the resistance of cancer cells to cisplatin-induced apoptosis. Arctigenin dramatically promoted cisplatin-induced cell death in cancer cells, indicating that arctigenin enhanced the sensitivity of cancer cells to cisplatin mainly via STAT3 suppression. These observations suggest a novel anticancer function of arctigenin and a potential therapeutic strategy of using arctigenin in combination with chemotherapeutic agents for cancer treatment. Copyright © 2011 Wiley-Liss, Inc.

  16. Joint Maximum Likelihood Time Delay Estimation of Unknown Event-Related Potential Signals for EEG Sensor Signal Quality Enhancement

    Science.gov (United States)

    Kim, Kyungsoo; Lim, Sung-Ho; Lee, Jaeseok; Kang, Won-Seok; Moon, Cheil; Choi, Ji-Woong

    2016-01-01

    Electroencephalograms (EEGs) measure a brain signal that contains abundant information about the human brain function and health. For this reason, recent clinical brain research and brain computer interface (BCI) studies use EEG signals in many applications. Due to the significant noise in EEG traces, signal processing to enhance the signal to noise power ratio (SNR) is necessary for EEG analysis, especially for non-invasive EEG. A typical method to improve the SNR is averaging many trials of event related potential (ERP) signal that represents a brain’s response to a particular stimulus or a task. The averaging, however, is very sensitive to variable delays. In this study, we propose two time delay estimation (TDE) schemes based on a joint maximum likelihood (ML) criterion to compensate the uncertain delays which may be different in each trial. We evaluate the performance for different types of signals such as random, deterministic, and real EEG signals. The results show that the proposed schemes provide better performance than other conventional schemes employing averaged signal as a reference, e.g., up to 4 dB gain at the expected delay error of 10°. PMID:27322267

  17. Joint Maximum Likelihood Time Delay Estimation of Unknown Event-Related Potential Signals for EEG Sensor Signal Quality Enhancement

    Directory of Open Access Journals (Sweden)

    Kyungsoo Kim

    2016-06-01

    Full Text Available Electroencephalograms (EEGs measure a brain signal that contains abundant information about the human brain function and health. For this reason, recent clinical brain research and brain computer interface (BCI studies use EEG signals in many applications. Due to the significant noise in EEG traces, signal processing to enhance the signal to noise power ratio (SNR is necessary for EEG analysis, especially for non-invasive EEG. A typical method to improve the SNR is averaging many trials of event related potential (ERP signal that represents a brain’s response to a particular stimulus or a task. The averaging, however, is very sensitive to variable delays. In this study, we propose two time delay estimation (TDE schemes based on a joint maximum likelihood (ML criterion to compensate the uncertain delays which may be different in each trial. We evaluate the performance for different types of signals such as random, deterministic, and real EEG signals. The results show that the proposed schemes provide better performance than other conventional schemes employing averaged signal as a reference, e.g., up to 4 dB gain at the expected delay error of 10°.

  18. Exponential signaling gain at the receptor level enhances signal-to-noise ratio in bacterial chemotaxis.

    Directory of Open Access Journals (Sweden)

    Silke Neumann

    Full Text Available Cellular signaling systems show astonishing precision in their response to external stimuli despite strong fluctuations in the molecular components that determine pathway activity. To control the effects of noise on signaling most efficiently, living cells employ compensatory mechanisms that reach from simple negative feedback loops to robustly designed signaling architectures. Here, we report on a novel control mechanism that allows living cells to keep precision in their signaling characteristics - stationary pathway output, response amplitude, and relaxation time - in the presence of strong intracellular perturbations. The concept relies on the surprising fact that for systems showing perfect adaptation an exponential signal amplification at the receptor level suffices to eliminate slowly varying multiplicative noise. To show this mechanism at work in living systems, we quantified the response dynamics of the E. coli chemotaxis network after genetically perturbing the information flux between upstream and downstream signaling components. We give strong evidence that this signaling system results in dynamic invariance of the activated response regulator against multiplicative intracellular noise. We further demonstrate that for environmental conditions, for which precision in chemosensing is crucial, the invariant response behavior results in highest chemotactic efficiency. Our results resolve several puzzling features of the chemotaxis pathway that are widely conserved across prokaryotes but so far could not be attributed any functional role.

  19. SIP Signaling Implementations and Performance Enhancement over MANET: A Survey

    OpenAIRE

    Alshamrani, M; Cruickshank, Haitham; Sun, Zhili; Ansa, G; Alshahwan, F

    2016-01-01

    The implementation of the Session Initiation Protocol (SIP)-based Voice over Internet Protocol (VoIP) and multimedia over MANET is still a challenging issue. Many routing factors affect the performance of SIP signaling and the voice Quality of Service (QoS). Node mobility in MANET causes dynamic changes to route calculations, topology, hop numbers, and the connectivity status between the correspondent nodes. SIP-based VoIP depends on the caller’s registration, call initiation, and call termin...

  20. A SIGNAL ENHANCED PORTABLE RAMAN PROBE FOR ANESTHETIC GAS MONITORING

    Directory of Open Access Journals (Sweden)

    S. Schlüter

    2015-03-01

    Full Text Available The spontaneous Raman scattering technique is an excellent tool for a quantitative analysis of multi-species gas mixtures. It is a noninvasive optical method for species identification and gas phase concentration measurement of all Raman active molecules, since the intensity of the species specific Raman signal is linearly dependent on the concentration. Applying a continuous wave (CW laser it typically takes a few seconds to capture a gas phase Raman spectrum at room temperature. Nevertheless in contrast to these advantages the weak Raman signal intensity is a major drawback. Thus, it is still challenging to detect gas phase Raman spectra in alow-pressure regime with a temporal resolution of only a few 100 ms. In this work a fully functional gas phase Raman system for measurements in the low-pressure regime (p ≥ 980 hPa (absolute is presented. It overcomes the drawback of a weak Raman signal by using a multipass cavity. A description of the sensor setup and of the multipass arrangement will be presented. Moreover the complete functionality of the sensor system will be demonstrated by measurements at an anesthesia simulator under clinical relevant conditions and in comparison to a conventional gas monitor.

  1. Enhancement of small signal stability of a DFIG-based wind power ...

    African Journals Online (AJOL)

    International Journal of Engineering, Science and Technology ... logic controllers for enhancing the small signal stability of DFIG-based wind integrated power system. ... state space model, eigenvalue analysis, fuzzy logic based tuning circuits ...

  2. Preheat-induced signal enhancement in the infrared stimulated luminescence of young and bleached sediment samples

    International Nuclear Information System (INIS)

    Richardson, C.A.

    2000-01-01

    Natural and laboratory bleached surface and young samples of potassium feldspar sand separates and polymineral silt had their infrared stimulated luminescence (IRSL) signal measured before and after preheating at 220 deg. C for 10 min or 160 deg. C for 16 h. For both preheats, the laboratory bleached sand samples underwent a signal enhancement which was stable with laboratory storage. The youngest samples also showed natural signal enhancement. The silt sample showed no recuperation of bleached signal on preheating, but some in the natural signal. A range of filtered bleaches was applied to one surface sand sample. Signal levels before and after preheating were reduced by filtering out the UV from the bleaching spectrum. The unfiltered bleach, however, most closely reproduced the behaviour of the natural sample

  3. Formation and biochemical characterization of tube/pelle death domain complexes: critical regulators of postreceptor signaling by the Drosophila toll receptor.

    Science.gov (United States)

    Schiffmann, D A; White, J H; Cooper, A; Nutley, M A; Harding, S E; Jumel, K; Solari, R; Ray, K P; Gay, N J

    1999-09-07

    In Drosophila, the Toll receptor signaling pathway is required for embryonic dorso-ventral patterning and at later developmental stages for innate immune responses. It is thought that dimerization of the receptor by binding of the ligand spätzle causes the formation of a postreceptor activation complex at the cytoplasmic surface of the membrane. Two components of this complex are the adaptor tube and protein kinase pelle. These proteins both have "death domains", protein interaction motifs found in a number of signaling pathways, particularly those involved in apoptotic cell death. It is thought that pelle is bound by tube during formation of the activation complexes, and that this interaction is mediated by the death domains. In this paper, we show using the yeast two-hybrid system that the wild-type tube and pelle death domains bind together. Mutant tube proteins which do not support signaling in the embryo are also unable to bind pelle in the 2-hybrid assay. We have purified proteins corresponding to the death domains of tube and pelle and show that these form corresponding heterodimeric complexes in vitro. Partial proteolysis reveals a smaller core consisting of the minimal death domain sequences. We have studied the tube/pelle interaction with the techniques of surface plasmon resonance, analytical ultracentrifugation and isothermal titration calorimetry. These measurements produce a value of K(d) for the complex of about 0.5 microM.

  4. Enhanced induction of apoptosis by combined treatment of human carcinoma cells with X rays and death receptor agonists

    International Nuclear Information System (INIS)

    Hamasu, Taku; Inanami, Osamu; Asanuma, Taketoshi; Kuwabara, Mikinori

    2005-01-01

    The death receptors Fas and DR5 are known to be expressed not only in immune cells but also in various tumor cells. The aim of the present study was to determine whether X irradiation enhanced induction of apoptosis in Tp53 wild type and Tp53-mutated tumor cell lines treated with agonists against these death receptors. We showed that 5 Gy of X irradiation significantly up-regulated the expression of death receptors Fas and DR5 on the plasma membrane in gastric cancer cell lines MKN45 and MKN28, lung cancer cell line A549, and prostate cancer cell line DU145, and that subsequent treatments with agonistic molecules for these death receptors, Fas antibody CHl1 and TRAIL, increased the formation of active fragment p20 of caspase 3 followed by the induction of apoptosis. This death-receptor-mediated apoptosis was independent of Tp53 status since MKN28 and DU145 were Tp53-mutated. The post-irradiation treatment of the cells with N-acetyl-L-cysteine (NAC) abolished the up-regulation of the expression of Fas and DR5 on the plasma membrane. NAC also attenuated the increase in the formation of p20 and the induction of apoptosis by agonistic molecules. These results suggested that the increase in the induction of apoptosis by combined treatment with X irradiation and CHl1 or TRAIL occurred through a change of the intracellular redox state independent of Tp53 status in human carcinoma cell lines. (author)

  5. Mine detection using SF-GPR: A signal processing approach for resolution enhancement and clutter reduction

    DEFF Research Database (Denmark)

    Karlsen, Brian; Jakobsen, Kaj Bjarne; Larsen, Jan

    2001-01-01

    Proper clutter reduction is essential for Ground Penetrating Radar data since low signal-to-clutter ratio prevent correct detection of mine objects. A signal processing approach for resolution enhancement and clutter reduction used on Stepped-Frequency Ground Penetrating Radar (SF-GPR) data is pr....... The clutter reduction method is based on basis function decomposition of the SF-GPR time-series from which the clutter and the signal are separated....

  6. Singapore grouper iridovirus, a large DNA virus, induces nonapoptotic cell death by a cell type dependent fashion and evokes ERK signaling.

    Science.gov (United States)

    Huang, Xiaohong; Huang, Youhua; Ouyang, Zhengliang; Xu, Lixiao; Yan, Yang; Cui, Huachun; Han, Xin; Qin, Qiwei

    2011-08-01

    Virus induced cell death, including apoptosis and nonapoptotic cell death, plays a critical role in the pathogenesis of viral diseases. Singapore grouper iridovirus (SGIV), a novel iridovirus of genus Ranavirus, causes high mortality and heavy economic losses in grouper aquaculture. Here, using fluorescence microscopy, electron microscopy and biochemical assays, we found that SGIV infection in host (grouper spleen, EAGS) cells evoked nonapoptotic programmed cell death (PCD), characterized by appearance of cytoplasmic vacuoles and distended endoplasmic reticulum, in the absence of DNA fragmentation, apoptotic bodies and caspase activation. In contrast, SGIV induced typical apoptosis in non-host (fathead minnow, FHM) cells, as evidenced by caspase activation and DNA fragmentation, suggesting that SGIV infection induced nonapoptotic cell death by a cell type dependent fashion. Furthermore, viral replication was essential for SGIV induced nonapoptotic cell death, but not for apoptosis. Notably, the disruption of mitochondrial transmembrane potential (ΔΨm) and externalization of phosphatidylserine (PS) were not detected in EAGS cells but in FHM cells after SGIV infection. Moreover, the extracellular signal-regulated kinase (ERK) signaling was involved in SGIV infection induced nonapoptotic cell death and viral replication. This is a first demonstration of ERK-mediated nonapoptotic cell death induced by a DNA virus. These findings contribute to understanding the mechanisms of iridovirus pathogenesis.

  7. Parametric Adaptive Radar Detector with Enhanced Mismatched Signals Rejection Capabilities

    Directory of Open Access Journals (Sweden)

    Liu Bin

    2010-01-01

    Full Text Available We consider the problem of adaptive signal detection in the presence of Gaussian noise with unknown covariance matrix. We propose a parametric radar detector by introducing a design parameter to trade off the target sensitivity with sidelobes energy rejection. The resulting detector merges the statistics of Kelly's GLRT and of the Rao test and so covers Kelly's GLRT and the Rao test as special cases. Both invariance properties and constant false alarm rate (CFAR behavior for this detector are studied. At the analysis stage, the performance of the new receiver is assessed and compared with several traditional adaptive detectors. The results highlight better rejection capabilities of this proposed detector for mismatched signals. Further, we develop two two-stage detectors, one of which consists of an adaptive matched filter (AMF followed by the aforementioned detector, and the other is obtained by cascading a GLRT-based Subspace Detector (SD and the proposed adaptive detector. We show that the former two-stage detector outperforms traditional two-stage detectors in terms of selectivity, and the latter yields more robustness.

  8. Enhancement of MS Signal Processing For Improved Cancer Biomarker Discovery

    Science.gov (United States)

    Si, Qian

    Technological advances in proteomics have shown great potential in detecting cancer at the earliest stages. One way is to use the time of flight mass spectroscopy to identify biomarkers, or early disease indicators related to the cancer. Pattern analysis of time of flight mass spectra data from blood and tissue samples gives great hope for the identification of potential biomarkers among the complex mixture of biological and chemical samples for the early cancer detection. One of the keys issues is the pre-processing of raw mass spectra data. A lot of challenges need to be addressed: unknown noise character associated with the large volume of data, high variability in the mass spectroscopy measurements, and poorly understood signal background and so on. This dissertation focuses on developing statistical algorithms and creating data mining tools for computationally improved signal processing for mass spectrometry data. I have introduced an advanced accurate estimate of the noise model and a half-supervised method of mass spectrum data processing which requires little knowledge about the data.

  9. Disorder in convergent floral nanostructures enhances signalling to bees

    Science.gov (United States)

    Moyroud, Edwige; Wenzel, Tobias; Middleton, Rox; Rudall, Paula J.; Banks, Hannah; Reed, Alison; Mellers, Greg; Killoran, Patrick; Westwood, M. Murphy; Steiner, Ullrich; Vignolini, Silvia; Glover, Beverley J.

    2017-10-01

    Diverse forms of nanoscale architecture generate structural colour and perform signalling functions within and between species. Structural colour is the result of the interference of light from approximately regular periodic structures; some structural disorder is, however, inevitable in biological organisms. Is this disorder functional and subject to evolutionary selection, or is it simply an unavoidable outcome of biological developmental processes? Here we show that disordered nanostructures enable flowers to produce visual signals that are salient to bees. These disordered nanostructures (identified in most major lineages of angiosperms) have distinct anatomies but convergent optical properties; they all produce angle-dependent scattered light, predominantly at short wavelengths (ultraviolet and blue). We manufactured artificial flowers with nanoscale structures that possessed tailored levels of disorder in order to investigate how foraging bumblebees respond to this optical effect. We conclude that floral nanostructures have evolved, on multiple independent occasions, an effective degree of relative spatial disorder that generates a photonic signature that is highly salient to insect pollinators.

  10. Effect of the luminol signal enhancer on the chemiluminescence intensity and kinetics

    International Nuclear Information System (INIS)

    Liang Yanli; Yu Fei; Yu Songcheng; Wu Yongjun; Zhang Hongquan; Qu Lingbo

    2012-01-01

    The novel p-phenol derivatives, 4-(1-imidazolyl)-phenol, 4-hydroxybiphenyl, 4-hydroxy-4′-iodobiphenyl were employed as highly potent signal enhancers of luminol-hydrogen peroxide (H 2 O 2 )-horseradish peroxidase (HRP) chemiluminescence (CL) system. The CL reaction conditions were optimized, and the enhancement characteristics of these enhancers were compared with each other. The employment of these molecules greatly affected important assay parameters. Practically, the use of a novel enhancer, even a slightly change of the structure (or concentration) of 4-substituted phenol derivative, could affect assay properties quite dramatically. Furthermore, the use of different enhancers in the luminol–H 2 O 2 –HRP system can affect not only the intensity of the CL signal, which is well known, but also its kinetics. The experiment data indicated that the stronger intensity was combined with a more rapid decrease of the CL signal. - Highlights: ► 4-IMP, 4-BIP and HIOP take on different signal enhancement and light kinetics. ► The employment of 4-BIP resulted in a significant improvement of the detection limit. ► The magnitude of the signal enhancement was about 2.5-fold in the same system.

  11. MR imaging signal enhancement of normal intracranial and extracranial structures

    International Nuclear Information System (INIS)

    Muraki, A.S.; Carvlin, M.J.; Francisco, J.; Rocklage, S.M.; Quay, S.

    1988-01-01

    The authors report their initial experience using a paramagnetic manganese chelate complex as a contrast agent for magnetic resonance (MR) imaging of the central nervous system. Five female cats weighing 2-4 kg were used, and anesthesia was induced and maintained with intravenous nembutal (15-25 mg/kg). This contrast agent, manganese (II) N, N'-bis(pyridoxal-5-phosphate) ethylenediamine-N,N'-diacetic acid, or Mn(DPDP)(Salutar), has previously shown efficacy for MR imaging of the hepatobiliary axis but has not been employed in neuroradiologic imaging. T1-weighted (repetition time, 400 msec, echo time, 15, 26 msec; 4-mm sections) spin-echo images were acquired before and after intravenous administration (100 μmol/kg) of the contrast agent. On post-contrast images, the pituitary gland, infundibulum and portohypophyseal system of the hypothalamus and choroid lexus demonstrated signal increase at t=0-30 minutes after injection

  12. Enhancement of speech signals - with a focus on voiced speech models

    DEFF Research Database (Denmark)

    Nørholm, Sidsel Marie

    This thesis deals with speech enhancement, i.e., noise reduction in speech signals. This has applications in, e.g., hearing aids and teleconference systems. We consider a signal-driven approach to speech enhancement where a model of the speech is assumed and filters are generated based...... on this model. The basic model used in this thesis is the harmonic model which is a commonly used model for describing the voiced part of the speech signal. We show that it can be beneficial to extend the model to take inharmonicities or the non-stationarity of speech into account. Extending the model...

  13. Enhancement of crack detection in stud bolts of nuclear reactor by ultrasonic signal processing technique

    International Nuclear Information System (INIS)

    Lee, J.H.; Oh, W.D.; Choi, S.W.; Park, M.H.

    2004-01-01

    'Full-text:' The stud bolts is one of the most critical parts for safety of reactor vessels in the nuclear power plants. However, in the application of ultrasonic technique for crack detection in stud bolt, some difficulties encountered are classification of crack signal from the signals reflected from threads part in stud bolt. In this study, shadow effect technique combined with new signal processing method is Investigated to enhance the detectability of small crack initiated from root of thread in stud bolt. The key idea of signal processing is based on the fact that the shape of waveforms from the threads is uniform since the shape of the threads in a bolt is same. If some cracks exist in the thread, the flaw signals are different to the reference signals. It is demonstrated that the small flaws are efficiently detected by novel ultrasonic technique combined with this new signal processing concept. (author)

  14. Dexamethasone enhances necrosis-like neuronal death in ischemic rat hippocampus involving μ-calpain activation

    DEFF Research Database (Denmark)

    Müller, Georg Johannes; Hasseldam, Henrik; Rasmussen, Rune Skovgaard

    2014-01-01

    - and necrosis-like cell death morphologies in CA1 of rats treated with dexamethasone prior to TFI (DPTI). In addition, apoptosis- (casp-9, casp-3, casp-3-cleaved PARP and cleaved α-spectrin 145/150 and 120kDa) and necrosis-related (calpain-specific casp-9 cleavage, μ-calpain upregulation and cleaved α......Transient forebrain ischemia (TFI) leads to hippocampal CA1 pyramidal cell death which is aggravated by glucocorticoids (GC). It is unknown how GC affect apoptosis and necrosis in cerebral ischemia. We therefore investigated the co-localization of activated caspase-3 (casp-3) with apoptosis......-spectrin 145/150kDa) cell death mechanisms were investigated by Western blot analysis. DPTI expedited CA1 neuronal death from day 4 to day 1 and increased the magnitude of CA1 neuronal death from 66.2% to 91.3% at day 7. Furthermore, DPTI decreased the overall (days 1-7) percentage of dying neurons displaying...

  15. ERK1/2 signalling protects against apoptosis following endoplasmic reticulum stress but cannot provide long-term protection against BAX/BAK-independent cell death.

    Science.gov (United States)

    Darling, Nicola J; Balmanno, Kathryn; Cook, Simon J

    2017-01-01

    Disruption of protein folding in the endoplasmic reticulum (ER) causes ER stress. Activation of the unfolded protein response (UPR) acts to restore protein homeostasis or, if ER stress is severe or persistent, drive apoptosis, which is thought to proceed through the cell intrinsic, mitochondrial pathway. Indeed, cells that lack the key executioner proteins BAX and BAK are protected from ER stress-induced apoptosis. Here we show that chronic ER stress causes the progressive inhibition of the extracellular signal-regulated kinase (ERK1/2) signalling pathway. This is causally related to ER stress since reactivation of ERK1/2 can protect cells from ER stress-induced apoptosis whilst ERK1/2 pathway inhibition sensitises cells to ER stress. Furthermore, cancer cell lines harbouring constitutively active BRAFV600E are addicted to ERK1/2 signalling for protection against ER stress-induced cell death. ERK1/2 signalling normally represses the pro-death proteins BIM, BMF and PUMA and it has been proposed that ER stress induces BIM-dependent cell death. We found no evidence that ER stress increased the expression of these proteins; furthermore, BIM was not required for ER stress-induced death. Rather, ER stress caused the PERK-dependent inhibition of cap-dependent mRNA translation and the progressive loss of pro-survival proteins including BCL2, BCLXL and MCL1. Despite these observations, neither ERK1/2 activation nor loss of BAX/BAK could confer long-term clonogenic survival to cells exposed to ER stress. Thus, ER stress induces cell death by at least two biochemically and genetically distinct pathways: a classical BAX/BAK-dependent apoptotic response that can be inhibited by ERK1/2 signalling and an alternative ERK1/2- and BAX/BAK-independent cell death pathway.

  16. ERK1/2 signalling protects against apoptosis following endoplasmic reticulum stress but cannot provide long-term protection against BAX/BAK-independent cell death.

    Directory of Open Access Journals (Sweden)

    Nicola J Darling

    Full Text Available Disruption of protein folding in the endoplasmic reticulum (ER causes ER stress. Activation of the unfolded protein response (UPR acts to restore protein homeostasis or, if ER stress is severe or persistent, drive apoptosis, which is thought to proceed through the cell intrinsic, mitochondrial pathway. Indeed, cells that lack the key executioner proteins BAX and BAK are protected from ER stress-induced apoptosis. Here we show that chronic ER stress causes the progressive inhibition of the extracellular signal-regulated kinase (ERK1/2 signalling pathway. This is causally related to ER stress since reactivation of ERK1/2 can protect cells from ER stress-induced apoptosis whilst ERK1/2 pathway inhibition sensitises cells to ER stress. Furthermore, cancer cell lines harbouring constitutively active BRAFV600E are addicted to ERK1/2 signalling for protection against ER stress-induced cell death. ERK1/2 signalling normally represses the pro-death proteins BIM, BMF and PUMA and it has been proposed that ER stress induces BIM-dependent cell death. We found no evidence that ER stress increased the expression of these proteins; furthermore, BIM was not required for ER stress-induced death. Rather, ER stress caused the PERK-dependent inhibition of cap-dependent mRNA translation and the progressive loss of pro-survival proteins including BCL2, BCLXL and MCL1. Despite these observations, neither ERK1/2 activation nor loss of BAX/BAK could confer long-term clonogenic survival to cells exposed to ER stress. Thus, ER stress induces cell death by at least two biochemically and genetically distinct pathways: a classical BAX/BAK-dependent apoptotic response that can be inhibited by ERK1/2 signalling and an alternative ERK1/2- and BAX/BAK-independent cell death pathway.

  17. Supramolecular Nanofibers Enhance Growth Factor Signaling by Increasing Lipid Raft Mobility

    Energy Technology Data Exchange (ETDEWEB)

    Newcomb, Christina J.; Sur, Shantanu; Lee, Sungsoo S.; Yu, Jeong Min; Zhou, Yan; Snead, Malcolm L.; Stupp, Samuel I. (NWU); (USC)

    2016-04-12

    The nanostructures of self-assembling biomaterials have been previously designed to tune the release of growth factors in order to optimize biological repair and regeneration. We report here on the discovery that weakly cohesive peptide nanostructures in terms of intermolecular hydrogen bonding, when combined with low concentrations of osteogenic growth factor, enhance both BMP-2 and Wnt mediated signaling in myoblasts and bone marrow stromal cells, respectively. Conversely, analogous nanostructures with enhanced levels of internal hydrogen bonding and cohesion lead to an overall reduction in BMP-2 signaling. We propose that the mechanism for enhanced growth factor signaling by the nanostructures is related to their ability to increase diffusion within membrane lipid rafts. The phenomenon reported here could lead to new nanomedicine strategies to mediate growth factor signaling for translational targets.

  18. Involvement of ERK-Nrf-2 signaling in ionizing radiation induced cell death in normal and tumor cells.

    Directory of Open Access Journals (Sweden)

    Raghavendra S Patwardhan

    Full Text Available Prolonged oxidative stress favors tumorigenic environment and inflammation. Oxidative stress may trigger redox adaptation mechanism(s in tumor cells but not normal cells. This may increase levels of intracellular antioxidants and establish a new redox homeostasis. Nrf-2, a master regulator of battery of antioxidant genes is constitutively activated in many tumor cells. Here we show that, murine T cell lymphoma EL-4 cells show constitutive and inducible radioresistance via activation of Nrf-2/ERK pathway. EL-4 cells contained lower levels of ROS than their normal counterpart murine splenic lymphocytes. In response to radiation, the thiol redox circuits, GSH and thioredoxin were modified in EL-4 cells. Pharmacological inhibitors of ERK and Nrf-2 significantly enhanced radiosensitivity and reduced clonogenic potential of EL-4 cells. Unirradiated lymphoma cells showed nuclear accumulation of Nrf-2, upregulation of its dependent genes and protein levels. Interestingly, MEK inhibitor abrogated its nuclear translocation suggesting role of ERK in basal and radiation induced Nrf-2 activation in tumor cells. Double knockdown of ERK and Nrf-2 resulted in higher sensitivity to radiation induced cell death as compared to individual knockdown cells. Importantly, NF-kB which is reported to be constitutively active in many tumors was not present at basal levels in EL-4 cells and its inhibition did not influence radiosensitivity of EL-4 cells. Thus our results reveal that, tumor cells which are subjected to heightened oxidative stress employ master regulator cellular redox homeostasis Nrf-2 for prevention of radiation induced cell death. Our study reveals the molecular basis of tumor radioresistance and highlights role of Nrf-2 and ERK.

  19. Use and Protection of GPS Sidelobe Signals for Enhanced Navigation Performance in High Earth Orbit

    Science.gov (United States)

    Parker, Joel J. K.; Valdez, Jennifer E.; Bauer, Frank H.; Moreau, Michael C.

    2016-01-01

    GPS (Global Positioning System) Space Service Volume (SSV) signal environment is from 3,000-36,000 kilometers altitude. Current SSV specifications only capture performance provided by signals transmitted within 23.5(L1) or 26(L2-L5) off-nadir angle. Recent on-orbit data lessons learned show significant PNT (Positioning, Navigation and Timing) performance improvements when the full aggregate signal is used. Numerous military civil operational missions in High Geosynchronous Earth Orbit (HEOGEO) utilize the full signal to enhance vehicle PNT performance

  20. Domain-Specific Activation of Death-Associated Intracellular Signalling Cascades by the Cellular Prion Protein in Neuroblastoma Cells.

    Science.gov (United States)

    Vilches, Silvia; Vergara, Cristina; Nicolás, Oriol; Mata, Ágata; Del Río, José A; Gavín, Rosalina

    2016-09-01

    The biological functions of the cellular prion protein remain poorly understood. In fact, numerous studies have aimed to determine specific functions for the different protein domains. Studies of cellular prion protein (PrP(C)) domains through in vivo expression of molecules carrying internal deletions in a mouse Prnp null background have provided helpful data on the implication of the protein in signalling cascades in affected neurons. Nevertheless, understanding of the mechanisms underlying the neurotoxicity induced by these PrP(C) deleted forms is far from complete. To better define the neurotoxic or neuroprotective potential of PrP(C) N-terminal domains, and to overcome the heterogeneity of results due to the lack of a standardized model, we used neuroblastoma cells to analyse the effects of overexpressing PrP(C) deleted forms. Results indicate that PrP(C) N-terminal deleted forms were properly processed through the secretory pathway. However, PrPΔF35 and PrPΔCD mutants led to death by different mechanisms sharing loss of alpha-cleavage and activation of caspase-3. Our data suggest that both gain-of-function and loss-of-function pathogenic mechanisms may be associated with N-terminal domains and may therefore contribute to neurotoxicity in prion disease. Dissecting the molecular response induced by PrPΔF35 may be the key to unravelling the physiological and pathological functions of the prion protein.

  1. Vorinostat-induced autophagy switches from a death-promoting to a cytoprotective signal to drive acquired resistance.

    Science.gov (United States)

    Dupéré-Richer, D; Kinal, M; Ménasché, V; Nielsen, T H; Del Rincon, S; Pettersson, F; Miller, W H

    2013-02-07

    Histone deacetylase inhibitors (HDACi) have shown promising activity against hematological malignancies in clinical trials and have led to the approval of vorinostat for the treatment of cutaneous T-cell lymphoma. However, de novo or acquired resistance to HDACi therapy is inevitable, and their molecular mechanisms are still unclear. To gain insight into HDACi resistance, we developed vorinostat-resistant clones from the hematological cell lines U937 and SUDHL6. Although cross-resistant to some but not all HDACi, the resistant cell lines exhibit dramatically increased sensitivity toward chloroquine, an inhibitor of autophagy. Consistent with this, resistant cells growing in vorinostat show increased autophagy. Inhibition of autophagy in vorinostat-resistant U937 cells by knockdown of Beclin-1 or Lamp-2 (lysosome-associated membrane protein 2) restores sensitivity to vorinostat. Interestingly, autophagy is also activated in parental U937 cells by de novo treatment with vorinostat. However, in contrast to the resistant cells, inhibition of autophagy decreases sensitivity to vorinostat. These results indicate that autophagy can switch from a proapoptotic signal to a prosurvival function driving acquired resistance. Moreover, inducers of autophagy (such as mammalian target of rapamycin inhibitors) synergize with vorinostat to induce cell death in parental cells, whereas the resistant cells remain insensitive. These data highlight the complexity of the design of combination strategies using modulators of autophagy and HDACi for the treatment of hematological malignancies.

  2. CXCL10/CXCR3 signaling in glia cells differentially affects NMDA-induced cell death in CA and DG neurons of the mouse hippocampus

    DEFF Research Database (Denmark)

    van Weering, Hilmar R J; Boddeke, Hendrikus W G M; Vinet, Jonathan

    2011-01-01

    are far from understood. Here, we investigated the potential role for CXCL10/CXCR3 signaling in neuronal cell death and glia activation in response to N-methyl-D-aspartic acid (NMDA)-induced excitotoxicity in mouse organotypic hippocampal slice cultures (OHSCs). Our findings demonstrate that astrocytes...

  3. Activation of apoptosis signal-regulating kinase 1 is a key factor in paraquat-induced cell death : modulation by the Nrf2/Trx axis

    NARCIS (Netherlands)

    Niso-Santano, Mireia; González-Polo, Rosa A; Bravo-San Pedro, José M; Gómez-Sánchez, Rubén; Lastres-Becker, Isabel; Ortiz-Ortiz, Miguel A; Soler, Germán; Morán, José M; Cuadrado, Antonio; Fuentes, José M

    2010-01-01

    Although oxidative stress is fundamental to the etiopathology of Parkinson disease, the signaling molecules involved in transduction after oxidant exposure to cell death are ill-defined, thus making it difficult to identify molecular targets of therapeutic relevance. We have addressed this question

  4. METHODS FOR QUALITY ENHANCEMENT OF USER VOICE SIGNAL IN VOICE AUTHENTICATION SYSTEMS

    Directory of Open Access Journals (Sweden)

    O. N. Faizulaieva

    2014-03-01

    Full Text Available The reasonability for the usage of computer systems user voice in the authentication process is proved. The scientific task for improving the signal/noise ratio of the user voice signal in the authentication system is considered. The object of study is the process of input and output of the voice signal of authentication system user in computer systems and networks. Methods and means for input and extraction of voice signal against external interference signals are researched. Methods for quality enhancement of user voice signal in voice authentication systems are suggested. As modern computer facilities, including mobile ones, have two-channel audio card, the usage of two microphones is proposed in the voice signal input system of authentication system. Meanwhile, the task of forming a lobe of microphone array in a desired area of voice signal registration (100 Hz to 8 kHz is solved. The usage of directional properties of the proposed microphone array gives the possibility to have the influence of external interference signals two or three times less in the frequency range from 4 to 8 kHz. The possibilities for implementation of space-time processing of the recorded signals using constant and adaptive weighting factors are investigated. The simulation results of the proposed system for input and extraction of signals during digital processing of narrowband signals are presented. The proposed solutions make it possible to improve the value of the signal/noise ratio of the useful signals recorded up to 10, ..., 20 dB under the influence of external interference signals in the frequency range from 4 to 8 kHz. The results may be useful to specialists working in the field of voice recognition and speaker’s discrimination.

  5. Oxygen in human health from life to death – An approach to teaching redox biology and signaling to graduate and medical students

    Directory of Open Access Journals (Sweden)

    Margaret M. Briehl

    2015-08-01

    Full Text Available In the absence of oxygen human life is measured in minutes. In the presence of oxygen, normal metabolism generates reactive species (ROS that have the potential to cause cell injury contributing to human aging and disease. Between these extremes, organisms have developed means for sensing oxygen and ROS and regulating their cellular processes in response. Redox signaling contributes to the control of cell proliferation and death. Aberrant redox signaling underlies many human diseases. The attributes acquired by altered redox homeostasis in cancer cells illustrate this particularly well. This teaching review and the accompanying illustrations provide an introduction to redox biology and signaling aimed at instructors of graduate and medical students.

  6. Both Autocrine Signaling and Paracrine Signaling of HB-EGF Enhance Ocular Neovascularization.

    Science.gov (United States)

    Inoue, Yuki; Shimazawa, Masamitsu; Nakamura, Shinsuke; Takata, Shinsuke; Hashimoto, Yuhei; Izawa, Hiroshi; Masuda, Tomomi; Tsuruma, Kazuhiro; Sakaue, Tomohisa; Nakayama, Hironao; Higashiyama, Shigeki; Hara, Hideaki

    2018-01-01

    The incidence of blindness is increasing because of the increase in abnormal ocular neovascularization. Anti-VEGF (vascular endothelial growth factor) therapies have led to good results, although they are not a cure for the blindness. The purpose of this study was to determine what role HB-EGF (heparin-binding epidermal growth factor-like growth factor) plays in ocular angiogenesis. We examined the role played by HB-EGF in ocular neovascularization in 2 animal models of neovascularization: laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy. We also studied human retinal microvascular endothelial cells in culture. Our results showed that the neovascularization was decreased in both the CNV and oxygen-induced retinopathy models in HB-EGF conditional knockout mice compared with that in wild-type mice. Moreover, the expressions of HB-EGF and VEGF were increased after laser-induced CNV and oxygen-induced retinopathy, and their expression sites were located around the neovascular areas. Exposure of human retinal microvascular endothelial cells to HB-EGF and VEGF increased their proliferation and migration, and CRM-197 (cross-reactive material-197), an HB-EGF inhibitor, decreased the HB-EGF-induced and VEGF-induced cell proliferation and migration. VEGF increased the expression of HB-EGF mRNA. VEGF-dependent activation of EGFR (epidermal growth factor receptor)/ERK1/2 (extracellular signal-regulated kinase 1/2) signaling and cell proliferation of endothelial cells required stimulation of the ADAM17 (a disintegrin and metalloprotease) and ADAM12. CRM-197 decreased the grades of the fluorescein angiograms and size of the CNV areas in marmoset monkeys. These findings suggest that HB-EGF plays an important role in the development of CNV. Therefore, further investigations of HB-EGF are needed as a potential therapeutic target in the treatment of exudative age-related macular degeneration. © 2017 American Heart Association, Inc.

  7. Enhancement of Chiroptical Signals by Circular Differential Mie Scattering of Nanoparticles.

    Science.gov (United States)

    Yoo, SeokJae; Park, Q-Han

    2015-09-25

    We enhance the weak optical signals of small chiral molecules via circular differential Mie scattering (CDMS) of nanoparticles immersed in them. CDMS is the preferential Mie scattering of left- and right-handed circularly polarized light by nanoparticles whose sizes are about the same as the wavelength of light. Solving the Mie scattering theory for chiral media, we find that the CDMS signal of the particle is linearly proportional to the chirality parameter κ of the molecules. This linear amplitude enhancement by CDMS of the particle holds, even for large particles, which have a retardation effect. We also demonstrate that the CDMS of a nanoparticle is sensitive to changes of molecular concentration, and that the nanoparticle can be utilized as a chiroptical biosensor detecting the concentration of analyte. We expect that the enhancement of molecular chiroptical signals by CDMS will pave the way for novel chiroptical spectroscopy using nanostructures.

  8. Multichannel Signal Enhancement using Non-Causal, Time-Domain Filters

    DEFF Research Database (Denmark)

    Jensen, Jesper Rindom; Christensen, Mads Græsbøll; Benesty, Jacob

    2013-01-01

    In the vast amount of time-domain filtering methods for speech enhancement, the filters are designed to be causal. Recently, however, it was shown that the noise reduction and signal distortion capabilities of such single-channel filters can be improved by allowing the filters to be non-causal. W......In the vast amount of time-domain filtering methods for speech enhancement, the filters are designed to be causal. Recently, however, it was shown that the noise reduction and signal distortion capabilities of such single-channel filters can be improved by allowing the filters to be non......-causal, multichannel filters for enhancement based on an orthogonal decomposition is proposed. The evaluation shows that there is a potential gain in noise reduction and signal distortion by introducing non-causality. Moreover, experiments on real-life speech show that we can improve the perceptual quality....

  9. Enhancement of Chiroptical Signals by Circular Differential Mie Scattering of Nanoparticles

    OpenAIRE

    SeokJae Yoo; Q-Han Park

    2015-01-01

    We enhance the weak optical signals of small chiral molecules via circular differential Mie scattering (CDMS) of nanoparticles immersed in them. CDMS is the preferential Mie scattering of left- and right-handed circularly polarized light by nanoparticles whose sizes are about the same as the wavelength of light. Solving the Mie scattering theory for chiral media, we find that the CDMS signal of the particle is linearly proportional to the chirality parameter κ of the molecules. This linear am...

  10. Enhanced Global Signal of Neutral Hydrogen Due to Excess Radiation at Cosmic Dawn

    Science.gov (United States)

    Feng, Chang; Holder, Gilbert

    2018-05-01

    We revisit the global 21 cm signal calculation incorporating a possible radio background at early times, and find that the global 21 cm signal shows a much stronger absorption feature, which could enhance detection prospects for future 21 cm experiments. In light of recent reports of a possible low-frequency excess radio background, we propose that detailed 21 cm calculations should include a possible early radio background.

  11. An Enhanced Empirical Wavelet Transform for Features Extraction from Wind Turbine Condition Monitoring Signals

    Directory of Open Access Journals (Sweden)

    Pu Shi

    2017-07-01

    Full Text Available Feature extraction from nonlinear and non-stationary (NNS wind turbine (WT condition monitoring (CM signals is challenging. Previously, much effort has been spent to develop advanced signal processing techniques for dealing with CM signals of this kind. The Empirical Wavelet Transform (EWT is one of the achievements attributed to these efforts. The EWT takes advantage of Empirical Mode Decomposition (EMD in dealing with NNS signals but is superior to the EMD in mode decomposition and robustness against noise. However, the conventional EWT meets difficulty in properly segmenting the frequency spectrum of the signal, especially when lacking pre-knowledge of the signal. The inappropriate segmentation of the signal spectrum will inevitably lower the accuracy of the EWT result and thus raise the difficulty of WT CM. To address this issue, an enhanced EWT is proposed in this paper by developing a feasible and efficient spectrum segmentation method. The effectiveness of the proposed method has been verified by using the bearing and gearbox CM data that are open to the public for the purpose of research. The experiment has shown that, after adopting the proposed method, it becomes much easier and more reliable to segment the frequency spectrum of the signal. Moreover, benefitting from the correct segmentation of the signal spectrum, the fault-related features of the CM signals are presented more explicitly in the time-frequency map of the enhanced EWT, despite the considerable noise contained in the signal and the shortage of pre-knowledge about the machine being investigated.

  12. Low dose gamma irradiation enhances defined signaling components of intercellular reactive oxygen-mediated apoptosis induction

    International Nuclear Information System (INIS)

    Bauer, G

    2011-01-01

    Transformed cells are selectively removed by intercellular ROS-mediated induction of apoptosis. Signaling is based on the HOCl and the NO/peroxynitrite pathway (major pathways) and the nitryl chloride and the metal-catalyzed Haber-Weiss pathway (minor pathways). During tumor progression, resistance against intercellular induction of apoptosis is acquired through expression of membrane-associated catalase. Low dose radiation of nontransformed cells has been shown to enhance intercellular induction of apoptosis. The present study was performed to define the signaling components which are modulated by low dose gamma irradiation. Low dose radiation induced the release of peroxidase from nontransformed, transformed and tumor cells. Extracellular superoxide anion generation was strongly enhanced in the case of transformed cells and tumor cells, but not in nontransformed cells. Enhancement of peroxidase release and superoxide anion generation either increased intercellular induction of apoptosis of transformed cells, or caused a partial protection under specific signaling conditions. In tumor cells, low dose radiation enhanced the production of major signaling components, but this had no effect on apoptosis induction, due to the strong resistance mechanism of tumor cells. Our data specify the nature of low dose radiation-induced effects on specific signaling components of intercellular induction of apoptosis at defined stages of multistep carcinogenesis.

  13. Death Receptor-Induced Apoptosis Signalling Regulation by Ezrin Is Cell Type Dependent and Occurs in a DISC-Independent Manner in Colon Cancer Cells

    Science.gov (United States)

    Iessi, Elisabetta; Zischler, Luciana; Etringer, Aurélie; Bergeret, Marion; Morlé, Aymeric; Jacquemin, Guillaume; Morizot, Alexandre; Shirley, Sarah; Lalaoui, Najoua; Elifio-Esposito, Selene L.; Fais, Stefano; Garrido, Carmen; Solary, Eric; Micheau, Olivier

    2015-01-01

    Ezrin belongs to the ERM (ezrin-radixin-moesin) protein family and has been demonstrated to regulate early steps of Fas receptor signalling in lymphoid cells, but its contribution to TRAIL-induced cell death regulation in adherent cancer cells remains unknown. In this study we report that regulation of FasL and TRAIL-induced cell death by ezrin is cell type dependant. Ezrin is a positive regulator of apoptosis in T-lymphoma cell line Jurkat, but a negative regulator in colon cancer cells. Using ezrin phosphorylation or actin-binding mutants, we provide evidence that negative regulation of death receptor-induced apoptosis by ezrin occurs in a cytoskeleton- and DISC-independent manner, in colon cancer cells. Remarkably, inhibition of apoptosis induced by these ligands was found to be tightly associated with regulation of ezrin phosphorylation on serine 66, the tumor suppressor gene WWOX and activation of PKA. Deficiency in WWOX expression in the liver cancer SK-HEP1 or the pancreatic Mia PaCa-2 cell lines as well as WWOX silencing or modulation of PKA activation by pharmacological regulators, in the colon cancer cell line SW480, abrogated regulation of TRAIL signalling by ezrin. Altogether our results show that death receptor pro-apoptotic signalling regulation by ezrin can occur downstream of the DISC in colon cancer cells. PMID:26010871

  14. Death Receptor-Induced Apoptosis Signalling Regulation by Ezrin Is Cell Type Dependent and Occurs in a DISC-Independent Manner in Colon Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Elisabetta Iessi

    Full Text Available Ezrin belongs to the ERM (ezrin-radixin-moesin protein family and has been demonstrated to regulate early steps of Fas receptor signalling in lymphoid cells, but its contribution to TRAIL-induced cell death regulation in adherent cancer cells remains unknown. In this study we report that regulation of FasL and TRAIL-induced cell death by ezrin is cell type dependant. Ezrin is a positive regulator of apoptosis in T-lymphoma cell line Jurkat, but a negative regulator in colon cancer cells. Using ezrin phosphorylation or actin-binding mutants, we provide evidence that negative regulation of death receptor-induced apoptosis by ezrin occurs in a cytoskeleton- and DISC-independent manner, in colon cancer cells. Remarkably, inhibition of apoptosis induced by these ligands was found to be tightly associated with regulation of ezrin phosphorylation on serine 66, the tumor suppressor gene WWOX and activation of PKA. Deficiency in WWOX expression in the liver cancer SK-HEP1 or the pancreatic Mia PaCa-2 cell lines as well as WWOX silencing or modulation of PKA activation by pharmacological regulators, in the colon cancer cell line SW480, abrogated regulation of TRAIL signalling by ezrin. Altogether our results show that death receptor pro-apoptotic signalling regulation by ezrin can occur downstream of the DISC in colon cancer cells.

  15. Dragon enhances BMP signaling and increases transepithelial resistance in kidney epithelial cells.

    Science.gov (United States)

    Xia, Yin; Babitt, Jodie L; Bouley, Richard; Zhang, Ying; Da Silva, Nicolas; Chen, Shanzhuo; Zhuang, Zhenjie; Samad, Tarek A; Brenner, Gary J; Anderson, Jennifer L; Hong, Charles C; Schneyer, Alan L; Brown, Dennis; Lin, Herbert Y

    2010-04-01

    The neuronal adhesion protein Dragon acts as a bone morphogenetic protein (BMP) coreceptor that enhances BMP signaling. Given the importance of BMP signaling in nephrogenesis and its putative role in the response to injury in the adult kidney, we studied the localization and function of Dragon in the kidney. We observed that Dragon localized predominantly to the apical surfaces of tubular epithelial cells in the thick ascending limbs, distal convoluted tubules, and collecting ducts of mice. Dragon expression was weak in the proximal tubules and glomeruli. In mouse inner medullary collecting duct (mIMCD3) cells, Dragon generated BMP signals in a ligand-dependent manner, and BMP4 is the predominant endogenous ligand for the Dragon coreceptor. In mIMCD3 cells, BMP4 normally signaled through BMPRII, but Dragon enhanced its signaling through the BMP type II receptor ActRIIA. Dragon and BMP4 increased transepithelial resistance (TER) through the Smad1/5/8 pathway. In epithelial cells isolated from the proximal tubule and intercalated cells of collecting ducts, we observed coexpression of ActRIIA, Dragon, and BMP4 but not BMPRII. Taken together, these results suggest that Dragon may enhance BMP signaling in renal tubular epithelial cells and maintain normal renal physiology.

  16. Ethanol-induced transcriptional activation of programmed cell death 4 (Pdcd4 is mediated by GSK-3β signaling in rat cortical neuroblasts.

    Directory of Open Access Journals (Sweden)

    Amanjot Kaur Riar

    Full Text Available Ingestion of ethanol (ETOH during pregnancy induces grave abnormalities in developing fetal brain. We have previously reported that ETOH induces programmed cell death 4 (PDCD4, a critical regulator of cell growth, in cultured fetal cerebral cortical neurons (PCNs and in the cerebral cortex in vivo and affect protein synthesis as observed in Fetal Alcohol Spectrum Disorder (FASD. However, the mechanism which activates PDCD4 in neuronal systems is unclear and understanding this regulation may provide a counteractive strategy to correct the protein synthesis associated developmental changes seen in FASD. The present study investigates the molecular mechanism by which ethanol regulates PDCD4 in cortical neuroblasts, the immediate precursor of neurons. ETOH treatment significantly increased PDCD4 protein and transcript expression in spontaneously immortalized rat brain neuroblasts. Since PDCD4 is regulated at both the post-translational and post-transcriptional level, we assessed ETOH's effect on PDCD4 protein and mRNA stability. Chase experiments demonstrated that ETOH does not significantly impact either PDCD4 protein or mRNA stabilization. PDCD4 promoter-reporter assays confirmed that PDCD4 is transcriptionally regulated by ETOH in neuroblasts. Given a critical role of glycogen synthase kinase 3β (GSK-3β signaling in regulating protein synthesis and neurotoxic mechanisms, we investigated the involvement of GSK-3β and showed that multifunctional GSK-3β was significantly activated in response to ETOH in neuroblasts. In addition, we found that ETOH-induced activation of PDCD4 was inhibited by pharmacologic blockade of GSK-3β using inhibitors, lithium chloride (LiCl and SB-216763 or siRNA mediated silencing of GSK-3β. These results suggest that ethanol transcriptionally upregulates PDCD4 by enhancing GSK-3β signaling in cortical neuroblasts. Further, we demonstrate that canonical Wnt-3a/GSK-3β signaling is involved in regulating PDCD4 protein

  17. 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.

    Directory of Open Access Journals (Sweden)

    Joanna Kacprzyk

    Full Text Available 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

  18. A biological inspired fuzzy adaptive window median filter (FAWMF) for enhancing DNA signal processing.

    Science.gov (United States)

    Ahmad, Muneer; Jung, Low Tan; Bhuiyan, Al-Amin

    2017-10-01

    Digital signal processing techniques commonly employ fixed length window filters to process the signal contents. DNA signals differ in characteristics from common digital signals since they carry nucleotides as contents. The nucleotides own genetic code context and fuzzy behaviors due to their special structure and order in DNA strand. Employing conventional fixed length window filters for DNA signal processing produce spectral leakage and hence results in signal noise. A biological context aware adaptive window filter is required to process the DNA signals. This paper introduces a biological inspired fuzzy adaptive window median filter (FAWMF) which computes the fuzzy membership strength of nucleotides in each slide of window and filters nucleotides based on median filtering with a combination of s-shaped and z-shaped filters. Since coding regions cause 3-base periodicity by an unbalanced nucleotides' distribution producing a relatively high bias for nucleotides' usage, such fundamental characteristic of nucleotides has been exploited in FAWMF to suppress the signal noise. Along with adaptive response of FAWMF, a strong correlation between median nucleotides and the Π shaped filter was observed which produced enhanced discrimination between coding and non-coding regions contrary to fixed length conventional window filters. The proposed FAWMF attains a significant enhancement in coding regions identification i.e. 40% to 125% as compared to other conventional window filters tested over more than 250 benchmarked and randomly taken DNA datasets of different organisms. This study proves that conventional fixed length window filters applied to DNA signals do not achieve significant results since the nucleotides carry genetic code context. The proposed FAWMF algorithm is adaptive and outperforms significantly to process DNA signal contents. The algorithm applied to variety of DNA datasets produced noteworthy discrimination between coding and non-coding regions contrary

  19. Hyperthermia-enhanced TRAIL- and mapatumumab-induced apoptotic death is mediated through mitochondria in human colon cancer cells.

    Science.gov (United States)

    Song, Xinxin; Kim, Han-Cheon; Kim, Seog-Young; Basse, Per; Park, Bae-Hang; Lee, Byeong-Chel; Lee, Yong J

    2012-05-01

    Colorectal cancer is the third leading cause of cancer-related mortality in the world; death usually results from uncontrolled metastatic disease. Previously, we developed a novel strategy of TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) in combination with hyperthermia to treat hepatic colorectal metastases. However, previous studies suggest a potential hepatocyte cytotoxicity with TRAIL. Unlike TRAIL, anti-human TRAIL receptor antibody induces apoptosis without hepatocyte toxicity. In this study, we evaluated the anti-tumor efficacy of humanized anti-death receptor 4 (DR4) antibody mapatumumab (Mapa) by comparing it with TRAIL in combination with hyperthermia. TRAIL, which binds to both DR4 and death receptor 5 (DR5), was approximately tenfold more effective than Mapa in inducing apoptosis. However, hyperthermia enhances apoptosis induced by either agent. We observed that the synergistic effect was mediated through elevation of reactive oxygen species, c-Jun N-terminal kinase activation, Bax oligomerization, and translocalization to the mitochondria, loss of mitochondrial membrane potential, release of cytochrome c to cytosol, activation of caspases, and increase in poly(ADP-ribose) polymerase cleavage. We believe that the successful outcome of this study will support the application of Mapa in combination with hyperthermia to colorectal hepatic metastases. Copyright © 2011 Wiley Periodicals, Inc.

  20. LUBAC-Recruited CYLD and A20 Regulate Gene Activation and Cell Death by Exerting Opposing Effects on Linear Ubiquitin in Signaling Complexes

    Directory of Open Access Journals (Sweden)

    Peter Draber

    2015-12-01

    Full Text Available Ubiquitination and deubiquitination are crucial for assembly and disassembly of signaling complexes. LUBAC-generated linear (M1 ubiquitin is important for signaling via various immune receptors. We show here that the deubiquitinases CYLD and A20, but not OTULIN, are recruited to the TNFR1- and NOD2-associated signaling complexes (TNF-RSC and NOD2-SC, at which they cooperate to limit gene activation. Whereas CYLD recruitment depends on its interaction with LUBAC, but not on LUBAC’s M1-chain-forming capacity, A20 recruitment requires this activity. Intriguingly, CYLD and A20 exert opposing effects on M1 chain stability in the TNF-RSC and NOD2-SC. While CYLD cleaves M1 chains, and thereby sensitizes cells to TNF-induced death, A20 binding to them prevents their removal and, consequently, inhibits cell death. Thus, CYLD and A20 cooperatively restrict gene activation and regulate cell death via their respective activities on M1 chains. Hence, the interplay between LUBAC, M1-ubiquitin, CYLD, and A20 is central for physiological signaling through innate immune receptors.

  1. Cadmium toxicity in cultured tomato cells - Role of ethylene, proteases and oxidative stress in cell death signaling

    NARCIS (Netherlands)

    Iakimova, E.T.; Woltering, E.J.; Kapchina-Toteva, V.M.; Harren, F.J.M.; Cristescu, S.M.

    2008-01-01

    Our aim was to investigate the ability of cadmium to induce programmed cell death in tomato suspension cells and to determine the involvement of proteolysis, oxidative stress and ethylene. Tomato suspension cells were exposed to treatments with CdSO4 and cell death was calculated after fluorescein

  2. Involvement of ethylene and lipid signalling in cadmium-induced programmed cell death in tomato suspension cells

    NARCIS (Netherlands)

    Yakimova, E.T.; Kapchina-Toteva, V.M.; Laarhoven, L.J.J.; Harren, F.J.M.; Woltering, E.J.

    2006-01-01

    Cadmium-induced cell death was studied in suspension-cultured tomato (Lycopersicon esculentum Mill.) cells (line MsK8) treated with CdSO4. Within 24 h, cadmium treatment induced cell death in a concentration-dependent manner. Cell cultures showed recovery after 23 days which indicates the existence

  3. Involvement of ethylene and lipid signalling in cadmium-induced programmed cell death in tomato suspension cells

    NARCIS (Netherlands)

    Iakimova, E.T.; Kapchina-Toteva, V.M.; Laarhoven, L.J.; Harren, F.; Woltering, E.J.

    2006-01-01

    Cadmium-induced cell death was studied in suspension-cultured tomato (Lycopersicon esculentum Mill.) cells (line MsK8) treated with CdSO4. Within 24 h, cadmium treatment induced cell death in a concentration-dependent manner. Cell cultures showed recovery after 2¿3 days which indicates the existence

  4. Death and Death Anxiety

    OpenAIRE

    Gonca Karakus; Zehra Ozturk; Lut Tamam

    2012-01-01

    Although death and life concepts seem so different from each other, some believe that death and life as a whole that death is accepted as the goal of life and death completes life. In different cultures, societies and disciplines, there have been very different definitions of death which changes according to personality, age, religion and cultural status of the individual. Attitudes towards death vary dramatically according to individuals. As for the death anxiety, it is a feeling which start...

  5. Cross-modal enhancement of speech detection in young and older adults: does signal content matter?

    Science.gov (United States)

    Tye-Murray, Nancy; Spehar, Brent; Myerson, Joel; Sommers, Mitchell S; Hale, Sandra

    2011-01-01

    The purpose of the present study was to examine the effects of age and visual content on cross-modal enhancement of auditory speech detection. Visual content consisted of three clearly distinct types of visual information: an unaltered video clip of a talker's face, a low-contrast version of the same clip, and a mouth-like Lissajous figure. It was hypothesized that both young and older adults would exhibit reduced enhancement as visual content diverged from the original clip of the talker's face, but that the decrease would be greater for older participants. Nineteen young adults and 19 older adults were asked to detect a single spoken syllable (/ba/) in speech-shaped noise, and the level of the signal was adaptively varied to establish the signal-to-noise ratio (SNR) at threshold. There was an auditory-only baseline condition and three audiovisual conditions in which the syllable was accompanied by one of the three visual signals (the unaltered clip of the talker's face, the low-contrast version of that clip, or the Lissajous figure). For each audiovisual condition, the SNR at threshold was compared with the SNR at threshold for the auditory-only condition to measure the amount of cross-modal enhancement. Young adults exhibited significant cross-modal enhancement with all three types of visual stimuli, with the greatest amount of enhancement observed for the unaltered clip of the talker's face. Older adults, in contrast, exhibited significant cross-modal enhancement only with the unaltered face. Results of this study suggest that visual signal content affects cross-modal enhancement of speech detection in both young and older adults. They also support a hypothesized age-related deficit in processing low-contrast visual speech stimuli, even in older adults with normal contrast sensitivity.

  6. Transmission Property of Directly Modulated Signals Enhanced by a Micro-ring Resonator

    DEFF Research Database (Denmark)

    An, Yi; Lorences Riesgo, Abel; Seoane, Jorge

    2012-01-01

    A silicon micro-ring resonator is used to enhance the modulation speed of a 10-Gbit/s directly modulated laser to 40 Gbit/s. The generated signal is transmitted error free over 4.5 km SSMF. Dispersion tolerance is also studied....

  7. Laser Induced Breakdown Spectroscopy Based on Single Beam Splitting and Geometric Configuration for Effective Signal Enhancement

    Science.gov (United States)

    Yang, Guang; Lin, Qingyu; Ding, Yu; Tian, Di; Duan, Yixiang

    2015-01-01

    A new laser induced breakdown spectroscopy (LIBS) based on single-beam-splitting (SBS) and proper optical geometric configuration has been initially explored in this work for effective signal enhancement. In order to improve the interaction efficiency of laser energy with the ablated material, a laser beam operated in pulse mode was divided into two streams to ablate/excite the target sample in different directions instead of the conventional one beam excitation in single pulse LIBS (SP-LIBS). In spatial configuration, the laser beam geometry plays an important role in the emission signal enhancement. Thus, an adjustable geometric configuration with variable incident angle between the two splitted laser beams was constructed for achieving maximum signal enhancement. With the optimized angles of 60° and 70° for Al and Cu atomic emission lines at 396.15 nm and 324.75 nm respectively, about 5.6- and 4.8-folds signal enhancements were achieved for aluminum alloy and copper alloy samples compared to SP-LIBS. Furthermore, the temporal analysis, in which the intensity of atomic lines in SP-LIBS decayed at least ten times faster than the SBS-LIBS, proved that the energy coupling efficiency of SBS-LIBS was significantly higher than that of SP-LIBS. PMID:25557721

  8. Optimizing signal intensity correction during evaluation of hepatic parenchymal enhancement on gadoxetate disodium-enhanced MRI: Comparison of three methods

    International Nuclear Information System (INIS)

    Onoda, Minori; Hyodo, Tomoko; Murakami, Takamichi; Okada, Masahiro; Uto, Tatsuro; Hori, Masatoshi; Miyati, Tosiaki

    2015-01-01

    Highlights: •Signal intensity is often used to evaluate hepatic enhancement with Gd-EOB-DTPA in the hepatobiliary phase. •Comparison of uncorrected signal intensity with T 1 value revealed signal intensity instability. •Measurement of uncorrected liver SI or SNR often yields erroneous results on late-phase gadoxetate MRI due to shimming and other optimization techniques. •Signal intensity corrected by scale and rescale slope from DICOM data gave comparable results. -- Abstract: Objective: To compare signal intensity (SI) correction using scale and rescale slopes with SI correction using SIs of spleen and muscle for quantifying multiphase hepatic contrast enhancement with Gd-EOB-DTPA by assessing their correlation with T 1 values generated from Look-Locker turbo-field-echo (LL-TFE) sequence data (ER-T 1 ). Materials and methods: Thirty patients underwent Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) in this prospective clinical study. For each patient, breath-hold T 1 -weighted fat-suppressed three-dimensional (3D) gradient echo sequences (e-THRIVE) were acquired before and 2 (first phase), 10 (second phase), and 20 min (third phase) after intravenous Gd-EOB-DTPA. Look-Locker turbo-field-echo (LL-TFE) sequences were acquired before and 1.5 (first phase), 8 (second phase), and 18 min (third phase) postcontrast. The liver parenchyma enhancement ratios (ER) of each phase were calculated using the SI from e-THRIVE sequences (ER-SI) and the T 1 values generated from LL-TFE sequence data (ER-T 1 ) respectively. ER-SIs were calculated in three ways: (1) comparing with splenic SI (ER-SI-s), (2) comparing with muscle SI (ER-SI-m), (3) using scale and rescale slopes obtained from DICOM headers (ER-SI-c), to eliminate the effects of receiver gain and scaling. For each of the first, second and third phases, correlation and agreement were assessed between each ER-SI and ER-T 1 . Results: In the first phase, all ER-SIs correlated weakly with ER-T 1 . In the second

  9. ASIC channel inhibition enhances excitotoxic neuronal death in an in vitro model of spinal cord injury.

    Science.gov (United States)

    Mazzone, Graciela L; Veeraraghavan, Priyadharishini; Gonzalez-Inchauspe, Carlota; Nistri, Andrea; Uchitel, Osvaldo D

    2017-02-20

    In the spinal cord high extracellular glutamate evokes excitotoxic damage with neuronal loss and severe locomotor impairment. During the cell dysfunction process, extracellular pH becomes acid and may activate acid-sensing ion channels (ASICs) which could be important contributors to neurodegenerative pathologies. Our previous studies have shown that transient application of the glutamate analog kainate (KA) evokes delayed excitotoxic death of spinal neurons, while white matter is mainly spared. The present goal was to enquire if ASIC channels modulated KA damage in relation to locomotor network function and cell death. Mouse spinal cord slices were treated with KA (0.01 or 0.1mM) for 1h, and then washed out for 24h prior to analysis. RT-PCR results showed that KA (at 0.01mM concentration that is near-threshold for damage) increased mRNA expression of ASIC1a, ASIC1b, ASIC2 and ASIC3, an effect reversed by the ASIC inhibitor 4',6-diamidino-2-phenylindole (DAPI). A KA neurotoxic dose (0.1mM) reduced ASIC1a and ASIC2 expression. Cell viability assays demonstrated KA-induced large damage in spinal slices from mice with ASIC1a gene ablation. Likewise, immunohistochemistry indicated significant neuronal loss when KA was followed by the ASIC inhibitors DAPI or amiloride. Electrophysiological recording from ventral roots of isolated spinal cords showed that alternating oscillatory cycles were slowed down by 0.01mMKA, and intensely inhibited by subsequently applied DAPI or amiloride. Our data suggest that early rise in ASIC expression and function counteracted deleterious effects on spinal networks by raising the excitotoxicity threshold, a result with potential implications for improving neuroprotection. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  10. Data-Driven Iterative Vibration Signal Enhancement Strategy Using Alpha Stable Distribution

    Directory of Open Access Journals (Sweden)

    Grzegorz Żak

    2017-01-01

    Full Text Available The authors propose a novel procedure for enhancement of the signal to noise ratio in vibration data acquired from machines working in mining industry environment. Proposed method allows performing data-driven reduction of the deterministic, high energy, and low frequency components. Furthermore, it provides a way to enhance signal of interest. Procedure incorporates application of the time-frequency decomposition, α-stable distribution based signal modeling, and stability parameter in the time domain as a stoppage criterion for iterative part of the procedure. An advantage of the proposed algorithm is data-driven, automative detection of the informative frequency band as well as band with high energy due to the properties of the used distribution. Furthermore, there is no need to have knowledge regarding kinematics, speed, and so on. The proposed algorithm is applied towards real data acquired from the belt conveyor pulley drive’s gearbox.

  11. Raman signal enhancement by multiple beam excitation and its application for the detection of chemicals

    Energy Technology Data Exchange (ETDEWEB)

    Gupta, Sakshi [Laser Science and Technology Centre, Metcalfe House, Delhi 110054 (India); Instrument Design and Development Centre, Indian Institute of Technology, Hauz Khas, New Delhi 110016 (India); Ahmad, Azeem; Mehta, Dalip S., E-mail: mehtads@physics.iitd.ac.in [Department of Physics, Indian Institute of Technology, Hauz Khas, New Delhi 110016 (India); Gambhir, Vijayeta; Reddy, Martha N. [Laser Science and Technology Centre, Metcalfe House, Delhi 110054 (India)

    2015-08-31

    In a typical Raman based sensor, a single laser beam is used for exciting the sample and the backscattered or forward scattered light is collected using collection optics and is analyzed by a spectrometer. We have investigated that by means of exciting the sample with multiple beams, i.e., by dividing the same input power of the single beam into two or three or more beams and exciting the sample from different angles, the Raman signal enhances significantly. Due to the presence of multiple beams passing through the same volume of the sample, an interference pattern is formed and the volume of interaction of excitation beams with the sample increases. By means of this geometry, the enhancement in the Raman signal is observed and it was found that the signal strength increases linearly with the increase in number of excitation beams. Experimental results of this scheme for excitation of the samples are reported for explosive detection at a standoff distance.

  12. Protective effect of sauchinone against regional myocardial ischemia/reperfusion injury: inhibition of p38 MAPK and JNK death signaling pathways.

    Science.gov (United States)

    Kim, Seok Jai; Jeong, Cheol Won; Bae, Hong Beom; Kwak, Sang Hyun; Son, Jong-Keun; Seo, Chang-Seob; Lee, Hyun-Jung; Lee, JongUn; Yoo, Kyung Yeon

    2012-05-01

    Sauchinone has been known to have anti-inflammatory and antioxidant effects. We determined whether sauchinone is beneficial in regional myocardial ischemia/reperfusion (I/R) injury. Rats were subjected to 20 min occlusion of the left anterior descending coronary artery, followed by 2 hr reperfusion. Sauchinone (10 mg/kg) was administered intraperitoneally 30 min before the onset of ischemia. The infarct size was measured 2 hr after resuming the perfusion. The expression of cell death kinases (p38 and JNK) and reperfusion injury salvage kinases (phosphatidylinositol-3-OH kinases-Akt, extra-cellular signal-regulated kinases [ERK1/2])/glycogen synthase kinase (GSK)-3β was determined 5 min after resuming the perfusion. Sauchinone significantly reduced the infarct size (29.0% ± 5.3% in the sauchinone group vs 44.4% ± 6.1% in the control, P death signaling pathways.

  13. Fibrin-Enhanced Canonical Wnt Signaling Directs Plasminogen Expression in Cementoblasts

    Directory of Open Access Journals (Sweden)

    Saeed Ur Rahman

    2017-11-01

    Full Text Available Cementum is a mineralized layer on the tooth’s root surface and facilitates the biomechanical anchoring of fibrous connective tissues as a part of tooth-supportive complexes. Previously, we observed that OCCM30 cementoblasts cultured on fibrin matrices underwent apoptosis due to fibrin degradation through the expression of proteases. Here, we demonstrated that OCCM30 on fibrin matrices (OCCM30-fibrin enhanced canonical Wnt signaling, which directed to plasminogen expression. The OCCM30-fibrin showed higher levels of Wnt3a expression, nuclear translocation of β-catenin, and T-cell factor (TCF optimal motif (TOP reporter activity than the cells on tissue culture dishes (OCCM30-TCD, indicating that the OCCM30-fibrin enhanced canonical Wnt/β-catenin signaling. Also, OCCM30-fibrin expressed biomineralization-associated markers at higher levels than OCCM30-TCD, of which levels were further increased with LiCl, a Wnt signaling activator. The OCCM30 cementoblasts simultaneously showed that high levels of plasminogen, a critical component of fibrinolysis, were expressed in the OCCM30-fibrin. Activation of canonical Wnt signaling with LiCl treatment or with forced lymphoid enhancer factor 1 (LEF1-expression increased the expression of plasminogen. On the contrary, the inhibition of canonical Wnt signaling with siRNAs against Wnt3a or β-catenin abrogated fibrin-enhanced plasminogen expression. Furthermore, there are three conserved putative response elements for the LEF1/β-catenin complex in the plasminogen proximal promoter regions (−900 to +54. Site-directed mutations and chromatin immunoprecipitation indicated that canonical Wnt signaling directed plasminogen expression. Taken together, this study suggests that fibrin-based materials can modulate functional periodontal formations in controlling cementoblast differentiation and fibrin degradation.

  14. NADE, a p75NTR-associated cell death executor, is involved in signal transduction mediated by the common neurotrophin receptor p75NTR.

    Science.gov (United States)

    Mukai, J; Hachiya, T; Shoji-Hoshino, S; Kimura, M T; Nadano, D; Suvanto, P; Hanaoka, T; Li, Y; Irie, S; Greene, L A; Sato, T A

    2000-06-09

    The low affinity neurotrophin receptor p75NTR can mediate cell survival as well as cell death of neural cells by NGF and other neurotrophins. To elucidate p75NTR-mediated signal transduction, we screened p75NTR-associated proteins by a yeast two-hybrid system. We identified one positive clone and named NADE (p75NTR-associated cell death executor). Mouse NADE has marked homology to the human HGR74 protein. NADE specifically binds to the cell-death domain of p75NTR. Co-expression of NADE and p75NTR induced caspase-2 and caspase-3 activities and the fragmentation of nuclear DNA in 293T cells. However, in the absence of p75NTR, NADE failed to induce apoptosis, suggesting that NADE expression is necessary but insufficient for p75NTR-mediated apoptosis. Furthermore, p75NTR/NADE-induced cell death was dependent on NGF but not BDNF, NT-3, or NT-4/5, and the recruitment of NADE to p75NTR (intracellular domain) was dose-dependent. We obtained similar results from PC12 cells, nnr5 cells, and oligodendrocytes. Taken together, NADE is the first signaling adaptor molecule identified in the involvement of p75NTR-mediated apoptosis induced by NGF, and it may play an important role in the pathogenesis of neurogenetic diseases.

  15. EELS signal enhancement by means of beam precession in the TEM

    International Nuclear Information System (INIS)

    Estradé, Sonia; Portillo, Joaquim; Yedra, Lluís; Rebled, José Manuel; Peiró, Francesca

    2012-01-01

    EELS is nowadays a most relevant characterization tool as it provides chemical and electronic information with an extraordinary spatial resolution. When a crystal is viewed in zone axis in the TEM, there is channelling of the electrons along the atom columns, which strongly reduce the EELS signal, so that it is generally advised to work slightly off the zone axis to collect EELS data, which may not always be possible or advantageous. In the present work, we demonstrate the use of precession to compensate for the reduction of EELS signal when in the zone axis. -- Highlights: ► Channelling compromises EELS signal in zone axis. ► Precession can be used to get rid of channelling effects. ► Use of precession to enhance EELS signal in the zone axis is demonstrated.

  16. Downhole microseismic signal-to-noise ratio enhancement via strip matching shearlet transform

    Science.gov (United States)

    Li, Juan; Ji, Shuo; Li, Yue; Qian, Zhihong; Lu, Weili

    2018-04-01

    Shearlet transform has been proved effective in noise attenuation. However, because of the low magnitude and high frequency of downhole microseismic signals, the coefficient values of valid signals and noise are similar in the shearlet domain. As a result, it is hard to suppress the noise. In this paper, we present a novel signal-to-noise ratio enhancement scheme called strip matching shearlet transform. The method takes into account the directivity of microseismic events and shearlets. Through strip matching, the matching degree in direction between them has been promoted. Then the coefficient values of valid signals are much larger than those of the noise. Consequently, we can separate them well with the help of thresholding. The experimental results on both synthetic records and field data illustrate that our proposed method preserves the useful components and attenuates the noise well.

  17. Oxidative stress activates the TRPM2-Ca2+-CaMKII-ROS signaling loop to induce cell death in cancer cells.

    Science.gov (United States)

    Wang, Qian; Huang, Lihong; Yue, Jianbo

    2017-06-01

    High intracellular levels of reactive oxygen species (ROS) cause oxidative stress that results in numerous pathologies, including cell death. Transient potential receptor melastatin-2 (TRPM2), a Ca 2+ -permeable cation channel, is mainly activated by intracellular adenosine diphosphate ribose (ADPR) in response to oxidative stress. Here we studied the role and mechanisms of TRPM2-mediated Ca 2+ influx on oxidative stress-induced cell death in cancer cells. We found that oxidative stress activated the TRPM2-Ca 2+ -CaMKII cascade to inhibit early autophagy induction, which ultimately led to cell death in TRPM2 expressing cancer cells. On the other hand, TRPM2 knockdown switched cells from cell death to autophagy for survival in response to oxidative stress. Moreover, we found that oxidative stress activated the TRPM2-CaMKII cascade to further induce intracellular ROS production, which led to mitochondria fragmentation and loss of mitochondrial membrane potential. In summary, our data demonstrated that oxidative stress activates the TRPM2-Ca 2+ -CaMKII-ROS signal loop to inhibit autophagy and induce cell death. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Chemokine CCL2–CCR2 Signaling Induces Neuronal Cell Death via STAT3 Activation and IL-1β Production after Status Epilepticus

    Science.gov (United States)

    Tian, Dai-Shi; Feng, Li-Jie; Liu, Jun-Li

    2017-01-01

    Elevated levels of chemokine C-C motif ligand 2 (CCL2) and its receptor CCR2 have been reported in patients with temporal lobe epilepsy and in experimental seizures. However, the functional significance and molecular mechanism underlying CCL2–CCR2 signaling in epileptic brain remains largely unknown. In this study, we found that the upregulated CCL2 was mainly expressed in hippocampal neurons and activated microglia from mice 1 d after kainic acid (KA)-induced seizures. Taking advantage of CX3CR1GFP/+:CCR2RFP/+ double-transgenic mice, we demonstrated that CCL2–CCR2 signaling has a role in resident microglial activation and blood-derived monocyte infiltration. Moreover, seizure-induced degeneration of neurons in the hippocampal CA3 region was attenuated in mice lacking CCL2 or CCR2. We further showed that CCR2 activation induced STAT3 (signal transducer and activator of transcription 3) phosphorylation and IL-1β production, which are critical for promoting neuronal cell death after status epilepticus. Consistently, pharmacological inhibition of STAT3 by WP1066 reduced seizure-induced IL-1β production and subsequent neuronal death. Two weeks after KA-induced seizures, CCR2 deficiency not only reduced neuronal loss, but also attenuated seizure-induced behavioral impairments, including anxiety, memory decline, and recurrent seizure severity. Together, we demonstrated that CCL2–CCR2 signaling contributes to neurodegeneration via STAT3 activation and IL-1β production after status epilepticus, providing potential therapeutic targets for the treatment of epilepsy. SIGNIFICANCE STATEMENT Epilepsy is a global concern and epileptic seizures occur in many neurological conditions. Neuroinflammation associated with microglial activation and monocyte infiltration are characteristic of epileptic brains. However, molecular mechanisms underlying neuroinflammation in neuronal death following epilepsy remain to be elucidated. Here we demonstrate that CCL2–CCR2 signaling is

  19. Visible light communications using predistortion signal to enhance the response of passive optical receiver

    Science.gov (United States)

    Liu, Yang; Chen, Hung-Yu; Liang, Kevin; Wei, Liang-Yu; Chow, Chi-Wai; Yeh, Chien-Hung

    2016-01-01

    Traditional visible light communication (VLC) uses positive-intrinsic-negative photodiode (PD) or avalanche PD as the optical receivers (Rx). We demonstrate using a solar cell as the VLC Rx. The solar cell is flexible and low cost and converts the optical signal into an electrical signal directly without the need of external power supply. In addition to acting as the VLC passive Rx, the converted electrical signal from the solar cell can charge up the battery of the Rx nodes. Hence, the proposed scheme can be a promising candidate for the future Internet of Things network. However, a solar cell acting as a VLC Rx is very challenging, since the response of the solar cell is limited. Here, we propose and demonstrate using predistortion to significantly enhance the solar cell Rx response for the first time up to the authors' knowledge. Experimental results show that the response of the solar cell Rx is significantly enhanced; and the original 2-kHz detection bandwidth of the solar cell can be enhanced by 250 times for receiving 500-kbit/s VLC signal at a transmission distance of 1 m. The operation principle, the generated voltage by the solar cell, and the maximum data rates achieved at different transmission distances are also studied.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-08-01

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

  1. Genistein, a tyrosine kinase inhibitor, enhanced radiosensitivity in human esophageal cancer cell lines in vitro: Possible involvement of inhibition of survival signal transduction pathways

    International Nuclear Information System (INIS)

    Akimoto, Tetsuo; Nonaka, Tetsuo; Ishikawa, Hitoshi; Sakurai, Hideyuki; Saitoh, Jun-ichi; Takahashi, Takeo; Mitsuhashi, Norio

    2001-01-01

    Purpose: The effect of genistein, a tyrosine kinase inhibitor, on radiosensitivity was examined, especially focusing on 'survival signal transduction pathways'. Methods and Materials: Two human esophageal squamous cell cancer cell lines, TE-1 (p53, mutant) and TE-2 (p53, wild), were used. Radiosensitivity was determined by clonogenic assay, and activation of survival signals was examined by Western blot. Results: Genistein (30 μM) greatly enhanced radiosensitivity in these cell lines by suppressing radiation-induced activation of survival signals, p42/p44 extracellular signal-regulated kinase and AKT/PKB. Significant increase in the percentage of apoptotic cells and increased poly[ADP-ribose] polymerase cleavage were observed in TE-2, but not in TE-1 even after combination of genistein with irradiation. In terms of changes in expression of p53-related proteins, increase in expression of Bax and decrease in that of Bcl-2 were observed in TE-2 but not in TE-1, suggesting that the main mode of cell death induced by genistein in a cell line with wild type p53 differed from that with mutant p53. Conclusions: This study suggested that survival signals, including p42/p44 ERK and AKT/PKB, may be involved in determining radiosensitivity, and genistein would be a potent therapeutic agent that has an enhancing effect on radiation

  2. A study on hybrid split-spectrum processing technique for enhanced reliability in ultrasonic signal analysis

    International Nuclear Information System (INIS)

    Huh, Hyung; Koo, Kil Mo; Cheong, Yong Moo; Kim, G. J.

    1995-01-01

    Many signal-processing techniques have been found to be useful in ultrasonic and nondestructive evaluation. Among the most popular techniques are signal averaging, spatial compounding, matched filters, and homomorphic processing. One of the significant new process is split-spectrum processing(SSP), which can be equally useful in signal-to-noise ratio(SNR) improvement and grain characterization in several engineering materials. The purpose of this paper is to explore the utility of SSP in ultrasonic NDE. A wide variety of engineering problems are reviewed and suggestions for implementation of the technique are provided. SSP uses the frequency-dependent response of the interfering coherent noise produced by unresolvable scatters in the resolution range cell of a transducer. It is implemented by splitting the Sequency spectrum of the received signal by using Gaussian bandpass filters. The theoretical basis for the potential of SSP for grain characterization in SUS 304 material is discussed, and some experimental-evidence for the feasibility of the approach is presented. Results of SNR enhancement in signals obtained from real four samples of SUS 304. The influence of various processing parameters on the performance of the processing technique is also discussed. The minimization algorithm. which provides an excellent SNR enhancement when used either in conjunction with other SSP algorithms like polarity-check or by itself, is also presented.

  3. A Study on Hybrid Split-Spectrum Processing Technique for Enhanced Reliability in Ultrasonic Signal Analysis

    International Nuclear Information System (INIS)

    Huh, H.; Koo, K. M.; Kim, G. J.

    1996-01-01

    Many signal-processing techniques have been found to be useful in ultrasonic and nondestructive evaluation. Among the most popular techniques are signal averaging, spatial compounding, matched filters and homomorphic processing. One of the significant new process is split-spectrum processing(SSP), which can be equally useful in signal-to-noise ratio(SNR) improvement and grain characterization in several specimens. The purpose of this paper is to explore the utility of SSP in ultrasonic NDE. A wide variety of engineering problems are reviewed, and suggestions for implementation of the technique are provided. SSP uses the frequency-dependent response of the interfering coherent noise produced by unresolvable scatters in the resolution range cell of a transducer. It is implemented by splitting the frequency spectrum of the received signal by using gaussian bandpass filter. The theoretical basis for the potential of SSP for grain characterization in SUS 304 material is discussed, and some experimental evidence for the feasibility of the approach is presented. Results of SNR enhancement in signals obtained from real four samples of SUS 304. The influence of various processing parameters on the performance of the processing technique is also discussed. The minimization algorithm, which provides an excellent SNR enhancement when used either in conjunction with other SSP algorithms like polarity-check or by itself, is also presented

  4. Ultra-violet B (UVB)-induced skin cell death occurs through a cyclophilin D intrinsic signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Ji, Chao [Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210024, Jiangsu (China); Yang, Bo [Department of Dermatology, Huashan Hospital, Fudan University, Shanghai 200040 (China); Yang, Zhi; Tu, Ying [Department of Dermatology, The First Affiliated Hospital of Kunming Medical University, Yunnan Provincial Institute of Dermatology, Kunming 650032, Yunnan (China); Yang, Yan-li [Department of Otorhinolaryngology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210024, Jiangsu (China); He, Li, E-mail: heli2662@yahoo.com.cn [Department of Otorhinolaryngology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210024, Jiangsu (China); Bi, Zhi-Gang, E-mail: eltonbibenqhospital@yahoo.com.cn [Department of Dermatology, BenQ Medical Center, Nanjing Medical University, Nanjing 210019, Jiangsu (China)

    2012-09-07

    Highlights: Black-Right-Pointing-Pointer UVB radiated skin keratinocytes show cyclophilin D (Cyp-D) upregulation. Black-Right-Pointing-Pointer NAC inhibits UVB induced Cyp-D expression, while H{sub 2}O{sub 2} facilitates it. Black-Right-Pointing-Pointer Cyp-D-deficient cells are significantly less susceptible to UVB induced cell death. Black-Right-Pointing-Pointer Over-expression of Cyp-D causes spontaneous keratinocytes cell death. -- Abstract: UVB-induced skin cell damage involves the opening of mitochondrial permeability transition pore (mPTP), which leads to both apoptotic and necrotic cell death. Cyclophilin D (Cyp-D) translocation to the inner membrane of mitochondrion acts as a key component to open the mPTP. Our Western-Blot results in primary cultured human skin keratinocytes and in HaCaT cell line demonstrated that UVB radiation and hydrogen peroxide (H{sub 2}O{sub 2}) induced Cyp-D expression, which was inhibited by anti-oxidant N-acetyl cysteine (NAC). We created a stable Cyp-D deficiency skin keratinocytes by expressing Cyp-D-shRNA through lentiviral infection. Cyp-D-deficient cells were significantly less susceptible than their counterparts to UVB- or H{sub 2}O{sub 2}-induced cell death. Further, cyclosporine A (Cs-A), a Cyp-D inhibitor, inhibited UVB- or H{sub 2}O{sub 2}-induced keratinocytes cell death. Reversely, over-expression of Cyp-D in primary keratinocytes caused spontaneous keratinocytes cell death. These results suggest Cyp-D's critical role in UVB/oxidative stress-induced skin cell death.

  5. Ultra-violet B (UVB)-induced skin cell death occurs through a cyclophilin D intrinsic signaling pathway

    International Nuclear Information System (INIS)

    Ji, Chao; Yang, Bo; Yang, Zhi; Tu, Ying; Yang, Yan-li; He, Li; Bi, Zhi-Gang

    2012-01-01

    Highlights: ► UVB radiated skin keratinocytes show cyclophilin D (Cyp-D) upregulation. ► NAC inhibits UVB induced Cyp-D expression, while H 2 O 2 facilitates it. ► Cyp-D-deficient cells are significantly less susceptible to UVB induced cell death. ► Over-expression of Cyp-D causes spontaneous keratinocytes cell death. -- Abstract: UVB-induced skin cell damage involves the opening of mitochondrial permeability transition pore (mPTP), which leads to both apoptotic and necrotic cell death. Cyclophilin D (Cyp-D) translocation to the inner membrane of mitochondrion acts as a key component to open the mPTP. Our Western-Blot results in primary cultured human skin keratinocytes and in HaCaT cell line demonstrated that UVB radiation and hydrogen peroxide (H 2 O 2 ) induced Cyp-D expression, which was inhibited by anti-oxidant N-acetyl cysteine (NAC). We created a stable Cyp-D deficiency skin keratinocytes by expressing Cyp-D-shRNA through lentiviral infection. Cyp-D-deficient cells were significantly less susceptible than their counterparts to UVB- or H 2 O 2 -induced cell death. Further, cyclosporine A (Cs-A), a Cyp-D inhibitor, inhibited UVB- or H 2 O 2 -induced keratinocytes cell death. Reversely, over-expression of Cyp-D in primary keratinocytes caused spontaneous keratinocytes cell death. These results suggest Cyp-D’s critical role in UVB/oxidative stress-induced skin cell death.

  6. Poly-L-arginine: Enhancing Cytotoxicity and Cellular Uptake of Doxorubicin and Necrotic Cell Death.

    Science.gov (United States)

    Movafegh, Bahareh; Jalal, Razieh; Mohammadi, Zobeideh; Aldaghi, Seyyede Araste

    2018-04-11

    Cell resistance to doxorubicin and its toxicity to healthy tissue reduce its efficiency. The use of cell penetrating peptides as drug delivery system along with doxorubicin is a strategy to reduce its side effects. In this study, the influence of poly-L-arginine on doxorubicin cytotoxicity, its cellular uptake and doxorubicin-induced apoptosis on human prostate cancer DU145 cells are assessed. The cytotoxicity of doxorubicin and poly-L-arginine, alone and in combination, in DU145 cells was evaluated at different exposure times using MTT assay. The influence of poly-L-arginine on doxorubicin delivery into cells was evaluated by fluorescence microscopy and ultraviolet spectroscopy. DAPI and ethidium bromide-acridine orange stainings, flow cytometry using annexin V/propidium iodide, western blot analysis with anti-p21 antibody and caspase-3 activity were used to examine the influence of poly-L-arginine on doxorubicin-induced cell death. Poly-L-arginine had no cytotoxicity at low concentrations and short exposure times. Poly-L-arginine increased the cytotoxic effect of doxorubicin in DU145 cells in a time-dependent manner. But no significant reduction was found in HFF cell viability. Poly-L-arginine seems to facilitate doxorubicin uptake and increase its intracellular concentration. 24 h combined treatment of cells with doxorubicin (0.5 μM) and poly-L-arginine (1 μg ml-1) caused a small increase in doxorubicin-induced apoptosis and significant elevated necrosis in DU145 cells as compared to each agent alone. Conlusion: Our results indicate that poly-L-arginine at lowest and highest concentrations act as proliferation-inducing and antiproliferative agents, respectively. Between these concentrations, poly-L-arginine increases the cellular uptake of doxorubicin and its cytotoxicity through induction of necrosis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  7. Inhibition of TGF-β Signaling in SHED Enhances Endothelial Differentiation.

    Science.gov (United States)

    Xu, J G; Gong, T; Wang, Y Y; Zou, T; Heng, B C; Yang, Y Q; Zhang, C F

    2018-02-01

    Low efficiency of deriving endothelial cells (ECs) from adult stem cells hampers their utilization in tissue engineering studies. The purpose of this study was to investigate whether suppression of transforming growth factor beta (TGF-β) signaling could enhance the differentiation efficiency of dental pulp-derived stem cells into ECs. We initially used vascular endothelial growth factor A (VEGF-A) to stimulate 2 dental pulp-derived stem cells (dental pulp stem cells and stem cells from human exfoliated deciduous teeth [SHED]) and compared their differentiation capacity into ECs. We further evaluated whether the vascular endothelial growth factor receptor I (VEGF-RI)-specific ligand placental growth factor-1 (PlGF-1) could mediate endothelial differentiation. Finally, we investigated whether the TGF-β signaling inhibitor SB-431542 could enhance the inductive effect of VEGF-A on endothelial differentiation, as well as the underlying mechanisms involved. ECs differentiated from dental pulp-derived stem cells exhibited the typical phenotypes of primary ECs, with SHED possessing a higher endothelial differentiation potential than dental pulp stem cells. VEGFR1-specific ligand-PLGF exerted a negligible effect on SHED-ECs differentiation. Compared with VEGF-A alone, the combination of VEGF-A and SB-431542 significantly enhanced the endothelial differentiation of SHED. The presence of SB-431542 inhibited the phosphorylation of Suppressor of Mothers Against Decapentaplegic 2/3 (SMAD2/3), allowing for VEGF-A-dependent phosphorylation and upregulation of VEGFR2. Our results indicate that the combination of VEGF-A and SB-431542 could enhance the differentiation of dental pulp-derived stem cells into endothelial cells, and this process is mediated through enhancement of VEGF-A-VEGFR2 signaling and concomitant inhibition of TGF-β-SMAD2/3 signaling.

  8. Using neural networks to enhance the Higgs boson signal at hadron colliders

    International Nuclear Information System (INIS)

    Field, R.D.; Kanev, Y.; Tayebnejad, M.; Griffin, P.A.

    1995-01-01

    Neural networks are used to help distinguish the ZZ → ell + ell - -jet-jet signal produced by the decay of a 400 GeV Higgs boson at a proton-proton collider energy of 15 TeV from the ''ordinary'' QCD Z + jets background. The ideal case where only one event at a time enters the detector (no pile-up) and the case of multiple interactions per beam crossing (pile-up) are examined. In both cases, when used in conjunction with the standard cuts, neural networks provide an additional signal to background enhancement

  9. Hippo Signaling Influences HNF4A and FOXA2 Enhancer Switching during Hepatocyte Differentiation

    Directory of Open Access Journals (Sweden)

    Olivia Alder

    2014-10-01

    Full Text Available Summary: Cell fate acquisition is heavily influenced by direct interactions between master regulators and tissue-specific enhancers. However, it remains unclear how lineage-specifying transcription factors, which are often expressed in both progenitor and mature cell populations, influence cell differentiation. Using in vivo mouse liver development as a model, we identified thousands of enhancers that are bound by the master regulators HNF4A and FOXA2 in a differentiation-dependent manner, subject to chromatin remodeling, and associated with differentially expressed target genes. Enhancers exclusively occupied in the embryo were found to be responsive to developmentally regulated TEAD2 and coactivator YAP1. Our data suggest that Hippo signaling may affect hepatocyte differentiation by influencing HNF4A and FOXA2 interactions with temporal enhancers. In summary, transcription factor-enhancer interactions are not only tissue specific but also differentiation dependent, which is an important consideration for researchers studying cancer biology or mammalian development and/or using transformed cell lines. : It is unclear how key transcription factors are critical for both lineage specification during embryonic development and maintenance of a differentiated, adult phenotype. By profiling the enhancer occupancy of the key transcription factors HNF4A and FOXA2 during mouse liver development, Alder et al. have found that YAP1 can influence enhancer interactions and target gene expression levels. Enhancer switching enables HNF4A and FOXA2 to fulfill distinct roles during organ development.

  10. Ultra-violet B (UVB)-induced skin cell death occurs through a cyclophilin D intrinsic signaling pathway.

    Science.gov (United States)

    Ji, Chao; Yang, Bo; Yang, Zhi; Tu, Ying; Yang, Yan-li; He, Li; Bi, Zhi-Gang

    2012-09-07

    UVB-induced skin cell damage involves the opening of mitochondrial permeability transition pore (mPTP), which leads to both apoptotic and necrotic cell death. Cyclophilin D (Cyp-D) translocation to the inner membrane of mitochondrion acts as a key component to open the mPTP. Our Western-Blot results in primary cultured human skin keratinocytes and in HaCaT cell line demonstrated that UVB radiation and hydrogen peroxide (H(2)O(2)) induced Cyp-D expression, which was inhibited by anti-oxidant N-acetyl cysteine (NAC). We created a stable Cyp-D deficiency skin keratinocytes by expressing Cyp-D-shRNA through lentiviral infection. Cyp-D-deficient cells were significantly less susceptible than their counterparts to UVB- or H(2)O(2)-induced cell death. Further, cyclosporine A (Cs-A), a Cyp-D inhibitor, inhibited UVB- or H(2)O(2)-induced keratinocytes cell death. Reversely, over-expression of Cyp-D in primary keratinocytes caused spontaneous keratinocytes cell death. These results suggest Cyp-D's critical role in UVB/oxidative stress-induced skin cell death. Copyright © 2012 Elsevier Inc. All rights reserved.

  11. Enhancement of the automatic ultrasonic signal processing system using digital technology

    International Nuclear Information System (INIS)

    Koo, In Soo; Park, H. Y.; Suh, Y. S.; Kim, D. Hoon; Huh, S.; Sung, S. H.; Jang, G. S.; Ryoo, S. G.; Choi, J. H.; Kim, Y. H.; Lee, J. C.; Kim, D. Hyun; Park, H. J.; Kim, Y. C.; Lee, J. P.; Park, C. H.; Kim, M. S.

    1999-12-01

    The objective of this study is to develop the automatic ultrasonic signal processing system which can be used in the inspection equipment to assess the integrity of the reactor vessel by enhancing the performance of the ultrasonic signal processing system. Main activities of this study divided into three categories such as the development of the circuits for generating ultrasonic signal and receiving the signal from the inspection equipment, the development of signal processing algorithm and H/W of the data processing system, and the development of the specification for application programs and system S/W for the analysis and evaluation computer. The results of main activities are as follows 1) the design of the ultrasonic detector and the automatic ultrasonic signal processing system by using the investigation of the state-of-the-art technology in the inside and outside of the country. 2) the development of H/W and S/W of the data processing system based on the results. Especially, the H/W of the data processing system, which have both advantages of digital and analog controls through the real-time digital signal processing, was developed using the DSP which can process the digital signal in the real-time, and was developed not only firmware of the data processing system in order for the peripherals but also the test algorithm of specimen for the calibration. The application programs and the system S/W of the analysis/evaluation computer were developed. Developed equipment was verified by the performance test. Based on developed prototype for the automatic ultrasonic signal processing system, the localization of the overall ultrasonic inspection equipment for nuclear industries would be expected through the further studies of the H/W establishment of real applications, developing the S/W specification of the analysis computer. (author)

  12. Efficient Techniques of Sparse Signal Analysis for Enhanced Recovery of Information in Biomedical Engineering and Geosciences

    KAUST Repository

    Sana, Furrukh

    2016-11-01

    Sparse signals are abundant among both natural and man-made signals. Sparsity implies that the signal essentially resides in a small dimensional subspace. The sparsity of the signal can be exploited to improve its recovery from limited and noisy observations. Traditional estimation algorithms generally lack the ability to take advantage of signal sparsity. This dissertation considers several problems in the areas of biomedical engineering and geosciences with the aim of enhancing the recovery of information by exploiting the underlying sparsity in the problem. The objective is to overcome the fundamental bottlenecks, both in terms of estimation accuracies and required computational resources. In the first part of dissertation, we present a high precision technique for the monitoring of human respiratory movements by exploiting the sparsity of wireless ultra-wideband signals. The proposed technique provides a novel methodology of overcoming the Nyquist sampling constraint and enables robust performance in the presence of noise and interferences. We also present a comprehensive framework for the important problem of extracting the fetal electrocardiogram (ECG) signals from abdominal ECG recordings of pregnant women. The multiple measurement vectors approach utilized for this purpose provides an efficient mechanism of exploiting the common structure of ECG signals, when represented in sparse transform domains, and allows leveraging information from multiple ECG electrodes under a joint estimation formulation. In the second part of dissertation, we adopt sparse signal processing principles for improved information recovery in large-scale subsurface reservoir characterization problems. We propose multiple new algorithms for sparse representation of the subsurface geological structures, incorporation of useful prior information in the estimation process, and for reducing computational complexities of the problem. The techniques presented here enable significantly

  13. Proteolytic activation of proapoptotic kinase protein kinase Cδ by tumor necrosis factor α death receptor signaling in dopaminergic neurons during neuroinflammation

    Directory of Open Access Journals (Sweden)

    Gordon Richard

    2012-04-01

    Full Text Available Abstract Background The mechanisms of progressive dopaminergic neuronal loss in Parkinson’s disease (PD remain poorly understood, largely due to the complex etiology and multifactorial nature of disease pathogenesis. Several lines of evidence from human studies and experimental models over the last decade have identified neuroinflammation as a potential pathophysiological mechanism contributing to disease progression. Tumor necrosis factor α (TNF has recently emerged as the primary neuroinflammatory mediator that can elicit dopaminergic cell death in PD. However, the signaling pathways by which TNF mediates dopaminergic cell death have not been completely elucidated. Methods In this study we used a dopaminergic neuronal cell model and recombinant TNF to characterize intracellular signaling pathways activated during TNF-induced dopaminergic neurotoxicity. Etanercept and neutralizing antibodies to tumor necrosis factor receptor 1 (TNFR1 were used to block TNF signaling. We confirmed the results from our mechanistic studies in primary embryonic mesencephalic cultures and in vivo using the stereotaxic lipopolysaccharide (LPS model of nigral dopaminergic degeneration. Results TNF signaling in dopaminergic neuronal cells triggered the activation of protein kinase Cδ (PKCδ, an isoform of the novel PKC family, by caspase-3 and caspase-8 dependent proteolytic cleavage. Both TNFR1 neutralizing antibodies and the soluble TNF receptor Etanercept blocked TNF-induced PKCδ proteolytic activation. Proteolytic activation of PKCδ was accompanied by translocation of the kinase to the nucleus. Notably, inhibition of PKCδ signaling by small interfering (siRNA or overexpression of a PKCδ cleavage-resistant mutant protected against TNF-induced dopaminergic neuronal cell death. Further, primary dopaminergic neurons obtained from PKCδ knockout (−/− mice were resistant to TNF toxicity. The proteolytic activation of PKCδ in the mouse substantia nigra in the

  14. MR imaging of renal cell carcinoma. Associations among signal intensity, tumor enhancement, and pathologic findings

    Energy Technology Data Exchange (ETDEWEB)

    Yabuki, Takayuki; Togami, Izumi; Kitagawa, Takahiro; Sasai, Nobuya; Tsushima, Tomoyasu; Shirasaki, Yoshinori; Hiraki, Yoshio [Okayama Univ. (Japan). Graduate School of Medicine and Dentistry

    2003-08-01

    The purpose of this study was to compare the MR characteristics of renal cell carcinomas against histologic findings and to assess the correlations among signal intensity, tumor enhancement, and pathologic findings. Fifty-four patients (56 lesions) were examined by MR imaging and then underwent partial or radical nephrectomy. The pathologic diagnosis of all lesions was renal cell carcinoma. All MR examinations were performed as dynamic studies using the same 1.5-T scanner. MR characteristics were compared against pathologic findings after resection, and the correlations among signal intensity, tumor enhancement, and pathologic findings were then assessed. A significant correlation was observed between tumor grade and tumor enhancement, with G3 lesions tending to show little enhancement. Regardless of the histologic classification, G3 tumors were found to contain highly heterotypic cancer cells and very few vessels by histopathologic examination. No significant correlations were noted between the other MR characteristics and pathologic findings. Renal cell carcinomas showing little enhancement tend to be highly malignant lesions based on the pathologic findings. Special consideration is required for these tumors with regard to the selection of surgical intervention and follow-up observation. (author)

  15. MR imaging of renal cell carcinoma. Associations among signal intensity, tumor enhancement, and pathologic findings

    International Nuclear Information System (INIS)

    Yabuki, Takayuki; Togami, Izumi; Kitagawa, Takahiro; Sasai, Nobuya; Tsushima, Tomoyasu; Shirasaki, Yoshinori; Hiraki, Yoshio

    2003-01-01

    The purpose of this study was to compare the MR characteristics of renal cell carcinomas against histologic findings and to assess the correlations among signal intensity, tumor enhancement, and pathologic findings. Fifty-four patients (56 lesions) were examined by MR imaging and then underwent partial or radical nephrectomy. The pathologic diagnosis of all lesions was renal cell carcinoma. All MR examinations were performed as dynamic studies using the same 1.5-T scanner. MR characteristics were compared against pathologic findings after resection, and the correlations among signal intensity, tumor enhancement, and pathologic findings were then assessed. A significant correlation was observed between tumor grade and tumor enhancement, with G3 lesions tending to show little enhancement. Regardless of the histologic classification, G3 tumors were found to contain highly heterotypic cancer cells and very few vessels by histopathologic examination. No significant correlations were noted between the other MR characteristics and pathologic findings. Renal cell carcinomas showing little enhancement tend to be highly malignant lesions based on the pathologic findings. Special consideration is required for these tumors with regard to the selection of surgical intervention and follow-up observation. (author)

  16. Canonical Wnt signaling transiently stimulates proliferation and enhances neurogenesis in neonatal neural progenitor cultures

    International Nuclear Information System (INIS)

    Hirsch, Cordula; Campano, Louise M.; Woehrle, Simon; Hecht, Andreas

    2007-01-01

    Canonical Wnt signaling triggers the formation of heterodimeric transcription factor complexes consisting of β-catenin and T cell factors, and thereby controls the execution of specific genetic programs. During the expansion and neurogenic phases of embryonic neural development canonical Wnt signaling initially controls proliferation of neural progenitor cells, and later neuronal differentiation. Whether Wnt growth factors affect neural progenitor cells postnatally is not known. Therefore, we have analyzed the impact of Wnt signaling on neural progenitors isolated from cerebral cortices of newborn mice. Expression profiling of pathway components revealed that these cells are fully equipped to respond to Wnt signals. However, Wnt pathway activation affected only a subset of neonatal progenitors and elicited a limited increase in proliferation and neuronal differentiation in distinct subsets of cells. Moreover, Wnt pathway activation only transiently stimulated S-phase entry but did not support long-term proliferation of progenitor cultures. The dampened nature of the Wnt response correlates with the predominant expression of inhibitory pathway components and the rapid actuation of negative feedback mechanisms. Interestingly, in differentiating cell cultures activation of canonical Wnt signaling reduced Hes1 and Hes5 expression suggesting that during postnatal neural development, Wnt/β-catenin signaling enhances neurogenesis from progenitor cells by interfering with Notch pathway activity

  17. Proton nuclear magnetic resonance imaging of regionally ischemic canine hearts: effects of paramagnetic proton signal enhancement

    International Nuclear Information System (INIS)

    Brady, T.J.; Goldman, M.R.; Pykett, I.L.; Buonanno, F.S.; Kistler, J.P.; Newhouse, J.H.; Burt, C.T.; Hinshaw, W.S.; Pohost, G.M.

    1982-01-01

    In a study to evaluate the potential of proton nuclear magnetic resonance (NMR) imaging with and without manganese contrast enhancement for detecting acute myocardial infarction, 12 dogs underwent 90-minute occlusion of the left circumflex coronary artery. Transverse-section NMR images of the excised, nonbeating heart were obtained at 1-cm intervals using the steady-state-free-precession (SSFP) technique. All NMR images revealed detailed structure of the heart. The three hearts without manganese showed no difference in intensity between the normal and the ischemic posterior regions, whereas those with manganese demonstrated a clearly demarcated zone of reduced signal intensity consistent with the ischemic zone. It is concluded that high-resolution tomograms of the excised canine myocardium can be obtained using proton NMR imaging. With the SSFP imaging technique, proton signal enhancement with manganese infusion is necessary to differentiate between ischemic and nonischemic myocardium after 90 minutes of coronary occlusion

  18. Modulation of notch signaling pathway to prevent H2O2/menadione-induced SK-N-MC cells death by EUK134.

    Science.gov (United States)

    Kamarehei, Maryam; Yazdanparast, Razieh

    2014-10-01

    The brain in Alzheimer's disease is under increased oxidative stress, and this may have a role in the pathogenesis and neural death in this disorder. It has been verified that numerous signaling pathways involved in neurodegenerative disorders are activated in response to reactive oxygen species (ROS). EUK134, a synthetic salen-manganese antioxidant complex, has been found to possess many interesting pharmacological activities awaiting exploration. The present study is to characterize the role of Notch signaling in apoptotic cell death of SK-N-MC cells. The cells were treated with hydrogen peroxide (H2O2) or menadione to induce oxidative stress. The free-radical scavenging capabilities of EUK134 were studied through the MTT assay, glutathione peroxidase (GPx) enzyme activity assay, and glutathione (GSH) Levels. The extents of lipid peroxidation, protein carbonyl formation, and intracellular ROS levels, as markers of oxidative stress, were also studied. Our results showed that H2O2/menadione reduced GSH levels and GPx activity. However, EUK134 protected cells against ROS-induced cell death by down-regulation of lipid peroxidation and protein carbonyl formation as well as restoration of antioxidant enzymes activity. ROS induced apoptosis and increased NICD and HES1 expression. Inhibition of NICD production proved that Notch signaling is involved in apoptosis through p53 activation. Moreover, H2O2/menadione led to Numb protein down-regulation which upon EUK134 pretreatment, its level increased and subsequently prevented Notch pathway activation. We indicated that EUK134 can be a promising candidate in designing natural-based drugs for ROS-induced neurodegenerative diseases. Collectively, ROS activated Notch signaling in SK-N-MC cells leading to cell apoptosis.

  19. Magnetic nanoparticles of Fe3O4 enhance docetaxel-induced prostate cancer cell death

    Directory of Open Access Journals (Sweden)

    Sato A

    2013-08-01

    Full Text Available Akiko Sato,1 Naoki Itcho,1 Hitoshi Ishiguro,2,3 Daiki Okamoto,1 Naohito Kobayashi,4 Kazuaki Kawai,5 Hiroshi Kasai,5 Daisuke Kurioka,1 Hiroji Uemura,2 Yoshinobu Kubota,2 Masatoshi Watanabe11Laboratory for Medical Engineering, Division of Materials Science and Chemical Engineering, Graduate School of Engineering, Yokohama National University, Yokohama, Japan; 2Department of Urology, Yokohama City University Graduate School of Medicine, Yokohama, Japan; 3Photocatalyst Group, Kanagawa Academy of Science and Technology, Kawasaki, Japan; 4Department of Molecular Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Japan; 5Department of Environmental Oncology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyushu, JapanAbstract: Docetaxel (DTX is one of the most important anticancer drugs; however, the severity of its adverse effects detracts from its practical use in the clinic. Magnetic nanoparticles of Fe3O4 (MgNPs-Fe3O4 can enhance the delivery and efficacy of anticancer drugs. We investigated the effects of MgNPs-Fe3O4 or DTX alone, and in combination with prostate cancer cell growth in vitro, as well as with the mechanism underlying the cytotoxic effects. MgNPs-Fe3O4 caused dose-dependent increases in reactive oxygen species levels in DU145, PC-3, and LNCaP cells; 8-hydroxydeoxyguanosine levels were also elevated. MgNPs-Fe3O4 alone reduced the viability of LNCaP and PC-3 cells; however, MgNPs-Fe3O4 enhanced the cytotoxic effect of a low dose of DTX in all three cell lines. MgNPs-Fe3O4 also augmented the percentage of DU145 cells undergoing apoptosis following treatment with low dose DTX. Expression of nuclear transcription factor κB in DU145 was not affected by MgNPs-Fe3O4 or DTX alone; however, combined treatment suppressed nuclear transcription factor κB expression. These findings offer the possibility that MgNPs-Fe3O4–low dose DTX combination therapy may be

  20. MR imaging of renal cell carcinoma: associations among signal intensity, tumor enhancement, and pathologic findings.

    OpenAIRE

    Yabuki, Takayuki; Togami, Izumi; Kitagawa, Takahiro; Sasai, Nobuya; Tsushima, Tomoyasu; Shirasaki, Yoshinori; Hiraki, Yoshio

    2003-01-01

    The purpose of this study was to compare the MR characteristics of renal cell carcinomas against histologic findings and to assess the correlations among signal intensity, tumor enhancement, and pathologic findings. Fifty-four patients (56 lesions) were examined by MR imaging and then underwent partial or radical nephrectomy. The pathologic diagnosis of all lesions was renal cell carcinoma. All MR examinations were performed as dynamic studies using the same 1.5-T scanner. MR characteristics ...

  1. Enhanced Schottky signals from electron-cooled, coasting beams in a heavy-ion storage ring

    Energy Technology Data Exchange (ETDEWEB)

    Krantz, C., E-mail: claude.krantz@mpi-hd.mpg.d [Max-Planck-Institut fuer Kernphysik, Saupfercheckweg 1, D-69117 Heidelberg (Germany); Blaum, K.; Grieser, M. [Max-Planck-Institut fuer Kernphysik, Saupfercheckweg 1, D-69117 Heidelberg (Germany); Litvinov, Yu.A. [Max-Planck-Institut fuer Kernphysik, Saupfercheckweg 1, D-69117 Heidelberg (Germany); GSI Helmholtzzentrum fuer Schwerionenforschung, Planckstrasse 1, D-64291 Darmstadt (Germany); Repnow, R.; Wolf, A. [Max-Planck-Institut fuer Kernphysik, Saupfercheckweg 1, D-69117 Heidelberg (Germany)

    2011-02-11

    Measurements at the Test Storage Ring of the Max-Planck-Institut fuer Kernphysik in Heidelberg (Germany) have shown that the signal amplitude induced in a Schottky-noise pickup electrode by a coasting electron-cooled ion beam can be greatly enhanced by exposure of the latter to a perturbing radiofrequency signal which is detuned from the true beam revolution frequency. The centre frequencies obtained from harmonic analysis of the observed pickup signal closely follow those imposed on the ions by the electron cooling force. The phenomenon can be exploited to measure the true revolution frequency of ion beams of very low intensity, whose pure Schottky noise is too weak to be measurable under normal circumstances.

  2. Extinction ratio enhancement of SOA-based delayed-interference signal converter using detuned filtering

    Science.gov (United States)

    Zhang, B.; Kumar, S.; Yan, L.-S.; Willner, A. E.

    2007-12-01

    We demonstrate experimentally >3 dB extinction ratio improvement at the output of SOA-based delayed-interference signal converter (DISC) using optical off-centered filtering. Through careful modeling of the carrier and the phase dynamics, we explain in detail the origin of sub-pulses in the wavelength converted output, with an emphasis on the time-resolved frequency chirping of the output signal. Through our simulations we conclude that the sub-pulses and the main-pulses are oppositely chirped, which is also verified experimentally by analyzing the output with a chirp form analyzer. We propose and demonstrate an optical off-center filtering technique which effectively suppresses these sub-pulses. The effects of filter detuning and phase bias adjustment in the delayed-interferometer are experimentally characterized and optimized, leading to a >3 dB extinction ratio enhancement of the output signal.

  3. Involvement of phospholipase D-related signal transduction in chemical-induced programmed cell death in tomato cell cultures

    NARCIS (Netherlands)

    Iakimova, E.T.; Michaeli, R.; Woltering, E.J.

    2013-01-01

    Phospholipase D (PLD) and its product phosphatidic acid (PA) are incorporated in a complex metabolic network in which the individual PLD isoforms are suggested to regulate specific developmental and stress responses, including plant programmed cell death (PCD). Despite the accumulating knowledge,

  4. Prevalence and signal characteristics of late gadolinium enhancement on contrast-enhanced magnetic resonance imaging in patients with takotsubo cardiomyopathy

    International Nuclear Information System (INIS)

    Nakamori, Shiro; Matsuoka, Koji; Onishi, Katsuya

    2012-01-01

    The background of this study was to determine the prevalence and signal intensity (SI) characteristics of late gadolinium enhancement (LGE) on magnetic resonance imaging (MRI) in takotsubo cardiomyopathy (TC). Cine, black-blood T2-weighted and LGE MR images were acquired in 23 patients with TC within 72h of onset. Wall motion abnormality (WMA), edema and LGE were evaluated with a 16-segment model. The SI characteristics of LGE were analyzed using SI distribution in remote normal segments as reference. Follow-up MRI was performed 3 months later. Retrospective analysis of LGE MRI was also performed in 10 patients with acute myocardial infarction (AMI) to compare the SI characteristics between TC and AMI. In acute phase, WMA and edema were observed in 236 (64%) and 205 (56%) of 368 segments. LGE was observed in 10 (2.7%) of 368 segments and in 5 (22%) of 23 patients. All LGE lesions in TC exhibited transmural enhancement. The contrast-to-noise ratio (CNR) in TC was significantly lower than that of AMI (3.1±0.3 standard deviations (SD) vs. 6.1±1.2 SD, P<0.01), and CNR value of 4 was useful for distinguishing TC from AMI. Both LGE and WMA disappeared within 12 months. Grey myocardial signal on LGE MRI may be observed in patients with TC. However, the extent of LGE is substantially less than that of WMA and edema, and disappears within 12 months. (author)

  5. Effectiveness of an experiential workshop for enhancing helping professionals' self-competence in death work in Hong Kong: a randomised controlled trial.

    Science.gov (United States)

    Chan, Wallace Chi Ho; Tin, Agnes Fong; Wong, Karen Lok Yi

    2017-05-01

    Helping professionals require self-competence in coping with the existential and emotional challenges of death work. Previous training often focused on knowledge and skills rather than on this competence. This study aimed to examine the effectiveness of a 3-day workshop in Hong Kong to enhance helping professionals' self-competence in death work. A randomised controlled trial was conducted to examine the effects of the training between January and May 2014. Targeted participants were helping professionals who had been doing death work for at least 6 months. The 112 participants were openly recruited from hospitals and NGOs and were assigned to an intervention group or a waitlist control group. Data were collected at pre-intervention and post-intervention. Primary outcome was self-competence in death work. All participants were grouped for analysing the changes in outcomes at pre-intervention, post-intervention and 3-month follow-up. Participants in the intervention group experienced a significant increase in the total score of the Self-competence in Death Work Scale (SC-DWS) and in scores of the Existential and Emotional subscales of SC-DWS. The positive effects of training on self-competence in death work were maintained at the 3-month follow-up. This study provides evidence of the effectiveness of training in enhancing helping professionals' self-competence in death work. Further research is required to examine the long-term effects of training. © 2016 John Wiley & Sons Ltd.

  6. Integration and enhancement of low-level signals from air-pollution monitoring sensors

    Energy Technology Data Exchange (ETDEWEB)

    Dowd, G F; Dubois, L; Monkman, J L

    1975-09-01

    In this paper, we have demonstrated how signal enhancement techniques would be advantageous in the low-level analysis of air pollutants. We have further shown what type of signal-to-noise gain may be expected from an off-the-shelf, inexpensive run-of-the-mill mercury monitor. As long as an evoked response time constant is introduced into the measuring system, noise of a random nature may be reduced to such an extent that trace signals, buried deep in the electrical background, may be reliably measured. If we couple this type of analysis to a multi-parameter mercury analyzer, contributing factors may be evaluated. This will result in a more efficient system application. We have also reported a manner in which evoked response time is related to instrument onset time. However, there are other methods for obtaining an evoked response. Of note is the use of wavelength in the enhancement of spectrophotometric signals. In additional work now being carried out in our laboratory, there are indications that it is possible to relate this type of processing to SO/sub 2/ analyzing systems using conductometry. (auth)

  7. Effect of microbubble ligation to cells on ultrasound signal enhancement: implications for targeted imaging.

    Science.gov (United States)

    Lankford, Miles; Behm, Carolyn Z; Yeh, James; Klibanov, Alexander L; Robinson, Peter; Lindner, Jonathan R

    2006-10-01

    Molecular imaging with contrast-enhanced ultrasound (CEU) relies on the detection of microbubbles retained in regions of disease. The aim of this study was to determine whether microbubble attachment to cells influences their acoustic signal generation and stability. Biotinylated microbubbles were attached to streptavidin-coated plates to derive density versus intensity relations during low- and high-power imaging. To assess damping from microbubble attachment to solid or cell surfaces, in vitro imaging was performed for microbubbles charge-coupled to methacrylate spheres and for vascular cell adhesion molecule-1-targeted microbubbles attached to endothelial cells. Signal enhancement on plates increased according to acoustic power and microbubble site density up to 300 mm. Microbubble signal was reduced by attachment to solid spheres during high- and low-power imaging but was minimally reduced by attachment to endothelial cells and only at low power. Attachment of targeted microbubbles to rigid surfaces results in damping and a reduction of their acoustic signal, which is not seen when microbubbles are attached to cells. A reliable concentration versus intensity relationship can be expected from microbubble attachment to 2-dimensional surfaces until a very high site density is reached.

  8. Wnt signaling in ovarian development inhibits Sf1 activation of Sox9 via the Tesco enhancer.

    Science.gov (United States)

    Bernard, Pascal; Ryan, Janelle; Sim, Helena; Czech, Daniel P; Sinclair, Andrew H; Koopman, Peter; Harley, Vincent R

    2012-02-01

    Genome analysis of patients with disorders of sex development, and gain- and loss-of-function studies in mice indicate that gonadal development is regulated by opposing signals. In females, the Wnt/β-catenin canonical pathway blocks testicular differentiation by repressing the expression of the Sertoli cell-specific gene Sox9 by an unknown mechanism. Using cell and embryonic gonad culture models, we show that activation of the Wnt/β-catenin pathway inhibits the expression of Sox9 and Amh, whereas mRNA and protein levels of Sry and steroidogenic factor 1 (Sf1), two key transcriptional regulators of Sox9, are not altered. Ectopic activation of Wnt/β-catenin signaling in male gonads led to a loss of Sf1 binding to the Tesco enhancer and absent Sox9 expression that we also observed in wild-type ovaries. Moreover, ectopic Wnt/β-catenin signaling induced the expression of the female somatic cell markers, Bmp2 and Rspo1, as a likely consequence of Sox9 loss. Wnt/β-catenin signaling in XY gonads did not, however, affect gene expression of the steroidogenic Leydig cell Sf1 target gene, Cyp11a1, or Sf1 binding to the Cyp11a1 promoter. Our data support a model in ovary development whereby activation of β-catenin prevents Sf1 binding to the Sox9 enhancer, thereby inhibiting Sox9 expression and Sertoli cell differentiation.

  9. The inhibition of IGF-1 signaling promotes proteostasis by enhancing protein aggregation and deposition.

    Science.gov (United States)

    Moll, Lorna; Ben-Gedalya, Tziona; Reuveni, Hadas; Cohen, Ehud

    2016-04-01

    The discovery that the alteration of aging by reducing the activity of the insulin/IGF-1 signaling (IIS) cascade protects nematodes and mice from neurodegeneration-linked, toxic protein aggregation (proteotoxicity) raises the prospect that IIS inhibitors bear therapeutic potential to counter neurodegenerative diseases. Recently, we reported that NT219, a highly efficient IGF-1 signaling inhibitor, protects model worms from the aggregation of amyloid β peptide and polyglutamine peptides that are linked to the manifestation of Alzheimer's and Huntington's diseases, respectively. Here, we employed cultured cell systems to investigate whether NT219 promotes protein homeostasis (proteostasis) in mammalian cells and to explore its underlying mechanisms. We found that NT219 enhances the aggregation of misfolded prion protein and promotes its deposition in quality control compartments known as "aggresomes." NT219 also elevates the levels of certain molecular chaperones but, surprisingly, reduces proteasome activity and impairs autophagy. Our findings show that IGF-1 signaling inhibitors in general and NT219 in particular can promote proteostasis in mammalian cells by hyperaggregating hazardous proteins, thereby bearing the potential to postpone the onset and slow the progression of neurodegenerative illnesses in the elderly.-Moll, L., Ben-Gedalya, T., Reuveni, H., Cohen, E. The inhibition of IGF-1 signaling promotes proteostasis by enhancing protein aggregation and deposition. © FASEB.

  10. An enhanced functional interrogation/manipulation of intracellular signaling pathways with the peptide 'stapling' technology.

    Science.gov (United States)

    He, Y; Chen, D; Zheng, W

    2015-11-12

    Specific protein-protein interactions (PPIs) constitute a key underlying mechanism for the presence of a multitude of intracellular signaling pathways, which are essential for the survival of normal and cancer cells. Specific molecular blockers for a crucial PPI would therefore be invaluable tools for an enhanced functional interrogation of the signaling pathway harboring this particular PPI. On the other hand, if a particular PPI is essential for the survival of cancer cells but is absent in or dispensable for the survival of normal cells, its specific molecular blockers could potentially be developed into effective anticancer therapeutics. Due to the flat and extended PPI interface, it would be conceivably difficult for small molecules to achieve an effective blockade, a problem which could be potentially circumvented with peptides or proteins. However, the well-documented proteolytic instability and cellular impermeability of peptides and proteins in general would make their developing into effective intracellular PPI blockers quite a challenge. With the advent of the peptide 'stapling' technology which was demonstrated to be able to stabilize the α-helical conformation of a peptide via bridging two neighboring amino-acid side chains with a 'molecular staple', a linear parent peptide could be transformed into a stronger PPI blocker with enhanced proteolytic stability and cellular permeability. This review will furnish an account on the peptide 'stapling' technology and its exploitation in efforts to achieve an enhanced functional interrogation or manipulation of intracellular signaling pathways especially those that are cancer relevant.

  11. Enhancement of the conductivity detection signal in capillary electrophoresis systems using neutral cyclodextrins as sweeping agents.

    Science.gov (United States)

    Boublík, Milan; Riesová, Martina; Dubský, Pavel; Gaš, Bohuslav

    2018-06-01

    Conductivity detection is a universal detection technique often encountered in electrophoretic separation systems, especially in modern chip-electrophoresis based devices. On the other hand, it is sparsely combined with another contemporary trend of enhancing limits of detection by means of various preconcentration strategies. This can be attributed to the fact that a preconcentration experimental setup usually brings about disturbances in a conductivity baseline. Sweeping with a neutral sweeping agent seems a good candidate for overcoming this problem. A neutral sweeping agent does not hinder the conductivity detection while a charged analyte may preconcentrate on its boundary due to a decrease in its effective mobility. This study investigates such sweeping systems theoretically, by means of computer simulations, and experimentally. A formula is provided for the reliable estimation of the preconcentration factor. Additionally, it is demonstrated that the conductivity signal can significantly benefit from slowing down the analyte and thus the overall signal enhancement can easily overweight amplification caused solely by the sweeping process. The overall enhancement factor can be deduced a priori from the linearized theory of electrophoresis implemented in the PeakMaster freeware. Sweeping by neutral cyclodextrin is demonstrated on an amplification of a conductivity signal of flurbiprofen in a real drug sample. Finally, a possible formation of unexpected system peaks in systems with a neutral sweeping agent is revealed by the computer simulation and confirmed experimentally. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. Fusarium oxysporum volatiles enhance plant growth via affecting auxin transport and signaling

    Directory of Open Access Journals (Sweden)

    Vasileios eBitas

    2015-11-01

    Full Text Available Volatile organic compounds (VOCs have well-documented roles in plant-plant communication and directing animal behavior. In this study, we examine the less understood roles of VOCs in plant-fungal relationships. Phylogenetically and ecologically diverse strains of Fusarium oxysporum, a fungal species complex that often resides in the rhizosphere of assorted plants, produce volatile compounds that augment shoot and root growth of Arabidopsis thaliana and tobacco. Growth responses of A. thaliana hormone signaling mutants and expression patterns of a GUS reporter gene under the auxin-responsive DR5 promoter supported the involvement of auxin signaling in F. oxysporum volatile-mediated growth enhancement. In addition, 1-naphthylthalamic acid, an inhibitor of auxin efflux, negated F. oxysporum volatile-mediated growth enhancement in both plants. Comparison of the profiles of volatile compounds produced by F. oxysporum strains that differentially affected plant growth suggests that the relative compositions of both growth inhibitory and stimulatory compounds may determine the degree of plant growth enhancement. Volatile-mediated signaling between fungi and plants may represent a potentially conserved, yet mostly overlooked, mechanism underpinning plant-fungus interactions and fungal niche adaption.

  13. Lenalidomide induces lipid raft assembly to enhance erythropoietin receptor signaling in myelodysplastic syndrome progenitors.

    Science.gov (United States)

    McGraw, Kathy L; Basiorka, Ashley A; Johnson, Joseph O; Clark, Justine; Caceres, Gisela; Padron, Eric; Heaton, Ruth; Ozawa, Yukiyasu; Wei, Sheng; Sokol, Lubomir; List, Alan F

    2014-01-01

    Anemia remains the principal management challenge for patients with lower risk Myelodysplastic Syndromes (MDS). Despite appropriate cytokine production and cellular receptor display, erythropoietin receptor (EpoR) signaling is impaired. We reported that EpoR signaling is dependent upon receptor localization within lipid raft microdomains, and that disruption of raft integrity abolishes signaling capacity. Here, we show that MDS erythroid progenitors display markedly diminished raft assembly and smaller raft aggregates compared to normal controls (p = 0.005, raft number; p = 0.023, raft size). Because lenalidomide triggers raft coalescence in T-lymphocytes promoting immune synapse formation, we assessed effects of lenalidomide on raft assembly in MDS erythroid precursors and UT7 cells. Lenalidomide treatment rapidly induced lipid raft formation accompanied by EpoR recruitment into raft fractions together with STAT5, JAK2, and Lyn kinase. The JAK2 phosphatase, CD45, a key negative regulator of EpoR signaling, was displaced from raft fractions. Lenalidomide treatment prior to Epo stimulation enhanced both JAK2 and STAT5 phosphorylation in UT7 and primary MDS erythroid progenitors, accompanied by increased STAT5 DNA binding in UT7 cells, and increased erythroid colony forming capacity in both UT7 and primary cells. Raft induction was associated with F-actin polymerization, which was blocked by Rho kinase inhibition. These data indicate that deficient raft integrity impairs EpoR signaling, and provides a novel strategy to enhance EpoR signal fidelity in non-del(5q) MDS.

  14. Optimizing signal intensity correction during evaluation of hepatic parenchymal enhancement on gadoxetate disodium-enhanced MRI: Comparison of three methods

    Energy Technology Data Exchange (ETDEWEB)

    Onoda, Minori, E-mail: onoda@radt.med.kindai.ac.jp [Department of Radiological Technology, Kinki University Hospital, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511 (Japan); Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, Ishikawa 920-0942 (Japan); Hyodo, Tomoko, E-mail: neneth@m.ehime-u.ac.jp [Department of Radiology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511 (Japan); Murakami, Takamichi, E-mail: murakami@med.kindai.ac.jp [Department of Radiology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511 (Japan); Okada, Masahiro, E-mail: okada777@med.u-ryukyu.ac.jp [Department of Radiology, Kinki University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511 (Japan); Uto, Tatsuro, E-mail: chuho@med.kindai.ac.jp [Department of Radiological Technology, Kinki University Hospital, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511 (Japan); Hori, Masatoshi, E-mail: mhori@radiol.med.osaka-u.ac.jp [Department of Radiology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Miyati, Tosiaki, E-mail: ramiyati@mhs.mp.kanazawa-u.ac.jp [Division of Health Sciences, Graduate School of Medical Science, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, Ishikawa 920-0942 (Japan)

    2015-03-15

    Highlights: •Signal intensity is often used to evaluate hepatic enhancement with Gd-EOB-DTPA in the hepatobiliary phase. •Comparison of uncorrected signal intensity with T{sub 1} value revealed signal intensity instability. •Measurement of uncorrected liver SI or SNR often yields erroneous results on late-phase gadoxetate MRI due to shimming and other optimization techniques. •Signal intensity corrected by scale and rescale slope from DICOM data gave comparable results. -- Abstract: Objective: To compare signal intensity (SI) correction using scale and rescale slopes with SI correction using SIs of spleen and muscle for quantifying multiphase hepatic contrast enhancement with Gd-EOB-DTPA by assessing their correlation with T{sub 1} values generated from Look-Locker turbo-field-echo (LL-TFE) sequence data (ER-T{sub 1}). Materials and methods: Thirty patients underwent Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) in this prospective clinical study. For each patient, breath-hold T{sub 1}-weighted fat-suppressed three-dimensional (3D) gradient echo sequences (e-THRIVE) were acquired before and 2 (first phase), 10 (second phase), and 20 min (third phase) after intravenous Gd-EOB-DTPA. Look-Locker turbo-field-echo (LL-TFE) sequences were acquired before and 1.5 (first phase), 8 (second phase), and 18 min (third phase) postcontrast. The liver parenchyma enhancement ratios (ER) of each phase were calculated using the SI from e-THRIVE sequences (ER-SI) and the T{sub 1} values generated from LL-TFE sequence data (ER-T{sub 1}) respectively. ER-SIs were calculated in three ways: (1) comparing with splenic SI (ER-SI-s), (2) comparing with muscle SI (ER-SI-m), (3) using scale and rescale slopes obtained from DICOM headers (ER-SI-c), to eliminate the effects of receiver gain and scaling. For each of the first, second and third phases, correlation and agreement were assessed between each ER-SI and ER-T{sub 1}. Results: In the first phase, all ER-SIs correlated

  15. Kazinol Q from Broussonetia kazinoki Enhances Cell Death Induced by Cu(ll through Increased Reactive Oxygen Species

    Directory of Open Access Journals (Sweden)

    Hsue-Yin Hsu

    2011-04-01

    Full Text Available The ability of the flavan kazinol Q (KQ to induce DNA breakage in the presence of Cu(II was examined by agarose gel electrophoresis using supercoiled plasmid DNA. In KQ-mediated DNA breakage reaction, the involvement of reactive oxygen species (ROS, H2O2 and O2 - was established by the inhibition of DNA breakage by catalase and revealed DNA breakage by superoxide dismutase (SOD. The cell viability of gastric carcinoma SCM-1 cells treated with various concentrations of KQ was significantly decreased by cotreatment with Cu(II. Treatment of SCM-1 cells with 300 μM Cu(II enhanced the necrosis induced by 100 μM KQ. Treatment of SCM-1 cells with 100 mM KQ in the presence of 300 mM Cu(II increased the generation of H2O2. Taken together, the above finding suggested that KQ cotreatment with Cu(II produced increased amounts of H2O2, thus enhancing subsequent cell death due to necrosis.

  16. 1,4 Naphthoquinone protects radiation induced cell death and DNA damage in lymphocytes by activation Nrf2/are pathway and enhancing DNA repair

    Energy Technology Data Exchange (ETDEWEB)

    Khan, Nazir M; Sandur, Santosh K; Checker, Rahul; Sharma, Deepak; Poduval, T.B., E-mail: nazirbiotech@rediffmail.com [Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai (India)

    2012-07-01

    1,4-Naphthoquinone (NQ) is the parent molecule of many clinically approved anticancer, anti-infective, and antiparasitic drugs such as anthracycline, mitomycin, daunorubicin, doxorubicin, diospyrin, and malarone. Presence of NQ during a-irradiation (4Gy) significantly reduced the death of irradiated murine splenic lymphocytes in a dose dependent manner (0.05-liM), with complete protection at liM as assessed by PI staining. Radioprotection by NQ was further confirmed by inhibition of caspase activation, decrease in cell size, DNA-fragmentation, nuclear-blebbing and clonogenic assay. All trans retinoic acid which is inhibitor of Nrf-2 pathway, completely abrogated the radioprotective effect of NQ, suggesting that radioprotective activity of NQ may be due to activation of Nrf-2 signaling pathways. Further, addition of NQ to lymphocytes activated Nrf-2 in time dependent manner as shown by confocal microscopy, electrophoretic mobility shift assay and quantitative real time PCR. It also increased the expression of Nrf-2 dependent cytoprotective genes like hemeoxygenase-1, MnSOD, catalse as demonstrated by real time PCR and flowcytometry. NQ protected lymphocytes significantly against radiation-induced cell death even when added after irradiation. Complete protection was observed by addition of NQ up to 2 h after irradiation. However, percentage protection decreased with increasing time interval. These results suggested that NQ may offer protection to lymphocytes activating repair pathways. Repair of radiation induced DNA strand breaks was studied by comet assay. Pretreatment of lymphocytes with NQ induced single strand breaks up to 6h but not double strand breaks in DNA. However, NQ mediated single strand breaks were repaired completely at longer time intervals. Addition of NQ to lymphocytes prior to 4 Gy a-radiation exposure showed decrease in the yield of DNA double strand breaks. The observed time-dependent decrease in the DNA strand breaks could be attributed to

  17. Age dependence of spleen- and muscle-corrected hepatic signal enhancement on hepatobiliary phase gadoxetate MRI

    Energy Technology Data Exchange (ETDEWEB)

    Matoori, Simon [Paracelsus Medical University Salzburg, Department of Radiology, Salzburg (Austria); Hirslanden Clinic St. Anna, Clinical Research Group, Lucerne (Switzerland); Froehlich, Johannes M. [Hirslanden Clinic St. Anna, Clinical Research Group, Lucerne (Switzerland); ETH Zurich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Zurich (Switzerland); Cantonal Hospital Winterthur, Department of Radiology, Winterthur (Switzerland); Breitenstein, Stefan [Cantonal Hospital Winterthur, Department of Surgery, Clinic for Visceral and Thoracic Surgery, Winterthur (Switzerland); Doert, Aleksis [Cantonal Hospital Winterthur, Department of Radiology, Winterthur (Switzerland); Pozdniakova, Viktoria [Stavanger University Hospital, Department of Radiology, Stavanger (Norway); Koh, Dow-Mu [Royal Marsden Hospital, Department of Radiology, Surrey, England (United Kingdom); Gutzeit, Andreas [Paracelsus Medical University Salzburg, Department of Radiology, Salzburg (Austria); Hirslanden Clinic St. Anna, Clinical Research Group, Lucerne (Switzerland); Cantonal Hospital Winterthur, Department of Radiology, Winterthur (Switzerland)

    2016-06-15

    To identify correlations of signal enhancements (SE) and SE normalized to reference tissues of the spleen, kidney, liver, musculus erector spinae (MES) and ductus hepatocholedochus (DHC) on hepatobiliary phase gadoxetate-enhanced MRI with patient age in non-cirrhotic patients. A heterogeneous cohort of 131 patients with different clinical backgrounds underwent a standardized 3.0-T gadoxetate-enhanced liver MRI between November 2008 and June 2013. After exclusion of cirrhotic patients, a cohort of 75 patients with no diagnosed diffuse liver disease was selected. The ratio of signal intensity 20 min post- to pre-contrast administration (SE) in the spleen, kidney, liver, MES and DHC, and the SE of the kidney, liver and DHC normalized to the reference tissues spleen or MES were compared to patient age. Patient age was inversely correlated with the liver SE normalized to the spleen and MES SE (both p < 0.001) and proportionally with the SE of the spleen (p = 0.043), the MES (p = 0.030) and the kidney (p = 0.022). No significant correlations were observed for the DHC (p = 0.347) and liver SE (p = 0.606). The age dependence of hepatic SE normalized to the enhancement in the spleen and MES calls for a cautious interpretation of these quantification methods. (orig.)

  18. Age dependence of spleen- and muscle-corrected hepatic signal enhancement on hepatobiliary phase gadoxetate MRI

    International Nuclear Information System (INIS)

    Matoori, Simon; Froehlich, Johannes M.; Breitenstein, Stefan; Doert, Aleksis; Pozdniakova, Viktoria; Koh, Dow-Mu; Gutzeit, Andreas

    2016-01-01

    To identify correlations of signal enhancements (SE) and SE normalized to reference tissues of the spleen, kidney, liver, musculus erector spinae (MES) and ductus hepatocholedochus (DHC) on hepatobiliary phase gadoxetate-enhanced MRI with patient age in non-cirrhotic patients. A heterogeneous cohort of 131 patients with different clinical backgrounds underwent a standardized 3.0-T gadoxetate-enhanced liver MRI between November 2008 and June 2013. After exclusion of cirrhotic patients, a cohort of 75 patients with no diagnosed diffuse liver disease was selected. The ratio of signal intensity 20 min post- to pre-contrast administration (SE) in the spleen, kidney, liver, MES and DHC, and the SE of the kidney, liver and DHC normalized to the reference tissues spleen or MES were compared to patient age. Patient age was inversely correlated with the liver SE normalized to the spleen and MES SE (both p < 0.001) and proportionally with the SE of the spleen (p = 0.043), the MES (p = 0.030) and the kidney (p = 0.022). No significant correlations were observed for the DHC (p = 0.347) and liver SE (p = 0.606). The age dependence of hepatic SE normalized to the enhancement in the spleen and MES calls for a cautious interpretation of these quantification methods. (orig.)

  19. The application of empirical mode decomposition for the enhancement of cardiotocograph signals

    International Nuclear Information System (INIS)

    Krupa, B N; Mohd Ali, M A; Zahedi, E

    2009-01-01

    Cardiotocograph (CTG) is widely used in everyday clinical practice for fetal surveillance, where it is used to record fetal heart rate (FHR) and uterine activity (UA). These two biosignals can be used for antepartum and intrapartum fetal monitoring and are, in fact, nonlinear and non-stationary. CTG recordings are often corrupted by artifacts such as missing beats in FHR, high-frequency noise in FHR and UA signals. In this paper, an empirical mode decomposition (EMD) method is applied on CTG signals. A recursive algorithm is first utilized to eliminate missing beats. High-frequency noise is reduced using EMD followed by the partial reconstruction (PAR) method, where the noise order is identified by a statistical method. The obtained signal enhancement from the proposed method is validated by comparing the resulting traces with the output obtained by applying classical signal processing methods such as Butterworth low-pass filtering, linear interpolation and a moving average filter on 12 CTG signals. Three obstetricians evaluated all 12 sets of traces and rated the proposed method, on average, 3.8 out of 5 on a scale of 1(lowest) to 5 (highest)

  20. Tyk2 expression and its signaling enhances the invasiveness of prostate cancer cells

    International Nuclear Information System (INIS)

    Ide, Hisamitsu; Nakagawa, Takashi; Terado, Yuichi; Kamiyama, Yutaka; Muto, Satoru; Horie, Shigeo

    2008-01-01

    Protein tyrosine kinase plays a central role in the proliferation and differentiation of various types of cells. One of these protein kinases, Tyk2, a member of the Jak family kinases, is known to play important roles in receptor signal transduction by interferons, interleukins, growth factors, and other hormones. In the present study, we investigated Tyk2 expression and its role in the growth and invasiveness of human prostate cancer cells. We used a small interfering RNA targeting Tyk2 and an inhibitor of Tyk2, tyrphostin A1, to suppress the expression and signaling of Tyk2 in prostate cancer cells. We detected mRNAs for Jak family kinases in prostate cancer cell lines by RT-PCR and Tyk2 protein in human prostate cancer specimens by immunohistochemistry. Inhibition of Tyk2 signaling resulted in attenuation of the urokinase-type plasminogen activator-enhanced invasiveness of prostate cancer cells in vitro without affecting the cellular growth rate. These results suggest that Tyk2 signaling in prostate cancer cells facilitate invasion of these cells, and interference with this signaling may be a potential therapeutic pathway

  1. Blocking type I interferon signaling enhances T cell recovery and reduces HIV-1 reservoirs.

    Science.gov (United States)

    Cheng, Liang; Ma, Jianping; Li, Jingyun; Li, Dan; Li, Guangming; Li, Feng; Zhang, Qing; Yu, Haisheng; Yasui, Fumihiko; Ye, Chaobaihui; Tsao, Li-Chung; Hu, Zhiyuan; Su, Lishan; Zhang, Liguo

    2017-01-03

    Despite the efficient suppression of HIV-1 replication that can be achieved with combined antiretroviral therapy (cART), low levels of type I interferon (IFN-I) signaling persist in some individuals. This sustained signaling may impede immune recovery and foster viral persistence. Here we report studies using a monoclonal antibody to block IFN-α/β receptor (IFNAR) signaling in humanized mice (hu-mice) that were persistently infected with HIV-1. We discovered that effective cART restored the number of human immune cells in HIV-1-infected hu-mice but did not rescue their immune hyperactivation and dysfunction. IFNAR blockade fully reversed HIV-1-induced immune hyperactivation and rescued anti-HIV-1 immune responses in T cells from HIV-1-infected hu-mice. Finally, we found that IFNAR blockade in the presence of cART reduced the size of HIV-1 reservoirs in lymphoid tissues and delayed HIV-1 rebound after cART cessation in the HIV-1-infected hu-mice. We conclude that low levels of IFN-I signaling contribute to HIV-1-associated immune dysfunction and foster HIV-1 persistence in cART-treated hosts. Our results suggest that blocking IFNAR may provide a potential strategy to enhance immune recovery and reduce HIV-1 reservoirs in individuals with sustained elevations in IFN-I signaling during suppressive cART.

  2. Enhancement of the Signal-to-Noise Ratio in Sonic Logging Waveforms by Seismic Interferometry

    KAUST Repository

    Aldawood, Ali

    2012-04-01

    Sonic logs are essential tools for reliably identifying interval velocities which, in turn, are used in many seismic processes. One problem that arises, while logging, is irregularities due to washout zones along the borehole surfaces that scatters the transmitted energy and hence weakens the signal recorded at the receivers. To alleviate this problem, I have extended the theory of super-virtual refraction interferometry to enhance the signal-to-noise ratio (SNR) sonic waveforms. Tests on synthetic and real data show noticeable signal-to-noise ratio (SNR) enhancements of refracted P-wave arrivals in the sonic waveforms. The theory of super-virtual interferometric stacking is composed of two redatuming steps followed by a stacking procedure. The first redatuming procedure is of correlation type, where traces are correlated together to get virtual traces with the sources datumed to the refractor. The second datuming step is of convolution type, where traces are convolved together to dedatum the sources back to their original positions. The stacking procedure following each step enhances the signal to noise ratio of the refracted P-wave first arrivals. Datuming with correlation and convolution of traces introduces severe artifacts denoted as correlation artifacts in super-virtual data. To overcome this problem, I replace the datuming with correlation step by datuming with deconvolution. Although the former datuming method is more robust, the latter one reduces the artifacts significantly. Moreover, deconvolution can be a noise amplifier which is why a regularization term is utilized, rendering the datuming with deconvolution more stable. Tests of datuming with deconvolution instead of correlation with synthetic and real data examples show significant reduction of these artifacts. This is especially true when compared with the conventional way of applying the super-virtual refraction interferometry method.

  3. Dealing with the problem of non-specific in situ mRNA hybridization signals associated with plant tissues undergoing programmed cell death

    Directory of Open Access Journals (Sweden)

    Jokela Anne

    2010-02-01

    Full Text Available Abstract Background In situ hybridization is a general molecular method typically used for the localization of mRNA transcripts in plants. The method provides a valuable tool to unravel the connection between gene expression and anatomy, especially in species such as pines which show large genome size and shortage of sequence information. Results In the present study, expression of the catalase gene (CAT related to the scavenging of reactive oxygen species (ROS and the polyamine metabolism related genes, diamine oxidase (DAO and arginine decarboxylase (ADC, were localized in developing Scots pine (Pinus sylvestris L. seeds. In addition to specific signals from target mRNAs, the probes continually hybridized non-specifically in the embryo surrounding region (ESR of the megagametophyte tissue, in the remnants of the degenerated suspensors as well as in the cells of the nucellar layers, i.e. tissues exposed to cell death processes and extensive nucleic acid fragmentation during Scots pine seed development. Conclusions In plants, cell death is an integral part of both development and defence, and hence it is a common phenomenon in all stages of the life cycle. Our results suggest that extensive nucleic acid fragmentation during cell death processes can be a considerable source of non-specific signals in traditional in situ mRNA hybridization. Thus, the visualization of potential nucleic acid fragmentation simultaneously with the in situ mRNA hybridization assay may be necessary to ensure the correct interpretation of the signals in the case of non-specific hybridization of probes in plant tissues.

  4. XIAP is not required for human tumor cell survival in the absence of an exogenous death signal

    International Nuclear Information System (INIS)

    Sensintaffar, John; Scott, Fiona L; Peach, Robert; Hager, Jeffrey H

    2010-01-01

    The X-linked Inhibitor of Apoptosis (XIAP) has attracted much attention as a cancer drug target. It is the only member of the IAP family that can directly inhibit caspase activity in vitro, and it can regulate apoptosis and other biological processes through its C-terminal E3 ubiquitin ligase RING domain. However, there is controversy regarding XIAP's role in regulating tumor cell proliferation and survival under normal growth conditions in vitro. We utilized siRNA to systematically knock down XIAP in ten human tumor cell lines and then monitored both XIAP protein levels and cell viability over time. To examine the role of XIAP in the intrinsic versus extrinsic cell death pathways, we compared the viability of XIAP depleted cells treated either with a variety of mechanistically distinct, intrinsic pathway inducing agents, or the canonical inducer of the extrinsic pathway, TNF-related apoptosis-inducing ligand (TRAIL). XIAP knockdown had no effect on the viability of six cell lines, whereas the effect in the other four was modest and transient. XIAP knockdown only sensitized tumor cells to TRAIL and not the mitochondrial pathway inducing agents. These data indicate that XIAP has a more central role in regulating death receptor mediated apoptosis than it does the intrinsic pathway mediated cell death

  5. Insulin receptor substrate 1 expression enhances the sensitivity of 32D cells to chemotherapy-induced cell death

    Science.gov (United States)

    Porter, Holly A.; Carey, Gregory B.; Keegan, Achsah D.

    2012-01-01

    The adaptors IRS1 and IRS2 link growth factor receptors to downstream signaling pathways that regulate proliferation and survival. Both suppress factor-withdrawal-induced apoptosis and have been implicated in cancer progression. However, recent studies suggest IRS1 and IRS2 mediate differential functions in cancer pathogenesis. IRS1 promoted breast cancer proliferation, while IRS2 promoted metastasis. The role of IRS1 and IRS2 in controlling cell responses to chemotherapy is unknown. To determine the role of IRS1 and IRS2 in the sensitivity of cells to chemotherapy, we treated 32D cells lacking or expressing IRS proteins with various concentrations of chemotherapeutic agents. We found that expression of IRS1, in contrast to IRS2, enhanced the sensitivity of 32D cells to chemotherapy-induced apoptosis. When IRS2 was expressed with IRS1, the cells no longer showed enhanced sensitivity. Expression of IRS1 did not alter the expression of pro- and anti-apoptotic proteins; however, 32D-IRS1 cells expressed higher levels of Annexin A2. In 32D-IRS1 cells, IRS1 and Annexin A2 were both located in cytoplasmic and membrane fractions. We also found that IRS1 coprecipitated with Annexin A2, while IRS2 did not. Decreasing Annexin A2 levels reduced 32D-IRS1 cell sensitivity to chemotherapy. These results suggest IRS1 enhances sensitivity to chemotherapy in part through Annexin A2. PMID:22652453

  6. Real-time implementations of acoustic signal enhancement techniques for aerial based surveillance and rescue applications

    Science.gov (United States)

    Ramos, Antonio L. L.; Shao, Zhili; Holthe, Aleksander; Sandli, Mathias F.

    2017-05-01

    The introduction of the System-on-Chip (SoC) technology has brought exciting new opportunities for the development of smart low cost embedded systems spanning a wide range of applications. Currently available SoC devices are capable of performing high speed digital signal processing tasks in software while featuring relatively low development costs and reduced time-to-market. Unmanned aerial vehicles (UAV) are an application example that has shown tremendous potential in an increasing number of scenarios, ranging from leisure to surveillance as well as in search and rescue missions. Video capturing from UAV platforms is a relatively straightforward task that requires almost no preprocessing. However, that does not apply to audio signals, especially in cases where the data is to be used to support real-time decision making. In fact, the enormous amount of acoustic interference from the surroundings, including the noise from the UAVs propellers, becomes a huge problem. This paper discusses a real-time implementation of the NLMS adaptive filtering algorithm applied to enhancing acoustic signals captured from UAV platforms. The model relies on a combination of acoustic sensors and a computational inexpensive algorithm running on a digital signal processor. Given its simplicity, this solution can be incorporated into the main processing system of an UAV using the SoC technology, and run concurrently with other required tasks, such as flight control and communications. Simulations and real-time DSP-based implementations have shown significant signal enhancement results by efficiently mitigating the interference from the noise generated by the UAVs propellers as well as from other external noise sources.

  7. Activation of apoptosis signal-regulating kinase 1 is a key factor in paraquat-induced cell death: modulation by the Nrf2/Trx axis.

    Science.gov (United States)

    Niso-Santano, Mireia; González-Polo, Rosa A; Bravo-San Pedro, José M; Gómez-Sánchez, Rubén; Lastres-Becker, Isabel; Ortiz-Ortiz, Miguel A; Soler, Germán; Morán, José M; Cuadrado, Antonio; Fuentes, José M

    2010-05-15

    Although oxidative stress is fundamental to the etiopathology of Parkinson disease, the signaling molecules involved in transduction after oxidant exposure to cell death are ill-defined, thus making it difficult to identify molecular targets of therapeutic relevance. We have addressed this question in human dopaminergic neuroblastoma SH-SY5Y cells exposed to the parkinsonian toxin paraquat (PQ). This toxin elicited a dose-dependent increase in reactive oxygen species and cell death that correlated with activation of ASK1 and the stress kinases p38 and JNK. The relevance of these kinases in channeling PQ neurotoxicity was demonstrated with the use of interference RNA for ASK1 and two well-established pharmaceutical inhibitors for JNK and p38. The toxic effect of PQ was substantially attenuated by preincubation with vitamin E, blocking ASK1 pathways and preventing oxidative stress and cell death. In a search for a physiological pathway that might counterbalance PQ-induced ASK1 activation, we analyzed the role of the transcription factor Nrf2, master regulator of redox homeostasis, and its target thioredoxin (Trx), which binds and inhibits ASK1. Trx levels were undetectable in Nrf2-deficient mouse embryo fibroblasts (MEFs), whereas they were constitutively high in Keap1-deficient MEFs as well as in SH-SY5Y cells treated with sulforaphane (SFN). Consistent with these data, Nrf2-deficient MEFs were more sensitive and Keap1-deficient MEFs and SH-SY5Y cells incubated with SFN were more resistant to PQ-induced cell death. This study identifies ASK1/JNK and ASK1/p38 as two critical pathways involved in the activation of cell death under oxidative stress conditions and identifies the Nrf2/Trx axis as a new target to block these pathways and protect from oxidant exposure such as that found in Parkinson and other neurodegenerative diseases. Copyright 2010 Elsevier Inc. All rights reserved.

  8. Mycotoxin zearalenone induces AIF- and ROS-mediated cell death through p53- and MAPK-dependent signaling pathways in RAW264.7 macrophages.

    Science.gov (United States)

    Yu, Ji-Yeon; Zheng, Zhong-Hua; Son, Young-Ok; Shi, Xianglin; Jang, Young-Oh; Lee, Jeong-Chae

    2011-12-01

    Zearalenone (ZEN) is commonly found in many food commodities and is known to cause reproductive disorders and genotoxic effects. However, the mode of ZEN-induced cell death of macrophages and the mechanisms by which ZEN causes cytotoxicity remain unclear. The present study shows that ZEN treatment reduces viability of RAW264.7 cells in a dose-dependent manner. ZEN causes predominantly necrotic and late apoptotic cell death. ZEN treatment also results in the loss of mitochondrial membrane potential (MMP), mitochondrial changes in Bcl-2 and Bax proteins, and cytoplasmic release of cytochrome c and apoptosis-inducing factor (AIF). Pre-treatment of the cells with either z-VAD-fmk or z-IETD-fmk does not attenuate ZEN-mediated cell death, whereas catalase suppresses the ZEN-induced decrease in viability in RAW264.7 cells. Treating the cells with c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), or p53 inhibitor prevented ZEN-mediated changes, such as MMP loss, cellular reactive oxygen species (ROS) increase, and cell death. JNK or p38 MAPK inhibitor inhibited mitochondrial alterations of Bcl-2 and Bax proteins with attendant decreases in cellular ROS levels. Knockdown of AIF via siRNA transfection also diminished ZEN-induced cell death. Further, adenosine triphosphate was markedly depleted in the ZEN-exposed cells. Collectively, these results suggest that ZEN induces cytotoxicity in RAW264.7 cells via AIF- and ROS-mediated signaling, in which the activations of p53 and JNK/p38 play a key role. Copyright © 2011 Elsevier Ltd. All rights reserved.

  9. Select polyphenolic fractions from dried plum enhance osteoblast activity through BMP-2 signaling.

    Science.gov (United States)

    Graef, Jennifer L; Rendina-Ruedy, Elizabeth; Crockett, Erica K; Ouyang, Ping; King, Jarrod B; Cichewicz, Robert H; Lucas, Edralin A; Smith, Brenda J

    2018-05-01

    Dried plum supplementation has been shown to enhance bone formation while suppressing bone resorption. Evidence from previous studies has demonstrated that these responses can be attributed in part to the fruit's polyphenolic compounds. The purpose of this study was to identify the most bioactive polyphenolic fractions of dried plum with a focus on their osteogenic activity and to investigate their mechanisms of action under normal and inflammatory conditions. Utilizing chromatographic techniques, six fractions of polyphenolic compounds were prepared from a crude extract of dried plum. Initial screening assays revealed that two fractions (DP-FrA and DP-FrB) had the greatest osteogenic potential. Subsequent experiments using primary bone-marrow-derived osteoblast cultures demonstrated these two fractions enhanced extracellular alkaline phosphatase (ALP), an indicator of osteoblast activity, and mineralized nodule formation under normal conditions. Both fractions enhanced bone morphogenetic protein (BMP) signaling, as indicated by increased Bmp2 and Runx2 gene expression and protein levels of phosphorylated Smad1/5. DP-FrB was most effective at up-regulating Tak1 and Smad1, as well as protein levels of phospho-p38. Under inflammatory conditions, TNF-α suppressed ALP and tended to decrease nodule formation (P=.0674). This response coincided with suppressed gene expression of Bmp2 and the up-regulation of Smad6, an inhibitor of BMP signaling. DP-FrA and DP-FrB partially normalized these responses. Our results show that certain fractions of polyphenolic compounds in dried plum up-regulate osteoblast activity by enhancing BMP signaling, and when this pathway is inhibited by TNF-α, the osteogenic response is attenuated. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Enhancement of cell death by TNF α-related apoptosis-inducing ligand (TRAIL) in human lung carcinoma A549 cells exposed to X rays under hypoxia

    International Nuclear Information System (INIS)

    Takahashi, Momoko; Inanami, Osamu; Yasui, Hironobu; Ogura, Aki; Kuwabara, Mikinori; Kubota, Nobuo; Tsujitani, Michihiko

    2007-01-01

    Our previous study showed that ionizing radiation induced the expression of death receptor DR5 on the cell surface in tumor cell lines and that the death receptor of the TNF α-related apoptosis-inducing ligand TRAIL enhanced the apoptotic pathway (Hamasu et al., (2005) Journal of Radiation Research, 46:103-110). The present experiments were performed to examine whether treatment with TRAIL enhanced the cell killing in tumor cells exposed to ionizing radiation under hypoxia, since the presence of radioresistant cells in hypoxic regions of solid tumors is a serious problem in radiation therapy for tumors. When human lung carcinoma A549 cells were irradiated under normoxia and hypoxia, respectively, radiation-induced enhancement of expression of DR5 was observed under both conditions. Incubation in the presence of TRAIL enhanced the caspase-dependent and chymotrypsin-like-protease-dependent apoptotic cell death in A549 cells exposed to X rays. Furthermore, it was shown that treatment with TRAIL enhanced apoptotic cell death and loss of clonogenic ability in A549 cells exposed to X rays not only under normoxia but also under hypoxia, suggesting that combination treatment with TRAIL and X irradiation is effective for hypoxic tumor cells. (author)

  11. Effect of the size of silver nanoparticles on SERS signal enhancement

    Science.gov (United States)

    He, Rui Xiu; Liang, Robert; Peng, Peng; Norman Zhou, Y.

    2017-08-01

    The localized surface plasmon resonance arising from plasmonic materials is beneficial in solution-based and thin-film sensing applications, which increase the sensitivity of the analyte being tested. Silver nanoparticles from 35 to 65 nm in diameter were synthesized using a low-temperature method and deposited in a monolayer on a (3-aminopropyl)triethoxysilane (APTES)-functionalized glass slide. The effect of particle size on monolayer structure, optical behavior, and surface-enhanced Raman scattering (SERS) is studied. While increasing particle size decreases particle coverage, it also changes the localized surface plasmon resonance and thus the SERS activity of individual nanoparticles. Using a laser excitation wavelength of 633 nm, the stronger localized surface plasmon resonance coupling to this excitation wavelength at larger particle sizes trumps the loss in surface coverage, and greater SERS signals are observed. The SERS signal enhancement accounts for the higher SERS signal, which was verified using a finite element model of a silver nanoparticle dimer with various nanoparticle sizes and separation distances.

  12. Correlation dynamics and enhanced signals for the identification of serial biomolecules and DNA bases

    International Nuclear Information System (INIS)

    Ahmed, Towfiq; Haraldsen, Jason T; Balatsky, Alexander V; Rehr, John J; Di Ventra, Massimiliano; Schuller, Ivan

    2014-01-01

    Nanopore-based sequencing has demonstrated a significant potential for the development of fast, accurate, and cost-efficient fingerprinting techniques for next generation molecular detection and sequencing. We propose a specific multilayered graphene-based nanopore device architecture for the recognition of single biomolecules. Molecular detection and analysis can be accomplished through the detection of transverse currents as the molecule or DNA base translocates through the nanopore. To increase the overall signal-to-noise ratio and the accuracy, we implement a new ‘multi-point cross-correlation’ technique for identification of DNA bases or other molecules on the single molecular level. We demonstrate that the cross-correlations between each nanopore will greatly enhance the transverse current signal for each molecule. We implement first-principles transport calculations for DNA bases surveyed across a multilayered graphene nanopore system to illustrate the advantages of the proposed geometry. A time-series analysis of the cross-correlation functions illustrates the potential of this method for enhancing the signal-to-noise ratio. This work constitutes a significant step forward in facilitating fingerprinting of single biomolecules using solid state technology. (paper)

  13. Correlation dynamics and enhanced signals for the identification of serial biomolecules and DNA bases

    Science.gov (United States)

    Ahmed, Towfiq; Haraldsen, Jason T.; Rehr, John J.; Di Ventra, Massimiliano; Schuller, Ivan; Balatsky, Alexander V.

    2014-03-01

    Nanopore-based sequencing has demonstrated a significant potential for the development of fast, accurate, and cost-efficient fingerprinting techniques for next generation molecular detection and sequencing. We propose a specific multilayered graphene-based nanopore device architecture for the recognition of single biomolecules. Molecular detection and analysis can be accomplished through the detection of transverse currents as the molecule or DNA base translocates through the nanopore. To increase the overall signal-to-noise ratio and the accuracy, we implement a new ‘multi-point cross-correlation’ technique for identification of DNA bases or other molecules on the single molecular level. We demonstrate that the cross-correlations between each nanopore will greatly enhance the transverse current signal for each molecule. We implement first-principles transport calculations for DNA bases surveyed across a multilayered graphene nanopore system to illustrate the advantages of the proposed geometry. A time-series analysis of the cross-correlation functions illustrates the potential of this method for enhancing the signal-to-noise ratio. This work constitutes a significant step forward in facilitating fingerprinting of single biomolecules using solid state technology.

  14. Insulin receptor substrate 1 expression enhances the sensitivity of 32D cells to chemotherapy-induced cell death

    International Nuclear Information System (INIS)

    Porter, Holly A.; Carey, Gregory B.; Keegan, Achsah D.

    2012-01-01

    The adapters IRS1 and IRS2 link growth factor receptors to downstream signaling pathways that regulate proliferation and survival. Both suppress factor-withdrawal-induced apoptosis and have been implicated in cancer progression. However, recent studies suggest IRS1 and IRS2 mediate differential functions in cancer pathogenesis. IRS1 promoted breast cancer proliferation, while IRS2 promoted metastasis. The role of IRS1 and IRS2 in controlling cell responses to chemotherapy is unknown. To determine the role of IRS1 and IRS2 in the sensitivity of cells to chemotherapy, we treated 32D cells lacking or expressing IRS proteins with various concentrations of chemotherapeutic agents. We found that expression of IRS1, in contrast to IRS2, enhanced the sensitivity of 32D cells to chemotherapy-induced apoptosis. When IRS2 was expressed with IRS1, the cells no longer showed enhanced sensitivity. Expression of IRS1 did not alter the expression of pro- and anti-apoptotic proteins; however, 32D-IRS1 cells expressed higher levels of Annexin A2. In 32D-IRS1 cells, IRS1 and Annexin A2 were both located in cytoplasmic and membrane fractions. We also found that IRS1 coprecipitated with Annexin A2, while IRS2 did not. Decreasing Annexin A2 levels reduced 32D-IRS1 cell sensitivity to chemotherapy. These results suggest IRS1 enhances sensitivity to chemotherapy in part through Annexin A2. -- Highlights: ► IRS1 enhanced the sensitivity of 32D cells to chemotherapy-induced apoptosis. ► This sensitivity is abrogated by the expression of IRS2. ► Expressing IRS1 in 32D cells increased levels of Annexin A2. ► Both IRS1 and Annexin A2 were located in cytoplasmic and membrane fractions. ► Decreasing Annexin A2 in 32D-IRS1 cells abated their sensitivity to chemotherapy.

  15. Temporal dependence of in vivo USPIO-enhanced MRI signal changes in human carotid atheromatous plaques

    Energy Technology Data Exchange (ETDEWEB)

    Tang, T.Y.; Sadat, U. [Cambridge University Hospitals NHS Foundation Trust, University Department of Radiology, Cambridge (United Kingdom); Cambridge University Hospitals NHS Foundation Trust, Cambridge Vascular Unit, Cambridge (United Kingdom); Patterson, A.J.; Graves, M.J.; Howarth, S.P.S.; U-King-Im, J.M.; Li, Z.Y.; Young, V.E.; Gillard, J.H. [Cambridge University Hospitals NHS Foundation Trust, University Department of Radiology, Cambridge (United Kingdom); Miller, S.R. [GlaxoSmithKline, Biostatistics and Data Sciences, Harlow (United Kingdom); Walsh, S.R.; Boyle, J.R.; Gaunt, M.E. [Cambridge University Hospitals NHS Foundation Trust, Cambridge Vascular Unit, Cambridge (United Kingdom)

    2009-07-15

    Ultrasmall superparamagnetic iron oxide (USPIO)-enhanced MRI has been shown to be a useful modality to image activated macrophages in vivo, which are principally responsible for plaque inflammation. This study determined the optimum imaging time-window to detect maximal signal change post-USPIO infusion using T{sub 1}-weighted (T{sub 1}w), T{sub 2}*-weighted (T{sub 2}*w) and quantitative T{sub 2}* (qT{sub 2}*) imaging. Six patients with an asymptomatic carotid stenosis underwent high resolution T{sub 1}w, T{sub 2}*w and qT{sub 2}* MR imaging of their carotid arteries at 1.5 T. Imaging was performed before and at 24, 36, 48, 72 and 96 h after USPIO (Sinerem trademark, Guerbet, France) infusion. Each slice showing atherosclerotic plaque was manually segmented into quadrants and signal changes in each quadrant were fitted to an exponential power function to model the optimum time for post-infusion imaging. The power function determining the mean time to convergence for all patients was 46, 41 and 39 h for the T{sub 1}w, T{sub 2}*w and qT{sub 2}* sequences, respectively. When modelling each patient individually, 90% of the maximum signal intensity change was observed at 36 h for three, four and six patients on T{sub 1}w, T{sub 2}*w and qT{sub 2}*, respectively. The rates of signal change decrease after this period but signal change was still evident up to 96 h. This study showed that a suitable imaging window for T{sub 1}w, T{sub 2}*w and qT{sub 2}* signal changes post-USPIO infusion was between 36 and 48 h. Logistically, this would be convenient in bringing patients back for one post-contrast MRI, but validation is required in a larger cohort of patients. (orig.)

  16. Temporal dependence of in vivo USPIO-enhanced MRI signal changes in human carotid atheromatous plaques

    International Nuclear Information System (INIS)

    Tang, T.Y.; Sadat, U.; Patterson, A.J.; Graves, M.J.; Howarth, S.P.S.; U-King-Im, J.M.; Li, Z.Y.; Young, V.E.; Gillard, J.H.; Miller, S.R.; Walsh, S.R.; Boyle, J.R.; Gaunt, M.E.

    2009-01-01

    Ultrasmall superparamagnetic iron oxide (USPIO)-enhanced MRI has been shown to be a useful modality to image activated macrophages in vivo, which are principally responsible for plaque inflammation. This study determined the optimum imaging time-window to detect maximal signal change post-USPIO infusion using T 1 -weighted (T 1 w), T 2 *-weighted (T 2 *w) and quantitative T 2 * (qT 2 *) imaging. Six patients with an asymptomatic carotid stenosis underwent high resolution T 1 w, T 2 *w and qT 2 * MR imaging of their carotid arteries at 1.5 T. Imaging was performed before and at 24, 36, 48, 72 and 96 h after USPIO (Sinerem trademark, Guerbet, France) infusion. Each slice showing atherosclerotic plaque was manually segmented into quadrants and signal changes in each quadrant were fitted to an exponential power function to model the optimum time for post-infusion imaging. The power function determining the mean time to convergence for all patients was 46, 41 and 39 h for the T 1 w, T 2 *w and qT 2 * sequences, respectively. When modelling each patient individually, 90% of the maximum signal intensity change was observed at 36 h for three, four and six patients on T 1 w, T 2 *w and qT 2 *, respectively. The rates of signal change decrease after this period but signal change was still evident up to 96 h. This study showed that a suitable imaging window for T 1 w, T 2 *w and qT 2 * signal changes post-USPIO infusion was between 36 and 48 h. Logistically, this would be convenient in bringing patients back for one post-contrast MRI, but validation is required in a larger cohort of patients. (orig.)

  17. Enhanced NMDA receptor-mediated intracellular calcium signaling in magnocellular neurosecretory neurons in heart failure rats.

    Science.gov (United States)

    Stern, Javier E; Potapenko, Evgeniy S

    2013-08-15

    An enhanced glutamate excitatory function within the hypothalamic supraoptic and paraventricluar nuclei is known to contribute to increased neurosecretory and presympathetic neuronal activity, and hence, neurohumoral activation, during heart failure (HF). Still, the precise mechanisms underlying enhanced glutamate-driven neuronal activity in HF remain to be elucidated. Here, we performed simultaneous electrophysiology and fast confocal Ca²⁺ imaging to determine whether altered N-methyl-d-aspartate (NMDA) receptor-mediated changes in intracellular Ca²⁺ levels (NMDA-ΔCa²⁺) occurred in hypothalamic magnocellular neurosecretory cells (MNCs) in HF rats. We found that activation of NMDA receptors resulted in a larger ΔCa²⁺ in MNCs from HF when compared with sham rats. The enhanced NMDA-ΔCa²⁺ was neither dependent on the magnitude of the NMDA-mediated current (voltage clamp) nor on the degree of membrane depolarization or firing activity evoked by NMDA (current clamp). Differently from NMDA receptor activation, firing activity evoked by direct membrane depolarization resulted in similar changes in intracellular Ca²⁺ in sham and HF rats. Taken together, our results support a relatively selective alteration of intracellular Ca²⁺ homeostasis and signaling following activation of NMDA receptors in MNCs during HF. The downstream functional consequences of such altered ΔCa²⁺ signaling during HF are discussed.

  18. Human engineering design considerations for the use of signal color enhancement in ASW displays

    Energy Technology Data Exchange (ETDEWEB)

    Banks, W.W.

    1990-11-01

    The Lawrence Livermore National Laboratory (LLNL) was requested to examine and define man-machine limits as part of the Office of Naval Technology's High Gain Initiative program (HGI). As an initial investigative area, LLNL's Systems and Human Performance effort focused upon color display interfaces and the use of color enhancement techniques to define human and system interface limits in signal detection and discrimination tasks. The knowledgeable and prudent use of color in different types of display is believed to facilitate human visual detection, discrimination and recognition in complex visual tasks. The consideration and understanding of the complex set of interacting variables associated with the prudent use of color is essential to optimize human performance, especially in the ASW community. The designers of advanced display technology and signal processing algorithms may be eventually called upon to present pre-processed information to ASW operators and researchers using the latest color enhancement techniques. These techniques, however, may be limited if one does not understand the complexity and limits of human information processing which reflects the assessed state of knowledge relevant to the use of color in displays. The initial sections of this report discuss various aspects of color presentation and the problems typically encountered, while the last section deals with a specific research proposal required to further our understanding and proper use of color enhancement methods.

  19. Using hyperentanglement to enhance resolution, signal-to-noise ratio, and measurement time

    Science.gov (United States)

    Smith, James F.

    2017-03-01

    A hyperentanglement-based atmospheric imaging/detection system involving only a signal and an ancilla photon will be considered for optical and infrared frequencies. Only the signal photon will propagate in the atmosphere and its loss will be classical. The ancilla photon will remain within the sensor experiencing low loss. Closed form expressions for the wave function, normalization, density operator, reduced density operator, symmetrized logarithmic derivative, quantum Fisher information, quantum Cramer-Rao lower bound, coincidence probabilities, probability of detection, probability of false alarm, probability of error after M measurements, signal-to-noise ratio, quantum Chernoff bound, time-on-target expressions related to probability of error, and resolution will be provided. The effect of noise in every mode will be included as well as loss. The system will provide the basic design for an imaging/detection system functioning at optical or infrared frequencies that offers better than classical angular and range resolution. Optimization for enhanced resolution will be included. The signal-to-noise ratio will be increased by a factor equal to the number of modes employed during the hyperentanglement process. Likewise, the measurement time can be reduced by the same factor. The hyperentanglement generator will typically make use of entanglement in polarization, energy-time, orbital angular momentum and so on. Mathematical results will be provided describing the system's performance as a function of loss mechanisms and noise.

  20. BAMBI Promotes C2C12 Myogenic Differentiation by Enhancing Wnt/β-Catenin Signaling

    Directory of Open Access Journals (Sweden)

    Qiangling Zhang

    2015-08-01

    Full Text Available Bone morphogenic protein and activin membrane-bound inhibitor (BAMBI is regarded as an essential regulator of cell proliferation and differentiation that represses transforming growth factor-β and enhances Wnt/β-catenin signaling in various cell types. However, its role in skeletal muscle remains largely unknown. In the current study, we found that the expression level of BAMBI peaked in the early differentiation phase of the C2C12 rodent myoblast cell line. Knockdown of BAMBI via siRNA inhibited C2C12 differentiation, indicated by repressed MyoD, MyoG, and MyHC expression as well as reductions in the differentiation and fusion indices. BAMBI knockdown reduced the activity of Wnt/β-catenin signaling, as characterized by the decreased nuclear translocation of β-catenin and the lowered transcription of Axin2, which is a well-documented target gene of the Wnt/β-catenin signaling pathway. Furthermore, treatment with LiCl, an activator of Wnt/β-catenin signaling, rescued the reduction in C2C12 differentiation caused by BAMBI siRNA. Taken together, our data suggest that BAMBI is required for normal C2C12 differentiation, and that its role in myogenesis is mediated by the Wnt/β-catenin pathway.

  1. RBP-Jκ-dependent Notch signaling enhances retinal pigment epithelial cell proliferation in transgenic mice.

    Science.gov (United States)

    Schouwey, K; Aydin, I T; Radtke, F; Beermann, F

    2011-01-20

    The Notch signaling pathway is an ubiquitous cell-cell interaction mechanism, which is essential in controlling processes like cell proliferation, cell fate decision, differentiation or stem cell maintenance. Recent data have shown that Notch signaling is RBP-Jκ-dependent in melanocytes, being required for survival of these pigment cells that are responsible for coloration of the skin and hairs in mammals. In addition, Notch is believed to function as an oncogene in melanoma, whereas it is a tumor suppressor in mouse epidermis. In this study, we addressed the implication of the Notch signaling in the development of another population of pigment cells forming the retinal pigment epithelium (RPE) in mammalian eyes. The constitutive activity of Notch in Tyrp1::NotchIC/° transgenic mice enhanced RPE cell proliferation, and the resulting RPE-derived pigmented tumor severely affected the overall eye structure. This RPE cell proliferation is dependent on the presence of the transcription factor RBP-Jκ, as it is rescued in mice lacking RBP-Jκ in the RPE. In conclusion, Notch signaling in the RPE uses the canonical pathway, which is dependent on the transcription factor RBP-Jκ. In addition, it is of importance for RPE development, and constitutive Notch activity leads to hyperproliferation and benign tumors of these pigment cells.

  2. Distal axotomy enhances retrograde presynaptic excitability onto injured pyramidal neurons via trans-synaptic signaling.

    Science.gov (United States)

    Nagendran, Tharkika; Larsen, Rylan S; Bigler, Rebecca L; Frost, Shawn B; Philpot, Benjamin D; Nudo, Randolph J; Taylor, Anne Marion

    2017-09-20

    Injury of CNS nerve tracts remodels circuitry through dendritic spine loss and hyper-excitability, thus influencing recovery. Due to the complexity of the CNS, a mechanistic understanding of injury-induced synaptic remodeling remains unclear. Using microfluidic chambers to separate and injure distal axons, we show that axotomy causes retrograde dendritic spine loss at directly injured pyramidal neurons followed by retrograde presynaptic hyper-excitability. These remodeling events require activity at the site of injury, axon-to-soma signaling, and transcription. Similarly, directly injured corticospinal neurons in vivo also exhibit a specific increase in spiking following axon injury. Axotomy-induced hyper-excitability of cultured neurons coincides with elimination of inhibitory inputs onto injured neurons, including those formed onto dendritic spines. Netrin-1 downregulation occurs following axon injury and exogenous netrin-1 applied after injury normalizes spine density, presynaptic excitability, and inhibitory inputs at injured neurons. Our findings show that intrinsic signaling within damaged neurons regulates synaptic remodeling and involves netrin-1 signaling.Spinal cord injury can induce synaptic reorganization and remodeling in the brain. Here the authors study how severed distal axons signal back to the cell body to induce hyperexcitability, loss of inhibition and enhanced presynaptic release through netrin-1.

  3. Nanopolyaniline as immobilization template for signal enhancement of surface plasmon resonance biosensor - A preliminary study

    Science.gov (United States)

    Kamarun, Dzaraini; Abdul Azem, Nor Hazirah Kamel; Sarijo, Siti Halimah; Mohd, Ahmad Faiza; Abdullah @ Mohd Noor, Mashita

    2012-07-01

    A technique for the enhancement of Surface Plasmon Resonance (SPR) signal for sensing biomolecular interactions is described. Polyaniline (PANI) of particle size in the range of 1 to 15 nm was synthesized and used as the template for the immobilization of protein molecules. Biomolecular interactions of unbound and PANI-bound proteins with antibody molecules were SPR-monitored using a model system comprising of Bovine Serum Albumin (BSA) and anti BSA. A 7-fold increased in the signal was recorded from interactions of the PANI-bound BSA with anti BSA compared to the interactions of its unbound counterpart. This preliminary observation provides new avenue in immunosensor technology for improving the detection sensitivity of SPR biosensor; and thereby increasing the lower detection limit of biomolecules.

  4. 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

    International Nuclear Information System (INIS)

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

    2011-01-01

    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 (20 μmol/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.

  5. Homocysteine enhances MMP-9 production in murine macrophages via ERK and Akt signaling pathways

    International Nuclear Information System (INIS)

    Lee, Seung Jin; Lee, Yi Sle; Seo, Kyo Won; Bae, Jin Ung; Kim, Gyu Hee; Park, So Youn; Kim, Chi Dae

    2012-01-01

    Homocysteine (Hcy) at elevated levels is an independent risk factor of cardiovascular diseases, including atherosclerosis. In the present study, we investigated the effect of Hcy on the production of matrix metalloproteinases (MMP) in murine macrophages. Among the MMP known to regulate the activities of collagenase and gelatinase, Hcy exclusively increased the gelatinolytic activity of MMP-9 in J774A.1 cells as well as in mouse peritoneal macrophages. Furthermore, this activity was found to be correlated with Western blot findings in J774A.1 cells, which showed that MMP-9 expression was concentration- and time-dependently increased by Hcy. Inhibition of the ERK and Akt pathways led to a significant decrease in Hcy-induced MMP-9 expression, and combined treatment with inhibitors of the ERK and Akt pathways showed an additive effects. Activity assays for ERK and Akt showed that Hcy increased the phosphorylation of both, but these phosphorylation were not affected by inhibitors of the Akt and ERK pathways. In line with these findings, the molecular inhibition of ERK and Akt using siRNA did not affect the Hcy-induced phosphorylation of Akt and ERK, respectively. Taken together, these findings suggest that Hcy enhances MMP-9 production in murine macrophages by separately activating the ERK and Akt signaling pathways. -- Highlights: ► Homocysteine (Hcy) induced MMP-9 production in murine macrophages. ► Hcy induced MMP-9 production through ERK and Akt signaling pathways. ► ERK and Akt signaling pathways were activated by Hcy in murine macrophages. ► ERK and Akt pathways were additively act on Hcy-induced MMP-9 production. ► Hcy enhances MMP-9 production in macrophages via activation of ERK and Akt signaling pathways in an independent manner.

  6. Homocysteine enhances MMP-9 production in murine macrophages via ERK and Akt signaling pathways

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Seung Jin; Lee, Yi Sle; Seo, Kyo Won; Bae, Jin Ung; Kim, Gyu Hee; Park, So Youn; Kim, Chi Dae, E-mail: chidkim@pusan.ac.kr

    2012-04-01

    Homocysteine (Hcy) at elevated levels is an independent risk factor of cardiovascular diseases, including atherosclerosis. In the present study, we investigated the effect of Hcy on the production of matrix metalloproteinases (MMP) in murine macrophages. Among the MMP known to regulate the activities of collagenase and gelatinase, Hcy exclusively increased the gelatinolytic activity of MMP-9 in J774A.1 cells as well as in mouse peritoneal macrophages. Furthermore, this activity was found to be correlated with Western blot findings in J774A.1 cells, which showed that MMP-9 expression was concentration- and time-dependently increased by Hcy. Inhibition of the ERK and Akt pathways led to a significant decrease in Hcy-induced MMP-9 expression, and combined treatment with inhibitors of the ERK and Akt pathways showed an additive effects. Activity assays for ERK and Akt showed that Hcy increased the phosphorylation of both, but these phosphorylation were not affected by inhibitors of the Akt and ERK pathways. In line with these findings, the molecular inhibition of ERK and Akt using siRNA did not affect the Hcy-induced phosphorylation of Akt and ERK, respectively. Taken together, these findings suggest that Hcy enhances MMP-9 production in murine macrophages by separately activating the ERK and Akt signaling pathways. -- Highlights: ► Homocysteine (Hcy) induced MMP-9 production in murine macrophages. ► Hcy induced MMP-9 production through ERK and Akt signaling pathways. ► ERK and Akt signaling pathways were activated by Hcy in murine macrophages. ► ERK and Akt pathways were additively act on Hcy-induced MMP-9 production. ► Hcy enhances MMP-9 production in macrophages via activation of ERK and Akt signaling pathways in an independent manner.

  7. PTP1B Inhibition Causes Rac1 Activation by Enhancing Receptor Tyrosine Kinase Signaling

    Directory of Open Access Journals (Sweden)

    Ayako Tsuchiya

    2014-04-01

    Full Text Available Background/Aims: The present study investigated the signaling pathway underlying Rac1 activation induced by the linoleic acid derivative 8-[2-(2-pentyl-cyclopropylmethyl-cyclopropyl]-octanoic acid (DCP-LA. Methods: Activity of protein tyrosine phosphatase 1B (PTP1B was assayed under cell-free conditions. Western blot was carried out to quantify phosphorylation of insulin receptor substrate-1 (IRS-1 and Akt in PC-12 cells. Rac1 activity was monitored in the föerster resonance energy transfer (FRET analysis using living and fixed PC-12 cells. Results: DCP-LA markedly suppressed PTP1B activity in a concentration (100 pM-100 µM-dependent manner. In the DCP-LA binding assay, fluorescein-conjugated DCP-LA produced a single fluorescent signal band at 60 kDa, corresponding to the molecule of PTP1B, and the signal was attenuated or abolished by co-treatment or pretreatment with non-conjugated DCP-LA. DCP-LA significantly enhanced nerve growth factor (NGF-stimulated phosphorylation of IRS-1 at Tyr1222 and Akt1/2 at Thr308/309 and Ser473/474 in PC-12 cells. In the FRET analysis, DCP-LA significantly enhanced NGF-stimulated Rac1 activation, which is abrogated by the phosphatidylinositol 3 kinase (PI3K inhibitor wortmannin, the 3-phosphoinositide-dependent protein kinase-1 (PDK1 inhibitor BX912, or the Akt inhibitor MK2206. Conclusion: The results of the present study show that DCP-LA-induced PTP1B inhibition, possibly through its direct binding, causes Rac1 activation by enhancing a pathway along a receptor tyrosine kinase (RTK/IRS-1/PI3K/Akt/Rac1 axis.

  8. Alpha-ketoglutarate enhances freeze-thaw tolerance and prevents carbohydrate-induced cell death of the yeast Saccharomyces cerevisiae.

    Science.gov (United States)

    Bayliak, Maria M; Hrynkiv, Olha V; Knyhynytska, Roksolana V; Lushchak, Volodymyr I

    2018-01-01

    Stress resistance and fermentative capability are important quality characteristics of baker's yeast. In the present study, we examined protective effects of exogenous alpha-ketoglutarate (AKG), an intermediate of the tricarboxylic acid cycle and amino acid metabolism, against freeze-thaw and carbohydrate-induced stresses in the yeast Saccharomyces cerevisiae. Growth on AKG-supplemented medium prevented a loss of viability and improved fermentative capacity of yeast cells after freeze-thaw treatment. The cells grown in the presence of AKG had higher levels of amino acids (e.g., proline), higher metabolic activity and total antioxidant capacity, and higher activities of catalase, NADP-dependent glutamate dehydrogenase and glutamine synthase compared to control ones. Both synthesis of amino acids and enhancement of antioxidant system capacity could be involved in AKG-improved freeze-thaw tolerance in S. cerevisiae. Cell viability dramatically decreased under incubation of stationary-phase yeast cells in 2% glucose or fructose solutions (in the absence of the other nutrients) as compared with incubation in distilled water or in 10 mM AKG solution. The decrease in cell viability was accompanied by acidification of the medium, and decrease in cellular respiration, aconitase activity, and levels of total protein and free amino acids. The supplementation with 10 mM AKG effectively prevented carbohydrate-induced yeast death. Protective mechanisms of AKG could be associated with the intensification of respiration and prevention of decreasing protein level as well as with direct antioxidant AKG action.

  9. Quantitative Phospho-proteomic Analysis of TNFα/NFκB Signaling Reveals a Role for RIPK1 Phosphorylation in Suppressing Necrotic Cell Death.

    Science.gov (United States)

    Mohideen, Firaz; Paulo, Joao A; Ordureau, Alban; Gygi, Steve P; Harper, J Wade

    2017-07-01

    TNFα is a potent inducer of inflammation due to its ability to promote gene expression, in part via the NFκB pathway. Moreover, in some contexts, TNFα promotes Caspase-dependent apoptosis or RIPK1/RIPK3/MLKL-dependent necrosis. Engagement of the TNF Receptor Signaling Complex (TNF-RSC), which contains multiple kinase activities, promotes phosphorylation of several downstream components, including TAK1, IKKα/IKKβ, IκBα, and NFκB. However, immediate downstream phosphorylation events occurring in response to TNFα signaling are poorly understood at a proteome-wide level. Here we use Tandem Mass Tagging-based proteomics to quantitatively characterize acute TNFα-mediated alterations in the proteome and phosphoproteome with or without inhibition of the cIAP-dependent survival arm of the pathway with a SMAC mimetic. We identify and quantify over 8,000 phosphorylated peptides, among which are numerous known sites in the TNF-RSC, NFκB, and MAP kinase signaling systems, as well as numerous previously unrecognized phosphorylation events. Functional analysis of S320 phosphorylation in RIPK1 demonstrates a role for this event in suppressing its kinase activity, association with CASPASE-8 and FADD proteins, and subsequent necrotic cell death during inflammatory TNFα stimulation. This study provides a resource for further elucidation of TNFα-dependent signaling pathways. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Enhancement of single-molecule fluorescence signals by colloidal silver nanoparticles in studies of protein translation.

    Science.gov (United States)

    Bharill, Shashank; Chen, Chunlai; Stevens, Benjamin; Kaur, Jaskiran; Smilansky, Zeev; Mandecki, Wlodek; Gryczynski, Ignacy; Gryczynski, Zygmunt; Cooperman, Barry S; Goldman, Yale E

    2011-01-25

    Metal-enhanced fluorescence (MEF) increased total photon emission of Cy3- and Cy5-labeled ribosomal initiation complexes near 50 nm silver particles 4- and 5.5-fold, respectively. Fluorescence intensity fluctuations above shot noise, at 0.1-5 Hz, were greater on silver particles. Overall signal-to-noise ratio was similar or slightly improved near the particles. Proximity to silver particles did not compromise ribosome function, as measured by codon-dependent binding of fluorescent tRNA, dynamics of fluorescence resonance energy transfer between adjacent tRNAs in the ribosome, and tRNA translocation induced by elongation factor G.

  11. Enhancement of Single Molecule Fluorescence Signals by Colloidal Silver Nanoparticles in Studies of Protein Translation

    Science.gov (United States)

    Bharill, Shashank; Chen, Chunlai; Stevens, Benjamin; Kaur, Jaskiran; Smilansky, Zeev; Mandecki, Wlodek; Gryczynski, Ignacy; Gryczynski, Zygmunt; Cooperman, Barry S.; Goldman, Yale E.

    2011-01-01

    Metal enhanced fluorescence (MEF) increased total photon emission of Cy3- and Cy5-labeled ribosomal initiation complexes near 50 nm silver particles 4- and 5.5-fold respectively. Fluorescence intensity fluctuations above shot noise, at 0.1 – 5 Hz, were greater on silver particles. Overall signal to noise ratio was similar or slightly improved near the particles. Proximity to silver particles did not compromise ribosome function, as measured by codon-dependent binding of fluorescent tRNA, dynamics of fluorescence resonance energy transfer between adjacent tRNAs in the ribosome, and tRNA translocation induced by elongation factor G. PMID:21158483

  12. Enhanced signaling scheme with admission control in the hybrid optical wireless (HOW) networks

    DEFF Research Database (Denmark)

    Yan, Ying; Yu, Hao; Wessing, Henrik

    2009-01-01

    that it can support stringent Quality of Service (QoS) requirements. In this paper, we describe and evaluate a resource management framework designed for the HOW networks. There are two parts in the resource management framework The first part is the Enhanced MPCP (E-MPCP) scheme aiming at improving signaling...... dropping probability depend on several factors. These factors include the frame duration, the traffic load and the total number of shared users. The results also highlight that our proposed system achieves significant improvements over the traditional approach in terms of user QoS guarantee and network...

  13. TRAIL death receptor 4 signaling via lysosome fusion and membrane raft clustering in coronary arterial endothelial cells: evidence from ASM knockout mice.

    Science.gov (United States)

    Li, Xiang; Han, Wei-Qing; Boini, Krishna M; Xia, Min; Zhang, Yang; Li, Pin-Lan

    2013-01-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptor, death receptor 4 (DR4), have been implicated in the development of endothelial dysfunction and atherosclerosis. However, the signaling mechanism mediating DR4 activation leading to endothelial injury remains unclear. We recently demonstrated that ceramide production via hydrolysis of membrane sphingomyelin by acid sphingomyelinase (ASM) results in membrane raft (MR) clustering and the formation of important redox signaling platforms, which play a crucial role in amplifying redox signaling in endothelial cells leading to endothelial dysfunction. The present study aims to investigate whether TRAIL triggers MR clustering via lysosome fusion and ASM activation, thereby conducting transmembrane redox signaling and changing endothelial function. Using confocal microscopy, we found that TRAIL induced MR clustering and co-localized with DR4 in coronary arterial endothelial cells (CAECs) isolated from wild-type (Smpd1 (+/+)) mice. Furthermore, TRAIL triggered ASM translocation, ceramide production, and NADPH oxidase aggregation in MR clusters in Smpd1 ( +/+ ) CAECs, whereas these observations were not found in Smpd1 (-/-) CAECs. Moreover, ASM deficiency reduced TRAIL-induced O(2) (-[Symbol: see text]) production in CAECs and abolished TRAIL-induced impairment on endothelium-dependent vasodilation in small resistance arteries. By measuring fluorescence resonance energy transfer, we found that Lamp-1 (lysosome membrane marker protein) and ganglioside G(M1) (MR marker) were trafficking together in Smpd1 (+/+) CAECs, which was absent in Smpd1 (-/-) CAECs. Consistently, fluorescence imaging of living cells with specific lysosome probes demonstrated that TRAIL-induced lysosome fusion with membrane was also absent in Smpd1 (-/-) CAECs. Taken together, these results suggest that ASM is essential for TRAIL-induced lysosomal trafficking, membrane fusion and formation of MR redox signaling platforms

  14. N-acetylcysteine attenuates hexavalent chromium-induced hypersensitivity through inhibition of cell death, ROS-related signaling and cytokine expression.

    Directory of Open Access Journals (Sweden)

    Yu-Hsuan Lee

    Full Text Available Chromium hypersensitivity (chromium-induced allergic contact dermatitis is an important issue in occupational skin disease. Hexavalent chromium (Cr (VI can activate the Akt, Nuclear factor κB (NF-κB, and Mitogen-activated protein kinase (MAPK pathways and induce cell death, via the effects of reactive oxygen species (ROS. Recently, cell death stimuli have been proposed to regulate the release of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α and interleukin-1 (IL-1. However, the exact effects of ROS on the signaling molecules and cytotoxicity involved in Cr(VI-induced hypersensitivity have not yet been fully demonstrated. N-acetylcysteine (NAC could increase glutathione levels in the skin and act as an antioxidant. In this study, we investigated the effects of NAC on attenuating the Cr(VI-triggered ROS signaling in both normal keratinocyte cells (HaCaT cells and a guinea pig (GP model. The results showed the induction of apoptosis, autophagy and ROS were observed after different concentrations of Cr(VI treatment. HaCaT cells pretreated with NAC exhibited a decrease in apoptosis and autophagy, which could affect cell viability. In addition, Cr (VI activated the Akt, NF-κB and MAPK pathways thereby increasing IL-1α and TNF-α production. However, all of these stimulation phenomena could be inhibited by NAC in both of in vitro and in vivo studies. These novel findings indicate that NAC may prevent the development of chromium hypersensitivity by inhibiting of ROS-induced cell death and cytokine expression.

  15. The enhanced greenhouse signal versus natural variations in observed climate time series: a statistical approach

    Energy Technology Data Exchange (ETDEWEB)

    Schoenwiese, C D [J.W. Goethe Univ., Frankfurt (Germany). Inst. for Meteorology and Geophysics

    1996-12-31

    It is a well-known fact that human activities lead to an atmospheric concentration increase of some IR-active trace gases (greenhouse gases GHG) and that this influence enhances the `greenhouse effect`. However, there are major quantitative and regional uncertainties in the related climate model projections and the observational data reflect the whole complex of both anthropogenic and natural forcing of the climate system. This contribution aims at the separation of the anthropogenic enhanced greenhouse signal in observed global surface air temperature data versus other forcing using statistical methods such as multiple (multiforced) regressions and neural networks. The competitive natural forcing considered are volcanic and solar activity, in addition the ENSO (El Nino/Southern Oscillation) mechanism. This analysis will be extended also to the NAO (North Atlantic Oscillation) and anthropogenic sulfate formation in the troposphere

  16. Enhanced insulin signaling in human skeletal muscle and adipose tissue following gastric bypass surgery

    DEFF Research Database (Denmark)

    Albers, Peter Hjorth; Bojsen-Moller, Kirstine N; Dirksen, Carsten

    2015-01-01

    Roux-en-Y gastric bypass (RYGB) leads to increased peripheral insulin sensitivity. The aim of this study was to investigate the effect of RYGB on expression and regulation of proteins involved in regulation of peripheral glucose metabolism. Skeletal muscle and adipose tissue biopsies from glucose...... tolerant and type 2 diabetic subjects at fasting and during a hyperinsulinemic-euglycemic clamp before as well as 1 week, 3 and 12 months after RYGB were analyzed for relevant insulin effector proteins/signaling components. Improvement in peripheral insulin sensitivity mainly occurred at 12 months post-surgery...... and glycogen synthase activity were enhanced 12 months post-surgery. In adipose tissue, protein expression of GLUT4, Akt2, TBC1D4 and acetyl-CoA carboxylase (ACC), phosphorylated levels of AMP-activated protein kinase and ACC as well as insulin-induced changes in phosphorylation of Akt and TBC1D4 were enhanced...

  17. The enhanced greenhouse signal versus natural variations in observed climate time series: a statistical approach

    Energy Technology Data Exchange (ETDEWEB)

    Schoenwiese, C.D. [J.W. Goethe Univ., Frankfurt (Germany). Inst. for Meteorology and Geophysics

    1995-12-31

    It is a well-known fact that human activities lead to an atmospheric concentration increase of some IR-active trace gases (greenhouse gases GHG) and that this influence enhances the `greenhouse effect`. However, there are major quantitative and regional uncertainties in the related climate model projections and the observational data reflect the whole complex of both anthropogenic and natural forcing of the climate system. This contribution aims at the separation of the anthropogenic enhanced greenhouse signal in observed global surface air temperature data versus other forcing using statistical methods such as multiple (multiforced) regressions and neural networks. The competitive natural forcing considered are volcanic and solar activity, in addition the ENSO (El Nino/Southern Oscillation) mechanism. This analysis will be extended also to the NAO (North Atlantic Oscillation) and anthropogenic sulfate formation in the troposphere

  18. Eurycomanone and Eurycomanol from Eurycoma longifolia Jack as Regulators of Signaling Pathways Involved in Proliferation, Cell Death and Inflammation

    Directory of Open Access Journals (Sweden)

    Shéhérazade Hajjouli

    2014-09-01

    Full Text Available Eurycomanone and eurycomanol are two quassinoids from the roots of Eurycoma longifolia Jack. The aim of this study was to assess the bioactivity of these compounds in Jurkat and K562 human leukemia cell models compared to peripheral blood mononuclear cells from healthy donors. Both eurycomanone and eurycomanol inhibited Jurkat and K562 cell viability and proliferation without affecting healthy cells. Interestingly, eurycomanone inhibited NF-κB signaling through inhibition of IκBα phosphorylation and upstream mitogen activated protein kinase (MAPK signaling, but not eurycomanol. In conclusion, both quassinoids present differential toxicity towards leukemia cells, and the presence of the α,β-unsaturated ketone in eurycomanone could be prerequisite for the NF-κB inhibition.

  19. Do not let death do us part: ‘find-me' signals in communication between dying cells and the phagocytes

    Science.gov (United States)

    Medina, C B; Ravichandran, K S

    2016-01-01

    The turnover and clearance of cells is an essential process that is part of many physiological and pathological processes. Improper or deficient clearance of apoptotic cells can lead to excessive inflammation and autoimmune disease. The steps involved in cell clearance include: migration of the phagocyte toward the proximity of the dying cells, specific recognition and internalization of the dying cell, and degradation of the corpse. The ability of phagocytes to recognize and react to dying cells to perform efficient and immunologically silent engulfment has been well-characterized in vitro and in vivo. However, how apoptotic cells themselves initiate the corpse removal and also influence the cells within the neighboring environment during clearance was less understood. Recent exciting observations suggest that apoptotic cells can attract phagocytes through the regulated release of ‘find-me' signals. More recent studies also suggest that these find-me signals can have additional roles outside of phagocyte attraction to help orchestrate engulfment. This review will discuss our current understanding of the different find-me signals released by apoptotic cells, how they may be relevant in vivo, and their additional roles in facilitating engulfment. PMID:26891690

  20. Neonatal Death

    Science.gov (United States)

    ... Home > Complications & Loss > Loss & grief > Neonatal death Neonatal death E-mail to a friend Please fill in ... cope with your baby’s death. What is neonatal death? Neonatal death is when a baby dies in ...

  1. Hydrogen sulfide interacts with calcium signaling to enhance the chromium tolerance in Setaria italica.

    Science.gov (United States)

    Fang, Huihui; Jing, Tao; Liu, Zhiqiang; Zhang, Liping; Jin, Zhuping; Pei, Yanxi

    2014-12-01

    The oscillation of intracellular calcium (Ca(2+)) concentration is a primary event in numerous biological processes in plants, including stress response. Hydrogen sulfide (H2S), an emerging gasotransmitter, was found to have positive effects in plants responding to chromium (Cr(6+)) stress through interacting with Ca(2+) signaling. While Ca(2+) resemblances H2S in mediating biotic and abiotic stresses, crosstalk between the two pathways remains unclear. In this study, Ca(2+) signaling interacted with H2S to produce a complex physiological response, which enhanced the Cr(6+) tolerance in foxtail millet (Setaria italica). Results indicate that Cr(6+) stress activated endogenous H2S synthesis as well as Ca(2+) signaling. Moreover, toxic symptoms caused by Cr(6+) stress were strongly moderated by 50μM H2S and 20mM Ca(2+). Conversely, treatments with H2S synthesis inhibitor and Ca(2+) chelators prior to Cr(6+)-exposure aggravated these toxic symptoms. Interestingly, Ca(2+) upregulated expression of two important factors in metal metabolism, MT3A and PCS, which participated in the biosynthesis of heavy metal chelators, in a H2S-dependent manner to cope with Cr(6+) stress. These findings also suggest that the H2S dependent pathway is a component of the Ca(2+) activating antioxidant system and H2S partially contributes Ca(2+)-activating antioxidant system. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Knockdown of TWIST1 enhances arsenic trioxide- and ionizing radiation-induced cell death in lung cancer cells by promoting mitochondrial dysfunction

    Energy Technology Data Exchange (ETDEWEB)

    Seo, Sung-Keum; Kim, Jae-Hee; Choi, Ha-Na [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul (Korea, Republic of); Choe, Tae-Boo [Department of Microbiological Engineering, Kon-Kuk University, Gwangjin-gu, Seoul (Korea, Republic of); Hong, Seok-Il [Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul (Korea, Republic of); Yi, Jae-Youn [Laboratory of Modulation of Radiobiological Responses, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul (Korea, Republic of); Hwang, Sang-Gu [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul (Korea, Republic of); Lee, Hyun-Gyu [Department of Microbiology and Immunology, College of Medicine, Yonsei University, 250 Seongsan-no, Seodaemun-gu, Seoul (Korea, Republic of); Lee, Yun-Han, E-mail: yhlee87@yuhs.ac [Department of Radiation Oncology, College of Medicine, Yonsei University, 250 Seongsan-no, Seodaemun-gu, Seoul (Korea, Republic of); Park, In-Chul, E-mail: parkic@kcch.re.kr [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul (Korea, Republic of)

    2014-07-11

    Highlights: • Knockdown of TWIST1 enhanced ATO- and IR-induced cell death in NSCLCs. • Intracellular ROS levels were increased in cells treated with TWIST1 siRNA. • TWIST1 siRNA induced MMP loss and mitochondrial fragmentation. • TWIST1 siRNA upregulated the fission-related proteins FIS1 and DRP1. - Abstract: TWIST1 is implicated in the process of epithelial mesenchymal transition, metastasis, stemness, and drug resistance in cancer cells, and therefore is a potential target for cancer therapy. In the present study, we found that knockdown of TWIST1 by small interfering RNA (siRNA) enhanced arsenic trioxide (ATO)- and ionizing radiation (IR)-induced cell death in non-small-cell lung cancer cells. Interestingly, intracellular reactive oxygen species levels were increased in cells treated with TWIST1 siRNA and further increased by co-treatment with ATO or IR. Pretreatment of lung cancer cells with the antioxidant N-acetyl-cysteine markedly suppressed the cell death induced by combined treatment with TWIST1 siRNA and ATO or IR. Moreover, treatment of cells with TWIST1 siRNA induced mitochondrial membrane depolarization and significantly increased mitochondrial fragmentation (fission) and upregulated the fission-related proteins FIS1 and DRP1. Collectively, our results demonstrate that siRNA-mediated TWIST1 knockdown induces mitochondrial dysfunction and enhances IR- and ATO-induced cell death in lung cancer cells.

  3. Fractal properties of background noise and target signal enhancement using CSEM data

    Science.gov (United States)

    Benavides, Alfonso; Everett, Mark E.; Pierce, Carl; Nguyen, Cam

    2003-09-01

    Controlled-source electromagnetic (CSEM) spatial profiles and 2-D conductivity maps were obtained on the Brazos Valley, TX floodplain to study the fractal statistics of geological signals and effects of man-made conductive targets using Geonics EM34, EM31 and EM63. Using target-free areas, a consistent power-law power spectrum (|A(k)| ~ k ^-β) for the profiles was found with β values typical of fractional Brownian motion (fBm). This means that the spatial variation of conductivity does not correspond to Gaussian statistics, where there are spatial correlations at different scales. The presence of targets tends to flatten the power-law power spectrum (PS) at small wavenumbers. Detection and localization of targets can be achieved using short-time Fourier transform (STFT). The presence of targets is enhanced because the signal energy is spread to higher wavenumbers (small scale numbers) in the positions occupied by the targets. In the case of poor spatial sampling or small amount of data, the information available from the power spectrum is not enough to separate spatial correlations from target signatures. Advantages are gained by using the spatial correlations of the fBm in order to reject the background response, and to enhance the signals from highly conductive targets. This approach was tested for the EM31 using a pre-processing step that combines apparent conductivity readings from two perpendicular transmitter-receiver orientations at each station. The response obtained using time-domain CSEM is influence to a lesser degree by geological noise and the target response can be processed to recover target features. The homotopy method is proposed to solve the inverse problem using a set of possible target models and a dynamic library of responses used to optimize the starting model.

  4. Enhancing dopaminergic signaling and histone acetylation promotes long-term rescue of deficient fear extinction

    Science.gov (United States)

    Whittle, N; Maurer, V; Murphy, C; Rainer, J; Bindreither, D; Hauschild, M; Scharinger, A; Oberhauser, M; Keil, T; Brehm, C; Valovka, T; Striessnig, J; Singewald, N

    2016-01-01

    Extinction-based exposure therapy is used to treat anxiety- and trauma-related disorders; however, there is the need to improve its limited efficacy in individuals with impaired fear extinction learning and to promote greater protection against return-of-fear phenomena. Here, using 129S1/SvImJ mice, which display impaired fear extinction acquisition and extinction consolidation, we revealed that persistent and context-independent rescue of deficient fear extinction in these mice was associated with enhanced expression of dopamine-related genes, such as dopamine D1 (Drd1a) and -D2 (Drd2) receptor genes in the medial prefrontal cortex (mPFC) and amygdala, but not hippocampus. Moreover, enhanced histone acetylation was observed in the promoter of the extinction-regulated Drd2 gene in the mPFC, revealing a potential gene-regulatory mechanism. Although enhancing histone acetylation, via administering the histone deacetylase (HDAC) inhibitor MS-275, does not induce fear reduction during extinction training, it promoted enduring and context-independent rescue of deficient fear extinction consolidation/retrieval once extinction learning was initiated as shown following a mild conditioning protocol. This was associated with enhanced histone acetylation in neurons of the mPFC and amygdala. Finally, as a proof-of-principle, mimicking enhanced dopaminergic signaling by L-dopa treatment rescued deficient fear extinction and co-administration of MS-275 rendered this effect enduring and context-independent. In summary, current data reveal that combining dopaminergic and epigenetic mechanisms is a promising strategy to improve exposure-based behavior therapy in extinction-impaired individuals by initiating the formation of an enduring and context-independent fear-inhibitory memory. PMID:27922638

  5. Physcomitrella patens activates reinforcement of the cell wall, programmed cell death and accumulation of evolutionary conserved defence signals, such as salicylic acid and 12-oxo-phytodienoic acid, but not jasmonic acid, upon Botrytis cinerea infection.

    Science.gov (United States)

    Ponce De León, Inés; Schmelz, Eric A; Gaggero, Carina; Castro, Alexandra; Álvarez, Alfonso; Montesano, Marcos

    2012-10-01

    The moss Physcomitrella patens is an evolutionarily basal model system suitable for the analysis of plant defence responses activated after pathogen assault. Upon infection with the necrotroph Botrytis cinerea, several defence mechanisms are induced in P. patens, including the fortification of the plant cell wall by the incorporation of phenolic compounds and the induced expression of related genes. Botrytis cinerea infection also activates the accumulation of reactive oxygen species and cell death with hallmarks of programmed cell death in moss tissues. Salicylic acid (SA) levels also increase after fungal infection, and treatment with SA enhances transcript accumulation of the defence gene phenylalanine ammonia-lyase (PAL) in P. patens colonies. The expression levels of the genes involved in 12-oxo-phytodienoic acid (OPDA) synthesis, including lipoxygenase (LOX) and allene oxide synthase (AOS), increase in P. patens gametophytes after pathogen assault, together with a rise in free linolenic acid and OPDA concentrations. However, jasmonic acid (JA) could not be detected in healthy or infected tissues of this plant. Our results suggest that, although conserved defence signals, such as SA and OPDA, are synthesized and are probably involved in the defence response of P. patens against B. cinerea infection, JA production appears to be missing. Interestingly, P. patens responds to OPDA and methyl jasmonate by reducing moss colony growth and rhizoid length, suggesting that jasmonate perception is present in mosses. Thus, P. patens can provide clues with regard to the evolution of different defence pathways in plants, including signalling and perception of OPDA and jasmonates in nonflowering and flowering plants. © 2012 THE AUTHORS. MOLECULAR PLANT PATHOLOGY © 2012 BSPP AND BLACKWELL PUBLISHING LTD.

  6. Sensitization of gastric cancer cells to alkylating agents by glaucocalyxin B via cell cycle arrest and enhanced cell death.

    Science.gov (United States)

    Ur Rahman, Muhammad Saif; Zhang, Ling; Wu, Lingyan; Xie, Yuqiong; Li, Chunchun; Cao, Jiang

    2017-01-01

    Severe side effects are major problems with chemotherapy of gastric cancer (GC). These side effects can be reduced by using sensitizing agents in combination with therapeutic drugs. In this study, the low/nontoxic dosage of glaucocalyxin B (GLB) was used with other DNA linker agents mitomycin C (MMC), cisplatin (DDP), or cyclophosphamide (CTX) to treat GC cells. Combined effectiveness of GLB with drugs was determined by proliferation assay. The molecular mechanisms associated with cell proliferation, migration, invasion, cell cycle, DNA repair/replication, apoptosis, and autophagy were investigated by immunoblotting for key proteins involved. Cell cycle and apoptosis analysis were performed by flow cytometry. Reactive oxygen species level was also examined for identification of its role in apoptosis. Proliferation assay revealed that the addition of 5 µM GLB significantly sensitizes gastric cancer SGC-7901 cells to MMC, DDP, and CTX by decreasing half-maximal inhibitory concentration (IC 50 ) by up to 75.40%±5%, 45.10%±5%, and 52.10%±5%, respectively. GLB + drugs decreased the expression level of proteins involved in proliferation and migration, suggesting the anticancer potential of GLB + drugs. GLB + MMC, GLB + CTX, and GLB + DDP arrest the cells in G 0 /G 1 and G 1 /S phase, respectively, which may be the consequence of significant decrease in the level of enzymes responsible for DNA replication and telomerase shortening. Combined use of GLB with these drugs also induces DNA damage and apoptosis by activating caspase/PARP pathways and increased production of reactive oxygen species and increased autophagy in GC cells. GLB dosage sensitizes GC cells to the alkylating agents via arresting the cell cycle and enhancing cell death. This is of significant therapeutic importance in the reduction of side effects associated with these drugs.

  7. Progranulin Reduced Neuronal Cell Death by Activation of Sortilin 1 Signaling Pathways After Subarachnoid Hemorrhage in Rats.

    Science.gov (United States)

    Li, Bo; He, Yue; Xu, Liang; Hu, Qin; Tang, Junjia; Chen, Yujie; Tang, Jiping; Feng, Hua; Zhang, John H

    2015-08-01

    abolished the beneficial effects of rat recombinant progranulin at 24 hours after subarachnoid hemorrhage. Rat recombinant progranulin alleviated neuronal death via sortilin 1-mediated and Akt-related antiapoptosis pathway. Rat recombinant progranulin may have potentials to ameliorate early brain injury for subarachnoid hemorrhage patients.

  8. Cold-inducible RNA-binding protein through TLR4 signaling induces mitochondrial DNA fragmentation and regulates macrophage cell death after trauma.

    Science.gov (United States)

    Li, Zhigang; Fan, Erica K; Liu, Jinghua; Scott, Melanie J; Li, Yuehua; Li, Song; Xie, Wen; Billiar, Timothy R; Wilson, Mark A; Jiang, Yong; Wang, Ping; Fan, Jie

    2017-05-11

    Trauma is a major cause of systemic inflammatory response syndrome and multiple organ dysfunction syndrome. Macrophages (Mφ) direct trauma-induced inflammation, and Mφ death critically influences the progression of the inflammatory response. In the current study, we explored an important role of trauma in inducing mitochondrial DNA (mtDNA) damage in Mφ and the subsequent regulation of Mφ death. Using an animal pseudo-fracture trauma model, we demonstrated that tissue damage induced NADPH oxidase activation and increased the release of reactive oxygen species via cold-inducible RNA-binding protein (CIRP)-TLR4-MyD88 signaling. This in turn, activates endonuclease G, which serves as an executor for the fragmentation of mtDNA in Mφ. We further showed that fragmented mtDNA triggered both p62-related autophagy and necroptosis in Mφ. However, autophagy activation also suppressed Mφ necroptosis and pro-inflammatory responses. This study demonstrates a previously unidentified intracellular regulation of Mφ homeostasis in response to trauma.

  9. Attenuated hypocholesterolemia following severe trauma signals risk for late ventilator-associated pneumonia, ventilator dependency, and death: a retrospective study of consecutive patients

    Directory of Open Access Journals (Sweden)

    Chirichella Thomas J

    2011-03-01

    Full Text Available Abstract Background Post-traumatic ventilator-associated pneumonia (VAP is a substantial clinical problem that increases hospital costs and typically adds to the duration of mechanical ventilation. We evaluated the impact of VAP on ventilator days. We also assessed 48-hour total blood cholesterol (TC and other potential risk factors for the development of VAP. Methods We performed a retrospective study of consecutive trauma patients requiring emergency tracheal intubation and evaluated TC, age, gender, ethanol status, smoker status, injury mechanism, chest injury, brain injury, Injury Severity Score (ISS, shock, day-one hypoxemia, and RBC transfusion as potential risks for VAP. Results The 152 patients had ISS 28.1, brain injury 68.4%, VAP 50.0%, ventilator days 14.3, and death 9.9%. Ventilator days were increased with late VAP (p Conclusions Severe traumatic injury produced substantial hypocholesterolemia that is greater with chest injury, shock, and RBC transfusion, but less with brain injury. Total blood cholesterol tended to decrease with increasing injury severity. However, attenuated hypocholesterolemia (ISS ≥ 20-&-TC ≥ 90 mg/dL represents a unique response that can occur with critical injury. Attenuated hypocholesterolemia signals early risk for late VAP, ventilator dependency, and death.

  10. Naja nigricollis CMS-9 enhances the mitochondria-mediated death pathway in adaphostin-treated human leukaemia U937 cells.

    Science.gov (United States)

    Chen, Ying-Jung; Wang, Jeh-Jeng; Chang, Long-Sen

    2011-11-01

    1. The aim of the present study was to explore the effect of the Naja nigricollis phospholipase A(2) CMS-9 on adaphostin-induced death of human leukaemia U937 cells. 2. Leukaemia U937 cells (Bcr/Abl-negative cells) were treated with adaphostin (0-10 μmol/L) and CMS-9 (0-1 μmol/L). The effects of CMS-9, adaphostin and their combination on cell viability, the generation reactive oxygen species (ROS), [Ca(2+) ](i) , p38 mitogen-activated protein kinase (MAPK) activation, Akt and extracellular signal-regulated kinase (ERK) inactivation, mitochondrial membrane potential (ΔΨ(m) ) and Bcl-2 family proteins were analysed. 3. Both adaphostin and CMS-9 induced U937 cell apoptosis, characterized by dissipation of ΔΨ(m) and ROS generation. Combined treatment further increased ΔΨ(m) loss and reduced the viability of adaphostin-treated cells. Unlike in CMS-9-treated cells, in adaphostin-treated cells ROS-induced increases in [Ca(2+) ](i) were observed. CMS-9-induced ROS generation resulted in p38 MAPK activation, whereas adaphostin treatment elicited ROS/Ca(2+) -mediated inactivation of Akt and ERK. Moreover, Akt was found to be involved in ERK phosphorylation. Suppression of p38 MAPK activation blocked CMS-9-induced ΔΨ(m) loss and Bcl-xL downregulation. Overexpression of constitutively active Akt and mitogen-activated protein kinase kinase (MEK) 1 rescued adaphostin-induced ΔΨ(m) loss and Bcl-2 downregulation. Similarly, CMS-9 augmented adaphostin toxicity in human leukaemia K562 cells via increased mitochondrial alterations. 4. The results suggest that two distinct pathways mediate adaphostin- and CMS-9-induced mitochondrial damage (i.e. the ROS-Ca(2+) -Akt-ERK and ROS-p38 MAPK pathways, respectively). These distinct pathway explain the augmentation by CMS-9 of ΔΨ(m) loss and apoptosis in adaphostin-treated U937 cells. © 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd.

  11. Cobalt oxide nanoparticles aggravate DNA damage and cell death in eggplant via mitochondrial swelling and NO signaling pathway.

    Science.gov (United States)

    Faisal, Mohammad; Saquib, Quaiser; Alatar, Abdulrahman A; Al-Khedhairy, Abdulaziz A; Ahmed, Mukhtar; Ansari, Sabiha M; Alwathnani, Hend A; Dwivedi, Sourabh; Musarrat, Javed; Praveen, Shelly

    2016-03-18

    Despite manifold benefits of nanoparticles (NPs), less information on the risks of NPs to human health and environment has been studied. Cobalt oxide nanoparticles (Co3O4-NPs) have been reported to cause toxicity in several organisms. In this study, we have investigated the role of Co3O4-NPs in inducing phytotoxicity, cellular DNA damage and apoptosis in eggplant (Solanum melongena L. cv. Violetta lunga 2). To the best of our knowledge, this is the first report on Co3O4-NPs showing phytotoxicity in eggplant. The data revealed that eggplant seeds treated with Co3O4-NPs for 2 h at a concentration of 1.0 mg/ml retarded root length by 81.5 % upon 7 days incubation in a moist chamber. Ultrastructural analysis by transmission electron microscopy (TEM) demonstrated the uptake and translocation of Co3O4-NPs into the cytoplasm. Intracellular presence of Co3O4-NPs triggered subcellular changes such as degeneration of mitochondrial cristae, abundance of peroxisomes and excessive vacuolization. Flow cytometric analysis of Co3O4-NPs (1.0 mg/ml) treated root protoplasts revealed 157, 282 and 178 % increase in reactive oxygen species (ROS), membrane potential (ΔΨm) and nitric oxide (NO), respectively. Besides, the esterase activity in treated protoplasts was also found compromised. About 2.4-fold greater level of DNA damage, as compared to untreated control was observed in Comet assay, and 73.2 % of Co3O4-NPs treated cells appeared apoptotic in flow cytometry based cell cycle analysis. This study demonstrate the phytotoxic potential of Co3O4-NPs in terms of reduction in seed germination, root growth, greater level of DNA and mitochondrial damage, oxidative stress and cell death in eggplant. The data generated from this study will provide a strong background to draw attention on Co3O4-NPs environmental hazards to vegetable crops.

  12. The neuroprotective effects of α-iso-cubebene on dopaminergic cell death: involvement of CREB/Nrf2 signaling.

    Science.gov (United States)

    Park, Sun Young; Son, Beung Gu; Park, Young Hoon; Kim, Cheol-Min; Park, Geuntae; Choi, Young-Whan

    2014-09-01

    As a part of ongoing studies to elucidate pharmacologically active components of Schisandra chinensis, we isolated and studied α-iso-cubebene. The neuroprotective mechanisms of α-iso-cubebene in human neuroblastoma SH-SY5Y cells were investigated. α-Iso-cubebene significantly inhibited cytotoxicity and apoptosis due to 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in dopaminergic SH-SY5Y cells. Pretreatment of cells with α-iso-cubebene reduced intracellular accumulation of ROS and calcium in response to 6-OHDA. The neuroprotective effects of α-iso-cubebene were found to result from protecting the mitochondrial membrane potential. Notably, α-iso-cubebene inhibited the release of apoptosis-inducing factor from the mitochondria into the cytosol and nucleus after 6-OHDA treatment. α-Iso-cubebene also induced the activation of PKA/PKB/CREB/Nrf2 and suppressed 6-OHDA-induced neurotoxicity. α-Iso-cubebene was found to induce phosphorylation of PKA and PKB and activate Nrf2 and CREB signaling pathways in a dose-dependent manner. Additionally, α-iso-cubebene stimulated the expression of the antioxidant response genes NQO1 and HO-1. Finally, α-iso-cubebene-mediated neuroprotective effects were found to be reversible after transfection with CREB and Nrf2 small interfering RNAs.

  13. Different Signal Enhancement Pathways of Attention and Consciousness Underlie Perception in Humans.

    Science.gov (United States)

    van Boxtel, Jeroen J A

    2017-06-14

    It is not yet known whether attention and consciousness operate through similar or largely different mechanisms. Visual processing mechanisms are routinely characterized by measuring contrast response functions (CRFs). In this report, behavioral CRFs were obtained in humans (both males and females) by measuring afterimage durations over the entire range of inducer stimulus contrasts to reveal visual mechanisms behind attention and consciousness. Deviations relative to the standard CRF, i.e., gain functions, describe the strength of signal enhancement, which were assessed for both changes due to attentional task and conscious perception. It was found that attention displayed a response-gain function, whereas consciousness displayed a contrast-gain function. Through model comparisons, which only included contrast-gain modulations, both contrast-gain and response-gain effects can be explained with a two-level normalization model, in which consciousness affects only the first level and attention affects only the second level. These results demonstrate that attention and consciousness can effectively show different gain functions because they operate through different signal enhancement mechanisms. SIGNIFICANCE STATEMENT The relationship between attention and consciousness is still debated. Mapping contrast response functions (CRFs) has allowed (neuro)scientists to gain important insights into the mechanistic underpinnings of visual processing. Here, the influence of both attention and consciousness on these functions were measured and they displayed a strong dissociation. First, attention lowered CRFs, whereas consciousness raised them. Second, attention manifests itself as a response-gain function, whereas consciousness manifests itself as a contrast-gain function. Extensive model comparisons show that these results are best explained in a two-level normalization model in which consciousness affects only the first level, whereas attention affects only the second level

  14. Enhancement of arachidonic acid signaling pathway by nicotinic acid receptor HM74A

    International Nuclear Information System (INIS)

    Tang, Yuting; Zhou, Lubing; Gunnet, Joseph W.; Wines, Pamela G.; Cryan, Ellen V.; Demarest, Keith T.

    2006-01-01

    HM74A is a G protein-coupled receptor for nicotinic acid (niacin), which has been used clinically to treat dyslipidemia for decades. The molecular mechanisms whereby niacin exerts its pleiotropic effects on lipid metabolism remain largely unknown. In addition, the most common side effect in niacin therapy is skin flushing that is caused by prostaglandin release, suggesting that the phospholipase A 2 (PLA 2 )/arachidonic acid (AA) pathway is involved. Various eicosanoids have been shown to activate peroxisome-proliferator activated receptors (PPAR) that play a diverse array of roles in lipid metabolism. To further elucidate the potential roles of HM74A in mediating the therapeutic effects and/or side effects of niacin, we sought to explore the signaling events upon HM74A activation. Here we demonstrated that HM74A synergistically enhanced UTP- and bradykinin-mediated AA release in a pertussis toxin-sensitive manner in A431 cells. Activation of HM74A also led to Ca 2+ -mobilization and enhanced bradykinin-promoted Ca 2+ -mobilization through Gi protein. While HM74A increased ERK1/2 activation by the bradykinin receptor, it had no effects on UTP-promoted ERK1/2 activation.Furthermore, UTP- and bradykinin-mediated AA release was significantly decreased in the presence of both MAPK kinase inhibitor PD 098059 and PKC inhibitor GF 109203X. However, the synergistic effects of HM74A were not dramatically affected by co-treatment with both inhibitors, indicating the cross-talk occurred at the receptor level. Finally, stimulation of A431 cells transiently transfected with PPRE-luciferase with AA significantly induced luciferase activity, mimicking the effects of PPARγ agonist rosiglitazone, suggesting that alteration of AA signaling pathway can regulate gene expression via endogenous PPARs

  15. Enhancement of arachidonic acid signaling pathway by nicotinic acid receptor HM74A

    Energy Technology Data Exchange (ETDEWEB)

    Tang, Yuting [Endocrine Therapeutics and Metabolic Disorders, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 1000 Rt. 202, Raritan, NJ 08869 (United States); Zhou, Lubing [Endocrine Therapeutics and Metabolic Disorders, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 1000 Rt. 202, Raritan, NJ 08869 (United States); Gunnet, Joseph W [Endocrine Therapeutics and Metabolic Disorders, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 1000 Rt. 202, Raritan, NJ 08869 (United States); Wines, Pamela G [Endocrine Therapeutics and Metabolic Disorders, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 1000 Rt. 202, Raritan, NJ 08869 (United States); Cryan, Ellen V [Endocrine Therapeutics and Metabolic Disorders, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 1000 Rt. 202, Raritan, NJ 08869 (United States); Demarest, Keith T [Endocrine Therapeutics and Metabolic Disorders, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 1000 Rt. 202, Raritan, NJ 08869 (United States)

    2006-06-23

    HM74A is a G protein-coupled receptor for nicotinic acid (niacin), which has been used clinically to treat dyslipidemia for decades. The molecular mechanisms whereby niacin exerts its pleiotropic effects on lipid metabolism remain largely unknown. In addition, the most common side effect in niacin therapy is skin flushing that is caused by prostaglandin release, suggesting that the phospholipase A{sub 2} (PLA{sub 2})/arachidonic acid (AA) pathway is involved. Various eicosanoids have been shown to activate peroxisome-proliferator activated receptors (PPAR) that play a diverse array of roles in lipid metabolism. To further elucidate the potential roles of HM74A in mediating the therapeutic effects and/or side effects of niacin, we sought to explore the signaling events upon HM74A activation. Here we demonstrated that HM74A synergistically enhanced UTP- and bradykinin-mediated AA release in a pertussis toxin-sensitive manner in A431 cells. Activation of HM74A also led to Ca{sup 2+}-mobilization and enhanced bradykinin-promoted Ca{sup 2+}-mobilization through Gi protein. While HM74A increased ERK1/2 activation by the bradykinin receptor, it had no effects on UTP-promoted ERK1/2 activation.Furthermore, UTP- and bradykinin-mediated AA release was significantly decreased in the presence of both MAPK kinase inhibitor PD 098059 and PKC inhibitor GF 109203X. However, the synergistic effects of HM74A were not dramatically affected by co-treatment with both inhibitors, indicating the cross-talk occurred at the receptor level. Finally, stimulation of A431 cells transiently transfected with PPRE-luciferase with AA significantly induced luciferase activity, mimicking the effects of PPAR{gamma} agonist rosiglitazone, suggesting that alteration of AA signaling pathway can regulate gene expression via endogenous PPARs.

  16. Curcumin enhances the radiosensitivity of renal cancer cells by suppressing NF-κB signaling pathway.

    Science.gov (United States)

    Li, Gang; Wang, Ziming; Chong, Tie; Yang, Jie; Li, Hongliang; Chen, Haiwen

    2017-10-01

    The radiation resistance of renal cell carcinoma (RCC) remains the primary obstacle to improve patient survival. This study aimed to investigate the effects of curcumin on the radiosensitivity of RCC cells. Human RCC cell (ACHN) was exposed to irradiation (IR) and/or curcumin treatment. Cell viability, DNA repair, cell cycle, and apoptosis, were evaluated by MTT, immunofluoresence staining and flow cytometry. Moreover, ACHN cells were xenografted into nude mice and subjected to IR and/or curcumin treatment. The expression of NF-κB signaling related proteins in ACHN cells and xenografts was detected by western blot analysis. The results showed that curcumin significantly increased radiosensitivity of ACHN cells by inhibiting the cell proliferation and DNA damage repair, causing cell cycle arrest at G2/M phase, inducing apoptosis in vitro, and suppressing the growth of xenografts in vivo. In addition, curcumin enhanced radiosensitivity was through markedly inhibiting IR-induced NF-κB signaling by modulating the related protein expressions including NF-κBP65, I-κB, VEGF, COX2, and Bcl-2 in ACHN cells, which was further strengthened by NF-κB inhibitor PDTC treatment. Thus, curcumin may confer radiosensitivity on RCC via inhibition of NF-κB activation and its downstream regulars, suggesting the potential application of curcumin as an adjuvant in radiotherapy of RCC. Copyright © 2017. Published by Elsevier Masson SAS.

  17. Sigma-1 receptor enhances neurite elongation of cerebellar granule neurons via TrkB signaling.

    Science.gov (United States)

    Kimura, Yuriko; Fujita, Yuki; Shibata, Kumi; Mori, Megumi; Yamashita, Toshihide

    2013-01-01

    Sigma-1 receptor (Sig-1R) is an integral membrane protein predominantly expressed in the endoplasmic reticulum. Sig-1R demonstrates a high affinity to various synthetic compounds including well-known psychotherapeutic drugs in the central nervous system (CNS). For that, it is considered as an alternative target for psychotherapeutic drugs. On the cellular level, when Sig-1R is activated, it is known to play a role in neuroprotection and neurite elongation. These effects are suggested to be mediated by its ligand-operated molecular chaperone activity, and/or upregulation of various Ca(2+) signaling. In addition, recent studies show that Sig-1R activation induces neurite outgrowth via neurotrophin signaling. Here, we tested the hypothesis that Sig-1R activation promotes neurite elongation through activation of tropomyosin receptor kinase (Trk), a family of neurotrophin receptors. We found that 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate (PRE-084), a selective Sig-1R agonist, significantly promoted neurite outgrowth, and K252a, a Trk inhibitor, attenuated Sig-1R-mediated neurite elongation in cerebellar granule neurons (CGNs). Moreover, we revealed that Sig-1R interacts with TrkB, and PRE-084 treatment enhances phosphorylation of Y515, but not Y706. Thus, our results indicate that Sig-1R activation promotes neurite outgrowth in CGNs through Y515 phosphorylation of TrkB.

  18. Activation of Gαq Signaling Enhances Memory Consolidation and Slows Cognitive Decline.

    Science.gov (United States)

    Arey, Rachel N; Stein, Geneva M; Kaletsky, Rachel; Kauffman, Amanda; Murphy, Coleen T

    2018-05-02

    Perhaps the most devastating decline with age is the loss of memory. Therefore, identifying mechanisms to restore memory function with age is critical. Using C. elegans associative learning and memory assays, we identified a gain-of-function G αq signaling pathway mutant that forms a long-term (cAMP response element binding protein [CREB]-dependent) memory following one conditioned stimulus-unconditioned stimulus (CS-US) pairing, which usually requires seven CS-US pairings. Increased CREB activity in AIM interneurons reduces the threshold for memory consolidation through transcription of a set of previously identified "long-term memory" genes. Enhanced G αq signaling in the AWC sensory neuron is both necessary and sufficient for improved memory and increased AIM CREB activity, and activation of G αq specifically in aged animals rescues the ability to form memory. Activation of G αq in AWC sensory neurons non-cell autonomously induces consolidation after one CS-US pairing, enabling both cognitive function maintenance with age and restoration of memory function in animals with impaired memory performance without decreased longevity. Copyright © 2018 Elsevier Inc. All rights reserved.

  19. A set of enhanced green fluorescent protein concatemers for quantitative determination of nuclear localization signal strength.

    Science.gov (United States)

    Böhm, Jennifer; Thavaraja, Ramya; Giehler, Susanne; Nalaskowski, Marcus M

    2017-09-15

    Regulated transport of proteins between nucleus and cytoplasm is an important process in the eukaryotic cell. In most cases, active nucleo-cytoplasmic protein transport is mediated by nuclear localization signal (NLS) and/or nuclear export signal (NES) motifs. In this study, we developed a set of vectors expressing enhanced GFP (EGFP) concatemers ranging from 2 to 12 subunits (2xEGFP to 12xEGFP) for analysis of NLS strength. As shown by in gel GFP fluorescence analysis and αGFP Western blotting, EGFP concatemers are expressed as fluorescent full-length proteins in eukaryotic cells. As expected, nuclear localization of concatemeric EGFPs decreases with increasing molecular weight. By oligonucleotide ligation this set of EGFP concatemers can be easily fused to NLS motifs. After determination of intracellular localization of EGFP concatemers alone and fused to different NLS motifs we calculated the size of a hypothetic EGFP concatemer showing a defined distribution of EGFP fluorescence between nucleus and cytoplasm (n/c ratio = 2). Clear differences of the size of the hypothetic EGFP concatemer depending on the fused NLS motif were observed. Therefore, we propose to use the size of this hypothetic concatemer as quantitative indicator for comparing strength of different NLS motifs. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Generation and tunable enhancement of a sum-frequency signal in lithium niobate nanowires

    Science.gov (United States)

    Sergeyev, Anton; Reig Escalé, Marc; Grange, Rachel

    2017-02-01

    Recent developments in the fabrication of lithium niobate (LiNbO3) structures down to the nanoscale opens up novel applications of this versatile material in nonlinear optics. Current nonlinear optical studies in sub-micron waveguides are mainly restricted to the generation of second and third harmonics. In this work, we demonstrate the generation and waveguiding of the sum-frequency generation (SFG) signal in a single LiNbO3 nanowire with a cross-section of 517 nm  ×  654 nm. Furthermore, we enhance the guided SFG signal 17.9 times by means of modal phase matching. We also display tuning of the phase-matched wavelength by varying the nanowire cross-section and changing the polarization of the incident laser. The results prove that LiNbO3 nanowires can be successfully used for nonlinear wave-mixing applications and assisting the miniaturization of optical devices. , which features invited work from the best early-career researchers working within the scope of J Phys D. This project is part of the Journal of Physics series’ 50th anniversary celebrations in 2017. Rachel Grange was selected by the Editorial Board of J Phys D as an Emerging Leader.

  1. Electrochemical immunoassay for thyroxine detection using cascade catalysis as signal amplified enhancer and multi-functionalized magnetic graphene sphere as signal tag

    Energy Technology Data Exchange (ETDEWEB)

    Han, Jing; Zhuo, Ying, E-mail: yingzhuo@swu.edu.cn; Chai, Yaqin; Yu, Yanqing; Liao, Ni; Yuan, Ruo, E-mail: yuanruo@swu.edu.cn

    2013-08-06

    Graphical abstract: -- Highlights: •A reusable electrochemical immunosensor is developed for thyroxine detection. •Cascade catalysis as signal amplified enhancer. •Multi-functionalized magnetic graphene sphere as signal tag. •The novel strategy has the advantages of high sensitivity, good selectivity and reproducibility. -- Abstract: This paper constructed a reusable electrochemical immunosensor for the detection of thyroxine at an ultralow concentration using cascade catalysis of cytochrome c (Cyt c) and glucose oxidase (GOx) as signal amplified enhancer. It is worth pointing out that numerous Cyt c and GOx were firstly carried onto the double-stranded DNA polymers based on hybridization chain reaction (HCR), and then the amplified responses could be achieved by cascade catalysis of Cyt c and GOx recycling with the help of glucose. Moreover, multi-functionalized magnetic graphene sphere was synthesized and used as signal tag, which not only exhibited good mechanical properties, large surface area and an excellent electron transfer rate of graphene, but also possessed excellent redox activity and desirable magnetic property. With a sandwich-type immunoreaction, the proposed cascade catalysis amplification strategy could greatly enhance the sensitivity for the detection of thyroxine. Under the optimal conditions, the immunosensor showed a wide linear ranged from 0.05 pg mL{sup −1} to 5 ng mL{sup −1} and a low detection limit down to 15 fg mL{sup −1}. Importantly, the proposed method offers promise for reproducible and cost-effective analysis of biological samples.

  2. Hypermethylation of TRIM59 and KLF14 Influences Cell Death Signaling in Familial Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Michalina Wezyk

    2018-01-01

    Full Text Available Epigenetic mechanisms play an important role in the development and progression of various neurodegenerative diseases. Abnormal methylation of numerous genes responsible for regulation of transcription, DNA replication, and apoptosis has been linked to Alzheimer’s disease (AD pathology. We have recently performed whole transcriptome profiling of familial early-onset Alzheimer’s disease (fEOAD patient-derived fibroblasts. On this basis, we demonstrated a strong dysregulation of cell cycle checkpoints and DNA damage response (DDR in both fibroblasts and reprogrammed neurons. Here, we show that the aging-correlated hypermethylation of KLF14 and TRIM59 genes associates with abnormalities in DNA repair and cell cycle control in fEOAD. Based on the resulting transcriptome networks, we found that the hypermethylation of KLF14 might be associated with epigenetic regulation of the chromatin organization and mRNA processing followed by hypermethylation of TRIM59 likely associated with the G2/M cell cycle phase and p53 role in DNA repair with BRCA1 protein as the key player. We propose that the hypermethylation of KLF14 could constitute a superior epigenetic mechanism for TRIM59 hypermethylation. The methylation status of both genes affects genome stability and might contribute to proapoptotic signaling in AD. Since this study combines data obtained from various tissues from AD patients, it reinforces the view that the genetic methylation status in the blood may be a valuable predictor of molecular processes occurring in affected tissues. Further research is necessary to define a detailed role of TRIM59 and KLF4 in neurodegeneration of neurons.

  3. Sensitization of gastric cancer cells to alkylating agents by glaucocalyxin B via cell cycle arrest and enhanced cell death

    Directory of Open Access Journals (Sweden)

    Ur Rahman MS

    2017-08-01

    cells to the alkylating agents via arresting the cell cycle and enhancing cell death. This is of significant therapeutic importance in the reduction of side effects associated with these drugs. Keywords: glaucocalyxin B, mitomycin C, cisplatin, cyclophosphamide, DNA linkers, side effects, gastric cancer

  4. The miR9863 family regulates distinct Mla alleles in barley to attenuate NLR receptor-triggered disease resistance and cell-death signaling.

    Directory of Open Access Journals (Sweden)

    Jie Liu

    2014-12-01

    Full Text Available Barley (Hordeum vulgare L. Mla alleles encode coiled-coil (CC, nucleotide binding, leucine-rich repeat (NB-LRR receptors that trigger isolate-specific immune responses against the powdery mildew fungus, Blumeria graminis f. sp. hordei (Bgh. How Mla or NB-LRR genes in grass species are regulated at post-transcriptional level is not clear. The microRNA family, miR9863, comprises four members that differentially regulate distinct Mla alleles in barley. We show that miR9863 members guide the cleavage of Mla1 transcripts in barley, and block or reduce the accumulation of MLA1 protein in the heterologous Nicotiana benthamiana expression system. Regulation specificity is determined by variation in a unique single-nucleotide-polymorphism (SNP in mature miR9863 family members and two SNPs in the Mla miR9863-binding site that separates these alleles into three groups. Further, we demonstrate that 22-nt miR9863s trigger the biogenesis of 21-nt phased siRNAs (phasiRNAs and together these sRNAs form a feed-forward regulation network for repressing the expression of group I Mla alleles. Overexpression of miR9863 members specifically attenuates MLA1, but not MLA10-triggered disease resistance and cell-death signaling. We propose a key role of the miR9863 family in dampening immune response signaling triggered by a group of MLA immune receptors in barley.

  5. Tobacco randomly inserted tt8 differenly enhance light signals and flavonoid accumulation

    International Nuclear Information System (INIS)

    Sompornpailin, K.; Kanthang, S.

    2015-01-01

    The individual lines of tobacco over-expressing TT8, a bHLH gene, were constructed and cultured under tissue culture condition radiating with photosynthetically activation radiation (PAR) or PAR+UVA. They were compared to wild type (WT). Leaf of treated plants was extracted and analyzed for flavonoid accumulations using a spectrophotometer. The extract of TT8 plants significantly contained flavone, flavonol and anthocyanin level, higher than the WT extract did. The petal extracts of mature transgenic under PAR had a similar absorbance profile of each substance, but these extracts had higher flavonoid contents than the leaf extracts did. All flavonoid subgroups and p-coumaric acid biosynthesis were significantly enhanced after the additional UVA radiation to plant. This UVA condition slightly stimulated an accumulation of these substances in normal plant. Some transgenic greatly increased flavonoid accumulation in responding to PAR+UVA, but the others were slightly different compared to WT. The distinct insertion site is directly affected TT8 gene expression. Transgenic seeds had a dark brown color more than WT seed, which indicated high content of polymer flavonoids (proanthocyanins). This over-expressing TT8 in transgenic tobacco may directly or indirectly enhance the signal transductions of PAR and UVA and raise up flavonoid accumulation. (author)

  6. Mediator Med23 deficiency enhances neural differentiation of murine embryonic stem cells through modulating BMP signaling.

    Science.gov (United States)

    Zhu, Wanqu; Yao, Xiao; Liang, Yan; Liang, Dan; Song, Lu; Jing, Naihe; Li, Jinsong; Wang, Gang

    2015-02-01

    Unraveling the mechanisms underlying early neural differentiation of embryonic stem cells (ESCs) is crucial to developing cell-based therapies of neurodegenerative diseases. Neural fate acquisition is proposed to be controlled by a 'default' mechanism, for which the molecular regulation is not well understood. In this study, we investigated the functional roles of Mediator Med23 in pluripotency and lineage commitment of murine ESCs. Unexpectedly, we found that, despite the largely unchanged pluripotency and self-renewal of ESCs, Med23 depletion rendered the cells prone to neural differentiation in different differentiation assays. Knockdown of two other Mediator subunits, Med1 and Med15, did not alter the neural differentiation of ESCs. Med15 knockdown selectively inhibited endoderm differentiation, suggesting the specificity of cell fate control by distinctive Mediator subunits. Gene profiling revealed that Med23 depletion attenuated BMP signaling in ESCs. Mechanistically, MED23 modulated Bmp4 expression by controlling the activity of ETS1, which is involved in Bmp4 promoter-enhancer communication. Interestingly, med23 knockdown in zebrafish embryos also enhanced neural development at early embryogenesis, which could be reversed by co-injection of bmp4 mRNA. Taken together, our study reveals an intrinsic, restrictive role of MED23 in early neural development, thus providing new molecular insights for neural fate determination. © 2015. Published by The Company of Biologists Ltd.

  7. Enhancing Linearity of Voltage Controlled Oscillator Thermistor Signal Conditioning Circuit Using Linear Search

    Science.gov (United States)

    Rana, K. P. S.; Kumar, Vineet; Prasad, Tapan

    2018-02-01

    Temperature to Frequency Converters (TFCs) are potential signal conditioning circuits (SCCs) usually employed in temperature measurements using thermistors. A NE/SE-566 based SCC has been recently used in several reported works as TFC. Application of NE/SE-566 based SCC requires a mechanism for finding the optimal values of SCC parameters yielding the optimal linearity and desired sensitivity performances. Two classical methods, namely, inflection point and three point have been employed for this task. In this work, the application of these two methods, on NE/SE-566 based SCC in TFC, is investigated in detail and the conditions for its effective usage are developed. Further, since these classical methods offer an approximate linearization of temperature and frequency relationship an application of a linear search based technique is proposed to further enhance the linearity. The implemented linear search method used results obtained from the above mentioned classical methods. The presented simulation studies, for three different industrial grade thermistors, revealed that the linearity enhancements of 21.7, 18.3 and 17.8% can be achieved over the inflection point method and 4.9, 4.7 and 4.7% over the three point method, for an input temperature range of 0-100 °C.

  8. Mesenchymal Stem Cells Enhance Liver Regeneration via Improving Lipid Accumulation and Hippo Signaling

    Directory of Open Access Journals (Sweden)

    Yang Liu

    2018-01-01

    Full Text Available The liver has the potential to regenerate after injury. It is a challenge to improve liver regeneration (LR after liver resection in clinical practice. Bone morrow-derived mesenchymal stem cells (MSCs have shown to have a role in various liver diseases. To explore the effects of MSCs on LR, we established a model of 70% partial hepatectomy (PHx. Results revealed that infusion of MSCs could improve LR through enhancing cell proliferation and cell growth during the first 2 days after PHx, and MSCs could also restore liver synthesis function. Infusion of MSCs also improved liver lipid accumulation partly via mechanistic target of rapamycin (mTOR signaling and enhanced lipid β-oxidation support energy for LR. Rapamycin-induced inhibition of mTOR decreased liver lipid accumulation at 24 h after PHx, leading to impaired LR. And after infusion of MSCs, a proinflammatory environment formed in the liver, evidenced by increased expression of IL-6 and IL-1β, and thus the STAT3 and Hippo-YAP pathways were activated to improve cell proliferation. Our results demonstrated the function of MSCs on LR after PHx and provided new evidence for stem cell therapy of liver diseases.

  9. AKT inhibitors promote cell death in cervical cancer through disruption of mTOR signaling and glucose uptake.

    Directory of Open Access Journals (Sweden)

    Ramachandran Rashmi

    Full Text Available PI3K/AKT pathway alterations are associated with incomplete response to chemoradiation in human cervical cancer. This study was performed to test for mutations in the PI3K pathway and to evaluate the effects of AKT inhibitors on glucose uptake and cell viability.Mutational analysis of DNA from 140 pretreatment tumor biopsies and 8 human cervical cancer cell lines was performed. C33A cells (PIK3CAR88Q and PTENR233* were treated with increasing concentrations of two allosteric AKT inhibitors (SC-66 and MK-2206 with or without the glucose analogue 2-deoxyglucose (2-DG. Cell viability and activation status of the AKT/mTOR pathway were determined in response to the treatment. Glucose uptake was evaluated by incubation with 18F-fluorodeoxyglucose (FDG. Cell migration was assessed by scratch assay.Activating PIK3CA (E545K, E542K and inactivating PTEN (R233* mutations were identified in human cervical cancer. SC-66 effectively inhibited AKT, mTOR and mTOR substrates in C33A cells. SC-66 inhibited glucose uptake via reduced delivery of Glut1 and Glut4 to the cell membrane. SC-66 (1 µg/ml-56% and MK-2206 (30 µM-49% treatment decreased cell viability through a non-apoptotic mechanism. Decreases in cell viability were enhanced when AKT inhibitors were combined with 2-DG. The scratch assay showed a substantial reduction in cell migration upon SC-66 treatment.The mutational spectrum of the PI3K/AKT pathway in cervical cancer is complex. AKT inhibitors effectively block mTORC1/2, decrease glucose uptake, glycolysis, and decrease cell viability in vitro. These results suggest that AKT inhibitors may improve response to chemoradiation in cervical cancer.

  10. Enhancement of Twins Fetal ECG Signal Extraction Based on Hybrid Blind Extraction Techniques

    Directory of Open Access Journals (Sweden)

    Ahmed Kareem Abdullah

    2017-07-01

    Full Text Available ECG machines are noninvasive system used to measure the heartbeat signal. It’s very important to monitor the fetus ECG signals during pregnancy to check the heat activity and to detect any problem early before born, therefore the monitoring of ECG signals have clinical significance and importance. For multi-fetal pregnancy case the classical filtering algorithms are not sufficient to separate the ECG signals between mother and fetal. In this paper the mixture consists of mixing from three ECG signals, the first signal is the mother ECG (M-ECG signal, second signal the Fetal-1 ECG (F1-ECG, and third signal is the Fetal-2 ECG (F2-ECG, these signals are extracted based on modified blind source extraction (BSE techniques. The proposed work based on hybridization between two BSE techniques to ensure that the extracted signals separated well. The results demonstrate that the proposed work very efficiently to extract the useful ECG signals

  11. Death Receptor 3 Signaling Controls the Balance between Regulatory and Effector Lymphocytes in SAMP1/YitFc Mice with Crohn’s Disease-Like Ileitis

    Directory of Open Access Journals (Sweden)

    Zhaodong Li

    2018-03-01

    Full Text Available Death receptor 3 (DR3, a member of the tumor necrosis factor receptor (TNFR superfamily, has been implicated in regulating T-helper type-1 (TH1, type-2 (TH2, and type-17 (TH17 responses as well as regulatory T cell (Treg and innate lymphoid cell (ILC functions during immune-mediated diseases. However, the role of DR3 in controlling lymphocyte functions in inflammatory bowel disease (IBD is not fully understood. Recent studies have shown that activation of DR3 signaling modulates Treg expansion suggesting that stimulation of DR3 represents a potential therapeutic target in human inflammatory diseases, including Crohn’s disease (CD. In this study, we tested a specific DR3 agonistic antibody (4C12 in SAMP1/YitFc (SAMP mice with CD-like ileitis. Interestingly, treatment with 4C12 prior to disease manifestation markedly worsened the severity of ileitis in SAMP mice despite an increase in FoxP3+ lymphocytes in mesenteric lymph node (MLN and small-intestinal lamina propria (LP cells. Disease exacerbation was dominated by overproduction of both TH1 and TH2 cytokines and associated with expansion of dysfunctional CD25−FoxP3+ and ILC group 1 (ILC1 cells. These effects were accompanied by a reduction in CD25+FoxP3+ and ILC group 3 (ILC3 cells. By comparison, genetic deletion of DR3 effectively reversed the inflammatory phenotype in SAMP mice by promoting the expansion of CD25+FoxP3+ over CD25−FoxP3+ cells and the production of IL-10 protein. Collectively, our data demonstrate that DR3 signaling modulates a multicellular network, encompassing Tregs, T effectors, and ILCs, governing disease development and progression in SAMP mice with CD-like ileitis. Manipulating DR3 signaling toward the restoration of the balance between protective and inflammatory lymphocytes may represent a novel and targeted therapeutic modality for patients with CD.

  12. Polarization-based enhancement of ocean color signal for estimating suspended particulate matter: radiative transfer simulations and laboratory measurements.

    Science.gov (United States)

    Liu, Jia; He, Xianqiang; Liu, Jiahang; Bai, Yan; Wang, Difeng; Chen, Tieqiao; Wang, Yihao; Zhu, Feng

    2017-04-17

    Absorption and scattering by molecules, aerosols and hydrosols, and the reflection and transmission over the sea surface can modify the original polarization state of sunlight. However, water-leaving radiance polarization, containing embedded water constituent information, has largely been neglected. Here, the efficiency of the parallel polarization radiance (PPR) for enhancing ocean color signal of suspended particulate matter is examined via vector radiative transfer simulations and laboratory experiments. The simulation results demonstrate that the PPR has a slightly higher ocean color signal at the top-of-atmosphere as compared with that of the total radiance. Moreover, both the simulations and laboratory measurements reveal that, compared with total radiance, PPR can effectively enhance the normalized ocean color signal for a large range of observation geometries, wavelengths, and suspended particle concentrations. Thus, PPR has great potential for improving the ocean color signal detection from satellite.

  13. Voluntary resistance running with short distance enhances spatial memory related to hippocampal BDNF signaling.

    Science.gov (United States)

    Lee, Min Chul; Okamoto, Masahiro; Liu, Yu Fan; Inoue, Koshiro; Matsui, Takashi; Nogami, Haruo; Soya, Hideaki

    2012-10-15

    Although voluntary running has beneficial effects on hippocampal cognitive functions if done abundantly, it is still uncertain whether resistance running would be the same. For this purpose, voluntary resistance wheel running (RWR) with a load is a suitable model, since it allows increased work levels and resultant muscular adaptation in fast-twitch muscle. Here, we examined whether RWR would have potential effects on hippocampal cognitive functions with enhanced hippocampal brain-derived neurotrophic factor (BDNF), as does wheel running without a load (WR). Ten-week-old male Wistar rats were assigned randomly to sedentary (Sed), WR, and RWR (to a maximum load of 30% of body weight) groups for 4 wk. We found that in RWR, work levels increased with load, but running distance decreased by about half, which elicited muscular adaptation for fast-twitch plantaris muscle without causing any negative stress effects. Both RWR and WR led to improved spatial learning and memory as well as gene expressions of hippocampal BDNF signaling-related molecules. RWR increased hippocampal BDNF, tyrosine-related kinase B (TrkB), and cAMP response element-binding (CREB) protein levels, whereas WR increased only BDNF. With both exercise groups, there were correlations between spatial memory and BDNF protein (r = 0.41), p-CREB protein (r = 0.44), and work levels (r = 0.77). These results suggest that RWR plays a beneficial role in hippocampus-related cognitive functions associated with hippocampal BDNF signaling, even with short distances, and that work levels rather than running distance are more determinant of exercise-induced beneficial effects in wheel running with and without a load.

  14. Spermidine-mediated hydrogen peroxide signaling enhances the antioxidant capacity of salt-stressed cucumber roots.

    Science.gov (United States)

    Wu, Jianqiang; Shu, Sheng; Li, Chengcheng; Sun, Jin; Guo, Shirong

    2018-07-01

    Hydrogen peroxide (H 2 O 2 ) is a key signaling molecule that mediates a variety of physiological processes and defense responses against abiotic stress in higher plants. In this study, our aims are to clarify the role of H 2 O 2 accumulation induced by the exogenous application of spermidine (Spd) to cucumber (Cucumis sativus) seedlings in regulating the antioxidant capacity of roots under salt stress. The results showed that Spd caused a significant increase in endogenous polyamines and H 2 O 2 levels, and peaked at 2 h after salt stress. Spd-induced H 2 O 2 accumulation was blocked under salt stress by pretreatment with a H 2 O 2 scavenger and respective inhibitors of cell wall peroxidase (CWPOD; EC: 1.11.1.7), polyamine oxidase (PAO; EC: 1.5.3.11) and NADPH oxidase (NOX; EC: 1.6.3.1); among these three inhibitors, the largest decrease was found in response to the addition of the inhibitor of polyamine oxidase. In addition, we observed that exogenous Spd could increase the activities of the enzymes superoxide dismutase (SOD; EC: 1.15.1.1), peroxidase (POD; EC: 1.11.1.7) and catalase (CAT; EC: 1.11.1.6) as well as the expression of their genes in salt-stressed roots, and the effects were inhibited by H 2 O 2 scavengers and polyamine oxidase inhibitors. These results suggested that, by regulating endogenous PAs-mediated H 2 O 2 signaling in roots, Spd could enhance antioxidant enzyme activities and reduce oxidative damage; the main source of H 2 O 2 was polyamine oxidation, which was associated with improved tolerance and root growth recovery of cucumber under salt stress. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  15. Arctigenin, a Natural Lignan Compound, Induces Apoptotic Death of Hepatocellular Carcinoma Cells via Suppression of PI3-K/Akt Signaling.

    Science.gov (United States)

    Jiang, Xiaoxin; Zeng, Leping; Huang, Jufang; Zhou, Hui; Liu, Yubin

    2015-04-28

    In this study, we explored the cytotoxic effects of arctigenin, a natural lignan compound, on human hepatocellular carcinoma (HCC) cells and check the involvement of phosphatidylinositol 3-kinase (PI3-K)/Akt signaling. HCC cells were treated with different concentrations of arctigenin and cell viability and apoptosis were assessed. Manipulating Akt signaling was used to determine its role in the action of arctigenin. Arctigenin significantly inhibited the viability of HCC cells in a concentration-dependent manner. Arctigenin induced apoptosis and activation of caspase-9 and -3. Overexpression of a constitutively active Akt mutant blocked arctigenin-induced apoptosis. Combinational treatment with arctigenin and the PI3-K inhibitor LY294002 significantly enhanced apoptosis. Arctigenin reduced the expression of Bcl-xL, Mcl-1, and survivin and the phosphorylation of mTOR and S6K, which were significantly reversed by overexpression of constitutively active Akt. This is the first report about the anticancer activity of arctigenin in HCC cells, which is mediated by inactivation of PI3-K/Akt signaling. © 2015 Wiley Periodicals, Inc.

  16. A Class of Optimal Rectangular Filtering Matrices for Single-Channel Signal Enhancement in the Time Domain

    DEFF Research Database (Denmark)

    Jensen, Jesper Rindom; Benesty, Jacob; Christensen, Mads Græsbøll

    2013-01-01

    In this paper, we introduce a new class of op- timal rectangular filtering matrices for single-channel speech enhancement. The new class of filters exploits the fact that the dimension of the signal subspace is lower than that of the full space. By doing this, extra degrees of freedom...... in the filters, that are otherwise reserved for preserving the signal subspace, can be used for achieving an improved output signal-to-noise ratio (SNR). Moreover, the filters allow for explicit control of the tradeoff between noise reduction and speech distortion via the chosen rank of the signal subspace...... and real signals. The results show a number of interesting things. Firstly, they show how speech distortion can be traded for noise reduction and vice versa in a seamless manner. Moreover, the introduced filter designs are capable of achieving both the upper and lower bounds for the output SNR via...

  17. CD70 reverse signaling enhances NK cell function and immunosurveillance in CD27-expressing B-cell malignancies.

    Science.gov (United States)

    Al Sayed, Mohamad F; Ruckstuhl, Carla A; Hilmenyuk, Tamara; Claus, Christina; Bourquin, Jean-Pierre; Bornhauser, Beat C; Radpour, Ramin; Riether, Carsten; Ochsenbein, Adrian F

    2017-07-20

    The interaction of the tumor necrosis factor receptor (TNFR) CD27 with its ligand CD70 is an emerging target to treat cancer. CD27 signaling provides costimulatory signals to cytotoxic T cells but also increases the frequency of regulatory T cells. Similar to other TNFR ligands, CD70 has been shown to initiate intracellular signaling pathways (CD70 reverse signaling). CD27 is expressed on a majority of B-cell non-Hodgkin lymphoma, but its role in the immune control of lymphoma and leukemia is unknown. We therefore generated a cytoplasmic deletion mutant of CD27 (CD27-trunc) to study the role of CD70 reverse signaling in the immunosurveillance of B-cell malignancies in vivo. Expression of CD27-trunc on malignant cells increased the number of tumor-infiltrating interferon γ-producing natural killer (NK) cells. In contrast, the antitumoral T-cell response remained largely unchanged. CD70 reverse signaling in NK cells was mediated via the AKT signaling pathway and increased NK cell survival and effector function. The improved immune control by activated NK cells prolonged survival of CD27-trunc-expressing lymphoma-bearing mice. Finally, CD70 reverse signaling enhanced survival and effector function of human NK cells in a B-cell acute lymphoblastic leukemia xenotransplants model. Therefore, CD70 reverse signaling in NK cells contributes to the immune control of CD27-expressing B-cell lymphoma and leukemia. © 2017 by The American Society of Hematology.

  18. Newly synthesized quinazolinone HMJ-38 suppresses angiogenetic responses and triggers human umbilical vein endothelial cell apoptosis through p53-modulated Fas/death receptor signaling

    Energy Technology Data Exchange (ETDEWEB)

    Chiang, Jo-Hua [Department of Life Sciences, National Chung Hsing University, 250, Kuo-Kuang Road, Taichung 402, Taiwan (China); Yang, Jai-Sing [Department of Pharmacology, China Medical University, Taichung 404, Taiwan (China); Lu, Chi-Cheng [Department of Life Sciences, National Chung Hsing University, 250, Kuo-Kuang Road, Taichung 402, Taiwan (China); Hour, Mann-Jen; Chang, Shu-Jen [School of Pharmacy, China Medical University, Taichung 40402, Taiwan (China); Lee, Tsung-Han, E-mail: thlee@email.nchu.edu.tw [Department of Life Sciences, National Chung Hsing University, 250, Kuo-Kuang Road, Taichung 402, Taiwan (China); Department of Biological Science and Technology, China Medical University, 91, Hsueh-Shih Road, Taichung 404, Taiwan (China); Chung, Jing-Gung, E-mail: jgchung@mail.cmu.edu.tw [Department of Biological Science and Technology, China Medical University, 91, Hsueh-Shih Road, Taichung 404, Taiwan (China); Department of Biotechnology, Asia University, Taichung 413, Taiwan (China)

    2013-06-01

    The current study aims to investigate the antiangiogenic responses and apoptotic death of human umbilical vein endothelial cells (HUVECs) by a newly synthesized compound named 2-(3′-methoxyphenyl)-6-pyrrolidinyl-4-quinazolinone (HMJ-38). This work attempted to not only explore the effects of angiogenesis on in vivo and ex vivo studies but also hypothesize the implications for HUVECs (an ideal cell model for angiogenesis in vitro) and further undermined apoptotic experiments to verify the underlying molecular signaling by HMJ-38. Our results demonstrated that HMJ-38 significantly inhibited blood vessel growth and microvessel formation by the mouse Matrigel plug assay of angiogenesis, and the suppression of microsprouting from the rat aortic ring assay was observed after HMJ-38 exposure. In addition, HMJ-38 disrupted the tube formation and blocked the ability of HUVECs to migrate in response to VEGF. We also found that HMJ-38 triggered cell apoptosis of HUVECs in vitro. HMJ-38 concentration-dependently suppressed viability and induced apoptotic damage in HUVECs. HMJ-38-influenced HUVECs were performed by determining the oxidative stress (ROS production) and ATM/p53-modulated Fas and DR4/DR5 signals that were examined by flow cytometry, Western blotting, siRNA and real-time RT-PCR analyses, respectively. Our findings demonstrate that p53-regulated extrinsic pathway might fully contribute to HMJ-38-provoked apoptotic death in HUVECs. In view of these observations, we conclude that HMJ-38 reduces angiogenesis in vivo and ex vivo as well as induces apoptosis of HUVECs in vitro. Overall, HMJ-38 has a potent anti-neovascularization effect and could warrant being a vascular targeting agent in the future. - Highlights: • HMJ-38 suppresses angiogenic actions in vivo and ex vivo. • Inhibitions of blood vessel and microvessel formation by HMJ-38 are acted. • Cytotoxic effects of HUVECs occur by HMJ-38 challenge. • p53-modulated extrinsic pathway contributes to HMJ-38

  19. Andrographolide protects liver cells from H2O2 induced cell death by upregulation of Nrf-2/HO-1 mediated via adenosine A2a receptor signalling.

    Science.gov (United States)

    Mittal, Smriti P K; Khole, Swati; Jagadish, Nidhi; Ghosh, Debjani; Gadgil, Vijay; Sinkar, Vilas; Ghaskadbi, Saroj S

    2016-11-01

    Andrographolide, principle constituent of Andrographis paniculata Nees is used in traditional medicine in Southeast Asia and is known to exhibit various biological activities. Its antioxidant activity is due to its ability to activate one of the antioxidant enzymes, heme oxygenase-1 (HO-1) which is regulated transcriptionally through Nrf-2. However, molecular mechanism underlying activation of Nrf-2/HO-1 has not yet been clearly understood. Protective effect of andrographolide against H2O2 induced cell death, reactive oxygen species and lipid peroxidation was observed in HepG2 cells. Ability of andrographolide to modulate G-protein coupled receptor (GPCR) mediated signalling was determined using in silico docking and gene expression was analyzed by qRT-PCR, confocal microscopy and western blot analysis. We clearly show that andrographolide via adenosine A2A receptor signalling leads to activation of p38 MAP kinase, resulting in upregulation of Nrf-2, its translocation to nucleus and activation of HO-1. Additionally, it activates adenylate cyclase resulting in cAMP formation which in turn activates protein kinase A leading to inhibition of GSK-3β by phosphorylation. Inactivated GSK-3β leads to retention of Nrf-2 in the nucleus leading to sustained expression of HO-1 by binding to its antioxidant response element (ARE). Thus, andrographolide probably by binding to adenosine A2a receptor activates Nrf-2 transcription and also inhibits its exclusion from the nucleus by inactivating GSK-3β, together resulting in activation of HO-1. We speculate that andrographolide can be used as a therapeutic drug to combat oxidative stress implicated in pathogenesis of various diseases such as diabetes, osteoporosis, neurodegenerative diseases etc. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Hedgehog signaling in tumor cells facilitates osteoblast-enhanced osteolytic metastases.

    Directory of Open Access Journals (Sweden)

    Shamik Das

    Full Text Available The remodeling process in bone yields numerous cytokines and chemokines that mediate crosstalk between osteoblasts and osteoclasts and also serve to attract and support metastatic tumor cells. The metastatic tumor cells disturb the equilibrium in bone that manifests as skeletal complications. The Hedgehog (Hh pathway plays an important role in skeletogenesis. We hypothesized that the Hh pathway mediates an interaction between tumor cells and osteoblasts and influences osteoblast differentiation in response to tumor cells. We have determined that breast tumor cells have an activated Hh pathway characterized by upregulation of the ligand, IHH and transcription factor GLI1. Breast cancer cells interact with osteoblasts and cause an enhanced differentiation of pre-osteoblasts to osteoblasts that express increased levels of the osteoclastogenesis factors, RANKL and PTHrP. There is sustained expression of osteoclast-promoting factors, RANKL and PTHrP, even after the osteoblast differentiation ceases and apoptosis sets in. Moreover, tumor cells that are deficient in Hh signaling are compromised in their ability to induce osteoblast differentiation and consequently are inefficient in causing osteolysis. The stimulation of osteoblast differentiation sets the stage for osteoclast differentiation and overall promotes osteolysis. Thus, in the process of developing newer therapeutic strategies against breast cancer metastasis to bone it would worthwhile to keep in mind the role of the Hh pathway in osteoblast differentiation in an otherwise predominant osteolytic phenomenon.

  1. Enhancement of signal sensitivity in a heterogeneous neural network refined from synaptic plasticity

    Energy Technology Data Exchange (ETDEWEB)

    Li Xiumin; Small, Michael, E-mail: ensmall@polyu.edu.h, E-mail: 07901216r@eie.polyu.edu.h [Department of Electronic and Information Engineering, Hong Kong Polytechnic University, Hung Hom, Kowloon (Hong Kong)

    2010-08-15

    Long-term synaptic plasticity induced by neural activity is of great importance in informing the formation of neural connectivity and the development of the nervous system. It is reasonable to consider self-organized neural networks instead of prior imposition of a specific topology. In this paper, we propose a novel network evolved from two stages of the learning process, which are respectively guided by two experimentally observed synaptic plasticity rules, i.e. the spike-timing-dependent plasticity (STDP) mechanism and the burst-timing-dependent plasticity (BTDP) mechanism. Due to the existence of heterogeneity in neurons that exhibit different degrees of excitability, a two-level hierarchical structure is obtained after the synaptic refinement. This self-organized network shows higher sensitivity to afferent current injection compared with alternative archetypal networks with different neural connectivity. Statistical analysis also demonstrates that it has the small-world properties of small shortest path length and high clustering coefficients. Thus the selectively refined connectivity enhances the ability of neuronal communications and improves the efficiency of signal transmission in the network.

  2. Enhancement of signal sensitivity in a heterogeneous neural network refined from synaptic plasticity

    International Nuclear Information System (INIS)

    Li Xiumin; Small, Michael

    2010-01-01

    Long-term synaptic plasticity induced by neural activity is of great importance in informing the formation of neural connectivity and the development of the nervous system. It is reasonable to consider self-organized neural networks instead of prior imposition of a specific topology. In this paper, we propose a novel network evolved from two stages of the learning process, which are respectively guided by two experimentally observed synaptic plasticity rules, i.e. the spike-timing-dependent plasticity (STDP) mechanism and the burst-timing-dependent plasticity (BTDP) mechanism. Due to the existence of heterogeneity in neurons that exhibit different degrees of excitability, a two-level hierarchical structure is obtained after the synaptic refinement. This self-organized network shows higher sensitivity to afferent current injection compared with alternative archetypal networks with different neural connectivity. Statistical analysis also demonstrates that it has the small-world properties of small shortest path length and high clustering coefficients. Thus the selectively refined connectivity enhances the ability of neuronal communications and improves the efficiency of signal transmission in the network.

  3. Antiproton and positron signal enhancement in dark matter mini-spikes scenarios

    International Nuclear Information System (INIS)

    Brun, Pierre; Bertone, Gianfranco; Lavalle, Julien; Salati, Pierre; Taillet, Richard

    2007-04-01

    The annihilation of dark matter (DM) in the Galaxy could produce specific imprints on the spectra of antimatter species in Galactic cosmic rays, which could be detected by upcoming experiments such as PAMELA and AMS02. Recent studies show that the presence of substructures can enhance the annihilation signal by a 'boost factor' that not only depends on energy, but that is intrinsically a statistical property of the distribution of DM substructures inside the Milky Way. We investigate a scenario in which substructures consist of ∼100 'mini-spikes' around intermediate-mass black holes. Focusing on primary positrons and antiprotons, we find large boost factors, up to a few thousand, that exhibit a large variance at high energy in the case of positrons and at low energy in the case of antiprotons. As a consequence, an estimate of the DM particle mass based on the observed cut-off in the positron spectrum could lead to a substantial underestimate of its actual value. (authors)

  4. Dengue vaccine safety signal: Immune enhancement, waning immunity, or chance occurrence?

    Science.gov (United States)

    Gessner, Bradford D; Halsey, Neal

    2017-06-14

    A new dengue vaccine was associated with increased risk of hospitalized virologically-confirmed disease during year 3 of follow-up among children age 2-5years. Among hypotheses to explain this finding, we could not distinguish definitively between antibody dependent enhancement, waning immunity, or chance occurrence. However, any theory must account for the following: (a) the signal occurred mainly because of decreased dengue among controls rather than increased dengue among vaccinees; (b) among 48 data points, a statistically significant increase in hospitalization among vaccinated children occurred for only one age group, during one year, and in one region; (c) cumulative risk was similar for vaccinated vs. control children age 2-5years at the end of year 5 and lower for vaccinated vs. control children among older age groups; (d) the protective effect of vaccine against hospitalization decreased from years 1-2 to years 3-5 of follow-up for all age groups and regions. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  5. Low noise signal-to-noise ratio enhancing readout circuit for current-mediated active pixel sensors

    International Nuclear Information System (INIS)

    Ottaviani, Tony; Karim, Karim S.; Nathan, Arokia; Rowlands, John A.

    2006-01-01

    Diagnostic digital fluoroscopic applications continuously expose patients to low doses of x-ray radiation, posing a challenge to both the digital imaging pixel and readout electronics when amplifying small signal x-ray inputs. Traditional switch-based amorphous silicon imaging solutions, for instance, have produced poor signal-to-noise ratios (SNRs) at low exposure levels owing to noise sources from the pixel readout circuitry. Current-mediated amorphous silicon pixels are an improvement over conventional pixel amplifiers with an enhanced SNR across the same low-exposure range, but whose output also becomes nonlinear with increasing dosage. A low-noise SNR enhancing readout circuit has been developed that enhances the charge gain of the current-mediated active pixel sensor (C-APS). The solution takes advantage of the current-mediated approach, primarily integrating the signal input at the desired frequency necessary for large-area imaging, while adding minimal noise to the signal readout. Experimental data indicates that the readout circuit can detect pixel outputs over a large bandwidth suitable for real-time digital diagnostic x-ray fluoroscopy. Results from hardware testing indicate that the minimum achievable C-APS output current that can be discerned at the digital fluoroscopic output from the enhanced SNR readout circuit is 0.341 nA. The results serve to highlight the applicability of amorphous silicon current-mediated pixel amplifiers for large-area flat panel x-ray imagers

  6. Restimulation-induced T-cell death through NTB-A/SAP signaling pathway is impaired in tuberculosis patients with depressed immune responses.

    Science.gov (United States)

    Hernández Del Pino, Rodrigo E; Pellegrini, Joaquín M; Rovetta, Ana I; Peña, Delfina; Álvarez, Guadalupe I; Rolandelli, Agustín; Musella, Rosa M; Palmero, Domingo J; Malbran, Alejandro; Pasquinelli, Virginia; García, Verónica E

    2017-09-01

    Production of IFN-γ contributes to host defense against Mycobacterium tuberculosis (Mtb) infection. We previously demonstrated that Signaling lymphocytic activation molecule-associated protein (SAP) expression on cells from tuberculosis (TB) patients was inversely correlated with IFN-γ production. Here we first investigated the role of NK, T- and B-cell antigen (NTB-A)/SAP pathway in the regulation of Th1 response against Mtb. Upon antigen stimulation, NTB-A phosphorylation rapidly increases and afterwards modulates IFN-γ and IL-17 secretion. To sustain a healthy immune system, controlled expansion and contraction of lymphocytes, both during and after an adaptive immune response, is essential. Besides, restimulation-induced cell death (RICD) results in an essential homeostatic mechanism for precluding excess T-cell accumulation and associated immunopathology during the course of certain infections. Accordingly, we found that the NTB-A/SAP pathway was required for RICD during active tuberculosis. In low responder (LR) TB patients, impaired RICD was associated with diminished FASL levels, IL-2 production and CD25 high expression after cell-restimulation. Interestingly, we next observed that SAP mediated the recruitment of the Src-related kinase FYNT, only in T cells from LR TB patients that were resistant to RICD. Together, we showed that the NTB-A/SAP pathway regulates T-cell activation and RICD during human TB. Moreover, the NTB-A/SAP/FYNT axis promotes polarization to an unfavorable Th2-phenotype.

  7. The influence of the maximal value and peak enhancement value of arterial and venous enhancement curve on CT perfusion parameters and signal-to-noise ratio

    International Nuclear Information System (INIS)

    Ju Haiyue; Gao Sijia; Xu Ke; Wang Qiang

    2007-01-01

    Objective: To explore the influence of the maximal value and peak enhancement value of arterial and venous enhancement curve on CT perfusion parameters and signal-to-noise ratio (SNR). Methods: Seventeen patients underwent brain CT perfusion scanning. All row data were analyzed with perfusion software for 6 times, and get different arterial and venous enhancement curves for each patient. The maximal values and peak enhancement values of each arterial and venous enhancement curves, as well as mean perfusion parameters including cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), permeability surface area product (PS), and their standard deviations (SD) in homolateral white and gray matter were measured and recorded. SNR was calculated by dividing the mean perfusion parameter value by its SD. Pearson correlation analysis and two-tailed paired Student t test were used for statistics. Results: The maximal values and peak enhancement values of arterial and venous curves were correlated with mean SNR CBF , SNR CBV and SNR MTT in both white matter and gray matters (r value range: 0.332-0.922, P PS in white matter(r=0.256, P PS (in both white matter and gray matters) and arterial peak enhancement values, the maximal values and venous peak enhancement values, or between SNR PS (in gray matter) and the maximal values of venous curve(r value range: -0.058-0.210, P>0.05). (2) Mean CBF, CBV and PS values in the group with low venous peak enhancement values were significantly different from the group with high venous peak enhancement values in both white and gray matters (t value range: 3.830-5.337, P 0.05). Conclusions: The mean perfusion parameters and SNR are influenced by the maximal values and peak enhancement values of the arterial and venous curves. Peak enhancement of arterial and venous curves should be adjusted to higher level to make parameter values more reliable and increase the SNR. (authors)

  8. Death Cafe.

    Science.gov (United States)

    Miles, Lizzy; Corr, Charles A

    2017-06-01

    This article explains the meaning of the phrase Death Cafe and describes what typically occurs at a Death Cafe gathering. The article traces the history of the Death Cafe movement, explores some reasons why people take part in a Death Cafe gathering, and gives examples of what individuals think they might derive from their participation. In addition, this article notes similarities between the Death Cafe movement and three other developments in the field of death, dying, and bereavement. Finally, this article identifies two provisional lessons that can be drawn from Death Cafe gatherings and the Death Cafe movement itself.

  9. Enhanced signal dispersion in saturation transfer difference experiments by conversion to a 1D-STD-homodecoupled spectrum

    Energy Technology Data Exchange (ETDEWEB)

    Martin-Pastor, Manuel; Vega-Vazquez, Marino [Universidade de Santiago de Compostela, Laboratorio Integral de Dinamica e Estructura de Biomoleculas Jose R. Carracido, Unidade de Resonancia Magnetica, Edificio CACTUS, RIAIDT (Spain); Capua, Antonia De [Seconda Universita degli Studi di Napoli, Dipartimento di Scienze Ambientali (Italy); Canales, Angeles [Centro de Investigaciones Biologicas, CSIC, Departamento de Estructura y funcion de proteinas (Spain); Andre, Sabine; Gabius, Hans-Joachim [Ludwig-Maximilians-Universitaet, Institut fuer Physiologische Chemie, Tieraerztliche Fakultaet (Germany); Jimenez-Barbero, Jesus [Centro de Investigaciones Biologicas, CSIC, Departamento de Estructura y funcion de proteinas (Spain)], E-mail: JJbarbero@cib.csic.es

    2006-10-15

    The saturation transfer difference (STD) experiment is a rich source of information on topological aspects of ligand binding to a receptor. The epitope mapping is based on a magnetization transfer after signal saturation from the receptor to the ligand, where interproton distances permit this process. Signal overlap in the STD spectrum can cause difficulties to correctly assign and/or quantitate the measured enhancements. To address this issue we report here a modified version of the routine experiment and a processing scheme that provides a 1D-STD homodecoupled spectrum (i.e. an experiment in which all STD signals appear as singlets) with line widths similar to those in original STD spectrum. These refinements contribute to alleviate problems of signal overlap. The experiment is based on 2D-J-resolved spectroscopy, one of the fastest 2D experiments under conventional data sampling in the indirect dimension, and provides excellent sensitivity, a key factor for the difference experiments.

  10. Enhancing Brassinosteroid Signaling via Overexpression of Tomato (Solanum lycopersicum SlBRI1 Improves Major Agronomic Traits

    Directory of Open Access Journals (Sweden)

    Shuming Nie

    2017-08-01

    Full Text Available Brassinosteroids (BRs play important roles in plant growth, development, and stress responses through the receptor, Brassinosteroid-insensitive 1 (BRI1, which perceives BRs and initiates BR signaling. There is considerable potential agricultural value in regulating BR signaling in crops. In this study, we investigated the effects of overexpressing the tomato (Solanum lycopersicum BRI1 gene, SlBRI1, on major agronomic traits, such as seed germination, vegetative growth, fruit ethylene production, carotenoid accumulation, yield, and quality attributes. SlBRI1 overexpression enhanced the endogenous BR signaling intensity thereby increasing the seed germination rate, lateral root number, hypocotyl length, CO2 assimilation, plant height, and flower size. The transgenic plants also showed an increase in fruit yield and fruit number per plant, although the mean weight of individual fruit was reduced, compared with wild type. SlBRI1 overexpression also promoted fruit ripening and ethylene production, and caused an increase in levels of carotenoids, ascorbic acid, soluble solids, and soluble sugars during fruit ripening. An increased BR signaling intensity mediated by SlBRI1 overexpression was therefore positively correlated with carotenoid accumulation and fruit nutritional quality. Our results indicate that enhancing BR signaling by overexpression of SlBRI1 in tomato has the potential to improve multiple major agronomic traits.

  11. Gemcitabine enhances cell invasion via activating HAb18G/CD147-EGFR-pSTAT3 signaling.

    Science.gov (United States)

    Xu, Bao-Qing; Fu, Zhi-Guang; Meng, Yao; Wu, Xiao-Qing; Wu, Bo; Xu, Liang; Jiang, Jian-Li; Li, Ling; Chen, Zhi-Nan

    2016-09-20

    Pancreatic cancer, one of the most lethal cancers, has very poor 5-year survival partly due to gemcitabine resistance. Recently, it was reported that chemotherapeutic agents may act as stressors to induce adaptive responses and to promote chemoresistance in cancer cells. During long-term drug treatment, the minority of cancer cells survive and acquire an epithelial-mesenchymal transition phenotype with increased chemo-resistance and metastasis. However, the short-term response of most cancer cells remains unclear. This study aimed to investigate the short-term response of pancreatic cancer cells to gemcitabine stress and to explore the corresponding mechanism. Our results showed that gemcitabine treatment for 24 hours enhanced pancreatic cancer cell invasion. In gemcitabine-treated cells, HAb18G/CD147 was up-regulated; and HAb18G/CD147 down-regulation or inhibition attenuated gemcitabine-enhanced invasion. Mechanistically, HAb18G/CD147 promoted gemcitabine-enhanced invasion by activating the EGFR (epidermal growth factor receptor)-STAT3 (signal transducer and activator of transcription 3) signaling pathway. Inhibition of EGFR-STAT3 signaling counteracted gemcitabine-enhanced invasion, and which relied on HAb18G/CD147 levels. In pancreatic cancer tissues, EGFR was highly expressed and positively correlated with HAb18G/CD147. These data indicate that pancreatic cancer cells enhance cell invasion via activating HAb18G/CD147-EGFR-pSTAT3 signaling. Our findings suggest that inhibiting HAb18G/CD147 is a potential strategy for overcoming drug stress-associated resistance in pancreatic cancer.

  12. Tight regulation between cell survival and programmed cell death in GBM stem-like cells by EGFR/GSK3b/PP2A signaling.

    Science.gov (United States)

    Gürsel, Demirkan B; Banu, Matei A; Berry, Nicholas; Marongiu, Roberta; Burkhardt, Jan-Karl; Kobylarz, Keith; Kaplitt, Michael G; Rafii, Shahin; Boockvar, John A

    2015-01-01

    Malignant gliomas represent one of the most aggressive forms of cancer, displaying high mortality rates and limited treatment options. Specific subpopulations of cells residing in the tumor niche with stem-like characteristics have been postulated to initiate and maintain neoplasticity while resisting conventional therapies. The study presented here aims to define the role of glycogen synthase kinase 3 beta (GSK3b) in patient-derived glioblastoma (GBM) stem-like cell (GSC) proliferation, apoptosis and invasion. To evaluate the potential role of GSK3b in GBM, protein profiles from 68 GBM patients and 20 normal brain samples were analyzed for EGFR-mediated PI3kinase/Akt and GSK3b signaling molecules including protein phosphatase 2A (PP2A). To better understand the function of GSK3b in GBM, GSCs were isolated from GBM patient samples. Blocking GSK3b phosphorylation at Serine 9 attenuated cell proliferation while concomitantly stimulating apoptosis through activation of Caspase-3 in patient-derived GSCs. Increasing GSK3b protein content resulted in the inhibition of cell proliferation, colony formation and stimulated programmed cell death. Depleting GSK3b in GSCs down regulated PP2A. Furthermore, knocking down PP2A or blocking its activity by okadaic acid inactivated GSK3b by increasing GSK3b phosphorylation at Serine 9. Our data suggests that GSK3b may function as a regulator of apoptosis and tumorigenesis in GSCs. Therapeutic approaches targeting GSK3b in glioblastoma stem-like cells may be a useful addition to our current therapeutic armamentarium.

  13. Enhanced recombinant factor VII expression in Chinese hamster ovary cells by optimizing signal peptides and fed-batch medium.

    Science.gov (United States)

    Peng, Lin; Yu, Xiao; Li, Chengyuan; Cai, Yanfei; Chen, Yun; He, Yang; Yang, Jianfeng; Jin, Jian; Li, Huazhong

    2016-04-01

    Signal peptides play an important role in directing and efficiently transporting secretory proteins to their proper locations in the endoplasmic reticulum of mammalian cells. The aim of this study was to enhance the expression of recombinant coagulation factor VII (rFVII) in CHO cells by optimizing the signal peptides and type of fed-batch culture medium used. Five sub-clones (O2, I3, H3, G2 and M3) with different signal peptide were selected by western blot (WB) analysis and used for suspension culture. We compared rFVII expression levels of 5 sub-clones and found that the highest rFVII expression level was obtained with the IgK signal peptide instead of Ori, the native signal peptide of rFVII. The high protein expression of rFVII with signal peptide IgK was mirrored by a high transcription level during suspension culture. After analyzing culture and feed media, the combination of M4 and F4 media yielded the highest rFVII expression of 20 mg/L during a 10-day suspension culture. After analyzing cell density and cell cycle, CHO cells feeding by F4 had a similar percentage of cells in G0/G1 and a higher cell density compared to F2 and F3. This may be the reason for high rFVII expression in M4+F4. In summary, rFVII expression was successfully enhanced by optimizing the signal peptide and fed-batch medium used in CHO suspension culture. Our data may be used to improve the production of other therapeutic proteins in fed-batch culture.

  14. Ribavirin enhances IFN-α signalling and MxA expression: a novel immune modulation mechanism during treatment of HCV.

    Directory of Open Access Journals (Sweden)

    Nigel J Stevenson

    Full Text Available The nucleoside analogue Ribavirin significantly increases patient response to IFN-α treatment of HCV, by directly inhibiting viral replication. Recent studies indicate that Ribavirin also regulates immunity and we propose that Ribavirin enhances specific interferon sensitive gene (ISG expression by amplifying the IFN-α-JAK/STAT pathway. We found that IFN-α-induced STAT1 and STAT3 phosphorylation was increased in hepatocytes co-treated with Ribavirin and IFN-α, compared to IFN-α alone. Ribavirin specifically enhanced IFN-α induced mRNA and protein of the anti-viral mediator MxA, which co-localised with HCV core protein. These novel findings indicate for the first time that Ribavirin, in addition to its viral incorporation, also enhances IFN-α-JAK/STAT signalling, leading to a novel MxA-mediated immuno-modulatory mechanism that may enhance IFN-α anti-viral activity against HCV.

  15. Ampelopsin-induced reactive oxygen species enhance the apoptosis of colon cancer cells by activating endoplasmic reticulum stress-mediated AMPK/MAPK/XAF1 signaling

    Science.gov (United States)

    Park, Ga Bin; Jeong, Jee-Yeong; Kim, Daejin

    2017-01-01

    Ampelopsin (Amp) is bioactive natural product and exerts anti-cancer effects against several cancer types. The present study investigated the anti-colon cancer activity of Amp and explored its mechanism of action. The treatment of colon cancer cells with Amp resulted in the dose- and time-dependent induction of apoptosis via the activation of endoplasmic reticulum (ER) stress, 5′ adenosine monophosphate-activated protein kinase (AMPK), and c-Jun N-terminal protein kinase (JNK)/p38 mitogen-activated protein kinases (MAPKs). Salubrinal, an ER stress inhibitor, prevented the upregulation of ER stress-associated proteins, including phosphorylated protein kinase RNA-like ER kinase, phosphorylated eukaryotic translation initiation factor 2α, glucose-regulated protein 78, and CCAAT/enhancer-binding protein homologous protein, as well as suppressing AMPK activation and the MAPK signaling pathway. Knockdown of AMPK by RNA interference failed to block ER stress. Additionally, SP600125 (a JNK inhibitor) and SB203580 (a p38-MAPK inhibitor) effectively inhibited apoptosis and attenuated the expression of X-linked IAP-associated factor 1 (XAF1) and apoptotic Bcl-2 family proteins (BCL2 antagonist/killer 1 and BCL2-associated X protein) in Amp-treated colon cancer cells. Furthermore, reactive oxygen species (ROS)-mediated ER stress/AMPK apoptotic signaling pathway in Amp-treated colon cancer cells were markedly inhibited by treatment with N-acetyl-L-cysteine, a ROS scavenger. These results demonstrate that treatment with Amp induces the apoptotic death of colon cancer cells through ER stress-initiated AMPK/MAPK/XAF1 signaling. These results also provide experimental information for developing Amp as therapeutic drug against colon cancer. PMID:29250183

  16. Application of adaptive digital signal processing to speech enhancement for the hearing impaired.

    Science.gov (United States)

    Chabries, D M; Christiansen, R W; Brey, R H; Robinette, M S; Harris, R W

    1987-01-01

    A major complaint of individuals with normal hearing and hearing impairments is a reduced ability to understand speech in a noisy environment. This paper describes the concept of adaptive noise cancelling for removing noise from corrupted speech signals. Application of adaptive digital signal processing has long been known and is described from a historical as well as technical perspective. The Widrow-Hoff LMS (least mean square) algorithm developed in 1959 forms the introduction to modern adaptive signal processing. This method uses a "primary" input which consists of the desired speech signal corrupted with noise and a second "reference" signal which is used to estimate the primary noise signal. By subtracting the adaptively filtered estimate of the noise, the desired speech signal is obtained. Recent developments in the field as they relate to noise cancellation are described. These developments include more computationally efficient algorithms as well as algorithms that exhibit improved learning performance. A second method for removing noise from speech, for use when no independent reference for the noise exists, is referred to as single channel noise suppression. Both adaptive and spectral subtraction techniques have been applied to this problem--often with the result of decreased speech intelligibility. Current techniques applied to this problem are described, including signal processing techniques that offer promise in the noise suppression application.

  17. Solid-State NMR on bacterial cells: selective cell wall signal enhancement and resolution improvement using dynamic nuclear polarization

    International Nuclear Information System (INIS)

    Takahashi, Hiroki; Bardet, Michel; De Paepe, Gael; Hediger, Sabine; Ayala, Isabel; Simorre, Jean-Pierre

    2013-01-01

    Dynamic nuclear polarization (DNP) enhanced solid-state nuclear magnetic resonance (NMR) has recently emerged as a powerful technique for the study of material surfaces. In this study, we demonstrate its potential to investigate cell surface in intact cells. Using Bacillus subtilis bacterial cells as an example, it is shown that the polarizing agent 1-(TEMPO-4-oxy)-3-(TEMPO-4-amino)propan-2-ol (TOTAPOL) has a strong binding affinity to cell wall polymers (peptidoglycan). This particular interaction is thoroughly investigated with a systematic study on extracted cell wall materials, disrupted cells, and entire cells, which proved that TOTAPOL is mainly accumulating in the cell wall. This property is used on one hand to selectively enhance or suppress cell wall signals by controlling radical concentrations and on the other hand to improve spectral resolution by means of a difference spectrum. Comparing DNP-enhanced and conventional solid-state NMR, an absolute sensitivity ratio of 24 was obtained on the entire cell sample. This important increase in sensitivity together with the possibility of enhancing specifically cell wall signals and improving resolution really opens new avenues for the use of DNP-enhanced solid-state NMR as an on-cell investigation tool. (authors)

  18. Solid-state NMR on bacterial cells: selective cell wall signal enhancement and resolution improvement using dynamic nuclear polarization.

    Science.gov (United States)

    Takahashi, Hiroki; Ayala, Isabel; Bardet, Michel; De Paëpe, Gaël; Simorre, Jean-Pierre; Hediger, Sabine

    2013-04-03

    Dynamic nuclear polarization (DNP) enhanced solid-state nuclear magnetic resonance (NMR) has recently emerged as a powerful technique for the study of material surfaces. In this study, we demonstrate its potential to investigate cell surface in intact cells. Using Bacillus subtilis bacterial cells as an example, it is shown that the polarizing agent 1-(TEMPO-4-oxy)-3-(TEMPO-4-amino)propan-2-ol (TOTAPOL) has a strong binding affinity to cell wall polymers (peptidoglycan). This particular interaction is thoroughly investigated with a systematic study on extracted cell wall materials, disrupted cells, and entire cells, which proved that TOTAPOL is mainly accumulating in the cell wall. This property is used on one hand to selectively enhance or suppress cell wall signals by controlling radical concentrations and on the other hand to improve spectral resolution by means of a difference spectrum. Comparing DNP-enhanced and conventional solid-state NMR, an absolute sensitivity ratio of 24 was obtained on the entire cell sample. This important increase in sensitivity together with the possibility of enhancing specifically cell wall signals and improving resolution really opens new avenues for the use of DNP-enhanced solid-state NMR as an on-cell investigation tool.

  19. A novel strategy for signal denoising using reweighted SVD and its applications to weak fault feature enhancement of rotating machinery

    Science.gov (United States)

    Zhao, Ming; Jia, Xiaodong

    2017-09-01

    Singular value decomposition (SVD), as an effective signal denoising tool, has been attracting considerable attention in recent years. The basic idea behind SVD denoising is to preserve the singular components (SCs) with significant singular values. However, it is shown that the singular values mainly reflect the energy of decomposed SCs, therefore traditional SVD denoising approaches are essentially energy-based, which tend to highlight the high-energy regular components in the measured signal, while ignoring the weak feature caused by early fault. To overcome this issue, a reweighted singular value decomposition (RSVD) strategy is proposed for signal denoising and weak feature enhancement. In this work, a novel information index called periodic modulation intensity is introduced to quantify the diagnostic information in a mechanical signal. With this index, the decomposed SCs can be evaluated and sorted according to their information levels, rather than energy. Based on that, a truncated linear weighting function is proposed to control the contribution of each SC in the reconstruction of the denoised signal. In this way, some weak but informative SCs could be highlighted effectively. The advantages of RSVD over traditional approaches are demonstrated by both simulated signals and real vibration/acoustic data from a two-stage gearbox as well as train bearings. The results demonstrate that the proposed method can successfully extract the weak fault feature even in the presence of heavy noise and ambient interferences.

  20. SIM-DSP: A DSP-Enhanced CAD Platform for Signal Integrity Macromodeling and Simulation

    Directory of Open Access Journals (Sweden)

    Chi-Un Lei

    2014-12-01

    Full Text Available Macromodeling-Simulation process for signal integrity verifications has become necessary for the high speed circuit system design. This paper aims to introduce a “VLSI Signal Integrity Macromodeling and Simulation via Digital Signal Processing Techniques” framework (known as SIM-DSP framework, which applies digital signal processing techniques to facilitate the SI verification process in the pre-layout design phase. Core identification modules and peripheral (pre-/post-processing modules have been developed and assembled to form a verification flow. In particular, a single-step discrete cosine transform truncation (DCTT module has been developed for modeling-simulation process. In DCTT, the response modeling problem is classified as a signal compression problem, wherein the system response can be represented by a truncated set of non-pole based DCT bases, and error can be analyzed through Parseval’s theorem. Practical examples are given to show the applicability of our proposed framework.

  1. Signal enhancement due to high-Z nanofilm electrodes in parallel plate ionization chambers with variable microgaps.

    Science.gov (United States)

    Brivio, Davide; Sajo, Erno; Zygmanski, Piotr

    2017-12-01

    We developed a method for measuring signal enhancement produced by high-Z nanofilm electrodes in parallel plate ionization chambers with variable thickness microgaps. We used a laboratory-made variable gap parallel plate ionization chamber with nanofilm electrodes made of aluminum-aluminum (Al-Al) and aluminum-tantalum (Al-Ta). The electrodes were evaporated on 1 mm thick glass substrates. The interelectrode air gap was varied from 3 μm to 1 cm. The gap size was measured using a digital micrometer and it was confirmed by capacitance measurements. The electric field in the chamber was kept between 0.1 kV/cm and 1 kV/cm for all the gap sizes by applying appropriate compensating voltages. The chamber was exposed to 120 kVp X-rays. The current was measured using a commercial data acquisition system with temporal resolution of 600 Hz. In addition, radiation transport simulations were carried out to characterize the dose, D(x), high-energy electron current, J(x), and deposited charge, Q(x), as a function of distance, x, from the electrodes. A deterministic method was selected over Monte Carlo due to its ability to produce results with 10 nm spatial resolution without stochastic uncertainties. Experimental signal enhancement ratio, SER(G) which we defined as the ratio of signal for Al-air-Ta to signal for Al-air-Al for each gap size, was compared to computations. The individual contributions of dose, electron current, and charge deposition to the signal enhancement were determined. Experimental signals matched computed data for all gap sizes after accounting for several contributions to the signal: (a) charge carrier generated via ionization due to the energy deposited in the air gap, D(x); (b) high-energy electron current, J(x), leaking from high-Z electrode (Ta) toward low-Z electrode (Al); (c) deposited charge in the air gap, Q(x); and (d) the decreased collection efficiency for large gaps (>~500 μm). Q(x) accounts for the electrons below 100 eV, which are

  2. Lithium chloride attenuates mitomycin C induced necrotic cell death in MDA-MB-231 breast cancer cells via HMGB1 and Bax signaling.

    Science.gov (United States)

    Razmi, Mahdieh; Rabbani-Chadegani, Azra; Hashemi-Niasari, Fatemeh; Ghadam, Parinaz

    2018-07-01

    The clinical use of potent anticancer drug mitomycin C (MMC) has limited due to side effects and resistance of cancer cells. The aim of this study was to investigate whether lithium chloride (LiCl), as a mood stabilizer, can affect the sensitivity of MDA-MB-231 breast cancer cells to mitomycin C. The cells were exposed to various concentrations of mitomycin C alone and combined with LiCl and the viability determined by trypan blue and MTT assays. Proteins were analyzed by western blot and mRNA expression of HMGB1 MMP9 and Bcl-2 were analyzed by RT-PCR. Flow cytometry was used to determine the cell cycle arrest and percent of apoptotic and necrotic cells. Concentration of Bax assessed by ELISA. Exposure of the cells to mitomycin C revealed IC 50 value of 20 μM, whereas pretreatment of the cells with LiCl induced synergistic cytotoxicity and IC 50 value declined to 5 μM. LiCl combined with mitomycin C significantly down-regulated HMGB1, MMP9 and Bcl-2 gene expression but significantly increased the level of Bax protein. In addition, the content of HMGB1 in the nuclei decreased and pretreatment with LiCl reduced the content of HMGB1 release induced by MMC. LiCl increased mitomycin C-induced cell shrinkage and PARP fragmentation suggesting induction of apoptosis in these cells. LiCl prevented mitomycin C-induced necrosis and changed the cell death arrest at G2/M-phase. Taking all together, it is suggested that LiCl efficiently enhances mitomycin C-induced apoptosis and HMGB1, Bax and Bcl-2 expression may play a major role in this process, the findings that provide a new therapeutic strategy for LiCl in combination with mitomycin C. Copyright © 2018 Elsevier GmbH. All rights reserved.

  3. Polyclonal immune responses to antigens associated with cancer signaling pathways and new strategies to enhance cancer vaccines.

    Science.gov (United States)

    Clay, Timothy M; Osada, Takuya; Hartman, Zachary C; Hobeika, Amy; Devi, Gayathri; Morse, Michael A; Lyerly, H Kim

    2011-04-01

    Aberrant signaling pathways are a hallmark of cancer. A variety of strategies for inhibiting signaling pathways have been developed, but monoclonal antibodies against receptor tyrosine kinases have been among the most successful. A challenge for these therapies is therapeutic unresponsiveness and acquired resistance due to mutations in the receptors, upregulation of alternate growth and survival pathways, or inadequate function of the monoclonal antibodies. Vaccines are able to induce polyclonal responses that can have a multitude of affects against the target molecule. We began to explore therapeutic vaccine development to antigens associated with these signaling pathways. We provide an illustrative example in developing therapeutic cancer vaccines inducing polyclonal adaptive immune responses targeting the ErbB family member HER2. Further, we will discuss new strategies to augment the clinical efficacy of cancer vaccines by enhancing vaccine immunogenicity and reversing the immunosuppressive tumor microenvironment.

  4. The Arabidopsis mutant cev1 has constitutively active jasmonate and ethylene signal pathways and enhanced resistance to pathogens.

    Science.gov (United States)

    Ellis, C; Turner, J G

    2001-05-01

    Jasmonates (JAs) inhibit plant growth and induce plant defense responses. To define genes in the Arabidopsis JA signal pathway, we screened for mutants with constitutive expression of a luciferase reporter for the JA-responsive promoter from the vegetative storage protein gene VSP1. One mutant, named constitutive expression of VSP1 (cev1), produced plants that were smaller than wild type, had stunted roots with long root hairs, accumulated anthocyanin, had constitutive expression of the defense-related genes VSP1, VSP2, Thi2.1, PDF1.2, and CHI-B, and had enhanced resistance to powdery mildew diseases. Genetic evidence indicated that the cev1 phenotype required both COI1, an essential component of the JA signal pathway, and ETR1, which encodes the ethylene receptor. We conclude that cev1 stimulates both the JA and the ethylene signal pathways and that CEV1 regulates an early step in an Arabidopsis defense pathway.

  5. A New Second-Order Generalized Integrator Based Quadrature Signal Generator With Enhanced Performance

    DEFF Research Database (Denmark)

    Xin, Zhen; Qin, Zian; Lu, Minghui

    2016-01-01

    Due to the simplicity and flexibility of the structure of the Second-Order Generalized Integrator based Quadrature Signal Generator (SOGI-QSG), it has been widely used over the past decade for many applications such as frequency estimation, grid synchronization, and harmonic extraction. However......, the SOGI-QSG will produce errors when its input signal contains a dc component or harmonic components with unknown frequencies. The accuracy of the signal detection methods using it may hence be compromised. To overcome the drawback, the First-Order System (FOS) concept is first used to illustrate...

  6. IL-6 Improves Energy and Glucose Homeostasis in Obesity via Enhanced Central IL-6 trans-Signaling.

    Science.gov (United States)

    Timper, Katharina; Denson, Jesse Lee; Steculorum, Sophie Marie; Heilinger, Christian; Engström-Ruud, Linda; Wunderlich, Claudia Maria; Rose-John, Stefan; Wunderlich, F Thomas; Brüning, Jens Claus

    2017-04-11

    Interleukin (IL)-6 engages similar signaling mechanisms to leptin. Here, we find that central application of IL-6 in mice suppresses feeding and improves glucose tolerance. In contrast to leptin, whose action is attenuated in obesity, the ability of IL-6 to suppress feeding is enhanced in obese mice. IL-6 suppresses feeding in the absence of neuronal IL-6-receptor (IL-6R) expression in hypothalamic or all forebrain neurons of mice. Conversely, obese mice exhibit increased soluble IL-6R levels in the cerebrospinal fluid. Blocking IL-6 trans-signaling in the CNS abrogates the ability of IL-6 to suppress feeding. Furthermore, gp130 expression is enhanced in the paraventricular nucleus of the hypothalamus (PVH) of obese mice, and deletion of gp130 in the PVH attenuates the beneficial central IL-6 effects on metabolism. Collectively, these experiments indicate that IL-6 trans-signaling is enhanced in the CNS of obese mice, allowing IL-6 to exert its beneficial metabolic effects even under conditions of leptin resistance. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  7. IL-6 Improves Energy and Glucose Homeostasis in Obesity via Enhanced Central IL-6 trans-Signaling

    Directory of Open Access Journals (Sweden)

    Katharina Timper

    2017-04-01

    Full Text Available Interleukin (IL-6 engages similar signaling mechanisms to leptin. Here, we find that central application of IL-6 in mice suppresses feeding and improves glucose tolerance. In contrast to leptin, whose action is attenuated in obesity, the ability of IL-6 to suppress feeding is enhanced in obese mice. IL-6 suppresses feeding in the absence of neuronal IL-6-receptor (IL-6R expression in hypothalamic or all forebrain neurons of mice. Conversely, obese mice exhibit increased soluble IL-6R levels in the cerebrospinal fluid. Blocking IL-6 trans-signaling in the CNS abrogates the ability of IL-6 to suppress feeding. Furthermore, gp130 expression is enhanced in the paraventricular nucleus of the hypothalamus (PVH of obese mice, and deletion of gp130 in the PVH attenuates the beneficial central IL-6 effects on metabolism. Collectively, these experiments indicate that IL-6 trans-signaling is enhanced in the CNS of obese mice, allowing IL-6 to exert its beneficial metabolic effects even under conditions of leptin resistance.

  8. Consequences of a dark disk for the Fermi and PAMELA signals in theories with a Sommerfeld enhancement

    International Nuclear Information System (INIS)

    Cholis, Ilias; Goodenough, Lisa

    2010-01-01

    Much attention has been given to dark matter explanations of the PAMELA positron fraction and Fermi electronic excesses. For those theories with a TeV-scale WIMP annihilating through a light force-carrier, the associated Sommerfeld enhancement provides a natural explanation of the large boost factor needed to explain the signals, and the light force-carrier naturally gives rise to hard cosmic ray spectra without excess π 0 -gamma rays or anti-protons. The Sommerfeld enhancement of the annihilation rate, which at low relative velocities v rel scales as 1/v rel , relies on the comparatively low velocity dispersion of the dark matter particles in the smooth halo. Dark matter substructures in which the velocity dispersion is smaller than in the smooth halo have even larger annihilation rates. N-body simulations containing only dark matter predict the existence of such structures, for example subhalos and caustics, and the effects of these substructures on dark matter indirect detection signals have been studied extensively. The addition of baryons into cosmological simulations of disk-dominated galaxies gives rise to an additional substructure component, a dark disk. The disk has a lower velocity dispersion than the spherical halo component by a factor ∼ 6, so the contributions to dark matter signals from the disk can be more significant in Sommerfeld models than for WIMPs without such low-velocity ehancements. We consider the consequences of a dark disk on the observed signals of e + e − , p p-bar and γ-rays as measured by Fermi and PAMELA in models where the WIMP annihilations are into a light boson. We find that both the PAMELA and Fermi results are easily accomodated by scenarios in which a disk signal is included with the standard spherical halo signal. If contributions from the dark disk are important, limits from extrapolations to the center of the galaxy contain significant uncertainties beyond those from the spherical halo profile alone

  9. Resveratrol enhances ultraviolet B-induced cell death through nuclear factor-κB pathway in human epidermoid carcinoma A431 cells

    International Nuclear Information System (INIS)

    Roy, Preeti; Kalra, Neetu; Nigam, Nidhi; George, Jasmine; Ray, Ratan Singh; Hans, Rajendra K.; Prasad, Sahdeo; Shukla, Yogeshwer

    2009-01-01

    Resveratrol has been reported to suppress cancer progression in several in vivo and in vitro models, whereas ultraviolet B (UVB), a major risk for skin cancer, is known to induce cell death in cancerous cells. Here, we investigated whether resveratrol can sensitize A431 human epidermoid carcinoma cells to UVB-induced cell death. We examined the combined effect of UVB (30 mJ/cm 2 ) and resveratrol (60 μM) on A431 cells. Exposure of A431 carcinoma cells to UVB radiation or resveratrol can inhibit cell proliferation and induce apoptosis. However, the combination of resveratrol and UVB exposure was associated with increased proliferation inhibition of A431 cells compared with either agent alone. Furthermore, results showed that resveratrol and UVB treatment of A431 cells disrupted the nuclear factor-kappaB (NF-κB) pathway by blocking phosphorylation of serine 536 and inactivating NF-κB and subsequent degradation of IκBα, which regulates the expression of survivin. Resveratrol and UVB treatment also decreased the phosphorylation of tyrosine 701 of the important transcription factor signal transducer activator of transcription (STAT1), which in turn inhibited translocation of phospho-STAT1 to the nucleus. Moreover, resveratrol/UVB also inhibited the metastatic protein LIMK1, which reduced the motility of A431 cells. In conclusion, our study demonstrates that the combination of resveratrol and UVB act synergistically against skin cancer cells. Thus, resveratrol is a potential chemotherapeutic agent against skin carcinogenesis.

  10. Resveratrol enhances ultraviolet B-induced cell death through nuclear factor-{kappa}B pathway in human epidermoid carcinoma A431 cells

    Energy Technology Data Exchange (ETDEWEB)

    Roy, Preeti; Kalra, Neetu; Nigam, Nidhi; George, Jasmine [Proteomics Laboratory, Indian Institute of Toxicology Research (CSIR), P.O. Box 80, M.G. Marg, Lucknow 226 001 (India); Ray, Ratan Singh; Hans, Rajendra K. [Photobiology Laboratory, Indian Institute of Toxicology Research (CSIR), P.O. Box 80, M.G. Marg, Lucknow 226 001 (India); Prasad, Sahdeo [Proteomics Laboratory, Indian Institute of Toxicology Research (CSIR), P.O. Box 80, M.G. Marg, Lucknow 226 001 (India); Shukla, Yogeshwer, E-mail: yogeshwer_shukla@hotmail.com [Proteomics Laboratory, Indian Institute of Toxicology Research (CSIR), P.O. Box 80, M.G. Marg, Lucknow 226 001 (India)

    2009-06-26

    Resveratrol has been reported to suppress cancer progression in several in vivo and in vitro models, whereas ultraviolet B (UVB), a major risk for skin cancer, is known to induce cell death in cancerous cells. Here, we investigated whether resveratrol can sensitize A431 human epidermoid carcinoma cells to UVB-induced cell death. We examined the combined effect of UVB (30 mJ/cm{sup 2}) and resveratrol (60 {mu}M) on A431 cells. Exposure of A431 carcinoma cells to UVB radiation or resveratrol can inhibit cell proliferation and induce apoptosis. However, the combination of resveratrol and UVB exposure was associated with increased proliferation inhibition of A431 cells compared with either agent alone. Furthermore, results showed that resveratrol and UVB treatment of A431 cells disrupted the nuclear factor-kappaB (NF-{kappa}B) pathway by blocking phosphorylation of serine 536 and inactivating NF-{kappa}B and subsequent degradation of I{kappa}B{alpha}, which regulates the expression of survivin. Resveratrol and UVB treatment also decreased the phosphorylation of tyrosine 701 of the important transcription factor signal transducer activator of transcription (STAT1), which in turn inhibited translocation of phospho-STAT1 to the nucleus. Moreover, resveratrol/UVB also inhibited the metastatic protein LIMK1, which reduced the motility of A431 cells. In conclusion, our study demonstrates that the combination of resveratrol and UVB act synergistically against skin cancer cells. Thus, resveratrol is a potential chemotherapeutic agent against skin carcinogenesis.

  11. Brucella Rough Mutant Induce Macrophage Death via Activating IRE1α Pathway of Endoplasmic Reticulum Stress by Enhanced T4SS Secretion.

    Science.gov (United States)

    Li, Peng; Tian, Mingxing; Bao, Yanqing; Hu, Hai; Liu, Jiameng; Yin, Yi; Ding, Chan; Wang, Shaohui; Yu, Shengqing

    2017-01-01

    Brucella is a Gram-negative facultative intracellular pathogen that causes the worldwide zoonosis, known as brucellosis. Brucella virulence relies mostly on its ability to invade and replicate within phagocytic cells. The type IV secretion system (T4SS) and lipopolysaccharide are two major Brucella virulence factors. Brucella rough mutants reportedly induce the death of infected macrophages, which is T4SS dependent. However, the underlying molecular mechanism remains unclear. In this study, the T4SS secretion capacities of Brucella rough mutant and its smooth wild-type strain were comparatively investigated, by constructing the firefly luciferase fused T4SS effector, BPE123 and VceC. In addition, quantitative real-time PCR and western blotting were used to analyze the T4SS expression. The results showed that T4SS expression and secretion were enhanced significantly in the Brucella rough mutant. We also found that the activity of the T4SS virB operon promoter was notably increased in the Brucella rough mutant, which depends on quorum sensing-related regulators of VjbR upregulation. Cell infection and cell death assays revealed that deletion of vjbR in the Brucella rough mutant absolutely abolished cytotoxicity within macrophages by downregulating T4SS expression. This suggests that up-regulation of T4SS promoted by VjbR in rough mutant Δ rfbE contribute to macrophage death. In addition, we found that the Brucella rough mutant induce macrophage death via activating IRE1α pathway of endoplasmic reticulum stress. Taken together, our study provide evidence that in comparison to the Brucella smooth wild-type strain, VjbR upregulation in the Brucella rough mutant increases transcription of the virB operon, resulting in overexpression of the T4SS gene, accompanied by the over-secretion of effecter proteins, thereby causing the death of infected macrophages via activating IRE1α pathway of endoplasmic reticulum stress, suggesting novel insights into the molecular

  12. Brucella Rough Mutant Induce Macrophage Death via Activating IRE1α Pathway of Endoplasmic Reticulum Stress by Enhanced T4SS Secretion

    Directory of Open Access Journals (Sweden)

    Peng Li

    2017-09-01

    Full Text Available Brucella is a Gram-negative facultative intracellular pathogen that causes the worldwide zoonosis, known as brucellosis. Brucella virulence relies mostly on its ability to invade and replicate within phagocytic cells. The type IV secretion system (T4SS and lipopolysaccharide are two major Brucella virulence factors. Brucella rough mutants reportedly induce the death of infected macrophages, which is T4SS dependent. However, the underlying molecular mechanism remains unclear. In this study, the T4SS secretion capacities of Brucella rough mutant and its smooth wild-type strain were comparatively investigated, by constructing the firefly luciferase fused T4SS effector, BPE123 and VceC. In addition, quantitative real-time PCR and western blotting were used to analyze the T4SS expression. The results showed that T4SS expression and secretion were enhanced significantly in the Brucella rough mutant. We also found that the activity of the T4SS virB operon promoter was notably increased in the Brucella rough mutant, which depends on quorum sensing-related regulators of VjbR upregulation. Cell infection and cell death assays revealed that deletion of vjbR in the Brucella rough mutant absolutely abolished cytotoxicity within macrophages by downregulating T4SS expression. This suggests that up-regulation of T4SS promoted by VjbR in rough mutant ΔrfbE contribute to macrophage death. In addition, we found that the Brucella rough mutant induce macrophage death via activating IRE1α pathway of endoplasmic reticulum stress. Taken together, our study provide evidence that in comparison to the Brucella smooth wild-type strain, VjbR upregulation in the Brucella rough mutant increases transcription of the virB operon, resulting in overexpression of the T4SS gene, accompanied by the over-secretion of effecter proteins, thereby causing the death of infected macrophages via activating IRE1α pathway of endoplasmic reticulum stress, suggesting novel insights into the

  13. Deliberating death.

    Science.gov (United States)

    Landes, Scott D

    2010-01-01

    Utilizing a particular case study of a woman attempting to come to terms with her death, this article explores the difficult metaphors of death present within the Christian tradition. Tracing a Christian understanding of death back to the work of Augustine, the case study is utilized to highlight the difficulties presented by past and present theology embracing ideas of punishment within death. Following the trajectory of the case study, alternative understandings of death present in recent Christian theology and within Native American spirituality are presented in an attempt to find room for a fuller meaning of death post-reconciliation, but premortem.

  14. Receptor protein tyrosine phosphatase alpha enhances rheumatoid synovial fibroblast signaling and promotes arthritis in mice

    NARCIS (Netherlands)

    Stanford, Stephanie M; Svensson, Mattias N D; Sacchetti, Cristiano; Pilo, Caila A; Wu, Dennis J; Kiosses, William B; Hellvard, Annelie; Bergum, Brith; Aleman Muench, German R; Elly, Christian; Liu, Yun-Cai; den Hertog, Jeroen; Elson, Ari; Sap, Jan; Mydel, Piotr; Boyle, David L; Corr, Maripat; Firestein, Gary S; Bottini, Nunzio

    2016-01-01

    OBJECTIVE: During rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) critically promote disease pathogenesis by aggressively invading the joint extracellular matrix. The focal adhesion kinase (FAK) signaling pathway is emerging as a contributor to RA FLS anomalous behavior. The receptor

  15. Efficient Techniques of Sparse Signal Analysis for Enhanced Recovery of Information in Biomedical Engineering and Geosciences

    KAUST Repository

    Sana, Furrukh

    2016-01-01

    precision technique for the monitoring of human respiratory movements by exploiting the sparsity of wireless ultra-wideband signals. The proposed technique provides a novel methodology of overcoming the Nyquist sampling constraint and enables robust

  16. Enhancing the blue shift of SHG signal in GaSe:B/Ce crystal

    Science.gov (United States)

    Karatay, Ahmet; Yuksek, Mustafa; Ertap, Hüseyin; Elmali, Ayhan; Karabulut, Mevlut

    2018-02-01

    The influence of Ce3+ on the wavelength of second harmonic generation (SHG) signal in boron doped GaSe crystals have been investigated. We found that by substitution of Ce3+ with B3+, SHG signal shifted to lower wavelength. In addition, the nonlinear absorption (NA) properties and ultrafast dynamics of pure, 1 at.% B3+ and 0.5 at.% B3++ 0.5 at.% Ce3+ doped GaSe crystals have been studied by open aperture Z-scan and ultrafast pump probe spectroscopy techniques. From the open aperture Z-scan experiments we observed that all of the crystals showed nonlinear absorption (NA). However, pump-probe experiments revealed that when GaSe crystal is doped, the NA signal turns into a bleaching signal with different lifetimes depending on the type and concentration of the dopant atoms.

  17. Inhibition of p38 MAPK enhances ABT-737-induced cell death in melanoma cell lines: novel regulation of PUMA.

    Science.gov (United States)

    Keuling, Angela M; Andrew, Susan E; Tron, Victor A

    2010-06-01

    The mitogen-activated protein kinase (MAPK) pathway is constitutively activated in the majority of melanomas, promoting cell survival, proliferation and migration. In addition, anti-apoptotic Bcl-2 family proteins Mcl-1, Bcl-xL and Bcl-2 are frequently overexpressed, contributing to melanoma's well-documented chemoresistance. Recently, it was reported that the combination of MAPK pathway inhibition by specific MEK inhibitors and Bcl-2 family inhibition by BH3-mimetic ABT-737 synergistically induces apoptotic cell death in melanoma cell lines. Here we provide the first evidence that inhibition of another key MAPK, p38, synergistically induces apoptosis in melanoma cells in combination with ABT-737. We also provide novel mechanistic data demonstrating that inhibition of p38 increases expression of pro-apoptotic Bcl-2 protein PUMA. Furthermore, we demonstrate that PUMA can be cleaved by a caspase-dependent mechanism during apoptosis and identify what appears to be the PUMA cleavage product. Thus, our findings suggest that the combination of ABT-737 and inhibition of p38 is a promising, new treatment strategy that acts through a novel PUMA-dependent mechanism.

  18. Beyond lesbian bed death: enhancing our understanding of the sexuality of sexual-minority women in relationships.

    Science.gov (United States)

    Cohen, Jacqueline N; Byers, E Sandra

    2014-01-01

    The goal of this study was to characterize the sexuality of sexual-minority (i.e., lesbian, bisexual, queer, unlabeled, questioning) women. Participants were 586 women (87% White) in a same-sex relationship of 1 to 36 years in duration. They completed measures assessing their sexual behavior (frequency of nongenital and genital sexual activities), motivation (sexual desire), and cognitive-affective responses (sexual satisfaction, sexual esteem, sexual anxiety, negative automatic thoughts). On average, the women reported experiencing their sexuality positively across all domains. Regardless of relationship duration, most of the women reported engaging in both genital and nongenital sexual behaviors with their partner once a week or more; few reported that they had not engaged in sexual activity in the previous month. A multiple regression analysis indicated that frequency of genital sexual activity, sexual desire, sexual anxiety, and automatic thoughts contributed uniquely to the prediction of sexual satisfaction over and above the other sexuality variables. The findings are discussed in terms of the idea that lesbians have sex less frequently than other couple types and that sexual frequency declines rapidly in lesbian relationships (i.e., "lesbian bed death") and descriptions of sexual-minority women's sexuality that suggest that genital sexual activity is not important to sexual satisfaction.

  19. Dynamic Range Enhancement of High-Speed Electrical Signal Data via Non-Linear Compression

    Science.gov (United States)

    Laun, Matthew C. (Inventor)

    2016-01-01

    Systems and methods for high-speed compression of dynamic electrical signal waveforms to extend the measuring capabilities of conventional measuring devices such as oscilloscopes and high-speed data acquisition systems are discussed. Transfer function components and algorithmic transfer functions can be used to accurately measure signals that are within the frequency bandwidth but beyond the voltage range and voltage resolution capabilities of the measuring device.

  20. Real-Time EEG Signal Enhancement Using Canonical Correlation Analysis and Gaussian Mixture Clustering

    Directory of Open Access Journals (Sweden)

    Chin-Teng Lin

    2018-01-01

    Full Text Available Electroencephalogram (EEG signals are usually contaminated with various artifacts, such as signal associated with muscle activity, eye movement, and body motion, which have a noncerebral origin. The amplitude of such artifacts is larger than that of the electrical activity of the brain, so they mask the cortical signals of interest, resulting in biased analysis and interpretation. Several blind source separation methods have been developed to remove artifacts from the EEG recordings. However, the iterative process for measuring separation within multichannel recordings is computationally intractable. Moreover, manually excluding the artifact components requires a time-consuming offline process. This work proposes a real-time artifact removal algorithm that is based on canonical correlation analysis (CCA, feature extraction, and the Gaussian mixture model (GMM to improve the quality of EEG signals. The CCA was used to decompose EEG signals into components followed by feature extraction to extract representative features and GMM to cluster these features into groups to recognize and remove artifacts. The feasibility of the proposed algorithm was demonstrated by effectively removing artifacts caused by blinks, head/body movement, and chewing from EEG recordings while preserving the temporal and spectral characteristics of the signals that are important to cognitive research.

  1. Resveratrol Enhances Neurite Outgrowth and Synaptogenesis Via Sonic Hedgehog Signaling Following Oxygen-Glucose Deprivation/Reoxygenation Injury

    Directory of Open Access Journals (Sweden)

    Fanren Tang

    2017-09-01

    Full Text Available Background/Aims: Neurite outgrowth and synaptogenesis are critical steps for functional recovery after stroke. Resveratrol promotes neurite outgrowth and synaptogenesis, but the underlying mechanism is not well understood, although the Sonic hedgehog (Shh signaling pathway may be involved. Given that resveratrol activates sirtuin (Sirt1, the present study examined whether this is mediated by Shh signaling. Methods: Primary cortical neuron cultures were pretreated with drugs before oxygen-glucose deprivation/reoxygenation (OGD/R. Cell viability and apoptosis were evaluated with Cell Counting Kit 8 and by terminal deoxynucleotidyl transferase dUTP nick end labeling, respectively. Neurite outgrowth and synaptogenesis were assessed by immunocytochemistry and western blotting, which was also used to examine the expression of Sirt1 and Shh signaling proteins. Results: Resveratrol and the Smoothened (Smo agonist purmophamine, which activates Shh signaling, increased viability, reduced apoptosis, and stimulated neurite outgrowth after OGD/R injury. Moreover, the expression of growth-associated protein(GAP-43, synaptophysin, Shh, Patched (Ptc-1, Smo, glioma-associated oncogene homolog (Gli-1, and Sirt1 were upregulated under these conditions. These effects were reversed by treatment with the Smo inhibitor cyclopamine, whereas the Sirt1 inhibitor sirtinol reduced the levels of Shh, Ptc-1, Smo, and Gli-1. Conclusions: Resveratrol reduces neuronal injury following OGD/R injury and enhances neurite outgrowth and synaptogenesis by activating Shh signaling, which in turn induces Sirt1.

  2. Hypoxia-response plasmid vector producing bcl-2 shRNA enhances the apoptotic cell death of mouse rectum carcinoma.

    Science.gov (United States)

    Fujioka, Takashi; Matsunaga, Naoya; Okazaki, Hiroyuki; Koyanagi, Satoru; Ohdo, Shigehiro

    2010-01-01

    Hypoxia-induced gene expression frequently occurs in malignant solid tumors because they often have hypoxic areas in which circulation is compromised due to structurally disorganized blood vessels. Hypoxia-response elements (HREs) are responsible for activating gene transcription in response to hypoxia. In this study, we constructed a hypoxia-response plasmid vector producing short hairpin RNA (shRNA) against B-cell leukemia/lymphoma-2 (bcl-2), an anti-apoptotic factor. The hypoxia-response promoter was made by inserting tandem repeats of HREs upstream of cytomegalovirus (CMV) promoter (HRE-CMV). HRE-CMV shbcl-2 vector consisted of bcl-2 shRNA under the control of HRE-CMV promoter. In hypoxic mouse rectum carcinoma cells (colon-26), the production of bcl-2 shRNA driven by HRE-CMV promoter was approximately 2-fold greater than that driven by CMV promoter. A single intratumoral (i.t.) injection of 40 microg HRE-CMV shbcl-2 to colon-26 tumor-bearing mice caused apoptotic cell death, and repetitive treatment with HRE-CMV shbcl-2 (40 microg/mouse, i.t.) also significantly suppressed the growth of colon-26 tumor cells implanted in mice. Apoptotic and anti-tumor effects were not observed in tumor-bearing mice treated with CMV shbcl-2. These results reveal the ability of HRE-CMV shbcl-2 vector to suppress the expression of bcl-2 in hypoxic tumor cells and suggest the usefulness of our constructed hypoxia-response plasmid vector to treat malignant tumors. [Supplementary Figures: available only at http://dx.doi.org/10.1254/jphs.10054FP].

  3. Redefining Death

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    The results of 20 years of research on brain death will be released to the public, the Chinese Ministry of Health reported in early April. A special ministry team has drafted the criteria for brain death in Criteria for the Diagnosis of Brain Death in Adults (Revised Edition) and Technical Specifications for the Diagnosis

  4. Andrographolide induces apoptotic and non-apoptotic death and enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in gastric cancer cells.

    Science.gov (United States)

    Lim, Sung-Chul; Jeon, Ho Jong; Kee, Keun Hong; Lee, Mi Ja; Hong, Ran; Han, Song Iy

    2017-05-01

    Andrographolide, a natural compound isolated from Andrographis paniculata , has been reported to possess antitumor activity. In the present study, the effect of andrographolide in human gastric cancer (GC) cells was investigated. Andrographolide induced cell death with apoptotic and non-apoptotic features. At a low concentration, andrographolide potentiated apoptosis and reduction of clonogenicity triggered by recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL). Exposure of GC cells to andrographolide altered the expression level of several growth-inhibiting and apoptosis-regulating proteins, including death receptors. It was demonstrated that activity of the TRAIL-R2 (DR5) pathway was critical in the development of andrographolide-mediated rhTRAIL sensitization, since its inhibition significantly reduced the extent of apoptosis induced by the combination of rhTRAIL and andrographolide. In addition, andrographolide increased reactive oxygen species (ROS) generation in a dose-dependent manner. N-acetyl cysteine prevented andrographolide-mediated DR5 induction and the apoptotic effect induced by the combination of rhTRAIL and andrographolide. Collectively, the present study demonstrated that andrographolide enhances TRAIL-induced apoptosis through induction of DR5 expression. This effect appears to involve ROS generation in GCs.

  5. Parg deficiency confers radio-sensitization through enhanced cell death in mouse ES cells exposed to various forms of ionizing radiation

    Energy Technology Data Exchange (ETDEWEB)

    Shirai, Hidenori; Fujimori, Hiroaki [Division of Genome Stability Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan); Gunji, Akemi [Biochemistry Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan); Maeda, Daisuke [Biochemistry Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan); ADP-Ribosylation in Oncology Project, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan); Hirai, Takahisa [Division of Genome Stability Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan); Department of Radiation Oncology, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan); Poetsch, Anna R. [ADP-Ribosylation in Oncology Project, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan); Harada, Hiromi [Division of Genome Stability Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan); Yoshida, Tomoko [Biochemistry Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan); Kyoritsu College of Pharmacy, 1-5-30 Shibakoen, Minatoku, Tokyo 105-8512 (Japan); Sasai, Keisuke [Department of Radiation Oncology, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421 (Japan); Okayasu, Ryuichi [International Open Laboratory, National Institute of Radiological Science, 4-9-1 Anagawa, Inage, Chiba 263-8555 (Japan); Masutani, Mitsuko, E-mail: mmasutan@ncc.go.jp [Division of Genome Stability Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan); Biochemistry Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan); ADP-Ribosylation in Oncology Project, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 (Japan)

    2013-05-24

    Highlights: •Parg{sup −/−} ES cells were more sensitive to γ-irradiation than Parp-1{sup −/−} ES cells. •Parg{sup −/−} cells were more sensitive to carbon-ion irradiation than Parp-1{sup −/−} cells. •Parg{sup −/−} cells showed defects in DSB repair after carbon-ion irradiation. •PAR accumulation was enhanced after carbon-ion irradiation compared to γ-irradiation. -- Abstract: Poly(ADP-ribose) glycohydrolase (Parg) is the main enzyme involved in poly(ADP-ribose) degradation. Here, the effects of Parg deficiency on sensitivity to low and high linear-energy-transfer (LET) radiation were investigated in mouse embryonic stem (ES) cells. Mouse Parg{sup −/−} and poly(ADP-ribose) polymerase-1 deficient (Parp-1{sup −/−}) ES cells were used and responses to low and high LET radiation were assessed by clonogenic survival and biochemical and biological analysis methods. Parg{sup −/−} cells were more sensitive to γ-irradiation than Parp-1{sup −/−} cells. Transient accumulation of poly(ADP-ribose) was enhanced in Parg{sup −/−} cells. Augmented levels of phosphorylated H2AX (γ-H2AX) from early phase were observed in Parg{sup −/−} ES cells. The induction level of p53 phophorylation at ser18 was similar in wild-type and Parp-1{sup −/−} cells and apoptotic cell death process was mainly observed in the both genotypes. These results suggested that the enhanced sensitivity of Parg{sup −/−} ES cells to γ-irradiation involved defective repair of DNA double strand breaks. The effects of Parg and Parp-1 deficiency on the ES cell response to carbon-ion irradiation (LET13 and 70 keV/μm) and Fe-ion irradiation (200 keV/μm) were also examined. Parg{sup −/−} cells were more sensitive to LET 70 keV/μm carbon-ion irradiation than Parp-1{sup −/−} cells. Enhanced apoptotic cell death also accompanied augmented levels of γ-H2AX in a biphasic manner peaked at 1 and 24 h. The induction level of p53 phophorylation at ser18 was

  6. Parg deficiency confers radio-sensitization through enhanced cell death in mouse ES cells exposed to various forms of ionizing radiation

    International Nuclear Information System (INIS)

    Shirai, Hidenori; Fujimori, Hiroaki; Gunji, Akemi; Maeda, Daisuke; Hirai, Takahisa; Poetsch, Anna R.; Harada, Hiromi; Yoshida, Tomoko; Sasai, Keisuke; Okayasu, Ryuichi; Masutani, Mitsuko

    2013-01-01

    Highlights: •Parg −/− ES cells were more sensitive to γ-irradiation than Parp-1 −/− ES cells. •Parg −/− cells were more sensitive to carbon-ion irradiation than Parp-1 −/− cells. •Parg −/− cells showed defects in DSB repair after carbon-ion irradiation. •PAR accumulation was enhanced after carbon-ion irradiation compared to γ-irradiation. -- Abstract: Poly(ADP-ribose) glycohydrolase (Parg) is the main enzyme involved in poly(ADP-ribose) degradation. Here, the effects of Parg deficiency on sensitivity to low and high linear-energy-transfer (LET) radiation were investigated in mouse embryonic stem (ES) cells. Mouse Parg −/− and poly(ADP-ribose) polymerase-1 deficient (Parp-1 −/− ) ES cells were used and responses to low and high LET radiation were assessed by clonogenic survival and biochemical and biological analysis methods. Parg −/− cells were more sensitive to γ-irradiation than Parp-1 −/− cells. Transient accumulation of poly(ADP-ribose) was enhanced in Parg −/− cells. Augmented levels of phosphorylated H2AX (γ-H2AX) from early phase were observed in Parg −/− ES cells. The induction level of p53 phophorylation at ser18 was similar in wild-type and Parp-1 −/− cells and apoptotic cell death process was mainly observed in the both genotypes. These results suggested that the enhanced sensitivity of Parg −/− ES cells to γ-irradiation involved defective repair of DNA double strand breaks. The effects of Parg and Parp-1 deficiency on the ES cell response to carbon-ion irradiation (LET13 and 70 keV/μm) and Fe-ion irradiation (200 keV/μm) were also examined. Parg −/− cells were more sensitive to LET 70 keV/μm carbon-ion irradiation than Parp-1 −/− cells. Enhanced apoptotic cell death also accompanied augmented levels of γ-H2AX in a biphasic manner peaked at 1 and 24 h. The induction level of p53 phophorylation at ser18 was not different between wild-type and Parg −/− cells. The augmented

  7. Ultrasound-targeted microbubble destruction enhances delayed BMC delivery and attenuates post-infarction cardiac remodelling by inducing engraftment signals.

    Science.gov (United States)

    Chen, Yanmei; Zhang, Chuanxi; Shen, Shuxin; Guo, Shengcun; Zhong, Lintao; Li, Xinzhong; Chen, Guojun; Chen, Gangbin; He, Xiang; Huang, Chixiong; He, Nvqin; Liao, Wangjun; Liao, Yulin; Bin, Jianping

    2016-12-01

    Delayed administration of bone marrow cells (BMCs) at 2-4 weeks after successful reperfusion in patients with acute myocardial infarction (MI) does not improve cardiac function. The reduction in engraftment signals observed following this time interval might impair the effects of delayed BMC treatment. In the present study, we aimed to determine whether ultrasound-targeted microbubble destruction (UTMD) treatment could increase engraftment signals, enhance the delivery of delayed BMCs and subsequently attenuate post-infarction cardiac remodelling. A myocardial ischaemia/reperfusion (I/R) model was induced in Wistar rats via left coronary ligation for 45 min followed by reperfusion. Western blotting revealed that engraftment signals peaked at 7 days post-I/R and were dramatically lower at 14 days post-I/R. The lower engraftment signals at 14 days post-I/R could be triggered by UTMD treatment at a mechanical index of 1.0-1.9. The troponin I levels in the 1.9 mechanical index group were higher than in the other groups. Simultaneous haematoxylin and eosin staining and fluorescence revealed that the number of engrafted BMCs in the ischaemic zone was greater in the group treated with both UTMD and delayed BMC transplantation than in the control groups (PBMC transplantation improved cardiac function and decreased cardiac fibrosis at 4 weeks after treatment, as compared with control groups (both PBMC transplantation increased capillary density, myocardial cell proliferation and c-kit + cell proliferation. These findings indicated that UTMD treatment could induce engraftment signals and enhance homing of delayed BMCs to ischaemic myocardium, attenuating post-infarction cardiac remodelling by promoting neovascularization, cardiomyogenesis and expansion of cardiac c-kit + cells. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

  8. Testin, a novel binding partner of the calcium-sensing receptor, enhances receptor-mediated Rho-kinase signalling

    International Nuclear Information System (INIS)

    Magno, Aaron L.; Ingley, Evan; Brown, Suzanne J.; Conigrave, Arthur D.; Ratajczak, Thomas; Ward, Bryan K.

    2011-01-01

    Highlights: → A yeast two-hybrid screen revealed testin bound to the calcium-sensing receptor. → The second zinc finger of LIM domain 1 of testin is critical for interaction. → Testin bound to a region of the receptor tail important for cell signalling. → Testin and receptor interaction was confirmed in mammalian (HEK293) cells. → Overexpression of testin enhanced receptor-mediated Rho signalling in HEK293 cells. -- Abstract: The calcium-sensing receptor (CaR) plays an integral role in calcium homeostasis and the regulation of other cellular functions including cell proliferation and cytoskeletal organisation. The multifunctional nature of the CaR is manifested through ligand-dependent stimulation of different signalling pathways that are also regulated by partner binding proteins. Following a yeast two-hybrid library screen using the intracellular tail of the CaR as bait, we identified several novel binding partners including the focal adhesion protein, testin. Testin has not previously been shown to interact with cell surface receptors. The sites of interaction between the CaR and testin were mapped to the membrane proximal region of the receptor tail and the second zinc-finger of LIM domain 1 of testin, the integrity of which was found to be critical for the CaR-testin interaction. The CaR-testin association was confirmed in HEK293 cells by coimmunoprecipitation and confocal microscopy studies. Ectopic expression of testin in HEK293 cells stably expressing the CaR enhanced CaR-stimulated Rho activity but had no effect on CaR-stimulated ERK signalling. These results suggest an interplay between the CaR and testin in the regulation of CaR-mediated Rho signalling with possible effects on the cytoskeleton.

  9. Fractional Gaussian noise-enhanced information capacity of a nonlinear neuron model with binary signal input

    Science.gov (United States)

    Gao, Feng-Yin; Kang, Yan-Mei; Chen, Xi; Chen, Guanrong

    2018-05-01

    This paper reveals the effect of fractional Gaussian noise with Hurst exponent H ∈(1 /2 ,1 ) on the information capacity of a general nonlinear neuron model with binary signal input. The fGn and its corresponding fractional Brownian motion exhibit long-range, strong-dependent increments. It extends standard Brownian motion to many types of fractional processes found in nature, such as the synaptic noise. In the paper, for the subthreshold binary signal, sufficient conditions are given based on the "forbidden interval" theorem to guarantee the occurrence of stochastic resonance, while for the suprathreshold binary signal, the simulated results show that additive fGn with Hurst exponent H ∈(1 /2 ,1 ) could increase the mutual information or bits count. The investigation indicated that the synaptic noise with the characters of long-range dependence and self-similarity might be the driving factor for the efficient encoding and decoding of the nervous system.

  10. Hyperthermia enhances mapatumumab-induced apoptotic death through ubiquitin-mediated degradation of cellular FLIP(long) in human colon cancer cells.

    Science.gov (United States)

    Song, X; Kim, S-Y; Zhou, Z; Lagasse, E; Kwon, Y T; Lee, Y J

    2013-04-04

    Colorectal cancer is the third leading cause of cancer-related mortality in the world; the main cause of death of colorectal cancer is hepatic metastases, which can be treated with hyperthermia using isolated hepatic perfusion (IHP). In this study, we report that mild hyperthermia potently reduced cellular FLIP(long), (c-FLIP(L)), a major regulator of the death receptor (DR) pathway of apoptosis, thereby enhancing humanized anti-DR4 antibody mapatumumab (Mapa)-mediated mitochondria-independent apoptosis. We observed that overexpression of c-FLIP(L) in CX-1 cells abrogated the synergistic effect of Mapa and hyperthermia, whereas silencing of c-FLIP in CX-1 cells enhanced Mapa-induced apoptosis. Hyperthermia altered c-FLIP(L) protein stability without concomitant reductions in FLIP mRNA. Ubiquitination of c-FLIP(L) was increased by hyperthermia, and proteasome inhibitor MG132 prevented heat-induced downregulation of c-FLIP(L). These results suggest the involvement of the ubiquitin-proteasome system in this process. We also found lysine residue 195 (K195) to be essential for c-FLIP(L) ubiquitination and proteolysis, as mutant c-FLIP(L) lysine 195 arginine (arginine replacing lysine) was left virtually un-ubiquitinated and was refractory to hyperthermia-triggered degradation, and thus partially blocked the synergistic effect of Mapa and hyperthermia. Our observations reveal that hyperthermia transiently reduced c-FLIP(L) by proteolysis linked to K195 ubiquitination, which contributed to the synergistic effect between Mapa and hyperthermia. This study supports the application of hyperthermia combined with other regimens to treat colorectal hepatic metastases.

  11. Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis.

    Science.gov (United States)

    Cisternas, Pedro; Salazar, Paulina; Silva-Álvarez, Carmen; Barros, L Felipe; Inestrosa, Nibaldo C

    2016-12-09

    The Wnt signaling pathway is critical for a number of functions in the central nervous system, including regulation of the synaptic cleft structure and neuroprotection against injury. Deregulation of Wnt signaling has been associated with several brain pathologies, including Alzheimer's disease. In recent years, it has been suggested that the Wnt pathway might act as a central integrator of metabolic signals from peripheral organs to the brain, which would represent a new role for Wnt signaling in cell metabolism. Energy metabolism is critical for normal neuronal function, which mainly depends on glucose utilization. Brain energy metabolism is important in almost all neurological disorders, to which a decrease in the capacity of the brain to utilize glucose has been linked. However, little is known about the relationship between Wnt signaling and neuronal glucose metabolism in the cellular context. In the present study, we found that acute treatment with the Wnt3a ligand induced a large increase in glucose uptake, without changes in the expression or localization of glucose transporter type 3. In addition, we observed that Wnt3a treatment increased the activation of the metabolic sensor Akt. Moreover, we observed an increase in the activity of hexokinase and in the glycolytic rate, and both processes were dependent on activation of the Akt pathway. Furthermore, we did not observe changes in the activity of glucose-6-phosphate dehydrogenase or in the pentose phosphate pathway. The effect of Wnt3a was independent of both the transcription of Wnt target genes and synaptic effects of Wnt3a. Together, our results suggest that Wnt signaling stimulates glucose utilization in cortical neurons through glycolysis to satisfy the high energy demand of these cells. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  12. Signal to noise ratio enhancement for Eddy Current testing of steam generator tubes in PWR's

    International Nuclear Information System (INIS)

    Georgel, B.

    1985-01-01

    Noise reduction is a compulsory task when we try to recognize and characterize flaws. The signals we deal with come from Eddy Current testings of steam generator steel tubes. We point out the need for a spectral invariant in digital spectral analysis of 2 components signals. We make clear the pros and cons of classical passband filtering and suggest the use of a new noise cancellation method first discussed by Moriwaki and Tlusty. We generalize this tricky technique and prove it is a very special case of the well-known Wiener filter. In that sense the M-T method is shown to be optimal. 6 refs

  13. Demonstration of a squeezed-light-enhanced power- and signal-recycled Michelson interferometer.

    Science.gov (United States)

    Vahlbruch, Henning; Chelkowski, Simon; Hage, Boris; Franzen, Alexander; Danzmann, Karsten; Schnabel, Roman

    2005-11-18

    We report on the experimental combination of three advanced interferometer techniques for gravitational wave detection, namely, power recycling, detuned signal recycling, and squeezed field injection. For the first time, we experimentally prove the compatibility of especially the latter two. To achieve a broadband nonclassical sensitivity improvement, we applied a filter cavity for compensation of quadrature rotation. The signal-to-noise ratio was improved by up to 2.8 dB beyond the coherent state's shot noise. The complete setup was stably locked for arbitrary times and characterized by injected single-sideband modulation fields.

  14. Dual‑sensitive HRE/Egr1 promoter regulates Smac overexpression and enhances radiation‑induced A549 human lung adenocarcinoma cell death under hypoxia.

    Science.gov (United States)

    Li, Chang-Feng; Chen, Li-Bo; Li, Dan-Dan; Yang, Lei; Zhang, Bao-Gang; Jin, Jing-Peng; Zhang, Ying; Zhang, Bin

    2014-08-01

    The aim of this study was to construct an expression vector carrying the hypoxia/radiation dual‑sensitive chimeric hypoxia response element (HRE)/early growth response 1 (Egr‑1) promoter in order to overexpress the therapeutic second mitochondria‑derived activator of caspases (Smac). Using this expression vector, the present study aimed to explore the molecular mechanism underlying radiotherapy‑induced A549 human lung adenocarcinoma cell death and apoptosis under hypoxia. The plasmids, pcDNA3.1‑Egr1‑Smac (pE‑Smac) and pcDNA3.1‑HRE/Egr-1‑Smac (pH/E‑Smac), were constructed and transfected into A549 human lung adenocarcinoma cells using the liposome method. CoCl2 was used to chemically simulate hypoxia, followed by the administration of 2 Gy X‑ray irradiation. An MTT assay was performed to detect cell proliferation and an Annexin V‑fluorescein isothiocyanate apoptosis detection kit was used to detect apoptosis. Quantitative polymerase chain reaction and western blot analyses were used for the detection of mRNA and protein expression, respectively. Infection with the pE‑Smac and pH/E‑Smac plasmids in combination with radiation and/or hypoxia was observed to enhance the expression of Smac. Furthermore, Smac overexpression was found to enhance the radiation‑induced inhibition of cell proliferation and promotion of cycle arrest and apoptosis. The cytochrome c/caspase‑9/caspase‑3 pathway was identified to be involved in this regulation of apoptosis. Plasmid infection in combination with X‑ray irradiation was found to markedly induce cell death under hypoxia. In conclusion, the hypoxia/radiation dual‑sensitive chimeric HRE/Egr‑1 promoter was observed to enhance the expression of the therapeutic Smac, as well as enhance the radiation‑induced inhibition of cell proliferation and promotion of cycle arrest and apoptosis under hypoxia. This apoptosis was found to involve the mitochondrial pathway.

  15. Microwave assisted in situ synthesis of Ag–NaCMC films and their reproducible surface-enhanced Raman scattering signals

    International Nuclear Information System (INIS)

    Jiang, Tao; Li, Junpeng; Zhang, Li; Wang, Binbing; Zhou, Jun

    2014-01-01

    Graphical abstract: Two kinds of Ag–NaCMC films for surface-enhanced Raman scattering (SERS) were prepared by conventional heating and microwave assisted in situ reduction methods without any additional capping or reducing agents. A relatively narrow and symmetric surface plasmon resonance band was observed in the absorption spectra of the films fabricated by the microwave assisted in situ reduction method. More uniform silver nanoparticles (NPs) implied by the symmetric absorption spectrum were further confirmed by the scanning electron microscopy images. After the simulation of the E-field intensity distribution around the silver NPs in NaCMC film, the Raman scattering enhancement factors (EFs) of these films were then investigated with 4-mercaptobenzoic acid molecule as a SERS reporter. Improved reproducibility of SERS signal was obtained in the microwave assisted synthesized Ag–NaCMC film, although it maintained an EF as only 1.11 × 10 8 . The reproducible SERS signal of the Ag–NaCMC film is particularly attractive and this microwave assisted in situ reduction method is suitable for the production of excellent substrate for biosensor application. - Highlights: • The synthesis of Ag–NaCMC films was successfully fulfilled by a low-cost microwave method. • More uniform silver nanoparticles were observed in Ag–NaCMC film synthesized by microwave. • Improved reproducibility of SERS signal was obtained in microwave synthesized Ag–NaCMC film. - Abstract: Two kinds of Ag–NaCMC films for surface-enhanced Raman scattering (SERS) were prepared by conventional heating and microwave assisted in situ reduction methods without any additional capping or reducing agents. A relatively narrow and symmetric surface plasmon resonance band was observed in the absorption spectra of the films fabricated by the microwave assisted in situ reduction method. More uniform silver nanoparticles (NPs) implied by the symmetric absorption spectrum were further confirmed by

  16. In contrast to BOLD: signal enhancement by extravascular water protons as an alternative mechanism of endogenous fMRI signal change.

    Science.gov (United States)

    Figley, Chase R; Leitch, Jordan K; Stroman, Patrick W

    2010-10-01

    Despite the popularity and widespread application of functional magnetic resonance imaging (fMRI) in recent years, the physiological bases of signal change are not yet fully understood. Blood oxygen level-dependant (BOLD) contrast - attributed to local changes in blood flow and oxygenation, and therefore magnetic susceptibility - has become the most prevalent means of functional neuroimaging. However, at short echo times, spin-echo sequences show considerable deviations from the BOLD model, implying a second, non-BOLD component of signal change. This has been dubbed "signal enhancement by extravascular water protons" (SEEP) and is proposed to result from proton-density changes associated with cellular swelling. Given that such changes are independent of magnetic susceptibility, SEEP may offer new and improved opportunities for carrying out fMRI in regions with close proximity to air-tissue and/or bone-tissue interfaces (e.g., the prefrontal cortex and spinal cord), as well as regions close to large blood vessels, which may not be ideally suited for BOLD imaging. However, because of the interdisciplinary nature of the literature, there has yet to be a thorough synthesis, tying together the various and sometimes disparate aspects of SEEP theory. As such, we aim to provide a concise yet comprehensive overview of SEEP, including recent and compelling evidence for its validity, its current applications and its future relevance to the rapidly expanding field of functional neuroimaging. Before presenting the evidence for a non-BOLD component of endogenous functional contrast, and to enable a more critical review for the nonexpert reader, we begin by reviewing the fundamental principles underlying BOLD theory. Copyright © 2010 Elsevier Inc. All rights reserved.

  17. Hepatocellular carcinoma: clinical significance of signal heterogeneity in the hepatobiliary phase of gadoxetic acid-enhanced MR imaging

    Energy Technology Data Exchange (ETDEWEB)

    Fujita, Nobuhiro; Nishie, Akihiro; Asayama, Yoshiki; Ushijima, Yasuhiro; Moirta, Koichiro; Honda, Hiroshi [Kyushu University, Department of Clinical Radiology, Graduate School of Medical Sciences, Fukuoka (Japan); Kubo, Yuichiro; Aishima, Shinichi [Kyushu University, Department of Anatomic Pathology, Graduate School of Medical Sciences, Fukuoka (Japan); Takayama, Yukihisa [Kyushu University, Department of Molecular Imaging and Diagnosis, Graduate School of Medical Sciences, Fukuoka (Japan); Shirabe, Ken [Kyushu University, Department of Surgery and Science, Graduate School of Medical Sciences, Fukuoka (Japan)

    2015-01-15

    To clarify the relationship between the biological behaviour of hepatocellular carcinomas (HCCs) and their signal intensity in the hepatobiliary phase of gadoxetic acid-enhanced MR imaging with a special focus on the signal heterogeneity. A total of 68 patients with 70 pathologically proven HCCs were enrolled. On the basis of the signal intensity in the hepatobiliary phase, the lesions were classified into three groups: group 1, homogeneous hypointensity (n = 44); group 2, heterogeneous hyperintensity (n = 20); and group 3, homogeneous hyperintensity (n = 6). The clinicopathological findings were compared among the three groups. The tumour size and the serum level of protein induced by vitamin K absence or antagonist-II (PIVKA-II) were significantly higher in group 2 compared to group 1 (p = 0.0155, p = 0.0215, respectively) and compared to group 3 (p = 0.0330, p = 0.0220, respectively). The organic anion transporting polypeptide 8 (OATP8) expression in group 2 and group 3 was significantly higher than in group 1 (p < 0.0001, p < 0.0001, respectively). Group 2 showed a significantly lower disease-free survival rate compared to group 1 (p = 0.0125), and group 2 was an independent prognostic factor for disease-free survival (p = 0.0308). HCCs in the hepatobiliary phase that are heterogeneously hyperintense on gadoxetic acid-enhanced MR imaging have more malignant potential than other types of HCCs. (orig.)

  18. Appearance of high signal intensity and gadolinium-DTPA contrast enhancement in hypertrophied myocardium by magnetic resonance imaging

    International Nuclear Information System (INIS)

    Nishimura, Tsunehiko; Yamada, Naoaki; Nagata, Seiki

    1989-01-01

    This study was undertaken to examine the potential role of magnetic resonance imaging (MRI) for evaluating myocardial tissue characterization in hypertrophic cardiomyopathy (HCM). ECG-gated MRI images were acquired in 32 HCM patients and 30 patients with hypertensive heart disease (HHD), using a 1.5 T superconducting magnet system. The thickened areas were depicted as high signal intensities in the septum of 12 HCM patients (38%) and the endocardium of 5 HHD patients (17%). Echocardiography revealed that MRI appearance of high signal intensity was associated with more thickened myocardial wall. For evaluable 16 patients receiving i.v. injection of Gd-DTPA in a dose of 0.1 mM/kg, enhancement effects were observed in 10 patients (63%). High signal intensity appearing in the hypertrophied myocardium, as well as contrast enhancement, may not be characteristic of HCM, but reflect the likelihood of myocardial degeneration associated with the hypertrophied myocardium. Although MRI may not be capable of differentiating tissue characterization in HCM from that in HHD, it may provide different information about tissue characterization in the hypertrophied myocardium from that obtained by other techniques. (N.K.)

  19. Helicobacter pylori-derived Heat shock protein 60 enhances angiogenesis via a CXCR2-mediated signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Lin, Chen-Si [Department of Biological Science and Technology, National Chiao-Tung University, Hsin-Chu, Taiwan (China); School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan (China); He, Pei-Juin; Hsu, Wei-Tung [Department of Biological Science and Technology, National Chiao-Tung University, Hsin-Chu, Taiwan (China); Wu, Ming-Shiang [Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan (China); Wu, Chang-Jer [Department of Food Science, National Taiwan Ocean University, Keelung, Taiwan (China); Shen, Hsiao-Wei [Institute of Molecular Medicine and Bioengineering, National Chiao-Tung University, Hsin-Chu, Taiwan (China); Hwang, Chia-Hsiang [Yung-Shin Pharmaceutical Industry Co., Ltd., Tachia, Taichung, Taiwan (China); Lai, Yiu-Kay [Department of Life Science, Institute of Biotechnology, National Tsing Hua University, Hsin-Chu, Taiwan (China); Tsai, Nu-Man [School of Medical Laboratory and Biotechnology, Chung Shan Medical University, Taichung, Taiwan (China); Liao, Kuang-Wen, E-mail: kitchhen@yahoo.com.tw [Institute of Molecular Medicine and Bioengineering, National Chiao-Tung University, Hsin-Chu, Taiwan (China)

    2010-06-25

    Helicobacter pylori is a potent carcinogen associated with gastric cancer malignancy. Recently, H. pylori Heat shock protein 60 (HpHSP60) has been reported to promote cancer development by inducing chronic inflammation and promoting tumor cell migration. This study demonstrates a role for HpHSP60 in angiogenesis, a necessary precursor to tumor growth. We showed that HpHSP60 enhanced cell migration and tube formation, but not cell proliferation, in human umbilical vein endothelial cells (HUVECs). HpHSP60 also indirectly promoted HUVEC proliferation when HUVECs were co-cultured with supernatants collected from HpHSP60-treated AGS or THP-1 cells. The angiogenic array showed that HpHSP60 dramatically induced THP-1 cells and HUVECs to produce the chemotactic factors IL-8 and GRO. Inhibition of CXCR2, the receptor for IL-8 and GRO, or downstream PLC{beta}2/Ca2+-mediated signaling, significantly abolished HpHSP60-induced tube formation. In contrast, suppression of MAP K or PI3 K signaling did not affect HpHSP60-mediated tubulogenesis. These data suggest that HpHSP60 enhances angiogenesis via CXCR2/PLC{beta}2/Ca2+ signal transduction in endothelial cells.

  20. Helicobacter pylori-derived Heat shock protein 60 enhances angiogenesis via a CXCR2-mediated signaling pathway

    International Nuclear Information System (INIS)

    Lin, Chen-Si; He, Pei-Juin; Hsu, Wei-Tung; Wu, Ming-Shiang; Wu, Chang-Jer; Shen, Hsiao-Wei; Hwang, Chia-Hsiang; Lai, Yiu-Kay; Tsai, Nu-Man; Liao, Kuang-Wen

    2010-01-01

    Helicobacter pylori is a potent carcinogen associated with gastric cancer malignancy. Recently, H. pylori Heat shock protein 60 (HpHSP60) has been reported to promote cancer development by inducing chronic inflammation and promoting tumor cell migration. This study demonstrates a role for HpHSP60 in angiogenesis, a necessary precursor to tumor growth. We showed that HpHSP60 enhanced cell migration and tube formation, but not cell proliferation, in human umbilical vein endothelial cells (HUVECs). HpHSP60 also indirectly promoted HUVEC proliferation when HUVECs were co-cultured with supernatants collected from HpHSP60-treated AGS or THP-1 cells. The angiogenic array showed that HpHSP60 dramatically induced THP-1 cells and HUVECs to produce the chemotactic factors IL-8 and GRO. Inhibition of CXCR2, the receptor for IL-8 and GRO, or downstream PLCβ2/Ca2+-mediated signaling, significantly abolished HpHSP60-induced tube formation. In contrast, suppression of MAP K or PI3 K signaling did not affect HpHSP60-mediated tubulogenesis. These data suggest that HpHSP60 enhances angiogenesis via CXCR2/PLCβ2/Ca2+ signal transduction in endothelial cells.

  1. Prognosis prediction of non-enhancing T2 high signal intensity lesions in glioblastoma patients after standard treatment: application of dynamic contrast-enhanced MR imaging

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Rihyeon; Yun, Tae Jin; Kim, Ji-Hoon; Sohn, Chul-Ho [Seoul National University Hospital, Department of Radiology, 101 Daehak-ro, Jongno-gu, Seoul (Korea, Republic of); Choi, Seung Hong [Seoul National University Hospital, Department of Radiology, 101 Daehak-ro, Jongno-gu, Seoul (Korea, Republic of); Seoul National University Medical Research Center, Department of Radiology, Seoul National University College of Medicine, and Institute of Radiation Medicine, 103 Daehak-ro, Jongno-gu, Seoul (Korea, Republic of); Seoul National University, Center for Nanoparticle Research, Institute for Basic Science (IBS), Daehak-dong, Gwanak-gu, Seoul (Korea, Republic of); Seoul National University, School of Chemical and Biological Engineering, Daehak-dong, Gwanak-gu, Seoul (Korea, Republic of); Lee, Soon-Tae [Seoul National University Hospital, Department of Neurology, Seoul (Korea, Republic of); Park, Chul-Kee [Seoul National University Hospital, Department of Neurosurgery, Seoul (Korea, Republic of); Kim, Tae Min [Seoul National University Hospital, Department of Internal Medicine, Seoul (Korea, Republic of); Park, Sun-Won [Seoul National University College of Medicine, Department of Radiology, SMG-SNU Boramae Medical Center, Seoul (Korea, Republic of); Park, Sung-Hye [Seoul National University Hospital, Department of Pathology, Seoul (Korea, Republic of); Kim, Il Han [Seoul National University Hospital, Department of Radiation Oncology, Seoul (Korea, Republic of)

    2017-03-15

    To identify candidate imaging biomarkers for early disease progression in glioblastoma multiforme (GBM) patients by analysis of dynamic contrast-enhanced (DCE) MR parameters of non-enhancing T2 high signal intensity (SI) lesions. Forty-nine GBM patients who had undergone preoperative DCE MR imaging and received standard treatment were retrospectively included. According to the Response Assessment in Neuro-Oncology criteria, patients were classified into progression (n = 21) or non-progression (n = 28) groups. We analysed the pharmacokinetic parameters of Ktrans, Ve and Vp within non-enhancing T2 high SI lesions of each tumour. The best percentiles of each parameter from cumulative histograms were identified by the area under the receiver operating characteristic curve (AUC) and were compared using multivariate stepwise logistic regression. For the differentiation of early disease progression, the highest AUC values were found in the 99th percentile of Ktrans (AUC 0.954), the 97th percentile of Ve (AUC 0.815) and the 94th percentile of Vp (AUC 0.786) (all p < 0.05). The 99th percentile of Ktrans was the only significant independent variable from the multivariate stepwise logistic regression (p = 0.002). We found that the Ktrans of non-enhancing T2 high SI lesions in GBM patients holds potential as a candidate prognostic marker in future prospective studies. (orig.)

  2. Disruption of estrogen receptor signaling enhances intestinal neoplasia in ApcMin/+ mice

    Science.gov (United States)

    Cleveland, Alicia G.; Oikarinen, Seija I.; Bynoté, Kimberly K.; Marttinen, Maija; Rafter, Joseph J.; Gustafsson, Jan-Åke; Roy, Shyamal K.; Pitot, Henry C.; Korach, Kenneth S.; Lubahn, Dennis B.; Mutanen, Marja; Gould, Karen A.

    2009-01-01

    Estrogen receptors (ERs) [ERα (Esr1) and ERβ (Esr2)] are expressed in the human colon, but during the multistep process of colorectal carcinogenesis, expression of both ERα and ERβ is lost, suggesting that loss of ER function might promote colorectal carcinogenesis. Through crosses between an ERα knockout and ApcMin mouse strains, we demonstrate that ERα deficiency is associated with a significant increase in intestinal tumor multiplicity, size and burden in ApcMin/+ mice. Within the normal intestinal epithelium of ApcMin/+ mice, ERα deficiency is associated with an accumulation of nuclear β-catenin, an indicator of activation of the Wnt–β-catenin-signaling pathway, which is known to play a critical role in intestinal cancers. Consistent with the hypothesis that ERα deficiency is associated with activation of Wnt–β-catenin signaling, ERα deficiency in the intestinal epithelium of ApcMin/+ mice also correlated with increased expression of Wnt–β-catenin target genes. Through crosses between an ERβ knockout and ApcMin mouse strains, we observed some evidence that ERβ deficiency is associated with an increased incidence of colon tumors in ApcMin/+ mice. This effect of ERβ deficiency does not involve modulation of Wnt–β-catenin signaling. Our studies suggest that ERα and ERβ signaling modulate colorectal carcinogenesis, and ERα does so, at least in part, by regulating the activity of the Wnt–β-catenin pathway. PMID:19520794

  3. PULSE REFERENCED CONTROL METHOD FOR ENHANCED POWER AMPLIFICATION OF A PULSE MODULATED SIGNAL

    DEFF Research Database (Denmark)

    1998-01-01

    , by introducing continuous delays on the individual pulse edges on the basis of error information provided by an error processing block. One preferred embodiment of the invention comprises: a Correction Unit with means to control the delays of the individual pulse edges as a function of a control input signal $i...

  4. Speech Enhancement by Classification of Noisy Signals Decomposed Using NMF and Wiener Filtering

    DEFF Research Database (Denmark)

    Fakhry, Mahmoud; Poorjam, Amir Hossein; Christensen, Mads Græsbøll

    2018-01-01

    are identified in the cepstral domain using the trained classifier. We apply unsupervised NMF followed by Wiener filtering for the decomposition, and use a support vector machine trained on the mel-frequency cepstral coefficients of the parts of training speech and noise signals for the classification...

  5. Relationship between Length and Surface-Enhanced Raman Spectroscopy Signal Strength in Metal Nanoparticle Chains: Ideal Models versus Nanofabrication

    Directory of Open Access Journals (Sweden)

    Kristen D. Alexander

    2012-01-01

    Full Text Available We have employed capillary force deposition on ion beam patterned substrates to fabricate chains of 60 nm gold nanospheres ranging in length from 1 to 9 nanoparticles. Measurements of the surface-averaged SERS enhancement factor strength for these chains were then compared to the numerical predictions. The SERS enhancement conformed to theoretical predictions in the case of only a few chains, with the vast majority of chains tested not matching such behavior. Although all of the nanoparticle chains appear identical under electron microscope observation, the extreme sensitivity of the SERS enhancement to nanoscale morphology renders current nanofabrication methods insufficient for consistent production of coupled nanoparticle chains. Notwithstanding this fact, the aggregate data also confirmed that nanoparticle dimers offer a large improvement over the monomer enhancement while conclusively showing that, within the limitations imposed by current state-of-the-art nanofabrication techniques, chains comprising more than two nanoparticles provide only a marginal signal boost over the already considerable dimer enhancement.

  6. Bacillus licheniformis Isolated from Traditional Korean Food Resources Enhances the Longevity of Caenorhabditis elegans through Serotonin Signaling.

    Science.gov (United States)

    Park, Mi Ri; Oh, Sangnam; Son, Seok Jun; Park, Dong-June; Oh, Sejong; Kim, Sae Hun; Jeong, Do-Youn; Oh, Nam Su; Lee, Youngbok; Song, Minho; Kim, Younghoon

    2015-12-02

    In this study, we investigated potentially probiotic Bacillus licheniformis strains isolated from traditional Korean food sources for ability to enhance longevity using the nematode Caenorhabditis elegans as a simple in vivo animal model. We first investigated whether B. licheniformis strains were capable of modulating the lifespan of C. elegans. Among the tested strains, preconditioning with four B. licheniformis strains significantly enhanced the longevity of C. elegans. Unexpectedly, plate counting and transmission electron microscopy (TEM) results indicated that B. licheniformis strains were not more highly attached to the C. elegans intestine compared with Escherichia coli OP50 or Lactobacillus rhamnosus GG controls. In addition, qRT-PCR and an aging assay with mutant worms showed that the conditioning of B. licheniformis strain 141 directly influenced genes associated with serotonin signaling in nematodes, including tph-1 (tryptophan hydroxylase), bas-1 (serotonin- and dopamine-synthetic aromatic amino acid decarboxylase), mod-1 (serotonin-gated chloride channel), ser-1, and ser-7 (serotonin receptors) during C. elegans aging. Our findings suggest that B. licheniformis strain 141, which is isolated from traditional Korean foods, is a probiotic generally recognized as safe (GRAS) strain that enhances the lifespan of C. elegans via host serotonin signaling.

  7. Enhanced detection of a low-frequency signal by using broad squeezed light and a bichromatic local oscillator

    Science.gov (United States)

    Li, Wei; Jin, Yuanbin; Yu, Xudong; Zhang, Jing

    2017-08-01

    We experimentally study a protocol of using the broadband high-frequency squeezed vacuum to detect the low-frequency signal. In this scheme, the lower sideband field of the squeezed light carries the low-frequency modulation signal, and the two strong coherent light fields are applied as the bichromatic local oscillator in the homodyne detection to measure the quantum entanglement of the upper and lower sideband for the broadband squeezed light. The power of one of the local oscillators for detecting the upper sideband can be adjusted to optimize the conditional variance in the low-frequency regime by subtracting the photocurrent of the upper sideband field of the squeezed light from that of the lower sideband field. By means of the quantum correlation of the upper and lower sideband for the broadband squeezed light, the low-frequency signal beyond the standard quantum limit is measured. This scheme is appropriate for enhancing the sensitivity of the low-frequency signal by the aid of the broad squeezed light, such as gravitational waves detection, and does not need to directly produce the low-frequency squeezing in an optical parametric process.

  8. Exercise training improves blood flow to contracting skeletal muscle of older men via enhanced cGMP signaling

    DEFF Research Database (Denmark)

    Piil, Peter Bergmann; Smith Jørgensen, Tue; Egelund, Jon

    2018-01-01

    Physical activity has the potential to offset age-related impairments in the regulation of blood flow and O2 delivery to the exercising muscles; however, the mechanisms underlying this effect of physical activity remain poorly understood. The present study examined the role of cGMP in training...... a period of aerobic high-intensity exercise training. To determine the role of cGMP signaling, pharmacological inhibition of phosphodiesterase 5 (PDE5) was performed. Before training, inhibition of PDE5 increased (P... group; however, these effects of PDE5 inhibition were not detected after training. These findings suggest a role for enhanced cGMP signaling in the training-induced improvement of regulation of blood flow in contracting skeletal muscle of older men....

  9. Laser-enhanced ionization of mercury atoms in an inert atmosphere with avalanche amplification of the signal.

    Science.gov (United States)

    Clevenger, W L; Matveev, O I; Cabredo, S; Omenetto, N; Smith, B W; Winefordner, J D

    1997-07-01

    A new method for laser-enhanced ionization detection of mercury atoms in an inert gas atmosphere is described. The method, which is based on the avalanche amplification of the signal resulting from the ionization from a selected Rydberg level reached by a three-step laser excitation of mercury vapor in a simple quartz cell, can be applied to the determination of this element in various matrices by the use of conventional cold atomization techniques. The overall (collisional + photo) ionization efficiency is investigated at different temperatures, and the avalanche amplification effect is reported for Ar and P-10 gases at atmospheric pressure. It is shown that the amplified signal is related to the number of charges produced in the laser-irradiated volume. Under amplifier noise-limited conditions, a detection limit of ∼15 Hg atoms/laser pulse in the interaction region is estimated.

  10. Aurora-A overexpression enhances cell-aggregation of Ha-ras transformants through the MEK/ERK signaling pathway

    International Nuclear Information System (INIS)

    Tseng, Ya-Shih; Lee, Jenq-Chang; Huang, Chi-Ying F; Liu, Hsiao-Sheng

    2009-01-01

    Overexpression of Aurora-A and mutant Ras (Ras V12 ) together has been detected in human bladder cancer tissue. However, it is not clear whether this phenomenon is a general event or not. Although crosstalk between Aurora-A and Ras signaling pathways has been reported, the role of these two genes acting together in tumorigenesis remains unclear. Real-time PCR and sequence analysis were utilized to identify Ha- and Ki-ras mutation (Gly -> Val). Immunohistochemistry staining was used to measure the level of Aurora-A expression in bladder and colon cancer specimens. To reveal the effect of overexpression of the above two genes on cellular responses, mouse NIH3T3 fibroblast derived cell lines over-expressing either Ras V12 and wild-type Aurora-A (designated WT) or Ras V12 and kinase-inactivated Aurora-A (KD) were established. MTT and focus formation assays were conducted to measure proliferation rate and focus formation capability of the cells. Small interfering RNA, pharmacological inhibitors and dominant negative genes were used to dissect the signaling pathways involved. Overexpression of wild-type Aurora-A and mutation of Ras V12 were detected in human bladder and colon cancer tissues. Wild-type Aurora-A induces focus formation and aggregation of the Ras V12 transformants. Aurora-A activates Ral A and the phosphorylation of AKT as well as enhances the phosphorylation of MEK, ERK of WT cells. Finally, the Ras/MEK/ERK signaling pathway is responsible for Aurora-A induced aggregation of the Ras V12 transformants. Wild-type-Aurora-A enhances focus formation and aggregation of the Ras V12 transformants and the latter occurs through modulating the Ras/MEK/ERK signaling pathway

  11. High throughput screening for small molecule enhancers of the interferon signaling pathway to drive next-generation antiviral drug discovery.

    Directory of Open Access Journals (Sweden)

    Dhara A Patel

    Full Text Available Most of current strategies for antiviral therapeutics target the virus specifically and directly, but an alternative approach to drug discovery might be to enhance the immune response to a broad range of viruses. Based on clinical observation in humans and successful genetic strategies in experimental models, we reasoned that an improved interferon (IFN signaling system might better protect against viral infection. Here we aimed to identify small molecular weight compounds that might mimic this beneficial effect and improve antiviral defense. Accordingly, we developed a cell-based high-throughput screening (HTS assay to identify small molecules that enhance the IFN signaling pathway components. The assay is based on a phenotypic screen for increased IFN-stimulated response element (ISRE activity in a fully automated and robust format (Z'>0.7. Application of this assay system to a library of 2240 compounds (including 2160 already approved or approvable drugs led to the identification of 64 compounds with significant ISRE activity. From these, we chose the anthracycline antibiotic, idarubicin, for further validation and mechanism based on activity in the sub-µM range. We found that idarubicin action to increase ISRE activity was manifest by other members of this drug class and was independent of cytotoxic or topoisomerase inhibitory effects as well as endogenous IFN signaling or production. We also observed that this compound conferred a consequent increase in IFN-stimulated gene (ISG expression and a significant antiviral effect using a similar dose-range in a cell-culture system inoculated with encephalomyocarditis virus (EMCV. The antiviral effect was also found at compound concentrations below the ones observed for cytotoxicity. Taken together, our results provide proof of concept for using activators of components of the IFN signaling pathway to improve IFN efficacy and antiviral immune defense as well as a validated HTS approach to identify

  12. Sphingosine-1-phosphate enhances satellite cell activation in dystrophic muscles through a S1PR2/STAT3 signaling pathway.

    Directory of Open Access Journals (Sweden)

    Kenneth C Loh

    Full Text Available Sphingosine-1-phosphate (S1P activates a widely expressed family of G protein-coupled receptors, serves as a muscle trophic factor and activates muscle stem cells called satellite cells (SCs through unknown mechanisms. Here we show that muscle injury induces dynamic changes in S1P signaling and metabolism in vivo. These changes include early and profound induction of the gene encoding the S1P biosynthetic enzyme SphK1, followed by induction of the catabolic enzyme sphingosine phosphate lyase (SPL 3 days later. These changes correlate with a transient increase in circulating S1P levels after muscle injury. We show a specific requirement for SphK1 to support efficient muscle regeneration and SC proliferation and differentiation. Mdx mice, which serve as a model for muscular dystrophy (MD, were found to be S1P-deficient and exhibited muscle SPL upregulation, suggesting that S1P catabolism is enhanced in dystrophic muscle. Pharmacological SPL inhibition increased muscle S1P levels, improved mdx muscle regeneration and enhanced SC proliferation via S1P receptor 2 (S1PR2-dependent inhibition of Rac1, thereby activating Signal Transducer and Activator of Transcription 3 (STAT3, a central player in inflammatory signaling. STAT3 activation resulted in p21 and p27 downregulation in a S1PR2-dependent fashion in myoblasts. Our findings suggest that S1P promotes SC progression through the cell cycle by repression of cell cycle inhibitors via S1PR2/STAT3-dependent signaling and that SPL inhibition may provide a therapeutic strategy for MD.

  13. Emodin Induces Apoptotic Death in Murine Myelomonocytic Leukemia WEHI-3 Cells In Vitro and Enhances Phagocytosis in Leukemia Mice In Vivo

    Directory of Open Access Journals (Sweden)

    Yuan-Chang Chang

    2011-01-01

    Full Text Available Emodin is one of major compounds in rhubarb (Rheum palmatum L., a plant used as herbal medicine in Chinese population. Although many reports have shown that emodin exhibits anticancer activity in many tumor cell types, there is no available information addressing emodin-affected apoptotic responses in the murine leukemia cell line (WEHI-3 and modulation of the immune response in leukemia mice. We investigated that emodin induced cytotoxic effects in vitro and affected WEHI-3 cells in vivo. This study showed that emodin decreased viability and induced DNA fragmentation in WEHI-3 cells. Cells after exposure to emodin for 24 h have shown chromatin condensation and DNA damage. Emodin stimulated the productions of ROS and Ca2+ and reduced the level of ΔΨm by flow cytometry. Our results from Western blotting suggest that emodin triggered apoptosis of WEHI-3 cells through the endoplasmic reticulum (ER stress, caspase cascade-dependent and -independent mitochondrial pathways. In in vivo study, emodin enhanced the levels of B cells and monocytes, and it also reduced the weights of liver and spleen compared with leukemia mice. Emodin promoted phagocytic activity by monocytes and macrophages in comparison to the leukemia mice group. In conclusions, emodin induced apoptotic death in murine leukemia WEHI-3 cells and enhanced phagocytosis in the leukemia animal model.

  14. Solid and liquid 129Xe NMR signals enhanced by spin-exchange optical pumping under flow

    International Nuclear Information System (INIS)

    Zhou Xin; Luo Jun; Sun Xianping; Zeng Xizhi; Liu Maili; Liu Wuyang

    2002-01-01

    Laser-polarized 129 Xe gas was produced by spin-exchange with Cs atom optically pumped with diode laser array in a low field under flow. The nuclear spin polarizations of the solid and liquid 129 Xe frozen from the laser-polarized 129 Xe gas were 2.16% and 1.45% respectively in the SY-80M NMR spectrometer, which corresponded to the enhancements of 6000 and 5000 compared to those without optical pumping under the same conditions. It could provide the base and possibility for quantum computers using laser-enhanced solid and liquid 129 Xe. Polarization loss of transport and state change was also discussed

  15. Giant Enhancement of Small Photoluminescent Signals on Glass Surfaces Covered by Self-Assembled Silver Nanorings.

    Science.gov (United States)

    Sousanis, A; Poulopoulos, P; Karoutsos, V; Trachylis, D; Politis, C

    2017-02-01

    Self-assembled nanostructures with the shape of nanospheres or nanorings were formed after annealing of ultrathin Ag films grown on glass, in a furnace with air at 460 °C. Intense localized surface plasmon resonances were recorded for these nanostructures with maxima at the green-blue light. The surface became functional in terms of enhancing the weak photoluminescence of glass between 2–400 times. This system provides an easy way of enhancing the photoluminescence emission of initially low performance materials.

  16. Influence of multi-microphone signal enhancement algorithms on auditory movement detection in acoustically complex situations

    DEFF Research Database (Denmark)

    Lundbeck, Micha; Hartog, Laura; Grimm, Giso

    2017-01-01

    The influence of hearing aid (HA) signal processing on the perception of spatially dynamic sounds has not been systematically investigated so far. Previously, we observed that interfering sounds impaired the detectability of left-right source movements and reverberation that of near-far source...... movements for elderly hearing-impaired (EHI) listeners (Lundbeck et al., 2017). Here, we explored potential ways of improving these deficits with HAs. To that end, we carried out acoustic analyses to examine the impact of two beamforming algorithms and a binaural coherence-based noise reduction scheme...... on the cues underlying movement perception. While binaural cues remained mostly unchanged, there were greater monaural spectral changes and increases in signal-to-noise ratio and direct-to-reverberant sound ratio as a result of the applied processing. Based on these findings, we conducted a listening test...

  17. Receptor downregulation and desensitization enhance the information processing ability of signalling receptors

    Directory of Open Access Journals (Sweden)

    Resat Haluk

    2007-11-01

    Full Text Available Abstract Background In addition to initiating signaling events, the activation of cell surface receptors also triggers regulatory processes that restrict the duration of signaling. Acute attenuation of signaling can be accomplished either via ligand-induced internalization of receptors (endocytic downregulation or via ligand-induced receptor desensitization. These phenomena have traditionally been viewed in the context of adaptation wherein the receptor system enters a refractory state in the presence of sustained ligand stimuli and thereby prevents the cell from over-responding to the ligand. Here we use the epidermal growth factor receptor (EGFR and G-protein coupled receptors (GPCR as model systems to respectively examine the effects of downregulation and desensitization on the ability of signaling receptors to decode time-varying ligand stimuli. Results Using a mathematical model, we show that downregulation and desensitization mechanisms can lead to tight and efficient input-output coupling thereby ensuring synchronous processing of ligand inputs. Frequency response analysis indicates that upstream elements of the EGFR and GPCR networks behave like low-pass filters with the system being able to faithfully transduce inputs below a critical frequency. Receptor downregulation and desensitization increase the filter bandwidth thereby enabling the receptor systems to decode inputs in a wider frequency range. Further, system-theoretic analysis reveals that the receptor systems are analogous to classical mechanical over-damped systems. This analogy enables us to metaphorically describe downregulation and desensitization as phenomena that make the systems more resilient in responding to ligand perturbations thereby improving the stability of the system resting state. Conclusion Our findings suggest that in addition to serving as mechanisms for adaptation, receptor downregulation and desensitization can play a critical role in temporal information

  18. Two Methods of Automatic Evaluation of Speech Signal Enhancement Recorded in the Open-Air MRI Environment

    Science.gov (United States)

    Přibil, Jiří; Přibilová, Anna; Frollo, Ivan

    2017-12-01

    The paper focuses on two methods of evaluation of successfulness of speech signal enhancement recorded in the open-air magnetic resonance imager during phonation for the 3D human vocal tract modeling. The first approach enables to obtain a comparison based on statistical analysis by ANOVA and hypothesis tests. The second method is based on classification by Gaussian mixture models (GMM). The performed experiments have confirmed that the proposed ANOVA and GMM classifiers for automatic evaluation of the speech quality are functional and produce fully comparable results with the standard evaluation based on the listening test method.

  19. Determination of Tobramycin in M9 Medium by LC-MS/MS: Signal Enhancement by Trichloroacetic Acid

    DEFF Research Database (Denmark)

    Huang, Liusheng; Haagensen, Janus Anders Juul; Verotta, Davide

    2018-01-01

    mM ammonium formate and 0.14% trifluoroacetic acid and acetonitrile containing 0.1% trifluoroacetic acid in a gradient mode. ESI+ and MRM with ion m/z 468 → 324 for tobramycin and m/z 473 -> 327 for the IS were used for quantification. The calibration curve concentration range was 50-25000 ng....../mL. Matrix effect from M9 media was not significant when compared with injection solvents, but signal enhancement by trichloroacetic acid was significant (∼ 3 fold). The method is simple, fast, and reliable. Using the method, the in vitro PK/PD model was tested with one bolus dose of tobramycin....

  20. Enhancing signal detection and completely eliminating scattering using quasi-phase-cycling in 2D IR experiments.

    Science.gov (United States)

    Bloem, Robbert; Garrett-Roe, Sean; Strzalka, Halina; Hamm, Peter; Donaldson, Paul

    2010-12-20

    We demonstrate how quasi-phase-cycling achieved by sub-cycle delay modulation can be used to replace optical chopping in a box-CARS 2D IR experiment in order to enhance the signal size, and, at the same time, completely eliminate any scattering contamination. Two optical devices are described that can be used for this purpose, a wobbling Brewster window and a photoelastic modulator. They are simple to construct, easy to incorporate into any existing 2D IR setup, and have attractive features such as a high optical throughput and a fast modulation frequency needed to phase cycle on a shot-to-shot basis.

  1. An enhanced data visualization method for diesel engine malfunction classification using multi-sensor signals.

    Science.gov (United States)

    Li, Yiqing; Wang, Yu; Zi, Yanyang; Zhang, Mingquan

    2015-10-21

    The various multi-sensor signal features from a diesel engine constitute a complex high-dimensional dataset. The non-linear dimensionality reduction method, t-distributed stochastic neighbor embedding (t-SNE), provides an effective way to implement data visualization for complex high-dimensional data. However, irrelevant features can deteriorate the performance of data visualization, and thus, should be eliminated a priori. This paper proposes a feature subset score based t-SNE (FSS-t-SNE) data visualization method to deal with the high-dimensional data that are collected from multi-sensor signals. In this method, the optimal feature subset is constructed by a feature subset score criterion. Then the high-dimensional data are visualized in 2-dimension space. According to the UCI dataset test, FSS-t-SNE can effectively improve the classification accuracy. An experiment was performed with a large power marine diesel engine to validate the proposed method for diesel engine malfunction classification. Multi-sensor signals were collected by a cylinder vibration sensor and a cylinder pressure sensor. Compared with other conventional data visualization methods, the proposed method shows good visualization performance and high classification accuracy in multi-malfunction classification of a diesel engine.

  2. Black ginseng activates Akt signaling, thereby enhancing myoblast differentiation and myotube growth

    Directory of Open Access Journals (Sweden)

    Soo-Yeon Lee

    2018-01-01

    Conclusion: BG enhances myoblast differentiation and myotube hypertrophy by activating Akt/mTOR/p70S6k axis. Thus, our study demonstrates that BG has promising potential to treat or prevent muscle loss related to aging or other pathological conditions, such as diabetes.

  3. Mathematical model for biomolecular quantification using surface-enhanced Raman spectroscopy based signal intensity distributions

    DEFF Research Database (Denmark)

    Palla, Mirko; Bosco, Filippo Giacomo; Yang, Jaeyoung

    2015-01-01

    This paper presents the development of a novel statistical method for quantifying trace amounts of biomolecules by surface-enhanced Raman spectroscopy (SERS) using a rigorous, single molecule (SM) theory based mathematical derivation. Our quantification framework could be generalized for planar...

  4. Estradiol attenuates ischemia-induced death of hippocampal neurons and enhances synaptic transmission in aged, long-term hormone-deprived female rats.

    Directory of Open Access Journals (Sweden)

    Tomoko Inagaki

    Full Text Available Transient global forebrain ischemia causes selective, delayed death of hippocampal CA1 pyramidal neurons, and the ovarian hormone 17β-estradiol (E2 reduces neuronal loss in young and middle-aged females. The neuroprotective efficacy of E2 after a prolonged period of hormone deprivation is controversial, and few studies examine this issue in aged animals given E2 treatment after induction of ischemia.The present study investigated the neuroprotective effects of E2 administered immediately after global ischemia in aged female rats (15-18 months after 6 months of hormone deprivation. We also used electrophysiological methods to assess whether CA1 synapses in the aging hippocampus remain responsive to E2 after prolonged hormone withdrawal. Animals were ovariohysterectomized and underwent 10 min global ischemia 6 months later. A single dose of E2 (2.25 µg infused intraventricularly after reperfusion significantly increased cell survival, with 45% of CA1 neurons surviving vs 15% in controls. Ischemia also induced moderate loss of CA3/CA4 pyramidal cells. Bath application of 1 nM E2 onto brain slices derived from non-ischemic aged females after 6 months of hormone withdrawal significantly enhanced excitatory transmission at CA1 synapses evoked by Schaffer collateral stimulation, and normal long-term potentiation (LTP was induced. The magnitude of LTP and of E2 enhancement of field excitatory postsynaptic potentials was indistinguishable from that recorded in slices from young rats.The data demonstrate that 1 acute post-ischemic infusion of E2 into the brain ventricles is neuroprotective in aged rats after 6 months of hormone deprivation; and 2 E2 enhances synaptic transmission in CA1 pyramidal neurons of aged long-term hormone deprived females. These findings provide evidence that the aging hippocampus remains responsive to E2 administered either in vivo or in vitro even after prolonged periods of hormone withdrawal.

  5. BMP and TGFbeta pathways in human central chondrosarcoma: enhanced endoglin and Smad 1 signaling in high grade tumors

    International Nuclear Information System (INIS)

    Boeuf, Stephane; Bovée, Judith VMG; Lehner, Burkhard; Akker, Brendy van den; Ruler, Maayke van; Cleton-Jansen, Anne-Marie; Richter, Wiltrud

    2012-01-01

    As major regulators of normal chondrogenesis, the bone morphogenic protein (BMP) and transforming growth factor β (TGFB) signaling pathways may be involved in the development and progression of central chondrosarcoma. In order to uncover their possible implication, the aim of this study was to perform a systematic quantitative study of the expression of BMPs, TGFBs and their receptors and to assess activity of the corresponding pathways in central chondrosarcoma. Gene expression analysis was performed by quantitative RT-PCR in 26 central chondrosarcoma and 6 healthy articular cartilage samples. Expression of endoglin and nuclear localization of phosphorylated Smad1/5/8 and Smad2 was assessed by immunohistochemical analysis. The expression of TGFB3 and of the activin receptor-like kinase ALK2 was found to be significantly higher in grade III compared to grade I chondrosarcoma. Nuclear phosphorylated Smad1/5/8 and Smad2 were found in all tumors analyzed and the activity of both signaling pathways was confirmed by functional reporter assays in 2 chondrosarcoma cell lines. Immunohistochemical analysis furthermore revealed that phosphorylated Smad1/5/8 and endoglin expression were significantly higher in high-grade compared to low-grade chondrosarcoma and correlated to each other. The BMP and TGFβ signaling pathways were found to be active in central chondrosarcoma cells. The correlation of Smad1/5/8 activity to endoglin expression suggests that, as described in other cell types, endoglin could enhance Smad1/5/8 signaling in high-grade chondrosarcoma cells. Endoglin expression coupled to Smad1/5/8 activation could thus represent a functionally important signaling axis for the progression of chondrosarcoma and a regulator of the undifferentiated phenotype of high-grade tumor cells

  6. BMP and TGFbeta pathways in human central chondrosarcoma: enhanced endoglin and Smad 1 signaling in high grade tumors

    Science.gov (United States)

    2012-01-01

    Background As major regulators of normal chondrogenesis, the bone morphogenic protein (BMP) and transforming growth factor β (TGFB) signaling pathways may be involved in the development and progression of central chondrosarcoma. In order to uncover their possible implication, the aim of this study was to perform a systematic quantitative study of the expression of BMPs, TGFBs and their receptors and to assess activity of the corresponding pathways in central chondrosarcoma. Methods Gene expression analysis was performed by quantitative RT-PCR in 26 central chondrosarcoma and 6 healthy articular cartilage samples. Expression of endoglin and nuclear localization of phosphorylated Smad1/5/8 and Smad2 was assessed by immunohistochemical analysis. Results The expression of TGFB3 and of the activin receptor-like kinase ALK2 was found to be significantly higher in grade III compared to grade I chondrosarcoma. Nuclear phosphorylated Smad1/5/8 and Smad2 were found in all tumors analyzed and the activity of both signaling pathways was confirmed by functional reporter assays in 2 chondrosarcoma cell lines. Immunohistochemical analysis furthermore revealed that phosphorylated Smad1/5/8 and endoglin expression were significantly higher in high-grade compared to low-grade chondrosarcoma and correlated to each other. Conclusions The BMP and TGFβ signaling pathways were found to be active in central chondrosarcoma cells. The correlation of Smad1/5/8 activity to endoglin expression suggests that, as described in other cell types, endoglin could enhance Smad1/5/8 signaling in high-grade chondrosarcoma cells. Endoglin expression coupled to Smad1/5/8 activation could thus represent a functionally important signaling axis for the progression of chondrosarcoma and a regulator of the undifferentiated phenotype of high-grade tumor cells. PMID:23088614

  7. CXCL10/CXCR3 Signaling in Glia Cells Differentially Affects NMDA-Induced Cell Death in CA and DG Neurons of the Mouse Hippocampus

    NARCIS (Netherlands)

    van Weering, Hilmar R. J.; Boddeke, Hendrikus W. G. M.; Vinet, Jonathan; Brouwer, Nieske; de Haas, Alexander H.; van Rooijen, Nico; Thomsen, Allan R.; Biber, Knut P. H.

    2011-01-01

    The chemokine CXCL10 and its receptor CXCR3 are implicated in various CNS pathologies since interference with CXCL10/CXCR3 signaling alters the onset and progression in various CNS disease models. However, the mechanism and cell-types involved in CXCL10/CXCR3 signaling under pathological conditions

  8. Regular Exercise Enhances the Immune Response Against Microbial Antigens Through Up-Regulation of Toll-like Receptor Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Qishi Zheng

    2015-09-01

    Full Text Available Background/Aims: Regular physical exercise can enhance resistance to many microbial infections. However, little is known about the mechanism underlying the changes in the immune system induced by regular exercise. Methods: We recruited members of a university badminton club as the regular exercise (RE group and healthy sedentary students as the sedentary control (SC group. We investigated the distribution of peripheral blood mononuclear cell (PBMC subsets and functions in the two groups. Results: There were no significant differences in plasma cytokine levels between the RE and SC groups in the true resting state. However, enhanced levels of IFN-γ, TNF-α, IL-6, IFN-α and IL-12 were secreted by PBMCs in the RE group following microbial antigen stimulation, when compared to the SC group. In contrast, the levels of TNF-α and IL-6 secreted by PBMC in the RE group were suppressed compared with those in SC group following non-microbial antigen stimulation (concanavalin A or α-galactosylceramide. Furthermore, PBMC expression of TLR2, TLR7 and MyD88 was significantly increased in the RE group in response to microbial antigen stimulation. Conclusion: Regular exercise enhances immune cell activation in response to pathogenic stimulation leading to enhanced cytokine production mediated via the TLR signaling pathways.

  9. Constitutive activation of extracellular signal-regulated kinase predisposes diffuse large B-cell lymphoma cell lines to CD40-mediated cell death

    DEFF Research Database (Denmark)

    Hollmann, C Annette; Owens, Trevor; Nalbantoglu, Josephine

    2006-01-01

    CD40 promotes survival, proliferation, and differentiation of normal B cells but can cause activation-induced cell death in malignant B lymphocytes. CD40 ligand and anti-CD40 antibodies have been used successfully to induce apoptosis in lymphoma lines both in vitro and in xenograft tumor models. ...

  10. Stem cell death and survival in heart regeneration and repair.

    Science.gov (United States)

    Abdelwahid, Eltyeb; Kalvelyte, Audrone; Stulpinas, Aurimas; de Carvalho, Katherine Athayde Teixeira; Guarita-Souza, Luiz Cesar; Foldes, Gabor

    2016-03-01

    Cardiovascular diseases are major causes of mortality and morbidity. Cardiomyocyte apoptosis disrupts cardiac function and leads to cardiac decompensation and terminal heart failure. Delineating the regulatory signaling pathways that orchestrate cell survival in the heart has significant therapeutic implications. Cardiac tissue has limited capacity to regenerate and repair. Stem cell therapy is a successful approach for repairing and regenerating ischemic cardiac tissue; however, transplanted cells display very high death percentage, a problem that affects success of tissue regeneration. Stem cells display multipotency or pluripotency and undergo self-renewal, however these events are negatively influenced by upregulation of cell death machinery that induces the significant decrease in survival and differentiation signals upon cardiovascular injury. While efforts to identify cell types and molecular pathways that promote cardiac tissue regeneration have been productive, studies that focus on blocking the extensive cell death after transplantation are limited. The control of cell death includes multiple networks rather than one crucial pathway, which underlies the challenge of identifying the interaction between various cellular and biochemical components. This review is aimed at exploiting the molecular mechanisms by which stem cells resist death signals to develop into mature and healthy cardiac cells. Specifically, we focus on a number of factors that control death and survival of stem cells upon transplantation and ultimately affect cardiac regeneration. We also discuss potential survival enhancing strategies and how they could be meaningful in the design of targeted therapies that improve cardiac function.

  11. Enhancing scatterometry CD signal-to-noise ratio for 1x logic and memory challenges

    Science.gov (United States)

    Shaughnessy, Derrick; Krishnan, Shankar; Wei, Lanhua; Shchegrov, Andrei V.

    2013-04-01

    The ongoing transition from 2D to 3D structures in logic and memory has led to an increased adoption of scatterometry CD (SCD) for inline metrology. However, shrinking device dimensions in logic and high aspect ratios in memory represent primary challenges for SCD and require a significant breakthrough in improving signal-to-noise performance. We present a report on the new generation of SCD technology, enabled by a new laser-driven plasma source. The developed light source provides several key advantages over conventional arc lamps typically used in SCD applications. The plasma color temperature of the laser driven source is considerably higher than available with arc lamps resulting in >5X increase in radiance in the visible and >10X increase in radiance in the DUV when compared to sources on previous generation SCD tools while maintaining or improving source intensity noise. This high radiance across such a broad spectrum allows for the use of a single light source from 190-1700nm. When combined with other optical design changes, the higher source radiance enables reduction of measurement box size of our spectroscopic ellipsometer from 45×45um box to 25×25um box without compromising signal to noise ratio. The benefits for 1×nm SCD metrology of the additional photons across the DUV to IR spectrum have been found to be greater than the increase in source signal to noise ratio would suggest. Better light penetration in Si and poly-Si has resulted in improved sensitivity and correlation breaking for critical parameters in 1xnm FinFET and HAR flash memory structures.

  12. Enhancement of molecular NMR signal induced by polarization transfer from laser-polarized 129Xe

    International Nuclear Information System (INIS)

    Sun Xianping

    2001-01-01

    There is a large non-equilibrium nuclear polarization and a longer relaxation time in the laser-polarized 129 Xe produced by means of optical pumping and spin exchange. The characteristics of the laser-polarized 129 Xe permit the transfer of the polarization to enhance the atomic nuclear spin in liquid, solid and surface of solid molecules. Therefore, the sensitivity in nuclear magnetic resonance measurements for the molecules is enhanced and applications in the investigations of materials and surface sciences are expanded. The progress in the investigations of materials and surface sciences are expanded. The progress in the investigations of the polarization transfer between laser-polarized 129 Xe and the atomic nuclei in the molecules, the relative physics and the measurement of some parameters are introduced

  13. Double pulse laser ablation and plasma: Laser induced breakdown spectroscopy signal enhancement

    International Nuclear Information System (INIS)

    Babushok, V.I.; DeLucia, F.C.; Gottfried, J.L.; Munson, C.A.; Miziolek, A.W.

    2006-01-01

    A review of recent results of the studies of double laser pulse plasma and ablation for laser induced breakdown spectroscopy applications is presented. The double pulse laser induced breakdown spectroscopy configuration was suggested with the aim of overcoming the sensitivity shortcomings of the conventional single pulse laser induced breakdown spectroscopy technique. Several configurations have been suggested for the realization of the double pulse laser induced breakdown spectroscopy technique: collinear, orthogonal pre-spark, orthogonal pre-heating and dual pulse crossed beam modes. In addition, combinations of laser pulses with different wavelengths, different energies and durations were studied, thus providing flexibility in the choice of wavelength, pulse width, energy and pulse sequence. The double pulse laser induced breakdown spectroscopy approach provides a significant enhancement in the intensity of laser induced breakdown spectroscopy emission lines up to two orders of magnitude greater than a conventional single pulse laser induced breakdown spectroscopy. The double pulse technique leads to a better coupling of the laser beam with the plasma plume and target material, thus providing a more temporally effective energy delivery to the plasma and target. The experimental results demonstrate that the maximum effect is obtained at some optimum separation delay time between pulses. The optimum value of the interpulse delay depends on several factors, such as the target material, the energy level of excited states responsible for the emission, and the type of enhancement process considered. Depending on the specified parameter, the enhancement effects were observed on different time scales ranging from the picosecond time level (e.g., ion yield, ablation mass) up to the hundred microsecond level (e.g., increased emission intensity for laser induced breakdown spectroscopy of submerged metal target in water). Several suggestions have been proposed to explain

  14. Bee deaths need analysing

    NARCIS (Netherlands)

    Boonekamp, P.M.

    2011-01-01

    Alarm bells are ringing all over the world about the death of bee populations. Although it is not known exactly how severe the decline is, it is important to take the problem seriously. The signals are alarming and the bee is important, not just for natural ecosystems but also for the pollination of

  15. Reward prediction error signal enhanced by striatum-amygdala interaction explains the acceleration of probabilistic reward learning by emotion.

    Science.gov (United States)

    Watanabe, Noriya; Sakagami, Masamichi; Haruno, Masahiko

    2013-03-06

    Learning does not only depend on rationality, because real-life learning cannot be isolated from emotion or social factors. Therefore, it is intriguing to determine how emotion changes learning, and to identify which neural substrates underlie this interaction. Here, we show that the task-independent presentation of an emotional face before a reward-predicting cue increases the speed of cue-reward association learning in human subjects compared with trials in which a neutral face is presented. This phenomenon was attributable to an increase in the learning rate, which regulates reward prediction errors. Parallel to these behavioral findings, functional magnetic resonance imaging demonstrated that presentation of an emotional face enhanced reward prediction error (RPE) signal in the ventral striatum. In addition, we also found a functional link between this enhanced RPE signal and increased activity in the amygdala following presentation of an emotional face. Thus, this study revealed an acceleration of cue-reward association learning by emotion, and underscored a role of striatum-amygdala interactions in the modulation of the reward prediction errors by emotion.

  16. Hardware-efficient signal generation of layered/enhanced ACO-OFDM for short-haul fiber-optic links.

    Science.gov (United States)

    Wang, Qibing; Song, Binhuang; Corcoran, Bill; Boland, David; Zhu, Chen; Zhuang, Leimeng; Lowery, Arthur J

    2017-06-12

    Layered/enhanced ACO-OFDM is a promising candidate for intensity modulation and direct-detection based short-haul fiber-optic links due to its both power and spectral efficiency. In this paper, we firstly demonstrate a hardware-efficient real-time 9.375 Gb/s QPSK-encoded layered/enhanced asymmetrical clipped optical OFDM (L/E-ACO-OFDM) transmitter using a Virtex-6 FPGA. This L/E-ACO-OFDM signal is successfully transmitted over 20-km uncompensated standard single-mode fiber (S-SMF) using a directly modulated laser. Several methods are explored to reduce the FPGA's logic resource utilization by taking advantage of the L/E-ACO-OFDM's signal characteristics. We show that the logic resource occupation of L/E-ACO-OFDM transmitter is almost the same as that of DC-biased OFDM transmitter when they achieve the same spectral efficiency, proving its great potential to be used in a real-time short-haul optical transmission link.

  17. Deficiency of thioredoxin binding protein-2 (TBP-2 enhances TGF-β signaling and promotes epithelial to mesenchymal transition.

    Directory of Open Access Journals (Sweden)

    So Masaki

    Full Text Available Transforming growth factor beta (TGF-β has critical roles in regulating cell growth, differentiation, apoptosis, invasion and epithelial-mesenchymal transition (EMT of various cancer cells. TGF-β-induced EMT is an important step during carcinoma progression to invasion state. Thioredoxin binding protein-2 (TBP-2, also called Txnip or VDUP1 is downregulated in various types of human cancer, and its deficiency results in the earlier onset of cancer. However, it remains unclear how TBP-2 suppresses the invasion and metastasis of cancer.In this study, we demonstrated that TBP-2 deficiency increases the transcriptional activity in response to TGF-β and also enhances TGF-β-induced Smad2 phosphorylation levels. Knockdown of TBP-2 augmented the TGF-β-responsive expression of Snail and Slug, transcriptional factors related to TGF-β-mediated induction of EMT, and promoted TGF-β-induced spindle-like morphology consistent with the depletion of E-Cadherin in A549 cells.Our results indicate that TBP-2 deficiency enhances TGF-β signaling and promotes TGF-β-induced EMT. The control of TGF-β-induced EMT is critical for the inhibition of the invasion and metastasis. Thus TBP-2, as a novel regulatory molecule of TGF-β signaling, is likely to be a prognostic indicator or a potential therapeutic target for preventing tumor progression.

  18. Huperzine A activates Wnt/β-catenin signaling and enhances the nonamyloidogenic pathway in an Alzheimer transgenic mouse model.

    Science.gov (United States)

    Wang, Chun-Yan; Zheng, Wei; Wang, Tao; Xie, Jing-Wei; Wang, Si-Ling; Zhao, Bao-Lu; Teng, Wei-Ping; Wang, Zhan-You

    2011-04-01

    Huperzine A (HupA) is a reversible and selective inhibitor of acetylcholinesterase (AChE), and it has multiple targets when used for Alzheimer's disease (AD) therapy. In this study, we searched for new mechanisms by which HupA could activate Wnt signaling and reduce amyloidosis in AD brain. A nasal gel containing HupA was prepared. No obvious toxicity of intranasal administration of HupA was found in mice. HupA was administered intranasally to β-amyloid (Aβ) precursor protein and presenilin-1 double-transgenic mice for 4 months. We observed an increase in ADAM10 and a decrease in BACE1 and APP695 protein levels and, subsequently, a reduction in Aβ levels and Aβ burden were present in HupA-treated mouse brain, suggesting that HupA enhances the nonamyloidogenic APP cleavage pathway. Importantly, our results further showed that HupA inhibited GSK3α/β activity, and enhanced the β-catenin level in the transgenic mouse brain and in SH-SY5Y cells overexpressing Swedish mutation APP, suggesting that the neuroprotective effect of HupA is not related simply to its AChE inhibition and antioxidation, but also involves other mechanisms, including targeting of the Wnt/β-catenin signaling pathway in AD brain.

  19. Enhanced Edar signalling has pleiotropic effects on craniofacial and cutaneous glands.

    Directory of Open Access Journals (Sweden)

    Shie Hong Chang

    2009-10-01

    Full Text Available The skin carries a number of appendages, including hair follicles and a range of glands, which develop under the influence of EDAR signalling. A gain of function allele of EDAR is found at high frequency in human populations of East Asia, with genetic evidence suggesting recent positive selection at this locus. The derived EDAR allele, estimated to have reached fixation more than 10,000 years ago, causes thickening of hair fibres, but the full spectrum of phenotypic changes induced by this allele is unknown. We have examined the changes in glandular structure caused by elevation of Edar signalling in a transgenic mouse model. We find that sebaceous and Meibomian glands are enlarged and that salivary and mammary glands are more elaborately branched with increased Edar activity, while the morphology of eccrine sweat and tracheal submucosal glands appears to be unaffected. Similar changes to gland sizes and structures may occur in human populations carrying the derived East Asian EDAR allele. As this allele attained high frequency in an environment that was notably cold and dry, increased glandular secretions could represent a trait that was positively selected to achieve increased lubrication and reduced evaporation from exposed facial structures and upper airways.

  20. Insulin resistance enhances the mitogen-activated protein kinase signaling pathway in ovarian granulosa cells.

    Directory of Open Access Journals (Sweden)

    Linghui Kong

    Full Text Available The ovary is the main regulator of female fertility. Granulosa cell dysfunction may be involved in various reproductive endocrine disorders. Here we investigated the effect of insulin resistance on the metabolism and function of ovarian granulosa cells, and dissected the functional status of the mitogen-activated protein kinase signaling pathway in these cells. Our data showed that dexamethasone-induced insulin resistance in mouse granulosa cells reduced insulin sensitivity, accompanied with an increase in phosphorylation of p44/42 mitogen-activated protein kinase. Furthermore, up-regulation of cytochrome P450 subfamily 17 and testosterone and down-regulation of progesterone were observed in insulin-resistant mouse granulosa cells. Inhibition of p44/42 mitogen-activated protein kinase after induction of insulin resistance in mouse granulosa cells decreased phosphorylation of p44/42 mitogen-activated protein kinase, downregulated cytochrome P450 subfamily 17 and lowered progesterone production. This insulin resistance cell model can successfully demonstrate certain mechanisms such as hyperandrogenism, which may inspire a new strategy for treating reproductive endocrine disorders by regulating cell signaling pathways.

  1. Using Differential Evolution to Optimize Learning from Signals and Enhance Network Security

    Energy Technology Data Exchange (ETDEWEB)

    Harmer, Paul K [Air Force Institute of Technology; Temple, Michael A [Air Force Institute of Technology; Buckner, Mark A [ORNL; Farquhar, Ethan [ORNL

    2011-01-01

    Computer and communication network attacks are commonly orchestrated through Wireless Access Points (WAPs). This paper summarizes proof-of-concept research activity aimed at developing a physical layer Radio Frequency (RF) air monitoring capability to limit unauthorizedWAP access and mprove network security. This is done using Differential Evolution (DE) to optimize the performance of a Learning from Signals (LFS) classifier implemented with RF Distinct Native Attribute (RF-DNA) fingerprints. Performance of the resultant DE-optimized LFS classifier is demonstrated using 802.11a WiFi devices under the most challenging conditions of intra-manufacturer classification, i.e., using emissions of like-model devices that only differ in serial number. Using identical classifier input features, performance of the DE-optimized LFS classifier is assessed relative to a Multiple Discriminant Analysis / Maximum Likelihood (MDA/ML) classifier that has been used for previous demonstrations. The comparative assessment is made using both Time Domain (TD) and Spectral Domain (SD) fingerprint features. For all combinations of classifier type, feature type, and signal-to-noise ratio considered, results show that the DEoptimized LFS classifier with TD features is uperior and provides up to 20% improvement in classification accuracy with proper selection of DE parameters.

  2. Female scent signals enhance the resistance of male mice to influenza.

    Directory of Open Access Journals (Sweden)

    Ekaterina A Litvinova

    Full Text Available BACKGROUND: The scent from receptive female mice functions as a signal, which stimulates male mice to search for potential mating partners. This searching behavior is coupled with infection risk due to sniffing both scent marks as well as nasal and anogenital areas of females, which harbor bacteria and viruses. Consideration of host evolution under unavoidable parasitic pressures, including helminthes, bacteria, viruses, etc., predicts adaptations that help protect hosts against the parasites associated with mating. METHODS AND FINDINGS: We propose that the perception of female signals by BALB/c male mice leads to adaptive redistribution of the immune defense directed to protection against respiratory infection risks. Our results demonstrate migration of macrophages and neutrophils to the upper airways upon exposure to female odor stimuli, which results in an increased resistance of the males to experimental influenza virus infection. This moderate leukocyte intervention had no negative effect on the aerobic performance in male mice. CONCLUSIONS: Our data provide the first demonstration of the adaptive immunological response to female odor stimuli through induction of nonspecific immune responses in the upper respiratory tract.

  3. Inactivation of EGFR/AKT signaling enhances TSA-induced ovarian cancer cell differentiation.

    Science.gov (United States)

    Shao, Genbao; Lai, Wensheng; Wan, Xiaolei; Xue, Jing; Wei, Ye; Jin, Jie; Zhang, Liuping; Lin, Qiong; Shao, Qixiang; Zou, Shengqiang

    2017-05-01

    Ovarian tumor is one of the most lethal gynecologic cancers, but differentiation therapy for this cancer is poorly characterized. Here, we show that thrichostatin A (TSA), the well known inhibitor of histone deacetylases (HDACs), can induce cell differentiation in HO8910 ovarian cancer cells. TSA-induced cell differentiation is characterized by typical morphological change, increased expression of the differentiation marker FOXA2, decreased expression of the pluripotency markers SOX2 and OCT4, suppressing cell proliferation, and cell cycle arrest in the G1 phase. TSA also induces an elevated expression of cell cycle inhibitory protein p21Cip1 along with a decrease in cell cycle regulatory protein cyclin D1. Significantly, blockage of epidermal growth factor receptor (EGFR) signaling pathway with specific inhibitors of this signaling cascade promotes the TSA-induced differentiation of HO8910 cells. These results imply that the EGFR cascade inhibitors in combination with TSA may represent a promising differentiation therapy strategy for ovarian cancer.

  4. Romantic Love Is Associated with Enhanced Inhibitory Control in an Emotional Stop-Signal Task

    Science.gov (United States)

    Song, Sensen; Zou, Zhiling; Song, Hongwen; Wang, Yongming; d’Oleire Uquillas, Federico; Wang, Huijun; Chen, Hong

    2016-01-01

    Purpose: This study explored whether romantic lovers differ in emotion-related inhibitory control capacity from those who are single. Methods: 88 healthy undergraduate college students participated in the study. Half were currently in love and in a romantic relationship (love group, LG), and half were single and had never been in a romantic relationship (single group, SG). Based on duration of romantic relationship (i.e., love duration), the LG were further divided into two subgroups: “early stage love” and “longer periods of love”. All participants completed an emotional Stop Signal Task, consisting of a variety of human face stimuli displaying either sad or neutral affect. Results: Results found that relative to SG, lovers showed greater inhibitory control [shorter stop-signal reaction time (SSRT)] during negative emotion condition trials. Furthermore, in early stages of love, SSRT for negative emotion condition trials was significantly shorter compared to that in “longer periods of love” or SG individuals, with no significant differences between the two latter groups. Conclusion: Compared with individuals who were single, early stage lovers showed greater capacity for inhibiting action during presentation of negative emotional stimuli. Within a greater social context, greater inhibitory control capacity during early stages of love may be related to the successful formation of romantic relationships, particularly to the ability to persevere in goal-directed action despite negative emotional contexts such as that of sadness. PMID:27826260

  5. Romantic love is associated with enhanced inhibitory control in an emotional stop-signal task

    Directory of Open Access Journals (Sweden)

    Sensen Song

    2016-10-01

    Full Text Available Purpose: This study explored whether romantic lovers differ in emotion-related inhibitory control capacity from those who are single. Methods: 88 healthy undergraduate college students participated in the study. Half were currently in love and in a romantic relationship (love group, LG, and half were single and had never been in a romantic relationship (single group, SG. Based on duration of romantic relationship (i.e., love duration, the LG were further divided into two subgroups: early stage love and longer periods of love. All participants completed an emotional Stop Signal Task (eSST, which consisted of a variety of human face stimuli representing sadness (a negative emotion, as well as neutral emotions. Results: Results found that relative to SG, lovers showed greater inhibitory control [shorter stop-signal reaction time (SSRT] during negative emotion condition trials. Furthermore, in early stages of love, SSRT for negative emotion condition trials was significantly shorter compared to that in longer periods of love or SG individuals, with no significant differences between the latter two groups. Conclusions: Compared with individuals who were single, early-stage lovers showed greater capacity for inhibiting action during presentation of negative emotional stimuli. Within a greater social context, greater inhibitory control capacity during early stages of love may be related to the successful formation of romantic relationships, particularly to the ability to persevere in goal-directed action despite negative emotional contexts such as that of sadness.

  6. Aerosol-delivered programmed cell death 4 enhanced apoptosis, controlled cell cycle and suppressed AP-1 activity in the lungs of AP-1 luciferase reporter mice.

    Science.gov (United States)

    Hwang, S-K; Jin, H; Kwon, J T; Chang, S-H; Kim, T H; Cho, C-S; Lee, K H; Young, M R; Colburn, N H; Beck, G R; Yang, H-S; Cho, M-H

    2007-09-01

    The long-term survival of lung cancer patients treated with conventional therapies remains poor and therefore the need for novel approaches remains high. This has led to the re-emergence of aerosol delivery as a therapeutic intervention. In this study, glucosylated polyethylenimine (GPEI) was used as carrier to investigate programmed cell death 4 (PDCD4) and PDCD4 mutant (D418A), an eIF4A-binding mutant, on PDCD4-related signaling and activator protein-1 (AP-1) activity in the lungs of AP-1 luciferase reporter mice. After confirming the efficiency of GPEI as a carrier in lungs, the effects of aerosol-delivered PDCD4 were investigated in AP-1 luciferase reporter mice. Aerosol delivery of GPEI/PDCD4 through a nose-only inhalation facilitated the apoptosis of lungs whereas aerosol PDCD4 mutant did not. Also, such aerosol delivery regulated proteins relevant to cell-cycle control and suppressed AP-1 activity. Results obtained by western blot analysis, immunohistochemistry, luciferase assay and deoxynucleotidyl-transferase-mediated nick end labeling study suggest that combined actions such as facilitating apoptosis, controlling cell cycle and suppression of AP-1 activity by PDCD4 may provide useful tool for designing lung tumor prevention and treatment by which PDCD4 functions as a transformation suppressor in the future.

  7. Methamphetamine-enhanced female sexual motivation is dependent on dopamine and progesterone signaling in the medial amygdala.

    Science.gov (United States)

    Holder, Mary K; Veichweg, Shaun S; Mong, Jessica A

    2015-01-01

    Methamphetamine (METH) is a psychomotor stimulant strongly associated with increases in sexual drive and impulsive sexual behaviors that often lead to unsafe sexual practices. In women METH users, such practices have been associated with increases in unplanned pregnancies and sexually transmitted diseases. Despite this significant heath concern, the neural mechanisms underlying this drug-sex association are not known. We previously established a rodent model of METH-facilitated female sexual behavior in which estradiol and progesterone interact with METH to increase motivational components of female behavior and neuronal activation in the posterodorsal medial amygdala (MePD) (Holder et al., 2010; Holder and Mong, 2010). The current study more directly examines the mechanisms underlying the drug-sex interaction. Here, we hypothesize that METH-induced increases in MePD dopamine signaling bridge the METH-hormone interaction. In support of this hypothesis, we found that excitotoxic lesions targeted to the MePD attenuated the METH-induced increases in proceptive behavior. Furthermore, infusion of a D1 agonist into the MePD increased proceptive behavior, while infusion of a D1 antagonist blocked the ability of METH to increase proceptive behaviors. Additionally, we found that METH-treatment increased progesterone receptor (PR) immunoreactivity in the MePD, suggesting an interaction between dopamine and progesterone signaling. Indeed, infusions of the PR antagonist, RU486, prevented METH-induced increases in sexual behavior. Thus, taken together, the current findings suggest that dopamine in the MePD modulates enhanced sexual motivation via an amplification of progesterone signaling and contributes to a better understanding of the neurobiology of drug-enhanced sexual behaviors. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Resistin Enhances Inflammatory Cytokine Production in Coronary Artery Tissues by Activating the NF-κB Signaling

    Directory of Open Access Journals (Sweden)

    Fang Gao

    2016-01-01

    Full Text Available Purpose. Kawasaki disease (KD is a systemic vasculitis and is a leading cause of coronary artery lesions (CALs in childhood. Our previous study has shown higher levels of serum Resistin in KD patients with coronary aneurysm. This study aimed at examining the association of Resistin with inflammatory cytokine expression in mouse model of coronary arteritis and determining the potential mechanisms. Methods. C57BL/6 mice were injected with Lactobacillus cell wall extract (LCWE to induce coronary arteritis. The relative levels of Resistin, TNF-α, IL-1β, and MMP-9 expression and inflammatory infiltrates in the coronary arteries were determined longitudinally by quantitative RT-PCR, ELISA, and histology. The effect of TLR4 and NF-κB activation on Resistin-induced TNF-α and IL-1β expression in human coronary artery endothelium cells (HCAECs was examined by quantitative RT-PCR. Results. Higher levels of Resistin, TNF-α, IL-1β, and MMP-9 expression were associated with the degrees of inflammatory infiltrates in the coronary artery walls of the LCWE-injected mice. Resistin enhanced TNF-α and IL-1β expression in HCAECs at 18 or 24 hours after stimulation. Pretreatment with anti-TLR4 attenuated Resistin-enhanced IL-1β, but not TNF-α, expression and pretreatment with parthenolide or QNZ demolished Resistin-enhanced TNF-α expression in HACECs. Pretreatment with parthenolide, but not QNZ, blocked Resistin-enhanced IL-1β expression in HCAECs. Conclusion. Resistin may enhance inflammation by cross-talking with TLR4/NF-κB signaling during the development of coronary arteritis in mice.

  9. Channel noise enhances signal detectability in a model of acoustic neuron through the stochastic resonance paradigm.

    Science.gov (United States)

    Liberti, M; Paffi, A; Maggio, F; De Angelis, A; Apollonio, F; d'Inzeo, G

    2009-01-01

    A number of experimental investigations have evidenced the extraordinary sensitivity of neuronal cells to weak input stimulations, including electromagnetic (EM) fields. Moreover, it has been shown that biological noise, due to random channels gating, acts as a tuning factor in neuronal processing, according to the stochastic resonant (SR) paradigm. In this work the attention is focused on noise arising from the stochastic gating of ionic channels in a model of Ranvier node of acoustic fibers. The small number of channels gives rise to a high noise level, which is able to cause a spike train generation even in the absence of stimulations. A SR behavior has been observed in the model for the detection of sinusoidal signals at frequencies typical of the speech.

  10. Enhancing the top-quark signal at Fermilab Tevatron using neural nets

    International Nuclear Information System (INIS)

    Ametller, L.; Garrido, L.; Talavera, P.

    1994-01-01

    We show, in agreement with previous studies, that neural nets can be useful for top-quark analysis at the Fermilab Tevatron. The main features of t bar t and background events in a mixed sample are projected on a single output, which controls the efficiency, purity, and statistical significance of the t bar t signal. We consider a feed-forward multilayer neural net for the CDF reported top-quark mass, using six kinematical variables as inputs. Our main results are based on the exhaustive comparison of the neural net performances with those obtainable from the standard experimental analysis, by imposing different sets of linear cuts over the same variables, showing how the neural net approach improves the standard analysis results

  11. Atorvastatin ameliorates arsenic-induced hypertension and enhancement of vascular redox signaling in rats

    International Nuclear Information System (INIS)

    Sarath, Thengumpallil Sasindran; Waghe, Prashantkumar; Gupta, Priyanka; Choudhury, Soumen; Kannan, Kandasamy; Pillai, Ayyappan Harikrishna; Harikumar, Sankaran Kutty; Mishra, Santosh Kumar; Sarkar, Souvendra Nath

    2014-01-01

    Chronic arsenic exposure has been linked to elevated blood pressure and cardiovascular diseases, while statins reduce the incidence of cardiovascular disease predominantly by their low density lipoprotein-lowering effect. Besides, statins have other beneficial effects, including antioxidant and anti-inflammatory activities. We evaluated whether atorvastatin, a widely used statin, can ameliorate arsenic-induced increase in blood pressure and alteration in lipid profile and also whether the amelioration could relate to altered NO and ROS signaling. Rats were exposed to sodium arsenite (100 ppm) through drinking water for 90 consecutive days. Atorvastatin (10 mg/kg bw, orally) was administered once daily during the last 30 days of arsenic exposure. On the 91st day, blood was collected for lipid profile. Western blot of iNOS and eNOS protein, NO and 3-nitrotyrosine production, Nox-4 and p22Phox mRNA expression, Nox activity, ROS generation, lipid peroxidation and antioxidants were evaluated in thoracic aorta. Arsenic increased systolic, diastolic and mean arterial blood pressure, while it decreased HDL-C and increased LDL-C, total cholesterol and triglycerides in serum. Arsenic down-regulated eNOS and up-regulated iNOS protein expression and increased basal NO and 3-nitrotyrosine level. Arsenic increased aortic Nox-4 and p22Phox mRNA expression, Nox activity, ROS generation and lipid peroxidation. Further, arsenic decreased the activities of superoxide dismutase, catalase, and glutathione peroxidase and depleted aortic GSH content. Atorvastatin regularized blood pressure, improved lipid profile and attenuated arsenic-mediated redox alterations. The results demonstrate that atorvastatin has the potential to ameliorate arsenic-induced hypertension by improving lipid profile, aortic NO signaling and restoring vascular redox homeostasis. - Highlights: • Arsenic increased systolic, diastolic and mean arterial blood pressure and caused dyslipidemia. • Arsenic increased

  12. Atorvastatin ameliorates arsenic-induced hypertension and enhancement of vascular redox signaling in rats

    Energy Technology Data Exchange (ETDEWEB)

    Sarath, Thengumpallil Sasindran; Waghe, Prashantkumar; Gupta, Priyanka; Choudhury, Soumen; Kannan, Kandasamy [Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh (India); Pillai, Ayyappan Harikrishna [Division of Animal Biochemistry, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh (India); Harikumar, Sankaran Kutty; Mishra, Santosh Kumar [Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh (India); Sarkar, Souvendra Nath, E-mail: snsarkar1911@rediffmail.com [Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, 243122 Bareilly, Uttar Pradesh (India)

    2014-11-01

    Chronic arsenic exposure has been linked to elevated blood pressure and cardiovascular diseases, while statins reduce the incidence of cardiovascular disease predominantly by their low density lipoprotein-lowering effect. Besides, statins have other beneficial effects, including antioxidant and anti-inflammatory activities. We evaluated whether atorvastatin, a widely used statin, can ameliorate arsenic-induced increase in blood pressure and alteration in lipid profile and also whether the amelioration could relate to altered NO and ROS signaling. Rats were exposed to sodium arsenite (100 ppm) through drinking water for 90 consecutive days. Atorvastatin (10 mg/kg bw, orally) was administered once daily during the last 30 days of arsenic exposure. On the 91st day, blood was collected for lipid profile. Western blot of iNOS and eNOS protein, NO and 3-nitrotyrosine production, Nox-4 and p22Phox mRNA expression, Nox activity, ROS generation, lipid peroxidation and antioxidants were evaluated in thoracic aorta. Arsenic increased systolic, diastolic and mean arterial blood pressure, while it decreased HDL-C and increased LDL-C, total cholesterol and triglycerides in serum. Arsenic down-regulated eNOS and up-regulated iNOS protein expression and increased basal NO and 3-nitrotyrosine level. Arsenic increased aortic Nox-4 and p22Phox mRNA expression, Nox activity, ROS generation and lipid peroxidation. Further, arsenic decreased the activities of superoxide dismutase, catalase, and glutathione peroxidase and depleted aortic GSH content. Atorvastatin regularized blood pressure, improved lipid profile and attenuated arsenic-mediated redox alterations. The results demonstrate that atorvastatin has the potential to ameliorate arsenic-induced hypertension by improving lipid profile, aortic NO signaling and restoring vascular redox homeostasis. - Highlights: • Arsenic increased systolic, diastolic and mean arterial blood pressure and caused dyslipidemia. • Arsenic increased

  13. Desferrioxamine, an iron chelator, enhances HIF-1α accumulation via cyclooxygenase-2 signaling pathway

    International Nuclear Information System (INIS)

    Woo, Kyung Jin; Lee, Tae-Jin; Park, Jong-Wook; Kwon, Taeg Kyu

    2006-01-01

    Cyclooxygenase-2 (COX-2) is an important inducible enzyme in inflammation and is overexpressed in a variety of cancers. Evidence is rapidly accumulating that chronic inflammation may contribute to carcinogenesis through increase of cell proliferation, angiogenesis, and metastasis in a number of neoplasms, including colorectal carcinoma. In the present study, we investigated some mechanistic aspects of DFX-induced hypoxia-driven COX-2 expression. Desferrioxamine (DFX), an iron chelator, is known to upregulate inflammatory mediators. DFX induced the expression of COX-2 and accumulation of HIF-1α protein in dose-dependent manners, but hypoxia mimetic agent cobalt chloride (CoCl 2 ) induced accumulation of HIF-1α protein but not increase of COX-2 expression. DFX-induced increase of COX-2 expression and HIF-1α protein level was attenuated by addition of ferric citrate. This result suggested that the iron chelating function of DFX was important to induce the increase of COX-2 and HIF-1α protein. PD98059 significantly inhibited the induction of COX-2 protein and accumulation of HIF-1α, suggesting that DFX-induced increase of HIF-1α and COX-2 protein was mediated, at least in part, through the ERK signaling pathway. In addition, pretreatment with NS-398 to inhibit COX-2 activity also effectively suppressed DFX-induced HIF-1α accumulation in human colon cancer cells, providing the evidence that COX-2 plays as a regulator of HIF-1α accumulation in DFX-treated colon cancer cells. Together, our findings suggest that iron metabolism may regulate stabilization of HIF-1α protein by modulating cyclooxygenase-2 signaling pathway

  14. On social death: ostracism and the accessibility of death thoughts.

    Science.gov (United States)

    Steele, Caroline; Kidd, David C; Castano, Emanuele

    2015-01-01

    Being rejected, excluded, or simply ignored is a painful experience. Ostracism researchers have shown its powerful negative consequences (Williams, 2007), and sociologists have referred to such experiences as social death (Bauman, 1992). Is this is just a metaphor or does being ostracized make death more salient in people's minds? An experiment was conducted in which participants experienced ostracism or inclusion using the Cyberball manipulation, and the accessibility of death-related thoughts was measured via a word-stem completion puzzle. Results showed enhanced death-thought accessibility in the ostracism condition, as well as a negative effect of dispositional self-esteem on the accessibility of death-related thoughts.

  15. Signal enhancement, not active suppression, follows the contingent capture of visual attention.

    Science.gov (United States)

    Livingstone, Ashley C; Christie, Gregory J; Wright, Richard D; McDonald, John J

    2017-02-01

    Irrelevant visual cues capture attention when they possess a task-relevant feature. Electrophysiologically, this contingent capture of attention is evidenced by the N2pc component of the visual event-related potential (ERP) and an enlarged ERP positivity over the occipital hemisphere contralateral to the cued location. The N2pc reflects an early stage of attentional selection, but presently it is unclear what the contralateral ERP positivity reflects. One hypothesis is that it reflects the perceptual enhancement of the cued search-array item; another hypothesis is that it is time-locked to the preceding cue display and reflects active suppression of the cue itself. Here, we varied the time interval between a cue display and a subsequent target display to evaluate these competing hypotheses. The results demonstrated that the contralateral ERP positivity is tightly time-locked to the appearance of the search display rather than the cue display, thereby supporting the perceptual enhancement hypothesis and disconfirming the cue-suppression hypothesis. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  16. Central GLP-2 enhances hepatic insulin sensitivity via activating PI3K signaling in POMC neurons

    Science.gov (United States)

    Shi, Xuemei; Zhou, Fuguo; Li, Xiaojie; Chang, Benny; Li, Depei; Wang, Yi; Tong, Qingchun; Xu, Yong; Fukuda, Makoto; Zhao, Jean J.; Li, Defa; Burrin, Douglas G.; Chan, Lawrence; Guan, Xinfu

    2013-01-01

    Glucagon-like peptides (GLP-1/2) are co-produced and highlighted as key modulators to improve glucose homeostasis and insulin sensitivity after bariatric surgery. However, it is unknown if CNS GLP-2 plays any physiological role in the control of glucose homeostasis and insulin sensitivity. We show that mice lacking GLP-2 receptor (GLP-2R) in POMC neurons display glucose intolerance and hepatic insulin resistance. GLP-2R activation in POMC neurons is required for GLP-2 to enhance insulin-mediated suppression of hepatic glucose production (HGP) and gluconeogenesis. GLP-2 directly modulates excitability of POMC neurons in GLP-2R- and PI3K-dependent manners. GLP-2 initiates GLP-2R-p85α interaction and facilitates PI3K-Akt-dependent FoxO1 nuclear exclusion in POMC neurons. Central GLP-2 suppresses basal HGP and enhances insulin sensitivity, which are abolished in POMC-p110α KO mice. Thus, CNS GLP-2 plays a key physiological role in the control of hepatic glucose production through activating PI3K-dependent modulation of membrane excitability and nuclear transcription of POMC neurons in the brain. PMID:23823479

  17. Central GLP-2 enhances hepatic insulin sensitivity via activating PI3K signaling in POMC neurons.

    Science.gov (United States)

    Shi, Xuemei; Zhou, Fuguo; Li, Xiaojie; Chang, Benny; Li, Depei; Wang, Yi; Tong, Qingchun; Xu, Yong; Fukuda, Makoto; Zhao, Jean J; Li, Defa; Burrin, Douglas G; Chan, Lawrence; Guan, Xinfu

    2013-07-02

    Glucagon-like peptides (GLP-1/GLP-2) are coproduced and highlighted as key modulators to improve glucose homeostasis and insulin sensitivity after bariatric surgery. However, it is unknown if CNS GLP-2 plays any physiological role in the control of glucose homeostasis and insulin sensitivity. We show that mice lacking GLP-2 receptor (GLP-2R) in POMC neurons display glucose intolerance and hepatic insulin resistance. GLP-2R activation in POMC neurons is required for GLP-2 to enhance insulin-mediated suppression of hepatic glucose production (HGP) and gluconeogenesis. GLP-2 directly modulates excitability of POMC neurons in GLP-2R- and PI3K-dependent manners. GLP-2 initiates GLP-2R-p85α interaction and facilitates PI3K-Akt-dependent FoxO1 nuclear exclusion in POMC neurons. Central GLP-2 suppresses basal HGP and enhances insulin sensitivity, which are abolished in POMC-p110α KO mice. Thus, CNS GLP-2 plays a key physiological role in the control of HGP through activating PI3K-dependent modulation of membrane excitability and nuclear transcription of POMC neurons in the brain. Copyright © 2013 Elsevier Inc. All rights reserved.

  18. Osteoblast-secreted collagen upregulates paracrine Sonic hedgehog signaling by prostate cancer cells and enhances osteoblast differentiation

    Directory of Open Access Journals (Sweden)

    Zunich Samantha M

    2012-07-01

    Full Text Available Abstract Background Induction of osteoblast differentiation by paracrine Sonic hedgehog (Shh signaling may be a mechanism through which Shh-expressing prostate cancer cells initiate changes in the bone microenvironment and promote metastases. A hallmark of osteoblast differentiation is the formation of matrix whose predominant protein is type 1 collagen. We investigated the formation of a collagen matrix by osteoblasts cultured with prostate cancer cells, and its effects on interactions between prostate cancer cells and osteoblasts. Results In the presence of exogenous ascorbic acid (AA, a co-factor in collagen synthesis, mouse MC3T3 pre-osteoblasts in mixed cultures with human LNCaP prostate cancer cells or LNCaP cells modified to overexpress Shh (LNShh cells formed collagen matrix with distinct fibril ultrastructural characteristics. AA increased the activity of alkaline phosphatase and the expression of the alkaline phosphatase gene Akp2, markers of osteoblast differentiation, in MC3T3 pre-osteoblasts cultured with LNCaP or LNShh cells. However, the AA-stimulated increase in Akp2 expression in MC3T3 pre-osteoblasts cultured with LNShh cells far exceeded the levels observed in MC3T3 cells cultured with either LNCaP cells with AA or LNShh cells without AA. Therefore, AA and Shh exert a synergistic effect on osteoblast differentiation. We determined whether the effect of AA on LNShh cell-induced osteoblast differentiation was mediated by Shh signaling. AA increased the expression of Gli1 and Ptc1, target genes of the Shh pathway, in MC3T3 pre-osteoblasts cultured with LNShh cells to at least twice their levels without AA. The ability of AA to upregulate Shh signaling and enhance alkaline phosphatase activity was blocked in MC3T3 cells that expressed a dominant negative form of the transcription factor GLI1. The AA-stimulated increase in Shh signaling and Shh-induced osteoblast differentiation was also inhibited by the specific collagen synthesis

  19. ALS skeletal muscle shows enhanced TGF-β signaling, fibrosis and induction of fibro/adipogenic progenitor markers.

    Directory of Open Access Journals (Sweden)

    David Gonzalez

    Full Text Available Amyotrophic lateral sclerosis (ALS is a fatal neurodegenerative disease in which upper and lower motoneurons degenerate leading to muscle wasting, paralysis and eventually death from respiratory failure. Several studies indicate that skeletal muscle contributes to disease progression; however the molecular mechanisms remain elusive. Fibrosis is a common feature in skeletal muscle under chronic damage conditions such as those caused by muscular dystrophies or denervation. However, the exact mechanisms of fibrosis induction and the cellular bases of this pathological response are unknown. We show that extracellular matrix (ECM components are augmented in skeletal muscles of symptomatic hSOD1G93A mice, a widely used murine model of ALS. These mice also show increased TGF-β1 mRNA levels, total Smad3 protein levels and p-Smad3 positive nuclei. Furthermore, platelet-derived growth factor receptor-α (PDGFRα, Tcf4 and α-smooth muscle actin (α-SMA levels are augmented in the skeletal muscle of symptomatic hSOD1G93A mice. Additionally, the fibro/adipogenic progenitors (FAPs, which are the main producers of ECM constituents, are also increased in these pathogenic conditions. Therefore, FAPs and ECM components are more abundant in symptomatic stages of the disease than in pre-symptomatic stages. We present evidence that fibrosis observed in skeletal muscle of symptomatic hSOD1G93A mice is accompanied with an induction of TGF-β signaling, and also that FAPs might be involved in triggering a fibrotic response. Co-localization of p-Smad3 positive cells together with PDGFRα was observed in the interstitial cells of skeletal muscles from symptomatic hSOD1G93A mice. Finally, the targeting of pro-fibrotic factors such as TGF-β, CTGF/CCN2 and platelet-derived growth factor (PDGF signaling pathway might be a suitable therapeutic approach to improve muscle function in several degenerative diseases.

  20. Bell's palsy: what is the prognostic value of measurements of signal intensity increases with contrast enhancement on MRI?

    International Nuclear Information System (INIS)

    Kress, B.P.J.; Efinger, K.; Solbach, T.; Gottschalk, A.; Baehren, W.; Griesbeck, F.; Kornhuber, A.W.

    2002-01-01

    Our objective was to assess the prognostic value of measurements of the degree of contrast enhancement of the intratemporal segments of the facial nerve. We prospectively obtained MRI, slice thickness <1 mm of 20 patients with a facial palsy on the first day of inpatient treatment, and measured contrast enhancement of the nerve. The data were compared with compound muscle action potential (CMAP) measurements and the clinical course. Analysis of the initial enabled differentiation of three patients whose palsy was to show no improvement from 17 whose palsy was to resolve as expected. No patient with a poor outcome showed lesser increase in signal in the internal auditory canal, pars tympanica and pars mastoidea than patients who fully recovered. In no patient who had been diagnosed on the basis of the initial MRI as having a ''normal'' palsy was the amplitude of the (CMAP) reduced to less than 20% that of the normal side. Measurement of contrast enhancement was thus shown to be a prognostic indicator and may provide a basis for a differential treatment of facial palsy. (orig.)

  1. Local synaptic signaling enhances the stochastic transport of motor-driven cargo in neurons

    KAUST Repository

    Newby, Jay

    2010-08-23

    The tug-of-war model of motor-driven cargo transport is formulated as an intermittent trapping process. An immobile trap, representing the cellular machinery that sequesters a motor-driven cargo for eventual use, is located somewhere within a microtubule track. A particle representing a motor-driven cargo that moves randomly with a forward bias is introduced at the beginning of the track. The particle switches randomly between a fast moving phase and a slow moving phase. When in the slow moving phase, the particle can be captured by the trap. To account for the possibility that the particle avoids the trap, an absorbing boundary is placed at the end of the track. Two local signaling mechanisms-intended to improve the chances of capturing the target-are considered by allowing the trap to affect the tug-of-war parameters within a small region around itself. The first is based on a localized adenosine triphosphate (ATP) concentration gradient surrounding a synapse, and the second is based on a concentration of tau-a microtubule-associated protein involved in Alzheimer\\'s disease-coating the microtubule near the synapse. It is shown that both mechanisms can lead to dramatic improvements in the capture probability, with a minimal increase in the mean capture time. The analysis also shows that tau can cause a cargo to undergo random oscillations, which could explain some experimental observations. © 2010 IOP Publishing Ltd.

  2. Estrogen enhanced cell-cell signalling in breast cancer cells exposed to targeted irradiation

    International Nuclear Information System (INIS)

    Shao, Chunlin; Folkard, Melvyn; Held, Kathryn D; Prise, Kevin M

    2008-01-01

    Radiation-induced bystander responses, where cells respond to their neighbours being irradiated are being extensively studied. Although evidence shows that bystander responses can be induced in many types of cells, it is not known whether there is a radiation-induced bystander effect in breast cancer cells, where the radiosensitivity may be dependent on the role of the cellular estrogen receptor (ER). This study investigated radiation-induced bystander responses in estrogen receptor-positive MCF-7 and estrogen receptor-negative MDA-MB-231 breast cancer cells. The influence of estrogen and anti-estrogen treatments on the bystander response was determined by individually irradiating a fraction of cells within the population with a precise number of helium-3 using a charged particle microbeam. Damage was scored as chromosomal damage measured as micronucleus formation. A bystander response measured as increased yield of micronucleated cells was triggered in both MCF-7 and MDA-MB-231 cells. The contribution of the bystander response to total cell damage in MCF-7 cells was higher than that in MDA-MB-231 cells although the radiosensitivity of MDA-MB-231 was higher than MCF-7. Treatment of cells with 17β-estradiol (E2) increased the radiosensitivity and the bystander response in MCF-7 cells, and the effect was diminished by anti-estrogen tamoxifen (TAM). E2 also increased the level of intracellular reactive oxygen species (ROS) in MCF-7 cells in the absence of radiation. In contrast, E2 and TAM had no influence on the bystander response and ROS levels in MDA-MB-231 cells. Moreover, the treatment of MCF-7 cells with antioxidants eliminated both the E2-induced ROS increase and E2-enhanced bystander response triggered by the microbeam irradiation, which indicates that ROS are involved in the E2-enhanced bystander micronuclei formation after microbeam irradiation. The observation of bystander responses in breast tumour cells may offer new potential targets for radiation

  3. Signal enhancement in amperometric peroxide detection by using graphene materials with low number of defects

    International Nuclear Information System (INIS)

    Zöpfl, Alexander; Matysik, Frank-Michael; Hirsch, Thomas; Sisakthi, Masoumeh; Eroms, Jonathan; Strunk, Christoph

    2016-01-01

    Two-dimensional carbon nanomaterials ranging from single-layer graphene to defective structures such as chemically reduced graphene oxide were studied with respect to their use in electrodes and sensors. Their electrochemical properties and utility in terms of fabrication of sensing devices are compared. Specifically, the electrodes have been applied to reductive amperometric determination of hydrogen peroxide. Low-defect graphene (SG) was obtained through mechanical exfoliation of natural graphite, while higher-defect graphenes were produced by chemical vapor deposition (CVDG) and by chemical oxidation of graphite and subsequent reduction (rGO). The carbonaceous materials were mainly characterized by Raman microscopy. They were applied as electrode material and the electrochemical behavior was investigated by chronocoulometry, cyclic voltammetry, electrochemical impedance spectroscopy and amperometry and compared to a carbon disc electrode. It is shown that the quality of the graphene has an enormous impact on the amperometric performance. The use of carbon materials with many defects (like rGO) does not result in a significant improvement in signal compared to a plain carbon disc electrode. The sensitivity is 173 mA · M −1  · cm −2 in case of using CVDG which is about 50 times better than that of a plain carbon disc electrode and about 7 times better than that of rGO. The limit of detection for hydrogen peroxide is 15.1 μM (at a working potential of −0.3 V vs SCE) for CVDG. It is concluded that the application of two-dimensional carbon nanomaterials offers large perspectives in amperometric detection systems due to electrocatalytic effects that result in highly sensitive detection. (author)

  4. Multiuser receiver for DS-CDMA signals in multipath channels: an enhanced multisurface method.

    Science.gov (United States)

    Mahendra, Chetan; Puthusserypady, Sadasivan

    2006-11-01

    This paper deals with the problem of multiuser detection in direct-sequence code-division multiple-access (DS-CDMA) systems in multipath environments. The existing multiuser detectors can be divided into two categories: (1) low-complexity poor-performance linear detectors and (2) high-complexity good-performance nonlinear detectors. In particular, in channels where the orthogonality of the code sequences is destroyed by multipath, detectors with linear complexity perform much worse than the nonlinear detectors. In this paper, we propose an enhanced multisurface method (EMSM) for multiuser detection in multipath channels. EMSM is an intermediate piecewise linear detection scheme with a run-time complexity linear in the number of users. Its bit error rate performance is compared with existing linear detectors, a nonlinear radial basis function detector trained by the new support vector learning algorithm, and Verdu's optimal detector. Simulations in multipath channels, for both synchronous and asynchronous cases, indicate that it always outperforms all other linear detectors, performing nearly as well as nonlinear detectors.

  5. Basal forebrain motivational salience signal enhances cortical processing and decision speed

    Directory of Open Access Journals (Sweden)

    Sylvina M Raver

    2015-10-01

    Full Text Available The basal forebrain (BF contains major projections to the cerebral cortex, and plays a well-documented role in arousal, attention, decision-making, and in modulating cortical activity. BF neuronal degeneration is an early event in Alzheimer’s disease and dementias, and occurs in normal cognitive aging. While the BF is best known for its population of cortically projecting cholinergic neurons, the region is anatomically and neurochemically diverse, and also contains prominent populations of non-cholinergic projection neurons. In recent years, increasing attention has been dedicated to these non-cholinergic BF neurons in order to better understand how non-cholinergic BF circuits control cortical processing and behavioral performance. In this review, we focus on a unique population of putative non-cholinergic BF neurons that encodes the motivational salience of stimuli with a robust ensemble bursting response. We review recent studies that describe the specific physiological and functional characteristics of these BF salience-encoding neurons in behaving animals. These studies support the unifying hypothesis whereby BF salience-encoding neurons act as a gain modulation mechanism of the decision-making process to enhance cortical processing of behaviorally relevant stimuli, and thereby facilitate faster and more precise behavioral responses. This function of BF salience-encoding neurons represents a critical component in determining which incoming stimuli warrant an animal’s attention, and is therefore a fundamental and early requirement of behavioral flexibility.

  6. Apigenin enhances the antitumor effects of cetuximab in nasopharyngeal carcinoma by inhibiting EGFR signaling.

    Science.gov (United States)

    Hu, Wen-Jian; Liu, Jing; Zhong, Lun-Kun; Wang, Jian

    2018-06-01

    Nasopharyngeal carcinoma (NPC) is a type of head and neck cancers with poor prognosis. Despite that platinum-based chemotherapy concurrent with radiotherapy have made great achievements for the treatment of NPC, the therapeutic reaction and toxicity varies dramatically among individuals. Apigenin (API), a naturally occurring plant flavone, is considered to have anti-cancer effect. Cetuximab (CET), a well known epidermal growth factor receptor (EGFR) inhibitor, is widely used in various cancers, especially head and neck cancers. The aim of our study was to measure the combination of API and CET for the treatment of NPC in vitro and in vivo. Results demonstrated that combining API and CET could better suppress the viability of the human nasopharyngeal carcinoma cell lines (HONE1 and CNE2) and inhibit the growth of NPC than API or CET used alone. Besides, the combination of API with CET produced greater pro-apoptosis effect. Moreover, the increased G2/M phase arrest caused by CET could be remarkably enhanced by adding API in HONE1 and CNE2 cells. Although, both API and CET could decrease the expressions of p-EGFR, p-Akt, p-STAT3 and Cyclin D1. Combining them produced greater inhibition effect. These results suggested that the combination of API and CET may be a promising therapeutic approach for the treatment of NPC. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  7. Cyproterone acetate enhances TRAIL-induced androgen-independent prostate cancer cell apoptosis via up-regulation of death receptor 5.

    Science.gov (United States)

    Chen, Linjie; Wolff, Dennis W; Xie, Yan; Lin, Ming-Fong; Tu, Yaping

    2017-03-07

    Virtually all prostate cancer deaths occur due to obtaining the castration-resistant phenotype after prostate cancer cells escaped from apoptosis and/or growth suppression initially induced by androgen receptor blockade. TNF-related apoptosis-inducing ligand (TRAIL) was an attractive cancer therapeutic agent due to its minimal toxicity to normal cells and remarkable apoptotic activity in tumor cells. However, most localized cancers including prostate cancer are resistant to TRAIL-induced apoptosis, thereby creating a therapeutic challenge of inducing TRAIL sensitivity in cancer cells. Herein the effects of cyproterone acetate, an antiandrogen steroid, on the TRAIL-induced apoptosis of androgen receptor-negative prostate cancer cells are reported. Cell apoptosis was assessed by both annexin V/propidium iodide labeling and poly (ADP-ribose) polymerase cleavage assays. Gene and protein expression changes were determined by quantitative real-time PCR and western blot assays. The effect of cyproterone acetate on gene promoter activity was determined by luciferase reporter assay. Cyproterone acetate but not AR antagonist bicalutamide dramatically increased the susceptibility of androgen receptor-negative human prostate cancer PC-3 and DU145 cells to TRAIL-induced apoptosis but no effects on immortalized human prostate stromal PS30 cells and human embryonic kidney HEK293 cells. Further investigation of the TRAIL-induced apoptosis pathway revealed that cyproterone acetate exerted its effect by selectively increasing death receptor 5 (DR5) mRNA and protein expression. Cyproterone acetate treatment also increased DR5 gene promoter activity, which could be abolished by mutation of a consensus binding domain of transcription factor CCAAT-enhancer-binding protein homologous protein (CHOP) in the DR5 gene promoter. Cyproterone acetate increases CHOP expression in a concentration and time-dependent manner and endoplasmic reticulum stress reducer 4-phenylbutyrate could block

  8. Enhanced leptin sensitivity and improved glucose homeostasis in mice lacking suppressor of cytokine signaling-3 in POMC-expressing cells.

    Science.gov (United States)

    Kievit, Paul; Howard, Jane K; Badman, Michael K; Balthasar, Nina; Coppari, Roberto; Mori, Hiroyuki; Lee, Charlotte E; Elmquist, Joel K; Yoshimura, Akihiko; Flier, Jeffrey S

    2006-08-01

    Suppressor of cytokine signaling-3 (Socs-3) negatively regulates the action of various cytokines, as well as the metabolic hormones leptin and insulin. Mice with haploinsufficiency of Socs-3, or those with neuronal deletion of Socs-3, are lean and more leptin and insulin sensitive. To examine the role of Socs-3 within specific neurons critical to energy balance, we created mice with selective deletion of Socs-3 within pro-opiomelanocortin (POMC)-expressing cells. These mice had enhanced leptin sensitivity, measured by weight loss and food intake after leptin infusion. On chow diet, glucose homeostasis was improved despite normal weight gain. On a high-fat diet, the rate of weight gain was reduced, due to increased energy expenditure rather than decreased food intake; glucose homeostasis and insulin sensitivity were substantially improved. These studies demonstrate that Socs-3 within POMC neurons regulates leptin sensitivity and glucose homeostasis, and plays a key role in linking high-fat diet to disordered metabolism.

  9. Stromal Adipocyte Enhancer-binding Protein (AEBP1) Promotes Mammary Epithelial Cell Hyperplasia via Proinflammatory and Hedgehog Signaling*

    Science.gov (United States)

    Holloway, Ryan W.; Bogachev, Oleg; Bharadwaj, Alamelu G.; McCluskey, Greg D.; Majdalawieh, Amin F.; Zhang, Lei; Ro, Hyo-Sung

    2012-01-01

    Disruption of mammary stromal-epithelial communication leads to aberrant mammary gland development and induces mammary tumorigenesis. Macrophages have been implicated in carcinogenesis primarily by creating an inflammatory microenvironment, which promotes growth of the adjacent epithelial cells. Adipocyte enhancer-binding protein 1 (AEBP1), a novel proinflammatory mediator, promotes macrophage inflammatory responsiveness by inducing NF-κB activity, which has been implicated in tumor cell growth and survival by aberrant sonic hedgehog (Shh) expression. Here, we show that stromal macrophage AEBP1 overexpression results in precocious alveologenesis in the virgin AEBP1 transgenic (AEBP1TG) mice, and the onset of ductal hyperplasia was accelerated in AEBP1TG mice fed a high fat diet, which induces endogenous AEBP1 expression. Transplantation of AEBP1TG bone marrow cells into non-transgenic (AEBP1NT) mice resulted in alveolar hyperplasia with up-regulation of NF-κB activity and TNFα expression as displayed in the AEBP1TG mammary macrophages and epithelium. Shh expression was induced in AEBP1TG macrophages and RAW264.7 macrophages overexpressing AEBP1. The Shh target genes Gli1 and Bmi1 expression was induced in the AEBP1TG mammary epithelium and HC11 mammary epithelial cells co-cultured with AEBP1TG peritoneal macrophages. The conditioned AEBP1TG macrophage culture media promoted NF-κB activity and survival signal, Akt activation, in HC11 cells, whereas such effects were abolished by TNFα neutralizing antibody treatment. Furthermore, HC11 cells displayed enhanced proliferation in response to AEBP1TG macrophages and their conditioned media. Our findings highlight the role of AEBP1 in the signaling pathways regulating the cross-talk between mammary epithelium and stroma that could predispose the mammary tissue to tumorigenesis. PMID:22995915

  10. Stromal adipocyte enhancer-binding protein (AEBP1) promotes mammary epithelial cell hyperplasia via proinflammatory and hedgehog signaling.

    Science.gov (United States)

    Holloway, Ryan W; Bogachev, Oleg; Bharadwaj, Alamelu G; McCluskey, Greg D; Majdalawieh, Amin F; Zhang, Lei; Ro, Hyo-Sung

    2012-11-09

    Disruption of mammary stromal-epithelial communication leads to aberrant mammary gland development and induces mammary tumorigenesis. Macrophages have been implicated in carcinogenesis primarily by creating an inflammatory microenvironment, which promotes growth of the adjacent epithelial cells. Adipocyte enhancer-binding protein 1 (AEBP1), a novel proinflammatory mediator, promotes macrophage inflammatory responsiveness by inducing NF-κB activity, which has been implicated in tumor cell growth and survival by aberrant sonic hedgehog (Shh) expression. Here, we show that stromal macrophage AEBP1 overexpression results in precocious alveologenesis in the virgin AEBP1 transgenic (AEBP1(TG)) mice, and the onset of ductal hyperplasia was accelerated in AEBP1(TG) mice fed a high fat diet, which induces endogenous AEBP1 expression. Transplantation of AEBP1(TG) bone marrow cells into non-transgenic (AEBP1(NT)) mice resulted in alveolar hyperplasia with up-regulation of NF-κB activity and TNFα expression as displayed in the AEBP1(TG) mammary macrophages and epithelium. Shh expression was induced in AEBP1(TG) macrophages and RAW264.7 macrophages overexpressing AEBP1. The Shh target genes Gli1 and Bmi1 expression was induced in the AEBP1(TG) mammary epithelium and HC11 mammary epithelial cells co-cultured with AEBP1(TG) peritoneal macrophages. The conditioned AEBP1(TG) macrophage culture media promoted NF-κB activity and survival signal, Akt activation, in HC11 cells, whereas such effects were abolished by TNFα neutralizing antibody treatment. Furthermore, HC11 cells displayed enhanced proliferation in response to AEBP1(TG) macrophages and their conditioned media. Our findings highlight the role of AEBP1 in the signaling pathways regulating the cross-talk between mammary epithelium and stroma that could predispose the mammary tissue to tumorigenesis.

  11. TRIM24 promotes glioma progression and enhances chemoresistance through activation of the PI3K/Akt signaling pathway.

    Science.gov (United States)

    Zhang, L-H; Yin, A-A; Cheng, J-X; Huang, H-Y; Li, X-M; Zhang, Y-Q; Han, N; Zhang, X

    2015-01-29

    The tripartite motif protein TRIM24 (tripartite motif-containing 24) has been found to play distinct roles in tumor development and progression, according to different tumor contexts. However, it remains elusive whether TRIM24 plays a role in malignant gliomas that are the most common and deadly primary brain tumors in adults. We report here that TRIM24 expression is positively correlated with glioma malignancy and is negatively associated with prognosis of patients with newly diagnosed glioblastoma, which is the most malignant form of gliomas but displays highly heterogeneous clinical outcome. The multivariate Cox regression analysis demonstrates the independent predictive value of TRIM24 expression level for overall and progression-free survival. Knockdown of TRIM24 suppresses cell proliferation, cell cycle progression, clone formation and in vivo tumor development, whereas overexpression of TRIM24 promotes cell growth. Chromatin immunoprecipitation, real-time reverse transcription-PCR and mutation analyses demonstrate that TRIM24 binds to the PIK3CA promoter via its PHD-Bromo domain to activate the transcription of PIK3CA gene, thus enhancing phosphatidylinositide 3-kinase (PI3K)/Akt signaling. The pan-PI3K inhibitor LY294002 and small interfering RNA targeting PIK3CA both abrogate the growth-promoting effect of TRIM24. Moreover, TRIM24 regulates the expression of DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) through PI3K/Akt/nuclear factor-κB signaling transduction and enhances resistance to temozolomide, the standard chemotherapeutic agent for glioblastoma. Finally, glioblastoma patients with low TRIM24 expression benefit from chemotherapy, whereas those with high TRIM24 expression do not have such benefit. Our results suggest that TRIM24 might serve as a potential prognostic marker and therapeutic target for the management of malignant gliomas.

  12. Repeated homotypic stress elevates 2-arachidonoylglycerol levels and enhances short-term endocannabinoid signaling at inhibitory synapses in basolateral amygdala.

    Science.gov (United States)

    Patel, Sachin; Kingsley, Philip J; Mackie, Ken; Marnett, Lawrence J; Winder, Danny G

    2009-12-01

    Psychosocial stress is a risk factor for development and exacerbation of neuropsychiatric illness. Repeated stress causes biochemical adaptations in endocannabinoid (eCB) signaling that contribute to stress-response habituation, however, the synaptic correlates of these adaptations have not been examined. Here, we show that the synthetic enzyme for the eCB 2-arachidonoylglycerol (2-AG), diacylglycerol (DAG) lipase alpha, is heterogeneously expressed in the amygdala, and that levels of 2-AG and precursor DAGs are increased in the basolateral amygdala (BLA) after 10 days, but not 1 day, of restraint stress. In contrast, arachidonic acid was decreased after both 1 and 10 days of restraint stress. To examine the synaptic correlates of these alterations in 2-AG metabolism, we used whole-cell electrophysiology to determine the effects of restraint stress on depolarization-induced suppression of inhibition (DSI) in the BLA. A single restraint stress exposure did not alter DSI compared with control mice. However, after 10 days of restraint stress, DSI duration, but not magnitude, was significantly prolonged. Inhibition of 2-AG degradation with MAFP also prolonged DSI duration; the effects of repeated restraint stress and MAFP were mutually occlusive. These data indicate that exposure to repeated, but not acute, stress produces neuroadaptations that confer BLA neurons with an enhanced capacity to elevate 2-AG content and engage in 2-AG-mediated short-term retrograde synaptic signaling. We suggest stress-induced enhancement of eCB-mediated suppression of inhibitory transmission in the BLA could contribute to affective dysregulation associated with chronic stress.

  13. Coconut oil protects cortical neurons from amyloid beta toxicity by enhancing signaling of cell survival pathways.

    Science.gov (United States)

    Nafar, F; Clarke, J P; Mearow, K M

    2017-05-01

    Alzheimer's disease is a progressive neurodegenerative disease that has links with other conditions that can often be modified by dietary and life-style interventions. In particular, coconut oil has received attention as having potentially having benefits in lessening the cognitive deficits associated with Alzheimer's disease. In a recent report, we showed that neuron survival in cultures co-treated with coconut oil and Aβ was rescued compared to cultures exposed only to Aβ. Here we investigated treatment with Aβ for 1, 6 or 24 h followed by addition of coconut oil for a further 24 h, or treatment with coconut oil for 24 h followed by Aβ exposure for various periods. Neuronal survival and several cellular parameters (cleaved caspase 3, synaptophysin labeling and ROS) were assessed. In addition, the influence of these treatments on relevant signaling pathways was investigated with Western blotting. In terms of the treatment timing, our data indicated that coconut oil rescues cells pre-exposed to Aβ for 1 or 6 h, but is less effective when the pre-exposure has been 24 h. However, pretreatment with coconut oil prior to Aβ exposure showed the best outcomes. Treatment with octanoic or lauric acid also provided protection against Aβ, but was not as effective as the complete oil. The coconut oil treatment reduced the number of cells with cleaved caspase and ROS labeling, as well as rescuing the loss of synaptophysin labeling observed with Aβ treatment. Treatment with coconut oil, as well as octanoic, decanoic and lauric acids, resulted in a modest increase in ketone bodies compared to controls. The biochemical data suggest that Akt and ERK activation may contribute to the survival promoting influence of coconut oil. This was supported by observations that a PI3-Kinase inhibitor blocked the rescue effect of CoOil on Aβ amyloid toxicity. Further studies into the mechanisms of action of coconut oil and its constituent medium chain fatty acids are warranted

  14. Porcine circovirus-2 capsid protein induces cell death in PK15 cells

    Energy Technology Data Exchange (ETDEWEB)

    Walia, Rupali; Dardari, Rkia, E-mail: rdardari@ucalgary.ca; Chaiyakul, Mark; Czub, Markus

    2014-11-15

    Studies have shown that Porcine circovirus (PCV)-2 induces apoptosis in PK15 cells. Here we report that cell death is induced in PCV2b-infected PK15 cells that express Capsid (Cap) protein and this effect is enhanced in interferon gamma (IFN-γ)-treated cells. We further show that transient PCV2a and 2b-Cap protein expression induces cell death in PK15 cells at rate similar to PCV2 infection, regardless of Cap protein localization. These data suggest that Cap protein may have the capacity to trigger different signaling pathways involved in cell death. Although further investigation is needed to gain deeper insights into the nature of the pathways involved in Cap-induced cell death, this study provides evidence that PCV2-induced cell death in kidney epithelial PK15 cells can be mapped to the Cap protein and establishes the need for future research regarding the role of Cap-induced cell death in PCV2 pathogenesis. - Highlights: • IFN-γ enhances PCV2 replication that leads to cell death in PK15 cells. • IFN-γ enhances nuclear localization of the PCV2 Capsid protein. • Transient PCV2a and 2b-Capsid protein expression induces cell death. • Cell death is not dictated by specific Capsid protein sub-localization.

  15. Signal enhancement in collinear double-pulse laser-induced breakdown spectroscopy applied to different soils

    Energy Technology Data Exchange (ETDEWEB)

    Nicolodelli, Gustavo, E-mail: gunicolodelli@hotmail.com [Embrapa Instrumentation, Rua XV de Novembro, 1452, CEP 13560-970 São Carlos, SP (Brazil); Senesi, Giorgio Saverio, E-mail: giorgio.senesi@imip.cnr.it [Institute of Inorganic Methodologies and Plasmas, CNR, Bari, 70126 Bari (Italy); Romano, Renan Arnon, E-mail: renan.romano@gmail.com [Embrapa Instrumentation, Rua XV de Novembro, 1452, CEP 13560-970 São Carlos, SP (Brazil); Physics Institute of São Carlos, University of São Paulo, IFSC-USP, Av. Trabalhador são-carlense, 400 Pq. Arnold Schimid, 13566-590 São Carlos, SP (Brazil); Oliveira Perazzoli, Ivan Luiz de, E-mail: ivanperazzoli@hotmail.com [Embrapa Instrumentation, Rua XV de Novembro, 1452, CEP 13560-970 São Carlos, SP (Brazil); Milori, Débora Marcondes Bastos Pereira, E-mail: debora.milori@embrapa.br [Embrapa Instrumentation, Rua XV de Novembro, 1452, CEP 13560-970 São Carlos, SP (Brazil)

    2015-09-01

    Laser-induced breakdown spectroscopy (LIBS) is a well-known consolidated analytical technique employed successfully for the qualitative and quantitative analysis of solid, liquid, gaseous and aerosol samples of very different nature and origin. Several techniques, such as dual-pulse excitation setup, have been used in order to improve LIBS's sensitivity. The purpose of this paper was to optimize the key parameters as excitation wavelength, delay time and interpulse, that influence the double pulse (DP) LIBS technique in the collinear beam geometry when applied to the analysis at atmospheric air pressure of soil samples of different origin and texture from extreme regions of Brazil. Additionally, a comparative study between conventional single pulse (SP) LIBS and DP LIBS was performed. An optimization of DP LIBS system, choosing the correct delay time between the two pulses, was performed allowing its use for different soil types and the use of different emission lines. In general, the collinear DP LIBS system improved the analytical performances of the technique by enhancing the intensity of emission lines of some elements up to about 5 times, when compared with conventional SP-LIBS, and reduced the continuum emission. Further, the IR laser provided the best performance in re-heating the plasma. - Highlights: • The correct choice of the delay time between the two pulses is crucial for the DP system. • An optimization of DP LIBS system was performed allowing its use for different soil and the use of different emission lines. • The DP LIBS system improved the analytical performances of the technique up to about 5 times, when compared with SP LIBS. • The IR laser provided the best performance in re-heating the plasma.

  16. A TOTP-Based Enhanced Route Optimization Procedure for Mobile IPv6 to Reduce Handover Delay and Signalling Overhead

    Science.gov (United States)

    Shah, Peer Azmat; Hasbullah, Halabi B.; Lawal, Ibrahim A.; Aminu Mu'azu, Abubakar; Tang Jung, Low

    2014-01-01

    Due to the proliferation of handheld mobile devices, multimedia applications like Voice over IP (VoIP), video conferencing, network music, and online gaming are gaining popularity in recent years. These applications are well known to be delay sensitive and resource demanding. The mobility of mobile devices, running these applications, across different networks causes delay and service disruption. Mobile IPv6 was proposed to provide mobility support to IPv6-based mobile nodes for continuous communication when they roam across different networks. However, the Route Optimization procedure in Mobile IPv6 involves the verification of mobile node's reachability at the home address and at the care-of address (home test and care-of test) that results in higher handover delays and signalling overhead. This paper presents an enhanced procedure, time-based one-time password Route Optimization (TOTP-RO), for Mobile IPv6 Route Optimization that uses the concepts of shared secret Token, time based one-time password (TOTP) along with verification of the mobile node via direct communication and maintaining the status of correspondent node's compatibility. The TOTP-RO was implemented in network simulator (NS-2) and an analytical analysis was also made. Analysis showed that TOTP-RO has lower handover delays, packet loss, and signalling overhead with an increased level of security as compared to the standard Mobile IPv6's Return-Routability-based Route Optimization (RR-RO). PMID:24688398

  17. A TOTP-Based Enhanced Route Optimization Procedure for Mobile IPv6 to Reduce Handover Delay and Signalling Overhead

    Directory of Open Access Journals (Sweden)

    Peer Azmat Shah

    2014-01-01

    Full Text Available Due to the proliferation of handheld mobile devices, multimedia applications like Voice over IP (VoIP, video conferencing, network music, and online gaming are gaining popularity in recent years. These applications are well known to be delay sensitive and resource demanding. The mobility of mobile devices, running these applications, across different networks causes delay and service disruption. Mobile IPv6 was proposed to provide mobility support to IPv6-based mobile nodes for continuous communication when they roam across different networks. However, the Route Optimization procedure in Mobile IPv6 involves the verification of mobile node’s reachability at the home address and at the care-of address (home test and care-of test that results in higher handover delays and signalling overhead. This paper presents an enhanced procedure, time-based one-time password Route Optimization (TOTP-RO, for Mobile IPv6 Route Optimization that uses the concepts of shared secret Token, time based one-time password (TOTP along with verification of the mobile node via direct communication and maintaining the status of correspondent node’s compatibility. The TOTP-RO was implemented in network simulator (NS-2 and an analytical analysis was also made. Analysis showed that TOTP-RO has lower handover delays, packet loss, and signalling overhead with an increased level of security as compared to the standard Mobile IPv6’s Return-Routability-based Route Optimization (RR-RO.

  18. Thiazolidinediones enhance sodium-coupled bicarbonate absorption from renal proximal tubules via PPARγ-dependent nongenomic signaling.

    Science.gov (United States)

    Endo, Yoko; Suzuki, Masashi; Yamada, Hideomi; Horita, Shoko; Kunimi, Motoei; Yamazaki, Osamu; Shirai, Ayumi; Nakamura, Motonobu; Iso-O, Naoyuki; Li, Yuehong; Hara, Masumi; Tsukamoto, Kazuhisa; Moriyama, Nobuo; Kudo, Akihiko; Kawakami, Hayato; Yamauchi, Toshimasa; Kubota, Naoto; Kadowaki, Takashi; Kume, Haruki; Enomoto, Yutaka; Homma, Yukio; Seki, George; Fujita, Toshiro

    2011-05-04

    Thiazolidinediones (TZDs) improve insulin resistance by activating a nuclear hormone receptor, peroxisome proliferator-activated receptor γ (PPARγ). However, the use of TZDs is associated with plasma volume expansion through a mechanism that remains to be clarified. Here we showed that TZDs rapidly stimulate sodium-coupled bicarbonate absorption from the renal proximal tubule in vitro and in vivo. TZD-induced transport stimulation is dependent on PPARγ-Src-EGFR-ERK and observed in rat, rabbit and human, but not in mouse proximal tubules where Src-EGFR is constitutively activated. The existence of PPARγ-Src-dependent nongenomic signaling, which requires the ligand-binding ability, but not the transcriptional activity of PPARγ, is confirmed in mouse embryonic fibroblast cells. The enhancement of the association between PPARγ and Src by TZDs supports an indispensable role of Src in this signaling. These results suggest that the PPARγ-dependent nongenomic stimulation of renal proximal transport is also involved in TZD-induced volume expansion. Copyright © 2011 Elsevier Inc. All rights reserved.

  19. A TOTP-based enhanced route optimization procedure for mobile IPv6 to reduce handover delay and signalling overhead.

    Science.gov (United States)

    Shah, Peer Azmat; Hasbullah, Halabi B; Lawal, Ibrahim A; Aminu Mu'azu, Abubakar; Tang Jung, Low

    2014-01-01

    Due to the proliferation of handheld mobile devices, multimedia applications like Voice over IP (VoIP), video conferencing, network music, and online gaming are gaining popularity in recent years. These applications are well known to be delay sensitive and resource demanding. The mobility of mobile devices, running these applications, across different networks causes delay and service disruption. Mobile IPv6 was proposed to provide mobility support to IPv6-based mobile nodes for continuous communication when they roam across different networks. However, the Route Optimization procedure in Mobile IPv6 involves the verification of mobile node's reachability at the home address and at the care-of address (home test and care-of test) that results in higher handover delays and signalling overhead. This paper presents an enhanced procedure, time-based one-time password Route Optimization (TOTP-RO), for Mobile IPv6 Route Optimization that uses the concepts of shared secret Token, time based one-time password (TOTP) along with verification of the mobile node via direct communication and maintaining the status of correspondent node's compatibility. The TOTP-RO was implemented in network simulator (NS-2) and an analytical analysis was also made. Analysis showed that TOTP-RO has lower handover delays, packet loss, and signalling overhead with an increased level of security as compared to the standard Mobile IPv6's Return-Routability-based Route Optimization (RR-RO).

  20. Hyaluronic acid enhances proliferation of human amniotic mesenchymal stem cells through activation of Wnt/β-catenin signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Ru-Ming; Sun, Ren-Gang; Zhang, Ling-Tao; Zhang, Qing-Fang; Chen, Dai-Xiong [Guizhou Center for Translational Medicine, Affiliated Hospital of Zunyi Medical University, 149 Dalian Road, Zunyi 563000 (China); Zhong, Jian-Jiang, E-mail: jjzhong@sjtu.edu.cn [State Key Laboratory of Microbial Metabolism, and School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai 200240 (China); Xiao, Jian-Hui, E-mail: jhxiao@yahoo.com [Guizhou Center for Translational Medicine, Affiliated Hospital of Zunyi Medical University, 149 Dalian Road, Zunyi 563000 (China)

    2016-07-15

    This study investigated the pro-proliferative effect of hyaluronic acid (HA) on human amniotic mesenchymal stem cells (hAMSCs) and the underlying mechanisms. Treatment with HA increased cell population growth in a dose- and time-dependent manner. Analyses by flow cytometry and immunocytochemistry revealed that HA did not change the cytophenotypes of hAMSCs. Additionally, the osteogenic, chondrogenic, and adipogenic differentiation capabilities of these hAMSCs were retained after HA treatment. Moreover, HA increased the mRNA expressions of wnt1, wnt3a, wnt8a, cyclin D1, Ki-67, and β-catenin as well as the protein level of β-catenin and cyclin D1 in hAMSCs; and the nuclear localization of β-catenin was also enhanced. Furthermore, the pro-proliferative effect of HA and up-regulated expression of Wnt/β-catenin pathway-associated proteins - wnt3a, β-catenin and cyclin D1 in hAMSCs were significantly inhibited upon pre-treatment with Wnt-C59, an inhibitor of the Wnt/β-catenin pathway. These results suggest that HA may positively regulate hAMSCs proliferation through regulation of the Wnt/β-catenin signaling pathway. - Highlights: • Hyaluronic acid (HA) could promote the proliferation of hAMSCs. • HA treatment dose not affect the pluripotency of hAMSCs. • HA increases hAMSCs proliferation through activation of Wnt/β-catenin signaling.

  1. Improving the arterial input function in dynamic contrast enhanced MRI by fitting the signal in the complex plane.

    Science.gov (United States)

    Simonis, Frank F J; Sbrizzi, Alessandro; Beld, Ellis; Lagendijk, Jan J W; van den Berg, Cornelis A T

    2016-10-01

    Dynamic contrast enhanced (DCE) imaging is a widely used technique in oncologic imaging. An essential prerequisite for obtaining quantitative values from DCE-MRI is the determination of the arterial input function (AIF). However, it is very challenging to accurately estimate the AIF using MR. A comprehensive model, which uses complex data instead of either magnitude or phase, was developed to improve AIF estimation. The model was first applied to simulated data. Subsequently, the accuracy of the estimated contrast agent concentration was validated in a phantom. Finally the method was applied to existing DCE scans of 13 prostate cancer patients. The complex signal method combines the complementary strengths of the magnitude and phase method, increasing the precision and accuracy of concentration estimation in simulated and phantom data. The in vivo AIFs show a good agreement between arterial voxels (standard deviation in the peak and tail equal 0.4 mM and 0.12 mM, respectively). Furthermore, the dynamic behavior closely followed the AIF obtained with DCE-CT in the same patients (mean correlation coefficient: 0.92). By using the complex signal, the AIF estimation becomes more accurate and precise. This might enable patient specific AIFs, thereby improving the quantitative values obtained from DCE-MRI. Magn Reson Med 76:1236-1245, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

  2. Strategies for enhancing adoptive T-cell immunotherapy against solid tumors using engineered cytokine signaling and other modalities.

    Science.gov (United States)

    Shum, Thomas; Kruse, Robert L; Rooney, Cliona M

    2018-05-04

    Cancer therapy has been transformed by the demonstration that tumor-specific T-cells can eliminate tumor cells in a clinical setting with minimal long-term toxicity. However, significant success in the treatment of leukemia and lymphoma with T-cells using native receptors or redirected with chimeric antigen receptors (CARs) has not been recapitulated in the treatment of solid tumors. This lack of success is likely related to the paucity of costimulatory and cytokine signaling available in solid tumors, in addition to a range of inhibitory mechanisms. Areas covered: We summarize the latest developments in engineered T-cell immunotherapy, describe the limitations of these approaches in treating solid tumors, and finally highlight several strategies that may be useful in mediating solid tumor responses in the future, while also ensuring safety of engineered cells. Expert opinion: CAR-T therapies require further engineering to achieve their potential against solid tumors. Facilitating cytokine signaling in CAR T-cells appears to be essential in achieving better responses. However, the engineering of T-cells with potentially unchecked proliferation and potency raises the question of whether the simultaneous combination of enhancements will prove safe, necessitating continued advancements in regulating CAR-T activity at the tumor site and methods to safely switch off these engineered cells.

  3. Lack of T-cell receptor-induced signaling is crucial for CD95 ligand up-regulation and protects cutaneous T-cell lymphoma cells from activation-induced cell death.

    Science.gov (United States)

    Klemke, Claus-Detlev; Brenner, Dirk; Weiss, Eva-Maria; Schmidt, Marc; Leverkus, Martin; Gülow, Karsten; Krammer, Peter H

    2009-05-15

    Restimulation of previously activated T cells via the T-cell receptor (TCR) leads to activation-induced cell death (AICD), which is, at least in part, dependent on the death receptor CD95 (APO-1, FAS) and its natural ligand (CD95L). Here, we characterize cutaneous T-cell lymphoma (CTCL) cells (CTCL tumor cell lines and primary CTCL tumor cells from CTCL patients) as AICD resistant. We show that CTCL cells have elevated levels of the CD95-inhibitory protein cFLIP. However, cFLIP is not responsible for CTCL AICD resistance. Instead, our data suggest that reduced TCR-proximal signaling in CTCL cells is responsible for the observed AICD resistance. CTCL cells exhibit no PLC-gamma1 activity, resulting in an impaired Ca(2+)release and reduced generation of reactive oxygen species upon TCR stimulation. Ca(2+) and ROS production are crucial for up-regulation of CD95L and reconstitution of both signals resulted in AICD sensitivity of CTCL cells. In accordance with these data, CTCL tumor cells from patients with Sézary syndrome do not up-regulate CD95L upon TCR-stimulation and are therefore resistant to AICD. These results show a novel mechanism of AICD resistance in CTCL that could have future therapeutic implications to overcome apoptosis resistance in CTCL patients.

  4. Enhanced Wnt signaling improves bone mass and strength, but not brittleness, in the Col1a1(+/mov13) mouse model of type I Osteogenesis Imperfecta.

    Science.gov (United States)

    Jacobsen, Christina M; Schwartz, Marissa A; Roberts, Heather J; Lim, Kyung-Eun; Spevak, Lyudmila; Boskey, Adele L; Zurakowski, David; Robling, Alexander G; Warman, Matthew L

    2016-09-01

    Osteogenesis Imperfecta (OI) comprises a group of genetic skeletal fragility disorders. The mildest form of OI, Osteogenesis Imperfecta type I, is frequently caused by haploinsufficiency mutations in COL1A1, the gene encoding the α1(I) chain of type 1 collagen. Children with OI type I have a 95-fold higher fracture rate compared to unaffected children. Therapies for OI type I in the pediatric population are limited to anti-catabolic agents. In adults with osteoporosis, anabolic therapies that enhance Wnt signaling in bone improve bone mass, and ongoing clinical trials are determining if these therapies also reduce fracture risk. We performed a proof-of-principle experiment in mice to determine whether enhancing Wnt signaling in bone could benefit children with OI type I. We crossed a mouse model of OI type I (Col1a1(+/Mov13)) with a high bone mass (HBM) mouse (Lrp5(+/p.A214V)) that has increased bone strength from enhanced Wnt signaling. Offspring that inherited the OI and HBM alleles had higher bone mass and strength than mice that inherited the OI allele alone. However, OI+HBM and OI mice still had bones with lower ductility compared to wild-type mice. We conclude that enhancing Wnt signaling does not make OI bone normal, but does improve bone properties that could reduce fracture risk. Therefore, agents that enhance Wnt signaling are likely to benefit children and adults with OI type 1. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Subversion of innate defenses by the interplay between DENV and pre-existing enhancing antibodies: TLRs signaling collapse.

    Directory of Open Access Journals (Sweden)

    Naphak Modhiran

    Full Text Available BACKGROUND: The phenomenon of antibody dependent enhancement as a major determinant that exacerbates disease severity in DENV infections is well accepted. While the detailed mechanism of antibody enhanced disease severity is unclear, evidence suggests that it is associated with both increased DENV infectivity and suppression of the type I IFN and pro-inflammatory cytokine responses. Therefore, it is imperative for us to understand the intracellular mechanisms altered during ADE infection to decipher the mechanism of severe pathogenesis. METHODOLOGY/PRINCIPAL FINDINGS: In this present work, qRT-PCR, immunoblotting and gene array analysis were conducted to determine whether DENV-antibody complex infection exerts a suppressive effect on the expression and/or function of the pathogen recognition patterns, focusing on the TLR-signaling pathway. We show here that FcγRI and FcγRIIa synergistically facilitated entry of DENV-antibody complexes into monocytic THP-1 cells. Ligation between DENV-antibody complexes and FcR not only down regulated TLRs gene expression but also up regulated SARM, TANK, and negative regulators of the NF-κB pathway, resulting in suppression of innate responses but increased viral production. These results were confirmed by blocking with anti-FcγRI or anti-FcγRIIa antibodies which reduced viral production, up-regulated IFN-β synthesis, and increased gene expression in the TLR-dependent signaling pathway. The negative impact of DENV-ADE infection on the TLR-dependent pathway was strongly supported by gene array screening which revealed that both MyD88-dependent and -independent signaling molecules were down regulated during DENV-ADE infection. Importantly, the same phenomenon was seen in PBMC of secondary DHF/DSS patients but not in PBMC of DF patients. CONCLUSIONS/SIGNIFICANCE: Our present work demonstrates the mechanism by which DENV uses pre-existing immune mediators to defeat the principal activating pathway of innate

  6. Dipalmitoleoylphosphoethanolamine as a PP2A enhancer obstructs insulin signaling by promoting Ser/Thr dephosphorylation of Akt.

    Science.gov (United States)

    Tsuchiya, Ayako; Kanno, Takeshi; Nishizaki, Tomoyuki

    2014-01-01

    The phospholipid phosphatidylethanolamine is implicated in the regulation of a variety of cellular processes. The present study investigated the effect of phosphatidylethanolamines such as 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine (DAPE), 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine (DLPE), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), and 1,2-dipalmitoleoyl-sn-glycero-3-phosphoethanolamine (DPPE) on protein phosphatases, Akt1/2 activity, GLUT4 mobilizations, and glucose uptake into cells. Activity of protein phosphatase 2A (PP2A) was assayed under the cell-free conditions, and Western blotting, intracellular GLUT4 trafficking, and glucose uptake into cells were monitored using differentiated 3T3-L1-GLUT4myc adipocytes. Of the investigated phosphatidylethanolamines, DLPE and DPPE significantly enhanced PP2A activity. DPPE inhibited insulin-induced phosphorylation of Akt1/2 at Thr308/309 and Ser473/474 in differentiated 3T3-L1-GLUT4myc adipocytes. DPPE also inhibited insulin-stimulated GLUT4 translocation to the cell surface and reduced insulin-stimulated glucose uptake into adipocytes. The results of the present study indicate that the PP2A enhancer DPPE obstructs insulin signaling by promoting serine/threonine dephosphorylation of Akt1/2, resulting in the suppression of GLUT4 translocation to the cell surface and glucose uptake into adipocytes. © 2014 S. Karger AG, Basel.

  7. Dipalmitoleoylphosphoethanolamine as a PP2A Enhancer Obstructs Insulin Signaling by Promoting Ser/Thr Dephosphorylation of Akt

    Directory of Open Access Journals (Sweden)

    Ayako Tsuchiya

    2014-08-01

    Full Text Available Background/Aims: The phospholipid phosphatidylethanolamine is implicated in the regulation of a variety of cellular processes. The present study investigated the effect of phosphatidylethanolamines such as 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine (DAPE, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine (DLPE, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE, and 1,2-dipalmitoleoyl-sn-glycero-3-phosphoethanolamine (DPPE on protein phosphatases, Akt1/2 activity, GLUT4 mobilizations, and glucose uptake into cells. Methods: Activity of protein phosphatase 2A (PP2A was assayed under the cell-free conditions, and Western blotting, intracellular GLUT4 trafficking, and glucose uptake into cells were monitored using differentiated 3T3-L1-GLUT4myc adipocytes. Results: Of the investigated phosphatidylethanolamines, DLPE and DPPE significantly enhanced PP2A activity. DPPE inhibited insulin-induced phosphorylation of Akt1/2 at Thr308/309 and Ser473/474 in differentiated 3T3-L1-GLUT4myc adipocytes. DPPE also inhibited insulin-stimulated GLUT4 translocation to the cell surface and reduced insulin-stimulated glucose uptake into adipocytes. Conclusion: The results of the present study indicate that the PP2A enhancer DPPE obstructs insulin signaling by promoting serine/threonine dephosphorylation of Akt1/2, resulting in the suppression of GLUT4 translocation to the cell surface and glucose uptake into adipocytes.

  8. Signal enhancement of neutral He emission lines by fast electron bombardment of laser-induced He plasma

    Directory of Open Access Journals (Sweden)

    Hery Suyanto

    2016-08-01

    Full Text Available A time-resolved spectroscopic study is performed on the enhancement signals of He gas plasma emission using nanosecond (ns and picosecond (ps lasers in an orthogonal configuration. The ns laser is used for the He gas plasma generation and the ps laser is employed for the ejection of fast electrons from a metal target, which serves to excite subsequently the He atoms in the plasma. The study is focused on the most dominant He I 587.6 nm and He I 667.8 nm emission lines suggested to be responsible for the He-assisted excitation (HAE mechanism. The time-dependent intensity enhancements induced by the fast electrons generated with a series of delayed ps laser ablations are deduced from the intensity time profiles of both He emission lines. The results clearly lead to the conclusion that the metastable excited triplet He atoms are actually the species overwhelmingly produced during the recombination process in the ns laser-induced He gas plasma. These metastable He atoms are believed to serve as the major energy source for the delayed excitation of analyte atoms in ns laser-induced breakdown spectroscopy (LIBS using He ambient gas.

  9. Proton detection for signal enhancement in solid-state NMR experiments on mobile species in membrane proteins

    Energy Technology Data Exchange (ETDEWEB)

    Ward, Meaghan E.; Ritz, Emily [University of Guelph, Department of Physics (Canada); Ahmed, Mumdooh A. M. [Suez University, The Department of Physics, Faculty of Science (Egypt); Bamm, Vladimir V.; Harauz, George [University of Guelph, Biophysics Interdepartmental Group (Canada); Brown, Leonid S.; Ladizhansky, Vladimir, E-mail: vladizha@uoguelph.ca [University of Guelph, Department of Physics (Canada)

    2015-12-15

    Direct proton detection is becoming an increasingly popular method for enhancing sensitivity in solid-state nuclear magnetic resonance spectroscopy. Generally, these experiments require extensive deuteration of the protein, fast magic angle spinning (MAS), or a combination of both. Here, we implement direct proton detection to selectively observe the mobile entities in fully-protonated membrane proteins at moderate MAS frequencies. We demonstrate this method on two proteins that exhibit different motional regimes. Myelin basic protein is an intrinsically-disordered, peripherally membrane-associated protein that is highly flexible, whereas Anabaena sensory rhodopsin is composed of seven rigid transmembrane α-helices connected by mobile loop regions. In both cases, we observe narrow proton linewidths and, on average, a 10× increase in sensitivity in 2D insensitive nuclear enhancement of polarization transfer-based HSQC experiments when proton detection is compared to carbon detection. We further show that our proton-detected experiments can be easily extended to three dimensions and used to build complete amino acid systems, including sidechain protons, and obtain inter-residue correlations. Additionally, we detect signals which do not correspond to amino acids, but rather to lipids and/or carbohydrates which interact strongly with membrane proteins.

  10. Signal enhancement of neutral He emission lines by fast electron bombardment of laser-induced He plasma

    Energy Technology Data Exchange (ETDEWEB)

    Suyanto, Hery [Department of Physics, Faculty of Mathematics and Natural Sciences, Udayana University, Kampus Bukit Jimbaran, Denpasar 80361, Bali (Indonesia); Pardede, Marincan [Department of Electrical Engineering, University of Pelita Harapan, 1100 M.H. Thamrin Boulevard, Lippo Village, Tangerang 15811 (Indonesia); Hedwig, Rinda [Department of Computer Engineering, Bina Nusantara University, 9 K.H. Syahdan, Jakarta 14810 (Indonesia); Marpaung, Alion Mangasi [Department of Physics, Faculty of Mathematics and Natural Sciences, Jakarta State University, Rawamangun, Jakarta 12440 (Indonesia); Ramli, Muliadi [Department of Chemistry, Faculty of Mathematics and Natural Sciences, Syiah Kuala University, Darussalam, Banda Aceh 23111, NAD (Indonesia); Lie, Tjung Jie; Kurniawan, Koo Hendrik, E-mail: kurnia18@cbn.net.id [Research Center of Maju Makmur Mandiri Foundation, 40 Srengseng Raya, Kembangan, Jakarta Barat 11630 (Indonesia); Abdulmadjid, Syahrun Nur [Department of Physics, Faculty of Mathematics and Natural Sciences, Syiah Kuala University, Darussalam, Banda Aceh 23111, NAD (Indonesia); Tjia, May On [Research Center of Maju Makmur Mandiri Foundation, 40 Srengseng Raya, Kembangan, Jakarta Barat 11630 (Indonesia); Physics of Magnetism and Photonics Group, Faculty of Mathematics and Natural Sciences, Bandung Institute of Technology, 10 Ganesha,Bandung 40132 (Indonesia); Kagawa, Kiichiro [Research Center of Maju Makmur Mandiri Foundation, 40 Srengseng Raya, Kembangan, Jakarta Barat 11630 (Indonesia); Fukui Science Education Academy, Takagi Chuo 2 chome, Fukui 910-0804 (Japan)

    2016-08-15

    A time-resolved spectroscopic study is performed on the enhancement signals of He gas plasma emission using nanosecond (ns) and picosecond (ps) lasers in an orthogonal configuration. The ns laser is used for the He gas plasma generation and the ps laser is employed for the ejection of fast electrons from a metal target, which serves to excite subsequently the He atoms in the plasma. The study is focused on the most dominant He I 587.6 nm and He I 667.8 nm emission lines suggested to be responsible for the He-assisted excitation (HAE) mechanism. The time-dependent intensity enhancements induced by the fast electrons generated with a series of delayed ps laser ablations are deduced from the intensity time profiles of both He emission lines. The results clearly lead to the conclusion that the metastable excited triplet He atoms are actually the species overwhelmingly produced during the recombination process in the ns laser-induced He gas plasma. These metastable He atoms are believed to serve as the major energy source for the delayed excitation of analyte atoms in ns laser-induced breakdown spectroscopy (LIBS) using He ambient gas.

  11. Inhibition of apoptosis signal-regulating kinase 1 alters the wound epidermis and enhances auricular cartilage regeneration.

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    Qian-Shi Zhang

    Full Text Available Why regeneration does not occur in mammals remains elusive. In lower vertebrates, epimorphic regeneration of the limb is directed by the wound epidermis, which controls blastema formation to promote regrowth of the appendage. Herein, we report that knockout (KO or inhibition of Apoptosis Signal-regulated Kinase-1 (ASK1, also known as mitogen-activated protein kinase kinase kinase 5 (MAP3K5, after full thickness ear punch in mice prolongs keratinocyte activation within the wound epidermis and promotes regeneration of auricular cartilage. Histological analysis showed the ASK1 KO ears displayed enhanced protein markers associated with blastema formation, hole closure and regeneration of auricular cartilage. At seven days after punch, the wound epidermis morphology was markedly different in the KO, showing a thickened stratum corneum with rounded cell morphology and a reduction of both the granular cell layer and decreased expression of filament aggregating protein. In addition, cytokeratin 6 was expressed in the stratum spinosum and granulosum. Topical application of inhibitors of ASK1 (NQDI-1, the upstream ASK1 activator, calcium activated mitogen kinase 2 (KN93, or the downstream target, c-Jun N-terminal kinase (SP600125 also resulted in enhanced regeneration; whereas inhibition of the other downstream target, the p38 α/β isoforms, (SB203580 had no effect. The results of this investigation indicate ASK1 inhibition prolongs keratinocyte and blastemal cell activation leading to ear regeneration.

  12. Inhibition of apoptosis signal-regulating kinase 1 alters the wound epidermis and enhances auricular cartilage regeneration

    Science.gov (United States)

    Zhang, Qian-Shi; Kurpad, Deepa S.; Mahoney, My G.; Steinbeck, Marla J.

    2017-01-01

    Why regeneration does not occur in mammals remains elusive. In lower vertebrates, epimorphic regeneration of the limb is directed by the wound epidermis, which controls blastema formation to promote regrowth of the appendage. Herein, we report that knockout (KO) or inhibition of Apoptosis Signal-regulated Kinase-1 (ASK1), also known as mitogen-activated protein kinase kinase kinase 5 (MAP3K5), after full thickness ear punch in mice prolongs keratinocyte activation within the wound epidermis and promotes regeneration of auricular cartilage. Histological analysis showed the ASK1 KO ears displayed enhanced protein markers associated with blastema formation, hole closure and regeneration of auricular cartilage. At seven days after punch, the wound epidermis morphology was markedly different in the KO, showing a thickened stratum corneum with rounded cell morphology and a reduction of both the granular cell layer and decreased expression of filament aggregating protein. In addition, cytokeratin 6 was expressed in the stratum spinosum and granulosum. Topical application of inhibitors of ASK1 (NQDI-1), the upstream ASK1 activator, calcium activated mitogen kinase 2 (KN93), or the downstream target, c-Jun N-terminal kinase (SP600125) also resulted in enhanced regeneration; whereas inhibition of the other downstream target, the p38 α/β isoforms, (SB203580) had no effect. The results of this investigation indicate ASK1 inhibition prolongs keratinocyte and blastemal cell activation leading to ear regeneration. PMID:29045420

  13. Chronic stress enhances progression of periodontitis via α1-adrenergic signaling: a potential target for periodontal disease therapy.

    Science.gov (United States)

    Lu, Huaixiu; Xu, Minguang; Wang, Feng; Liu, Shisen; Gu, Jing; Lin, Songshan

    2014-10-17

    This study assessed the roles of chronic stress (CS) in the stimulation of the sympathetic nervous system and explored the underlying mechanisms of periodontitis. Using an animal model of periodontitis and CS, the expression of tyrosine hydroxylase (TH) and the protein levels of the α1-adrenergic receptor (α1-AR) and β2-adrenergic receptor (β2-AR) were assessed. Furthermore, human periodontal ligament fibroblasts (HPDLFs) were stimulated with lipopolysaccharide (LPS) to mimic the process of inflammation. The proliferation of the HPDLFs and the expression of α1-AR and β2-AR were assessed. The inflammatory-related cytokines interleukin (IL)-1β, IL-6 and IL-8 were detected after pretreatment with the α1/β2-AR blockers phentolamine/propranolol, both in vitro and in vivo. Results show that periodontitis under CS conditions enhanced the expression of TH, α1-AR and β2-AR. Phentolamine significantly reduced the inflammatory cytokine levels. Furthermore, we observed a marked decrease in HPDLF proliferation and the increased expression of α1-ARfollowing LPS pretreatment. Pretreatment with phentolamine dramatically ameliorated LPS-inhibited cell proliferation. In addition, the blocking of α1-ARsignaling also hindered the upregulation of the inflammatory-related cytokines IL-1β, IL-6 and IL-8. These results suggest that CS can significantly enhance the pathological progression of periodontitis by an α1-adrenergic signaling-mediated inflammatory response. We have identified a potential therapeutic target for the treatment of periodontal disease, particularly in those patients suffering from concurrent CS.

  14. Adiponectin enhances osteogenic differentiation in human adipose-derived stem cells by activating the APPL1-AMPK signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Tong; Wu, Yu-wei; Lu, Hui; Guo, Yuan [Second Dental Center, Peking University School and Hospital of Stomatology, Beijing (China); National Engineering Laboratory for Digital and Material Technology of Stomatology, Peking University School and Hospital of Stomatology, Beijing (China); Tang, Zhi-hui, E-mail: tang_zhihui@live.cn [Second Dental Center, Peking University School and Hospital of Stomatology, Beijing (China); National Engineering Laboratory for Digital and Material Technology