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Sample records for extrinsic death receptor

  1. Association of death receptor 4 haplotype 626C-683C with an increased breast cancer risk

    National Research Council Canada - National Science Library

    Frank, Bernd; Hemminki, Kari; Shanmugam, Kalai S; Meindl, Alfons; Klaes, Rüdiger; Schmutzler, Rita K; Wappenschmidt, Barbara; Untch, Michael; Bugert, Peter; Bartram, Claus R; Burwinkel, Barbara

    2005-01-01

    Dysregulation of apoptosis plays a crucial role in carcinogenesis. Tumour necrosis factor-related apoptosis-inducing ligand stimulates the extrinsic apoptotic pathway by binding to death receptor 4 (DR4...

  2. Ambitions fulfilled? The effects of intrinsic and extrinsic goal attainment on older adults' ego-integrity and death attitudes.

    Science.gov (United States)

    Van Hiel, Alain; Vansteenkiste, Maarten

    2009-01-01

    The present research examined the effects of intrinsic and extrinsic goal attainment on older adults' ego-integrity, psychological well-being, and death attitudes. Hypotheses were derived from Self-Determination Theory (SDT; Deci & Ryan, 2000; Vansteenkiste, Ryan, & Deci, in press). Study 1 (N = 202, Mean age = 68.2 years) indicated that, after controlling for extrinsic goal attainment, intrinsic goal attainment contributed positively to subjective well-being and ego-integrity and negatively to despair, whereas extrinsic goal attainment was unrelated to psychological health and contributed positively to despair. Study 2 (N = 213, Mean age = 75.2 years) replicated and extended these results, showing that intrinsic goal attainment contributed to the acceptance of one's own death, lower ill-being, and less death anxiety, whereas extrinsic goal attainment was negatively associated with death acceptance. It is argued that the attainment of intrinsic goals is related to better psychological health, because intrinsic goals are more conducive to the satisfaction of basic psychological needs.

  3. Ambitions Fulfilled? The Effects of Intrinsic and Extrinsic Goal Attainment on Older Adults' Ego-Integrity and Death Attitudes

    Science.gov (United States)

    Van Hiel, Alain; Vansteenkiste, Maarten

    2009-01-01

    The present research examined the effects of intrinsic and extrinsic goal attainment on older adults' ego-integrity, psychological well-being, and death attitudes. Hypotheses were derived from Self-Determination Theory (SDT; Deci & Ryan, 2000; Vansteenkiste, Ryan, & Deci, in press). Study 1 (N = 202, Mean age = 68.2 years) indicated that, after…

  4. Advance research in apoptosis mediating by death receptor

    Institute of Scientific and Technical Information of China (English)

    JI Yu-bin; LIU Hong-juan; JI Chen-feng; ZHANG He

    2008-01-01

    Apoptosis is one of the main types of programmed cell deaths (PCD) and involves a series of biochemical events that lead to a variety of morphological changes and death. The initial and progress of apoptosis is precisely regulated. This review will summarize current knowledge of the signal transduction pathways of apoptosis. It is now well-established that the apoptotic signals generally involve the extrinsic or intrinsic pathways of apoptosis. The extrinsic pathway originates at the membrane and engages cell surface death receptors whereas the intrinsic pathway predominantly involves mitochondria. In the intrinsic pathway, the cell death signal induced changes of mitochondrial membrane permeability and the loss of membrane potential. Many proteins factors released, and then cytoplasmic cytochrome C and easpase-9 form of apoptosis. The activated caspase-9 cut caspase-3, then cell dead at last. In the case of extrinsic pathway, several death receptors exist including Fas, TNFR-1, DR3, DR4, DR5 and DR6. These death receptors contain an intracellular region of approximately 80 amino acids that is designated as "death domain". The death domain is an important structure that plays a key role in the transduction of apoptotic signals. The interaction between Fas and its ligand (FasL) triggers the formation of a death-inducing signaling complex (DISC), which subsequently recruits and activates caspase-8; this in turn activates other procaspases and culminates in the cleavage of cellular substrates and apoptosis. During the process of tumor cell lines apoptosis Inducted by chemotherapy. It is easy to see the increasing of the Fas receptors and inducing of FasL expression, it can inhibite apoptosis when the blocking Fas / FasL. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a type Ⅱ transmembrane protein belonging to the TNF family of death ligands. TRAIL has been suggested as a safe and tumorselective anticancer agent with low toxicity to normal

  5. Optimal receptor-cluster size determined by intrinsic and extrinsic noise

    CERN Document Server

    Aquino, Gerardo; Tollis, Sylvain; Endres, Robert G

    2011-01-01

    Biological cells sense external chemical stimuli in their environment using cell-surface receptors. To increase the sensitivity of sensing, receptors often cluster, most noticeably in bacterial chemotaxis, a paradigm for signaling and sensing in general. While amplification of weak stimuli is useful in absence of noise, its usefulness is less clear in presence of extrinsic input noise and intrinsic signaling noise. Here, exemplified on bacterial chemotaxis, we combine the allosteric Monod-Wyman- Changeux model for signal amplification by receptor complexes with calculations of noise to study their interconnectedness. Importantly, we calculate the signal-to-noise ratio, describing the balance of beneficial and detrimental effects of clustering for the cell. Interestingly, we find that there is no advantage for the cell to build receptor complexes for noisy input stimuli in absence of intrinsic signaling noise. However, with intrinsic noise, an optimal complex size arises in line with estimates of the sizes of ...

  6. Extrinsic factors regulate partial agonist efficacy of strychnine-sensitive glycine receptors

    Science.gov (United States)

    Farroni, Jeffrey S; McCool, Brian A

    2004-01-01

    the systems examine here, these effects are independent of both absolute expression level and any system-related alterations in the agonist binding site. We conclude that complex interactions between receptor composition and extrinsic factors may play a significant role in determining strychnine-sensitive glycine receptor partial agonist pharmacology. PMID:15301692

  7. Efficient induction of extrinsic cell death by dandelion root extract in human chronic myelomonocytic leukemia (CMML cells.

    Directory of Open Access Journals (Sweden)

    Pamela Ovadje

    Full Text Available BACKGROUND: Chronic Myelomonocytic Leukemia (CMML is a heterogeneous disease that is not only hard to diagnose and classify, but is also highly resistant to treatment. Available forms of therapy for this disease have not shown significant effects and patients rapidly develop resistance early on in therapy. These factors lead to the very poor prognosis observed with CMML patients, with median survival duration between 12 and 24 months after diagnosis. This study is therefore centered around evaluating the selective efficacy of a natural extract from dandelion roots, in inducing programmed cell death in aggressive and resistant CMML cell lines. METHODOLOGY/PRINCIPAL FINDINGS: To confirm the induction of programmed cell death in three human CMML cell lines, nuclear condensation and externalization of the phosphatidylserine, two main characteristics of apoptosis, were detected using Hoechst staining and annexin-V binding assay. The induction of another mode of cell death, autophagy, was determined using a monodansylcadaverine (MDC stain, to detect the formation of autophagy vacuoles. The results from this study indicate that Dandelion Root Extract (DRE is able to efficiently and selectively induce apoptosis and autophagy in these cell lines in a dose and time dependent manner, with no significant toxicity on non-cancerous peripheral blood mononuclear cells. More importantly, we observed early activation of initiator caspase-8, which led to mitochondrial destabilization and the induction of autophagy, suggesting that DRE acts through the extrinsic pathway of apoptosis. The inability of DRE to induce apoptosis in dominant-negative FADD cells, confirms the mechanism of action of DRE in in vitro models of CMML. CONCLUSION: The results from this study indicate that natural products, in particular Dandelion Root Extract, have great potential, as non-toxic and effective alternatives to conventional modes of chemotherapy available today.

  8. Ursodeoxycholic Acid Induces Death Receptor-mediated Apoptosis in Prostate Cancer Cells

    Science.gov (United States)

    Lee, Won Sup; Jung, Ji Hyun; Panchanathan, Radha; Yun, Jeong Won; Kim, Dong Hoon; Kim, Hye Jung; Kim, Gon Sup; Ryu, Chung Ho; Shin, Sung Chul; Hong, Soon Chan; Choi, Yung Hyun; Jung, Jin-Myung

    2017-01-01

    Background Bile acids have anti-cancer properties in a certain types of cancers. We determined anticancer activity and its underlying molecular mechanism of ursodeoxycholic acid (UDCA) in human DU145 prostate cancer cells. Methods Cell viability was measured with an MTT assay. UDCA-induced apoptosis was determined with flow cytometric analysis. The expression levels of apoptosis-related signaling proteins were examined with Western blotting. Results UDCA treatment significantly inhibited cell growth of DU145 in a dose-dependent manner. It induced cellular shrinkage and cytoplasmic blebs and accumulated the cells with sub-G1 DNA contents. Moreover, UDCA activated caspase 8, suggesting that UDCA-induced apoptosis is associated with extrinsic pathway. Consistent to this finding, UDCA increased the expressions of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor, death receptor 4 (DR4) and death receptor 5 (DR5), and TRAIL augmented the UDCA-induced cell death in DU145 cells. In addition, UDCA also increased the expressions of Bax and cytochrome c and decreased the expression of Bcl-xL in DU145 cells. This finding suggests that UDCA-induced apoptosis may be involved in intrinsic pathway. Conclusions UDCA induces apoptosis via extrinsic pathway as well as intrinsic pathway in DU145 prostate cancer cells. UDCA may be a promising anti-cancer agent against prostate cancer.

  9. Death receptors: Targets for cancer therapy

    Energy Technology Data Exchange (ETDEWEB)

    Mahmood, Zafar [Proteomics Laboratory, Indian Institute of Toxicology Research, Mahatma Gandhi Marg, Lucknow 226001 (India); Shukla, Yogeshwer, E-mail: yogeshwer_shukla@hotmail.com [Proteomics Laboratory, Indian Institute of Toxicology Research, Mahatma Gandhi Marg, Lucknow 226001 (India)

    2010-04-01

    Apoptosis is the cell's intrinsic program to death, which plays an important role in physiologic growth control and homeostasis. Apoptosis can be triggered by death receptors (DRs), without any adverse effects. DRs are the members of tumor necrosis factor (TNF) receptor superfamily, known to be involved in apoptosis signaling, independent of p53 tumor-supressor gene. Selective triggering of DR-mediated apoptosis in cancer cells is a novel approach in cancer therapy. So far, the best characterized DRs are CD95 (Fas/Apo1), TNF-related apoptosis-inducing ligand receptor (TRAILR) and tumor necrosis factor receptor (TNFR). Among these, TRAILR is emerging as most promising agent for cancer therapy, because it induces apoptosis in a variety of tumor and transformed cells without any toxicity to normal cells. TRAIL treatment in combination with chemotherapy or radiotherapy enhances TRAIL sensitivity or reverses TRAIL resistance by regulating downstream effectors. This review covers the current knowledge about the DRs, summarizes main signaling in DRs and also summarizes the preclinical approaches of these DRs in cancer therapy.

  10. Cell death-independent activities of the death receptors CD95, TRAILR1, and TRAILR2.

    Science.gov (United States)

    Siegmund, Daniela; Lang, Isabell; Wajant, Harald

    2017-04-01

    Since their identification more than 20 years ago, the death receptors CD95, TRAILR1, and TRAILR2 have been intensively studied with respect to their cell death-inducing activities. These receptors, however, can also trigger a variety of cell death-independent cellular responses reaching from the activation of proinflammatory gene transcription programs over the stimulation of proliferation and differentiation to induction of cell migration. The cell death-inducing signaling mechanisms of CD95 and the TRAIL death receptors are well understood. In contrast, despite the increasing recognition of the biological and pathophysiological relevance of the cell death-independent activities of CD95, TRAILR1, and TRAILR2, the corresponding signaling mechanisms are less understood and give no fully coherent picture. This review is focused on the cell death-independent activities of CD95 and the TRAIL death receptors and addresses mainly three questions: (a) how are these receptors linked to noncell death pathways at the molecular level, (b) which factors determine the balance of cell death and cell death-independent activities of CD95 and the TRAIL death receptors at the cellular level, and (c) what are the consequences of the cell death-independent functions of these receptors for their role in cancer and inflammatory diseases. © 2016 Federation of European Biochemical Societies.

  11. Membrane Trafficking of Death Receptors: Implications on Signalling

    Directory of Open Access Journals (Sweden)

    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.

  12. Expression of 5-HT3 receptors by extrinsic duodenal afferents contribute to intestinal inhibition of gastric emptying.

    Science.gov (United States)

    Raybould, Helen E; Glatzle, Jorg; Robin, Carla; Meyer, James H; Phan, Thomas; Wong, Helen; Sternini, Catia

    2003-03-01

    Intestinal perfusion with carbohydrates inhibits gastric emptying via vagal and spinal capsaicin-sensitive afferent pathways. The aim of the present study was to determine the role of 1) 5-hydroxytryptamine (5-HT)(3) receptors (5-HT(3)R) in mediating glucose-induced inhibition of gastric emptying and 2) 5-HT(3)R expression in vagal and spinal afferents in innervating the duodenum. In awake rats fitted with gastric and duodenal cannulas, perfusion of the duodenum with glucose (50 and 100 mg) inhibited gastric emptying. Intestinal perfusion of mannitol inhibited gastric emptying only at the highest concentration (990 mosm/kgH(2)O). Pretreatment with the 5-HT(3)R antagonist tropisetron abolished both glucose- and mannitol-induced inhibition of gastric emptying. Retrograde labeling of visceral afferents by injection of dextran-conjugated Texas Red into the duodenal wall was used to identify extrinsic primary afferents. Immunoreactivity for 5-HT(3)R, visualized with an antibody directed to the COOH terminus of the rat 5-HT(3)R, was found in >80% of duodenal vagal and spinal afferents. These results show that duodenal extrinsic afferents express 5-HT(3)R and that the receptor mediates specific glucose-induced inhibition of gastric emptying. These findings support the hypothesis that enterochromaffin cells in the intestinal mucosa release 5-HT in response to glucose, which activates 5-HT(3)R on afferent nerve terminals to evoke reflex changes in gastric motility. The primary glucose sensors of the intestine may be mucosal enterochromaffin cells.

  13. The Fas/Fas ligand death receptor pathway contributes to phenylalanine-induced apoptosis in cortical neurons.

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    Xiaodong Huang

    Full Text Available Phenylketonuria (PKU, an autosomal recessive disorder of amino acid metabolism caused by mutations in the phenylalanine hydroxylase (PAH gene, leads to childhood mental retardation by exposing neurons to cytotoxic levels of phenylalanine (Phe. A recent study showed that the mitochondria-mediated (intrinsic apoptotic pathway is involved in Phe-induced apoptosis in cultured cortical neurons, but it is not known if the death receptor (extrinsic apoptotic pathway and endoplasmic reticulum (ER stress-associated apoptosis also contribute to neurodegeneration in PKU. To answer this question, we used specific inhibitors to block each apoptotic pathway in cortical neurons under neurotoxic levels of Phe. The caspase-8 inhibitor Z-IETD-FMK strongly attenuated apoptosis in Phe-treated neurons (0.9 mM, 18 h, suggesting involvement of the Fas receptor (FasR-mediated cell death receptor pathway in Phe toxicity. In addition, Phe significantly increased cell surface Fas expression and formation of the Fas/FasL complex. Blocking Fas/FasL signaling using an anti-Fas antibody markedly inhibited apoptosis caused by Phe. In contrast, blocking the ER stress-induced cell death pathway with salubrinal had no effect on apoptosis in Phe-treated cortical neurons. These experiments demonstrate that the Fas death receptor pathway contributes to Phe-induced apoptosis and suggest that inhibition of the death receptor pathway may be a novel target for neuroprotection in PKU patients.

  14. Receptor-mediated choreography of life and death.

    Science.gov (United States)

    Bhardwaj, Anjana; Aggarwal, Bharat B

    2003-09-01

    The cytokine tumor necrosis factor was originally identified as a protein that kills tumor cells. So far, 18 distinct members of this family have been identified. All of them regulate cell survival, proliferation, differentiation, and cell death, also called apoptosis. The apoptosis induced by TNF, and other members of the family, for example, FasL, VEGI, and TRAIL is mediated through death receptors. The apoptotic signals by these cytokines are transduced by eight different death domain- (DD) containing receptors (TNFR1, also called DR1; Fas, also called DR2; DR3, DR4, DR5, DR6, NGFR, and EDAR). The intracellular portion of all these receptors contains a region approximately 80 amino acids long referred to as the "death domain." Upon activation by its ligand, the DD recruits various proteins that mediate both death and proliferation of the cells. These proteins in turn recruit other proteins via their DDs or death effector domains. The actual destruction of the cell, however, is accomplished by serial activation of a family of proteases referred to as caspases. Cell death is negatively regulated by a family of proteins that includes decoy receptors, silencer of DD, sentrin, cellular FLICE inhibitory protein, cellular inhibitors of apoptosis, and survivin. This review is an attempt to describe how these negative and positive players of cell death perform a harmonious dance with each other.

  15. Transient brain ischemia: NMDA receptor modulation and delayed neuronal death

    OpenAIRE

    Benquet, Pascal; Gee, Christine E.; Gerber, Urs

    2008-01-01

    Transient global ischemia induces delayed neuronal death in certain cell types and brain regions while sparing cells in other areas. A key process through which oxygen-glucose deprivation triggers cell death is the excessive accumulation of the neurotransmitter glutamate leading to over excitation of neurons. In certain neurons this increase in glutamate will potentiate the NMDA type of glutamate receptor, which can then initiate cell death. This review provides an update of the neurophysiolo...

  16. EP2 Receptor Signaling Regulates Microglia Death

    OpenAIRE

    Fu, Yujiao; Yang, Myung-Soon; Jiang, Jianxiong; Ganesh, Thota; Joe, Eunhye; Dingledine, Raymond

    2015-01-01

    The timely resolution of inflammation prevents continued tissue damage after an initial insult. In the brain, the death of activated microglia by apoptosis has been proposed as one mechanism to resolve brain inflammation. How microglial death is regulated after activation is still unclear. We reported that exposure to lipopolysaccharide (LPS) and interleukin (IL)-13 together initially activates and then kills rat microglia in culture by a mechanism dependent on cyclooxygenase-2 (COX-2). We sh...

  17. Distinct and atypical intrinsic and extrinsic cell death pathways between photoreceptor cell types upon specific ablation of Ranbp2 in cone photoreceptors.

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    Kyoung-In Cho

    2013-06-01

    Full Text Available Non-autonomous cell-death is a cardinal feature of the disintegration of neural networks in neurodegenerative diseases, but the molecular bases of this process are poorly understood. The neural retina comprises a mosaic of rod and cone photoreceptors. Cone and rod photoreceptors degenerate upon rod-specific expression of heterogeneous mutations in functionally distinct genes, whereas cone-specific mutations are thought to cause only cone demise. Here we show that conditional ablation in cone photoreceptors of Ran-binding protein-2 (Ranbp2, a cell context-dependent pleiotropic protein linked to neuroprotection, familial necrotic encephalopathies, acute transverse myelitis and tumor-suppression, promotes early electrophysiological deficits, subcellular erosive destruction and non-apoptotic death of cones, whereas rod photoreceptors undergo cone-dependent non-autonomous apoptosis. Cone-specific Ranbp2 ablation causes the temporal activation of a cone-intrinsic molecular cascade highlighted by the early activation of metalloproteinase 11/stromelysin-3 and up-regulation of Crx and CoREST, followed by the down-modulation of cone-specific phototransduction genes, transient up-regulation of regulatory/survival genes and activation of caspase-7 without apoptosis. Conversely, PARP1+ -apoptotic rods develop upon sequential activation of caspase-9 and caspase-3 and loss of membrane permeability. Rod photoreceptor demise ceases upon cone degeneration. These findings reveal novel roles of Ranbp2 in the modulation of intrinsic and extrinsic cell death mechanisms and pathways. They also unveil a novel spatiotemporal paradigm of progression of neurodegeneration upon cell-specific genetic damage whereby a cone to rod non-autonomous death pathway with intrinsically distinct cell-type death manifestations is triggered by cell-specific loss of Ranbp2. Finally, this study casts new light onto cell-death mechanisms that may be shared by human dystrophies with distinct

  18. [Transient brain ischemia: NMDA receptor modulation and delayed neuronal death].

    Science.gov (United States)

    Benquet, Pascal; Gee, Christine E; Gerber, Urs

    2008-02-01

    Transient global ischemia induces delayed neuronal death in certain cell types and brain regions while sparing cells in other areas. A key process through which oxygen-glucose deprivation triggers cell death is the excessive accumulation of the neurotransmitter glutamate leading to over excitation of neurons. In certain neurons this increase in glutamate will potentiate the NMDA type of glutamate receptor, which can then initiate cell death. This review provides an update of the neurophysiological, cellular and molecular mechanisms inducing post-ischemic plasticity of NMDA receptors, focusing on the sensitive CA1 pyramidal neurons in the hippocampus as compared to the relatively resistant neighboring CA3 neurons. Both a change in the equilibrium between protein tyrosine kinases/phosphatases and an increased density of surface NMDA receptors in response to ischemia may explain the selective vulnerability of specific cell types. Implications for the treatment of stroke and reasons for the failures of human clinical trials utilizing NMDA receptor antagonists are also discussed.

  19. Silencer of death domains controls cell death through tumour necrosis factor-receptor 1 and caspase-10 in acute lymphoblastic leukemia.

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    Adam Cisterne

    Full Text Available Resistance to apoptosis remains a significant problem in drug resistance and treatment failure in malignant disease. NO-aspirin is a novel drug that has efficacy against a number of solid tumours, and can inhibit Wnt signaling, and although we have shown Wnt signaling to be important for acute lymphoblastic leukemia (ALL cell proliferation and survival inhibition of Wnt signaling does not appear to be involved in the induction of ALL cell death. Treatment of B lineage ALL cell lines and patient ALL cells with NO-aspirin induced rapid apoptotic cell death mediated via the extrinsic death pathway. Apoptosis was dependent on caspase-10 in association with the formation of the death-inducing signaling complex (DISC incorporating pro-caspase-10 and tumor necrosis factor receptor 1 (TNF-R1. There was no measurable increase in TNF-R1 or TNF-α in response to NO-aspirin, suggesting that the process was ligand-independent. Consistent with this, expression of silencer of death domain (SODD was reduced following NO-aspirin exposure and lentiviral mediated shRNA knockdown of SODD suppressed expansion of transduced cells confirming the importance of SODD for ALL cell survival. Considering that SODD and caspase-10 are frequently over-expressed in ALL, interfering with these proteins may provide a new strategy for the treatment of this and potentially other cancers.

  20. Cell death sensitization of leukemia cells by opioid receptor activation

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    Friesen, Claudia; Roscher, Mareike; Hormann, Inis; Fichtner, Iduna; Alt, Andreas; Hilger, Ralf A.; Debatin, Klaus-Michael; Miltner, Erich

    2013-01-01

    Cyclic AMP (cAMP) regulates a number of cellular processes and modulates cell death induction. cAMP levels are altered upon stimulation of specific G-protein-coupled receptors inhibiting or activating adenylyl cyclases. Opioid receptor stimulation can activate inhibitory Gi-proteins which in turn block adenylyl cyclase activity reducing cAMP. Opioids such as D,L-methadone induce cell death in leukemia cells. However, the mechanism how opioids trigger apoptosis and activate caspases in leukemia cells is not understood. In this study, we demonstrate that downregulation of cAMP induced by opioid receptor activation using the opioid D,L-methadone kills and sensitizes leukemia cells for doxorubicin treatment. Enhancing cAMP levels by blocking opioid-receptor signaling strongly reduced D,L-methadone-induced apoptosis, caspase activation and doxorubicin-sensitivity. Induction of cell death in leukemia cells by activation of opioid receptors using the opioid D,L-methadone depends on critical levels of opioid receptor expression on the cell surface. Doxorubicin increased opioid receptor expression in leukemia cells. In addition, the opioid D,L-methadone increased doxorubicin uptake and decreased doxorubicin efflux in leukemia cells, suggesting that the opioid D,L-methadone as well as doxorubicin mutually increase their cytotoxic potential. Furthermore, we found that opioid receptor activation using D,L-methadone alone or in addition to doxorubicin inhibits tumor growth significantly in vivo. These results demonstrate that opioid receptor activation via triggering the downregulation of cAMP induces apoptosis, activates caspases and sensitizes leukemia cells for doxorubicin treatment. Hence, opioid receptor activation seems to be a promising strategy to improve anticancer therapies. PMID:23633472

  1. Role of interleukin 4 and its receptor in clinical presentation of chronic extrinsic allergic alveolitis: a pilot study.

    Science.gov (United States)

    Sterclova, Martina; Matej, Radoslav; Mandakova, Petra; Skibova, Jelena; Vasakova, Martina

    2013-05-30

    Th-2 cytokine milieu including interleukin 4 (IL-4) was detected in fibrotic lung diseases. Chronic extrinsic allergic alveolitis (EAA) may be also accompanied by marked fibrogenesis. The aim of this study was to determine if IL-4 and its receptor (IL-4R-alpha) play any role in the clinical presentation and pathogenesis of chronic EAA. Twenty patients originally investigated for interstitial lung disease and finally diagnosed affected with chronic EAA and sarcoidosis were prospectively enrolled into the study. Concentrations of IL-4, IL-4R-aplha and total protein were assessed in the bronchoalveolar lavage fluid (BALF) of all enrolled subjects as well as high resolution computed tomography (HRCT) scores and pulmonary function tests. BALF IL-4R-alpha and total protein concentrations were significantly higher in chronic EAA patients (p < 0.05). Concentrations of BALF IL-4R-alpha were significantly higher in men than in women (p < 0.05) in EAA group. Total protein BALF levels were significantly elevated in ex-smokers with EAA compared to nonsmokers (p < 0.05). A positive correlation (p < 0.01) between IL-4R-alpha BALF concentrations and HRCT interstitial scores were observed in chronic EAA group; the IL-4R-alpha/total protein ratio showed the same significant positive correlation. A negative correlation between lung function results and IL-4R-alpha, and IL-4R-alpha/total protein as well, was also found (p < 0.05). We suggest a clinical relevance for the IL-4/IL-4R axis in the etiopathogenesis of chronic EAA. IL-4R-alpha could serve as a potential biomarker of lung fibrogenesis.

  2. Kaempferol induces ATM/p53-mediated death receptor and mitochondrial apoptosis in human umbilical vein endothelial cells.

    Science.gov (United States)

    Lee, Chiu-Fang; Yang, Jai-Sing; Tsai, Fuu-Jen; Chiang, Ni-Na; Lu, Chi-Cheng; Huang, Yu-Syuan; Chen, Chun; Chen, Fu-An

    2016-05-01

    Kaempferol is a member of the flavonoid compounds found in vegetables and fruits. It is shown to exhibit biological impact and anticancer activity, but no report exists on the angiogenic effect of kaempferol and induction of cell apoptosis in vitro. In this study, we investigated the role of kaempferol on anti-angiogenic property and the apoptotic mechanism of human umbilical vein endothelial cells (HUVECs). Our results demonstrated that kaempferol decreased HUVEC viability in a time- and concentration-dependent manner. Kaempferol also induced morphological changes and sub-G1 phase cell population (apoptotic cells). Kaempferol triggered apoptosis of HUVECs as detecting by DNA fragmentation, comet assay and immunofluorescent staining for activated caspase-3. The caspase signals, including caspase-8, -9 and -3, were time-dependently activated in HUVECs after kaempferol exposure. Furthermore, pre-treatment with a specific inhibitor of caspase-8 (Z-IETD-FMK) significantly reduced the activity of caspase-8, -9 and -3, indicating that extrinsic pathway is a major signaling pathway in kaempferol-treated HUVECs. Importantly, kaempferol promoted reactive oxygen species (ROS) evaluated using flow cytometric assay in HUVECs. We further investigated the upstream extrinsic pathway and showed that kaempferol stimulated death receptor signals [Fas/CD95, death receptor 4 (DR4) and DR5] through increasing the levels of phosphorylated p53 and phosphorylated ATM pathways in HUVECs, which can be individually confirmed by N-acetylcysteine (NAC), ATM specific inhibitor (caffeine) and p53 siRNA. Based on these results, kaempferol-induced HUVEC apoptosis was involved in an ROS-mediated p53/ATM/death receptor signaling. Kaempferol might possess therapeutic effects on cancer treatment in anti-vascular targeting.

  3. Upregulation of DR5 receptor by the diaminothiazole DAT1 [4-amino-5-benzoyl-2-(4-methoxy phenyl amino) thiazole] triggers an independent extrinsic pathway of apoptosis in colon cancer cells with compromised pro and antiapoptotic proteins.

    Science.gov (United States)

    Thomas, Sannu A; Vasudevan, Smreti; Thamkachy, Reshma; Lekshmi, Swathi U; Santhoshkumar, Thankayyan R; Rajasekharan, Kallikat N; Sengupta, Suparna

    2013-06-01

    Mitochondria mediated signalling is the more common way of apoptosis induction exhibited by many chemotherapeutic agents in cancer cells. Death receptor mediated signalling for apoptosis in many cells also requires further amplification from the mitochondrial pathway activation through tBid. Thus the potential of most chemotherapeutic agents in tumours with intrinsic apoptosis resistance due to changes in molecules involved in the mitochondrial pathway is limited. Diaminothiazoles were shown earlier to bind to tubulin thereby exhibiting cytotoxicity towards different cancer cells. We observed that the lead diaminothiazole, DAT1 [4-amino-5-benzoyl-2-(4-methoxy phenyl amino) thiazole] could induce apoptosis in the colon cancer cell line HCT116 by both pathways. However, in contrast to many other chemotherapeutic agents, DAT1 triggered apoptosis where the intrinsic pathway was blocked by changing the pro and antiapoptotic proteins. An independent extrinsic pathway activation triggered by the upregulation of DR5 receptor accounted for that. The induction of DR5 occurred in the transcriptional level and the essential role of DR5 was confirmed by the fact that siRNA downregulation of DR5 significantly reduced DAT1 induced apoptosis. HCT116 cells were earlier shown to have a type II response for apoptosis induction where extrinsic pathway was connected to the intrinsic pathway via the mediator protein tBid. Our finding thus indicates that the signalling events in the manifestation of apoptosis depend not only on the cancer cell type, but also on the inducer. Our results also place diaminothiazoles in a promising position in the treatment of tumours with compromised apoptotic factors.

  4. Cardiac muscarinic receptor overexpression in sudden infant death syndrome.

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    Angelo Livolsi

    Full Text Available BACKGROUND: Sudden infant death syndrome (SIDS remains the leading cause of death among infants less than 1 year of age. Disturbed expression of some neurotransmitters and their receptors has been shown in the central nervous system of SIDS victims but no biological abnormality of the peripheral vago-cardiac system has been demonstrated to date. The present study aimed to seek vago-cardiac abnormalities in SIDS victims. The cardiac level of expression of muscarinic receptors, as well as acetylcholinesterase enzyme activity were investigated. METHODOLOGY/PRINCIPAL FINDINGS: Left ventricular samples and blood samples were obtained from autopsies of SIDS and children deceased from non cardiac causes. Binding experiments performed with [(3H]NMS, a selective muscarinic ligand, in cardiac membrane preparations showed that the density of cardiac muscarinic receptors was increased as shown by a more than doubled B(max value in SIDS (n = 9 SIDS versus 8 controls. On average, the erythrocyte acetylcholinesterase enzyme activity was also significantly increased (n = 9 SIDS versus 11 controls. CONCLUSIONS: In the present study, it has been shown for the first time that cardiac muscarinic receptor overexpression is associated with SIDS. The increase of acetylcholinesterase enzyme activity appears as a possible regulatory mechanism.

  5. Neuropeptide Y receptor gene y6: multiple deaths or resurrections?

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    Starbäck, P; Wraith, A; Eriksson, H; Larhammar, D

    2000-10-14

    The neuropeptide Y family of G-protein-coupled receptors consists of five cloned members in mammals. Four genes give rise to functional receptors in all mammals investigated. The y6 gene is a pseudogene in human and pig and is absent in rat, but generates a functional receptor in rabbit and mouse and probably in the collared peccary (Pecari tajacu), a distant relative of the pig family. We report here that the guinea pig y6 gene has a highly distorted nucleotide sequence with multiple frame-shift mutations. One evolutionary scenario may suggest that y6 was inactivated before the divergence of the mammalian orders and subsequently resurrected in some lineages. However, the pseudogene mutations seem to be distinct in human, pig, and guinea pig, arguing for separate inactivation events. In either case, the y6 gene has a quite unusual evolutionary history with multiple independent deaths or resurrections.

  6. Identification of the Calmodulin-Binding Domains of Fas Death Receptor.

    Directory of Open Access Journals (Sweden)

    Bliss J Chang

    Full Text Available The extrinsic apoptotic pathway is initiated by binding of a Fas ligand to the ectodomain of the surface death receptor Fas protein. Subsequently, the intracellular death domain of Fas (FasDD and that of the Fas-associated protein (FADD interact to form the core of the death-inducing signaling complex (DISC, a crucial step for activation of caspases that induce cell death. Previous studies have shown that calmodulin (CaM is recruited into the DISC in cholangiocarcinoma cells and specifically interacts with FasDD to regulate the apoptotic/survival signaling pathway. Inhibition of CaM activity in DISC stimulates apoptosis significantly. We have recently shown that CaM forms a ternary complex with FasDD (2:1 CaM:FasDD. However, the molecular mechanism by which CaM binds to two distinct FasDD motifs is not fully understood. Here, we employed mass spectrometry, nuclear magnetic resonance (NMR, biophysical, and biochemical methods to identify the binding regions of FasDD and provide a molecular basis for the role of CaM in Fas-mediated apoptosis. Proteolytic digestion and mass spectrometry data revealed that peptides spanning residues 209-239 (Fas-Pep1 and 251-288 (Fas-Pep2 constitute the two CaM-binding regions of FasDD. To determine the molecular mechanism of interaction, we have characterized the binding of recombinant/synthetic Fas-Pep1 and Fas-Pep2 peptides with CaM. Our data show that both peptides engage the N- and C-terminal lobes of CaM simultaneously. Binding of Fas-Pep1 to CaM is entropically driven while that of Fas-Pep2 to CaM is enthalpically driven, indicating that a combination of electrostatic and hydrophobic forces contribute to the stabilization of the FasDD-CaM complex. Our data suggest that because Fas-Pep1 and Fas-Pep2 are involved in extensive intermolecular contacts with the death domain of FADD, binding of CaM to these regions may hinder its ability to bind to FADD, thus greatly inhibiting the initiation of apoptotic signaling

  7. α-Hispanolol sensitizes hepatocellular carcinoma cells to TRAIL-induced apoptosis via death receptor up-regulation

    Energy Technology Data Exchange (ETDEWEB)

    Mota, Alba, E-mail: amota@iib.uam.es [Unidad de Terapias Farmacológicas, Área de Genética Humana, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III, Madrid (Spain); Jiménez-Garcia, Lidia, E-mail: ljimenez@isciii.es [Unidad de Terapias Farmacológicas, Área de Genética Humana, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III, Madrid (Spain); Herránz, Sandra, E-mail: sherranz@isciii.es [Unidad de Terapias Farmacológicas, Área de Genética Humana, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III, Madrid (Spain); Heras, Beatriz de las, E-mail: lasheras@ucm.es [Departamento de Farmacología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Madrid (Spain); Hortelano, Sonsoles, E-mail: shortelano@isciii.es [Unidad de Terapias Farmacológicas, Área de Genética Humana, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III, Madrid (Spain)

    2015-08-01

    Hispanolone derivatives have been previously described as anti-inflammatory and antitumoral agents. However, their effects on overcoming Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance remain to be elucidated. In this study, we analyzed the cytotoxic effects of the synthetic hispanolone derivative α-hispanolol (α-H) in several tumor cell lines, and we evaluated the induction of apoptosis, as well as the TRAIL-sensitizing potential of α-H in the hepatocellular carcinoma cell line HepG2. Our data show that α-H decreased cell viability in a dose-dependent manner in HeLa, MDA-MB231, U87 and HepG2 cell lines, with a more prominent effect in HepG2 cells. Interestingly, α-H had no effect on non-tumoral cells. α-H induced activation of caspase-8 and caspase-9 and also increased levels of the proapoptotic protein Bax, decreasing antiapoptotic proteins (Bcl-2, X-IAP and IAP-1) in HepG2 cells. Specific inhibition of caspase-8 abrogated the cascade of caspase activation, suggesting that the extrinsic pathway has a critical role in the apoptotic events induced by α-H. Furthermore, combined treatment of α-H with TRAIL enhanced apoptosis in HepG2 cells, activating caspase-8 and caspase-9. This correlated with up-regulation of both the TRAIL death receptor DR4 and DR5. DR4 or DR5 neutralizing antibodies abolished the effect of α-H on TRAIL-induced apoptosis, suggesting that sensitization was mediated through the death receptor pathway. Our results demonstrate that α-H induced apoptosis in the human hepatocellular carcinoma cell line HepG2 through activation of caspases and induction of the death receptor pathway. In addition, we describe a novel function of α-H as a sensitizer on TRAIL-induced apoptotic cell death in HepG2 cells. - Highlights: • α-Hispanolol induced apoptosis in the human hepatocellular carcinoma cell line HepG2. • α-Hispanolol induced activation of caspases and the death receptor pathway. • α-Hispanolol enhanced

  8. Secretory phospholipase A2-mediated neuronal cell death involves glutamate ionotropic receptors

    DEFF Research Database (Denmark)

    de Turco, Elena B; Diemer, Nils Henrik; Bazan, Nicolas G

    2002-01-01

    To define the significance of glutamate ionotropic receptors in sPLA -mediated neuronal cell death we used the NMDA receptor antagonist MK-801 and the AMPA receptor antagonist PNQX. In primary neuronal cell cultures both MK-801 and PNQX inhibited sPLA - and glutamate-induced neuronal death. [ H]A...

  9. BN 52021 (a platelet activating factor-receptor antagonist decreases alveolar macrophage-mediated lung injury in experimental extrinsic allergic alveolitis

    Directory of Open Access Journals (Sweden)

    J-L. Pérez-Arellano

    1998-01-01

    Full Text Available Several lines of research indirectly suggest that platelet activating factor (PAF may intervene in the pathogenesis of extrinsic allergic alveolitis (EAA. The specific aim of our study was to evaluate the participation of PAF on macrophage activation during the acute phase of EAA in an experimental model of this disease developed in guinea pigs. Initially we measured the concentration of PAF in bronchoalvedar lavage fluid, blood and lung tissue. In a second phase we evaluate the participation of PAF on alveolar macrophage activation and parenchymal lung injury. The effect of PAF on parenchymal lung injury was evaluated by m easuring several lung parenchymatous lesion indices (lung index, bronchoalvedar lavage fluid (BALF lactic hydrogenase activity and BALF alkaline phosphatase activity and parameters of systemic response to the challenge (acute phase reagents. We observed that induction of the experimental EAA gave rise to an increase in the concentration of PAF in blood and in lung tissue. The use of the PAF-receptor antagonist BN52021 decreases the release of lysosomal enzymes (β-glucuronidase and tartrate-sensitive acid phosphatase to the extracellular environment both in vivo and in vitro. Furthermore, antagonism of the PAF receptors notably decreases pulmonary parenchymatous lesion. These data suggest that lung lesions from acute EAA are partly mediated by local production of PAF.

  10. A promiscuous liaison between IL-15 receptor and Axl receptor tyrosine kinase in cell death control.

    Science.gov (United States)

    Budagian, Vadim; Bulanova, Elena; Orinska, Zane; Thon, Lutz; Mamat, Uwe; Bellosta, Paola; Basilico, Claudio; Adam, Dieter; Paus, Ralf; Bulfone-Paus, Silvia

    2005-12-21

    Discrimination between cytokine receptor and receptor tyrosine kinase (RTK) signaling pathways is a central paradigm in signal transduction research. Here, we report a 'promiscuous liaison' between both receptors that enables interleukin (IL)-15 to transactivate the signaling pathway of a tyrosine kinase. IL-15 protects murine L929 fibroblasts from tumor necrosis factor alpha (TNFalpha)-induced cell death, but fails to rescue them upon targeted depletion of the RTK, Axl; however, Axl-overexpressing fibroblasts are TNFalpha-resistant. IL-15Ralpha and Axl colocalize on the cell membrane and co-immunoprecipitate even in the absence of IL-15, whereby the extracellular part of Axl proved to be essential for Axl/IL-15Ralpha interaction. Most strikingly, IL-15 treatment mimics stimulation by the Axl ligand, Gas6, resulting in a rapid tyrosine phosphorylation of both Axl and IL-15Ralpha, and activation of the phosphatidylinositol 3-kinase/Akt pathway. This is also seen in mouse embryonic fibroblasts from wild-type but not Axl-/- or IL-15Ralpha-/- mice. Thus, IL-15-induced protection from TNFalpha-mediated cell death involves a hitherto unknown IL-15 receptor complex, consisting of IL-15Ralpha and Axl RTK, and requires their reciprocal activation initiated by ligand-induced IL-15Ralpha.

  11. Nortriptyline induces mitochondria and death receptor-mediated apoptosis in bladder cancer cells and inhibits bladder tumor growth in vivo.

    Science.gov (United States)

    Yuan, Sheau-Yun; Cheng, Chen-Li; Ho, Hao-Chung; Wang, Shian-Shiang; Chiu, Kun-Yuan; Su, Chung-Kuang; Ou, Yen-Chuan; Lin, Chi-Chen

    2015-08-15

    Nortriptyline (NTP), an antidepressant, has antitumor effects on some human cancer cells, but its effect on human bladder cancer cells is not known. In this study, we used a cell viability assay to demonstrate that NTP is cytotoxic to human TCCSUP and mouse MBT-2 bladder cancer cells in a concentration and time-dependent manner. We also performed cell cycle analysis, annexin V and mitochondrial membrane potential assays, and Western blot analysis to show that NTP inhibits cell growth in these cells by inducing both mitochondria-mediated and death receptor-mediated apoptosis. Specifically, NTP increases the expression of Fas, FasL, FADD, Bax, Bak, and cleaved forms of caspase-3, caspase-8, caspase-9, and poly(ADP-ribose) polymerase. In addition, NTP decreases the expression of Bcl-2, Bcl-xL, BH3 interacting domain death agonist, X-linked inhibitor of apoptosis protein, and survivin. Furthermore, NTP-induced apoptosis is associated with reactive oxygen species (ROS) production, which can be reduced by antioxidants, such as N-acetyl-L-cysteine. Finally, we showed that NTP suppresses tumor growth in mice inoculated with MBT-2 cells. Collectively, our results suggest that NTP induces both intrinsic and extrinsic apoptosis in human and mouse bladder cancer cells and that it may be a clinically useful chemotherapeutic agent for bladder cancer in humans. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Tumor-derived death receptor 6 modulates dendritic cell development.

    Science.gov (United States)

    DeRosa, David C; Ryan, Paul J; Okragly, Angela; Witcher, Derrick R; Benschop, Robert J

    2008-06-01

    Studies in murine models of cancer as well as in cancer patients have demonstrated that the immune response to cancer is often compromised. This paradigm is viewed as one of the major mechanisms of tumor escape. Many therapies focus on employing the professional antigen presenting dendritic cells (DC) as a strategy to overcome immune inhibition in cancer patients. Death receptor 6 (DR6) is an orphan member of the tumor necrosis factor receptor superfamily (TNFRSF21). It is overexpressed on many tumor cells and DR6(-/-) mice display altered immunity. We investigated whether DR6 plays a role in tumorigenesis by negatively affecting the generation of anti-tumor activity. We show that DR6 is uniquely cleaved from the cell surface of tumor cell lines by the membrane-associated matrix metalloproteinase (MMP)-14, which is often overexpressed on tumor cells and is associated with malignancy. We also demonstrate that >50% of monocytes differentiating into DC die when the extracellular domain of DR6 is present. In addition, DR6 affects the cell surface phenotype of the resulting immature DC and changes their cytokine production upon stimulation with LPS/IFN-gamma. The effects of DR6 are mostly amended when these immature DC are matured with IL-1beta/TNF-alpha, as measured by cell surface phenotype and their ability to present antigen. These results implicate MMP-14 and DR6 as a mechanism tumor cells can employ to actively escape detection by the immune system by affecting the generation of antigen presenting cells.

  13. Evidence that adiponectin receptor 1 activation exacerbates ischemic neuronal death

    Directory of Open Access Journals (Sweden)

    Thundyil John

    2010-08-01

    Full Text Available Abstract Background- Adiponectin is a hormone produced in and released from adipose cells, which has been shown to have anti-diabetic and anti-inflammatory actions in peripheral cells. Two cell surface adiponectin receptors (ADRs mediate the majority of the known biological actions of adiponectin. Thus far, ADR expression in the brain has been demonstrated in the arcuate and the paraventricular nucleus of hypothalamus, where its activation affects food intake. Recent findings suggest that levels of circulating adiponectin increase after an ischemic stroke, but the role of adiponectin receptor activation in stroke pathogenesis and its functional outcome is unclear. Methods- Ischemic stroke was induced in C57BL/6 mice by middle cerebral artery occlusion (MCAO for 1 h, followed by reperfusion. Primary cortical neuronal cultures were established from individual embryonic neocortex. For glucose deprivation (GD, cultured neurons were incubated in glucose-free Locke's medium for 6, 12 or 24 h. For combined oxygen and glucose deprivation (OGD, neurons were incubated in glucose-free Locke's medium in an oxygen-free chamber with 95% N2/5% CO2 atmosphere for either 3, 6, 9, 12 or 24 h. Primary neurons and brain tissues were analysed for Adiponectin and ADRs using reverse transcriptase polymerase chain reaction (RT-PCR, immunoblot and immunochemistry methods. Results- Cortical neurons express ADR1 and ADR2, and that the levels of ADR1 are increased in neurons in response to in vitro or in vivo ischemic conditions. Neurons treated with either globular or trimeric adiponectin exhibited increased vulnerability to oxygen and glucose deprivation which was associated with increased activation of a pro-apoptotic signaling cascade involving p38 mitogen-activated protein kinase (p38MAPK and AMP-activated protein kinase (AMPK. Conclusions- This study reveals a novel pathogenic role for adiponectin and adiponectin receptor activation in ischemic stroke. We show that

  14. Regulation of cell death receptor S-nitrosylation and apoptotic signaling by Sorafenib in hepatoblastoma cells.

    Science.gov (United States)

    Rodríguez-Hernández, A; Navarro-Villarán, E; González, R; Pereira, S; Soriano-De Castro, L B; Sarrias-Giménez, A; Barrera-Pulido, L; Álamo-Martínez, J M; Serrablo-Requejo, A; Blanco-Fernández, G; Nogales-Muñoz, A; Gila-Bohórquez, A; Pacheco, D; Torres-Nieto, M A; Serrano-Díaz-Canedo, J; Suárez-Artacho, G; Bernal-Bellido, C; Marín-Gómez, L M; Barcena, J A; Gómez-Bravo, M A; Padilla, C A; Padillo, F J; Muntané, J

    2015-12-01

    Nitric oxide (NO) plays a relevant role during cell death regulation in tumor cells. The overexpression of nitric oxide synthase type III (NOS-3) induces oxidative and nitrosative stress, p53 and cell death receptor expression and apoptosis in hepatoblastoma cells. S-nitrosylation of cell death receptor modulates apoptosis. Sorafenib is the unique recommended molecular-targeted drug for the treatment of patients with advanced hepatocellular carcinoma. The present study was addressed to elucidate the potential role of NO during Sorafenib-induced cell death in HepG2 cells. We determined the intra- and extracellular NO concentration, cell death receptor expression and their S-nitrosylation modifications, and apoptotic signaling in Sorafenib-treated HepG2 cells. The effect of NO donors on above parameters has also been determined. Sorafenib induced apoptosis in HepG2 cells. However, low concentration of the drug (10nM) increased cell death receptor expression, as well as caspase-8 and -9 activation, but without activation of downstream apoptotic markers. In contrast, Sorafenib (10 µM) reduced upstream apoptotic parameters but increased caspase-3 activation and DNA fragmentation in HepG2 cells. The shift of cell death signaling pathway was associated with a reduction of S-nitrosylation of cell death receptors in Sorafenib-treated cells. The administration of NO donors increased S-nitrosylation of cell death receptors and overall induction of cell death markers in control and Sorafenib-treated cells. In conclusion, Sorafenib induced alteration of cell death receptor S-nitrosylation status which may have a relevant repercussion on cell death signaling in hepatoblastoma cells.

  15. Non-canonical kinase signaling by the death ligand TRAIL in cancer cells : discord in the death receptor family

    NARCIS (Netherlands)

    Azijli, K.; Weyhenmeyer, B.; Peters, G. J.; de Jong, S.; Kruyt, F. A. E.

    2013-01-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based therapy is currently evaluated in clinical studies as a tumor cell selective pro-apoptotic approach. However, besides activating canonical caspase-dependent apoptosis by binding to TRAIL-specific death receptors, the TRAIL ligand

  16. α-Hispanolol sensitizes hepatocellular carcinoma cells to TRAIL-induced apoptosis via death receptor up-regulation.

    Science.gov (United States)

    Mota, Alba; Jiménez-Garcia, Lidia; Herránz, Sandra; de Las Heras, Beatriz; Hortelano, Sonsoles

    2015-08-01

    Hispanolone derivatives have been previously described as anti-inflammatory and antitumoral agents. However, their effects on overcoming Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance remain to be elucidated. In this study, we analyzed the cytotoxic effects of the synthetic hispanolone derivative α-hispanolol (α-H) in several tumor cell lines, and we evaluated the induction of apoptosis, as well as the TRAIL-sensitizing potential of α-H in the hepatocellular carcinoma cell line HepG2. Our data show that α-H decreased cell viability in a dose-dependent manner in HeLa, MDA-MB231, U87 and HepG2 cell lines, with a more prominent effect in HepG2 cells. Interestingly, α-H had no effect on non-tumoral cells. α-H induced activation of caspase-8 and caspase-9 and also increased levels of the proapoptotic protein Bax, decreasing antiapoptotic proteins (Bcl-2, X-IAP and IAP-1) in HepG2 cells. Specific inhibition of caspase-8 abrogated the cascade of caspase activation, suggesting that the extrinsic pathway has a critical role in the apoptotic events induced by α-H. Furthermore, combined treatment of α-H with TRAIL enhanced apoptosis in HepG2 cells, activating caspase-8 and caspase-9. This correlated with up-regulation of both the TRAIL death receptor DR4 and DR5. DR4 or DR5 neutralizing antibodies abolished the effect of α-H on TRAIL-induced apoptosis, suggesting that sensitization was mediated through the death receptor pathway. Our results demonstrate that α-H induced apoptosis in the human hepatocellular carcinoma cell line HepG2 through activation of caspases and induction of the death receptor pathway. In addition, we describe a novel function of α-H as a sensitizer on TRAIL-induced apoptotic cell death in HepG2 cells. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Activation of intracellular angiotensin AT2 receptors induces rapid cell death in human uterine leiomyosarcoma cells

    DEFF Research Database (Denmark)

    Zhao, Yi; Lützen, Ulf; Fritsch, Jürgen

    2015-01-01

    The presence of AT2 receptors in mitochondria and their role in NO generation and cell aging were recently demonstrated in various human and mouse non-tumour cells. We investigated the intracellular distribution of AT2 receptors including their presence in mitochondria and the role in the induction...... densities in mitochondria. Activation of the cell membrane AT2 receptors by a concomitant treatment with angiotensin II and the AT1 receptor antagonist, losartan, induces apoptosis but does not affect the rate of cell death. We demonstrate for the first time that the high-affinity, non-peptide AT2 receptor...... of apoptosis and cell death in cultured human uterine leiomyosarcoma (SK-UT-1) cells and control human uterine smooth muscle cells (HutSMC). The intracellular levels of the AT2 receptor are low in proliferating SK-UT-1 cells but the receptor is substantially up-regulated in quiescent SK-UT-1 cells with high...

  18. Extrinsic Curvature Embedding Diagrams

    CERN Document Server

    Lu, J L

    2003-01-01

    Embedding diagrams have been used extensively to visualize the properties of curved space in Relativity. We introduce a new kind of embedding diagram based on the {\\it extrinsic} curvature (instead of the intrinsic curvature). Such an extrinsic curvature embedding diagram, when used together with the usual kind of intrinsic curvature embedding diagram, carries the information of how a surface is {\\it embedded} in the higher dimensional curved space. Simple examples are given to illustrate the idea.

  19. Schizophrenia, dissociative anaesthesia and near-death experience; three events meeting at the NMDA receptor.

    Science.gov (United States)

    Bonta, Iván L

    2004-01-01

    The three events, viz. schizophrenia, dissociative anaesthesia and Near-Death Experience, despite their seemingly unrelated manifestation to each other, have nevertheless similar functional basis. All three events are linked to the glutamate sensitive N-methyl-D-aspartate (NMDA) receptor complex, which serves as their common functional denominator. Arguments and speculations are presented in favor of the view that, the three events might be considered as functional models of each other. Antagonism to the recognition NMDA-site of the receptor induces dissociative anaesthesia and precipitates Near-Death Experience. Agonist reinforcement at the modulatory glycine-site of the receptor counteracts negative symptoms of schizophrenia. Both types of challenges towards the receptor are compatible with a glutamate deficiency concept which underlies the meeting of the three events at the NMDA receptor.

  20. Analysis of TRAIL receptor expression using anti-TRAIL death receptor-5 monoclonal antibodies

    Institute of Scientific and Technical Information of China (English)

    马远方; 杨东亮; 陈有海

    2003-01-01

    ObjectiveTo establish hybridomas that produce anti-death receptor-5 (DR5) monoclonal antibodies (mAbs) and check the surface expression of DR5 (sDR5) on cell lines.MethodsThe cDNA of human DR5 was cloned into pGAPZα. Recombinant Pichia pastoris clones generated via homologous recombination secreted high levels of sDR5. The sDR5 was purified using a nickel ion column. BALB/c mice were immunized with sDR5 and spleen cells were fused with the SP2/0-Ag 14. Monoclonal antibodies were tested by ELISA for their abilities binding to sDR5 and by flow cytometry for thereactivities to surface DR5 of Jurkat cells. Surface expression of the TRAIL receptor was determined by flow cytometric analysis measuring the binding of anti-DR5 mAb. Resultse to sDR5 as observed through ELISA. It was discovered using flow cytometry that only IgG was able to bind to DR5 on the plasma membrane of Jurkat cells. sDR5was found to completely inhibit anti-DR5 mAb binding to Jurkat cells. Pproximately 95% of Jurkat cells, 98% SW480, 99% U937, 100% U87, 86% HCT116, 64% HL-60, 47% HeLa and 13% K562 cells express membrane DR5. ConclusionsThese results demonstrate that anti-DR5 mAb is able to specifically bind to DR5and that DR5 is expressed at high levels on Jurkat, SW480, U87, U937 and HCT116cell lines, and at medium levels on HL-60 and HeLa cell lines. The expressionof DR5 on K562 cell line is low.

  1. Activation of intracellular angiotensin AT₂ receptors induces rapid cell death in human uterine leiomyosarcoma cells.

    Science.gov (United States)

    Zhao, Yi; Lützen, Ulf; Fritsch, Jürgen; Zuhayra, Maaz; Schütze, Stefan; Steckelings, Ulrike M; Recanti, Chiara; Namsoleck, Pawel; Unger, Thomas; Culman, Juraj

    2015-05-01

    The presence of angiotensin type 2 (AT₂) receptors in mitochondria and their role in NO generation and cell aging were recently demonstrated in various human and mouse non-tumour cells. We investigated the intracellular distribution of AT₂ receptors including their presence in mitochondria and their role in the induction of apoptosis and cell death in cultured human uterine leiomyosarcoma (SK-UT-1) cells and control human uterine smooth muscle cells (HutSMC). The intracellular levels of the AT₂ receptor are low in proliferating SK-UT-1 cells but the receptor is substantially up-regulated in quiescent SK-UT-1 cells with high densities in mitochondria. Activation of the cell membrane AT₂ receptors by a concomitant treatment with angiotensin II and the AT₁ receptor antagonist, losartan, induces apoptosis but does not affect the rate of cell death. We demonstrate for the first time that the high-affinity, non-peptide AT₂ receptor agonist, Compound 21 (C21), penetrates the cell membrane of quiescent SK-UT-1 cells, activates intracellular AT₂ receptors and induces rapid cell death; approximately 70% of cells died within 24 h. The cells, which escaped cell death, displayed activation of the mitochondrial apoptotic pathway, i.e. down-regulation of the Bcl-2 protein, induction of the Bax protein and activation of caspase-3. All quiescent SK-UT-1 cells died within 5 days after treatment with a single dose of C21. C21 was devoid of cytotoxic effects in proliferating SK-UT-1 cells and in quiescent HutSMC. Our results point to a new, unique approach enabling the elimination non-cycling uterine leiomyosarcoma cells providing that they over-express the AT₂ receptor.

  2. Measuring glutamate receptor activation-induced apoptotic cell death in ischemic rat retina using the TUNEL assay

    OpenAIRE

    Ju, Won-Kyu; Kim, Keun-Young(School of Physics and Chemistry, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea)

    2011-01-01

    Glutamate receptor activation-mediated excitotoxicity has been hypothesized to cause cell death in both acute and chronic neurodegenerative diseases including glaucoma. Although the precise mechanisms of ischemia-induced neuronal death are unknown, glutamate excitotoxicty-induced apoptotic cell death is considered to be an important component of postischemic damage in the retina. The blockade of apoptotic cell death induced by glutamate receptor activation provides strong evidence that glutam...

  3. Dual-specific Phosphatase-6 (Dusp6) and ERK Mediate AMPA Receptor-induced Oligodendrocyte Death*

    Science.gov (United States)

    Domercq, Maria; Alberdi, Elena; Sánchez-Gómez, Maria Victoria; Ariz, Usue; Pérez-Samartín, Alberto; Matute, Carlos

    2011-01-01

    Oligodendrocytes, the myelinating cells of the CNS, are highly vulnerable to glutamate excitotoxicity, a mechanism involved in tissue damage in multiple sclerosis. Thus, understanding oligodendrocyte death at the molecular level is important to develop new therapeutic approaches to treat the disease. Here, using microarray analysis and quantitative PCR, we observed that dual-specific phosphatase-6 (Dusp6), an extracellular regulated kinase-specific phosphatase, is up-regulated in oligodendrocyte cultures as well as in optic nerves after AMPA receptor activation. In turn, Dusp6 is overexpressed in optic nerves from multiple sclerosis patients before the appearance of evident damage in this structure. We further analyzed the role of Dusp6 and ERK signaling in excitotoxic oligodendrocyte death and observed that AMPA receptor activation induces a rapid increase in ERK1/2 phosphorylation. Blocking Dusp6 expression, which enhances ERK1/2 phosphorylation, significantly diminished AMPA receptor-induced oligodendrocyte death. In contrast, MAPK/ERK pathway inhibition with UO126 significantly potentiates excitotoxic oligodendrocyte death and increases cytochrome c release, mitochondrial depolarization, and mitochondrial calcium overload produced by AMPA receptor stimulation. Upstream analysis demonstrated that MAPK/ERK signaling alters AMPA receptor properties. Indeed, Dusp6 overexpression as well as incubation with UO126 produced an increase in AMPA receptor-induced inward currents and cytosolic calcium overload. Together, these data suggest that levels of phosphorylated ERK, controlled by Dusp6 phosphatase, regulate glutamate receptor permeability and oligodendroglial excitotoxicity. Therefore, targeting Dusp6 may be a useful strategy to prevent oligodendrocyte death in multiple sclerosis and other diseases involving CNS white matter. PMID:21300799

  4. Androgen receptor coregulator ARA267-α interacts with death receptor-6 revealed by the yeast two-hybrid

    Institute of Scientific and Technical Information of China (English)

    2004-01-01

    ARA267-αis a newly identified androgen receptor coactivator.In order to further elucidate its precise role in cells,using the ARA267- α fragment containing four PHD and one SET conserved domains as bait we revealed an ARA267-α-PHD-SET-interacting protein,death receptor-6(DR6),in the yeast two-hybrid screening.DR6 is the member of TNF receptor family and has a death domain in its intracellular cytoplasmic portion(DR6cp)to mediate the cell apoptosis.The interaction between ARA267-α-PHD-SET and DR6cp was confirmed in vitro and in vivo.Our finding implied that androgen signaling pathway might cross talk with apoptosis signaling pathway through the interaction between ARA267-α and DR6.

  5. Enhancement of antitumor properties of rhTRAIL by affinity increase toward its death receptors.

    Science.gov (United States)

    Reis, Carlos R; van der Sloot, Almer M; Szegezdi, Eva; Natoni, Alessandro; Tur, Vicente; Cool, Robbert H; Samali, Afshin; Serrano, Luis; Quax, Wim J

    2009-03-17

    Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent and selective inducer of apoptosis in various tumor types, raising enthusiasm for TRAIL as a potential anticancer agent. TRAIL-induced apoptosis is mediated by death receptors 4 (DR4) and DR5. The design of rhTRAIL variants either with improved affinity or selectivity toward one or both death-inducing receptors is thought to enhance the therapeutical potential of TRAIL. Here we demonstrate that a single amino acid mutation at the position of glycine 131 to lysine or arginine in wild-type rhTRAIL significantly improved the affinity of rhTRAIL toward its death receptors, with the highest affinity increase observed for the DR4 receptor. These variants were able to induce higher in vitro levels of apoptosis in cancer cells responsive to only DR4 or to both death receptors and could therefore increase the potential use of rhTRAIL as an anticancer therapeutic agent.

  6. Critical role of the death receptor pathway in the antitumoral effects induced by hispanolone derivatives.

    Science.gov (United States)

    Través, P G; López-Fontal, R; Cuadrado, I; Luque, A; Boscá, L; de las Heras, B; Hortelano, S

    2013-01-10

    Labdane diterpenoids have a broad spectrum of biological activities including antibacterial, antiviral and anti-inflammatory properties. However, little is known about their possible role in the apoptotic cell death machinery. Here, we report that hispanolone derivatives, a group of labdane diterpenoids, induce apoptosis in different tumor cell lines by activating caspase-8 with subsequent participation of mitochondrial signaling. Activation of caspase-8 by hispanolone derivatives was followed by a decrease in mitochondrial membrane potential, the release of apoptotic factors from mitochondria to the cytosol, and activation of caspases-9 and 3. Hispanolone derivatives also led to a time-dependent cleavage of Bid. Inhibition of caspase-8 abrogated these processes, suggesting that the death receptor pathway has a critical role in the apoptotic events induced by hispanolone derivatives. In addition, silencing death receptors with small interfering RNA s or pretreating cells with neutralizing antibodies to Fas ligand, tumor necrosis factor receptor 1 (TNF-R1), and TNF-α receptor 2 (TRAIL) inhibited diterpenoid-induced apoptosis, revealing it to be dependent on these death receptors. Interestingly, hispanolone derivatives had no effect on non-tumor cells. Consistently, in vivo bioluminescence imaging corroborates this antineoplasic effect, as hispanolone derivatives significantly decrease cancer growth in tumor xenograft assays. These data demostrate the antitumoral effects of hispanolone derivatives and provide relevant preclinical validation for the use of these compounds as potent therapeutic agents in cancer treatment.

  7. A3 Adenosine receptors mediate oligodendrocyte death and ischemic damage to optic nerve.

    Science.gov (United States)

    González-Fernández, Estíbaliz; Sánchez-Gómez, María Victoria; Pérez-Samartín, Alberto; Arellano, Rogelio O; Matute, Carlos

    2014-02-01

    Adenosine receptor activation is involved in myelination and in apoptotic pathways linked to neurodegenerative diseases. In this study, we investigated the effects of adenosine receptor activation in the viability of oligodendrocytes of the rat optic nerve. Selective activation of A3 receptors in pure cultures of oligodendrocytes caused concentration-dependent apoptotic and necrotic death which was preceded by oxidative stress and mitochondrial membrane depolarization. Oligodendrocyte apoptosis induced by A3 receptor activation was caspase-dependent and caspase-independent. In addition to dissociated cultures, incubation of optic nerves ex vivo with adenosine and the A3 receptor agonist 2-CI-IB-MECA(1-[2-Chloro-6-[[(3-iodophenyl)methyl]amino]-9H-purin-9-yl]-1-deoxy-N-methyl-b-D-ribofuranuronamide)-induced caspase-3 activation, oligodendrocyte damage, and myelin loss, effects which were prevented by the presence of caffeine and the A3 receptor antagonist MRS 1220 (N-[9-Chloro-2-(2-furanyl)[1,2,4]-triazolo [1,5-c]quinazolin-5-yl]benzene acetamide). Finally, ischemia-induced injury and functional loss to the optic nerve was attenuated by blocking A3 receptors. Together, these results indicate that adenosine may trigger oligodendrocyte death via activation of A3 receptors and suggest that this mechanism contributes to optic nerve and white matter ischemic damage.

  8. Soluble TL1A is sufficient for activation of death receptor 3.

    Science.gov (United States)

    Bittner, Sebastian; Knoll, Gertrud; Füllsack, Simone; Kurz, Maria; Wajant, Harald; Ehrenschwender, Martin

    2016-01-01

    Death receptor 3 (DR3) is a typical member of the tumor necrosis factor receptor family, and was initially identified as a T-cell co-stimulatory molecule. However, further studies revealed a more complex and partly dichotomous role for DR3 and its ligand TL1A under (patho)physiological conditions. TL1A and DR3 are not only a driving force in the development of autoimmune and inflammatory diseases, but also play an important role in counteracting these processes through an increase in the number of regulatory T cells. Ligands of the tumor necrosis factor family typically occur in two forms, membrane-bound and soluble, that can differ strikingly with respect to their efficacy in activating their corresponding receptor(s). Ligand-based approaches to activate the TL1A-DR3 pathway therefore require understanding of the molecular prerequisites of TL1A-based DR3 activation. To date, this has not been addressed. Here, we show that recombinant soluble trimeric TL1A is fully sufficient to strongly activate DR3-associated pro- and anti-apoptotic signaling pathways. In contrast to the TRAIL death receptors, which are much better activated by soluble TRAIL upon secondary ligand oligomerization, but similarly to the death receptor tumor necrosis factor receptor 1, DR3 is efficiently activated by soluble TL1A trimers. Additionally, we have measured the affinity of TL1A-DR3 interaction in a cell-based system, and demonstrated TL1A-induced DR3 internalization. Identification of DR3 as a tumor necrosis factor receptor that responds to soluble ligand trimers without further oligomerization provides a basis for therapeutic exploitation of the TL1A-DR3 pathway.

  9. Extrinsic allergic alveolitis.

    Science.gov (United States)

    Ismail, Tengku; McSharry, Charles; Boyd, Gavin

    2006-05-01

    Extrinsic allergic alveolitis (also known as hypersensitivity pneumonitis) is caused by repeated inhalation of mainly organic antigens by sensitized subjects. This induces a hypersensitivity response in the distal bronchioles and alveoli and subjects may present clinically with a variety of symptoms. The aims of this review are to describe the current concepts of the immunological response, the diverse clinical presentation of this disease, the relevant investigations and management, and areas for future studies.

  10. TRAIL Death Receptor-4, Decoy Receptor-1 and Decoy Receptor-2 Expression on CD8+ T Cells Correlate with the Disease Severity in Patients with Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Bisgin Atil

    2010-08-01

    Full Text Available Abstract Background Rheumatoid Arthritis (RA is a chronic autoimmune inflammatory disorder. Although the pathogenesis of disease is unclear, it is well known that T cells play a major role in both development and perpetuation of RA through activating macrophages and B cells. Since the lack of TNF-Related Apoptosis Inducing Ligand (TRAIL expression resulted in defective thymocyte apoptosis leading to an autoimmune disease, we explored evidence for alterations in TRAIL/TRAIL receptor expression on peripheral T lymphocytes in the molecular mechanism of RA development. Methods The expression of TRAIL/TRAIL receptors on T cells in 20 RA patients and 12 control individuals were analyzed using flow cytometry. The correlation of TRAIL and its receptor expression profile was compared with clinical RA parameters (RA activity scored as per DAS28 using Spearman Rho Analysis. Results While no change was detected in the ratio of CD4+ to CD8+ T cells between controls and RA patient groups, upregulation of TRAIL and its receptors (both death and decoy was detected on both CD4+ and CD8+ T cells in RA patients compared to control individuals. Death Receptor-4 (DR4 and the decoy receptors DcR1 and DcR2 on CD8+ T cells, but not on CD4+ T cells, were positively correlated with patients' DAS scores. Conclusions Our data suggest that TRAIL/TRAIL receptor expression profiles on T cells might be important in revelation of RA pathogenesis.

  11. The P2X7 receptor supports both life and death in fibrogenic pancreatic stellate cells.

    Directory of Open Access Journals (Sweden)

    Kristian A Haanes

    Full Text Available The pancreatic stellate cells (PSCs have complex roles in pancreas, including tissue repair and fibrosis. PSCs surround ATP releasing exocrine cells, but little is known about purinergic receptors and their function in PSCs. Our aim was to resolve whether PSCs express the multifunctional P2X7 receptor and elucidate how it regulates PSC viability. The number of PSCs isolated from wild type (WT mice was 50% higher than those from the Pfizer P2X7 receptor knock out (KO mice. The P2X7 receptor protein and mRNA of all known isoforms were expressed in WT PSCs, while KO PSCs only expressed truncated versions of the receptor. In culture, the proliferation rate of the KO PSCs was significantly lower. Inclusion of apyrase reduced the proliferation rate in both WT and KO PSCs, indicating importance of endogenous ATP. Exogenous ATP had a two-sided effect. Proliferation of both WT and KO cells was stimulated with ATP in a concentration-dependent manner with a maximum effect at 100 µM. At high ATP concentration (5 mM, WT PSCs, but not the KO PSCs died. The intracellular Ca(2+ signals and proliferation rate induced by micromolar ATP concentrations were inhibited by the allosteric P2X7 receptor inhibitor az10606120. The P2X7 receptor-pore inhibitor A438079 partially prevented cell death induced by millimolar ATP concentrations. This study shows that ATP and P2X7 receptors are important regulators of PSC proliferation and death, and therefore might be potential targets for treatments of pancreatic fibrosis and cancer.

  12. M1 muscarinic receptor activation mediates cell death in M1-HEK293 cells.

    Science.gov (United States)

    Graham, E Scott; Woo, Kerhan K; Aalderink, Miranda; Fry, Sandie; Greenwood, Jeffrey M; Glass, Michelle; Dragunow, Mike

    2013-01-01

    HEK293 cells have been used extensively to generate stable cell lines to study G protein-coupled receptors, such as muscarinic acetylcholine receptors (mAChRs). The activation of M1 mAChRs in various cell types in vitro has been shown to be protective. To further investigate M1 mAChR-mediated cell survival, we generated stable HEK293 cell-lines expressing the human M1 mAChR. M1 mAChRs were efficiently expressed at the cell surface and efficiently internalised within 1 h by carbachol. Carbachol also induced early signalling cascades similar to previous reports. Thus, ectopically expressed M1 receptors behaved in a similar fashion to the native receptor over short time periods of analysis. However, substantial cell death was observed in HEK293-M1 cells within 24 h after carbachol application. Death was only observed in HEK cells expressing M1 receptors and fully blocked by M1 antagonists. M1 mAChR-stimulation mediated prolonged activation of the MEK-ERK pathway and resulted in prolonged induction of the transcription factor EGR-1 (>24 h). Blockade of ERK signalling with U0126 did not reduce M1 mAChR-mediated cell-death significantly but inhibited the acute induction of EGR-1. We investigated the time-course of cell death using time-lapse microscopy and xCELLigence technology. Both revealed the M1 mAChR cytotoxicity occurs within several hours of M1 activation. The xCELLigence assay also confirmed that the ERK pathway was not involved in cell-death. Interestingly, the MEK blocker did reduce carbachol-mediated cleaved caspase 3 expression in HEK293-M1 cells. The HEK293 cell line is a widely used pharmacological tool for studying G-protein coupled receptors, including mAChRs. Our results highlight the importance of investigating the longer term fate of these cells in short term signalling studies. Identifying how and why activation of the M1 mAChR signals apoptosis in these cells may lead to a better understanding of how mAChRs regulate cell-fate decisions.

  13. Rapid and efficient cancer cell killing mediated by high-affinity death receptor homotrimerizing TRAIL variants.

    Science.gov (United States)

    Reis, C R; van der Sloot, A M; Natoni, A; Szegezdi, E; Setroikromo, R; Meijer, M; Sjollema, K; Stricher, F; Cool, R H; Samali, A; Serrano, L; Quax, W J

    2010-10-21

    The tumour necrosis factor family member TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in a variety of cancer cells through the activation of death receptors 4 (DR4) and 5 (DR5) and is considered a promising anticancer therapeutic agent. As apoptosis seems to occur primarily via only one of the two death receptors in many cancer cells, the introduction of DR selectivity is thought to create more potent TRAIL agonists with superior therapeutic properties. By use of a computer-aided structure-based design followed by rational combination of mutations, we obtained variants that signal exclusively via DR4. Besides an enhanced selectivity, these TRAIL-DR4 agonists show superior affinity to DR4, and a high apoptosis-inducing activity against several TRAIL-sensitive and -resistant cancer cell lines in vitro. Intriguingly, combined treatment of the DR4-selective variant and a DR5-selective TRAIL variant in cancer cell lines signalling by both death receptors leads to a significant increase in activity when compared with wild-type rhTRAIL or each single rhTRAIL variant. Our results suggest that TRAIL induced apoptosis via high-affinity and rapid-selective homotrimerization of each DR represent an important step towards an efficient cancer treatment.

  14. Signal transduction mediated by Bid, a pro-death Bcl-2 family proteins, connects the death receptor and mitochondria apoptosis pathways

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Two major apoptosis pathways have been defined in mammalian cells, the Fas/TNF-R1 death receptor pathway and the mitochondria pathway. The Bcl-2 family proteins consist of both anti-apoptosis and pro- apoptosis members that regulate apoptosis, mainly by controlling the release of cytochrome c and other mitochondrial apoptotic events. However, death signals mediated by Fas/TNF-R1 receptors can usually activate caspases directly, bypassing the need for mitochondria and escaping the regulation by Bcl-2 family proteins. Bid is a novel pro-apoptosis Bcl-2 family protein that is activated by caspase 8 in response to Fas/TNF-R1 death receptor signals. Activated Bid is translocated to mitochondria and induces cytochrome c release, which in turn activates downstream caspases. Such a connection between the two apoptosis pathways could be important for induction of apoptosis in certain types of cells and responsible for the pathogenesis of a number of human diseases.

  15. Ionotropic receptors and ion channels in ischemic neuronal death and dysfunction

    Institute of Scientific and Technical Information of China (English)

    Nicholas L WEILINGER; Valentyna MASLIEIEVA; Jennifer BIALECKI; Sarup S SRIDHARAN; Peter L TANG; Roger J THOMPSON

    2013-01-01

    Loss of energy supply to neurons during stroke induces a rapid loss of membrane potential that is called the anoxic depolarization.Anoxic depolarizations result in tremendous physiological stress on the neurons because of the dysregulation of ionic fluxes and the loss of ATP to drive ion pumps that maintain electrochemical gradients.In this review,we present an overview of some of the ionotropic receptors and ion channels that are thought to contribute to the anoxic depolarization of neurons and subsequently,to cell death.The ionotropic receptors for glutamate and ATP that function as ligand-gated cation channels are critical in the death and dysfunction of neurons.Interestingly,two of these receptors (P2X7 and NMDAR) have been shown to couple to the pannexin-1 (Panx1) ion channel.We also discuss the important roles of transient receptor potential (TRP) channels and acid-sensing ion channels (ASICs) in responses to ischemia.The central challenge that emerges from our current understanding of the anoxic depolarization is the need to elucidate the mechanistic and temporal interrelations of these ion channels to fully appreciate their impact on neurons during stroke.

  16. The cytoplasmic nuclear receptor RARγ controls RIP1 initiated cell death when cIAP activity is inhibited.

    Science.gov (United States)

    Xu, Qing; Jitkaew, Siriporn; Choksi, Swati; Kadigamuwa, Chamila; Qu, Jianhui; Choe, Moran; Jang, Jonathan; Liu, Chengyu; Liu, Zheng-Gang

    2017-09-04

    Tumor necrosis factor (TNF) has a critical role in diverse cellular events including inflammation, apoptosis and necroptosis through different signaling complexes. However, little is known about how the transition from inflammatory signaling to the engagement of death pathways is modulated. Here we report that the cytoplasmic retinoic acid receptor gamma (RARγ) controls receptor-interacting protein kinase 1 (RIP1)-initiated cell death when cellular inhibitor of apoptosis (cIAP) activity is blocked. Through screening a short hairpin RNA library, we found that RARγ was essential for TNF-induced RIP1-initiated apoptosis and necroptosis. Our data suggests that RARγ initiates the formation of death signaling complexes by mediating RIP1 dissociation from TNF receptor 1. We demonstrate that RARγ is released from the nucleus to orchestrate the formation of the cytosolic death complexes. In addition, we demonstrate that RARγ has a similar role in TNF-induced necroptosis in vivo. Thus, our study suggests that nuclear receptor RARγ provides a key checkpoint for the transition from life to death.The molecular switch between how tumour necrosis factor (TNF) controls inflammation versus cell death is less well defined. Here, the authors show that the nuclear receptor retinoic acid receptor gamma is released from the nucleus to disrupt TNF initiated cell death complexes in the cytoplasm.

  17. Purinergic P2X7 receptors mediate cell death in mouse cerebellar astrocytes in culture.

    Science.gov (United States)

    Salas, Elvira; Carrasquero, Luz María G; Olivos-Oré, Luis A; Bustillo, Diego; Artalejo, Antonio R; Miras-Portugal, Maria Teresa; Delicado, Esmerilda G

    2013-12-01

    The brain distribution and functional role of glial P2X7 receptors are broader and more complex than initially anticipated. We characterized P2X7 receptors from cerebellar astrocytes at the molecular, immunocytochemical, biophysical, and cell physiologic levels. Mouse cerebellar astrocytes in culture express mRNA coding for P2X7 receptors, which is translated into P2X7 receptor protein as proven by Western blot analysis and immunocytochemistry. Fura-2 imaging showed cytosolic calcium responses to ATP and the synthetic analog 3'-O-(4-benzoyl)benzoyl-ATP (BzATP) exhibited two components, namely an initial transient and metabotropic component followed by a sustained one that depended on extracellular calcium. This latter component, which was absent in astrocytes from P2X7 receptor knockout mice (P2X7 KO), was modulated by extracellular Mg(2+), and was sensitive to Brilliant Blue G (BBG) and 3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methyl pyridine (A438079) antagonism. BzATP also elicited inwardly directed nondesensitizing whole-cell ionic currents that were reduced by extracellular Mg(2+) and P2X7 antagonists (BBG and calmidazolium). In contrast to that previously reported in rat cerebellar astrocytes, sustained BzATP application induced a gradual increase in membrane permeability to large cations, such as N-methyl-d-glucamine and 4-[3-methyl-2(3H)-benzoxazolylidene)-methyl]-1-[3-(triethylammonio)propyl]diiodide, which ultimately led to the death of mouse astrocytes. Cerebellar astrocyte cell death was prevented by BBG but not by calmidazolium, removal of extracellular calcium, or treatment with the caspase-3 inhibitor, benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethylketone, thus suggesting a necrotic-type mechanism of cell death. Since this cellular response was not observed in astrocytes from P2X7 KO mice, this study suggests that stimulation of P2X7 receptor may convey a cell death signal to cerebellar astrocytes in a species-specific manner.

  18. Humanization of an agonistic anti-death receptor 4 single chain variable fragment antibody and avidity-mediated enhancement of its cell death-inducing activity.

    Science.gov (United States)

    Lee, Seung-Hyun; Park, Dong-Woon; Sung, Eun-Sil; Park, Hye-Ran; Kim, Jin-Kyoo; Kim, Yong-Sung

    2010-01-01

    Development of agonistic monoclonal antibodies (mAbs) against the pro-apoptotic molecule death receptor 4 (DR4) [or tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) receptor 1] is an attractive anti-cancer strategy because of their potential for inducing tumor-specific cell death. In this study, we humanized an agonistic anti-DR4 AY4 scFv raised in mice (mAY4) by grafting the complementarity-determining regions (CDRs) onto a fixed human framework, while preserving the so-called Vernier zone residues, a group of framework (FR) residues directly underneath the CDRs, with the murine residues in the humanized antibody, hAY4. The humanized hAY4 scFv maintained the antigen binding affinity and epitope specificity of mAY4. To investigate how the valence of hAY4 scFv affects DR4-mediated cell death, bivalent and trivalent forms of hAY4 scFv were generated by linking a hinge region to the coiled-coil domain of a dimerizing leucine zipper and trimerizing isoleucine zipper, respectively. Compared to the monovalent and bivalent forms, the trivalent hAY4 scFv induced more potent caspase-dependent apoptotic cell death as evidenced by increased activation of caspase-8 and downstream pro-apoptotic molecules. Our results suggest that like other TNF family receptors, avidity-mediated oligomerization of DR4 augments the receptor-mediated apoptotic cell death by promoting intracellular cell death signaling.

  19. Biphasic coupling of neuronal nitric oxide synthase phosphorylation to the NMDA receptor regulates AMPA receptor trafficking and neuronal cell death.

    Science.gov (United States)

    Rameau, Gerald A; Tukey, David S; Garcin-Hosfield, Elsa D; Titcombe, Roseann F; Misra, Charu; Khatri, Latika; Getzoff, Elizabeth D; Ziff, Edward B

    2007-03-28

    Postsynaptic nitric oxide (NO) production affects synaptic plasticity and neuronal cell death. Ca2+ fluxes through the NMDA receptor (NMDAR) stimulate the production of NO by neuronal nitric oxide synthase (nNOS). However, the mechanisms by which nNOS activity is regulated are poorly understood. We evaluated the effect of neuronal stimulation with glutamate on the phosphorylation of nNOS. We show that, in cortical neurons, a low glutamate concentration (30 microM) induces rapid and transient NMDAR-dependent phosphorylation of S1412 by Akt, followed by sustained phosphorylation of S847 by CaMKII (calcium-calmodulin-dependent kinase II). We demonstrate that phosphorylation of S1412 by Akt is necessary for activation of nNOS by the NMDAR. nNOS mutagenesis confirms that these phosphorylations respectively activate and inhibit nNOS and, thus, transiently activate NO production. A constitutively active (S1412D), but not a constitutively repressed (S847D) nNOS mutant elevated surface glutamate receptor 2 levels, demonstrating that these phosphorylations can control AMPA receptor trafficking via NO. Notably, an excitotoxic stimulus (150 microM glutamate) induced S1412, but not S847 phosphorylation, leading to deregulated nNOS activation. S1412D did not kill neurons; however, it enhanced the excitotoxicity of a concomitant glutamate stimulus. We propose a swinging domain model for the regulation of nNOS: S1412 phosphorylation facilitates electron flow within the reductase module of nNOS, increasing nNOS sensitivity to Ca2+-calmodulin. These findings suggest a critical role for a kinetically complex and novel series of regulatory nNOS phosphorylations induced by the NMDA receptor for the in vivo control of nNOS.

  20. Functional analysis of the posttranslational modifications of the death receptor 6.

    Science.gov (United States)

    Klíma, Martin; Zájedová, Jitka; Doubravská, Lenka; Andera, Ladislav

    2009-10-01

    Death receptor 6 (DR6/TNFRSF21) is a death domain-containing receptor of the TNFR superfamily with an apparent regulatory function in hematopoietic and neuronal cells. In this study we document that DR6 is an extensively posttranslationally modified transmembrane protein and that N- and O-glycosylations of amino acids in its extracellular part are mainly responsible for its approximately 40 kDa mobility shift in SDS polyacrylamide gels. Site-directed mutagenesis confirmed that all six extracellular asparagines are N-glycosylated and that the Ser/Thr/Pro cluster in the "stalk" domain juxtaposed to the cysteine-rich domains (CRDs) is a major site for the likely mucine-type of O-glycosylation. Deletion of the entire linker region between CRDs and the transmembrane domain, spanning over 130 amino acids, severely compromises the plasma membrane localization of DR6 and leads to its intracellular retention. Biosynthetic labeling with radiolabeled palmitate and side-directed mutagenesis also revealed that the membrane-proximal Cys368 in the intracellular part of DR6 is, similarly as cysteines in Fas/CD95 or DR4 ICPs, S-palmitoylated. However, palmitoylation of Cys368 is apparently not required for DR6 targeting into Brij-98 insoluble lipid rafts. In contrast, we show that N-glycosylation of the extracellular part might participate in directing DR6 into these membrane microdomains.

  1. TRAF2 Sets a threshold for extrinsic apoptosis by tagging caspase-8 with a ubiquitin shutoff timer.

    Science.gov (United States)

    Gonzalvez, Francois; Lawrence, David; Yang, Becky; Yee, Sharon; Pitti, Robert; Marsters, Scot; Pham, Victoria C; Stephan, Jean-Philippe; Lill, Jennie; Ashkenazi, Avi

    2012-12-28

    Apoptotic caspase activation mechanisms are well defined, yet inactivation modes remain unclear. The death receptors (DRs), DR4, DR5, and Fas, transduce cell-extrinsic apoptotic signals by recruiting caspase-8 into a death-inducing signaling complex (DISC). At the DISC, Cullin3-dependent polyubiquitination on the small catalytic subunit of caspase-8 augments stimulation. Here we report that tumor necrosis factor receptor-associated factor 2 (TRAF2) interacts with caspase-8 at the DISC, downstream of Cullin3. TRAF2 directly mediates RING-dependent, K48-linked polyubiquitination on the large catalytic domain of caspase-8. This modification destines activated caspase-8 molecules to rapid proteasomal degradation upon autoprocessing and cytoplasmic translocation. TRAF2 depletion lowers the signal threshold for DR-mediated apoptosis, altering cell life versus death decisions in vitro and in vivo. Thus, TRAF2 sets a critical barrier for cell-extrinsic apoptosis commitment by tagging activated caspase-8 with a K48-ubiquitin shutoff timer. These results may have important implications for caspase regulation mechanisms. Copyright © 2012 Elsevier Inc. All rights reserved.

  2. Expression of tumour necrosis factor-related apoptosis-inducing ligand death receptors in sporadic and hereditary colorectal tumours : Potential targets for apoptosis induction

    NARCIS (Netherlands)

    Koornstra, JJ; Jalving, M; Rijcken, FEM; Westra, Jantine; Zwart, N; Hollema, H; de Vries, EGE; Hofstra, RWM; Plukker, JTM; de Jong, S; Kleibeuker, JH

    2005-01-01

    Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and antibodies against TRAIL receptors death receptor 4 (DR4) and death receptor 5 (DR5) are under investigation for cancer therapy. To study the potential application of these agents, the expression of DR4 and DR5 were studied immunoh

  3. Immunologic checkpoints in cancer therapy: focus on the programmed death-1 (PD-1 receptor pathway

    Directory of Open Access Journals (Sweden)

    Momtaz P

    2014-11-01

    Full Text Available Parisa Momtaz,1,2 Michael A Postow1,2 1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 2Weill Cornell Medical College, New York, NY, USA Abstract: T-lymphocytes have the potential to recognize cancer antigens as foreign and therefore eliminate them. However, immune checkpoints such as cytotoxic T-lymphocyte-associated antigen (CTLA-4 and programmed cell death (PD-1 receptor and its ligands (PD-L1, PD-L2 suppress the activity of T-lymphocytes. Advances in the understanding of immunology and its role in cancer have led to the development of immune checkpoint inhibitors that block CTLA-4 and PD-1 and result in durable responses in patients with a wide range of cancers. PD-1 and PD-L1 inhibitors are currently in many stages of clinical investigation, and the anti-PD-1 antibody, pembrolizumab, was recently approved by the US Food and Drug Administration. Many questions remain to be answered, such as the optimal administration schedule, biomarkers that associate with benefit, and potential for use of PD-1 agents in combination approaches. Nonetheless, immunotherapy with PD-1 blocking antibodies is now becoming an integral part in the management of cancer. Keyword: immune checkpoints, immunotherapy, programmed cell death protein-1, cytotoxic T-lymphocyte antigen 4

  4. E-cadherin couples death receptors to the cytoskeleton to regulate apoptosis.

    Science.gov (United States)

    Lu, Min; Marsters, Scot; Ye, Xiaofen; Luis, Elizabeth; Gonzalez, Lino; Ashkenazi, Avi

    2014-06-19

    Epithelial-to-mesenchymal transition (EMT) is a cellular process essential to the development and maintenance of solid tissues. In cancer, EMT suppresses apoptosis, but the mechanisms remain unclear. EMT selectively attenuated apoptosis signaling via the death receptors DR4 and DR5. Loss of the epithelial cell adhesion protein E-cadherin recapitulated this outcome, whereas homotypic E-cadherin engagement promoted apoptotic signaling via DR4/DR5, but not Fas. Depletion of α-catenin, which couples E-cadherin to the actin cytoskeleton, or actin polymerization inhibitors similarly attenuated DR4/DR5-induced apoptosis. E-cadherin bound specifically to ligated DR4/DR5, requiring extracellular cadherin domain 1 and calcium. E-cadherin augmented DR4/DR5 clustering and assembly of the death-inducing signaling complex (DISC), increasing caspase-8 activation in high molecular weight cell fractions. Conversely, EMT attenuated DR4/DR5-mediated DISC formation and caspase-8 stimulation. Consistent with these findings, epithelial cancer cell lines expressing higher E-cadherin levels displayed greater sensitivity to DR4/DR5-mediated apoptosis. These results have potential implications for tissue homeostasis as well as cancer therapy.

  5. Myeloid zinc finger 1 mediates sulindac sulfide-induced upregulation of death receptor 5 of human colon cancer cells

    OpenAIRE

    Mano Horinaka; Tatsushi Yoshida; Mitsuhiro Tomosugi; Shusuke Yasuda; Yoshihiro Sowa; Toshiyuki Sakai

    2014-01-01

    A combined therapy of sulindac sulfide and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising strategy for the treatment of cancer. Sulindac sulfide had been shown to induce the expression of death receptor 5 (DR5), a receptor for TRAIL, and sensitize cancer cells to TRAIL-induced apoptosis; however, the molecular mechanism underlying the upregulation of DR5 has not yet been elucidated. We demonstrate here that myeloid zinc finger 1 (MZF1) mediates the induction of...

  6. 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....

  7. Blocking NMDA receptors delays death in rats with acute liver failure by dual protective mechanisms in kidney and brain.

    Science.gov (United States)

    Cauli, Omar; González-Usano, Alba; Cabrera-Pastor, Andrea; Gimenez-Garzó, Carla; López-Larrubia, Pilar; Ruiz-Sauri, Amparo; Hernández-Rabaza, Vicente; Duszczyk, Malgorzata; Malek, Michal; Lazarewicz, Jerzy W; Carratalá, Arturo; Urios, Amparo; Miguel, Alfonso; Torregrosa, Isidro; Carda, Carmen; Montoliu, Carmina; Felipo, Vicente

    2014-06-01

    Treatment of patients with acute liver failure (ALF) is unsatisfactory and mortality remains unacceptably high. Blocking NMDA receptors delays or prevents death of rats with ALF. The underlying mechanisms remain unclear. Clarifying these mechanisms will help to design more efficient treatments to increase patient's survival. The aim of this work was to shed light on the mechanisms by which blocking NMDA receptors delays rat's death in ALF. ALF was induced by galactosamine injection. NMDA receptors were blocked by continuous MK-801 administration. Edema and cerebral blood flow were assessed by magnetic resonance. The time course of ammonia levels in brain, muscle, blood, and urine; of glutamine, lactate, and water content in brain; of glomerular filtration rate and kidney damage; and of hepatic encephalopathy (HE) and intracranial pressure was assessed. ALF reduces kidney glomerular filtration rate (GFR) as reflected by reduced inulin clearance. GFR reduction is due to both reduced renal perfusion and kidney tubular damage as reflected by increased Kim-1 in urine and histological analysis. Blocking NMDA receptors delays kidney damage, allowing transient increased GFR and ammonia elimination which delays hyperammonemia and associated changes in brain. Blocking NMDA receptors does not prevent cerebral edema or blood-brain barrier permeability but reduces or prevents changes in cerebral blood flow and brain lactate. The data show that dual protective effects of MK-801 in kidney and brain delay cerebral alterations, HE, intracranial pressure increase and death. NMDA receptors antagonists may increase survival of patients with ALF by providing additional time for liver transplantation or regeneration.

  8. Angiotensin receptor antagonists to prevent sudden death in heart failure: does the dose matter?

    Science.gov (United States)

    Francia, Pietro; Palano, Francesca; Tocci, Giuliano; Adduci, Carmen; Ricotta, Agnese; Semprini, Lorenzo; Caprinozzi, Massimo; Balla, Cristina; Volpe, Massimo

    2014-01-01

    International guidelines recommend ICD implantation in patients with severe left ventricular dysfunction of any origin only after careful optimization of medical therapy. Indeed, major randomized clinical trials suggest that suboptimal use of fundamental drugs, such as ACE inhibitors (ACE-i) and beta-blockers, may affect ICD shock-free survival, sudden cardiac death (SCD), and overall mortality. While solid evidence in favour of pharmacological therapy based on ACE-i with or without beta-blockers is available, data on SCD in HF patients treated with angiotensin receptor blockers (ARBs) are limited. The present paper systematically analyses the impact of ARBs on SCD in HF and reviews the contributory role of the renin-angiotensin system (RAS) to the establishment of arrhythmic substrates. The following hypothesis is supported: (1) the RAS is a critical component of the electrical remodelling of the failing myocardium, (2) RAS blockade reduces the risk of SCD, and (3) ARBs represent a powerful tool to improve overall survival and possibly reduce the risk of SCD provided that high doses are employed to achieve optimal AT1-receptor blockade.

  9. Expression of TRAIL and death receptor DR4 in Palmer type 2 TFCC lesions.

    Science.gov (United States)

    Unglaub, Frank; Thomas, Susanne B; Kroeber, Markus W; Dragu, Adrian; Fellenberg, Jörg; Mittlmeier, Thomas; Wolf, Maya B; Horch, Raymund E

    2010-10-01

    Degenerative articular disc perforations of the triangular fibrocartilage (TFC) of the wrist are characterized by fibrocartilage cell loss and are often associated with ulna-plus situations. Apoptosis has been found to play a crucial role in fibrocartilage cell loss, however, the molecular mechanism and mediators are still poorly understood. The purpose of this study was to identify receptors to apoptosis in degenerative disc lesions. Included in the study were 17 patients with degenerative articular disc tears of the TFC (Palmer type 2C). Following arthroscopic debridement of the TFC, histological sections were examined to assess the presence of apoptosis. Apoptosis was determined using TRAIL and death receptor DR4 agonists for immunohistochemical analyses. The number of cells positive for apoptosis was then correlated with ulna length. Cells positive for TRAIL and DR4 were found in all specimens. The number of cells positive for TRAIL was significantly increased in specimens of patients with an ulna positive variance (P = 0.040). However, DR4 was not significantly increased in ulna plus (P > 0.05). Both, TRAIL and DR4 positive cells were found to be evenly distributed throughout each specimen. There was no accumulation of any type of cells in any particular zone of the biopsies. This is the first study that shows that TFCC cells express TRAIL and DR4, which suggests that apoptosis, as well as, mechanical trauma are involved in the development of disc perforation. The TRAIL/DR4 receptor system is a molecular mediator of apoptosis induction in TFC cells and therefore plays a role in cell loss in degenerative disc lesions.

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

    Directory of Open Access Journals (Sweden)

    Kyung Min eChung

    2016-05-01

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

  11. Targeting a G-protein-coupled receptor overexpressed in endocrine tumors by magnetic nanoparticles to induce cell death.

    Science.gov (United States)

    Sanchez, Claire; El Hajj Diab, Darine; Connord, Vincent; Clerc, Pascal; Meunier, Etienne; Pipy, Bernard; Payré, Bruno; Tan, Reasmey P; Gougeon, Michel; Carrey, Julian; Gigoux, Véronique; Fourmy, Daniel

    2014-02-25

    Nanotherapy using targeted magnetic nanoparticles grafted with peptidic ligands of receptors overexpressed in cancers is a promising therapeutic strategy. However, nanoconjugation of peptides can dramatically affect their properties with respect to receptor recognition, mechanism of internalization, intracellular trafficking, and fate. Furthermore, investigations are needed to better understand the mechanism whereby application of an alternating magnetic field to cells containing targeted nanoparticles induces cell death. Here, we designed a nanoplatform (termed MG-IONP-DY647) composed of an iron oxide nanocrystal decorated with a ligand of a G-protein coupled receptor, the cholecystokinin-2 receptor (CCK2R) that is overexpressed in several malignant cancers. MG-IONP-DY647 did not stimulate inflammasome of Raw 264.7 macrophages. They recognized cells expressing CCK2R with a high specificity, subsequently internalized via a mechanism involving recruitment of β-arrestins, clathrin-coated pits, and dynamin and were directed to lysosomes. Binding and internalization of MG-IONP-DY647 were dependent on the density of the ligand at the nanoparticle surface and were slowed down relative to free ligand. Trafficking of CCK2R internalized with the nanoparticles was slightly modified relative to CCK2R internalized in response to free ligand. Application of an alternating magnetic field to cells containing MG-IONP-DY647 induced apoptosis and cell death through a lysosomal death pathway, demonstrating that cell death is triggered even though nanoparticles of low thermal power are internalized in minute amounts by the cells. Together with pioneer findings using iron oxide nanoparticles targeting tumoral cells expressing epidermal growth factor receptor, these data represent a solid basis for future studies aiming at establishing the proof-of-concept of nanotherapy of cancers using ligand-grafted magnetic nanoparticles specifically internalized via cell surface receptors.

  12. Evaluation of the contribution of multiple DAMPs and DAMP receptors in cell death-induced sterile inflammatory responses.

    Science.gov (United States)

    Kataoka, Hiroshi; Kono, Hajime; Patel, Zubin; Kimura, Yoshitaka; Rock, Kenneth L

    2014-01-01

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

  13. Evaluation of the contribution of multiple DAMPs and DAMP receptors in cell death-induced sterile inflammatory responses.

    Directory of Open Access Journals (Sweden)

    Hiroshi Kataoka

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

  14. Targeting breast to brain metastatic tumours with death receptor ligand expressing therapeutic stem cells.

    Science.gov (United States)

    Bagci-Onder, Tugba; Du, Wanlu; Figueiredo, Jose-Luiz; Martinez-Quintanilla, Jordi; Shah, Khalid

    2015-06-01

    Characterizing clinically relevant brain metastasis models and assessing the therapeutic efficacy in such models are fundamental for the development of novel therapies for metastatic brain cancers. In this study, we have developed an in vivo imageable breast-to-brain metastasis mouse model. Using real time in vivo imaging and subsequent composite fluorescence imaging, we show a widespread distribution of micro- and macro-metastasis in different stages of metastatic progression. We also show extravasation of tumour cells and the close association of tumour cells with blood vessels in the brain thus mimicking the multi-foci metastases observed in the clinics. Next, we explored the ability of engineered adult stem cells to track metastatic deposits in this model and show that engineered stem cells either implanted or injected via circulation efficiently home to metastatic tumour deposits in the brain. Based on the recent findings that metastatic tumour cells adopt unique mechanisms of evading apoptosis to successfully colonize in the brain, we reasoned that TNF receptor superfamily member 10A/10B apoptosis-inducing ligand (TRAIL) based pro-apoptotic therapies that induce death receptor signalling within the metastatic tumour cells might be a favourable therapeutic approach. We engineered stem cells to express a tumour selective, potent and secretable variant of a TRAIL, S-TRAIL, and show that these cells significantly suppressed metastatic tumour growth and prolonged the survival of mice bearing metastatic breast tumours. Furthermore, the incorporation of pro-drug converting enzyme, herpes simplex virus thymidine kinase, into therapeutic S-TRAIL secreting stem cells allowed their eradication post-tumour treatment. These studies are the first of their kind that provide insight into targeting brain metastasis with stem-cell mediated delivery of pro-apoptotic ligands and have important clinical implications.

  15. Extrinsic electromagnetic chirality in metamaterials

    OpenAIRE

    Plum, E.; Fedotov, V. A.; Zheludev, N. I.

    2009-01-01

    Three- and two-dimensional chirality arising from the mutual orientation of non-chiral planar metamaterial structures and the incident electromagnetic wave (extrinsic chirality) lead to pronounced optical activity, circular dichroism and asymmetric transmission indistinguishable from those seen in media consisting of three- and two-dimensionally chiral molecules (intrinsic chirality).

  16. 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, G; 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 DN

  17. Bone Morphogenetic Protein Type I Receptor Antagonists Decrease Growth and Induce Cell Death of Lung Cancer Cell Lines

    Science.gov (United States)

    Langenfeld, Elaine; Hong, Charles C.; Lanke, Gandhi; Langenfeld, John

    2013-01-01

    Bone morphogenetic proteins (BMPs) are highly conserved morphogens that are essential for normal development. BMP-2 is highly expressed in the majority of non-small cell lung carcinomas (NSCLC) but not in normal lung tissue or benign lung tumors. The effects of the BMP signaling cascade on the growth and survival of cancer cells is poorly understood. We show that BMP signaling is basally active in lung cancer cell lines, which can be effectively inhibited with selective antagonists of the BMP type I receptors. Lung cancer cell lines express alk2, alk3, and alk6 and inhibition of a single BMP receptor was not sufficient to decrease signaling. Inhibition of more than one type I receptor was required to decrease BMP signaling in lung cancer cell lines. BMP receptor antagonists and silencing of BMP type I receptors with siRNA induced cell death, inhibited cell growth, and caused a significant decrease in the expression of inhibitor of differentiation (Id1, Id2, and Id3) family members, which are known to regulate cell growth and survival in many types of cancers. BMP receptor antagonists also decreased clonogenic cell growth. Knockdown of Id3 significantly decreased cell growth and induced cell death of lung cancer cells. H1299 cells stably overexpressing Id3 were resistant to growth suppression and induction of cell death induced by the BMP antagonist DMH2. These studies suggest that BMP signaling promotes cell growth and survival of lung cancer cells, which is mediated through its regulation of Id family members. Selective antagonists of the BMP type I receptors represents a potential means to pharmacologically treat NSCLC and other carcinomas with an activated BMP signaling cascade. PMID:23593444

  18. Targeting Death Receptor TRAIL-R2 by Chalcones for TRAIL-Induced Apoptosis in Cancer Cells

    Directory of Open Access Journals (Sweden)

    Małgorzata Ksek

    2012-11-01

    Full Text Available Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL induces apoptosis in cancer cells without toxicity to normal cells. TRAIL binds to death receptors, TRAIL-R1 (DR4 and TRAIL-R2 (DR5 expressed on cancer cell surface and activates apoptotic pathways. Endogenous TRAIL plays an important role in immune surveillance and defense against cancer cells. However, as more tumor cells are reported to be resistant to TRAIL mediated death, it is important to search for and develop new strategies to overcome this resistance. Chalcones can sensitize cancer cells to TRAIL-induced apoptosis. We examined the cytotoxic and apoptotic effects of TRAIL in combination with four chalcones: chalcone, isobavachalcone, licochalcone A and xanthohumol on HeLa cancer cells. The cytotoxicity was measured by MTT and LDH assays. The apoptosis was detected using annexin V-FITC staining by flow cytometry and fluorescence microscopy. Death receptor expression was analyzed using flow cytometry. The decreased expression of death receptors in cancer cells may be the cause of TRAIL-resistance. Chalcones enhance TRAIL-induced apoptosis in HeLa cells through increased expression of TRAIL-R2. Our study has indicated that chalcones augment the antitumor activity of TRAIL and confirm their cancer chemopreventive properties.

  19. Targeting death receptor TRAIL-R2 by chalcones for TRAIL-induced apoptosis in cancer cells.

    Science.gov (United States)

    Szliszka, Ewelina; Jaworska, Dagmara; Ksek, Małgorzata; Czuba, Zenon P; Król, Wojciech

    2012-11-20

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells without toxicity to normal cells. TRAIL binds to death receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5) expressed on cancer cell surface and activates apoptotic pathways. Endogenous TRAIL plays an important role in immune surveillance and defense against cancer cells. However, as more tumor cells are reported to be resistant to TRAIL mediated death, it is important to search for and develop new strategies to overcome this resistance. Chalcones can sensitize cancer cells to TRAIL-induced apoptosis. We examined the cytotoxic and apoptotic effects of TRAIL in combination with four chalcones: chalcone, isobavachalcone, licochalcone A and xanthohumol on HeLa cancer cells. The cytotoxicity was measured by MTT and LDH assays. The apoptosis was detected using annexin V-FITC staining by flow cytometry and fluorescence microscopy. Death receptor expression was analyzed using flow cytometry. The decreased expression of death receptors in cancer cells may be the cause of TRAIL-resistance. Chalcones enhance TRAIL-induced apoptosis in HeLa cells through increased expression of TRAIL-R2. Our study has indicated that chalcones augment the antitumor activity of TRAIL and confirm their cancer chemopreventive properties.

  20. Death receptor 5 expression is inversely correlated with prostate cancer progression

    Science.gov (United States)

    HERNANDEZ-CUETO, ANGELES; HERNANDEZ-CUETO, DANIEL; ANTONIO-ANDRES, GABRIELA; MENDOZA-MARIN, MARISELA; JIMENEZ-GUTIERREZ, CARLOS; SANDOVAL-MEJIA, ANA LILIA; MORA-CAMPOS, ROSARIO; GONZALEZ-BONILLA, CESAR; VEGA, MARIO I.; BONAVIDA, BENJAMIN; HUERTA-YEPEZ, SARA

    2014-01-01

    Prostate carcinoma (PCa) is one of the most common cancers in men. Prostate-specific antigen (PSA) has been widely used to predict the outcome of PCa and screening with PSA has resulted in a decline in mortality. However, PSA is not an optimal prognostic tool as its sensitivity may be too low to reduce morbidity and mortality. Consequently, there is a demand for additional robust biomarkers for prostate cancer. Death receptor 5 (DR5) has been implicated in the prognosis of several cancers and it has been previously shown that it is negatively regulated by Yin Yang 1 (YY1) in prostate cancer cell lines. The present study investigated the clinical significance of DR5 expression in a prostate cancer patient cohort and its correlation with YY1 expression. Immunohistochemical analysis of protein expression distribution was performed using tissue microarray constructs from 54 primary PCa and 39 prostatic intraepithelial neoplasia (PIN) specimens. DR5 expression was dramatically reduced as a function of higher tumor grade. By contrast, YY1 expression was elevated in PCa tumors as compared with that in PIN, and was increased with higher tumor grade. DR5 had an inverse correlation with YY1 expression. Bioinformatic analyses corroborated these data. The present findings suggested that DR5 and YY1 expression levels may serve as progression biomarkers for prostate cancer. PMID:25174820

  1. Glutamate receptor GluR3 antibodies and death of cortical cells.

    Science.gov (United States)

    He, X P; Patel, M; Whitney, K D; Janumpalli, S; Tenner, A; McNamara, J O

    1998-01-01

    Rasmussen's encephalitis (RE), a childhood disease characterized by epileptic seizures associated with progressive destruction of a single cerebral hemisphere, is an autoimmune disease in which one of the autoantigens is a glutamate receptor, GluR3. The improvement of some affected children following plasma exchange that removed circulating GluR3 antibodies (anti-GluR3) suggested that anti-GluR3 gained access to the central nervous system where it exerted deleterious effects. Here, we demonstrate that a subset of rabbits immunized with a GluR3 fusion protein develops a neurological disorder mimicking RE. Anti-GluR3 IgG isolated from serum of both ill and healthy GluR3-immunized animals promoted death of cultured cortical cells by a complement-dependent mechanism. IgG immunoreactivity decorated neurons and their processes in neocortex and hippocampus in ill but not in healthy rabbits. Moreover, both IgG and complement membrane attack complex (MAC) immunoreactivity was evident on neurons and their processes in the cortex of a subset of patients with RE. We suggest that access of IgG to epitopes in the central nervous system triggers complement-mediated neuronal damage and contributes to the pathogenesis of both this animal model and RE.

  2. Low-affinity neurotrophin receptor with targeted mutation of exon 3 is capable of mediating the death of axotomized neurons.

    Science.gov (United States)

    Murray, Simon S; Bartlett, Perry F; Lopes, Elizabeth C; Coulson, Elizabeth J; Greferath, Una; Cheema, Surindar S

    2003-04-01

    1. In vivo studies have shown that the low-affinity 75 kDa neurotrophin receptor (p75NTR) is involved in axotomy-induced cell death of sensory and motor neurons. To further examine the importance of p75NTR in mediating neuronal death in vivo, we examined the effect of axotomy in the p75NTR-knockout mouse, which has a disrupted ligand-binding domain. 2. The extent of sensory and motor neuron loss in the p75NTR-knockout mouse following axotomy was not significantly different to that in wild-type mice. This suggests that disruption of the ligand-binding domain is insufficient to block the cell death process in axotomized neurons. 3. Immunohistochemical studies showed that axotomized neurons continue to express this mutant receptor with its intracellular death-signalling moiety intact. 4. Treatment with antisense oligonucleotides targeted against p75NTR resulted in significant reduction in the loss of axotomized neurons in the knockout mouse. 5. These data suggest that the intracellular domain of p75NTR is essential for death-signalling and that p75NTR can signal apoptosis, despite a disrupted ligand-binding domain.

  3. Maslinic Acid, a Natural Triterpene, Induces a Death Receptor-Mediated Apoptotic Mechanism in Caco-2 p53-Deficient Colon Adenocarcinoma Cells.

    Directory of Open Access Journals (Sweden)

    Fernando J Reyes-Zurita

    Full Text Available Maslinic acid (MA is a natural triterpene present in high concentrations in the waxy skin of olives. We have previously reported that MA induces apoptotic cell death via the mitochondrial apoptotic pathway in HT29 colon cancer cells. Here, we show that MA induces apoptosis in Caco-2 colon cancer cells via the extrinsic apoptotic pathway in a dose-dependent manner. MA triggered a series of effects associated with apoptosis, including the cleavage of caspases -8 and -3, and increased the levels of t-Bid within a few hours of its addition to the culture medium. MA had no effect on the expression of the Bax protein, release of cytochrome-c or on the mitochondrial membrane potential. This suggests that MA triggered the extrinsic apoptotic pathway in this cell type, as opposed to the intrinsic pathway found in the HT29 colon-cancer cell line. Our results suggest that the apoptotic mechanism induced in Caco-2 may be different from that found in HT29 colon-cancer cells, and that in Caco-2 cells MA seems to work independently of p53. Natural antitumoral agents capable of activating both the extrinsic and intrinsic apoptotic pathways could be of great use in treating colon-cancer of whatever origin.

  4. Maslinic Acid, a Natural Triterpene, Induces a Death Receptor-Mediated Apoptotic Mechanism in Caco-2 p53-Deficient Colon Adenocarcinoma Cells

    Science.gov (United States)

    Reyes-Zurita, Fernando J.; Rufino-Palomares, Eva E.; García-Salguero, Leticia; Peragón, Juan; Medina, Pedro P.; Parra, Andrés; Cascante, Marta; Lupiáñez, José A.

    2016-01-01

    Maslinic acid (MA) is a natural triterpene present in high concentrations in the waxy skin of olives. We have previously reported that MA induces apoptotic cell death via the mitochondrial apoptotic pathway in HT29 colon cancer cells. Here, we show that MA induces apoptosis in Caco-2 colon cancer cells via the extrinsic apoptotic pathway in a dose-dependent manner. MA triggered a series of effects associated with apoptosis, including the cleavage of caspases -8 and -3, and increased the levels of t-Bid within a few hours of its addition to the culture medium. MA had no effect on the expression of the Bax protein, release of cytochrome-c or on the mitochondrial membrane potential. This suggests that MA triggered the extrinsic apoptotic pathway in this cell type, as opposed to the intrinsic pathway found in the HT29 colon-cancer cell line. Our results suggest that the apoptotic mechanism induced in Caco-2 may be different from that found in HT29 colon-cancer cells, and that in Caco-2 cells MA seems to work independently of p53. Natural antitumoral agents capable of activating both the extrinsic and intrinsic apoptotic pathways could be of great use in treating colon-cancer of whatever origin. PMID:26751572

  5. Extrinsic incentives and tax compliance

    OpenAIRE

    Sour, Laura; Gutiérrez Andrade, Miguel Ángel

    2011-01-01

    This paper models the impact of extrinsic incentives in a tax compliance model. It also provides experimental evidence that confirms the existence of a positive relationship between rewards and tax compliance. If individuals are audited, rewards for honest taxpayers are effective in increasing the level of tax compliance. These results are particularly relevant in countries where there is little respect for tax law since rewards can contribute to crowding in the intrinsic motivation to comply.

  6. Extrinsic incentives and tax compliance

    OpenAIRE

    Sour, Laura; Gutiérrez Andrade, Miguel Ángel

    2011-01-01

    This paper models the impact of extrinsic incentives in a tax compliance model. It also provides experimental evidence that confirms the existence of a positive relationship between rewards and tax compliance. If individuals are audited, rewards for honest taxpayers are effective in increasing the level of tax compliance. These results are particularly relevant in countries where there is little respect for tax law since rewards can contribute to crowding in the intrinsic motivation to comply.

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

    Directory of Open Access Journals (Sweden)

    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

  8. Wide Bandgap Extrinsic Photoconductive Switches

    Energy Technology Data Exchange (ETDEWEB)

    Sullivan, James S. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2013-07-03

    Semi-insulating Gallium Nitride, 4H and 6H Silicon Carbide are attractive materials for compact, high voltage, extrinsic, photoconductive switches due to their wide bandgap, high dark resistance, high critical electric field strength and high electron saturation velocity. These wide bandgap semiconductors are made semi-insulating by the addition of vanadium (4H and 6HSiC) and iron (2H-GaN) impurities that form deep acceptors. These deep acceptors trap electrons donated from shallow donor impurities. The electrons can be optically excited from these deep acceptor levels into the conduction band to transition the wide bandgap semiconductor materials from a semi-insulating to a conducting state. Extrinsic photoconductive switches with opposing electrodes have been constructed using vanadium compensated 6H-SiC and iron compensated 2H-GaN. These extrinsic photoconductive switches were tested at high voltage and high power to determine if they could be successfully used as the closing switch in compact medical accelerators.

  9. Phenethyl isothiocyanate upregulates death receptors 4 and 5 and inhibits proliferation in human cancer stem-like cells

    OpenAIRE

    Wang, Dan; Upadhyaya, Bijaya; Liu, Yi; Knudsen, David; Dey, Moul

    2014-01-01

    Background The cytokine TRAIL (tumor necrotic factor-related apoptosis-inducing ligand) selectively induces apoptosis in cancer cells, but cancer stem cells (CSCs) that contribute to cancer-recurrence are frequently TRAIL-resistant. Here we examined hitherto unknown effects of the dietary anti-carcinogenic compound phenethyl isothiocyanate (PEITC) on attenuation of proliferation and tumorigenicity and on up regulation of death receptors and apoptosis in human cervical CSC. Methods Cancer stem...

  10. EphrinB3 blocks EphB3 dependence receptor functions to prevent cell death following traumatic brain injury.

    Science.gov (United States)

    Theus, M H; Ricard, J; Glass, S J; Travieso, L G; Liebl, D J

    2014-05-08

    Eph receptor tyrosine kinases and their membrane-bound ligands, ephrins, have a variety of roles in the developing and adult central nervous system that require direct cell-cell interactions; including regulating axon path finding, cell proliferation, migration and synaptic plasticity. Recently, we identified a novel pro-survival role for ephrins in the adult subventricular zone, where ephrinB3 blocks Eph-mediated cell death during adult neurogenesis. Here, we examined whether EphB3 mediates cell death in the adult forebrain following traumatic brain injury and whether ephrinB3 infusion could limit this effect. We show that EphB3 co-labels with microtubule-associated protein 2-positive neurons in the adult cortex and is closely associated with ephrinB3 ligand, which is reduced following controlled cortical impact (CCI) injury. In the complete absence of EphB3 (EphB3(-/-)), we observed reduced terminal deoxynucleotidyl transferase-dUTP nick end labeling (TUNEL), and functional improvements in motor deficits after CCI injury as compared with wild-type and ephrinB3(-/-) mice. We also demonstrated that EphB3 exhibits dependence receptor characteristics as it is cleaved by caspases and induces cell death, which is not observed in the presence of ephrinB3. Following trauma, infusion of pre-clustered ephrinB3-Fc molecules (eB3-Fc) into the contralateral ventricle reduced cortical infarct volume and TUNEL staining in the cortex, dentate gyrus and CA3 hippocampus of wild-type and ephrinB3(-/-) mice, but not EphB3(-/-) mice. Similarly, application of eB3-Fc improved motor functions after CCI injury. We conclude that EphB3 mediates cell death in the adult cortex through a novel dependence receptor-mediated cell death mechanism in the injured adult cortex and is attenuated following ephrinB3 stimulation.

  11. A mechanism for sudden infant death syndrome (SIDS): Stress-induced leak via ryanodine receptors

    Science.gov (United States)

    Tester, David J.; Dura, Miroslav; Carturan, Elisa; Reiken, Steven; Wronska, Anetta; Marks, Andrew R.; Ackerman, Michael J.

    2012-01-01

    BACKGROUND Sudden infant death syndrome (SIDS) is the leading cause of postneonatal mortality in the United States. Mutations in the RyR2-encoded cardiac ryanodine receptor cause the highly lethal catecholaminergic polymorphic ventricular tachycardia (CPVT1) in the young. OBJECTIVE The purpose of this study was to determine the spectrum and prevalence of RyR2 mutations in a large cohort of SIDS cases. METHODS Using polymerase chain reaction, denaturing high performance liquid chromatography, and direct DNA sequencing, a targeted mutational analysis of RyR2 was performed on genomic DNA isolated from frozen necropsy tissue on 134 unrelated cases of SIDS (57 females, 77 males; 83 white, 50 black, 1 Hispanic; average age = 2.7 months). RyR2 mutations were engineered by site-directed mutagenesis, heterologously expressed in HEK293 cells, and functionally characterized using single-channel recordings in planar lipid bilayers. RESULTS Overall, two distinct and novel RyR2 mutations were identified in two cases of SIDS. A 6-month-old black female hosted an R2267H missense mutation, and a 4-week-old white female infant harbored a S4565R mutation. Both nonconservative amino acid substitutions were absent in 400 reference alleles, involved conserved residues, and were localized to key functionally significant domains. Under conditions that simulate stress [Protein Kinase A (PKA) phosphorylation] during diastole (low activating [Ca2+]), SIDS-associated RyR2 mutant channels displayed a significant gain-of-function phenotype consistent with the functional effect of previously characterized CPVT-associated RyR2 mutations. CONCLUSIONS Here we report a novel pathogenic mechanism for SIDS, whereby SIDS-linked RyR2 mutations alter the response of the channels to sympathetic nervous system stimulation such that during stress the channels become “leaky” and thus potentially trigger fatal cardiac arrhythmias. PMID:17556193

  12. Detachment of esophageal carcinoma cells from extracellular matrix causes relocalization of death receptor 5 and apoptosis

    Institute of Scientific and Technical Information of China (English)

    Guang-Chao Liu; Jun Zhang; Shi-Gui Liu; Rong Gao; Zhang-Fu Long; Ke Tao; Yuan-Fang Ma

    2009-01-01

    AIM:To investigate the effect of detachment of esophageal cancer cells from extracellular matrix on the localization of death receptor 5 (DR5) and apoptosis.METHODS: Anchorage-dependent EC9706 cells of esophageal squamous cell carcinoma were pretreated or not treated with brefeldin A. Detached cells were harvested by ethylenediaminetetraacetic acid digestion. Expression and localization of DR5 in these cells were determined by immunocytochemical and immunofluorescence assays, as well as flow cytometry analysis. Apoptosis of EC9706 cells was detected by flow cytometry after stained with fluorescein isothiocyanate-labeled annexin V/propidium iodide. Activation of caspase 8 was detected by Western blot analysis.RESULTS: Immunocytochemical assay indicated that DR5 was predominantly perinuclear in adherent cells but was mainly localized in cell membrane in detached cells. In addition, immunofluorescence assay also confirmed the above-mentioned results, and further demonstrated that DR5 was present in the form of coarse granules in detached cells, but in the form of fine granules in adherent cells. Cytometry analysis revealed higher levels of DR5 expression on the surfaces of brefeldin-A-untreated cells than on the surfaces of brefeldin-A-treated cells, but brefeldin A treatment did not affect the total DR5 expression levels. Moreover, nocodazole did not influence the extracelluar DR5 expression levels in EC9706 cells. Apoptosis assay revealed that detached cells were more sensitive to DR5 antibody-induced apoptosis than adherent cells. Western blotting showed that caspase 8 was activated in temporarily detached cells 4 h earlier than in adherent cells.CONCLUSION: Progress from adhesion to detachment of EC9706 cells causes DR5 relocalization, and promotes cytoplasmic translocation of DR5 to cell surfaces via a Golgi-dependent pathway. Moreover, it might also result in DR5 aggregation to render apoptosis of detached cells.

  13. Ouabain-induced perturbations in intracellular ionic homeostasis regulate death receptor-mediated apoptosis

    Science.gov (United States)

    Panayiotidis, Mihalis I.; Franco, Rodrigo; Bortner, Carl D.; Cidlowski, John A.

    2012-01-01

    Apoptosis is defined by specific morphological and biochemical characteristics including cell shrinkage (termed apoptotic volume decrease), a process that results from the regulation of ion channels and plasma membrane transporter activity. The Na+-K+-ATPase is the predominant pump that controls cell volume and plasma membrane potential in cells and alterations in its function have been suggested to be associated with apoptosis. We report here that the Na+-K+-ATPase inhibitor ouabain, potentiates apoptosis in the human lymphoma Jurkat cells exposed to Fas ligand (FasL) or Tumor necrosis factor--related apoptosis-inducing ligand (TRAIL) but not other apoptotic agents such as H2O2, thapsigargin or UV-C implicating a role for the Na+-K+-ATPase in death receptor-induced apoptosis. Interestingly, ouabain also potentiated perturbations in cell Ca2+ homeostasis only in conjunction with the apoptotic inducer FasL but not TRAIL. Ouabain did not affect alterations in the intracellular Ca2+ levels in response to H2O2, thapsigargin or UV-C. FasL-induced alterations in Ca2+ were not abolished in Ca2+-free medium but incubation of cells with BAPTA-AM inhibited both Ca2+ perturbations and the ouabain-induced potentiation of FasL-induced apoptosis. Our data suggest that the impairment of the Na+-K+-ATPase activity during apoptosis is linked to perturbations in cell Ca2+ homeostasis that modulate apoptosis induced by the activation of Fas by FasL. PMID:20422450

  14. The P2X7 Receptor Supports Both Life and Death in Fibrogenic Pancreatic Stellate Cells

    DEFF Research Database (Denmark)

    Haanes, Kristian; Schwab, Albrecht; Novak, Ivana

    2012-01-01

    receptor and elucidate how it regulates PSC viability. The number of PSCs isolated from wild type (WT) mice was 50% higher than those from the Pfizer P2X7 receptor knock out (KO) mice. The P2X7 receptor protein and mRNA of all known isoforms were expressed in WT PSCs, while KO PSCs only expressed truncated...

  15. A receptor tyrosine kinase inhibitor, Tyrphostin A9 induces cancer cell death through Drp1 dependent mitochondria fragmentation

    Energy Technology Data Exchange (ETDEWEB)

    Park, So Jung; Park, Young Jun; Shin, Ji Hyun; Kim, Eun Sung [Graduate School of East-West Medical Science, Kyung Hee University, Gyeoggi-Do 446-701 (Korea, Republic of); Hwang, Jung Jin; Jin, Dong-Hoon; Kim, Jin Cheon [Institute for Innovative Cancer Research, Asan Medical Center, Seoul 138-736 (Korea, Republic of); Cho, Dong-Hyung, E-mail: dhcho@khu.ac.kr [Graduate School of East-West Medical Science, Kyung Hee University, Gyeoggi-Do 446-701 (Korea, Republic of)

    2011-05-13

    Highlights: {yields} We screened and identified Tyrphostin A9, a receptor tyrosine kinase inhibitor as a strong mitochondria fission inducer. {yields} Tyrphostin A9 treatment promotes mitochondria dysfunction and contributes to cytotoxicity in cancer cells. {yields} Tyrphostin A9 induces apoptotic cell death through a Drp1-mediated pathway. {yields} Our studies suggest that Tyrphostin A9 induces mitochondria fragmentation and apoptotic cell death via Drp1 dependently. -- Abstract: Mitochondria dynamics controls not only their morphology but also functions of mitochondria. Therefore, an imbalance of the dynamics eventually leads to mitochondria disruption and cell death. To identify specific regulators of mitochondria dynamics, we screened a bioactive chemical compound library and selected Tyrphostin A9, a tyrosine kinase inhibitor, as a potent inducer of mitochondrial fission. Tyrphostin A9 treatment resulted in the formation of fragmented mitochondria filament. In addition, cellular ATP level was decreased and the mitochondrial membrane potential was collapsed in Tyr A9-treated cells. Suppression of Drp1 activity by siRNA or over-expression of a dominant negative mutant of Drp1 inhibited both mitochondrial fragmentation and cell death induced by Tyrpohotin A9. Moreover, treatment of Tyrphostin A9 also evoked mitochondrial fragmentation in other cells including the neuroblastomas. Taken together, these results suggest that Tyrphostin A9 induces Drp1-mediated mitochondrial fission and apoptotic cell death.

  16. Erythropoietin (EPO-receptor signaling induces cell death of primary myeloma cells in vitro

    Directory of Open Access Journals (Sweden)

    Thea Kristin Våtsveen

    2016-08-01

    Full Text Available Abstract Background Multiple myeloma is an incurable complex disease characterized by clonal proliferation of malignant plasma cells in a hypoxic bone marrow environment. Hypoxia-dependent erythropoietin (EPO-receptor (EPOR signaling is central in various cancers, but the relevance of EPOR signaling in multiple myeloma cells has not yet been thoroughly investigated. Methods Myeloma cell lines and malignant plasma cells isolated from bone marrow of myeloma patients were used in this study. Transcript levels were analysed by quantitative PCR and cell surface levels of EPOR in primary cells by flow cytometry. Knockdown of EPOR by short interfering RNA was used to show specific EPOR signaling in the myeloma cell line INA-6. Flow cytometry was used to assess viability in primary cells treated with EPO in the presence and absence of neutralizing anti-EPOR antibodies. Gene expression data for total therapy 2 (TT2, total therapy 3A (TT3A trials and APEX 039 and 040 were retrieved from NIH GEO omnibus and EBI ArrayExpress. Results We show that the EPOR is expressed in myeloma cell lines and in primary myeloma cells both at the mRNA and protein level. Exposure to recombinant human EPO (rhEPO reduced viability of INA-6 myeloma cell line and of primary myeloma cells. This effect could be partially reversed by neutralizing antibodies against EPOR. In INA-6 cells and primary myeloma cells, janus kinase 2 (JAK-2 and extracellular signal regulated kinase 1 and 2 (ERK-1/2 were phosphorylated by rhEPO treatment. Knockdown of EPOR expression in INA-6 cells reduced rhEPO-induced phospo-JAK-2 and phospho-ERK-1/2. Co-cultures of primary myeloma cells with bone marrow-derived stroma cells did not protect the myeloma cells from rhEPO-induced cell death. In four different clinical trials, survival data linked to gene expression analysis indicated that high levels of EPOR mRNA were associated with better survival. Conclusions Our results demonstrate for the first time

  17. Erythropoietin (EPO)-receptor signaling induces cell death of primary myeloma cells in vitro.

    Science.gov (United States)

    Våtsveen, Thea Kristin; Sponaas, Anne-Marit; Tian, Erming; Zhang, Qing; Misund, Kristine; Sundan, Anders; Børset, Magne; Waage, Anders; Brede, Gaute

    2016-08-31

    Multiple myeloma is an incurable complex disease characterized by clonal proliferation of malignant plasma cells in a hypoxic bone marrow environment. Hypoxia-dependent erythropoietin (EPO)-receptor (EPOR) signaling is central in various cancers, but the relevance of EPOR signaling in multiple myeloma cells has not yet been thoroughly investigated. Myeloma cell lines and malignant plasma cells isolated from bone marrow of myeloma patients were used in this study. Transcript levels were analysed by quantitative PCR and cell surface levels of EPOR in primary cells by flow cytometry. Knockdown of EPOR by short interfering RNA was used to show specific EPOR signaling in the myeloma cell line INA-6. Flow cytometry was used to assess viability in primary cells treated with EPO in the presence and absence of neutralizing anti-EPOR antibodies. Gene expression data for total therapy 2 (TT2), total therapy 3A (TT3A) trials and APEX 039 and 040 were retrieved from NIH GEO omnibus and EBI ArrayExpress. We show that the EPOR is expressed in myeloma cell lines and in primary myeloma cells both at the mRNA and protein level. Exposure to recombinant human EPO (rhEPO) reduced viability of INA-6 myeloma cell line and of primary myeloma cells. This effect could be partially reversed by neutralizing antibodies against EPOR. In INA-6 cells and primary myeloma cells, janus kinase 2 (JAK-2) and extracellular signal regulated kinase 1 and 2 (ERK-1/2) were phosphorylated by rhEPO treatment. Knockdown of EPOR expression in INA-6 cells reduced rhEPO-induced phospo-JAK-2 and phospho-ERK-1/2. Co-cultures of primary myeloma cells with bone marrow-derived stroma cells did not protect the myeloma cells from rhEPO-induced cell death. In four different clinical trials, survival data linked to gene expression analysis indicated that high levels of EPOR mRNA were associated with better survival. Our results demonstrate for the first time active EPOR signaling in malignant plasma cells. EPO

  18. Nuclear receptor CAR represses TNFalpha-induced cell death by interacting with the anti-apoptotic GADD45B.

    Directory of Open Access Journals (Sweden)

    Yukio Yamamoto

    Full Text Available BACKGROUND: Phenobarbital (PB is the most well-known among numerous non-genotoxic carcinogens that cause the development of hepatocellular carcinoma (HCC. PB activates nuclear xenobiotic receptor Constitutive Active/Androstane Receptor (CAR; NR1I3 and this activation is shown to determine PB promotion of HCC in mice. The molecular mechanism of CAR-mediated tumor promotion, however, remains elusive at the present time. Here we have identified Growth Arrest and DNA Damage-inducible 45beta (GADD45B as a novel CAR target, through which CAR represses cell death. METHODOLOGY/PRINCIPAL FINDINGS: PB activation of nuclear xenobiotic receptor CAR is found to induce the Gadd45b gene in mouse liver throughout the development of HCC as well as in liver tumors. Given the known function of GADD45B as a factor that represses Mitogen-activated protein Kinase Kinase 7 - c-Jun N-terminal Kinase (MKK7-JNK pathway-mediated apoptosis, we have now demonstrated that CAR interacts with GADD45B to repress Tumor Necrosis Factor alpha ( TNFalpha-induced JNK1 phosphorylation as well as cell death. Primary hepatocytes, prepared from Car(+/+, Car(-/-, Gadd45b(+/+ and Gadd45b(-/- mice, were treated with TNFalpha and Actinomycin D to induce phosphorylation of JNK1 and cell death. Co-treatment with the CAR activating ligand TCPOBOP (1,4 bis[2-(3,5-dichloropyridyloxy]benzene has resulted in repression of both phosphorylation and cell death in the primary hepatocytes from Car(+/+ but not Car(-/- mice. Repression by TCPOBOP was not observed in those prepared from Gadd45b(-/- mice. In vitro protein-protein interaction and phosphorylation assays have revealed that CAR interacts with MKK7 and represses the MKK7-mediated phosphorylation of JNK1. CONCLUSIONS/SIGNIFICANCE: CAR can form a protein complex with GADD45B, through which CAR represses MKK7-mediated phosphorylation of JNK1. In addition to activating the Gadd45b gene, CAR may repress death of mouse primary hepatocytes by forming

  19. NMDA-Receptors Are Involved in Cu2+/Paraquat-Induced Death of Cultured Cerebellar Granule Neurons.

    Science.gov (United States)

    Stelmashook, E V; Genrikhs, E E; Aleksandrova, O P; Amelkina, G A; Zelenova, E A; Isaev, N K

    2016-08-01

    Rat cultured cerebellar granule neurons (CGNs) were not sensitive to CuCl2 (1-10 µM, 24 h), whereas paraquat (150 µM) decreased neuronal survival to 79 ± 3% of control level. Simultaneous treatment of CGNs with paraquat and CuCl2 (2, 5, or 10 µM Cu2+/paraquat) caused significant copper dose-dependent death, lowering their survival to 56 ± 4, 37 ± 3, or 16 ± 2%, respectively, and stimulating elevated production of free radicals in CGNs. Introduction of vitamin E, a non-competitive antagonist of NMDA subtype of glutamate receptors (MK-801), and also removal of glutamine from the incubation medium decreased toxicity of Cu2+/paraquat mixture. However, addition of Cu2+ into the incubation medium did not affect CGNs death caused by glutamate. These data emphasize that excessive copper in the brain may trigger oxidative stress, which in turn results in release of glutamate, overstimulation of glutamate receptors, and neuronal death.

  20. A Stringy (Holographic) Pomeron with Extrinsic Curvature

    CERN Document Server

    Qian, Yachao

    2014-01-01

    We model the soft pomeron in QCD using a scalar Polyakov string with extrinsic curvature in the bottom-up approach of holographic QCD. The overall dipole-dipole scattering amplitude in the soft pomeron kinematics is shown to be sensitive to the extrinsic curvature of the string for finite momentum transfer. The characteristics of the diffractive peak in the differential elastic $pp$ scattering are affected by a small extrinsic curvature of the string.

  1. Structure of human cytomegalovirus UL141 binding to TRAIL-R2 reveals novel, non-canonical death receptor interactions.

    Directory of Open Access Journals (Sweden)

    Ivana Nemčovičová

    2013-03-01

    Full Text Available The TRAIL (TNF-related apoptosis inducing ligand death receptors (DRs of the tumor necrosis factor receptor superfamily (TNFRSF can promote apoptosis and regulate antiviral immunity by maintaining immune homeostasis during infection. In turn, human cytomegalovirus (HCMV expresses immunomodulatory proteins that down-regulate cell surface expression of TNFRSF members as well as poliovirus receptor-related proteins in an effort to inhibit host immune effector pathways that would lead to viral clearance. The UL141 glycoprotein of human cytomegalovirus inhibits host defenses by blocking cell surface expression of TRAIL DRs (by retention in ER and poliovirus receptor CD155, a nectin-like Ig-fold molecule. Here we show that the immunomodulatory function of HCMV UL141 is associated with its ability to bind diverse proteins, while utilizing at least two distinct binding sites to selectively engage TRAIL DRs or CD155. Binding studies revealed high affinity interaction of UL141 with both TRAIL-R2 and CD155 and low affinity binding to TRAIL-R1. We determined the crystal structure of UL141 bound to TRAIL-R2 at 2.1 Å resolution, which revealed that UL141 forms a homodimer that engages two TRAIL-R2 monomers 90° apart to form a heterotetrameric complex. Our structural and biochemical data reveal that UL141 utilizes its Ig-domain to facilitate non-canonical death receptor interactions while UL141 partially mimics the binding site of TRAIL on TRAIL-R2, which we found to be distinct from that of CD155. Moreover, UL141 also binds to an additional surface patch on TRAIL-R2 that is distinct from the TRAIL binding site. Therefore, the breadth of UL141-mediated effects indicates that HCMV has evolved sophisticated strategies to evade the immune system by modulating multiple effector pathways.

  2. Structure of human cytomegalovirus UL141 binding to TRAIL-R2 reveals novel, non-canonical death receptor interactions.

    Science.gov (United States)

    Nemčovičová, Ivana; Benedict, Chris A; Zajonc, Dirk M

    2013-03-01

    The TRAIL (TNF-related apoptosis inducing ligand) death receptors (DRs) of the tumor necrosis factor receptor superfamily (TNFRSF) can promote apoptosis and regulate antiviral immunity by maintaining immune homeostasis during infection. In turn, human cytomegalovirus (HCMV) expresses immunomodulatory proteins that down-regulate cell surface expression of TNFRSF members as well as poliovirus receptor-related proteins in an effort to inhibit host immune effector pathways that would lead to viral clearance. The UL141 glycoprotein of human cytomegalovirus inhibits host defenses by blocking cell surface expression of TRAIL DRs (by retention in ER) and poliovirus receptor CD155, a nectin-like Ig-fold molecule. Here we show that the immunomodulatory function of HCMV UL141 is associated with its ability to bind diverse proteins, while utilizing at least two distinct binding sites to selectively engage TRAIL DRs or CD155. Binding studies revealed high affinity interaction of UL141 with both TRAIL-R2 and CD155 and low affinity binding to TRAIL-R1. We determined the crystal structure of UL141 bound to TRAIL-R2 at 2.1 Å resolution, which revealed that UL141 forms a homodimer that engages two TRAIL-R2 monomers 90° apart to form a heterotetrameric complex. Our structural and biochemical data reveal that UL141 utilizes its Ig-domain to facilitate non-canonical death receptor interactions while UL141 partially mimics the binding site of TRAIL on TRAIL-R2, which we found to be distinct from that of CD155. Moreover, UL141 also binds to an additional surface patch on TRAIL-R2 that is distinct from the TRAIL binding site. Therefore, the breadth of UL141-mediated effects indicates that HCMV has evolved sophisticated strategies to evade the immune system by modulating multiple effector pathways.

  3. Cardiomyocyte death induced by ischaemic/hypoxic stress is differentially affected by distinct purinergic P2 receptors.

    Science.gov (United States)

    Cosentino, Simona; Banfi, Cristina; Burbiel, Joachim C; Luo, Haijian; Tremoli, Elena; Abbracchio, Maria P

    2012-05-01

    Blood levels of extracellular nucleotides (e.g. ATP) are greatly increased during heart ischaemia, but, despite the presence of their specific receptors on cardiomyocytes (both P2X and P2Y subtypes), their effects on the subsequent myocardial damage are still unknown. In this study, we aimed at investigating the role of ATP and specific P2 receptors in the appearance of cell injury in a cardiac model of ischaemic/hypoxic stress. Cells were maintained in a modular incubator chamber in a controlled humidified atmosphere of 95% N(2) for 16 hrs in a glucose-free medium. In this condition, we detected an early increase in the release of ATP in the culture medium, which was followed by a massive increase in the release of cytoplasmic histone-associated-DNA-fragments, a marker of apoptosis. Addition of either apyrase, which degrades extracellular ATP, or various inhibitors of ATP release via connexin hemichannels fully abolished ischaemic/hypoxic stress-associated apoptosis. To dissect the role of specific P2 receptor subtypes, we used a combined approach: (i) non-selective and, when available, subtype-selective P2 antagonists, were added to cardiomyocytes before ischaemic/hypoxic stress; (ii) selected P2 receptors genes were silenced via specific small interfering RNAs. Both approaches indicated that the P2Y(2) and P2χ(7) receptor subtypes are directly involved in the induction of cell death during ischaemic/hypoxic stress, whereas the P2Y(4) receptor has a protective effect. Overall, these findings indicate a role for ATP and its receptors in modulating cardiomyocyte damage during ischaemic/hypoxic stress.

  4. Prognostic significance of TRAIL death receptors in Middle Eastern colorectal carcinomas and their correlation to oncogenic KRAS alterations

    Directory of Open Access Journals (Sweden)

    Hussain Azhar R

    2010-07-01

    Full Text Available Abstract Background Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL is a member of the tumour necrosis factor cytokine family that induces apoptosis upon binding to its death domain containing receptors, TRAIL receptor 1 (DR4 and TRAIL receptor 2 (DR5. Expression of TRAIL receptors is higher in colorectal carcinoma (CRC as compared to normal colorectal mucosa and targeted therapy with TRAIL leads to preferential killing of tumor cells sparing normal cells. Methods We investigated the expression of TRAIL and its receptors in a tissue microarray cohort of 448 Middle Eastern CRC. We also studied the correlation between TRAIL receptors and various clinico-pathological features including key molecular alterations and overall survival. Results CRC subset with TRAIL-R1 expression was associated with a less aggressive phenotype characterized by early stage (p = 0.0251 and a histology subtype of adenocarcinomas (p = 0.0355. Similarly CRC subset with TRAIL-R2 expression was associated with a well-differentiated tumors (p KIP1 and KRAS4A isoforms was significantly higher in CRC subset with TRAIL-R1 and TRAIL-R2 expression; TRAIL-R1 expression was also associated with cleaved caspase-3(p = 0.0011. Interestingly, TRAIL-R2 expression was associated with a microsatellite stable (MS--S/L phenotype (p = 0.0003 and with absence of KRAS mutations (p = 0.0481. Conclusion TRAIL-R1 expression was an independent prognostic marker for better survival in all CRC samples and even in the CRC group that received adjuvant therapy. The biological effects of TRAIL in CRC models, its enhancement of chemosensitivity towards standard chemotherapeutic agents and the effect of endogenous TRAIL receptor levels on survival make TRAIL an extremely attractive therapeutic target.

  5. Combination of TRAIL with bortezomib shifted apoptotic signaling from DR4 to DR5 death receptor by selective internalization and degradation of DR4.

    Directory of Open Access Journals (Sweden)

    Maxim L Bychkov

    Full Text Available TRAIL (tumor necrosis factor-related apoptosis-inducing ligand mediates apoptosis in cancer cells through death receptors DR4 and DR5 preferring often one receptor over another in the cells expressing both receptors. Receptor selective mutant variants of TRAIL and agonistic antibodies against DR4 and DR5 are highly promising anticancer agents. Here using DR5 specific mutant variant of TRAIL--DR5-B we have demonstrated for the first time that the sensitivity of cancer cells can be shifted from one TRAIL death receptor to another during co-treatment with anticancer drugs. First we have studied the contribution of DR4 and DR5 in HCT116 p53+/+ and HCT116 p53-/- cells and demonstrated that in HCT116 p53+/+ cells the both death receptors are involved in TRAIL-induced cell death while in HCT116 p53-/- cells prevailed DR4 signaling. The expression of death (DR4 and DR5 as well as decoy (DcR1 and DcR2 receptors was upregulated in the both cell lines either by TRAIL or by bortezomib. However, combined treatment of cells with two drugs induced strong time-dependent and p53-independent internalization and further lysosomal degradation of DR4 receptor. Interestingly DR5-B variant of TRAIL which do not bind with DR4 receptor also induced elimination of DR4 from cell surface in combination with bortezomib indicating the ligand-independent mechanism of the receptor internalization. Eliminatory internalization of DR4 resulted in activation of DR5 receptor thus DR4-dependent HCT116 p53-/- cells became highly sensitive to DR5-B in time-dependent manner. Internalization and degradation of DR4 receptor depended on activation of caspases as well as of lysosomal activity as it was completely inhibited by Z-VAD-FMK, E-64 and Baf-A1. In light of our findings, it is important to explore carefully which of the death receptors is active, when sensitizing drugs are combined with agonistic antibodies to the death receptors or receptor selective variants of TRAIL to enhance

  6. Combination of TRAIL with bortezomib shifted apoptotic signaling from DR4 to DR5 death receptor by selective internalization and degradation of DR4.

    Science.gov (United States)

    Bychkov, Maxim L; Gasparian, Marine E; Dolgikh, Dmitry A; Kirpichnikov, Mikhail P

    2014-01-01

    TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) mediates apoptosis in cancer cells through death receptors DR4 and DR5 preferring often one receptor over another in the cells expressing both receptors. Receptor selective mutant variants of TRAIL and agonistic antibodies against DR4 and DR5 are highly promising anticancer agents. Here using DR5 specific mutant variant of TRAIL--DR5-B we have demonstrated for the first time that the sensitivity of cancer cells can be shifted from one TRAIL death receptor to another during co-treatment with anticancer drugs. First we have studied the contribution of DR4 and DR5 in HCT116 p53+/+ and HCT116 p53-/- cells and demonstrated that in HCT116 p53+/+ cells the both death receptors are involved in TRAIL-induced cell death while in HCT116 p53-/- cells prevailed DR4 signaling. The expression of death (DR4 and DR5) as well as decoy (DcR1 and DcR2) receptors was upregulated in the both cell lines either by TRAIL or by bortezomib. However, combined treatment of cells with two drugs induced strong time-dependent and p53-independent internalization and further lysosomal degradation of DR4 receptor. Interestingly DR5-B variant of TRAIL which do not bind with DR4 receptor also induced elimination of DR4 from cell surface in combination with bortezomib indicating the ligand-independent mechanism of the receptor internalization. Eliminatory internalization of DR4 resulted in activation of DR5 receptor thus DR4-dependent HCT116 p53-/- cells became highly sensitive to DR5-B in time-dependent manner. Internalization and degradation of DR4 receptor depended on activation of caspases as well as of lysosomal activity as it was completely inhibited by Z-VAD-FMK, E-64 and Baf-A1. In light of our findings, it is important to explore carefully which of the death receptors is active, when sensitizing drugs are combined with agonistic antibodies to the death receptors or receptor selective variants of TRAIL to enhance cancer treatment

  7. Death receptor and mitochondria-mediated hepatocyte apoptosis underlies liver dysfunction in rats exposed to organic pollutants from drinking water.

    Science.gov (United States)

    Yang, Guanghong; Zhou, Zhiwei; Cen, Yanli; Gui, Xiaolin; Zeng, Qibing; Ao, Yunxia; Li, Qian; Wang, Shiran; Li, Jun; Zhang, Aihua

    2015-01-01

    Persistent organic pollutants in drinking water impose a substantial risk to the health of human beings, but the evidence for liver toxic effect and the underlying mechanism is scarce. This study aimed to examine the liver toxicity and elucidate the molecular mechanism of organic pollutants in drinking water in normal human liver cell line L02 cells and rats. The data showed that organic extraction from drinking water remarkably impaired rat liver function, evident from the increase in the serum level of alanine aminotransferase, aspartate aminotransferase, and cholinesterase, and decrease in the serum level of total protein and albumin. Organic extraction dose-dependently induced apoptotic cell death in rat liver and L02 cells. Administration of rats with organic extraction promoted death receptor signaling pathway through the increase in gene and protein expression level of Fas and FasL. Treatment of rats with organic extraction also induced mitochondria-mediated apoptosis via increasing the expression level of proapoptotic protein, Bax, but decreasing the expression level of antiapoptotic protein, Bcl-2, resulting in an upregulation of cytochrome c and activation of caspase cascade at both transcriptional and post-transcriptional levels. Moreover, organic extraction enhanced rat liver glutathione S-transferases activity and reactive oxygen species generation, and upregulated aryl hydrocarbon receptor and glutathione S-transferase A1 at both transcriptional and translational levels. Collectively, the results indicate that organic extraction from drinking water impairs liver function, with the involvement of death receptor and mitochondria-mediated apoptosis in rats. The results provide evidence and molecular mechanisms for organic pollutants in drinking water-induced liver dysfunction, which may help prevent and treat organic extraction-induced liver injury.

  8. Death receptor and mitochondria-mediated hepatocyte apoptosis underlies liver dysfunction in rats exposed to organic pollutants from drinking water

    Science.gov (United States)

    Yang, Guanghong; Zhou, Zhiwei; Cen, Yanli; Gui, Xiaolin; Zeng, Qibing; Ao, Yunxia; Li, Qian; Wang, Shiran; Li, Jun; Zhang, Aihua

    2015-01-01

    Persistent organic pollutants in drinking water impose a substantial risk to the health of human beings, but the evidence for liver toxic effect and the underlying mechanism is scarce. This study aimed to examine the liver toxicity and elucidate the molecular mechanism of organic pollutants in drinking water in normal human liver cell line L02 cells and rats. The data showed that organic extraction from drinking water remarkably impaired rat liver function, evident from the increase in the serum level of alanine aminotransferase, aspartate aminotransferase, and cholinesterase, and decrease in the serum level of total protein and albumin. Organic extraction dose-dependently induced apoptotic cell death in rat liver and L02 cells. Administration of rats with organic extraction promoted death receptor signaling pathway through the increase in gene and protein expression level of Fas and FasL. Treatment of rats with organic extraction also induced mitochondria-mediated apoptosis via increasing the expression level of proapoptotic protein, Bax, but decreasing the expression level of antiapoptotic protein, Bcl-2, resulting in an upregulation of cytochrome c and activation of caspase cascade at both transcriptional and post-transcriptional levels. Moreover, organic extraction enhanced rat liver glutathione S-transferases activity and reactive oxygen species generation, and upregulated aryl hydrocarbon receptor and glutathione S-transferase A1 at both transcriptional and translational levels. Collectively, the results indicate that organic extraction from drinking water impairs liver function, with the involvement of death receptor and mitochondria-mediated apoptosis in rats. The results provide evidence and molecular mechanisms for organic pollutants in drinking water-induced liver dysfunction, which may help prevent and treat organic extraction-induced liver injury. PMID:26316710

  9. “P2X7 Receptor Activation Regulates Microglial Cell Death During Oxygen-Glucose Deprivation”

    OpenAIRE

    Eyo, Ukpong B.; Miner, Sam A.; Ahlers, Katelin E.; Wu, Long-Jun; Dailey, Michael E.

    2013-01-01

    Brain-resident microglia may promote tissue repair following stroke but, like other cells, they are vulnerable to ischemia. Here we identify mechanisms involved in microglial ischemic vulnerability. Using time-lapse imaging of cultured BV2 microglia, we show that simulated ischemia (oxygen-glucose deprivation; OGD) induces BV2 microglial cell death. Removal of extracellular Ca2+ or application of Brilliant Blue G (BBG), a potent P2X7 receptor (P2X7R) antagonist, protected BV2 microglia from d...

  10. TRAF6 and p62 inhibit amyloid β-induced neuronal death through p75 neurotrophin receptor

    OpenAIRE

    Geetha, Thangiah; Zheng, Chen; McGregor, Wade C.; White, B. Douglas; Diaz-Meco, Maria T; Moscat, Jorge; Babu, Jeganathan Ramesh

    2012-01-01

    Amyloid β (Aβ) aggregates are the primary component of senile plaques in Alzheimer disease (AD) patient’s brain. Aβ is known to bind p75 neurotrophin receptor (p75NTR) and mediates Aβ-induced neuronal death. Recently, we showed that NGF leads to p75NTR polyubiquitination, which promotes neuronal cell survival. Here, we demonstrate that Aβ stimulation impaired the p75NTR polyubiquitination. TRAF6 and p62 are required for polyubiquitination of p75NTR on NGF stimulation. Interestingly, we found ...

  11. Protective effects of N-methyl-D-aspartate receptor antagonism on VX-induced neuronal cell death in cultured rat cortical neurons.

    Science.gov (United States)

    Wang, Yushan; Weiss, M Tracy; Yin, Junfei; Tenn, Catherine C; Nelson, Peggy D; Mikler, John R

    2008-01-01

    Exposure of the central nervous system to organophosphorus (OP) nerve agents induces seizures and neuronal cell death. Here we report that the OP nerve agent, VX, induces apoptotic-like cell death in cultured rat cortical neurons. The VX effects on neurons were concentration-dependent, with an IC(50) of approximately 30 microM. Blockade of N-methyl-D-aspartate receptors (NMDAR) with 50 microM. D-2-amino-5-phosphonovalerate (APV) diminished 30 microM VX-induced total cell death, as assessed by alamarBlue assay and Hoechst staining. In contrast, neither antagonists of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) nor metabotropic glutamate receptors (mGluRs) had any effect on VX-induced neurotoxicity. VX-induced neuronal cell death could not be solely attributed to acetylcholinesterase (AChE) inhibition, since neither the reversible pharmacological cholinesterase inhibitor, physostigmine, nor the muscarinic receptor antagonist, atropine, affected VX-induced cell death. Importantly, APV was found to be therapeutically effective against VX-induced cell death up to 2 h post VX exposure. These results suggest that NMDARs, but not AMPARs or mGluRs, play important roles in VX-induced cell death in cultured rat cortical neurons. Based on their therapeutic effects, NMDAR antagonists may be beneficial in the treatment of VX-induced neurotoxicities.

  12. 1-Benzyl-2-Phenylbenzimidazole (BPB, a Benzimidazole Derivative, Induces Cell Apoptosis in Human Chondrosarcoma through Intrinsic and Extrinsic Pathways

    Directory of Open Access Journals (Sweden)

    Ju-Fang Liu

    2012-12-01

    Full Text Available In this study, we investigated the anticancer effects of a new benzimidazole derivative, 1-benzyl-2-phenyl -benzimidazole (BPB, in human chondrosarcoma cells. BPB-mediated apoptosis was assessed by the MTT assay and flow cytometry analysis. The in vivo efficacy was examined in a JJ012 xenograft model. Here we found that BPB induced apoptosis in human chondrosarcoma cell lines (JJ012 and SW1353 but not in primary chondrocytes. BPB induced upregulation of Bax, Bad and Bak, downregulation of Bcl-2, Bid and Bcl-XL and dysfunction of mitochondria in chondrosarcoma. In addition, BPB also promoted cytosolic releases AIF and Endo G. Furthermore, it triggered extrinsic death receptor-dependent pathway, which was characterized by activating Fas, FADD and caspase-8. Most importantly, animal studies revealed a dramatic 40% reduction in tumor volume after 21 days of treatment. Thus, BPB may be a novel anticancer agent for the treatment of chondrosarcoma.

  13. Quercetin enhances TRAIL-induced apoptosis in prostate cancer cells via increased protein stability of death receptor 5

    Science.gov (United States)

    Jung, Young-Hwa; Heo, Jeonghoon; Lee, Yong J.; Kwon, Taeg Kyu; Kim, Young-Ho

    2010-01-01

    Aims Quercetin has been shown to enhance tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis of prostate cancer cells via mechanisms that include upregulation of death receptor (DR) 5, a protein reported to play an important role in sensitizing cancer cells to apoptosis. We aimed to determine the specific mechanisms underlying quercetin-induced DR5 expression. Main methods Human prostate cancer cells were exposed to quercetin and TRAIL. Trypan blue assays and terminal transferase dUTP nick-end labeling (TUNEL) assays evaluated changes in TRAIL resistance after quercetin treatment, and flow cytometry examined quercetin-induced death receptor expression in DU-145 cells. Western blotting, reverse transcription-polymerase chain reaction (RT-PCR) and transiently transfection were utilized to confirm apoptotic patterns of prostate cancer cells. Key findings After stimulation with quercetin, DU-145 cells exhibited stronger sensitization to TRAIL. Quercetin treatment enhanced TRAIL-induced activation proteins in the caspase pathway, such as poly (ADP-ribose) polymerase (PARP), caspase-3, and caspase-9. Quercetin dose-dependently increased DR5 levels in prostate cancer cells, which was mediated by increased transcription and protein stability, but not mRNA stability. Ectopic expression of DR5 dose-dependently increased TRAIL-induced apoptosis. Significance Our results showed that the role of quercetin and TRAIL combination therapy may provide a novel strategy for treating prostate cancer by overcoming critical mechanisms of apoptosis resistance. PMID:20096292

  14. The role of MAPK and FAS death receptor pathways in testicular germ cell apoptosis induced by lead

    Institute of Scientific and Technical Information of China (English)

    Shuying Dong; Duoping Liang; Na An; Li Jia; Yujuan Shan; Chao Chen; Kuo Sun; Fei Niu; Huiyan Li; Songbin Fu

    2009-01-01

    The aim of the present study is to investigate gene expression involved in the signal pathway of MAPK and death signal receptor pathway of FAS in lead-induced apoptosis of testicular germ cells. First, cell viabilities were determined by MTT assay. Second, using single cell gel-electrophoresis test (comet assay) and TUNEL staining technique, apoptotie rate and cell apoptosis localization of testicular germ cells were measured in mice treated with 0.15%, 0.3%, and 0.6% lead, respectively. Third, the immunolocalization of K-ras, c-fos, Fas, and active caspase-3 proteins was determined by immunohistochemistry. Finally, changes in the translational levels of K-ras, c-fos, Fas, and active caspase-3 were further detected by western blot analysis. Our results showed that lead could significantly induce testicular germ cell apoptosis in a dose-dependent manner (P < 0.01). The mechanisms were closely related to the increased expressions of K-ras, c-fos, Fas, and active caspase-3 in apoptotic germ cells. In conclusion, K-ras/c-fos and Fas/caspase-3 death signaling receptor pathways were involved in the lead-induced apoptosis of the testicular germ cells in mice.

  15. High-affinity olfactory receptor for the death-associated odor cadaverine.

    Science.gov (United States)

    Hussain, Ashiq; Saraiva, Luis R; Ferrero, David M; Ahuja, Gaurav; Krishna, Venkatesh S; Liberles, Stephen D; Korsching, Sigrun I

    2013-11-26

    Carrion smell is strongly repugnant to humans and triggers distinct innate behaviors in many other species. This smell is mainly carried by two small aliphatic diamines, putrescine and cadaverine, which are generated by bacterial decarboxylation of the basic amino acids ornithine and lysine. Depending on the species, these diamines may also serve as feeding attractants, oviposition attractants, or social cues. Behavioral responses to diamines have not been investigated in zebrafish, a powerful model system for studying vertebrate olfaction. Furthermore, olfactory receptors that detect cadaverine and putrescine have not been identified in any species so far. Here, we show robust olfactory-mediated avoidance behavior of zebrafish to cadaverine and related diamines, and concomitant activation of sparse olfactory sensory neurons by these diamines. The large majority of neurons activated by low concentrations of cadaverine expresses a particular olfactory receptor, trace amine-associated receptor 13c (TAAR13c). Structure-activity analysis indicates TAAR13c to be a general diamine sensor, with pronounced selectivity for odd chains of medium length. This receptor can also be activated by decaying fish extracts, a physiologically relevant source of diamines. The identification of a sensitive zebrafish olfactory receptor for these diamines provides a molecular basis for studying neural circuits connecting sensation, perception, and innate behavior.

  16. The P2X7 Receptor Supports Both Life and Death in Fibrogenic Pancreatic Stellate Cells

    DEFF Research Database (Denmark)

    Haanes, Kristian; Schwab, Albrecht; Novak, Ivana

    2012-01-01

    The pancreatic stellate cells (PSCs) have complex roles in pancreas, including tissue repair and fibrosis. PSCs surround ATP releasing exocrine cells, but little is known about purinergic receptors and their function in PSCs. Our aim was to resolve whether PSCs express the multifunctional P2X7...... receptor and elucidate how it regulates PSC viability. The number of PSCs isolated from wild type (WT) mice was 50% higher than those from the Pfizer P2X7 receptor knock out (KO) mice. The P2X7 receptor protein and mRNA of all known isoforms were expressed in WT PSCs, while KO PSCs only expressed truncated...... was stimulated with ATP in a concentration-dependent manner with a maximum effect at 100 µM. At high ATP concentration (5 mM), WT PSCs, but not the KO PSCs died. The intracellular Ca(2+) signals and proliferation rate induced by micromolar ATP concentrations were inhibited by the allosteric P2X7 receptor...

  17. Deficiency of GDNF Receptor GFRα1 in Alzheimer's Neurons Results in Neuronal Death

    Science.gov (United States)

    Konishi, Yoshihiro; Yang, Li-Bang; He, Ping; Lindholm, Kristina; Lu, Bai

    2014-01-01

    We have recently developed aged cortical neuron cultures from autopsied human brains with Alzheimer's disease (AD). During the culturing process, we found that glutamatergic cortical neurons from the AD brain lacked a response to glial cell line-derived neurotrophic factor (GDNF), including no axonal regrowth, and were starting to undergo apoptosis. Here we showed that, in cortical neurons from age- and gender-matched cognitively normal control (NC) subjects (NC neurons), GDNF enhanced the expression of GDNF family receptor subtype α1 (GFRα1), but not the other three subtypes (GFRα2, GFRα3, and GFRα4), whereas GDNF failed to induce GFRα1 expression in cortical neurons from the AD brain (AD neurons). The exogenous introduction of GFRα1, but not of its binding partner α1-neural cell adhesion molecule, or RET into AD neurons restored the effect of GDNF on neuronal survival. Moreover, between NC and AD neurons, the AMPA receptor blocker CNQX and the NMDA receptor blocker AP-5 had opposite effects on the GFRα1 expression induced by GDNF. In NC neurons, the presence of glutamate receptors was necessary for GDNF-linked GFRα1 expression, while in AD neurons the absence of glutamate receptors was required for GFRα1 expression by GDNF stimulation. These results suggest that, in AD neurons, specific impairments of GFRα1, which may be linked to glutamatergic neurotransmission, shed light on developing potential therapeutic strategies for AD by upregulation of GFRα1 expression. PMID:25253858

  18. Lysosomal Membrane Permeabilization is an Early Event in Sigma-2 Receptor Ligand Mediated Cell Death in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Hornick John R

    2012-05-01

    Full Text Available Abstract Background Sigma-2 receptor ligands have been studied for treatment of pancreatic cancer because they are preferentially internalized by proliferating cells and induce apoptosis. This mechanism of apoptosis is poorly understood, with varying reports of caspase-3 dependence. We evaluated multiple sigma-2 receptor ligands in this study, each shown to decrease tumor burden in preclinical models of human pancreatic cancer. Results Fluorescently labeled sigma-2 receptor ligands of two classes (derivatives of SW43 and PB282 localize to cell membrane components in Bxpc3 and Aspc1 pancreatic cancer cells and accumulate in lysosomes. We found that interactions in the lysosome are critical for cell death following sigma-2 ligand treatment because selective inhibition of a protective lysosomal membrane glycoprotein, LAMP1, with shRNA greatly reduced the viability of cells following treatment. Sigma-2 ligands induced lysosomal membrane permeabilization (LMP and protease translocation triggering downstream effectors of apoptosis. Subsequently, cellular oxidative stress was greatly increased following treatment with SW43, and the hydrophilic antioxidant N-acetylcysteine (NAC gave greater protection against this than a lipophilic antioxidant, α-tocopherol (α-toco. Conversely, PB282-mediated cytotoxicity relied less on cellular oxidation, even though α-toco did provide protection from this ligand. In addition, we found that caspase-3 induction was not as significantly inhibited by cathepsin inhibitors as by antioxidants. Both NAC and α-toco protected against caspase-3 induction following PB282 treatment, while only NAC offered protection following SW43 treatment. The caspase-3 inhibitor DEVD-FMK offered significant protection from PB282, but not SW43. Conclusions Sigma-2 ligand SW43 commits pancreatic cancer cells to death by a caspase-independent process involving LMP and oxidative stress which is protected from by NAC. PB282 however undergoes a

  19. Cudrania tricuspidata Stem Extract Induces Apoptosis via the Extrinsic Pathway in SiHa Cervical Cancer Cells.

    Science.gov (United States)

    Kwon, Sae-Bom; Kim, Min-Je; Yang, Jin Mo; Lee, Hee-Pom; Hong, Jin Tae; Jeong, Heon-Sang; Kim, Eun Suk; Yoon, Do-Young

    2016-01-01

    The focus of this study is the anti-cancer effects of Cudrania tricuspidata stem (CTS) extract on cervical cancer cells. The effect of CTS on cell viability was investigated in HPV-positive cervical cancer cells and HaCaT human normal keratinocytes. CTS showed significant dose-dependent cytotoxic effects in cervical cancer cells. However, there was no cytotoxic effect of CTS on HaCaT keratinocytes at concentrations of 0.125-0.5 mg/mL. Based on this cytotoxic effect, we demonstrated that CTS induced apoptosis by down-regulating the E6 and E7 viral oncogenes. Apoptosis was detected by DAPI staining, annexin V-FITC/PI staining, cell cycle analysis, western blotting, RT-PCR, and JC-1 staining in SiHa cervical cancer cells. The mRNA expression levels of extrinsic pathway molecules such as Fas, death receptor 5 (DR5), and TNF-related apoptosis-inducing ligand (TRAIL) were increased by CTS. Furthermore, CTS treatment activated caspase-3/caspase-8 and cleavage of poly (ADP-ribose) polymerase (PARP). However, the mitochondrial membrane potential and expression levels of intrinsic pathway molecules such as Bcl-2, Bcl-xL, Bax, and cytochrome C were not modulated by CTS. Taken together, these results indicate that CTS induced apoptosis by activating the extrinsic pathway, but not the intrinsic pathway, in SiHa cervical cancer cells. These results suggest that CTS can be used as a modulating agent in cervical cancer.

  20. Activation of extrinsic apoptosis pathway in HCV monoinfected and HIV-HCV coinfected patients, irrespective of liver disease severity.

    Science.gov (United States)

    Feuth, Thijs; Van Baarle, Debbie; Hoepelman, Andy I M; Van Erpecum, Karel J; Siersema, Peter D; Arends, Joop E

    2014-07-01

    Chronic hepatitis C virus (HCV) infection is associated with increased levels of peripheral T cell apoptosis. We aimed to study whether T cell apoptosis markers indicate pathways that may contribute to clinical progression in HCV monoinfected and HIV-HCV coinfected patients. Activation of the extrinsic apoptosis pathways was measured by levels of death receptor Fas, initiator caspase 8 and effector caspases 3 and 7 activity and Annexin V binding on peripheral CD4 and CD8 T cells of HCV monoinfected and HIV/HCV coinfected patients, as well as healthy controls and HIV-infected, hepatitis B virus-infected and primary biliary cirrhosis disease controls. Association with liver fibrosis was assessed by biopsy or by transient elastography. HCV monoinfected and HIV-HCV coinfected patients displayed enhanced peripheral CD4 and CD8 T cell apoptosis. Caspase 8 activity was highest in HIV-HCV coinfection, without enhanced downstream activity of caspases 3 and 7. Level of peripheral T cell apoptosis was independent of liver fibrosis or other disease parameters in all disease groups. The extrinsic apoptosis pathway is upregulated in HCV monoinfection and HIV-HCV coinfection, but this is independent of liver disease severity.

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

    Directory of Open Access Journals (Sweden)

    Ji Yang eKim

    2015-09-01

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

  2. Prenatal nicotine-exposure alters fetal autonomic activity and medullary neurotransmitter receptors: implications for sudden infant death syndrome.

    Science.gov (United States)

    Duncan, Jhodie R; Garland, Marianne; Myers, Michael M; Fifer, William P; Yang, May; Kinney, Hannah C; Stark, Raymond I

    2009-11-01

    During pregnancy, exposure to nicotine and other compounds in cigarette smoke increases the risk of the sudden infant death syndrome (SIDS) two- to fivefold. Serotonergic (5-HT) abnormalities are found, in infants who die of SIDS, in regions of the medulla oblongata known to modulate cardiorespiratory function. Using a baboon model, we tested the hypothesis that prenatal exposure to nicotine alters 5-HT receptor and/or transporter binding in the fetal medullary 5-HT system in association with cardiorespiratory dysfunction. At 87 (mean) days gestation (dg), mothers were continuously infused with saline (n = 5) or nicotine (n = 5) at 0.5 mg/h. Fetuses were surgically instrumented at 129 dg for cardiorespiratory monitoring. Cesarean section delivery and retrieval of fetal medulla were performed at 161 (mean) dg for autoradiographic analyses of nicotinic and 5-HT receptor and transporter binding. In nicotine-exposed fetuses, high-frequency heart rate variability was increased 55%, possibly reflecting increases in the parasympathetic control of heart rate. This effect was more pronounced with greater levels of fetal breathing and age. These changes in heart rate variability were associated with increased 5-HT(1A) receptor binding in the raphé obscurus (P = 0.04) and increased nicotinic receptor binding in the raphé obscurus and vagal complex (P < 0.05) in the nicotine-exposed animals compared with controls (n = 6). The shift in autonomic balance in the fetal primate toward parasympathetic predominance with chronic exposure to nicotine may be related, in part, to abnormal 5-HT-nicotine alterations in the raphé obscurus. Thus increased risk for SIDS due to maternal smoking may be partly related to the effects of nicotine on 5-HT and/or nicotinic receptors.

  3. The extrinsic apoptotic signaling pathway in gastric adenocarcinomas assessed by tissue microarray.

    Science.gov (United States)

    Gomes, Thiago S; Oshima, Celina T F; Segreto, Helena R C; Barrazueta, Luis M; Costa, Henrique O; Lima, Flavio O; Forones, Nora M; Ribeiro, Daniel A

    2011-10-15

    The purpose of this investigation was to analyze the immunoexpression of FasL, Fas, FADD, cleaved caspase 8, and cleaved caspase 3 in gastric cancer. Formalin-fixed and paraffin-embedded gastric adenocarcinoma tissues from 87 patients, including adjacent normal tissues, were included on tissue microarray by immunohistochemistry. The tumor and the adjacent normal tissues were positive for FasL in 66.7% and 90.6%, for Fas in 52.8% and 52.4%, for FADD in 67.4% and 82.3%, for cleaved caspase 8 in 27.9% and 37.7%, and for cleaved caspase 3 in 33.7% and 8.3%, respectively. FasL and the FADD from tumor were statistically different in relation to the histological type. Cleaved caspase 8 was statistically different in relation to clinical stage (p=0.031). The FADD from normal tissue was statistically different in relation to age (p=0.039), sex (p=0.055), clinical stage (p=0.019), and Fas was different in relation to tumor size (p=0.012). In the tumor, we observed a correlation between FasL and Fas, FasL and FADD, and FasL and cleaved caspase 3. In the adjacent normal tissue, a correlation was observed between FasL and Fas, FasL and FADD. There was no association of another marker with sex, age, clinical stage, and survival. Our results suggest that these proteins mediate the early extrinsic apoptotic pathway in gastric cancer and adjacent normal mucosa. FasL protein binds to Fas protein and subsequently binds to death receptor FADD signaling activation of the extrinsic apoptotic pathway. In this phase, there was inhibition of caspase 8 and, consequently, decreased apoptosis.

  4. Nitric oxide: promoter or suppressor of programmed cell death?

    Science.gov (United States)

    Wang, Yiqin; Chen, Chen; Loake, Gary J; Chu, Chengcai

    2010-02-01

    Nitric oxide (NO) is a short-lived gaseous free radical that predominantly functions as a messenger and effector molecule. It affects a variety of physiological processes, including programmed cell death (PCD) through cyclic guanosine monophosphate (cGMP)-dependent and - independent pathways. In this field, dominant discoveries are the diverse apoptosis networks in mammalian cells, which involve signals primarily via death receptors (extrinsic pathway) or the mitochondria (intrinsic pathway) that recruit caspases as effector molecules. In plants, PCD shares some similarities with animal cells, but NO is involved in PCD induction via interacting with pathways of phytohormones. NO has both promoting and suppressing effects on cell death, depending on a variety of factors, such as cell type, cellular redox status, and the flux and dose of local NO. In this article, we focus on how NO regulates the apoptotic signal cascade through protein S-nitrosylation and review the recent progress on mechanisms of PCD in both mammalian and plant cells.

  5. High-affinity olfactory receptor for the death-associated odor cadaverine

    OpenAIRE

    2013-01-01

    Cadaverine and putrescine, two diamines emanating from decaying flesh, are strongly repulsive odors to humans but serve as innate attractive or social cues in other species. Here we show that zebrafish, a vertebrate model system, exhibit powerful and innate avoidance behavior to both diamines, and identify a high-affinity olfactory receptor for cadaverine.

  6. The p75 neurotrophin receptor: at the crossroad of neural repair and death

    Directory of Open Access Journals (Sweden)

    Rick B Meeker

    2015-01-01

    Full Text Available The strong repair and pro-survival functions of neurotrophins at their primary receptors, TrkA, TrkB and TrkC, have made them attractive candidates for treatment of nervous system injury and disease. However, difficulties with the clinical implementation of neurotrophin therapies have prompted the search for treatments that are stable, easier to deliver and allow more precise regulation of neurotrophin actions. Recently, the p75 neurotrophin receptor (p75 NTR has emerged as a potential target for pharmacological control of neurotrophin activity, supported in part by studies demonstrating 1 regulation of neural plasticity in the mature nervous system, 2 promotion of adult neurogenesis and 3 increased expression in neurons, macrophages, microglia, astrocytes and/or Schwann cells in response to injury and neurodegenerative diseases. Although the receptor has no intrinsic catalytic activity it interacts with and modulates the function of TrkA, TrkB, and TrkC, as well as sortilin and the Nogo receptor. This provides substantial cellular and molecular diversity for regulation of neuron survival, neurogenesis, immune responses and processes that support neural function. Upregulation of the p75 NTR under pathological conditions places the receptor in a key position to control numerous processes necessary for nervous system recovery. Support for this possibility has come from recent studies showing that small, non-peptide p75 NTR ligands can selectively modify pro-survival and repair functions. While a great deal remains to be discovered about the wide ranging functions of the p75 NTR , studies summarized in this review highlight the immense potential for development of novel neuroprotective and neurorestorative therapies.

  7. Erythropoietin (EPO)-receptor signaling induces cell death of primary myeloma cells in vitro

    OpenAIRE

    Thea Kristin Våtsveen; Anne-Marit Sponaas; Erming Tian; Qing Zhang; Kristine Misund; Anders Sundan; Magne Børset; Anders Waage; Gaute Brede

    2016-01-01

    Background: Multiple myeloma is an incurable complex disease characterized by clonal proliferation of malignant plasma cells in a hypoxic bone marrow environment. Hypoxia-dependent erythropoietin (EPO)-receptor (EPOR) signaling is central in various cancers, but the relevance of EPOR signaling in multiple myeloma cells has not yet been thoroughly investigated. Methods: Myeloma cell lines and malignant plasma cells isolated from bone marrow of myeloma patients were used in this st...

  8. Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout.

    Science.gov (United States)

    Ehlken, H; Krishna-Subramanian, S; Ochoa-Callejero, L; Kondylis, V; Nadi, N E; Straub, B K; Schirmacher, P; Walczak, H; Kollias, G; Pasparakis, M

    2014-11-01

    Hepatocellular carcinoma (HCC) usually develops in the context of chronic hepatitis triggered by viruses or toxic substances causing hepatocyte death, inflammation and compensatory proliferation of liver cells. Death receptors of the TNFR superfamily regulate cell death and inflammation and are implicated in liver disease and cancer. Liver parenchymal cell-specific ablation of NEMO/IKKγ, a subunit of the IκB kinase (IKK) complex that is essential for the activation of canonical NF-κB signalling, sensitized hepatocytes to apoptosis and caused the spontaneous development of chronic hepatitis and HCC in mice. Here we show that hepatitis and HCC development in NEMO(LPC-KO) mice is triggered by death receptor-independent FADD-mediated hepatocyte apoptosis. TNF deficiency in all cells or conditional LPC-specific ablation of TNFR1, Fas or TRAIL-R did not prevent hepatocyte apoptosis, hepatitis and HCC development in NEMO(LPC-KO) mice. To address potential functional redundancies between death receptors we generated and analysed NEMO(LPC-KO) mice with combined LPC-specific deficiency of TNFR1, Fas and TRAIL-R and found that also simultaneous lack of all three death receptors did not prevent hepatocyte apoptosis, chronic hepatitis and HCC development. However, LPC-specific combined deficiency in TNFR1, Fas and TRAIL-R protected the NEMO-deficient liver from LPS-induced liver failure, showing that different mechanisms trigger spontaneous and LPS-induced hepatocyte apoptosis in NEMO(LPC-KO) mice. In addition, NK cell depletion did not prevent liver damage and hepatitis. Moreover, NEMO(LPC-KO) mice crossed into a RAG-1-deficient genetic background-developed hepatitis and HCC. Collectively, these results show that the spontaneous development of hepatocyte apoptosis, chronic hepatitis and HCC in NEMO(LPC-KO) mice occurs independently of death receptor signalling, NK cells and B and T lymphocytes, arguing against an immunological trigger as the critical stimulus driving

  9. Fitness, Extrinsic Complexity and Informing Science

    Directory of Open Access Journals (Sweden)

    Grandon Gill

    2017-03-01

    We raise concerns about society’s continuing investment in academic research that discounts the extrinsic complexity of the domains under study. Future Research We highlight a need for research to operationalize the concepts of fitness and complexity in practice.

  10. The contribution of low affinity NGF receptor (p75NGFR to delayed neuronal death after ischemia in the gerbil hippocampus.

    Directory of Open Access Journals (Sweden)

    Bagum MA

    2001-02-01

    Full Text Available The implication of low affinity nerve growth factor receptor (p75NGFR, which is believed to play a pro-apoptotic role, in delayed neuronal death (DND after ischemia in the gerbil hippocampus was investigated. Immunohistochemistry and Western blot analysis revealed that the presence of p75 NGFR immunoreactivity (IR was negligible in the hippocampus of the sham control gerbil but appeared clearly in CA1 neurons 3 and 4 days after 5-min transient ischemia. Terminal deoxynucleotidyl transferase-mediated UTP nick end labeling (TUNEL positive nuclei appeared when the level of p75NGFR IR increased. Furthermore, almost all TUNEL-positive CA1 neurons also costained for p75NGFR. These results suggest that p75NGFR contributes to DND after ischemia by an apoptotic mechanism.

  11. Antitumor effects of a sirtuin inhibitor, tenovin-6, against gastric cancer cells via death receptor 5 up-regulation.

    Directory of Open Access Journals (Sweden)

    Sachiko Hirai

    Full Text Available Up-regulated sirtuin 1 (SIRT1, an NAD+-dependent class III histone deacetylase, deacetylates p53 and inhibits its transcriptional activity, leading to cell survival. SIRT1 overexpression has been reported to predict poor survival in some malignancies, including gastric cancer. However, the antitumor effect of SIRT1 inhibition remains elusive in gastric cancer. Here, we investigated the antitumor mechanisms of a sirtuin inhibitor, tenovin-6, in seven human gastric cancer cell lines (four cell lines with wild-type TP53, two with mutant-type TP53, and one with null TP53. Interestingly, tenovin-6 induced apoptosis in all cell lines, not only those with wild-type TP53, but also mutant-type and null versions, accompanied by up-regulation of death receptor 5 (DR5. In the KatoIII cell line (TP53-null, DR5 silencing markedly attenuated tenovin-6-induced apoptosis, suggesting that the pivotal mechanism behind its antitumor effects is based on activation of the death receptor signal pathway. Although endoplasmic reticulum stress caused by sirtuin inhibitors was reported to induce DR5 up-regulation in other cancer cell lines, we could not find marked activation of its related molecules, such as ATF6, PERK, and CHOP, in gastric cancer cells treated with tenovin-6. Tenovin-6 in combination with docetaxel or SN-38 exerted a slight to moderate synergistic cytotoxicity against gastric cancer cells. In conclusion, tenovin-6 has potent antitumor activity against human gastric cancer cells via DR5 up-regulation. Our results should be helpful for the future clinical development of sirtuin inhibitors.

  12. Nuclear Receptor PPARα Agonist Wy-14,643 Ameliorates Hepatic Cell Death in Hepatic IKKβ-Deficient Mice.

    Science.gov (United States)

    Kim, Taehyeong; Wahyudi, Lilik Duwi; Gonzalez, Frank J; Kim, Jung-Hwan

    2017-09-01

    Inhibitor of nuclear factor kappa-B kinase beta (IKKβ) plays a critical role in cell proliferation and inflammation in various cells by activating NF-κB signaling. However, the interrelationship between peroxisome proliferator-activated receptor α (PPARα) and IKKβ in cell proliferation is not clear. In this study, we investigated the possible role of PPARα in the hepatic cell death in the absence of IKKβ gene using liver-specific Ikkb-null (Ikkb(F/F-AlbCre)) mice. To examine the function of PPARα activation in hepatic cell death, wild-type (Ikkb(F/F)) and Ikkb(F/F-AlbCre) mice were treated with PPARα agonist Wy-14,643 (0.1% w/w chow diet) for two weeks. As a result of Wy-14,643 treatment, apoptotic markers including caspase-3 cleavage, poly (ADP-ribose) polymerase (PARP) cleavage and TUNEL-positive staining were significantly decreased in the Ikkb(F/F-AlbCre) mice. Surprisingly, Wy-14,643 increased the phosphorylation of p65 and STAT3 in both Ikkb and Ikkb(F/F-AlbCre) mice. Furthermore, BrdU-positive cells were significantly increased in both groups after treatment with Wy-14,643. Our results suggested that IKKβ-derived hepatic apoptosis could be altered by PPARα activation in conjunction with activation of NF-κB and STAT3 signaling.

  13. Excessive activation of ionotropic glutamate receptors induces apoptotic hair-cell death independent of afferent and efferent innervation

    Science.gov (United States)

    Sheets, Lavinia

    2017-01-01

    Accumulation of excess glutamate plays a central role in eliciting the pathological events that follow intensely loud noise exposures and ischemia-reperfusion injury. Glutamate excitotoxicity has been characterized in cochlear nerve terminals, but much less is known about whether excess glutamate signaling also contributes to pathological changes in sensory hair cells. I therefore examined whether glutamate excitotoxicity damages hair cells in zebrafish larvae exposed to drugs that mimic excitotoxic trauma. Exposure to ionotropic glutamate receptor (iGluR) agonists, kainic acid (KA) or N-methyl-D-aspartate (NMDA), contributed to significant, progressive hair cell loss in zebrafish lateral-line organs. To examine whether hair-cell loss was a secondary effect of excitotoxic damage to innervating neurons, I exposed neurog1a morphants—fish whose hair-cell organs are devoid of afferent and efferent innervation—to KA or NMDA. Significant, dose-dependent hair-cell loss occurred in neurog1a morphants exposed to either agonist, and the loss was comparable to wild-type siblings. A survey of iGluR gene expression revealed AMPA-, Kainate-, and NMDA-type subunits are expressed in zebrafish hair cells. Finally, hair cells exposed to KA or NMDA appear to undergo apoptotic cell death. Cumulatively, these data reveal that excess glutamate signaling through iGluRs induces hair-cell death independent of damage to postsynaptic terminals. PMID:28112265

  14. The chemokine growth-related gene product β protects rat cerebellar granule cells from apoptotic cell death through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors

    Science.gov (United States)

    Limatola, Cristina; Ciotti, Maria Teresa; Mercanti, Delio; Vacca, Fabrizio; Ragozzino, Davide; Giovannelli, Aldo; Santoni, Angela; Eusebi, Fabrizio; Miledi, Ricardo

    2000-01-01

    Cultured cerebellar granule neurons are widely used as a cellular model to study mechanisms of neuronal cell death because they undergo programmed cell death when switched from a culture medium containing 25 mM to one containing 5 mM K+. We have found that the growth-related gene product β (GROβ) partially prevents the K+-depletion-induced cell death, and that the neuroprotective action of GROβ on granule cells is mediated through the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) type of ionotropic glutamate receptors. GROβ-induced survival was suppressed by 6-cyano-7-nitroquinoxaline-2,3-dione, which is a specific antagonist of AMPA/kainate receptors; it was not affected by the inhibitor of N-methyl-d-aspartate receptors, 2-amino-5-phosphonopentanoic acid, and was comparable to the survival of granule cells induced by AMPA (10 μM) treatment. Moreover, GROβ-induced neuroprotection was abolished when granule cells were treated with antisense oligonucleotides specific for the AMPA receptor subunits, which significantly reduced receptor expression, as verified by Western blot analysis with subunit-specific antibodies and by granule cell electrophysiological sensitivity to AMPA. Our data demonstrate that GROβ is neurotrophic for cerebellar granule cells, and that this activity depends on AMPA receptors. PMID:10811878

  15. Myeloid zinc finger 1 mediates sulindac sulfide-induced upregulation of death receptor 5 of human colon cancer cells.

    Science.gov (United States)

    Horinaka, Mano; Yoshida, Tatsushi; Tomosugi, Mitsuhiro; Yasuda, Shusuke; Sowa, Yoshihiro; Sakai, Toshiyuki

    2014-08-08

    A combined therapy of sulindac sulfide and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising strategy for the treatment of cancer. Sulindac sulfide had been shown to induce the expression of death receptor 5 (DR5), a receptor for TRAIL, and sensitize cancer cells to TRAIL-induced apoptosis; however, the molecular mechanism underlying the upregulation of DR5 has not yet been elucidated. We demonstrate here that myeloid zinc finger 1 (MZF1) mediates the induction of DR5 by sulindac sulfide. Sulindac sulfide induced the expression of DR5 at the protein and mRNA levels in colon cancer SW480 cells. Furthermore, sulindac sulfide increased DR5 promoter activity. We showed that sulindac sulfide stimulated DR5 promoter activity via the -301 to -253 region. This region contained a putative MZF1-binding site. Site-directed mutations in the site abrogated the enhancement in DR5 promoter activity by sulindac sulfide. MZF1 directly bound to the putative MZF1-binding site of the DR5 promoter and the binding was increased by sulindac sulfide. The expression of MZF1 was also increased by sulindac sulfide, and MZF1 siRNA attenuated the upregulation of DR5 by sulindac sulfide. These results indicate that sulindac sulfide induces the expression of DR5 by up-regulating MZF1.

  16. The Divergent Cardiovascular Effects of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers on Myocardial Infarction and Death.

    Science.gov (United States)

    Strauss, Martin H; Hall, Alistair S

    2016-01-01

    The renin angiotensin aldosterone system (RAAS) plays a central role in the pathophysiology of hypertension and vascular disease. Angiotensin converting enzyme inhibitors (ACEis) suppress angiotensin II (ANG II) concentrations, whereas angiotensin receptor blockers (ARBs) block the binding of ANG II to AT1 receptors. ACEis and ARBs are both effective anti-hypertensive agents and have similar risk reductions in stroke - a blood pressure dependent phenomenon. ACEis also reduce the risk of myocardial infarction (MI) and mortality in high risk hypertensive patients, as well as in diabetics, the elderly, those with vascular disease, and in congestive heart failure. ARBs, in contrast, do not reduce the risk of MI or death in clinical trials where the comparator has been another active therapy or even a placebo. Systematic reviews of ARBs that include meta-analyses or meta-regression analyses confirm that ARBs lack the cardiovascular protective effects of ACEis, which in part are "independent" of blood pressure lowering. Practice guidelines, especially those in high risk hypertensive patients, should reflect the evidence that ACEis and ARBs have divergent cardiovascular effects - ACEis reduce mortality, whereas ARBs do not. ACEis should be the preferred RAAS inhibitor in high risk patients. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Hypoxia in human colorectal adenocarcinoma: comparison between extrinsic and potential intrinsic hypoxia markers.

    NARCIS (Netherlands)

    Goethals, L.; Debucquoy, A.; Perneel, C.; Geboes, K.; Ectors, N.; Schutter, H. De; Penninckx, F.; McBride, W.H.; Begg, A.C.; Haustermans, K.

    2006-01-01

    PURPOSE: To detect and quantify hypoxia in colorectal adenocarcinomas by use of pimonidazole and iododeoxyuridine (IdUrd) as extrinsic markers and carbonic anhydrase IX (CA IX), microvessel density (MVD), epidermal growth-factor receptor (EGFR), and vascular endothelial growth factor (VEGF) as intri

  18. Parathyroid hormone related protein (PTHrP) inhibits TNFalpha-induced apoptosis by blocking the extrinsic and intrinsic pathways.

    Science.gov (United States)

    Okoumassoun, Liliane; Averill-Bates, Diana; Denizeau, Francine; Henderson, Janet E

    2007-02-01

    Parathyroid hormone related protein (PTHrP) is expressed at low levels in many fetal and adult tissues where it plays a central role in regulating cell proliferation, cell death, and tissue homeostasis. In vivo and in vitro, PTHrP has been shown to promote the survival of a variety of cells by regulating expression of the anti-apoptotic protein Bcl2. Additional work has shown that intra-nuclear accumulation of PTHrP in CFK2 (PTH1R positive) and 27m21 (PTH1R negative) condrogenic cells promotes their survival by closing down ribosome biogenesis and promoting quiescence. The current studies were undertaken to examine the role of wild-type PTHrP and a mutant form that cannot translocate to the nucleus in protecting cells from TNFalpha-induced apoptosis. Both forms of the protein were equally effective in blocking the extrinsic pathway by inhibiting expression of the TNF receptor death domain, activating Bid, and promoting cleavage of caspase 8. These observations suggest a direct mechanism of PTHrP action on components of the extrinsic pathway, involving a region of the protein outside of the NTS. PTHrP and M1PTHrP also inhibited the intrinsic pathway by preventing the exchange of anti-apoptotic for pro-apoptotic proteins at the mitochondrial membrane, thus maintaining its integrity and preventing the release of caspase-activating factors into the cytosol. In general, this mitochondrial-related activity was somewhat delayed and was mediated more effectively by PTHrP than by M1PTHrP, suggesting an indirect mechanism of action that might require the presence of an intact NTS.

  19. Structure and interactions of the human programmed cell death 1 receptor.

    Science.gov (United States)

    Cheng, Xiaoxiao; Veverka, Vaclav; Radhakrishnan, Anand; Waters, Lorna C; Muskett, Frederick W; Morgan, Sara H; Huo, Jiandong; Yu, Chao; Evans, Edward J; Leslie, Alasdair J; Griffiths, Meryn; Stubberfield, Colin; Griffin, Robert; Henry, Alistair J; Jansson, Andreas; Ladbury, John E; Ikemizu, Shinji; Carr, Mark D; Davis, Simon J

    2013-04-26

    PD-1, a receptor expressed by T cells, B cells, and monocytes, is a potent regulator of immune responses and a promising therapeutic target. The structure and interactions of human PD-1 are, however, incompletely characterized. We present the solution nuclear magnetic resonance (NMR)-based structure of the human PD-1 extracellular region and detailed analyses of its interactions with its ligands, PD-L1 and PD-L2. PD-1 has typical immunoglobulin superfamily topology but differs at the edge of the GFCC' sheet, which is flexible and completely lacks a C" strand. Changes in PD-1 backbone NMR signals induced by ligand binding suggest that, whereas binding is centered on the GFCC' sheet, PD-1 is engaged by its two ligands differently and in ways incompletely explained by crystal structures of mouse PD-1 · ligand complexes. The affinities of these interactions and that of PD-L1 with the costimulatory protein B7-1, measured using surface plasmon resonance, are significantly weaker than expected. The 3-4-fold greater affinity of PD-L2 versus PD-L1 for human PD-1 is principally due to the 3-fold smaller dissociation rate for PD-L2 binding. Isothermal titration calorimetry revealed that the PD-1/PD-L1 interaction is entropically driven, whereas PD-1/PD-L2 binding has a large enthalpic component. Mathematical simulations based on the biophysical data and quantitative expression data suggest an unexpectedly limited contribution of PD-L2 to PD-1 ligation during interactions of activated T cells with antigen-presenting cells. These findings provide a rigorous structural and biophysical framework for interpreting the important functions of PD-1 and reveal that potent inhibitory signaling can be initiated by weakly interacting receptors.

  20. Blowing in the (social) wind: implications of extrinsic esteem contingencies for terror management and health.

    Science.gov (United States)

    Arndt, Jamie; Cox, Cathy R; Goldenberg, Jamie L; Vess, Matthew; Routledge, Clay; Cooper, Douglas P; Cohen, Florette

    2009-06-01

    In 4 studies, the role of extrinsic esteem contingencies in adjusting to shifting health-relevant standards when managing existential fears was examined. Study 1 demonstrated that after reminders of death, higher dispositional focus on extrinsic self-esteem contingencies predicted greater interest in tanning. Using a more domain-specific approach, Study 2 showed that, after being reminded of death, the more individuals smoke for social esteem reasons, the more compelling they find an antismoking commercial that exposes adverse social consequences of smoking. Study 3 explored how situational factors (i.e., priming a contingent relational schema) that implicate extrinsic contingencies facilitated the impact of shifting standard primes on tanning intentions after mortality salience. Finally, Study 4 found that mortality salience led to increased endorsement of exercise as a basis of self-worth when participants who derive self-esteem from extrinsic sources visualized someone who exercises. Together, these studies demonstrate that reminders of death interact with prevalent social standards to influence everyday health decisions.

  1. Toll like receptor 4 mediates cell death in a mouse MPTP model of Parkinson disease

    Science.gov (United States)

    Noelker, Carmen; Morel, Lydie; Lescot, Thomas; Osterloh, Anke; Alvarez-Fischer, Daniel; Breloer, Minka; Henze, Carmen; Depboylu, Candan; Skrzydelski, Delphine; Michel, Patrick P.; Dodel, Richard C.; Lu, Lixia; Hirsch, Etienne C.; Hunot, Stéphane; Hartmann, Andreas

    2013-01-01

    In mammalians, toll-like receptors (TLR) signal-transduction pathways induce the expression of a variety of immune-response genes, including inflammatory cytokines. It is therefore plausible to assume that TLRs are mediators in glial cells triggering the release of cytokines that ultimately kill DA neurons in the substantia nigra in Parkinson disease (PD). Accordingly, recent data indicate that TLR4 is up-regulated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in a mouse model of PD. Here, we wished to evaluate the role of TLR4 in the acute mouse MPTP model of PD: TLR4-deficient mice and wild-type littermates control mice were used for the acute administration way of MPTP or a corresponding volume of saline. We demonstrate that TLR4-deficient mice are less vulnerable to MPTP intoxication than wild-type mice and display a decreased number of Iba1+ and MHC II+ activated microglial cells after MPTP application, suggesting that the TLR4 pathway is involved in experimental PD. PMID:23462811

  2. ATM Inhibition Potentiates Death of Androgen Receptor-inactivated Prostate Cancer Cells with Telomere Dysfunction.

    Science.gov (United States)

    Reddy, Vidyavathi; Wu, Min; Ciavattone, Nicholas; McKenty, Nathan; Menon, Mani; Barrack, Evelyn R; Reddy, G Prem-Veer; Kim, Sahn-Ho

    2015-10-16

    Androgen receptor (AR) plays a role in maintaining telomere stability in prostate cancer cells, as AR inactivation induces telomere dysfunction within 3 h. Since telomere dysfunction in other systems is known to activate ATM (ataxia telangiectasia mutated)-mediated DNA damage response (DDR) signaling pathways, we investigated the role of ATM-mediated DDR signaling in AR-inactivated prostate cancer cells. Indeed, the induction of telomere dysfunction in cells treated with AR-antagonists (Casodex or MDV3100) or AR-siRNA was associated with a dramatic increase in phosphorylation (activation) of ATM and its downstream effector Chk2 and the presenceof phosphorylated ATM at telomeres, indicating activation of DDR signaling at telomeres. Moreover, Casodex washout led to the reversal of telomere dysfunction, indicating repair of damaged telomeres. ATM inhibitor blocked ATM phosphorylation, induced PARP cleavage, abrogated cell cycle checkpoint activation and attenuated the formation of γH2AX foci at telomeres in AR-inactivated cells, suggesting that ATM inhibitor induces apoptosis in AR-inactivated cells by blocking the repair of damaged DNA at telomeres. Finally, colony formation assay revealed a dramatic decrease in the survival of cells co-treated with Casodex and ATM inhibitor as compared with those treated with either Casodex or ATM inhibitor alone. These observations indicate that inhibitors of DDR signaling pathways may offer a unique opportunity to enhance the potency of AR-targeted therapies for the treatment of androgen-sensitive as well as castration-resistant prostate cancer.

  3. Structure-function analysis of barley NLR immune receptor MLA10 reveals its cell compartment specific activity in cell death and disease resistance.

    Directory of Open Access Journals (Sweden)

    Shiwei Bai

    Full Text Available Plant intracellular immune receptors comprise a large number of multi-domain proteins resembling animal NOD-like receptors (NLRs. Plant NLRs typically recognize isolate-specific pathogen-derived effectors, encoded by avirulence (AVR genes, and trigger defense responses often associated with localized host cell death. The barley MLA gene is polymorphic in nature and encodes NLRs of the coiled-coil (CC-NB-LRR type that each detects a cognate isolate-specific effector of the barley powdery mildew fungus. We report the systematic analyses of MLA10 activity in disease resistance and cell death signaling in barley and Nicotiana benthamiana. MLA10 CC domain-triggered cell death is regulated by highly conserved motifs in the CC and the NB-ARC domains and by the C-terminal LRR of the receptor. Enforced MLA10 subcellular localization, by tagging with a nuclear localization sequence (NLS or a nuclear export sequence (NES, shows that MLA10 activity in cell death signaling is suppressed in the nucleus but enhanced in the cytoplasm. By contrast, nuclear localized MLA10 is sufficient to mediate disease resistance against powdery mildew fungus. MLA10 retention in the cytoplasm was achieved through attachment of a glucocorticoid receptor hormone-binding domain (GR, by which we reinforced the role of cytoplasmic MLA10 in cell death signaling. Together with our data showing an essential and sufficient nuclear MLA10 activity in disease resistance, this suggests a bifurcation of MLA10-triggered cell death and disease resistance signaling in a compartment-dependent manner.

  4. P2 receptors in human heart: upregulation of P2X6 in patients undergoing heart transplantation, interaction with TNFalpha and potential role in myocardial cell death.

    Science.gov (United States)

    Banfi, Cristina; Ferrario, Silvia; De Vincenti, Ombretta; Ceruti, Stefania; Fumagalli, Marta; Mazzola, Alessia; D' Ambrosi, Nadia; Volontè, Cinzia; Fratto, Pasquale; Vitali, Ettore; Burnstock, Geoffrey; Beltrami, Elena; Parolari, Alessandro; Polvani, GianLuca; Biglioli, Paolo; Tremoli, Elena; Abbracchio, Maria P

    2005-12-01

    ATP acts as a neurotransmitter via seven P2X receptor-channels for Na(+) and Ca(2+), and eight G-protein-coupled P2Y receptors. Despite evidence suggesting roles in human heart, the map of myocardial P2 receptors is incomplete, and their involvement in chronic heart failure (CHF) has never received adequate attention. In left myocardia from five to nine control and 5-12 CHF subjects undergoing heart transplantation, we analyzed the full repertoire of P2 receptors and of 10 "orphan" P2Y-like receptors. All known P2Y receptors (i.e. P2Y(1,2,4,6,11,12,13,14)) and two P2Y-like receptors (GPR91 and GPR17) were detected in all subjects. All known P2X(1-7) receptors were also detected; of these, only P2X(6) was upregulated in CHF, as confirmed by quantitative real time-PCR. The potential significance of this change was studied in primary cardiac fibroblasts freshly isolated from young pigs. Exposure of cardiac fibroblasts to ATP or its hydrolysis-resistant-analog benzoylATP induced apoptosis. TNFalpha (a cytokine implicated in CHF progression) exacerbated cell death. Similar effects were induced by ATP and TNFalpha in a murine cardiomyocytic cell line. In cardiac fibroblasts, TNFalpha inhibited the downregulation of P2X(6) mRNA associated to prolonged agonist exposure, suggesting that, by preventing ATP-induced P2X(6) desensitization, TNFalpha may abolish a defense mechanism meant at avoiding Ca(2+) overload and, ultimately, Ca(2+)-dependent cell death. This may provide a basis for P2X(6) upregulation in CHF. In conclusion, we provide the first characterization of P2 receptors in the human heart and suggest that the interaction between TNFalpha and the upregulated P2X(6) receptor may represent a novel pathogenic mechanism in CHF.

  5. Preparation and functional studies of hydroxyethyl chitosan nanoparticles loaded with anti-human death receptor 5 single-chain antibody

    Directory of Open Access Journals (Sweden)

    Yang J

    2014-05-01

    Full Text Available Jingjing Yang,1,3,* Xiaoping Huang,1,3,* Fanghong Luo,1 Xiaofeng Cheng,3 Lianna Cheng,3 Bin Liu,4 Lihong Chen,2 Ruyi Hu,1,3 Chunyan Shi,1,3 Guohong Zhuang,1,3 Ping Yin2 1Anti-Cancer Research Center, Medical College, Xiamen University, Fujian, People's Republic of China, 2The Department of Pathology, Zhongshan Hospital, Xiamen University, Xiamen, People's Republic of China, 3Organ transplantation institution, Xiamen University, Xiamen, People's Republic of China, 4Jilin Vocational College of Industry and Technology, Jilin, People's Republic of China  *These authors contributed equally to this work Objective: To prepare hydroxyethyl chitosan nanoparticles loaded with anti-human death receptor 5 single-chain antibody, and study their characteristics, functions, and mechanisms of action. Materials and methods: The anti-human death receptor 5 single-chain antibody was constructed and expressed. Protein-loaded hydroxyethyl chitosan nanoparticles were prepared, and their size, morphology, particle-size distribution and surface zeta potential were measured by scanning electron microscopy and laser particle-size analysis. Mouse H22 hepatocellular carcinoma cells were cultured, and growth inhibition was examined using the CellTiter-Blue cell-viability assay. Flow cytometry and Hoechst 33342 were employed to measure cell apoptosis. Kunming mice with H22 tumor models were treated with protein-loaded hydroxyethyl chitosan nanoparticles, and their body weight and tumor size were measured, while hematoxylin and eosin staining was used to detect antitumor effects in vivo and side effects from tumors. Results: The protein-loaded hydroxyethyl chitosan nanoparticles had good stability; the zeta potential was -24.2±0.205, and the dispersion index was 0.203. The inhibition of the protein-loaded hydroxyethyl chitosan nanoparticles on H22 growth was both time- and dose-dependent. Increased expressions of active caspase 8, active caspase 3, and BAX were detected

  6. Tumor necrosis factor alpha and Fas receptor contribute to cognitive deficits independent of cell death after concussive traumatic brain injury in mice.

    Science.gov (United States)

    Khuman, Jugta; Meehan, William P; Zhu, Xiaoxia; Qiu, Jianhua; Hoffmann, Ulrike; Zhang, Jimmy; Giovannone, Eric; Lo, Eng H; Whalen, Michael J

    2011-02-01

    Tumor necrosis factor alpha (TNFα) and Fas receptor contribute to cell death and cognitive dysfunction after focal traumatic brain injury (TBI). We examined the role of TNFα/Fas in postinjury functional outcome independent of cell death in a novel closed head injury (CHI) model produced with weight drop and free rotational head movement in the anterior-posterior plane. The CHI produced no cerebral edema or blood-brain barrier damage at 24 to 48 hours, no detectable cell death, occasional axonal injury (24 hours), and no brain atrophy or hippocampal cell loss (day 60). Microglia and astrocytes were activated (48 to 72 hours). Tumor necrosis factor-α mRNA, Fas mRNA, and TNFα protein were increased in the brain at 3 to 6 hours after injury (Pcell death after CHI. Therapies targeting TNFα/Fas together may be inappropriate for patients with concussive TBI.

  7. Extrinsic curvature induced 2-d gravity

    CERN Document Server

    Viswanathan, K S

    1993-01-01

    Abtract: 2-dimensional fermions are coupled to extrinsic geometry of a conformally immersed surface in ${\\bf R}^3$ through gauge coupling. By integrating out the fermions, we obtain a WZNW action involving extrinsic curvature of the surface. Restricting the resulting effective action to surfaces of $h\\sqrt g=1$, an explicit form of the action invariant under Virasaro symmetry is obtained. This action is a sum of the geometric action for the Virasaro group and the light-cone action of 2-d gravity plus an interaction term. The central charges of the theory in both the left and right sectors are calculated.

  8. Lipid rafts and raft-mediated supramolecular entities in the regulation of CD95 death receptor apoptotic signaling.

    Science.gov (United States)

    Gajate, Consuelo; Mollinedo, Faustino

    2015-05-01

    Membrane lipid rafts are highly ordered membrane domains enriched in cholesterol, sphingolipids and gangliosides that have the property to segregate and concentrate proteins. Lipid and protein composition of lipid rafts differs from that of the surrounding membrane, thus providing sorting platforms and hubs for signal transduction molecules, including CD95 death receptor-mediated signaling. CD95 can be recruited to rafts in a reversible way through S-palmitoylation following activation of cells with its physiological cognate ligand as well as with a wide variety of inducers, including several antitumor drugs through ligand-independent intracellular mechanisms. CD95 translocation to rafts can be modulated pharmacologically, thus becoming a target for the treatment of apoptosis-defective diseases, such as cancer. CD95-mediated signaling largely depends on protein-protein interactions, and the recruitment and concentration of CD95 and distinct downstream apoptotic molecules in membrane raft domains, forming raft-based supramolecular entities that act as hubs for apoptotic signaling molecules, favors the generation and amplification of apoptotic signals. Efficient CD95-mediated apoptosis involves CD95 and raft internalization, as well as the involvement of different subcellular organelles. In this review, we briefly summarize and discuss the involvement of lipid rafts in the regulation of CD95-mediated apoptosis that may provide a new avenue for cancer therapy.

  9. Expression of brain-derived neurotrophic factor and TrkB receptor in the sudden infant death syndrome brainstem.

    Science.gov (United States)

    Tang, Samantha; Machaalani, Rita; Waters, Karen A

    2012-01-15

    This study compared the expression of BDNF (proBDNF and rhBDNF forms) and its receptor TrkB, in the medulla of sudden infant death syndrome (SIDS) infants and infants who died from known causes (non-SIDS). This study also evaluated these markers in association with SIDS clinical risk factors including, sleep position, cigarette smoke exposure and gender. Brainstem tissue was immunohistochemically stained and quantitative analyses were made for eight nuclei of the caudal and rostral medulla. Compared to non-SIDS, SIDS infants had lower rhBDNF in the caudal nucleus of the solitary tract and higher TrkB in the caudal dorsal motor nucleus of the vagus. Within the SIDS cohort, prone sleep position was associated with lower rhBDNF in the caudal arcuate nucleus, and cigarette smoke exposure was associated with lower rhBDNF and TrkB in the inferior olivary nucleus. Abnormal expression of BDNF and TrkB suggests that neuroprotective functions of the BDNF/TrkB system may be reduced in respiratory-related nuclei of SIDS infants.

  10. TRAF6 and p62 inhibit amyloid β-induced neuronal death through p75 neurotrophin receptor

    Science.gov (United States)

    Geetha, Thangiah; Zheng, Chen; McGregor, Wade C.; White, B. Douglas; Diaz-Meco, Maria T.; Moscat, Jorge; Babu, Jeganathan Ramesh

    2014-01-01

    Amyloid β (Aβ) aggregates are the primary component of senile plaques in Alzheimer disease (AD) patient’s brain. Aβ is known to bind p75 neurotrophin receptor (p75NTR) and mediates Aβ-induced neuronal death. Recently, we showed that NGF leads to p75NTR polyubiquitination, which promotes neuronal cell survival. Here, we demonstrate that Aβ stimulation impaired the p75NTR polyubiquitination. TRAF6 and p62 are required for polyubiquitination of p75NTR on NGF stimulation. Interestingly, we found that overexpression of TRAF6/p62 restored p75NTR polyubiquitination upon Aβ/NGF treatment. Aβ significantly reduced NF-κB activity by attenuating the interaction of p75NTR with IKKβ. p75NTR increased NF-κB activity by recruiting TRAF6/p62, which thereby mediated cell survival. These findings indicate that TRAF6/p62 abrogated the Aβ-mediated inhibition of p75NTR polyubiquitination and restored neuronal cell survival. PMID:23017601

  11. Role of gamma-aminobutyricacidB(GABA(B)) receptors in the regulation of kainic acid-induced cell death in mouse hippocampus.

    Science.gov (United States)

    Lee, Han Kyu; Seo, Young Jun; Choi, Seong Soo; Kwon, Min Soo; Shim, Eon Jeong; Lee, Jin Young; Suh, Hong Won

    2005-12-31

    Kainic acid (KA) is well-known as an excitatory, neurotoxic substance. In mice, KA administered intracerebroventricularly (i.c.v.) lead to morphological damage of hippocampus expecially concentrated on the CA3 pyramidal neurons. In the present study, the possible role of gamma-aminobutyric acid B (GABA(B)) receptors in hippocampal cell death induced by KA (0.1 microg) administered i.c.v. was examined. 5-Aminovaleric acid (5-AV; GABA(B) receptors antagonist, 20 mug) reduced KA-induced CA3 pyramidal cell death. KA increased the phosphorylated extracellular signal-regulated kinase (p-ERK) and Ca(2+)/calmodulin-dependent protein kinase II (p-CaMK II) immunoreactivities (IRs) 30 min after KA treatment, and c-Fos, c-Jun IR 2 h, and glial fibrillary acidic protein (GFAP), complement receptor type 3 (OX-42) IR 1 day in hippocampal area in KA-injected mice. 5-AV attenuated KA-induced p-CaMK II, GFAP and OX-42 IR in the hippocampal CA3 region. These results suggest that p-CaMK II may play as an important regulator on hippocampal cell death induced by KA administered i.c.v. in mice. Activated astrocytes, which was presented by GFAP IR, and activated microglia, which was presented by the OX-42 IR, may be a good indicator for measuring the cell death in hippocampal regions by KA excitotoxicity. Furthermore, it showed that GABA(B) receptors appear to be involved in hippocampal CA3 pyramidal cell death induced by KA administered i.c.v. in mice.

  12. Block of P2X7 receptors could partly reverse the delayed neuronal death in area CA1 of the hippocampus after transient global cerebral ischemia.

    Science.gov (United States)

    Yu, Qiang; Guo, Zhili; Liu, Xiaofeng; Ouyang, Qing; He, Cheng; Burnstock, Geoffrey; Yuan, Hongbin; Xiang, Zhenghua

    2013-12-01

    Transient global ischemia (which closely resembles clinical situations such as cardiac arrest, near drowning or severe systemic hypotension during surgical procedures), often induces delayed neuronal death in the brain, especially in the hippocampal CA1 region. The mechanism of ischemia/reperfusion (I/R) injury is not fully understood. In this study, we have shown that the P2X7 receptor antagonist, BBG, reduced delayed neuronal death in the hippocampal CA1 region after I/R injury; P2X7 receptor expression levels increased before delayed neuronal death after I/R injury; inhibition of the P2X7 receptor reduced I/R-induced microglial microvesicle-like components, IL-1β expression, P38 phosphorylation, and glial activation in hippocampal CA1 region after I/R injury. These results indicate that antagonism of the P2X7 receptor and signaling pathways of microglial MV shedding, such as src-protein tyrosine kinase, P38 MAP kinase and A-SMase, might be a promising therapeutic strategy for clinical treatment of transient global cerebral I/R injury.

  13. Intrinsic and Extrinsic Motivation among Collegiate Instrumentalists

    Science.gov (United States)

    Diaz, Frank M.

    2010-01-01

    The purpose of this study was to gather and compare information on measures of intrinsic and extrinsic motivation among instrumentalists enrolled in collegiate ensembles. A survey instrument was developed to gather information concerning demographic data and responses to questions on motivational preference. Participants were undergraduate and…

  14. Intrinsic and Extrinsic Motivation among Collegiate Instrumentalists

    Science.gov (United States)

    Diaz, Frank M.

    2010-01-01

    The purpose of this study was to gather and compare information on measures of intrinsic and extrinsic motivation among instrumentalists enrolled in collegiate ensembles. A survey instrument was developed to gather information concerning demographic data and responses to questions on motivational preference. Participants were undergraduate and…

  15. Encouraging Classroom Participation with Empty Extrinsic Rewards

    Science.gov (United States)

    Guinee, William

    2012-01-01

    In this article, the author talks about how to encourage classroom participation with empty extrinsic rewards. He uses "bonus points" in awarding students for particularly interesting or well thought-out contributions to the class discussion. These bonus points have absolutely no effect on the student's course grade. But the students respond…

  16. The intracellular domain of the low affinity p75 nerve growth factor receptor is a death effector domain.

    Science.gov (United States)

    Park, Hyun H

    2009-01-01

    The death domain superfamily, comprising the death domain, death effector domain, caspase recruitment domain and pyrin domain subfamilies, is one of the largest classes of protein interaction modules, and plays a particularly critical function in the assembly and activation of apoptotic and inflammatory complexes. Members of the death domain superfamily share a common structural feature, the 6-helical bundle fold. However, individual subfamilies exhibit distinct structural and sequence characteristics. The most distinct feature identified in structural studies is that only the death effector domain contains a charge triad, which is formed by the E/D-RxDL motif. However, using sequence alignment and structural comparison, in the present study we found that the p75-NGFR death domain also contains a charge triad. We therefore suggest that the p75-NGFR death domain should be classified as belonging to the death effector domain.

  17. Intrinsic and extrinsic factors influencing large African herbivore movements

    NARCIS (Netherlands)

    Venter, J.A.; Prins, H.H.T.; Mashanova, A.; Boer, de W.F.; Slotow, R.

    2015-01-01

    Understanding environmental as well as anthropogenic factors that influence large herbivore ecological patterns and processes should underpin their conservation and management. We assessed the influence of intrinsic, extrinsic environmental and extrinsic anthropogenic factors on movement behaviour o

  18. Effects of Extrinsic Rewards on Intrinsic Motivation in the Classroom.

    Science.gov (United States)

    Workman, Edward A.; Williams, Robert L.

    1980-01-01

    Reviews classroom behavior management studies to see if extrinsic rewards affect intrinsic reinforcement value of appropriate classroom behaviors. Conclusion indicates extrinsic rewards are useful. Teachers need not avoid the use of rewards in fear of undermining intrinsic interest. (LAB)

  19. Effects of Extrinsic Rewards on Intrinsic Motivation in the Classroom.

    Science.gov (United States)

    Workman, Edward A.; Williams, Robert L.

    1980-01-01

    Reviews classroom behavior management studies to see if extrinsic rewards affect intrinsic reinforcement value of appropriate classroom behaviors. Conclusion indicates extrinsic rewards are useful. Teachers need not avoid the use of rewards in fear of undermining intrinsic interest. (LAB)

  20. Vitamin D Receptor Activator Use and Cause-specific Death among dialysis Patients: a Nationwide Cohort Study using Coarsened Exact Matching

    Science.gov (United States)

    Obi, Yoshitsugu; Hamano, Takayuki; Wada, Atsushi; Tsubakihara, Yoshiharu; Nakai, Shigeru; Hanafusa, Norio; Masakane, Ikuto; Itami, Noritomo; Yamagata, Kunihiro; Shinoda, Toshio; Kazama, Junichiro James; Watanabe, Yuzo; Shigematsu, Takashi; Marubayashi, Seiji; Morita, Osamu; Kimata, Naoki; Wakai, Kenji; Ogata, Satoshi; Iseki, Kunitoshi; Yamamoto, Keiichi; Shintani, Ayumu

    2017-01-01

    Vitamin D receptor activators (VDRA) may exert pleiotropic effects on cardiovascular disease, malignancy, and infections among dialysis patients, but recent studies have mainly focused on cardiovascular outcomes. Among 8,675 patients who started dialysis in 2007 and who survived until January 1, 2010, listed in the Renal Data Registry of the Japanese Society for Dialysis Therapy, 5,365 VDRA users were matched to 3,203 non-users based on clinically relevant variables at the end of 2009 using the coarsened exact matching procedure. Until December 31, 2011, a total of 1,128 deaths occurred, of which 468 (42%) were cardiovascular deaths, 229 (20%) were infection-related deaths, and 141 (12%) were malignancy-related deaths. Multivariable survival analyses accounting for intra-region correlation revealed that VDRA use was significantly associated with lower rates of infection- and malignancy-related deaths [subhazard ratio 0.62 (95% CI, 0.52–0.73) and 0.70 (95% CI, 0.50–0.97), respectively] but not with cardiovascular death [subhazard ratio 0.86 (95% CI, 0.72–1.04)]. Future randomized clinical trials with a sufficient sample size and an adequate follow-up period are warranted to test the clinical effectiveness of VDRA on infection and malignancy, rather than cardiovascular disease, among dialysis patients. PMID:28139665

  1. Ayanin diacetate-induced cell death is amplified by TRAIL in human leukemia cells

    Energy Technology Data Exchange (ETDEWEB)

    Marrero, Maria Teresa; Estevez, Sara; Negrin, Gledy; Quintana, Jose [Departamento de Bioquimica, Unidad Asociada al Consejo Superior de Investigaciones Cientificas, Universidad de Las Palmas de Gran Canaria, Plaza Dr. Pasteur s/n, 35016 Las Palmas de Gran Canaria (Spain); Lopez, Mariana; Perez, Francisco J.; Triana, Jorge [Departamento de Quimica, Universidad de Las Palmas de Gran Canaria, Instituto Canario de Investigacion del Cancer, 35017 Las Palmas de Gran Canaria (Spain); Leon, Francisco [Instituto de Productos Naturales y Agrobiologia, Consejo Superior de Investigaciones Cientificas, Avda. Astrofisico F. Sanchez 3, 38206 La Laguna, Tenerife (Spain); Estevez, Francisco, E-mail: festevez@dbbf.ulpgc.es [Departamento de Bioquimica, Unidad Asociada al Consejo Superior de Investigaciones Cientificas, Universidad de Las Palmas de Gran Canaria, Plaza Dr. Pasteur s/n, 35016 Las Palmas de Gran Canaria (Spain)

    2012-11-09

    Highlights: Black-Right-Pointing-Pointer Ayanin diacetate as apoptotic inducer in leukemia cells. Black-Right-Pointing-Pointer Cell death was prevented by caspase inhibitors and by the overexpression of Bcl-x{sub L}. Black-Right-Pointing-Pointer The intrinsic and the extrinsic pathways are involved in the mechanism of action. Black-Right-Pointing-Pointer Death receptors are up-regulated and TRAIL enhances apoptotic cell death. -- Abstract: Here we demonstrate that the semi-synthetic flavonoid ayanin diacetate induces cell death selectively in leukemia cells without affecting the proliferation of normal lymphocytes. Incubation of human leukemia cells with ayanin diacetate induced G{sub 2}-M phase cell cycle arrest and apoptosis which was prevented by the non-specific caspase inhibitor z-VAD-fmk and reduced by the overexpression of Bcl-x{sub L}. Ayanin diacetate-induced cell death was found to be associated with: (i) loss of inner mitochondrial membrane potential, (ii) the release of cytochrome c, (iii) the activation of multiple caspases, (iv) cleavage of poly(ADP-ribose) polymerase and (v) the up-regulation of death receptors for TRAIL, DR4 and DR5. Moreover, the combined treatment with ayanin diacetate and TRAIL amplified cell death, compared to single treatments. These results provide a basis for further exploring the potential applications of this combination for the treatment of cancer.

  2. Cudrania tricuspidata Stem Extract Induces Apoptosis via the Extrinsic Pathway in SiHa Cervical Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Sae-Bom Kwon

    Full Text Available The focus of this study is the anti-cancer effects of Cudrania tricuspidata stem (CTS extract on cervical cancer cells. The effect of CTS on cell viability was investigated in HPV-positive cervical cancer cells and HaCaT human normal keratinocytes. CTS showed significant dose-dependent cytotoxic effects in cervical cancer cells. However, there was no cytotoxic effect of CTS on HaCaT keratinocytes at concentrations of 0.125-0.5 mg/mL. Based on this cytotoxic effect, we demonstrated that CTS induced apoptosis by down-regulating the E6 and E7 viral oncogenes. Apoptosis was detected by DAPI staining, annexin V-FITC/PI staining, cell cycle analysis, western blotting, RT-PCR, and JC-1 staining in SiHa cervical cancer cells. The mRNA expression levels of extrinsic pathway molecules such as Fas, death receptor 5 (DR5, and TNF-related apoptosis-inducing ligand (TRAIL were increased by CTS. Furthermore, CTS treatment activated caspase-3/caspase-8 and cleavage of poly (ADP-ribose polymerase (PARP. However, the mitochondrial membrane potential and expression levels of intrinsic pathway molecules such as Bcl-2, Bcl-xL, Bax, and cytochrome C were not modulated by CTS. Taken together, these results indicate that CTS induced apoptosis by activating the extrinsic pathway, but not the intrinsic pathway, in SiHa cervical cancer cells. These results suggest that CTS can be used as a modulating agent in cervical cancer.

  3. Bacillus bombysepticus α-Toxin Binding to G Protein-Coupled Receptor Kinase 2 Regulates cAMP/PKA Signaling Pathway to Induce Host Death.

    Directory of Open Access Journals (Sweden)

    Ping Lin

    2016-03-01

    Full Text Available Bacterial pathogens and their toxins target host receptors, leading to aberrant behavior or host death by changing signaling events through subversion of host intracellular cAMP level. This is an efficient and widespread mechanism of microbial pathogenesis. Previous studies describe toxins that increase cAMP in host cells, resulting in death through G protein-coupled receptor (GPCR signaling pathways by influencing adenylyl cyclase or G protein activity. G protein-coupled receptor kinase 2 (GRK2 has a central role in regulation of GPCR desensitization. However, little information is available about the pathogenic mechanisms of toxins associated with GRK2. Here, we reported a new bacterial toxin-Bacillus bombysepticus (Bb α-toxin that was lethal to host. We showed that Bb α-toxin interacted with BmGRK2. The data demonstrated that Bb α-toxin directly bound to BmGRK2 to promote death by affecting GPCR signaling pathways. This mechanism involved stimulation of Gαs, increase level of cAMP and activation of protein kinase A (PKA. Activated cAMP/PKA signal transduction altered downstream effectors that affected homeostasis and fundamental biological processes, disturbing the structural and functional integrity of cells, resulting in death. Preventing cAMP/PKA signaling transduction by inhibitions (NF449 or H-89 substantially reduced the pathogenicity of Bb α-toxin. The discovery of a toxin-induced host death specifically linked to GRK2 mediated signaling pathway suggested a new model for bacterial toxin action. Characterization of host genes whose expression and function are regulated by Bb α-toxin and GRK2 will offer a deeper understanding of the pathogenesis of infectious diseases caused by pathogens that elevate cAMP.

  4. Identification of an anabolic selective androgen receptor modulator that actively induces death of androgen-independent prostate cancer cells.

    Science.gov (United States)

    Schmidt, Azriel; Meissner, Robert S; Gentile, Michael A; Chisamore, Michael J; Opas, Evan E; Scafonas, Angela; Cusick, Tara E; Gambone, Carlo; Pennypacker, Brenda; Hodor, Paul; Perkins, James J; Bai, Chang; Ferraro, Damien; Bettoun, David J; Wilkinson, Hilary A; Alves, Stephen E; Flores, Osvaldo; Ray, William J

    2014-09-01

    Prostate cancer (PCa) initially responds to inhibition of androgen receptor (AR) signaling, but inevitably progresses to hormone ablation-resistant disease. Much effort is focused on optimizing this androgen deprivation strategy by improving hormone depletion and AR antagonism. However we found that bicalutamide, a clinically used antiandrogen, actually resembles a selective AR modulator (SARM), as it partially regulates 24% of endogenously 5α-dihydrotestosterone (DHT)-responsive genes in AR(+) MDA-MB-453 breast cancer cells. These data suggested that passive blocking of all AR functions is not required for PCa therapy. Hence, we adopted an active strategy that calls for the development of novel SARMs, which induce a unique gene expression profile that is intolerable to PCa cells. Therefore, we screened 3000 SARMs for the ability to arrest the androgen-independent growth of AR(+) 22Rv1 and LNCaP PCa cells but not AR(-) PC3 or DU145 cells. We identified only one such compound; the 4-aza-steroid, MK-4541, a potent and selective SARM. MK-4541 induces caspase-3 activity and cell death in both androgen-independent, AR(+) PCa cell lines but spares AR(-) cells or AR(+) non-PCa cells. This activity correlates with its promoter context- and cell-type dependent transcriptional effects. In rats, MK-4541 inhibits the trophic effects of DHT on the prostate, but not the levator ani muscle, and triggers an anabolic response in the periosteal compartment of bone. Therefore, MK-4541 has the potential to effectively manage prostatic hypertrophic diseases owing to its antitumor SARM-like mechanism, while simultaneously maintaining the anabolic benefits of natural androgens.

  5. Chronic blockade of extrasynaptic NMDA receptors ameliorates synaptic dysfunction and pro-death signaling in Huntington disease transgenic mice.

    Science.gov (United States)

    Dau, Alejandro; Gladding, Clare M; Sepers, Marja D; Raymond, Lynn A

    2014-02-01

    In the YAC128 mouse model of Huntington disease (HD), elevated extrasynaptic NMDA receptor (Ex-NMDAR) expression contributes to the onset of striatal dysfunction and atrophy. A shift in the balance of synaptic-extrasynaptic NMDAR signaling and localization is paralleled by early stage dysregulation of intracellular calcium signaling pathways, including calpain and p38 MAPK activation, that couple to pro-death cascades. However, whether aberrant calcium signaling is a consequence of elevated Ex-NMDAR expression in HD is unknown. Here, we aimed to identify calcium-dependent pathways downstream of Ex-NMDARs in HD. Chronic (2-month) treatment of YAC128 and WT mice with memantine (1 and 10mg/kg/day), which at a low dose selectively blocks Ex-NMDARs, reduced striatal Ex-NMDAR expression and current in 4-month old YAC128 mice without altering synaptic NMDAR levels. In contrast, calpain activity was not affected by memantine treatment, and was elevated in untreated YAC128 mice at 1.5months but not 4months of age. In YAC128 mice, memantine at 1mg/kg/day rescued CREB shut-off, while both doses suppressed p38 MAPK activation to WT levels. Taken together, our results indicate that Ex-NMDAR activity perpetuates increased extrasynaptic NMDAR expression and drives dysregulated p38 MAPK and CREB signaling in YAC128 mice. Elucidation of the pathways downstream of Ex-NMDARs in HD could help provide novel therapeutic targets for this disease. Copyright © 2013 Elsevier Inc. All rights reserved.

  6. Distinguishing subtypes of extrinsic motivation among people with mild to borderline intellectual disability : Distinguishing subtypes of extrinsic motivation

    NARCIS (Netherlands)

    Frielink, N.; Schuengel, C.; Embregts, P.J.C.M.

    Background According to self-determination theory, motivation is ordered in types, including amotivation, extrinsic motivation and intrinsic motivation. Self-determination theory defines four subtypes of extrinsic motivation: external motivation, introjected motivation, identified motivation and

  7. Hispolon from Phellinus linteus induces apoptosis and sensitizes human cancer cells to the tumor necrosis factor-related apoptosis-inducing ligand through upregulation of death receptors.

    Science.gov (United States)

    Kim, Ji-Hun; Kim, Yu Chul; Park, Byoungduck

    2016-02-01

    The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent anticancer agent possessing the ability to induce apoptosis in various cancer cells but not in non‑malignant cells. However, certain type of cancer cells are resistant to TRAIL‑induced apoptosis and some acquire resistance after the first treatment. So development of an agent that can reduce or avoid resistance in TRAIL‑induced apoptosis has garnered significant attention. The present study evaluated the anticancer potential of hispolon in TRAIL‑induced apoptosis and indicated hispolon can sensitize cancer cells to TRAIL. As the mechanism of action was examined, hispolon was found to activate caspase‑3, caspase‑8 and caspase‑9, while downregulating the expression of cell survival proteins such as cFLIP, Bcl‑2 and Bcl‑xL and upregulating the expression of Bax and truncated Bid. We also found hispolon induced death receptors in a non‑cell type‑specific manner. Upregulation of death receptors by hispolon was found to be p53-independent but linked to the induction of CAAT enhancer binding protein homologous protein (CHOP). Overall, hispolon was demonstrated to potentiate the apoptotic effects of TRAIL through downregulation of anti‑apoptotic proteins and upregulation of death receptors linked with CHOP and pERK elevation.

  8. Cell death is induced by ciglitazone, a peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) agonist, independently of PPAR{gamma} in human glioma cells

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Myoung Woo; Kim, Dae Seong; Kim, Hye Ryung; Kim, Hye Jin; Yang, Jin Mo; Ryu, Somi; Noh, Yoo Hun; Lee, Soo Hyun; Son, Meong Hi; Jung, Hye Lim; Yoo, Keon Hee [Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Koo, Hong Hoe, E-mail: hhkoo@skku.edu [Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Sung, Ki Woong, E-mail: kwsped@skku.edu [Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer Greater than 30 {mu}M ciglitazone induces cell death in glioma cells. Black-Right-Pointing-Pointer Cell death by ciglitazone is independent of PPAR{gamma} in glioma cells. Black-Right-Pointing-Pointer CGZ induces cell death by the loss of MMP via decreased Akt. -- Abstract: Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) regulates multiple signaling pathways, and its agonists induce apoptosis in various cancer cells. However, their role in cell death is unclear. In this study, the relationship between ciglitazone (CGZ) and PPAR{gamma} in CGZ-induced cell death was examined. At concentrations of greater than 30 {mu}M, CGZ, a synthetic PPAR{gamma} agonist, activated caspase-3 and induced apoptosis in T98G cells. Treatment of T98G cells with less than 30 {mu}M CGZ effectively induced cell death after pretreatment with 30 {mu}M of the PPAR{gamma} antagonist GW9662, although GW9662 alone did not induce cell death. This cell death was also observed when cells were co-treated with CGZ and GW9662, but was not observed when cells were treated with CGZ prior to GW9662. In cells in which PPAR{gamma} was down-regulated cells by siRNA, lower concentrations of CGZ (<30 {mu}M) were sufficient to induce cell death, although higher concentrations of CGZ ( Greater-Than-Or-Slanted-Equal-To 30 {mu}M) were required to induce cell death in control T98G cells, indicating that CGZ effectively induces cell death in T98G cells independently of PPAR{gamma}. Treatment with GW9662 followed by CGZ resulted in a down-regulation of Akt activity and the loss of mitochondrial membrane potential (MMP), which was accompanied by a decrease in Bcl-2 expression and an increase in Bid cleavage. These data suggest that CGZ is capable of inducing apoptotic cell death independently of PPAR{gamma} in glioma cells, by down-regulating Akt activity and inducing MMP collapse.

  9. {beta}1-Adrenergic receptor activation induces mouse cardiac myocyte death through both L-type calcium channel-dependent and -independent pathways.

    Science.gov (United States)

    Wang, Wei; Zhang, Hongyu; Gao, Hui; Kubo, Hajime; Berretta, Remus M; Chen, Xiongwen; Houser, Steven R

    2010-08-01

    Cardiac diseases persistently increase the contractility demands of cardiac myocytes, which require activation of the sympathetic nervous system and subsequent increases in myocyte Ca(2+) transients. Persistent exposure to sympathetic and/or Ca(2+) stress is associated with myocyte death. This study examined the respective roles of persistent beta-adrenergic receptor (beta-AR) agonist exposure and high Ca(2+) concentration in myocyte death. Ventricular myocytes (VMs) were isolated from transgenic (TG) mice with cardiac-specific and inducible expression of the beta(2a)-subunit of the L-type Ca(2+) channel (LTCC). VMs were cultured, and the rate of myocyte death was measured in the presence of isoproterenol (ISO), other modulators of Ca(2+) handling and the beta-adrenergic system, and inhibitors of caspases and reactive oxygen species generation. The rate of myocyte death was greater in TG vs. wild-type myocytes and accelerated by ISO in both groups, although ISO did not increase LTCC current (I(Ca-L)) in TG-VMs. Nifedipine, an LTCC antagonist, only partially prevented myocyte death. These results suggest both LTCC-dependent and -independent mechanisms in ISO induced myocyte death. ISO increased the contractility of wild type and TG-VMs by enhancing sarcoplasmic reticulum function and inhibiting sarco(endo)plasmic reticulum Ca(2+)-ATPase, Na(+)/Ca(2+) exchanger, and CaMKII partially protected myocyte from death induced by both Ca(2+) and ISO. Caspase and reactive oxygen species inhibitors did not, but beta(2)-AR activation did, reduce myocyte death induced by enhanced I(Ca-L) and ISO stimulation. Our results suggest that catecholamines induce myocyte necrosis primarily through beta(1)-AR-mediated increases in I(Ca-L), but other mechanisms are also involved in rodents.

  10. Gefitinib upregulates death receptor 5 expression to mediate rmhTRAIL-induced apoptosis in Gefitinib-sensitive NSCLC cell line

    Directory of Open Access Journals (Sweden)

    Yan D

    2015-07-01

    Full Text Available Dong Yan,1,2 Yang Ge,1 Haiteng Deng,3 Wenming Chen,4 Guangyu An1 1Department of Oncology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Translational Molecular pathology, M.D Anderson Cancer Center, Houston, TX, USA; 3School of Sciences, Tsinghua University, 4Department of Hematology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, People’s Republic of China Background: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL triggers apoptosis in tumor cells, but when used alone, it is not effective in the treatment of TRAIL-resistant tumors. Some studies have shown that gefitinib interacts with recombinant mutant human TRAIL (rmhTRAIL to induce high levels of apoptosis in gefitinib-responsive bladder cancer cell lines; however, the molecular mechanisms underlying the anticancer effects are not fully understood. Several reports have shown that the death receptor 5 (DR5 plays an important role in sensitizing cancer cells to apoptosis induced by TRAIL. Therefore, we investigated the effects of the combination of drugs and the expression of the DR5 to analyze the growth of a gefitinib-responsive non-small cell lung cancer cell line PC9, which was treated with rmhTRAIL and gefitinib individually or in combination.Methods: Human PC9 non-small cell lung cancer cells harboring an epidermal growth factor receptor mutation were used as a model for the identification of the therapeutic effects of gefitinib alone or in combination with rmhTRAIL, and cytotoxicity was assessed by MTT assays. Cell cycle and apoptosis were investigated using flow cytometry. Moreover, the effects of drugs on DR5, BAX, FLIP, and cleaved-caspase3 proteins expressions were analyzed using Western blot analyses. Finally, quantitative polymerase chain reaction analysis was carried out to assess whether rmhTRAIL and gefitinib modulate the expression of genes related to drug activity.Results: Gefitinib and rmh

  11. Extrinsic and intrinsic curvatures in thermodynamic geometry

    Energy Technology Data Exchange (ETDEWEB)

    Hosseini Mansoori, Seyed Ali, E-mail: shossein@bu.edu [Department of Physics, Boston University, 590 Commonwealth Ave., Boston, MA 02215 (United States); Department of Physics, Isfahan University of Technology, Isfahan 84156-83111 (Iran, Islamic Republic of); Mirza, Behrouz, E-mail: b.mirza@cc.iut.ac.ir [Department of Physics, Isfahan University of Technology, Isfahan 84156-83111 (Iran, Islamic Republic of); Sharifian, Elham, E-mail: e.sharifian@ph.iut.ac.ir [Department of Physics, Isfahan University of Technology, Isfahan 84156-83111 (Iran, Islamic Republic of)

    2016-08-10

    We investigate the intrinsic and extrinsic curvatures of a certain hypersurface in thermodynamic geometry of a physical system and show that they contain useful thermodynamic information. For an anti-Reissner–Nordström-(A)de Sitter black hole (Phantom), the extrinsic curvature of a constant Q hypersurface has the same sign as the heat capacity around the phase transition points. The intrinsic curvature of the hypersurface can also be divergent at the critical points but has no information about the sign of the heat capacity. Our study explains the consistent relationship holding between the thermodynamic geometry of the KN-AdS black holes and those of the RN (J-zero hypersurface) and Kerr black holes (Q-zero hypersurface) ones [1]. This approach can easily be generalized to an arbitrary thermodynamic system.

  12. Extrinsic allergic alveolitis in Scottish maltworkers.

    Science.gov (United States)

    Grant, I W; Blackadder, E S; Greenberg, M; Blyth, W

    1976-01-01

    In a survey of respiratory disease in the Scottish malting industry 5.2% of employees were found to have symptoms of extrinsic allergic alveolitis. In most cases the disease was mild and not associated with any serious respiratory disability. It was significantly less common where modern mechanical methods of malting were used. Mycological and serological studies suggested that it was usually caused by a type 3 allergic reaction to Aspergillus clavatus. PMID:1252813

  13. Intrinsic-extrinsic factors in sport motivation.

    Science.gov (United States)

    Pedersen, Darhl M

    2002-10-01

    Participants were 83 students (36 men and 47 women). 10 intrinsic-extrinsic factors involved in sport motivation were obtained. The factors were generated from items obtained from the participants rather than items from the experimenter. This was done to avoid the possible influence of preconceptions on the part of the experimenter regarding what the final dimensions may be. Obtained motivational factors were Social Reinforcement, Fringe Benefits, Fame and Fortune, External Forces, Proving Oneself, Social Benefits, Mental Enrichment, Expression of Self, Sense of Accomplishment, and Self-enhancement. Each factor was referred to an intrinsic-extrinsic dimension to describe its relative position on that dimension. The order of the factors as listed indicates increasing intrinsic motivation. i.e., the first four factors were rated in the extrinsic range, whereas the remaining six were rated to be in the intrinsic range. Next, the participants rated the extent to which each of the various factors was involved in their decision to participate in sport activities. The pattern of use of the motivational factors was the same for both sexes except that men indicated greater use of the Fringe Benefits factor. Overall, the more intrinsic a sport motivation factor was rated, the more likely it was to be rated as a factor in actual sport participation.

  14. Poxvirus tumor necrosis factor receptor (TNFR)-like T2 proteins contain a conserved preligand assembly domain that inhibits cellular TNFR1-induced cell death.

    Science.gov (United States)

    Sedger, Lisa M; Osvath, Sarah R; Xu, Xiao-Ming; Li, Grace; Chan, Francis K-M; Barrett, John W; McFadden, Grant

    2006-09-01

    The poxvirus tumor necrosis factor receptor (TNFR) homologue T2 has immunomodulatory properties; secreted myxoma virus T2 (M-T2) protein binds and inhibits rabbit TNF-alpha, while intracellular M-T2 blocks virus-induced lymphocyte apoptosis. Here, we define the antiapoptotic function as inhibition of TNFR-mediated death via a highly conserved viral preligand assembly domain (vPLAD). Jurkat cell lines constitutively expressing M-T2 were generated and shown to be resistant to UV irradiation-, etoposide-, and cycloheximide-induced death. These cells were also resistant to human TNF-alpha, but M-T2 expression did not alter surface expression levels of TNFRs. Previous studies indicated that T2's antiapoptotic function was conferred by the N-terminal region of the protein, and further examination of this region revealed a highly conserved N-terminal vPLAD, which is present in all poxvirus T2-like molecules. In cellular TNFRs and TNF-alpha-related apoptosis-inducing ligand (TRAIL) receptors (TRAILRs), PLAD controls receptor signaling competency prior to ligand binding. Here, we show that M-T2 potently inhibits TNFR1-induced death in a manner requiring the M-T2 vPLAD. Furthermore, we demonstrate that M-T2 physically associates with and colocalizes with human TNFRs but does not prevent human TNF-alpha binding to cellular receptors. Thus, M-T2 vPLAD is a species-nonspecific dominant-negative inhibitor of cellular TNFR1 function. Given that the PLAD is conserved in all known poxvirus T2-like molecules, we predict that it plays an important function in each of these proteins. Moreover, that the vPLAD confers an important antiapoptotic function confirms this domain as a potential target in the development of the next generation of TNF-alpha/TNFR therapeutics.

  15. Excitotoxic death induced by released glutamate in depolarized primary cultures of mouse cerebellar granule cells is dependent on GABAA receptors and niflumic acid-sensitive chloride channels.

    Science.gov (United States)

    Babot, Zoila; Cristòfol, Rosa; Suñol, Cristina

    2005-01-01

    Excitotoxic neuronal death has been linked to neurological and neurodegenerative diseases. Several studies have sought to clarify the involvement of Cl(-) channels in neuronal excitotoxicity using either N-methyl-D-aspartic acid (NMDA) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate/kainic acid agonists. In this work we induced excitotoxic death in primary cultures of cerebellar granule cells by means of endogenously released glutamate. Excitotoxicity was provoked by exposure to high extracellular K(+) concentrations ([K(+)](o)) for 5 min. Under these conditions, a Ca(2+)-dependent release of glutamate was evoked. When extracellular glutamate concentration rose to between 2 and 4 microM, cell viability was significantly reduced by 30-40%. The NMDA receptor antagonists (MK-801 and D-2-amino-5-phosphonopentanoic acid) prevented cell death. Exposure to high [K(+)](o) produced a (36)Cl(-) influx which was significantly reduced by picrotoxinin. In addition, the GABA(A) receptor antagonists (bicuculline, picrotoxinin and SR 95531) protected cells from high [K(+)](o)-triggered excitotoxicity and reduced extracellular glutamate concentration. The Cl(-) channel blockers niflumic acid and 5-nitro-2-(3-phenylpropylamino)benzoic acid also exerted a neuroprotective effect and reduced extracellular glutamate concentration, even though they did not reduce high [K(+)](o)-induced (36)Cl(-) influx. Primary cultures of cerebellar granule cells also contain a population of GABAergic neurons that released GABA in response to high [K(+)](o). Chronic treatment of primary cultures with kainic acid abolished GABA release and rendered granule cells insensitive to high [K(+)](o) exposure, even though NMDA receptors were functional. Altogether, these results demonstrate that, under conditions of membrane depolarization, low micromolar concentrations of extracellular glutamate might induce an excitotoxic process through both NMDA and GABA(A) receptors and niflumic acid-sensitive Cl

  16. Anti-cancer effect of bee venom toxin and melittin in ovarian cancer cells through induction of death receptors and inhibition of JAK2/STAT3 pathway

    Energy Technology Data Exchange (ETDEWEB)

    Jo, Miran; Park, Mi Hee; Kollipara, Pushpa Saranya [College of Pharmacy and Medical Research Center, Chungbuk National University, 48, Gaeshin-dong, Heungduk-gu, Cheongju, Chungbuk, 361-763 (Korea, Republic of); An, Byeong Jun; Song, Ho Sueb [College of Oriental Medicine, Kyungwon University, San 65, Bokjeong-dong, Sujeong-gu, Seongnam, Gyeonggii 461-701 (Korea, Republic of); Han, Sang Bae [College of Pharmacy and Medical Research Center, Chungbuk National University, 48, Gaeshin-dong, Heungduk-gu, Cheongju, Chungbuk, 361-763 (Korea, Republic of); Kim, Jang Heub [Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, 505, Banpo-dong, Seocho-gu, Seoul 137-040 (Korea, Republic of); Song, Min Jong, E-mail: bitsugar@catholic.ac.kr [Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, 505, Banpo-dong, Seocho-gu, Seoul 137-040 (Korea, Republic of); Hong, Jin Tae, E-mail: jinthong@chungbuk.ac.kr [College of Pharmacy and Medical Research Center, Chungbuk National University, 48, Gaeshin-dong, Heungduk-gu, Cheongju, Chungbuk, 361-763 (Korea, Republic of)

    2012-01-01

    We investigated whether bee venom and melittin, a major component of bee venom, inhibit cell growth through enhancement of death receptor expressions in the human ovarian cancer cells, SKOV3 and PA-1. Bee venom (1–5 μg/ml) and melittin (0.5–2 μg/ml) inhibited the growth of SKOV3 and PA-1 ovarian cancer cells by the induction of apoptotic cell death in a dose dependent manner. Consistent with apoptotic cell death, expression of death receptor (DR) 3 and DR6 was increased in both cancer cells, but expression of DR4 was increased only in PA-1 cells. Expression of DR downstream pro-apoptotic proteins including caspase-3, 8, and Bax was concomitantly increased, but the phosphorylation of JAK2 and STAT3 and the expression of Bcl-2 were inhibited by treatment with bee venom and melittin in SKOV3 and PA-1 cells. Expression of cleaved caspase-3 was increased in SKOV3, but cleaved caspase-8 was increased in PA-1 cells. Moreover, deletion of DR3, DR4, and DR6 by small interfering RNA significantly reversed bee venom and melittin-induced cell growth inhibitory effect as well as down regulation of STAT3 by bee venom and melittin in SKOV3 and PA-1 ovarian cancer cell. These results suggest that bee venom and melittin induce apoptotic cell death in ovarian cancer cells through enhancement of DR3, DR4, and DR6 expression and inhibition of STAT3 pathway. -- Highlights: ► Some studies have showed that bee venom and/or melittin have anti-cancer effects. ► We found that bee venom and melittin inhibited cell growth in ovarian cancer cells. ► Bee venom and melittin induce apoptosis in SKOV3 and PA-1.

  17. Differential effects of grape seed extract against human colorectal cancer cell lines: the intricate role of death receptors and mitochondria.

    Science.gov (United States)

    Derry, Molly; Raina, Komal; Agarwal, Rajesh; Agarwal, Chapla

    2013-06-28

    Failure of anti-cancer therapy in colorectal cancer (CRC) cells involves resistance to death mechanisms. We investigated grape seed extract (GSE) ability to target CRC cells and delineated the mechanisms involved in GSE-induced CRC cell death. GSE selectively induced apoptotic death in human CRC cells; efficacy increased as the metastatic potential of the cancer cells increased. Oxidative stress, loss of mitochondrial membrane potential, modulation of pro- and anti-apoptotic proteins, and involvement of both caspase-dependent/independent apoptotic pathways contributed to GSE-induced CRC cell death. GSE intervention may serve as a multi-targeted CRC therapeutic capable of inducing selective cancer cell death. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  18. Poncirin Induces Apoptosis in AGS Human Gastric Cancer Cells through Extrinsic Apoptotic Pathway by up-Regulation of Fas Ligand

    Directory of Open Access Journals (Sweden)

    Venu Venkatarame Gowda Saralamma

    2015-09-01

    Full Text Available Poncirin, a natural bitter flavanone glycoside abundantly present in many species of citrus fruits, has various biological benefits such as anti-oxidant, anti-microbial, anti-inflammatory and anti-cancer activities. The anti-cancer mechanism of Poncirin remains elusive to date. In this study, we investigated the anti-cancer effects of Poncirin in AGS human gastric cancer cells (gastric adenocarcinoma. The results revealed that Poncirin could inhibit the proliferation of AGS cells in a dose-dependent manner. It was observed Poncirin induced accumulation of sub-G1 DNA content, apoptotic cell population, apoptotic bodies, chromatin condensation, and DNA fragmentation in a dose-dependent manner in AGS cells. The expression of Fas Ligand (FasL protein was up-regulated dose dependently in Poncirin-treated AGS cells Moreover, Poncirin in AGS cells induced activation of Caspase-8 and -3, and subsequent cleavage of poly(ADP-ribose polymerase (PARP. Inhibitor studies’ results confirm that the induction of caspase-dependent apoptotic cell death in Poncirin-treated AGS cells was led by the Fas death receptor. Interestingly, Poncirin did not show any effect on mitochondrial membrane potential (ΔΨm, pro-apoptotic proteins (Bax and Bak and anti-apoptotic protein (Bcl-xL in AGS-treated cells followed by no activation in the mitochondrial apoptotic protein caspase-9. This result suggests that the mitochondrial-mediated pathway is not involved in Poncirin-induced cell death in gastric cancer. These findings suggest that Poncirin has a potential anti-cancer effect via extrinsic pathway-mediated apoptosis, possibly making it a strong therapeutic agent for human gastric cancer.

  19. Poncirin Induces Apoptosis in AGS Human Gastric Cancer Cells through Extrinsic Apoptotic Pathway by up-Regulation of Fas Ligand.

    Science.gov (United States)

    Saralamma, Venu Venkatarame Gowda; Nagappan, Arulkumar; Hong, Gyeong Eun; Lee, Ho Jeong; Yumnam, Silvia; Raha, Suchismita; Heo, Jeong Doo; Lee, Sang Joon; Lee, Won Sup; Kim, Eun Hee; Kim, Gon Sup

    2015-09-18

    Poncirin, a natural bitter flavanone glycoside abundantly present in many species of citrus fruits, has various biological benefits such as anti-oxidant, anti-microbial, anti-inflammatory and anti-cancer activities. The anti-cancer mechanism of Poncirin remains elusive to date. In this study, we investigated the anti-cancer effects of Poncirin in AGS human gastric cancer cells (gastric adenocarcinoma). The results revealed that Poncirin could inhibit the proliferation of AGS cells in a dose-dependent manner. It was observed Poncirin induced accumulation of sub-G1 DNA content, apoptotic cell population, apoptotic bodies, chromatin condensation, and DNA fragmentation in a dose-dependent manner in AGS cells. The expression of Fas Ligand (FasL) protein was up-regulated dose dependently in Poncirin-treated AGS cells Moreover, Poncirin in AGS cells induced activation of Caspase-8 and -3, and subsequent cleavage of poly(ADP-ribose) polymerase (PARP). Inhibitor studies' results confirm that the induction of caspase-dependent apoptotic cell death in Poncirin-treated AGS cells was led by the Fas death receptor. Interestingly, Poncirin did not show any effect on mitochondrial membrane potential (ΔΨm), pro-apoptotic proteins (Bax and Bak) and anti-apoptotic protein (Bcl-xL) in AGS-treated cells followed by no activation in the mitochondrial apoptotic protein caspase-9. This result suggests that the mitochondrial-mediated pathway is not involved in Poncirin-induced cell death in gastric cancer. These findings suggest that Poncirin has a potential anti-cancer effect via extrinsic pathway-mediated apoptosis, possibly making it a strong therapeutic agent for human gastric cancer.

  20. Phosphorylation-dependent differential regulation of plant growth, cell death, and innate immunity by the regulatory receptor-like kinase BAK1

    DEFF Research Database (Denmark)

    Schwessinger, Benjamin; Roux, Milena; Kadota, Yasuhiro;

    2011-01-01

    Plants rely heavily on receptor-like kinases (RLKs) for perception and integration of external and internal stimuli. The Arabidopsis regulatory leucine-rich repeat RLK (LRR-RLK) BAK1 is involved in steroid hormone responses, innate immunity, and cell death control. Here, we describe the different......Plants rely heavily on receptor-like kinases (RLKs) for perception and integration of external and internal stimuli. The Arabidopsis regulatory leucine-rich repeat RLK (LRR-RLK) BAK1 is involved in steroid hormone responses, innate immunity, and cell death control. Here, we describe...... the differential regulation of three different BAK1-dependent signaling pathways by a novel allele of BAK1, bak1-5. Innate immune signaling mediated by the BAK1-dependent RKs FLS2 and EFR is severely compromised in bak1-5 mutant plants. However, bak1-5 mutants are not impaired in BR signaling or cell death control...... of FLS2 or EFR with BAK1 in planta, revealing another pathway specific mechanistic difference. The specific suppression of FLS2- and EFR-dependent signaling in bak1-5 is not due to a differential interaction of BAK1-5 with the respective ligand-binding RK but requires BAK1-5 kinase activity. Overall our...

  1. HIV infection enhances TRAIL-induced cell death in macrophage by down-regulating decoy receptor expression and generation of reactive oxygen species.

    Directory of Open Access Journals (Sweden)

    Dan-Ming Zhu

    Full Text Available BACKGROUND: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL could induce apoptosis of HIV-1-infected monocyte-derived macrophage (MDM, but the molecular mechanisms are not well understood. METHODOLOGY/PRINCIPAL FINDINGS: By using an HIV-1 Env-pseudotyped virus (HIV-1 PV-infected MDM cell model we demonstrate that HIV-1 PV infection down-regulates the expression of TRAIL decoy receptor 1 (DcR1 and 2 (DcR2, and cellular FLICE-inhibitory protein (c-FLIP, but dose not affect the expression of death receptor 4 and 5 (DR4, DR5, and Bcl-2 family members in MDM cells. Furthermore, recombinant soluble TRAIL and an agonistic anti-DR5 antibody, AD5-10, treatment stimulates reactive oxygen species (ROS generation and JNK phosphorylation. CONCLUSIONS/SIGNIFICANCE: HIV infection facilitates TRIAL-induced cell death in MDM by down-regulating the expression of TRAIL decoy receptors and intracellular c-FLIP. Meanwhile, the agonistic anti-DR5 antibody, AD5-10, induces apoptosis synergistically with TRAIL in HIV-1-infected cells. ROS generation and JNK phosphorylation are involved in this process. These findings potentiate clinical usage of the combination of TRAIL and AD5-10 in eradication of HIV-infected macrophage and AIDS.

  2. Fulvestrant-induced cell death and proteasomal degradation of estrogen receptor α protein in MCF-7 cells require the CSK c-Src tyrosine kinase.

    Directory of Open Access Journals (Sweden)

    Wei-Lan Yeh

    Full Text Available Fulvestrant is a representative pure antiestrogen and a Selective Estrogen Receptor Down-regulator (SERD. In contrast to the Selective Estrogen Receptor Modulators (SERMs such as 4-hydroxytamoxifen that bind to estrogen receptor α (ERα as antagonists or partial agonists, fulvestrant causes proteasomal degradation of ERα protein, shutting down the estrogen signaling to induce proliferation arrest and apoptosis of estrogen-dependent breast cancer cells. We performed genome-wide RNAi knockdown screenings for protein kinases required for fulvestrant-induced apoptosis of the MCF-7 estrogen-dependent human breast caner cells and identified the c-Src tyrosine kinase (CSK, a negative regulator of the oncoprotein c-Src and related protein tyrosine kinases, as one of the necessary molecules. Whereas RNAi knockdown of CSK in MCF-7 cells by shRNA-expressing lentiviruses strongly suppressed fulvestrant-induced cell death, CSK knockdown did not affect cytocidal actions of 4-hydroxytamoxifen or paclitaxel, a chemotherapeutic agent. In the absence of CSK, fulvestrant-induced proteasomal degradation of ERα protein was suppressed in both MCF-7 and T47D estrogen-dependent breast cancer cells whereas the TP53-mutated T47D cells were resistant to the cytocidal action of fulvestrant in the presence or absence of CSK. MCF-7 cell sensitivities to fulvestrant-induced cell death or ERα protein degradation was not affected by small-molecular-weight inhibitors of the tyrosine kinase activity of c-Src, suggesting possible involvement of other signaling molecules in CSK-dependent MCF-7 cell death induced by fulvestrant. Our observations suggest the importance of CSK in the determination of cellular sensitivity to the cytocidal action of fulvestrant.

  3. Calmodulin protects cells from death under normal growth conditions and mitogenic starvation but plays a mediating role in cell death upon B-cell receptor stimulation

    DEFF Research Database (Denmark)

    Schmalzigaug, R; Ye, Q; Berchtold, M W

    2001-01-01

    MII gene causes the intracellular CaM level to decrease by 60%. CaMII-/- cells grow more slowly and die more frequently as compared to wild type (wt) cells but do not exhibit significant differences in their cell cycle profile. Both phenotypes are more pronounced at reduced serum concentrations. Upon......Calmodulin (CaM) is the main intracellular Ca2+ sensor protein responsible for mediating Ca2+ triggered processes. Chicken DT40 lymphoma B cells express CaM from the two genes, CaMI and CaMII. Here we report the phenotypes of DT40 cells with the CaMII gene knocked out. The disruption of the Ca...... stimulation of the B-cell receptor (BCR), the resting Ca2+ levels remain elevated after the initial transient in CaMII-/- cells. Despite higher Ca2+ resting levels, the CaMII-/- cells are partially protected from BCR induced apoptosis indicating that CaM plays a dual role in apoptotic processes....

  4. Arabidopsis Lectin Receptor Kinases LecRK-IX.1 and LecRK-IX.2 Are Functional Analogs in Regulating Phytophthora Resistance and Plant Cell Death.

    Science.gov (United States)

    Wang, Yan; Cordewener, Jan H G; America, Antoine H P; Shan, Weixing; Bouwmeester, Klaas; Govers, Francine

    2015-09-01

    L-type lectin receptor kinases (LecRK) are potential immune receptors. Here, we characterized two closely-related Arabidopsis LecRK, LecRK-IX.1 and LecRK-IX.2, of which T-DNA insertion mutants showed compromised resistance to Phytophthora brassicae and Phytophthora capsici, with double mutants showing additive susceptibility. Overexpression of LecRK-IX.1 or LecRK-IX.2 in Arabidopsis and transient expression in Nicotiana benthamiana increased Phytophthora resistance but also induced cell death. Phytophthora resistance required both the lectin domain and kinase activity, but for cell death, the lectin domain was not needed. Silencing of the two closely related mitogen-activated protein kinase genes NbSIPK and NbNTF4 in N. benthamiana completely abolished LecRK-IX.1-induced cell death but not Phytophthora resistance. Liquid chromatography-mass spectrometry analysis of protein complexes coimmunoprecipitated in planta with LecRK-IX.1 or LecRK-IX.2 as bait, resulted in the identification of the N. benthamiana ABC transporter NbPDR1 as a potential interactor of both LecRK. The closest homolog of NbPDR1 in Arabidopsis is ABCG40, and coimmunoprecipitation experiments showed that ABCG40 associates with LecRK-IX.1 and LecRK-IX.2 in planta. Similar to the LecRK mutants, ABCG40 mutants showed compromised Phytophthora resistance. This study shows that LecRK-IX.1 and LecRK-IX.2 are Phytophthora resistance components that function independent of each other and independent of the cell-death phenotype. They both interact with the same ABC transporter, suggesting that they exploit similar signal transduction pathways.

  5. Programmed death-1 expression on HIV-1-specific CD8+ T cells is shaped by epitope specificity, T-cell receptor clonotype usage and antigen load

    DEFF Research Database (Denmark)

    Kløverpris, Henrik N; McGregor, Reuben; McLaren, James E

    2014-01-01

    OBJECTIVES: Although CD8+ T cells play a critical role in the control of HIV-1 infection,their antiviral efficacy can be limited by antigenic variation and immune exhaustion.The latter phenomenon is characterized by the upregulation of multiple inhibitory receptors, such as programmed death-1 (PD-1......), CD244 and lymphocyte activation gene-3 (LAG-3), which modulate the functional capabilities of CD8+ T cells. DESIGN AND METHODS: Here, we used an array of different human leukocyte antigen(HLA)-B*15:03 and HLA-B*42:01 tetramers to characterize inhibitory receptor expression as a function...... by effector memory CD8+ T cells. CONCLUSION: Collectively, these data suggest that PD-1 expression on HIV-1-specific CD8+ T cells tracks antigen load at the level of epitope specificity and TCR clonotype usage. These findings are important because they provide evidence that PD-1 expression levels...

  6. [Recent advances in extrinsic allergic alveolitis].

    Science.gov (United States)

    Sennekamp, J; Joest, M

    2008-01-01

    Extrinsic allergic alveolitis (hypersensitivity pneumonitis), especially humidifier lung, has been more frequently diagnosed over the last decades, whereas farmer's lung has decreased over the same time period. Today two types of the chronic course of extrinsic allergic alveolitis can be distinguished. The recurrent chronic course with a good prognosis may be differentiated from the insidious course with a poor prognosis by means of different histological patterns (UIP, NSIP, BOOP pattern). The characteristic neutrophilic infiltration of the lung in the insidious course cannot be detected by bronchoalveolar lavage (BAL) methods. Furthermore, lymphocytosis in the BAL can be absent or present at a low level. The CD4/CD8 ratio is not always decreased and may be normal or even increased in these insidious cases with a poor prognosis. Granulomas in the lung tissue, however, point to a good prognosis. In the diagnostic work-up of machine operator's and humidifier lung, it is advisable not only to look for serum antibodies against bacteria and molds but also for rapid growing mycobacteria in a sample of machine or humidifier water. IgM and IgG rheumatoid factors occur frequently in allergic alveolitis, especially in humidifier lung. The patients, however, do not suffer from arthritis. The IgM rheumatoid factor may simulate IgM antibodies against numerous infectious agents (e. g., Bordetella pertussis or Mycoplasma pneumoniae). Taking this phenomenon into account may improve the current differential diagnosis of allergic alveolitis.

  7. Evolving extrinsic curvature and the cosmological constant problem

    Science.gov (United States)

    Capistrano, Abraão J. S.; Cabral, Luis A.

    2016-10-01

    The concept of smooth deformation of Riemannian manifolds associated with the extrinsic curvature is explained and applied to the Friedmann-Lemaître-Robertson-Walker cosmology. We show that such deformation can be derived from the Einstein-Hilbert-like dynamical principle may produce an observable effect in the sense of Noether. As a result, we show how the extrinsic curvature compensates both quantitative and qualitative differences between the cosmological constant Λ and the vacuum energy {ρ }{vac} obtaining the observed upper bound for the cosmological constant problem at electroweak scale. The topological characteristics of the extrinsic curvature are discussed showing that the produced extrinsic scalar curvature is an evolving dynamical quantity.

  8. Induction of intrinsic and extrinsic apoptosis through oxidative stress in drug-resistant cancer by a newly synthesized Schiff base copper chelate.

    Science.gov (United States)

    Banerjee, Kaushik; Basu, Soumya; Das, Satyajit; Sinha, Abhinaba; Biswas, Manas Kumar; Choudhuri, Soumitra Kumar

    2016-01-01

    Multidrug resistance (MDR) in cancer represents a variety of strategies employed by tumor cells to evade the beneficial cytotoxic effects of structurally different anticancer drugs and thus confers impediments to the successful treatment of cancers. Efflux of drugs by MDR protein-1, functional P-glycoprotein and elevated level of reduced glutathione confer resistance to cell death or apoptosis and thus provide a possible therapeutic target for overcoming MDR in cancer. Previously, we reported that a Schiff base ligand, potassium-N-(2-hydroxy 3-methoxy-benzaldehyde)-alaninate (PHMBA) overcomes MDR in both in vivo and in vitro by targeting intrinsic apoptotic/necrotic pathway through induction of reactive oxygen species (ROS). The present study describes the synthesis and spectroscopic characterization of a copper chelate of Schiff base, viz., copper (II)-N-(2-hydroxy-3-methoxy-benzaldehyde)-alaninate (CuPHMBA) and the underlying mechanism of cell death induced by CuPHMBA in vitro. CuPHMBA kills both the drug-resistant and sensitive cell types irrespective of their drug resistance phenotype. The cell death induced by CuPHMBA follows apoptotic pathway and moreover, the cell death is associated with intrinsic mitochondrial and extrinsic receptor-mediated pathways. Oxidative stress plays a pivotal role in the process as proved by the fact that antioxidant enzyme; polyethylene glycol conjugated-catalase completely blocked CuPHMBA-induced ROS generation and abrogated cell death. To summarize, the present work provides a compelling rationale for the future clinical use of CuPHMBA, a redox active copper chelate in the treatment of cancer patients, irrespective of their drug-resistance status.

  9. Natriuretic peptide receptor A inhibition suppresses gastric cancer development through reactive oxygen species-mediated G2/M cell cycle arrest and cell death.

    Science.gov (United States)

    Li, Zheng; Wang, Ji-Wei; Wang, Wei-Zhi; Zhi, Xiao-Fei; Zhang, Qun; Li, Bo-Wen; Wang, Lin-Jun; Xie, Kun-Ling; Tao, Jin-Qiu; Tang, Jie; Wei, Song; Zhu, Yi; Xu, Hao; Zhang, Dian-Cai; Yang, Li; Xu, Ze-Kuan

    2016-10-01

    Natriuretic peptide receptor A (NPRA), the major receptor for atrial natriuretic peptide (ANP), has been implicated in tumorigenesis; however, the role of ANP-NPRA signaling in the development of gastric cancer remains unclear. Immunohistochemical analyses indicated that NPRA expression was positively associated with gastric tumor size and cancer stage. NPRA inhibition by shRNA induced G2/M cell cycle arrest, cell death, and autophagy in gastric cancer cells, due to accumulation of reactive oxygen species (ROS). Either genetic or pharmacologic inhibition of autophagy led to caspase-dependent cell death. Therefore, autophagy induced by NPRA silencing may represent a cytoprotective mechanism. ROS accumulation activated c-Jun N-terminal kinase (JNK) and AMP-activated protein kinase (AMPK). ROS-mediated activation of JNK inhibited cell proliferation by disturbing cell cycle and decreased cell viability. In addition, AMPK activation promoted autophagy in NPRA-downregulated cancer cells. Overall, our results indicate that the inhibition of NPRA suppresses gastric cancer development and targeting NPRA may represent a promising strategy for the treatment of gastric cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Deletion of apolipoprotein E receptor-2 in mice lowers brain selenium and causes severe neurological dysfunction and death when a low-selenium diet is fed.

    Science.gov (United States)

    Burk, Raymond F; Hill, Kristina E; Olson, Gary E; Weeber, Edwin J; Motley, Amy K; Winfrey, Virginia P; Austin, Lori M

    2007-06-01

    Selenoprotein P (Sepp1) is a plasma and extracellular protein that is rich in selenium. Deletion of Sepp1 results in sharp decreases of selenium levels in the brain and testis with dysfunction of those organs. Deletion of Sepp1 also causes increased urinary selenium excretion, leading to moderate depletion of whole-body selenium. The lipoprotein receptor apolipoprotein E receptor-2 (apoER2) binds Sepp1 and facilitates its uptake by Sertoli cells, thus providing selenium for spermatogenesis. Experiments were performed to assess the effect of apoER2 on the concentration and function of selenium in the brain and on whole-body selenium. ApoER2-/- and apoER2+/+ male mice were fed a semipurified diet with selenite added as the source of selenium. ApoER2-/- mice had depressed brain and testis selenium, but normal levels in liver, kidney, muscle, and the whole body. Feeding a selenium-deficient diet to apoER2-/- mice led to neurological dysfunction and death, with some of the characteristics exhibited by Sepp1-/- mice fed the same diet. Thus, although it does not affect whole-body selenium, apoER2 is necessary for maintenance of brain selenium and for prevention of neurological dysfunction and death under conditions of selenium deficiency, suggesting an interaction of apoER2 with Sepp1 in the brain.

  11. PARP-1 activation causes neuronal death in the hippocampal CA1 region by increasing the expression of Ca(2+)-permeable AMPA receptors.

    Science.gov (United States)

    Gerace, E; Masi, A; Resta, F; Felici, R; Landucci, E; Mello, T; Pellegrini-Giampietro, D E; Mannaioni, G; Moroni, F

    2014-10-01

    An excessive activation of poly(ADP-ribose) polymerases (PARPs) may trigger a form of neuronal death similar to that occurring in neurodegenerative disorders. To investigate this process, we exposed organotypic hippocampal slices to N-methyl-N'-nitro-N'-nitrosoguanidine (MNNG, 100μM for 5min), an alkylating agent widely used to activate PARP-1. MNNG induced a pattern of degeneration of the CA1 pyramidal cells morphologically similar to that observed after a brief period of oxygen and glucose deprivation (OGD). MNNG exposure was also associated with a dramatic increase in PARP-activity and a robust decrease in NAD(+) and ATP content. These effects were prevented by PARP-1 but not PARP-2 inhibitors. In our experimental conditions, cell death was not mediated by AIF translocation (parthanatos) or caspase-dependent apoptotic processes. Furthermore, we found that PARP activation was followed by a significant deterioration of neuronal membrane properties. Using electrophysiological recordings we firstly investigated the suggested ability of ADP-ribose to open TRPM2 channels in MNNG-induced cells death, but the results we obtained showed that TRPM2 channels are not involved. We then studied the involvement of glutamate receptor-ion channel complex and we found that NBQX, a selective AMPA receptor antagonist, was able to effectively prevent CA1 neuronal loss while MK801, a NMDA antagonist, was not active. Moreover, we observed that MNNG treatment increased the ratio of GluA1/GluA2 AMPAR subunit expression, which was associated with an inward rectification of the IV relationship of AMPA sEPSCs in the CA1 but not in the CA3 subfield. Accordingly, 1-naphthyl acetyl spermine (NASPM), a selective blocker of Ca(2+)-permeable GluA2-lacking AMPA receptors, reduced MNNG-induced CA1 pyramidal cell death. In conclusion, our results show that activation of the nuclear enzyme PARP-1 may change the expression of membrane proteins and Ca(2+) permeability of AMPA channels, thus affecting

  12. Risk of treatment-related deaths with vascular endothelial growth factor receptor tyrosine kinase inhibitors: a meta-analysis of 41 randomized controlled trials

    Directory of Open Access Journals (Sweden)

    Hong SD

    2014-10-01

    Full Text Available Shaodong Hong,1,* Wenfeng Fang,1,* Wenhua Liang,1,* Yue Yan,1 Ting Zhou,1 Tao Qin,1 Xuan Wu,1 Yuxiang Ma,1 Yuanyuan Zhao,1 Yunpeng Yang,1 Zhihuang Hu,1 Cong Xue,1 Xue Hou,1 Yue Chen,2 Yan Huang,1 Hongyun Zhao,1 Li Zhang1 1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China; 2Medical School, University of South China, Hengyang, Hunan, People's Republic of China *These authors contributed equally to this work Background: Vascular endothelial growth factor receptor (VEGFR tyrosine kinase inhibitors (TKIs have widely been used in advanced cancer. However, these drugs may also lead to serious adverse events. The present meta-analysis aimed to determine the overall incidence and risk of deaths due to VEGFR-TKIs with more detailed subgroup analysis. Materials and methods: PubMed, Web of Science, and Cochrane databases were searched for randomized controlled trials (RCTs that compared VEGFR-TKIs with non-VEGFR-TKIs in the treatment of solid cancer. Pooled incidence, odds ratios (ORs and 95% confidence intervals (CIs were calculated using random-effects or fixed-effects models based on the heterogeneity of included trials. Results: A total of 14,139 participants from 41 RCTs were enrolled. The pooled incidence of death due to VEGFR-TKIs was 1.9% (95% CI: 1.6%–2.3% with an OR of 1.85 (95% CI: 1.33–2.58; P<0.01 when compared with control groups. On subgroup analysis, significantly increased risk of death was found in patients with nonsmall-cell lung cancer (OR: 2.37; 95% CI: 1.19–4.73; P=0.01 and colorectal cancer (OR: 2.84; 95% CI: 1.02–7.96; P=0.05. Among different VEGFR-TKIs, sorafenib and sunitinib had significant risk of death when compared with control arms, respectively. VEGFR-TKIs in combination with other antineoplastic agents, but not VEGFR-TKI monotherapy, significantly increased the risk of treatment

  13. Survival advantages conferred to colon cancer cells by E-selectin-induced activation of the PI3K-NFκB survival axis downstream of Death receptor-3

    Directory of Open Access Journals (Sweden)

    Paquet Éric R

    2011-07-01

    Full Text Available Abstract Background Extravasation of circulating cancer cells is a key event of metastatic dissemination that is initiated by the adhesion of cancer cells to endothelial cells. It requires interactions between adhesion receptors on endothelial cells and their counter-receptors on cancer cells. Notably, E-selectin, a major endothelial adhesion receptor, interacts with Death receptor-3 present on metastatic colon carcinoma cells. This interaction confers metastatic properties to colon cancer cells by promoting the adhesion of cancer cells to endothelial cells and triggering the activation of the pro-migratory p38 and pro-survival ERK pathways in the cancer cells. In the present study, we investigated further the mechanisms by which the E-selectin-activated pathways downstream of DR3 confer a survival advantage to colon cancer cells. Methods Cell survival has been ascertained by using the WST-1 assay and by evaluating the activation of the PI3 kinase/NFκB survival axis. Apoptosis has been assayed by determining DNA fragmentation by Hoechst staining and by measuring cleavage of caspases-8 and -3. DR3 isoforms have been identified by PCR. For more precise quantification, targeted PCR reactions were carried out, and the amplified products were analyzed by automated chip-based microcapillary electrophoresis on an Agilent 2100 Bioanalyzer instrument. Results Interaction between DR3-expressing HT29 colon carcinoma cells and E-selectin induces the activation of the PI3K/Akt pathway. Moreover, p65/RelA, the anti-apoptotic subunit of NFκB, is rapidly translocated to the nucleus in response to E-selectin. This translocation is impaired by the PI3K inhibitor LY294002. Furthermore, inhibition of the PI3K/Akt pathway increases the cleavage of caspase 8 in colon cancer cells treated with E-selectin and this effect is still further increased when both ERK and PI3K pathways are concomitantly inhibited. Intriguingly, metastatic colon cancer cell lines such as HT

  14. NVP-BKM120 potentiates apoptosis in tumor necrosis factor-related apoptosis-inducing ligand-resistant glioma cell lines via upregulation of Noxa and death receptor 5.

    Science.gov (United States)

    Foster, Kimberly A; Jane, Esther P; Premkumar, Daniel R; Morales, Alejandro; Pollack, Ian F

    2015-08-01

    We previously observed that glioma cells are differentially sensitive to TRAIL-induced toxicity. Based on our observation that TRAIL-resistant glioma cell lines typically exhibited high levels of Akt activation, we hypothesized that inhibition of Akt signaling using the PI3 kinase inhibitor NVP-BKM120 could promote TRAIL-induced apoptosis in gliomas. We assessed this combination in established and primary cultured glioma cells. Combination treatment led to significant cellular death when compared to either drug alone, but had no effect in normal human astrocytes, and demonstrated activation of the caspase cascade. This enhanced apoptosis appears dependent upon the loss of mitochondrial membrane potential and the release of Smac/DIABLO, AIF and cytochrome c into the cytosol. The upregulation of Noxa and sequestration of Mcl-1 by Noxa were important factors for cell death. Knockdown of Noxa abrogated apoptosis and suggested dependency on Noxa in combination-induced apoptosis. BKM120 upregulated cell surface expression of death receptor 5 (DR5), but did not increase levels of the other major TRAIL receptor, death receptor 4 (DR4). This study demonstrates that antagonizing apoptosis-resistance pathways, such as the PI3/Akt pathway, in combination with death receptor activation, may induce cell death in TRAIL-resistant glioma.

  15. Extrinsic allergic alveolitis caused by misting fountains.

    Science.gov (United States)

    Koschel, Dirk; Stark, Wolfram; Karmann, Fritz; Sennekamp, Jochen; Müller-Wening, Dietrich

    2005-08-01

    Recently, an increasing number of patients were presented to our clinics with febrile and respiratory symptoms associated with exposure to a new type of domestic ultrasonic humidifier. We report on 11 patients who developed recurrent episodes of fever, cough and dyspnea after repeated exposure to ultrasonic misting fountains at home. A diagnosis of extrinsic allergic alveolitis (EAA) or toxic alveolitis was made on the basis of the history and the clinical, radiological, laboratory and immunological findings. Eight patients were subjected to inhalative challenge tests with their own ultrasonic misting fountains, and all of them exhibited positive reactions. Nine patients were diagnosed with an EAA (humidifier lung) and two patients with a toxic alveolitis (humidifier fever). This study demonstrates the potential for ultrasonic misting fountains to cause illness in the home. In view of the increasing popularity of these devices, humidifier lung and humidifier fever should be considered in the differential diagnosis of patients with unexplained pulmonary or flu-like illnesses with fever.

  16. [Extrinsic allergic alveolitis--rarely diagnosed disease].

    Science.gov (United States)

    Lauková, D; Marget, I; Plutinský, J

    2009-05-01

    Extrinsic allergic alveolitis (EAA), known as hypersensitive pneumonitis, causes interstitial lung involvement by inhaled antigen. The clinical presentation of the disease has been defined as acute, subacute and chronic. The most often symptoms of the acute form of the disease are flu-like symptoms, dyspnoe and cough. The progressive dyspnoe in particullary is characterized for the chronic form of EAA. Dyspnoe is worsed, if the disease is combinied with usual respiratory infection or reexposition of inhaled antigen. It seems the diagnostic definition of EAA should be easy and prevalence of EAA relative high. The disease belongs to the group of interstitial lung diseases and it is underestimated as a matter of fact. The clinic, radiographic, laboratory and histologic abnormalities are results of inhaled antigen contact and support the diagnosis of EAA. Specific IgG antibodies against the offending antigen along with them are consedered to be detected (established) of EAA.

  17. Extrinsic and intrinsic determinants of nerve regeneration

    Directory of Open Access Journals (Sweden)

    Toby A. Ferguson

    2011-01-01

    Full Text Available After central nervous system (CNS injury axons fail to regenerate often leading to persistent neurologic deficit although injured peripheral nervous system (PNS axons mount a robust regenerative response that may lead to functional recovery. Some of the failures of CNS regeneration arise from the many glial-based inhibitory molecules found in the injured CNS, whereas the intrinsic regenerative potential of some CNS neurons is actively curtailed during CNS maturation and limited after injury. In this review, the molecular basis for extrinsic and intrinsic modulation of axon regeneration within the nervous system is evaluated. A more complete understanding of the factors limiting axonal regeneration will provide a rational basis, which is used to develop improved treatments for nervous system injury.

  18. Intrinsic and Extrinsic Motivation for Stereotypic and Repetitive Behavior

    Science.gov (United States)

    Joosten, Annette V.; Bundy, Anita C.; Einfeld, Stewart L.

    2009-01-01

    This study provides evidence for intrinsic and extrinsic motivators for stereotypical and repetitive behavior in children with autism and intellectual disability and children with intellectual disability alone. We modified the Motivation Assessment Scale (MAS) (1988b); dividing it into intrinsic and extrinsic measures and adding items to assess…

  19. A prototype empirical framework of intrinsic and extrinsic EERQI indicators

    NARCIS (Netherlands)

    Mooij, Ton

    2012-01-01

    The research question is: What do statistical analyses show us about the relationships between intrinsic and extrinsic indicators of quality and what does this mean when constructing a prototype EERQI framework? The pilot study involved the scoring on both intrinsic and extrinsic indica-tors for 177

  20. Extrinsic Isoperimetric Analysis on Submanifolds with Curvatures bounded from below

    DEFF Research Database (Denmark)

    Markvorsen, Steen; Palmer, Vicente

    2010-01-01

    within the extrinsic ball from a given starting point before they hit the boundary of the extrinsic ball. In those cases, where we may extend our analysis to hold all the way to infinity, we apply a capacity comparison technique to obtain a sufficient condition for the submanifolds to be parabolic, i...

  1. Recruiter-Applicant Differences in Perceptions of Extrinsic Rewards.

    Science.gov (United States)

    David, Kermit R., Jr.; And Others

    1991-01-01

    Examined how accurate recruiters would be in estimating relative preferences of college seniors for important category of extrinsic rewards. Compared preferences of 602 graduating college seniors for 11 extrinsic rewards with preference estimates of 486 recruiters. Recruiters underestimated importance of medical and life insurance, pension plans,…

  2. Extrinsic Rewards Are Education's Past, Not Its Future.

    Science.gov (United States)

    Schaps, Eric; Lewis, Catherine

    1991-01-01

    Robert Slavin's position--that extrinsic rewards promote student motivation and learning--may be valid within the context of a "facts-and-skills" curriculum. However, extrinsic rewards are unnecessary when schools offer engaging learning activities; programs addressing social, ethical, and cognitive development; and a supportive…

  3. Apoptosis in experimental NASH is associated with p53 activation and TRAIL receptor expression.

    Science.gov (United States)

    Farrell, Geoffrey C; Larter, Claire Z; Hou, Jing Yun; Zhang, Rena H; Yeh, Matthew M; Williams, Jacqueline; dela Pena, Aileen; Francisco, Rona; Osvath, Sarah R; Brooling, John; Teoh, Narcissus; Sedger, Lisa M

    2009-03-01

    We examined extrinsic and intrinsic (endogenous) mitochondrial apoptosis pathways in experimental non-alcoholic steatohepatitis (NASH). To assess extrinsic pathways, we measured hepatic expression of death-inducing cytokine receptors (tumor necrosis factor-alpha-receptor (TNF-R)1, TNF-R2, Fas, and TNFalpha-related apoptosis-inducing ligand-receptor (TRAIL-R) mRNA, TUNEL, caspase 3 activation, liver injury and liver pathology in mice fed a methionine and choline deficient (MCD) diet. For endogenous stress pathways, we determined serum insulin-like growth factor-1 (IGF-1), hepatic p53, Bcl-XL, tBid and p21 expression. Methionine and choline deficient feeding increased alanine aminotransferase (ALT) and apoptosis from day 10, without increases in TNF-R1, TNF-R2, and Fas. However, murine TRAIL receptors, particularly decoyTRAIL-R1/TNFRSFH23 and Killer/DR5 mRNA increased. MCD feeding enhanced hepatic p53 expression, corresponding to approximately 50% fall in serum IGF-1, decreased Bcl-XL, enhanced Bid cleavage to tBid, and up-regulation of p21. Nutritional restitution experiments showed that correcting either methionine or choline deficiency suppressed liver inflammation (extrinsic pathway), but failed to correct apoptosis, IGF-1 or p53. Methionine and choline deficiency lower IGF-1 to de-repress p53 during induction of steatohepatitis. The p53 induced by nutritional stress is biologically active in mediating mitochondrial cell death pathways, but may also be responsible for TRAIL receptor expression, thereby linking intrinsic and exogenous apoptosis pathways in NASH.

  4. GLYCINE-RICH RNA-BINDING PROTEIN1 interacts with RECEPTOR-LIKE CYTOPLASMIC PROTEIN KINASE1 and suppresses cell death and defense responses in pepper (Capsicum annuum).

    Science.gov (United States)

    Kim, Dae Sung; Kim, Nak Hyun; Hwang, Byung Kook

    2015-01-01

    Plants use a variety of innate immune regulators to trigger cell death and defense responses against pathogen attack. We identified pepper (Capsicum annuum) GLYCINE-RICH RNA-BINDING PROTEIN1 (CaGRP1) as a RECEPTOR-LIKE CYTOPLASMIC PROTEIN KINASE1 (CaPIK1)-interacting partner, based on bimolecular fluorescence complementation and coimmunoprecipitation analyses as well as gene silencing and transient expression analysis. CaGRP1 contains an N-terminal RNA recognition motif and a glycine-rich region at the C-terminus. The CaGRP1 protein had DNA- and RNA-binding activity in vitro. CaGRP1 interacted with CaPIK1 in planta. CaGRP1 and CaGRP1-CaPIK1 complexes were localized to the nucleus in plant cells. CaPIK1 phosphorylated CaGRP1 in vitro and in planta. Transient coexpression of CaGRP1 with CaPIK1 suppressed the CaPIK1-triggered cell death response, accompanied by a reduced CaPIK1-triggered reactive oxygen species (ROS) burst. The RNA recognition motif region of CaGRP1 was responsible for the nuclear localization of CaGRP1 as well as the suppression of the CaPIK1-triggered cell death response. CaGRP1 silencing in pepper conferred enhanced resistance to Xanthomonas campestris pv vesicatoria (Xcv) infection; however, CaPIK1-silenced plants were more susceptible to Xcv. CaGRP1 interacts with CaPIK1 and negatively regulates CaPIK1-triggered cell death and defense responses by suppressing ROS accumulation.

  5. Ionotropic glutamate receptors and glutamate transporters are involved in necrotic neuronal cell death induced by oxygen-glucose deprivation of hippocampal slice cultures.

    Science.gov (United States)

    Bonde, C; Noraberg, J; Noer, H; Zimmer, J

    2005-01-01

    Organotypic hippocampal slice cultures represent a feasible model for studies of cerebral ischemia and the role of ionotropic glutamate receptors in oxygen-glucose deprivation-induced neurodegeneration. New results and a review of existing data are presented in the first part of this paper. The role of glutamate transporters, with special reference to recent results on inhibition of glutamate transporters under normal and energy-failure (ischemia-like) conditions is reviewed in the last part of the paper. The experimental work is based on hippocampal slice cultures derived from 7 day old rats and grown for about 3 weeks. In such cultures we investigated the subfield neuronal susceptibility to oxygen-glucose deprivation, the type of induced cell death and the involvement of ionotropic glutamate receptors. Hippocampal slice cultures were also used in our studies on glutamate transporters reviewed in the last part of this paper. Neurodegeneration was monitored and/or shown by cellular uptake of propidium iodide, loss of immunocytochemical staining for microtubule-associated protein 2 and staining with Fluoro-Jade B. To distinguish between necrotic vs. apoptotic neuronal cell death we used immunocytochemical staining for active caspase-3 (apoptosis indicator) and Hoechst 33342 staining of nuclear chromatin. Our experimental studies on oxygen-glucose deprivation confirmed that CA1 pyramidal cells were the most susceptible to this ischemia-like condition. Judged by propidium iodide uptake, a selective CA1 lesion, with only minor affection on CA3, occurred in cultures exposed to oxygen-glucose deprivation for 30 min. Nuclear chromatin staining by Hoechst 33342 and staining for active caspase-3 showed that oxygen-glucose deprivation induced necrotic cell death only. Addition of 10 microM of the N-methyl-D-aspartate glutamate receptor antagonist MK-801, and 20 microM of the non-N-methyl-D-aspartate glutamate receptor antagonist 2,3-dihyroxy-6-nitro-7-sulfamoyl

  6. Induction of apoptosis in leukemia cell lines by new copper(II) complexes containing naphthyl groups via interaction with death receptors.

    Science.gov (United States)

    Fernandes, Christiane; Horn, Adolfo; Lopes, Bruna F; Bull, Erika S; Azeredo, Nathália F B; Kanashiro, Milton M; Borges, Franz V; Bortoluzzi, Adailton J; Szpoganicz, Bruno; Pires, Anderson B; Franco, Roberto W A; Almeida, João Carlos de A; Maciel, Leide L F; Resende, Jackson A L C; Schenk, Gerhard

    2015-12-01

    The synthesis, physico-chemical characterization and cytotoxicity of four new ligands and their respective copper(II) complexes toward two human leukemia cell lines (THP-1 and U937) are reported (i.e. [(HL1)Cu(μ-Cl)2Cu(HL1)]Cl2·H2O (1), [(H2L2)Cu(μ-Cl)2Cu(H2L2)]Cl2·5H2O (2), [(HL3)Cu(μ-Cl)2Cu(HL3)]Cl2·4H2O (3), [(H2L4)Cu(μ-Cl)2Cu(H2L4)]Cl2·6H2O (4)). Ligands HL1 and HL3 contain two pyridines, amine and alcohol moieties with a naphthyl pendant unit yielding a N3O coordination metal environment. Ligands H2L2 and H2L4 have pyridine, phenol, amine and alcohol groups with a naphthyl pendant unit providing a N2O2 coordination metal environment. These compounds are likely to be dinuclear in the solid state but form mononuclear species in solution. The complexes have an antiproliferative effect against both leukemia cell lines; complex (2) exhibits higher activity than cisplatin against U937 (8.20 vs 16.25μmoldm(-3)) and a comparable one against THP-1. These human neoplastic cells are also more susceptible than peripheral blood mononuclear cells (PBMCs) toward the tested compounds. Using C57BL/6 mice an LD50 of 55mgkg(-1) was determined for complex (2), suggesting that this compound is almost four times less toxic than cisplatin (LD50=14.5mgkg(-1)). The mechanism of cell death promoted by ligand H2L2 and by complexes (2) and (4) was investigated by a range of techniques demonstrating that the apoptosis signal triggered at least by complex (2) starts from an extrinsic pathway involving the activation of caspases 4 and 8. This signal is amplified by mitochondria with the concomitant release of cytochrome c and the activation of caspase 9.

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

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    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

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

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    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

  9. Role Of S-Nitrosylation In The Extrinsic Apoptotic Signalling Pathway In Cancer

    Directory of Open Access Journals (Sweden)

    Stéphanie Plenchette

    2015-08-01

    Full Text Available One of the key features of tumour cells is the acquisition of resistance to apoptosis. Thus, determining therapeutic strategies that circumvent apoptotic resistance and result in tumor regression is a challenge. One strategy to induce apoptosis is to activate death receptor signalling pathways. Members of the Tumor Necrosis Factor TNF-family death receptors ligand (TRAIL, FasL and TNF-α can originate from immune and non-immune cells. Death receptors, engaged by cognate ligands, can initiate multiple signaling pathways, which can generate diverse outcomes, including non-apoptosis-related signal. Knowledge on the molecular mechanisms (that determine death or survival of tumour cells following exposure to the TNF-family death receptors ligands have demonstrated that post-translational modifications of the signaling pathway components play a critical role in determining cell fate. Cell death can be sensed by nitric oxide (NO in a wide variety of tumour cells. S-nitrosylation, the covalent modification of a protein cysteine thiol by an NO moiety, has emerged as an important post-translational regulation for the TNF-family death receptor signaling pathways. It has been demonstrated that death receptor DR4 (TRAIL-R1 becomes S-nitrosylated and promotes apoptosis following a specific NO donor treatment (Tang et al., 2006. Then, our group has shown that S-nitrosylation of Fas, following glyceryl trinitrate (GTN exposure, promotes redistribution of the receptor to lipid rafts, formation of the death-inducing signal complex (DISC, and induction of cell death. Finally, I will discuss our recent efforts to decipher regulatory mechanism of the TNF-α/TNFR1 signalling cell death pathway by S-nitrosylation following GTN treatment.

  10. The chalcone 2'-hydroxy-4',5'-dimethoxychalcone activates death receptor 5 pathway and leads to apoptosis in human nonsmall cell lung cancer cells.

    Science.gov (United States)

    Yang, Lina; Su, Ling; Cao, Congmei; Xu, Linyan; Zhong, Diansheng; Xu, Lijia; Liu, Xiangguo

    2013-06-01

    Natural chalcones have been proved to inhibit cancer cells with therapeutic potential, but the underlying molecular mechanism is still largely unexplored. Here, we identified a novel chalcone, 2'-hydroxy-4',5'-dimethoxychalcone (HDMC) and demonstrated that HDMC induced apoptosis in various nonsmall cell lung cancer cells. Further study showed that HDMC elevated cellular reactive oxygen species (ROS) levels, thus inducing expressions of ATF4 and C/EBP homologous protein (CHOP). Then, death receptor 5 (DR5) was upregulated through ATF4-CHOP axis and eventually resulted in apoptosis. We also found that downregulation of c-FLIPL contributed to HDMC-induced apoptosis. In conclusion, HDMC induces apoptosis in human nonsmall cell lung cancer cells via activation of DR5 signaling pathway, and ROS-mediated ATF4-CHOP axis is involved in the process. Our results further supported the potential for HDMC to be developed as a new antitumor agent for cancer therapy or chemoprevention.

  11. Effect of TRA-8 anti-death receptor 5 antibody in combination with chemotherapy in an ex vivo human ovarian cancer model.

    Science.gov (United States)

    Frederick, Peter J; Kendrick, James E; Straughn, J Michael; Della Manna, Debbie L; Oliver, Patsy G; Lin, Hui-Yi; Grizzle, William E; Stockard, Cecil R; Alvarez, Ronald D; Zhou, Tong; LoBuglio, Albert F; Buchsbaum, Donald J

    2009-07-01

    To investigate the cytotoxicity of TRA-8, an antibody that specifically binds death receptor 5, alone and in combination with chemotherapy, using an ex vivo human ovarian cancer model. Twenty-six ovarian cancer specimens were obtained during ovarian cancer debulking, and tumor slices were prepared with the Krumdieck tissue slicer. The tumor slices were exposed to varying concentrations of TRA-8, carboplatin/paclitaxel, or the combination of TRA-8 and chemotherapy. Using nonlinear modeling, dose-response curves and IC50 values were generated for specimens treated with TRA-8. The additive and synergistic cytotoxic effects of chemotherapy combination with TRA-8 were evaluated in specimens. In addition to adenosine triphosphate viability assays, the treated and untreated slices were assessed by immunohistochemistry to confirm apoptosis induction. Specimens from 13 patients yielded TRA-8-induced IC50 values. Of these specimens, 15% were found to be sensitive to TRA-8-induced cytotoxicity at IC50 doses less than 500 ng/mL. Specimens from 13 patients underwent combination treatment with TRA-8 and carboplatin/paclitaxel. Of these specimens, 77% exhibited additive cytotoxicity in comparison with those treated with either agent alone, whereas 15% exhibited synergistic cytotoxicity. Immunohistochemical analysis of terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling and cleaved caspase 3 staining demonstrated a dose-dependent increase in apoptosis with the combination treatment. This study demonstrates the efficacy of the death receptor monoclonal antibody TRA-8 in combination with conventional chemotherapy in an ex vivo human ovarian cancer model. This model can be used to assess cytotoxicity of novel agents in combination with chemotherapy in ovarian cancer.

  12. Treatment with gemcitabine and TRA-8 anti-death receptor-5 mAb reduces pancreatic adenocarcinoma cell viability in vitro and growth in vivo.

    Science.gov (United States)

    DeRosier, Leo Christopher; Huang, Zhi-Qiang; Sellers, Jeffrey C; Buchsbaum, Donald J; Vickers, Selwyn M

    2006-11-01

    Gemcitabine is a first line agent for pancreatic cancer, but yields minimal survival benefit. This study evaluated in vitro and in vivo effects of a monoclonal antibody (TRA-8) to human death receptor 5, combined with gemcitabine, using two human pancreatic cancer cell lines, S2VP10 and MIA PaCa-2. A subcutaneous model of pancreatic cancer was employed to test in vivo efficacy. S2VP10 and MIA PaCa-2 cells were treated with varying doses of gemcitabine and TRA-8. Cell viability and apoptosis were determined with an adenosine triphosphate assay and annexin V staining, respectively. Mitochondrial membrane destabilization was evaluated with fluorescence-activated cell sorting analysis of JC-1 stained cells. Caspase activation was evaluated by Western blot analysis. MIA PaCa-2 subcutaneous xenografts in athymic nude mice were evaluated for response to treatment with 200 mug of TRA-8 (intraperitoneal on days 9, 13, 16, 20, 23, and 27 postimplant) and 120 mg/kg gemcitabine (I.P. on days 10, 17, and 24). Tumor growth was measured with calipers. MIA PaCa-2 and S2VP10 cells receiving combination treatment with TRA-8 and gemcitabine demonstrated enhanced cytotoxicity, annexin V staining, and mitochondrial destabilization compared to either agent alone. Combination treatment produced enhanced caspase-3 and -8 activation in both cell lines compared with either agent alone. In vivo studies demonstrated mean subcutaneous tumor surface area (produce of two largest diameters) doubling times of 38 days untreated, 32 days gemcitabine, 49 days TRA-8, and 64 days combination treatment. TRA-8 is an apoptosis-inducing agonistic monoclonal antibody that produced synergistic cytotoxicity in combination with gemcitabine in vitro through enhanced caspase activation. These findings, with substantial inhibition of tumor growth in a mouse pancreatic cancer xenograft model receiving combination therapy, are encouraging for anti-death receptor therapy in the treatment of pancreatic cancer.

  13. Zinc sensing receptor signaling, mediated by GPR39, reduces butyrate-induced cell death in HT29 colonocytes via upregulation of clusterin.

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    Limor Cohen

    Full Text Available Zinc enhances epithelial proliferation, protects the digestive epithelial layer and has profound antiulcerative and antidiarrheal roles in the colon. Despite the clinical significance of this ion, the mechanisms linking zinc to these cellular processes are poorly understood. We have previously identified an extracellular Zn(2+ sensing G-protein coupled receptor (ZnR that activates Ca(2+ signaling in colonocytes, but its molecular identity as well as its effects on colonocytes' survival remained elusive. Here, we show that Zn(2+, by activation of the ZnR, protects HT29 colonocytes from butyrate induced cell death. Silencing of the G-protein coupled receptor GPR39 expression abolished ZnR-dependent Ca(2+ release and Zn(2+-dependent survival of butyrate-treated colonocytes. Importantly, GPR39 also mediated ZnR-dependent upregulation of Na(+/H(+ exchange activity as this activity was found in native colon tissue but not in tissue obtained from GPR39 knock-out mice. Although ZnR-dependent upregulation of Na(+/H(+ exchange reduced the cellular acid load induced by butyrate, it did not rescue HT29 cells from butyrate induced cell death. ZnR/GPR39 activation however, increased the expression of the anti-apoptotic protein clusterin in butyrate-treated cells. Furthermore, silencing of clusterin abolished the Zn(2+-dependent survival of HT29 cells. Altogether, our results demonstrate that extracellular Zn(2+, acting through ZnR, regulates intracellular pH and clusterin expression thereby enhancing survival of HT29 colonocytes. Moreover, we identify GPR39 as the molecular moiety of ZnR in HT29 and native colonocytes.

  14. Involvement of transient receptor potential melastatin-8 (TRPM8) in menthol-induced calcium entry, reactive oxygen species production and cell death in rheumatoid arthritis rat synovial fibroblasts.

    Science.gov (United States)

    Zhu, Shuyan; Wang, Yuxiang; Pan, Leiting; Yang, Shuang; Sun, Yonglin; Wang, Xinyu; Hu, Fen

    2014-02-15

    Rheumatoid arthritis is most prominently characterized by synoviocyte hyperplasia which therefore serves as an important target for clinical therapy. In the present study, it was observed that menthol, the specific agonist of transient receptor potential melastatin subtype 8 (TRPM8), could induce sustained increases of cytosolic calcium concentration ([Ca(2+)]c) in synoviocytes isolated from collagen-induced arthritis rats in dose-dependent manner, which was evidently blocked by applying an extracellular Ca(2+)-free buffer. Menthol-induced [Ca(2+)]c increase was also significantly inhibited by potent TRPM8 antagonist capsazepine (CZP), indicating that this [Ca(2+)]c elevation was mostly attributed to TRPM8-mediated Ca(2+) entry. Besides, RT-PCR indeed demonstrated presence of TRPM8 in the synoviocytes. Meanwhile, it was found that menthol evoked production of intracellular reactive oxygen species, which could be abolished by Ca(2+) free solutions or CZP. Further experiments showed that menthol reduced the cell numbers and survival of synoviocytes. This reduction was associated with apoptosis as suggested by mitochondrial membrane depolarization, nuclear condensation and a caspase 3/7 apoptotic assay. Menthol-induced death and apoptosis of synoviocytes both were obviously inhibited by CZP, intracellular calcium chelator BAPTA-AM, and reactive oxygen species inhibitor diphenylene iodonium, respectively. Taken together, our data indicated that menthol resulted in synoviocyte death associated with apoptosis via calcium entry and reactive oxygen species production depending on TRPM8 activation.

  15. Prostate stem cell antigen is an endogenous lynx1-like prototoxin that antagonizes alpha7-containing nicotinic receptors and prevents programmed cell death of parasympathetic neurons.

    Science.gov (United States)

    Hruska, Martin; Keefe, Julie; Wert, David; Tekinay, Ayse Begum; Hulce, Jonathan J; Ibañez-Tallon, Ines; Nishi, Rae

    2009-11-25

    Vertebrate alpha-bungarotoxin-like molecules of the Ly-6 superfamily have been implicated as balancers of activity and survival in the adult nervous system. To determine whether a member of this family could be involved in the development of the avian ciliary ganglion, we identified 6 Gallus genes by their homology in structure to mouse lynx1 and lynx2. One of these genes, an ortholog of prostate stem cell antigen (psca), is barely detectable at embryonic day (E) 8, before neuronal cell loss in the ciliary ganglion, but increases >100-fold as the number of neurons begins to decline between E9 and E14. PSCA is highly expressed in chicken and mouse telencephalon and peripheral ganglia and correlates with expression of alpha7-containing nicotinic acetylcholine receptors (alpha7-nAChRs). Misexpressing PSCA before cell death in the ciliary ganglion blocks alpha7-nAChR activation by nicotine and rescues the choroid subpopulation from dying. Thus, PSCA, a molecule previously identified as a marker of prostate cancer, is a member of the Ly-6 neurotoxin-like family in the nervous system, and is likely to play a role as a modulator of alpha7 signaling-induced cell death during development.

  16. Combination treatment with TRA-8 anti death receptor 5 antibody and CPT-11 induces tumor regression in an orthotopic model of pancreatic cancer.

    Science.gov (United States)

    DeRosier, Leo Christopher; Buchsbaum, Donald J; Oliver, Patsy G; Huang, Zhi-Qiang; Sellers, Jeffrey C; Grizzle, William E; Wang, Wenquan; Zhou, Tong; Zinn, Kurt R; Long, Joshua W; Vickers, Selwyn M

    2007-09-15

    Evaluate the response of human pancreatic cancer cell lines and orthotopic tumors to TRA-8, an agonistic antibody to death receptor 5, in combination with irinotecan (CPT-11). MIA PaCa-2 and S2VP10 cells were treated with TRA-8 and/or CPT 11. Cell viability was determined by ATP assay. JC-1 mitochondrial depolarization and Annexin V assays confirmed cell death by apoptosis. Immunoblotting was used to evaluate protein changes. MIA PaCa-2 cells were injected into the pancreas of severe combined immunodeficient mice. Mice underwent abdominal ultrasound to quantitate tumor size before and after treatment with twice weekly injections of 200 microg TRA-8 and/or 25 mg/kg CPT-11 for one or two treatment cycles, each lasting 2 weeks. MIA PaCa-2 cells were more sensitive to TRA-8 and showed additive cytotoxicity, whereas S2VP10 cells showed synergistic cytotoxicity when treated with TRA-8 and CPT-11. Cell death occurred via apoptosis with increased cleavage of caspase-3, caspase-8, and caspase-9 and proapoptotic proteins Bid and poly(ADP)ribose polymerase after combination treatment compared with either agent alone. XIAP and Bcl-XL inhibitors of apoptosis were down-regulated. After a single cycle of in vivo combination therapy, tumor sizes had diminished significantly (PTRA-8; and there was a 50-day increase in survival with combination treatment over untreated controls (P=0.0002), 30 days over TRA-8, and a 36-day increase over CPT-11 monotherapy (P=0.0003). With two cycles of TRA-8/CPT-11 treatment, mean survival time increased significantly (PTRA-8 or CPT-11 (76, 121, or 108 days, respectively). Combination TRA-8 and CPT-11 therapy produced enhanced cytotoxicity and survival in the MIA PaCa-2 orthotopic model of pancreatic cancer.

  17. Expression of the glucocorticoid receptor from the 1A promoter correlates with T lymphocyte sensitivity to glucocorticoid-induced cell death.

    Science.gov (United States)

    Purton, Jared F; Monk, Julie A; Liddicoat, Douglas R; Kyparissoudis, Konstantinos; Sakkal, Samy; Richardson, Samantha J; Godfrey, Dale I; Cole, Timothy J

    2004-09-15

    Glucocorticoid (GC) hormones cause pronounced T cell apoptosis, particularly in immature thymic T cells. This is possibly due to tissue-specific regulation of the glucocorticoid receptor (GR) gene. In mice the GR gene is transcribed from five separate promoters designated: 1A, 1B, 1C, 1D, and 1E. Nearly all cells express GR from promoters 1B-1E, but the activity of the 1A promoter has only been reported in the whole thymus or lymphocyte cell lines. To directly assess the role of GR promoter use in sensitivity to glucocorticoid-induced cell death, we have compared the activity of the GR 1A promoter with GC sensitivity in different mouse lymphocyte populations. We report that GR 1A promoter activity is restricted to thymocyte and peripheral lymphocyte populations and the cortex of the brain. The relative level of expression of the 1A promoter to the 1B-1E promoters within a lymphocyte population was found to directly correlate with susceptibility to GC-induced cell death, with the extremely GC-sensitive CD4+CD8+ thymocytes having the highest levels of GR 1A promoter activity, and the relatively GC-resistant alphabetaTCR+CD24(int/low) thymocytes and peripheral T cells having the lowest levels. DNA sequencing of the mouse GR 1A promoter revealed a putative glucocorticoid-response element. Furthermore, GR 1A promoter use and GR protein levels were increased by GC treatment in thymocytes, but not in splenocytes. These data suggest that tissue-specific differences in GR promoter use determine T cell sensitivity to glucocorticoid-induced cell death. Copyright 2004 The American Association of Immunologists, Inc.

  18. Free Radicals and Extrinsic Skin Aging

    Directory of Open Access Journals (Sweden)

    Borut Poljšak

    2012-01-01

    Full Text Available Human skin is constantly directly exposed to the air, solar radiation, environmental pollutants, or other mechanical and chemical insults, which are capable of inducing the generation of free radicals as well as reactive oxygen species (ROS of our own metabolism. Extrinsic skin damage develops due to several factors: ionizing radiation, severe physical and psychological stress, alcohol intake, poor nutrition, overeating, environmental pollution, and exposure to UV radiation (UVR. It is estimated that among all these environmental factors, UVR contributes up to 80%. UV-induced generation of ROS in the skin develops oxidative stress, when their formation exceeds the antioxidant defence ability of the target cell. The primary mechanism by which UVR initiates molecular responses in human skin is via photochemical generation of ROS mainly formation of superoxide anion (O2−•, hydrogen peroxide (H2O2, hydroxyl radical (OH•, and singlet oxygen (1O2. The only protection of our skin is in its endogenous protection (melanin and enzymatic antioxidants and antioxidants we consume from the food (vitamin A, C, E, etc.. The most important strategy to reduce the risk of sun UVR damage is to avoid the sun exposure and the use of sunscreens. The next step is the use of exogenous antioxidants orally or by topical application and interventions in preventing oxidative stress and in enhanced DNA repair.

  19. Plasma opening switch with extrinsic magnetic field

    CERN Document Server

    Dolgachev, G; Maslennikov, D

    2001-01-01

    Summary form only given, as follows. We have demonstrated in series of experiments that plasma opening switch (POS) switching voltage (UPOS) is defined by energy density (w) deposited in the POS plasma. If we then consider a plasma erosion mainly responsible for the effect of POS switching (the erosion effect could be described by Hall or Child-Langmuir models) the energy density (w) could be measured as a function of a system "macro-parameter" such as the initial charging voltage of the capacity storage system (the Marx pulsed voltage generator) UMarx. The POS voltage in this case could be given by UPOS"aw=aUMarx4/7, where a is a constant. This report demonstrates that for the high-impedance POS which has limited charge density transferred through the POS plasma a"2.5 (MV3/7) with no external magnetic field applied. The use of the extrinsic magnetic field allows to increase a up to 3.6 (MV3/7) and to achieve higher voltages at the opening phase - UPOS=3.6UMarx4/7. To verify this approach set of experimental ...

  20. Twisting Fluorescence through Extrinsic Chiral Antennas.

    Science.gov (United States)

    Yan, Chen; Wang, Xiaolong; Raziman, T V; Martin, Olivier J F

    2017-03-22

    Plasmonic antennas and planar structures have been undergoing intensive developments in order to control the scattering and absorption of light. One specific class, extrinsic chiral surfaces, that does not possess 2-fold rotational symmetry exhibits strong asymmetric transmission for different circular polarizations under obliquely incident illumination. In this work, we show that the design of those surfaces can be optimized with complex multipolar resonances in order to twist the fluorescence emission from nearby molecules. While this emission is usually dipolar and linearly polarized, the interaction with these resonances twists it into a multipolar radiation pattern with opposite helicity in different directions. The proposed structure maximizes this effect and provides control over the polarization of light. Splitting of left- and right-handed circularly polarized light is experimentally obtained in the backward direction. These results highlight the intricate interplay between the near-field absorption and the far-field scattering of a plasmonic nanostructure and are further used for modifying the emission of incoherent quantum sources. Our finding can potentially lead to the development of polarization- and angle-resolved ultracompact optical devices.

  1. The HRCT features of extrinsic allergic alveolitis.

    Science.gov (United States)

    Hartman, Thomas E

    2003-08-01

    Exposure to organic dusts can produce an immune-mediated inflammatory response in sensitized individuals. The pulmonary disease caused by this response has been called extrinsic allergic alveolitis (EAA) or hypersensitivity pneumonitis. The clinical phases associated with this process have been termed acute, subacute, and chronic. There are corresponding imaging findings that are characteristic of each of these phases, although there is some overlap between the phases. The acute phase is characterized by confluent opacities that may mimic infection or edema. The subacute phase is characterized by centrilobular nodules, areas of ground-glass attenuation, a mosaic perfusion pattern, and air trapping on expiratory imaging. The chronic phase is characterized by subpleural irregular linear opacities with associated architectural distortion. Honeycombing may sometimes also be present. In the acute and subacute phases, the disease is predominantly in the lower lungs, whereas in chronic EAA the findings are predominant in the mid to upper lungs. Although the high-resolution computed tomography findings individually are nonspecific, the combination of the findings coupled with the distribution of the findings can often narrow the differential or allow a presumptive diagnosis of EAA to be made.

  2. Gomisin N enhances TRAIL-induced apoptosis via reactive oxygen species-mediated up-regulation of death receptors 4 and 5.

    Science.gov (United States)

    Inoue, Hiroki; Waiwut, Pornthip; Saiki, Ikuo; Shimada, Yutaka; Sakurai, Hiroaki

    2012-04-01

    Pharmacological studies have revealed that lignans isolated from Schisandra chinensis, including gomisin N, show anticancer, anti-hepatotoxic, anti-oxidative and anti-inflammatory activities. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an important member of the tumor necrosis factor superfamily with great potential in cancer therapy. The present study investigated whether pretreatment with gomisin N significantly enhanced TRAIL-induced cleavage of caspase-3, caspase-8 and PARP-1, which are key markers of apoptosis. Pretreatment with z-VAD-FMK, a pan-caspase inhibitor, was able to inhibit apoptosis enhanced by the combination of gomisin N and TRAIL. These results suggested that gomisin N could promote TRAIL-induced apoptosis through the caspase cascade. In search of the molecular mechanisms, we elucidated that such enhancement was achieved through transcriptional up-regulation of TRAIL receptors, death receptor 4 (DR4) and DR5. Neutralization of DR4 and DR5 could significantly reduce apoptosis induced by gomisin N and TRAIL. We also revealed that gomisin N increased the generation of reactive oxygen species (ROS). N-acetyl cysteine (NAC), an antioxidant, could inhibit ROS production and up-regulation of DR4 and DR5. Overall, our results indicated that gomisin N was able to potentiate TRAIL-induced apoptosis through ROS-mediated up-regulation of DR4 and DR5.

  3. Inhibition of the Receptor for Advanced Glycation End-Products (RAGE) Attenuates Neuroinflammation While Sensitizing Cortical Neurons Towards Death in Experimental Subarachnoid Hemorrhage.

    Science.gov (United States)

    Li, Hua; Yu, Jia-Sheng; Zhang, Ding-Ding; Yang, Yi-Qing; Huang, Li-Tian; Yu, Zhuang; Chen, Ru-Dong; Yang, Hong-Kuan; Hang, Chun-Hua

    2017-01-01

    Subarachnoid hemorrhage (SAH) is a threatening and devastating neurological insult with high mortality and morbidity rates. Despite considerable efforts, the underlying pathophysiological mechanisms are still poorly understood. The receptor for advanced glycation end products (RAGE) is a multiligand receptor that has been implicated in various pathological conditions. We previously showed that RAGE was upregulated and may be involved in pathophysiology of SAH. In the current study, we investigated its potential role in SAH. We found that the upregulation of RAGE after SAH was NF-κB-dependent positive feedback regulation. Further, pharmacological inhibition of RAGE attenuated neuroinflammation, indicating a possible contributive role of RAGE in inflammation-associated brain injury after SAH. Conversely, however, inhibition of RAGE sensitized neurons, exacerbating cell death, which correlated with augmented apoptosis and diminished autophagy, suggesting that activation of RAGE may protect against SAH-induced neuronal injury. Furthermore, we demonstrate that inhibition of RAGE significantly reduced brain edema and improved neurological function at day 1 but not at day 3 post-SAH. Taken together, these results suggest that RAGE exerts dual role after SAH. Our findings also suggest caution should be exercised in setting RAGE-targeted treatment for SAH.

  4. Bleomycin induced sensitivity to TRAIL/Apo-2L-mediated apoptosis in human seminomatous testicular cancer cells is correlated with upregulation of death receptors.

    Science.gov (United States)

    Timur, Mujgan; Cort, Aysegul; Ozdemir, Evrim; Sarikcioglu, Sureyya Bilmen; Sanlioglu, Salih; Sanlioglu, Ahter Dilsad; Ozben, Tomris

    2015-01-01

    The most common solid tumor is testicular cancer among young men. Bleomycin is an antitumor antibiotic used for the therapy of testicular cancer. TRAIL is a proapoptotic cytokine that qualified as an apoptosis inducer in cancer cells. Killing cancer cells selectively via apoptosis induction is an encouraging therapeutic strategy in clinical settings. Combination of TRAIL with chemotherapeutics has been reported to enhance TRAIL-mediated apoptosis of different kinds of cancer cell lines. The molecular ground for sensitization of tumour cells to TRAIL by chemotherapeutics might involve upregulation of TRAIL-R1 (TR/1, DR4) and/or TRAIL-R2 (TR/2, DR5) receptors or activation of proapoptotic proteins including caspases. The curative potential of TRAIL to eradicate cancer cells selectively in testicular cancer has not been studied before. In this study, we investigated apoptotic effects of bleomycin, TRAIL, and their combined application in NTera-2 and NCCIT testicular cancer cell lines. We measured caspase 3 levels as an apoptosis indicator, and TRAIL receptor expressions using flow cytometry. Both NTera-2 and NCCIT cells were fairly resistant to TRAIL's apoptotic effect. Incubation of bleomycin alone caused a significant increase in caspase 3 activity in NCCIT. Combined incubation with bleomycin and TRAIL lead to elevated caspase 3 activity in Ntera-2. Exposure to 72 h of bleomycin increased TR/1, TR/2, and TR/3 cell-surface expressions in NTera-2. Elevation in TR/1 cell-surface expression was evident only at 24 h of bleomycin application in NCCIT. It can be concluded that TRAIL death receptor expressions in particular are increased in testicular cancer cells via bleomycin treatment, and TRAIL-induced apoptosis is initiated.

  5. An exploratory investigation into the role of extrinsic factors in ...

    African Journals Online (AJOL)

    Seugnet

    extrinsic factors in consumer decision-making for interior soft ... buy, in a passive manner, what retailers have to offer. Instead, they .... one's self-concept: the consumption of interior prod- .... important influencing variable in consumer decision-.

  6. Luteolin induces intrinsic apoptosis via inhibition of E6/E7 oncogenes and activation of extrinsic and intrinsic signaling pathways in HPV-18-associated cells.

    Science.gov (United States)

    Ham, Sunyoung; Kim, Ki Hong; Kwon, Tae Ho; Bak, Yesol; Lee, Dong Hun; Song, Yong Seok; Park, Su-Ho; Park, Yun Sun; Kim, Man Sub; Kang, Jeong Woo; Hong, Jin Tae; Yoon, Do-Young

    2014-06-01

    Luteolin, a flavonoid extracted from a number of plants with recognized anticancer, anti-inflammatory and anti-oxidative activities, inhibits angiogenic processes and modulates multidrug resistance. However, the efficacy and mechanisms of action of this flavonoid agent are still undergoing study. In order to elucidate whether luteolin exhibits an anticancer effect in cervical cancer cells, HeLa cells were incubated with luteolin and apoptosis was assessed by observing nuclear morphological changes, and performing Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining. Cell cycle analysis, western blotting, RT-PCR and mitochondrial membrane potential measurements were also carried out. Luteolin showed a significant dose-dependent cytotoxic effect only in human papillomavirus (HPV)-positive cervical cancer cells, when compared to its effect on HPV-negative cervical cancer C33A cells. Expression levels of human papilloma virus E6 and E7 oncogenes were suppressed, those of related factors pRb and p53 were recovered and E2F5 was increased by luteolin treatment. Furthermore, luteolin enhanced the expression of death receptors and death receptor downstream factors such as Fas/FasL, DR5/TRAIL and FADD in HeLa cells, and activated caspase cascades. In particular, luteolin enhanced the activity of caspase-3 and -8 in a dose-dependent manner. Activation of caspase-3 induced caspase-8 activity and vice versa. Luteolin also induced mitochondrial membrane potential collapse and cytochrome c release, and inhibited Bcl-2 and Bcl-xL expression. In conclusion, luteolin exerts anticarcinogenic activity through inhibition of E6 and E7 expression and cross-activation of caspase-3 and -8. Taken together, these results suggest that luteolin induces inactivation of HPV-18 oncogene expression and apoptosis by activating the intrinsic and extrinsic pathways.

  7. The effects of extrinsic rewards on children's intrinsic motivation

    OpenAIRE

    大槻, 千秋

    1981-01-01

    An experiment was conducted with preschool children to test whether a person's intrinsic motivation in an activity may be decreased by extrinsic salient rewards in Japan like in America. Children solved some jigsaw puzzles and received assorted candies, then they were observed how long they did other jigsaw puzzles. The results showed that the effects of extrinsic rewards on intrinsic motivation in an activity varied with the subject's social background. In uptown children's intrinsic motivat...

  8. The effects of extrinsic rewards on children's intrinsic motivation

    OpenAIRE

    大槻, 千秋

    1981-01-01

    An experiment was conducted with preschool children to test whether a person's intrinsic motivation in an activity may be decreased by extrinsic salient rewards in Japan like in America. Children solved some jigsaw puzzles and received assorted candies, then they were observed how long they did other jigsaw puzzles. The results showed that the effects of extrinsic rewards on intrinsic motivation in an activity varied with the subject's social background. In uptown children's intrinsic motivat...

  9. Extrinsic Rewards: An Adventist Curriculum Perspective for Classroom Management

    OpenAIRE

    Nadine A. Joseph

    2014-01-01

    Extrinsic rewards refer to gifts used as a form of motivation for students’ to attain an academic goal, or given when that particular goal is reached. Though the use of extrinsic rewards have been proven to have some impact on’ behavior change, such as academic performance, the absence of rewards can cause students’ to revert to the initial unwanted behavior. Consequently, the curricula focus in the Adventist classroom should address the deeper issues that affect behavior and implement the us...

  10. Ethanolic extract of Thevetia peruviana flowers enhances TNF-α and TRAIL-induced apoptosis of human cervical cancer cells via intrinsic and extrinsic pathways.

    Science.gov (United States)

    Managit, Chittima; Sakurai, Hiroaki; Saiki, Ikuo

    2017-04-01

    Tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) are promising candidates for cancer treatment due to their ability to induce apoptosis through death receptor stimulation. However, their usage may be limited due to the resistance of cancer cells to TNF-α- and TRAIL-induced apoptosis. Currently, there is interest in screening for natural products that can sensitize cancer cells to TNF-α- and TRAIL-induced apoptosis for their use in combination with TNF-α or TRAIL. It was previously reported that the bark extract of Thevetia peruviana showed a reversal effect on TRAIL-resistance in human gastric adenocarcinoma cell lines. In the present study, the effects of the ethanolic extract of T. peruviana flowers on TNF-α- and TRAIL-induced apoptosis of human cervical cancer HeLa cells were investigated in vitro by determining cell viability and apoptosis using a WST-1 cell proliferation assay and immunoblot analysis, respectively. The ethanolic extract of T. peruviana flowers promoted TNF-α and TRAIL-mediated cell death through the activation of the caspase cascade, poly(ADP-ribose) polymerase and BH3-interacting domain death agonist cleavage. Combined treatment using the extract plus TNF-α resulted in downregulation of anti-apoptotic protein, including myeloid cell leukemia sequence-1, B-cell lymphoma-extra large (Bcl-XL), X-linked inhibitor of apoptosis protein and survivin, while the combined treatment with TRAIL downregulated Bcl-XL. Thus, the ethanolic extract of T. peruviana flowers has potential in sensitizing the TNF-α- and TRAIL-induced apoptosis of HeLa cells via the intrinsic and extrinsic pathways.

  11. Novel levamisole derivative induces extrinsic pathway of apoptosis in cancer cells and inhibits tumor progression in mice.

    Directory of Open Access Journals (Sweden)

    Mahesh Hegde

    Full Text Available BACKGROUND: Levamisole, an imidazo(2,1-bthiazole derivative, has been reported to be a potential antitumor agent. In the present study, we have investigated the mechanism of action of one of the recently identified analogues, 4a (2-benzyl-6-(4'-fluorophenyl-5-thiocyanato-imidazo[2,1-b][1], [3], [4]thiadiazole. MATERIALS AND METHODS: ROS production and expression of various apoptotic proteins were measured following 4a treatment in leukemia cell lines. Tumor animal models were used to evaluate the effect of 4a in comparison with Levamisole on progression of breast adenocarcinoma and survival. Immunohistochemistry and western blotting studies were performed to understand the mechanism of 4a action both ex vivo and in vivo. RESULTS: We have determined the IC(50 value of 4a in many leukemic and breast cancer cell lines and found CEM cells most sensitive (IC(50 5 µM. Results showed that 4a treatment leads to the accumulation of ROS. Western blot analysis showed upregulation of pro-apoptotic proteins t-BID and BAX, upon treatment with 4a. Besides, dose-dependent activation of p53 along with FAS, FAS-L, and cleavage of CASPASE-8 suggest that it induces death receptor mediated apoptotic pathway in CEM cells. More importantly, we observed a reduction in tumor growth and significant increase in survival upon oral administration of 4a (20 mg/kg, six doses in mice. In comparison, 4a was found to be more potent than its parental analogue Levamisole based on both ex vivo and in vivo studies. Further, immunohistochemistry and western blotting studies indicate that 4a treatment led to abrogation of tumor cell proliferation and activation of apoptosis by the extrinsic pathway even in animal models. CONCLUSION: Thus, our results suggest that 4a could be used as a potent chemotherapeutic agent.

  12. Novel Levamisole Derivative Induces Extrinsic Pathway of Apoptosis in Cancer Cells and Inhibits Tumor Progression in Mice

    Science.gov (United States)

    Hegde, Mahesh; Karki, Subhas S.; Thomas, Elizabeth; Kumar, Sujeet; Panjamurthy, Kuppusamy; Ranganatha, Somasagara R.; Rangappa, Kanchugarakoppal S.; Choudhary, Bibha; Raghavan, Sathees C.

    2012-01-01

    Background Levamisole, an imidazo(2,1-b)thiazole derivative, has been reported to be a potential antitumor agent. In the present study, we have investigated the mechanism of action of one of the recently identified analogues, 4a (2-benzyl-6-(4′-fluorophenyl)-5-thiocyanato-imidazo[2,1-b][1], [3], [4]thiadiazole). Materials and Methods ROS production and expression of various apoptotic proteins were measured following 4a treatment in leukemia cell lines. Tumor animal models were used to evaluate the effect of 4a in comparison with Levamisole on progression of breast adenocarcinoma and survival. Immunohistochemistry and western blotting studies were performed to understand the mechanism of 4a action both ex vivo and in vivo. Results We have determined the IC50 value of 4a in many leukemic and breast cancer cell lines and found CEM cells most sensitive (IC50 5 µM). Results showed that 4a treatment leads to the accumulation of ROS. Western blot analysis showed upregulation of pro-apoptotic proteins t-BID and BAX, upon treatment with 4a. Besides, dose-dependent activation of p53 along with FAS, FAS-L, and cleavage of CASPASE-8 suggest that it induces death receptor mediated apoptotic pathway in CEM cells. More importantly, we observed a reduction in tumor growth and significant increase in survival upon oral administration of 4a (20 mg/kg, six doses) in mice. In comparison, 4a was found to be more potent than its parental analogue Levamisole based on both ex vivo and in vivo studies. Further, immunohistochemistry and western blotting studies indicate that 4a treatment led to abrogation of tumor cell proliferation and activation of apoptosis by the extrinsic pathway even in animal models. Conclusion Thus, our results suggest that 4a could be used as a potent chemotherapeutic agent. PMID:22970136

  13. A Fucus vesiculosus extract inhibits estrogen receptor activation and induces cell death in female cancer cell lines.

    Science.gov (United States)

    Zhang, Jianqing; Riby, Jacques E; Conde, Lucia; Grizzle, William E; Cui, Xiangqin; Skibola, Christine F

    2016-05-28

    We previously reported the anti-estrogenic activity of the brown seaweed, Fucus vesiculosus. The present study aimed to further investigate its anti-estrogenic modes of action and to assess other potentially biologically relevant anti-tumorigenic effects in estrogen receptor (ER)-dependent and -independent female cancer cell lines. The CALUX® assay was used to determine the effect of a F. vesiculosus extract (FVE) on activation of the ER. Aromatase enzymatic activity was measured to determine the potential effect of FVE on estradiol (E2) biosynthesis. Transcriptional activity profiling of 248 genes involved in cancer, immunity, hormonal regulation, protein phosphorylation, transcription, metabolism, and cellular structure was conducted using the NanoString nCounter® analysis system in FVE-treated breast, ovarian and endometrial cancer cell lines. The effects of FVE on cell viability, morphology, membrane integrity, mitochondrial toxicity, induction of apoptotic and autophagic markers, and cell signaling were also analyzed. In co-treatments with 12.5 pM (EC50) E2, FVE (2 %) reduced ER activation by 50 %, exhibiting potent ER antagonistic effects. FVE inhibited aromatase activity in an in vitro assay (IC50 2.0 %). ER-dependent and -independent cancer cell lines showed significantly decreased viability that correlated with increasing FVE concentrations and altered morphological features suggestive of apoptosis and autophagy. Expression of genes that were significantly altered by FVE (p vesiculosus. Moreover, the induction of autophagy and apoptosis on breast, endometrial and ovarian cancer cell lines suggests additional anti-tumorigenic actions of FVE that are independent of ER status in female cancers.

  14. Interferon-gamma (IFN-γ-mediated retinal ganglion cell death in human tyrosinase T cell receptor transgenic mouse.

    Directory of Open Access Journals (Sweden)

    Shahid Husain

    Full Text Available We have recently demonstrated the characterization of human tyrosinase TCR bearing h3T-A2 transgenic mouse model, which exhibits spontaneous autoimmune vitiligo and retinal dysfunction. The purpose of current study was to determine the role of T cells and IFN-γ in retina dysfunction and retinal ganglion cell (RGC death using this model. RGC function was measured by pattern electroretinograms (ERGs in response to contrast reversal of patterned visual stimuli. RGCs were visualized by fluorogold retrograde-labeling. Expression of CD3, IFN-γ, GFAP, and caspases was measured by immunohistochemistry and Western blotting. All functional and structural changes were measured in 12-month-old h3T-A2 mice and compared with age-matched HLA-A2 wild-type mice. Both pattern-ERGs (42%, p = 0.03 and RGC numbers (37%, p = 0.0001 were reduced in h3T-A2 mice when compared with wild-type mice. The level of CD3 expression was increased in h3T-A2 mice (h3T-A2: 174 ± 27% vs. HLA-A2: 100%; p = 0.04. The levels of effector cytokine IFN-γ were also increased significantly in h3T-A2 mice (h3T-A2: 189 ± 11% vs. HLA-A2: 100%; p = 0.023. Both CD3 and IFN-γ immunostaining were increased in nerve fiber (NF and RGC layers of h3T-A2 mice. In addition, we have seen a robust increase in GFAP staining in h3T-A2 mice (mainly localized to NF layer, which was substantially reduced in IFN-γ ((-/- knockout h3T-A2 mice. We also have seen an up-regulation of caspase-3 and -9 in h3T-A2 mice. Based on our data we conclude that h3T-A2 transgenic mice exhibit visual defects that are mostly associated with the inner retinal layers and RGC function. This novel h3T-A2 transgenic mouse model provides opportunity to understand RGC pathology and test neuroprotective strategies to rescue RGCs.

  15. Extrinsic value orientation and affective forecasting: overestimating the rewards, underestimating the costs.

    Science.gov (United States)

    Sheldon, Kennon M; Gunz, Alexander; Nichols, Charles P; Ferguson, Yuna

    2010-02-01

    We examined affective forecasting errors as a possible explanation of the perennial appeal of extrinsic values and goals. Study 1 found that although people relatively higher in extrinsic (money, fame, image) compared to intrinsic (growth, intimacy, community) value orientation (REVO) are less happy, they nevertheless believe that attaining extrinsic goals offers a strong potential route to happiness. Study 2's longitudinal experimental design randomly assigned participants to pursue either 3 extrinsic or 3 intrinsic goals over 4 weeks, and REVO again predicted stronger forecasts regarding extrinsic goals. However, not even extrinsically oriented participants gained well-being benefits from attaining extrinsic goals, whereas all participants tended to gain in happiness from attaining intrinsic goals. Study 3 showed that the effect of REVO on forecasts is mediated by extrinsic individuals' belief that extrinsic goals will satisfy autonomy and competence needs. It appears that some people overestimate the emotional benefits of achieving extrinsic goals, to their potential detriment.

  16. 1,1-Bis(3'-indolyl-1-(p-substituted phenylmethanes induce autophagic cell death in estrogen receptor negative breast cancer

    Directory of Open Access Journals (Sweden)

    Chadalapaka Gayathri

    2010-12-01

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

  17. Structural basis of LaDR5, a novel agonistic anti-death receptor 5 (DR5 monoclonal antibody, to inhibit DR5/TRAIL complex formation

    Directory of Open Access Journals (Sweden)

    Qiao Chunxia

    2012-07-01

    Full Text Available Abstract Background As a member of the TNF superfamily, TRAIL could induce human tumor cell apoptosis through its cognate death receptors DR4 or DR5, which can induce formation of the death inducing signaling complex (DISC and activation of the membrane proximal caspases (caspase-8 or caspase-10 and mitochondrial pathway. Some monoclonal antibodies against DR4 or DR5 have been reported to have anti-tumor activity. Results In this study, we reported a novel mouse anti-human DR5 monoclonal antibody, named as LaDR5, which could compete with TRAIL to bind DR5 and induce the apoptosis of Jurkat cells in the absence of second cross-linking in vitro. Using computer-guided molecular modeling method, the 3-D structure of LaDR5 Fv fragment was constructed. According to the crystal structure of DR5, the 3-D complex structure of DR5 and LaDR5 was modeled using molecular docking method. Based on distance geometry method and intermolecular hydrogen bonding analysis, the key functional domain in DR5 was predicted and the DR5 mutants were designed. And then, three mutants of DR5 was expressed in prokaryotic system and purified by affinity chromatograph to determine the epitope of DR5 identified by LaDR5, which was consistent with the theoretical results of computer-aided analysis. Conclusions Our results demonstrated the specific epitope located in DR5 that plays a crucial role in antibody binding and even antineoplastic bioactivity. Meanwhile, revealed structural features of DR5 may be important to design or screen novel drugs agonist DR5.

  18. Hesperidin from Citrus seed induces human hepatocellular carcinoma HepG2 cell apoptosis via both mitochondrial and death receptor pathways.

    Science.gov (United States)

    Banjerdpongchai, Ratana; Wudtiwai, Benjawan; Khaw-On, Patompong; Rachakhom, Wasitta; Duangnil, Natthachai; Kongtawelert, Prachya

    2016-01-01

    Citrus seeds are full of phenolic compounds, such as flavonoids. The aims of this study were to identify the types of flavonoids in Citrus seed extracts, the cytotoxic effect, mode of cell death, and signaling pathway in human hepatic cancer HepG2 cells. The flavonoids contain anticancer, free radical scavenging, and antioxidant activities. Neohesperidin, hesperidin, and naringin, active flavanone glycosides, were identified in Citrus seed extract. The cytotoxic effect of three compounds was in a dose-dependent manner, and IC50 levels were determined. The sensitivity of human HepG2 cells was as follows: hesperidin > naringin > neohesperidin > naringenin. Hesperidin induced HepG2 cells to undergo apoptosis in a dose-dependent manner as evidenced by the externalization of phosphatidylserine and determined by annexin V-fluorescein isothiocyanate and propidium iodide staining using flow cytometry. Hesperidin did not induce the generation of reactive oxygen species, which was determined by using 2',7'-dichlorohydrofluorescein diacetate and flow cytometry method. The number of hesperidin-treated HepG2 cells with the loss of mitochondrial transmembrane potential increased concentration dependently, using 3,3'-dihexyloxacarbocyanine iodide employing flow cytometry. Caspase-9, -8, and -3 activities were activated and increased in hesperidin-treated HepG2 cells. Bcl-xL protein was downregulated whereas Bax, Bak, and tBid protein levels were upregulated after treatment with hesperidin in a dose-dependent manner. In conclusion, the bioflavanone from Citrus seeds, hesperidin, induced human HepG2 cell apoptosis via mitochondrial pathway and death receptor pathway. Citrus seed flavonoids are beneficial and can be developed as anticancer drug or food supplement, which still needs further in vivo investigation in animals and human beings.

  19. Salt stress-induced production of reactive oxygen- and nitrogen species and cell death in the ethylene receptor mutant Never ripe and wild type tomato roots.

    Science.gov (United States)

    Poór, Péter; Kovács, Judit; Borbély, Péter; Takács, Zoltán; Szepesi, Ágnes; Tari, Irma

    2015-12-01

    The salt stress triggered by sublethal, 100 mM and lethal, 250 mM NaCl induced ethylene production as well as rapid accumulation of superoxide radical and H2O2 in the root tips of tomato (Solanum lycopersicum cv. Ailsa Craig) wild type and ethylene receptor mutant, Never ripe (Nr/Nr) plants. In the wild type plants superoxide accumulation confined to lethal salt concentration while H2O2 accumulated more efficiently under sublethal salt stress. However, in Nr roots the superoxide production was higher and unexpectedly, H2O2 level was lower than in the wild type under sublethal salt stress. Nitric oxide production increased significantly under sublethal and lethal salt stress in both genotypes especially in mutant plants, while peroxynitrite accumulated significantly under lethal salt stress. Thus, the nitro-oxidative stress may be stronger in Nr roots, which leads to the programmed death of tissues, characterized by the DNA and protein degradation and loss of cell viability under moderate salt stress. In Nr mutants the cell death was induced in the absence of ethylene perception. Although wild type roots could maintain their potassium content under moderate salt stress, K(+) level significantly declined leading to small K(+)/Na(+) ratio in Nr roots. Thus Nr mutants were more sensitive to salt stress than the wild type and the viability of root cells decreased significantly under moderate salt stress. These changes can be attributed to a stronger ionic stress due to the K(+) loss from the root tissues.

  20. 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

  1. Expression of Peroxisome Proferator-Activated Receptor γ (PPARγ in Human Transitional Bladder Cancer and its Role in Inducing Cell Death

    Directory of Open Access Journals (Sweden)

    You-Fei Guan

    1999-10-01

    Full Text Available The present study examined the expression and role of the thiazolidinedione (TZD-activated transcription factor, peroxisome proliferator-activated receptor γ (PPARγ, in human bladder cancers. In situ hybridization shows that PPARγ mRNA is highly expressed in all human transitional epithelial cell cancers (TCCa's studied (n=11. PPARγ was also expressed in five TCCa cell lines as determined by RNase protection assays and immunoblot. Retinoid X receptor α (RXRα, a 9-cis-retinoic acid stimulated (9-cis-RA heterodimeric partner of PPARγ, was also co-expressed in all TCCa tissues and cell lines. Treatment of the T24 bladder cancer cells with the TZD PPARγ agonist troglitazone, dramatically inhibited 3H-thymidine incorporation and induced cell death. Addition of the RXRα ligands, 9-cis-RA or LG100268, sensitized T24 bladder cancer cells to the lethal effect of troglitazone and two other PPARγ activators, ciglitazone and 15-deoxy-Δ12,14-PGJ2 (15dPGJ2. Troglitazone treatment increased expression of two cyclin-dependent kinase inhibitors, p21wAF1/CIP1 and p16INK4, reduced cyclin D1 expression, consistent with G1 arrest. Troglitazone also induced an endogenous PPARγ target gene in T24 cells, adipocyte-type fatty acid binding protein (A-FABP, the expression of which correlates with bladder cancer differentiation. In situ hybridization shows that A-FABP expression is localized to normal uroepithelial cells as well as some TCCa's. Taken together, these results demonstrate that PPARγ is expressed in human TCCa where it may play a role in regulating TCCa differentiation and survival, thereby providing a potential target for therapy of uroepithelial cancers.

  2. Adaptive responses induced by 24S-hydroxycholesterol through liver X receptor pathway reduce 7-ketocholesterol-caused neuronal cell death.

    Science.gov (United States)

    Okabe, Akishi; Urano, Yasuomi; Itoh, Sayoko; Suda, Naoto; Kotani, Rina; Nishimura, Yuki; Saito, Yoshiro; Noguchi, Noriko

    2013-01-01

    Lipid peroxidation products have been known to induce cellular adaptive responses and enhance tolerance against subsequent oxidative stress through up-regulation of antioxidant compounds and enzymes. 24S-hydroxycholesterol (24SOHC) which is endogenously produced oxysterol in the brain plays an important role in maintaining brain cholesterol homeostasis. In this study, we evaluated adaptive responses induced by brain-specific oxysterol 24SOHC in human neuroblastoma SH-SY5Y cells. Cells treated with 24SOHC at sub-lethal concentrations showed significant reduction in cell death induced by subsequent treatment with 7-ketocholesterol (7KC) in both undifferentiated and retinoic acid-differentiated SH-SY5Y cells. These adaptive responses were also induced by other oxysterols such as 25-hydroxycholesterol and 27-hydroxycholesterol which are known to be ligands of liver X receptor (LXR). Co-treatment of 24SOHC with 9-cis retinoic acid, a retinoid X receptor ligand, enhanced the adaptive responses. Knockdown of LXRβ by siRNA diminished the adaptive responses induced by 24SOHC almost completely. The treatment with 24SOHC induced the expression of LXR target genes, such as ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1). The 24SOHC-induced adaptive responses were significantly attenuated by siRNA for ABCG1 but not by siRNA for ABCA1. Taken together, these results strongly suggest that 24SOHC at sub-lethal concentrations induces adaptive responses via transcriptional activation of LXR signaling pathway, thereby protecting neuronal cells from subsequent 7KC-induced cytotoxicity.

  3. Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in human transitional bladder cancer and its role in inducing cell death.

    Science.gov (United States)

    Guan, Y F; Zhang, Y H; Breyer, R M; Davis, L; Breyer, M D

    1999-10-01

    The present study examined the expression and role of the thiazolidinedione (TZD)-activated transcription factor, peroxisome proliferator-activated receptor gamma (PPARgamma), in human bladder cancers. In situ hybridization shows that PPARgamma mRNA is highly expressed in all human transitional epithelial cell cancers (TCCa's) studied (n=11). PPARgamma was also expressed in five TCCa cell lines as determined by RNase protection assays and immunoblot. Retinoid X receptor alpha (RXRalpha), a 9-cis-retinoic acid stimulated (9-cis-RA) heterodimeric partner of PPARgamma, was also co-expressed in all TCCa tissues and cell lines. Treatment of the T24 bladder cancer cells with the TZD PPARgamma agonist troglitazone, dramatically inhibited 3H-thymidine incorporation and induced cell death. Addition of the RXRalpha ligands, 9-cis-RA or LG100268, sensitized T24 bladder cancer cells to the lethal effect of troglitazone and two other PPAR- activators, ciglitazone and 15-deoxy-delta(12,14)-PGJ2 (15dPGJ(2)). Troglitazone treatment increased expression of two cyclin-dependent kinase inhibitors, p21(WAF1/CIP1) and p16(INK4), and reduced cyclin D1 expression, consistent with G1 arrest. Troglitazone also induced an endogenous PPARgamma target gene in T24 cells, adipocyte-type fatty acid binding protein (A-FABP), the expression of which correlates with bladder cancer differentiation. In situ hybridization shows that A-FABP expression is localized to normal uroepithelial cells as well as some TCCa's. Taken together, these results demonstrate that PPARgamma is expressed in human TCCa where it may play a role in regulating TCCa differentiation and survival, thereby providing a potential target for therapy of uroepithelial cancers.

  4. An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins.

    Science.gov (United States)

    Subramaniam, Aruljothi; Loo, Ser Yue; Rajendran, Peramaiyan; Manu, Kanjoormana A; Perumal, Ekambaram; Li, Feng; Shanmugam, Muthu K; Siveen, Kodappully Sivaraman; Park, Joo-In; Ahn, Kwang Seok; Hui, Kam M; Kumar, Alan P; Sethi, Gautam

    2013-10-01

    Recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is currently under clinical trials for cancer, however many tumor cells, including hepatocellular carcinoma (HCC) develop resistance to TRAIL-induced apoptosis. Hence, novel agents that can alleviate TRAIL-induced resistance are urgently needed. In the present report, we investigated the potential of emodin to enhance apoptosis induced by TRAIL in HCC cells. As observed by MTT cytotoxicity assay and the externalization of the membrane phospholipid phosphatidylserine, we found that emodin can significantly potentiate TRAIL-induced apoptosis in HCC cells. When investigated for the mechanism(s), we observed that emodin can downregulate the expression of various cell survival proteins, and induce the cell surface expression of both TRAIL receptors, death receptors (DR) 4 as well as 5. In addition, emodin increased the expression of C/EBP homologous protein (CHOP) in a time-dependent manner. Knockdown of CHOP by siRNA decreased the induction of emodin-induced DR5 expression and apoptosis. Emodin-induced induction of DR5 was mediated through the generation of reactive oxygen species (ROS), as N-acetylcysteine blocked the induction of DR5 and the induction of apoptosis. Also, the knockdown of X-linked inhibitor of apoptosis protein by siRNA significantly reduced the sensitization effect of emodin on TRAIL-induced apoptosis. Overall, our experimental results clearly indicate that emodin can indeed potentiate TRAIL-induced apoptosis through the downregulation of antiapoptotic proteins, increased expression of apoptotic proteins, and ROS mediated upregulation of DR in HCC cells.

  5. Perfectionism and life aspirations in intrinsically and extrinsically religious individuals.

    Science.gov (United States)

    Steffen, Patrick R

    2014-08-01

    Religiosity is related to positive health and life satisfaction but the pathways through which this occurs have not been clearly delineated. The purpose of this study was to examine potential mediators of the relationships between intrinsic and extrinsic religiosity and negative affect and life satisfaction. Perfectionism and life aspirations are two possible pathways through which religious orientation is related to outcome. It was hypothesized that adaptive perfectionism and intrinsic life aspirations would act as mediators between intrinsic religiosity and negative affect and life satisfaction, and that maladaptive perfectionism and extrinsic life aspirations would act as mediators between the extrinsic religiosity and negative affect and life satisfaction. Two consecutive samples of religious college students (N = 540 and N = 485) completed measures of the Age Universal Religious Orientation Index, the Frost Multi-Dimensional Perfectionism Scale, the Aspiration Index, the Beck Depression Inventory-II, the Spielberger State-Trait Anxiety Inventory, and the Satisfaction with Life Scale. Intrinsic religiosity had a direct negative relationship with negative affect and positive relationship with life satisfaction. Contrary to the hypotheses, intrinsic religiosity had its strongest indirect effect via maladaptive perfectionism such that increased intrinsic religiosity was related to decreased maladaptive perfectionism which in turn lead to better negative affect and life satisfaction. Extrinsic religiosity was related to increased maladaptive perfectionism and thereby indirectly contributed to worse negative affect and life satisfaction. Interestingly, when the effects of maladaptive perfectionism were controlled, the direct effects of extrinsic religiosity were related to reduced negative affect and increased life satisfaction. Overall, the strongest mediator in this study of both intrinsic and extrinsic religiosity was maladaptive perfectionism, with intrinsic

  6. INTRINSIC AND EXTRINSIC MOTIVATION - AN INVESTIGATION OF PERFORMANCE CORRELATION

    Directory of Open Access Journals (Sweden)

    Abrudan Maria-Madela

    2011-07-01

    Full Text Available A series of research untaken in the last decade have revealed some interesting aspects regarding the effects of different types of motivation on performance. Among the researchers who have shown interest in this field we can number: Richard Ryan, Edward Deci, Sam Glucksberg, Dan Ariely, Robert Eisenhower, Linda Shanock, analysts from London School of Economics, and others. Their findings suggest that extrinsic incentives may have a negative impact on overall performance, but a general agreement in this respect has not been reached. In this paper we intend to shed some light upon the relationship between intrinsic and extrinsic motivation and performance. Experts define intrinsic motivation as being the execution of a task or activity because of the inherent satisfaction arising from it rather than due to some separate outcome. In contrast with intrinsic motivation, we speak of extrinsic motivation whenever an activity is done in order to attain some separable outcome. With the purpose of contributing to the clarification of the links between concepts, we initiated and conducted an explanatory research. The research is based on the analysis of the relations between the results obtained by third year students and their predominant type of motivation. For this, we formulated and tested four work hypotheses using a combination of quantitative methods (investigation and qualitative methods (focus group. After the validation of the questionnaires, the respondents were divided into four categories: intrinsically motivated, extrinsically motivated, both intrinsically and extrinsically motivated and unmotivated. To analyze the collected data, we made use of Excel and SPSS. Some of the primary conclusions of the research are as follows: as the average increases, the percent of individuals having both extrinsic and intrinsic motivation is decreasing; the highest percentage of unmotivated students is concentrated in the highest average category; Female

  7. 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.

  8. Insights into the mechanism of cell death induced by saporin delivered into cancer cells by an antibody fusion protein targeting the transferrin receptor 1

    Science.gov (United States)

    Daniels-Wells, Tracy R.; Helguera, Gustavo; Rodríguez, José A.; Leoh, Lai Sum; Erb, Michael A.; Diamante, Graciel; Casero, David; Pellegrini, Matteo; Martínez-Maza, Otoniel; Penichet, Manuel L.

    2012-01-01

    We previously developed an antibody-avidin fusion protein (ch128.1Av) that targets the human transferrin receptor 1 (TfR1) and exhibits direct cytotoxicity against malignant B cells in an iron-dependent manner. ch128.1Av is also a delivery system and its conjugation with biotinylated saporin (b-SO6), a plant ribosome-inactivating toxin, results in a dramatic iron-independent cytotoxicity, both in malignant cells that are sensitive or resistant to ch128.1Av alone, in which the toxin effectively inhibits protein synthesis and triggers caspase activation. We have now found that the ch128.1Av/b-SO6 complex induces a transcriptional response consistent with oxidative stress and DNA damage, a response that is not observed with ch128.1Av alone. Furthermore, we show that the antioxidant N-acetylcysteine partially blocks saporin-induced apoptosis suggesting that oxidative stress contributes to DNA damage and ultimately saporin-induced cell death. Interestingly, the toxin was detected in nuclear extracts by immunoblotting, suggesting the possibility that saporin might induce direct DNA damage. However, confocal microscopy did not show a clear and consistent pattern of intranuclear localization. Finally, using the long-term culture-initiating cell assay we found that ch128.1Av/b-SO6 is not toxic to normal human hematopoietic stem cells suggesting that this critical cell population would be preserved in therapeutic interventions using this immunotoxin. PMID:23085102

  9. Insights into the mechanism of cell death induced by saporin delivered into cancer cells by an antibody fusion protein targeting the transferrin receptor 1.

    Science.gov (United States)

    Daniels-Wells, Tracy R; Helguera, Gustavo; Rodríguez, José A; Leoh, Lai Sum; Erb, Michael A; Diamante, Graciel; Casero, David; Pellegrini, Matteo; Martínez-Maza, Otoniel; Penichet, Manuel L

    2013-02-01

    We previously developed an antibody-avidin fusion protein (ch128.1Av) that targets the human transferrin receptor 1 (TfR1) and exhibits direct cytotoxicity against malignant B cells in an iron-dependent manner. ch128.1Av is also a delivery system and its conjugation with biotinylated saporin (b-SO6), a plant ribosome-inactivating toxin, results in a dramatic iron-independent cytotoxicity, both in malignant cells that are sensitive or resistant to ch128.1Av alone, in which the toxin effectively inhibits protein synthesis and triggers caspase activation. We have now found that the ch128.1Av/b-SO6 complex induces a transcriptional response consistent with oxidative stress and DNA damage, a response that is not observed with ch128.1Av alone. Furthermore, we show that the antioxidant N-acetylcysteine partially blocks saporin-induced apoptosis suggesting that oxidative stress contributes to DNA damage and ultimately saporin-induced cell death. Interestingly, the toxin was detected in nuclear extracts by immunoblotting, suggesting the possibility that saporin might induce direct DNA damage. However, confocal microscopy did not show a clear and consistent pattern of intranuclear localization. Finally, using the long-term culture-initiating cell assay we found that ch128.1Av/b-SO6 is not toxic to normal human hematopoietic stem cells suggesting that this critical cell population would be preserved in therapeutic interventions using this immunotoxin.

  10. Effect of β-phenylethyl isothiocyanate from cruciferous vegetables on growth inhibition and apoptosis of cervical cancer cells through the induction of death receptors 4 and 5.

    Science.gov (United States)

    Huong, Le Diem; Shim, Jung-Hyung; Choi, Kyeong-Hee; Shin, Ji-Ae; Choi, Eun-Sun; Kim, Hyung-Seop; Lee, Sook-Jeong; Kim, Sun-Ju; Cho, Nam-Pyo; Cho, Sung-Dae

    2011-08-10

    Cruciferous vegetables have been shown to have the possibility to protect against multistep carcinogenesis. β-Phenylethyl isothiocyanate (PEITC) is one component of these vegetables demonstrated to help fight many types of cancer. The present study examined the apoptotic effects of PEITC and its molecular mechanism in human cervical cancer cell lines (HEp-2 and KB). PEITC induced apoptosis to inhibit cell proliferation. According to the protein chip assay, PEITC increased the expression of the death receptors (DR4 and DR5) and cleaved caspase-3 compared to the DMSO treatment group. PEITC also induced caspase-8 and truncated BID. PEITC down-regulated the phosphorylation of extracellular-related kinase (ERK)1/2, whereas neither phospho-c-Jun NH(2)-terminal kinases (JNK) nor phospho-p38 MAPK was changed. The role of ERK in PEITC-induced apoptosis was also investigated using MEK inhibitor (PD98059). PD98059 increased the expression of DR4 and DR5, activated caspase-3, and cleaved PARP. In addition, PEITC decreased the phosphorylation of MEK. Therefore, the apoptotic mechanism of PEITC in cervical cancer cells involves the induction of DR4 and DR5 through the inactivation of ERK and MEK.

  11. Death Receptor 3 (TNFRSF25 Increases Mineral Apposition by Osteoblasts and Region Specific New Bone Formation in the Axial Skeleton of Male DBA/1 Mice

    Directory of Open Access Journals (Sweden)

    Fraser L. Collins

    2015-01-01

    Full Text Available Objectives. Genome wide association studies identified TNFSF member TNF-like protein 1A (TL1A, TNFSF15 as a potential modulator of ankylosing spondylitis (AS. TL1A is the only confirmed TNFSF ligand of death receptor 3 (DR3, TNFRSF25; however, its role in disease pathology is not characterised. We evaluated DR3’s role in controlling osteoblast- (OB- dependent bone formation in vitro and in vivo. Methods. Osteoprogenitor cells and OB were cultured from male DR3-deficient (DR3ko and wild-type (DR3wt DBA/1 mice. DR3 and RANKL expression were tested by flow cytometry. Alkaline phosphatase and mineralization were quantified. Osteopontin, osteoprotegerin, and pro MMP-9 were measured by ELISA. A fluorescent probe (BoneTag was used to measure in vivo mineralization in 10-month-old mice. Results. DR3 was expressed on osteoprogenitors and OB from DR3wt mice. Alkaline phosphatase, osteopontin, and mineral apposition were significantly elevated in DR3wt cultures. Levels of RANKL were comparable whilst osteoprotegerin was significantly increased in DR3wt cultures. In vivo incorporation of BoneTag was significantly lower in the thoracic vertebrae of 10-month-old DR3ko mice. Conclusions. These data identify new roles for DR3 in regulating OB-dependent bone mineral apposition. They potentially begin to explain the atypical pattern of new bone formation observed in the axial skeleton of grouped, aging DBA/1 mice.

  12. Crosstalk between complement and Toll-like receptor activation in relation to donor brain death and renal ischemia-reperfusion injury.

    Science.gov (United States)

    Damman, Jeffrey; Daha, Mohamed R; van Son, Willem J; Leuvenink, Henri G; Ploeg, Rutger J; Seelen, Marc A

    2011-04-01

    Two central pathways of innate immunity, complement and Toll-like receptors (TLRs), play an important role in the pathogenesis of renal injury inherent to kidney transplantation. Recent findings indicate close crosstalk between complement and TLR signaling pathways. It is suggested that mitogen activated protein kinases (MAPKs) might be the key molecules linking both the complement and TLR pathways together. Complement and TLRs are important mediators of renal ischemia-reperfusion injury (IRI). Besides IRI, complement C3 can also be upregulated and activated in the kidney before transplantation as a direct result of brain death (BD) in the donor. This local upregulation and activation of complement in the donor kidney has been proven to be detrimental for renal allograft outcome. Also TLR4 and several of its major ligands are upregulated by donor BD compared to living donors. Important and in line with the observations above, kidney transplant recipients have a benefit when receiving a kidney from a TLR4 Asp299Gly/Thr399Ile genotypic donor. The role of complement and TLRs and crosstalk between these two innate immune systems in relation to renal injury during donor BD and ischemia-reperfusion are focus of this review. Future strategies to target complement and TLR activation in kidney transplantation are considered.

  13. Combination of treatment with death receptor 5-specific antibody with therapeutic HPV DNA vaccination generates enhanced therapeutic anti-tumor effects.

    Science.gov (United States)

    Tseng, Chih Wen; Monie, Archana; Trimble, Cornelia; Alvarez, Ronald D; Huh, Warner K; Buchsbaum, Donald J; Straughn, J Michael; Wang, Mei-Cheng; Yagita, Hideo; Hung, Chien-Fu; Wu, T-C

    2008-08-12

    There is currently a vital need for the development of novel therapeutic strategies for the control of advanced stage cancers. Antigen-specific immunotherapy and the employment of antibodies against the death receptor 5 (DR5) have emerged as two potentially promising strategies for cancer treatment. In the current study, we hypothesize that the combination of treatment with the anti-DR5 monoclonal antibody, MD5-1 with a DNA vaccine encoding calreticulin (CRT) linked to human papillomavirus type 16 (HPV-16) E7 antigen (CRT/E7(detox)) administered via gene gun would lead to further enhancement of E7-specific immune responses as well as anti-tumor effects. Our results indicated that mice bearing the E7-expressing tumor, TC-1 treated with MD5-1 monoclonal antibody followed by CRT/E7(detox) DNA vaccination generated the most potent therapeutic anti-tumor effects as well as highest levels of E7-specific CD8+ T cells among all the groups tested. In addition, treatment with MD5-1 monoclonal antibody was capable of rendering the TC-1 tumor cells more susceptible to lysis by E7-specific cytotoxic T lymphocytes. Our findings serve as an important foundation for future clinical translation.

  14. Extrinsic versus intrinsic hand muscle dominance in finger flexion.

    Science.gov (United States)

    Al-Sukaini, A; Singh, H P; Dias, J J

    2016-05-01

    This study aims to identify the patterns of dominance of extrinsic or intrinsic muscles in finger flexion during initiation of finger curl and mid-finger flexion. We recorded 82 hands of healthy individuals (18-74 years) while flexing their fingers and tracked the finger joint angles of the little finger using video motion tracking. A total of 57 hands (69.5%) were classified as extrinsic dominant, where the finger flexion was initiated and maintained at proximal interphalangeal and distal interphalangeal joints. A total of 25 (30.5%) were classified as intrinsic dominant, where the finger flexion was initiated and maintained at the metacarpophalangeal joint. The distribution of age, sex, dominance, handedness and body mass index was similar in the two groups. This knowledge may allow clinicians to develop more efficient rehabilitation regimes, since intrinsic dominant individuals would not initiate extrinsic muscle contraction till later in finger flexion, and might therefore be allowed limited early active motion. For extrinsic dominant individuals, by contrast, initial contraction of extrinsic muscles would place increased stress on the tendon repair site if early motion were permitted. © The Author(s) 2016.

  15. The effect of extrinsic noise on cellular decision making

    Science.gov (United States)

    Roberts, Elijah; Assaf, Michael; Luthey-Schulten, Zaida; Goldenfeld, Nigel

    2013-03-01

    Many cellular processes are not deterministic, i.e., genetically identical cells can display different phenotypic behavior even in identical environments. Such processes involve cellular decision making, in which individual cells randomly make choices determining their fate. One view is that the stochastic nature of cellular decision making is due to noise present in the biomolecular interaction networks. Most previous work has focused on the role of intrinsic noise of these networks. Yet, especially in the high copy-number regime, extrinsic noise may be much more significant, likely governing the overall dynamics. Here we develop a theoretical framework describing the combined effect of intrinsic and extrinsic noise on the stochastic dynamics of genetic switches responsible for cellular decision making. We do so by devising a semi-classical theory accounting for extrinsic noise as an effective species. Our theory, corroborated by extensive Monte-Carlo simulations, is tested on a simple bistable self-regulating gene model, and is then generalized to gain insight on the behavior of the lac genetic switch under extrinsic noise. We show that extrinsic noise not only significantly lowers the escape time from a phenotypic state, but can fundamentally change the actual escape process.

  16. The Capsicum annuum class IV chitinase ChitIV interacts with receptor-like cytoplasmic protein kinase PIK1 to accelerate PIK1-triggered cell death and defence responses

    OpenAIRE

    2015-01-01

    The pepper receptor-like cytoplasmic protein kinase, CaPIK1, which mediates signalling of plant cell death and defence responses was previously identified. Here, the identification of a class IV chitinase, CaChitIV, from pepper plants (Capsicum annuum), which interacts with CaPIK1 and promotes CaPIK1-triggered cell death and defence responses, is reported. CaChitIV contains a signal peptide, chitin-binding domain, and glycol hydrolase domain. CaChitIV expression was up-regulated by Xanthomona...

  17. Extrinsic Motivation Index: A New Tool for Managing Labor Productivity

    Directory of Open Access Journals (Sweden)

    Berumen, S.A.

    2016-07-01

    Full Text Available The objective of this paper is to provide a tool of practical significance for HR managers and firm executives. This tool, which is called Extrinsic Motivation Index (EMI, is meant to measure the extrinsic motivation of employees. By measuring employees' extrinsic motivation, managers are able to track job satisfaction and, subsequently, implement measures aiming both to raise job satisfaction and to improve organizational commitment. In order to test the validity of the model, we apply the EMI to Faculty members at Spanish and German universities. We also carry out simulation experiments in order to to address all possible situations an organization most probably will have to deal with. The results point out significant differences in the level of motivation and commitment of Faculty members. Additionally, the analysis shows several ways in which an organization may manage job satisfaction issues according to on its level of resources.

  18. Intrinsic and Extrinsic Spin Hall Effects of Dirac Electrons

    Science.gov (United States)

    Fukazawa, Takaaki; Kohno, Hiroshi; Fujimoto, Junji

    2017-09-01

    We investigate the spin Hall effect (SHE) of electrons described by the Dirac equation, which is used as an effective model near the L-points in bismuth. By considering short-range nonmagnetic impurities, we calculate the extrinsic as well as intrinsic contributions on an equal footing. The vertex corrections are taken into account within the ladder type and the so-called skew-scattering type. The intrinsic SHE which we obtain is consistent with that of Fuseya et al. [https://doi.org/10.1143/JPSJ.81.093704" xlink:type="simple">J. Phys. Soc. Jpn. 81, 093704 (2012)]. It is found that the extrinsic contribution dominates the intrinsic one when the system is metallic. The extrinsic SHE due to the skew scattering is proportional to Δ/niu, where 2Δ is the band gap, ni is the impurity concentration, and u is the strength of the impurity potential.

  19. Intrinsic and extrinsic motivation for stereotypic and repetitive behavior.

    Science.gov (United States)

    Joosten, Annette V; Bundy, Anita C; Einfeld, Stewart L

    2009-03-01

    This study provides evidence for intrinsic and extrinsic motivators for stereotypical and repetitive behavior in children with autism and intellectual disability and children with intellectual disability alone. We modified the Motivation Assessment Scale (MAS) (1988b); dividing it into intrinsic and extrinsic measures and adding items to assess anxiety as an intrinsic motivator. Rasch analysis of data from 279 MASs (74 children) revealed that the items formed two unidimensional scales. Anxiety was a more likely intrinsic motivator than sensory seeking for children with dual diagnoses; the reverse was true for children with intellectual disability only. Escape and gaining a tangible object were the most common extrinsic motivators for those with dual diagnoses and attention and escape for children with intellectual disability.

  20. On Death

    Institute of Scientific and Technical Information of China (English)

    Zhangyan

    2016-01-01

    Death is not a terrible word, but a provoking one. Different people have different opinions, but no one can convince others of what death really means. This article made a tentative and superficial analysis on death according to the true feeing and experiences of the author. In her opinion, we needn’t consider more about death; the important for the death is how to live meaningfully.

  1. Mortality trends in asbestosis, extrinsic allergic alveolitis and sarcoidosis in England and Wales.

    Science.gov (United States)

    Hanley, A; Hubbard, R B; Navaratnam, V

    2011-09-01

    To ascertain the trends in mortality from Asbestosis, Extrinsic Allergic Alveolitis (EAA) and Sarcoidosis in England and Wales, we analysed mortality data from the Office of National Statistics. We calculated age and stratum specific mortality rates between 1968 and 2008 and applied these to the 2008 population to generate annual standardised expected number of deaths. Poisson regression was used to calculate annual mortality rate ratios. From 1968 to 2008 there were 1958 registered deaths from Asbestosis, 878 deaths from EAA and 3544 deaths from Sarcoidosis. The Asbestosis mortality rate increased from 0.04 (95% CI 0.03-0.05) in the 1968-1972 calendar period to 0.12 (95% CI 0.10-0.13) in the 2005-2008 period whist the mortality from EAA increased marginally from 0.04 (95% CI 0.03-0.05) in the 1968-1972 calendar period to 0.08 (95% CI 0.07-0.09) in the 2005-2008 period. Mortality from Sarcoidosis increased by approximately 9% a year. Our findings show that the mortality from Asbestosis continues to rise in the UK. Overall mortality rates from EAA remained stable throughout the same period but it was higher in males and in older people. There was a slight increase in mortality from Sarcoidosis over the study period which was greater in women. Copyright © 2011 Elsevier Ltd. All rights reserved.

  2. Extrinsic allergic alveolitis with an atypical immune expression.

    Science.gov (United States)

    Costa, Teresa; Rodrigues, Cidália; Arrobas, Ana

    2009-01-01

    Extrinsic allergic alveolitis and sarcoidosis are two granulomatosis of the lung characterized by non- -necrotizing granuloma. Both have typical bronchoalveolar lavage immunology, with opposite CD4/CD8 relation. However, sarcoidosis does not have such well defined etiology as extrinsic allergic alveolitis. The authors present two cases with similar clinical course, imagiology, lung function and immunology, although they both had an histology that was not concordant with the bronchoalveolar lavage, and with the peculiarity of being two elements of the same family, co -inhabitants and with a clinical presentation only a few weeks apart.

  3. CONSUMER EVALUATIONS OF BEAUTIFICATION PRODUCTS: EFFECTS OF EXTRINSIC CUES

    Directory of Open Access Journals (Sweden)

    Md. Humayun Kabir Chowdhury

    2006-01-01

    Full Text Available This study investigates the influence of extrinsic cues, i.e. brand image, perceived price, perceived quality, and perceived country of origin on consumers' evaluative judgments for beautification products. Multi-item measures were used for data collection. Resultsrevealed that three extrinsic cues: brand image, perceived quality, and perceived country of origin have positive and significant influence on consumers' brand evaluation of beautification brands. Only perceived price has shown no such influence on consumers' brand evaluation. Finally, unanswered questions and future researchdirections are presented.

  4. Intrinsic and extrinsic motivation and intention to breast-feed.

    Science.gov (United States)

    Wells, Kristen J; Thompson, Nancy J; Kloeblen-Tarver, Amy S

    2002-01-01

    To examine the feasibility of using the cognitive evaluation theory to examine pregnant women's intention to breast-feed. A questionnaire designed to measure intrinsic and extrinsic motivation was administered to 228 pregnant women. Results provide evidence for reliability and validity of the revised instrument in this population. A factor analysis suggests the instrument measures 2 types of intrinsic motivation, one type of extrinsic motivation, and motivation related to the baby. The instrument distinguished differences in motivation between women who intend to breast-feed and those who intend to formula feed. This study helps elucidate motivational factors involved in infant-feeding decisions.

  5. 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.

  6. Mechanisms of drug sensitization to TRA-8, an agonistic death receptor 5 antibody, involve modulation of the intrinsic apoptotic pathway in human breast cancer cells.

    Science.gov (United States)

    Amm, Hope M; Zhou, Tong; Steg, Adam D; Kuo, Huichien; Li, Yufeng; Buchsbaum, Donald J

    2011-04-01

    TRA-8, a monoclonal antibody to death receptor 5 induces apoptosis in various cancer cells; however, the degree of sensitivity varies from highly sensitive to resistant. We have previously shown that resistance to TRA-8 can be reversed by using chemotherapeutic agents, but the mechanism underlying this sensitization was not fully understood. Here, we examined the combination of TRA-8 with doxorubicin or bortezomib in breast cancer cells. In TRA-8-resistant BT-474 and T47D cells, both chemotherapy agents synergistically sensitized cells to TRA-8 cytotoxicity with enhanced activation of apoptosis shown by cleavage of caspases and PARP, reduced Bid, increased proapoptotic Bcl-2 proteins, and increased mitochondrial membrane depolarization. Doxorubicin or bortezomib combined with TRA-8 also reduced Bcl-XL and X-linked inhibitors of apoptosis (XIAP) in treated cells. Furthermore, targeting these proteins with pharmacologic modulators, AT-101, BH3I-2' and AT-406, produced sensitization to TRA-8. TRA-8 combined with AT-101 or BH3I-2', inhibitors of antiapoptotic Bcl-2 proteins, produced synergistic cytotoxicity against ZR-75-1, BT-474, and T47D cells. The IAP-targeting compound, AT-406, was synergistic with TRA-8 in BT-474 cells, and to a lesser extent T47D cells. Activation of the intrinsic apoptotic pathway was a common mechanism associated with sensitization of TRA-8-resistant breast cancer cell lines. Collectively, these studies show that the Bcl-2 and IAP families of proteins are involved in TRA-8 and chemotherapy resistance via their modulation of the intrinsic apoptotic pathway. Targeting these proteins with novel agents sensitized TRA-8-resistant breast cancer cells, suggesting this approach may represent a potent therapeutic strategy in the treatment of breast cancer. ©2011 AACR.

  7. Anti-tumor activity of TRA-8 anti-death receptor 5 (DR5) monoclonal antibody in combination with chemotherapy and radiation therapy in a cervical cancer model.

    Science.gov (United States)

    Straughn, J Michael; Oliver, Patsy G; Zhou, Tong; Wang, Wenquan; Alvarez, Ronald D; Grizzle, William E; Buchsbaum, Donald J

    2006-04-01

    There is substantial evidence that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) causes apoptosis via activation of death receptors 4 and 5 (DR4 and DR5). We sought to determine the therapeutic potential of TRA-8 (anti-DR5 monoclonal antibody) in combination with chemotherapy and radiation therapy in a cervical cancer model. DR5 expression in 7 human cervical cancer cell lines was analyzed by indirect immunofluorescence using murine TRA-8 in combination with flow cytometry. Cell lines were treated with TRA-8 alone or in combination with cisplatin, topotecan, or radiation, and cytotoxicity assays were performed. Mice were inoculated with ME-180 cancer cells and treated with different combinations of therapy. Animals receiving antibody were injected intraperitoneally with 200 microg of TRA-8. Animals received 9 Gy 60Co radiation divided into 3 fractions and 3 intraperitoneal doses of cisplatin (6 mg/kg) 1 h before radiation. A similar experiment was performed using topotecan (2 mg/kg) as the chemotherapeutic agent. DR5 was expressed to a varying degree on the cervical cancer cell lines. Combination treatment with TRA-8 and chemotherapy or radiation resulted in synergistic cytotoxicity in vitro. In vivo, combination therapy with TRA-8, cisplatin, and radiation produced tumor growth inhibition that was significantly greater than the other groups. Similar results were seen in combination studies with topotecan. These data suggest that DR5 is a good target for activation of the apoptotic pathway. Monoclonal antibodies such as TRA-8 may play an important role in the development of an effective treatment strategy for patients with advanced cervical cancer.

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

    Science.gov (United States)

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

    2016-01-01

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

  9. Influence of air pollution on extrinsic childhood asthma

    Energy Technology Data Exchange (ETDEWEB)

    Berciano, F.A.; Dominguez, J.; Alvarez, F.V.

    1989-02-01

    A crossed comparative study was done with 248 extrinsic asthmatic children living either in polluted or non-polluted areas (mean emission per year of sedimentary material greater than or less than 300 mg/m2/day, respectively) to establish the influence of air pollution on childhood extrinsic asthma. The mean number of wheezing crises per year was significantly higher for the children living in polluted areas (10.4 versus 7.69). In addition, incidence of severe asthma (types II, III, and IV) in children living in polluted areas was markedly increased whereas the slight form of asthma (type I) was more frequent in children living in non-polluted areas. No correlation, however, between the wheezing episodes and levels of atmospheric contaminants (fumes and SO/sub 2/) was detected when a group of 84 extrinsic asthmatic children living in polluted areas was studied longitudinally for a year. The data indicate that air pollution, as an isolated agent, plays a transient role in the appearance of wheezing episodes in subjects with extrinsic asthma. Results also suggest that the air pollution may potentiate wheezing episodes via alternative mechanisms.

  10. On the isoperimetric rigidity of extrinsic minimal balls

    DEFF Research Database (Denmark)

    Markvorsen, Steen; Palmer, V.

    2003-01-01

    We consider an m-dimensional minimal submanifold P and a metric R-sphere in the Euclidean space R-n. If the sphere has its center p on P, then it will cut out a well defined connected component of P which contains this center point. We call this connected component an extrinsic minimal R-ball of ...

  11. The role of time scales in extrinsic noise propagation

    Science.gov (United States)

    Iyer-Biswas, Srividya; Pedraza, Juan Manuel; Jayaprakash, C.

    2009-03-01

    Cell-to cell variability in the number of proteins has been studied extensively experimentally. There are many sources of this stochastic variability or noise that can be classified as intrinsic, due to the stochasticity of chemical reactions and extrinsic, due to environmental differences. The different stages in the production of proteins in response to a stimulus, the signaling cascade before transcription, transcription, and translation are characterized by different time scales. We analyze how these time scales determine the effect of the reactions at each stage on different sources of noise. For example, even if intrinsic noise dominates the fluctuations in mRNA number, for typical degradation rates, extrinsic noise can dominate corresponding protein number fluctuations. Such results are important in determining the importance of intrinsic noise at earlier stages of a genetic network on the products of subsequent stages. We examine cases in which the dynamics of the extrinsic noise can lead to differences from cases in which extrinsic noise arises from static (in time) cell-to-cell variations. We will interpret the experiments of Pedraza et al*. in the light of these results. *J. M. Pedraza et al, Science 25 March 2005:Vol. 307. no. 5717, pp. 1965 - 1969.

  12. Intrinsic and extrinsic contributions to stochasticity in gene expression

    Science.gov (United States)

    Swain, Peter S.; Elowitz, Michael B.; Siggia, Eric D.

    2002-10-01

    Gene expression is a stochastic, or "noisy," process. This noise comes about in two ways. The inherent stochasticity of biochemical processes such as transcription and translation generates "intrinsic" noise. In addition, fluctuations in the amounts or states of other cellular components lead indirectly to variation in the expression of a particular gene and thus represent "extrinsic" noise. Here, we show how the total variation in the level of expression of a given gene can be decomposed into its intrinsic and extrinsic components. We demonstrate theoretically that simultaneous measurement of two identical genes per cell enables discrimination of these two types of noise. Analytic expressions for intrinsic noise are given for a model that involves all the major steps in transcription and translation. These expressions give the sensitivity to various parameters, quantify the deviation from Poisson statistics, and provide a way of fitting experiment. Transcription dominates the intrinsic noise when the average number of proteins made per mRNA transcript is greater than 2. Below this number, translational effects also become important. Gene replication and cell division, included in the model, cause protein numbers to tend to a limit cycle. We calculate a general form for the extrinsic noise and illustrate it with the particular case of a single fluctuating extrinsic variablea repressor protein, which acts on the gene of interest. All results are confirmed by stochastic simulation using plausible parameters for Escherichia coli.

  13. A note on optical activity and extrinsic chirality

    CERN Document Server

    Arteaga, Oriol

    2015-01-01

    It has been assumed that optical activity can be measured by illuminating alternatively a material with left- and right- handed circular polarized light and analyzing the differential response. This simple and intuitive approach is in general incorrect, and has led to misleading idea that extrinsic chirality involves optical activity.

  14. VOL 6. NO. 1 2015 EXTRINSIC FACTORS THAT AFFECT ...

    African Journals Online (AJOL)

    Frederick Iraki

    The general objective of this study was to identify the extrinsic factors affect employee ... individual mechanisms that directly affect job performance in an organization(Colquitt, ... Benjamin (2010) posits that fringe benefits are significant and positive ... Mouly (2009) asserts that questionnaires add value to research because.

  15. Extrinsic Reinforcement in the Classroom: Bribery or Best Practice

    Science.gov (United States)

    Akin-Little, K. Angeleque; Eckert, Tanya L.; Lovett, Benjamin J.; Little, Steven G.

    2004-01-01

    The debate over the effects of the use of extrinsic reinforcement in classrooms, businesses, and societal settings has been occurring for over 30 years. Some theorists have cautioned against the use of reward, whereas others have found little, if any, detrimental effect. This article examines the debate with an emphasis on data-based findings. The…

  16. The Effects of Extrinsic Reinforcement on Intrinsic Motivation.

    Science.gov (United States)

    Blocker, Richard A.; Edwards, R. P.

    1982-01-01

    Discusses the role of extrinsic reinforcement in intrinsic motivation in cognitive attribution theory. Concludes that cognitive attribution theory lacks parsimony, in that extant reinforcement analysis can account for undermining with equal facility. Suggests undermining is of little significance due to its elusive and transient impact on operant…

  17. Extrinsic allergic alveolitis after exposure to the yeast Rhodotorula rubra.

    Science.gov (United States)

    Siersted, H C; Gravesen, S

    1993-05-01

    A case of extrinsic allergic alveolitis following exposure to the red yeast Rhodotorula rubra is reported--to our knowledge, for the first time. Extensive growth of the yeast in the patient's environment was demonstrated, explaining an elevated titer of Rhodotorula-specific precipitating antibodies in his serum. A bronchial provocation test confirmed the diagnosis.

  18. Visible Spectrum Circular Dichroism in Extrinsic Chirality Metamaterials

    CERN Document Server

    Lee, Seoungjun; Feng, Cheng; Jiao, Jiao; Khan, Ashfaq; Li, Lin

    2012-01-01

    We present the new planar extrinsic chirality metamaterial (ECM) design that manifests giant circular dichroism (CD) in the visible spectrum range rather than usual near-infrared and terahertz range. Effects of incident beam angles and meta-molecules unit sizes on the CD spectrums were theoretically analyzed; Physical mechanism was illustrated in new figures of asymmetrical current excitation in neighboring unit cells.

  19. The Impact of Extrinsic Demographic Factors on Cantonese Speech Acquisition

    Science.gov (United States)

    To, Carol K. S.; Cheung, Pamela S. P.; McLeod, Sharynne

    2013-01-01

    This study modeled the associations between extrinsic demographic factors and children's speech acquisition in Hong Kong Cantonese. The speech of 937 Cantonese-speaking children aged 2;4 to 6;7 in Hong Kong was assessed using a standardized speech test. Demographic information regarding household income, paternal education, maternal education,…

  20. The Effects of Extrinsic Rewards on Admissions Counselors' Performance

    Science.gov (United States)

    Gardner-Engel, Miriam

    2010-01-01

    This study examines the best ways to motivate college admissions counselors. A review of literature revealed multiple perspectives on intrinsic and extrinsic as well as tangible and intangible rewards. Primary research was designed to examine the impact of tangible rewards and verbal reinforcements with a convenience sample of nine college…

  1. Extrinsic Rewards and Intrinsic Motivation in Education: Reconsidered Once Again.

    Science.gov (United States)

    Deci, Edward L.; Koestner, Richard; Ryan, Richard M.

    2001-01-01

    Reviews the results of a meta analysis (E. Deci, R. Koestner, and R. Ryan, 1999) that shows that tangible extrinsic rewards do have a substantial undermining effect on intrinsic motivation. Discusses results, which support cognitive evaluation theory, in terms of their relevance for educational practice. (SLD)

  2. Extrinsic and Intrinsic Motivation at 30: Unresolved Scientific Issues

    Science.gov (United States)

    Reiss, Steven

    2005-01-01

    The undermining effect of extrinsic reward on intrinsic motivation remains unproven. The key unresolved issues are construct invalidity (all four definitions are unproved and two are illogical); measurement unreliability (the free-choice measure requires unreliable, subjective judgments to infer intrinsic motivation); inadequate experimental…

  3. Extrinsic Rewards and Intrinsic Motivation in Education: Reconsidered Once Again.

    Science.gov (United States)

    Deci, Edward L.; Koestner, Richard; Ryan, Richard M.

    2001-01-01

    Reviews the results of a meta analysis (E. Deci, R. Koestner, and R. Ryan, 1999) that shows that tangible extrinsic rewards do have a substantial undermining effect on intrinsic motivation. Discusses results, which support cognitive evaluation theory, in terms of their relevance for educational practice. (SLD)

  4. Extrinsic and Intrinsic Motivation at 30: Unresolved Scientific Issues

    Science.gov (United States)

    Reiss, Steven

    2005-01-01

    The undermining effect of extrinsic reward on intrinsic motivation remains unproven. The key unresolved issues are construct invalidity (all four definitions are unproved and two are illogical); measurement unreliability (the free-choice measure requires unreliable, subjective judgments to infer intrinsic motivation); inadequate experimental…

  5. Cot Deaths.

    Science.gov (United States)

    Tyrrell, Shelagh

    1985-01-01

    Addresses the tragedy of crib deaths, giving particular attention to causes, prevention, and medical research on Sudden Infant Death Syndrome (SIDS). Gives anecdotal accounts of coping strategies used by parents and families of SIDS infants. (DT)

  6. 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

  7. Distinguishing subtypes of extrinsic motivation among people with mild to borderline intellectual disability

    NARCIS (Netherlands)

    Frielink, N.; Schuengel, C.; Embregts, P.J.C.M.

    Background According to self-determination theory, motivation is ordered in types, including amotivation, extrinsic motivation and intrinsic motivation. Self-determination theory defines four subtypes of extrinsic motivation: external motivation, introjected motivation, identified motivation and

  8. Engagement in Classroom Learning: Creating Temporal Participation Incentives for Extrinsically Motivated Students through Bonus Credits

    Science.gov (United States)

    Rassuli, Ali

    2012-01-01

    Extrinsic inducements to adjust students' learning motivations have evolved within 2 opposing paradigms. Cognitive evaluation theories claim that controlling factors embedded in extrinsic rewards dissipate intrinsic aspirations. Behavioral theorists contend that if engagement is voluntary, extrinsic reinforcements enhance learning without ill…

  9. Engagement in Classroom Learning: Creating Temporal Participation Incentives for Extrinsically Motivated Students through Bonus Credits

    Science.gov (United States)

    Rassuli, Ali

    2012-01-01

    Extrinsic inducements to adjust students' learning motivations have evolved within 2 opposing paradigms. Cognitive evaluation theories claim that controlling factors embedded in extrinsic rewards dissipate intrinsic aspirations. Behavioral theorists contend that if engagement is voluntary, extrinsic reinforcements enhance learning without ill…

  10. Role of the Calcium-Sensing Receptor in Cardiomyocyte Apoptosis via the Sarcoplasmic Reticulum and Mitochondrial Death Pathway in Cardiac Hypertrophy and Heart Failure

    Directory of Open Access Journals (Sweden)

    Fang-Hao Lu

    2013-05-01

    Full Text Available Aims: Alterations in calcium homeostasis in the intracellular endo/sarcoplasmic reticulum (ER/SR and mitochondria of cardiomyocytes cause cell death via the SR and mitochondrial apoptotic pathway, contributing to ventricular dysfunction. However, the role of the calcium-sensing receptor (CaR in cardiac hypertrophy and heart failure has not been studied. This study examined the possible involvement of CaR in the SR and mitochondrial apoptotic pathway in an experimental model of heart failure. Methods and Results: In Wistar rats, cardiac hypertrophy and heart failure were induced by subcutaneous injection of isoproterenol (Iso. Calindol, an activator of CaR, and calhex231, an inhibitor of CaR, were administered by caudal vein injection. Cardiac remodeling and left ventricular function were then analyzed in these rats. After 2, 4, 6 and 8 weeks after the administration of Iso, the rats developed cardiac hypertrophy and failure. The cardiac expression of ER chaperones and related apoptotic proteins was significantly increased in the failing hearts. Furthermore, the expression of ER chaperones and the apoptotic rate were also increased with the administration of calindol, whereas the expression of these proteins was reduced with the treatment of calhex231. We also induced cardiac hypertrophy and failure via thoracic aorta constriction (TAC in mice. After 2 and 4 weeks of TAC, the expression of ER chaperones and apoptotic proteins were increased in the mouse hearts. Furthermore, Iso induced ER stress and apoptosis in cultured cardiomyocytes, while pretreatment with calhex231 prevented ER stress and protected the myocytes against apoptosis. To further investigate the effect of CaR on the concentration of intracellular calcium, the calcium concentration in the SR and mitochondria was determined with Fluo-5N and x-rhod-1 and the mitochondrial membrane potential was examined with JC-1 using laser confocal microscopy. After treatment with Iso for 48 hours

  11. Role of the calcium-sensing receptor in cardiomyocyte apoptosis via the sarcoplasmic reticulum and mitochondrial death pathway in cardiac hypertrophy and heart failure.

    Science.gov (United States)

    Lu, Fang-Hao; Fu, Song-Bin; Leng, Xiaoning; Zhang, Xinying; Dong, Shiyun; Zhao, Ya-Jun; Ren, Huan; Li, Hulun; Zhong, Xin; Xu, Chang-Qing; Zhang, Wei-Hua

    2013-01-01

    Alterations in calcium homeostasis in the intracellular endo/sarcoplasmic reticulum (ER/SR) and mitochondria of cardiomyocytes cause cell death via the SR and mitochondrial apoptotic pathway, contributing to ventricular dysfunction. However, the role of the calcium-sensing receptor (CaR) in cardiac hypertrophy and heart failure has not been studied. This study examined the possible involvement of CaR in the SR and mitochondrial apoptotic pathway in an experimental model of heart failure. In Wistar rats, cardiac hypertrophy and heart failure were induced by subcutaneous injection of isoproterenol (Iso). Calindol, an activator of CaR, and calhex231, an inhibitor of CaR, were administered by caudal vein injection. Cardiac remodeling and left ventricular function were then analyzed in these rats. After 2, 4, 6 and 8 weeks after the administration of Iso, the rats developed cardiac hypertrophy and failure. The cardiac expression of ER chaperones and related apoptotic proteins was significantly increased in the failing hearts. Furthermore, the expression of ER chaperones and the apoptotic rate were also increased with the administration of calindol, whereas the expression of these proteins was reduced with the treatment of calhex231. We also induced cardiac hypertrophy and failure via thoracic aorta constriction (TAC) in mice. After 2 and 4 weeks of TAC, the expression of ER chaperones and apoptotic proteins were increased in the mouse hearts. Furthermore, Iso induced ER stress and apoptosis in cultured cardiomyocytes, while pretreatment with calhex231 prevented ER stress and protected the myocytes against apoptosis. To further investigate the effect of CaR on the concentration of intracellular calcium, the calcium concentration in the SR and mitochondria was determined with Fluo-5N and x-rhod-1 and the mitochondrial membrane potential was examined with JC-1 using laser confocal microscopy. After treatment with Iso for 48 hours, activation of CaR reduced [Ca(2+)]SR

  12. receptores

    Directory of Open Access Journals (Sweden)

    Salete Regina Daronco Benetti

    2006-01-01

    Full Text Available Se trata de un estudio etnográfico, que tuvo lo objetivo de interpretar el sistema de conocimiento y del significado atribuidos a la sangre referente a la transfusión sanguínea por los donadores y receptores de un banco de sangre. Para la colecta de las informaciones se observaron los participantes y la entrevista etnográfica se realizó el análisis de dominio, taxonómicos y temáticos. Los dominios culturales fueron: la sangre es vida: fuente de vida y alimento valioso; creencias religiosas: fuentes simbólicas de apoyos; donación sanguínea: un gesto colaborador que exige cuidarse, gratifica y trae felicidad; donación sanguínea: fuente simbólica de inseguridad; estar enfermo es una condición para realizar transfusión sanguínea; transfusión sanguínea: esperanza de vida; Creencias populares: transfusión sanguínea como riesgo para la salud; donadores de sangre: personas benditas; donar y recibir sangre: como significado de felicidad. Temática: “líquido precioso que origina, sostiene, modifica la vida, provoca miedo e inseguridad”.

  13. Generalized isoperimetric inequalities for extrinsic balls in minimal submanifolds

    DEFF Research Database (Denmark)

    Markvorsen, Steen; Palmer, Vicente

    2002-01-01

    The volume of an extrinsic ball in a minimal submanifold has a well defined lower bound when the ambient manifold has an upper bound on its sectional curvatures, see e.g. [2] and [10]. When this upper bound is non-positive, the second named author has shown an isoperimetric inequality for such do......The volume of an extrinsic ball in a minimal submanifold has a well defined lower bound when the ambient manifold has an upper bound on its sectional curvatures, see e.g. [2] and [10]. When this upper bound is non-positive, the second named author has shown an isoperimetric inequality...... for such domains, see [11]. This result again gives the comparison result for volumes alluded to above together with a characterization of the totally geodesic submanifolds of hyperbolic space forms. In the present paper we find a corresponding sharp isoperimetric inequality for minimal submanifolds in spaces...

  14. [Actualities in extrinsic allergic alveolities or hypersensitivity pneumonitis].

    Science.gov (United States)

    Ndiaye, M; Soumah, M; Sow, M L

    2007-01-01

    Significant advances have been noticed in the pathogenesis and the diagnosis of extrinsic allergic alveolitis during the last few years. Indeed the immune mechanism and the enabling conditions have been more precisely defined, the clinical stages and the diagnosis criterias clearly defined, new antigens incriminated and some etiological agents have been reclassified. The present pathogenic explanation insists on the type IV hypersensitivity reaction with sensitization of T lymphocytes, activation macrophages, the formation of IgG type antibodies and immune complexes, activation of complement and secretion of cytokines. The involvement of certain HLA classes (HLA2, DR3, DRB1, DQB1), interaction of genetics and environments factors, the role of infections agents and smoking have been demonstrated in several studies. The development of news clinical and biological diagnosis criteria have led the discovery of new extrinsic allergic alveolitis in the work places, a better knowledge of the prognostic elements and an appropriate adaptation of prevention measures.

  15. Implications on the cosmic coincidence by a dynamical extrinsic curvature

    CERN Document Server

    Capistrano, A J S

    2015-01-01

    In this work, we apply the smooth deformation concept in order to obtain a modification of Friedmann equations. It is shown that the cosmic coincidence can be at least alleviated using the dynamical properties of the extrinsic curvature. We investigate the transition from nucleosynthesis to the coincidence era obtaining a very small variation of the ratio $r=\\frac{\\rho_{m}}{\\rho_{ext}}$, that compares the matter energy density to extrinsic energy density, compatible with the known behavior of the deceleration parameter. We also show that the calculated "equivalence" redshift matches the transition redshift from a deceleration to accelerated phase and the coincidence ceases to be. The dynamics on $r$ is also studied based on Hubble parameter observations as the latest Baryons Acoustic Oscillations/Cosmic Microwave Background Radiation (BAO/CMBR) + SNIa.

  16. Spotlight on the diagnosis of extrinsic allergic alveolitis (hypersensitivity pneumonitis).

    Science.gov (United States)

    Baur, Xaver; Fischer, Axel; Budnik, Lygia T

    2015-01-01

    Repeated inhalative exposures to antigenic material from a variety of sources, mainly from moulds, thermophilic Actinomycetes, and avians, respectively, can induce immune responses with the clinical picture of extrinsic allergic alveolitis (EAA) or hypersensitivity pneumonitis. Delays of years or even decades till the diagnosis is made are not uncommon; frequent misdiagnoses include allergic asthma, COPD, recurrent flue and other infections. We provide here the state of the art references, a detailed case description and recommend a current diagnostics schema.

  17. Extrinsic allergic alveolitis with IgA deficiency.

    Science.gov (United States)

    Sennekamp, J; Morr, H; Behr, J

    2004-12-22

    Up to now only 3 cases of extrinsic allergic alveolitis (hypersensitivity pneumonitis) with IgA deficiency have been published worldwide. We had the opportunity to detect two additional cases which will be presented here. Summarizing all cases IgA deficiency is a risk factor for a severe course of the disease and an increased susceptibility to acquire allergic alveolitis by low dose antigen exposure.

  18. Mathematical Model of Extrinsic Blood Coagulation Cascade Dynamic System

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    The blood coagulation system is very important to life. This paper presents a mathematical blood coagulation model for the extrinsic pathway. This model simulates clotting factor VIII, which plays an important role in the coagulation mechanism. The mathematical model is used to study the equilibrium stability, orbit structure, attractors and global stability behavior, with conclusions in accordance with the physiological phenomena. Moreover, the results provide information about blood related illnesses, which can be used for further study of the coagulation mechanism.

  19. Interactional Motivation in Artificial Systems: Between Extrinsic and Intrinsic Motivation

    OpenAIRE

    Georgeon, Olivier; Marshall, James; Gay, Simon

    2012-01-01

    International audience; This paper introduces Interactional Motivation (IM) as a way to implement self-motivation in artificial systems. An interactionally motivated agent selects behaviors for the sake of enacting the behavior itself rather than for the value of the behavior’s outcome. IM contrasts with extrinsic motivation by the fact that it defines the agent’s motivation independently from the environment’s state. Because IM does not refer to the environment’s states, we argue that IM is ...

  20. Integrating extrinsic and intrinsic cues into a minimal model of lineage commitment for hematopoietic progenitors.

    Directory of Open Access Journals (Sweden)

    Santhosh Palani

    2009-09-01

    Full Text Available Autoregulation of transcription factors and cross-antagonism between lineage-specific transcription factors are a recurrent theme in cell differentiation. An equally prevalent event that is frequently overlooked in lineage commitment models is the upregulation of lineage-specific receptors, often through lineage-specific transcription factors. Here, we use a minimal model that combines cell-extrinsic and cell-intrinsic elements of regulation in order to understand how both instructive and stochastic events can inform cell commitment decisions in hematopoiesis. Our results suggest that cytokine-mediated positive receptor feedback can induce a "switch-like" response to external stimuli during multilineage differentiation by providing robustness to both bipotent and committed states while protecting progenitors from noise-induced differentiation or decommitment. Our model provides support to both the instructive and stochastic theories of commitment: cell fates are ultimately driven by lineage-specific transcription factors, but cytokine signaling can strongly bias lineage commitment by regulating these inherently noisy cell-fate decisions with complex, pertinent behaviors such as ligand-mediated ultrasensitivity and robust multistability. The simulations further suggest that the kinetics of differentiation to a mature cell state can depend on the starting progenitor state as well as on the route of commitment that is chosen. Lastly, our model shows good agreement with lineage-specific receptor expression kinetics from microarray experiments and provides a computational framework that can integrate both classical and alternative commitment paths in hematopoiesis that have been observed experimentally.

  1. Extrinsic and intrinsic CPT asymmetries in neutrino oscillations

    Directory of Open Access Journals (Sweden)

    Tommy Ohlsson

    2015-04-01

    Full Text Available We reconsider the extrinsic and possible intrinsic CPT violation in neutrino oscillations, and point out an identity, i.e., AαβCP=AβαCPT+AαβT, among the CP, T, and CPT asymmetries in oscillations. For three-flavor oscillations in matter of constant density, the extrinsic CPT asymmetries AeeCPT, AeμCPT, AμeCPT, and AμμCPT caused by Earth matter effects have been calculated in the plane of different neutrino energies and baseline lengths. It is found that two analytical conditions can be implemented to describe the main structure of the contours of vanishing extrinsic CPT asymmetries. Finally, without assuming intrinsic CPT symmetry in the neutrino sector, we investigate the possibility to constrain the difference of the neutrino CP-violating phase δ and the antineutrino one δ¯ using a low-energy neutrino factory and the super-beam experiment ESSνSB. We find that |δ−δ¯|≲0.35π in the former case and |δ−δ¯|≲0.7π in the latter case can be achieved at the 3σ confidence level if δ=δ¯=π/2 is assumed.

  2. Mechanisms of rotator cuff tendinopathy: intrinsic, extrinsic, or both?

    Science.gov (United States)

    Seitz, Amee L; McClure, Philip W; Finucane, Sheryl; Boardman, N Douglas; Michener, Lori A

    2011-01-01

    The etiology of rotator cuff tendinopathy is multi-factorial, and has been attributed to both extrinsic and intrinsic mechanisms. Extrinsic factors that encroach upon the subacromial space and contribute to bursal side compression of the rotator cuff tendons include anatomical variants of the acromion, alterations in scapular or humeral kinematics, postural abnormalities, rotator cuff and scapular muscle performance deficits, and decreased extensibility of pectoralis minor or posterior shoulder. A unique extrinsic mechanism, internal impingement, is attributed to compression of the posterior articular surface of the tendons between the humeral head and glenoid and is not related to subacromial space narrowing. Intrinsic factors that contribute to rotator cuff tendon degradation with tensile/shear overload include alterations in biology, mechanical properties, morphology, and vascularity. The varied nature of these mechanisms indicates that rotator cuff tendinopathy is not a homogenous entity, and thus may require different treatment interventions. Treatment aimed at addressing mechanistic factors appears to be beneficial for patients with rotator cuff tendinopathy, however, not for all patients. Classification of rotator cuff tendinopathy into subgroups based on underlying mechanism may improve treatment outcomes.

  3. Are competition and extrinsic motivation reliable predictors of academic cheating?

    Directory of Open Access Journals (Sweden)

    Gábor eOrosz

    2013-02-01

    Full Text Available Previous studies suggest that extrinsic motivation and competition are reliable predictors of academic cheating. The aim of the present questionnaire study was to separate the effects of motivation- and competition-related variables on academic cheating by Hungarian high school students (N = 620, M = 264, F = 356. Structural equation modeling showed that intrinsic motivation has a negative effect, and amotivation has a positive indirect effect on self-reported academic cheating. In contrast, extrinsic motivation had no significant effect. Indirect positive influence on cheating, based on some characteristics of hypercompetition, was also found, whereas attitudes towards self-developmental competition had a mediated negative influence. Neither constructive nor destructive competitive classroom climate had a significant impact on academic dishonesty. Acceptance of cheating and guilt has significant and direct effect on self-reported cheating. In comparison with them, the effects of motivational and competition-related variables are relatively small, even negligible. These results suggest that extrinsic motivation and competition are not amongst the most reliable predictors of academic cheating behavior.

  4. Effects of empathic paraphrasing - Extrinsic emotion regulation in social conflict

    Directory of Open Access Journals (Sweden)

    Maria eSeehausen

    2012-11-01

    Full Text Available In the present study, we investigated the effects of empathic paraphrasing as an extrinsic emotion regulation technique in social conflict. We hypothesized that negative emotions elicited by social conflict can be regulated extrinsically in a conversation by a listener following the narrator’s perspective and verbally expressing cognitive empathy.20 participants were interviewed on an ongoing or recently self-experienced social conflict. The interviewer utilized ten standardized open questions inviting participants to describe their perception of the conflict. After each of the ten descriptions, the interviewer responded by either paraphrasing or taking notes (control condition. Valence ratings pertaining to the current emotional state were assessed during the interview along with psychophysiological and voice recordings.Participants reported feeling less negative after hearing the interviewer paraphrase what they had said. In addition, we found a lower sound intensity of participants' voices when answering to questions following a paraphrase. At the physiological level, skin conductance response, as well as heart rate, was higher during paraphrasing than during taking notes, while blood volume pulse amplitude was lower during paraphrasing, indicating higher autonomic arousal.The results show that demonstrating cognitive empathy through paraphrasing can extrinsically regulate negative emotion on a short-term basis. Paraphrasing led to enhanced autonomic activation in recipients, while at the same time influencing emotional valence in the direction of feeling better. A possible explanation for these results is that being treated in an empathic manner may stimulate a more intense emotion processing helping to transform and resolve the conflict.

  5. Extrinsic Calibration of Camera Networks Based on Pedestrians.

    Science.gov (United States)

    Guan, Junzhi; Deboeverie, Francis; Slembrouck, Maarten; Van Haerenborgh, Dirk; Van Cauwelaert, Dimitri; Veelaert, Peter; Philips, Wilfried

    2016-05-09

    In this paper, we propose a novel extrinsic calibration method for camera networks by analyzing tracks of pedestrians. First of all, we extract the center lines of walking persons by detecting their heads and feet in the camera images. We propose an easy and accurate method to estimate the 3D positions of the head and feet w.r.t. a local camera coordinate system from these center lines. We also propose a RANSAC-based orthogonal Procrustes approach to compute relative extrinsic parameters connecting the coordinate systems of cameras in a pairwise fashion. Finally, we refine the extrinsic calibration matrices using a method that minimizes the reprojection error. While existing state-of-the-art calibration methods explore epipolar geometry and use image positions directly, the proposed method first computes 3D positions per camera and then fuses the data. This results in simpler computations and a more flexible and accurate calibration method. Another advantage of our method is that it can also handle the case of persons walking along straight lines, which cannot be handled by most of the existing state-of-the-art calibration methods since all head and feet positions are co-planar. This situation often happens in real life.

  6. Are competition and extrinsic motivation reliable predictors of academic cheating?

    Science.gov (United States)

    Orosz, Gábor; Farkas, Dávid; Roland-Lévy, Christine

    2013-01-01

    Previous studies suggest that extrinsic motivation and competition are reliable predictors of academic cheating. The aim of the present questionnaire study was to separate the effects of motivation- and competition-related variables on academic cheating by Hungarian high school students (N = 620, M = 264, F = 356). Structural equation modeling showed that intrinsic motivation has a negative effect, and amotivation has a positive indirect effect on self-reported academic cheating. In contrast, extrinsic motivation had no significant effect. Indirect positive influence on cheating, based on some characteristics of hypercompetition, was also found, whereas attitudes toward self-developmental competition had a mediated negative influence. Neither constructive nor destructive competitive classroom climate had a significant impact on academic dishonesty. Acceptance of cheating and guilt has significant and direct effect on self-reported cheating. In comparison with them, the effects of motivational and competition-related variables are relatively small, even negligible. These results suggest that extrinsic motivation and competition are not amongst the most reliable predictors of academic cheating behavior.

  7. Stochastic synchronization of neuronal populations with intrinsic and extrinsic noise.

    KAUST Repository

    Bressloff, Paul C

    2011-05-03

    We extend the theory of noise-induced phase synchronization to the case of a neural master equation describing the stochastic dynamics of an ensemble of uncoupled neuronal population oscillators with intrinsic and extrinsic noise. The master equation formulation of stochastic neurodynamics represents the state of each population by the number of currently active neurons, and the state transitions are chosen so that deterministic Wilson-Cowan rate equations are recovered in the mean-field limit. We apply phase reduction and averaging methods to a corresponding Langevin approximation of the master equation in order to determine how intrinsic noise disrupts synchronization of the population oscillators driven by a common extrinsic noise source. We illustrate our analysis by considering one of the simplest networks known to generate limit cycle oscillations at the population level, namely, a pair of mutually coupled excitatory (E) and inhibitory (I) subpopulations. We show how the combination of intrinsic independent noise and extrinsic common noise can lead to clustering of the population oscillators due to the multiplicative nature of both noise sources under the Langevin approximation. Finally, we show how a similar analysis can be carried out for another simple population model that exhibits limit cycle oscillations in the deterministic limit, namely, a recurrent excitatory network with synaptic depression; inclusion of synaptic depression into the neural master equation now generates a stochastic hybrid system.

  8. Natural death.

    Science.gov (United States)

    Oehmichen, M; Meissner, C

    2000-01-01

    The increasing age of every human being is the beginning of the end of life, an obviously natural process, but any attempt to define the term 'natural death' soon encounters difficulties in defining what is meant by 'natural'. In the industrialized countries of the West, for example 'natural death' is thought of as the opposite of non-natural types of death such as accidental death, suicide, and homicide. The aim of our present survey is to discuss the meaning of the term 'natural death' under a clinical, a forensic and a scientific point of view with regard to recent developments especially in molecular biology. If there are 'external' physical influences, a medical-technical manipulation, a therapeutic or molecular biological intervention cannot be definitely ruled out as the cause of death, then use of the term 'natural death' in general is open to question. It will only remain meaningful if it can be applied with a specific meaning in definite practical situations. Current research and medical technology, however, do not allow use of the term 'natural death' in its conventional sense: it can thus be stricken from the medical vocabulary. Copyright 2000 S. Karger AG, Basel

  9. Distinct spatial activation of intrinsic and extrinsic apoptosis pathways in natural scrapie: association with prion-related lesions

    Science.gov (United States)

    Serrano, Carmen; Lyahyai, Jaber; Bolea, Rosa; Varona, Luis; Monleón, Eva; Badiola, Juan J.; Zaragoza, Pilar; Martín-Burriel, Inmaculada

    2009-01-01

    Neurodegeneration and gliosis are the main neuropathological features of prion diseases. However, the molecular mechanisms involved in these processes remain unclear. Several studies have demonstrated changes in the expression of apoptotic factors and inflammatory cytokines in animals with experimental infection. Here we present the expression profiles of 15 genes implicated in the intrinsic and extrinsic apoptotic pathways in the central nervous systems of sheep naturally infected with scrapie. Expression changes obtained by real-time RT-PCR were also compared with the extent of classical scrapie lesions, such as prion deposition, neuronal vacuolisation, spongiosis, and astrogliosis as well as with the activation of caspase-3, using a stepwise regression. The results suggest that the factors assessed participate in apoptotic or inflammatory functions, depending on the affected area. The mitochondrial apoptosis pathway was associated with prion deposition in the prefrontal cortex (the less affected area), and with activation of caspase-3-mediated cell death via over-expression of BAK. In addition to its known association with astroglial activation, the extrinsic apoptosis pathway was also related to cell death and neuronal vacuolisation. PMID:19401142

  10. Induction of intrinsic and extrinsic apoptosis pathways in the human leukemic MOLT-4 cell line by terpinen-4-ol.

    Science.gov (United States)

    Khaw-on, Patompong; Banjerdpongchai, Ratana

    2012-01-01

    Terpinen-4-ol is a terpene found in the rhizome of Plai (Zingiber montanum (Koenig) Link ex Dietr.). In this study apoptogenic activity and mechanisms of cell death induced by terpinen-4-ol were investigated in the human leukemic MOLT-4 cell line. Terpinen-4-ol exhibited cytotoxicity in MOLT-4 cells, with characteristic morphological features of apoptosis by Wright's staining. The mode of cell death was confirmed to be apoptosis by flow cytometric analysis after staining with annexin V-FITC and propidium iodide. A sub-G1 peak in DNA histograms of cell cycle assays was observed. Terpinen-4-ol induced-MOLT-4 cell apoptosis mediated through an intrinsic pathway involving the loss of mitochondrial transmembrane potential (MTP) and release of cytochrome c into the cytosol. In addition, terpinen-4-ol also induced apoptosis via an extrinsic pathway by caspase-8 activation resulting in the cleavage of cytosolic Bid. Truncated-Bid (tBid) translocated to mitochondria and activated the mitochondrial pathway in conjunction with down-regulation of Bcl-2 protein expression. Caspase-3 activity also increased. In conclusion, terpinen-4-ol can induce human leukemic MOLT-4 cell apoptosis via both intrinsic and extrinsic pathways.

  11. Pivotal Role of Receptor-Interacting Protein Kinase 1 and Mixed Lineage Kinase Domain-Like in Neuronal Cell Death Induced by the Human Neuroinvasive Coronavirus OC43.

    Science.gov (United States)

    Meessen-Pinard, Mathieu; Le Coupanec, Alain; Desforges, Marc; Talbot, Pierre J

    2017-01-01

    Human coronaviruses (HCoV) are respiratory pathogens with neuroinvasive, neurotropic, and neurovirulent properties, highlighting the importance of studying the potential implication of these viruses in neurological diseases. The OC43 strain (HCoV-OC43) was reported to induce neuronal cell death, which may participate in neuropathogenesis. Here, we show that HCoV-OC43 harboring two point mutations in the spike glycoprotein (rOC/Us183-241) was more neurovirulent than the wild-type HCoV-OC43 (rOC/ATCC) in mice and induced more cell death in murine and human neuronal cells. To evaluate the role of regulated cell death (RCD) in HCoV-OC43-mediated neural pathogenesis, we determined if knockdown of Bax, a key regulator of apoptosis, or RIP1, a key regulator of necroptosis, altered the percentage of neuronal cell death following HCoV-OC43 infection. We found that Bax-dependent apoptosis did not play a significant role in RCD following infection, as inhibition of Bax expression mediated by RNA interference did not confer cellular protection against the cell death process. On the other hand, we demonstrated that RIP1 and MLKL were involved in neuronal cell death, as RIP1 knockdown and chemical inhibition of MLKL significantly increased cell survival after infection. Taken together, these results indicate that RIP1 and MLKL contribute to necroptotic cell death after HCoV-OC43 infection to limit viral replication. However, this RCD could lead to neuronal loss in the mouse CNS and accentuate the neuroinflammation process, reflecting the severity of neuropathogenesis. Because they are naturally neuroinvasive and neurotropic, human coronaviruses are suspected to participate in the development of neurological diseases. Given that the strain OC43 is neurovirulent in mice and induces neuronal cell death, we explored the neuronal response to infection by characterizing the activation of RCD. Our results revealed that classical apoptosis associated with the Bax protein does not play a

  12. Treatment of human colon cancer xenografts with TRA-8 anti-death receptor 5 antibody alone or in combination with CPT-11.

    Science.gov (United States)

    Oliver, Patsy G; LoBuglio, Albert F; Zinn, Kurt R; Kim, Hyunki; Nan, Li; Zhou, Tong; Wang, Wenquan; Buchsbaum, Donald J

    2008-04-01

    This study was designed to evaluate the in vitro cytotoxicity and in vivo efficacy of TRA-8, a mouse monoclonal antibody that binds to the DR5 death receptor for tumor necrosis factor-related apoptosis-inducing ligand (also called Apo2L), alone and in combination with CPT-11, against human colon cancer cells and xenografts. DR5 expression was assessed on human colon cancer cell lines using flow cytometry, and cellular cytotoxicity after TRA-8 treatment, alone and in combination with SN-38, was determined by measuring cellular ATP levels. Tumor growth inhibition and regression rates of well-established subcutaneous COLO 205, SW948, HCT116, and HT-29 colon cancer xenografts in athymic nude mice treated with TRA-8 or CPT-11 alone and in combination were determined. (99m)Tc-TRA-8 was used to examine tumor localization of TRA-8 in animals bearing each of the four xenografts. In addition, whole-body biodistribution and imaging was carried out in COLO 205-bearing animals using in vivo single-photon emission computed tomography imaging and tissue counting. DR5 expression was highest on HCT116, intermediate on SW948 and COLO 205 cells, and lowest on HT-29 cells. COLO 205 cells were the most sensitive to TRA-8-induced cytotoxicity in vitro, SW948 and HCT116 cell lines were moderately sensitive, and HT-29 cells were resistant. Combination treatment with TRA-8 and SN-38 produced additive to synergistic cytotoxicity against all cell lines compared with either single agent. The levels of apoptosis in all cell lines, including HT-29, were increased by combination treatment with SN-38. In vivo, combination therapy with TRA-8 and CPT-11 was superior to either single-agent regimen for three of the xenografts: COLO 205, SW948, and HCT116. COLO 205 tumors were most responsive to therapy with 73% complete regressions after combination therapy. HT-29 cells derived no antitumor efficacy from TRA-8 therapy. Tumor xenografts established from the four colon cancer cell lines had comparable

  13. Caspase-10 Negatively Regulates Caspase-8-Mediated Cell Death, Switching the Response to CD95L in Favor of NF-κB Activation and Cell Survival

    Directory of Open Access Journals (Sweden)

    Sebastian Horn

    2017-04-01

    Full Text Available Formation of the death-inducing signaling complex (DISC initiates extrinsic apoptosis. Caspase-8 and its regulator cFLIP control death signaling by binding to death-receptor-bound FADD. By elucidating the function of the caspase-8 homolog, caspase-10, we discover that caspase-10 negatively regulates caspase-8-mediated cell death. Significantly, we reveal that caspase-10 reduces DISC association and activation of caspase-8. Furthermore, we extend our co-operative/hierarchical binding model of caspase-8/cFLIP and show that caspase-10 does not compete with caspase-8 for binding to FADD. Utilizing caspase-8-knockout cells, we demonstrate that caspase-8 is required upstream of both cFLIP and caspase-10 and that DISC formation critically depends on the scaffold function of caspase-8. We establish that caspase-10 rewires DISC signaling to NF-κB activation/cell survival and demonstrate that the catalytic activity of caspase-10, and caspase-8, is redundant in gene induction. Thus, our data are consistent with a model in which both caspase-10 and cFLIP coordinately regulate CD95L-mediated signaling for death or survival.

  14. Let's stay together? Intrinsic and extrinsic factors involved in pair bond dissolution in a recolonizing wolf population.

    Science.gov (United States)

    Milleret, Cyril; Wabakken, Petter; Liberg, Olof; Åkesson, Mikael; Flagstad, Øystein; Andreassen, Harry Peter; Sand, Håkan

    2017-01-01

    For socially monogamous species, breeder bond dissolution has important consequences for population dynamics, but the extent to which extrinsic or intrinsic population factors causes pair dissolution remain poorly understood, especially among carnivores. Using an extensive life-history data set, a survival analysis and competing risks framework, we examined the fate of 153 different wolf (Canis lupus) pairs in the recolonizing Scandinavian wolf population, during 14 winters of snow tracking and DNA monitoring. Wolf pair dissolution was generally linked to a mortality event and was strongly affected by extrinsic (i.e. anthropogenic) causes. No divorce was observed, and among the pair dissolution where causes have been identified, death of one or both wolves was always involved. Median time from pair formation to pair dissolution was three consecutive winters (i.e. approximately 2 years). Pair dissolution was mostly human-related, primarily caused by legal control actions (36·7%), verified poaching (9·2%) and traffic-related causes (2·1%). Intrinsic factors, such as disease and age, accounted for only 7·7% of pair dissolutions. The remaining 44·3% of dissolution events were from unknown causes, but we argue that a large portion could be explained by an additional source of human-caused mortality, cryptic poaching. Extrinsic population factors, such as variables describing the geographical location of the pair, had a stronger effect on risk of pair dissolution compared to anthropogenic landscape characteristics. Population intrinsic factors, such as the inbreeding coefficient of the male pair member, had a negative effect on pair bond duration. The mechanism behind this result remains unknown, but might be explained by lower survival of inbred males or more complex inbreeding effects mediated by behaviour. Our study provides quantitative estimates of breeder bond duration in a social carnivore and highlights the effect of extrinsic (i.e. anthropogenic) and

  15. Retinoic acids acting through retinoid receptors protect hippocampal neurons from oxygen-glucose deprivation-mediated cell death by inhibition of c-jun-N-terminal kinase and p38 mitogen-activated protein kinase.

    Science.gov (United States)

    Shinozaki, Y; Sato, Y; Koizumi, S; Ohno, Y; Nagao, T; Inoue, K

    2007-06-15

    Retinoic acids (RAs), including all-trans retinoic acid (ATRA) and 9-cis retinoic acid (9-cis RA), play fundamental roles in a variety of physiological events in vertebrates, through their specific nuclear receptors: retinoic acid receptor (RAR) and retinoid X receptor (RXR). Despite the physiological importance of RA, their functional significance under pathological conditions is not well understood. We examined the effect of ATRA on oxygen/glucose-deprivation/reperfusion (OGD/Rep)-induced neuronal damage in cultured rat hippocampal slices, and found that ATRA significantly reduced neuronal death. The cytoprotective effect of ATRA was observed not only in cornu ammonis (CA) 1 but also in CA2 and dentate gyrus (DG), and was attenuated by selective antagonists for RAR or RXR. By contrast, in the CA3 region, no protective effects of ATRA were observed. The OGD/Rep also increased phosphorylated forms of c-jun-N-terminal kinase (P-JNK) and p38 (P-p38) in hippocampus, and specific inhibitors for these kinases protected neurons. ATRA prevented the increases in P-JNK and P-p38 after OGD/Rep, as well as the decrease in NeuN and its shrinkage, all of which were inhibited by antagonists for RAR or RXR. These findings suggest that the ATRA signaling via retinoid receptors results in the inhibition of JNK and p38 activation, leading to the protection of neurons against OGD/Rep-induced damage in the rat hippocampus.

  16. Expression of Peroxisome Proferator-Activated Receptor γ (PPARγ) in Human Transitional Bladder Cancer and its Role in Inducing Cell Death

    OpenAIRE

    1999-01-01

    The present study examined the expression and role of the thiazolidinedione (TZD)-activated transcription factor, peroxisome proliferator-activated receptor γ (PPARγ), in human bladder cancers. In situ hybridization shows that PPARγ mRNA is highly expressed in all human transitional epithelial cell cancers (TCCa's) studied (n=11). PPARγ was also expressed in five TCCa cell lines as determined by RNase protection assays and immunoblot. Retinoid X receptor α (RXRα), a 9-cis-retinoic acid stimul...

  17. Expression of Peroxisome Proliferator-Activated Receptor γ (PPARγ) in Human Transitional Bladder Cancer and its Role in Inducing Cell Death1

    OpenAIRE

    1999-01-01

    The present study examined the expression and role of the thiazolidinedione (TZD)-activated transcription factor, peroxisome proliferator-activated receptor γ (PPARγ), in human bladder cancers. In situ hybridization shows that PPARγ mRNA is highly expressed in all human transitional epithelial cell cancers (TCCa's) studied (n=11). PPARγ was also expressed in five TCCa cell lines as determined by RNase protection assays and immunoblot. Retinoid X receptor α (RXRα), a 9-cis-retinoic acid stimul...

  18. The Capsicum annuum class IV chitinase ChitIV interacts with receptor-like cytoplasmic protein kinase PIK1 to accelerate PIK1-triggered cell death and defence responses.

    Science.gov (United States)

    Kim, Dae Sung; Kim, Nak Hyun; Hwang, Byung Kook

    2015-04-01

    The pepper receptor-like cytoplasmic protein kinase, CaPIK1, which mediates signalling of plant cell death and defence responses was previously identified. Here, the identification of a class IV chitinase, CaChitIV, from pepper plants (Capsicum annuum), which interacts with CaPIK1 and promotes CaPIK1-triggered cell death and defence responses, is reported. CaChitIV contains a signal peptide, chitin-binding domain, and glycol hydrolase domain. CaChitIV expression was up-regulated by Xanthomonas campestris pv. vesicatoria (Xcv) infection. Notably, avirulent Xcv infection rapidly induced CaChitIV expression in pepper leaves. Bimolecular fluorescence complementation and co-immunoprecipitation revealed that CaPIK1 interacts with CaChitIV in planta, and that the CaPIK1-CaChitIV complex is localized mainly in the cytoplasm and plasma membrane. CaChitIV is also localized in the endoplasmic reticulum. Transient co-expression of CaChitIV with CaPIK1 enhanced CaPIK1-triggered cell death response and reactive oxygen species (ROS) and nitric oxide (NO) bursts. Co-silencing of both CaChitIV and CaPIK1 in pepper plants conferred enhanced susceptibility to Xcv infection, which was accompanied by a reduced induction of cell death response, ROS and NO bursts, and defence response genes. Ectopic expression of CaPIK1 in Arabidopsis enhanced basal resistance to Hyaloperonospora arabidopsidis infection. Together, the results suggest that CaChitIV positively regulates CaPIK1-triggered cell death and defence responses through its interaction with CaPIK1.

  19. Regulation of TRAIL-Receptor Expression by the Ubiquitin-Proteasome System

    Directory of Open Access Journals (Sweden)

    Dhifaf Sarhan

    2014-10-01

    Full Text Available The tumor necrosis factor (TNF-related apoptosis-inducing ligand- receptor (TRAIL-R family has emerged as a key mediator of cell fate and survival. Ligation of TRAIL ligand to TRAIL-R1 or TRAIL-R2 initiates the extrinsic apoptotic pathway characterized by the recruitment of death domains, assembly of the death-inducing signaling complex (DISC, caspase activation and ultimately apoptosis. Conversely the decoy receptors TRAIL-R3 and TRAIL-R4, which lack the pro-apoptotic death domain, function to dampen the apoptotic response by competing for TRAIL ligand. The tissue restricted expression of the decoy receptors on normal but not cancer cells provides a therapeutic rational for the development of selective TRAIL-mediated anti-tumor therapies. Recent clinical trials using agonistic antibodies against the apoptosis-inducing TRAIL receptors or recombinant TRAIL have been promising; however the number of patients in complete remission remains stubbornly low. The mechanisms of TRAIL resistance are relatively unexplored but may in part be due to TRAIL-R down-regulation or shedding of TRAIL-R by tumor cells. Therefore a better understanding of the mechanisms underlying TRAIL resistance is required. The ubiquitin-proteasome system (UPS has been shown to regulate TRAIL-R members suggesting that pharmacological inhibition of the UPS may be a novel strategy to augment TRAIL-based therapies and increase efficacies. We recently identified b-AP15 as an inhibitor of proteasome deubiquitinase (DUB activity. Interestingly, exposure of tumor cell lines to b-AP15 resulted in increased TRAIL-R2 expression and enhanced sensitivity to TRAIL-mediated apoptosis and cell death in vitro and in vivo. In conclusion, targeting the UPS may represent a novel strategy to increase the cell surface expression of pro-apoptotic TRAIL-R on cancer cells and should be considered in clinical trials targeting TRAIL-receptors in cancer patients.

  20. Neonatal Death

    Science.gov (United States)

    ... a premature baby include pneumonia (a lung infection), sepsis (a blood infection) and meningitis (an infection in the fluid around the brain and spinal cord). What birth defects most often cause neonatal death? The most common birth defects that cause ...

  1. The influence of extrinsic motivation on competition-based selection.

    Science.gov (United States)

    Sänger, Jessica; Wascher, Edmund

    2011-10-10

    The biased competition approach to visuo-spatial attention proposes that the selection of competing information is effected by the saliency of the stimulus as well as by an intention-based bias of attention towards behavioural goals. Wascher and Beste (2010) [32] showed that the detection of relevant information depends on its relative saliency compared to irrelevant conflicting stimuli. Furthermore the N1pc, N2pc and N2 of the EEG varied with the strength of the conflict. However, this system could also be modulated by rather global mechanisms like attentional effort. The present study investigates such modulations by testing the influence of extrinsic motivation on the selection of competing stimuli. Participants had to detect a luminance change in various conditions among others against an irrelevant orientation change. Half of the participants were motivated to maximize their performance by the announcement of a monetary reward for correct responses. Participants who were motivated had lower error rates than participants who were not motivated. The event-related lateralizations of the EEG showed no motivation-related effect on the N1pc, which reflects the initial saliency driven orientation of attention towards the more salient stimulus. The subsequent N2pc was enhanced in the motivation condition. Extrinsic motivation was also accompanied by enhanced fronto-central negativities. Thus, the data provide evidence that the improvement of selection performance when participants were extrinsically motivated by announcing a reward was not due to changes in the initial saliency based processing of information but was foremost mediated by improved higher-level mechanisms.

  2. Cytotoxicity of synthetic cannabinoids on primary neuronal cells of the forebrain: the involvement of cannabinoid CB{sub 1} receptors and apoptotic cell death

    Energy Technology Data Exchange (ETDEWEB)

    Tomiyama, Ken-ichi; Funada, Masahiko, E-mail: mfunada@ncnp.go.jp

    2014-01-01

    The abuse of herbal products containing synthetic cannabinoids has become an issue of public concern. The purpose of this paper was to evaluate the acute cytotoxicity of synthetic cannabinoids on mouse brain neuronal cells. Cytotoxicity induced by synthetic cannabinoid (CP-55,940, CP-47,497, CP-47,497-C8, HU-210, JWH-018, JWH-210, AM-2201, and MAM-2201) was examined using forebrain neuronal cultures. These synthetic cannabinoids induced cytotoxicity in the forebrain cultures in a concentration-dependent manner. The cytotoxicity was suppressed by preincubation with the selective CB{sub 1} receptor antagonist AM251, but not with the selective CB{sub 2} receptor antagonist AM630. Furthermore, annexin-V-positive cells were found among the treated forebrain cells. Synthetic cannabinoid treatment induced the activation of caspase-3, and preincubation with a caspase-3 inhibitor significantly suppressed the cytotoxicity. These synthetic cannabinoids induced apoptosis through a caspase-3-dependent mechanism in the forebrain cultures. Our results indicate that the cytotoxicity of synthetic cannabinoids towards primary neuronal cells is mediated by the CB{sub 1} receptor, but not by the CB{sub 2} receptor, and further suggest that caspase cascades may play an important role in the apoptosis induced by these synthetic cannabinoids. In conclusion, excessive synthetic cannabinoid abuse may present a serious acute health concern due to neuronal damage or deficits in the brain. - Highlights: • Synthetic cannabinoids (classical cannabinoids, non-classical cannabinoids, and aminoalkylindole derivatives) induce cytotoxicity in mouse forebrain cultures. • Synthetic cannabinoid-induced cytotoxicity towards forebrain cultures is mediated by the CB{sub 1} receptor, but not by the CB{sub 2} receptor, and involves caspase-dependent apoptosis. • A high concentration of synthetic cannabinoids may be toxic to neuronal cells that express CB{sub 1} receptors.

  3. Extrinsic allergic alveolitis: a disease commoner in non-smokers.

    Science.gov (United States)

    Warren, C P

    1977-01-01

    The smoking habits of 18 patients with extrinsic allergic alveolitis, 22 with cryptogenic fibrosing alveolitis, and 75 patients with sarcoidosis were compared with the smoking habits of the normal population of the Prairie Region for 1973. The patients were diagnosed at the same two hospitals over the four-year period November 1971--75 and were of comparable age. Non-smoking was significantly associated with allergic alveolitis in men and the three cases in women were all non-smokers. For the other two diseases, smoking habits were similar to those of the local population. PMID:594937

  4. [Extrinsic allergic alveolitis: a review for the practitioner].

    Science.gov (United States)

    Pralong, G; Leuenberger, P

    1998-08-22

    Extrinsic allergic alveolitis (EAA) or hypersensitivity pneumonitis (HP) is a clinical syndrome characterised by an inflammatory, partly granulomatous, immune disorder involving interstitial and alveolar spaces secondary to inhalation of organic substances. The disorder is mainly due to occupational exposure, farmer's lung being the best-known example. Acute, subacute or chronic forms can be clinically differentiated. Given the fact that chronic forms may present a pattern of irreversible pulmonary fibrosis, clinicians must be aware of the diagnosis of EAA in every situation where the history shows a potential antigenic exposure. Prevention should be reinforced by increasing individual protective measures and by improving techniques used at the workplace.

  5. Extrinsic sound stimulations and development of periphery auditory synapses

    Institute of Scientific and Technical Information of China (English)

    Kun Hou; Shiming Yang; Ke Liu

    2015-01-01

    The development of auditory synapses is a key process for the maturation of hearing function. However, it is still on debate regarding whether the development of auditory synapses is dominated by acquired sound stimulations. In this review, we summarize relevant publications in recent decades to address this issue. Most reported data suggest that extrinsic sound stimulations do affect, but not govern the development of periphery auditory synapses. Overall, periphery auditory synapses develop and mature according to its intrinsic mechanism to build up the synaptic connections between sensory neurons and/or interneurons.

  6. Spectral dependences of extrinsic optical absorption in sillenite crystals

    Energy Technology Data Exchange (ETDEWEB)

    Kisteneva, M G; Khudyakova, E S; Shandarov, S M; Akrestina, A S; Dyu, V G [Tomsk State University of Control Systems and Radioelectronics, Tomsk (Russian Federation); Kargin, Yu F [A.A.Baikov Institute of Metallurgy and Materials Science, Russian Academy of Sciences, Moscow (Russian Federation)

    2015-07-31

    The influence of laser irradiation at wavelengths of 532 and 655 nm and annealing in air at temperatures from 200 to 370 °C on optical absorption spectra of undoped bismuth silicon oxide and bismuth germanium oxide and aluminium-doped bismuth titanium oxide crystals has been studied experimentally. The experimental data have been interpreted in terms of a model for extrinsic absorption that takes into account not only the contribution of the photoexcitation of electrons from deep donor centres with a normal distribution of their concentration with respect to ionisation energy but also that of intracentre transitions. (laser applications and other topics in quantum electronics)

  7. Older adults' intrinsic and extrinsic motivation toward physical activity.

    Science.gov (United States)

    Dacey, Marie; Baltzell, Amy; Zaichkowsky, Len

    2008-01-01

    To examine how motives discriminate 3 physical activity levels of inactive, active, and sustained maintainers. Six hundred forty-five adults (M age = 63.8) completed stage-of-change and Exercise Motivations Inventory (EMI-2) scales. Exploratory factor analysis established psychometric properties of the EMI-2 suitable for older adults. Six factors emerged in the EMI-2: health and fitness, social/emotional benefits, weight management, stress management, enjoyment, and appearance. Enjoyment contributed most to differentiating activity levels. Moderators of age and gender were delineated. Intrinsic motivation and self-determined extrinsic motivation distinguish older adults' activity levels.

  8. Myeloid cell death associated with Toll-like receptor 7/8-mediated inflammatory response. Implication of ASK1, HIF-1 alpha, IL-1 beta and TNF-alpha.

    Science.gov (United States)

    Nicholas, Sally A; Oniku, Abraham E; Sumbayev, Vadim V

    2010-01-01

    Programmed cell death or apoptosis is an important part of the host innate immune defence, especially against ssRNA viruses (influenza virus, HIV-1, ebola virus, hepatitis C virus and many others). Viral ssRNA is recognised by endosomal Toll-like receptors 7 and 8 (TLR7/8) which induce further stages of immune defence against these pathogens. Some of the immune cells die because of inflammatory stress allowing for the selection of those cells which are resistant to stress-induced apoptosis and which are used in further stages of the host immune response. On the other hand, apoptosis could be used as an instrument to suppress the function of activated inflammatory cells. However, the mechanisms underlying death of the inflammatory cells associated with stress induced by ligands of TLR7/8 remain unclear. In this study we have found that programmed death of human myeloid cells from different cell lines associated with ligand-induced TLR7/8-mediated inflammatory stress depends on activation of apoptosis signal-regulating kinase 1 (ASK1). This enzyme is, however, not required for the production of pro-inflammatory cytokines - TNF-α and IL-1β. We have found that released IL-1β and TNF-α are involved in apoptosis of myeloid cells associated with TLR7/8-mediated inflammatory stress. The pro-apoptotic effect of released TNF-α in this case is much lower compared to that of IL-1β.

  9. Tumor necrosis factor (TNF) receptor-associated factor 7 is required for TNFα-induced Jun NH2-terminal kinase activation and promotes cell death by regulating polyubiquitination and lysosomal degradation of c-FLIP protein.

    Science.gov (United States)

    Scudiero, Ivan; Zotti, Tiziana; Ferravante, Angela; Vessichelli, Mariangela; Reale, Carla; Masone, Maria C; Leonardi, Antonio; Vito, Pasquale; Stilo, Romania

    2012-02-17

    The pro-inflammatory cytokine tumor necrosis factor (TNF) α signals both cell survival and death. The biological outcome of TNFα treatment is determined by the balance between survival factors and Jun NH(2)-terminal kinase (JNK) signaling, which promotes cell death. Here, we show that TRAF7, the most recently identified member of the TNF receptor-associated factors (TRAFs) family of proteins, is essential for activation of JNK following TNFα stimulation. We also show that TRAF6 and TRAF7 promote unconventional polyubiquitination of the anti-apoptotic protein c-FLIP(L) and demonstrate that degradation of c-FLIP(L) also occurs through a lysosomal pathway. RNA interference-mediated depletion of TRAF7 correlates with increased c-FLIP(L) expression level, which, in turn, results in resistance to TNFα cytotoxicity. Collectively, our results indicate an important role for TRAF7 in the activation of JNK following TNFα stimulation and clearly point to an involvement of this protein in regulating the turnover of c-FLIP and, consequently, cell death.

  10. Tumor Necrosis Factor (TNF) Receptor-associated Factor 7 Is Required for TNFα-induced Jun NH2-terminal Kinase Activation and Promotes Cell Death by Regulating Polyubiquitination and Lysosomal Degradation of c-FLIP Protein*

    Science.gov (United States)

    Scudiero, Ivan; Zotti, Tiziana; Ferravante, Angela; Vessichelli, Mariangela; Reale, Carla; Masone, Maria C.; Leonardi, Antonio; Vito, Pasquale; Stilo, Romania

    2012-01-01

    The pro-inflammatory cytokine tumor necrosis factor (TNF) α signals both cell survival and death. The biological outcome of TNFα treatment is determined by the balance between survival factors and Jun NH2-terminal kinase (JNK) signaling, which promotes cell death. Here, we show that TRAF7, the most recently identified member of the TNF receptor-associated factors (TRAFs) family of proteins, is essential for activation of JNK following TNFα stimulation. We also show that TRAF6 and TRAF7 promote unconventional polyubiquitination of the anti-apoptotic protein c-FLIPL and demonstrate that degradation of c-FLIPL also occurs through a lysosomal pathway. RNA interference-mediated depletion of TRAF7 correlates with increased c-FLIPL expression level, which, in turn, results in resistance to TNFα cytotoxicity. Collectively, our results indicate an important role for TRAF7 in the activation of JNK following TNFα stimulation and clearly point to an involvement of this protein in regulating the turnover of c-FLIP and, consequently, cell death. PMID:22219201

  11. TURBO DECODER USING LOCAL SUBSIDIARY MAXIMUM LIKELIHOOD DECODING IN PRIOR ESTIMATION OF THE EXTRINSIC INFORMATION

    Institute of Scientific and Technical Information of China (English)

    Yang Fengfan

    2004-01-01

    A new technique for turbo decoder is proposed by using a local subsidiary maximum likelihood decoding and a probability distributions family for the extrinsic information. The optimal distribution of the extrinsic information is dynamically specified for each component decoder.The simulation results show that the iterative decoder with the new technique outperforms that of the decoder with the traditional Gaussian approach for the extrinsic information under the same conditions.

  12. Coordination of intrinsic and extrinsic foot muscles during walking.

    Science.gov (United States)

    Zelik, Karl E; La Scaleia, Valentina; Ivanenko, Yuri P; Lacquaniti, Francesco

    2015-04-01

    The human foot undergoes complex deformations during walking due to passive tissues and active muscles. However, based on prior recordings it is unclear if muscles that contribute to flexion/extension of the metatarsophalangeal (MTP) joints are activated synchronously to modulate joint impedance, or sequentially to perform distinct biomechanical functions. We investigated the coordination of MTP flexors and extensors with respect to each other, and to other ankle-foot muscles. We analyzed surface electromyographic (EMG) recordings of intrinsic and extrinsic foot muscles for healthy individuals during level treadmill walking, and also during sideways and tiptoe gaits. We computed stride-averaged EMG envelopes and used the timing of peak muscle activity to assess synchronous vs. sequential coordination. We found that peak MTP flexor activity occurred significantly before peak MTP extensor activity during walking (P walking tended to dissociate during other locomotor tasks. For instance, extensor hallucis brevis and extensor digitorum brevis muscle activation peaks decoupled during sideways gait. The sequential peak activity of MTP flexors followed by MTP extensors suggests that their biomechanical contributions may be largely separable from each other and from other extrinsic foot muscles during walking. Meanwhile, the task-specific coordination of the foot muscles during other modes of locomotion indicates a high-level of specificity in their function and control.

  13. Intrinsic and Extrinsic Science: A Dialectic of Scientific Fame.

    Science.gov (United States)

    Feist, Gregory J

    2016-11-01

    In this article, I argue that scientific fame and impact exists on a continuum from the mundane to the transformative/revolutionary. Ideally, one achieves fame and impact in science by synthesizing two extreme career prototypes: intrinsic and extrinsic research. The former is guided by interest, curiosity, passion, gut, and intuition for important untapped topics. The latter is guided by money, grants, and/or what is being published in top-tier journals. Assessment of fame and impact in science ultimately rests on productivity (publication) and some variation of its impact (citations). In addition to those traditional measures of impact, there are some relatively new metrics (e.g., the h index and altmetrics). If psychology is to achieve consensual cumulative progress and better rates of replication, I propose that upcoming psychologists would do well to understand that success is not equal to fame and that individual career success is not necessarily the same as disciplinary success. Finally, if one is to have a successful and perhaps even famous career in psychological science, a good strategy would be to synthesize intrinsic and extrinsic motives for one's research.

  14. The effect of extrinsic attributes on liking of cottage cheese.

    Science.gov (United States)

    Hubbard, E M; Jervis, S M; Drake, M A

    2016-01-01

    Preference mapping studies with cottage cheese have demonstrated that cottage cheese liking is influenced by flavor, texture, curd size, and dressing content. However, extrinsic factors such as package, label claims, and brand name may also influence liking and have not been studied. The objective of this study was to evaluate the role of package attributes and brand on the liking of cottage cheese. A conjoint survey with Kano analysis (n=460) was conducted to explore the effect of extrinsic attributes (brand, label claim, milkfat content, and price) on liking. Following the survey, 150 consumers evaluated intrinsic attributes of 7 cottage cheeses with and without brand information in a 2-d crossover design. Results were evaluated by 2-way ANOVA and multivariate analyses. Milkfat content and price had the highest influence on liking by conjoint analysis. Cottage cheese with 2% milkfat and a low price was preferred. Specific label claims such as "excellent source of calcium (>10%)" were more attractive to consumers than "low sodium" or "extra creamy." Branding influenced overall liking and purchase intent for cottage cheeses to differing degrees. For national brands, acceptance scores were enhanced in the presence of the brand. An all-natural claim was more appealing than organic by conjoint analysis and this result was also confirmed with consumer acceptance testing. Findings from this study can help manufacturers, as well as food marketers, better target their products and brands with attributes that drive consumer choice.

  15. Extrinsic labelling of zinc and calcium in bread

    Energy Technology Data Exchange (ETDEWEB)

    Fredlund, Kerstin E-mail: mlw@fsc.chalmers.se; Rossander-Hulthen, Lena; Isaksson, Mats; Almgren, Annette; Sandberg, A.-S

    2002-08-01

    This study investigated the effect of different means of extrinsic administration of {sup 65}Zn and {sup 47}Ca in white wheat flour bread on the measured absorption. Eight healthy subjects were served 80 g of labelled bread as a standardized breakfast after an overnight fast on three occasions. Extrinsic labelling of the meals with {sup 65}Zn and {sup 47}Ca was done in three ways: (a) by adding the isotopes to the bread 16 h before it was served, (b) by adding the isotopes shortly before serving or (c) by adding the isotopes to the water used in dough making. Zinc and calcium chloride corresponding to 3.2 mg (49 {mu}mol) zinc and 275 mg (6.9 mmol) calcium in one portion were added to the dough. Whole-body retention was measured by whole-body counting. The fractional absorption of zinc was (a) 0.243{+-}0.122, (b) 0.217{+-}0.101 and (c) 0.178{+-}0.063 (mean{+-}SD), and the fractional absorption of calcium (expressed as calcium retention on day 7) was (a) 0.351{+-}0.108, (b) 0.357{+-}0.131 and (c) 0.334{+-}0.117 (mean{+-}SD). No significant difference (p>0.05) was seen between the different ways for either zinc nor calcium.

  16. In/extrinsic granularity in superconducting boron-doped diamond

    Energy Technology Data Exchange (ETDEWEB)

    Willems, B.L. [INPAC - Institute for Nanoscale Physics and Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200D, B - 3001 Leuven (Belgium); Facultad de Ciencias Fisicas, Universidad Nacional Mayor de San Marcos, P.O. 14-0149, Lima-14 (Peru); Zhang, G. [INPAC - Institute for Nanoscale Physics and Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200D, B - 3001 Leuven (Belgium); Vanacken, J., E-mail: johan.vanacken@fys.kuleuven.b [INPAC - Institute for Nanoscale Physics and Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200D, B - 3001 Leuven (Belgium); Moshchalkov, V.V. [INPAC - Institute for Nanoscale Physics and Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200D, B - 3001 Leuven (Belgium); Guillamon, I.; Suderow, H.; Vieira, S. [Laboratorio de Bajas Temperaturas, Departamento de Fisica de la Materia Condensada, Universidad Autonoma de Madrid (Spain); Janssens, S.D. [Hasselt University, Institute for Materials Research, Wetenschapspark 1, B-3590 Diepenbeek (Belgium); Haenen, K.; Wagner, P. [Hasselt University, Institute for Materials Research, Wetenschapspark 1, B-3590 Diepenbeek (Belgium); Division IMOMEC, IMEC vzw, Wetenschapspark 1, B-3590 Diepenbeek (Belgium)

    2010-10-01

    When charge carriers are introduced in diamond, e.g. by chemical doping with Boron (B), the C{sub 1-x}B{sub x} diamond:B can exhibit an insulator-to-metal transition (p{sub Mott{approx}}2x10{sup 20}cm{sup -3}). Under even heavier boron doping (n{sub B{approx}}10{sup 21}cm{sup -3}), diamond becomes superconducting. Using microwave plasma-assisted chemical vapor deposition (MPCVD) we have prepared diamond:B thin films with critical offset temperatures T{sub C} below 3 K. We have investigated the transport properties of these diamond:B thin films, which show pronounced granular effects. It turns out, that this granularity is both intrinsic as well as extrinsic. The extrinsic granularity is the effect of the growth method which needs to start from a seeding of the substrate with detonation nanodiamond, which acts as nucleation centers for further MPCVD growth of the film. In using SPM/STM techniques, we also observed intrinsic granularity, meaning that within physical grains, we observe also a strong intragrain modulation of the order parameter. As a consequence of these granularities, the transport properties show evidence of (i) strong superconducting fluctuations and (ii) Cooper pair tunneling and/or quasiparticle tunneling. The latter effects explain the observed negative magnetoresistance.

  17. Intrinsic and extrinsic influences on children's acceptance of new foods.

    Science.gov (United States)

    Blissett, Jackie; Fogel, Anna

    2013-09-10

    The foods that tend to be rejected by children include those which may have greatest importance for later health. This paper reviews some of the intrinsic and extrinsic influences on preschool children's eating behavior, with particular reference to their acceptance of new foods into their diet. Factors conceptualized as intrinsic to the child in this review include sensory processing, taste perception, neophobia, and temperament. The important extrinsic determinants of children's food acceptance which are reviewed include parental and peer modeling, the family food environment, infant feeding practices including breastfeeding and age at weaning, concurrent feeding practices including restriction, pressure to eat, prompting and reward, and the taste & energy content of foods. Children's willingness to accept new foods is influenced by a wide range of factors that likely have individual and also interactive effects on children's willingness to taste, and then continue to eat, new foods. The literature lacks longitudinal and experimental studies, which will be particularly important in determining interventions most likely to be effective in facilitating children's acceptance of healthy foods.

  18. Cytotoxicity of synthetic cannabinoids on primary neuronal cells of the forebrain: the involvement of cannabinoid CB1 receptors and apoptotic cell death.

    Science.gov (United States)

    Tomiyama, Ken-ichi; Funada, Masahiko

    2014-01-01

    The abuse of herbal products containing synthetic cannabinoids has become an issue of public concern. The purpose of this paper was to evaluate the acute cytotoxicity of synthetic cannabinoids on mouse brain neuronal cells. Cytotoxicity induced by synthetic cannabinoid (CP-55,940, CP-47,497, CP-47,497-C8, HU-210, JWH-018, JWH-210, AM-2201, and MAM-2201) was examined using forebrain neuronal cultures. These synthetic cannabinoids induced cytotoxicity in the forebrain cultures in a concentration-dependent manner. The cytotoxicity was suppressed by preincubation with the selective CB1 receptor antagonist AM251, but not with the selective CB2 receptor antagonist AM630. Furthermore, annexin-V-positive cells were found among the treated forebrain cells. Synthetic cannabinoid treatment induced the activation of caspase-3, and preincubation with a caspase-3 inhibitor significantly suppressed the cytotoxicity. These synthetic cannabinoids induced apoptosis through a caspase-3-dependent mechanism in the forebrain cultures. Our results indicate that the cytotoxicity of synthetic cannabinoids towards primary neuronal cells is mediated by the CB1 receptor, but not by the CB2 receptor, and further suggest that caspase cascades may play an important role in the apoptosis induced by these synthetic cannabinoids. In conclusion, excessive synthetic cannabinoid abuse may present a serious acute health concern due to neuronal damage or deficits in the brain.

  19. Crosstalk between Complement and Toll-like Receptor Activation in Relation to Donor Brain Death and Renal Ischemia-Reperfusion Injury

    NARCIS (Netherlands)

    Damman, Jeffrey; Daha, Mohamed R.; van Son, Willem J.; Leuvenink, Henri G.; Ploeg, Rutger J.; Seelen, Marc A.

    2011-01-01

    Two central pathways of innate immunity, complement and Toll-like receptors (TLRs), play an important role in the pathogenesis of renal injury inherent to kidney transplantation. Recent findings indicate close crosstalk between complement and TLR signaling pathways. It is suggested that mitogen acti

  20. Crosstalk between Complement and Toll-like Receptor Activation in Relation to Donor Brain Death and Renal Ischemia-Reperfusion Injury

    NARCIS (Netherlands)

    Damman, Jeffrey; Daha, Mohamed R.; van Son, Willem J.; Leuvenink, Henri G.; Ploeg, Rutger J.; Seelen, Marc A.

    2011-01-01

    Two central pathways of innate immunity, complement and Toll-like receptors (TLRs), play an important role in the pathogenesis of renal injury inherent to kidney transplantation. Recent findings indicate close crosstalk between complement and TLR signaling pathways. It is suggested that mitogen acti

  1. Surviving death

    DEFF Research Database (Denmark)

    Gerstroem, Anna

    2013-01-01

    such phases. The aim of this paper is to explore how an organization’s identity is re-constructed after organizational death. Based on interviews with members of a bankrupted bank who narrate their bankruptcy experiences, the paper explores how legacy organizational identity is constructed after...... organizational death. The paper shows how members draw on their legacy organizational identity to justify their past interpretations and responses to the intensifying bankruptcy threats. Members refer to their firm belief in the bank’s solid and robust identity claim when they explain how they disregarded...

  2. Hesperidin from Citrus seed induces human hepatocellular carcinoma HepG2 cell apoptosis via both mitochondrial and death receptor pathways

    OpenAIRE

    2015-01-01

    Citrus seeds are full of phenolic compounds, such as flavonoids. The aims of this study were to identify the types of flavonoids in Citrus seed extracts, the cytotoxic effect, mode of cell death, and signaling pathway in human hepatic cancer HepG2 cells. The flavonoids contain anticancer, free radical scavenging, and antioxidant activities. Neohesperidin, hesperidin, and naringin, active flavanone glycosides, were identified in Citrus seed extract. The cytotoxic effect of three compounds was ...

  3. Death cap

    DEFF Research Database (Denmark)

    Rudbæk, Torsten R; Kofoed, Pernille Bouteloup; Bove, Jeppe

    2014-01-01

    Death cap (Amanita phalloides) is commonly found and is one of the five most toxic fungi in Denmark. Toxicity is due to amatoxin, and poisoning is a serious medical condition, causing organ failure with potential fatal outcome. Acknowledgement and clarification of exposure, symptomatic and focused...

  4. Death Drive

    OpenAIRE

    Stühler, Rebekka Hellstrøm

    2012-01-01

    The aim of this project is to investigate why the Freudian term Death Drive is not acknowledged in modern psychological therapy. On basis of psychoanalytical theory and through a literary analysis, the project will present a discussion of the significance and presence of the term within these practises.

  5. "Spectacular Death"

    DEFF Research Database (Denmark)

    Jacobsen, Michael Hviid

    2016-01-01

    be labelled ‘spectacular death’ in which death, dying and mourning have increasingly become spectacles. Moreover, the author proposes that what is currently happening in contemporary Western society can be interpreted as an expression of a ‘partial re-reversal’ of ‘forbidden death’ to some...

  6. Solanum lyratum Extracts Induce Extrinsic and Intrinsic Pathways of Apoptosis in WEHI-3 Murine Leukemia Cells and Inhibit Allograft Tumor

    Directory of Open Access Journals (Sweden)

    Jai-Sing Yang

    2012-01-01

    Full Text Available We investigated the molecular mechanisms of cell cycle arrest and apoptotic death induced by Solanum lyratum extracts (SLE or diosgenin in WEHI-3 murine leukemia cells in vitro and antitumor activity in vivo. Diosgenin is one of the components of SLE. Our study showed that SLE and diosgenin decreased the viable WEHI-3 cells and induced G0/G1 phase arrest and apoptosis in concentration- or time-dependent manners. Both reagents increased the levels of ROS production and decreased the mitochondrial membrane potential (ΔΨm. SLE- and diosgenin-triggered apoptosis is mediated through modulating the extrinsic and intrinsic signaling pathways. Intriguingly, the p53 inhibitor (pifithrin-α, anti-Fas ligand (FasL mAb, and specific inhibitors of caspase-8 (z-IETD-fmk, caspase-9 (z-LEHD-fmk, and caspase-3 (z-DEVD-fmk blocked SLE- and diosgenin-reduced cell viability of WEHI-3 cells. The in vivo study demonstrated that SLE has marked antitumor efficacy against tumors in the WEHI-3 cell allograft model. In conclusion, SLE- and diosgenin-induced G0/G1 phase arrest and triggered extrinsic and intrinsic apoptotic pathways via p53 activation in WEHI-3 cells. SLE also exhibited antitumor activity in vivo. Our findings showed that SLE may be potentially efficacious in the treatment of leukemia in the future.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2014-08-15

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

  8. Activation of Adenosine Receptor A2A Increases HSC Proliferation and Inhibits Death and Senescence by Down-regulation of p53 and Rb

    Directory of Open Access Journals (Sweden)

    Md. Kaimul eAhsan

    2014-04-01

    Full Text Available Background & Aims: During fibrosis hepatic stellate cells (HSC undergo activation, proliferation and senescence but the regulation of these important processes is poorly understood. The adenosine A2A receptor (A2A is known to be present on HSC, and its activation results in liver fibrosis. In this study, we tested if A2A has a role in the regulation of HSC proliferation, apoptosis, senescence, and the relevant molecular mechanism.Methods: The ability of adenosine to regulate p53 and Rb protein levels, proliferation, apoptosis and senescence was tested in the human HSC cell line LX-2 and rat primary HSC.Results: Adenosine receptor activation down-regulates p53 and Rb protein levels, increases BrdU incorporation and increases cell survival in LX-2 cells and in primary rat HSC. These effects of NECA were reproduced by an adenosine A2A receptor specific agonist (CGS21680 and blocked by a specific antagonist (ZM241385. By day twenty-one of culture primary rat HSC entered senescence and expressed -gal which was significantly inhibited by NECA. Furthermore, NECA induced down regulation of p53 and Rb and Rac1, and decreased phosphorylation of p44-42 MAP Kinase in LX-2 cells and primary rat HSC. These effects were reproduced by the cAMP analog 8-Bromo-cAMP, and the adenylyl cyclase activator forskolin, and were blocked by PKA inhibitors.Conclusions: These results demonstrate that A2A receptor regulates a number of HSC fate decisions and induces greater HSC proliferation, reduces apoptosis and senescence by decreasing p53 and Rb through cAMP-PKA/Rac1/p38 MAPK pathway. This provides a mechanism for adenosine induced HSC regulation and liver fibrosis.

  9. TNF receptor-associated factor-2 binding site is involved in TNFR75-dependent enhancement of TNFR55-induced cell death

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    TNF recepter-55 is the main mediator of TNF-induced apoptosis. TNF receptor-75-dependent induction or enhancement of cytotoxicity has been explained by intracellular signaling, “ligand passing”, or induction of endogenous TNF. To study the function of human TNF receptor-75 (hTR75) and the interaction between human TNF receptor-55 (hTR55) and hTR75 in hTNFc-induced cytotoxicity, Hep-2 cells were transfected with bicistronic expression vector of hTR75 and its deletion mutants genes. hTNFα-induced cytotoxicity was determined by crystal violet colorimetric method. The expression of hTR75 and its deletion mutants in Hep-2 cells was demonstrated by RT-PCR and indirect ELISA. We found that the overexpressed hTR75 could significantly increase the susceptibility of Hep-2 cells to hTNFα which especiαlly required TRAF2 binding site. hTR75 could not only mediate partial hTNFα-induced cytotoxicity independently but also fulfill an accessory role in enhancing or synergizing hTR55-mediated cytotoxicity.

  10. Intraspecific variation in social organization by genetic variation, developmental plasticity, social flexibility or entirely extrinsic factors.

    Science.gov (United States)

    Schradin, Carsten

    2013-05-19

    Previously, it was widely believed that each species has a specific social organization, but we know now that many species show intraspecific variation in their social organization. Four different processes can lead to intraspecific variation in social organization: (i) genetic variation between individuals owing to local adaptation (between populations) or evolutionarily stable strategies within populations; (ii) developmental plasticity evolved in long-term (more than one generation) unpredictable and short-term (one generation) predictable environments, which is mediated by organizational physiological effects during early ontogeny; (iii) social flexibility evolved in highly unpredictable environments, which is mediated by activational physiological effects in adults; (iv) entirely extrinsic factors such as the death of a dominant breeder. Variation in social behaviour occurs between individuals in the case of genetic variation and developmental plasticity, but within individuals in the case of social flexibility. It is important to study intraspecific variation in social organization to understand the social systems of species because it reveals the mechanisms by which species can adapt to changing environments, offers a useful tool to study the ultimate and proximate causes of sociality, and is an interesting phenomenon by itself that needs scientific explanation.

  11. Extrinsic factors can mediate resistance to BRAF inhibition in central nervous system melanoma metastases.

    Science.gov (United States)

    Seifert, Heike; Hirata, Eishu; Gore, Martin; Khabra, Komel; Messiou, Christina; Larkin, James; Sahai, Erik

    2016-01-01

    Here, we retrospectively review imaging of 68 consecutive unselected patients with BRAF V600-mutant metastatic melanoma for organ-specific response and progression on vemurafenib. Complete or partial responses were less often seen in the central nervous system (CNS) (36%) and bone (16%) compared to lung (89%), subcutaneous (83%), spleen (71%), liver (85%) and lymph nodes/soft tissue (83%), P < 0.001. CNS was also the most common site of progression. Based on this, we tested in vitro the efficacy of the BRAF inhibitors PLX4720 and dabrafenib in the presence of cerebrospinal fluid (CSF). Exogenous CSF dramatically reduced cell death in response to both BRAF inhibitors. Effective cell killing was restored by co-administration of a PI-3 kinase inhibitor. We conclude that the efficacy of vemurafenib is variable in different organs with CNS being particularly prone to resistance. Extrinsic factors, such as ERK- and PI3K-activating factors in CSF, may mediate BRAF inhibitor resistance in the CNS.

  12. Efficacy test of a toothpaste in reducing extrinsic dental stain

    Science.gov (United States)

    Agustanti, A.; Ramadhani, S. A.; Adiatman, M.; Rahardjo, A.; Callea, M.; Yavuz, I.; Maharani, D. A.

    2017-08-01

    This clinical trial compared the external dental stain reduction achieved by tested toothpaste versus placebo in adult patients. In this double-blind, parallel, randomised clinical trial, 45 female volunteers with a mean age of 20 years old were included. All study subjects front teeth were topically applicated with Silver Diamine Fluoride (SDF) to create external dental stains. Subjects were randomized into test (n=22) and control (n=23) groups. Toothpastes were used for two days to analyse the effects of removing external stains on the labial surfaces of all anterior teeth. VITA Easyshade Advance 4.0 was used to measure dental extrinsic stains changes. The analysis showed statistically significant efficacy of the tested toothpaste in reducing external dental stain caused by SDF, comparing to the placebo toothpaste, after one and two days of usage. The tested toothpaste was effective in reducing dental stain.

  13. Extrinsic factors affecting accuracy of ultrasonic flowmeters for LMFBRs

    Energy Technology Data Exchange (ETDEWEB)

    Managan, W.W.

    1976-08-01

    Assuming that ultrasonic flowmeters of suitable intrinsic accuracy are feasible, this report explores factors extrinsic to the flowmeter which affect the accuracy such as asymmetric flow profile, regions of high turbulence and thermal stratification. By integrating isovelocity flow profile maps, the predicted performance of various flowmeter configurations may be compared to experimental data. For the two pipe arrangements analyzed, the single diametral path flowmeter results were within 5 percent of true flow rate. Theoretical correction factors could reduce the error for the straight pipe but increased the error for asymmetrical flow. On the same pipe arrangements a four path ultrasonic flowmeter spaced for Gaussian integration gave less than 1 percent error. For more general conclusions a range of flow profiles produced by typical LMFBR piping arrangements must be analyzed.

  14. Extrinsic allergic alveolitis induced by the yeast Debaryomyces hansenii.

    Science.gov (United States)

    Yamamoto, Y; Osanai, S; Fujiuchi, S; Yamazaki, K; Nakano, H; Ohsaki, Y; Kikuchi, K

    2002-11-01

    A 65-yr-old female developed cough, fever and dyspnoea following repeated exposure to a home ultrasonic humidifier. High-resolution computed tomography showed ground-glass opacity in both lung fields. Arterial blood gas analysis gave an oxygen tension of 8.38 kPa (63 Torr). Pulmonary function testing revealed restrictive ventilatory impairment with a reduction in the diffusing capacity. The diagnosis of extrinsic allergic alveolitis (EAA) was confirmed by radiographic findings, pathological evidence of alveolitis and reproductive development by a provocation test to the humidifier water. The yeast Debaryomyces Hansenii was the only microorganism cultured from the water of the humidifier. The double diffusion precipitating test and lymphocyte proliferative response was positive for an extract of D. Hansenii, providing evidence to incriminate this fungus. This is the first described case of EAA caused by D. Hansenii.

  15. MATERIAL ELEMENT MODEL FOR EXTRINSIC SEMICONDUCTORS WITH DEFECTS OF DISLOCATION

    Directory of Open Access Journals (Sweden)

    Maria Paola Mazzeo

    2011-07-01

    Full Text Available In a previous paper we outlined a geometric model for the thermodynamic description of extrinsic semiconductors with defects of dislocation.Applying a geometrization technique, within the rationalextended irreversible thermodynamics with internal variables, the dynamical system for simple material elements of these media, the expressions of the entropy function and the entropy 1-form were obtained. In this contribution we deepen the study of this geometric model. We give a detailed description of the defective media under consideration and of the dislocation core tensor, we introduce the transformation induced by the process and, applying the closure conditions for the entropy 1-form, we derive the necessary conditions for the existence of the entropy function. These and other results are new in the paper.The derivation of the relevant entropy 1-form is the starting point to introduce an extended thermodynamical phase space.

  16. Measurement of Spin Pumping Voltage Separated from Extrinsic Microwave Effects

    Science.gov (United States)

    Iguchi, Ryo; Saitoh, Eiji

    2017-01-01

    Conversions between spin and charge currents are core technologies in recent spintronics. In this article, we provide methods for estimating inverse spin Hall effects (ISHEs) induced by using microwave-driven spin pumping (SP) as a spin-current generator. ISHE and SP induce an electromotive force at the ferromagnetic or spin-wave resonance, which offers a valuable electric method of studying spin physics in materials. At the resonance, a microwave for exciting the magnetization dynamics induces an additional electromotive force via rf-current rectification and thermoelectric effects. We discuss methods of separating the signals generated from such extrinsic microwave effects by controlling sample structures and configurations. These methods are helpful in performing accurate measurements on ISHE induced by SP, enabling quantitative studies on the conversion between spin and charge currents on various kinds of materials.

  17. Alberta Consumers' Valuation of Extrinsic and Intrinsic Red Meat Attributes

    DEFF Research Database (Denmark)

    Steiner, Bodo; Gao, Fei; Unterschultz, Jim

    2010-01-01

    This paper analyzes Alberta consumers’ perceptions toward extrinsic and intrinsic attributes of bison and beef steaks. In contrast to published Canadian consumer studies on bison meat that were undertaken prior to May 2003, before the first BSE case of Canadian origin was identified in beef cattle......, this study provides a “post-BSE” assessment of consumer perceptions toward selected bison meat attributes. The results from an attribute-based choice experiment provide little support that simple traceability assurance schemes have value to consumers of bison and beef steaks, thus confirming similar findings...... of earlier beef studies that have employed different methodological approaches. The results also suggest that consumers are willing to pay significant premiums for bison steaks that are certified as being produced without genetically modified organisms, an attribute that has so far been unexplored...

  18. Extrinsic and intrinsic motivation at 30: Unresolved scientific issues.

    Science.gov (United States)

    Reiss, Steven

    2005-01-01

    The undermining effect of extrinsic reward on intrinsic motivation remains unproven. The key unresolved issues are construct invalidity (all four definitions are unproved and two are illogical); measurement unreliability (the free-choice measure requires unreliable, subjective judgments to infer intrinsic motivation); inadequate experimental controls (negative affect and novelty, not cognitive evaluation, may explain "undermining" effects); and biased metareviews (studies with possible floor effects excluded, but those with possible ceiling effects included). Perhaps the greatest error with the undermining theory, however, is that it does not adequately recognize the multifaceted nature of intrinsic motivation (Reiss, 2004a). Advice to limit the use of applied behavior analysis based on "hidden" undermining effects is ideologically inspired and is unsupported by credible scientific evidence.

  19. The Technologies of Normalization and Self: Thinking about IRBs and Extrinsic Research Ethics with Foucault

    Science.gov (United States)

    Koro-Ljungberg, Mirka; Gemignani, Marco; Brodeur, Cheri Winton; Kmiec, Cheryl

    2007-01-01

    In this article, the authors discuss the technologies of normalization and self in relation to ethics and the problematization of extrinsic research ethics. They argue that institutional review boards (IRBs) and other similar institutional mechanisms promote extrinsic forms of ethics that are exemplified through institutionalized structures such…

  20. Intrinsic and Extrinsic School Motivation as a Function of Age: The Mediating Role of Autonomy Support

    Science.gov (United States)

    Gillet, Nicolas; Vallerand, Robert J.; Lafreniere, Marc-Andre K.

    2012-01-01

    The main purpose of the present research was to investigate school intrinsic and extrinsic motivation, and amotivation as a function of age in a sample of 1,600 elementary and high school students aged 9-17 years. First, results revealed a systematic decrease in intrinsic motivation and self-determined extrinsic motivation from age 9 to 12 years,…

  1. Creating Rich Portraits: A Mixed-Methods Approach to Understanding Profiles of Intrinsic and Extrinsic Motivations

    Science.gov (United States)

    Corpus, Jennifer Henderlong; Wormington, Stephanie V.; Haimovitz, Kyla

    2016-01-01

    A person-centered, mixed-methods approach (self-report surveys, semistructured interviews, school records) was used to characterize and evaluate profiles of intrinsic and extrinsic motivations among 243 third- through eighth-grade students. Cluster analysis suggested four distinct profiles: high quantity (high intrinsic, high extrinsic), primarily…

  2. Intrinsic and Extrinsic School Motivation as a Function of Age: The Mediating Role of Autonomy Support

    Science.gov (United States)

    Gillet, Nicolas; Vallerand, Robert J.; Lafreniere, Marc-Andre K.

    2012-01-01

    The main purpose of the present research was to investigate school intrinsic and extrinsic motivation, and amotivation as a function of age in a sample of 1,600 elementary and high school students aged 9-17 years. First, results revealed a systematic decrease in intrinsic motivation and self-determined extrinsic motivation from age 9 to 12 years,…

  3. Intrinsic and Extrinsic Origins of the Polar Kerr Effect in a Chiral p-WAVE Superconductor

    Science.gov (United States)

    Goryo, Jun

    Recently, the measurement of the polar Kerr effect (PKE) in the quasi two-dimensional superconductor Sr2RuO4, which is motivated to observe the chirality of px + ipy-wave pairing, has been reported. We clarify that the PKE has intrinsic and extrinsic (disorder-induced) origins. The extrinsic contribution would be dominant in the PKE experiment.

  4. Do people differentiate between intrinsic and extrinsic goals for physical activity?

    Science.gov (United States)

    McLachlan, Sarah; Hagger, Martin S

    2011-04-01

    The distinction between intrinsic and extrinsic goals, and between goal pursuit for intrinsically and extrinsically motivated reasons, is a central premise of self-determination theory. Proponents of the theory have proposed that the pursuit of intrinsic goals and intrinsically motivated goal striving each predict adaptive psychological and behavioral outcomes relative to the pursuit of extrinsic goals and extrinsically motivated goal striving. Despite evidence to support these predictions, research has not explored whether individuals naturally differentiate between intrinsic and extrinsic goals. Two studies tested whether people make this differentiation when recalling goals for leisure-time physical activity. Using memory-recall methods, participants in Study 1 were asked to freely generate physical activity goals. A subsample (N = 43) was asked to code their freely generated goals as intrinsic or extrinsic. In Study 2, participants were asked to recall intrinsic and extrinsic goals after making a decision regarding their future physical activity. Results of these studies revealed that individuals' goal generation and recall exhibited significant clustering by goal type. Participants encountered some difficulties when explicitly coding goals. Findings support self-determination theory and indicate that individuals discriminate between intrinsic and extrinsic goals.

  5. Creating Rich Portraits: A Mixed-Methods Approach to Understanding Profiles of Intrinsic and Extrinsic Motivations

    Science.gov (United States)

    Corpus, Jennifer Henderlong; Wormington, Stephanie V.; Haimovitz, Kyla

    2016-01-01

    A person-centered, mixed-methods approach (self-report surveys, semistructured interviews, school records) was used to characterize and evaluate profiles of intrinsic and extrinsic motivations among 243 third- through eighth-grade students. Cluster analysis suggested four distinct profiles: high quantity (high intrinsic, high extrinsic), primarily…

  6. Proprioceptive bimanual test in intrinsic and extrinsic coordinates.

    Science.gov (United States)

    Iandolo, Riccardo; Squeri, Valentina; De Santis, Dalia; Giannoni, Psiche; Morasso, Pietro; Casadio, Maura

    2015-01-01

    Is there any difference between matching the position of the hands by asking the subjects to move them to the same spatial location or to mirror-symmetric locations with respect to the body midline? If the motion of the hands were planned in the extrinsic space, the mirror-symmetric task would imply an additional challenge, because we would need to flip the coordinates of the target on the other side of the workspace. Conversely, if the planning were done in intrinsic coordinates, in order to move both hands to the same spot in the workspace, we should compute different joint angles for each arm. Even if both representations were available to the subjects, the two tasks might lead to different results, providing some cue on the organization of the "body schema". In order to answer such questions, the middle fingertip of the non-dominant hand of a population of healthy subjects was passively moved by a manipulandum to 20 different target locations. Subjects matched these positions with the middle fingertip of their dominant hand. For most subjects, the matching accuracy was higher in the extrinsic modality both in terms of systematic error and variability, even for the target locations in which the configuration of the arms was the same for both modalities. This suggests that the matching performance of the subjects could be determined not only by proprioceptive information but also by the cognitive representation of the task: expressing the goal as reaching for the physical location of the hand in space is apparently more effective than requiring to match the proprioceptive representation of joint angles.

  7. Surviving death

    DEFF Research Database (Denmark)

    Gerstroem, Anna

    2013-01-01

    such phases. The aim of this paper is to explore how an organization’s identity is re-constructed after organizational death. Based on interviews with members of a bankrupted bank who narrate their bankruptcy experiences, the paper explores how legacy organizational identity is constructed after...... organizational death. The paper shows how members draw on their legacy organizational identity to justify their past interpretations and responses to the intensifying bankruptcy threats. Members refer to their firm belief in the bank’s solid and robust identity claim when they explain how they disregarded...... increasing threats and fought to defend and preserve the organization. When the bank was declared bankrupt and the solid and robust identity claim was disconfirmed, members found comfort and guidance in an identity claim of local care and support. After the bankruptcy, part of the bank was acquired...

  8. Brain death.

    Science.gov (United States)

    Wijdicks, Eelco F M

    2013-01-01

    The diagnosis of brain death should be based on a simple premise. If every possible confounder has been excluded and all possible treatments have been tried or considered, irreversible loss of brain function is clinically recognized as the absence of brainstem reflexes, verified apnea, loss of vascular tone, invariant heart rate, and, eventually, cardiac standstill. This condition cannot be reversed - not even partly - by medical or surgical intervention, and thus is final. Many countries in the world have introduced laws that acknowledge that a patient can be declared brain-dead by neurologic standards. The U.S. law differs substantially from all other brain death legislation in the world because the U.S. law does not spell out details of the neurologic examination. Evidence-based practice guidelines serve as a standard. In this chapter, I discuss the history of development of the criteria, the current clinical examination, and some of the ethical and legal issues that have emerged. Generally, the concept of brain death has been accepted by all major religions. But patients' families may have different ideas and are mostly influenced by cultural attitudes, traditional customs, and personal beliefs. Suggestions are offered to support these families.

  9. The role of P2X7 receptor in ATP-mediated human leukemia cell death:calcium influx-independent

    Institute of Scientific and Technical Information of China (English)

    Xiujun Zhang; Lijun Meng; Baoling He; Jing Chen; Peng Liu; Jie Zhao; Yufen Zhang; Ming Li; Dong An

    2009-01-01

    Activation of the P2X7 receptor leads to a rapid,bidirectional flux of cations, causing broad range of hiological responses including cytotoxicity.However,the mechanism of P2X7-mediated cytotoxicity remains largely unexplored.In our previous study,the lack of P2X7-mediated calcium response under normal conditions was found in P2X7+ hematopoietic cell lines.In this study, the P2X7-mediated cytotoxicity in different type of cells(P2X7-,P2X7+ with calcium response,and P2X7+ without calcium response)was investigated.Our results showed that P2X7 agonists, adenosine 5'-triphosphate(ATP)or 2'+3'-O-(4 benzoylbenzoyl)ATP,dose-dependently reduced the cell viability in all P2X7+ cells tested,including J6-1,LCL,and Namalva cells which are negative for P2X7-mediated calcium response, although these effects were lower than those observed in KG1a cells which has normal P2X7 functions.The cytotoxic effect could be blocked by P2X7antagonists, oxidized ATP and 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine.In addition,externalization of phosphatidylserine could be detected in a time-dependent manner and apoptotic morphological changes Could be observed after the activation of P2X7 receptor in J6-1 cells.Furthermore,P2X7-mediated pore formation could be detected in KG1a and J6-1 cells under low-ionic conditions,but not under low-divalent conditions.These effects could not be observed in P2X7-Ramos cells.These results suggested that P2X7 receptor-mediated cytotoxic effects may occur independent of calcium response.

  10. Neuroprotective effects of the allosteric agonist of metabotropic glutamate receptor 7 AMN082 on oxygen-glucose deprivation- and kainate-induced neuronal cell death.

    Science.gov (United States)

    Domin, Helena; Jantas, Danuta; Śmiałowska, Maria

    2015-09-01

    Although numerous studies demonstrated a neuroprotective potency of unspecific group III mGluR agonists in in vitro and in vivo models of excitotoxicity, little is known about the protective role of group III mGlu receptor activation against neuronal cell injury evoked by ischemic conditions. The aim of the present study was to assess neuroprotective potential of the allosteric agonist of mGlu7 receptor, N,N'-Bis(diphenylmethyl)-1,2-ethanediamine dihydrochloride (AMN082) against oxygen-glucose deprivation (OGD)- and kainate (KA)-evoked neuronal cell damage in primary neuronal cultures, with special focus on its efficacy after delayed application. We demonstrated that in cortical neuronal cultures exposed to a 180 min OGD, AMN082 (0.01-1 µM) in a concentration- and time-dependent way attenuated the OGD-induced changes in the LDH release and MTT reduction assays. AMN082 (0.5 and 1 µM) produced also neuroprotective effects against KA-evoked neurotoxicity both in cortical and hippocampal cultures. Of particular importance was the finding that AMN082 attenuated excitotoxic neuronal injury after delayed application (30 min after OGD, or 30 min-1 h after KA). In both models of neurotoxicity, namely OGD- and KA-induced injury, the neuroprotective effects of AMN082 (1 µM) were reversed by the selective mGlu7 antagonist, 6-(4-Methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one hydrochloride (MMPIP, 1 µM), suggesting the mGlu7-dependent mechanism of neuroprotective effects of AMN082. Next, we showed that AMN082 (0.5 and 1 µM) attenuated the OGD-induced increase in the number of necrotic nuclei as well inhibited the OGD-evoked calpain activation, suggesting the participation of these processes in the mechanism of AMN082-mediated protection. Additionally, we showed that protection evoked by AMN082 (1 µM) in KA model was connected with the inhibition of toxin-induced caspase-3 activity, and this effect was abolished by the mGlu7

  11. Quercetin enhances apoptotic effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in ovarian cancer cells through reactive oxygen species (ROS) mediated CCAAT enhancer-binding protein homologous protein (CHOP)-death receptor 5 pathway

    Science.gov (United States)

    Yi, Liu; Zongyuan, Yang; Cheng, Gong; Lingyun, Zhang; GuiLian, Yu; Wei, Gong

    2014-01-01

    Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown efficacy in a phase 2 clinical trial, development of resistance to TRAIL by tumor cells is a major roadblock. We investigated whether quercetin, a flavonoid, can sensitize human ovarian cancer cells to TRAIL. Results indicate that quercetin sensitized cancer cells to TRAIL. The quercetin induced expression of death receptor DR5 but did not affect expression of DR4 in cancer cells. The induction of DR5 was mediated through activation of JNK and through upregulation of a transcription factor CCAAT enhancer-binding protein homologous protein (CHOP); as silencing of these signaling molecules abrogated the effect of quercetin. Upregulation of DR5 was mediated through the generation of reactive oxygen species (ROS), as ROS scavengers reduced the effect of quercetin on JNK activation, CHOP upregulation, DR induction, TRAIL sensitization, downregulated the expression of cell survival proteins and upregulated the proapoptotic proteins. Furthermore, quercetin enhances TRAIL mediated inhibition of tumor growth of human SKOV-3 xenograft was associated with induction of apoptosis, activation of caspase-3, CHOP and DR5. Overall, our data suggest that quercetin enhances apoptotic death of ovarian cancer cells to TRAIL through upregulation of CHOP-induced DR5 expression following ROS mediated endoplasmic reticulum-stress. PMID:24612139

  12. Toll-Like Receptor 7 Agonist Therapy with Imidazoquinoline Enhances Cancer Cell Death and Increases Lymphocytic Infiltration and Proinflammatory Cytokine Production in Established Tumors of a Renal Cell Carcinoma Mouse Model

    Directory of Open Access Journals (Sweden)

    Eric C. Kauffman

    2012-01-01

    Full Text Available Imidazoquinolines are synthetic toll-like receptor 7 and 8 agonists and potent dendritic cell activators with established anticancer activity. Here we test the hypothesis that imidazoquinoline has in vivo efficacy within established renal cell carcinoma (RCC tumors. Immunocompetent mice bearing syngeneic RCC xenografts were treated with imidazoquinoline or placebo at two separate time points. Harvested tumors were assayed by TUNEL/caspase-3/Ki67 immunostains to evaluate cell death/apoptosis/proliferation, and CD3/B220/CD45 immunostains to evaluate T-cell lymphocyte/B-cell lymphocyte/pan-leukocyte tumor infiltration. ELISA measurement of tumor and serum levels of proinflammatory cytokines, IL-6 and MCP-1, was performed. A single imidazoquinoline dose significantly decreased RCC tumor growth by 50% and repeat dosing compounded the effect, without observed weight loss or other toxicity. Tumor immunostaining revealed significant increases in cell death and apoptosis without changes in cell proliferation, supporting induction of apoptosis as the primary mechanism of tumor growth suppression. Imidazoquinoline treatment also significantly enhanced peritumoral aggregation and intratumoral infiltration by T-cell lymphocytes, while increasing intratumoral (but not serum levels of proinflammatory cytokines. In conclusion, imidazoquinoline treatment enhances T-cell lymphocyte infiltration and proinflammatory cytokine production within established mouse RCC tumors, while suppressing tumor growth via induction of cancer cell apoptosis. These findings support a therapeutic role for imidazoquinoline in RCC.

  13. High fasting blood glucose and obesity significantly and independently increase risk of breast cancer death in hormone receptor-positive disease.

    Science.gov (United States)

    Minicozzi, Pamela; Berrino, Franco; Sebastiani, Federica; Falcini, Fabio; Vattiato, Rosa; Cioccoloni, Francesca; Calagreti, Gioia; Fusco, Mario; Vitale, Maria Francesca; Tumino, Rosario; Sigona, Aurora; Budroni, Mario; Cesaraccio, Rosaria; Candela, Giuseppa; Scuderi, Tiziana; Zarcone, Maurizio; Campisi, Ildegarda; Sant, Milena

    2013-12-01

    We investigated the effect of fasting blood glucose and body mass index (BMI) at diagnosis on risk of breast cancer death for cases diagnosed in five Italian cancer registries in 2003-2005 and followed up to the end of 2008. For 1607 Italian women (≥15 years) with information on BMI or blood glucose or diabetes, we analysed the risk of breast cancer death in relation to glucose tertiles (≤84.0, 84.1-94.0, >94.0 mg/dl) plus diabetic and unspecified categories; BMI tertiles (≤23.4, 23.5-27.3, >27.3 kg/m(2), unspecified), stage (T1-3N0M0, T1-3N+M0 plus T4anyNM0, M1, unspecified), oestrogen (ER) and progesterone (PR) status (ER+PR+, ER-PR-, ER and PR unspecified, other), age, chemotherapy and endocrine therapy, using multiple regression models. Separate models for ER+PR+ and ER-PR- cases were also run. Patients often had T1-3N0M0, ER+PR+ cancers and received chemotherapy or endocrine therapy; only 6% were M1 and 17% ER-PR-. Diabetic patients were older and had more often high BMI (>27 kg/m(2)), ER-PR-, M1 cancers than other patients. For ER+PR+ cases, with adjustment for other variables, breast cancer mortality was higher in women with high BMI than those with BMI 23.5-27.3 kg/m(2) (hazard ratio (HR)=2.9, 95% confidence interval (CI) 1.2-6.9). Breast cancer mortality was also higher in women with high (>94 mg/dl) blood glucose compared to those with glucose 84.1-94.0mg/dl (HR=2.6, 95% CI 1.2-5.7). Our results provide evidence that in ER+PR+ patients, high blood glucose and high BMI are independently associated with increased risk of breast cancer death. Detection and correction of these factors in such patients may improve prognosis. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Relaxin-3/RXFP3 Signaling and Neuroendocrine Function - A Perspective on Extrinsic Hypothalamic Control.

    Science.gov (United States)

    Ganella, Despina E; Ma, Sherie; Gundlach, Andrew L

    2013-09-18

    Complex neural circuits within the hypothalamus that govern essential autonomic processes and associated behaviors signal using amino acid and monoamine transmitters and a variety of neuropeptide (hormone) modulators, often via G-protein coupled receptors (GPCRs) and associated cellular pathways. Relaxin-3 is a recently identified neuropeptide that is highly conserved throughout evolution. Neurons expressing relaxin-3 are located in the brainstem, but broadly innervate the entire limbic system including the hypothalamus. Extensive anatomical data in rodents and non-human primate, and recent regulatory and functional data, suggest relaxin-3 signaling via its cognate GPCR, RXFP3, has a broad range of effects on neuroendocrine function associated with stress responses, feeding and metabolism, motivation and reward, and possibly sexual behavior and reproduction. Therefore, this article aims to highlight the growing appreciation of the relaxin-3/RXFP3 system as an important "extrinsic" regulator of the neuroendocrine axis by reviewing its neuroanatomy and its putative roles in arousal-, stress-, and feeding-related behaviors and links to associated neural substrates and signaling networks. Current evidence identifies RXFP3 as a potential therapeutic target for treatment of neuroendocrine disorders and related behavioral dysfunction.

  15. Protein S blocks the extrinsic apoptotic cascade in tissue plasminogen activator/N-methyl D-aspartate-treated neurons via Tyro3-Akt-FKHRL1 signaling pathway

    Directory of Open Access Journals (Sweden)

    Freeman Robert S

    2011-02-01

    Full Text Available Abstract Background Thrombolytic therapy with tissue plasminogen activator (tPA benefits patients with acute ischemic stroke. However, tPA increases the risk for intracerebral bleeding and enhances post-ischemic neuronal injury if administered 3-4 hours after stroke. Therefore, combination therapies with tPA and neuroprotective agents have been considered to increase tPA's therapeutic window and reduce toxicity. The anticoagulant factor protein S (PS protects neurons from hypoxic/ischemic injury. PS also inhibits N-methyl-D-aspartate (NMDA excitotoxicity by phosphorylating Bad and Mdm2 which blocks the downstream steps in the intrinsic apoptotic cascade. To test whether PS can protect neurons from tPA toxicity we studied its effects on tPA/NMDA combined injury which in contrast to NMDA alone kills neurons by activating the extrinsic apoptotic pathway. Neither Bad nor Mdm2 which are PS's targets and control the intrinsic apoptotic pathway can influence the extrinsic cascade. Thus, based on published data one cannot predict whether PS can protect neurons from tPA/NMDA injury by blocking the extrinsic pathway. Neurons express all three TAM (Tyro3, Axl, Mer receptors that can potentially interact with PS. Therefore, we studied whether PS can activate TAM receptors during a tPA/NMDA insult. Results We show that PS protects neurons from tPA/NMDA-induced apoptosis by suppressing Fas-ligand (FasL production and FasL-dependent caspase-8 activation within the extrinsic apoptotic pathway. By transducing neurons with adenoviral vectors expressing the kinase-deficient Akt mutant AktK179A and a triple FKHRL1 Akt phosphorylation site mutant (FKHRL1-TM, we show that Akt activation and Akt-mediated phosphorylation of FKHRL1, a member of the Forkhead family of transcription factors, are critical for FasL down-regulation and caspase-8 inhibition. Using cultured neurons from Tyro3, Axl and Mer mutants, we show that Tyro3, but not Axl and Mer, mediates

  16. Dietary and nutritional manipulation of the nuclear transcription factors peroxisome proliferator-activated receptor and sterol regulatory element-binding proteins as a tool for reversing the primary diseases of premature death and delaying aging.

    Science.gov (United States)

    Kurtak, Karen A

    2014-04-01

    Evolution over 2.1 billion years has equipped us with a biochemical pathway that has the power to literally reverse the primary disease etiologies that have become the leading causes of death and aging in the developed world. Activation of the peroxisome proliferator-activated receptor (PPAR) pathway arrests inflammatory signaling throughout the body, reverses damage to tissues, reverses insulin resistance, and can even dissolve beta-amyloid plaque in the brain. It has played a critical role in the evolution of the metazoans and the successful migration of humans to all corners of the Earth. For two decades, various pharmaceuticals have been designed to activate the PPAR pathway but have consistently fallen short of expectations. There is nothing wrong with these drugs. The problem has been the standard "healthy" diet creating mixed signals that render the drugs ineffective. This article explores the ongoing dance between the two primary nuclear receptors that mediate gene regulation of fatty acids. It discusses their interaction with sirtuins and telomerase, optimization of their obligate heterodimers, and why manipulation of dietary and nutritional factors, like the ketogenic diet, is the most effective means of activation. These are effective tools that we can start implementing now to slow, and in some cases reverse, the diseases of aging.

  17. Acute Malaria Induces PD1+CTLA4+ Effector T Cells with Cell-Extrinsic Suppressor Function.

    Directory of Open Access Journals (Sweden)

    Maria Sophia Mackroth

    2016-11-01

    Full Text Available In acute Plasmodium falciparum (P. falciparum malaria, the pro- and anti-inflammatory immune pathways must be delicately balanced so that the parasitemia is controlled without inducing immunopathology. An important mechanism to fine-tune T cell responses in the periphery is the induction of coinhibitory receptors such as CTLA4 and PD1. However, their role in acute infections such as P. falciparum malaria remains poorly understood. To test whether coinhibitory receptors modulate CD4+ T cell functions in malaria, blood samples were obtained from patients with acute P. falciparum malaria treated in Germany. Flow cytometric analysis showed a more frequent expression of CTLA4 and PD1 on CD4+ T cells of malaria patients than of healthy control subjects. In vitro stimulation with P. falciparum-infected red blood cells revealed a distinct population of PD1+CTLA4+CD4+ T cells that simultaneously produced IFNγ and IL10. This antigen-specific cytokine production was enhanced by blocking PD1/PDL1 and CTLA4. PD1+CTLA4+CD4+ T cells were further isolated based on surface expression of PD1 and their inhibitory function investigated in-vitro. Isolated PD1+CTLA4+CD4+ T cells suppressed the proliferation of the total CD4+ population in response to anti-CD3/28 and plasmodial antigens in a cell-extrinsic manner. The response to other specific antigens was not suppressed. Thus, acute P. falciparum malaria induces P. falciparum-specific PD1+CTLA4+CD4+ Teffector cells that coproduce IFNγ and IL10, and inhibit other CD4+ T cells. Transient induction of regulatory Teffector cells may be an important mechanism that controls T cell responses and might prevent severe inflammation in patients with malaria and potentially other acute infections.

  18. P2X7 Cell Death Receptor Activation and Mitochondrial Impairment in Oxaliplatin-Induced Apoptosis and Neuronal Injury: Cellular Mechanisms and In Vivo Approach.

    Directory of Open Access Journals (Sweden)

    France Massicot

    Full Text Available Limited information is available regarding the cellular mechanisms of oxaliplatin-induced painful neuropathy during exposure of patients to this drug. We therefore determined oxidative stress in cultured cells and evaluated its occurrence in C57BL/6 mice. Using both cultured neuroblastoma (SH-SY5Y and macrophage (RAW 264.7 cell lines and also brain tissues of oxaliplatin-treated mice, we investigated whether oxaliplatin (OXA induces oxidative stress and apoptosis. Cultured cells were treated with 2-200 µM OXA for 24 h. The effects of pharmacological inhibitors of oxidative stress or inflammation (N-acetyl cysteine, ibuprofen, acetaminophen were also tested. Inhibitors were added 30 min before OXA treatment and then in combination with OXA for 24 h. In SH-SY5Y cells, OXA caused a significant dose-dependent decrease in viability, a large increase in ROS and NO production, lipid peroxidation and mitochondrial impairment as assessed by a drop in mitochondrial membrane potential, which are deleterious for the cell. An increase in levels of negatively charged phospholipids such as cardiolipin but also phosphatidylserine and phosphatidylinositol, was also observed. Additionally, OXA caused concentration-dependent P2X7 receptor activation, increased chromatin condensation and caspase-3 activation associated with TNF-α and IL-6 release. The majority of these toxic effects were equally observed in Raw 264.7 which also presented high levels of PGE2. Pretreatment of SH-SY5Y cells with pharmacological inhibitors significantly reduced or blocked all the neurotoxic OXA effects. In OXA-treated mice (28 mg/kg cumulated dose significant cold hyperalgesia and oxidative stress in the tested brain areas were shown. Our study suggests that targeting P2X7 receptor activation and mitochondrial impairment might be a potential therapeutic strategy against OXA-induced neuropathic pain.

  19. Targeting urokinase and the transferrin receptor with novel, anti-mitotic N-alkylisatin cytotoxin conjugates causes selective cancer cell death and reduces tumor growth.

    Science.gov (United States)

    Vine, K L; Indira Chandran, V; Locke, J M; Matesic, L; Lee, J; Skropeta, D; Bremner, J B; Ranson, M

    2012-01-01

    Tumor-specific delivery of ligand-directed prodrugs can increase the therapeutic window of chemotherapeutics by maintaining efficacy whilst decreasing toxic side effects. We have previously described a series of synthetic N-alkylated isatin cytotoxins that destabilize microtubules and induce apoptosis with 10-fold greater potency than conventional anti-mitotics in vitro. Here, we report the characterization, in vitro cytotoxicity and in vivo efficacy of a lead compound, 5,7-dibromo-N-(p-hydroxymethylbenzyl)isatin (N-AI) conjugated via an esterase-labile linker (N-AIE) to two proven targeting ligands, transferrin (Tf) and plasminogen activator inhibitor type 2 (PAI-2/serpinB2). N-AI was released from N-AIE and the targeting ligands Tf/PAI-2 in an esterase-dependent manner at 37 C and both Tf- and PAI-2-N-AIE conjugates were stable at physiological pH. Human cancer cell lines which vary in their expression levels of Tf receptor (TfR/CD71) and PAI-2 target, receptor bound urokinase (uPA) selectively internalized the conjugates. Tf-N-AIE was up to 24 times more active than the free drug and showed clear selectivity patterns based on TfR levels. PAI-2-N-AIE showed equivalent activity compared to the parent drug and strong selectivity patterns for uPA levels. In preliminary in vivo experiments, the PAI-2- and Tf-N-AIE conjugates were efficacious at 1/20(th) and 1/10(th) of the dose of the free N-AI, respectively, in a metastatic, orthotopic human breast tumor xenograft mouse model. Thus, this strategy specifically delivers and concentrates a novel class of isatin-based, tubulin destabilizing agents to tumors in vivo and warrants further detailed preclinical investigation.

  20. Births and deaths including fetal deaths

    Data.gov (United States)

    U.S. Department of Health & Human Services — Access to a variety of United States birth and death files including fetal deaths: Birth Files, 1968-2009; 1995-2005; Fetal death file, 1982-2005; Mortality files,...

  1. Distinguishing subtypes of extrinsic motivation among people with mild to borderline intellectual disability.

    Science.gov (United States)

    Frielink, N; Schuengel, C; Embregts, P

    2017-07-01

    According to self-determination theory, motivation is ordered in types, including amotivation, extrinsic motivation and intrinsic motivation. Self-determination theory defines four subtypes of extrinsic motivation: external motivation, introjected motivation, identified motivation and integrated motivation. Although it has been argued theoretically that the different types of motivation are universally applicable, Reid et al. () proposed a dichotomy of broad subtypes of extrinsic motivation for people with intellectual disability (ID) due to their cognitive limitations. The current study challenges this proposal by testing whether the four subtypes of extrinsic motivation can be differentiated among people with ID as well. The subtypes of extrinsic motivation were measured using two adapted versions of the Self-Regulation Questionnaire, one regarding exercise and one regarding support. In total, 186 adults with mild to borderline ID participated in the study. Results supported the distinction between the four subtypes of extrinsic motivation regarding both exercise and support. In addition, the correlation coefficients supported a quasi-simplex pattern of correlations among the subtypes, indicating that adjacent subtypes were more closely related than non-adjacent subtypes. Moreover, the study showed sufficient Cronbach's alphas and test-retest reliabilities for early stage research. Overall, the results of the current study provide initial evidence for the universality of the four subtypes of extrinsic motivation across populations with and without ID. © 2017 The Authors. Journal of Intellectual Disability Research published by MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disibilities and John Wiley & Sons Ltd.

  2. Intrinsic and Extrinsic Motivation Among Adolescent Ten-Pin Bowlers in Kuala Lumpur, Malaysia

    Directory of Open Access Journals (Sweden)

    Teo Eng-Wah

    2015-03-01

    Full Text Available Motivation has long been associated with sports engagement. However, to date no research has been performed to understand the domain of motivation among ten-pin bowlers. The purpose of this study was to investigate different types of motivation (i.e., intrinsic vs. extrinsic based on self-determination theory from the perspective of gender and the bowler type (competitive vs. casual. A total of 240 bowlers (104 male, 136 female; 152 competitive, 88 casual with a mean age of 16.61 ± 0.78 years were recruited in Kuala Lumpur. The Sport Motivation Scale, a 28-item self-report questionnaire measuring seven subscales (i.e., intrinsic motivation to know, intrinsic motivation to accomplish, intrinsic motivation to experience stimulation, extrinsic motivation to identify regulation, extrinsic motivation for introjection regulation, extrinsic motivation to external regulation, and amotivation was administered. Results showed significant differences (t=10.43, df=239, p=0.01 between total scores of intrinsic and extrinsic motivation among tenpin bowlers. There were significant gender differences with respect to intrinsic motivation to know, intrinsic motivation to accomplish, intrinsic motivation to experience stimulation, and extrinsic motivation to identify regulation. However, no significant bowler type differences were found for either the intrinsic (t=-1.15, df=238, p=0.25 or extrinsic (t=-0.51, df=238, p=0.61 motivation dimensions. In conclusion, our study demonstrated substantial intrinsic motivation for gender effects, but no bowler type effects among adolescent ten-pin bowlers.

  3. Intrinsic and extrinsic motivation among adolescent ten-pin bowlers in kuala lumpur, malaysia.

    Science.gov (United States)

    Teo, Eng-Wah; Khoo, Selina; Wong, Rebecca; Wee, Eng-Hoe; Lim, Boon-Hooi; Rengasamy, Shabesan Sit

    2015-03-29

    Motivation has long been associated with sports engagement. However, to date no research has been performed to understand the domain of motivation among ten-pin bowlers. The purpose of this study was to investigate different types of motivation (i.e., intrinsic vs. extrinsic) based on self-determination theory from the perspective of gender and the bowler type (competitive vs. casual). A total of 240 bowlers (104 male, 136 female; 152 competitive, 88 casual) with a mean age of 16.61 ± 0.78 years were recruited in Kuala Lumpur. The Sport Motivation Scale, a 28-item self-report questionnaire measuring seven subscales (i.e., intrinsic motivation to know, intrinsic motivation to accomplish, intrinsic motivation to experience stimulation, extrinsic motivation to identify regulation, extrinsic motivation for introjection regulation, extrinsic motivation to external regulation, and amotivation) was administered. Results showed significant differences (t=10.43, df=239, p=0.01) between total scores of intrinsic and extrinsic motivation among ten-pin bowlers. There were significant gender differences with respect to intrinsic motivation to know, intrinsic motivation to accomplish, intrinsic motivation to experience stimulation, and extrinsic motivation to identify regulation. However, no significant bowler type differences were found for either the intrinsic (t=-1.15, df=238, p=0.25) or extrinsic (t=-0.51, df=238, p=0.61) motivation dimensions. In conclusion, our study demonstrated substantial intrinsic motivation for gender effects, but no bowler type effects among adolescent ten-pin bowlers.

  4. Bridging the gap between extrinsic and intrinsic motivation in the cognitive remediation of schizophrenia.

    Science.gov (United States)

    Silverstein, Steven M

    2010-09-01

    An important development in cognitive remediation of schizophrenia is a focus on motivation. However, following a distinction between the concepts of intrinsic motivation (IM) and extrinsic motivation, discussions of IM-based methods have downplayed or misrepresented the role that extrinsic rewards can, and actually do, serve to promote positive treatment outcomes in cognitive remediation. Therefore, the purpose of this article is to explore the rationale for using techniques incorporating extrinsic rewards into cognitive treatment of people with schizophrenia. To do this, evidence is presented on each of the following points: (1) there is a long history of research demonstrating that delivery of extrinsic reward is associated with positive outcomes in both behavioral and cognitive rehabilitation; (2) basic human brain systems respond strongly to tangible rewards, and this can directly enhance attention, working memory, and other cognitive functions; (3) nearly all data on the negative effects of extrinsic reward on IM have come from studies of healthy children and adults in school or work settings who have adequate IM for target tasks; these findings do not generalize well to cognitive remediation settings for people with schizophrenia, who often have abnormally low levels of IM and low base rates of attentive behaviors; and (4) in real-world situations, cognitive remediation interventions already utilize a combination of intrinsic and extrinsic reinforcers. Future studies are needed to clarify state and trait factors responsible for individual differences in the extent to which extrinsic rewards are necessary to set the conditions under which IM can develop.

  5. Diatom-derived polyunsaturated aldehydes activate cell death in human cancer cell lines but not normal cells.

    Directory of Open Access Journals (Sweden)

    Clementina Sansone

    Full Text Available Diatoms are an important class of unicellular algae that produce bioactive polyunsaturated aldehydes (PUAs that induce abortions or malformations in the offspring of invertebrates exposed to them during gestation. Here we compare the effects of the PUAs 2-trans,4-trans-decadienal (DD, 2-trans,4-trans-octadienal (OD and 2-trans,4-trans-heptadienal (HD on the adenocarcinoma cell lines lung A549 and colon COLO 205, and the normal lung/brunch epithelial BEAS-2B cell line. Using the viability MTT/Trypan blue assays, we show that PUAs have a toxic effect on both A549 and COLO 205 tumor cells but not BEAS-2B normal cells. DD was the strongest of the three PUAs tested, at all time-intervals considered, but HD was as strong as DD after 48 h. OD was the least active of the three PUAs. The effect of the three PUAs was somewhat stronger for A549 cells. We therefore studied the death signaling pathway activated in A549 showing that cells treated with DD activated Tumor Necrosis Factor Receptor 1 (TNFR1 and Fas Associated Death Domain (FADD leading to necroptosis via caspase-3 without activating the survival pathway Receptor-Interacting Protein (RIP. The TNFR1/FADD/caspase pathway was also observed with OD, but only after 48 h. This was the only PUA that activated RIP, consistent with the finding that OD causes less damage to the cell compared to DD and HD. In contrast, cells treated with HD activated the Fas/FADD/caspase pathway. This is the first report that PUAs activate an extrinsic apoptotic machinery in contrast to other anticancer drugs that promote an intrinsic death pathway, without affecting the viability of normal cells from the same tissue type. These findings have interesting implications also from the ecological viewpoint considering that HD is one of the most common PUAs produced by diatoms.

  6. Diatom-derived polyunsaturated aldehydes activate cell death in human cancer cell lines but not normal cells.

    Science.gov (United States)

    Sansone, Clementina; Braca, Alessandra; Ercolesi, Elena; Romano, Giovanna; Palumbo, Anna; Casotti, Raffaella; Francone, Maria; Ianora, Adrianna

    2014-01-01

    Diatoms are an important class of unicellular algae that produce bioactive polyunsaturated aldehydes (PUAs) that induce abortions or malformations in the offspring of invertebrates exposed to them during gestation. Here we compare the effects of the PUAs 2-trans,4-trans-decadienal (DD), 2-trans,4-trans-octadienal (OD) and 2-trans,4-trans-heptadienal (HD) on the adenocarcinoma cell lines lung A549 and colon COLO 205, and the normal lung/brunch epithelial BEAS-2B cell line. Using the viability MTT/Trypan blue assays, we show that PUAs have a toxic effect on both A549 and COLO 205 tumor cells but not BEAS-2B normal cells. DD was the strongest of the three PUAs tested, at all time-intervals considered, but HD was as strong as DD after 48 h. OD was the least active of the three PUAs. The effect of the three PUAs was somewhat stronger for A549 cells. We therefore studied the death signaling pathway activated in A549 showing that cells treated with DD activated Tumor Necrosis Factor Receptor 1 (TNFR1) and Fas Associated Death Domain (FADD) leading to necroptosis via caspase-3 without activating the survival pathway Receptor-Interacting Protein (RIP). The TNFR1/FADD/caspase pathway was also observed with OD, but only after 48 h. This was the only PUA that activated RIP, consistent with the finding that OD causes less damage to the cell compared to DD and HD. In contrast, cells treated with HD activated the Fas/FADD/caspase pathway. This is the first report that PUAs activate an extrinsic apoptotic machinery in contrast to other anticancer drugs that promote an intrinsic death pathway, without affecting the viability of normal cells from the same tissue type. These findings have interesting implications also from the ecological viewpoint considering that HD is one of the most common PUAs produced by diatoms.

  7. Intrinsic and extrinsic motivations for healthful dietary change in African Americans.

    Science.gov (United States)

    Satia, Jessie A; Galanko, Joseph A

    2007-01-01

    To describe associations of intrinsic and extrinsic motivations for dietary change with participant characteristics and current diet among African Americans. Cross-sectional survey of 658 African American adults in North Carolina provided information on intrinsic (self-image and health concerns) and extrinsic (social influence) motivation scales, participant characteristics, and diet. Most respondents considered it important to change their diet for health reasons; fewer were motivated by self-image or social influence. Motivation scales were significantly associated with demographic, behavioral, and psychosocial characteristics and fat, but not fruit/vegetable consumption, after adjustment for covariates (Pintrinsic and extrinsic motives may improve the effectiveness of dietary interventions in African Americans.

  8. Intrinsic and extrinsic motivational orientations in the competitive context: an examination of person-situation interactions.

    Science.gov (United States)

    Abuhamdeh, Sami; Csikszentmihalyi, Mihaly

    2009-10-01

    The current study examined Intrinsic Motivation Orientation and Extrinsic Motivation Orientation (Work Preference Inventory; Amabile, Hill, Hennessey, & Tighe, 1994) as potential trait-level moderators of the way Internet chess players responded to the intrinsic and extrinsic rewards of the chess games they played. On the basis of the defining characteristics of these 2 types of motivational orientations, we predicted that (a) Intrinsic Motivation Orientation would be associated with a stronger curvilinear relationship between challenge and enjoyment and (b) Extrinsic Motivation Orientation would be associated with a heightened affective responsivity to competitive outcome (i.e., winning vs. losing). Results supported the predictions. Implications of the findings are discussed.

  9. Invariant death

    Science.gov (United States)

    Frank, Steven A.

    2016-01-01

    In nematodes, environmental or physiological perturbations alter death’s scaling of time. In human cancer, genetic perturbations alter death’s curvature of time. Those changes in scale and curvature follow the constraining contours of death’s invariant geometry. I show that the constraints arise from a fundamental extension to the theories of randomness, invariance and scale. A generalized Gompertz law follows. The constraints imposed by the invariant Gompertz geometry explain the tendency of perturbations to stretch or bend death’s scaling of time. Variability in death rate arises from a combination of constraining universal laws and particular biological processes.

  10. Measurements of extrinsic fluorescence in Intralipid and polystyrene microspheres

    Science.gov (United States)

    Du Le, Vinh Nguyen; Nie, Zhaojun; Hayward, Joseph E.; Farrell, Thomas J.; Fang, Qiyin

    2014-01-01

    The fluorescence of Intralipid and polystyrene microspheres with sphere diameter of 1 µm at a representative lipid and microsphere concentration for simulation of mucosal tissue scattering has not been a subject of extensive experimental study. In order to elucidate the quantitative relationship between lipid and microsphere concentration and the respective fluorescent intensity, the extrinsic fluorescence spectra between 360 nm and 650 nm (step size of 5 nm) were measured at different lipid concentrations (from 0.25% to 5%) and different microsphere concentrations (0.00364, 0.0073, 0.0131 spheres per cubic micrometer) using laser excitation at 355 nm with pulse energy of 2.8 µJ. Current findings indicated that Intralipid has a broadband emission between 360 and 650 nm with a primary peak at 500 nm and a secondary peak at 450 nm while polystyrene microspheres have a single peak at 500 nm. In addition, for similar scattering properties the fluorescence of Intralipid solutions is approximately three-fold stronger than that of the microsphere solutions. Furthermore, Intralipid phantoms with lipid concentrations ~2% (simulating the bottom layer of mucosa) produce up to seven times stronger fluorescent emission than phantoms with lipid concentration ~0.25% (simulating the top layer of mucosa). The fluoresence decays of Intralipid and microsphere solutions were also recorded for estimation of fluorescence lifetime. PMID:25136497

  11. [Pathologic diagnosis and clinical analysis of chronic extrinsic allergic alveolitis].

    Science.gov (United States)

    Diao, Xiao-li; Jin, Mu-lan; Dai, Hua-ping; Li, Xue; Wei, Ping; Zhang, Yun-gang

    2011-11-01

    To study the clinicopathologic features and diagnostic approach of chronic extrinsic allergic alveolitis (EAA). Seven cases of chronic EAA diagnosed by open lung biopsy or lung transplant were enrolled into the study. The clinical and pathologic features were analyzed and the literature was reviewed. There were altogether 4 men and 3 women. The age of the patients ranged from 30 to 65 years (mean = 48 years). All cases represented chronic form and five cases diagnosed by open lung biopsy also showed features of recent aggravation, leading to hospitalization. Four cases had known history of exposure to inciting gases, pollens and pets, and only 2 cases were positive for allergens. High-resolution CT scan showed ground-glass attenuation and reticular pattern that often had a patchy distribution and central predominance. Bronchoalveolar lavage analysis showed marked lymphocytosis, with CD4(+)/CD8(+) ratio less than 1. Lung function test demonstrated a restrictive ventilatory defect, with decreased compliance, reduced diffusion capacity and high airway obstruction. Five cases had open lung biopsy performed and two cases had undergone lung transplantation. Pathologic examination showed bronchiolocentric cellular interstitial pneumonia, interstitial fibrosis, non-caseating epithelioid granulomas, epithelioid histiocytic infiltrate in the respiratory bronchioles and intraluminal budding fibrosis. The five cases with open lung biopsy performed also showed neutrophilic infiltrate in the alveoli. The two lung transplant cases were complicated by severe fibrotic changes. Chronic EAA demonstrates characteristic pathologic features. Definitive diagnosis requires correlation with clinical and radiologic findings due to possible morphologic mimicry of other diffuse parenchymal lung diseases.

  12. An outbreak of extrinsic alveolitis at a car engine plant.

    Science.gov (United States)

    Dawkins, Paul; Robertson, Alastair; Robertson, Wendy; Moore, Vicky; Reynolds, John; Langman, Gerald; Robinson, Edward; Harris-Roberts, Joanne; Crook, Brian; Burge, Sherwood

    2006-12-01

    Twelve workers from a car engine-manufacturing plant presented with extrinsic allergic alveolitis (EAA), with heterogeneous clinical, radiological and pathological findings. They were exposed to metalworking fluids (MWF) that cooled, lubricated and cleaned the machines. They were characterized by history, examination, lung function testing, radiology, bronchoscopic lavage, lung biopsy and serology. Sera were tested for precipitins to a crude extract of used MWF and to reference cultures of bacteria suspected to be implicated. All were males and none were current smokers. All had dyspnoea, many had weight loss and cough, but only half had influenza-like symptoms. Only half had auscultatory crackles. Five had peak flow variability, four with an occupational component. There was overall restrictive spirometry, decreased lung volumes and reduced gas transfers. Ten had radiological evidence of interstitial lung disease. Seven (of eight) had lymphocytosis on bronchial lavage, including the two with inconclusive radiology. Seven (of 11) had lung biopsies showing inflammatory infiltrates, two with fibrosis and one with granulomas. Three (of 11) had strong positive precipitins to an extract of the used MWF from the plant. Molecular biological analysis of the MWF revealed Acinetobacter and Ochrobactrum. Precipitins to Acinetobacter were detected in seven of 11 workers tested (and four of 11 control workers). Precipitins to Ochrobactrum were detected in three of 11 workers tested (and three of 11 control workers). This is the largest series reported in Europe of EAA due to an aerosol of microbiologically contaminated MWF in heavy manufacturing industry.

  13. Effect of extrinsic curvature on quark--hadron phase transition

    CERN Document Server

    Heydari-Fard, Malihe

    2009-01-01

    The last phase transition predicted by the standard model of particle physics took place at the QCD scale $T\\sim200$ MeV when the universe was about $t\\sim10^{-5}$ seconds old and the Hubble radius was around 10 Km. In this paper, we consider the quark--hadron phase transition in the context of brane-world cosmology where our universe is a 3-brane embedded in a $m$-dimensional bulk and localization of matter on the brane is achieved by means of a confining potential. We study the behavior of the physical quantities relevant to the description of the early universe like the energy density, temperature and scale factor, before, during, and after the phase transition and investigate the effects of extrinsic curvature on the cosmological phase transition. We show that the brane-world effects reduce the effective temperature of the quark--gluon plasma and of the hadronic fluid. Finally, we discuss the case where the universe evolved through a mixed phase with a small initial supercooling and monotonically growing ...

  14. [Swimming pool lung -- extrinsic allergic alveolitis or mycobacterial disease?].

    Science.gov (United States)

    Koschel, D; Pietrzyk, C; Sennekamp, J; Müller-Wening, D

    2006-05-01

    There have been several recent reports of pulmonary disease resulting from exposure to Mycobacterium avium complex in indoor hot tubs. The disease is thought to be due either to infection or extrinsic allergic alveolitis (EAA). In this report we describe the case of a patient who developed episodes of fever, dyspnea and cough 4-6 hours after cleaning his indoor swimming pool. A diagnosis of EAA was made on finding a restrictive lung function pattern with gas exchange abnormalities, a predominant lymphocytosis in the bronchoalveolar lavage, diffuse ground-glass opacities in the lower lobes on high-resolution computer tomography, and specific IgG antibody activity to the swimming pool water. There was no precipitin reaction or specific IgG antibody activity to microbes extracted from the water. Interestingly, the water contained Mycobacterium avium complex (MAC) in huge amounts and in this case the histopathological features of the lung biopsy specimens differed from those seen in typical EAA, but were similar to those described in "hot tub lung" caused by mycobacteria. Solely by avoidance of cleaning the swimming pool, without any pharmacological treatment, the patient recovered completely within three months. To the best of our knowledge, this is the first report of EAA possibly associated with MAC exposure in a swimming pool environment.

  15. Enabling complex genetic circuits to respond to extrinsic environmental signals.

    Science.gov (United States)

    Hoynes-O'Connor, Allison; Shopera, Tatenda; Hinman, Kristina; Creamer, John Philip; Moon, Tae Seok

    2017-03-06

    Genetic circuits have the potential to improve a broad range of metabolic engineering processes and address a variety of medical and environmental challenges. However, in order to engineer genetic circuits that can meet the needs of these real-world applications, genetic sensors that respond to relevant extrinsic and intrinsic signals must be implemented in complex genetic circuits. In this work, we construct the first AND and NAND gates that respond to temperature and pH, two signals that have relevance in a variety of real-world applications. A previously identified pH-responsive promoter and a temperature-responsive promoter were extracted from the E. coli genome, characterized, and modified to suit the needs of the genetic circuits. These promoters were combined with components of the type III secretion system in Salmonella typhimurium and used to construct a set of AND gates with up to 23-fold change. Next, an antisense RNA was integrated into the circuit architecture to invert the logic of the AND gate and generate a set of NAND gates with up to 1168-fold change. These circuits provide the first demonstration of complex pH- and temperature-responsive genetic circuits, and lay the groundwork for the use of similar circuits in real-world applications. Biotechnol. Bioeng. 2017;9999: 1-6. © 2017 Wiley Periodicals, Inc.

  16. Intrinsic and extrinsic rewards in a nonformal environmental education program.

    Science.gov (United States)

    Price, Emily A; Vining, Joanne; Saunders, Carol D

    2009-09-01

    Humans are surrounded by threats to the environment, many of their own making. The severity of environmental problems will not decrease unless action is taken to develop and encourage greater environmentally responsible behavior (ERB) in the general populace. Environmental education (EE) is one method for strengthening precursors to ERB such as knowledge and attitudes, but research on the connection is currently unclear. In this paper we present the results of a study investigating the role played by rewards in encouraging ERB precursors for adults and children involved in a zoo-based Nature Swap program. We used semistructured interviews to question 91 participants, including 38 children, 38 adult guardians, and 15 staff members regarding the importance of rewards in the program. We content analyzed the interviews to identify and describe major themes and then coded them. We found that adult guardians and Play Partners perceived intrinsic and extrinsic rewards as aiding in maintaining motivation and interest in the nonformal Nature Swap program. In addition, both children and adult companion participants in the program mentioned strengthened precursors to ERB. Overall we found that adult companions perceived that children who participated in the program spent more quality time outdoors and had a heightened awareness of their surroundings as a result of program-based rewards. Implications for other EE and conservation education programs are discussed.

  17. Iterative procedure for camera parameters estimation using extrinsic matrix decomposition

    Science.gov (United States)

    Goshin, Yegor V.; Fursov, Vladimir A.

    2016-03-01

    This paper addresses the problem of 3D scene reconstruction in cases when the extrinsic parameters (rotation and translation) of the camera are unknown. This problem is both important and urgent because the accuracy of the camera parameters significantly influences the resulting 3D model. A common approach is to determine the fundamental matrix from corresponding points on two views of a scene and then to use singular value decomposition for camera projection matrix estimation. However, this common approach is very sensitive to fundamental matrix errors. In this paper we propose a novel approach in which camera parameters are determined directly from the equations of the projective transformation by using corresponding points on the views. The proposed decomposition allows us to use an iterative procedure for determining the parameters of the camera. This procedure is implemented in two steps: the translation determination and the rotation determination. The experimental results of the camera parameters estimation and 3D scene reconstruction demonstrate the reliability of the proposed approach.

  18. Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on all-cause mortality, cardiovascular deaths, and cardiovascular events in patients with diabetes mellitus: a meta-analysis.

    Science.gov (United States)

    Cheng, Jun; Zhang, Wen; Zhang, Xiaohui; Han, Fei; Li, Xiayu; He, Xuelin; Li, Qun; Chen, Jianghua

    2014-05-01

    Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) may have different effects on cardiovascular (CV) events in patients with diabetes mellitus (DM). To conduct a meta-analysis to separately evaluate the effects of ACEIs and ARBs on all-cause mortality, CV deaths, and major CV events in patients with DM. DATA SOURCES Data sources included MEDLINE (1966-2012), EMBASE (1988-2012), the Cochrane Central Register of Controlled Trials, conference proceedings, and article reference lists. We included randomized clinical trials reporting the effects of ACEI and ARB regimens for DM on all-cause mortality, CV deaths, and major CV events with an observation period of at least 12 months. Studies were excluded if they were crossover trials. Dichotomous outcome data from individual trials were analyzed using the risk ratio (RR) measure and its 95% CI with random-effects models. We estimated the difference between the estimates of the subgroups according to tests for interaction. We performed meta-regression analyses to identify sources of heterogeneity. Primary end points were all-cause mortality and death from CV causes. Secondary end points were the effects of ACEIs and ARBs on major CV events. Twenty-three of 35 identified trials compared ACEIs with placebo or active drugs (32,827 patients) and 13 compared ARBs with no therapy (controls) (23,867 patients). When compared with controls (placebo/active treatment), ACEIs significantly reduced the risk of all-cause mortality by 13% (RR, 0.87; 95% CI, 0.78-0.98), CV deaths by 17% (0.83; 0.70-0.99), and major CV events by 14% (0.86; 0.77-0.95), including myocardial infarction by 21% (0.79; 0.65-0.95) and heart failure by 19% (0.81; 0.71-0.93). Treatment with ARBs did not significantly affect all-cause mortality (RR, 0.94; 95% CI, 0.82-1.08), CV death rate (1.21; 0.81-1.80), and major CV events (0.94; 0.85-1.01) with the exception of heart failure (0.70; 0.59-0.82). Both ACEIs and ARBs were

  19. TNF α and reactive oxygen species in necrotic cell death

    Institute of Scientific and Technical Information of China (English)

    Michael J Morgan; You-Sun Kim; Zheng-gang Liu

    2008-01-01

    Death receptors, including the TNF receptor-1 (TNF-RI), have been shown to be able to initiate caspase-independent cell death. This form of "necrotic cell death" appears to be dependent on the generation of reactive oxygen species. Recent data have indicated that superoxide generation is dependent on the activation of NADPH oxidases, which form a complex with the adaptor molecules RIP1 and TRADD. The mechanism of superoxide generation further establishes RIP1 as the central molecule in ROS production and cell death initiated by TNFa and other death receptors. A role for the sustained JNK activation in necrotic cell death is also suggested. The sensitization of virus-infected cells to TNFa indicates that necrotic cell death may represent an alternative cell death pathway for clearance of infected cells.

  20. A Dynamic Assignment of Extrinsic Information Distribution by a Frequency Means for Iterative Turbo Decoder

    Institute of Scientific and Technical Information of China (English)

    YANGFengfan

    2003-01-01

    In this paper, a new strategy for iterative turbo decoding is proposed, where a Generalized Gaussian distribution (GGD) is applied to model the statistical distributions of the extrinsic information generated by the component decoders. An Euclidean distance criterion is also introduced to choose a most likely candidate of the extrinsic information distribution before the each constituent decoding by a novel frequency means. The simulation results show that performance of an iterative decoder with this new technique surpasses the conventional Gaussian solution for the extrinsic information under the same channel conditions. Meanwhile, the evolution process of the extrinsic information density function can be tracked from iteration to iteration in the sense of the proposed criterion.

  1. Topological implications of the extrinsic curvature for the cosmological constant problem

    CERN Document Server

    Capistrano, Abraao J S

    2014-01-01

    The concept of smooth deformation of a Riemannian manifolds associated with the extrinsic curvature is explained and applied to FLRW cosmology. We show that such deformation can be derived from an Einstein-Hilbert-like dynamical principle producing an observable effect in the sense of Noether. The Gupta equations are used to address the problem of the cosmological constant to provide the expression of the function $b(t)$ which is a consequence of the effect of extrinsic curvature. When using such a modification, we notice on how the extrinsic curvature compensates both quantitative and qualitative difference between $ \\Lambda$ and $\\rho_{\\; vac}$ due to the topological characteristics of the extrinsic geometry. It is also shown that the coincidence problem can be alleviated in this framework.

  2. The detrimental effects of extrinsic reinforcement on “Intrinsic motivation”

    Science.gov (United States)

    Dickinson, Alyce M.

    1989-01-01

    Extrinsic consequences have been criticized on the grounds that they decrease intrinsic motivation or internally initiated behavior. Two popular rationales for this criticism, Lepper's overjustification hypothesis (1981) and Deci's motivational theory (Deci & Ryan, 1985), are reviewed and the criticism is then redefined behaviorally. “Intrinsically controlled” behavior is defined as behavior maintained by response-produced reinforcers, and the question concerning extrinsic consequences is thus restated as follows: When behavior is maintained by response-produced stimuli, does extrinsic reinforcement decrease the reinforcing value of those stimuli? The empirical support for this detrimental effect is summarized briefly, and several possible explanations for the phenomenon are offered. Research results that reflect on the effect's generality and social significance are discussed next, with the conclusion that the effect is transient and not likely to occur at all if extrinsic rewards are reinforcing, noncompetitive, based on reasonable performance standards, and delivered repetitively. PMID:22478013

  3. Time is on my side: time, general mental ability, human capital, and extrinsic career success.

    Science.gov (United States)

    Judge, Timothy A; Klinger, Ryan L; Simon, Lauren S

    2010-01-01

    The present study linked general mental ability (GMA) to extrinsic career success using a multilevel framework that included time and 3 possible time-based mediators of the GMA-career success relationship. Results, based on a large national sample, revealed that over a 28-year period, GMA affected growth in 2 indicators of extrinsic career success (income and occupational prestige), such that the careers of high-GMA individuals ascended more steeply over time than those of low-GMA individuals. Part of the reason high-GMA individuals had steeper growth in extrinsic success over time was because they attained more education, completed more job training, and gravitated toward more complex jobs. GMA also moderated the degree to which within-individual variation in the mediating variables affected within-individual variation in extrinsic career success over time: Education, training, and job complexity were much more likely to translate into career success for more intelligent individuals.

  4. First principles studies of extrinsic and intrinsic defects in boron nitride nanotubes

    CSIR Research Space (South Africa)

    Mashapa, MG

    2012-10-01

    Full Text Available Spin polarized density functional theory has been used to investigate the structural stability and electronic properties of extrinsic and intrinsic defects in boron nitride nanotubes. Carbon substitutional defects under nitrogen rich and boron...

  5. Relationships of Parental Behavior to "Disadvantaged" Children's Intrinsic-Extrinsic Motivation for Task Striving

    Science.gov (United States)

    Solomon, Daniel; Houlihan, Kevin A.

    1972-01-01

    In this study, the relevance of striving situations to intrinsic and extrinsic motivation was manipulated by varying the degree of involvement in the child's performance displayed by the experimenter. (Authors)

  6. Intrinsic and Extrinsic Motivation Among Adolescent Ten-Pin Bowlers in Kuala Lumpur, Malaysia

    National Research Council Canada - National Science Library

    Eng-Wah Teo; Selina Khoo; Rebecca Wong; Eng-Hoe Wee; Boon-Hooi Lim; Shabesan Sit Rengasamy

    2015-01-01

    .... The purpose of this study was to investigate different types of motivation (i.e., intrinsic vs. extrinsic) based on self-determination theory from the perspective of gender and the bowler type...

  7. MECHANISMS UNDERLYING CREATIVE PERFORMANCE: EMPLOYEE PERCEPTIONS OF INTRINSIC AND EXTRINSIC REWARDS FOR CREATIVITY

    National Research Council Canada - National Science Library

    Hye Jung Yoon; Sun Young Sung; Jin Nam Choi

    2015-01-01

      In this study, we clarified some of the ambiguities in the rewards-creativity relationship by focusing on creative performance in organizations that is contingent on intrinsic and extrinsic rewards...

  8. Consolidation power of extrinsic rewards: reward cues enhance long-term memory for irrelevant past events.

    Science.gov (United States)

    Murayama, Kou; Kitagami, Shinji

    2014-02-01

    Recent research suggests that extrinsic rewards promote memory consolidation through dopaminergic modulation processes. However, no conclusive behavioral evidence exists given that the influence of extrinsic reward on attention and motivation during encoding and consolidation processes are inherently confounded. The present study provides behavioral evidence that extrinsic rewards (i.e., monetary incentives) enhance human memory consolidation independently of attention and motivation. Participants saw neutral pictures, followed by a reward or control cue in an unrelated context. Our results (and a direct replication study) demonstrated that the reward cue predicted a retrograde enhancement of memory for the preceding neutral pictures. This retrograde effect was observed only after a delay, not immediately upon testing. An additional experiment showed that emotional arousal or unconscious resource mobilization cannot explain the retrograde enhancement effect. These results provide support for the notion that the dopaminergic memory consolidation effect can result from extrinsic reward.

  9. Cell-Extrinsic TNF Collaborates with TRIF Signaling To Promote Yersinia-Induced Apoptosis.

    Science.gov (United States)

    Peterson, Lance W; Philip, Naomi H; Dillon, Christopher P; Bertin, John; Gough, Peter J; Green, Douglas R; Brodsky, Igor E

    2016-11-15

    Innate immune responses that are crucial for control of infection are often targeted by microbial pathogens. Blockade of NF-κB and MAPK signaling by the Yersinia virulence factor YopJ inhibits cytokine production by innate immune cells but also triggers cell death. This cell death requires RIPK1 kinase activity and caspase-8, which are engaged by TLR4 and the adaptor protein TRIF. Nevertheless, TLR4- and TRIF-deficient cells undergo significant apoptosis, implicating TLR4/TRIF-independent pathways in the death of Yersinia-infected cells. In this article, we report a key role for TNF/TNFR1 in Yersinia-induced cell death of murine macrophages, which occurs despite the blockade of NF-κB and MAPK signaling imposed by Yersinia on infected cells. Intriguingly, direct analysis of YopJ injection revealed a heterogeneous population of injection-high and injection-low cells, and demonstrated that TNF expression came from the injection-low population. Moreover, TNF production by this subpopulation was necessary for maximal apoptosis in the population of highly injected cells, and TNFR-deficient mice displayed enhanced susceptibility to Yersinia infection. These data demonstrate an important role for collaboration between TNF and pattern recognition receptor signals in promoting maximal apoptosis during bacterial infection, and demonstrate that heterogeneity in virulence factor injection and cellular responses play an important role in promoting anti-Yersinia immune defense. Copyright © 2016 by The American Association of Immunologists, Inc.

  10. Effects of cigarette smoke exposure on nicotinic acetylcholine receptor subunits {alpha}7 and {beta}2 in the sudden infant death syndrome (SIDS) brainstem

    Energy Technology Data Exchange (ETDEWEB)

    Machaalani, Rita, E-mail: rita.machaalani@sydney.edu.au [Department of Medicine, The University of Sydney, NSW 2006 (Australia); Bosch Institute, The University of Sydney, NSW 2006 (Australia); The Children' s Hospital at Westmead, NSW 2145 (Australia); Say, Meichien [Department of Medicine, The University of Sydney, NSW 2006 (Australia); Bosch Institute, The University of Sydney, NSW 2006 (Australia); Waters, Karen A. [Department of Medicine, The University of Sydney, NSW 2006 (Australia); Bosch Institute, The University of Sydney, NSW 2006 (Australia); The Children' s Hospital at Westmead, NSW 2145 (Australia)

    2011-12-15

    It is postulated that nicotine, as the main neurotoxic constituent of cigarette smoke, influences SIDS risk through effects on nicotinic acetylcholine receptors (nAChRs) in brainstem nuclei that control respiration and arousal. This study compared {alpha}7 and {beta}2 nAChR subunit expression in eight nuclei of the caudal and rostral medulla and seven nuclei of the pons between SIDS (n = 46) and non-SIDS infants (n = 14). Evaluation for associations with known SIDS risk factors included comparison according to whether infants had a history of exposure to cigarette smoke in the home, and stratification for sleep position and gender. Compared to non-SIDS infants, SIDS infants had significantly decreased {alpha}7 in the caudal nucleus of the solitary tract (cNTS), gracile and cuneate nuclei, with decreased {beta}2 in the cNTS and increased {beta}2 in the facial. When considering only the SIDS cohort: 1-cigarette smoke exposure was associated with increased {alpha}7 in the vestibular nucleus and increased {beta}2 in the rostral dorsal motor nucleus of the vagus, rNTS and Cuneate, 2-there was a gender interaction for {alpha}7 in the gracile and cuneate, and {beta}2 in the cNTS and rostral arcuate nucleus, and 3-there was no effect of sleep position on {alpha}7, but prone sleep was associated with decreased {beta}2 in three nuclei of the pons. In conclusion, SIDS infants demonstrate differences in expression of {alpha}7 and {beta}2 nAChRs within brainstem nuclei that control respiration and arousal, which is independent on prior history of cigarette smoke exposure, especially for the NTS, with additional differences for smoke exposure ({beta}2), gender ({alpha}7 and {beta}2) and sleep position ({beta}2) evident. -- Highlights: Black-Right-Pointing-Pointer The 'normal' response to smoke exposure is decreased {alpha}7 and {beta}2 in certain nuclei. Black-Right-Pointing-Pointer SIDS infants have decreased {alpha}7 in cNTS, Grac and Cun. Black

  11. Optical phase modulator utilizing a transparent piezofilm for use with the extrinsic fiber interferometer

    Science.gov (United States)

    Sudarshanam, V. S.; Claus, Richard O.

    1993-03-01

    A piezoelectnc polyvinylidene flouride (PVF2) film with transparent indium tin oxide electrode metallization is placed directly in the path of a single mode fiber output, to form an extrinsic optical interferometer. This device can be used concurrently with another extrinsic inteferometer on a fiber directional coupler to generate a carrier phase modulation on which the signal phase shift is superimposed. Experimental results of the induced phase shifting coefficient are presented for two arrangements of the piezofilm differing in their boundary clamping conditions.

  12. Sulfasalazine-induced extrinsic allergic alveolitis in a patient with psoriatic arthritis.

    Science.gov (United States)

    Woltsche, M; Woltsche-Kahr, I; Roeger, G M; Aberer, W; Popper, H

    2001-11-20

    We report the first case of a well defined extrinsic allergic alveolitis as a complication of sulfasalazine therapy in a patient treated for psoriatic arthritis. CT of the chest showed small nodular densities over both lungs, BAL demonstrated a highly active lymphocytic alveolitis and transbronchial biopsies revealed lymphoplasmocytic interstitial infiltration. Sulfasalazine as causative agent was proven by an inadvertent rechallenge three years later and a positive lymphocyte transformation test. sulfasalazine; psoriatic arthritis; extrinsic allergic alveolitis

  13. Multiexciton complex from extrinsic centers in AlGaAs epilayers on Ge and Si substrates

    Energy Technology Data Exchange (ETDEWEB)

    Sarti, F.; Muñoz Matutano, G.; Bauer, D.; Dotti, N.; Vinattieri, A.; Gurioli, M., E-mail: gurioli@lens.unifi.it [Dipartimento di Fisica e Astronomia, LENS and CNISM, Università di Firenze, Via Sansone 1, I-50019 Firenze (Italy); Bietti, S.; Sanguinetti, S. [Dipartimento di Scienza dei Materiali and L-NESS, Università di Milano Bicocca, Via Cozzi 53, I-20125 Milano (Italy); Isella, G. [Dipartimento di Fisica and L-NESS, Politecnico di Milano, Via Anzani 42, 22100 Como (Italy)

    2013-12-14

    The multiexciton properties of extrinsic centers from AlGaAs layers on Ge and Si substrates are addressed. The two photon cascade is found both in steady state and in time resolved experiments. Polarization analysis of the photoluminescence provides clearcut attribution to neutral biexciton complexes. Our findings demonstrate the prospect of exploiting extrinsic centers for generating entangled photon pairs on a Si based device.

  14. A validity generalization procedure to test relations between intrinsic and extrinsic motivation and influence tactics.

    Science.gov (United States)

    Barbuto, John E; Moss, Jennifer A

    2006-08-01

    The relations of intrinsic and extrinsic motivation with use of consultative, legitimating, and pressure influence tactics were examined using validity generalization procedures. 5 to 7 field studies with cumulative samples exceeding 800 were used to test each relationship. Significance was found for relation between agents' intrinsic motivation and their use of consultative influence tactics and agents' extrinsic motivation and their use of legitimating influence tactics.

  15. Extrinsic Calibration for Vehicle-based Mobile Mapping System

    Directory of Open Access Journals (Sweden)

    SHI Limei

    2015-01-01

    Full Text Available Having the advantage of 360° imaging and rotation invariance, panoramic camera has gradually been used in mobile mapping systems(MMS. Calibration is an essential requirement to make sure that MMS can get high quality geo-information. This paper presents a way to address the extrinsic calibration for vehicle-based MMS composed of panoramic camera and Position and Orientation System (POS. Firstly, control points in the natural scene are set up, whose spatial coordinates are measured with high precision. Secondly, a panoramic spherical model is constructed and panoramic image can be projected to this model by means of spherical reverse transformation projection. Then, localize and select the control points in 3D spherical panoramic view but not in panoramic distorted image directly, the spherical coordinates of control points in panoramic image are gotten. After points correspondence is established, make use of direct geo-reference positioning equation and coordinate transformation, the translation and rotation parameters of panoramic camera relative to POS are computed. Experiments are conducted separately in space city calibration site located in Beijing and the Binhai New Area in Tianjin using our approach. Test results are listed as follows. When the GPS signal are of good quality, absolute positioning mean square error of a point is 10.3 cm in two-dimension plane and 16.5 cm in height direction; Otherwise, it is 35.4 cm in two-dimension plane and 54.8 cm in height direction. The max relative error of distance measurement is about 5 cm over a short distance (distance<3 km, which is not obviously affected by the GPS signal quality.

  16. Extrinsic information influences taste and flavor perception: a review from psychological and neuroimaging perspectives.

    Science.gov (United States)

    Okamoto, Masako; Dan, Ippeita

    2013-03-01

    The perception of taste and flavor can be greatly biased by extrinsic cues, or the information about a food that comes from outside of the food itself, such as package designs, brands, prices, and so on. In order to understand taste/flavor experiences in a broader context, it is necessary to consider factors other than the food/tastants themselves. This review aims to summarize some of the relevant findings from psychological and neuroimaging studies, focusing on depicting how extrinsic cues exert their effect on taste and flavor. Currently, the most frequently considered psychological mediator for the effects of extrinsic cues is expectation. Depending on the gap between expectation and taste/flavor experience, four major models predict outcomes of expectation effects: (1) assimilation, (2) generalized-negativity, (3) contrast, and (4) assimilation-contrast. Among them, the most influential is the assimilation model proposing that taste/flavor experiences are modified toward what one expects. Thus far, all the neuroimaging studies examining the influence of extrinsic cues have dealt with assimilation effects. They suggest that when extrinsic cues influence taste/flavor perception, cortical representations of taste/flavor are also modulated. Collectively neuroimaging findings partly answer questions arising from psychological aspects: the influence of extrinsic cues is not due to superficial response bias but to truly changed perception. These findings, albeit limited to assimilation effects, suggest that combined understanding from both psychological and neuroimaging studies would help deepen our understanding of the taste experience. Copyright © 2012. Published by Elsevier Ltd.

  17. Quantifying extrinsic noise in gene expression using the maximum entropy framework.

    Science.gov (United States)

    Dixit, Purushottam D

    2013-06-18

    We present a maximum entropy framework to separate intrinsic and extrinsic contributions to noisy gene expression solely from the profile of expression. We express the experimentally accessible probability distribution of the copy number of the gene product (mRNA or protein) by accounting for possible variations in extrinsic factors. The distribution of extrinsic factors is estimated using the maximum entropy principle. Our results show that extrinsic factors qualitatively and quantitatively affect the probability distribution of the gene product. We work out, in detail, the transcription of mRNA from a constitutively expressed promoter in Escherichia coli. We suggest that the variation in extrinsic factors may account for the observed wider-than-Poisson distribution of mRNA copy numbers. We successfully test our framework on a numerical simulation of a simple gene expression scheme that accounts for the variation in extrinsic factors. We also make falsifiable predictions, some of which are tested on previous experiments in E. coli whereas others need verification. Application of the presented framework to more complex situations is also discussed.

  18. The interplay of intrinsic and extrinsic bounded noises in biomolecular networks.

    Directory of Open Access Journals (Sweden)

    Giulio Caravagna

    Full Text Available After being considered as a nuisance to be filtered out, it became recently clear that biochemical noise plays a complex role, often fully functional, for a biomolecular network. The influence of intrinsic and extrinsic noises on biomolecular networks has intensively been investigated in last ten years, though contributions on the co-presence of both are sparse. Extrinsic noise is usually modeled as an unbounded white or colored gaussian stochastic process, even though realistic stochastic perturbations are clearly bounded. In this paper we consider Gillespie-like stochastic models of nonlinear networks, i.e. the intrinsic noise, where the model jump rates are affected by colored bounded extrinsic noises synthesized by a suitable biochemical state-dependent Langevin system. These systems are described by a master equation, and a simulation algorithm to analyze them is derived. This new modeling paradigm should enlarge the class of systems amenable at modeling. We investigated the influence of both amplitude and autocorrelation time of a extrinsic Sine-Wiener noise on: (i the Michaelis-Menten approximation of noisy enzymatic reactions, which we show to be applicable also in co-presence of both intrinsic and extrinsic noise, (ii a model of enzymatic futile cycle and (iii a genetic toggle switch. In (ii and (iii we show that the presence of a bounded extrinsic noise induces qualitative modifications in the probability densities of the involved chemicals, where new modes emerge, thus suggesting the possible functional role of bounded noises.

  19. Structural Coupling of Extrinsic Proteins with the Oxygen-Evolving Center in Photosystem II

    Directory of Open Access Journals (Sweden)

    Kentaro eIfuku

    2016-02-01

    Full Text Available Photosystem II (PSII, which catalyzes photosynthetic water oxidation, is composed of more than 20 subunits, including membrane-intrinsic and -extrinsic proteins. The PSII extrinsic proteins shield the catalytic Mn4CaO5 cluster from the outside bulk solution and enhance binding of inorganic cofactors, such as Ca2+ and Cl-, in the oxygen-evolving center (OEC of PSII. Among PSII extrinsic proteins, PsbO is commonly found in all oxygenic organisms, while PsbP and PsbQ are specific to higher plants and green algae, and PsbU, PsbV, CyanoQ, and CyanoP exist in cyanobacteria. In addition, red algae and diatoms have unique PSII extrinsic proteins, such as PsbQ’ and Psb31, suggesting functional divergence during evolution. Recent studies with reconstitution experiments combined with Fourier transform infrared spectroscopy have revealed how the individual PSII extrinsic proteins affect the structure and function of the OEC in different organisms. In this review, we summarize our recent results and discuss changes that have occurred in the structural coupling of extrinsic proteins with the OEC during evolutionary history.

  20. Dynamics of degeneration and regeneration in developing zebrafish peripheral axons reveals a requirement for extrinsic cell types

    Directory of Open Access Journals (Sweden)

    Villegas Rosario

    2012-06-01

    Full Text Available Abstract Background Understanding the cellular mechanisms regulating axon degeneration and regeneration is crucial for developing treatments for nerve injury and neurodegenerative disease. In neurons, axon degeneration is distinct from cell body death and often precedes or is associated with the onset of disease symptoms. In the peripheral nervous system of both vertebrates and invertebrates, after degeneration of detached fragments, axons can often regenerate to restore function. Many studies of axonal degeneration and regeneration have used in vitro approaches, but the influence of extrinsic cell types on these processes can only be fully addressed in live animals. Because of its simplicity and superficial location, the larval zebrafish posterior lateral line (pLL nerve is an ideal model system for live studies of axon degeneration and regeneration. Results We used laser axotomy and time-lapse imaging of pLL axons to characterize the roles of leukocytes, Schwann cells and target sensory hair cells in axon degeneration and regeneration in vivo. Immune cells were essential for efficient removal of axonal debris after axotomy. Schwann cells were required for proper fasciculation and pathfinding of regenerating axons to their target cells. Intact target hair cells were not themselves required for regeneration, but chemical ablation of neuromasts caused axons to transiently deviate from their normal paths. Conclusions Macrophages, Schwann cells, and target sensory organs are required for distinct aspects of pLL axon degeneration or regeneration in the zebrafish larva. Our work introduces a powerful vertebrate model for analyzing axonal degeneration and regeneration in the living animal and elucidating the role of extrinsic cell types in these processes.

  1. Spermatocyte apoptosis, which involves both intrinsic and extrinsic pathways, explains the sterility of Graomys griseoflavus x Graomys centralis male hybrids.

    Science.gov (United States)

    Rodriguez, Valeria; Diaz de Barboza, Gabriela; Ponce, Ruben; Merico, Valeria; Garagna, Silvia; Tolosa de Talamoni, Nori

    2010-01-01

    Spermatogenic impairment and the apoptotic pathways involved in establishing sterility of male hybrids obtained from crossing Graomys griseoflavus females with Graomys centralis males were studied. Testes from G. centralis, G. griseoflavus and hybrids were compared at different ages. Terminal transferase-mediated dUTP nick-end labelling assay (TUNEL), Fas, Bax and cytochrome c labelling were used for apoptosis evaluation, and calbindin D(28k) staining as an anti-apoptotic molecule. In 1-month-old animals, spermatocytes were positive for all apoptotic markers, but moderate TUNEL (+) spermatocyte frequency was only found in G. centralis. At subsequent ages, the apoptotic markers were downregulated in testes from parental cytotypes, but not in hybrid testes. TUNEL (+) spermatocytes were present at 78% and 44% per tubule cross-section in 2- and 3-month-old hybrid animals, respectively. Pachytene spermatocyte death in adult hybrids occurs via apoptosis, as revealed by high caspase-3 expression. Calbindin was highly expressed in spermatocytes of adult hybrids, in which massive cell death occurs via apoptosis. Calbindin co-localisation with TUNEL or Fas, Bax and cytochrome c was very limited, suggesting an inverse regulation of calbindin and apoptotic markers. Hybrid sterility is due to breakdown of spermatogenesis at the pachytene spermatocyte stage. Both extrinsic and intrinsic pathways are involved in apoptosis of spermatocytes, which are the most sensitive cell type to apoptotic stimuli.

  2. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation.

    Science.gov (United States)

    Chemnitz, Jens M; Parry, Richard V; Nichols, Kim E; June, Carl H; Riley, James L

    2004-07-15

    To study the cis- and trans-acting factors that mediate programmed death 1 (PD-1) signaling in primary human CD4 T cells, we constructed a chimeric molecule consisting of the murine CD28 extracellular domain and human PD-1 cytoplasmic tail. When introduced into CD4 T cells, this construct mimics the activity of endogenous PD-1 in terms of its ability to suppress T cell expansion and cytokine production. The cytoplasmic tail of PD-1 contains two structural motifs, an ITIM and an immunoreceptor tyrosine-based switch motif (ITSM). Mutation of the ITIM had little effect on PD-1 signaling or functional activity. In contrast, mutation of the ITSM abrogated the ability of PD-1 to block cytokine synthesis and to limit T cell expansion. Further biochemical analyses revealed that the ability of PD-1 to block T cell activation correlated with recruitment of Src homology region 2 domain-containing phosphatase-1 (SHP-1) and SHP-2, and not the adaptor Src homology 2 domain-containing molecule 1A, to the ITSM domain. In TCR-stimulated T cells, SHP-2 associated with PD-1, even in the absence of PD-1 engagement. Despite this interaction, the ability of PD-1 to block T cell activation required receptor ligation, suggesting that colocalization of PD-1 with CD3 and/or CD28 may be necessary for inhibition of T cell activation.

  3. 纳秒脉冲诱导SKOV3细胞凋亡的死亡受体途径分析%Analysis on Death Receptor Apoptotic Pathway of SKOV3 Cells Induced by Nanosecond Pulsed Electric Field

    Institute of Scientific and Technical Information of China (English)

    郭飞; 姚陈果; 王建; 孙才新; 夏如民; 唐均英

    2012-01-01

    The specific bioelectric effect of tumor cells apoptosis induced by nanosecond pulsed electric field ( nsPEF) has aroused great attention. Based on the latest studies, the effects of nsPEF on plasma membrane were illustrated to study the signaling pathway of death receptor apoptotic. Therefore, optimized parameters (voltage amplitude of 9 kV, pulse duration of 100 ns, pulse number of 30, repetition frequency of 1 Hz) of nsPEF were performed on SKOVa cells. Cell death and apoptosis were tested by flow cytometry, massager ribonucleic acid[mRNA) release of Fas, FasL, cysteine aspartic acid specific protease-8 (Caspase 8) and Bid were examined by reverse transcription-polymerase chain reaction(RT-PCR) method, and protein release of Fas, FasL, Caspase-8 and Bid were studied by western blot technology. Experimental results indicate that release of Fas, FasL, Caspase-8 and Bid greatly increase when tumor cell apoptosis with nsPEF, in advance to trigger the apoptotic signaling pathway of death receptor. The results provide a theoretic support for clinical tumor treatment with boarding the mechanism study of nsPEF-indueed apoptosis.%ns脉冲电场独特的诱导肿瘤细胞凋亡的生物电效应,引起了相关学者广泛的关注。为此,结合最新研究成果,侧重于ns脉冲对细胞膜结构和功能的影响,重点研究ns脉冲电场诱导肿瘤细胞凋亡的死亡受体途径。将优化的脉冲电场参数组合(电压幅值为9kV,脉宽为100ns,脉冲为30个,频率为1Hz)作用于人卵巢浆液性囊腺癌细胞SKOV3。利用流式细胞术和凝胶电泳法检测细胞凋亡、坏死情况;逆转录聚合酶链式扩增反应(reverse transcription-polymerase chain reaction,RT-PCR)法检测Fas、FasL、半胱氨酸天冬氨酸蛋白酶-8(cysteine aspartic acid specific protease-8,Caspase-8)和Bid的信使核糖核酸(messager ribonucleic acid,mRNA)释放水平;蛋白质印迹(western blot

  4. Combination therapy of established cancer using a histone deacetylase inhibitor and a TRAIL receptor agonist.

    Science.gov (United States)

    Frew, Ailsa J; Lindemann, Ralph K; Martin, Ben P; Clarke, Christopher J P; Sharkey, Janelle; Anthony, Desiree A; Banks, Kellie-Marie; Haynes, Nicole M; Gangatirkar, Pradnya; Stanley, Kym; Bolden, Jessica E; Takeda, Kazuyoshi; Yagita, Hideo; Secrist, J Paul; Smyth, Mark J; Johnstone, Ricky W

    2008-08-12

    Histone deacetylase inhibitors (HDACi) and agents such as recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic anti-TRAIL receptor (TRAIL-R) antibodies are anticancer agents that have shown promise in preclinical settings and in early phase clinical trials as monotherapies. Although HDACi and activators of the TRAIL pathway have different molecular targets and mechanisms of action, they share the ability to induce tumor cell-selective apoptosis. The ability of HDACi to induce expression of TRAIL-R death receptors 4 and 5 (DR4/DR5), and induce tumor cell death via the intrinsic apoptotic pathway provides a molecular rationale to combine these agents with activators of the TRAIL pathway that activate the alternative (death receptor) apoptotic pathway. Herein, we demonstrate that the HDACi vorinostat synergizes with the mouse DR5-specific monoclonal antibody MD5-1 to induce rapid and robust tumor cell apoptosis in vitro and in vivo. Importantly, using a preclinical mouse breast cancer model, we show that the combination of vorinostat and MD5-1 is safe and induces regression of established tumors, whereas single agent treatment had little or no effect. Functional analyses revealed that rather than mediating enhanced tumor cell apoptosis via the simultaneous activation of the intrinsic and extrinsic apoptotic pathways, vorinostat augmented MD5-1-induced apoptosis concomitant with down-regulation of the intracellular apoptosis inhibitor cellular-FLIP (c-FLIP). These data demonstrate that combination therapies involving HDACi and activators of the TRAIL pathway can be efficacious for the treatment of cancer in experimental mouse models.

  5. Bimanual motor coordination controlled by cooperative interactions in intrinsic and extrinsic coordinates.

    Science.gov (United States)

    Sakurada, Takeshi; Ito, Koji; Gomi, Hiroaki

    2016-01-01

    Although strong motor coordination in intrinsic muscle coordinates has frequently been reported for bimanual movements, coordination in extrinsic visual coordinates is also crucial in various bimanual tasks. To explore the bimanual coordination mechanisms in terms of the frame of reference, here we characterized implicit bilateral interactions in visuomotor tasks. Visual perturbations (finger-cursor gain change) were applied while participants performed a rhythmic tracking task with both index fingers under an in-phase or anti-phase relationship in extrinsic coordinates. When they corrected the right finger's amplitude, the left finger's amplitude unintentionally also changed [motor interference (MI)], despite the instruction to keep its amplitude constant. Notably, we observed two specificities: one was large MI and low relative-phase variability (PV) under the intrinsic in-phase condition, and the other was large MI and high PV under the extrinsic in-phase condition. Additionally, using a multiple-interaction model, we successfully decomposed MI into intrinsic components caused by motor correction and extrinsic components caused by visual-cursor mismatch of the right finger's movements. This analysis revealed that the central nervous system facilitates MI by combining intrinsic and extrinsic components in the condition with in-phases in both intrinsic and extrinsic coordinates, and that under-additivity of the effects is explained by the brain's preference for the intrinsic interaction over extrinsic interaction. In contrast, the PV was significantly correlated with the intrinsic component, suggesting that the intrinsic interaction dominantly contributed to bimanual movement stabilization. The inconsistent features of MI and PV suggest that the central nervous system regulates multiple levels of bilateral interactions for various bimanual tasks.

  6. Intrinsic and extrinsic negative regulators of nuclear protein transport processes

    OpenAIRE

    Sekimoto, Toshihiro; Yoneda, Yoshihiro

    2012-01-01

    The nuclear–cytoplasmic protein transport is a critical process in cellular events. The identification of transport signals (nuclear localization signal and nuclear export signal) and their receptors has facilitated our understanding of this expanding field. Nuclear transport must be appropriately regulated to deliver proteins through the nuclear pore when their functions are required in the nucleus, and to export them into the cytoplasm when they are not needed in the nucleus. Altered nuclea...

  7. Death: 'nothing' gives insight.

    Science.gov (United States)

    Ettema, Eric J

    2013-08-01

    According to a widely accepted belief, we cannot know our own death--death means 'nothing' to us. At first sight, the meaning of 'nothing' just implies the negation or absence of 'something'. Death then simply refers to the negation or absence of life. As a consequence, however, death has no meaning of itself. This leads to an ontological paradox in which death is both acknowledged and denied: death is … nothing. In this article, I investigate whether insight into the ontological paradox of the nothingness of death can contribute to a good end-of-life. By analysing Aquinas', Heidegger's and Derrida's understanding of death as nothingness, I explore how giving meaning to death on different ontological levels connects to, and at the same time provides resistance against, the harsh reality of death. By doing so, I intend to demonstrate that insight into the nothingness of death can count as a framework for a meaningful dealing with death.

  8. Predictors of employment in schizophrenia: The importance of intrinsic and extrinsic motivation.

    Science.gov (United States)

    Reddy, L Felice; Llerena, Katiah; Kern, Robert S

    2016-10-01

    Unemployment is a primary functional deficit for the majority of adults with schizophrenia. Research indicates that over two-thirds of adults living in the community with schizophrenia are unemployed. Despite effective programs to assist with job identification and placement, the ability to attain and maintain employment remains a pressing concern. A contributing factor that may be relevant but has received little attention in the work rehabilitation literature is motivation. People with schizophrenia show marked deficits in both intrinsic and extrinsic motivation but these deficits have not been directly examined in relation to work outcomes. The present study sought to examine the relationship between intrinsic and extrinsic motivation and work outcome among a sample of 65 adults with schizophrenia enrolled in a supported employment program. One-third of the participants in the study obtained work. Intrinsic motivation related to valuing and feeling useful in a work role significantly predicted who would obtain employment. Extrinsic motivation related to gaining rewards and avoiding obstacles showed a non-significant trend-level relationship such that workers had higher extrinsic motivation than nonworkers. These findings highlight the importance of considering both intrinsic and extrinsic motivation in work-related interventions and supported employment for individuals with schizophrenia. The results are discussed in terms of clinical implications for improving rehabilitation and occupational outcomes in schizophrenia. Published by Elsevier B.V.

  9. Correlation of the expression of YY1 and Fas cell surface death receptor with apoptosis of peripheral blood mononuclear cells, and the development of multiple organ dysfunction in children with sepsis

    Science.gov (United States)

    Reséndiz-Martínez, Judith; Asbun-Bojalil, Juan; Huerta-Yepez, Sara; Vega, Mario

    2017-01-01

    Multiple organ dysfunction (MOD) is a lethal complication in children with sepsis. Apoptosis of several cell types is involved in this process, and it is associated with increased Fas cell surface death receptor (Fas) expression. As YY1 transcription factor (YY1) negatively regulates the expression of Fas in cancer models, and is associated with the clinical outcome, it may be important in MOD. The present study aimed to determine the association between the expression of Fas, YY1 and apoptosis in children with sepsis, and its association with MOD, these factors were analyzed in 30 pediatric patients that had been diagnosed with sepsis. Peripheral blood mononuclear cells were purified from patients, and YY1 and Fas protein expression was assessed by immunocytochemistry. Apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick-end labeling. Sepsis was monitored using clinical parameters, pediatric logistic organ dysfunction (PELOD) score and the pediatric mortality index. The results demonstrated that Fas expression was directly correlated with apoptosis levels and the expression of YY1 was inversely correlated with apoptosis levels. Patients with high levels of apoptosis exhibited increased disease severity and poor clinical outcome. Notably, the findings of the present study demonstrated that there were higher survival rates in patients with high YY1 expression, compared with those with low YY1 expression. Additionally, patients with MOD exhibited lower proportions of apoptotic cells compared with sepsis patients without MOD. Furthermore, the PELOD score was positively correlated with Fas and inversely correlated with YY1 expression. Finally, high apoptosis and low YY1 expression were prognostic factors associated with poor survival rates. These data suggested that YY1 may be important for apoptosis induction via the regulation of Fas during sepsis. Therefore, Fas may be a potential therapeutic target to prevent MOD through regulation of YY1

  10. Induction of apoptotic cell death by phytoestrogens by up-regulating the levels of phospho-p53 and p21 in normal and malignant estrogen receptor α-negative breast cells.

    Science.gov (United States)

    Seo, Hye-Sook; Ju, Ji-Hyun; Jang, Kibeom; Shin, Incheol

    2011-02-01

    In this study, we investigated the underlying mechanism by which phytoestrogens suppress the growth of normal (MCF-10A) and malignant (MDA-MB-231) estrogen receptor α (ERα)-negative breast cells. We hypothesized that phytoestrogen inhibits the proliferation of ERα-negative breast cancer cells. We found that all tested phytoestrogens (genistein, apigenin, and quercetin) suppressed the growth of both MCF-10A and MDA-MB-231 cells, as revealed by proliferation assays. These results were accompanied by an increase in the sub-G0/G1 apoptotic fractions as well as an increase in the cell population in the G2/M phase in both cell types, as revealed by cell cycle analysis. When we assessed the effect of phytoestrogens on the level of intracellular signaling molecules by Western blot analysis, we found that phytoestrogens increased the level of active p53 (phospho-p53) without changing the p53 level in both MCF-10A and MDA-MB-231 cells. Phytoestrogens also induced an increase in p21, a p53 target gene, and a decrease in either Bcl-xL or cyclin B1 in both cell types. In contrast, the protein levels of phosphatase and tensin homolog, cyclin D1, cell division control protein 2 homolog, phospho-cell division control protein 2 homolog, and p27 were not changed after phytoestrogen treatment. Our data indicate that phytoestrogens induce apoptotic cell death of ERα-negative breast cancer cells via p53-dependent pathway and suggest that phytoestrogens may be promising agents in the treatment and prevention of ERα-negative breast cancer.

  11. Extrinsic Contribution and Instability Properties in Lead-Based and Lead-Free Piezoceramics

    Directory of Open Access Journals (Sweden)

    José Eduardo García

    2015-11-01

    Full Text Available Piezoceramic materials generally exhibit a notable instability of their functional properties when they work under real external conditions. This undesirable effect, known as nonlinear behavior, is mostly associated with the extrinsic contribution to material response. In this article, the role of the ferroelectric domain walls’ motion in the nonlinear response in the most workable lead-based and lead-free piezoceramics is reviewed. Initially, the extrinsic origin of the nonlinear response is discussed in terms of the temperature dependence of material response. The influence of the crystallographic phase and of the phase boundaries on the material response are then reviewed. Subsequently, the impact of the defects created by doping in order to control the extrinsic contribution is discussed as a way of tuning material properties. Finally, some aspects related to the grain-size effect on the nonlinear response of piezoceramics are surveyed.

  12. Intrinsic and extrinsic mechanical properties related to the differentiation of mesenchymal stem cells.

    Science.gov (United States)

    Lee, Jin-Ho; Park, Hun-Kuk; Kim, Kyung Sook

    2016-05-06

    Diverse intrinsic and extrinsic mechanical factors have a strong influence on the regulation of stem cell fate. In this work, we examined recent literature on the effects of mechanical environments on stem cells, especially on differentiation of mesenchymal stem cells (MSCs). We provide a brief review of intrinsic mechanical properties of single MSC and examined the correlation between the intrinsic mechanical property of MSC and the differentiation ability. The effects of extrinsic mechanical factors relevant to the differentiation of MSCs were considered separately. The effect of nanostructure and elasticity of the matrix on the differentiation of MSCs were summarized. Finally, we consider how the extrinsic mechanical properties transfer to MSCs and then how the effects on the intrinsic mechanical properties affect stem cell differentiation.

  13. The Path Taken: Consequences of Attaining Intrinsic and Extrinsic Aspirations in Post-College Life.

    Science.gov (United States)

    Niemiec, Christopher P; Ryan, Richard M; Deci, Edward L

    2009-06-01

    Life goals, or aspirations, organize and direct behavior over extended periods of time. The present study, guided by self-determination theory, examined the consequences of pursuing and attaining aspirations over a one-year period in a post-college sample. Results indicated that placing importance on either intrinsic or extrinsic aspirations related positively to attainment of those goals. Yet, whereas attainment of intrinsic aspirations related positively to psychological health, attainment of extrinsic aspirations did not; indeed, attainment of extrinsic aspirations related positively to indicators of ill-being. Also as predicted, the association between change in attainment of intrinsic aspirations and change in psychological health was mediated by change in the satisfaction of the basic psychological needs for autonomy, competence, and relatedness. Discussion focuses on the idea that not all goal attainment is beneficial; rather, attainment of aspirations with different contents relates differentially to psychological health.

  14. Dissipationless spin-Hall current contribution in the extrinsic spin-Hall effect

    Institute of Scientific and Technical Information of China (English)

    Yan Yu-Zhen; Li Hui-Wu; Hu Liang-Bin

    2009-01-01

    This paper shows that a substantial amount of dissipationless spin-Hall current contribution may exist in the extrinsic spin-Hall effect, which originates from the spin-orbit coupling induced by the applied external electric field itself that drives the extrinsic spin-Hall effect in a nonmagnetic semiconductor (or metal). By assuming that the impurity density is in a moderate range such that the total scattering potential due to all randomly distributed impurities is a smooth function of the space coordinate, it is shown that this dissipationless contribution shall be of the same orders of magnitude as the usual extrinsic contribution from spin-orbit dependent impurity scatterings (or may even be larger than the latter one). The theoretical results obtained are in good agreement with recent relevant experimental results.

  15. The relationship between extrinsic motivation, job satisfaction and life satisfaction amongst employees in a public organisation

    Directory of Open Access Journals (Sweden)

    Chengedzai Mafini

    2014-02-01

    Full Text Available Orientation: There is much research on extrinsic motivation, job satisfaction and life satisfaction in organisations. However, empirical evidence on how such factors affect employees in public organisations in developing countries is lacking.Research purpose: To examine the relationships between extrinsic motivation, job satisfaction and life satisfaction amongst employees in a public organisation.Motivation for the study: Labour strife is an endemic phenomenon in South Africa’s public sector as evidenced by the high incidences of industrial action and labour turnover. This study contributes to this subject by identifying the extrinsic factors that could be optimised with a view to enhancing job and life satisfaction amongst government employees.Research approach, design and method: The study used the quantitative research survey approach: a questionnaire was administered to 246 employees in a South African public organisation. Extrinsic motivation factors were identified using principal components analysis. Mean score ranking was used to compare the relative importance of all factors. The conceptual framework was tested using Spearman’s rank correlation analysis and linear regression analysis.Main findings: Statistically significant relationships were observed between job satisfaction and four extrinsic motivation factors: remuneration, quality of work life, supervision and teamwork. The relationship with promotion was insignificant, but a statistically significant relationship was established with life satisfaction.Practical/managerial implications: The findings may be used to implement strategies for enhancing employee performance and industrial relations within public organisations.Contribution/value-add: The study provides evidence of the interplay between extrinsic motivation, job satisfaction and life satisfaction for public servants in developing countries.

  16. Limitations of surface EMG signals of extrinsic muscles in predicting postures of human hand.

    Science.gov (United States)

    Vinjamuri, Ramana; Mao, Zhi-Hong; Sclabassi, Robert; Sun, Mingui

    2006-01-01

    This paper explores the limitations of sEMG (surface Electromyography) signals collected from the extrinsic muscles in the forearm in predicting the postures of human hand. Four subjects were asked to try ten extreme postures of hand which need high effort. Two of these four subjects were asked to try ten more normal postures which did not need effort During the experiments, muscle activity and static postures of the hand were measured. The data obtained were analyzed by principal component analysis. The results obtained revealed the limitations of sEMG signals of extrinsic muscles in reproducing the postures of the hand.

  17. Computer tomographic patterns in extrinsic allergic alveolitis - a comparison with conventional radiological findings

    Energy Technology Data Exchange (ETDEWEB)

    Hieckel, H.G.; Mueller, S.; Luening, M.

    1986-10-01

    Seventeen patients with extrinsic allergic alveolitis or bird-fancier's lung were examined by standard radiological techniques and classified after Hapke's classification. In addition, the patients were examined by CT. The CT patterns have been analysed and compared with standard radiological findings. The methodological advantages of CT are discussed. Radiological investigation is of limited value in the diagnosis of extrinsic allergic alveolitis. Conventional radiography remains the standard of initial X-ray examination. In early cases, however, CT may be a valuable addition within the diagnostic strategy of a diagnostic imaging department.

  18. Substance use by college students: the role of intrinsic versus extrinsic motivation for athletic involvement.

    Science.gov (United States)

    Rockafellow, Bradley D; Saules, Karen K

    2006-09-01

    Certain types of athletic involvement may confer risk for substance use by college students. This study investigated whether motivational factors play a role in the relationship between athletic involvement and substance use. Intercollegiate athletes (n=98) and exercisers (n=120) were surveyed about substance use and motivation for athletic involvement. Athletes and exercisers who were extrinsically motivated had significantly higher rates of alcohol use than their intrinsically motivated counterparts. Results suggest that college students who are extrinsically motivated for involvement in physical activity/athletics--particularly those involved in team sports--may be in need of targeted prevention efforts. ((c) 2006 APA, all rights reserved).

  19. Brain Death Determination.

    Science.gov (United States)

    Spinello, Irene M

    2015-09-01

    In the United States, each year 1% to 2% of deaths are brain deaths. Considerable variation in the practice of determining brain death still remains, despite the publication of practice parameters in 1995 and an evidence-based guideline update in 2010. This review is intended to give bedside clinicians an overview of definition, the causes and pitfalls of misdiagnosing brain death, and a focus on the specifics of the brain death determination process.

  20. Work Motivation and the Negative Effects of Extrinsic Rewards: A Reward With Implications for Theory and Practice

    Science.gov (United States)

    Notz, William W.

    1975-01-01

    Summarizes and discusses findings on two hypotheses predicting interaction between intrinsic and extrinsic motivation: extrinsic rewards are those which provide satisfaction independent of the actual activity itself and are controlled by someone other than the employee, whereas intrinsic rewards are those over which the employee has a high degree…

  1. Structural and Functional Analysis of the N-terminal Region of Death Receptor 5%死亡受体5氨基末端的结构与功能

    Institute of Scientific and Technical Information of China (English)

    张鹏; 陈采凤; 刘士廉; 郑德先; 刘彦信

    2011-01-01

    目的 研究死亡受体5(DR5)氨基末端的结构与功能.方法 利用基因工程技术构建一系列DR5胞外区(DR5-ECD)缺失突变体并获得相应的重组蛋白.利用蛋白免疫印迹及ELISA技术研究重组蛋白与小鼠抗人DR5单克隆抗体AD5-10的结合情况.结果 含有完整氨基末端结构的DR5-ECD缺失突变体能够与AD5-10结合,而缺失氨基末端的重组蛋白则不能与AD5-10相互作用.结论 DR5氨基末端含有AD5-10激动性抗体的靶点,该靶点可能在发展肿瘤免疫治疗新策略中发挥重要作用.%Objective To investigate the structure and function of the N-terminal region (NTR) of death receptor 5 (DR5). Methods A series of deletions of the DR5 extraeellular domain (DR5-ECD) proteins were expressed in E. coli. and purified by affinity chromatography. The binding ability of these deletant proteins to AD5-10, a mouse anti-human DR5 monoelonal antibody, was evaluated by immunoblotting and ELISA. Results Recombinant DR5-ECD proteins containing the NTR were recognized and bound by AD510, while the other deletant proteins without the NTR failed to interact with AD5-10. Conclusion There is an AD5-10 targeting site in the NTR of DR5, which may play a role in developing novel immunotherapies for cancers.

  2. 15-deoxy-Delta12,14-prostaglandin J2 up-regulates death receptor 5 gene expression in HCT116 cells: involvement of reactive oxygen species and C/EBP homologous transcription factor gene transcription.

    Science.gov (United States)

    Su, Rong-Ying; Chi, Kwan-Hwa; Huang, Duen-Yi; Tai, Ming-Hui; Lin, Wan-Wan

    2008-10-01

    Although 15-deoxy-Delta(12,14)-prostaglandin J(2) (15dPGJ(2)) was reported to up-regulate death receptor 5 (DR5) protein expression and sensitize TRAIL-induced cytotoxicity, its action mechanism remains unclear. Using HCT116 colon cancer cells, we found that sensitization of TRAIL-induced cytotoxicity by 15dPGJ(2) resulted from up-regulation of DR5 via gene transcription but was not associated with PPAR-gamma activation. Moreover, 15dPGJ(2) induced GRP78, XBP1, and C/EBP homologous transcription factor (CHOP) expression in HCT116 cells, confirming that 15dPGJ(2) is an endoplasmic reticulum stress inducer. Knockdown of the CHOP gene by siRNA attenuated DR5 up-regulation and the sensitized cytotoxicity in colon cancer HCT116 and SW480. With deletion plasmids of DR5 promoters, we found that the CHOP-binding site was involved in activating the DR5 gene by 15dPGJ(2). A mechanistic study showed the contributions of reactive oxygen species (ROS) and intracellular calcium in CHOP and DR5 gene up-regulation. 15dPGJ(2) was also found to induce DR5 in two prostate cancer cell lines, LNCaP and PC3. Although in LNCaP DR5 up-regulation was accompanied by CHOP expression by 15dPGJ(2), no significant increase in CHOP expression or DR5 promoter activity was observed in PC3 cells. Intriguingly, 15dPGJ(2) induced ROS and calcium production in PC3 cells. This inability to induce CHOP was not due to the p53-null in PC3 cells, as similar extents of increase in CHOP protein were found due to 15dPGJ(2) in both wild-type and p53-null HCT116 cells. In summary, the effect of up-regulation of DR5 by 15dPGJ(2) in colon cancer cells is independent of PPAR-gamma and p53 but relies on CHOP induction through gene transcription involving ROS and calcium.

  3. The receptor like kinase at Rhg1-a/Rfs2 caused pleiotropic resistance to sudden death syndrome and soybean cyst nematode as a transgene by altering signaling responses

    Directory of Open Access Journals (Sweden)

    Srour Ali

    2012-08-01

    Full Text Available Abstract Background Soybean (Glycine max (L. Merr. resistance to any population of Heterodera glycines (I., or Fusarium virguliforme (Akoi, O’Donnell, Homma & Lattanzi required a functional allele at Rhg1/Rfs2. H. glycines, the soybean cyst nematode (SCN was an ancient, endemic, pest of soybean whereas F. virguliforme causal agent of sudden death syndrome (SDS, was a recent, regional, pest. This study examined the role of a receptor like kinase (RLK GmRLK18-1 (gene model Glyma_18_02680 at 1,071 kbp on chromosome 18 of the genome sequence within the Rhg1/Rfs2 locus in causing resistance to SCN and SDS. Results A BAC (B73p06 encompassing the Rhg1/Rfs2 locus was sequenced from a resistant cultivar and compared to the sequences of two susceptible cultivars from which 800 SNPs were found. Sequence alignments inferred that the resistance allele was an introgressed region of about 59 kbp at the center of which the GmRLK18-1 was the most polymorphic gene and encoded protein. Analyses were made of plants that were either heterozygous at, or transgenic (and so hemizygous at a new location with, the resistance allele of GmRLK18-1. Those plants infested with either H. glycines or F. virguliforme showed that the allele for resistance was dominant. In the absence of Rhg4 the GmRLK18-1 was sufficient to confer nearly complete resistance to both root and leaf symptoms of SDS caused by F. virguliforme and provided partial resistance to three different populations of nematodes (mature female cysts were reduced by 30–50%. In the presence of Rhg4 the plants with the transgene were nearly classed as fully resistant to SCN (females reduced to 11% of the susceptible control as well as SDS. A reduction in the rate of early seedling root development was also shown to be caused by the resistance allele of the GmRLK18-1. Field trials of transgenic plants showed an increase in foliar susceptibility to insect herbivory. Conclusions The inference that soybean has

  4. 死亡受体途径在丙烯酰胺致PC12细胞凋亡中的影响%EFFECT OF DEATH RECEPTOR PATHWAY IN APOPTOSIS OF NEUROCYTES INDUCED BY ACRYLAMIDE

    Institute of Scientific and Technical Information of China (English)

    刘燕群; 吴丽娜; 鲁雄兵; 宋文剑; 乐明

    2011-01-01

    [Objective] To explore the potential mechanisms of neural apoptosis induced by acrylamide. [Methods] After PC12 cells were exposed to acrylamide with different concentrations (0.5mmol/L, 1mmol/L, 5mmoVL and 10mmol/L) , Fas,Fas-L and TNFR1 protein in PC12 cells were qualitatively determined by immunocytochemistry Fas, FasL and TNFR1 protein were indirectly marked with flow cytometry. Meanwhile the apoptosis of PC12 cells was studied using flow cytometry with PI staining at 24 hours after acrylamide treatment. [ Results] The expressions of Fas, Fas-L and TNFR1 and apoptosis rate in acrylamide treated group were sigificantly higher than those in control group (P < 0.05). [Conclusion] Apoptosis of PC12 cells induced by acrylamide may be mediated by death receptor Fas.%[目的] 研究丙烯酰胺诱导神经细胞凋亡及其神经毒作用机制.[方法] 不同浓度水平(0.5 mmol/L,1mmol/L,5 mmol/L,10 mmol/L)的丙烯酰胺染毒后,用免疫细胞化学法检测PC12细胞Fas、Fas-L、TNFR1蛋白表达情况;流式细胞仪定量检测Fas、Fas-L、TNFR1蛋白含量及PC12细胞凋亡情况.[结果] 丙烯酰胺各剂量染毒后PC12细胞凋亡率及Fas、Fas-L、TNFR1蛋白表达与对照组比较差异均有统计学意义(P<0.05).[结论] 丙烯酰胺可能通过死亡受体Fas诱导PC12细胞调亡.

  5. Extrinsic Motivation as Correlates of Work Attitude of the Nigerian Police Force: Implications for Counselling

    Science.gov (United States)

    Igun, Sylvester Nosakhare

    2008-01-01

    The study examined Extrinsic motivation as correlates of work attitude of the Nigeria Police Force and its implications for counselling. 300 Police personnel were selected by random sampling technique from six departments that make up police force Headquarters, Abuja. The personnel were selected from each department using simple sampling…

  6. Extrinsic functions of lectin domains in O-N-acetylgalactosamine glycan biosynthesis

    DEFF Research Database (Denmark)

    Lorenz, Virginia; Ditamo, Yanina; Cejas, Romina B;

    2016-01-01

    Glycan biosynthesis occurs mainly in Golgi. Molecular organization and functional regulation of this process are not well understood. We evaluated the extrinsic effect of lectin domains (β-trefoil fold) of polypeptide GalNAc-transferases (ppGalNAc-Ts) on catalytic activity of glycosyltransferases...

  7. Perceived Constraints on Recreational Sport Participation: Investigating Their Relationship with Intrinsic Motivation, Extrinsic Motivation and Amotivation.

    Science.gov (United States)

    Alexandris, Konstantinos; Tsorbatzoudis, Charalambos; Grouios, George

    2002-01-01

    Investigated the influence of constraint dimensions on intrinsic motivation, extrinsic motivation, and amotivation among Greek adults who reported participation in some type of sport and physical activity. Data from the Sport Motivation Scale and leisure constraints questionnaire revealed that intrapersonal constraints acted as de-motivating…

  8. Tangible and Intangible Rewards and Employee Creativity: The Mediating Role of Situational Extrinsic Motivation

    Science.gov (United States)

    Yoon, Hye Jung; Sung, Sun Young; Choi, Jin Nam; Lee, Kyungmook; Kim, Seongsu

    2015-01-01

    This study examined the effects of tangible and intangible forms of creativity-contingent rewards on employee creativity. Situation-specific intrinsic and extrinsic motivations were proposed as mediators of the reward-creativity link. Based on data collected from 271 employees and their supervisors, results revealed the following: (a) intangible…

  9. A Novel Extrinsic Fiber-Optic Fabry-Perot Strain Sensor System Based on Optical Amplification

    Institute of Scientific and Technical Information of China (English)

    Yun-Jiang Rao; Jian Jiang; Zheng-Lin Ran

    2003-01-01

    A novel extrinsic fiber-optic Fabry-Perot interferometric strain sensor system is demonstrated based on the simultaneous use of the amplified spontaneous emission and optical amplification. The improvement of 3~4 orders of magnitude in signal level can be achieved.

  10. A Quantitative Analysis of the Extrinsic and Intrinsic Turnover Factors of Relational Database Support Professionals

    Science.gov (United States)

    Takusi, Gabriel Samuto

    2010-01-01

    This quantitative analysis explored the intrinsic and extrinsic turnover factors of relational database support specialists. Two hundred and nine relational database support specialists were surveyed for this research. The research was conducted based on Hackman and Oldham's (1980) Job Diagnostic Survey. Regression analysis and a univariate ANOVA…

  11. The fragmented self : imbalance between intrinsic and extrinsic self-networks in psychotic disorders

    NARCIS (Netherlands)

    Ebisch, Sjoerd J. H.; Aleman, Andre

    2016-01-01

    Self-disturbances are among the core features of schizophrenia and related psychotic disorders. The basic structure of the self could depend on the balance between intrinsic and extrinsic self-processing. We discuss studies on self-related processing in psychotic disorders that provide converging ev

  12. A family with extrinsic allergic alveolitis caused by wild city pigeons: A case report

    NARCIS (Netherlands)

    G.J. du Marchie Sarvaas; P.J.F.M. Merkus (Peter); J.C. de Jongste (Johan)

    2000-01-01

    textabstractWe describe a family in which the mother died of unresolved lung disease and whose 5 children, some of whom had previous signs of asthma, were subsequently affected by extrinsic allergic alveolitis caused by contact with wild city pigeon antigens. The children received

  13. Intrinsic and Extrinsic Motivation: Evaluating Benefits and Drawbacks from College Instructors' Perspectives

    Science.gov (United States)

    Lei, Simon A.

    2010-01-01

    A growing body of literature has been examined and discussed the effects of intrinsic and extrinsic motivation on student learning at the college level. Intrinsically motivated individuals have been able to develop high regards for learning various types of course information without the inclusion of external rewards or reinforcements. In…

  14. Extrinsic Tooth Enamel Color Changes and Their Relationship with the Quality of Water Consumed

    Directory of Open Access Journals (Sweden)

    Maria da Luz Rosário de Sousa

    2012-10-01

    Full Text Available The quality of the consumed drinking water may affect oral health. For example, the presence of iron in drinking water can cause aesthetic problems related to changes in dental enamel color. This study assessed the prevalence of extrinsic enamel color changes and their relationship with the quality of the water in the town of Caapiranga/AM-Brazil. Three hundred and forty six residents of the urban area were examined, and they also answered a questionnaire on eating habits and self-perceived oral health. As the initial results indicated an insufficient number of observations for the application of variance analysis (one-way ANOVA, the Student t test was chosen to compare levels of iron content in the water coming from two sources. The change in tooth color had a prevalence of 5.78% (20 people. The majority of the population (n = 261, 75.43% consumed well water. Those who presented extrinsic stains were uncomfortable with the appearance of their teeth (15.09%. We conclude that while there is excess of iron in the water in this region of Brazil, no association between extrinsic stains on the enamel and the level of iron in the water was found. There was a low prevalence of extrinsic stains in Caaparinga, being found only in children and adolescents. In the present study, an association between the presence of stains and the consumption of açai was determined, and those who presented them felt uncomfortable about their aesthetics.

  15. Creep of current-driven domain-wall lines: intrinsic versus extrinsic pinning

    NARCIS (Netherlands)

    Duine, R.A.; de Morais Smith, C.

    2008-01-01

    We present a model for current-driven motion of a magnetic domain-wall line, in which the dynamics of the domain wall is equivalent to that of an overdamped vortex line in an anisotropic pinning potential. This potential has both extrinsic contributions due to, e.g., sample inhomogeneities, and an

  16. Profiles of Intrinsic and Extrinsic Motivations in Elementary School: A Longitudinal Analysis

    Science.gov (United States)

    Corpus, Jennifer Henderlong; Wormington, Stephanie V.

    2014-01-01

    The authors used a person-centered, longitudinal approach to identify and evaluate naturally occurring combinations of intrinsic and extrinsic motivations among 490 third- through fifth-grade students. Cluster analysis revealed 3 groups, characterized by high levels of both motivations ("high quantity"): high intrinsic motivation but low…

  17. Students' Extrinsic and Intrinsic Motivation Level and Its Relationship with Their Mathematics Achievement

    Science.gov (United States)

    Acar Güvendir, Meltem

    2016-01-01

    This study focused on the extrinsic and intrinsic motivation levels of eighth grade students and its relationship with their mathematical achievement. The participants of the study included 6,829 students who took TIMSS in 2011 and 239 mathematics teachers. The data obtained from the student and teacher questionnaires that are included in the…

  18. Intrinsic Motivation, Extrinsic Motivation, and Academic Achievement among Indian Adolescents in Canada and India

    Science.gov (United States)

    Areepattamannil, Shaljan; Freeman, John G.; Klinger, Don A.

    2011-01-01

    The purpose of the present study was to examine the relationships among intrinsic motivation, extrinsic motivation, and academic achievement for the Indian immigrant adolescents in Canada in comparison to their counterparts in India. Descriptive discriminant analysis indicated that the Indian immigrant adolescents in Canada had higher intrinsic…

  19. Intrinsic and Extrinsic Reading Motivation as Predictors of Reading Literacy: A Longitudinal Study

    Science.gov (United States)

    Becker, Michael; McElvany, Nele; Kortenbruck, Marthe

    2010-01-01

    The purpose in this study was to examine the longitudinal relationships of intrinsic and extrinsic motivation with reading literacy development. In particular, the authors (a) investigated reading amount as mediator between motivation and reading literacy and (b) probed for bidirectional relationships between reading motivation and reading…

  20. Extrinsic and intrinsic drivers of corporate social performance: evidence from foreign and domestic firms in Mexico

    NARCIS (Netherlands)

    Muller, A.; Kolk, A.

    2010-01-01

    The literature on corporate social performance (CSP) is largely split between approaches that consider CSP to be extrinsically driven and those that consider it to be intrinsically driven. While the management literature has paid attention to drivers of both types, the relationship between the two

  1. A family with extrinsic allergic alveolitis caused by wild city pigeons: A case report

    NARCIS (Netherlands)

    G.J. du Marchie Sarvaas; P.J.F.M. Merkus (Peter); J.C. de Jongste (Johan)

    2000-01-01

    textabstractWe describe a family in which the mother died of unresolved lung disease and whose 5 children, some of whom had previous signs of asthma, were subsequently affected by extrinsic allergic alveolitis caused by contact with wild city pigeon antigens. The children received

  2. The fragmented self: imbalance between intrinsic and extrinsic self-networks in psychotic disorders.

    Science.gov (United States)

    Ebisch, Sjoerd J H; Aleman, André

    2016-08-01

    Self-disturbances are among the core features of schizophrenia and related psychotic disorders. The basic structure of the self could depend on the balance between intrinsic and extrinsic self-processing. We discuss studies on self-related processing in psychotic disorders that provide converging evidence for disrupted communication between neural networks subserving the so-called intrinsic self and extrinsic self. This disruption might be mainly caused by impaired integrity of key brain hubs. The intrinsic self has been associated with cortical midline structures involved in self-referential processing, autobiographical memory, and emotional evaluation. Additionally, we highlight central aspects of the extrinsic self in its interaction with the environment using sensorimotor networks, including self-experience in sensation and actions. A deficient relationship between these self-aspects because of disrupted between-network interactions offers a framework to explain core clinical features of psychotic disorders. In particular, we show how relative isolation and reduced modularity of networks subserving intrinsic and extrinsic self-processing might trigger the emergence of hallucinations and delusions, and why patients with psychosis typically have difficulties with self-other relationships and do not recognise mental problems.

  3. Comparing Intrinsic and Extrinsic Evaluation of MT Output in a Dialogue System.

    NARCIS (Netherlands)

    van der Sluis, Ielka; Luz, S.; Schneider, A.

    2010-01-01

    We present an exploratory study to assess machine translation output for application in a dialogue system using an intrinsic and an extrinsic evaluation method. For the intrinsic evaluation we developed an annotation scheme to determine the quality of the translated utterances in isolation. For the

  4. A Novel Extrinsic Fiber-Optic Fabry-Perot Strain Sensor System Based on Optical Amplification

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    A novel extrinsic fiber-optic Fabry-Perot interferometric strain sensor system is demonstrated based on the simultaneous use of the amplified spontaneous emission and optical amplification. The improvement of 3~4 orders of magnitude in signal level can be achieved.

  5. The efficacy of two prototype chewing gums for the removal of extrinsic tooth stain

    NARCIS (Netherlands)

    Ozcan, M; Kulak, Y; Kazazoglu, E

    2003-01-01

    Aim: To compare the potential efficacy of two prototype chewing gums in extrinsic stain removal on natural teeth. Setting: Dental school clinics. Design: Double-blind, two groups, parallel design. Participants: 76 adult volunteers (32m, 44f, mean age: 20.6 years old). Methods: Oral hard and soft tis

  6. Further Examining the American Dream: Differential Correlates of Intrinsic and Extrinsic Goals.

    Science.gov (United States)

    Kasser, Tim; Ryan, Richard M.

    1996-01-01

    In a sample of adult subjects (Study One), the relative importance and efficacy of extrinsic aspirations for financial success, an appealing appearance, and social recognition were associated with lower vitality and self-actualization and more physical symptoms. Study Two replicated these findings in a sample of college students. (JPS)

  7. Intrinsic and Extrinsic Factors That Influence Black Males to Attend Institutions of Higher Education

    Science.gov (United States)

    Etheridge, Robert

    2013-01-01

    The purpose of this qualitative, narrative study was to explore the intrinsic and extrinsic factors that motivated Black males to attend institutions of higher education. The Self-determination theory and the Integrated Model for Educational Choice formed the theoretical framework for this study. Eight Black males who were between the ages of 18…

  8. Indirect Correspondence-Based Robust Extrinsic Calibration of LiDAR and Camera.

    Science.gov (United States)

    Sim, Sungdae; Sock, Juil; Kwak, Kiho

    2016-06-22

    LiDAR and cameras have been broadly utilized in computer vision and autonomous vehicle applications. However, in order to convert data between the local coordinate systems, we must estimate the rigid body transformation between the sensors. In this paper, we propose a robust extrinsic calibration algorithm that can be implemented easily and has small calibration error. The extrinsic calibration parameters are estimated by minimizing the distance between corresponding features projected onto the image plane. The features are edge and centerline features on a v-shaped calibration target. The proposed algorithm contributes two ways to improve the calibration accuracy. First, we use different weights to distance between a point and a line feature according to the correspondence accuracy of the features. Second, we apply a penalizing function to exclude the influence of outliers in the calibration datasets. Additionally, based on our robust calibration approach for a single LiDAR-camera pair, we introduce a joint calibration that estimates the extrinsic parameters of multiple sensors at once by minimizing one objective function with loop closing constraints. We conduct several experiments to evaluate the performance of our extrinsic calibration algorithm. The experimental results show that our calibration method has better performance than the other approaches.

  9. Intrinsic and Extrinsic Reading Motivation as Predictors of Reading Literacy: A Longitudinal Study

    Science.gov (United States)

    Becker, Michael; McElvany, Nele; Kortenbruck, Marthe

    2010-01-01

    The purpose in this study was to examine the longitudinal relationships of intrinsic and extrinsic motivation with reading literacy development. In particular, the authors (a) investigated reading amount as mediator between motivation and reading literacy and (b) probed for bidirectional relationships between reading motivation and reading…

  10. Profiles of Intrinsic and Extrinsic Motivations in Elementary School: A Longitudinal Analysis

    Science.gov (United States)

    Corpus, Jennifer Henderlong; Wormington, Stephanie V.

    2014-01-01

    The authors used a person-centered, longitudinal approach to identify and evaluate naturally occurring combinations of intrinsic and extrinsic motivations among 490 third- through fifth-grade students. Cluster analysis revealed 3 groups, characterized by high levels of both motivations ("high quantity"): high intrinsic motivation but low…

  11. The dark side of monetary incentive: how does extrinsic reward crowd out intrinsic motivation.

    Science.gov (United States)

    Ma, Qingguo; Jin, Jia; Meng, Liang; Shen, Qiang

    2014-02-12

    It was widely believed that incentives could effectively enhance the motivation of both students and employees. However, psychologists reported that extrinsic reward actually could undermine individuals' intrinsic motivation to a given interesting task, which challenged viewpoints from traditional incentive theories. Numerous studies have been carried out to test and explain the undermining effect; however, the neural basis of this effect is still elusive. Here, we carried out an electrophysiological study with a simple but interesting stopwatch task to explore to what extent the performance-based monetary reward undermines individuals' intrinsic motivation toward the task. The electrophysiological data showed that the differentiated feedback-related negativity amplitude toward intrinsic success failure divergence was prominently reduced once the extrinsic reward was imposed beforehand. However, such a difference was not observed in the control group, in which no extrinsic reward was provided throughout the experiment. Furthermore, such a pattern was not observed for P300 amplitude. Therefore, the current results indicate that extrinsic reward demotivates the intrinsic response of individuals toward success-failure outcome, which was reflected in the corresponding reduced motivational-related differentiated feedback-related negativity, but not in amplitude of P300.

  12. Intrinsic Motivation, Extrinsic Motivation, and Academic Achievement among Indian Adolescents in Canada and India

    Science.gov (United States)

    Areepattamannil, Shaljan; Freeman, John G.; Klinger, Don A.

    2011-01-01

    The purpose of the present study was to examine the relationships among intrinsic motivation, extrinsic motivation, and academic achievement for the Indian immigrant adolescents in Canada in comparison to their counterparts in India. Descriptive discriminant analysis indicated that the Indian immigrant adolescents in Canada had higher intrinsic…

  13. Students' Extrinsic and Intrinsic Motivation Level and Its Relationship with Their Mathematics Achievement

    Science.gov (United States)

    Acar Güvendir, Meltem

    2016-01-01

    This study focused on the extrinsic and intrinsic motivation levels of eighth grade students and its relationship with their mathematical achievement. The participants of the study included 6,829 students who took TIMSS in 2011 and 239 mathematics teachers. The data obtained from the student and teacher questionnaires that are included in the…

  14. Promoting Intrinsic and Extrinsic Motivation among Chemistry Students Using Computer-Assisted Instruction

    Science.gov (United States)

    Gambari, Isiaka A.; Gbodi, Bimpe E.; Olakanmi, Eyitao U.; Abalaka, Eneojo N.

    2016-01-01

    The role of computer-assisted instruction in promoting intrinsic and extrinsic motivation among Nigerian secondary school chemistry students was investigated in this study. The study employed two modes of computer-assisted instruction (computer simulation instruction and computer tutorial instructional packages) and two levels of gender (male and…

  15. Intrinsic and Extrinsic Motivation: Evaluating Benefits and Drawbacks from College Instructors' Perspectives

    Science.gov (United States)

    Lei, Simon A.

    2010-01-01

    A growing body of literature has been examined and discussed the effects of intrinsic and extrinsic motivation on student learning at the college level. Intrinsically motivated individuals have been able to develop high regards for learning various types of course information without the inclusion of external rewards or reinforcements. In…

  16. Effects of Success/Failure and Extrinsic Rewards on Intrinsic Motivation Using a Competitive Motor Task.

    Science.gov (United States)

    McCaughan, Lindsay R.; McKinlay, Sue

    1981-01-01

    Female high school students participated in a motor task to assess the effects of success/failure feedback and extrinsic rewards on intrinsic motivation. It was found that a significant change in intrinsic motivation was due to the effects of success/failure feedback, but not to the effect of a tangible reward. (Authors/FG)

  17. Interactive Impact of Intrinsic Motivators and Extrinsic Rewards on Behavior and Motivation Outcomes

    Science.gov (United States)

    Xiang, Ping; Bruene, April; Chen, Ang

    2005-01-01

    In this study we examined the interrelationship among extrinsic rewards and achievement goals (including a work-avoidance goal), competence beliefs, and task values associated with health-enhancing running tasks over a school year. A group of elementary school students (n = 119) from a program that promoted running for running's sake and another…

  18. Interactive Impact of Intrinsic Motivators and Extrinsic Rewards on Behavior and Motivation Outcomes

    Science.gov (United States)

    Xiang, Ping; Bruene, April; Chen, Ang

    2005-01-01

    In this study we examined the interrelationship among extrinsic rewards and achievement goals (including a work-avoidance goal), competence beliefs, and task values associated with health-enhancing running tasks over a school year. A group of elementary school students (n = 119) from a program that promoted running for running's sake and another…

  19. Teacher Rewards: Going beyond the Stickers--Moving beyond Extrinsic Motivation

    Science.gov (United States)

    Taylor, Cheryl; McNaney-Funk, Claire; Jardine, Don; Lehman, Geannette; Fok-Chan, Evelyn

    2014-01-01

    Studies have shown that teachers appreciate intrinsic rewards, such as student achievement, positive relationships with students, self-growth, and mastery of professional skills, far greater than extrinsic motivators, like holidays and salary (Plihal, 1981; Plihal, 1982; Ashiedu & Scott-Ladd, 2012; Baleghizadeh & Gordani, 2012). This paper…

  20. Increasing Elementary and High School Student Motivation through the Use of Extrinsic and Intrinsic Rewards

    Science.gov (United States)

    Haywood, Joey; Kuespert, Sarah; Madecky, Dani; Nor, Abbey

    2008-01-01

    This action research project report examined strategies to motivate students from extrinsically rewarding behaviors to intrinsically motivating behaviors. The action research was conducted in two different schools by four different teacher researchers within the same district. Three teachers in an elementary building (Site A) and one teacher in a…

  1. The role of extrinsic rewards and cue-intention association in prospective memory in young children

    NARCIS (Netherlands)

    Sheppard, D.P.; Kretschmer, A.; Knispel, E.; Vollert, B.; Altgassen, A.M.

    2015-01-01

    The current study examined, for the first time, the effect of cue-intention association, as well as the effects of promised extrinsic rewards, on prospective memory in young children, aged 5-years-old (n = 39) and 7-years-old (n = 40). Children were asked to name pictures for a toy mole, whilst also

  2. Effects of Success/Failure and Extrinsic Rewards on Intrinsic Motivation Using a Competitive Motor Task.

    Science.gov (United States)

    McCaughan, Lindsay R.; McKinlay, Sue

    1981-01-01

    Female high school students participated in a motor task to assess the effects of success/failure feedback and extrinsic rewards on intrinsic motivation. It was found that a significant change in intrinsic motivation was due to the effects of success/failure feedback, but not to the effect of a tangible reward. (Authors/FG)

  3. Intrinsic Motivation and Extrinsic Rewards: A Commentary on Cameron and Pierce's Meta-Analysis.

    Science.gov (United States)

    Lepper, Mark R.; And Others

    1996-01-01

    Provides a critical analysis of the meta-analysis of J. Cameron and W. D. Pierce (1994) of the experimental literature on the effects of extrinsic rewards on intrinsic motivation. Their overly simplistic conclusion has little theoretical or practical value and results from misuse of meta-analytic procedures. (SLD)

  4. Tangible and Intangible Rewards and Employee Creativity: The Mediating Role of Situational Extrinsic Motivation

    Science.gov (United States)

    Yoon, Hye Jung; Sung, Sun Young; Choi, Jin Nam; Lee, Kyungmook; Kim, Seongsu

    2015-01-01

    This study examined the effects of tangible and intangible forms of creativity-contingent rewards on employee creativity. Situation-specific intrinsic and extrinsic motivations were proposed as mediators of the reward-creativity link. Based on data collected from 271 employees and their supervisors, results revealed the following: (a) intangible…

  5. The fragmented self : imbalance between intrinsic and extrinsic self-networks in psychotic disorders

    NARCIS (Netherlands)

    Ebisch, Sjoerd J. H.; Aleman, Andre

    2016-01-01

    Self-disturbances are among the core features of schizophrenia and related psychotic disorders. The basic structure of the self could depend on the balance between intrinsic and extrinsic self-processing. We discuss studies on self-related processing in psychotic disorders that provide converging ev

  6. An Analysis of Intrinsic and Extrinsic Hand Muscle EMG for Improved Pattern Recognition Control.

    Science.gov (United States)

    Adewuyi, Adenike A; Hargrove, Levi J; Kuiken, Todd A

    2016-04-01

    Pattern recognition control combined with surface electromyography (EMG) from the extrinsic hand muscles has shown great promise for control of multiple prosthetic functions for transradial amputees. There is, however, a need to adapt this control method when implemented for partial-hand amputees, who possess both a functional wrist and information-rich residual intrinsic hand muscles. We demonstrate that combining EMG data from both intrinsic and extrinsic hand muscles to classify hand grasps and finger motions allows up to 19 classes of hand grasps and individual finger motions to be decoded, with an accuracy of 96% for non-amputees and 85% for partial-hand amputees. We evaluated real-time pattern recognition control of three hand motions in seven different wrist positions. We found that a system trained with both intrinsic and extrinsic muscle EMG data, collected while statically and dynamically varying wrist position increased completion rates from 73% to 96% for partial-hand amputees and from 88% to 100% for non-amputees when compared to a system trained with only extrinsic muscle EMG data collected in a neutral wrist position. Our study shows that incorporating intrinsic muscle EMG data and wrist motion can significantly improve the robustness of pattern recognition control for application to partial-hand prosthetic control.

  7. Death Education and Death-Related Attitudes.

    Science.gov (United States)

    Hoelter, Jon W.; Epley, Rita J.

    1979-01-01

    Assessed the impact of a death and dying course. Results showed no significant pre-test/post-test differences for the experimental or the control group, but indicated initial differences between the two groups, suggesting that students enrolling in a death and dying course have more favorable attitudes toward both suicide and abortion. (Author)

  8. Death Education and Death-Related Attitudes.

    Science.gov (United States)

    Hoelter, Jon W.; Epley, Rita J.

    1979-01-01

    Assessed the impact of a death and dying course. Results showed no significant pre-test/post-test differences for the experimental or the control group, but indicated initial differences between the two groups, suggesting that students enrolling in a death and dying course have more favorable attitudes toward both suicide and abortion. (Author)

  9. Whither brain death?

    Science.gov (United States)

    Bernat, James L

    2014-01-01

    The publicity surrounding the recent McMath and Muñoz cases has rekindled public interest in brain death: the familiar term for human death determination by showing the irreversible cessation of clinical brain functions. The concept of brain death was developed decades ago to permit withdrawal of therapy in hopeless cases and to permit organ donation. It has become widely established medical practice, and laws permit it in all U.S. jurisdictions. Brain death has a biophilosophical justification as a standard for determining human death but remains poorly understood by the public and by health professionals. The current controversies over brain death are largely restricted to the academy, but some practitioners express ambivalence over whether brain death is equivalent to human death. Brain death remains an accepted and sound concept, but more work is necessary to establish its biophilosophical justification and to educate health professionals and the public.

  10. PARP Inhibition Restores Extrinsic Apoptotic Sensitivity in Glioblastoma

    Science.gov (United States)

    Karpel-Massler, Georg; Pareja, Fresia; Aimé, Pascaline; Shu, Chang; Chau, Lily; Westhoff, Mike-Andrew; Halatsch, Marc-Eric; Crary, John F.; Canoll, Peter; Siegelin, Markus D.

    2014-01-01

    Background Resistance to apoptosis is a paramount issue in the treatment of Glioblastoma (GBM). We show that targeting PARP by the small molecule inhibitors, Olaparib (AZD-2281) or PJ34, reduces proliferation and lowers the apoptotic threshold of GBM cells in vitro and in vivo. Methods The sensitizing effects of PARP inhibition on TRAIL-mediated apoptosis and potential toxicity were analyzed using viability assays and flow cytometry in established GBM cell lines, low-passage neurospheres and astrocytes in vitro. Molecular analyses included western blots and gene silencing. In vivo, effects on tumor growth were examined in a murine subcutaneous xenograft model. Results The combination treatment of PARP inhibitors and TRAIL led to an increased cell death with activation of caspases and inhibition of formation of neurospheres when compared to single-agent treatment. Mechanistically, pharmacological PARP inhibition elicited a nuclear stress response with up-regulation of down-stream DNA-stress response proteins, e.g., CCAAT enhancer binding protein (C/EBP) homology protein (CHOP). Furthermore, Olaparib and PJ34 increased protein levels of DR5 in a concentration and time-dependent manner. In turn, siRNA-mediated suppression of DR5 mitigated the effects of TRAIL/PARP inhibitor-mediated apoptosis. In addition, suppression of PARP-1 levels enhanced TRAIL-mediated apoptosis in malignant glioma cells. Treatment of human astrocytes with the combination of TRAIL/PARP inhibitors did not cause toxicity. Finally, the combination treatment of TRAIL and PJ34 significantly reduced tumor growth in vivo when compared to treatment with each agent alone. Conclusions PARP inhibition represents a promising avenue to overcome apoptotic resistance in GBM. PMID:25531448

  11. Intrinsic and extrinsic drivers of source-sink dynamics.

    Science.gov (United States)

    Heinrichs, Julie A; Lawler, Joshua J; Schumaker, Nathan H

    2016-02-01

    Many factors affect the presence and exchange of individuals among subpopulations and influence not only the emergence, but the strength of ensuing source-sink dynamics within metapopulations. Yet their relative contributions remain largely unexplored. To help identify the characteristics of empirical systems that are likely to exhibit strong versus weak source-sink dynamics and inform their differential management, we compared the relative roles of influential factors in strengthening source-sink dynamics. In a series of controlled experiments within a spatially explicit individual-based model framework, we varied patch quality, patch size, the dispersion of high- and low-quality patches, population growth rates, dispersal distances, and environmental stochasticity in a factorial design. We then recorded source-sink dynamics that emerged from the simulated habitat and population factors. Long-term differences in births and deaths were quantified for sources and sinks in each system and used in a statistical model to rank the influences of key factors. Our results suggest that systems with species capable of rapid growth, occupying habitat patches with more disparate qualities, with interspersed higher- and lower-quality habitats, and that experience relatively stable environments (i.e., fewer negative perturbations) are more likely to exhibit strong source-sink dynamics. Strong source-sink dynamics emerged under diverse combinations of factors, suggesting that simple inferences of process from pattern will likely be inadequate to predict and assess the strength of source-sink dynamics. Our results also suggest that it may be more difficult to detect and accurately measure source-sink dynamics in slow-growing populations, highly variable environments, and where a subtle gradient of habitat quality exists.

  12. Flavor Profile of Chinese Liquor Is Altered by Interactions of Intrinsic and Extrinsic Microbes.

    Science.gov (United States)

    Wu, Qun; Kong, Yu; Xu, Yan

    2015-10-16

    The flavor profile of Chinese liquor is the result of the metabolic activity of its microbial community. Given the importance of the microbial interaction, a novel way to control the liquor's flavor is by regulating the composition of the community. In this study, we efficiently improved the liquor's flavor by perturbing the intrinsic microbial metabolism with extrinsic microbes. We first constructed a basic microbial group (intrinsic) containing Saccharomyces cerevisiae, Wickerhamomyces anomalus, and Issatchenkia orientalis and added special flavor producers (extrinsic), Saccharomyces uvarum and Saccharomyces servazzii, to this intrinsic group. Upon the addition of the extrinsic microbes, the maximum specific growth rates of S. cerevisiae and I. orientalis increased from 6.19 to 43.28/day and from 1.15 to 14.32/day, respectively, but that of W. anomalus changed from 1.00 to 0.96/day. In addition, most volatile compounds known to be produced by the extrinsic strains were not produced. However, more esters, alcohols, and acids were produced by S. cerevisiae and I. orientalis. Six compounds were significantly different by random forest analysis after perturbation. Among them, increases in ethyl hexanoate, isobutanol, and 3-methylbutyric acid were correlated with S. cerevisiae and I. orientalis, and a decrease in geranyl acetone was correlated with W. anomalus. Variations in ethyl acetate and 2-phenylethanol might be due to the varied activity of W. anomalus and S. cerevisiae. This work showed the effect of the interaction between the intrinsic and extrinsic microbes on liquor flavor, which would be beneficial for improving the quality of Chinese liquor. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  13. National Death Index

    Data.gov (United States)

    U.S. Department of Health & Human Services — The National Death Index (NDI) is a centralized database of death record information on file in state vital statistics offices. Working with these state offices, the...

  14. Death and Grief

    Science.gov (United States)

    ... Loss Surgery? A Week of Healthy Breakfasts Shyness Death and Grief KidsHealth > For Teens > Death and Grief Print A A A What's in ... the reaction we have in response to a death or loss. Grief can affect our body, mind, ...

  15. Dreams of Death.

    Science.gov (United States)

    Barrett, Deirdre

    1989-01-01

    Examined frequency and characteristics of overt dreams of dying among healthy young adults. Dreams of dying were found to be rare but distinctive content category, representing overwhelmingly pleasant dreams. Over one-half of death dreams involved lengthy afterlife sequence, remainder focused on process of death. Death dreams of these healthy…

  16. Raising trophy kids: The role of mothers' contingent self-esteem in maternal promotion of extrinsic goals.

    Science.gov (United States)

    Soenens, Bart; Wuyts, Dorien; Vansteenkiste, Maarten; Mageau, Geneviève A; Brenning, Katrijn

    2015-07-01

    This study examined the role of mothers' child-invested contingent self-esteem, that is, their tendency to hinge their self-worth on their child's achievements, in maternal promotion of extrinsic goals, as perceived by adolescents. It was also examined whether maternal promotion of extrinsic goals would, in turn, relate to adolescents' Social Dominance Orientation (SDO). Participants were 184 mothers and their adolescent children (66% female). Maternal child-invested contingent self-esteem predicted adolescent-perceived maternal promotion of extrinsic goals, even when taking into account the variance shared between the promotion of extrinsic goals and mothers' use of a controlling parenting style. Maternal child-invested contingent self-esteem also moderated associations between mothers' personal pursuit of extrinsic goals and their promotion of those goals, such that the association between mothers' own extrinsic goals and their promotion of those goals was significant only among mothers high on child-invested contingent self-esteem. Maternal promotion of extrinsic goals was, in turn, related to adolescent SDO, suggesting that the dynamics examined in this study ultimately relate to adolescents' social and ideological development. Copyright © 2015 The Foundation for Professionals in Services for Adolescents. Published by Elsevier Ltd. All rights reserved.

  17. Coordination of intrinsic and extrinsic hand muscle activity as a function of wrist joint angle during two-digit grasping.

    Science.gov (United States)

    Johnston, Jamie A; Bobich, Lisa R; Santello, Marco

    2010-04-26

    Fingertip forces result from the activation of muscles that cross the wrist and muscles whose origins and insertions reside within the hand (extrinsic and intrinsic hand muscles, respectively). Thus, tasks that involve changes in wrist angle affect the moment arm and length, hence the force-producing capabilities, of extrinsic muscles only. If a grasping task requires the exertion of constant fingertip forces, the Central Nervous System (CNS) may respond to changes in wrist angle by modulating the neural drive to extrinsic or intrinsic muscles only or by co-activating both sets of muscles. To distinguish between these scenarios, we recorded electromyographic (EMG) activity of intrinsic and extrinsic muscles of the thumb and index finger as a function of wrist angle during a two-digit object hold task. We hypothesized that changes in wrist angle would elicit EMG amplitude modulation of the extrinsic and intrinsic hand muscles. In one experimental condition we asked subjects to exert the same digit forces at each wrist angle, whereas in a second condition subjects could choose digit forces for holding the object. EMG activity was significantly modulated in both extrinsic and intrinsic muscles as a function of wrist angle (both pmuscles. We conclude that the CNS controlled both extrinsic and intrinsic muscles as a muscle synergy. These findings are discussed within the theoretical frameworks of synergies and common neural input across motor nuclei of hand muscles. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

  18. Eyelid closure at death

    Directory of Open Access Journals (Sweden)

    A D Macleod

    2009-01-01

    Full Text Available Aim: To observe the incidence of full or partial eyelid closure at death. Materials and Methods: The presence of ptosis was recorded in 100 consecutive hospice patient deaths. Results: Majority (63% of the patients died with their eyes fully closed, however, 37% had bilateral ptosis at death, with incomplete eye closure. In this study, central nervous system tumor involvement and/or acute hepatic encephalopathy appeared to be pre-mortem risk factors of bilateral ptosis at death. Conclusion: Organicity and not psychogenicity is, therefore, the likely etiology of failure of full eyelid closure at death.

  19. Unrecognised HIV related deaths.

    OpenAIRE

    McCormick, A.

    1991-01-01

    OBJECTIVES--To establish whether follow up of deaths from selected HIV related causes could increase the number of cases of HIV infection reported to the Public Health Laboratory Service Communicable Disease Surveillance Centre (CDSC), and to estimate the proportion of deaths among HIV positive men that occurred in men who were not known to be HIV positive at the time of death by the person who signed the death certificate. DESIGN--Follow up of draft death entries received by the Office of Po...

  20. Infant death scene investigation.

    Science.gov (United States)

    Tabor, Pamela D; Ragan, Krista

    2015-01-01

    The sudden unexpected death of an infant is a tragedy to the family, a concern to the community, and an indicator of national health. To accurately determine the cause and manner of the infant's death, a thorough and accurate death scene investigation by properly trained personnel is key. Funding and resources are directed based on autopsy reports, which are only as accurate as the scene investigation. The investigation should include a standardized format, body diagrams, and a photographed or videotaped scene recreation utilizing doll reenactment. Forensic nurses, with their basic nursing knowledge and additional forensic skills and abilities, are optimally suited to conduct infant death scene investigations as well as train others to properly conduct death scene investigations. Currently, 49 states have child death review teams, which is an idea avenue for a forensic nurse to become involved in death scene investigations.