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  1. Proteomic analysis of MG132-treated germinating pollen reveals expression signatures associated with proteasome inhibition.

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    Candida Vannini

    Full Text Available Chemical inhibition of the proteasome has been previously found to effectively impair pollen germination and tube growth in vitro. However, the mediators of these effects at the molecular level are unknown. By performing 2DE proteomic analysis, 24 differentially expressed protein spots, representing 14 unique candidate proteins, were identified in the pollen of kiwifruit (Actinidia deliciosa germinated in the presence of the MG132 proteasome inhibitor. qPCR analysis revealed that 11 of these proteins are not up-regulated at the mRNA level, but are most likely stabilized by proteasome inhibition. These differentially expressed proteins are predicted to function in various pathways including energy and lipid metabolism, cell wall synthesis, protein synthesis/degradation and stress responses. In line with this evidence, the MG132-induced changes in the proteome were accompanied by an increase in ATP and ROS content and by an alteration in fatty acid composition.

  2. Inhibition effect of proteasome inhibitor MG132 combined with X-ray irradiation on cell growth, metastasis and cycle distribution of human lung adenocarcinoma cells

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    Liu Jing; Tang Yiting; Zhou Jundong; Zhang Shuyu; Cao Han; Wu Jinchang; Luo Judong; Chen Guanglie; Cao Jianping

    2014-01-01

    Objective: To study the effects of proteasome inhibitor MG132 on the growth, metastasis, and cell cycle distribution of human lung adenocarcinoma cells A549 irradiated by X-rays. Methods: After treatment of MG132 and irradiation,cell proliferation was detected by MTT assay. Survival was measured by clonogenic assay. Cell migration ability was detected by the Scratch migration assay. Cell invasion ability was detected by transwell migration assay. Cell cycle distribution were analyzed by flow cytometry assay. Protein expression was detected by Western blot assay. Results: MG132 alone inhibited cell growth in a dose-and time-dependent manner. MG132 in combination with radiation significantly suppressed the growth, migration and invasion of A549 cells compared to the control (F =554.78, 954.64, P<0.01). MG132 enhanced radiation-induced G 1 -arrest (t =4.44, 12.41, 3.52, 6.72, P<0.05). The G 1 cell cycle distribution rate of MG132 plus RT group was increased to (71.05 ± 4.17)%. The expressions of MMP-2, MMP-9 and Cyclin D1 were significantly suppressed by MG132 in combination with radiation, while the expression of P53 was up-regulated. Conclusions: MG132 inhibits cell growth, migration and invasion ability, and induces G 1 cell cycle arrest of A549 cells treated with MG132 in combination with radiation, in which the down-regulation of MMPs and Cyclin D1 and up-regulation of P53 may be involved. (authors)

  3. MG132 as a proteasome inhibitor induces cell growth inhibition and cell death in A549 lung cancer cells via influencing reactive oxygen species and GSH level.

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    Han, Yong Hwan; Park, Woo Hyun

    2010-07-01

    Carbobenzoxy-Leu-Leu-leucinal (MG132) as a proteasome inhibitor has been shown to induce apoptotic cell death through formation of reactive oxygen species (ROS). In the present study, we evaluated the effects of MG132 on the growth of A549 lung cancer cells in relation to cell growth, ROS and glutathione (GSH) levels. Treatment with MG132 inhibited the growth of A549 cells with an IC(50) of approximately 20 microM at 24 hours. DNA flow cytometric analysis indicated that 0.5 approximately 30 microM MG132 induced a G1 phase arrest of the cell cycle in A549 cells. Treatment with 10 or 30 microM MG132 also induced apoptosis, as evidenced by sub-G1 cells and annexin V staining cells. This was accompanied by the loss of mitochondrial membrane potential (MMP; Delta psi m). The intracellular ROS levels including O(2) (*-) were strongly increased in 10 or 30 microM MG132-treated A549 cells but were down-regulated in 0.1, 0.5 or 1 microM MG132-treated cells. Furthermore, 10 or 30 microM MG132 increased mitochondrial O(2) (*- ) level but 0.1, 0.5 or 1 microM MG132 decreased that. In addition, 10 or 30 microM MG132 induced GSH depletion in A549 cells. In conclusion, MG132 inhibited the growth of human A549 cells via inducing the cell cycle arrest as well as triggering apoptosis, which was in part correlated with the changes of ROS and GSH levels. Our present data provide important information on the anti-growth mechanisms of MG132 in A549 lung cancer cells in relation to ROS and GSH.

  4. MCPIP1 contributes to the toxicity of proteasome inhibitor MG-132 in HeLa cells by the inhibition of NF-κB.

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    Skalniak, Lukasz; Dziendziel, Monika; Jura, Jolanta

    2014-10-01

    Recently, we have shown that the treatment of cells with proteasome inhibitor MG-132 results in the induction of expression of monocyte chemotactic protein-1 induced protein 1 (MCPIP1). MCPIP1 is a ribonuclease, responsible for the degradation of transcripts encoding certain pro-inflammatory cytokines. The protein is also known as an inhibitor of NF-κB transcription factor. Thanks to its molecular properties, MCPIP1 is considered as a regulator of inflammation, differentiation, and survival. Using siRNA technology, we show here that MCPIP1 expression contributes to the toxic properties of MG-132 in HeLa cells. The inhibition of proteasome by MG-132 and epoxomicin markedly increased MCPIP1 expression. While MG-132 induces HeLa cell death, down-regulation of MCPIP1 expression by siRNA partially protects HeLa cells from MG-132 toxicity and restores Nuclear factor-κB (NF-κB) activity, inhibited by MG-132 treatment. Inversely, overexpression of MCPIP1 decreased constitutive activity of NF-κB and limited the survival of HeLa cells, as we have shown in the previous study. Interestingly, although MG-132 decreased the expression of IκBα and increased p65 phosphorylation, the inhibition of constitutive NF-κB activity was observed in MG-132-treated cells. Since the elevated constitutive activity of NF-κB is one of the mechanisms providing increased survival of cancer cells, including HeLa cells, we propose that death-promoting properties of MCPIP1 in MG-132-treated HeLa cells may, at least partially, derive from the negative effect on the constitutive NF-κB activity.

  5. MG132, a proteasome inhibitor, induces human pulmonary fibroblast cell death via increasing ROS levels and GSH depletion.

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    Park, Woo Hyun; Kim, Suhn Hee

    2012-04-01

    MG132 as a proteasome inhibitor can induce apoptotic cell death in lung cancer cells. However, little is known about the toxicological cellular effects of MG132 on normal primary lung cells. Here, we investigated the effects of N-acetyl cysteine (NAC) and vitamin C (well known antioxidants) or L-buthionine sulfoximine (BSO; an inhibitor of GSH synthesis) on MG132-treated human pulmonary fibroblast (HPF) cells in relation to cell death, reactive oxygen species (ROS) and glutathione (GSH). MG132 induced growth inhibition and death in HPF cells, accompanied by the loss of mitochondrial membrane potential (MMP; ∆ψm). MG132 increased ROS levels and GSH-depleted cell numbers in HPF cells. Both antioxidants, NAC and vitamin C, prevented growth inhibition, death and MMP (∆ψm) loss in MG132-treated HPF cells and also attenuated ROS levels in these cells. BSO showed a strong increase in ROS levels in MG132-treated HPF cells and slightly enhanced the growth inhibition, cell death, MMP (∆ψm) loss and GSH depletion. In addition, NAC decreased anonymous ubiquitinated protein levels in MG132-treated HPF cells. Furthermore, superoxide dismutase (SOD) 2, catalase (CTX) and GSH peroxidase (GPX) siRNAs enhanced HPF cell death by MG132, which was not correlated with ROS and GSH level changes. In conclusion, MG132 induced the growth inhibition and death of HPF cells, which were accompanied by increasing ROS levels and GSH depletion. Both NAC and vitamin C attenuated HPF cell death by MG132, whereas BSO slightly enhanced the death.

  6. Post-fusion treatment with MG132 increases transcription factor expression in somatic cell nuclear transfer embryos in pigs.

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    You, Jinyoung; Lee, Joohyeong; Kim, Jinyoung; Park, Junhong; Lee, Eunsong

    2010-02-01

    The objective of this study was to examine the effect of post-fusion treatment of somatic cell nuclear transfer (SCNT) oocytes with the proteasomal inhibitor MG132 on maturation promoting factor (MPF) activity, nuclear remodeling, embryonic development, and gene expression of cloned pig embryos. Immediately after electrofusion, SCNT oocytes were treated with MG132 and/or caffeine for 2 hr, vanadate for 0.5 hr, or vanadate for 0.5 hr followed by MG132 for 1.5 hr. Of the MG132 concentrations tested (0-5 microM), the 1 microM concentration showed a higher rate of blastocyst formation (25.9%) than 0 (14.2%), 0.5 (16.9%), and 5 microM (16.9%). Post-fusion treatment with MG132, caffeine, and both MG132 and caffeine improved blastocyst formation (22.1%, 21.4%, and 24.4%, respectively), whereas vanadate treatment inhibited blastocyst formation (6.5%) compared to the control (11.1%). When examined 2 hr after fusion and 1 hr after activation, MPF activity remained at a higher (P fusion with caffeine and/or MG132, but it was decreased by vanadate. The rate of oocytes showing premature chromosome condensation was not altered by MG132 but was decreased by vanadate treatment. In addition, formation of single pronuclei was increased by MG132 compared to control and vanadate treatment. MG132-treated embryos showed increased expression of POU5F1, DPPA2, DPPA3, DPPA5, and NDP52l1 genes compared to control embryos. Our results demonstrate that post-fusion treatment of SCNT oocytes with MG132 prevents MPF degradation and increases expression of transcription factors in SCNT embryos, which are necessary for normal development of SCNT embryos. (c) 2009 Wiley-Liss, Inc.

  7. Combination therapy for hepatitis C virus with heat-shock protein 90 inhibitor 17-AAG and proteasome inhibitor MG132.

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    Ujino, Saneyuki; Yamaguchi, Saori; Shimotohno, Kunitada; Takaku, Hiroshi

    2010-03-09

    Hepatitis C virus (HCV) infection is a major cause of chronic liver disease. Here, we report a new and effective strategy for inhibiting HCV replication using an inhibitor of heat-shock protein 90, 17-AAG (17-allylamino-17demethoxygeldanamycin), and a proteasome inhibitor, MG132. To explore the virological basis of combination therapy, we analysed the effects of 17-AAG and MG132, singly and in combination on HCV replication in an HCV replicon cell system. In HCV replicon cells, HCV RNA replication was suppressed by 17-AAG in a dose-dependent manner. As shown in the present study, the 50% inhibitory concentration values were 0.82 nM for 17-AAG and 0.21 nM for MG132. Low concentrations of MG132 had strong synergistic inhibitory effects with low toxicity on HCV replicon cells. The results of this study suggest that the different effects and synergistic actions of 17-AAG and MG132 could provide a new therapeutic approach to HCV infection.

  8. Proteasome inhibitor MG132 sensitizes HPV-positive human cervical cancer cells to rhTRAIL-induced apoptosis

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    Hougardy, BMT; Maduro, JH; van der Zee, AGJ; de Groot, DJA; van den Heuvel, FAJ; de Vries, EGE; de Jong, S

    2006-01-01

    In cervical carcinogenesis, the p53 tumor suppressor pathway is disrupted by HPV (human papilloma virus) E6 oncogene expression. E6 targets p53 for rapid proteasome-mediated degradation. We therefore investigated whether proteasome inhibition by MG132 could restore wild-type p53 levels and sensitize

  9. Combination of Proteasomal Inhibitors Lactacystin and MG132 Induced Synergistic Apoptosis in Prostate Cancer Cells

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    Robert B. Shirley

    2005-12-01

    Full Text Available The proteasome inhibitor Velcade (bortezomib/PS-341 has been shown to block the targeted proteolytic degradation of short-lived proteins that are involved in cell maintenance, growth, division, and death, advocating the use of proteasomal inhibitors as therapeutic agents. Although many studies focused on the use of one proteasomal inhibitor for therapy, we hypothesized that the combination of proteasome inhibitors Lactacystin (AG Scientific, Inc., San Diego, CA and MG132 (Biomol International, Plymouth Meeting, PA may be more effective in inducing apoptosis. Additionally, this regimen would enable the use of sublethal doses of individual drugs, thus reducing adverse effects. Results indicate a significant increase in apoptosis when LNCaP prostate cancer cells were treated with increasing levels of Lactacystin, MG132, or a combination of sublethal doses of these two inhibitors. Furthermore, induction in apoptosis coincided with a significant loss of IKKα, IKKβ, and IKKγ proteins and NFκB activity. In addition to describing effective therapeutic agents, we provide a model system to facilitate the investigation of the mechanism of action of these drugs and their effects on the IKK-NFκB axis.

  10. MG132 plus apoptosis antigen-1 (APO-1) antibody cooperate to restore p53 activity inducing autophagy and p53-dependent apoptosis in HPV16 E6-expressing keratinocytes.

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    Lagunas-Martínez, Alfredo; García-Villa, Enrique; Arellano-Gaytán, Magaly; Contreras-Ochoa, Carla O; Dimas-González, Jisela; López-Arellano, María E; Madrid-Marina, Vicente; Gariglio, Patricio

    2017-01-01

    The E6 oncoprotein can interfere with the ability of infected cells to undergo programmed cell death through the proteolytic degradation of proapoptotic proteins such as p53, employing the proteasome pathway. Therefore, inactivation of the proteasome through MG132 should restore the activity of several proapoptotic proteins. We investigated whether in HPV16 E6-expressing keratinocytes (KE6 cells), the restoration of p53 levels mediated by MG132 and/or activation of the CD95 pathway through apoptosis antigen-1 (APO-1) antibody are responsible for the induction of apoptosis. We found that KE6 cells underwent apoptosis mainly after incubation for 24 h with MG132 alone or APO-1 plus MG132. Both treatments activated the extrinsic and intrinsic apoptosis pathways. Autophagy was also activated, principally by APO-1 plus MG132. Inhibition of E6-mediated p53 proteasomal degradation by MG132 resulted in the elevation of p53 protein levels and its phosphorylation in Ser46 and Ser20; the p53 protein was localized mainly at nucleus after treatment with MG132 or APO-1 plus MG132. In addition, induction of its transcriptional target genes such as p21, Bax and TP53INP was observed 3 and 6 h after treatment. Also, LC3 mRNA was induced after 3 and 6 h, which correlates with lipidation of LC3B protein and induction of autophagy. Finally, using pifithrin alpha we observed a decrease in apoptosis induced by MG132, and by APO-1 plus MG132, suggesting that restoration of APO-1 sensitivity occurs in part through an increase in both the levels and the activity of p53. The use of small molecules to inhibit the proteasome pathway might permit the activation of cell death, providing new opportunities for CC treatment.

  11. A robust ex vivo model for evaluation of induction of apoptosis by rhTRAIL in combination with proteasome inhibitor MG132 in human premalignant cervical explants

    NARCIS (Netherlands)

    Hougardy, Brigitte M. T.; Reesink-Peters, Nathalie; van den Heuvel, Fiona A. J.; ten Hoor, Klaske A.; Hollema, Harry; de Vries, Elisabeth G. E.; de Jong, Steven; van der Zee, Ate G. J.

    2008-01-01

    Development of medical therapies for high-grade cervical intraepithelial neoplasia (CIN II/III) is hampered by the lack of CIN II/III cell lines. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis upon binding to its receptors DR4 or DR5. Proteasome inhibition by MG132

  12. Synergism between arsenite and proteasome inhibitor MG132 over cell death in myeloid leukaemic cells U937 and the induction of low levels of intracellular superoxide anion

    International Nuclear Information System (INIS)

    Lombardo, Tomás; Cavaliere, Victoria; Costantino, Susana N.; Kornblihtt, Laura; Alvarez, Elida M.; Blanco, Guillermo A.

    2012-01-01

    Increased oxygen species production has often been cited as a mechanism determining synergism on cell death and growth inhibition effects of arsenic-combined drugs. However the net effect of drug combination may not be easily anticipated solely from available knowledge of drug-induced death mechanisms. We evaluated the combined effect of sodium arsenite with the proteasome inhibitor MG132, and the anti-leukaemic agent CAPE, on growth-inhibition and cell death effect in acute myeloid leukaemic cells U937 and Burkitt's lymphoma-derived Raji cells, by the Chou–Talalay method. In addition we explored the association of cytotoxic effect of drugs with changes in intracellular superoxide anion (O 2 − ) levels. Our results showed that combined arsenite + MG132 produced low levels of O 2 − at 6 h and 24 h after exposure and were synergic on cell death induction in U937 cells over the whole dose range, although the combination was antagonistic on growth inhibition effect. Exposure to a constant non-cytotoxic dose of 80 μM hydrogen peroxide together with arsenite + MG132 changed synergism on cell death to antagonism at all effect levels while increasing O 2 − levels. Arsenite + hydrogen peroxide also resulted in antagonism with increased O 2 − levels in U937 cells. In Raji cells, arsenite + MG132 also produced low levels of O 2 − at 6 h and 24 h but resulted in antagonism on cell death and growth inhibition. By contrast, the combination arsenite + CAPE showed high levels of O 2 − production at 6 h and 24 h post exposure but resulted in antagonism over cell death and growth inhibition effects in U937 and Raji cells. We conclude that synergism between arsenite and MG132 in U937 cells is negatively associated to O 2 − levels at early time points after exposure. -- Highlights: ► Arsenic combined cytotoxic and anti-proliferative effects by Chou–Talalay method. ► Cytotoxic effect associated with superoxide levels as assessed by flow cytometry. ► Synergism

  13. Synergism between arsenite and proteasome inhibitor MG132 over cell death in myeloid leukaemic cells U937 and the induction of low levels of intracellular superoxide anion

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    Lombardo, Tomás [Laboratorio de Immunotoxicologia (LaITO), IDEHU-CONICET, Hospital de Clínicas, José de San Martín, Universidad de Buenos Aires (UBA), Buenos Aires (Argentina); Cavaliere, Victoria; Costantino, Susana N. [Laboratorio de Inmunología Tumoral (LIT), IDEHU-CONICET, Facultad de Farmacia y Bioquímica, UBA, Buenos Aires (Argentina); Kornblihtt, Laura [Servicio de Hematología, Hospital de Clínicas, José de San Martín (UBA), Buenos Aires (Argentina); Alvarez, Elida M. [Laboratorio de Inmunología Tumoral (LIT), IDEHU-CONICET, Facultad de Farmacia y Bioquímica, UBA, Buenos Aires (Argentina); Blanco, Guillermo A., E-mail: gblanco@ffyb.uba.ar [Laboratorio de Immunotoxicologia (LaITO), IDEHU-CONICET, Hospital de Clínicas, José de San Martín, Universidad de Buenos Aires (UBA), Buenos Aires (Argentina)

    2012-02-01

    Increased oxygen species production has often been cited as a mechanism determining synergism on cell death and growth inhibition effects of arsenic-combined drugs. However the net effect of drug combination may not be easily anticipated solely from available knowledge of drug-induced death mechanisms. We evaluated the combined effect of sodium arsenite with the proteasome inhibitor MG132, and the anti-leukaemic agent CAPE, on growth-inhibition and cell death effect in acute myeloid leukaemic cells U937 and Burkitt's lymphoma-derived Raji cells, by the Chou–Talalay method. In addition we explored the association of cytotoxic effect of drugs with changes in intracellular superoxide anion (O{sub 2}{sup −}) levels. Our results showed that combined arsenite + MG132 produced low levels of O{sub 2}{sup −} at 6 h and 24 h after exposure and were synergic on cell death induction in U937 cells over the whole dose range, although the combination was antagonistic on growth inhibition effect. Exposure to a constant non-cytotoxic dose of 80 μM hydrogen peroxide together with arsenite + MG132 changed synergism on cell death to antagonism at all effect levels while increasing O{sub 2}{sup −} levels. Arsenite + hydrogen peroxide also resulted in antagonism with increased O{sub 2}{sup −} levels in U937 cells. In Raji cells, arsenite + MG132 also produced low levels of O{sub 2}{sup −} at 6 h and 24 h but resulted in antagonism on cell death and growth inhibition. By contrast, the combination arsenite + CAPE showed high levels of O{sub 2}{sup −} production at 6 h and 24 h post exposure but resulted in antagonism over cell death and growth inhibition effects in U937 and Raji cells. We conclude that synergism between arsenite and MG132 in U937 cells is negatively associated to O{sub 2}{sup −} levels at early time points after exposure. -- Highlights: ► Arsenic combined cytotoxic and anti-proliferative effects by Chou–Talalay method. ► Cytotoxic effect

  14. The proteasome inhibitor MG-132 sensitizes PC-3 prostate cancer cells to ionizing radiation by a DNA-PK-independent mechanism

    International Nuclear Information System (INIS)

    Pajonk, Frank; Ophoven, Arndt van; Weissenberger, Christian; McBride, William H

    2005-01-01

    By modulating the expression levels of specific signal transduction molecules, the 26S proteasome plays a central role in determining cell cycle progression or arrest and cell survival or death in response to stress stimuli, including ionizing radiation. Inhibition of proteasome function by specific drugs results in cell cycle arrest, apoptosis and radiosensitization of many cancer cell lines. This study investigates whether there is also a concomitant increase in cellular radiosensitivity if proteasome inhibition occurs only transiently before radiation. Further, since proteasome inhibition has been shown to activate caspase-3, which is involved in apoptosis, and caspase-3 can cleave DNA-PKcs, which is involved in DNA-double strand repair, the hypothesis was tested that caspase-3 activation was essential for both apoptosis and radiosensitization following proteasome inhibition. Prostate carcinoma PC-3 cells were treated with the reversible proteasome inhibitor MG-132. Cell cycle distribution, apoptosis, caspase-3 activity, DNA-PKcs protein levels and DNA-PK activity were monitored. Radiosensitivity was assessed using a clonogenic assay. Inhibition of proteasome function caused cell cycle arrest and apoptosis but this did not involve early activation of caspase-3. Short-time inhibition of proteasome function also caused radiosensitization but this did not involve a decrease in DNA-PKcs protein levels or DNA-PK activity. We conclude that caspase-dependent cleavage of DNA-PKcs during apoptosis does not contribute to the radiosensitizing effects of MG-132

  15. The Proteasome Inhibitor MG-132 Protects Hypoxic SiHa Cervical Carcinoma Cells after Cyclic Hypoxia/Reoxygenation from Ionizing Radiation

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    Frank Pajonk

    2006-12-01

    Full Text Available INTRODUCTION: Transient hypoxia and subsequent reoxygenation are common phenomena in solid tumors that greatly influence the outcome of radiation therapy. This study was designed to determine how varying cycles of hypoxia/reoxygenation affect the response of cervical carcinoma cells irradiated under oxic and hypoxic conditions and whether this could be modulated by proteasome inhibition. MATERIALS AND METHODS: Plateau-phase SiHa cervical carcinoma cells in culture were exposed to varying numbers of 30-minute cycles of hypoxia/reoxygenation directly before irradiation under oxic or hypoxic conditions. 26S Proteasome activity was blocked by addition of MG-132. Clonogenic survival was measured by a colonyforming assay. RESULTS: Under oxic conditions, repeated cycles of hypoxia/reoxygenation decreased the clonogenic survival of SiHa cells. This effect was even more pronounced after the inhibition of 26S proteasome complex. In contrast, under hypoxic conditions, SiHa cells were radioresistant, as expected, but this was increased by proteasome inhibition. CONCLUSIONS: Proteasome inhibition radiosensitizes oxygenated tumor cells but may also protect tumor cells from ionizing radiation under certain hypoxic conditions.

  16. Upregulated ROS production induced by the proteasome inhibitor MG-132 on XBP1 gene expression and cell apoptosis in Tca-8113 cells.

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    Chen, Hai-ying; Ren, Xiao-yan; Wang, Wei-hua; Zhang, Ying-xin; Chen, Shuang-feng; Zhang, Bin; Wang, Le-xin

    2014-07-01

    Exposure of Tca-8113 cells to proteasome inhibitor carbobenzoxy-Leu-Leu-leucinal (MG-132) causing apoptosis is associated with endoplasmic reticulum (ER) stress. X-box-binding protein-1 (XBP1) is an important regulator of a subset of genes active during ER stress, which is related to cell survival and is required for tumor growth. The present study is to evaluate the effect of MG-132 on ROS production, XBP1 gene expression, tumor necrosis factor receptor-associated factor 2 (TRAF2), ASK1 and c-jun protein expression in tongue squamous cell carcinoma cell line Tca-8113 cells. ROS production was measured by reactive oxygen species assay. X-box binding protein-1 (XBP1) mRNA was analyzed by real-time-PCR, TRAF2, ASK1 and c-jun protein were investigated by western blot and immunocytochemistry respectively. The result indicated that ROS production, TRAF2, ASK1 and c-jun were elevated in MG-132 treated cells. Giving ROS scavenger N-acetyl-L-cysteine (NAC) largely prevented the effects of MG-132. Furthermore, treating with MG-132 lead to decreased XBP1 mRNA expression but could not completely block the expression of XBP1. Taken together, these findings provide the evidence that MG-132 induced ER stress lead to Tca-8113 cells apoptosis through ROS generation and TRAF2-ASK1-JNK signal pathway activation. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  17. Electroacupuncture Confers Antinociceptive Effects via Inhibition of Glutamate Transporter Downregulation in Complete Freund's Adjuvant-Injected Rats

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    Ha-Neui Kim

    2012-01-01

    Full Text Available When we evaluated changes of glial fibrillary acidic protein (GFAP and two glutamate transporter (GTs by immunohistochemistry, expression of GFAP showed a significant increase in complete Freund's adjuvant (CFA-injected rats; however, this expression was strongly inhibited by electroacupuncture (EA stimulation. Robust downregulation of glutamate-aspartate transporter (GLAST and glutamate transporter-1 (GLT-1 was observed in CFA-injected rats; however, EA stimulation resulted in recovery of this expression. Double-labeling staining showed co-localization of a large proportion of GLAST or GLT-1 with GFAP. Using Western blot, we confirmed protein expression of two GTs, but no differences in the mRNA content of these GTs were observed. Because EA treatment resulted in strong inhibition of CFA-induced proteasome activities, we examined the question of whether thermal sensitivities and GTs expression could be regulated by proteasome inhibitor MG132. CFA-injected rats co-treated with EA and MG132 showed a significantly longer thermal sensitivity, compared with CFA-injected rats with or without MG132. Both EA and MG132 blocked CFA-induced GLAST and GLT-1 downregulation within the spinal cord. These results provide evidence for involvement of GLAST and GLT-1 in response to activation of spinal astrocytes in an EA antinociceptive effect. Antinociceptive effect of EA may be induced via proteasome-mediated regulation of spinal GTs.

  18. Inhibition of autophagy induced by proteasome inhibition increases cell death in human SHG-44 glioma cells.

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    Ge, Peng-Fei; Zhang, Ji-Zhou; Wang, Xiao-Fei; Meng, Fan-Kai; Li, Wen-Chen; Luan, Yong-Xin; Ling, Feng; Luo, Yi-Nan

    2009-07-01

    The ubiquitin-proteasome system (UPS) and lysosome-dependent macroautophagy (autophagy) are two major intracellular pathways for protein degradation. Recent studies suggest that proteasome inhibitors may reduce tumor growth and activate autophagy. Due to the dual roles of autophagy in tumor cell survival and death, the effect of autophagy on the destiny of glioma cells remains unclear. In this study, we sought to investigate whether inhibition of the proteasome can induce autophagy and the effects of autophagy on the fate of human SHG-44 glioma cells. The proteasome inhibitor MG-132 was used to induce autophagy in SHG-44 glioma cells, and the effect of autophagy on the survival of SHG-44 glioma cells was investigated using an autophagy inhibitor 3-MA. Cell viability was measured by MTT assay. Apoptosis and cell cycle were detected by flow cytometry. The expression of autophagy related proteins was determined by Western blot. MG-132 inhibited cell proliferation, induced cell death and cell cycle arrest at G(2)/M phase, and activated autophagy in SHG-44 glioma cells. The expression of autophagy-related Beclin-1 and LC3-I was significantly up-regulated and part of LC3-I was converted into LC3-II. However, when SHG-44 glioma cells were co-treated with MG-132 and 3-MA, the cells became less viable, but cell death and cell numbers at G(2)/M phase increased. Moreover, the accumulation of acidic vesicular organelles was decreased, the expression of Beclin-1 and LC3 was significantly down-regulated and the conversion of LC3-II from LC3-I was also inhibited. Inhibition of the proteasome can induce autophagy in human SHG-44 glioma cells, and inhibition of autophagy increases cell death. This discovery may shed new light on the effect of autophagy on modulating the fate of SHG-44 glioma cells.Acta Pharmacologica Sinica (2009) 30: 1046-1052; doi: 10.1038/aps.2009.71.

  19. Coeliac disease autoantibodies mediate significant inhibition of tissue transglutaminase.

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    Byrne, Greg

    2012-02-01

    The detection of antibodies directed against tissue transglutaminase (tTG) in serum is a sensitive and specific test for suspected coeliac disease. tTG is a ubiquitous, multifunctional enzyme that has been implicated in many important physiological processes as well as the site-specific deamidation of glutamine residues in gluten-derived peptides. This modification of gluten peptides facilitates their binding to HLA-DQ2, which results in amplification of the T-cell response to gluten. The purpose of this study was to investigate the possibility that patient IgA autoantibodies directed against tTG interfere with the crosslinking activity of the enzyme. IgA autoantibodies against tTG were isolated\\/depleted from patient serum and tested for their capacity to interfere with tTG activity in vitro using a sensitive fluorescence-based activity assay. We have demonstrated that autoantibodies cause significant inhibition of tTG-mediated crosslinking at equimolar and 2:1 ratios of antibody to enzyme.

  20. The influence of proteasome inhibitor MG132, external radiation and unlabeled antibody on the tumor uptake and biodistribution of 188Re-labeled anti-E6 C1P5 antibody in cervical cancer in mice

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    Phaeton, Rébécca; Wang, Xing Guo; Einstein, Mark H.; Goldberg, Gary L.; Casadevall, Arturo; Dadachova, Ekaterina

    2009-01-01

    Background Human Papillomavirus (HPV) infection is considered a necessary step for the development of cervical cancer and >95% of all cervical cancers have detectable HPV sequences. We have recently demonstrated the efficacy of radioimmunotherapy (RIT) which targeted viral oncoprotein E6 in treatment of experimental cervical cancer We hypothesized that pre-treatment of tumor cells with various agents which cause cell death and/or elevation of E6 levels would increase the accumulation of radiolabeled antibodies to E6 in cervical tumors. Methods HPV-16 positive CasKi cells were treated in vitro with up to 6 Gy of external radiation, or proteasome inhibitor MG-132 or unlabeled anti-E6 antibody C1P5 and cell death was assessed. Biodistribution of 188Rhenium (188Re)-labeled C1P5 antibody was performed in both control and radiation MG-132 treated CasKi tumor-bearing nude mice. Results . 188Re-C1P5 antibody demonstrated tumor specificity and very low uptake and fast clearance from the major organs. The amount of tumor uptake was enhanced by MG-132 but was unaffected by pre-treatment with radiation. In addition, in vitro studies demonstrated an unanticipated effect of unlabeled antibody on the amount of cell death, a finding that was suggested by our previous in vivo studies in CasKi tumor model. Conclusion We demonstrated that pre-treatment of cervical tumors with proteasome inhibitor MG-132 and with unlabeled antibody to E6 can serve as a means to generate non-viable cancer cells and to elevate the levels of target oncoproteins in the cells for increasing the accumulation of targeted radiolabeled antibodies in tumors. These results favor further development of RIT of cervical cancers targeting viral antigens. PMID:20127955

  1. Impact of High Glucose and Proteasome Inhibitor MG132 on Histone H2A and H2B Ubiquitination in Rat Glomerular Mesangial Cells

    Directory of Open Access Journals (Sweden)

    Chenlin Gao

    2013-01-01

    Full Text Available Background. Hyperglycemia plays a pivotal role in the development of diabetic nephropathy (DN and may be related to epigenetic metabolic memory. One of the most crucial epigenetic mechanisms is histone modification, which is associated with the expression of a fibrosis factor in vascular injury. Aim .In this study, we investigated the ubiquitination of histones H2A and H2B to explore the epigenetic mechanisms of DN. Materials and Methods. The GMCs were cultured as follows: normal group, high glucose group, mannitol group, and intervention group. After 12 hr, 24 hr, and 48 hr, histones ubiquitination, transforming growth factor-β (TGF-β, and fibronectin (FN were measured using WB, RT-PCR, and IF. Result. High glucose can induce the upregulation of FN. H2A ubiquitination in GMCs increased in high glucose group (P<0.01, whereas it decreased significantly in intervention group (P<0.05. In contrast, H2B ubiquitination decreased with an increasing concentration of glucose, but it was recovered in the intervention group (P<0.05. Expression of TGF-β changed in response to abnormal histone ubiquitination. Conclusions. The high glucose may induce H2A ubiquitination and reduce H2B ubiquitination in GMCs. The changes of histone ubiquitination may be due in part to DN by activating TGF-β signaling pathway.

  2. Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation

    Science.gov (United States)

    Wang, Jing; Luo, Cheng; Shan, Changliang; You, Qiancheng; Lu, Junyan; Elf, Shannon; Zhou, Yu; Wen, Yi; Vinkenborg, Jan L.; Fan, Jun; Kang, Heebum; Lin, Ruiting; Han, Dali; Xie, Yuxin; Karpus, Jason; Chen, Shijie; Ouyang, Shisheng; Luan, Chihao; Zhang, Naixia; Ding, Hong; Merkx, Maarten; Liu, Hong; Chen, Jing; Jiang, Hualiang; He, Chuan

    2015-12-01

    Copper is a transition metal that plays critical roles in many life processes. Controlling the cellular concentration and trafficking of copper offers a route to disrupt these processes. Here we report small molecules that inhibit the human copper-trafficking proteins Atox1 and CCS, and so provide a selective approach to disrupt cellular copper transport. The knockdown of Atox1 and CCS or their inhibition leads to a significantly reduced proliferation of cancer cells, but not of normal cells, as well as to attenuated tumour growth in mouse models. We show that blocking copper trafficking induces cellular oxidative stress and reduces levels of cellular ATP. The reduced level of ATP results in activation of the AMP-activated protein kinase that leads to reduced lipogenesis. Both effects contribute to the inhibition of cancer cell proliferation. Our results establish copper chaperones as new targets for future developments in anticancer therapies.

  3. Significance of bacterial flora in abdominal irradiation-induced inhibition of lung metastases

    International Nuclear Information System (INIS)

    Matsumoto, T.; Ando, K.; Koike, S.

    1988-01-01

    We have previously reported that abdominal irradiation prior to i.v. injection of syngeneic tumor cells reduced metastases in lung. Our report described an investigation of the significance of intestinal organisms in the radiation effect. We found that eliminating intestinal organisms with antibiotics totally abolished the radiation effect. Monoassociation of germ-free mice revealed that the radiation effect was observable only for Enterobacter cloacae, never for Streptococcus faecium, Bifidobacterium adlesentis, or Escherichia coli. After abdominal irradiation of regular mice, E. cloacae multiplied in cecal contents, adhered to mucous membranes, invaded the cecal wall, and translocated to mesenteric lymph nodes. Intravenous administration of E. cloacae in place of abdominal irradiation inhibited metastases. E. cloacae-monoassociated mice developed fewer metastases than germ-free mice, and the reduction was further enhanced by abdominal irradiation. We concluded that abdominal irradiation caused the invasion of E. cloacae from the mucous membrane of the intestine and inhibited formation of lung metastases

  4. Graphene oxide significantly inhibits cell growth at sublethal concentrations by causing extracellular iron deficiency.

    Science.gov (United States)

    Yu, Qilin; Zhang, Bing; Li, Jianrong; Du, Tingting; Yi, Xiao; Li, Mingchun; Chen, Wei; Alvarez, Pedro J J

    Graphene oxide (GO)-based materials are increasingly being used in medical materials and consumer products. However, their sublethal effects on biological systems are poorly understood. Here, we report that GO (at 10 to 160 mg/L) induced significant inhibitory effects on the growth of different unicellular organisms, including eukaryotes (i.e. Saccharomyces cerevisiae, Candida albicans, and Komagataella pastoris) and prokaryotes (Pseudomonas fluorescens). Growth inhibition could not be explained by commonly reported cytotoxicity mechanisms such as plasma membrane damage or oxidative stress. Based on transcriptomic analysis and measurement of extra- and intracellular iron concentrations, we show that the inhibitory effect of GO was mainly attributable to iron deficiency caused by binding to the O-functional groups of GO, which sequestered iron and disrupted iron-related physiological and metabolic processes. This inhibitory mechanism was corroborated with supplementary experiments, where adding bathophenanthroline disulfonate-an iron chelating agent-to the culture medium exerted similar inhibition, whereas removing surface O-functional groups of GO decreased iron sequestration and significantly alleviated the inhibitory effect. These findings highlight a potential indirect detrimental effect of nanomaterials (i.e. scavenging of critical nutrients), and encourage research on potential biomedical applications of GO-based materials to sequester iron and enhance treatment of iron-dependent diseases such as cancer and some pathogenic infections.

  5. Continuous delivery of propranolol from liposomes-in-microspheres significantly inhibits infantile hemangioma growth

    Directory of Open Access Journals (Sweden)

    Guo XN

    2017-09-01

    Full Text Available Xiaonan Guo,1,* Xiaoshuang Zhu,1,* Dakan Liu,1 Yubin Gong,1 Jing Sun,2 Changxian Dong1 1Department of Hemangioma and Vascular Malformation, Henan Provincial People’s Hospital, Zhengzhou, People’s Republic of China; 2Department of Pharmacy, Second Military Medical University, Shanghai, People’s Republic of China *These authors contributed equally to this work Purpose: To reduce the adverse effects and high frequency of administration of propranolol to treat infantile hemangioma, we first utilized propranolol-loaded liposomes-in-microsphere (PLIM as a novel topical release system to realize sustained release of propranolol.Methods: PLIM was developed from encapsulating propranolol-loaded liposomes (PLs in microspheres made of poly(lactic-co-glycolic acid-b-poly(ethylene glycol-b-poly(lactic-co-glycolic acid copolymers (PLGA-PEG-PLGA. The release profile of propranolol from PLIM was evaluated, and its biological activity was investigated in vitro using proliferation assays on hemangioma stem cells (HemSCs. Tumor inhibition was studied in nude mice bearing human subcutaneous infantile hemangioma.Results: The microspheres were of desired particle size (~77.8 µm and drug encapsulation efficiency (~23.9% and achieved sustained drug release for 40 days. PLIM exerted efficient inhibition of the proliferation of HemSCs and significantly reduced the expression of two angiogenesis factors (vascular endothelial growth factor-A [VEGF-A] and basic fibroblast growth factor [bFGF] in HemSCs. Notably, the therapeutic effect of PLIM in hemangioma was superior to that of propranolol and PL in vivo, as reflected by significantly reduced hemangioma volume, weight, and microvessel density. The mean hemangioma weight of the PLIM-treated group was significantly lower than that of other groups (saline =0.28 g, propranolol =0.21 g, PL =0.13 g, PLIM =0.03 g; PLIM vs saline: P<0.001, PLIM vs propranolol: P<0.001, PLIM vs PL: P<0.001. The mean microvessel density of

  6. Pharmacological kynurenine 3-monooxygenase enzyme inhibition significantly reduces neuropathic pain in a rat model.

    Science.gov (United States)

    Rojewska, Ewelina; Piotrowska, Anna; Makuch, Wioletta; Przewlocka, Barbara; Mika, Joanna

    2016-03-01

    Recent studies have highlighted the involvement of the kynurenine pathway in the pathology of neurodegenerative diseases, but the role of this system in neuropathic pain requires further extensive research. Therefore, the aim of our study was to examine the role of kynurenine 3-monooxygenase (Kmo), an enzyme that is important in this pathway, in a rat model of neuropathy after chronic constriction injury (CCI) to the sciatic nerve. For the first time, we demonstrated that the injury-induced increase in the Kmo mRNA levels in the spinal cord and the dorsal root ganglia (DRG) was reduced by chronic administration of the microglial inhibitor minocycline and that this effect paralleled a decrease in the intensity of neuropathy. Further, minocycline administration alleviated the lipopolysaccharide (LPS)-induced upregulation of Kmo mRNA expression in microglial cell cultures. Moreover, we demonstrated that not only indirect inhibition of Kmo using minocycline but also direct inhibition using Kmo inhibitors (Ro61-6048 and JM6) decreased neuropathic pain intensity on the third and the seventh days after CCI. Chronic Ro61-6048 administration diminished the protein levels of IBA-1, IL-6, IL-1beta and NOS2 in the spinal cord and/or the DRG. Both Kmo inhibitors potentiated the analgesic properties of morphine. In summary, our data suggest that in neuropathic pain model, inhibiting Kmo function significantly reduces pain symptoms and enhances the effectiveness of morphine. The results of our studies show that the kynurenine pathway is an important mediator of neuropathic pain pathology and indicate that Kmo represents a novel pharmacological target for the treatment of neuropathy. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Inhibition of the 26S proteasome blocks progesterone receptor-dependent transcription through failed recruitment of RNA polymerase II.

    Science.gov (United States)

    Dennis, Andrew P; Lonard, David M; Nawaz, Zafar; O'Malley, Bert W

    2005-03-01

    In the present study, we investigated the involvement of protein degradation via the 26S proteasome during progesterone receptor (PR)-mediated transcription in T-47D cells containing a stably integrated MMTV-CAT reporter construct (CAT0 cells). Progesterone induced CAT and HSD11beta2 transcription while co-treatment with the proteasome inhibitor, MG132, blocked PR-induced transcription in a time-dependent fashion. MG132 treatment also inhibited transcription of beta-actin and cyclophilin, but not two proteasome subunit genes, PSMA1 and PSMC1, indicating that proteasome inhibition affects a subset of RNA polymerase II (RNAP(II))-regulated genes. Progesterone-mediated recruitment of RNAP(II) was blocked by MG132 treatment at time points later than 1 h that was not dependent on the continued presence of PR, associated cofactors, and components of the general transcription machinery, supporting the concept that proteasome-mediated degradation is needed for continued transcription. Surprisingly, progesterone-mediated acetylation of histone H4 was inhibited by MG132 with the concomitant recruitment of HDAC3, NCoR, and SMRT. We demonstrate that the steady-state protein levels of SMRT and NCoR are higher in the presence of MG132 in CAT0 cells, consistent with other reports that SMRT and NCoR are targets of the 26S proteasome. However, inhibition of histone deacetylation by trichostatin A (TSA) treatment or SMRT/NCoR knockdown by siRNA did not restore MG132-inhibited progesterone-dependent transcription. Therefore, events other than histone deacetylation and stability of SMRT and NCoR must also play a role in inhibition of PR-mediated transcription.

  8. Escherichia coli DinB inhibits replication fork progression without significantly inducing the SOS response.

    Science.gov (United States)

    Mori, Tetsuya; Nakamura, Tatsuro; Okazaki, Naoto; Furukohri, Asako; Maki, Hisaji; Akiyama, Masahiro Tatsumi

    2012-01-01

    The SOS response is readily triggered by replication fork stalling caused by DNA damage or a dysfunctional replicative apparatus in Escherichia coli cells. E. coli dinB encodes DinB DNA polymerase and its expression is upregulated during the SOS response. DinB catalyzes translesion DNA synthesis in place of a replicative DNA polymerase III that is stalled at a DNA lesion. We showed previously that DNA replication was suppressed without exogenous DNA damage in cells overproducing DinB. In this report, we confirm that this was due to a dose-dependent inhibition of ongoing replication forks by DinB. Interestingly, the DinB-overproducing cells did not significantly induce the SOS response even though DNA replication was perturbed. RecA protein is activated by forming a nucleoprotein filament with single-stranded DNA, which leads to the onset of the SOS response. In the DinB-overproducing cells, RecA was not activated to induce the SOS response. However, the SOS response was observed after heat-inducible activation in strain recA441 (encoding a temperature-sensitive RecA) and after replication blockage in strain dnaE486 (encoding a temperature-sensitive catalytic subunit of the replicative DNA polymerase III) at a non-permissive temperature when DinB was overproduced in these cells. Furthermore, since catalytically inactive DinB could avoid the SOS response to a DinB-promoted fork block, it is unlikely that overproduced DinB takes control of primer extension and thus limits single-stranded DNA. These observations suggest that DinB possesses a feature that suppresses DNA replication but does not abolish the cell's capacity to induce the SOS response. We conclude that DinB impedes replication fork progression in a way that does not activate RecA, in contrast to obstructive DNA lesions and dysfunctional replication machinery.

  9. Interpreting the clinical significance of the differential inhibition of cyclooxygenase-1 and cyclooxygenase-2

    NARCIS (Netherlands)

    Brooks, P; Emery, P; Evans, JF; Fenner, H; Hawkey, CJ; Patrono, C; Smolen, J; Breeveld, F; Day, R; Dougados, M; Ehrich, EW; Gijon-Banos, J; Kvien, TK; Van Rijswijk, MH; Warner, T; Zeidler, H

    The International Consensus Meeting on the Mode of Action of COX-2 Inhibition (ICMMAC) brought together 17 international experts in arthritis, gastroenterology and pharmacology on 5-6 December 1997. The meeting was convened to provide a definition of COX-2 specificity and to consider the clinical

  10. Reactor design for minimizing product inhibition during enzymatic lignocellulose hydrolysis: I. Significance and mechanism of cellobiose and glucose inhibition on cellulolytic enzymes

    DEFF Research Database (Denmark)

    Andric, Pavle; Meyer, Anne S.; Jensen, Peter Arendt

    2010-01-01

    Achievement of efficient enzymatic degradation of cellulose to glucose is one of the main prerequisites and one of the main challenges in the biological conversion of lignocellulosic biomass to liquid fuels and other valuable products. The specific inhibitory interferences by cellobiose and glucose...... on enzyme-catalyzed cellulose hydrolysis reactions impose significant limitations on the efficiency of lignocellulose conversion especially at high-biomass dry matter conditions. To provide the base for selecting the optimal reactor conditions, this paper reviews the reaction kinetics, mechanisms......, and significance of this product inhibition, notably the cellobiose and glucose inhibition, on enzymatic cellulose hydrolysis. Particular emphasis is put on the distinct complexity of cellulose as a substrate, the multi-enzymatic nature of the cellulolytic degradation, and the particular features of cellulase...

  11. Cytochrome c oxidase inhibition by calcium at physiological ionic composition of the medium: Implications for physiological significance of the effect.

    Science.gov (United States)

    Vygodina, Tatiana V; Mukhaleva, Elizaveta; Azarkina, Natalia V; Konstantinov, Alexander A

    2017-12-01

    Cytochrome c oxidase (CcO) from mammalian mitochondria binds Ca 2+ and Na + in a special cation binding site. Binding of Ca 2+ brings about partial inhibition of the enzyme while Na + competes with Ca 2+ for the binding site and protects the enzyme from the inhibition [Vygodina, T., Kirichenko, A. and Konstantinov, A.A. (2013). Direct Regulation of Cytochrome c oxidase by Calcium Ions. PLoS One 8(9): e74436]. In the original studies, the inhibition was found to depend significantly on the ionic composition of the buffer. Here we describe inhibition of CcO by Ca 2+ in media containing the main ionic components of cytoplasm (150mM KCl, 12mM NaCl and 1mM MgCl 2 ). Under these conditions, Ca 2+ inhibits CcO with effective K i of 20-26μM, that is an order of magnitude higher than determined earlier in the absence of Na + . At physiological value of ionic strength, the inhibition can be observed at any turnover number of CcO, rather than only at low TN (calcium matches closely the known value of "K m " for Ca 2+ -induced activation of the mitochondrial calcium uniporter. The inhibition of CcO by Ca 2+ is proposed to modulate mitochondrial Ca 2+ -uptake via the mitochondrial calcium uniporter, promote permeability transition pore opening and induce reduction of Mia40 in the mitochondrial intermembrane space. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Quercetin suppresses hypoxia-induced accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha) through inhibiting protein synthesis.

    Science.gov (United States)

    Lee, Dae-Hee; Lee, Yong J

    2008-10-01

    Quercetin, a ubiquitous bioactive plant flavonoid, has been shown to inhibit the proliferation of cancer cells and induce the accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha) in normoxia. In this study, under hypoxic conditions (1% O(2)), we examined the effect of quercetin on the intracellular level of HIF-1alpha and extracellular level of vascular endothelial growth factor (VEGF) in a variety of human cancer cell lines. Surprisingly, we observed that quercetin suppressed the HIF-1alpha accumulation during hypoxia in human prostate cancer LNCaP, colon cancer CX-1, and breast cancer SkBr3 cells. Quercetin treatment also significantly reduced hypoxia-induced secretion of VEGF. Suppression of HIF-1alpha accumulation during treatment with quercetin in hypoxia was not prevented by treatment with 26S proteasome inhibitor MG132 or PI3K inhibitor LY294002. Interestingly, hypoxia (1% O(2)) in the presence of 100 microM quercetin inhibited protein synthesis by 94% during incubation for 8 h. Significant quercetin concentration-dependent inhibition of protein synthesis and suppression of HIF-1alpha accumulation were observed under hypoxic conditions. Treatment with 100 microM cycloheximide, a protein synthesis inhibitor, replicated the effect of quercetin by inhibiting HIF-1alpha accumulation during hypoxia. These results suggest that suppression of HIF-1alpha accumulation during treatment with quercetin under hypoxic conditions is due to inhibition of protein synthesis. (c) 2008 Wiley-Liss, Inc.

  13. Proteasome inhibition-induced p38 MAPK/ERK signaling regulates autophagy and apoptosis through the dual phosphorylation of glycogen synthase kinase 3β

    International Nuclear Information System (INIS)

    Choi, Cheol-Hee; Lee, Byung-Hoon; Ahn, Sang-Gun; Oh, Seon-Hee

    2012-01-01

    Highlights: ► MG132 induces the phosphorylation of GSK3β Ser9 and, to a lesser extent, of GSK3β Thr390 . ► MG132 induces dephosphorylation of p70S6K Thr389 and phosphorylation of p70S6K Thr421/Ser424 . ► Inactivation of p38 dephosphorylates GSK3β Ser9 and phosphorylates GSK3β Thr390 . ► Inactivation of p38 phosphorylates p70S6K Thr389 and increases the phosphorylation of p70S6K Thr421/Ser424 . ► Inactivation of p38 decreases autophagy and increases apoptosis induced by MG132. -- Abstract: Proteasome inhibition is a promising approach for cancer treatment; however, the underlying mechanisms involved have not been fully elucidated. Here, we show that proteasome inhibition-induced p38 mitogen-activated protein kinase regulates autophagy and apoptosis by modulating the phosphorylation status of glycogen synthase kinase 3β (GSK3β) and 70 kDa ribosomal S6 kinase (p70S6K). The treatment of MDA-MB-231 cells with MG132 induced endoplasmic reticulum stress through the induction of ATF6a, PERK phosphorylation, and CHOP, and apoptosis through the cleavage of Bax and procaspase-3. MG132 caused the phosphorylation of GSK3β at Ser 9 and, to a lesser extent, Thr 390 , the dephosphorylation of p70S6K at Thr 389 , and the phosphorylation of p70S6K at Thr 421 and Ser 424 . The specific p38 inhibitor SB203080 reduced the p-GSK3β Ser9 and autophagy through the phosphorylation of p70S6K Thr389 ; however, it augmented the levels of p-ERK, p-GSK3β Thr390 , and p-70S6K Thr421/Ser424 induced by MG132, and increased apoptotic cell death. The GSK inhibitor SB216763, but not lithium, inhibited the MG132-induced phosphorylation of p38, and the downstream signaling pathway was consistent with that in SB203580-treated cells. Taken together, our data show that proteasome inhibition regulates p38/GSK Ser9 /p70S6K Thr380 and ERK/GSK3β Thr390 /p70S6K Thr421/Ser424 kinase signaling, which is involved in cell survival and cell death.

  14. Metabonomics-based analysis of Brachyspira pilosicoli's response to tiamulin reveals metabolic activity despite significant growth inhibition.

    Science.gov (United States)

    Le Roy, Caroline Ivanne; Passey, Jade Louise; Woodward, Martin John; La Ragione, Roberto Marcello; Claus, Sandrine Paule

    2017-06-01

    Pathogenic anaerobes Brachyspira spp. are responsible for an increasing number of Intestinal Spirochaetosis (IS) cases in livestock against which few approved treatments are available. Tiamulin is used to treat swine dysentery caused by Brachyspira spp. and recently has been used to handle avian intestinal spirochaetosis (AIS). The therapeutic dose used in chickens requires further evaluation since cases of bacterial resistance to tiamulin have been reported. In this study, we evaluated the impact of tiamulin at varying concentrations on the metabolism of B. pilosicoli using a 1 H-NMR-based metabonomics approach allowing the capture of the overall bacterial metabolic response to antibiotic treatment. Based on growth curve studies, tiamulin impacted bacterial growth even at very low concentration (0.008 μg/mL) although its metabolic activity was barely affected 72 h post exposure to antibiotic treatment. Only the highest dose of tiamulin tested (0.250 μg/mL) caused a major metabolic shift. Results showed that below this concentration, bacteria could maintain a normal metabolic trajectory despite significant growth inhibition by the antibiotic, which may contribute to disease reemergence post antibiotic treatment. Indeed, we confirmed that B. pilosicoli remained viable even after exposition to the highest antibiotic dose. This paper stresses the need to ensure new evaluation of bacterial viability post bacteriostatic exposure such as tiamulin to guarantee treatment efficacy and decrease antibiotic resistance development. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Puromycin induces SUMO and ubiquitin redistribution upon proteasome inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Matsumoto, Hotaru [Course for Biological Sciences, Faculty of Science, Kumamoto University, Kumamoto (Japan); Saitoh, Hisato, E-mail: hisa@kumamoto-u.ac.jp [Course for Biological Sciences, Faculty of Science, Kumamoto University, Kumamoto (Japan); Department of Biological Sciences, Graduate School of Science and Technology, Kumamoto University, Kumamoto (Japan)

    2016-07-29

    We have previously reported the co-localization of O-propargyl-puromycin (OP-Puro) with SUMO-2/3 and ubiquitin at promyelocytic leukemia-nuclear bodies (PML-NBs) in the presence of the proteasome inhibitor MG132, implying a role for the ubiquitin family in sequestering OP-puromycylated immature polypeptides to the nucleus during impaired proteasome activity. Here, we found that as expected puromycin induced SUMO-1/2/3 accumulation with ubiquitin at multiple nuclear foci in HeLa cells when co-exposed to MG132. Co-administration of puromycin and MG132 also facilitated redistribution of PML and the SUMO-targeted ubiquitin ligase RNF4 concurrently with SUMO-2/3. As removal of the drugs from the medium led to disappearance of the SUMO-2/3-ubiquitin nuclear foci, our findings indicated that nuclear assembly/disassembly of SUMO-2/3 and ubiquitin was pharmacologically manipulable, supporting our previous observation on OP-Puro, which predicted the ubiquitin family function in sequestrating aberrant proteins to the nucleus. -- Highlights: •Puromycin exhibits the O-propargyl-puromycin effect. •Puromycin induces SUMO redistribution upon proteasome inhibition. •Ubiquitin and RNF4 accumulate at PML-nuclear bodies with SUMO-2/3. •The ubiquitin family may function in nuclear sequestration of immature proteins.

  16. Puromycin induces SUMO and ubiquitin redistribution upon proteasome inhibition

    International Nuclear Information System (INIS)

    Matsumoto, Hotaru; Saitoh, Hisato

    2016-01-01

    We have previously reported the co-localization of O-propargyl-puromycin (OP-Puro) with SUMO-2/3 and ubiquitin at promyelocytic leukemia-nuclear bodies (PML-NBs) in the presence of the proteasome inhibitor MG132, implying a role for the ubiquitin family in sequestering OP-puromycylated immature polypeptides to the nucleus during impaired proteasome activity. Here, we found that as expected puromycin induced SUMO-1/2/3 accumulation with ubiquitin at multiple nuclear foci in HeLa cells when co-exposed to MG132. Co-administration of puromycin and MG132 also facilitated redistribution of PML and the SUMO-targeted ubiquitin ligase RNF4 concurrently with SUMO-2/3. As removal of the drugs from the medium led to disappearance of the SUMO-2/3-ubiquitin nuclear foci, our findings indicated that nuclear assembly/disassembly of SUMO-2/3 and ubiquitin was pharmacologically manipulable, supporting our previous observation on OP-Puro, which predicted the ubiquitin family function in sequestrating aberrant proteins to the nucleus. -- Highlights: •Puromycin exhibits the O-propargyl-puromycin effect. •Puromycin induces SUMO redistribution upon proteasome inhibition. •Ubiquitin and RNF4 accumulate at PML-nuclear bodies with SUMO-2/3. •The ubiquitin family may function in nuclear sequestration of immature proteins.

  17. Insights into significance of combined inhibition of MEK and m-TOR signalling output in KRAS mutant non-small-cell lung cancer.

    Science.gov (United States)

    Broutin, Sophie; Stewart, Adam; Thavasu, Parames; Paci, Angelo; Bidart, Jean-Michel; Banerji, Udai

    2016-08-23

    We aimed to understand the dependence of MEK and m-TOR inhibition in EGFR(WT)/ALK(non-rearranged) NSCLC cell lines. In a panel of KRAS(M) and KRAS(WT) NSCLC cell lines, we determined growth inhibition (GI) following maximal reduction in p-ERK and p-S6RP caused by trametinib (MEK inhibitor) and AZD2014 (m-TOR inhibitor), respectively. GI caused by maximal m-TOR inhibition was significantly greater than GI caused by maximal MEK inhibition in the cell line panel (52% vs 18%, PTOR compared with maximal m-TOR+MEK inhibition. However, GI caused by the combination was significantly greater in the KRAS(M) cell lines (79% vs 61%, P=0.017). m-TOR inhibition was more critical to GI than MEK inhibition in EGFR(WT)/ALK(non-rearranged) NSCLC cells. The combination of MEK and m-TOR inhibition was most effective in KRAS(M) cells.

  18. Polypyridylruthenium(II complexes exert in vitro and in vivo nematocidal activity and show significant inhibition of parasite acetylcholinesterases

    Directory of Open Access Journals (Sweden)

    Madhu Sundaraneedi

    2018-04-01

    Full Text Available Over 4.5 billion people are at risk of infection with soil transmitted helminths and there are concerns about the development of resistance to the handful of frontline nematocides in endemic populations. We investigated the anti-nematode efficacy of a series of polypyridylruthenium(II complexes and showed they were active against L3 and adult stages of Trichuris muris, the rodent homologue of the causative agent of human trichuriasis, T. trichiura. One of the compounds, Rubb12-mono, which was among the most potent in its ability to kill L3 (IC50 = 3.1 ± 0.4 μM and adult (IC50 = 5.2 ± 0.3 μM stage worms was assessed for efficacy in a mouse model of trichuriasis by administering 3 consecutive daily oral doses of the drug 3 weeks post infection with the murine whipworm Trichuris muris. Mice treated with Rubb12-mono showed an average 66% reduction (P = 0.015 in faecal egg count over two independent trials. The drugs partially exerted their activity through inhibition of acetylcholinesterases, as worms treated in vitro and in vivo showed significant decreases in the activity of this class of enzymes. Our data show that ruthenium complexes are effective against T. muris, a model gastro-intestinal nematode and soil-transmitted helminth. Further, knowledge of the target of ruthenium drugs can facilitate modification of current compounds to identify analogues which are even more effective and selective against Trichuris and other helminths of human and veterinary importance. Keywords: Acetylcholinesterase, Trichuris muris, Ruthenium complex, Anthelmintic

  19. Compounds from Terminalia mantaly L. (Combretaceae Stem Bark Exhibit Potent Inhibition against Some Pathogenic Yeasts and Enzymes of Metabolic Significance

    Directory of Open Access Journals (Sweden)

    Marthe Aimée Tchuente Tchuenmogne

    2017-01-01

    Full Text Available Background: Pathogenic yeasts resistance to current drugs emphasizes the need for new, safe, and cost-effective drugs. Also, new inhibitors are needed to control the effects of enzymes that are implicated in metabolic dysfunctions such as cancer, obesity, and epilepsy. Methods: The anti-yeast extract from Terminalia mantaly (Combretaceae was fractionated and the structures of the isolated compounds established by means of spectroscopic analysis and comparison with literature data. Activity was assessed against Candida albicans, C. parapsilosis and C. krusei using the microdilution method, and against four enzymes of metabolic significance: glucose-6-phosphate dehydrogenase, human erythrocyte carbonic anhydrase I and II, and glutathione S-transferase. Results: Seven compounds, 3,3′-di-O-methylellagic acid 4′-O-α-rhamnopyranoside; 3-O-methylellagic acid; arjungenin or 2,3,19,23-tetrahydroxyolean-12-en-28-oïc acid; arjunglucoside or 2,3,19,23-tetrahydroxyolean-12-en-28-oïc acid glucopyranoside; 2α,3α,24-trihydroxyolean-11,13(18-dien-28-oïc acid; stigmasterol; and stigmasterol 3-O-β-d-glucopyranoside were isolated from the extract. Among those, 3,3′-di-O-methylellagic acid 4′-O-α-rhamnopyranoside, 3-O-methylellagic acid, and arjunglucoside showed anti-yeast activity comparable to that of reference fluconazole with minimal inhibitory concentrations (MIC below 32 µg/mL. Besides, Arjunglucoside potently inhibited the tested enzymes with 50% inhibitory concentrations (IC50 below 4 µM and inhibitory constant (Ki <3 µM. Conclusions: The results achieved indicate that further SAR studies will likely identify potent hit derivatives that should subsequently enter the drug development pipeline.

  20. AAV-Mediated Gene Targeting Is Significantly Enhanced by Transient Inhibition of Nonhomologous End Joining or the Proteasome In Vivo

    Science.gov (United States)

    Paulk, Nicole K.; Loza, Laura Marquez; Finegold, Milton J.

    2012-01-01

    Abstract Recombinant adeno-associated virus (rAAV) vectors have clear potential for use in gene targeting but low correction efficiencies remain the primary drawback. One approach to enhancing efficiency is a block of undesired repair pathways like nonhomologous end joining (NHEJ) to promote the use of homologous recombination. The natural product vanillin acts as a potent inhibitor of NHEJ by inhibiting DNA-dependent protein kinase (DNA-PK). Using a homology containing rAAV vector, we previously demonstrated in vivo gene repair frequencies of up to 0.1% in a model of liver disease hereditary tyrosinemia type I. To increase targeting frequencies, we administered vanillin in combination with rAAV. Gene targeting frequencies increased up to 10-fold over AAV alone, approaching 1%. Fah−/−Ku70−/− double knockout mice also had increased gene repair frequencies, genetically confirming the beneficial effects of blocking NHEJ. A second strategy, transient proteasomal inhibition, also increased gene-targeting frequencies but was not additive to NHEJ inhibition. This study establishes the benefit of transient NHEJ inhibition with vanillin, or proteasome blockage with bortezomib, for increasing hepatic gene targeting with rAAV. Functional metabolic correction of a clinically relevant disease model was demonstrated and provided evidence for the feasibility of gene targeting as a therapeutic strategy. PMID:22486314

  1. Combination treatment with ionising radiation and gefitinib ('Iressa', ZD1839), an epidermal growth factor receptor (EGFR) inhibitor, significantly inhibits bladder cancer cell growth in vitro and in vivo

    International Nuclear Information System (INIS)

    Colquhoun, AJ; Mchugh, LA; Tulchinsky, E.; Kriajevska, M.; Mellon, JK

    2007-01-01

    External beam radiotherapy (EBRT) is the principal bladder-preserving monotherapy for muscle-invasive bladder cancer. Seventy percent of muscle-invasive bladder cancers express epidermal growth factor receptor (EGFR), which is associated with poor prognosis. Ionising radiation (IR) stimulates EGFR causing activation of cytoprotective signalling cascades and thus may be an underlying cause of radioresistance in bladder tumours. We assessed the ability of IR to activate EGFR in bladder cancer cells and the effect of the anti-EGFR therapy, gefitinib on potential radiation-induced activation. Subsequently we assessed the effect of IR on signalling pathways downstream of EGFR. Finally we assessed the activity of gefitinib as a monotherapy, and in combination with IR, using clonogenic assay in vitro, and a murine model in vivo. IR activated EGFR and gefitinib partially inhibited this activation. Radiation-induced activation of EGFR activated the MAPK and Akt pathways. Gefitinib partially inhibited activation of the MAPK pathway but not the Akt pathway. Treatment with combined gefitinib and IR significantly inhibited bladder cancer cell colony formation more than treatment with gefitinib alone (p=0.001-0.03). J82 xenograft tumours treated with combined gefitinib and IR showed significantly greater growth inhibition than tumours treated with IR alone (p=0.04). Combining gefitinib and IR results in significantly greater inhibition of invasive bladder cancer cell colony formation in vitro and significantly greater tumour growth inhibition in vivo. Given the high frequency of EGFR expression by bladder tumours and the low toxicity of gefitinib there is justification to translate this work into a clinical trial. (author)

  2. Fusion of protegrin-1 and plectasin to MAP30 shows significant inhibition activity against dengue virus replication.

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    Hussin A Rothan

    Full Text Available Dengue virus (DENV broadly disseminates in tropical and sub-tropical countries and there are no vaccine or anti-dengue drugs available. DENV outbreaks cause serious economic burden due to infection complications that requires special medical care and hospitalization. This study presents a new strategy for inexpensive production of anti-DENV peptide-fusion protein to prevent and/or treat DENV infection. Antiviral cationic peptides protegrin-1 (PG1 and plectasin (PLSN were fused with MAP30 protein to produce recombinant antiviral peptide-fusion protein (PG1-MAP30-PLSN as inclusion bodies in E. coli. High yield production of PG1-MAP30-PLSN protein was achieved by solubilization of inclusion bodies in alkaline buffer followed by the application of appropriate refolding techniques. Antiviral PG1-MAP30-PLSN protein considerably inhibited DENV protease (NS2B-NS3pro with half-maximal inhibitory concentration (IC50 0.5±0.1 μM. The real-time proliferation assay (RTCA and the end-point proliferation assay (MTT assay showed that the maximal-nontoxic dose of the peptide-fusion protein against Vero cells is approximately 0.67±0.2 μM. The cell-based assays showed considerable inhibition of the peptide-fusion protein against binding and proliferating stages of DENV2 into the target cells. The peptide-fusion protein protected DENV2-challeged mice with 100% of survival at the dose of 50 mg/kg. In conclusion, producing recombinant antiviral peptide-fusion protein by combining short antiviral peptide with a central protein owning similar activity could be useful to minimize the overall cost of short peptide production and take advantage of its synergistic antiviral activities.

  3. Metformin combined with aspirin significantly inhibit pancreatic cancer cell growth in vitro and in vivo by suppressing anti-apoptotic proteins Mcl-1 and Bcl-2

    Science.gov (United States)

    Yue, Wen; Zheng, Xi; Lin, Yong; Yang, Chung S.; Xu, Qing; Carpizo, Darren; Huang, Huarong; DiPaola, Robert S.; Tan, Xiang-Lin

    2015-01-01

    Metformin and aspirin have been studied extensively as cancer preventive or therapeutic agents. However, the effects of their combination on pancreatic cancer cells have not been investigated. Herein, we evaluated the effects of metformin and aspirin, alone or in combination, on cell viability, migration, and apoptosis as well as the molecular changes in mTOR, STAT3 and apoptotic signaling pathways in PANC-1 and BxPC3 cells. Metformin and aspirin, at relatively low concentrations, demonstrated synergistically inhibitory effects on cell viability. Compared to the untreated control or individual drug, the combination of metformin and aspirin significantly inhibited cell migration and colony formation of both PANC-1 and BxPC-3 cells. Metformin combined with aspirin significantly inhibited the phosphorylation of mTOR and STAT3, and induced apoptosis as measured by caspase-3 and PARP cleavage. Remarkably, metformin combined with aspirin significantly downregulated the anti-apoptotic proteins Mcl-1 and Bcl-2, and upregulated the pro-apoptotic proteins Bim and Puma, as well as interrupted their interactions. The downregulation of Mcl-1 and Bcl-2 was independent of AMPK or STAT3 pathway but partially through mTOR signaling and proteasome degradation. In a PANC-1 xenograft mouse model, we demonstrated that the combination of metformin and aspirin significantly inhibited tumor growth and downregulated the protein expression of Mcl-1 and Bcl-2 in tumors. Taken together, the combination of metformin and aspirin significantly inhibited pancreatic cancer cell growth in vitro and in vivo by regulating the pro- and anti-apoptotic Bcl-2 family members, supporting the continued investigation of this two drug combination as chemopreventive or chemotherapeutic agents for pancreatic cancer. PMID:26056043

  4. Toscana virus NSs protein inhibits the induction of type I interferon by interacting with RIG-I.

    Science.gov (United States)

    Gori-Savellini, Gianni; Valentini, Melissa; Cusi, Maria Grazia

    2013-06-01

    Toscana virus (TOSV) is a phlebovirus, of the Bunyaviridae family, that is responsible for central nervous system (CNS) injury in humans. Previous data have shown that the TOSV NSs protein is a gamma interferon (IFN-β) antagonist when transiently overexpressed in mammalian cells, inhibiting IRF-3 induction (G. Gori Savellini, F. Weber, C. Terrosi, M. Habjan, B. Martorelli, and M. G. Cusi, J. Gen. Virol. 92:71-79, 2011). In this study, we investigated whether an upstream sensor, which has a role in the signaling cascade leading to the production of type I IFN, was involved. We found a significant decrease in RIG-I protein levels in cells overexpressing TOSV NSs, suggesting that the nonstructural protein interacts with RIG-I and targets it for proteasomal degradation. In fact, the MG-132 proteasome inhibitor was able to restore IFN-β promoter activation in cells expressing NSs, demonstrating the existence of an evasion mechanism based on inhibition of the RIG-I sensor. Furthermore, a C-terminal truncated NSs protein (ΔNSs), although able to interact with RIG-I, did not affect the RIG-I-mediated IFN-β promoter activation, suggesting that the NSs domains responsible for RIG-I-mediated signaling and interaction with RIG-I are mapped on different regions. These results contribute to identify a novel mechanism for bunyaviruses by which TOSV NSs counteracts the early IFN response.

  5. Arborvitae (Thuja plicata essential oil significantly inhibited critical inflammation- and tissue remodeling-related proteins and genes in human dermal fibroblasts

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    Xuesheng Han

    2017-06-01

    Full Text Available Arborvitae (Thuja plicata essential oil (AEO is becoming increasingly popular in skincare, although its biological activity in human skin cells has not been investigated. Therefore, we sought to study AEO's effect on 17 important protein biomarkers that are closely related to inflammation and tissue remodeling by using a pre-inflamed human dermal fibroblast culture model. AEO significantly inhibited the expression of vascular cell adhesion molecule 1 (VCAM-1, intracellular cell adhesion molecule 1 (ICAM-1, interferon gamma-induced protein 10 (IP-10, interferon-inducible T-cell chemoattractant (I-TAC, monokine induced by interferon gamma (MIG, and macrophage colony-stimulating factor (M-CSF. It also showed significant antiproliferative activity and robustly inhibited collagen-I, collagen-III, plasminogen activator inhibitor-1 (PAI-1, and tissue inhibitor of metalloproteinase 1 and 2 (TIMP-1 and TIMP-2. The inhibitory effect of AEO on increased production of these protein biomarkers suggests it has anti-inflammatory property. We then studied the effect of AEO on the genome-wide expression of 21,224 genes in the same cell culture. AEO significantly and diversely modulated global gene expression. Ingenuity pathway analysis (IPA showed that AEO robustly affected numerous critical genes and signaling pathways closely involved in inflammatory and tissue remodeling processes. The findings of this study provide the first evidence of the biological activity and beneficial action of AEO in human skin cells.

  6. Inhibition of infection and transmission of HIV-1 and lack of significant impact on the vaginal commensal lactobacilli by carbohydrate-binding agents.

    Science.gov (United States)

    Petrova, Mariya I; Mathys, Leen; Lebeer, Sarah; Noppen, Sam; Van Damme, Els J M; Tanaka, Haruo; Igarashi, Yasuhiro; Vaneechoutte, Mario; Vanderleyden, Jos; Balzarini, Jan

    2013-09-01

    A selection of carbohydrate-binding agents (CBAs) with different glycan specificities were evaluated for their inhibitory effect against HIV infection and transmission, and their interaction with vaginal commensal bacteria. Several assays were used for the antiviral evaluation: (i) cell-free virus infection of human CD4+ T lymphocyte C8166 cells; (ii) syncytium formation in co-cultures of persistently HIV-1-infected HUT-78/HIV-1 and non-infected CD4+ SupT1 cells; (iii) DC-SIGN-directed capture of HIV-1 particles; and (iv) transmission of DC-SIGN-captured HIV-1 particles to uninfected CD4+ C8166 cells. CBAs were also examined for their interaction with vaginal commensal lactobacilli using several viability, proliferation and adhesion assays. The CBAs showed efficient inhibitory activity in the nanomolar to low-micromolar range against four events that play a crucial role in HIV-1 infection and transmission: cell-free virus infection, fusion between HIV-1-infected and non-infected cells, HIV-1 capture by DC-SIGN and transmission of DC-SIGN-captured virus to T cells. As candidate microbicides should not interfere with the normal human microbiota, we examined the effect of CBAs against Lactobacillus strains, including a variety of vaginal strains, a gastrointestinal strain and several non-human isolates. None of the CBAs included in our studies inhibited the growth of these bacteria in several media, affected their viability or had any significant impact on their adhesion to HeLa cell monolayers. The CBAs in this study were inhibitory to HIV-1 in several in vitro infection and transmission models, and may therefore qualify as potential microbicide candidates. The lack of significant impact on commensal vaginal lactobacilli is an important property of these CBAs in view of their potential microbicidal use.

  7. Exposure of Human Lung Cells to Tobacco Smoke Condensate Inhibits the Nucleotide Excision Repair Pathway.

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    Nathaniel Holcomb

    Full Text Available Exposure to tobacco smoke is the number one risk factor for lung cancer. Although the DNA damaging properties of tobacco smoke have been well documented, relatively few studies have examined its effect on DNA repair pathways. This is especially true for the nucleotide excision repair (NER pathway which recognizes and removes many structurally diverse DNA lesions, including those introduced by chemical carcinogens present in tobacco smoke. The aim of the present study was to investigate the effect of tobacco smoke on NER in human lung cells. We studied the effect of cigarette smoke condensate (CSC, a surrogate for tobacco smoke, on the NER pathway in two different human lung cell lines; IMR-90 lung fibroblasts and BEAS-2B bronchial epithelial cells. To measure NER, we employed a slot-blot assay to quantify the introduction and removal of UV light-induced 6-4 photoproducts and cyclobutane pyrimidine dimers. We find a dose-dependent inhibition of 6-4 photoproduct repair in both cell lines treated with CSC. Additionally, the impact of CSC on the abundance of various NER proteins and their respective RNAs was investigated. The abundance of XPC protein, which is required for functional NER, is significantly reduced by treatment with CSC while the abundance of XPA protein, also required for NER, is unaffected. Both XPC and XPA RNA levels are modestly reduced by CSC treatment. Finally, treatment of cells with MG-132 abrogates the reduction in the abundance of XPC protein produced by treatment with CSC, suggesting that CSC enhances proteasome-dependent turnover of the protein that is mediated by ubiquitination. Together, these findings indicate that tobacco smoke can inhibit the same DNA repair pathway that is also essential for the removal of some of the carcinogenic DNA damage introduced by smoke itself, increasing the DNA damage burden of cells exposed to tobacco smoke.

  8. Proteasome inhibition-induced p38 MAPK/ERK signaling regulates autophagy and apoptosis through the dual phosphorylation of glycogen synthase kinase 3{beta}

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Cheol-Hee [Research Center for Resistant Cells, Chosun University, Seosuk-dong, Dong-gu, Gwangju 501-759 (Korea, Republic of); Department of Pharmacology, College of Medicine, Chosun University, Seosuk-dong, Dong-gu, Gwangju 501-759 (Korea, Republic of); Lee, Byung-Hoon [College of Pharmacy and Multiscreening Center for Drug Development, Seoul National University, Seoul 151-742 (Korea, Republic of); Ahn, Sang-Gun [Department of Pathology, College of Dentistry, Chosun University, Gwangju 501-759 (Korea, Republic of); Oh, Seon-Hee, E-mail: oshccw@hanmail.net [Research Center for Resistant Cells, Chosun University, Seosuk-dong, Dong-gu, Gwangju 501-759 (Korea, Republic of)

    2012-02-24

    Highlights: Black-Right-Pointing-Pointer MG132 induces the phosphorylation of GSK3{beta}{sup Ser9} and, to a lesser extent, of GSK3{beta}{sup Thr390}. Black-Right-Pointing-Pointer MG132 induces dephosphorylation of p70S6K{sup Thr389} and phosphorylation of p70S6K{sup Thr421/Ser424}. Black-Right-Pointing-Pointer Inactivation of p38 dephosphorylates GSK3{beta}{sup Ser9} and phosphorylates GSK3{beta}{sup Thr390}. Black-Right-Pointing-Pointer Inactivation of p38 phosphorylates p70S6K{sup Thr389} and increases the phosphorylation of p70S6K{sup Thr421/Ser424}. Black-Right-Pointing-Pointer Inactivation of p38 decreases autophagy and increases apoptosis induced by MG132. -- Abstract: Proteasome inhibition is a promising approach for cancer treatment; however, the underlying mechanisms involved have not been fully elucidated. Here, we show that proteasome inhibition-induced p38 mitogen-activated protein kinase regulates autophagy and apoptosis by modulating the phosphorylation status of glycogen synthase kinase 3{beta} (GSK3{beta}) and 70 kDa ribosomal S6 kinase (p70S6K). The treatment of MDA-MB-231 cells with MG132 induced endoplasmic reticulum stress through the induction of ATF6a, PERK phosphorylation, and CHOP, and apoptosis through the cleavage of Bax and procaspase-3. MG132 caused the phosphorylation of GSK3{beta} at Ser{sup 9} and, to a lesser extent, Thr{sup 390}, the dephosphorylation of p70S6K at Thr{sup 389}, and the phosphorylation of p70S6K at Thr{sup 421} and Ser{sup 424}. The specific p38 inhibitor SB203080 reduced the p-GSK3{beta}{sup Ser9} and autophagy through the phosphorylation of p70S6K{sup Thr389}; however, it augmented the levels of p-ERK, p-GSK3{beta}{sup Thr390}, and p-70S6K{sup Thr421/Ser424} induced by MG132, and increased apoptotic cell death. The GSK inhibitor SB216763, but not lithium, inhibited the MG132-induced phosphorylation of p38, and the downstream signaling pathway was consistent with that in SB203580-treated cells. Taken together, our

  9. Inhibition of basophil histamine release by gangliosides. Further studies on the significance of cell membrane sialic acid in the histamine release process

    DEFF Research Database (Denmark)

    Jensen, C; Norn, S; Thastrup, Ole

    1987-01-01

    with the glucolipid mixture increased the sialic acid content of the cells, and this increase was attributed to an insertion of gangliosides into the cell membrane. The inhibition of histamine release was abolished by increasing the calcium concentration, which substantiates our previous findings that cell membrane......Histamine release from human basophils was inhibited by preincubation of the cells with a glucolipid mixture containing sialic acid-containing gangliosides. This was true for histamine release induced by anti-IgE, Concanavalin A and the calcium ionophore A23187, whereas the release induced by S....... aureus Wood 46 was not affected. It was demonstrated that the inhibitory capacity of the glucolipid mixture could be attributed to the content of gangliosides, since no inhibition was obtained with cerebrosides or with gangliosides from which sialic acid was removed. Preincubation of the cells...

  10. Critical significance of the region between Helix 1 and 2 for efficient dominant-negative inhibition by conversion-incompetent prion protein.

    Directory of Open Access Journals (Sweden)

    Yuzuru Taguchi

    Full Text Available Prion diseases are fatal infectious neurodegenerative disorders in man and animals associated with the accumulation of the pathogenic isoform PrP(Sc of the host-encoded prion protein (PrP(c. A profound conformational change of PrP(c underlies formation of PrP(Sc and prion propagation involves conversion of PrP(c substrate by direct interaction with PrP(Sc template. Identifying the interfaces and modalities of inter-molecular interactions of PrPs will highly advance our understanding of prion propagation in particular and of prion-like mechanisms in general. To identify the region critical for inter-molecular interactions of PrP, we exploited here dominant-negative inhibition (DNI effects of conversion-incompetent, internally-deleted PrP (ΔPrP on co-expressed conversion-competent PrP. We created a series of ΔPrPs with different lengths of deletions in the region between first and second α-helix (H1∼H2 which was recently postulated to be of importance in prion species barrier and PrP fibril formation. As previously reported, ΔPrPs uniformly exhibited aberrant properties including detergent insolubility, limited protease digestion resistance, high-mannose type N-linked glycans, and intracellular localization. Although formerly controversial, we demonstrate here that ΔPrPs have a GPI anchor attached. Surprisingly, despite very similar biochemical and cell-biological properties, DNI efficiencies of ΔPrPs varied significantly, dependant on location and inversely correlated with the size of deletion. This data demonstrates that H1∼H2 and the region C-terminal to it are critically important for efficient DNI. It also suggests that this region is involved in PrP-PrP interaction and conversion of PrP(C into PrP(Sc. To reconcile the paradox of how an intracellular PrP can exert DNI, we demonstrate that ΔPrPs are subject to both proteasomal and lysosomal/autophagic degradation pathways. Using autophagy pathways ΔPrPs obtain access to the locale

  11. Effects of Danggui Sini decoction on neuropathic pain: experimental studies and clinical pharmacological significance of inhibiting glial activation and proinflammatory cytokines in the spinal cord
.

    Science.gov (United States)

    Liu, Ming; Qiang, Qiu Hong; Ling, Qian; Yu, Chang Xi; Li, Xuejun; Liu, Suhuan; Yang, Shuyu

    2017-05-01

    Neuropathic pain responds poorly to drug treatments. Partial relief is achieved in only about half of the patients. Danggui Sini decoction (DSD), an aqueous extract of Angelica sinensis, Ramulus Cinnamomi, and Radix Puerariae, has been used extensively in China to treat inflammatory and ischemic diseases. The current study examined the putative effects of DSD on neuropathic pain. We used two commonly-used animal models: chronic constriction injury (CCI) and diabetic neuropathy for the study. And we examined effects of DSD on pain response, activation of microglia and astroglia in spinal dorsal horn, and expression of proinflammatory cytokines in the spinal cord. Consecutive intragastric administration of DSD (25 - 100 mg/kg) for 10 days inhibited the mechanical and thermal nociceptive response induced by CCI and diabetes without interfering with the normal pain response. Meanwhile, in both models, DSD inhibited the over-expression of specific markers for microglia (Iba-1) and astroglia (GFAP) activation in the spinal dorsal horn. DSD also reduced the elevated nuclear NF-κB level and inhibited the up-regulation of proinflammatory cytokines, such as IL-6, IL-1β, and TNF-α, in the spinal cord. DSD can alleviate CCI and diabetes-induced neuropathic pain, and its effectiveness might be due to the inhibition of neuroinflammation in the spinal dorsal horn. The anti-inflammation effect of DSD may be related to the suppression of spinal NF-κB activation and/or cytokines expression.
.

  12. Apoptosis and radiosensitization of Hodgkin cells by proteasome inhibition

    International Nuclear Information System (INIS)

    Pajonk, Frank; Pajonk, Katja; McBride, William H.

    2000-01-01

    Purpose: Malignant cells from Hodgkin's disease have been reported to be defective in regulation of NF-κB activity. Ionizing radiation is known to activate NF-κB, and it has been suggested that this pathway may protect cells from apoptosis following exposure to radiation and other therapeutic agents. Defective NF-κB regulation in Hodgkin cells could therefore dictate the response of this disease to therapy, as well as be responsible for maintaining the malignant phenotype. The purpose of this study was to explore whether NF-κB activity could be modulated in Hodgkin cells and whether it determines the response of these cells to treatment with ionizing radiation and/or dexamethasone. Methods and Materials: Activation of NF-κB in cells is accomplished in large part by degradation of its inhibitor IκB through the 26s proteasome. HD-My-Z Hodgkin cells were treated with the proteasome inhibitor MG-132 or transduced with a dominant negative super-repressor IκBα. Clonogenic survival, apoptosis, proteasome activity, and NF-κB binding activity were monitored in response to ionizing radiation and/or dexamethasone treatment. Results: HD-My-Z Hodgkin cells had modest NF-κB levels but, unlike other cell types, did not decrease their level of constitutively active NF-κB in response to proteasome inhibition with MG-132. In contrast, transduction with a non-phosphorable IκBα construct abolished expression. MG-132 did, however, induce apoptosis in HD-My-Z cells and sensitized them to ionizing radiation. Dexamethasone treatment had no effect on NF-κB activity or clonogenic survival of Hodgkin cells, but protected them from irradiation. Conclusion: We conclude that inhibition of 26s proteasome activity can induce apoptosis in HD-My-Z Hodgkin cells and radiosensitize them, in spite of the fact that their constitutively active NF-κB levels are unaltered. The proteasome may be a promising new therapeutic target for intervention in this disease. In contrast, the use of

  13. A chimeric peptide of intestinal trefoil factor containing cholesteryl ester transfer protein B cell epitope significantly inhibits atherosclerosis in rabbits after oral administration.

    Science.gov (United States)

    Qi, Gaofu; Li, Jingjing; Wang, Shengying; Xin, Shanshan; Du, Peng; Zhang, Qingye; Zhao, Xiuyun

    2011-04-01

    Vaccination against cholesteryl ester transfer protein (CETP) is proven to be effective for inhibiting atherosclerosis in animal models. In this study, the proteases-resistant intestinal trefoil factor (TFF3) was used as a molecular vehicle to construct chimeric TFF3 (cTFF3) containing CETP B cell epitope and tetanus toxin helper T cell epitope. It was found that cTFF3 still preserved a trefoil structure, and can resist proteases digestion in vitro. After oral immunization with cTFF3, the CETP-specific IgA and IgG could be found in intestine lavage fluid and serum, and the anti-CETP antibodies could inhibit partial CETP activity to increase high-density lipoprotein cholesterol, decrease low-density lipoprotein cholesterol, and inhibit atherosclerosis in animals. Therefore, TFF3 is a potential molecular vehicle for developing oral peptide vaccines. Our research highlights a novel strategy for developing oral peptide vaccines in the future. Copyright © 2010 Elsevier Inc. All rights reserved.

  14. -NH-dansyl isocolchicine exhibits a significantly improved tubulin-binding affinity and microtubule inhibition in comparison to isocolchicine by binding tubulin through its A and B rings.

    Science.gov (United States)

    Das, Lalita; Datta, Ajit B; Gupta, Suvroma; Poddar, Asim; Sengupta, Suparna; Janik, Mark E; Bhattacharyya, Bhabatarak

    2005-03-08

    Structure-activity relationship studies have established that the A and C rings of colchicine comprise the minimum structural feature necessary for high affinity drug-tubulin binding. Thus, colchicine acts as a bifunctional ligand by making two points of attachment to the protein. Furthermore, analogues belonging to the iso series of colchicine are virtually inactive in binding to tubulin and inhibiting microtubule assembly. In the present study, we found that the substitution of a hydrophobic dansyl group on the B-ring side chain (C7 position) of isocolchicine reverses the structural alterations at the C ring and the newly synthesized -NH-dansyl isocolchicine restores the lost biological activity of the compound. It inhibits microtubule assembly efficiently with an IC(50) value of 10 microM and competes with [(3)H]colchicine for binding to tubulin. Moreover, although -NH-dansyl colchicine binding to tubulin involves two steps, the -NH-dansyl isocolchicine-tubulin interaction has been found to occur via a one-step process. Also, the affinity constant of the -NH-dansyl isocolchicine-tubulin interaction is roughly only 3 times lower than that of the -NH-dansyl colchicine-tubulin interaction. These results suggest that the enhanced microtubule inhibitory ability of -NH-dansyl isocolchicine is therefore related to the affinity of the drug-tubulin interaction and not to any conformational changes upon binding tubulin. We also observed that the competition of -NH-dansyl isocolchicine with [(3)H]colchicine for binding to tubulin was dependent on the tubulin concentration. In conclusion, this paper for the first time indicates that a biologically active bifuntional colchicine analogue can be designed where the drug binds tubulin through its A and B rings, while the C ring remains inactive.

  15. The inhibition of subchondral bone lesions significantly reversed the weight-bearing deficit and the overexpression of CGRP in DRG neurons, GFAP and Iba-1 in the spinal dorsal horn in the monosodium iodoacetate induced model of osteoarthritis pain.

    Directory of Open Access Journals (Sweden)

    Degang Yu

    Full Text Available Chronic pain is the most prominent and disabling symptom of osteoarthritis (OA. Clinical data suggest that subchondral bone lesions contribute to the occurrence of joint pain. The present study investigated the effect of the inhibition of subchondral bone lesions on joint pain.Osteoarthritic pain was induced by an injection of monosodium iodoacetate (MIA into the rat knee joint. Zoledronic acid (ZOL, a third generation of bisphosphonate, was used to inhibit subchondral bone lesions. Joint histomorphology was evaluated using X-ray micro computed tomography scanning and hematoxylin-eosin staining. The activity of osteoclast in subchondral bone was evaluated using tartrate-resistant acid phosphatase staining. Joint pain was evaluated using weight-bearing asymmetry, the expression of calcitonin gene-related peptide (CGRP in the dorsal root ganglion (DRG, and spinal glial activation status using glial fibrillary acidic protein (GFAP and ionized calcium binding adaptor molecule-1 (Iba-1 immunofluorescence. Afferent neurons in the DRGs that innervated the joints were identified using retrograde fluorogold labeling.MIA injections induced significant histomorphological alterations and joint pain. The inhibition of subchondral bone lesions by ZOL significantly reduced the MIA-induced weight-bearing deficit and overexpression of CGRP in DRG neurons, GFAP and Iba-1 in the spinal dorsal horn at 3 and 6 weeks after MIA injection; however, joint swelling and synovial reaction were unaffected.The inhibition of subchondral bone lesions alleviated joint pain. Subchondral bone lesions should be a key target in the management of osteoarthritic joint pain.

  16. 1,2,3,4,6-Penta-O-Galloyl-Beta-D-Glucopyranoside Inhibits Proliferation of Multiple Myeloma Cells Accompanied with Suppression of MYC Expression

    Directory of Open Access Journals (Sweden)

    Duurenjargal Tseeleesuren

    2018-02-01

    Full Text Available Multiple myeloma (MM still remains an incurable disease, therefore discovery of novel drugs boosts the therapeutics for MM. The natural compound 1,2,3,4,6-Penta-O-galloyl-beta-D-glucopyranoside (PGG has been shown to exhibit antitumor activities against various cancer cells. Here, we aim to evaluate antitumor effects of PGG on MM cell lines. PGG inhibited the growth of three different MM cell lines in a dose- and time-dependent manner. Cell cycle analysis revealed that PGG treatment caused cell cycle arrest in G1 phase. It also induced apoptosis which was indicated by significant increases of Annexin V positive cells, caspase 3/7 activity, and cleaved caspase 3 expression in PGG treated MM cell. Since MYC is frequently hyperactivated in MM and inhibition of MYC leads to MM cell death. We further demonstrated that PGG decreased MYC expression in protein and mRNA levels and reversed the mRNA expression of MYC target genes such as p21, p27, and cyclin D2. In addition, PGG also reduced protein expression of DEPTOR which is commonly overexpressed in MM. Unexpectedly, PGG antagonized the cytotoxic effect of bortezomib in the combination treatment. However, PGG treatment sensitized MM cells to another proteasome inhibitor MG132 induced cytotoxicity. Moreover, MYC inhibitor JQ1 enhanced the cytotoxic effect of bortezomib on MM cells. Our findings raised concerns about the combinatory use of bortezomib with particular types of chemicals. The evidence also provide useful insights into the combination of MYC and proteasome-inhibitors for MM therapy. Finally, PGG has a therapeutic potential for treatment of MM and further development is mandatory.

  17. D-Glucosamine down-regulates HIF-1{alpha} through inhibition of protein translation in DU145 prostate cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jee-Young; Park, Jong-Wook; Suh, Seong-Il [Chronic Disease Research Center, School of Medicine, Keimyung University, 194 Dongsan-Dong, Jung-Gu, Daegu 700-712 (Korea, Republic of); Baek, Won-Ki, E-mail: wonki@dsmc.or.kr [Chronic Disease Research Center, School of Medicine, Keimyung University, 194 Dongsan-Dong, Jung-Gu, Daegu 700-712 (Korea, Republic of)

    2009-04-24

    D-Glucosamine has been reported to inhibit proliferation of cancer cells in culture and in vivo. In this study we report a novel response to D-glucosamine involving the translation regulation of hypoxia inducible factor (HIF)-1{alpha} expression. D-Glucosamine caused a decreased expression of HIF-1{alpha} under normoxic and hypoxic conditions without affecting HIF-1{alpha} mRNA expression in DU145 prostate cancer cells. D-Glucosamine inhibited HIF-1{alpha} accumulation induced by proteasome inhibitor MG132 and prolyl hydroxylase inhibitor DMOG suggesting D-glucosamine reduces HIF-1{alpha} protein expression through proteasome-independent pathway. Metabolic labeling assays indicated that D-glucosamine inhibits translation of HIF-1{alpha} protein. In addition, D-glucosamine inhibited HIF-1{alpha} expression induced by serum stimulation in parallel with inhibition of p70S6K suggesting D-glucosamine inhibits growth factor-induced HIF-1{alpha} expression, at least in part, through p70S6K inhibition. Taken together, these results suggest that D-glucosamine inhibits HIF-1{alpha} expression through inhibiting protein translation and provide new insight into a potential mechanism of the anticancer properties of D-glucosamine.

  18. Distinctive G Protein-Dependent Signaling by Protease-Activated Receptor 2 (PAR2 in Smooth Muscle: Feedback Inhibition of RhoA by cAMP-Independent PKA.

    Directory of Open Access Journals (Sweden)

    Wimolpak Sriwai

    Full Text Available We examined expression of protease-activated receptors 2 (PAR2 and characterized their signaling pathways in rabbit gastric muscle cells. The PAR2 activating peptide SLIGRL (PAR2-AP stimulated Gq, G13, Gi1, PI hydrolysis, and Rho kinase activity, and inhibited cAMP formation. Stimulation of PI hydrolysis was partly inhibited in cells expressing PAR2 siRNA, Gaq or Gai minigene and in cells treated with pertussis toxin, and augmented by expression of dominant negative regulator of G protein signaling (RGS4(N88S. Stimulation of Rho kinase activity was abolished by PAR-2 or Ga13 siRNA, and by Ga13 minigene. PAR2-AP induced a biphasic contraction; initial contraction was selectively blocked by the inhibitor of PI hydrolysis (U73122 or MLC kinase (ML-9, whereas sustained contraction was selectively blocked by the Rho kinase inhibitor (Y27632. PAR2-AP induced phosphorylation of MLC20, MYPT1 but not CPI-17. PAR2-AP also caused a decrease in the association of NF-kB and PKA catalytic subunit: the effect of PAR2-AP was blocked by PAR2 siRNA or phosphorylation-deficient RhoA (RhoA(S188A. PAR2-AP-induced degradation of IkBa and activation of NF-kB were abolished by the blockade of RhoA activity by Clostridium botulinum C3 exoenzyme suggesting RhoA-dependent activation of NF-kB. PAR2-AP-stimulated Rho kinase activity was significantly augmented by the inhibitors of PKA (myristoylated PKI, IKK2 (IKKIV or NF-kB (MG132, and in cells expressing dominant negative mutants of IKK (IKK(K44A, IkBa (IkBa (S32A/S36A or RhoA(S188A, suggesting feedback inhibition of Rho kinase activity via PKA derived from NF-kB pathway. PAR2-AP induced phosphorylation of RhoA and the phosphorylation was attenuated in cells expressing phosphorylation-deficient RhoA(S188A. Our results identified signaling pathways activated by PAR2 to mediate smooth muscle contraction and a novel pathway for feedback inhibition of PAR2-stimulated RhoA. The pathway involves activation of the NF-kB to

  19. GABA and GABA-Alanine from the Red Microalgae Rhodosorus marinus Exhibit a Significant Neuro-Soothing Activity through Inhibition of Neuro-Inflammation Mediators and Positive Regulation of TRPV1-Related Skin Sensitization

    Science.gov (United States)

    Scandolera, Amandine; Hubert, Jane; Humeau, Anne; Lambert, Carole; De Bizemont, Audrey; Winkel, Chris; Kaouas, Abdelmajid; Renault, Jean-Hugues; Reynaud, Romain

    2018-01-01

    The aim of the present study was to investigate the neuro-soothing activity of a water-soluble hydrolysate obtained from the red microalgae Rhodosorus marinus Geitler (Stylonemataceae). Transcriptomic analysis performed on ≈100 genes related to skin biological functions firstly revealed that the crude Rhodosorus marinus extract was able to significantly negatively modulate specific genes involved in pro-inflammation (interleukin 1α encoding gene, IL1A) and pain detection related to tissue inflammation (nerve growth factor NGF and its receptor NGFR). An in vitro model of normal human keratinocytes was then used to evaluate the ability of the Rhodosorus marinus extract to control the release of neuro-inflammation mediators under phorbol myristate acetate (PMA)-induced inflammatory conditions. The extract incorporated at 1% and 3% significantly inhibited the release of IL-1α and NGF secretion. These results were confirmed in a co-culture system of reconstructed human epithelium and normal human epidermal keratinocytes on which a cream formulated with the Rhodosorus marinus extract at 1% and 3% was topically applied after systemic induction of neuro-inflammation. Finally, an in vitro model of normal human astrocytes was developed for the evaluation of transient receptor potential vanilloid 1 (TRPV1) receptor modulation, mimicking pain sensing related to neuro-inflammation as observed in sensitive skins. Treatment with the Rhodosorus marinus extract at 1% and 3% significantly decreased PMA-mediated TRPV1 over-expression. In parallel with these biological experiments, the crude Rhodosorus marinus extract was fractionated by centrifugal partition chromatography (CPC) and chemically profiled by a recently developed 13C NMR-based dereplication method. The CPC-generated fractions as well as pure metabolites were tested again in vitro in an attempt to identify the biologically active constituents involved in the neuro-soothing activity of the Rhodosorus marinus extract

  20. GABA and GABA-Alanine from the Red Microalgae Rhodosorus marinus Exhibit a Significant Neuro-Soothing Activity through Inhibition of Neuro-Inflammation Mediators and Positive Regulation of TRPV1-Related Skin Sensitization

    Directory of Open Access Journals (Sweden)

    Amandine Scandolera

    2018-03-01

    Full Text Available The aim of the present study was to investigate the neuro-soothing activity of a water-soluble hydrolysate obtained from the red microalgae Rhodosorus marinus Geitler (Stylonemataceae. Transcriptomic analysis performed on ≈100 genes related to skin biological functions firstly revealed that the crude Rhodosorus marinus extract was able to significantly negatively modulate specific genes involved in pro-inflammation (interleukin 1α encoding gene, IL1A and pain detection related to tissue inflammation (nerve growth factor NGF and its receptor NGFR. An in vitro model of normal human keratinocytes was then used to evaluate the ability of the Rhodosorus marinus extract to control the release of neuro-inflammation mediators under phorbol myristate acetate (PMA-induced inflammatory conditions. The extract incorporated at 1% and 3% significantly inhibited the release of IL-1α and NGF secretion. These results were confirmed in a co-culture system of reconstructed human epithelium and normal human epidermal keratinocytes on which a cream formulated with the Rhodosorus marinus extract at 1% and 3% was topically applied after systemic induction of neuro-inflammation. Finally, an in vitro model of normal human astrocytes was developed for the evaluation of transient receptor potential vanilloid 1 (TRPV1 receptor modulation, mimicking pain sensing related to neuro-inflammation as observed in sensitive skins. Treatment with the Rhodosorus marinus extract at 1% and 3% significantly decreased PMA-mediated TRPV1 over-expression. In parallel with these biological experiments, the crude Rhodosorus marinus extract was fractionated by centrifugal partition chromatography (CPC and chemically profiled by a recently developed 13C NMR-based dereplication method. The CPC-generated fractions as well as pure metabolites were tested again in vitro in an attempt to identify the biologically active constituents involved in the neuro-soothing activity of the Rhodosorus

  1. The metabolism of L-arginine and its significance for the biosynthesis of endothelium-derived relaxing factor: L-glutamine inhibits the generation of L-arginine by cultured endothelial cells

    International Nuclear Information System (INIS)

    Sessa, W.C.; Hecker, M.; Mitchell, J.A.; Vane, J.R.

    1990-01-01

    The mechanism by which L-glutamine (L-Gln) inhibits the release of endothelium-derived factor from bovine aortic cultured endothelial cells was investigated. The intracellular concentration of L-arginine (L-Arg) in Arg-depleted endothelial cells was inversely related to the level of L-Gln. Removal of L-Gln from the culture medium (usually containing L-Gln at 2 mM) abolished the inhibitory effect of the culture medium on L-Arg generation. L-Gln (0.2 and 2 mM) but not D-Gln inhibited the generation of L-Arg by both Arg-depleted and nondepleted endothelial cells. L-Gln did not interfere with the uptake of L-Arg or the metabolism of L-Arg-L-Phe to L-Arg but inhibited the formation of L-Arg from L-citrulline (L-Cit), L-Cit-L-Phe, and N G -monomethyl-L-arginine. L-Gln also inhibited the conversion of L-[ 14 C]Cit to L-[ 14 C]Arg by Arg-depleted endothelial cells. However, L-Gln did not inhibit the conversion of L-argininosuccinic acid to L-Arg by endothelial cell homogenates. Thus, L-Gln interferes with the conversion of L-Cit to L-Arg probably by acting on argininosuccinate synthetase rather than argininosuccinate lyase. L-Gln also inhibited the generation of L-Arg by the monocyte-macrophage cell line J774 but had no effect on the conversion of L-Cit to L-Arg by these cells. As the release of endothelium-derived relaxing factor from cultured and non-cultured endothelial cells is limited by the availability of L-Arg, endogenous L-Gln may play a regulatory role in the biosynthesis of endothelium-derived relaxing factor

  2. Inhibition of the host proteasome facilitates papaya ringspot virus accumulation and proteosomal catalytic activity is modulated by viral factor HcPro.

    Directory of Open Access Journals (Sweden)

    Nandita Sahana

    Full Text Available The ubiquitin/26S proteasome system plays an essential role not only in maintaining protein turnover, but also in regulating many other plant responses, including plant-pathogen interactions. Previous studies highlighted different roles of the 20S proteasome in plant defense during virus infection, either indirectly through viral suppressor-mediated degradation of Argonaute proteins, affecting the RNA interference pathway, or directly through modulation of the proteolytic and RNase activity of the 20S proteasome, a component of the 20S proteasome, by viral proteins, affecting the levels of viral proteins and RNAs. Here we show that MG132, a cell permeable proteasomal inhibitor, caused an increase in papaya ringspot virus (PRSV accumulation in its natural host papaya (Carica papaya. We also show that the PRSV HcPro interacts with the papaya homologue of the Arabidopsis PAA (α1 subunit of the 20S proteasome, but not with the papaya homologue of Arabidopsis PAE (α5 subunit of the 20S proteasome, associated with the RNase activity, although the two 20S proteasome subunits interacted with each other. Mutated forms of PRSV HcPro showed that the conserved KITC54 motif in the N-terminal domain of HcPro was necessary for its binding to PAA. Co-agroinfiltration assays demonstrated that HcPro expression mimicked the action of MG132, and facilitated the accumulation of bothtotal ubiquitinated proteins and viral/non-viral exogenous RNA in Nicotiana benthamiana leaves. These effects were not observed by using an HcPro mutant (KITS54, which impaired the HcPro - PAA interaction. Thus, the PRSV HcPro interacts with a proteasomal subunit, inhibiting the action of the 20S proteasome, suggesting that HcPro might be crucial for modulating its catalytic activities in support of virus accumulation.

  3. [THE SPIRIT CHOLESTEROL, BIOLOGICA L ROLE AT STAGES OF PHYLOGENESIS, MECHANISMS OF INHIBITION OF SYNTHESIS OF STEROL BY STATINS, FACTORS OF PHARMACOGENOMICS AND DIAGNOSTIC SIGNIFICANCE OF CHOLESTEROL OF LIPOPROTEINS OF LOW DENSITY].

    Science.gov (United States)

    Titov, V N; Kotlovskii, M Yu; Pokrovskii, A A; Kotlovskaia, O S; Osedko, A V; Titova, N M; Kotlovskii, Yu V; Digaii, A M

    2015-04-01

    The hypolipidemic effect of statins is realized by inhibition of synthesis of local pool of cholesterol spirit in endoplasmic net of hepatocytes. The cholesterol spirit covers all hydrophobic medium of triglycerides with polar mono layer of phosphatidylcholines and cholesterol spirit prior to secretion of lipoproteins of very low density into hydrophilic medium. The lesser mono layer between lipase enzyme and triglycerides substrate contains of cholesterol spirit the higher are the parameters of hydrolysis of palmitic and oleic lipoproteins of very low density. The sequence of effect of statins is as follows: blocking of synthesis in hepatocytes and decreasing of content of unesterified cholesterol spirit in blood plasma; activation of hydrolysis of triglycerides in palmitic and oleic lipoproteins of very low density; formation of ligand lipoproteins of very low density and their absorption by cells by force of apoB-100 endocytosis; decreasing in blood of content of polyenoic fatty acids, equimolar esterified by cholesterol spirit, polyethers of cholesterol spirit and decreasing of level of cholesterol spirit-lipoproteins of very low density. There is no way to eliminate aphysiological effect of disordered biological function of trophology (nutrition) on metabolism of fatty acids in population by means of pharmaceuticals intake. It is necessary to eliminate aphysiological effect of environment. To decrease rate of diseases of cardiovascular system one has to decrease in food content of saturated fatty acids and in the first instance palmitic saturated fatty acid, trans-form fatty acid, palmitoleic fatty acids up to physiological values and increase to the same degree the content of polyenoic fatty acids. The saturated fatty acids block absorption of polyenoic fatty acids by cells. The atherosclerosis is a deficiency of polyenoic fatty acids under surplus of palmitic saturated fatty acid.

  4. miR-155, identified as anti-metastatic by global miRNA profiling of a metastasis model, inhibits cancer cell extravasation and colonization in vivo and causes significant signaling alterations

    DEFF Research Database (Denmark)

    Gravgaard, Karina Hedelund; Terp, Mikkel G; Lund, Rikke R

    2015-01-01

    To gain insight into miRNA regulation in metastasis formation, we used a metastasis cell line model that allows investigation of extravasation and colonization of circulating cancer cells to lungs in mice. Using global miRNA profiling, 28 miRNAs were found to exhibit significantly altered...... proliferation or apoptosis in established lung tumors. To identify proteins regulated by miR-155 and thus delineate its function in our cell model, we compared the proteome of xenograft tumors derived from miR-155-overexpressing CL16 cells and CL16 control cells using mass spectrometry-based proteomics. >4......,000 proteins were identified, of which 92 were consistently differentially expressed. Network analysis revealed that the altered proteins were associated with cellular functions such as movement, growth and survival as well as cell-to-cell signaling and interaction. Downregulation of the three metastasis...

  5. Steviol reduces MDCK Cyst formation and growth by inhibiting CFTR channel activity and promoting proteasome-mediated CFTR degradation.

    Directory of Open Access Journals (Sweden)

    Chaowalit Yuajit

    Full Text Available Cyst enlargement in polycystic kidney disease (PKD involves cAMP-activated proliferation of cyst-lining epithelial cells and transepithelial fluid secretion into the cyst lumen via cystic fibrosis transmembrane conductance regulator (CFTR chloride channel. This study aimed to investigate an inhibitory effect and detailed mechanisms of steviol and its derivatives on cyst growth using a cyst model in Madin-Darby canine kidney (MDCK cells. Among 4 steviol-related compounds tested, steviol was found to be the most potent at inhibiting MDCK cyst growth. Steviol inhibition of cyst growth was dose-dependent; steviol (100 microM reversibly inhibited cyst formation and cyst growth by 72.53.6% and 38.2±8.5%, respectively. Steviol at doses up to 200 microM had no effect on MDCK cell viability, proliferation and apoptosis. However, steviol acutely inhibited forskolin-stimulated apical chloride current in MDCK epithelia, measured with the Ussing chamber technique, in a dose-dependent manner. Prolonged treatment (24 h with steviol (100 microM also strongly inhibited forskolin-stimulated apical chloride current, in part by reducing CFTR protein expression in MDCK cells. Interestingly, proteasome inhibitor, MG-132, abolished the effect of steviol on CFTR protein expression. Immunofluorescence studies demonstrated that prolonged treatment (24 h with steviol (100 microM markedly reduced CFTR expression at the plasma membrane. Taken together, the data suggest that steviol retards MDCK cyst progression in two ways: first by directly inhibiting CFTR chloride channel activity and second by reducing CFTR expression, in part, by promoting proteasomal degradation of CFTR. Steviol and related compounds therefore represent drug candidates for treatment of polycystic kidney disease.

  6. Corrosion inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Fisher, A O

    1965-12-29

    An acid corrosion-inhibiting composition consists essentially of a sugar, and an alkali metal salt selected from the group consisting of iodides and bromides. The weight ratio of the sugar to the alkali metal salt is between 2:1 and about 20,000:1. Also, a corrosion- inhibited phosphoric acid composition comprising at least about 20 wt% of phosphoric acid and between about 0.1 wt% and about 10 wt% of molasses, and between about 0.0005 wt% and about 1 wt% of potassium iodide. The weight ratio of molasses to iodide is greater than about 2:1. (11 claims)

  7. Gpn3 is polyubiquitinated on lysine 216 and degraded by the proteasome in the cell nucleus in a Gpn1-inhibitable manner.

    Science.gov (United States)

    Méndez-Hernández, Lucía E; Robledo-Rivera, Angelica Y; Macías-Silva, Marina; Calera, Mónica R; Sánchez-Olea, Roberto

    2017-11-01

    Gpn1 associates with Gpn3, and both are required for RNA polymerase II nuclear targeting. Global studies have identified by mass spectrometry that human Gpn3 is ubiquitinated on lysines 189 and 216. Our goals here were to determine the type, physiological importance, and regulation of Gpn3 ubiquitination. After inhibiting the proteasome with MG132, Gpn3-Flag was polyubiquitinated on K216, but not K189, in HEK293T cells. Gpn3-Flag exhibited nucleo-cytoplasmic shuttling, but polyubiquitination and proteasomal degradation of Gpn3-Flag occurred only in the cell nucleus. Polyubiquitination-deficient Gpn3-Flag K216R displayed a longer half-life than Gpn3-Flag in two cell lines. Interestingly, Gpn1-EYFP inhibited Gpn3-Flag polyubiquitination in a dose-dependent manner. In conclusion, Gpn1-inhibitable, nuclear polyubiquitination on lysine 216 regulates the half-life of Gpn3 by tagging it for proteasomal degradation. © 2017 Federation of European Biochemical Societies.

  8. Celecoxib promotes c-FLIP degradation through Akt-independent inhibition of GSK3.

    Science.gov (United States)

    Chen, Shuzhen; Cao, Wei; Yue, Ping; Hao, Chunhai; Khuri, Fadlo R; Sun, Shi-Yong

    2011-10-01

    Celecoxib is a COX-2 inhibitor that reduces the risk of colon cancer. However, the basis for its cancer chemopreventive activity is not fully understood. In this study, we defined a mechanism of celecoxib action based on degradation of cellular FLICE-inhibitory protein (c-FLIP), a major regulator of the death receptor pathway of apoptosis. c-FLIP protein levels are regulated by ubiquitination and proteasome-mediated degradation. We found that celecoxib controlled c-FLIP ubiquitination through Akt-independent inhibition of glycogen synthase kinase-3 (GSK3), itself a candidate therapeutic target of interest in colon cancer. Celecoxib increased the levels of phosphorylated GSK3, including the α and β forms, even in cell lines, where phosphorylated Akt levels were not increased. Phosphoinositide 3-kinase inhibitors abrogated Akt phosphorylation as expected but had no effect on celecoxib-induced GSK3 phosphorylation. In contrast, protein kinase C (PKC) inhibitors abolished celecoxib-induced GSK3 phosphorylation, implying that celecoxib influenced GSK3 phosphorylation through a mechanism that relied upon PKC and not Akt. GSK3 blockade either by siRNA or kinase inhibitors was sufficient to attenuate c-FLIP levels. Combining celecoxib with GSK3 inhibition enhanced attenuation of c-FLIP and increased apoptosis. Proteasome inhibitor MG132 reversed the effects of GSK3 inhibition and increased c-FLIP ubiquitination, confirming that c-FLIP attenuation was mediated by proteasomal turnover as expected. Our findings reveal a novel mechanism through which the regulatory effects of c-FLIP on death receptor signaling are controlled by GSK3, which celecoxib acts at an upstream level to control independently of Akt.

  9. TSH-Mediated TNFα Production in Human Fibrocytes Is Inhibited by Teprotumumab, an IGF-1R Antagonist.

    Directory of Open Access Journals (Sweden)

    Hong Chen

    Full Text Available Fibrocytes (FC are bone marrow-derived progenitor cells that are more abundant and infiltrate the thyroid and orbit in Graves orbitopathy (GO. FCs express high levels of thyrotropin receptor (TSHR and insulin-like growth factor-1 receptor (IGF-1R. These receptors are physically and functionally associated, but their role in GO pathogenesis is not fully delineated. Treatment of FCs with thyroid stimulating hormone (TSH or M22 (activating antibody to TSHR induces the production of numerous cytokines, including tumor necrosis factor α (TNFα. Teprotumumab (TMB is a human monoclonal IGF-1R blocking antibody currently in clinical trial for GO and inhibits TSHR-mediated actions in FCs.To characterize the molecular mechanisms underlying TSH-induced TNFα production by FCs, and the role of IGF-1R blockade by TMB.FCs from healthy and GD patients were treated with combinations of TSH, M22, MG132 and AKTi (inhibitors of NF-κB and Akt, respectively, and TMB. TNFα protein production was measured by Luminex and flow cytometry. Messenger RNA expression was quantified by real time PCR.Treatment with TSH/M22 induced TNFα protein and mRNA production by FCs, both of which were reduced when FCs were pretreated with MG132 and AKTi (p<0.0001. TMB decreased TSH-induced TNFα protein production in circulating FCs from mean fluorescent index (MFI value of 2.92 to 1.91, and mRNA expression in cultured FCs from 141- to 52-fold expression (p<0.0001. TMB also decreased M22-induced TNFα protein production from MFI of 1.67 to 1.12, and mRNA expression from 6- to 3-fold expression (p<0.0001.TSH/M22 stimulates FC production of TNFα mRNA and protein. This process involves the transcription factor NF-κB and its regulator Akt. Blocking IGF-1R attenuates TSH/M22-induced TNFα production. This further delineates the interaction of TSHR and IGF1-R signaling pathways. By modulating the proinflammatory properties of FCs such as TNFα production, TMB may be a promising

  10. Inhibition of Rac1 activity induces G1/S phase arrest through the GSK3/cyclin D1 pathway in human cancer cells.

    Science.gov (United States)

    Liu, Linna; Zhang, Hongmei; Shi, Lei; Zhang, Wenjuan; Yuan, Juanli; Chen, Xiang; Liu, Juanjuan; Zhang, Yan; Wang, Zhipeng

    2014-10-01

    Rac1 has been shown to regulate the cell cycle in cancer cells. Yet, the related mechanism remains unclear. Thus, the present study aimed to investigate the mechanism involved in the regulation of G1/S phase transition by Rac1 in cancer cells. Inhibition of Rac1 by inhibitor NSC23766 induced G1/S phase arrest and inhibited the proliferation of A431, SW480 and U2-OS cells. Suppression of GSK3 by shRNA partially rescued G1/S phase arrest and inhibition of proliferation. Incubation of cells with NSC23766 reduced p-AKT and inactivated p-GSK3α and p-GSK3β, increased p-cyclin D1 expression and decreased the level of cyclin D1 protein. Consequently, cyclin D1 targeting transcriptional factor E2F1 expression, which promotes G1 to S phase transition, was also reduced. In contrast, constitutive active Rac1 resulted in increased p-AKT and inactivated p-GSK3α and p-GSK3β, decreased p-cyclin D1 expression and enhanced levels of cyclin D1 and E2F1 expression. Moreover, suppression of GSK3 did not alter p-AKT or Rac1 activity, but decreased p-cyclin D1 and increased total cyclin D1 protein. However, neither Rac1 nor GSK3 inhibition altered cyclin D1 at the RNA level. Moreover, after inhibition of Rac1 or GSK3 following proteasome inhibitor MG132 treatment, cyclin D1 expression at the protein level remained constant, indicating that Rac1 and GSK3 may regulate cyclin D1 turnover through phosphorylation and degradation. Therefore, our findings suggest that inhibition of Rac1 induces cell cycle G1/S arrest in cancer cells by regulation of the GSK3/cyclin D1 pathway.

  11. Hsp90 inhibition differentially destabilises MAP kinase and TGF-beta signalling components in cancer cells revealed by kinase-targeted chemoproteomics

    International Nuclear Information System (INIS)

    Haupt, Armin; Dahl, Andreas; Lappe, Michael; Lehrach, Hans; Gonzalez, Cayetano; Drewes, Gerard; Lange, Bodo MH; Joberty, Gerard; Bantscheff, Marcus; Fröhlich, Holger; Stehr, Henning; Schweiger, Michal R; Fischer, Axel; Kerick, Martin; Boerno, Stefan T

    2012-01-01

    The heat shock protein 90 (Hsp90) is required for the stability of many signalling kinases. As a target for cancer therapy it allows the simultaneous inhibition of several signalling pathways. However, its inhibition in healthy cells could also lead to severe side effects. This is the first comprehensive analysis of the response to Hsp90 inhibition at the kinome level. We quantitatively profiled the effects of Hsp90 inhibition by geldanamycin on the kinome of one primary (Hs68) and three tumour cell lines (SW480, U2OS, A549) by affinity proteomics based on immobilized broad spectrum kinase inhibitors ('kinobeads'). To identify affected pathways we used the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway classification. We combined Hsp90 and proteasome inhibition to identify Hsp90 substrates in Hs68 and SW480 cells. The mutational status of kinases from the used cell lines was determined using next-generation sequencing. A mutation of Hsp90 candidate client RIPK2 was mapped onto its structure. We measured relative abundances of > 140 protein kinases from the four cell lines in response to geldanamycin treatment and identified many new potential Hsp90 substrates. These kinases represent diverse families and cellular functions, with a strong representation of pathways involved in tumour progression like the BMP, MAPK and TGF-beta signalling cascades. Co-treatment with the proteasome inhibitor MG132 enabled us to classify 64 kinases as true Hsp90 clients. Finally, mutations in 7 kinases correlate with an altered response to Hsp90 inhibition. Structural modelling of the candidate client RIPK2 suggests an impact of the mutation on a proposed Hsp90 binding domain. We propose a high confidence list of Hsp90 kinase clients, which provides new opportunities for targeted and combinatorial cancer treatment and diagnostic applications

  12. Inhibition Performance in Children with Math Disabilities

    OpenAIRE

    Winegar, Kathryn Lileth

    2013-01-01

    This study examined the inhibition deficit hypothesis in children with math disabilities (MD). Children with and without MD were compared on two inhibition tasks that included the random generation of numbers and letters. The results addressed three hypotheses. Weak support was found for the first hypothesis which stated difficulties related to inhibition are significantly related to math performance. I found partial support for this hypothesis in that inhibition was related to math problem s...

  13. E11/Podoplanin Protein Stabilization Through Inhibition of the Proteasome Promotes Osteocyte Differentiation in Murine in Vitro Models.

    Science.gov (United States)

    Staines, Katherine A; Prideaux, Matt; Allen, Steve; Buttle, David J; Pitsillides, Andrew A; Farquharson, Colin

    2016-06-01

    The transmembrane glycoprotein E11 is considered critical in early osteoblast-osteocyte transitions (osteocytogenesis), however its function and regulatory mechanisms are still unknown. Using the late osteoblast MLO-A5 cell line we reveal increased E11 protein/mRNA expression (P < 0.001) concomitant with extensive osteocyte dendrite formation and matrix mineralization (P < 0.001). Transfection with E11 significantly increased mRNA levels (P < 0.001), but immunoblotting failed to detect any correlative increases in E11 protein levels, suggestive of post-translational degradation. We found that exogenous treatment of MLO-A5 and osteocytic IDG-SW3 cells with 10 μM ALLN (calpain and proteasome inhibitor) stabilized E11 protein levels and induced a profound increase in osteocytic dendrite formation (P < 0.001). Treatment with other calpain inhibitors failed to promote similar osteocytogenic changes, suggesting that these effects of ALLN rely upon its proteasome inhibitor actions. Accordingly we found that proteasome-selective inhibitors (MG132/lactacystin/ Bortezomib/Withaferin-A) produced similar dose-dependent increases in E11 protein levels in MLO-A5 and primary osteoblast cells. This proteasomal targeting was confirmed by immunoprecipitation of ubiquitinylated proteins, which included E11, and by increased levels of ubiquitinylated E11 protein upon addition of the proteasome inhibitors MG132/Bortezomib. Activation of RhoA, the small GTPase, was found to be increased concomitant with the peak in E11 levels and its downstream signaling was also observed to promote MLO-A5 cell dendrite formation. Our data indicate that a mechanism reliant upon blockade of proteasome-mediated E11 destabilization contributes to osteocytogenesis and that this may involve downstream targeting of RhoA. This work adds to our mechanistic understanding of the factors regulating bone homeostasis, which may lead to future therapeutic approaches. © 2015 The Authors. Journal of

  14. Detecting Novelty and Significance

    Science.gov (United States)

    Ferrari, Vera; Bradley, Margaret M.; Codispoti, Maurizio; Lang, Peter J.

    2013-01-01

    Studies of cognition often use an “oddball” paradigm to study effects of stimulus novelty and significance on information processing. However, an oddball tends to be perceptually more novel than the standard, repeated stimulus as well as more relevant to the ongoing task, making it difficult to disentangle effects due to perceptual novelty and stimulus significance. In the current study, effects of perceptual novelty and significance on ERPs were assessed in a passive viewing context by presenting repeated and novel pictures (natural scenes) that either signaled significant information regarding the current context or not. A fronto-central N2 component was primarily affected by perceptual novelty, whereas a centro-parietal P3 component was modulated by both stimulus significance and novelty. The data support an interpretation that the N2 reflects perceptual fluency and is attenuated when a current stimulus matches an active memory representation and that the amplitude of the P3 reflects stimulus meaning and significance. PMID:19400680

  15. Significant NRC Enforcement Actions

    Data.gov (United States)

    Nuclear Regulatory Commission — This dataset provides a list of Nuclear Regulartory Commission (NRC) issued significant enforcement actions. These actions, referred to as "escalated", are issued by...

  16. Behavioral inhibition and obsessive-compulsive disorder.

    Science.gov (United States)

    Coles, Meredith E; Schofield, Casey A; Pietrefesa, Ashley S

    2006-01-01

    Behavioral inhibition is frequently cited as a vulnerability factor for development of anxiety. However, few studies have examined the unique relationship between behavioral inhibition and obsessive-compulsive disorder (OCD). Therefore, the current study addressed the relationship between behavioral inhibition and OCD in a number of ways. In a large unselected student sample, frequency of current OC symptoms was significantly correlated with retrospective self-reports of total levels of childhood behavioral inhibition. In addition, frequency of current OC symptoms was also significantly correlated with both social and nonsocial components of behavioral inhibition. Further, there was evidence for a unique relationship between behavioral inhibition and OC symptoms beyond the relationship of behavioral inhibition and social anxiety. In addition, results showed that reports of childhood levels of behavioral inhibition significantly predicted levels of OCD symptoms in adulthood. Finally, preliminary evidence suggested that behavioral inhibition may be more strongly associated with some types of OC symptoms than others, and that overprotective parenting may moderate the impact of behavioral inhibition on OC symptoms. The current findings suggest the utility of additional research examining the role of behavioral inhibition in the etiology of OCD.

  17. Significant Tsunami Events

    Science.gov (United States)

    Dunbar, P. K.; Furtney, M.; McLean, S. J.; Sweeney, A. D.

    2014-12-01

    Tsunamis have inflicted death and destruction on the coastlines of the world throughout history. The occurrence of tsunamis and the resulting effects have been collected and studied as far back as the second millennium B.C. The knowledge gained from cataloging and examining these events has led to significant changes in our understanding of tsunamis, tsunami sources, and methods to mitigate the effects of tsunamis. The most significant, not surprisingly, are often the most devastating, such as the 2011 Tohoku, Japan earthquake and tsunami. The goal of this poster is to give a brief overview of the occurrence of tsunamis and then focus specifically on several significant tsunamis. There are various criteria to determine the most significant tsunamis: the number of deaths, amount of damage, maximum runup height, had a major impact on tsunami science or policy, etc. As a result, descriptions will include some of the most costly (2011 Tohoku, Japan), the most deadly (2004 Sumatra, 1883 Krakatau), and the highest runup ever observed (1958 Lituya Bay, Alaska). The discovery of the Cascadia subduction zone as the source of the 1700 Japanese "Orphan" tsunami and a future tsunami threat to the U.S. northwest coast, contributed to the decision to form the U.S. National Tsunami Hazard Mitigation Program. The great Lisbon earthquake of 1755 marked the beginning of the modern era of seismology. Knowledge gained from the 1964 Alaska earthquake and tsunami helped confirm the theory of plate tectonics. The 1946 Alaska, 1952 Kuril Islands, 1960 Chile, 1964 Alaska, and the 2004 Banda Aceh, tsunamis all resulted in warning centers or systems being established.The data descriptions on this poster were extracted from NOAA's National Geophysical Data Center (NGDC) global historical tsunami database. Additional information about these tsunamis, as well as water level data can be found by accessing the NGDC website www.ngdc.noaa.gov/hazard/

  18. Inhibition of MMPs by alcohols

    Science.gov (United States)

    Tezvergil-Mutluay, Arzu; Agee, Kelli A.; Hoshika, Tomohiro; Uchiyama, Toshikazu; Tjäderhane, Leo; Breschi, Lorenzo; Mazzoni, Annalisa; Thompson, Jeremy M.; McCracken, Courtney E.; Looney, Stephen W.; Tay, Franklin R.; Pashley, David H.

    2011-01-01

    Objectives While screening the activity of potential inhibitors of matrix metalloproteinases (MMPs), due to the limited water solubility of some of the compounds, they had to be solubilized in ethanol. When ethanol solvent controls were run, they were found to partially inhibit MMPs. Thus, the purpose of this study was to compare the MMP-inhibitory activity of a series of alcohols. Methods The possible inhibitory activity of a series of alcohols was measured against soluble rhMMP-9 and insoluble matrix-bound endogenous MMPs of dentin in completely demineralized dentin. Increasing concentrations (0.17, 0.86, 1.71 and 4.28 moles/L) of a homologous series of alcohols (i.e. methanol, ethanol, propanols, butanols, pentanols, hexanols, the ethanol ester of methacrylic acid, heptanols and octanol) were compared to ethanediol, and propanediol by regression analysis to calculate the molar concentration required to inhibit MMPs by 50% (i.e. the IC50). Results Using two different MMP models, alcohols were shown to inhibit rhMMP-9 and the endogenous proteases of dentin matrix in a dose-dependent manner. The degree of MMP inhibition by alcohols increased with chain length up to 4 methylene groups. Based on the molar concentration required to inhibit rhMMP-9 fifty percent, 2-hydroxyethylmethacrylate (HEMA), 3-hexanol, 3-heptanol and 1-octanol gave the strongest inhibition. Significance The results indicate that alcohols with 4 methylene groups inhibit MMPs more effectively than methanol or ethanol. MMP inhibition was inversely related to the Hoy's solubility parameter for hydrogen bonding forces of the alcohols (i.e. to their hydrophilicity). PMID:21676453

  19. Testing Significance Testing

    Directory of Open Access Journals (Sweden)

    Joachim I. Krueger

    2018-04-01

    Full Text Available The practice of Significance Testing (ST remains widespread in psychological science despite continual criticism of its flaws and abuses. Using simulation experiments, we address four concerns about ST and for two of these we compare ST’s performance with prominent alternatives. We find the following: First, the 'p' values delivered by ST predict the posterior probability of the tested hypothesis well under many research conditions. Second, low 'p' values support inductive inferences because they are most likely to occur when the tested hypothesis is false. Third, 'p' values track likelihood ratios without raising the uncertainties of relative inference. Fourth, 'p' values predict the replicability of research findings better than confidence intervals do. Given these results, we conclude that 'p' values may be used judiciously as a heuristic tool for inductive inference. Yet, 'p' values cannot bear the full burden of inference. We encourage researchers to be flexible in their selection and use of statistical methods.

  20. Safety significance evaluation system

    International Nuclear Information System (INIS)

    Lew, B.S.; Yee, D.; Brewer, W.K.; Quattro, P.J.; Kirby, K.D.

    1991-01-01

    This paper reports that the Pacific Gas and Electric Company (PG and E), in cooperation with ABZ, Incorporated and Science Applications International Corporation (SAIC), investigated the use of artificial intelligence-based programming techniques to assist utility personnel in regulatory compliance problems. The result of this investigation is that artificial intelligence-based programming techniques can successfully be applied to this problem. To demonstrate this, a general methodology was developed and several prototype systems based on this methodology were developed. The prototypes address U.S. Nuclear Regulatory Commission (NRC) event reportability requirements, technical specification compliance based on plant equipment status, and quality assurance assistance. This collection of prototype modules is named the safety significance evaluation system

  1. Predicting significant torso trauma.

    Science.gov (United States)

    Nirula, Ram; Talmor, Daniel; Brasel, Karen

    2005-07-01

    Identification of motor vehicle crash (MVC) characteristics associated with thoracoabdominal injury would advance the development of automatic crash notification systems (ACNS) by improving triage and response times. Our objective was to determine the relationships between MVC characteristics and thoracoabdominal trauma to develop a torso injury probability model. Drivers involved in crashes from 1993 to 2001 within the National Automotive Sampling System were reviewed. Relationships between torso injury and MVC characteristics were assessed using multivariate logistic regression. Receiver operating characteristic curves were used to compare the model to current ACNS models. There were a total of 56,466 drivers. Age, ejection, braking, avoidance, velocity, restraints, passenger-side impact, rollover, and vehicle weight and type were associated with injury (p < 0.05). The area under the receiver operating characteristic curve (83.9) was significantly greater than current ACNS models. We have developed a thoracoabdominal injury probability model that may improve patient triage when used with ACNS.

  2. Gas revenue increasingly significant

    International Nuclear Information System (INIS)

    Megill, R.E.

    1991-01-01

    This paper briefly describes the wellhead prices of natural gas compared to crude oil over the past 70 years. Although natural gas prices have never reached price parity with crude oil, the relative value of a gas BTU has been increasing. It is one of the reasons that the total amount of money coming from natural gas wells is becoming more significant. From 1920 to 1955 the revenue at the wellhead for natural gas was only about 10% of the money received by producers. Most of the money needed for exploration, development, and production came from crude oil. At present, however, over 40% of the money from the upstream portion of the petroleum industry is from natural gas. As a result, in a few short years natural gas may become 50% of the money revenues generated from wellhead production facilities

  3. Inhibition of cortiocosteroidogenesis by delta-9-tetrahydrocannabinol.

    Science.gov (United States)

    Warner, W; Harris, L S; Carchman, R A

    1977-12-01

    ACTH, cholera toxin, cyclic AMP but not pregnenolone-induced steroidogenesis in Y-1 functional mouse adrenal tumor cells was significantly inhibited by delta-9-tetrahydrocannabinol, cannabidiol, and cannabinol. The inhibition of steroidogenesis could not be correlated with a general depression in cell function or viability. The data suggest that cannabinoids inhibit corticosteroidogenesis at a site between the synthesis of cAMP and of pregnenolone.

  4. Tumor significant dose

    International Nuclear Information System (INIS)

    Supe, S.J.; Nagalaxmi, K.V.; Meenakshi, L.

    1983-01-01

    In the practice of radiotherapy, various concepts like NSD, CRE, TDF, and BIR are being used to evaluate the biological effectiveness of the treatment schedules on the normal tissues. This has been accepted as the tolerance of the normal tissue is the limiting factor in the treatment of cancers. At present when various schedules are tried, attention is therefore paid to the biological damage of the normal tissues only and it is expected that the damage to the cancerous tissues would be extensive enough to control the cancer. Attempt is made in the present work to evaluate the concent of tumor significant dose (TSD) which will represent the damage to the cancerous tissue. Strandquist in the analysis of a large number of cases of squamous cell carcinoma found that for the 5 fraction/week treatment, the total dose required to bring about the same damage for the cancerous tissue is proportional to T/sup -0.22/, where T is the overall time over which the dose is delivered. Using this finding the TSD was defined as DxN/sup -p/xT/sup -q/, where D is the total dose, N the number of fractions, T the overall time p and q are the exponents to be suitably chosen. The values of p and q are adjusted such that p+q< or =0.24, and p varies from 0.0 to 0.24 and q varies from 0.0 to 0.22. Cases of cancer of cervix uteri treated between 1978 and 1980 in the V. N. Cancer Centre, Kuppuswamy Naidu Memorial Hospital, Coimbatore, India were analyzed on the basis of these formulations. These data, coupled with the clinical experience, were used for choice of a formula for the TSD. Further, the dose schedules used in the British Institute of Radiology fraction- ation studies were also used to propose that the tumor significant dose is represented by DxN/sup -0.18/xT/sup -0.06/

  5. Uranium chemistry: significant advances

    International Nuclear Information System (INIS)

    Mazzanti, M.

    2011-01-01

    The author reviews recent progress in uranium chemistry achieved in CEA laboratories. Like its neighbors in the Mendeleev chart uranium undergoes hydrolysis, oxidation and disproportionation reactions which make the chemistry of these species in water highly complex. The study of the chemistry of uranium in an anhydrous medium has led to correlate the structural and electronic differences observed in the interaction of uranium(III) and the lanthanides(III) with nitrogen or sulfur molecules and the effectiveness of these molecules in An(III)/Ln(III) separation via liquid-liquid extraction. Recent work on the redox reactivity of trivalent uranium U(III) in an organic medium with molecules such as water or an azide ion (N 3 - ) in stoichiometric quantities, led to extremely interesting uranium aggregates particular those involved in actinide migration in the environment or in aggregation problems in the fuel processing cycle. Another significant advance was the discovery of a compound containing the uranyl ion with a degree of oxidation (V) UO 2 + , obtained by oxidation of uranium(III). Recently chemists have succeeded in blocking the disproportionation reaction of uranyl(V) and in stabilizing polymetallic complexes of uranyl(V), opening the way to to a systematic study of the reactivity and the electronic and magnetic properties of uranyl(V) compounds. (A.C.)

  6. Meaning and significance of

    Directory of Open Access Journals (Sweden)

    Ph D Student Roman Mihaela

    2011-05-01

    Full Text Available The concept of "public accountability" is a challenge for political science as a new concept in this area in full debate and developement ,both in theory and practice. This paper is a theoretical approach of displaying some definitions, relevant meanings and significance odf the concept in political science. The importance of this concept is that although originally it was used as a tool to improve effectiveness and eficiency of public governance, it has gradually become a purpose it itself. "Accountability" has become an image of good governance first in the United States of America then in the European Union.Nevertheless,the concept is vaguely defined and provides ambiguous images of good governance.This paper begins with the presentation of some general meanings of the concept as they emerge from specialized dictionaries and ancyclopaedies and continues with the meanings developed in political science. The concept of "public accontability" is rooted in economics and management literature,becoming increasingly relevant in today's political science both in theory and discourse as well as in practice in formulating and evaluating public policies. A first conclusin that emerges from, the analysis of the evolution of this term is that it requires a conceptual clarification in political science. A clear definition will then enable an appropriate model of proving the system of public accountability in formulating and assessing public policies, in order to implement a system of assessment and monitoring thereof.

  7. INHIBITION IN SPEAKING PERFORMANCE

    OpenAIRE

    Humaera, Isna

    2015-01-01

    The most common problem encountered by the learner in the languageacquisition process is learner inhibition. Inhibition refers to a temperamentaltendency to display wariness, fearfulness, or restrain in response tounfamiliar people, objects, and situations. There are some factors that causeinhibition, such as lack of motivation, shyness, self-confidence, self-esteem,and language ego. There are also levels of inhibition, it refers to kinds ofinhibition and caused of inhibition itself. Teacher ...

  8. Significant Radionuclides Determination

    Energy Technology Data Exchange (ETDEWEB)

    Jo A. Ziegler

    2001-07-31

    The purpose of this calculation is to identify radionuclides that are significant to offsite doses from potential preclosure events for spent nuclear fuel (SNF) and high-level radioactive waste expected to be received at the potential Monitored Geologic Repository (MGR). In this calculation, high-level radioactive waste is included in references to DOE SNF. A previous document, ''DOE SNF DBE Offsite Dose Calculations'' (CRWMS M&O 1999b), calculated the source terms and offsite doses for Department of Energy (DOE) and Naval SNF for use in design basis event analyses. This calculation reproduces only DOE SNF work (i.e., no naval SNF work is included in this calculation) created in ''DOE SNF DBE Offsite Dose Calculations'' and expands the calculation to include DOE SNF expected to produce a high dose consequence (even though the quantity of the SNF is expected to be small) and SNF owned by commercial nuclear power producers. The calculation does not address any specific off-normal/DBE event scenarios for receiving, handling, or packaging of SNF. The results of this calculation are developed for comparative analysis to establish the important radionuclides and do not represent the final source terms to be used for license application. This calculation will be used as input to preclosure safety analyses and is performed in accordance with procedure AP-3.12Q, ''Calculations'', and is subject to the requirements of DOE/RW-0333P, ''Quality Assurance Requirements and Description'' (DOE 2000) as determined by the activity evaluation contained in ''Technical Work Plan for: Preclosure Safety Analysis, TWP-MGR-SE-000010'' (CRWMS M&O 2000b) in accordance with procedure AP-2.21Q, ''Quality Determinations and Planning for Scientific, Engineering, and Regulatory Compliance Activities''.

  9. The novel Akt inhibitor API-1 induces c-FLIP degradation and synergizes with TRAIL to augment apoptosis independent of Akt inhibition.

    Science.gov (United States)

    Li, Bo; Ren, Hui; Yue, Ping; Chen, Mingwei; Khuri, Fadlo R; Sun, Shi-Yong

    2012-04-01

    API-1 (pyrido[2,3-d]pyrimidines) is a novel small-molecule inhibitor of Akt, which acts by binding to Akt and preventing its membrane translocation and has promising preclinical antitumor activity. In this study, we reveal a novel function of API-1 in regulation of cellular FLICE-inhibitory protein (c-FLIP) levels and TRAIL-induced apoptosis, independent of Akt inhibition. API-1 effectively induced apoptosis in tested cancer cell lines including activation of caspase-8 and caspase-9. It reduced the levels of c-FLIP without increasing the expression of death receptor 4 (DR4) or DR5. Accordingly, it synergized with TRAIL to induce apoptosis. Enforced expression of ectopic c-FLIP did not attenuate API-1-induced apoptosis but inhibited its ability to enhance TRAIL-induced apoptosis. These data indicate that downregulation of c-FLIP mediates enhancement of TRAIL-induced apoptosis by API-1 but is not sufficient for API-1-induced apoptosis. API-1-induced reduction of c-FLIP could be blocked by the proteasome inhibitor MG132. Moreover, API-1 increased c-FLIP ubiquitination and decreased c-FLIP stability. These data together suggest that API-1 downregulates c-FLIP by facilitating its ubiquitination and proteasome-mediated degradation. Because other Akt inhibitors including API-2 and MK2206 had minimal effects on reducing c-FLIP and enhancement of TRAIL-induced apoptosis, it is likely that API-1 reduces c-FLIP and enhances TRAIL-induced apoptosis independent of its Akt-inhibitory activity. 2012 AACR

  10. Curcumin significantly enhances dual PI3K/Akt and mTOR inhibitor NVP-BEZ235-induced apoptosis in human renal carcinoma Caki cells through down-regulation of p53-dependent Bcl-2 expression and inhibition of Mcl-1 protein stability.

    Directory of Open Access Journals (Sweden)

    Bo Ram Seo

    Full Text Available The PI3K/Akt and mTOR signaling pathways are important for cell survival and growth, and they are highly activated in cancer cells compared with normal cells. Therefore, these signaling pathways are targets for inducing cancer cell death. The dual PI3K/Akt and mTOR inhibitor NVP-BEZ235 completely inhibited both signaling pathways. However, NVP-BEZ235 had no effect on cell death in human renal carcinoma Caki cells. We tested whether combined treatment with natural compounds and NVP-BEZ235 could induce cell death. Among several chemopreventive agents, curcumin, a natural biologically active compound that is extracted from the rhizomes of Curcuma species, markedly induced apoptosis in NVP-BEZ235-treated cells. Co-treatment with curcumin and NVP-BEZ235 led to the down-regulation of Mcl-1 protein expression but not mRNA expression. Ectopic expression of Mcl-1 completely inhibited curcumin plus NVP-NEZ235-induced apoptosis. Furthermore, the down-regulation of Bcl-2 was involved in curcumin plus NVP-BEZ235-induced apoptosis. Curcumin or NVP-BEZ235 alone did not change Bcl-2 mRNA or protein expression, but co-treatment reduced Bcl-2 mRNA and protein expression. Combined treatment with NVP-BEZ235 and curcumin reduced Bcl-2 expression in wild-type p53 HCT116 human colon carcinoma cells but not p53-null HCT116 cells. Moreover, Bcl-2 expression was completely reversed by treatment with pifithrin-α, a p53-specific inhibitor. Ectopic expression of Bcl-2 also inhibited apoptosis in NVP-BE235 plus curcumin-treated cells. In contrast, NVP-BEZ235 combined with curcumin did not have a synergistic effect on normal human skin fibroblasts and normal human mesangial cells. Taken together, combined treatment with NVP-BEZ235 and curcumin induces apoptosis through p53-dependent Bcl-2 mRNA down-regulation at the transcriptional level and Mcl-1 protein down-regulation at the post-transcriptional level.

  11. SIRT1 inhibits proliferation of pancreatic cancer cells expressing pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, by suppression of β-catenin

    International Nuclear Information System (INIS)

    Cho, Il-Rae; Koh, Sang Seok; Malilas, Waraporn; Srisuttee, Ratakorn; Moon, Jeong; Choi, Young-Whan; Horio, Yoshiyuki; Oh, Sangtaek; Chung, Young-Hwa

    2012-01-01

    Highlights: ► SIRT1 inhibits protein levels of β-catenin and its transcriptional activity. ► Nuclear localization of SIRT1 is not required for the decrease of β-catenin expression. ► SIRT1-mediated degradation of β-catenin is not required for GSK-3β and Siah-1 but for proteosome. ► SIRT1 activation inhibits proliferation of pancreatic cancer cells expressing PAUF. -- Abstract: Because we found in a recent study that pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, induces a rapid proliferation of pancreatic cells by up-regulation of β-catenin, we postulated that β-catenin might be a target molecule for pancreatic cancer treatment. We thus speculated whether SIRT1, known to target β-catenin in a colon cancer model, suppresses β-catenin in those pancreatic cancer cells that express PAUF (Panc-PAUF). We further evaluated whether such suppression would lead to inhibition of the proliferation of these cells. The ectopic expression of either SIRT1 or resveratrol (an activator of SIRT1) suppressed levels of β-catenin protein and its transcriptional activity in Panc-PAUF cells. Conversely, suppression of SIRT1 expression by siRNA enhanced β-catenin expression and transcriptional activity. SIRT1 mutant analysis showed that nuclear localization of SIRT1 is not required for reduction of β-catenin. Treatment with MG132, a proteasomal inhibitor, restored β-catenin protein levels, suggesting that SIRT1-mediated degradation of β-catenin requires proteasomal activity. It was reported that inhibition of GSK-3β or Siah-1 stabilizes β-catenin in colon cancer cells, but suppression of GSK-3β or Siah-1 using siRNA in the presence of resveratrol instead diminished β-catenin protein levels in Panc-PAUF cells. This suggests that GSK-3β and Siah-1 are not involved in SIRT1-mediated degradation of β-catenin in the cells. Finally, activation of SIRT1 inhibited the proliferation of Panc-PAUF cells by down-regulation of cyclin-D1, a target

  12. SIRT1 inhibits proliferation of pancreatic cancer cells expressing pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, by suppression of {beta}-catenin

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Il-Rae [WCU, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735 (Korea, Republic of); Koh, Sang Seok [Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333 (Korea, Republic of); Department of Functional Genomics, University of Science and Technology, Daejeon 305-333 (Korea, Republic of); Malilas, Waraporn; Srisuttee, Ratakorn; Moon, Jeong [WCU, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735 (Korea, Republic of); Choi, Young-Whan [Department of Horticultural Bioscience, Pusan National University, Miryang 627-706 (Korea, Republic of); Horio, Yoshiyuki [Department of Pharmacology, Sapporo Medical University, Sapporo 060-8556 (Japan); Oh, Sangtaek [Department of Advanced Fermentation Fusion Science and Technology, Kookmin University, Seoul 136-702 (Korea, Republic of); Chung, Young-Hwa, E-mail: younghc@pusan.ac.kr [WCU, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan 609-735 (Korea, Republic of)

    2012-06-29

    Highlights: Black-Right-Pointing-Pointer SIRT1 inhibits protein levels of {beta}-catenin and its transcriptional activity. Black-Right-Pointing-Pointer Nuclear localization of SIRT1 is not required for the decrease of {beta}-catenin expression. Black-Right-Pointing-Pointer SIRT1-mediated degradation of {beta}-catenin is not required for GSK-3{beta} and Siah-1 but for proteosome. Black-Right-Pointing-Pointer SIRT1 activation inhibits proliferation of pancreatic cancer cells expressing PAUF. -- Abstract: Because we found in a recent study that pancreatic adenocarcinoma up-regulated factor (PAUF), a novel oncogene, induces a rapid proliferation of pancreatic cells by up-regulation of {beta}-catenin, we postulated that {beta}-catenin might be a target molecule for pancreatic cancer treatment. We thus speculated whether SIRT1, known to target {beta}-catenin in a colon cancer model, suppresses {beta}-catenin in those pancreatic cancer cells that express PAUF (Panc-PAUF). We further evaluated whether such suppression would lead to inhibition of the proliferation of these cells. The ectopic expression of either SIRT1 or resveratrol (an activator of SIRT1) suppressed levels of {beta}-catenin protein and its transcriptional activity in Panc-PAUF cells. Conversely, suppression of SIRT1 expression by siRNA enhanced {beta}-catenin expression and transcriptional activity. SIRT1 mutant analysis showed that nuclear localization of SIRT1 is not required for reduction of {beta}-catenin. Treatment with MG132, a proteasomal inhibitor, restored {beta}-catenin protein levels, suggesting that SIRT1-mediated degradation of {beta}-catenin requires proteasomal activity. It was reported that inhibition of GSK-3{beta} or Siah-1 stabilizes {beta}-catenin in colon cancer cells, but suppression of GSK-3{beta} or Siah-1 using siRNA in the presence of resveratrol instead diminished {beta}-catenin protein levels in Panc-PAUF cells. This suggests that GSK-3{beta} and Siah-1 are not involved in SIRT1

  13. Use of bacillus subtilis strains to inhibit postharvest pathogenic fungi

    International Nuclear Information System (INIS)

    Arras, G.; Gambella, F.; Demontis, S.; Petretto, A.

    1995-01-01

    An isolate (87) of the bacillus subtilis strains isolated from cold stored citrus fruit 13 proved to inhibit the growth in vitro of the penicillium italicum used in the experiment (from 50.6% to 92.2%) and to inhibit botrytis cinerea (from 65.3% to 95.9%). A further test, superimposing on plates containing PDA strains Nos. 13, 173, and 160, totally inhibited the fungi. Tested in vivo on artificially bruised oranges, they significantly inhibited two fungi

  14. Concurrent Inhibition of Pim and FLT3 Kinases Enhances Apoptosis of FLT3-ITD Acute Myeloid Leukemia Cells through Increased Mcl-1 Proteasomal Degradation.

    Science.gov (United States)

    Kapoor, Shivani; Natarajan, Karthika; Baldwin, Patrick R; Doshi, Kshama A; Lapidus, Rena G; Mathias, Trevor J; Scarpa, Mario; Trotta, Rossana; Davila, Eduardo; Kraus, Manfred; Huszar, Dennis; Tron, Adriana E; Perrotti, Danilo; Baer, Maria R

    2018-01-01

    Purpose: fms -like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is present in 30% of acute myeloid leukemia (AML), and these patients have short disease-free survival. FLT3 inhibitors have limited and transient clinical activity, and concurrent treatment with inhibitors of parallel or downstream signaling may improve responses. The oncogenic serine/threonine kinase Pim-1 is upregulated downstream of FLT3-ITD and also promotes its signaling in a positive feedback loop, suggesting benefit of combined Pim and FLT3 inhibition. Experimental Design: Combinations of clinically active Pim and FLT3 inhibitors were studied in vitro and in vivo Results: Concurrent treatment with the pan-Pim inhibitor AZD1208 and FLT3 inhibitors at clinically applicable concentrations abrogated in vitro growth of FLT3-ITD, but not wild-type FLT3 (FLT3-WT), cell lines. AZD1208 cotreatment increased FLT3 inhibitor-induced apoptosis of FLT3-ITD, but not FLT3-WT, cells measured by sub-G 1 fraction, annexin V labeling, mitochondrial membrane potential, and PARP and caspase-3 cleavage. Concurrent treatment with AZD1208 and the FLT3 inhibitor quizartinib decreased growth of MV4-11 cells, with FLT3-ITD, in mouse xenografts, and prolonged survival, enhanced apoptosis of FLT3-ITD primary AML blasts, but not FLT3-WT blasts or remission marrow cells, and decreased FLT3-ITD AML blast colony formation. Mechanistically, AZD1208 and quizartinib cotreatment decreased expression of the antiapoptotic protein Mcl-1. Decrease in Mcl-1 protein expression was abrogated by treatment with the proteasome inhibitor MG132, and was preceded by downregulation of the Mcl-1 deubiquitinase USP9X, a novel mechanism of Mcl-1 regulation in AML. Conclusions: The data support clinical testing of Pim and FLT3 inhibitor combination therapy for FLT3-ITD AML. Clin Cancer Res; 24(1); 234-47. ©2017 AACR . ©2017 American Association for Cancer Research.

  15. Inhibition of lactation.

    Science.gov (United States)

    Llewellyn-Jones, D

    1975-01-01

    The mechanism and hormonal regulation of lactation is explained and illustrated with a schematic representation. Circulating estrogen above a critical amount seems to be the inhibitory factor controlling lactation during pregnancy. Once delivery occurs, the level of estrogen falls, that of prolactin rises, and lactation begins. Nonsuckling can be used to inhibit lactation. Estrogens can also be used to inhibit lactation more quickly and with less pain. The reported association between estrogens and puerperal thromboembolism cannot be considered conclusive due to defects in the reporting studies. There is no reason not to use estrogens in lactation inhibition except for women over 35 who experienced a surgical delivery. Alternative therapy is available for these women. The recently-developed drug, brom-ergocryptine, may replace other methods of lactation inhibition.

  16. Anticancer activity of calyx of Diospyros kaki Thunb. through downregulation of cyclin D1 via inducing proteasomal degradation and transcriptional inhibition in human colorectal cancer cells.

    Science.gov (United States)

    Park, Su Bin; Park, Gwang Hun; Song, Hun Min; Son, Ho-Jun; Um, Yurry; Kim, Hyun-Seok; Jeong, Jin Boo

    2017-09-05

    Although it has been reported to contain high polyphenols, the pharmacological studies of the calyx of Diospyros kaki Thunb (DKC) have not been elucidated in detail. In this study, we elucidated anti-cancer activity and potential molecular mechanism of DKC against human colorectal cancer cells. Anti-cell proliferative effect of 70% ethanol extracts from the calyx of Diospyros kaki (DKC-E70) was evaluated by MTT assay. The effect of DKC-E70 on the expression of cyclin D1 in the protein and mRNA level was evaluated by Western blot and RT-PCR, respectively. DKC-E70 suppressed the proliferation of human colorectal cancer cell lines such as HCT116, SW480, LoVo and HT-29. Although DKC-E70 decreased cyclin D1 expression in protein and mRNA level, decreased level of cyclin D1 protein by DKC-E70 occurred at the earlier time than that of cyclin D1 mRNA, which indicates that DKC-E70-mediated downregulation of cyclin D1 protein may be a consequence of the induction of degradation and transcriptional inhibition of cyclin D1. In cyclin D1 degradation, we found that cyclin D1 downregulation by DKC-E70 was attenuated in presence of MG132. In addition, DKC-E70 phosphorylated threonine-286 (T286) of cyclin D1 and T286A abolished cyclin D1 downregulation by DKC-E70. We also observed that DKC-E70-mediated T286 phosphorylation and subsequent cyclin D1 degradation was blocked in presence of the inhibitors of ERK1/2, p38 or GSK3β. In cyclin D1 transcriptional inhibition, DKC-E70 inhibited the expression of β-catenin and TCF4, and β-catenin/TCF-dependent luciferase activity. Our results suggest that DKC-E70 may downregulate cyclin D1 as one of the potential anti-cancer targets through cyclin D1 degradation by T286 phosphorylation dependent on ERK1/2, p38 or GSK3β, and cyclin D1 transcriptional inhibition through Wnt signaling. From these findings, DKC-E70 has potential to be a candidate for the development of chemoprevention or therapeutic agents for human colorectal cancer.

  17. Down-regulation of cellular FLICE-inhibitory protein (Long Form contributes to apoptosis induced by Hsp90 inhibition in human lung cancer cells

    Directory of Open Access Journals (Sweden)

    Wang Qilin

    2012-12-01

    Full Text Available Abstract Background Cellular FLICE-Inhibitory Protein (long form, c-FLIPL is a critical negative regulator of death receptor-mediated apoptosis. Overexpression of c-FLIPL has been reported in many cancer cell lines and is associated with chemoresistance. In contrast, down-regulation of c-FLIP may drive cancer cells into cellular apoptosis. This study aims to demonstrate that inhibition of the heat shock protein 90 (Hsp90 either by inhibitors geldanamycin/17-N-Allylamino-17-demethoxygeldanamycin (GA/17-AAG or siRNA technique in human lung cancer cells induces c-FLIPL degradation and cellular apoptosis through C-terminus of Hsp70-interacting protein (CHIP-mediated mechanisms. Methods Calu-1 and H157 cell lines (including H157-c-FLIPL overexpressing c-FLIPL and control cell H157-lacZ were treated with 17-AAG and the cell lysates were prepared to detect the given proteins by Western Blot and the cell survival was assayed by SRB assay. CHIP and Hsp90 α/β proteins were knocked down by siRNA technique. CHIP and c-FLIPL plasmids were transfected into cells and immunoprecipitation experiments were performed to testify the interactions between c-FLIPL, CHIP and Hsp90. Results c-FLIPL down-regulation induced by 17-AAG can be reversed with the proteasome inhibitor MG132, which suggested that c-FLIPL degradation is mediated by a ubiquitin-proteasome system. Inhibition of Hsp90α/β reduced c-FLIPL level, whereas knocking down CHIP expression with siRNA technique inhibited c-FLIPL degradation. Furthermore, c-FLIPL and CHIP were co-precipitated in the IP complexes. In addition, overexpression of c-FLIPL can rescue cancer cells from apoptosis. When 17-AAG was combined with an anti-cancer agent celecoxib(CCB, c-FLIPL level declined further and there was a higher degree of caspase activation. Conclusion We have elucidated c-FLIPL degradation contributes to apoptosis induced by Hsp90 inhibition, suggesting c-FLIP and Hsp90 may be the promising combined targets

  18. Enzyme inhibition by iminosugars

    DEFF Research Database (Denmark)

    López, Óscar; Qing, Feng-Ling; Pedersen, Christian Marcus

    2013-01-01

    Imino- and azasugar glycosidase inhibitors display pH dependant inhibition reflecting that both the inhibitor and the enzyme active site have groups that change protonation state with pH. With the enzyme having two acidic groups and the inhibitor one basic group, enzyme-inhibitor complexes...

  19. Quorum sensing inhibition

    DEFF Research Database (Denmark)

    Persson, T.; Givskov, Michael Christian; Nielsen, J.

    2005-01-01

    /receptor transcriptional regulator in some clinically relevant Gram-negative bacteria. The present review contains all reported compound types that are currently known to inhibit the QS transcriptional regulator in Gram-negative bacteria. These compounds are sub-divided into two main groups, one comprising structural...

  20. Cooperation for Better Inhibiting.

    Science.gov (United States)

    Novoa, Eva Maria; Ribas de Pouplana, Lluís

    2015-06-18

    Cladosporin is an antimalarial drug that acts as an ATP-mimetic to selectively inhibit Plasmodium lysyl-tRNA synthetase. Using multiple crystal structures, Fang et al. (2015) reveal in this issue of Chemistry & Biology the fascinating mechanism responsible for cladosporin selectivity. Copyright © 2015 Elsevier Ltd. All rights reserved.

  1. Inhibition of ethylene production by putrescine alleviates aluminium-induced root inhibition in wheat plants.

    Science.gov (United States)

    Yu, Yan; Jin, Chongwei; Sun, Chengliang; Wang, Jinghong; Ye, Yiquan; Zhou, Weiwei; Lu, Lingli; Lin, Xianyong

    2016-01-08

    Inhibition of root elongation is one of the most distinct symptoms of aluminium (Al) toxicity. Although putrescine (Put) has been identified as an important signaling molecule involved in Al tolerance, it is yet unknown how Put mitigates Al-induced root inhibition. Here, the possible mechanism was investigated by using two wheat genotypes differing in Al resistance: Al-tolerant Xi Aimai-1 and Al-sensitive Yangmai-5. Aluminium caused more root inhibition in Yangmai-5 and increased ethylene production at the root apices compared to Xi Aimai-1, whereas the effects were significantly reversed by ethylene biosynthesis inhibitors. The simultaneous exposure of wheat seedlings to Al and ethylene donor, ethephon, or ethylene biosynthesis precursor, 1-aminocyclopropane-1-carboxylic acid (ACC), increased ethylene production and aggravated root inhibition, which was more pronounced in Xi Aimai-1. In contrast, Put treatment decreased ethylene production and alleviated Al-induced root inhibition in both genotypes, and the effects were more conspicuous in Yangmai-5. Furthermore, our results indicated that Al-induced ethylene production was mediated by ACC synthase (ACS) and ACC oxidase, and that Put decreased ethylene production by inhibiting ACS. Altogether, these findings indicate that ethylene is involved in Al-induced root inhibition and this process could be alleviated by Put through inhibiting ACS activity.

  2. Plastics for corrosion inhibition

    CERN Document Server

    Goldade, Victor A; Makarevich, Anna V; Kestelman, Vladimir N

    2005-01-01

    The development of polymer composites containing inhibitors of metal corrosion is an important endeavour in modern materials science and technology. Corrosion inhibitors can be located in a polymer matrix in the solid, liquid or gaseous phase. This book details the thermodynamic principles for selecting these components, their compatibility and their effectiveness. The various mechanisms of metal protection – barrier, inhibiting and electromechanical – are considered, as are the conflicting requirements placed on the structure of the combined material. Two main classes of inhibited materials (structural and films/coatings) are described in detail. Examples are given of structural plastics used in friction units subjected to mechano-chemical wear and of polymer films/coatings for protecting metal objects against corrosion.

  3. Inhibiting the inevitable

    DEFF Research Database (Denmark)

    Shashoua, Yvonne

    2006-01-01

    conservation is to ‘buy time’ for the object. Inhibitive conservation of plastics involves the removal or reduction of factors causing or accelerating degradation including light, oxygen, acids, relative humidity and acidic breakdown products. Specific approaches to conservation have been developed......Once plastics objects are registered in museum collections, the institution becomes responsible for their long term preservation, until the end of their useful lifetime. Plastics appear to deteriorate faster than other materials in museum collections and have a useful lifetime between 5 and 25...... years. Preventive or inhibitive conservation involves controlling the environments in which objects are placed during storage and display, with the aim of slowing the major deterioration reactions. Once in progress, degradation of plastics cannot be stopped or reversed, so the aim of preventive...

  4. Historical Significant Volcanic Eruption Locations

    Data.gov (United States)

    Department of Homeland Security — A significant eruption is classified as one that meets at least one of the following criteriacaused fatalities, caused moderate damage (approximately $1 million or...

  5. Transcriptional upregulation of BAG3 upon proteasome inhibition

    International Nuclear Information System (INIS)

    Wang Huaqin; Liu Haimei; Zhang Haiyan; Guan Yifu; Du Zhenxian

    2008-01-01

    Proteasome inhibitors exhibit antitumoral activity against malignancies of different histology. Emerging evidence indicates that antiapoptotic factors may also accumulate as a consequence of exposure to these drugs, thus it seems plausible that activation of survival signaling cascades might compromise their antitumoral effects. Bcl-2-associated athanogene (BAG) family proteins are characterized by their property of interaction with a variety of partners involved in modulating the proliferation/death balance, including heat shock proteins (HSP), Bcl-2, Raf-1. In this report, we demonstrated that BAG3 is a novel antiapoptotic molecule induced by proteasome inhibitors in various cancer cells at the transcriptional level. Moreover, we demonstrated that BAG3 knockdown by siRNA sensitized cancer cells to MG132-induced apoptosis. Taken together, our results suggest that BAG3 induction might represents as an unwanted molecular consequence of utilizing proteasome inhibitors to combat tumors

  6. Action inhibition in Tourette syndrome.

    Science.gov (United States)

    Ganos, Christos; Kühn, Simone; Kahl, Ursula; Schunke, Odette; Feldheim, Jan; Gerloff, Christian; Roessner, Veit; Bäumer, Tobias; Thomalla, Götz; Haggard, Patrick; Münchau, Alexander

    2014-10-01

    Tourette syndrome is a neuropsychiatric disorder characterized by tics. Tic generation is often linked to dysfunction of inhibitory brain networks. Some previous behavioral studies found deficiencies in inhibitory motor control in Tourette syndrome, but others suggested normal or even better-than-normal performance. Furthermore, neural correlates of action inhibition in these patients are poorly understood. We performed event-related functional magnetic resonance imaging during a stop-signal reaction-time task in 14 uncomplicated adult Tourette patients and 15 healthy controls. In patients, we correlated activations in stop-signal reaction-time task with their individual motor tic frequency. Task performance was similar in both groups. Activation of dorsal premotor cortex was stronger in the StopSuccess than in the Go condition in healthy controls. This pattern was reversed in Tourette patients. A significant positive correlation was present between motor tic frequency and activations in the supplementary motor area during StopSuccess versus Go in patients. Inhibitory brain networks differ between healthy controls and Tourette patients. In the latter the supplementary motor area is probably a key relay of inhibitory processes mediating both suppression of tics and inhibition of voluntary action. © 2014 International Parkinson and Movement Disorder Society.

  7. Significance evaluation in factor graphs

    DEFF Research Database (Denmark)

    Madsen, Tobias; Hobolth, Asger; Jensen, Jens Ledet

    2017-01-01

    in genomics and the multiple-testing issues accompanying them, accurate significance evaluation is of great importance. We here address the problem of evaluating statistical significance of observations from factor graph models. Results Two novel numerical approximations for evaluation of statistical...... significance are presented. First a method using importance sampling. Second a saddlepoint approximation based method. We develop algorithms to efficiently compute the approximations and compare them to naive sampling and the normal approximation. The individual merits of the methods are analysed both from....... Conclusions The applicability of saddlepoint approximation and importance sampling is demonstrated on known models in the factor graph framework. Using the two methods we can substantially improve computational cost without compromising accuracy. This contribution allows analyses of large datasets...

  8. Significant Lactic Acidosis from Albuterol

    Directory of Open Access Journals (Sweden)

    Deborah Diercks

    2018-03-01

    Full Text Available Lactic acidosis is a clinical entity that demands rapid assessment and treatment to prevent significant morbidity and mortality. With increased lactate use across many clinical scenarios, lactate values themselves cannot be interpreted apart from their appropriate clinical picture. The significance of Type B lactic acidosis is likely understated in the emergency department (ED. Given the mortality that sepsis confers, a serum lactate is an important screening study. That said, it is with extreme caution that we should interpret and react to the resultant elevated value. We report a patient with a significant lactic acidosis. Though he had a high lactate value, he did not require aggressive resuscitation. A different classification scheme for lactic acidosis that focuses on the bifurcation of the “dangerous” and “not dangerous” causes of lactic acidosis may be of benefit. In addition, this case is demonstrative of the potential overuse of lactates in the ED.

  9. The historical significance of oak

    Science.gov (United States)

    J. V. Thirgood

    1971-01-01

    A brief history of the importance of oak in Europe, contrasting the methods used in France and Britain to propagate the species and manage the forests for continued productivity. The significance of oak as a strategic resource during the sailing-ship era is stressed, and mention is made of the early development of oak management in North America. The international...

  10. Significance of inhibited development in the epidemiology of Chabertia ovina and Oesophagostomum venulosum

    NARCIS (Netherlands)

    Eysker, M.

    Worm counts from ewes, lambs and tracer lambs during a study on the epidemiology of gastro-intestinal nematode infections in sheep at Utrecht State University between 1974 and 1977 substantiated the following descriptions of the epidemiology of Chabertia ovina and Oesophagostomum venulosum

  11. Biochemical Effects of Cadmium Exposure and the Potential Pharmacologic Significance of Cadmium Mediated Hydrolase Inhibition

    Science.gov (United States)

    1997-04-18

    DNA polymerase Alcohol dehydrogenase Hexokinase Glucose-6- phosphatase Arginase Pyruvate kinase (also requires Mg2•) Urease Nitrate...cyclohexane. The layers are separated by centrifugation (5 min at 1000 x g), the top organic layer is removed and dried with anhydrous sodium sulfate...An aliquot of the dried organic layer is transferred to a clean tube and evaporated under a gentle stream of nitrogen at room temperature

  12. Genetic or chemical protease inhibition causes significant changes in the Bacillus subtilis exoproteome

    NARCIS (Netherlands)

    Westers, Lidia; Westers, Helga; Zanen, Geeske; Antelmann, Haike; Hecker, Michael; Noone, David; Devine, Kevin M.; van Dijl, Jan Maarten; Quax, Wim J.

    Bacillus subtilis is a prolific producer of enzymes and biopharmaceuticals. However, the susceptibility of heterologous proteins to degradation by (extracellular) proteases is a major limitation for use of B. subtilis as a protein cell factory. An increase in protein production levels has previously

  13. Inhibition of GABA transporters fails to afford significant protection following focal cerebral ischemia

    DEFF Research Database (Denmark)

    Lie, Maria Ek; Gowing, Emma K; Clausen, Rasmus P

    2017-01-01

    Brain ischemia triggers excitotoxicity and cell death, yet no neuroprotective drugs have made it to the clinic. While enhancing GABAergic signaling to counterbalance excitotoxicity has shown promise in animal models, clinical studies have failed. Blockade of GABA transporters (GATs) offers...... show that tiagabine can promote protection, our findings indicate that caution should be had when using GAT1 and GAT3 inhibitors for conditions of brain ischemia....

  14. Progression of pancreatic adenocarcinoma is significantly impeded with a combination of vaccine and COX-2 inhibition.

    Science.gov (United States)

    Mukherjee, Pinku; Basu, Gargi D; Tinder, Teresa L; Subramani, Durai B; Bradley, Judy M; Arefayene, Million; Skaar, Todd; De Petris, Giovanni

    2009-01-01

    With a 5-year survival rate of <5%, pancreatic cancer is one of the most rapidly fatal malignancies. Current protocols for the treatment of pancreas cancer are not as effective as we desire. In this study, we show that a novel Mucin-1 (MUC1)-based vaccine in combination with a cyclooxygenase-2 inhibitor (celecoxib), and low-dose chemotherapy (gemcitabine) was effective in preventing the progression of preneoplastic intraepithelial lesions to invasive pancreatic ductal adenocarcinomas. The study was conducted in an appropriate triple transgenic model of spontaneous pancreatic cancer induced by the KRAS(G12D) mutation and that expresses human MUC1 as a self molecule. The combination treatment elicited robust antitumor cellular and humoral immune responses and was associated with increased apoptosis in the tumor. The mechanism for the increased immune response was attributed to the down-regulation of circulating prostaglandin E(2) and indoleamine 2, 3,-dioxygenase enzymatic activity, as well as decreased levels of T regulatory and myeloid suppressor cells within the tumor microenvironment. The preclinical data provide the rationale to design clinical trials with a combination of MUC1-based vaccine, celecoxib, and gemcitabine for the treatment of pancreatic cancer.

  15. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1994-03-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (October - December 1993) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  16. Synthetic definition of biological significance

    International Nuclear Information System (INIS)

    Buffington, J.D.

    1975-01-01

    The central theme of the workshop is recounted and the views of the authors are summarized. Areas of broad agreement or disagreement, unifying principles, and research needs are identified. Authors' views are consolidated into concepts that have practical utility for the scientist making impact assessments. The need for decision-makers and managers to be cognizant of the recommendations made herein is discussed. Finally, bringing together the diverse views of the workshop participants, a conceptual definition of biological significance is synthesized

  17. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1992-11-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (July - September 1992) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  18. Simvastatin inhibits Candida albicans biofilm in vitro.

    Science.gov (United States)

    Liu, Geoffrey; Vellucci, Vincent F; Kyc, Stephanie; Hostetter, Margaret K

    2009-12-01

    By inhibiting the conversion of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) to mevalonate, statins impair cholesterol metabolism in humans. We reasoned that statins might similarly interfere with the biosynthesis of ergosterol, the major sterol of the yeast cell membrane. As assessed by spectrophotometric and microscopic analysis, significant inhibition of biofilm production was noted after 16-h incubation with 1, 2.5, and 5 muM simvastatin, concentrations that did not affect growth, adhesion, or hyphal formation by C. albicans in vitro. Higher concentrations (10, 20, and 25 muM simvastatin) inhibited biofilm by >90% but also impaired growth. Addition of exogenous ergosterol (90 muM) overcame the effects of 1 and 2.5 muM simvastatin, suggesting that at least one mechanism of inhibition is interference with ergosterol biosynthesis. Clinical isolates from blood, skin, and mucosal surfaces produced biofilms; biofilms from bloodstream isolates were similarly inhibited by simvastatin. In the absence of fungicidal activity, simvastatin's interruption of a critical step in an essential metabolic pathway, highly conserved from yeast to man, has unexpected effects on biofilm production by a eukaryotic pathogen.

  19. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1993-09-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (April--June 1993) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  20. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1990-05-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (January--March 1990) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. Also included are a number of enforcement actions that had been previously resolved but not published in this NUREG. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  1. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1991-05-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (January--March 1991) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  2. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1991-02-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (October--December 1990) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  3. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1990-03-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (October--December 1989) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  4. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1990-11-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (July--September 1990) and includes copies of letters, notices, and orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  5. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1992-08-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (April--June 1992) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  6. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1990-09-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (April--June 1990) and includes copies of letters, notices, and orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  7. Clinical significance of neonatal menstruation.

    Science.gov (United States)

    Brosens, Ivo; Benagiano, Giuseppe

    2016-01-01

    Past studies have clearly shown the existence of a spectrum of endometrial progesterone responses in neonatal endometrium, varying from proliferation to full decidualization with menstrual-like shedding. The bleedings represent, similar to what occurs in adult menstruation, a progesterone withdrawal bleeding. Today, the bleeding is completely neglected and considered an uneventful episode of no clinical significance. Yet clinical studies have linked the risk of bleeding to a series of events indicating fetal distress. The potential link between the progesterone response and major adolescent disorders requires to be investigated by prospective studies. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  8. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1993-06-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (January--March 1993) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  9. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1992-05-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (January--March 1992) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  10. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1993-12-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (July--September 1993) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  11. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1993-03-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (October--December 1992) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  12. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1991-07-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (April-June 1991) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  13. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1991-11-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (July--September 1991) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  14. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1992-03-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (October--December 1991) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  15. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1989-06-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (January--March 1989) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. Also included are a number of enforcement actions that had been previously resolved but not published in this NUREG. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  16. Enforcement actions: Significant actions resolved

    International Nuclear Information System (INIS)

    1989-12-01

    This compilation summarizes significant enforcement actions that have been resolved during one quarterly period (July--September 1989) and includes copies of letters, Notices, and Orders sent by the Nuclear Regulatory Commission to licensees with respect to these enforcement actions. It is anticipated that the information in this publication will be widely disseminated to managers and employees engaged in activities licensed by the NRC, so that actions can be taken to improve safety by avoiding future violations similar to those described in this publication

  17. Moral significance of phenomenal consciousness.

    Science.gov (United States)

    Levy, Neil; Savulescu, Julian

    2009-01-01

    Recent work in neuroimaging suggests that some patients diagnosed as being in the persistent vegetative state are actually conscious. In this paper, we critically examine this new evidence. We argue that though it remains open to alternative interpretations, it strongly suggests the presence of consciousness in some patients. However, we argue that its ethical significance is less than many people seem to think. There are several different kinds of consciousness, and though all kinds of consciousness have some ethical significance, different kinds underwrite different kinds of moral value. Demonstrating that patients have phenomenal consciousness--conscious states with some kind of qualitative feel to them--shows that they are moral patients, whose welfare must be taken into consideration. But only if they are subjects of a sophisticated kind of access consciousness--where access consciousness entails global availability of information to cognitive systems--are they persons, in the technical sense of the word employed by philosophers. In this sense, being a person is having the full moral status of ordinary human beings. We call for further research which might settle whether patients who manifest signs of consciousness possess the sophisticated kind of access consciousness required for personhood.

  18. Clinical significance of the fabella

    International Nuclear Information System (INIS)

    Dodevski, A.; Lazarova-Tosovska, D.; Zhivadinovik, J.; Lazareska, M.

    2012-01-01

    Full text: Introduction: There is variable number of sesamoid bones in the human body; one of them is fabella, located in the tendon of the gastrocnemius muscle. Aim of this study was to investigate the frequency of occurrence of fabella in the Macedonian population and to discuss about clinical importance of this bone. Materials and methods: We retrospectively examined radiographs of 53 patients who had knee exams undertaken for a variety of clinical reasons, performed as a part of their medical treatment. Over a time span of six months, 53 patients (38 males and 15 females, age range 19-60 years, mean age of 36.7±12.3 years) were examined. Results: In seven (13.2%) patients of 53 analyzed reports, fabella was found in the lateral tendon of gastrocnemius muscle. We did not find a significant gender or side difference in the appearance of fabella. Conclusion: Although anatomic studies emphasized a lack of significance of the fabella, this bone has been associated with a spectrum of pathology affecting the knee as fabellar syndrome, perineal nerve injury and fracture. We should think of this sesamoid bone while performing diagnostic and surgical procedures

  19. The significance of small streams

    Science.gov (United States)

    Wohl, Ellen

    2017-09-01

    Headwaters, defined here as first- and secondorder streams, make up 70%‒80% of the total channel length of river networks. These small streams exert a critical influence on downstream portions of the river network by: retaining or transmitting sediment and nutrients; providing habitat and refuge for diverse aquatic and riparian organisms; creating migration corridors; and governing connectivity at the watershed-scale. The upstream-most extent of the channel network and the longitudinal continuity and lateral extent of headwaters can be difficult to delineate, however, and people are less likely to recognize the importance of headwaters relative to other portions of a river network. Consequently, headwaters commonly lack the legal protections accorded to other portions of a river network and are more likely to be significantly altered or completely obliterated by land use.

  20. No significant fuel failures (NSFF)

    International Nuclear Information System (INIS)

    Domaratzki, Z.

    1979-01-01

    It has long been recognized that no emergency core cooling system (ECCS) could be absolutely guaranteed to prevent fuel failures. In 1976 the Atomic Energy Control Board decided that the objective for an ECCS should be to prevent fuel failures, but if the objective could not be met it should be shown that the consequences are acceptable for dual failures comprising any LOCA combined with an assumed impairment of containment. Out of the review of the Bruce A plant came the definition of 'no significant fuel failures': for any postulated LOCA combined with any one mode of containment impairment the resultant dose to a person at the edge of the exclusion zone is less than the reference dose limits for dual failures

  1. Ritual Significance in Mycenaean Hairstyles

    Directory of Open Access Journals (Sweden)

    Hsu, Florence Sheng-chieh

    2012-04-01

    Full Text Available Although the frescoes excavated from Bronze Age sites on the Greek mainland provide evidence for female figures in the Mycenaean society, the hairstyles of these figures have not been studied in detail. As in many other ancient cultures, hairstyles were not only an exhibition of beauty and fashion, but they also represented certain age groups or a person’s social status. The Mycenaeans inherited many of their hairstyles from their Minoan predecessors, although differences existed as well. It is also possible there may have been a shift in meaning for seemingly similar looking hairstyles from the Minoan to the Mycenaean periods. Female figures, which compose most of the Mycenaean figures in frescoes known to date, are fine examples for discussing the artistic representation and potential significance of Mycenaean hairstyles. By comparing with Minoan hairstyles, discussions of Mycenaean examples lead to conclusions in the relationship between hairstyles and ritual activities in the Mycenaean society.

  2. The energetic significance of cooking.

    Science.gov (United States)

    Carmody, Rachel N; Wrangham, Richard W

    2009-10-01

    While cooking has long been argued to improve the diet, the nature of the improvement has not been well defined. As a result, the evolutionary significance of cooking has variously been proposed as being substantial or relatively trivial. In this paper, we evaluate the hypothesis that an important and consistent effect of cooking food is a rise in its net energy value. The pathways by which cooking influences net energy value differ for starch, protein, and lipid, and we therefore consider plant and animal foods separately. Evidence of compromised physiological performance among individuals on raw diets supports the hypothesis that cooked diets tend to provide energy. Mechanisms contributing to energy being gained from cooking include increased digestibility of starch and protein, reduced costs of digestion for cooked versus raw meat, and reduced energetic costs of detoxification and defence against pathogens. If cooking consistently improves the energetic value of foods through such mechanisms, its evolutionary impact depends partly on the relative energetic benefits of non-thermal processing methods used prior to cooking. We suggest that if non-thermal processing methods such as pounding were used by Lower Palaeolithic Homo, they likely provided an important increase in energy gain over unprocessed raw diets. However, cooking has critical effects not easily achievable by non-thermal processing, including the relatively complete gelatinisation of starch, efficient denaturing of proteins, and killing of food borne pathogens. This means that however sophisticated the non-thermal processing methods were, cooking would have conferred incremental energetic benefits. While much remains to be discovered, we conclude that the adoption of cooking would have led to an important rise in energy availability. For this reason, we predict that cooking had substantial evolutionary significance.

  3. Anxiety and retrieval inhibition: support for an enhanced inhibition account.

    Science.gov (United States)

    Nuñez, Mia; Gregory, Josh; Zinbarg, Richard E

    2017-02-01

    Retrieval inhibition of negative associations is important for exposure therapy for anxiety, but the relationship between memory inhibition and anxiety is not well understood-anxiety could either be associated with enhanced or deficient inhibition. The present study tested these two competing hypotheses by measuring retrieval inhibition of negative stimuli by related neutral stimuli. Non-clinically anxious undergraduates completed measures of trait and state anxiety and completed a retrieval induced forgetting task. Adaptive forgetting varied with state anxiety. Low levels of state anxiety were associated with no evidence for retrieval inhibition for either threatening or non-threatening categories. Participants in the middle tertile of state anxiety scores exhibited retrieval inhibition for non-threatening categories but not for threatening categories. Participants in the highest tertile of state anxiety, however, exhibited retrieval inhibition for both threatening and non-threatening categories with the magnitude of retrieval inhibition being greater for threatening than non-threatening categories. The data are in line with the avoidance aspect of the vigilance-avoidance theory of anxiety and inhibition. Implications for cognitive behavioural therapy practices are discussed.

  4. Significant biases affecting abundance determinations

    Science.gov (United States)

    Wesson, Roger

    2015-08-01

    I have developed two highly efficient codes to automate analyses of emission line nebulae. The tools place particular emphasis on the propagation of uncertainties. The first tool, ALFA, uses a genetic algorithm to rapidly optimise the parameters of gaussian fits to line profiles. It can fit emission line spectra of arbitrary resolution, wavelength range and depth, with no user input at all. It is well suited to highly multiplexed spectroscopy such as that now being carried out with instruments such as MUSE at the VLT. The second tool, NEAT, carries out a full analysis of emission line fluxes, robustly propagating uncertainties using a Monte Carlo technique.Using these tools, I have found that considerable biases can be introduced into abundance determinations if the uncertainty distribution of emission lines is not well characterised. For weak lines, normally distributed uncertainties are generally assumed, though it is incorrect to do so, and significant biases can result. I discuss observational evidence of these biases. The two new codes contain routines to correctly characterise the probability distributions, giving more reliable results in analyses of emission line nebulae.

  5. Astrobiological significance of chemolithoautotrophic acidophiles

    Science.gov (United States)

    Pikuta, Elena V.; Hoover, Richard B.

    2004-02-01

    For more than a century (since Winogradsky discovered lithautotrophic bacteria) there has been a dilemma in microbiology about life that first inhabited the Earth. Which types of life forms first appeared in the primordial oceans during the earliest geological period on Earth as the primary ancestors of modern biological diversity? How did a metabolism of ancestors evolve: from lithoautotrophic to lithoheterotrophic and organoheterotrophic or from organoheterotrophic to organautotrophic and lithomixotrophic types? At the present time, it is known that chemolithoheterotrophic and chemolithoautotrophic metabolizing bacteria are wide spread in different ecosystems. On Earth the acidic ecosystems are associated with geysers, volcanic fumaroles, hot springs, deep sea hydrothermal vents, caves, acid mine drainage and other technogenic ecosystems. Bioleaching played a significant roel on a global geological scale during the Earth's formation. This important feature of bacteria has been successfully applied in industry. The lithoautotrophs include Bacteria and Archaea belonging to diverse genera containing thermophilic and mesophilic species. In this paper we discuss the lithotrophic microbial acidophiles and present some data with a description of new acidophilic iron- and sulfur-oxidizing bacterium isolated from the Chena Hot Springs in Alaska. We also consider the possible relevance of microbial acidophiles to Venus, Io, and acidic inclusions in glaciers and icy moons.

  6. Determining Semantically Related Significant Genes.

    Science.gov (United States)

    Taha, Kamal

    2014-01-01

    GO relation embodies some aspects of existence dependency. If GO term xis existence-dependent on GO term y, the presence of y implies the presence of x. Therefore, the genes annotated with the function of the GO term y are usually functionally and semantically related to the genes annotated with the function of the GO term x. A large number of gene set enrichment analysis methods have been developed in recent years for analyzing gene sets enrichment. However, most of these methods overlook the structural dependencies between GO terms in GO graph by not considering the concept of existence dependency. We propose in this paper a biological search engine called RSGSearch that identifies enriched sets of genes annotated with different functions using the concept of existence dependency. We observe that GO term xcannot be existence-dependent on GO term y, if x- and y- have the same specificity (biological characteristics). After encoding into a numeric format the contributions of GO terms annotating target genes to the semantics of their lowest common ancestors (LCAs), RSGSearch uses microarray experiment to identify the most significant LCA that annotates the result genes. We evaluated RSGSearch experimentally and compared it with five gene set enrichment systems. Results showed marked improvement.

  7. Statistically significant relational data mining :

    Energy Technology Data Exchange (ETDEWEB)

    Berry, Jonathan W.; Leung, Vitus Joseph; Phillips, Cynthia Ann; Pinar, Ali; Robinson, David Gerald; Berger-Wolf, Tanya; Bhowmick, Sanjukta; Casleton, Emily; Kaiser, Mark; Nordman, Daniel J.; Wilson, Alyson G.

    2014-02-01

    This report summarizes the work performed under the project (3z(BStatitically significant relational data mining.(3y (BThe goal of the project was to add more statistical rigor to the fairly ad hoc area of data mining on graphs. Our goal was to develop better algorithms and better ways to evaluate algorithm quality. We concetrated on algorithms for community detection, approximate pattern matching, and graph similarity measures. Approximate pattern matching involves finding an instance of a relatively small pattern, expressed with tolerance, in a large graph of data observed with uncertainty. This report gathers the abstracts and references for the eight refereed publications that have appeared as part of this work. We then archive three pieces of research that have not yet been published. The first is theoretical and experimental evidence that a popular statistical measure for comparison of community assignments favors over-resolved communities over approximations to a ground truth. The second are statistically motivated methods for measuring the quality of an approximate match of a small pattern in a large graph. The third is a new probabilistic random graph model. Statisticians favor these models for graph analysis. The new local structure graph model overcomes some of the issues with popular models such as exponential random graph models and latent variable models.

  8. Statistical Significance for Hierarchical Clustering

    Science.gov (United States)

    Kimes, Patrick K.; Liu, Yufeng; Hayes, D. Neil; Marron, J. S.

    2017-01-01

    Summary Cluster analysis has proved to be an invaluable tool for the exploratory and unsupervised analysis of high dimensional datasets. Among methods for clustering, hierarchical approaches have enjoyed substantial popularity in genomics and other fields for their ability to simultaneously uncover multiple layers of clustering structure. A critical and challenging question in cluster analysis is whether the identified clusters represent important underlying structure or are artifacts of natural sampling variation. Few approaches have been proposed for addressing this problem in the context of hierarchical clustering, for which the problem is further complicated by the natural tree structure of the partition, and the multiplicity of tests required to parse the layers of nested clusters. In this paper, we propose a Monte Carlo based approach for testing statistical significance in hierarchical clustering which addresses these issues. The approach is implemented as a sequential testing procedure guaranteeing control of the family-wise error rate. Theoretical justification is provided for our approach, and its power to detect true clustering structure is illustrated through several simulation studies and applications to two cancer gene expression datasets. PMID:28099990

  9. Inhibitors of the proteasome reduce the accelerated proteolysis in atrophying rat skeletal muscles.

    OpenAIRE

    Tawa, N E; Odessey, R; Goldberg, A L

    1997-01-01

    Several observations have suggested that the enhanced proteolysis and atrophy of skeletal muscle in various pathological states is due primarily to activation of the ubiquitin-proteasome pathway. To test this idea, we investigated whether peptide aldehyde inhibitors of the proteasome, N-acetyl-leucyl-leucyl-norleucinal (LLN), or the more potent CBZ-leucyl-leucyl-leucinal (MG132) suppressed proteolysis in incubated rat skeletal muscles. These agents (e.g., MG132 at 10 microM) inhibited nonlyso...

  10. Detection of significant protein coevolution.

    Science.gov (United States)

    Ochoa, David; Juan, David; Valencia, Alfonso; Pazos, Florencio

    2015-07-01

    The evolution of proteins cannot be fully understood without taking into account the coevolutionary linkages entangling them. From a practical point of view, coevolution between protein families has been used as a way of detecting protein interactions and functional relationships from genomic information. The most common approach to inferring protein coevolution involves the quantification of phylogenetic tree similarity using a family of methodologies termed mirrortree. In spite of their success, a fundamental problem of these approaches is the lack of an adequate statistical framework to assess the significance of a given coevolutionary score (tree similarity). As a consequence, a number of ad hoc filters and arbitrary thresholds are required in an attempt to obtain a final set of confident coevolutionary signals. In this work, we developed a method for associating confidence estimators (P values) to the tree-similarity scores, using a null model specifically designed for the tree comparison problem. We show how this approach largely improves the quality and coverage (number of pairs that can be evaluated) of the detected coevolution in all the stages of the mirrortree workflow, independently of the starting genomic information. This not only leads to a better understanding of protein coevolution and its biological implications, but also to obtain a highly reliable and comprehensive network of predicted interactions, as well as information on the substructure of macromolecular complexes using only genomic information. The software and datasets used in this work are freely available at: http://csbg.cnb.csic.es/pMT/. pazos@cnb.csic.es Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  11. Inhibition of polyphenoloxidase by sulfite

    International Nuclear Information System (INIS)

    Sayavedra-Soto, L.A.; Montgomery, M.W.

    1986-01-01

    When polyphenoloxidase (PPO) was exposed to sulfite prior to substrate addition, inhibition was irreversible. Trials to regenerate PPO activity, using extensive dialysis, column chromatography, and addition of copper salts were not successful. Increased concentrations of sulfite and pH levels less than 5 enhanced the inhibition of PPO by sulfite. At pH 4, concentrations greater than 0.04 mg/mL completely inhibited 1000 units of PPO activity almost instantaneously. This suggested that the HSO 3 - molecule was the main component in the sulfite system inhibiting PPO. Column chromatography, extensive dialysis, and gel electrophoresis did not demonstrate 35 SO 2 bound to purified pear PPO protein. Formation of extra protein bands of sulfite inhibited purified pear PPO fractions on gel electrophoresis was demonstrated. This and other evidence suggested that the major mode of direct irreversible inhibition of PPO was modification of the protein structure, with retention of its molecular unity

  12. Reactor design for minimizing product inhibition during enzymatic lignocellulose hydrolysis II. Quantification of inhibition and suitability of membrane reactors

    DEFF Research Database (Denmark)

    Andric, Pavle; Meyer, Anne S.; Jensen, Peter Arendt

    2010-01-01

    conversion are required for alleviation of glucose product inhibition. Supported by numerous calculations this review assesses the quantitative aspects of glucose product inhibition on enzyme-catalyzed cellulose degradation rates. The significance of glucose product inhibition on dimensioning of different......Product inhibition of cellulolytic enzymes affects the efficiency of the biocatalytic conversion of lignocellulosic biomass to ethanol and other valuable products. New strategies that focus on reactor designs encompassing product removal, notably glucose removal, during enzymatic cellulose...... reactor features, including system set-up, dilution rate, glucose output profile, and the problem of cellobiose are examined to illustrate the quantitative significance of the glucose product inhibition and the total glucose concentration on the cellulolytic conversion rate. Comprehensive overviews...

  13. Shoot-supplied ammonium targets the root auxin influx carrier AUX1 and inhibits lateral root emergence in Arabidopsis

    KAUST Repository

    Li, Baohai; Li, Qing; Su, Yanhua; Chen, Hao; Xiong, Liming; Mi, Guohua; Kronzucker, Herbert J.; Shi, Weiming

    2011-01-01

    . In this study, we show that SSA significantly affects lateral root (LR) development. We show that SSA inhibits lateral root primordium (LRP) emergence, but not LRP initiation, resulting in significantly impaired LR number. We show that the inhibition

  14. A speculated cause of respiratory inhibition in infants.

    Science.gov (United States)

    Minowa, Hideki; Arai, Ikuyo; Yasuhara, Hajime; Ebisu, Reiko; Ohgitani, Ayako

    2018-10-01

    In our previous studies, we documented that threatened premature labor and asymmetrical intrauterine growth restriction were risk factors for respiratory inhibition. The goal of this study was to determine the cause of respiratory inhibition by considering perinatal risk factors. We examined 1497 infants with a gestational age of 36 weeks or greater. All infants were monitored using pulse oximetry and examined via cranial sonography. Respiratory inhibition was defined as severe hypoxemia caused by respiratory inhibition immediately after crying or gastroesophageal reflux or as a respiratory pause during feeding. We examined the relationships between respiratory inhibition and perinatal factors and speculated on the cause of respiratory inhibition. The median gestational age, birth weight, Apgar score at 1 min, and Apgar score at 5 min of the subjects were 38.9 weeks, 2930 g, 8.0 points, and 9.0 points, respectively. Respiratory inhibition was observed in 422 infants. Lateral ventricle enlargement and increased echogenicity in the ganglionic eminence were observed in 417 and 516 infants, respectively. Respiratory inhibition was significantly correlated with shorter gestational periods, twin pregnancies, lateral ventricle enlargement, and increased echogenicity in the ganglionic eminence. We speculate that umbilical cord compression is a major cause of respiratory inhibition.

  15. Inhibition of lignin-derived phenolic compounds to cellulase.

    Science.gov (United States)

    Qin, Lei; Li, Wen-Chao; Liu, Li; Zhu, Jia-Qing; Li, Xia; Li, Bing-Zhi; Yuan, Ying-Jin

    2016-01-01

    Lignin-derived phenolic compounds are universal in the hydrolysate of pretreated lignocellulosic biomass. The phenolics reduce the efficiency of enzymatic hydrolysis and increase the cost of ethanol production. We investigated inhibition of phenolics on cellulase during enzymatic hydrolysis using vanillin as one of the typical lignin-derived phenolics and Avicel as cellulose substrate. As vanillin concentration increased from 0 to 10 mg/mL, cellulose conversion after 72-h enzymatic hydrolysis decreased from 53 to 26 %. Enzyme deactivation and precipitation were detected with the vanillin addition. The enzyme concentration and activity consecutively decreased during hydrolysis, but the inhibition degree, expressed as the ratio of the cellulose conversion without vanillin to the conversion with vanillin (A 0 /A), was almost independent on hydrolysis time. Inhibition can be mitigated by increasing cellulose loading or cellulase concentration. The inhibition degree showed linear relationship with the vanillin concentration and exponential relationship with the cellulose loading and the cellulase concentration. The addition of calcium chloride, BSA, and Tween 80 did not release the inhibition of vanillin significantly. pH and temperature for hydrolysis also showed no significant impact on inhibition degree. The presence of hydroxyl group, carbonyl group, and methoxy group in phenolics affected the inhibition degree. Besides phenolics concentration, other factors such as cellulose loading, enzyme concentration, and phenolic structure also affect the inhibition of cellulose conversion. Lignin-blocking agents have little effect on the inhibition effect of soluble phenolics, indicating that the inhibition mechanism of phenolics to enzyme is likely different from insoluble lignin. The inhibition of soluble phenolics can hardly be entirely removed by increasing enzyme concentration or adding blocking proteins due to the dispersity and multiple binding sites of phenolics

  16. Peptide inhibition of human cytomegalovirus infection

    Directory of Open Access Journals (Sweden)

    Morris Cindy A

    2011-02-01

    Full Text Available Abstract Background Human cytomegalovirus (HCMV is the most prevalent congenital viral infection in the United States and Europe causing significant morbidity and mortality to both mother and child. HCMV is also an opportunistic pathogen in immunocompromised individuals, including human immunodeficiency virus (HIV- infected patients with AIDS, and solid organ and allogeneic stem cell transplantation recipients. Current treatments for HCMV-associated diseases are insufficient due to the emergence of drug-induced resistance and cytotoxicity, necessitating novel approaches to limit HCMV infection. The aim of this study was to develop therapeutic peptides targeting glycoprotein B (gB, a major glycoprotein of HCMV that is highly conserved across the Herpesviridae family, that specifically inhibit fusion of the viral envelope with the host cell membrane preventing HCMV entry and infection. Results Using the Wimley-White Interfacial Hydrophobicity Scale (WWIHS, several regions within gB were identified that display a high potential to interact with lipid bilayers of cell membranes and hydrophobic surfaces within proteins. The ability of synthetic peptides analogous to WWIHS-positive sequences of HCMV gB to inhibit viral infectivity was evaluated. Human foreskin fibroblasts (HFF were infected with the Towne-GFP strain of HCMV (0.5 MOI, preincubated with peptides at a range of concentrations (78 nm to 100 μM, and GFP-positive cells were visualized 48 hours post-infection by fluorescence microscopy and analyzed quantitatively by flow cytometry. Peptides that inhibited HCMV infection demonstrated different inhibitory concentration curves indicating that each peptide possesses distinct biophysical properties. Peptide 174-200 showed 80% inhibition of viral infection at a concentration of 100 μM, and 51% and 62% inhibition at concentrations of 5 μM and 2.5 μM, respectively. Peptide 233-263 inhibited infection by 97% and 92% at concentrations of 100

  17. Targeting fibroblast growth factor receptor signaling inhibits prostate cancer progression.

    Science.gov (United States)

    Feng, Shu; Shao, Longjiang; Yu, Wendong; Gavine, Paul; Ittmann, Michael

    2012-07-15

    Extensive correlative studies in human prostate cancer as well as studies in vitro and in mouse models indicate that fibroblast growth factor receptor (FGFR) signaling plays an important role in prostate cancer progression. In this study, we used a probe compound for an FGFR inhibitor, which potently inhibits FGFR-1-3 and significantly inhibits FGFR-4. The purpose of this study is to determine whether targeting FGFR signaling from all four FGFRs will have in vitro activities consistent with inhibition of tumor progression and will inhibit tumor progression in vivo. Effects of AZ8010 on FGFR signaling and invasion were analyzed using immortalized normal prostate epithelial (PNT1a) cells and PNT1a overexpressing FGFR-1 or FGFR-4. The effect of AZ8010 on invasion and proliferation in vitro was also evaluated in prostate cancer cell lines. Finally, the impact of AZ8010 on tumor progression in vivo was evaluated using a VCaP xenograft model. AZ8010 completely inhibits FGFR-1 and significantly inhibits FGFR-4 signaling at 100 nmol/L, which is an achievable in vivo concentration. This results in marked inhibition of extracellular signal-regulated kinase (ERK) phosphorylation and invasion in PNT1a cells expressing FGFR-1 and FGFR-4 and all prostate cancer cell lines tested. Treatment in vivo completely inhibited VCaP tumor growth and significantly inhibited angiogenesis and proliferation and increased cell death in treated tumors. This was associated with marked inhibition of ERK phosphorylation in treated tumors. Targeting FGFR signaling is a promising new approach to treating aggressive prostate cancer.

  18. Modeling intentional inhibition of actions

    NARCIS (Netherlands)

    Thilakarathne, D.J.; Treur, J.

    2015-01-01

    Inspired by cognitive and neurological literature on action ownership and action awareness, in this paper a computational cognitive model for intentional inhibition (i.e.; the capacity to voluntarily suspend or inhibit an action) is introduced. The interplay between (positive) potential selection of

  19. Can Arousal Modulate Response Inhibition?

    Science.gov (United States)

    Weinbach, Noam; Kalanthroff, Eyal; Avnit, Amir; Henik, Avishai

    2015-01-01

    The goal of the present study was to examine if and how arousal can modulate response inhibition. Two competing hypotheses can be drawn from previous literature. One holds that alerting cues that elevate arousal should result in an impulsive response and therefore impair response inhibition. The other suggests that alerting enhances processing of…

  20. Polysulfonate suramin inhibits Zika virus infection.

    Science.gov (United States)

    Tan, Chee Wah; Sam, I-Ching; Chong, Wei Lim; Lee, Vannajan Sanghiran; Chan, Yoke Fun

    2017-07-01

    Zika virus (ZIKV) is an arthropod-borne flavivirus that causes newborn microcephaly and Guillian-Barré syndrome in adults. No therapeutics are available to treat ZIKV infection or other flaviviruses. In this study, we explored the inhibitory effect of glycosaminoglycans and analogues against ZIKV infection. Highly sulfated heparin, dextran sulfate and suramin significantly inhibited ZIKV infection in Vero cells. De-sulfated heparin analogues lose inhibitory effect, implying that sulfonate groups are critical for viral inhibition. Suramin, an FDA-approved anti-parasitic drug, inhibits ZIKV infection with 3-5 log 10  PFU viral reduction with IC 50 value of ∼2.5-5 μg/ml (1.93 μM-3.85 μM). A time-of-drug-addition study revealed that suramin remains potent even when administrated at 1-24 hpi. Suramin inhibits ZIKV infection by preventing viral adsorption, entry and replication. Molecular dynamics simulation revealed stronger interaction of suramin with ZIKV NS3 helicase than with the envelope protein. Suramin warrants further investigation as a potential antiviral candidate for ZIKV infection. Heparan sulfate (HS) is a cellular attachment receptor for multiple flaviviruses. However, no direct ZIKV-heparin interaction was observed in heparin-binding analysis, and downregulate or removal of cellular HS with sodium chlorate or heparinase I/III did not inhibit ZIKV infection. This indicates that cell surface HS is not utilized by ZIKV as an attachment receptor. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Neural Synchrony during Response Production and Inhibition

    Science.gov (United States)

    Müller, Viktor; Anokhin, Andrey P.

    2012-01-01

    Inhibition of irrelevant information (conflict monitoring) and/or of prepotent actions is an essential component of adaptive self-organized behavior. Neural dynamics underlying these functions has been studied in humans using event-related brain potentials (ERPs) elicited in Go/NoGo tasks that require a speeded motor response to the Go stimuli and withholding a prepotent response when a NoGo stimulus is presented. However, averaged ERP waveforms provide only limited information about the neuronal mechanisms underlying stimulus processing, motor preparation, and response production or inhibition. In this study, we examine the cortical representation of conflict monitoring and response inhibition using time-frequency analysis of electroencephalographic (EEG) recordings during continuous performance Go/NoGo task in 50 young adult females. We hypothesized that response inhibition would be associated with a transient boost in both temporal and spatial synchronization of prefrontal cortical activity, consistent with the role of the anterior cingulate and lateral prefrontal cortices in cognitive control. Overall, phase synchronization across trials measured by Phase Locking Index and phase synchronization between electrode sites measured by Phase Coherence were the highest in the Go and NoGo conditions, intermediate in the Warning condition, and the lowest under Neutral condition. The NoGo condition was characterized by significantly higher fronto-central synchronization in the 300–600 ms window, whereas in the Go condition, delta- and theta-band synchronization was higher in centro-parietal regions in the first 300 ms after the stimulus onset. The present findings suggest that response production and inhibition is supported by dynamic functional networks characterized by distinct patterns of temporal and spatial synchronization of brain oscillations. PMID:22745691

  2. Neural synchrony during response production and inhibition.

    Directory of Open Access Journals (Sweden)

    Viktor Müller

    Full Text Available Inhibition of irrelevant information (conflict monitoring and/or of prepotent actions is an essential component of adaptive self-organized behavior. Neural dynamics underlying these functions has been studied in humans using event-related brain potentials (ERPs elicited in Go/NoGo tasks that require a speeded motor response to the Go stimuli and withholding a prepotent response when a NoGo stimulus is presented. However, averaged ERP waveforms provide only limited information about the neuronal mechanisms underlying stimulus processing, motor preparation, and response production or inhibition. In this study, we examine the cortical representation of conflict monitoring and response inhibition using time-frequency analysis of electroencephalographic (EEG recordings during continuous performance Go/NoGo task in 50 young adult females. We hypothesized that response inhibition would be associated with a transient boost in both temporal and spatial synchronization of prefrontal cortical activity, consistent with the role of the anterior cingulate and lateral prefrontal cortices in cognitive control. Overall, phase synchronization across trials measured by Phase Locking Index and phase synchronization between electrode sites measured by Phase Coherence were the highest in the Go and NoGo conditions, intermediate in the Warning condition, and the lowest under Neutral condition. The NoGo condition was characterized by significantly higher fronto-central synchronization in the 300-600 ms window, whereas in the Go condition, delta- and theta-band synchronization was higher in centro-parietal regions in the first 300 ms after the stimulus onset. The present findings suggest that response production and inhibition is supported by dynamic functional networks characterized by distinct patterns of temporal and spatial synchronization of brain oscillations.

  3. Attention Inhibition Training Can Reduce Betel-Nut Chewing Time

    Directory of Open Access Journals (Sweden)

    Ming-Chou Ho

    2011-05-01

    Full Text Available Betel nut (or areca is the fourth most commonly used drug worldwide after tobacco, alcohol, and caffeine. Many chemical ingredients of betel nut are carcinogenic. We examined whether the manipulation of attentional inhibition toward the areca-related stimuli could affect betel-nut chewing time. Three matched groups of habitual chewers were recruited: inhibit-areca, inhibit-non-areca, and control. This study consisted of a Go/No-Go task for inhibition training, followed by a taste test for observing chewing behavior. The Go/No-Go task constituted three phases (pretest, training and posttest. In the taste test, the habitual chewers were asked to rate the flavors of one betel nut and one gum. The purpose (blind to the chewers of this taste test was to observe whether their picking order and chewing time were affected by experimental manipulation. Results from the Go/No-Go task showed successful training. Further, the training groups (the inhibit-areca and inhibit-non-areca groups showed a significant reduction in betel nut chewing time, in comparison to the control group. Since both training groups showed reduced chewing time, the inhibition training may affect general control ability, in regardless of the stimulus (areca or not to be inhibited. Reduced chewing time is important for reducing areca-related diseases.

  4. Pseudomonas aeruginosa inhibits the growth of Cryptococcus species.

    Science.gov (United States)

    Rella, Antonella; Yang, Mo Wei; Gruber, Jordon; Montagna, Maria Teresa; Luberto, Chiara; Zhang, Yong-Mei; Del Poeta, Maurizio

    2012-06-01

    Pseudomonas aeruginosa is a ubiquitous and opportunistic bacterium that inhibits the growth of different microorganisms, including Gram-positive bacteria and fungi such as Candida spp. and Aspergillus fumigatus. In this study, we investigated the interaction between P. aeruginosa and Cryptococcus spp. We found that P. aeruginosa PA14 and, to a lesser extent, PAO1 significantly inhibited the growth of Cryptococcus spp. The inhibition of growth was observed on solid medium by the visualization of a zone of inhibition of yeast growth and in liquid culture by viable cell counting. Interestingly, such inhibition was only observed when P. aeruginosa and Cryptococcus were co-cultured. Minimal inhibition was observed when cell-cell contact was prevented using a separation membrane, suggesting that cell contact is required for inhibition. Using mutant strains of Pseudomonas quinoline signaling, we showed that P. aeruginosa inhibited the growth of Cryptococcus spp. by producing antifungal molecules pyocyanin, a redox-active phenazine, and 2-heptyl-3,4-dihydroxyquinoline (PQS), an extracellular quorum-sensing signal. Because both P. aeruginosa and Cryptococcus neoformans are commonly found in lung infections of immunocompromised patients, this study may have important implication for the interaction of these microbes in both an ecological and a clinical point of view.

  5. Antiangiogenic and Antitumor Effects of Src Inhibition in Ovarian Carcinoma

    Science.gov (United States)

    Han, Liz Y.; Landen, Charles N.; Trevino, Jose G.; Halder, Jyotsnabaran; Lin, Yvonne G.; Kamat, Aparna A.; Kim, Tae-Jin; Merritt, William M.; Coleman, Robert L.; Gershenson, David M.; Shakespeare, William C.; Wang, Yihan; Sundaramoorth, Raji; Metcalf, Chester A.; Dalgarno, David C.; Sawyer, Tomi K.; Gallick, Gary E.; Sood, Anil K.

    2011-01-01

    Src, a nonreceptor tyrosine kinase, is a key mediator for multiple signaling pathways that regulate critical cellular functions and is often aberrantly activated in a number of solid tumors, including ovarian carcinoma. The purpose of this study was to determine the role of activated Src inhibition on tumor growth in an orthotopic murine model of ovarian carcinoma. In vitro studies on HeyA8 and SKOV3ip1 cell lines revealed that Src inhibition by the Src-selective inhibitor, AP23846, occurred within 1 hour and responded in a dose-dependent manner. Furthermore, Src inhibition enhanced the cytotoxicity of docetaxel in both chemosensitive and chemoresistant ovarian cancer cell lines, HeyA8 and HeyA8-MDR, respectively. In vivo, Src inhibition by AP23994, an orally bioavailable analogue of AP23846, significantly decreased tumor burden in HeyA8 (P = 0.02), SKOV3ip1 (P = 0.01), as well as HeyA8-MDR (P < 0.03) relative to the untreated controls. However, the greatest effect on tumor reduction was observed in combination therapy with docetaxel (P < 0.001, P = 0.002, and P = 0.01, for the above models, respectively). Proliferating cell nuclear antigen staining showed that Src inhibition alone (P = 0.02) and in combination with docetaxel (P = 0.007) significantly reduced tumor proliferation. In addition, Src inhibition alone and in combination with docetaxel significantly down-regulated tumoral production of vascular endothelial growth factor and interleukin 8, whereas combination therapy decreased the microvessel density (P = 0.02) and significantly affected vascular permeability (P < 0.05). In summary, Src inhibition with AP23994 has potent antiangiogenic effects and significantly reduces tumor burden in preclinical ovarian cancer models. Thus, Src inhibition may be an attractive therapeutic approach for patients with ovarian carcinoma. PMID:16951177

  6. Selective inhibition of distracting input.

    Science.gov (United States)

    Noonan, MaryAnn P; Crittenden, Ben M; Jensen, Ole; Stokes, Mark G

    2017-10-16

    We review a series of studies exploring distractor suppression. It is often assumed that preparatory distractor suppression is controlled via top-down mechanisms of attention akin to those that prepare brain areas for target enhancement. Here, we consider two alternative mechanisms: secondary inhibition and expectation suppression within a predictive coding framework. We draw on behavioural studies, evidence from neuroimaging and some animal studies. We conclude that there is very limited evidence for selective top-down control of preparatory inhibition. By contrast, we argue that distractor suppression often relies secondary inhibition of non-target items (relatively non-selective inhibition) and on statistical regularities of the environment, learned through direct experience. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

  7. Agnus castus extracts inhibit prolactin secretion of rat pituitary cells.

    Science.gov (United States)

    Sliutz, G; Speiser, P; Schultz, A M; Spona, J; Zeillinger, R

    1993-05-01

    In our studies on prolactin inhibition by plant extracts we focused on the effects of extracts of Vitex agnus castus and its preparations on rat pituitary cells under basal and stimulated conditions in primary cell culture. Both extracts from Vitex agnus castus as well as synthetic dopamine agonists (Lisuride) significantly inhibit basal as well as TRH-stimulated prolactin secretion of rat pituitary cells in vitro and as a consequence inhibition of prolactin secretion could be blocked by adding a dopamine receptor blocker. Therefore because of its dopaminergic effect Agnus castus could be considered as an efficient alternative phytotherapeutic drug in the treatment of slight hyperprolactinaemia.

  8. [Concepts of inhibition in psychiatry].

    Science.gov (United States)

    Auroux, Y; Bourrat, M M; Brun, J P

    1978-01-01

    Following a historical approach, the authors first describe the original development of the concept of inhibition in neurophysiology and then analyze the subsequent adaptations made in psychiatry around such concept including those of: -- Pavlov, Hull, Watson and the behaviorists, -- Freud and the Freudian School, -- clinicians and psychopharmacologists. The concept of inhibition has thus various meanings in psychiatry. Although some unity is achieved on the semiological level, this aspect cannot explain the extent of the process.

  9. Inhibiting prenylation augments chemotherapy efficacy in renal cell carcinoma through dual inhibition on mitochondrial respiration and glycolysis.

    Science.gov (United States)

    Huang, Jiangrong; Yang, Xiaoyu; Peng, Xiaochun; Huang, Wei

    2017-11-18

    Prenylation is a posttranslational lipid modification required for the proper functions of a number of proteins involved in cell regulation. Here, we show that prenylation inhibition is important for renal cell carcinoma (RCC) growth, survival and response to chemotherapy, and its underlying mechanism may be contributed to mitochondrial dysfunction. We first demonstrated that a HMG-CoA reductase inhibitor pitavastatin inhibited mevalonate pathway and thereby prenylation in RCC cells. In addition, pitavastatin is effective in inhibiting growth and inducing apoptosis in a panel of RCC cell lines. Combination of pitavastatin and paclitaxel is significantly more effective than pitavastatin or paclitaxel alone as shown by both in vitro cell culture system and in vivo RCC xenograft model. Importantly, pitavastatin treatment inhibits mitochondrial respiration via suppressing mitochondrial complex I and II enzyme activities. Interestingly, different from mitochondrial inhibitor phenformin that inhibits mitochondrial respiration but activates glycolytic rate in RCC cells, pitavastatin significantly decreases glycolytic rate. The dual inhibitory action of pitavastatin on mitochondrial respiration and glycolysis results in remarkable energy depletion and oxidative stress in RCC cells. In addition, inhibition of prenylation by depleting Isoprenylcysteine carboxylmethyltransferase (Icmt) also mimics the inhibitory effects of pitavastatin in RCC cells. Our work demonstrates the previously unappreciated association between prenylation inhibition and energy metabolism in RCC, which can be therapeutically exploited, likely in tumors that largely rely on energy metabolism. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Methanol Extract of Myelophycus caespitosus Inhibits the ...

    African Journals Online (AJOL)

    Methanol Extract of Myelophycus caespitosus Inhibits the Inflammatory Response in Lipopolysaccharidestimulated BV2 Microglial Cells by Downregulating NF-kB via Inhibition of the Akt Signaling Pathway.

  11. Lysophospholipase inhibition by organophosphorus toxicants

    International Nuclear Information System (INIS)

    Quistad, Gary B.; Casida, John E.

    2004-01-01

    Lysophospholipases (LysoPLAs) are a large family of enzymes for removing lysophospholipids from cell membranes. Potent inhibitors are needed to define the importance of LysoPLAs as targets for toxicants and potential therapeutics. This study considers organophosphorus (OP) inhibitors with emphasis on mouse brain total LysoPLA activity relative to the mipafox-sensitive neuropathy target esterase (NTE)-LysoPLA recently established as 17% of the total activity and important in the action of OP delayed toxicants. The most potent inhibitors of total LysoPLA in mouse brain are isopropyl dodecylphosphonofluoridate (also for LysoPLA of Vibrio bacteria), ethyl octylphosphonofluoridate (EOPF), and two alkyl-benzodioxaphosphorin 2-oxides (BDPOs)[(S)-octyl and dodecyl] (IC50 2-8 nM). OP inhibitors acting in vitro and in vivo differentiate a more sensitive portion but not a distinct NTE-LysoPLA compared with total LysoPLA activity. For 10 active inhibitors, NTE-LysoPLA is 17-fold more sensitive than total LysoPLA, but structure-activity comparisons give a good correlation (r 2 = 0.94) of IC50 values, suggesting active site structural similarity or identity. In mice 4 h after intraperitoneal treatment with discriminating doses, EOPF, tribufos (a plant defoliant), and dodecanesulfonyl fluoride inhibit 41-57% of the total brain LysoPLA and 85-99% of the NTE-LysoPLA activity. Total LysoPLA as well as NTE-LysoPLA is decreased in activity in Nte +/- -haploinsufficient mice compared to their Nte +/+ littermates. The lysolecithin level of spinal cord but not brain is elevated significantly following EOPF treatment (3 mg/kg), thereby focusing attention on localized rather than general alterations in lysophospholipid metabolism in OP-induced hyperactivity and toxicity

  12. The Inhibiting Bisection Problem

    Energy Technology Data Exchange (ETDEWEB)

    Pinar, Ali; Fogel, Yonatan; Lesieutre, Bernard

    2006-12-18

    Given a graph where each vertex is assigned a generation orconsumption volume, we try to bisect the graph so that each part has asignificant generation/consumption mismatch, and the cutsize of thebisection is small. Our motivation comes from the vulnerability analysisof distribution systems such as the electric power system. We show thatthe constrained version of the problem, where we place either the cutsizeor the mismatch significance as a constraint and optimize the other, isNP-complete, and provide an integer programming formulation. We alsopropose an alternative relaxed formulation, which can trade-off betweenthe two objectives and show that the alternative formulation of theproblem can be solved in polynomial time by a maximum flow solver. Ourexperiments with benchmark electric power systems validate theeffectiveness of our methods.

  13. Trace element inhibition of phytase activity.

    Science.gov (United States)

    Santos, T; Connolly, C; Murphy, R

    2015-02-01

    Nowadays, 70 % of global monogastric feeds contains an exogenous phytase. Phytase supplementation has enabled a more efficient utilisation of phytate phosphorous (P) and reduction of P pollution. Trace minerals, such as iron (Fe), zinc (Zn), copper (Cu) and manganese (Mn) are essential for maintaining health and immunity as well as being involved in animal growth, production and reproduction. Exogenous sources of phytase and trace elements are regularly supplemented to monogastric diets and usually combined in a premix. However, the possibility for negative interaction between individual components within the premix is high and is often overlooked. Therefore, this initial study focused on assessing the potential in vitro interaction between inorganic and organic chelated sources of Fe, Zn, Cu and Mn with three commercially available phytase preparations. Additionally, this study has investigated if the degree of enzyme inhibition was dependent of the type of chelated sources. A highly significant relationship between phytase inhibition, trace mineral type as well as mineral source and concentration, p phytases for Fe and Zn, as well as for Cu with E. coli and Aspergillus niger phytases. Different chelate trace mineral sources demonstrated diversifying abilities to inhibit exogenous phytase activity.

  14. Neural correlates of central inhibition during physical fatigue.

    Directory of Open Access Journals (Sweden)

    Masaaki Tanaka

    Full Text Available Central inhibition plays a pivotal role in determining physical performance during physical fatigue. Classical conditioning of central inhibition is believed to be associated with the pathophysiology of chronic fatigue. We tried to determine whether classical conditioning of central inhibition can really occur and to clarify the neural mechanisms of central inhibition related to classical conditioning during physical fatigue using magnetoencephalography (MEG. Eight right-handed volunteers participated in this study. We used metronome sounds as conditioned stimuli and maximum handgrip trials as unconditioned stimuli to cause central inhibition. Participants underwent MEG recording during imagery of maximum grips of the right hand guided by metronome sounds for 10 min. Thereafter, fatigue-inducing maximum handgrip trials were performed for 10 min; the metronome sounds were started 5 min after the beginning of the handgrip trials. The next day, neural activities during imagery of maximum grips of the right hand guided by metronome sounds were measured for 10 min. Levels of fatigue sensation and sympathetic nerve activity on the second day were significantly higher relative to those of the first day. Equivalent current dipoles (ECDs in the posterior cingulated cortex (PCC, with latencies of approximately 460 ms, were observed in all the participants on the second day, although ECDs were not identified in any of the participants on the first day. We demonstrated that classical conditioning of central inhibition can occur and that the PCC is involved in the neural substrates of central inhibition related to classical conditioning during physical fatigue.

  15. The somatotopy of tic inhibition: Where and how much?

    Science.gov (United States)

    Ganos, Christos; Bongert, Jens; Asmuss, Luisa; Martino, Davide; Haggard, Patrick; Münchau, Alexander

    2015-08-01

    Tics are the hallmark feature of Tourette syndrome. The basic phenomenological and neurophysiological characteristics of tics have been widely investigated. Interestingly, the spatial distribution of tics across different body parts has received little attention. No previous study has investigated whether the capacity for voluntary tic inhibition also varies across body parts. We analyzed video sequences of 26 adolescents with Tourette syndrome in a "tic freely" condition, and in a "voluntary tic inhibition" condition, to obtain absolute tic counts for different body parts. Two measures of the spatial distribution of tics were then analyzed. Linear regression analyses were employed to investigate the relation between the contribution of each body part to overall tic behavior and the ability to inhibit tics in that body part, averaged over our patient group. Tic distribution across patients showed a characteristic somatotopic pattern, with the face most strongly represented. A significant negative relation was found between the ability to inhibit tics and pooled tic frequency across body parts. The body parts that exhibited the fewest tics were the ones for which tic inhibition was most effective. Our data are consistent with the idea that tic recruitment order reflects a "tic generator" spreading across a somatotopic map in the brain. Voluntary tic inhibition did not simply cause a proportional reduction of tics in each body part. Rather, the least affected body parts showed most effective voluntary tic inhibition. The results are discussed in terms of signal and noise within cortical-subcortical motor loops. © 2015 International Parkinson and Movement Disorder Society.

  16. The development of children's inhibition: does parenting matter?

    Science.gov (United States)

    Roskam, Isabelle; Stievenart, Marie; Meunier, Jean-Christophe; Noël, Marie-Pascale

    2014-06-01

    Whereas a large body of research has investigated the maturation of inhibition in relation to the prefrontal cortex, far less research has been devoted to environmental factors that could contribute to inhibition improvement. The aim of the current study was to test whether and to what extent parenting matters for inhibition development from 2 to 8years of age. Data were collected from 421 families, with 348 mother-child dyads and 342 father-child dyads participating. Children's inhibition capacities and parenting behaviors were assessed in a three-wave longitudinal data collection. The main analyses examined the impact of parenting on the development of children's inhibition capacities. They were conducted using a multilevel modeling (MLM) framework. The results lead to the conclusion that both mothers and fathers contribute through their child-rearing behavior to their children's executive functioning, even when controlling for age-related improvement (maturation) and important covariates such as gender, verbal IQ, and place of enrollment. More significant relations between children's inhibition development and parenting were displayed for mothers than for fathers. More precisely, parenting behaviors that involve higher monitoring, lower discipline, inconsistency and negative controlling, and a positive parenting style are associated with good development of inhibition capacities in children. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. Fermentation of lignocellulosic hydrolysates: Inhibition and detoxification

    Energy Technology Data Exchange (ETDEWEB)

    Palmqvist, E.

    1998-02-01

    The ethanol yield and productivity obtained during fermentation of lignocellulosic hydrolysates is decreased due to the presence of inhibiting compounds, such as weak acids, furans and phenolic compounds produced during hydrolysis. Evaluation of the effect of various biological, physical and chemical detoxification treatments by fermentation assays using Saccharomyces cerevisiae was used to characterise inhibitors. Inhibition of fermentation was decreased after removal of the non-volatile compounds, pre-fermentation by the filamentous fungus Trichoderma reesei, treatment with the lignolytic enzyme laccase, extraction with ether, and treatment with alkali. Yeast growth in lignocellulosic hydrolysates was inhibited below a certain fermentation pH, most likely due to high concentrations of undissociated weak acids. The effect of individual compounds were studied in model fermentations. Furfural is reduced to furfuryl alcohol by yeast dehydrogenases, thereby affecting the intracellular redox balance. As a result, acetaldehyde accumulated during furfural reduction, which most likely contributed to inhibition of growth. Acetic acid (10 g 1{sup -1}) and furfural (3 g 1{sup -1}) interacted antagonistically causing decreased specific growth rate, whereas no significant individual or interaction effects were detected by the lignin-derived compound 4-hydroxybenzoic acid (2 g 1{sup -1}). By maintaining a high cell mass density in the fermentor, the process was less sensitive to inhibitors affecting growth and to fluctuations in fermentation pH, and in addition the depletion rate of bioconvertible inhibitors was increased. A theoretical ethanol yield and high productivity was obtained in continuous fermentation of spruce hydrolysate when the cell mass concentration was maintained at a high level by applying cell recirculation 164 refs, 16 figs, 5 tabs

  18. Evidence of dopaminergic processing of executive inhibition.

    Directory of Open Access Journals (Sweden)

    Rajendra D Badgaiyan

    Full Text Available Inhibition of unwanted response is an important function of the executive system. Since the inhibitory system is impaired in patients with dysregulated dopamine system, we examined dopamine neurotransmission in the human brain during processing of a task of executive inhibition. The experiment used a recently developed dynamic molecular imaging technique to detect and map dopamine released during performance of a modified Eriksen's flanker task. In this study, young healthy volunteers received an intravenous injection of a dopamine receptor ligand ((11C-raclopride after they were positioned in the PET camera. After the injection, volunteers performed the flanker task under Congruent and Incongruent conditions in a single scan session. They were required to inhibit competing options to select an appropriate response in the Incongruent but not in the Congruent condition. The PET data were dynamically acquired during the experiment and analyzed using two variants of the simplified reference region model. The analysis included estimation of a number of receptor kinetic parameters before and after initiation of the Incongruent condition. We found increase in the rate of ligand displacement (from receptor sites and decrease in the ligand binding potential in the Incongruent condition, suggesting dopamine release during task performance. These changes were observed in small areas of the putamen and caudate bilaterally but were most significant on the dorsal aspect of the body of left caudate. The results provide evidence of dopaminergic processing of executive inhibition and demonstrate that neurochemical changes associated with cognitive processing can be detected and mapped in a single scan session using dynamic molecular imaging.

  19. Irreversible inhibition of RANK expression as a possible mechanism for IL-3 inhibition of RANKL-induced osteoclastogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Khapli, Shruti M.; Tomar, Geetanjali B.; Barhanpurkar, Amruta P.; Gupta, Navita; Yogesha, S.D.; Pote, Satish T. [National Center for Cell Science, University of Pune Campus, Pune 411 007 (India); Wani, Mohan R., E-mail: mohanwani@nccs.res.in [National Center for Cell Science, University of Pune Campus, Pune 411 007 (India)

    2010-09-03

    Research highlights: {yields} IL-3 inhibits receptor activator of NF-{kappa}B ligand (RANKL)-induced osteoclastogenesis. {yields} IL-3 inhibits RANKL-induced JNK activation. {yields} IL-3 down-regulates expression of c-Fos and NFATc1 transcription factors. {yields} IL-3 down-regulates RANK expression posttranscriptionally and irreversibly. {yields} IL-3 inhibits in vivo RANK expression. -- Abstract: IL-3, a cytokine secreted by activated T lymphocytes, stimulates the proliferation, differentiation and survival of pluripotent hematopoietic stem cells. In this study, we investigated the mechanism of inhibitory action of IL-3 on osteoclast differentiation. We show here that IL-3 significantly inhibits receptor activator of NF-{kappa}B (RANK) ligand (RANKL)-induced activation of c-Jun N-terminal kinase (JNK). IL-3 down-regulates expression of c-Fos and nuclear factor of activated T cells (NFATc1) transcription factors. In addition, IL-3 down-regulates RANK expression posttranscriptionally in both purified osteoclast precursors and whole bone marrow cells. Furthermore, the inhibitory effect of IL-3 on RANK expression was irreversible. Interestingly, IL-3 inhibits in vivo RANK expression in mice. Thus, we provide the first evidence that IL-3 irreversibly inhibits RANK expression that results in inhibition of important signaling molecules induced by RANKL.

  20. Irreversible inhibition of RANK expression as a possible mechanism for IL-3 inhibition of RANKL-induced osteoclastogenesis

    International Nuclear Information System (INIS)

    Khapli, Shruti M.; Tomar, Geetanjali B.; Barhanpurkar, Amruta P.; Gupta, Navita; Yogesha, S.D.; Pote, Satish T.; Wani, Mohan R.

    2010-01-01

    Research highlights: → IL-3 inhibits receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis. → IL-3 inhibits RANKL-induced JNK activation. → IL-3 down-regulates expression of c-Fos and NFATc1 transcription factors. → IL-3 down-regulates RANK expression posttranscriptionally and irreversibly. → IL-3 inhibits in vivo RANK expression. -- Abstract: IL-3, a cytokine secreted by activated T lymphocytes, stimulates the proliferation, differentiation and survival of pluripotent hematopoietic stem cells. In this study, we investigated the mechanism of inhibitory action of IL-3 on osteoclast differentiation. We show here that IL-3 significantly inhibits receptor activator of NF-κB (RANK) ligand (RANKL)-induced activation of c-Jun N-terminal kinase (JNK). IL-3 down-regulates expression of c-Fos and nuclear factor of activated T cells (NFATc1) transcription factors. In addition, IL-3 down-regulates RANK expression posttranscriptionally in both purified osteoclast precursors and whole bone marrow cells. Furthermore, the inhibitory effect of IL-3 on RANK expression was irreversible. Interestingly, IL-3 inhibits in vivo RANK expression in mice. Thus, we provide the first evidence that IL-3 irreversibly inhibits RANK expression that results in inhibition of important signaling molecules induced by RANKL.

  1. Homo economicus belief inhibits trust.

    Directory of Open Access Journals (Sweden)

    Ziqiang Xin

    Full Text Available As a foundational concept in economics, the homo economicus assumption regards humans as rational and self-interested actors. In contrast, trust requires individuals to believe partners' benevolence and unselfishness. Thus, the homo economicus belief may inhibit trust. The present three experiments demonstrated that the direct exposure to homo economicus belief can weaken trust. And economic situations like profit calculation can also activate individuals' homo economicus belief and inhibit their trust. It seems that people's increasing homo economicus belief may serve as one cause of the worldwide decline of trust.

  2. Homo Economicus Belief Inhibits Trust

    Science.gov (United States)

    Xin, Ziqiang; Liu, Guofang

    2013-01-01

    As a foundational concept in economics, the homo economicus assumption regards humans as rational and self-interested actors. In contrast, trust requires individuals to believe partners’ benevolence and unselfishness. Thus, the homo economicus belief may inhibit trust. The present three experiments demonstrated that the direct exposure to homo economicus belief can weaken trust. And economic situations like profit calculation can also activate individuals’ homo economicus belief and inhibit their trust. It seems that people’s increasing homo economicus belief may serve as one cause of the worldwide decline of trust. PMID:24146907

  3. Inhibition of Retinoblastoma Protein Inactivation

    Science.gov (United States)

    2017-11-01

    CONTRACT NUMBER Inhibition of Retinoblastoma Protein Inactivation 5b. GRANT NUMBER W81XWH-14-1-0329 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Seth M...confirmed 108 compounds as giving a dose-response curve with at least 30% inhibition at 10 µM. The flowchart of hit progression is shown on the...Cancer Research Program under Award No. W81XWH-14-1-0329 to S.M.R. Opinions, interpretations, conclusions, and recommendations are those of the author

  4. Inhibition of nitric oxide synthesis for four days induces vascular abnormalities and myocardial infarct areas but not significant arterial hypertension Inibição da síntese do óxido nítrico durante quatro dias induz anormalidades vasculares e áreas de infarto miocárdico, porém, não induz hipertensão arterial significativa

    Directory of Open Access Journals (Sweden)

    Ricardo Xavier-Vidal

    2012-06-01

    Full Text Available BACKGROUND: Nitric oxide is an endothelium vasorelaxing factor and at least in some cases is the main cause of arterial hypertension, which is one of the most important risk factors of cardiovascular diseases. In Brazil, cardiovascular diseases are the first cause of mortality, representing about 30% of the total deaths. The L-NAME (Nω-nitro-arginine-methyl-ester blocks the nitric oxide synthesis necessary to maintain the normal arterial pressure. OBJECTIVE: To study lesions in myocardium due to the inhibition of nitric oxide synthesis during four days (via L-NAME oral administration, concentration: 75 mgs versus 100 mL-1. METHODS: Fourteen normotensive young adults Wistar rats were submitted, during four days, to L-NAME. Six rats were utilized as the Control Group. At day 4 of the experiment, the animals were anesthetized, weighed, and their thoraxes were opened, and the cardiotomy was performed. The hearts were weighed, fixed, and processed using routine methods, and they were sectioned in 3 µm and stained. RESULTS: Abnormalities were observed in the wall of arterial vessels of any dimension, as vascular damage with increasing wall thickness related mainly to proliferation of arterial smooth muscle cell in submitted animals. Proliferation of cells in the intimal layer and its thickening were also observed in small arterial vessels (arteriole. Infarct areas were present. CONCLUSIONS: The present data suggested that inhibition of nitric oxide synthesis for four days induces vascular abnormalities and myocardial infarct areas, but not arterial hypertension.CONTEXTO: O óxido nítrico é um fator de relaxamento vascular e, pelo menos em certos casos, é a principal causa de hipertensão arterial no ser humano. A hipertensão arterial é um importante fator de risco de doenças cardiovasculares. No Brasil, as doenças cardiovasculares são a primeira causa de mortalidade, representando cerca de 30% do total de óbitos. O L-NAME (N

  5. Affective picture modulation: valence, arousal, attention allocation and motivational significance.

    Science.gov (United States)

    Leite, Jorge; Carvalho, Sandra; Galdo-Alvarez, Santiago; Alves, Jorge; Sampaio, Adriana; Gonçalves, Oscar F

    2012-03-01

    The present study analyses the modulatory effects of affective pictures in the early posterior negativity (EPN), the late positive potential (LPP) and the human startle response on both the peripheral (eye blink EMG) and central neurophysiological levels (Probe P3), during passive affective pictures viewing. The affective pictures categories were balanced in terms of valence (pleasant; unpleasant) and arousal (high; low). The data shows that EPN may be sensitive to specific stimulus characteristics (affective relevant pictures versus neutral pictures) associated with early stages of attentional processing. In later stages, the heightened attentional resource allocation as well as the motivated significance of the affective stimuli was found to elicit enhanced amplitudes of slow wave processes thought to be related to enhanced encoding, namely LPP,. Although pleasant low arousing pictures were effective in engaging the resources involved in the slow wave processes, the highly arousing affective stimuli (pleasant and unpleasant) were found to produce the largest enhancement of the LPP, suggesting that high arousing stimuli may are associated with increased motivational significance. Additionally the response to high arousing stimuli may be suggestive of increased motivational attention, given the heightened attentional allocation, as expressed in the P3 probe, especially for the pleasant pictures. The hedonic valence may then serve as a mediator of the attentional inhibition to the affective priming, potentiating or inhibiting a shift towards defensive activation, as measured by the startle reflex. Copyright © 2011 Elsevier B.V. All rights reserved.

  6. Is forgetting caused by inhibition?

    NARCIS (Netherlands)

    Raaijmakers, J.G.W.; Jakab, E.

    2013-01-01

    A well-known finding in memory research is the forgetting effect that occurs because of practicing some Item A on the recall of a related Item B. The traditional explanation for such interference effects is based on the notion of competition. According to the inhibition theory of forgetting,

  7. Testing of Biologically Inhibiting Surface

    DEFF Research Database (Denmark)

    Bill Madsen, Thomas; Larsen, Erup

    2003-01-01

    The main purpose of this course is to examine a newly developed biologically inhibiting material with regards to galvanic corrosion and electrochemical properties. More in detail, the concern was how the material would react when exposed to cleaning agents, here under CIP cleaning (Cleaning...

  8. Impact significance determination-Back to basics

    International Nuclear Information System (INIS)

    Lawrence, David P.

    2007-01-01

    Impact significance determination is widely recognized as a vital and critical EIA activity. But impact significance related concepts are poorly understood. And the quality of approaches for impact significance determination in EIA practice remains highly variable. This article seeks to help establish a sound and practical conceptual foundation for formulating and evaluating impact significance determination approaches. It addresses the nature (what is impact significance?), the core characteristics (what are the major properties of significance determination?), the rationale (why are impact significance determinations necessary?), the procedural and substantive objectives (what do impact significance determinations seek to achieve?), and the process for making impact significance judgments (how is impact significance determination conducted?). By identifying fundamental attributes and key distinctions associated with impact significance determinations, a basis is provided for designing and evaluating impact significance determination procedures at both the regulatory and applied levels

  9. Protection against murine osteoarthritis by inhibition of the 26S proteasome and lysine-48 linked ubiquitination.

    Science.gov (United States)

    Radwan, Marta; Wilkinson, David J; Hui, Wang; Destrument, Auriane P M; Charlton, Sarah H; Barter, Matt J; Gibson, Beth; Coulombe, Josée; Gray, Douglas A; Rowan, Andrew D; Young, David A

    2015-08-01

    To determine whether the process of ubiquitination and/or activity of the 26S proteasome are involved in the induction of osteoarthritis (OA). Bovine cartilage resorption assays, chondrocyte cell-line SW1353 and primary human articular chondrocytes were used with the general proteasome inhibitor MG132 or vehicle to identify a role of the ubiquitin-proteasome system (UPS) in cartilage destruction and matrix metalloproteinase-13 (MMP13) expression. In vivo, MG132 or vehicle, were delivered subcutaneously to mice following destabilisation of the medial meniscus (DMM)-induced OA. Subsequently, DMM was induced in Lys-to-Arg (K48R and K63R) mutant ubiquitin (Ub) transgenic mice. Cytokine signalling in SW1353s was monitored by immunoblotting and novel ubiquitinated substrates identified using Tandem Ubiquitin Binding Entities purification followed by mass spectrometry. The ubiquitination of TRAFD1 was assessed via immunoprecipitation and immunoblotting and its role in cytokine signal-transduction determined using RNA interference and real-time RT-PCR for MMP13 and interleukin-6 (IL6). Supplementation with the proteasome inhibitor MG132 protected cartilage from cytokine-mediated resorption and degradation in vivo in mice following DMM-induced OA. Using transgenic animals only K48R-mutated Ub partially protected against OA compared to wild-type or wild-type Ub transgenic mice, and this was only evident on the medial femoral condyle. After confirming ubiquitination was vital for NF-κB signalling and MMP13 expression, a screen for novel ubiquitinated substrates involved in cytokine-signalling identified TRAFD1; the depletion of which reduced inflammatory mediator-induced MMP13 and IL6 expression. Our data for the first time identifies a role for ubiquitination and the proteasome in the induction of OA via regulation of inflammatory mediator-induced MMP13 expression. These data open avenues of research to determine whether the proteasome, or K48-linked ubiquitination, are

  10. Inhibitors of the proteasome reduce the accelerated proteolysis in atrophying rat skeletal muscles.

    Science.gov (United States)

    Tawa, N E; Odessey, R; Goldberg, A L

    1997-07-01

    Several observations have suggested that the enhanced proteolysis and atrophy of skeletal muscle in various pathological states is due primarily to activation of the ubiquitin-proteasome pathway. To test this idea, we investigated whether peptide aldehyde inhibitors of the proteasome, N-acetyl-leucyl-leucyl-norleucinal (LLN), or the more potent CBZ-leucyl-leucyl-leucinal (MG132) suppressed proteolysis in incubated rat skeletal muscles. These agents (e.g., MG132 at 10 microM) inhibited nonlysosomal protein breakdown by up to 50% (P protein synthesis or amino acid pools, but improved overall protein balance in the muscle. Upon treatment with MG132, ubiquitin-conjugated proteins accumulated in the muscle. The inhibition of muscle proteolysis correlated with efficacy against the proteasome, although these agents could also inhibit calpain-dependent proteolysis induced with Ca2+. These inhibitors had much larger effects on proteolysis in atrophying muscles than in controls. In the denervated soleus undergoing atrophy, the increase in ATP-dependent proteolysis was reduced 70% by MG132 (P muscle proteolysis induced by administering thyroid hormones was reduced 40-70% by the inhibitors. Finally, in rats made septic by cecal puncture, the increase in muscle proteolysis was completely blocked by MG132. Thus, the enhanced proteolysis in many catabolic states (including denervation, hyperthyroidism, and sepsis) is due to a proteasome-dependent pathway, and inhibition of proteasome function may be a useful approach to reduce muscle wasting.

  11. Targeting neuroblastoma stem cells with retinoic acid and proteasome inhibitor.

    Directory of Open Access Journals (Sweden)

    Barbara Hämmerle

    Full Text Available Neuroblastma cell lines contain a side-population of cells which express stemness markers. These stem-like cells may represent the potential underlying mechanism for resistance to conventional therapy and recurrence of neuroblastoma in patients.To develop novel strategies for targeting the side-population of neurobastomas, we analyzed the effects of 13-cis-retinoic acid (RA combined with the proteasome inhibitor MG132. The short-term action of the treatment was compared with effects after a 5-day recovery period during which both chemicals were withdrawn. RA induced growth arrest and differentiation of SH-SY5Y and SK-N-BE(2 neuroblastoma cell lines. Inhibition of the proteasome caused apoptosis in both cell lines, thus, revealing the critical role of this pathway in the regulated degradation of proteins involved in neuroblastoma proliferation and survival. The combination of RA with MG132 induced apoptosis in a dose-dependent manner, in addition to promoting G2/M arrest in treated cultures. Interestingly, expression of stem cell markers such as Nestin, Sox2, and Oct4 were reduced after the recovery period of combined treatment as compared with untreated cells or treated cells with either compound alone. Consistent with this, neurosphere formation was significantly impaired by the combined treatment of RA and MG132.Given that stem-like cells are associated with resistant to conventional therapy and are thought to be responsible for relapse, our results suggest that dual therapy of RA and proteasome inhibitor might be beneficial for targeting the side-population of cells associated residual disease in high-risk neuroblastoma.

  12. Inhibiting cancer cell hallmark features through nuclear export inhibition.

    Science.gov (United States)

    Sun, Qingxiang; Chen, Xueqin; Zhou, Qiao; Burstein, Ezra; Yang, Shengyong; Jia, Da

    2016-01-01

    Treating cancer through inhibition of nuclear export is one of the best examples of basic research translation into clinical application. Nuclear export factor chromosomal region maintenance 1 (CRM1; Xpo1 and exportin-1) controls cellular localization and function of numerous proteins that are critical for the development of many cancer hallmarks. The diverse actions of CRM1 are likely to explain the broad ranging anti-cancer potency of CRM1 inhibitors observed in pre-clinical studies and/or clinical trials (phase I-III) on both advanced-stage solid and hematological tumors. In this review, we compare and contrast the mechanisms of action of different CRM1 inhibitors, and discuss the potential benefit of unexplored non-covalent CRM1 inhibitors. This emerging field has uncovered that nuclear export inhibition is well poised as an attractive target towards low-toxicity broad-spectrum potent anti-cancer therapy.

  13. Acrolein in cigarette smoke inhibits T-cell responses.

    Science.gov (United States)

    Lambert, Cherie; McCue, Jesica; Portas, Mary; Ouyang, Yanli; Li, JiMei; Rosano, Thomas G; Lazis, Alexander; Freed, Brian M

    2005-10-01

    Cigarette smoking inhibits T-cell responses in the lungs, but the immunosuppressive compounds have not been fully identified. Cigarette smoke extracts inhibit IL-2, IFN-gamma, and TNF-alpha production in stimulated lymphocytes obtained from peripheral blood, even when the extracts were diluted 100-fold to 1000-fold. The objective of these studies was to identify the immunosuppressive compounds found in cigarette smoke. Gas chromatography/mass spectroscopy and HPLC were used to identify and quantitate volatile compounds found in cigarette smoke extracts. Bioactivity was measured by viability and production of cytokine mRNA and protein levels in treated human lymphocytes. The vapor phase of the cigarette smoke extract inhibited cytokine production, indicating that the immunosuppressive compounds were volatile. Among the volatile compounds identified in cigarette smoke extracts, only the alpha,beta-unsaturated aldehydes, acrolein (inhibitory concentration of 50% [IC50] = 3 micromol/L) and crotonaldehyde (IC50 = 6 micromol/L), exhibited significant inhibition of cytokine production. Although the levels of aldehydes varied 10-fold between high-tar (Camel) and ultralow-tar (Carlton) extracts, even ultralow-tar cigarettes produced sufficient levels of acrolein (34 micromol/L) to suppress cytokine production by >95%. We determined that the cigarette smoke extract inhibited transcription of cytokine genes. The inhibitory effects of acrolein could be blocked with the thiol compound N-acetylcysteine. The vapor phase from cigarette smoke extracts potently suppresses cytokine production. The compound responsible for this inhibition appears to be acrolein.

  14. Response inhibition under alcohol: effects of cognitive and motivational conflict.

    Science.gov (United States)

    Fillmore, M T; Vogel-Sprott, M

    2000-03-01

    This experiment tested the effect of cognitive and motivational conflict on response inhibition under alcohol. Fifty-six male social drinkers were randomly assigned to one of eight groups (n = 8). Four pairs of groups received 0.62 g/kg of alcohol, or a placebo, and each pair performed a go/stop choice reaction time task under one of four conflict conditions. One condition (C) produced cognitive conflict by presenting "go" and "stop" signals in the task. Another condition (IR) added motivational conflict by administering an equal monetary reward for inhibiting responses to stop-signals, and for responding to go-signals. The remaining two conditions resolved the motivational conflict by administering the monetary reward only for inhibitions (I), or only for responses (R). Compared with placebo, alcohol reduced inhibitions (i.e., impaired inhibitory control) under cognitive conflict (C; p = .041) and under motivational conflict (IR; p = .012). No significant effect of alcohol on inhibitions was observed in conditions where conflict was resolved (i.e., I and R). The study shows that alcohol can reduce the ability to inhibit a response. However, impaired inhibitory control is not an inevitable outcome of the drug action, because it can be counteracted by the consequences of behavior in the situation.

  15. Iron chelators ICL670 and 311 inhibit HIV-1 transcription

    International Nuclear Information System (INIS)

    Debebe, Zufan; Ammosova, Tatyana; Jerebtsova, Marina; Kurantsin-Mills, Joseph; Niu, Xiaomei; Charles, Sharroya; Richardson, Des R.; Ray, Patricio E.; Gordeuk, Victor R.; Nekhai, Sergei

    2007-01-01

    HIV-1 replication is induced by an excess of iron and iron chelation by desferrioxamine (DFO) inhibits viral replication by reducing proliferation of infected cells. Treatment of cells with DFO and 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) inhibit expression of proteins that regulate cell-cycle progression, including cycle-dependent kinase 2 (CDK2). Our recent studies showed that CDK2 participates in HIV-1 transcription and viral replication suggesting that inhibition of CDK2 by iron chelators might also affect HIV-1 transcription. Here we evaluated the effect of a clinically approved orally effective iron chelator, 4-[3,5-bis-(hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid (ICL670) and 311 on HIV-1 transcription. Both ICL670 and 311 inhibited Tat-induced HIV-1 transcription in CEM-T cells, 293T and HeLa cells. Neither ICL670 nor 311 induced cytotoxicity at concentrations that inhibited HIV-1 transcription. The chelators decreased cellular activity of CDK2 and reduced HIV-1 Tat phosphorylation by CDK2. Neither ICL670A or 311 decreased CDK9 protein level but significantly reduced association of CDK9 with cyclin T1 and reduced phosphorylation of Ser-2 residues of RNA polymerase II C-terminal domain. In conclusion, our findings add to the evidence that iron chelators can inhibit HIV-1 transcription by deregulating CDK2 and CDK9. Further consideration should be given to the development of iron chelators for future anti-retroviral therapeutics

  16. Diclofenac inhibits 27-hydroxycholesterol-induced inflammation.

    Science.gov (United States)

    Kim, Bo-Young; Son, Yonghae; Eo, Seong-Kug; Park, Young Chul; Kim, Koanhoi

    2016-09-23

    27-Hydroxycholesterol (27OHChol) is a cholesterol oxidation product that induces inflammation. In the current study we investigated the effects of diclofenac on inflammatory responses caused by 27OHChol using human monocyte/macrophage (THP-1) cells. Transcription and secretion of CCL2, CCL3, and CCL4 chemokines enhanced by 27OHChol were significantly attenuated by diclofenac in a concentration dependent manner. Migrations of monocytic cells and CCR5-positive Jurkat T cells were reduced proportionally to the concentrations of diclofenac. Superproduction of CCL2 and monocytic cell migration induced by 27OHChol plus LPS were significantly attenuated by diclofenac. Diclofenac also attenuated transcription of MMP-9 and release of its active gene product. These results indicate that diclofenac inhibits 27OHChol-induced inflammatory responses, thereby suppressing inflammation in a milieu rich in cholesterol oxidation products. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Novel Antimicrobial Peptides That Inhibit Gram Positive Bacterial Exotoxin Synthesis

    Science.gov (United States)

    Merriman, Joseph A.; Nemeth, Kimberly A.; Schlievert, Patrick M.

    2014-01-01

    Gram-positive bacteria, such as Staphylococcus aureus, cause serious human illnesses through combinations of surface virulence factors and secretion of exotoxins. Our prior studies using the protein synthesis inhibitor clindamycin and signal transduction inhibitors glycerol monolaurate and α-globin and β-globin chains of hemoglobin indicate that their abilities to inhibit exotoxin production by S. aureus are separable from abilities to inhibit growth of the organism. Additionally, our previous studies suggest that inhibition of exotoxin production, in absence of ability to kill S. aureus and normal flora lactobacilli, will prevent colonization by pathogenic S. aureus, while not interfering with lactobacilli colonization. These disparate activities may be important in development of novel anti-infective agents that do not alter normal flora. We initiated studies to explore the exotoxin-synthesis-inhibition activity of hemoglobin peptides further to develop potential agents to prevent S. aureus infections. We tested synthesized α-globin chain peptides, synthetic variants of α-globin chain peptides, and two human defensins for ability to inhibit exotoxin production without significantly inhibiting S. aureus growth. All of these peptides were weakly or not inhibitory to bacterial growth. However, the peptides were inhibitory to exotoxin production with increasing activity dependent on increasing numbers of positively-charged amino acids. Additionally, the peptides could be immobilized on agarose beads or have amino acid sequences scrambled and still retain exotoxin-synthesis-inhibition. The peptides are not toxic to human vaginal epithelial cells and do not inhibit growth of normal flora L. crispatus. These peptides may interfere with plasma membrane signal transduction in S. aureus due to their positive charges. PMID:24748386

  18. Functional significance of brain glycogen in sustaining glutamatergic neurotransmission.

    Science.gov (United States)

    Sickmann, Helle M; Walls, Anne B; Schousboe, Arne; Bouman, Stephan D; Waagepetersen, Helle S

    2009-05-01

    The involvement of brain glycogen in sustaining neuronal activity has previously been demonstrated. However, to what extent energy derived from glycogen is consumed by astrocytes themselves or is transferred to the neurons in the form of lactate for oxidative metabolism to proceed is at present unclear. The significance of glycogen in fueling glutamate uptake into astrocytes was specifically addressed in cultured astrocytes. Moreover, the objective was to elucidate whether glycogen derived energy is important for maintaining glutamatergic neurotransmission, induced by repetitive exposure to NMDA in co-cultures of cerebellar neurons and astrocytes. In the astrocytes it was shown that uptake of the glutamate analogue D-[3H]aspartate was impaired when glycogen degradation was inhibited irrespective of the presence of glucose, signifying that energy derived from glycogen degradation is important for the astrocytic compartment. By inhibiting glycogen degradation in co-cultures it was evident that glycogen provides energy to sustain glutamatergic neurotransmission, i.e. release and uptake of glutamate. The relocation of glycogen derived lactate to the neuronal compartment was investigated by employing d-lactate, a competitive substrate for the monocarboxylate transporters. Neurotransmitter release was affected by the presence of d-lactate indicating that glycogen derived energy is important not only in the astrocytic but also in the neuronal compartment.

  19. Characterization and biological significance of deacetylase

    International Nuclear Information System (INIS)

    Dipaola, E.A.

    1985-01-01

    An attempt is made to clarify the mechanism by which the one known deacetylase inhibitor, sodium butyrate, works and to identify other inhibitors of deacetylase activity. In doing so it was hoped to characterize the enzyme and to better understand its role in regulating genomic expression. The data showed that deacetylases not only showed activity toward their natural histone substrates, but also toward free acetyllysine and to a lesser degree toward acetylcholine, the latter being the natural substrate for acetylcholinesterases. Conversely, acetylcholinesterase was shown to be able to deacetylate groups from acetyllysine and acetylated histones. Decamethonium bromide, a well-known binder of acetylcholinesterase would not absorb the deacetylase. Diisopropylfluorophosphate (DFP), an anti-cholinesterase, exhibited no inhibitory effect on deacetylase activity, while acetylcholinesterase showed little or no sensitivity to butyrate inhibition. These findings along with the use of 3 H-DFP binding to fingerprint enzyme bands on gels became the basic criteria for distinguishing between deacetylase and acetylcholinesterase activity

  20. Aspergillus ficuum phytase activity is inhibited by cereal grain components.

    Science.gov (United States)

    Bekalu, Zelalem Eshetu; Madsen, Claus Krogh; Dionisio, Giuseppe; Brinch-Pedersen, Henrik

    2017-01-01

    In the current study, we report for the first time that grain components of barley, rice, wheat and maize can inhibit the activity of Aspergillus ficuum phytase. The phytase inhibition is dose dependent and varies significantly between cereal species, between cultivars of barley and cultivars of wheat and between Fusarium graminearum infected and non-infected wheat grains. The highest endpoint level of phytase activity inhibition was 90%, observed with grain protein extracts (GPE) from F. graminearum infected wheat. Wheat GPE from grains infected with F. graminearum inhibits phytase activity significantly more than GPE from non-infected grains. For four barley cultivars studied, the IC50 value ranged from 0.978 ± 0.271 to 3.616 ± 0.087 mg×ml-1. For two non-infected wheat cultivars investigated, the IC50 values were varying from 2.478 ± 0.114 to 3.038 ± 0.097 mg×ml-1. The maize and rice cultivars tested gaveIC50 values on 0.983 ± 0.205 and 1.972 ± 0.019 mg×ml-1, respectively. After purifying the inhibitor from barley grains via Superdex G200, an approximately 30-35 kDa protein was identified. No clear trend for the mechanism of inhibition could be identified via Michaelis-Menten kinetics and Lineweaver-Burk plots. However, testing of the purified phytase inhibitor together with the A. ficuum phytase and the specific protease inhibitors pepstatin A, E64, EDTA and PMSF revealed that pepstatin A repealed the phytase inhibition. This indicates that the observed inhibition of A. ficuum phytase by cereal grain extracts is caused by protease activity of the aspartic proteinase type.

  1. On inhibition of dental erosion.

    Science.gov (United States)

    Rölla, Gunnar; Jonski, Grazyna; Saxegaard, Erik

    2013-11-01

    To examine the erosion-inhibiting effect of different concentrations of hydrofluoric acid. Thirty-six human molars were individually treated with 10 ml of 0.1 M citric acid for 30 min (Etch 1), acid was collected and stored until analysis. The teeth were randomly divided into six groups and then individually treated with 10 ml of one of six dilutions (from 0.1-1%) of hydrofluoric acid. The teeth were then again treated with citric acid (Etch 2). The individual acid samples from Etch 1 and 2 were analyzed for calcium by flame atomic absorption spectroscopy and difference in calcium loss was calculated. The highest erosion inhibiting effect was obtained in groups with the highest concentrations of hydrofluoric acid, where the pH was lowest, below pKa of 3.17, thus the hydrofluoric acids being mainly in an undissociated state. Diluted hydrofluoric acid is present in aqueous solution of SnF2 and TiF4 (which are known to inhibit dental erosion): SnF2 + 3H2O = Sn(OH)2 + 2HF + H2O and TiF4 + 5H2O = Ti(OH)4 + 4HF + H2O. It is also known that pure, diluted hydrofluoric acid can inhibit dental erosion. Teeth treated with hydrofluoric acid are covered by a layer of CaF2-like mineral. This mineral is acid resistant at pH acid resistant mineral, initiated by tooth enamel treatment with hydrofluoric acid. Hydrofluoric acid is different in having fluoride as a conjugated base, which provides this acid with unique properties.

  2. Entanglement and inhibited quantum evolution

    International Nuclear Information System (INIS)

    Toschek, P E; Balzer, Chr; Hannemann, Th; Wunderlich, Ch; Neuhauser, W

    2003-01-01

    The evolution of a quantum system is impeded by the system's state being observed. A test on an ensemble neither proves the causal nexus nor discloses the nature of the inhibition. Two recent experiments that make use of sequential optical or microwave-optical double resonance on an individual trapped ion disprove a dynamical effect of back action by meter or environment. They rather indicate the ionic states involved in the evolution being entangled with the potentially recorded bivalued scattered-light signal

  3. A rhodanine derivative CCR-11 inhibits bacterial proliferation by inhibiting the assembly and GTPase activity of FtsZ.

    Science.gov (United States)

    Singh, Parminder; Jindal, Bhavya; Surolia, Avadhesha; Panda, Dulal

    2012-07-10

    A perturbation of FtsZ assembly dynamics has been shown to inhibit bacterial cytokinesis. In this study, the antibacterial activity of 151 rhodanine compounds was assayed using Bacillus subtilis cells. Of 151 compounds, eight strongly inhibited bacterial proliferation at 2 μM. Subsequently, we used the elongation of B. subtilis cells as a secondary screen to identify potential FtsZ-targeted antibacterial agents. We found that three compounds significantly increased bacterial cell length. One of the three compounds, namely, CCR-11 [(E)-2-thioxo-5-({[3-(trifluoromethyl)phenyl]furan-2-yl}methylene)thiazolidin-4-one], inhibited the assembly and GTPase activity of FtsZ in vitro. CCR-11 bound to FtsZ with a dissociation constant of 1.5 ± 0.3 μM. A docking analysis indicated that CCR-11 may bind to FtsZ in a cavity adjacent to the T7 loop and that short halogen-oxygen, H-bonding, and hydrophobic interactions might be important for the binding of CCR-11 with FtsZ. CCR-11 inhibited the proliferation of B. subtilis cells with a half-maximal inhibitory concentration (IC(50)) of 1.2 ± 0.2 μM and a minimal inhibitory concentration of 3 μM. It also potently inhibited proliferation of Mycobacterium smegmatis cells. Further, CCR-11 perturbed Z-ring formation in B. subtilis cells; however, it neither visibly affected nucleoid segregation nor altered the membrane integrity of the cells. CCR-11 inhibited HeLa cell proliferation with an IC(50) value of 18.1 ± 0.2 μM (∼15 × IC(50) of B. subtilis cell proliferation). The results suggested that CCR-11 inhibits bacterial cytokinesis by inhibiting FtsZ assembly, and it can be used as a lead molecule to develop FtsZ-targeted antibacterial agents.

  4. AI-2 of Aggregatibacter actinomycetemcomitans Inhibits Candida albicans Biofilm Formation

    Directory of Open Access Journals (Sweden)

    Endang W. Bachtiar

    2014-07-01

    Full Text Available Aggregatibacter actinomycetemcomitans, a Gram-negative bacterium, and Candida albicans, a polymorphic fungus, are both commensals of the oral cavity but both are opportunistic pathogens that can cause oral diseases. A. actinomycetemcomitans produces a quorum-sensing molecule called autoinducer-2 (AI-2, synthesized by LuxS, that plays an important role in expression of virulence factors, in intra- but also in interspecies communication. The aim of this study was to investigate the role of AI-2 based signaling in the interactions between C. albicans and A. actinomycetemcomitans. A. actinomycetemcomitans adhered to C. albicans and inhibited biofilm formation by means of a molecule that was secreted during growth. C. albicans biofilm formation increased significantly when co-cultured with A. actinomycetemcomitans luxS, lacking AI-2 production. Addition of wild-type-derived spent medium or synthetic AI-2 to spent medium of the luxS strain, restored inhibition of C. albicans biofilm formation to wild-type levels. Addition of synthetic AI-2 significantly inhibited hypha formation of C. albicans possibly explaining the inhibition of biofilm formation. AI-2 of A. actinomycetemcomitans is synthesized by LuxS, accumulates during growth and inhibits C. albicans hypha- and biofilm formation. Identifying the molecular mechanisms underlying the interaction between bacteria and fungi may provide important insight into the balance within complex oral microbial communities.

  5. Creating Significant Learning Experiences across Disciplines

    Science.gov (United States)

    Levine, Laura E.; Fallahi, Carolyn R.; Nicoll-Senft, Joan M.; Tessier, Jack T.; Watson, Cheryl L.; Wood, Rebecca M.

    2008-01-01

    The purpose of this study was to use Fink's (2003) taxonomy of significant learning to redesign courses and assess student learning. Significant improvements were found across the semester for students in the six courses, but there were differences in which taxa showed improvement in each course. The meta-analysis showed significant, positive…

  6. 23 CFR 630.1010 - Significant projects.

    Science.gov (United States)

    2010-04-01

    ... 23 Highways 1 2010-04-01 2010-04-01 false Significant projects. 630.1010 Section 630.1010 Highways... PRECONSTRUCTION PROCEDURES Work Zone Safety and Mobility § 630.1010 Significant projects. (a) A significant project is one that, alone or in combination with other concurrent projects nearby is anticipated to cause...

  7. Sprouting inhibition of rhizomes by gamma irradiation

    International Nuclear Information System (INIS)

    Hilmy, Nazly; Chosdu, Rahayu

    1985-01-01

    Sprouting inhibition by gamma irradiation to prolong the storage life of 4 species of rhizomes, namely curcuma domestica, kaemferia galanga, curcuma xanthoriza and curcuma aeruginosa, has been carried out. Two groups of samples were used, freshly harvested rhizomes and fresh rhizomes which have been stored for about two weeks. The samples were packed in a plastic net bag, each contained about 100 grams of rhizomes. Irradiation was carried out at room temperature at the doses of 0, 0.02, 0.04, 0.06, 0.08, 0.10, 0.15, 0.20 and 0.25 kGy. Post irradiation storage was done at room temperature with relative humidity ranging between 85 and 95%. The results showed that irradiation doses of 0.06 to 0.08 kGy was sufficient to inhibit sprouting of freshly harvested rhizomes and prolonged its storage life for 6 weeks, while in the other group sprouting still occured at the dose of 0.25 kGy. Irradiation dose up to 0.25 kGy did not cause significant effect on moisture and volatile oil contents, as well as volatile oil characteristics of the samples. About 50% of weight losses were found either in irradiated or unirradiated samples after being stored for 8 weeks. Odour and texture were evaluated organoleptically while mould growth and insect damage were observed visually. (author)

  8. Platelets Inhibit Migration of Canine Osteosarcoma Cells.

    Science.gov (United States)

    Bulla, S C; Badial, P R; Silva, R C; Lunsford, K; Bulla, C

    2017-01-01

    The interaction between platelets and tumour cells is important for tumour growth and metastasis. Thrombocytopenia or antiplatelet treatment negatively impact on cancer metastasis, demonstrating potentially important roles for platelets in tumour progression. To our knowledge, there is no information regarding the role of platelets in cancer progression in dogs. This study was designed to test whether canine platelets affected the migratory behaviour of three canine osteosarcoma cell lines and to give insights of molecular mechanisms. Intact platelets, platelet lysate and platelet releasate inhibited the migration of canine osteosarcoma cell lines. Addition of blood leucocytes to the platelet samples did not alter the inhibitory effect on migration. Platelet treatment also significantly downregulated the transcriptional levels of SNAI2 and TWIST1 genes. The interaction between canine platelets or molecules released during platelet activation and these tumour cell lines inhibits their migration, which suggests that canine platelets might antagonize metastasis of canine osteosarcoma. This effect is probably due to, at least in part, downregulation of genes related to epithelial-mesenchymal transition. Copyright © 2016. Published by Elsevier Ltd.

  9. Kaempferol inhibits thrombosis and platelet activation.

    Science.gov (United States)

    Choi, Jun-Hui; Park, Se-Eun; Kim, Sung-Jun; Kim, Seung

    2015-08-01

    The objectives of the present study were to investigate whether kaempferol affects pro-coagulant proteinase activity, fibrin clot formation, blood clot and thrombin (or collagen/epinephrine)-stimulated platelet activation, thrombosis, and coagulation in ICR (Imprinting Control Region) mice and SD (Sprague-Dawley) rats. Kaempferol significantly inhibited the enzymatic activities of thrombin and FXa by 68 ± 1.6% and 52 ± 2.4%, respectively. Kaempferol also inhibited fibrin polymer formation in turbidity. Microscopic analysis was performed using a fluorescent conjugate. Kaempferol completely attenuated phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, p38, c-Jun N-terminal kinase (JNK) 1/2, and phosphoinositide 3-kinase (PI3K)/PKB (AKT) in thrombin-stimulated platelets and delayed aggregation time (clotting) by 34.6% in an assay of collagen/epinephrine-stimulated platelet activation. Moreover, kaempferol protected against thrombosis development in 3 animal models, including collagen/epinephrine- and thrombin-induced acute thromboembolism models and an FeCl3-induced carotid arterial thrombus model. The ex vivo anticoagulant effect of kaempferol was further confirmed in ICR mice. This study demonstrated that kaempferol may be clinically useful due to its ability to reduce or prevent thrombotic challenge. Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  10. Neocortex and allocortex respond differentially to cellular stress in vitro and aging in vivo.

    Directory of Open Access Journals (Sweden)

    Jessica M Posimo

    Full Text Available In Parkinson's and Alzheimer's diseases, the allocortex accumulates aggregated proteins such as synuclein and tau well before neocortex. We present a new high-throughput model of this topographic difference by microdissecting neocortex and allocortex from the postnatal rat and treating them in parallel fashion with toxins. Allocortical cultures were more vulnerable to low concentrations of the proteasome inhibitors MG132 and PSI but not the oxidative poison H2O2. The proteasome appeared to be more impaired in allocortex because MG132 raised ubiquitin-conjugated proteins and lowered proteasome activity in allocortex more than neocortex. Allocortex cultures were more vulnerable to MG132 despite greater MG132-induced rises in heat shock protein 70, heme oxygenase 1, and catalase. Proteasome subunits PA700 and PA28 were also higher in allocortex cultures, suggesting compensatory adaptations to greater proteasome impairment. Glutathione and ceruloplasmin were not robustly MG132-responsive and were basally higher in neocortical cultures. Notably, neocortex cultures became as vulnerable to MG132 as allocortex when glutathione synthesis or autophagic defenses were inhibited. Conversely, the glutathione precursor N-acetyl cysteine rendered allocortex resilient to MG132. Glutathione and ceruloplasmin levels were then examined in vivo as a function of age because aging is a natural model of proteasome inhibition and oxidative stress. Allocortical glutathione levels rose linearly with age but were similar to neocortex in whole tissue lysates. In contrast, ceruloplasmin levels were strikingly higher in neocortex at all ages and rose linearly until middle age. PA28 levels rose with age and were higher in allocortex in vivo, also paralleling in vitro data. These neo- and allocortical differences have implications for the many studies that treat the telencephalic mantle as a single unit. Our observations suggest that the topographic progression of protein

  11. Inhibition and Kinetic Studies of Tortoise (Kinixys erosa) Liver arginase

    African Journals Online (AJOL)

    The effect of amino acid on tortoise liver arginase showed that L-lysine, L-valine, L-serine, L-aspartic acid and L aspartic acid had significant inhibitory effect on the enzyme but proline and glutamic acid showed slight inhibition. Ethylenediaminetetraacetic acid (EDTA), citrate, ascorbic acid, boric acid and sodium borate ...

  12. Catalytic Deoxygenation of Fatty Acids: Elucidation of the Inhibition Process

    NARCIS (Netherlands)

    Hollak, S.A.W.; Jong, de K.P.; Es, van D.S.

    2014-01-01

    Catalytic deoxygenation of unsaturated fatty acids in the absence of H2 is known to suffer from significant catalyst inhibition. Thus far, no conclusive results have been reported on the cause of deactivation. Here we show that CC double bonds present in the feed or the products dramatically reduce

  13. Cyperus scariosus Chloroform Fraction Inhibits T cell Responses in ...

    African Journals Online (AJOL)

    Erah

    CSC did not significantly (p < 0.01) suppress Th2 (IL-4) system. Conclusion: The findings from this investigation reveal that C. scariosus causes immunosuppression by inhibiting Th1 cytokines. Keywords: Cyperus scariosus; Immunosuppression; Humoral antibody titre; Cell-mediated immune response; CD 4+ T- helper cells ...

  14. Glycation inhibits trichloroacetic acid (TCA)-induced whey protein precipitation

    Science.gov (United States)

    Four different WPI saccharide conjugates were successfully prepared to test whether glycation could inhibit WPI precipitation induced by trichloroacetic acid (TCA). Conjugates molecular weights after glycation were analyzed with SDS-PAGE. No significant secondary structure change due to glycation wa...

  15. Flavonoids apigenin and quercetin inhibit melanoma growth and metastatic potential.

    Science.gov (United States)

    Caltagirone, S; Rossi, C; Poggi, A; Ranelletti, F O; Natali, P G; Brunetti, M; Aiello, F B; Piantelli, M

    2000-08-15

    Flavonoids are a class of polyphenolic compounds widely distributed in the plant kingdom, which display a variety of biological activities, including chemoprevention and tumor growth inhibition. Our aim was to investigate the effects of several polyphenols on the growth and metastatic potential of B16-BL6 melanoma cells in vivo. Intraperitoneal administration of quercetin, apigenin, (-)-epigallocathechin-3-gallate (EGCG), resveratrol, and the anti-estrogen tamoxifen, at the time of i.m. injection of B16-BL6 cells into syngeneic mice, resulted in a significant, dose-dependent delay of tumor growth, without toxicity. The relative descending order of potency was EGCG > apigenin = quercetin = tamoxifen > resveratrol > control. Furthermore, polyphenols significantly potentiated the inhibitory effect of a non-toxic dose of cisplatin. When tested for the ability to inhibit lung colonization, quercetin, apigenin, and tamoxifen (but not EGCG or resveratrol) significantly decreased the number of B16-BL6 colonies in the lungs in a dose-dependent manner, with quercetin and apigenin being more effective than tamoxifen. Interestingly, quercetin, apigenin, and tamoxifen (but not EGCG or resveratrol) significantly decreased the invasion of B16-BL6 cells in vitro, with quercetin and apigenin being more effective than tamoxifen. This suggests that anti-invasive activity is one of the mechanisms underlying inhibition of lung colonization by quercetin and apigenin. In conclusion, quercetin and apigenin inhibit melanoma growth and invasive and metastatic potential; therefore, they may constitute a valuable tool in the combination therapy of metastatic melanoma. Copyright 2000 Wiley-Liss, Inc.

  16. Inhibition of brain tumor cell proliferation by alternating electric fields

    International Nuclear Information System (INIS)

    Jeong, Hyesun; Oh, Seung-ick; Hong, Sunghoi; Sung, Jiwon; Jeong, Seonghoon; Yoon, Myonggeun; Koh, Eui Kwan

    2014-01-01

    This study was designed to investigate the mechanism by which electric fields affect cell function, and to determine the optimal conditions for electric field inhibition of cancer cell proliferation. Low-intensity (<2 V/cm) and intermediate-frequency (100–300 kHz) alternating electric fields were applied to glioblastoma cell lines. These electric fields inhibited cell proliferation by inducing cell cycle arrest and abnormal mitosis due to the malformation of microtubules. These effects were significantly dependent on the intensity and frequency of applied electric fields

  17. Inhibition of brain tumor cell proliferation by alternating electric fields

    Energy Technology Data Exchange (ETDEWEB)

    Jeong, Hyesun; Oh, Seung-ick; Hong, Sunghoi, E-mail: shong21@korea.ac.kr, E-mail: radioyoon@korea.ac.kr [School of Biosystem and Biomedical Science, Korea University, Seoul 136-703 (Korea, Republic of); Sung, Jiwon; Jeong, Seonghoon; Yoon, Myonggeun, E-mail: shong21@korea.ac.kr, E-mail: radioyoon@korea.ac.kr [Department of Bio-convergence Engineering, Korea University, Seoul 136-703 (Korea, Republic of); Koh, Eui Kwan [Seoul Center, Korea Basic Science Institute, Seoul 136-713 (Korea, Republic of)

    2014-11-17

    This study was designed to investigate the mechanism by which electric fields affect cell function, and to determine the optimal conditions for electric field inhibition of cancer cell proliferation. Low-intensity (<2 V/cm) and intermediate-frequency (100–300 kHz) alternating electric fields were applied to glioblastoma cell lines. These electric fields inhibited cell proliferation by inducing cell cycle arrest and abnormal mitosis due to the malformation of microtubules. These effects were significantly dependent on the intensity and frequency of applied electric fields.

  18. Methodology, theoretical framework and scholarly significance: An ...

    African Journals Online (AJOL)

    Methodology, theoretical framework and scholarly significance: An overview ... AFRICAN JOURNALS ONLINE (AJOL) · Journals · Advanced Search ... Keywords: Legal Research, Methodology, Theory, Pedagogy, Legal Training, Scholarship ...

  19. Impact significance determination-Pushing the boundaries

    International Nuclear Information System (INIS)

    Lawrence, David P.

    2007-01-01

    Impact significance determination practice tends to be highly variable. Too often insufficient consideration is given to good practice insights. Also, impact significance determinations are frequently narrowly defined addressing, for example, only individual, negative impacts, focusing on bio-physical impacts, and not seeking to integrate either the Precautionary Principle or sustainability. This article seeks to extend the boundaries of impact significance determination practice by providing an overview of good general impact significance practices, together with stakeholder roles and potential methods for addressing significance determination challenges. Relevant thresholds, criteria, contextual considerations and support methods are also highlighted. The analysis is then extended to address how impact significance determination practices change for positive as compared with negative impacts, for cumulative as compared with individual impacts, for socio-economic as compared with bio-physical impacts, when the Precautionary Principle is integrated into the process, and when sustainability contributions drive the EIA process and related impact significance determinations. These refinements can assist EIA practitioners in ensuring that the scope and nature of impact significance determinations reflect the broadened scope of emerging EIA requirements and practices. Suggestions are included for further refining and testing of the proposed changes to impact significance determination practice

  20. Regionally Significant Ecological Areas - MLCCS derived 2008

    Data.gov (United States)

    Minnesota Department of Natural Resources — This is an analysis of regionally significant Terrestrial and Wetland Ecological Areas in the seven county metropolitan area. Individual forest, grassland and...

  1. Central Region Regionally Ecological Significant Areas

    Data.gov (United States)

    Minnesota Department of Natural Resources — This is an analysis of regionally significant Terrestrial and Wetland Ecological Areas in the seven county metropolitan area. Individual forest, grassland and...

  2. Dietary Polyphenols and Their Biological Significance

    Directory of Open Access Journals (Sweden)

    Hongxiang Lou

    2007-09-01

    Full Text Available Dietary polyphenols represent a wide variety of compounds that occur in fruits,vegetables, wine, tea, extra virgin olive oil, chocolate and other cocoa products. They aremostly derivatives and/or isomers of flavones, isoflavones, flavonols, catechins andphenolic acids, and possess diverse biological properties such as antioxidant, antiapoptosis,anti-aging, anticarcinogen, anti-inflammation, anti-atherosclerosis, cardiovascularprotection, improvement of the endothelial function, as well as inhibition of angiogenesisand cell proliferation activity. Most of these biological actions have been attributed to theirintrinsic reducing capabilities. They may also offer indirect protection by activatingendogenous defense systems and by modulating cellular signaling processes such asnuclear factor-kappa B (NF-кB activation, activator protein-1(AP-1 DNA binding,glutathione biosynthesis, phosphoinositide 3 (PI3-kinase/protein kinase B (Akt pathway,mitogen-activated protein kinase (MAPK proteins [extracellular signal-regulated proteinkinase (ERK, c-jun N-terminal kinase (JNK and P38 ] activation, and the translocationinto the nucleus of nuclear factor erythroid 2 related factor 2 (Nrf2. This paper covers themost recent literature on the subject, and describes the biological mechanisms of action andprotective effects of dietary polyphenols.

  3. Entanglement and inhibited quantum evolution

    Energy Technology Data Exchange (ETDEWEB)

    Toschek, P E; Balzer, Chr; Hannemann, Th; Wunderlich, Ch; Neuhauser, W [Universitaet Hamburg, Institut fuer Laser-Physik, Jungiusstrasse 9, D-20355 Hamburg (Germany)

    2003-03-14

    The evolution of a quantum system is impeded by the system's state being observed. A test on an ensemble neither proves the causal nexus nor discloses the nature of the inhibition. Two recent experiments that make use of sequential optical or microwave-optical double resonance on an individual trapped ion disprove a dynamical effect of back action by meter or environment. They rather indicate the ionic states involved in the evolution being entangled with the potentially recorded bivalued scattered-light signal.

  4. The thresholds for statistical and clinical significance

    DEFF Research Database (Denmark)

    Jakobsen, Janus Christian; Gluud, Christian; Winkel, Per

    2014-01-01

    BACKGROUND: Thresholds for statistical significance are insufficiently demonstrated by 95% confidence intervals or P-values when assessing results from randomised clinical trials. First, a P-value only shows the probability of getting a result assuming that the null hypothesis is true and does...... not reflect the probability of getting a result assuming an alternative hypothesis to the null hypothesis is true. Second, a confidence interval or a P-value showing significance may be caused by multiplicity. Third, statistical significance does not necessarily result in clinical significance. Therefore...... of the probability that a given trial result is compatible with a 'null' effect (corresponding to the P-value) divided by the probability that the trial result is compatible with the intervention effect hypothesised in the sample size calculation; (3) adjust the confidence intervals and the statistical significance...

  5. What if there were no significance tests?

    CERN Document Server

    Harlow, Lisa L; Steiger, James H

    2013-01-01

    This book is the result of a spirited debate stimulated by a recent meeting of the Society of Multivariate Experimental Psychology. Although the viewpoints span a range of perspectives, the overriding theme that emerges states that significance testing may still be useful if supplemented with some or all of the following -- Bayesian logic, caution, confidence intervals, effect sizes and power, other goodness of approximation measures, replication and meta-analysis, sound reasoning, and theory appraisal and corroboration. The book is organized into five general areas. The first presents an overview of significance testing issues that sythesizes the highlights of the remainder of the book. The next discusses the debate in which significance testing should be rejected or retained. The third outlines various methods that may supplement current significance testing procedures. The fourth discusses Bayesian approaches and methods and the use of confidence intervals versus significance tests. The last presents the p...

  6. Myostatin inhibits porcine intramuscular preadipocyte differentiation in vitro.

    Science.gov (United States)

    Sun, W X; Dodson, M V; Jiang, Z H; Yu, S G; Chu, W W; Chen, J

    2016-04-01

    This study assessed the effect of myostatin on adipogenesis by porcine intramuscular preadipocytes. Intramuscular preadipocytes were isolated from the longissimus dorsi muscle of newborn pigs. Myostatin inhibited intramuscular preadipocyte differentiation in a dose-dependent manner. Myostatin treatment during preadipocyte differentiation significantly (P Myostatin also significantly (P myostatin acts as an extrinsic regulatory factor in regulating intramuscular adipogenesis. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Repellents inhibit P450 enzymes in Stegomyia (Aedes aegypti.

    Directory of Open Access Journals (Sweden)

    Gloria Isabel Jaramillo Ramirez

    Full Text Available The primary defence against mosquitoes and other disease vectors is often the application of a repellent. Despite their common use, the mechanism(s underlying the activity of repellents is not fully understood, with even the mode of action of DEET having been reported to be via different mechanisms; e.g. interference with olfactory receptor neurones or actively detected by olfactory receptor neurones on the antennae or maxillary palps. In this study, we discuss a novel mechanism for repellence, one of P450 inhibition. Thirteen essential oil extracts from Colombian plants were assayed for potency as P450 inhibitors, using a kinetic fluorometric assay, and for repellency using a modified World Health Organisation Pesticide Evaluations Scheme (WHOPES arm-in cage assay with Stegomyia (Aedes aegypti mosquitoes. Bootstrap analysis on the inhibition analysis revealed a significant correlation between P450-inhibition and repellent activity of the oils.

  8. Inhibition of existing denitrification enzyme activity by chloramphenicol

    Science.gov (United States)

    Brooks, M.H.; Smith, R.L.; Macalady, D.L.

    1992-01-01

    Chloramphenicol completely inhibited the activity of existing denitrification enzymes in acetylene-block incubations with (i) sediments from a nitrate-contaminated aquifer and (ii) a continuous culture of denitrifying groundwater bacteria. Control flasks with no antibiotic produced significant amounts of nitrous oxide in the same time period. Amendment with chloramphenicol after nitrous oxide production had begun resulted in a significant decrease in the rate of nitrous oxide production. Chloramphenicol also decreased (>50%) the activity of existing denitrification enzymes in pure cultures of Pseudomonas denitrificans that were harvested during log- phase growth and maintained for 2 weeks in a starvation medium lacking electron donor. Short-term time courses of nitrate consumption and nitrous oxide production in the presence of acetylene with P. denitrificans undergoing carbon starvation were performed under optimal conditions designed to mimic denitrification enzyme activity assays used with soils. Time courses were linear for both chloramphenicol and control flasks, and rate estimates for the two treatments were significantly different at the 95% confidence level. Complete or partial inhibition of existing enzyme activity is not consistent with the current understanding of the mode of action of chloramphenicol or current practice, in which the compound is frequently employed to inhibit de novo protein synthesis during the course of microbial activity assays. The results of this study demonstrate that chloramphenicol amendment can inhibit the activity of existing denitrification enzymes and suggest that caution is needed in the design and interpretation of denitrification activity assays in which chloramphenicol is used to prevent new protein synthesis.

  9. Self-regulation, ego depletion, and inhibition.

    Science.gov (United States)

    Baumeister, Roy F

    2014-12-01

    Inhibition is a major form of self-regulation. As such, it depends on self-awareness and comparing oneself to standards and is also susceptible to fluctuations in willpower resources. Ego depletion is the state of reduced willpower caused by prior exertion of self-control. Ego depletion undermines inhibition both because restraints are weaker and because urges are felt more intensely than usual. Conscious inhibition of desires is a pervasive feature of everyday life and may be a requirement of life in civilized, cultural society, and in that sense it goes to the evolved core of human nature. Intentional inhibition not only restrains antisocial impulses but can also facilitate optimal performance, such as during test taking. Self-regulation and ego depletion- may also affect less intentional forms of inhibition, even chronic tendencies to inhibit. Broadly stated, inhibition is necessary for human social life and nearly all societies encourage and enforce it. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Substituent effect of phenolic aldehyde inhibition on alcoholic fermentation by Saccharomyces cerevisiae

    Science.gov (United States)

    Rui Xie; Maobing Tu; Thomas Elder

    2016-01-01

    Phenolic compounds significantly inhibit microbial fermentation of biomass hydrolysates. To understand thequantitative structure-inhibition relationship of phenolic aldehydes on alcoholic fermentation, the effect of 11 differentsubstituted benzaldehydes on the final ethanol yield was examined. The results showed that the degree of phenolic...

  11. Recruitment of Perisomatic Inhibition during Spontaneous Hippocampal Activity In Vitro.

    Directory of Open Access Journals (Sweden)

    Anna Beyeler

    Full Text Available It was recently shown that perisomatic GABAergic inhibitory postsynaptic potentials (IPSPs originating from basket and chandelier cells can be recorded as population IPSPs from the hippocampal pyramidal layer using extracellular electrodes (eIPSPs. Taking advantage of this approach, we have investigated the recruitment of perisomatic inhibition during spontaneous hippocampal activity in vitro. Combining intracellular and extracellular recordings from pyramidal cells and interneurons, we confirm that inhibitory signals generated by basket cells can be recorded extracellularly, but our results suggest that, during spontaneous activity, eIPSPs are mostly confined to the CA3 rather than CA1 region. CA3 eIPSPs produced the powerful time-locked inhibition of multi-unit activity expected from perisomatic inhibition. Analysis of the temporal dynamics of spike discharges relative to eIPSPs suggests significant but moderate recruitment of excitatory and inhibitory neurons within the CA3 network on a 10 ms time scale, within which neurons recruit each other through recurrent collaterals and trigger powerful feedback inhibition. Such quantified parameters of neuronal interactions in the hippocampal network may serve as a basis for future characterisation of pathological conditions potentially affecting the interactions between excitation and inhibition in this circuit.

  12. Graphene: corrosion-inhibiting coating.

    Science.gov (United States)

    Prasai, Dhiraj; Tuberquia, Juan Carlos; Harl, Robert R; Jennings, G Kane; Rogers, Bridget R; Bolotin, Kirill I

    2012-02-28

    We report the use of atomically thin layers of graphene as a protective coating that inhibits corrosion of underlying metals. Here, we employ electrochemical methods to study the corrosion inhibition of copper and nickel by either growing graphene on these metals, or by mechanically transferring multilayer graphene onto them. Cyclic voltammetry measurements reveal that the graphene coating effectively suppresses metal oxidation and oxygen reduction. Electrochemical impedance spectroscopy measurements suggest that while graphene itself is not damaged, the metal under it is corroded at cracks in the graphene film. Finally, we use Tafel analysis to quantify the corrosion rates of samples with and without graphene coatings. These results indicate that copper films coated with graphene grown via chemical vapor deposition are corroded 7 times slower in an aerated Na(2)SO(4) solution as compared to the corrosion rate of bare copper. Tafel analysis reveals that nickel with a multilayer graphene film grown on it corrodes 20 times slower while nickel surfaces coated with four layers of mechanically transferred graphene corrode 4 times slower than bare nickel. These findings establish graphene as the thinnest known corrosion-protecting coating.

  13. Mining Significant Semantic Locations from GPS Data

    DEFF Research Database (Denmark)

    Cao, Xin; Cong, Gao; Jensen, Christian Søndergaard

    2010-01-01

    With the increasing deployment and use of GPS-enabled devices, massive amounts of GPS data are becoming available. We propose a general framework for the mining of semantically meaningful, significant locations, e.g., shopping malls and restaurants, from such data. We present techniques capable...... of extracting semantic locations from GPS data. We capture the relationships between locations and between locations and users with a graph. Significance is then assigned to locations using random walks over the graph that propagates significance among the locations. In doing so, mutual reinforcement between...

  14. Discovering the Significance of Scientific Design Practice

    DEFF Research Database (Denmark)

    Pries-Heje, Jan; Baskerville, Richard

    2016-01-01

    This paper discusses and defines the achievement of significance in design science research. We review the values and processes of old-science and how this mode of science attacks the complexity of scientific knowledge production through analysis. We then explain how new-science attacks...... the complexity of scientific knowledge production through synthesis. The work argues that significance of the new-science contribution in design science can be obfuscated when wrapped in old-science. This understanding helps reveal how new-science, such as design science research, constitutes its significance...

  15. Mining significant semantic locations from GPS data

    DEFF Research Database (Denmark)

    Cao, Xin; Cong, Gao; Jensen, Christian S.

    2010-01-01

    With the increasing deployment and use of GPS-enabled devices, massive amounts of GPS data are becoming available. We propose a general framework for the mining of semantically meaningful, significant locations, e.g., shopping malls and restaurants, from such data. We present techniques capable...... of extracting semantic locations from GPS data. We capture the relationships between locations and between locations and users with a graph. Significance is then assigned to locations using random walks over the graph that propagates significance among the locations. In doing so, mutual reinforcement between...

  16. Role of the brain stem in tibial inhibition of the micturition reflex in cats.

    Science.gov (United States)

    Ferroni, Matthew C; Slater, Rick C; Shen, Bing; Xiao, Zhiying; Wang, Jicheng; Lee, Andy; Roppolo, James R; de Groat, William C; Tai, Changfeng

    2015-08-01

    This study examined the role of the brain stem in inhibition of bladder reflexes induced by tibial nerve stimulation (TNS) in α-chloralose-anesthetized decerebrate cats. Repeated cystometrograms (CMGs) were performed by infusing saline or 0.25% acetic acid (AA) to elicit normal or overactive bladder reflexes, respectively. TNS (5 or 30 Hz) at three times the threshold (3T) intensity for inducing toe movement was applied for 30 min between CMGs to induce post-TNS inhibition or applied during the CMGs to induce acute TNS inhibition. Inhibition was evident as an increase in bladder capacity without a change in amplitude of bladder contractions. TNS applied for 30 min between saline CMGs elicited prolonged (>2 h) poststimulation inhibition that significantly (P reflexes but are not involved in inhibition of normal bladder reflexes. Copyright © 2015 the American Physiological Society.

  17. Metabonomics-based analysis of Brachyspira pilosicoli's response to tiamulin reveals metabolic activity despite significant growth inhibition

    OpenAIRE

    Le Roy, Caroline Ivanne; Passey, Jade Louise; Woodward, Martin John; La Ragione, Roberto Marcello; Claus, Sandrine Paule

    2017-01-01

    Pathogenic anaerobes Brachyspira spp. are responsible for an increasing number of Intestinal Spirochaetosis (IS) cases in livestock against which few approved treatments are available. Tiamulin is used to treat swine dysentery caused by Brachyspira spp. and recently has been used to handle avian intestinal spirochaetosis (AIS). The therapeutic dose used in chickens requires further evaluation since cases of bacterial resistance to tiamulin have been reported. In this study, we evaluated the i...

  18. Progression of Pancreatic Adenocarcinoma Is Significantly Impeded with a Combination of Vaccine and COX-2 Inhibition1

    Science.gov (United States)

    Mukherjee, Pinku; Basu, Gargi D.; Tinder, Teresa L.; Subramani, Durai B.; Bradley, Judy M.; Arefayene, Million; Skaar, Todd; De Petris, Giovanni

    2013-01-01

    With a 5-year survival rate of <5%, pancreatic cancer is one of the most rapidly fatal malignancies. Current protocols for the treatment of pancreas cancer are not as effective as we desire. In this study, we show that a novel Mucin-1 (MUC1)-based vaccine in combination with a cyclooxygenase-2 inhibitor (celecoxib), and low-dose chemotherapy (gemcitabine) was effective in preventing the progression of preneoplastic intraepithelial lesions to invasive pancreatic ductal adenocarcinomas. The study was conducted in an appropriate triple transgenic model of spontaneous pancreatic cancer induced by the KRASG12D mutation and that expresses human MUC1 as a self molecule. The combination treatment elicited robust antitumor cellular and humoral immune responses and was associated with increased apoptosis in the tumor. The mechanism for the increased immune response was attributed to the down-regulation of circulating prostaglandin E2 and indoleamine 2, 3,-dioxygenase enzymatic activity, as well as decreased levels of T regulatory and myeloid suppressor cells within the tumor microenvironment. The preclinical data provide the rationale to design clinical trials with a combination of MUC1-based vaccine, celecoxib, and gemcitabine for the treatment of pancreatic cancer. PMID:19109152

  19. Therapeutic metabolic inhibition: hydrogen sulfide significantly mitigates skeletal muscle ischemia reperfusion injury in vitro and in vivo

    NARCIS (Netherlands)

    Henderson, Peter W.; Singh, Sunil P.; Weinstein, Andrew L.; Nagineni, Vijay; Rafii, Daniel C.; Kadouch, Daniel; Krijgh, David D.; Spector, Jason A.

    2010-01-01

    BACKGROUND:: Recent evidence suggests that hydrogen sulfide is capable of mitigating the degree of cellular damage associated with ischemia-reperfusion injury. The purpose of this study was to determine whether it is protective in skeletal muscle. METHODS:: This study used both in vitro (cultured

  20. Global inhibition of reactive oxygen species (ROS inhibits paclitaxel-induced painful peripheral neuropathy.

    Directory of Open Access Journals (Sweden)

    Mehmet Fidanboylu

    Full Text Available Paclitaxel (Taxol® is a widely used chemotherapeutic agent that has a major dose limiting side-effect of painful peripheral neuropathy. Currently there is no effective therapy for the prevention or treatment of chemotherapy-induced painful peripheral neuropathies. Evidence for mitochondrial dysfunction during paclitaxel-induced pain was previously indicated with the presence of swollen and vacuolated neuronal mitochondria. As mitochondria are a major source of reactive oxygen species (ROS, the aim of this study was to examine whether pharmacological inhibition of ROS could reverse established paclitaxel-induced pain or prevent the development of paclitaxel-induced pain. Using a rat model of paclitaxel-induced pain (intraperitoneal 2 mg/kg paclitaxel on days 0, 2, 4 & 6, the effects of a non-specific ROS scavenger, N-tert-Butyl-α-phenylnitrone (PBN and a superoxide selective scavenger, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL were compared. Systemic 100 mg/kg PBN administration markedly inhibited established paclitaxel-induced mechanical hypersensitivity to von Frey 8 g and 15 g stimulation and cold hypersensitivity to plantar acetone application. Daily systemic administration of 50 mg/kg PBN (days -1 to 13 completely prevented mechanical hypersensitivity to von Frey 4 g and 8 g stimulation and significantly attenuated mechanical hypersensitivity to von Frey 15 g. Systemic 100 mg/kg TEMPOL had no effect on established paclitaxel-induced mechanical or cold hypersensitivity. High dose (250 mg/kg systemic TEMPOL significantly inhibited mechanical hypersensitivity to von Frey 8 g & 15 g, but to a lesser extent than PBN. Daily systemic administration of 100 mg/kg TEMPOL (day -1 to 12 did not affect the development of paclitaxel-induced mechanical hypersensitivity. These data suggest that ROS play a causal role in the development and maintenance of paclitaxel-induced pain, but such effects cannot be attributed to superoxide radicals

  1. SRS Process Facility Significance Fire Frequency

    Energy Technology Data Exchange (ETDEWEB)

    Sarrack, A.G. [Westinghouse Savannah River Company, AIKEN, SC (United States)

    1995-10-01

    This report documents the method and assumptions of a study performed to determine a site generic process facility significant fire initiator frequency and explains the proper way this value should be used.

  2. Can a significance test be genuinely Bayesian?

    OpenAIRE

    Pereira, Carlos A. de B.; Stern, Julio Michael; Wechsler, Sergio

    2008-01-01

    The Full Bayesian Significance Test, FBST, is extensively reviewed. Its test statistic, a genuine Bayesian measure of evidence, is discussed in detail. Its behavior in some problems of statistical inference like testing for independence in contingency tables is discussed.

  3. 40 CFR 1508.27 - Significantly.

    Science.gov (United States)

    2010-07-01

    ... Register of Historic Places or may cause loss or destruction of significant scientific, cultural, or... cultural resources, park lands, prime farmlands, wetlands, wild and scenic rivers, or ecologically critical...

  4. Economically Significant Sites - OSPR [ds356

    Data.gov (United States)

    California Natural Resource Agency — This point data set shows locations of Economically Significant Sites along the California coast from Del Norte to San Diego counties. Data for locating these points...

  5. Contribution of radiodiagnosis to genetically significant dose

    International Nuclear Information System (INIS)

    Pele, J.M.; Ouvrard, R.

    Surveys were carried out in France on 33,000 X-ray medical examinations. The genetically significant dose to the whole population from roentgenography and fluoroscopy, for typical examinations, should be about 65mrads [fr

  6. SRS Process Facility Significance Fire Frequency

    International Nuclear Information System (INIS)

    Sarrack, A.G.

    1995-10-01

    This report documents the method and assumptions of a study performed to determine a site generic process facility significant fire initiator frequency and explains the proper way this value should be used

  7. SIGWX Charts - High Level Significant Weather

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — High level significant weather (SIGWX) forecasts are provided for the en-route portion of international flights. NOAA's National Weather Service Aviation Center...

  8. Asymptomatic bacteriuria. Clinical significance and management.

    Science.gov (United States)

    Raz, Raul

    2003-10-01

    The clinical significance and management of asymptomatic bacteriuria (ASB) differs according to different groups of patients. ASB requires antibiotic treatment in pregnant women, children aged 5-6 years and prior to invasive genitourinary procedures. However, there is a consensus that ASB in the elderly, healthy school girls and young women, diabetic women and patients with indwelling catheters or intermittent catheterization has no clinical significance and antibiotic prescription is not indicated.

  9. Formal conditions for the significance-effect

    DEFF Research Database (Denmark)

    Thellefsen, Torkild Leo; Sørensen, Bent; Thellefsen, Martin

    2006-01-01

    The significance-effect is the right effect of meaning caused upon an interpreting mind. The right effect is understood as the right interpretation of an intended meaning caused by a sign communicated by an utterer. In the article, which is inspired by Charles S. Peirce's doctrine of signs, his s...... semeiotics and his theory of communication, we account for the formal conditions that have to be present for the release of the significance-effect....

  10. Significance of Hemispheric Security for Mexico

    Science.gov (United States)

    2003-04-07

    La Seguridad Internacional, la Nueva Geopolitica Continental y Mexico ,” Seminario Internacional sobre Misiones de Paz, Seguridad y Defensa, Rio de...USAWC STRATEGY RESEARCH PROJECT SIGNIFICANCE OF HEMISPHERIC SECURITY FOR MEXICO by LTC Enrique Garcia Jaramillo Cavalry, Mexican Army COL Joseph R...xx-xx-2002 to xx-xx-2003 4. TITLE AND SUBTITLE Significance of Hemispheric Security for Mexico Unclassified 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c

  11. Building stones can be of geoheritage significance

    Science.gov (United States)

    Brocx, Margaret; Semeniuk, Vic

    2017-04-01

    Building stones have generally been assigned values according to their cultural, aesthetic, and rarity significance, amongst other criteria, but they also may have geoheritage significance. This is akin to the geoheritage significance ascribed to minerals and fossils housed as ex situ specimens in museums. We proffer the notion that building stones can be of geoheritage value particularly where they comprise permanent buildings, they illustrate significant windows into the history of the Earth, and they can be visited as an ex situ museum locality (e.g., the "Blue Granite" of Iceland) for education as part of building-stone tours. For some rocks the quarries that supplied the building stone are no longer in existence and hence the building stones provide the only record of that type of material; for other rocks, the building stone may illustrate features in the lithology no longer present in the quarry itself (e.g., rare and large xenoliths). Building stones are particularly significant as they are often polished and manifest structures, fabrics, and textures not evident in outcrop. We illustrate here examples of building stone of geoheritage significance using Australian and International examples. Australian designated stones could include the "Sydney Sandstone" or "Victorian Bluestone". For international examples, there is the famous "Carrara Marble" in Italy and the widely known "Portland Limestone" from southern England, the latter having been utilized for St Pauls Cathedral in London and the UN building in New York City.

  12. Efficacy of ALK5 inhibition in myelofibrosis

    Science.gov (United States)

    Zhao, Wanke; Ho, Wanting Tina; Han, Ying; Murdun, Cem; Mailloux, Adam W.; Zhang, Ling; Wang, Xuefeng; Budhathoki, Anjali; Pradhan, Kith; Rapaport, Franck; Wang, Huaquan; Shao, Zonghong; Ren, Xiubao; Steidl, Ulrich; Levine, Ross L.; Zhao, Zhizhuang Joe; Verma, Amit; Epling-Burnette, Pearlie K.

    2017-01-01

    Myelofibrosis (MF) is a bone marrow disorder characterized by clonal myeloproliferation, aberrant cytokine production, extramedullary hematopoiesis, and bone marrow fibrosis. Although somatic mutations in JAK2, MPL, and CALR have been identified in the pathogenesis of these diseases, inhibitors of the Jak2 pathway have not demonstrated efficacy in ameliorating MF in patients. TGF-β family members are profibrotic cytokines and we observed significant TGF-β1 isoform overexpression in a large cohort of primary MF patient samples. Significant overexpression of TGF-β1 was also observed in murine clonal MPLW515L megakaryocytic cells. TGF-β1 stimulated the deposition of excessive collagen by mesenchymal stromal cells (MSCs) by activating the TGF-β receptor I kinase (ALK5)/Smad3 pathway. MSCs derived from MPLW515L mice demonstrated sustained overproduction of both collagen I and collagen III, effects that were abrogated by ALK5 inhibition in vitro and in vivo. Importantly, use of galunisertib, a clinically active ALK5 inhibitor, significantly improved MF in both MPLW515L and JAK2V617F mouse models. These data demonstrate the role of malignant hematopoietic stem cell (HSC)/TGF-β/MSC axis in the pathogenesis of MF, and provide a preclinical rationale for ALK5 blockade as a therapeutic strategy in MF. PMID:28405618

  13. [The mechanisms of p21WAF1/Cip-1 expression in MOLT-4 cell line induced by TSA].

    Science.gov (United States)

    Song, Yi; Liu, Mei-Ju; Zhao, Guo-Wei; Qian, Jun-Jie; Dong, Yan; Liu, Hua; Sun, Guo-Jing; Mei, Zhu-Zhong; Liu, Bin; Tian, Bao-Lei; Sun, Zhi-Xian

    2005-04-01

    To investigate the function and molecular mechanism of p21(WAF1/Cip-1) expression in MOLT-4 cells induced by HDAC inhibitor TSA, the expression pattern of p21(WAF1/Cip-1) and the distribution of cell cycle in TSA treated cells were analyzed. The results showed that TSA could effectively induce G(2)/M arrest and apoptosis of MOLT-4 cells. Kinetic experiments demonstrated that p21(WAF1/Cip-1) were upregulated quickly before cell arrested in G(2)/M and began decreasing at the early stage of apoptosis. Meanwhile, the proteasome inhibitor MG-132 could inhibit the decrease of p21(WAF1/Cip-1) at the early stage of apoptosis, which showed that proteasome pathway involved in p21(WAF1/Cip-1) degradation during the TSA induced G(2)/M arrest and apoptosis responses. This study also identified that the protein level of p21(WAF1/Cip-1) was highly associated with the cell cycle change induced by TSA. Compared to cells treated by TSA only, exposure MOLT-4 cells to TSA meanwhile treatment with MG-132 increased the protein level of p21(WAF1/Cip-1) and increased the numbers of cell in G(2)/M-phase, whereas the cell apoptosis were delayed. It is concluded that p21(WAF1/Cip-1) plays a significant role in G(2)/M arrest and apoptosis signaling induced by TSA in MOLT-4 cells.

  14. Significance of Lead Residues in Mallard Tissues

    Science.gov (United States)

    Longcore, J.R.; Locke, L.N.; Bagley, George E.; Andrews, R.

    1974-01-01

    Tissues of adult, lead-dosed mallards that either died or were sacrificed were analyzed for lead. Lead levels in brains, tibiae, and breast muscle of ducks that died and in tibiae of ducks that were sacrificed increased significantly from dosage until death. Lead in the heart, lung, and blood from sacrificed ducks decreased significantly from dosage until death. Lead concentrations in tissues from ducks in the two groups were not significantly different except for the liver, kidney, and lung. Average lead levels in the livers and kidneys of ducks that died were significantly higher than those in ducks that were sacrificed. The mean concentration of lead in the lungs of the ducks sacrificed was significantly higher than the mean level in the lungs of ducks that died. Measurements of the lead concentrations in this study, when compared with lead levels reported in the literature for avian and non-avian species, showed that arbitrary diagnostic levels indicating lead poisoning could be set. In mallard ducks, lead levels exceeding 3 ppm in the brain, 6 to 20 ppm in the kidney or liver, or 10 ppm in clotted blood from the heart indicated acute exposure to lead.

  15. Clinical significance of anismus in encopresis.

    Science.gov (United States)

    Catto-Smith, A G; Nolan, T M; Coffey, C M

    1998-09-01

    Treatments designed to relieve paradoxical contraction of the anal sphincters during defecation (anismus) have had limited success in children with encopresis. This has raised doubts as to the clinical relevance of this diagnosis in childhood as anorectal dysfunction. Our aim was to determine whether, in patients who had treatment-resistant encopresis, the presence of electromyographic anismus was associated with increased faecal retention. Sixty-eight children with soiling (mean age 8.7+/-2.06 years) were assessed by clinical examination, abdominal radiography and then with anorectal manometry. Patients with electromyographic anismus (n=32; 47%) had significantly increased radiographic rectal faecal retention and were significantly less likely to be able to defecate water-filled balloons. There were no significant differences in response to prior therapy, history of primary encopresis, behavioural adjustment or in sociodemographic data. Our results suggest that electromyographic anismus is associated with obstructed defecation and faecal retention.

  16. Statistical significance of cis-regulatory modules

    Directory of Open Access Journals (Sweden)

    Smith Andrew D

    2007-01-01

    Full Text Available Abstract Background It is becoming increasingly important for researchers to be able to scan through large genomic regions for transcription factor binding sites or clusters of binding sites forming cis-regulatory modules. Correspondingly, there has been a push to develop algorithms for the rapid detection and assessment of cis-regulatory modules. While various algorithms for this purpose have been introduced, most are not well suited for rapid, genome scale scanning. Results We introduce methods designed for the detection and statistical evaluation of cis-regulatory modules, modeled as either clusters of individual binding sites or as combinations of sites with constrained organization. In order to determine the statistical significance of module sites, we first need a method to determine the statistical significance of single transcription factor binding site matches. We introduce a straightforward method of estimating the statistical significance of single site matches using a database of known promoters to produce data structures that can be used to estimate p-values for binding site matches. We next introduce a technique to calculate the statistical significance of the arrangement of binding sites within a module using a max-gap model. If the module scanned for has defined organizational parameters, the probability of the module is corrected to account for organizational constraints. The statistical significance of single site matches and the architecture of sites within the module can be combined to provide an overall estimation of statistical significance of cis-regulatory module sites. Conclusion The methods introduced in this paper allow for the detection and statistical evaluation of single transcription factor binding sites and cis-regulatory modules. The features described are implemented in the Search Tool for Occurrences of Regulatory Motifs (STORM and MODSTORM software.

  17. Inhibition of the immune response to experimental fresh osteoarticular allografts

    International Nuclear Information System (INIS)

    Rodrigo, J.J.; Schnaser, A.M.; Reynolds, H.M. Jr.; Biggart, J.M. III; Leathers, M.W.; Chism, S.E.; Thorson, E.; Grotz, T.; Yang, Q.M.

    1989-01-01

    The immune response to osteoarticular allografts is capable of destroying the cartilage--a tissue that has antigens on its cells identical to those on the bone and marrow cells. Osteoarticular allografts of the distal femur were performed in rats using various methods to attempt to temporarily inhibit the antibody response. The temporary systemic immunosuppressant regimens investigated were cyclophosphamide, azathioprine and prednisolone, cyclosporine A, and total lymphoid irradiation. The most successful appeared to be cyclosporine A, but significant side effects were observed. To specifically inhibit the immune response in the allograft antigens without systemically inhibiting the entire immune system, passive enhancement and preadministration of donor blood were tried. Neither was as effective as coating the donor bone with biodegradable cements, a method previously found to be successful. Cyclosporine A was investigated in dogs in a preliminary study of medial compartmental knee allografts and was found to be successful in inhibiting the antibody response and in producing a more successful graft; however, some significant side effects were similarly observed

  18. How do we make sense of significance?

    DEFF Research Database (Denmark)

    Lyhne, Ivar; Kørnøv, Lone

    2013-01-01

    Determination of significance is widely recognised as an important step in environmental assessment (EA) processes. The prescriptive literature and guidance on significance determination is comprehensive within the field of EA, whereas descriptive and explorative studies of how we go about making......' sense-making, including important differences in the way individuals screen and scope. These patterns concern what we notice, how fast we frame the choice, and when we are critical about the provided information. The indications provide a basis for reflections on practice and on how to organise EA...

  19. Iron inhibits hydroxyapatite crystal growth in vitro.

    Science.gov (United States)

    Guggenbuhl, Pascal; Filmon, Robert; Mabilleau, Guillaume; Baslé, Michel F; Chappard, Daniel

    2008-07-01

    Hemochromatosis is a known cause of osteoporosis in which the pathophysiology of bone loss is largely unknown and the role of iron remains questionable. We have investigated the effects of iron on the growth of hydroxyapatite crystals in vitro on carboxymethylated poly(2-hydroxyethyl methacrylate) pellets. This noncellular and enzyme-independent model mimics the calcification of woven bone (composed of calcospherites made of hydroxyapatite crystals). Polymer pellets were incubated with body fluid containing iron at increasing concentrations (20, 40, 60 micromol/L). Hydroxyapatite growth was studied by chemical analysis, scanning electron microscopy, and Raman microscopy. When incubated in body fluid containing iron, significant differences were observed with control pellets. Iron was detected at a concentration of 5.41- to 7.16-fold that of controls. In pellets incubated with iron, there was a approximately 3- to 4-fold decrease of Ca and P and a approximately 1.3- to 1.4-fold increase in the Ca/P ratio. There was no significant difference among the iron groups of pellets, but a trend to a decrease of Ca with the increase of iron concentration was noted. Calcospherite diameters were significantly lower on pellets incubated with iron. Raman microspectroscopy showed a decrease in crystallinity (measured by the full width of the half height of the 960 Deltacm(-1) band) with a significant increase in carbonate substitution (measured by the intensity ratio of 1071 to 960 Deltacm(-1) band). Energy dispersive x-ray analysis identified iron in the calcospherites. In vitro, iron is capable to inhibit bone crystal growth with significant changes in crystallinity and carbonate substitution.

  20. Anxiety Impacts Cognitive Inhibition in Remitted Anorexia Nervosa.

    Science.gov (United States)

    Ely, Alice V; Wierenga, Christina E; Kaye, Walter H

    2016-07-01

    Eating disorders are complex psychiatric disorders, associated with alterations in neural and cognitive functioning. Research suggests inhibition and set-shifting deficits in anorexia nervosa (AN), but less is known about the persistence of these deficits after recovery, or their relationship to comorbid psychiatric symptoms. Women aged 19-45 remitted from AN (RAN, N = 47) and controls (CW, N = 24) completed the Delis-Kaplan Executive Function System Color-Word Interference Test. It was hypothesized that RAN, and those with higher anxiety or depression, would demonstrate worse Inhibition and Switching task performance than CW. Differences in performance between groups trended toward significance on Inhibition Ratio (p = 0.08) but were nonsignificant on Inhibition/Switching Ratio (p = 0.93). A model including State Anxiety and diagnosis revealed a significant independent effect of State Anxiety (p = 0.026), but not of diagnosis nor their interaction. Regressing State Anxiety on Color-Word Interference Test Inhibition among just the RAN group was significant [β = 0.37, t(46) = 2.63, p = 0.012] but among just CW was not (p = 0.54). Interference control for neutral stimuli is influenced by anxiety in women with a history of AN. Anxiety is linked with greater symptom severity among AN individuals, and state anxiety may account for larger deficits seen on tasks using disorder-specific stimuli. Future research is warranted to elucidate the nature of neuropsychological deficits in eating disorders. Copyright © 2016 John Wiley & Sons, Ltd and Eating Disorders Association. Copyright © 2016 John Wiley & Sons, Ltd and Eating Disorders Association.

  1. TNF-α inhibits trophoblast integration into endothelial cellular networks.

    Science.gov (United States)

    Xu, B; Nakhla, S; Makris, A; Hennessy, A

    2011-03-01

    Preeclampsia has been linked to shallow trophoblast invasion and failure of uterine spiral artery transformation. Interaction between trophoblast cells and maternal uterine endothelium is critically important for this remodelling. The aim of our study was to investigate the effect of TNF-α on the interactions of trophoblast-derived JEG-3 cells into capillary-like cellular networks. We have employed an in vitro trophoblast-endothelial cell co-culture model to quantify trophoblast integration into endothelial cellular networks and to investigate the effects of TNF-α. Controlled co-cultures were also treated with anti-TNF-α antibody (5 μg/ml) to specifically block the effect of TNF-α. The invasion was evaluated by performing quantitative PCR (Q-PCR) to analyse gene expression of matrix metalloproteinases-2 (MMP-2), MMP-9, tissue inhibitor of matrix metalloproteinase (TIMP)-1, integrins (α(1)β(1) and α(6)β(4)), plasminogen activator inhibitor (PAI)-1, E-cadherin and VE-cadherin. JEG-3 cell integration into endothelial networks was significantly inhibited by exogenous TNF-α. The inhibition was observed in the range of 0.2-5 ng/ml, to a maximum 56% inhibition at the highest concentration. This inhibition was reversed by anti-TNF-α antibody. Q-PCR analysis showed that mRNA expression of integrins α(1)β(1) and MMP-2 was significantly decreased. VE-cadherin mRNA expression was significantly up-regulated (32-80%, p integration into maternal endothelial cellular networks, and this process involves the inhibition of MMP-2 and a failure of integrins switch from α(6)β(4) to α(1)β(1.) These molecular correlations reflect the changes identified in human preeclampsia. Copyright © 2011 Elsevier Ltd. All rights reserved.

  2. Relations between episodic memory, suggestibility, theory of mind, and cognitive inhibition in the preschool child.

    Science.gov (United States)

    Melinder, Annika; Endestad, Tor; Magnussen, Svein

    2006-12-01

    The development of episodic memory, its relation to theory of mind (ToM), executive functions (e.g., cognitive inhibition), and to suggestibility was studied. Children (n= 115) between 3 and 6 years of age saw two versions of a video film and were tested for their memory of critical elements of the videos. Results indicated similar developmental trends for all memory measures, ToM, and inhibition, but ToM and inhibition were not associated with any memory measures. Correlations involving source memory was found in relation to specific questions, whereas inhibition and ToM were significantly correlated to resistance to suggestions. A regression analysis showed that age was the main contributor to resistance to suggestions, to correct source monitoring, and to correct responses to specific questions. Inhibition was also a significant main predictor of resistance to suggestive questions, whereas the relative contribution of ToM was wiped out when an extended model was tested.

  3. Inhibition of Neurogenesis by Zika virus Infection.

    Science.gov (United States)

    Ahmad, Fahim; Siddiqui, Amna; Kamal, Mohammad A; Sohrab, Sayed S

    2018-02-01

    The association between Zika virus infection and neurological disorder has raised urgent global alarm. The ongoing epidemic has triggered quick responses in the scientific community. The first case of Zika virus was reported in 2015 from Brazil and now has spread over 30 countries. Nearly four hundred cases of travel-associated Zika virus infection have also been reported in the United States. Zika virus is primarily transmitted by mosquito belongs to the genus Aedes that are widely distributed throughout the world including the Southern United States. Additionally, the virus can also be transmitted from males to females by sexual contact. The epidemiological investigations during the current outbreak found a causal link between infection in pregnant women and development of microcephaly in their unborn babies. This finding is a cause for grave concern since microcephaly is a serious neural developmental disorder that can lead to significant post-natal developmental abnormalities and disabilities. Recently, published data indicate that Zika virus infection affects the growth of fetal neural progenitor cells and cerebral neurons that results in malformation of cerebral cortex leading to microcephaly. Recently, it has been reported that Zika virus infection deregulates the signaling pathway of neuronal cell and inhibit the neurogenesis resulting into dementia. In this review we have discussed about the information about cellular and molecular mechanisms in neurodegeneration of human neuronal cells and inhibit the neurogenesis. Additionally, this information will be very helpful further not only in neuro-scientific research but also designing and development of management strategies for microcephaly and other mosquito borne disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  4. Spice phenolics inhibit human PMNL 5-lipoxygenase.

    Science.gov (United States)

    Prasad, N Satya; Raghavendra, R; Lokesh, B R; Naidu, K Akhilender

    2004-06-01

    A wide variety of phenolic compounds and flavonoids present in spices possess potent antioxidant, antimutagenic and anticarcinogenic activities. We examined whether 5-lipoxygenase (5-LO), the key enzyme involved in biosynthesis of leukotrienes is a possible target for the spices. Effect of aqueous extracts of turmeric, cloves, pepper, chili, cinnamon, onion and also their respective active principles viz., curcumin, eugenol, piperine, capsaicin, cinnamaldehyde, quercetin, and allyl sulfide were tested on human PMNL 5-LO activity by spectrophotomeric and HPLC methods. The formation of 5-LO product 5-HETE was significantly inhibited in a concentration-dependent manner with IC(50) values of 0.122-1.44 mg for aqueous extracts of spices and 25-83 microM for active principles, respectively. The order of inhibitory activity was of quercetin>eugenol>curcumin>cinnamaldehyde>piperine>capsaicin>allyl sulfide. Quercetin, eugenol and curcumin with one or more phenolic ring and methoxy groups in their structure showed high inhibitory effect, while the non-phenolic spice principle allyl sulfide showed least inhibitory effect on 5-LO. The inhibitory effect of quercetin, curcumin and eugenol was similar to that of synthetic 5-LO inhibitors-phenidone and NDGA. Moreover, the inhibitory potency of aqueous extracts of spice correlated with the active principles of their respective spices. The synergistic or antagonistic effect of mixtures of spice active principles and spice extracts were investigated and all the combinations of spice active principles/extracts exerted synergistic effect in inhibiting 5-LO activity. These findings clearly suggest that phenolic compounds present in spices might have physiological role in modulating 5-LO pathway.

  5. Inhibition of Zika Virus Replication by Silvestrol

    Directory of Open Access Journals (Sweden)

    Fabian Elgner

    2018-03-01

    Full Text Available The Zika virus (ZIKV outbreak in 2016 in South America with specific pathogenic outcomes highlighted the need for new antiviral substances with broad-spectrum activities to react quickly to unexpected outbreaks of emerging viral pathogens. Very recently, the natural compound silvestrol isolated from the plant Aglaia foveolata was found to have very potent antiviral effects against the (−-strand RNA-virus Ebola virus as well as against Corona- and Picornaviruses with a (+-strand RNA-genome. This antiviral activity is based on the impaired translation of viral RNA by the inhibition of the DEAD-box RNA helicase eukaryotic initiation factor-4A (eIF4A which is required to unwind structured 5´-untranslated regions (5′-UTRs of several proto-oncogenes and thereby facilitate their translation. Zika virus is a flavivirus with a positive-stranded RNA-genome harboring a 5′-capped UTR with distinct secondary structure elements. Therefore, we investigated the effects of silvestrol on ZIKV replication in A549 cells and primary human hepatocytes. Two different ZIKV strains were used. In both infected A549 cells and primary human hepatocytes, silvestrol has the potential to exert a significant inhibition of ZIKV replication for both analyzed strains, even though the ancestor strain from Uganda is less sensitive to silvestrol. Our data might contribute to identify host factors involved in the control of ZIKV infection and help to develop antiviral concepts that can be used to treat a variety of viral infections without the risk of resistances because a host protein is targeted.

  6. Kindergarteners' self-reported social inhibition and observed social reticence: moderation by adult-reported social inhibition and social anxiety disorder symptoms.

    Science.gov (United States)

    Kiel, Elizabeth J; Buss, Kristin A; Molitor, Joseph G

    2015-04-01

    Prevention of later anxiety problems would best be accomplished by identifying at-risk children early in development. For example, children who develop Social Anxiety Disorder (SAD) may show social withdrawal in the form of social inhibition (i.e., shyness with unfamiliar adults and peers) at school entry. Although the use of children's perceptions of their own social inhibition would provide insight into early risk, the utility of young children's self-reports remains unclear. The current study examined whether children deemed more extreme on social inhibition or social anxiety by adult report provided self-report of social inhibition that related to observed social reticence in the laboratory. Participants included 85 kindergarten children (36 female, 49 male), their parents, and their teachers. Moderation analyses revealed that children's self-reported social inhibition related significantly to observed social reticence under the conditions of high parent-reported social inhibition, high teacher-reported social inhibition, and high SAD symptoms. These results suggest that the most inhibited children are aware of their behavior and can report it in a meaningfully way as young as kindergarten age.

  7. Kindergarteners’ Self-Reported Social Inhibition and Observed Social Reticence: Moderation by Adult-Reported Social Inhibition and Social Anxiety Disorder Symptoms

    Science.gov (United States)

    Kiel, Elizabeth J.; Buss, Kristin A.; Molitor, Joseph G.

    2014-01-01

    Prevention of later anxiety problems would best be accomplished by identifying at-risk children early in development. For example, children who develop Social Anxiety Disorder (SAD) may show social withdrawal in the form of social inhibition (i.e., shyness with unfamiliar adults and peers) at school entry. Although the use of children’s perceptions of their own social inhibition would provide insight into early risk, the utility of young children’s self-reports remains unclear. The current study examined whether children deemed more extreme on social inhibition or social anxiety by adult report provided self-report of social inhibition that related to observed social reticence in the laboratory. Participants included 85 kindergarten children (36 female, 49 male), their parents, and their teachers. Moderation analyses revealed that children’s self-reported social inhibition related significantly to observed social reticence under the conditions of high parent-reported social inhibition, high teacher-reported social inhibition, and high SAD symptoms. These results suggest that the most inhibited children are aware of their behavior and can report it in a meaningfully way as young as kindergarten age. PMID:25113397

  8. Changing relationships with significant others: Reflections of ...

    African Journals Online (AJOL)

    Symbolic interactionism provides the framework for analysing the building of relationships between elite athletes and their significant others. In-depth interviews were conducted with elite throwers and decathlon athletes. The sample included current (n=15) and retired (n=5) student-athletes, parents (n=5), coaches (n=2) ...

  9. Mycotoxins: significance to global economics and health

    Science.gov (United States)

    Mycotoxins are fungal metabolites produced my micro-fungi (molds and mildews) that have significant impacts on global economics and health. Some of these metabolites are beneficial, but most are harmful and have been associated with well-known epidemics dating back to medieval times. The terms ‘myco...

  10. Incidence and Significance of Haematemesis in Cirrhosis

    African Journals Online (AJOL)

    1974-06-08

    Jun 8, 1974 ... veloped encephalopathy and coma. It was found that more patients fell into the latter group (50 cases) than into the group with haematemesis (with or without encephalopathy). (45 cases), but there was no significant difference in the mortality rate of the groups. s. Afr. Med. l., 48, 1155 (1974). It has for some ...

  11. Encounter Probability of Significant Wave Height

    DEFF Research Database (Denmark)

    Liu, Z.; Burcharth, H. F.

    The determination of the design wave height (often given as the significant wave height) is usually based on statistical analysis of long-term extreme wave height measurement or hindcast. The result of such extreme wave height analysis is often given as the design wave height corresponding to a c...

  12. The Significance of the Nursery School

    Science.gov (United States)

    Gesell, Arnold

    2017-01-01

    From the standpoint of mental health and perhaps even from the standpoint of human culture, the complete realization of the educational possibilities of the preschool child is of foundational significance. Normative and comparative studies performed at a psychological clinic at Yale examining norms of development in children from one month to five…

  13. Scope and Significance of Eating Disorders.

    Science.gov (United States)

    Mitchell, James E.; Eckert, Elke D.

    1987-01-01

    Describes the increasing prevalence of anorexia nervosa and bulimia in many industrialized societies, and their association with significant morbidity and mortality. Discusses the genetic risks for the development of anorexia nervosa, and treatment strategies. Of these, pharmacotherapy and psychotherapy, particularly those incorporating…

  14. Soil physicochemical properties and their significance for ...

    African Journals Online (AJOL)

    Soil physicochemical properties and their significance for sustainable sugarcane production in Kesem Allaideghe plains irrigation project area, Eastern Ethiopia. ... In order to improve soil structure and water availability, addition of gypsum, plant residues and organic matter are recommended. Keywords: Soil survey ...

  15. Petrochemistry and geotectonic significance of enderbite ...

    African Journals Online (AJOL)

    Petrochemistry and geotectonic significance of enderbite-charnockite association in the Pan-African Obudu plateau, southeastern Nigeria. VU Ukaegbu, FT Beka. Abstract. No Abstract. Journal of Mining and Geology Vol. 43 (1) 2007: pp. 1-14. Full Text: EMAIL FULL TEXT EMAIL FULL TEXT · DOWNLOAD FULL TEXT ...

  16. The Historical Significance of the Universal Declaration.

    Science.gov (United States)

    Eide, Asbjorn

    1998-01-01

    Explains the historical significance of the Universal Declaration of Human Rights. Focuses on the initiative for the Declaration and its elaboration, the precursors to modern human rights, the foundation of the Declaration, the rights contained in the Universal Declaration, three modes of human rights analysis, and global governance and human…

  17. Bullying in Academe: Prevalent, Significant, and Incessant

    Science.gov (United States)

    Cassell, Macgorine A.

    2011-01-01

    This paper examines the top-down perspective of bullying and mobbing of professors by analyzing why it is prevalent, significant, and incessant and then proposes a framework to produce a caring, respectful, and safe environment for professors to engage in their teaching, scholarship, and service. The author suggests that the failure of…

  18. Cystic echinococcosis: prevalence and economic significance in ...

    African Journals Online (AJOL)

    A cross-sectional study was conducted from November 2015 to April 2016 at ELFORA export abattoir to determine the prevalence, cyst viability, organ distribution and economic significance of small ruminant cystic echinococcosis. A total of 850 small ruminants (400 sheep and 450 goats), were examined for the presence of ...

  19. Significance of Literature in Foreign Language Teaching

    Science.gov (United States)

    Babaee, Ruzbeh; Yahya, Wan Roselezam Bt Wan

    2014-01-01

    This research aims to consider literature as a significant tool for teaching fundamental language skills including speaking, listening, reading and writing. Reasons for the use of literature in language classrooms and major factors for choosing appropriate kinds of literary texts in such classes should be highlighted in order to make readers aware…

  20. 32 CFR 651.39 - Significance.

    Science.gov (United States)

    2010-07-01

    ... existing pollution standards; cause water, air, noise, soil, or underground pollution; impair visibility... Defense Department of Defense (Continued) DEPARTMENT OF THE ARMY (CONTINUED) ENVIRONMENTAL QUALITY ENVIRONMENTAL ANALYSIS OF ARMY ACTIONS (AR 200-2) Environmental Assessment § 651.39 Significance. (a) If the...

  1. [Current clinical significance of anaerobic bacteremia].

    Science.gov (United States)

    Jirsa, Roman; Marešová, Veronika; Brož, Zdeněk

    2010-10-01

    to estimate tje current clinical significance of anaerobic bacteremia in a group of Czech hospitals. this retrospective analysis comprised 8 444 anaerobic blood cultures in patients admitted to four Czech hospitals between 2004 and 2007. in 16 patients, blood cultures yielded significant anaerobic bacteria. Thus, anaerobic bacteremia accounted for less than 2 % of clinically significant bacteremia. Four patients (18 %) died but none of the deaths could be clearly attributable to anaerobic bacteria in the bloodstream. The most common comorbidities predisposing to anaerobic bacteremia and the most frequent sources of infection were similar to those reported by other authors. The majority of anaerobic bacteremia cases were due to gram-negative bacteria, followed by Clostridium perfringens and, surprisingly, Eubacterium spp. (particularly Eubacterium lentum). anaerobic bacteremia remains rare. The comparison of our data with those by other authors suggests that (despite the reported high mortality) the actual clinical significance of anaerobic bacteremia is rather controversial and that the anaerobic bacteremia might not correspond to more serious pathogenic role of the anaerobic bacteria as the source of infection.

  2. Discovering the Significance of Scientific Design Practice

    DEFF Research Database (Denmark)

    Pries-Heje, Jan; Baskerville, Richard

    This paper aims at discussing and defining what it is that makes design science research significant. First it reviews the values and processes of old science and how this attacks complexity through analysis. It then shows how new science attacks complexity through synthesis. Then the paper argue...

  3. STIR: Assessing and Training Response Inhibition Abilities

    Science.gov (United States)

    2014-07-30

    Learning to stop responding to alcohol cues reduces alcohol intake via reduced affective associations rather than increased response inhibition. Addiction ...requires an abstract application of the core learning principle1,2, and viable examples are often hard to find and/or assess. If exposure to non...inhibition training that expands upon previous successful “near transfer” response inhibition training efforts—such as treating alcohol addictions by

  4. Neural signature of behavioural inhibition in women with bulimia nervosa.

    Science.gov (United States)

    Skunde, Mandy; Walther, Stephan; Simon, Joe J; Wu, Mudan; Bendszus, Martin; Herzog, Wolfgang; Friederich, Hans-Christoph

    2016-08-01

    Impaired inhibitory control is considered a behavioural phenotype in patients with bulimia nervosa. However, the underlying neural correlates of impaired general and food-specific behavioural inhibition are largely unknown. Therefore, we investigated brain activation during the performance of behavioural inhibition to general and food-related stimuli in adults with bulimia nervosa. Women with bulimia and healthy control women underwent event-related fMRI while performing a general and a food-specific no-go task. We included 28 women with bulimia nervosa and 29 healthy control women in our study. On a neuronal level, we observed significant group differences in response to general no-go stimuli in women with bulimia nervosa with high symptom severity; compared with healthy controls, the patients showed reduced activation in the right sensorimotor area (postcentral gyrus, precentral gyrus) and right dorsal striatum (caudate nucleus, putamen). The present results are limited to adult women with bulimia nervosa. Furthermore, it remains unclear whether impaired behavioural inhibition in patients with this disorder are a cause or consequence of chronic illness. Our findings suggest that diminished frontostriatal brain activation in patients with bulimia nervosa contribute to the severity of binge eating symptoms. Gaining further insight into the neural mechanisms of behavioural inhibition problems in individuals with this disorder may inform brain-directed treatment approaches and the development of response inhibition training approaches to improve inhibitory control in patients with bulimia nervosa. The present study does not support greater behavioural and neural impairments to food-specific behavioural inhibition in these patients.

  5. Neural signature of behavioural inhibition in women with bulimia nervosa

    Science.gov (United States)

    Skunde, Mandy; Walther, Stephan; Simon, Joe J.; Wu, Mudan; Bendszus, Martin; Herzog, Wolfgang; Friederich, Hans-Christoph

    2016-01-01

    Background Impaired inhibitory control is considered a behavioural phenotype in patients with bulimia nervosa. However, the underlying neural correlates of impaired general and food-specific behavioural inhibition are largely unknown. Therefore, we investigated brain activation during the performance of behavioural inhibition to general and food-related stimuli in adults with bulimia nervosa. Methods Women with bulimia and healthy control women underwent event-related fMRI while performing a general and a food-specific no-go task. Results We included 28 women with bulimia nervosa and 29 healthy control women in our study. On a neuronal level, we observed significant group differences in response to general no-go stimuli in women with bulimia nervosa with high symptom severity; compared with healthy controls, the patients showed reduced activation in the right sensorimotor area (postcentral gyrus, precentral gyrus) and right dorsal striatum (caudate nucleus, putamen). Limitations The present results are limited to adult women with bulimia nervosa. Furthermore, it remains unclear whether impaired behavioural inhibition in patients with this disorder are a cause or consequence of chronic illness. Conclusion Our findings suggest that diminished frontostriatal brain activation in patients with bulimia nervosa contribute to the severity of binge eating symptoms. Gaining further insight into the neural mechanisms of behavioural inhibition problems in individuals with this disorder may inform brain-directed treatment approaches and the development of response inhibition training approaches to improve inhibitory control in patients with bulimia nervosa. The present study does not support greater behavioural and neural impairments to food-specific behavioural inhibition in these patients. PMID:27575858

  6. Ammonium inhibition of nitrogenase activity in Herbaspirillum seropedicae

    Energy Technology Data Exchange (ETDEWEB)

    Fu, H.; Burris, R.H. (Univ. of Wisconsin, Madison (USA))

    1989-06-01

    The effect of oxygen, ammonium ion, and amino acids on nitrogenase activity in the root-associated N{sub 2}-fixing bacterium Herbaspirillum seropedicae was investigated in comparison with Azospirillum spp. and Rhodospirillum rubrum. H. seropedicae is microaerophilic, and its optimal dissolved oxygen level is from 0.04 to 0.2 kPa for dinitrogen fixation but higher when it is supplied with fixed nitrogen. No nitrogenase activity was detected when the dissolved O{sub 2} level corresponded to 4.0 kPa. Ammonium, a product of the nitrogenase reaction, reversible inhibited nitrogenase activity when added to derepressed cell cultures. However, the inhibition of nitrogenase activity was only partial even with concentrations of ammonium chloride as high as 20 mM. Amides such as glutamine and asparagine partially inhibited nitrogenase activity, but glutamate did not. Nitrogenase in crude extracts prepared from ammonium-inhibited cells showed activity as high as in extracts from N{sub 2}-fixing cells. The pattern of the dinitrogenase and the dinitrogenase reductase revealed by the immunoblotting technique did not change upon ammonium chloride treatment of cells in vivo. No homologous sequences were detected with the draT-draG probe from Azospirillum lipoferum. There is no clear evidence that ADP-ribosylation of the dinitrogenase reductase is involved in the ammonium inhibition of H. seropedicae. The uncoupler carbonyl cyanide m-chlorophenylhydrazone decreased the intracellular ATP concentration and inhibited the nitrogenase activity of whole cells. The ATP pool was significantly disturbed when cultures were treated with ammonium in vivo.

  7. Response inhibition signals and miscoding of direction in dorsomedial striatum

    Directory of Open Access Journals (Sweden)

    Daniel W Bryden

    2012-09-01

    Full Text Available The ability to inhibit action is critical for everyday behavior and is affected by a variety of disorders. Behavioral control and response inhibition is thought to depend on a neural circuit that includes the dorsal striatum, yet the neural signals that lead to response inhibition and its failure are unclear. To address this issue, we recorded from neurons in rat dorsomedial striatum (mDS in a novel task in which rats responded to a spatial cue that signaled that reward would be delivered either to the left or to the right. On 80% of trials rats were instructed to respond in the direction cued by the light (GO. On 20% of trials a second light illuminated instructing the rat to refrain from making the cued movement and move in the opposite direction (STOP. Many neurons in mDS encoded direction, firing more or less strongly for GO movements made ipsilateral or contralateral to the recording electrode. Neurons that fired more strongly for contralateral GO responses were more active when rats were faster, showed reduced activity on STOP trials, and miscoded direction on errors, suggesting that when these neurons were overly active, response inhibition failed. Neurons that decreased firing for contralateral movement were excited during trials in which the rat was required to stop the ipsilateral movement. For these neurons activity was reduced when errors were made and was negatively correlated with movement time suggesting that when these neurons were less active on STOP trials, response inhibition failed. Finally, the activity of a significant number of neurons represented a global inhibitory signal, firing more strongly during response inhibition regardless of response direction. Breakdown by cell type suggests that putative medium spiny neurons tended to fire more strongly under STOP trials, whereas putative interneurons exhibited both activity patterns. 

  8. An IP-10 (CXCL10)-Derived Peptide Inhibits Angiogenesis

    Science.gov (United States)

    Yates-Binder, Cecelia C.; Rodgers, Margaret; Jaynes, Jesse; Wells, Alan; Bodnar, Richard J.; Turner, Timothy

    2012-01-01

    Angiogenesis plays a critical role in processes such as organ development, wound healing, and tumor growth. It requires well-orchestrated integration of soluble and matrix factors and timely recognition of such signals to regulate this process. Previous work has shown that newly forming vessels express the chemokine receptor CXC receptor 3 (CXCR3) and, activation by its ligand IP-10 (CXCL10), both inhibits development of new vasculature and causes regression of newly formed vessels. To identify and develop new therapeutic agents to limit or reverse pathological angiogenesis, we identified a 21 amino acid fragment of IP-10, spanning the α-helical domain residues 77–98, that mimic the actions of the whole IP-10 molecule on endothelial cells. Treatment of the endothelial cells with the 22 amino acid fragment referred to as IP-10p significantly inhibited VEGF-induced endothelial motility and tube formation in vitro, properties critical for angiogenesis. Using a Matrigel plug assay in vivo, we demonstrate that IP-10p both prevented vessel formation and induced involution of nascent vessels. CXCR3 neutralizing antibody was able to block the inhibitory effects of the IP-10p, demonstrating specificity of the peptide. Inhibition of endothelial function by IP-10p was similar to that described for IP-10, secondary to CXCR3-mediated increase in cAMP production, activation of PKA inhibiting cell migration, and inhibition of VEGF-mediated m-calpain activation. IP-10p provides a novel therapeutic agent that inhibits endothelial cell function thus, allowing for the modulation of angiogenesis. PMID:22815829

  9. Inhibition of apparent photosynthesis by nitrogen oxides

    Energy Technology Data Exchange (ETDEWEB)

    Hill, A C; Bennett, J H

    1970-01-01

    The nitrogen oxides (NO/sub 2/ and NO) inhibited apparent photosynthesis of oats and alfalfa at concentrations below those required to cause visible injury. There appeared to be a threshold concentration of about 0.6 ppm for each pollutant. An additive effect in depressing apparent photosynthesis occurred when the plants were exposed to a mixture of NO and NO/sub 2/. Although NO produced a more rapid effect on the plants, lower concentrations of NO/sub 2/ were required to cause a given inhibition after 2 hour of exposure. Inhibition by nitric oxide was more closely related to its partial pressure than was inhibition by NO/sub 2/.

  10. Magnolol Inhibits the Growth of Non-Small Cell Lung Cancer via Inhibiting Microtubule Polymerization

    Directory of Open Access Journals (Sweden)

    Jia Shen

    2017-07-01

    Full Text Available Background: The tubulin/microtubule system, which is an integral component of the cytoskeleton, plays an essential role in mitosis. Targeting mitotic progression by disturbing microtubule dynamics is a rational strategy for cancer treatment. Methods: Microtubule polymerization assay was performed to examine the effect of Magnolol (a novel natural phenolic compound isolated from Magnolia obovata on cellular microtubule polymerization in human non-small cell lung cancer (NSCLC cells. Cell cycle analysis, mitotic index assay, cell proliferation assay, colony formation assay, western blotting analysis of cell cycle regulators, Annexin V-FITC/PI staining, and live/dead viability staining were carried out to investigate the Magnolol’s inhibitory effect on proliferation and viability of NSCLS cells in vitro. Xenograft model of human A549 NSCLC tumor was used to determine the Magnolol’s efficacy in vivo. Results: Magnolol treatment effectively inhibited cell proliferation and colony formation of NSCLC cells. Further study proved that Magnolol induced the mitotic phase arrest and inhibited G2/M progression in a dose-dependent manner, which were mechanistically associated with expression alteration of a series of cell cycle regulators. Furthermore, Magnolol treatment disrupted the cellular microtubule organization via inhibiting the polymerization of microtubule. We also found treatment with NSCLC cells with Magnolol resulted in apoptosis activation through a p53-independent pathway, and autophgy induction via down-regulation of the Akt/mTOR pathway. Finally, Magnolol treatment significantly suppressed the NSCLC tumor growth in mouse xenograft model in vivo. Conclusion: These findings identify Magnolol as a promising candidate with anti-microtubule polymerization activity for NSCLC treatment.

  11. Local anesthetic-induced inhibition of human neutrophil priming: the influence of structure, lipophilicity, and charge

    NARCIS (Netherlands)

    Picardi, Susanne; Cartellieri, Sibylle; Groves, Danja; Hahnenekamp, Klaus; Gerner, Peter; Durieux, Marcel E.; Stevens, Markus F.; Lirk, Philipp; Hollmann, Markus W.

    2013-01-01

    Local anesthetics (LAs) are widely known for inhibition of voltage-gated sodium channels underlying their antiarrhythmic and antinociceptive effects. However, LAs have significant immunomodulatory properties and were shown to affect human neutrophil functions independent of sodium-channel blockade.

  12. Significant incidents in nuclear fuel cycle facilities

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-03-01

    In contrast to nuclear power plants, events in nuclear fuel cycle facilities are not well documented. The INES database covers all the nuclear fuel cycle facilities; however, it was developed in the early 1990s and does not contain information on events prior to that. The purpose of the present report is to collect significant events and analyze them in order to give a safety related overview of nuclear fuel cycle facilities. Significant incidents were selected using the following criteria: release of radioactive material or exposure to radiation; degradation of items important to safety; and deficiencies in design, quality assurance, etc. which include criticality incidents, fire, explosion, radioactive release and contamination. This report includes an explanation, where possible, of root causes, lessons learned and action taken. 4 refs, 4 tabs.

  13. Significant incidents in nuclear fuel cycle facilities

    International Nuclear Information System (INIS)

    1996-03-01

    In contrast to nuclear power plants, events in nuclear fuel cycle facilities are not well documented. The INES database covers all the nuclear fuel cycle facilities; however, it was developed in the early 1990s and does not contain information on events prior to that. The purpose of the present report is to collect significant events and analyze them in order to give a safety related overview of nuclear fuel cycle facilities. Significant incidents were selected using the following criteria: release of radioactive material or exposure to radiation; degradation of items important to safety; and deficiencies in design, quality assurance, etc. which include criticality incidents, fire, explosion, radioactive release and contamination. This report includes an explanation, where possible, of root causes, lessons learned and action taken. 4 refs, 4 tabs

  14. Respiratory neuroplasticity - Overview, significance and future directions.

    Science.gov (United States)

    Fuller, David D; Mitchell, Gordon S

    2017-01-01

    Neuroplasticity is an important property of the neural system controlling breathing. However, our appreciation for its importance is still relatively new, and we have much to learn concerning different forms of plasticity, their underlying mechanisms, and their biological and clinical significance. In this brief review, we discuss several well-studied models of respiratory plasticity, including plasticity initiated by inactivity in the respiratory system, intermittent and sustained hypoxia, and traumatic injury to the spinal cord. Other aspects of respiratory plasticity are considered in other contributions to this special edition of Experimental Neurology on respiratory plasticity. Finally, we conclude with discussions concerning the biological and clinical significance of respiratory motor plasticity, and areas in need of future research effort. Copyright © 2016. Published by Elsevier Inc.

  15. Dual purpose or not? The significant factors

    International Nuclear Information System (INIS)

    Bak, W.; Roland, V.

    1999-01-01

    The development of spent fuel storage systems requires consideration of many factors in making design decisions. A significant issue affecting the design is the need to incorporate transportability of the canister or cask system design, which results in major changes to the storage system design. This paper presents a review of the significant factors affecting storage system design to incorporate transportation requirements and looks at the trends in both the United States and Europe where Transnucleaire and its US affiliated companies Transnuclear Inc., Transnuclear West and PacTec are active. A discussion is also presented relative to the pros and cons of whether the spent fuel storage system vendor should anticipate these transportation needs in the design of their systems. (author)

  16. Cross wavelet analysis: significance testing and pitfalls

    Directory of Open Access Journals (Sweden)

    D. Maraun

    2004-01-01

    Full Text Available In this paper, we present a detailed evaluation of cross wavelet analysis of bivariate time series. We develop a statistical test for zero wavelet coherency based on Monte Carlo simulations. If at least one of the two processes considered is Gaussian white noise, an approximative formula for the critical value can be utilized. In a second part, typical pitfalls of wavelet cross spectra and wavelet coherency are discussed. The wavelet cross spectrum appears to be not suitable for significance testing the interrelation between two processes. Instead, one should rather apply wavelet coherency. Furthermore we investigate problems due to multiple testing. Based on these results, we show that coherency between ENSO and NAO is an artefact for most of the time from 1900 to 1995. However, during a distinct period from around 1920 to 1940, significant coherency between the two phenomena occurs.

  17. Significance and radioimmunoassay of gastric inhibitory polypeptide

    International Nuclear Information System (INIS)

    Zheng Ping; Zeng Minde; Yuan Jimin

    1995-01-01

    We have established the GIP Radioimmunoassay which has high sensitivity and specificity by labelling with iodogen and purified with HPLC. Using this method, the plasma GIP level was measured in 64 cases of which there are 10 normal individuals, 25 cases of diabetes and 29 cases of liver cirrhosis . The results showed that the plasma GIP level was significantly increased in patients with liver cirrhosis and correlated to degree of glucose tolerance damage

  18. Prevalence of significant bacteriuria among symptomatic and ...

    African Journals Online (AJOL)

    Data were analyzed using the Statistical Package for Social Sciences (SPSS) version 16.0 (SPSS, Inc., Chicago, Ill). Results: A total of 100 consenting participants were recruited into the study. The mean age was: 23.42 ± 8.31 years and a range of 14‑50 years. Only 9% (9/100) had significant bacteriuria while 44.4% (4/9) ...

  19. Impact significance determination-Designing an approach

    International Nuclear Information System (INIS)

    Lawrence, David P.

    2007-01-01

    The question of how best to go about determining the significance of impacts has, to date, only been addressed in a partial and preliminary way. The assumption tends to be made that it is either only necessary to provide explicit, justified reasons for a judgment about significance and/or to explicitly apply a prescribed procedure-a procedure usually involving the staged application of thresholds and/or criteria. The detailed attributes, strengths and limitations of such approaches and possible alternative approaches have yet to be explored systematically. This article addresses these deficiencies by analyzing the characteristics, specific methods and positive and negative tendencies of three general impact significance determination approaches-the technical approach, the collaborative approach and the reasoned argumentation approach. A range of potential composite approaches are also described. With an enhanced understanding of these approaches, together with potential combinations, EIA practitioners and other EIA participants can be in a better position to select an approach appropriate to their needs, to reinforce the positive tendencies and offset the negative tendencies of the selected approach and to combine the best qualities of more than one approach

  20. Significance of postoperative irradiation for breast cancer

    International Nuclear Information System (INIS)

    Murai, Nobuko; Ogami, Koji; Nishikawa, Kiyoshi; Koga, Kenji; Waki, Norio; Higashi, Hidefumi; Hayashi, Asami; Shibata, Koichiro; Watanabe, Katsuji

    1986-01-01

    From 1978 through 1983, 27 patients were treated with surgery followed by irradiation (irradiated group) and 29 with surery alone (non-irradiated group). In the irradiated group, 10 had stage II and 17 stage III; in the non-irradiated group, 25 had stage II and 4 stage III. The most common histology was medullary tubular carcinoma (MTC). There was no significant difference in survivals at 3 years and 5 years between the groups. Similarly, no significant difference was seen among stage II patients. Patients with MTC tended to have worse survivals in the irradiated group than in the non-irradiated group, with no statistically significant difference. Among stage II patients, no major differences in local recurrence were seen between the groups; the incidence of distant metastases tended to be high in the irradiated group. The incidence of both local recurrence and distant metastases for stage III patients showed a tendency to be higher in the irradiated group than in the non-irradiated group. The results indicated no apparent benifit of postoperative irradiation for breast cancer. A randomized clinical trial is needed for the evaluation of postoperative irradiation for breast cancer. (Namekawa, K.)

  1. Clinical significance of dental root canal microflora.

    Science.gov (United States)

    Gomes, B P; Lilley, J D; Drucker, D B

    1996-01-01

    Previous work by this group has shown that a significant association exists between pain and the presence of either Prevotella or Peptostreptococcus spp. in dental root canals. The aim of this study was to examine a more extensive series of canals microbiologically, to determine whether any other particular endodontic symptoms or clinical signs showed specific associations with individual bacterial species. Seventy root canals were examined microbiologically and clinical data collected to investigate in detail such associations. Of the canals studied, 37 were associated with pain, 49 with tenderness to percussion, 23 with swelling, six with purulent exudate and 57 presented with wet root canals. Anaerobes were isolated from 70.3% of painful canals and from 29.7% of pain-free canals. Significant associations were found between (a) pain and either Prevotella spp. or peptostreptococci, both with P spp. (P Eubacterium spp. (P spp. or Pstr. micros, both with P spp. (each P Eubacterium, Peptostreptococcus, Prevotella or Propionibacterium (each P < 0.05). It was concluded that several different endodontic clinical signs and symptoms are significantly associated with specific bacterial species.

  2. Lycopene Inhibits Propagation of Chlamydia Infection

    Directory of Open Access Journals (Sweden)

    Naylia A. Zigangirova

    2017-01-01

    Full Text Available Chlamydiaceae is a family of obligate intracellular pathogenic bacteria with similar developmental cycles and cell biology responsible for a wide range of diseases in different hosts including genital and eye inflammatory diseases, arthritis, and inflammatory diseases of the respiratory and cardiovascular systems. In the present paper, we report that lycopene, one of the main dietary carotenoids, which is present in tomato and some other fruits, has a strong inhibitory effect on C. trachomatis and C. pneumoniae infections in alveolar macrophages. This finding was documented by both immunofluorescence analysis and electron microscopy. It was noted that lycopene treatment inhibited intracellular phase of the chlamydial developmental cycle and resulted in a significant loss of infectious progeny. The antichlamydial effect of lycopene was also confirmed in a clinical setting. There was a significant reduction of IgG antibodies against C. pneumoniae in the serum of volunteers treated for a month with oral ingestion of 7 mg of lycopene. Additional studies are needed to further explore the antichlamydial activity of lycopene and its possible effect on C. pneumoniae in relation to antichlamydial activity of lycopene to mechanisms of atherosclerosis.

  3. Monoamine Oxidase-A Inhibition and Associated Antioxidant Activity in Plant Extracts with Potential Antidepressant Actions

    Directory of Open Access Journals (Sweden)

    Tomás Herraiz

    2018-01-01

    Full Text Available Monoamine oxidase (MAO catalyzes the oxidative deamination of amines and neurotransmitters and is involved in mood disorders, depression, oxidative stress, and adverse pharmacological reactions. This work studies the inhibition of human MAO-A by Hypericum perforatum, Peganum harmala, and Lepidium meyenii, which are reported to improve and affect mood and mental conditions. Subsequently, the antioxidant activity associated with the inhibition of MAO is determined in plant extracts for the first time. H. perforatum inhibited human MAO-A, and extracts from flowers gave the highest inhibition (IC50 of 63.6 μg/mL. Plant extracts were analyzed by HPLC-DAD-MS and contained pseudohypericin, hypericin, hyperforin, adhyperforin, hyperfirin, and flavonoids. Hyperforin did not inhibit human MAO-A and hypericin was a poor inhibitor of this isoenzyme. Quercetin and flavonoids significantly contributed to MAO-A inhibition. P. harmala seed extracts highly inhibited MAO-A (IC50 of 49.9 μg/L, being a thousand times more potent than H. perforatum extracts owing to its content of β-carboline alkaloids (harmaline and harmine. L. meyenii root (maca extracts did not inhibit MAO-A. These plants may exert protective actions related to antioxidant effects. Results in this work show that P. harmala and H. perforatum extracts exhibit antioxidant activity associated with the inhibition of MAO (i.e., lower production of H2O2.

  4. Reinforcement and stimulant medication ameliorate deficient response inhibition in children with Attention-Deficit/Hyperactivity Disorder

    Science.gov (United States)

    Rosch, Keri S.; Fosco, Whitney D.; Pelham, William E.; Waxmonsky, James G.; Bubnik, Michelle G.; Hawk, Larry W.

    2015-01-01

    This study examined the degree to which reinforcement, stimulant medication, and their combination impact response inhibition in children with Attention-Deficit/Hyperactivity Disorder (ADHD). Across three studies, participants with ADHD (n=111, 25 girls) and typically-developing (TD) controls (n=33, 6 girls) completed a standard version of the stop signal task (SST) and/or a reinforcement-manipulation SST with performance-contingent points. In two of these studies, these tasks were performed under placebo or 0.3 and 0.6 mg/kg methylphenidate (MPH) conditions. Cross-study comparisons were conducted to test hypotheses regarding the separate and combined effects of reinforcement and methylphenidate on response inhibition among children with ADHD relative to TD controls. Baseline response inhibition was worse among children with ADHD compared to controls. MPH produced dose-related improvements in response inhibition in children with ADHD; compared to non-medicated TD controls, 0.3 mg/kg MPH normalized deficient response inhibition, and 0.6 mg/kg MPH resulted in better inhibition in children with ADHD. Reinforcement improved response inhibition to a greater extent for children with ADHD than for TD children, normalizing response inhibition. The combination of MPH and reinforcement improved response inhibition among children with ADHD compared to reinforcement alone and MPH alone, also resulting in normalization of response inhibition despite repeated task exposure. Deficient response inhibition commonly observed in children with ADHD is significantly improved with MPH and/or reinforcement, normalizing inhibition relative to TD children tested under standard conditions. PMID:25985978

  5. Combination of rapamycin, CI-1040, and 17-AAG inhibits metastatic capacity of prostate cancer via Slug inhibition.

    Directory of Open Access Journals (Sweden)

    Guanxiong Ding

    Full Text Available Though prostate cancer (PCa has slow progression, the hormone refractory (HRCP and metastatic entities are substantially lethal and lack effective treatments. Transcription factor Slug is critical in regulating metastases of various tumors including PCa. Here we studied targeted therapy against Slug using combination of 3 drugs targeting 3 pathways respectively converging via Slug and further regulating PCa metastasis. Using in vitro assays we confirmed that Slug up-regulation incurred inhibition of E-cadherin that was anti-metastatic, and inhibited Bim-regulated cell apoptosis in PCa. Upstream PTEN/Akt, mTOR, Erk, and AR/Hsp90 pathways were responsible for Slug up-regulation and each of these could be targeted by rapamycin, CI-1040, and 17-AAG respectively. In 4 PCa cell lines with different traits in terms of PTEN loss and androgen sensitivity we tested the efficacy of mono- and combined therapy with the drugs. We found that metastatic capacity of the cells was maximally inhibited only when all 3 drugs were combined, due to the crosstalk between the pathways. 17-AAG decreases Slug expression via blockade of HSP90-dependent AR stability. Combination of rapamycin and CI-1040 diminishes invasiveness more potently in PCa cells that are androgen insensitive and with PTEN loss. Slug inhibited Bim-mediated apoptosis that could be rescued by mTOR/Erk/HSP90 inhibitors. Using mouse models for circulating PCa DNA quantification, we found that combination of mTOR/Erk/HSP90 inhibitors reduced circulating PCa cells in vivo significantly more potently than combination of 2 or monotherapy. Conclusively, combination of mTOR/Erk/Hsp90 inhibits metastatic capacity of prostate cancer via Slug inhibition.

  6. Feedforward and feedback inhibition in neostriatal GABAergic spiny neurons.

    Science.gov (United States)

    Tepper, James M; Wilson, Charles J; Koós, Tibor

    2008-08-01

    There are two distinct inhibitory GABAergic circuits in the neostriatum. The feedforward circuit consists of a relatively small population of GABAergic interneurons that receives excitatory input from the neocortex and exerts monosynaptic inhibition onto striatal spiny projection neurons. The feedback circuit comprises the numerous spiny projection neurons and their interconnections via local axon collaterals. This network has long been assumed to provide the majority of striatal GABAergic inhibition and to sharpen and shape striatal output through lateral inhibition, producing increased activity in the most strongly excited spiny cells at the expense of their less strongly excited neighbors. Recent results, mostly from recording experiments of synaptically connected pairs of neurons, have revealed that the two GABAergic circuits differ markedly in terms of the total number of synapses made by each, the strength of the postsynaptic response detected at the soma, the extent of presynaptic convergence and divergence and the net effect of the activation of each circuit on the postsynaptic activity of the spiny neuron. These data have revealed that the feedforward inhibition is powerful and widespread, with spiking in a single interneuron being capable of significantly delaying or even blocking the generation of spikes in a large number of postsynaptic spiny neurons. In contrast, the postsynaptic effects of spiking in a single presynaptic spiny neuron on postsynaptic spiny neurons are weak when measured at the soma, and unable to significantly affect spike timing or generation. Further, reciprocity of synaptic connections between spiny neurons is only rarely observed. These results suggest that the bulk of the fast inhibition that has the strongest effects on spiny neuron spike timing comes from the feedforward interneuronal system whereas the axon collateral feedback system acts principally at the dendrites to control local excitability as well as the overall level of

  7. Inhibition of 5-Lipoxygenase Pathway Attenuates Acute Liver Failure by Inhibiting Macrophage Activation

    Directory of Open Access Journals (Sweden)

    Lu Li

    2014-01-01

    Full Text Available This study aimed to investigate the role of 5-lipoxygenase (5-LO in acute liver failure (ALF and changes in macrophage activation by blocking it. ALF was induced in rats by administration of D-galactosamine (D-GalN/lipopolysaccharide (LPS. Rats were injected intraperitoneally with AA-861 (a specific 5-LO inhibitor, 24 hr before D-GalN/LPS administration. After D-GalN/LPS injection, the liver tissue was collected for assessment of histology, macrophage microstructure, macrophage counts, 5-LO mRNA formation, protein expression, and concentration of leukotrienes. Serum was collected for detecting alanine aminotransferase (ALT, aspartate transaminase (AST, total bilirubin (Tbil, and tumor necrosis factor- (TNF-α. Twenty-four hours after injection, compared with controls, ALF rats were characterized by widespread hepatocyte necrosis and elevated ALT, AST, and Tbil, and 5-LO protein expression reached a peak. Liver leukotriene B4 was also significantly elevated. However, 5-LO mRNA reached a peak 8 hr after D-GalN/LPS injection. Simultaneously, the microstructure of macrophages was changed most significantly and macrophages counts were increased significantly. Moreover, serum TNF-α was also elevated. By contrast, AA-861 pretreatment significantly decreased liver necrosis as well as all of the parameters compared with the rats without pretreatment. Macrophages, via the 5-LO pathway, play a critical role in ALF, and 5-LO inhibitor significantly alleviates ALF, possibly related to macrophage inhibition.

  8. Assessing the significance of Heidegger's Black Notebooks

    Directory of Open Access Journals (Sweden)

    J. Malpas

    2018-03-01

    Full Text Available The publication of Heidegger's Black Notebooks (Schwarze Hefte has provoked a storm of controversy. Much of this has centred on the pro-Nazi and anti-Semitic comments the volumes contain. But these aspects of the Notebooks are perhaps the least surprising and important. This essay offers a summary overview of the issues to which the Notebooks give rise, at the same time as it also aims to provide a preliminary assessment of their overall significance, especially in relation to what they show about the nature and development of Heidegger's thinking from the early 1930s to the late 1940s.

  9. Os odontoideum: a significant radiographic finding

    International Nuclear Information System (INIS)

    Choit, Rachel L.; Reilly, Christopher W.; Jamieson, Douglas H.

    2005-01-01

    Os odontoideum can lead to instability of the atlantoaxial joint and places the spinal cord at significant risk for acute catastrophic events after minor trauma or chronic neurological change. We present two cases of os odontoideum in pediatric patients that were not appreciated at earlier remote imaging but were, in retrospect, detectable. One patient presented with an acute spinal cord injury. Incorporating assessment of dens integrity into the evaluation algorithm for all pediatric cervical spine studies should lead to early detection of os odontoideum lesions and allow referral to appropriate clinical spinal services for evaluation, surveillance and possible surgery to prevent future complications. (orig.)

  10. Detecting significant changes in protein abundance

    Directory of Open Access Journals (Sweden)

    Kai Kammers

    2015-06-01

    Full Text Available We review and demonstrate how an empirical Bayes method, shrinking a protein's sample variance towards a pooled estimate, leads to far more powerful and stable inference to detect significant changes in protein abundance compared to ordinary t-tests. Using examples from isobaric mass labelled proteomic experiments we show how to analyze data from multiple experiments simultaneously, and discuss the effects of missing data on the inference. We also present easy to use open source software for normalization of mass spectrometry data and inference based on moderated test statistics.

  11. Perspectives on Gandhi’s Significance Today

    Directory of Open Access Journals (Sweden)

    Michael Simpson

    2016-12-01

    Full Text Available Gandhi’s example has inspired countless political struggles worldwide over the past century. We might then ask how his thought has been transferred and translated when taken out of the particular historical and geographic context in which he lived. How have Gandhi’s ideas been changed or altered when adopted in different contexts? Which aspects of Gandhi’s thinking remain most relevant to struggles for social and environmental justice today? These are just a few of the questions that were discussed at the “Perspectives on Gandhi’s Significance Workshop” hosted by Reed College in Portland Oregon (USA, on April 16th, 2016.

  12. Sucralfate significantly reduces ciprofloxacin concentrations in serum.

    OpenAIRE

    Garrelts, J C; Godley, P J; Peterie, J D; Gerlach, E H; Yakshe, C C

    1990-01-01

    The effect of sucralfate on the bioavailability of ciprofloxacin was evaluated in eight healthy subjects utilizing a randomized, crossover design. The area under the concentration-time curve from 0 to 12 h was reduced from 8.8 to 1.1 micrograms.h/ml by sucralfate (P less than 0.005). Similarly, the maximum concentration of ciprofloxacin in serum was reduced from 2.0 to 0.2 micrograms/ml (P less than 0.005). We conclude that concurrent ingestion of sucralfate significantly reduces the concentr...

  13. Significant events caused by extraneous acts

    International Nuclear Information System (INIS)

    Verlaeken, J.

    1987-01-01

    The operating experience feedback system of VINCOTTE, called ARIANE, consists, among others, of preparing synthesis reports on specific safety concerns. A recent report deals with significant events caused by extranous acts. Events attributable to human error are numerous. Confusion errors have already been analysed in several publications (NES IRS 664 etc.). However, are described here some ten incidents where extranous acts occurred: ZION 2 (September 76), OYSTER CREEK (May 79), PALISADES (January 81), CATAWBA (August 85), etc. The contributing factors for these unfortunate initiatives are explained; several resort to psychological influences. Corrective actions are discussed, and some general lessons are drawn. (author)

  14. Medical significance of the essential biological metals

    International Nuclear Information System (INIS)

    Davies, I.J.T.

    1977-01-01

    The medical significance of the essential biological metals such as zinc, copper and molybdenum as well as their nutritional and biochemical importance are reviewed. The following topics are treated: biochemical actions of the essential biological metals; the concept of essentiality; the development of knowledge about the essential biological metals. Data are given on zinc deficiency and hypogonadismi in humans, zinc and acrodermatitis enterophatica, zinc and the skin, zinc in diabetes mellitus, zinc and insulin, zinc and the liver; copper functions, copper deficiency - ''sway back'' in sheep, copper and haemopoiesis, copper and the function of blood vessels; molybdenum and dental caries in humans, oesophageal carcinoma and molybdenum deficiency in humans. (T.G.)

  15. Non-destructive testing: significant facts

    International Nuclear Information System (INIS)

    Espejo, Hector; Ruch, Marta C.

    2006-01-01

    In the last fifty years different organisations, both public and private, have been assigned to the mission of introducing into the country the most relevant aspects of the modern technological discipline 'Non Destructive Testing' (NDT) through a manifold of activities, such as training and education, research, development, technical assistance and services, personnel qualification/certification and standardisation. A review is given of the significant facts in this process, in which the Argentine Atomic Energy Commission, CNEA, played a leading part, a balance of the accomplishments is made and a forecast of the future of the activity is sketched. (author) [es

  16. Os odontoideum: a significant radiographic finding

    Energy Technology Data Exchange (ETDEWEB)

    Choit, Rachel L.; Reilly, Christopher W. [BC Children' s Hospital, Department of Orthopaedics, Vancouver, BC (Canada); Jamieson, Douglas H. [BC Children' s Hospital, Department of Radiology, Vancouver (Canada)

    2005-08-01

    Os odontoideum can lead to instability of the atlantoaxial joint and places the spinal cord at significant risk for acute catastrophic events after minor trauma or chronic neurological change. We present two cases of os odontoideum in pediatric patients that were not appreciated at earlier remote imaging but were, in retrospect, detectable. One patient presented with an acute spinal cord injury. Incorporating assessment of dens integrity into the evaluation algorithm for all pediatric cervical spine studies should lead to early detection of os odontoideum lesions and allow referral to appropriate clinical spinal services for evaluation, surveillance and possible surgery to prevent future complications. (orig.)

  17. Significant exposures to isoeugenol derivaties in perfumes

    DEFF Research Database (Denmark)

    Rastogi, Suresh Chandra; Johansen, Jeanne Duus

    2008-01-01

    in perfumes/aftershaves. MATERIALS AND METHODS: 29 international brand perfumes/aftershaves were analysed for the target fragrance ingredient by gas chromatography-mass spectrometry. All samples were analysed in duplicate at detection levels of 1-5 p.p.m. RESULTS: 16 products (55%) contained isoeugenol...... was not detected in any of the investigated products. CONCLUSIONS: Isoeugenyl acetate is present in perfumes/aftershaves, in some products in significant amounts. This may lead to elicitation of contact allergy in isoeugenol-sensitized individuals and may contribute to unchanged levels of isoeugenol sensitization....

  18. pancreatic steatosis: diagnosis and clinical significance

    Directory of Open Access Journals (Sweden)

    Murat Daðdeviren

    2017-03-01

    Full Text Available Pancreatic steatosis (PS, with increased use of abdominal imaging in recent years generally appears as incidental. But it is a condition that is often overlooked. The reason for this is not yet fully demonstrated the clinical significance of PS while. However, in recent years, there are some studies conducted on the relationship with ps and other disease such as diabetes, metabolic syndrome, acute and chronic pancreatitis and pancreatic cancer. In this review, the etiology, diagnosis, treatment and clinical characteristics of ps were evaluated in the light of recent literature and current approaches. [J Contemp Med 2017; 7(1.000: 107-112

  19. Significance of abolishing British National Oil Corporation

    Energy Technology Data Exchange (ETDEWEB)

    Mabro, R

    1985-04-01

    The decision to abolish British National Oil Corporation has greater significance than any commentator, so far, has cared to admit. Mr. Mabro says the Government has done much more than get rid of an institution it had previously weakened and emasculated; in effect, it had abdicated its responsibilities for the pricing of North Sea oil. He further observes that these moves may be consistent with the tenets of a simplistic free-market ideology: they betray, however, a lack of understanding of the economics of oil, and of the UK economic interest in oil.

  20. Angiotensin-converting enzyme inhibition in diabetic nephropathy

    DEFF Research Database (Denmark)

    Parving, H H; Rossing, P; Hommel, E

    1995-01-01

    The aim of our prospective study was to evaluate putative progression promoters, kidney function, and prognosis during long-term treatment with angiotensin-converting enzyme inhibition in insulin-dependent diabetes mellitus patients suffering from diabetic nephropathy. Eighteen consecutive......, albuminuria (geometric mean +/- antilog SE) 982 +/- 1.2 micrograms/min, and GFR 98 +/- 5 mL/min/1.73 m2. Angiotensin-converting enzyme inhibition induced a significant reduction during the whole treatment period of blood pressure (137/85 +/- 3/1 mm Hg; P ....01), and the rate of decline in GFR was 4.4 +/- 0.7 mL/min/yr, in contrast to previous reports of 10 to 14 mL/min/yr (natural history). Univariate analysis revealed a significant correlation between the rate of decline in GFR and mean arterial blood pressure (r = 0.58, P = 0.01), albuminuria (r = 0.67, P

  1. Inhibition of photosynthesis by carbon monoxide and suspension of the carbon monoxide inhibition by light

    Energy Technology Data Exchange (ETDEWEB)

    Gewitz, H S; Voelker, W

    1963-08-01

    The experimental subject was the autotroph Chlorella pyrenoidosa. It was found that growth conditions determine whether the alga is inhibited by carbon monoxide or not. Respiration and photosynthesis are inhibited by carbon monoxide if the cells have grown rapidly under high light intensities. The inhibition of respiration and photosynthesis found in such cells is completely reversible. The inhibition depends not only on carbon monoxide pressure, but also on the oxygen pressure prevailing at the same time. 5 references, 1 figure, 3 tables.

  2. Sonographic ally Detected Architectural Distortion: Clinical Significance

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Shin Kee; Seo, Bo Kyoung; Yi, Ann; Cha, Sang Hoon; Kim, Baek Hyun; Cho, Kyu Ran; Kim, Young Sik; Son, Gil Soo; Kim, Young Soo; Kim, Hee Young [Korea University Ansan Hospital, Ansan (Korea, Republic of)

    2008-12-15

    Architectural distortion is a suspicious abnormality for the diagnosis of breast cancer. The aim of this study was to investigate the clinical significance of sonographic ally detected architectural distortion. From January 2006 to June 2008, 20 patients were identified who had sonographic ally detected architectural distortions without a history of trauma or surgery and abnormal mammographic findings related to an architectural distortion. All of the lesions were pathologically verified. We evaluated the clinical and pathological findings and then assessed the clinical significance of the sonographic ally detected architectural distortions. Based on the clinical findings, one (5%) of the 20 patients had a palpable lump and the remaining 19 patients had no symptoms. No patient had a family history of breast cancer. Based on the pathological findings, three (15%) patients had malignancies. The malignant lesions included invasive ductal carcinomas (n = 2) and ductal carcinoma in situ (n = 1). Four (20%) patients had high-risk lesions: atypical ductal hyperplasia (n = 3) and lobular carcinoma in situ (n = 1). The remaining 13 (65%) patients had benign lesions, however, seven (35%) out of 13 patients had mild-risk lesions (three intraductal papillomas, three moderate or florid epithelial hyperplasia and one sclerosing adenosis). Of the sonographic ally detected architectural distortions, 35% were breast cancers or high-risk lesions and 35% were mild-risk lesions. Thus, a biopsy might be needed for an architectural distortion without an associated mass as depicted on breast ultrasound, even though the mammographic findings are normal

  3. Adaptive significance of root grafting in trees

    Energy Technology Data Exchange (ETDEWEB)

    Loehle, C.; Jones, R.

    1988-12-31

    Root grafting has long been observed in forest trees but the adaptive significance of this trait has not been fully explained. Various authors have proposed that root grafting between trees contributes to mechanical support by linking adjacent root systems. Keeley proposes that this trait would be of greatest advantage in swamps where soils provide poor mechanical support. He provides as evidence a greenhouse study of Nyssa sylvatica Marsh in which seedlings of swamp provenance formed between-individual root grafts more frequently than upland provenance seedlings. In agreement with this within-species study, Keeley observed that arid zone species rarely exhibit grafts. Keeley also demonstrated that vines graft less commonly than trees, and herbs never do. Since the need for mechanical support coincides with this trend, these data seem to support his model. In this paper, the authors explore the mechanisms and ecological significance of root grafting, leading to predictions of root grafting incidence. Some observations support and some contradict the mechanical support hypothesis.

  4. Could patients' coughing have communicative significance?

    Science.gov (United States)

    Bailey, Julia V

    2008-01-01

    Medical discourse positions patients with coughs and colds negatively, so consulting health services with 'minor' respiratory illness is therefore more accountable than for other medical problems. Patients face dilemmas since they must persuade doctors of the doctorability of their illness without being seen as hypochondriacal, and they risk losing face if doctors decide that there is nothing much wrong. It is known that the placement of non-lexical features of talk such as laughing or crying can have interactional meaning. Using a data set of video-recorded doctor-patient cough and cold consultations, this study explores whether patients' coughing could have communicative significance. The study is a qualitative analysis of 33 consultations drawing on a constructionist, sociolinguistic analytic approach. Coughing is co-ordinated with talk rather than occurring randomly. Coughing helps patients to demonstrate the doctorability of their symptoms and to legitimize their claims for medical attention. Coughing is also associated with resistance to 'no problem' diagnoses, resulting in changes in the trajectory of talk (for example, soliciting more explanation from doctors and/or re-negotiation of doctors' investigation or treatment plans). Coughing is undoubtedly a manifestation of respiratory illness, but also has communicative significance in consultations for coughs and colds.

  5. Significance and popularity in music production

    Science.gov (United States)

    Monechi, Bernardo; Gravino, Pietro; Servedio, Vito D. P.; Tria, Francesca; Loreto, Vittorio

    2017-07-01

    Creative industries constantly strive for fame and popularity. Though highly desirable, popularity is not the only achievement artistic creations might ever acquire. Leaving a longstanding mark in the global production and influencing future works is an even more important achievement, usually acknowledged by experts and scholars. `Significant' or `influential' works are not always well known to the public or have sometimes been long forgotten by the vast majority. In this paper, we focus on the duality between what is successful and what is significant in the musical context. To this end, we consider a user-generated set of tags collected through an online music platform, whose evolving co-occurrence network mirrors the growing conceptual space underlying music production. We define a set of general metrics aiming at characterizing music albums throughout history, and their relationships with the overall musical production. We show how these metrics allow to classify albums according to their current popularity or their belonging to expert-made lists of important albums. In this way, we provide the scientific community and the public at large with quantitative tools to tell apart popular albums from culturally or aesthetically relevant artworks. The generality of the methodology presented here lends itself to be used in all those fields where innovation and creativity are in play.

  6. Sonographic ally Detected Architectural Distortion: Clinical Significance

    International Nuclear Information System (INIS)

    Kim, Shin Kee; Seo, Bo Kyoung; Yi, Ann; Cha, Sang Hoon; Kim, Baek Hyun; Cho, Kyu Ran; Kim, Young Sik; Son, Gil Soo; Kim, Young Soo; Kim, Hee Young

    2008-01-01

    Architectural distortion is a suspicious abnormality for the diagnosis of breast cancer. The aim of this study was to investigate the clinical significance of sonographic ally detected architectural distortion. From January 2006 to June 2008, 20 patients were identified who had sonographic ally detected architectural distortions without a history of trauma or surgery and abnormal mammographic findings related to an architectural distortion. All of the lesions were pathologically verified. We evaluated the clinical and pathological findings and then assessed the clinical significance of the sonographic ally detected architectural distortions. Based on the clinical findings, one (5%) of the 20 patients had a palpable lump and the remaining 19 patients had no symptoms. No patient had a family history of breast cancer. Based on the pathological findings, three (15%) patients had malignancies. The malignant lesions included invasive ductal carcinomas (n = 2) and ductal carcinoma in situ (n = 1). Four (20%) patients had high-risk lesions: atypical ductal hyperplasia (n = 3) and lobular carcinoma in situ (n = 1). The remaining 13 (65%) patients had benign lesions, however, seven (35%) out of 13 patients had mild-risk lesions (three intraductal papillomas, three moderate or florid epithelial hyperplasia and one sclerosing adenosis). Of the sonographic ally detected architectural distortions, 35% were breast cancers or high-risk lesions and 35% were mild-risk lesions. Thus, a biopsy might be needed for an architectural distortion without an associated mass as depicted on breast ultrasound, even though the mammographic findings are normal

  7. Significance and popularity in music production.

    Science.gov (United States)

    Monechi, Bernardo; Gravino, Pietro; Servedio, Vito D P; Tria, Francesca; Loreto, Vittorio

    2017-07-01

    Creative industries constantly strive for fame and popularity. Though highly desirable, popularity is not the only achievement artistic creations might ever acquire. Leaving a longstanding mark in the global production and influencing future works is an even more important achievement, usually acknowledged by experts and scholars. 'Significant' or 'influential' works are not always well known to the public or have sometimes been long forgotten by the vast majority. In this paper, we focus on the duality between what is successful and what is significant in the musical context. To this end, we consider a user-generated set of tags collected through an online music platform, whose evolving co-occurrence network mirrors the growing conceptual space underlying music production. We define a set of general metrics aiming at characterizing music albums throughout history, and their relationships with the overall musical production. We show how these metrics allow to classify albums according to their current popularity or their belonging to expert-made lists of important albums. In this way, we provide the scientific community and the public at large with quantitative tools to tell apart popular albums from culturally or aesthetically relevant artworks. The generality of the methodology presented here lends itself to be used in all those fields where innovation and creativity are in play.

  8. Origin and significance of defects in welds

    International Nuclear Information System (INIS)

    Lundin, C.D.

    1984-01-01

    In the past 10 to 15 years significant advances have taken place in the understanding of the origin and nature of weld discontinuities. The furthering of the knowledge of hot cracking, cold cracking, lamellar tearing and porosity formation is due to the development and utilization of sophisticated techniques for microscopy and microanalysis and the concerted efforts of many researchers in the U.S. and abroad. Concurrent with the progress toward better definition of the metallurgical mechanisms for discontinuity formation, the development of the fracture mechanics approach for the assessment of the significance of the discontinuities was brought into focus. It is the marriage of the metallurgical understanding of formation and the mechanics assessment of relevance that permits discontinuities to be treated with a new degree of sophistication. The many types of cracking and porosity formation were the subjects of numerous studies in the intervening years. This presentation will treat the various types of weld discontinuities which have their origin closely related to a metallurgical mechanism. Emphasis will be placed on hot cracking, and porosity formation with information presented on cold cracking, reheat cracking and lamellar tearing. The employment of the newer metallurgical tools will be discussed in terms of their utilization in determining the cause of discontinuity formation

  9. Arctigenin Inhibits Liver Cancer Tumorigenesis by Inhibiting Gankyrin Expression via C/EBPα and PPARα

    Science.gov (United States)

    Sun, Ying; Tan, Yu-jun; Lu, Zhan-zhao; Li, Bing-bing; Sun, Cheng-hong; Li, Tao; Zhao, Li-li; Liu, Zhong; Zhang, Gui-min; Yao, Jing-chun; Li, Jie

    2018-01-01

    Burdock (Arctium lappa) is a popular vegetable in China and Japan that is consumed for its general health benefits. The principal active component of burdock is arctigenin, which shows a range of bioactivities in vivo and in vitro. Here, we investigated the potential anti-tumor effects of arctigenin using two human hepatocellular carcinoma (HCC) cell lines, HepG2 and Hep3B, and sought to elucidate its potential mechanisms of action. Our results showed that arctigenin treatment inhibited cell growth in both HepG2 and Hep3B cell lines (IC50 of 4.74 nM for HepG2 cells, and of 59.27 nM for Hep3B cells). In addition, migration, invasion, and colony formation by HepG2 cells were significantly inhibited by arctigenin. By contrast, treatment of Hep3B cells with arctigenin did not alter these parameters. Arctigenin also significantly reduced the levels of gankyrin mRNA and protein in HepG2 cells, but not in Hep3B cells. A luciferase assay indicated that arctigenin targeted the -450 to -400 region of the gankyrin promoter. This region is also the potential binding site for both C/EBPα and PPARα, as predicted and confirmed by an online software analysis and ChIP assay. Additionally, a co-immunoprecipitation (Co-IP) assay showed that binding between C/EBPα and PPARα was increased in the presence of arctigenin. However, arctigenin did not increase the expression of C/EBPα or PPARα protein. A binding screening assay and liquid chromatography–mass spectrometry (LC–MS) were performed to identify the mechanisms by which arctigenin regulates gankyrin expression. The results suggested that arctigenin could directly increase C/EBPα binding to the gankyrin promoter (-432 to -422 region), but did not affect PPARα binding. Expression of gankyrin, C/EBPα, and PPARα were analyzed in tumor tissues of patients using real-time PCR. Both C/EBPα and PPARα showed negative correlations with gankyrin. In tumor-bearing mice, arctigenin had a significant inhibitory effect on HCC

  10. Arctigenin Inhibits Liver Cancer Tumorigenesis by Inhibiting Gankyrin Expression via C/EBPα and PPARα

    Directory of Open Access Journals (Sweden)

    Ying Sun

    2018-03-01

    Full Text Available Burdock (Arctium lappa is a popular vegetable in China and Japan that is consumed for its general health benefits. The principal active component of burdock is arctigenin, which shows a range of bioactivities in vivo and in vitro. Here, we investigated the potential anti-tumor effects of arctigenin using two human hepatocellular carcinoma (HCC cell lines, HepG2 and Hep3B, and sought to elucidate its potential mechanisms of action. Our results showed that arctigenin treatment inhibited cell growth in both HepG2 and Hep3B cell lines (IC50 of 4.74 nM for HepG2 cells, and of 59.27 nM for Hep3B cells. In addition, migration, invasion, and colony formation by HepG2 cells were significantly inhibited by arctigenin. By contrast, treatment of Hep3B cells with arctigenin did not alter these parameters. Arctigenin also significantly reduced the levels of gankyrin mRNA and protein in HepG2 cells, but not in Hep3B cells. A luciferase assay indicated that arctigenin targeted the -450 to -400 region of the gankyrin promoter. This region is also the potential binding site for both C/EBPα and PPARα, as predicted and confirmed by an online software analysis and ChIP assay. Additionally, a co-immunoprecipitation (Co-IP assay showed that binding between C/EBPα and PPARα was increased in the presence of arctigenin. However, arctigenin did not increase the expression of C/EBPα or PPARα protein. A binding screening assay and liquid chromatography–mass spectrometry (LC–MS were performed to identify the mechanisms by which arctigenin regulates gankyrin expression. The results suggested that arctigenin could directly increase C/EBPα binding to the gankyrin promoter (-432 to -422 region, but did not affect PPARα binding. Expression of gankyrin, C/EBPα, and PPARα were analyzed in tumor tissues of patients using real-time PCR. Both C/EBPα and PPARα showed negative correlations with gankyrin. In tumor-bearing mice, arctigenin had a significant inhibitory

  11. Arctigenin Inhibits Liver Cancer Tumorigenesis by Inhibiting Gankyrin Expression via C/EBPα and PPARα.

    Science.gov (United States)

    Sun, Ying; Tan, Yu-Jun; Lu, Zhan-Zhao; Li, Bing-Bing; Sun, Cheng-Hong; Li, Tao; Zhao, Li-Li; Liu, Zhong; Zhang, Gui-Min; Yao, Jing-Chun; Li, Jie

    2018-01-01

    Burdock ( Arctium lappa ) is a popular vegetable in China and Japan that is consumed for its general health benefits. The principal active component of burdock is arctigenin, which shows a range of bioactivities in vivo and in vitro . Here, we investigated the potential anti-tumor effects of arctigenin using two human hepatocellular carcinoma (HCC) cell lines, HepG2 and Hep3B, and sought to elucidate its potential mechanisms of action. Our results showed that arctigenin treatment inhibited cell growth in both HepG2 and Hep3B cell lines (IC 50 of 4.74 nM for HepG2 cells, and of 59.27 nM for Hep3B cells). In addition, migration, invasion, and colony formation by HepG2 cells were significantly inhibited by arctigenin. By contrast, treatment of Hep3B cells with arctigenin did not alter these parameters. Arctigenin also significantly reduced the levels of gankyrin mRNA and protein in HepG2 cells, but not in Hep3B cells. A luciferase assay indicated that arctigenin targeted the -450 to -400 region of the gankyrin promoter. This region is also the potential binding site for both C/EBPα and PPARα, as predicted and confirmed by an online software analysis and ChIP assay. Additionally, a co-immunoprecipitation (Co-IP) assay showed that binding between C/EBPα and PPARα was increased in the presence of arctigenin. However, arctigenin did not increase the expression of C/EBPα or PPARα protein. A binding screening assay and liquid chromatography-mass spectrometry (LC-MS) were performed to identify the mechanisms by which arctigenin regulates gankyrin expression. The results suggested that arctigenin could directly increase C/EBPα binding to the gankyrin promoter (-432 to -422 region), but did not affect PPARα binding. Expression of gankyrin, C/EBPα , and PPARα were analyzed in tumor tissues of patients using real-time PCR. Both C/EBPα and PPARα showed negative correlations with gankyrin. In tumor-bearing mice, arctigenin had a significant inhibitory effect on HCC

  12. Improving response inhibition systems in frontotemporal dementia with citalopram.

    Science.gov (United States)

    Hughes, Laura E; Rittman, Timothy; Regenthal, Ralf; Robbins, Trevor W; Rowe, James B

    2015-07-01

    Disinhibition is a cardinal feature of the behavioural variant of frontotemporal dementia, presenting as impulsive and impetuous behaviours that are often difficult to manage. The options for symptomatic treatments are limited, but a potential target for therapy is the restoration of serotonergic function, which is both deficient in behavioural variant frontotemporal dementia and closely associated with inhibitory control. Based on preclinical studies and psychopharmacological interventions in other disorders, we predicted that inhibition would be associated with the right inferior frontal gyrus and dependent on serotonin. Using magnetoencephalography and electroencephalography of a Go-NoGo paradigm, we investigated the neural basis of behavioural disinhibition in behavioural variant frontotemporal dementia and the effect of selective serotonin reuptake inhibition on the neural systems for response inhibition. In a randomized double-blinded placebo-controlled crossover design study, 12 patients received either a single 30 mg dose of citalopram or placebo. Twenty age-matched healthy controls underwent the same magnetoencephalography/electroencephalography protocol on one session without citalopram, providing normative data for this task. In the control group, successful NoGo trials evoked two established indices of successful response inhibition: the NoGo-N2 and NoGo-P3. Both of these components were significantly attenuated by behavioural variant frontotemporal dementia. Cortical sources associated with successful inhibition in control subjects were identified in the right inferior frontal gyrus and anterior temporal lobe, which have been strongly associated with behavioural inhibition in imaging and lesion studies. These sources were impaired by behavioural variant frontotemporal dementia. Critically, citalopram enhanced the NoGo-P3 signal in patients, relative to placebo treatment, and increased the evoked response in the right inferior frontal gyrus. Voxel

  13. 7-Piperazinethylchrysin inhibits melanoma cell proliferation by ...

    African Journals Online (AJOL)

    In B16F10 and A375 cells, treatment with PEC caused the inhibition ... Conclusion: PEC inhibited melanoma cell proliferation, apparently by blocking the cell cycle at G0/G1 .... all statistical analyses. .... Financial support from the Department of.

  14. A Qualitative Approach to Enzyme Inhibition

    Science.gov (United States)

    Waldrop, Grover L.

    2009-01-01

    Most general biochemistry textbooks present enzyme inhibition by showing how the basic Michaelis-Menten parameters K[subscript m] and V[subscript max] are affected mathematically by a particular type of inhibitor. This approach, while mathematically rigorous, does not lend itself to understanding how inhibition patterns are used to determine the…

  15. Inhibition: Mental Control Process or Mental Resource?

    Science.gov (United States)

    Im-Bolter, Nancie; Johnson, Janice; Ling, Daphne; Pascual-Leone, Juan

    2015-01-01

    The current study tested 2 models of inhibition in 45 children with language impairment and 45 children with normally developing language; children were aged 7 to 12 years. Of interest was whether a model of inhibition as a mental-control process (i.e., executive function) or as a mental resource would more accurately reflect the relations among…

  16. The pharmacology of visuospatial attention and inhibition

    NARCIS (Netherlands)

    Logemann, H.N.A.

    2013-01-01

    Attention and inhibition are of vital importance in everyday functioning. Problems of attention and inhibition are central to disorders such as Attention Deficit/Hyperactivity Disorder (ADHD). Both bias and disengagement key components of visuospatial attention. Bias refers to neuronal signals that

  17. Screening of plant extracts for human tyrosinase inhibiting effects.

    Science.gov (United States)

    Kim, M; Park, J; Song, K; Kim, H G; Koh, J-S; Boo, Y C

    2012-04-01

    Screening for tyrosinase (TYR) inhibitors potentially useful for control of skin pigmentation has been hampered by the limited availability of human TYR. To overcome this hurdle, we have established human embryonic kidney (HEK293)-TYR cells that constitutively express human TYR. In the current study, we assayed human TYR inhibition activities of 50 plant extracts using the lysates of transformed HEK293-TYR cells. The strongest inhibition of human TYR was shown by the extract of Vaccinium bracteatum Thunberg, followed by the extract of Morus bombycis Koidzumi. The former extract did not inhibit mushroom TYR activity whereas significant inhibition was observed with the latter extract, demonstrating the importance of using human TYR in the screening for human TYR inhibitors. Upon liquid-liquid partitioning of the extract from V. bracteatum, the active constituents were enriched in the ethyl acetate fraction, and the subsequent preparatory thin-layer chromatography identified p-coumaric acid (PCA) as the main active constituent. The hypo-pigmentation of PCA was verified in the MelanoDerm™ Skin Model. This study demonstrates that transformed HEK293-TYR cells could expedite the discovery of human TYR-specific inhibitors from natural sources which might be useful in the control of skin pigmentation. © 2012 The Authors. ICS © 2012 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

  18. Phytotoxicity of nanoparticles: Inhibition of seed germination and root growth

    International Nuclear Information System (INIS)

    Lin Daohui; Xing Baoshan

    2007-01-01

    Plants need to be included to develop a comprehensive toxicity profile for nanoparticles. Effects of five types of nanoparticles (multi-walled carbon nanotube, aluminum, alumina, zinc, and zinc oxide) on seed germination and root growth of six higher plant species (radish, rape, ryegrass, lettuce, corn, and cucumber) were investigated. Seed germination was not affected except for the inhibition of nanoscale zinc (nano-Zn) on ryegrass and zinc oxide (nano-ZnO) on corn at 2000 mg/L. Inhibition on root growth varied greatly among nanoparticles and plants. Suspensions of 2000 mg/L nano-Zn or nano-ZnO practically terminated root elongation of the tested plant species. Fifty percent inhibitory concentrations (IC 50 ) of nano-Zn and nano-ZnO were estimated to be near 50 mg/L for radish, and about 20 mg/L for rape and ryegrass. The inhibition occurred during the seed incubation process rather than seed soaking stage. These results are significant in terms of use and disposal of engineered nanoparticles. - Engineered nanoparticles can inhibit the seed germination and root growth

  19. Arginase Inhibition Ameliorates Hepatic Metabolic Abnormalities in Obese Mice

    Science.gov (United States)

    Moon, Jiyoung; Do, Hyun Ju; Cho, Yoonsu; Shin, Min-Jeong

    2014-01-01

    Objectives We examined whether arginase inhibition influences hepatic metabolic pathways and whole body adiposity in diet-induced obesity. Methods and Results After obesity induction by a high fat diet (HFD), mice were fed either the HFD or the HFD with an arginase inhibitor, Nω-hydroxy-nor-L-arginine (nor-NOHA). Nor-NOHA significantly prevented HFD-induced increases in body, liver, and visceral fat tissue weight, and ameliorated abnormal lipid profiles. Furthermore, nor-NOHA treatment reduced lipid accumulation in oleic acid-induced hepatic steatosis in vitro. Arginase inhibition increased hepatic nitric oxide (NO) in HFD-fed mice and HepG2 cells, and reversed the elevated mRNA expression of hepatic genes in lipid metabolism. Expression of phosphorylated 5′ AMPK-activated protein kinase α was increased by arginase inhibition in the mouse livers and HepG2 cells. Conclusions Arginase inhibition ameliorated obesity-induced hepatic lipid abnormalities and whole body adiposity, possibly as a result of increased hepatic NO production and subsequent activation of metabolic pathways involved in hepatic triglyceride metabolism and mitochondrial function. PMID:25057910

  20. Phytotoxicity of nanoparticles: Inhibition of seed germination and root growth

    Energy Technology Data Exchange (ETDEWEB)

    Lin Daohui [Department of Environmental Science, Zhejiang University, Hangzhou 310028 (China); Department of Plant, Soil and Insect Sciences, University of Massachusetts, Stockbridge Hall, Amherst, MA 01003 (United States); Xing Baoshan [Department of Plant, Soil and Insect Sciences, University of Massachusetts, Stockbridge Hall, Amherst, MA 01003 (United States)], E-mail: bx@pssci.umass.edu

    2007-11-15

    Plants need to be included to develop a comprehensive toxicity profile for nanoparticles. Effects of five types of nanoparticles (multi-walled carbon nanotube, aluminum, alumina, zinc, and zinc oxide) on seed germination and root growth of six higher plant species (radish, rape, ryegrass, lettuce, corn, and cucumber) were investigated. Seed germination was not affected except for the inhibition of nanoscale zinc (nano-Zn) on ryegrass and zinc oxide (nano-ZnO) on corn at 2000 mg/L. Inhibition on root growth varied greatly among nanoparticles and plants. Suspensions of 2000 mg/L nano-Zn or nano-ZnO practically terminated root elongation of the tested plant species. Fifty percent inhibitory concentrations (IC{sub 50}) of nano-Zn and nano-ZnO were estimated to be near 50 mg/L for radish, and about 20 mg/L for rape and ryegrass. The inhibition occurred during the seed incubation process rather than seed soaking stage. These results are significant in terms of use and disposal of engineered nanoparticles. - Engineered nanoparticles can inhibit the seed germination and root growth.

  1. Inhibition of endogenous lactate turnover with lactate infusion in humans

    International Nuclear Information System (INIS)

    Searle, G.L.; Feingold, K.R.; Hsu, F.S.; Clark, O.H.; Gertz, E.W.; Stanley, W.C.

    1989-01-01

    The extent to which lactate infusion may inhibit endogenous lactate production, though previously considered, has never been critically assessed. To examine this proposition, single injection tracer methodology (U- 14 C Lactate) has been used for the estimation of lactate kinetics in 12 human subjects under basal conditions and with the infusion of sodium lactate. The basal rate of lactate turnover was measured on a day before the study with lactate infusion, and averaged 63.7 + 5.5 mg/kg/h. Six of these individuals received a stable lactate infusion at an approximate rate of 160 mg/kg/h, while the remaining six individuals were infused at the approximate rate of 100 mg/kg/h. It has been found that stable lactate infused at rates approximating 160 mg/kg/h consistently produced a complete inhibition of endogenous lactate production. Infusion of lactate at 100 mg/kg/h caused a lesser and more variable inhibition of endogenous lactate production (12% to 64%). In conclusion, lactate infusion significantly inhibits endogenous lactate production

  2. Maturation of cognitive control: delineating response inhibition and interference suppression.

    Directory of Open Access Journals (Sweden)

    Christopher R Brydges

    Full Text Available Cognitive control is integral to the ability to attend to a relevant task whilst suppressing distracting information or inhibiting prepotent responses. The current study examined the development of these two subprocesses by examining electrophysiological indices elicited during each process. Thirteen 18 year-old adults and thirteen children aged 8-11 years (mean=9.77 years completed a hybrid Go/Nogo flanker task while continuous EEG data were recorded. The N2 topography for both response inhibition and interference suppression changed with increasing age. The neural activation associated with response inhibition became increasingly frontally distributed with age, and showed decreases of both amplitude and peak latency from childhood to adulthood, possibly due to reduced cognitive demands and myelination respectively occurring during this period. Interestingly, a significant N2 effect was apparent in adults, but not observed in children during trials requiring interference suppression. This could be due to more diffuse activation in children, which would require smaller levels of activation over a larger region of the brain than is reported in adults. Overall, these results provide evidence of distinct maturational processes occurring throughout late childhood and adolescence, highlighting the separability of response inhibition and interference suppression.

  3. Proteasome Inhibition Suppresses Dengue Virus Egress in Antibody Dependent Infection.

    Directory of Open Access Journals (Sweden)

    Milly M Choy

    2015-11-01

    Full Text Available The mosquito-borne dengue virus (DENV is a cause of significant global health burden, with an estimated 390 million infections occurring annually. However, no licensed vaccine or specific antiviral treatment for dengue is available. DENV interacts with host cell factors to complete its life cycle although this virus-host interplay remains to be fully elucidated. Many studies have identified the ubiquitin proteasome pathway (UPP to be important for successful DENV production, but how the UPP contributes to DENV life cycle as host factors remains ill defined. We show here that proteasome inhibition decouples infectious virus production from viral RNA replication in antibody-dependent infection of THP-1 cells. Molecular and imaging analyses in β-lactone treated THP-1 cells suggest that proteasome function does not prevent virus assembly but rather DENV egress. Intriguingly, the licensed proteasome inhibitor, bortezomib, is able to inhibit DENV titers at low nanomolar drug concentrations for different strains of all four serotypes of DENV in primary monocytes. Furthermore, bortezomib treatment of DENV-infected mice inhibited the spread of DENV in the spleen as well as the overall pathological changes. Our findings suggest that preventing DENV egress through proteasome inhibition could be a suitable therapeutic strategy against dengue.

  4. Gas hydrate inhibition by perturbation of liquid water structure

    Science.gov (United States)

    Sa, Jeong-Hoon; Kwak, Gye-Hoon; Han, Kunwoo; Ahn, Docheon; Lee, Kun-Hong

    2015-06-01

    Natural gas hydrates are icy crystalline materials that contain hydrocarbons, which are the primary energy source for this civilization. The abundance of naturally occurring gas hydrates leads to a growing interest in exploitation. Despite their potential as energy resources and in industrial applications, there is insufficient understanding of hydrate kinetics, which hinders the utilization of these invaluable resources. Perturbation of liquid water structure by solutes has been proposed to be a key process in hydrate inhibition, but this hypothesis remains unproven. Here, we report the direct observation of the perturbation of the liquid water structure induced by amino acids using polarized Raman spectroscopy, and its influence on gas hydrate nucleation and growth kinetics. Amino acids with hydrophilic and/or electrically charged side chains disrupted the water structure and thus provided effective hydrate inhibition. The strong correlation between the extent of perturbation by amino acids and their inhibition performance constitutes convincing evidence for the perturbation inhibition mechanism. The present findings bring the practical applications of gas hydrates significantly closer, and provide a new perspective on the freezing and melting phenomena of naturally occurring gas hydrates.

  5. Thrombomodulin inhibits the activation of eosinophils and mast cells.

    Science.gov (United States)

    Roeen, Ziaurahman; Toda, Masaaki; D'Alessandro-Gabazza, Corina N; Onishi, Masahiro; Kobayashi, Tetsu; Yasuma, Taro; Urawa, Masahito; Taguchi, Osamu; Gabazza, Esteban C

    2015-01-01

    Eosinophils and mast cells play critical roles in the pathogenesis of bronchial asthma. Activation of both cells leads to the release of pro-inflammatory mediators in the airway of asthmatic patients. Recently, we have shown that inhaled thrombomodulin inhibits allergic bronchial asthma in a mouse model. In the present study, we hypothesize that thrombomodulin can inhibit the activation of eosinophils and mast cells. The effect of thrombomodulin on the activation and release of inflammatory mediators from eosinophils and mast cells was evaluated. Thrombomodulin inhibited the eotaxin-induced chemotaxis, upregulation of CD11b and degranulation of eosinophils. Treatment with thrombomodulin also significantly suppressed the degranulation and synthesis of inflammatory cytokines and chemokines in eosinophils and mast cells. Mice treated with a low-dose of inhaled thrombomodulin have decreased number of eosinophils and activated mast cells and Th2 cytokines in the lungs compared to untreated mice. The results of this study suggest that thrombomodulin may modulate allergic responses by inhibiting the activation of both eosinophils and mast cells. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Adrenaline inhibits osteogenesis via repressing miR-21 expression.

    Science.gov (United States)

    Chen, Danying; Wang, Zuolin

    2017-01-01

    Sympathetic signaling is involved in bone homeostasis; however, the cellular and molecular mechanisms remain unknown. In this study, we found that the psychological stress mediator adrenaline inhibited osteogenic differentiation of human bone marrow-derived stem cells (hMSC) by reducing microRNA-21 (miR-21) expression. Briefly, adrenaline significantly inhibited the osteogenic differentiation of hMSCs, as observed with both Alizarin red staining and maker gene expression (RUNX2, OSX, OCN, and OPN). During this process, miR-21 was suppressed by adrenaline via inhibition of histone acetylation, as verified by H3K9Ac chromatin immunoprecipitation (ChIP) assay. MiR-21 was confirmed to promote hMSC osteogenic differentiation, and overexpression of miR-21 reversed the impeditive effect of adrenaline on hMSC osteogenic differentiation. Our results demonstrate that down-regulation of miR-21 is responsible for the adrenaline-mediated inhibition of hMSC osteogenic differentiation. These findings indicate a regulation of bone metabolism by psychological stress and also provide a molecular basis for psychological stress-associated bone diseases. © 2016 International Federation for Cell Biology.

  7. Arcuate foramen and its clinical significance

    International Nuclear Information System (INIS)

    Cakmark, O.; Gurdal, E.; Cavdar, S.; Ekinci, G.; Yildiz, E.

    2005-01-01

    The present study determines the degree of ossification of the posterior atlanto-occipital membrane in dry bone, plane lateral cervical spine radiographs and computer tomography (CT). The average length, width and the area of the arcuate foramen were measured on dry bone and on cervical CT. Further, age, gender and complaints of the patients of shoulder and arm pain, neck pain, headache, vertigo, and lacrimation in relation to the presence of bony complete or incomplete arcuate foramen were evaluated. From February 2004 to January 2005 60 dry atlases were obtained from the Anatomy Department, University of Marmara, Istanbul, Turkey and 416 lateral cervical spine radiographs were obtained from the Radiology department for neurological and orthopedic evaluations. Each complete arcuate foramen was calculated with the aid of Clemex Vision PE demo version computer program. Among the 60 dry atlases examined 7 (11.7%) had complete and 2 (3.3 %) had incomplete bony bridge formation. Of the 416 plane lateral cervical spine radiographs examined, 30 (7.2%) had complete and 26 (6.25%) had incomplete bony bridge formation. Of the 30 complete arcuate foramen 24 (80%) were females and 6 (20%) were males. The frequency of having a complete arcuate foramen in females was 8.45%, and in males it was 4.55%. Further, of the 26 incomplete arcuate foramen 20 (76.9%) were females and 6 (23.1%) were males. The frequency of having an incomplete arcuate foramen in females was 7%, and in males was 4.55%. The statistical evaluations showed that patients with complete arcuate foramen had significant complaints of shoulder-arm pain (p=0.0072), neck pain (p=0.0072) and vertigo (p=0.0598) compared to patients with incomplete arcuate foramen. The patients with complete arcuate foramen had a headache ratio of 12:30 and this ratio was 2:26 in patients with incomplete arcuate foramen and the difference between complete and incomplete arcuate foramen was statistically significant (p=0.0062). Further

  8. Mitochondrial thiol modification by a targeted electrophile inhibits metabolism in breast adenocarcinoma cells by inhibiting enzyme activity and protein levels

    Directory of Open Access Journals (Sweden)

    M. Ryan Smith

    2016-08-01

    Full Text Available Many cancer cells follow an aberrant metabolic program to maintain energy for rapid cell proliferation. Metabolic reprogramming often involves the upregulation of glutaminolysis to generate reducing equivalents for the electron transport chain and amino acids for protein synthesis. Critical enzymes involved in metabolism possess a reactive thiolate group, which can be modified by certain oxidants. In the current study, we show that modification of mitochondrial protein thiols by a model compound, iodobutyl triphenylphosphonium (IBTP, decreased mitochondrial metabolism and ATP in MDA-MB 231 (MB231 breast adenocarcinoma cells up to 6 days after an initial 24 h treatment. Mitochondrial thiol modification also depressed oxygen consumption rates (OCR in a dose-dependent manner to a greater extent than a non-thiol modifying analog, suggesting that thiol reactivity is an important factor in the inhibition of cancer cell metabolism. In non-tumorigenic MCF-10A cells, IBTP also decreased OCR; however the extracellular acidification rate was significantly increased at all but the highest concentration (10 µM of IBTP indicating that thiol modification can have significantly different effects on bioenergetics in tumorigenic versus non-tumorigenic cells. ATP and other adenonucleotide levels were also decreased by thiol modification up to 6 days post-treatment, indicating a decreased overall energetic state in MB231 cells. Cellular proliferation of MB231 cells was also inhibited up to 6 days post-treatment with little change to cell viability. Targeted metabolomic analyses revealed that thiol modification caused depletion of both Krebs cycle and glutaminolysis intermediates. Further experiments revealed that the activity of the Krebs cycle enzyme, aconitase, was attenuated in response to thiol modification. Additionally, the inhibition of glutaminolysis corresponded to decreased glutaminase C (GAC protein levels, although other protein levels were

  9. Regional and global significance of nuclear energy

    International Nuclear Information System (INIS)

    Schilling, H.D.

    1995-01-01

    Measures to combat poverty and improve the standard of living in countries of the Third World will inevitably boost global demand for energy, and energy conservation measures will not be able to offset this increase. Nuclear energy will regain significance in the framework of approaches adopted to resolve the energy problem, which primarily is an ecologic problem created by an extremely large flow of materials. The extraordinarily high energy density of nuclear fuels can contribute to markedly reduce the flow of materials; and at that, electric energy is an efficient substitute for primary energy forms. Thus nuclear electricity generation is of double benefit to the ecology. Engineering goals in nuclear technology thus gain a service aspect, with progress in power plant engineering and design aiming not only at enhanced engineered safety, but also at regaining public acceptance of and confidence in nuclear power plant technology. (orig./UA) [de

  10. Response to a spill of national significance

    International Nuclear Information System (INIS)

    Jensen, D.S.; Pond, R.; Johnson, M.H.

    1993-01-01

    Responding to a spill of national significance (SONS), such as the 1989 Exxon Valdez spill, requires an augmenting organization to support the local response organization. The US Coast Guard has developed SONS protocol to be better prepared to respond to these infrequent catastrophic spills. A flag-level Coast Guard officer assumes the role of national incident commander (NIC) and federal on-scene coordinator (OSC), and is supported by a national incident task force (NITF). The major role of the NITF is to develop a national response strategy, acquire response resources and allocate them efficiently, and effectively deal with many peripheral national issues. Unified command concepts have been incorporated into the NITF and its primary organizational elements. In addition, frequent training and exercising is essential to keep the SONS protocol's preparedness at an acceptable level

  11. The significance of vector magnetic field measurements

    Science.gov (United States)

    Hagyard, M. J.

    1990-01-01

    Observations of four flaring solar active regions, obtained during 1980-1986 with the NASA Marshall vector magnetograph (Hagyard et al., 1982 and 1985), are presented graphically and characterized in detail, with reference to nearly simultaneous Big Bear Solar Observatory and USAF ASW H-alpha images. It is shown that the flares occurred where local photospheric magnetic fields differed most from the potential field, with initial brightening on either side of a magnetic-neutral line near the point of maximum angular shear (rather than that of maximum magnetic-field strength, typically 1 kG or greater). Particular emphasis is placed on the fact that these significant nonpotential features were detected only by measuring all three components of the vector magnetic field.

  12. Global warming: the significance of methane

    International Nuclear Information System (INIS)

    Dessus, B.; Le Treut, H.; Laponche, B.

    2008-01-01

    the concept of Global Warming Potential (GWP) indicates the relative contribution to global warming over a given period (for example 100 years) of a pulse emission at the start of the period of 1 kg of a specific greenhouse gas (GHG) in comparison to the contribution, over the same period, of an emission of 1 kg of CO 2 . The GWPs calculated for different time intervals take into account the differences in atmospheric lifetimes of the different GHGs. Using the '100-year GWP' to measure non CO 2 GHG emissions is not well suited to the case of permanent or long lifetime measures whose effectiveness is to be assessed at a given time horizon. In this context, it contributes to significantly playing down the importance of reducing emissions of GHGs with short atmospheric lifetimes. Thus, for example, methane which is not emitted over the period 2020- 2100 as a result of a landfill site being closed in 2020 will have an impact (as opposed to if the site remained in operation) that would be far greater towards 2100 compared to a CO 2 emission source that has also been stopped permanently and whose climate impact is measured in an equivalent manner. Using the GWP is only appropriate if applied year after year to time horizons considered to be of concern or decisive by climate studies, thus in particular 2050, 2100 and 2150. This is all the more significant as climate experts' current concerns lead them not only to advocate long-term stabilisation of GHG concentrations but also to avoid as far as possible intermediate excess of these concentrations over the coming century. Finally, it is noted that CH 4 prevention policies implemented in the short term may continue to have a long-term impact greater than merely taking into account the current GWP would imply. To more or less ignore the impact of CH 4 as it is unsuitable for accounting purposes affects the exclusive character of the link that may exist between the issue of GHGs and that of energy. Furthermore, if the

  13. Bayesian approaches for detecting significant deterioration

    International Nuclear Information System (INIS)

    Roed, Willy; Aven, Terje

    2009-01-01

    Risk indicators can provide useful input to risk management processes and are given increased attention in the Norwegian petroleum industry. Examples include indicators expressing the proportion of test failures of safety and barrier systems. Such indicators give valuable information about the performance of the systems and provide a basis for trend evaluations. Early warning of a possible deterioration is essential due to the importance of the systems in focus, but what should be the basis for the warning criterion? This paper presents and discusses several Bayesian approaches for the establishment of a warning criterion to disclose significant deterioration. The Norwegian petroleum industry is the starting point for this paper, but the study is relevant for other application areas as well

  14. Swiss solar power statistics 2007 - Significant expansion

    International Nuclear Information System (INIS)

    Hostettler, T.

    2008-01-01

    This article presents and discusses the 2007 statistics for solar power in Switzerland. A significant number of new installations is noted as is the high production figures from newer installations. The basics behind the compilation of the Swiss solar power statistics are briefly reviewed and an overview for the period 1989 to 2007 is presented which includes figures on the number of photovoltaic plant in service and installed peak power. Typical production figures in kilowatt-hours (kWh) per installed kilowatt-peak power (kWp) are presented and discussed for installations of various sizes. Increased production after inverter replacement in older installations is noted. Finally, the general political situation in Switzerland as far as solar power is concerned are briefly discussed as are international developments.

  15. THRESHOLD OF SIGNIFICANCE IN STRESS MANAGEMENT

    Directory of Open Access Journals (Sweden)

    Elena RUSE

    2015-12-01

    Full Text Available Stress management is the individual's ability to handle any situation, external conditions, to match the demands of the external environment. The researchers revealed several stages in the stress response. A first phase was called ‘‘alert reaction'' or ‘‘immediate reaction to stress‘‘, phase in which there are physiological modifications and manifestations that occur under psychological aspect. Adaptation phase is the phase in which the reactions from the first phase diminishes or disappears. Exhaustion phase is related to the diversity of stress factors and time and may exceed the resources of the human body to adapt. Influencing factors may be: limited, cognitive, perceptual, and a priori. But there is a threshold of significance in stress management. Once the reaction to external stimuli occurs, awareness is needed. The capability effect occurs, any side effect goes away and comes out the ''I AM'' effect.

  16. The insignificance of statistical significance testing

    Science.gov (United States)

    Johnson, Douglas H.

    1999-01-01

    Despite their use in scientific journals such as The Journal of Wildlife Management, statistical hypothesis tests add very little value to the products of research. Indeed, they frequently confuse the interpretation of data. This paper describes how statistical hypothesis tests are often viewed, and then contrasts that interpretation with the correct one. I discuss the arbitrariness of P-values, conclusions that the null hypothesis is true, power analysis, and distinctions between statistical and biological significance. Statistical hypothesis testing, in which the null hypothesis about the properties of a population is almost always known a priori to be false, is contrasted with scientific hypothesis testing, which examines a credible null hypothesis about phenomena in nature. More meaningful alternatives are briefly outlined, including estimation and confidence intervals for determining the importance of factors, decision theory for guiding actions in the face of uncertainty, and Bayesian approaches to hypothesis testing and other statistical practices.

  17. Significance and potential benefits of the CTBT

    International Nuclear Information System (INIS)

    Sato, M.

    1999-01-01

    This presentation is based on the Treaty stipulation on international cooperation: 'The States parties undertake to promote cooperation among themselves to facilitate and participate in the fullest possible exchange relating to technologies used in the verification of the Non-proliferation Treaty in order to enable States to strengthen national implementation of verification measures; and to enable States to benefit from the application of such technologies for peaceful purposes'. Political significance of the Treaty and the potential benefits of participating in the CTBT regime are exposed. It is concluded that international cooperation under the CTBT regime is an element in broadening Treaty support and participation, thereby contributing to an early establishment and the efficient operation of the Treaty verification regime. The PTS will assist the States Signatories to facilitate and promote cooperation among themselves in the fullest exchange of information relating to verification-related technologies so that they may benefit from participation in the Treaty regime

  18. Significant enhancement by biochar of caproate production via chain elongation.

    Science.gov (United States)

    Liu, Yuhao; He, Pinjing; Shao, Liming; Zhang, Hua; Lü, Fan

    2017-08-01

    In this study, biochar was introduced into a chain elongation system to enhance the bioproduction of caproate and caprylate. The concentration of caproate increased to 21.1 g/L upon the addition of biochar, which is the highest level of caproate reported for such a system to date when ethanol was used as electron donor. The addition of biochar created a tougher system with more stable microorganism community structure for chain elongation, in which no obvious inhibition by products or substrates was observed, moreover, the lag phase was reduced 2.3-fold compared to the system without biochar. These reinforcement effect of biochar are attributed to the enhanced conductivity due to the significant enrichment of functional microorganisms via the microbial network surrounding smaller biochar particles, and via the adsorption on the rough surfaces or pores of larger particles, which facilitated electron transfer. Higher amounts of extracellular polymer substances and higher conductivity induced by biochar could contribute to the reinforcement effect in chain elongation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Clinical significance of melatonin receptors in the human myometrium.

    Science.gov (United States)

    Olcese, James; Beesley, Stephen

    2014-08-01

    To review and update the research on melatonin receptor expression in the human myometrium, in particular as it pertains to uterine contractility at labor. Summary of previous studies with the addition of new data on the transcriptional regulation of melatonin receptor expression in human myometrial cells. Not applicable. Late-term pregnant volunteers. Biopsy collection for in vitro analyses provided the original data. More recently, uterine contractions in late-term pregnant volunteers were assessed before, during, and after acute white-light exposure. Melatonin receptor signaling in myometrial cells and uterine contractions in late-term pregnant volunteers. Melatonin acts through the MTNR1B melatonin receptor that is expressed in the myometrium at late term to synergistically enhance oxytocin-dependent signaling and contractions. Acute inhibition of endogenous melatonin levels with light reversibly suppresses uterine contractions. These results point to a significant role for circulating melatonin in the timing and degree of uterine contractions in late-term pregnancy. Understanding the regulation of melatonin receptors remains a future objective. Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  20. Risk control and the minimum significant risk

    International Nuclear Information System (INIS)

    Seiler, F.A.; Alvarez, J.L.

    1996-01-01

    Risk management implies that the risk manager can, by his actions, exercise at least a modicum of control over the risk in question. In the terminology of control theory, a management action is a control signal imposed as feedback on the system to bring about a desired change in the state of the system. In the terminology of risk management, an action is taken to bring a predicted risk to lower values. Even if it is assumed that the management action taken is 100% effective and that the projected risk reduction is infinitely well known, there is a lower limit to the desired effects that can be achieved. It is based on the fact that all risks, such as the incidence of cancer, exhibit a degree of variability due to a number of extraneous factors such as age at exposure, sex, location, and some lifestyle parameters such as smoking or the consumption of alcohol. If the control signal is much smaller than the variability of the risk, the signal is lost in the noise and control is lost. This defines a minimum controllable risk based on the variability of the risk over the population considered. This quantity is the counterpart of the minimum significant risk which is defined by the uncertainties of the risk model. Both the minimum controllable risk and the minimum significant risk are evaluated for radiation carcinogenesis and are shown to be of the same order of magnitude. For a realistic management action, the assumptions of perfectly effective action and perfect model prediction made above have to be dropped, resulting in an effective minimum controllable risk which is determined by both risk limits. Any action below that effective limit is futile, but it is also unethical due to the ethical requirement of doing more good than harm. Finally, some implications of the effective minimum controllable risk on the use of the ALARA principle and on the evaluation of remedial action goals are presented

  1. Quantifying the Clinical Significance of Cannabis Withdrawal

    Science.gov (United States)

    Allsop, David J.; Copeland, Jan; Norberg, Melissa M.; Fu, Shanlin; Molnar, Anna; Lewis, John; Budney, Alan J.

    2012-01-01

    Background and Aims Questions over the clinical significance of cannabis withdrawal have hindered its inclusion as a discrete cannabis induced psychiatric condition in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV). This study aims to quantify functional impairment to normal daily activities from cannabis withdrawal, and looks at the factors predicting functional impairment. In addition the study tests the influence of functional impairment from cannabis withdrawal on cannabis use during and after an abstinence attempt. Methods and Results A volunteer sample of 49 non-treatment seeking cannabis users who met DSM-IV criteria for dependence provided daily withdrawal-related functional impairment scores during a one-week baseline phase and two weeks of monitored abstinence from cannabis with a one month follow up. Functional impairment from withdrawal symptoms was strongly associated with symptom severity (p = 0.0001). Participants with more severe cannabis dependence before the abstinence attempt reported greater functional impairment from cannabis withdrawal (p = 0.03). Relapse to cannabis use during the abstinence period was associated with greater functional impairment from a subset of withdrawal symptoms in high dependence users. Higher levels of functional impairment during the abstinence attempt predicted higher levels of cannabis use at one month follow up (p = 0.001). Conclusions Cannabis withdrawal is clinically significant because it is associated with functional impairment to normal daily activities, as well as relapse to cannabis use. Sample size in the relapse group was small and the use of a non-treatment seeking population requires findings to be replicated in clinical samples. Tailoring treatments to target withdrawal symptoms contributing to functional impairment during a quit attempt may improve treatment outcomes. PMID:23049760

  2. Prognostic significance of serum bilirubin in stroke

    International Nuclear Information System (INIS)

    Arslan, A.; Ismail, M.; Khan, F.; Khan, A.; Khattak, M.B.; Anwar, M.J.

    2011-01-01

    Background: Oxidative injury is an important cause of the neurologic lesion in stroke. Serum bilirubin is considered a natural antioxidant that may affect the prognosis of stroke. The purpose of this study was to evaluate the prognostic significance of bilirubin in stroke patients. Methods: A prospective cross-sectional study was conducted in Medical Units of Khyber Teaching Hospital, Peshawar. Inpatients admitted with acute attack of stroke were included in this study. Data regarding serum bilirubin and concurrent cerebrovascular risk factors were collected. National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) were used to analyse stroke's severity and functional outcomes, respectively. Results: Hypertension, diabetes mellitus and heart diseases were the most common risk factors. Patients were divided into 3 groups on the basis of serum bilirubin, i.e., =0.6 mg/dl (Group-1), 0.7-0.9 mg/dl (Group-2), and =1.0 mg/dl (Group-3). The mean pre-hospitalisation NIHSS score for Groups 1, 2 and 3 was 5.62, 11.66 and 25.33, respectively; and post-hospitalisation score was 0.875, 3.76 and 16.26, respectively. The pre-hospitalisation mRS score was 4 for Group-1, 4.52 for Group-2 and 4.93 for Group-3; while post-hospitalisation Mrs Score was 1.50, 2.38 and 4.26, respectively. Average serum bilirubin level was significantly higher in patients with poor outcomes as compared with good outcomes (p<0.01). Conclusions: This study suggests that higher serum bilirubin levels were associated with increased stroke severity, longer hospitalisation and poor prognosis. (author)

  3. Quantifying the clinical significance of cannabis withdrawal.

    Directory of Open Access Journals (Sweden)

    David J Allsop

    Full Text Available Questions over the clinical significance of cannabis withdrawal have hindered its inclusion as a discrete cannabis induced psychiatric condition in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV. This study aims to quantify functional impairment to normal daily activities from cannabis withdrawal, and looks at the factors predicting functional impairment. In addition the study tests the influence of functional impairment from cannabis withdrawal on cannabis use during and after an abstinence attempt.A volunteer sample of 49 non-treatment seeking cannabis users who met DSM-IV criteria for dependence provided daily withdrawal-related functional impairment scores during a one-week baseline phase and two weeks of monitored abstinence from cannabis with a one month follow up. Functional impairment from withdrawal symptoms was strongly associated with symptom severity (p=0.0001. Participants with more severe cannabis dependence before the abstinence attempt reported greater functional impairment from cannabis withdrawal (p=0.03. Relapse to cannabis use during the abstinence period was associated with greater functional impairment from a subset of withdrawal symptoms in high dependence users. Higher levels of functional impairment during the abstinence attempt predicted higher levels of cannabis use at one month follow up (p=0.001.Cannabis withdrawal is clinically significant because it is associated with functional impairment to normal daily activities, as well as relapse to cannabis use. Sample size in the relapse group was small and the use of a non-treatment seeking population requires findings to be replicated in clinical samples. Tailoring treatments to target withdrawal symptoms contributing to functional impairment during a quit attempt may improve treatment outcomes.

  4. Immunophenotyping in leukemia and its diagnostic significance

    Directory of Open Access Journals (Sweden)

    S. B. Kresno

    2004-09-01

    Full Text Available The identification of cell surface markers, defined as clusters of differentiation antigens (CD’s could be used to classify and sub-classify leukemia. Although the same antigens are expressed on normal cells, the phenotype on malignant cells are aberrantly and frequently asynchronously expressed and may be present in combinations not observed in normal blood or bone marrow. Aberrant expression of surface antigens corresponds with poor therapeutic response and short survival. Additional surface marker analysis complementary to morphologic evaluation and cytochemical staining has greatly improved our ability to characterize hematologic malignancies. A review and illustration on the diagnostic significance of immunophenotyping in leukemia will be presented. Data from 225 patients having complete assessments including morphology, cytochemistry and immunophenotyping in the period of 1994-2001 were collected and analyzed. Based on morphologic evaluation and cytochemistry, the diagnosis of acute myeloid leukemia and acute lymphoblastic leukemia were established in 51.1% and 48.9% of cases, respectively. Based on immunophenotyping AML was found in 49.0% of the cases. ALL could be classified into 4.9% pre-B-ALL, 18.7% B-ALL, and 14.7% T-ALL. Cases expressing cross-lineage antigens were found in 12.7%. The prognostic significance of these aberrant expression of antigens for those cases has yet to be established but some of the cases responded poorly to therapy. Immunophenotyping provides the tool to: 1 distinguish normal from clonal populations of leukemic cells; 2 define lineage and reveal the stage of maturation; 3 identify inappropriate expression of lineage associated antigens; 4 provides more informations to establish diagnosis and prognosis compared to standard methods. (Med J Indones 2004; 13: 195-202 Keywords: Immunophenotyping, clusters of differentiation antigens, lineage associated antigens

  5. Real significance of skin contamination is

    International Nuclear Information System (INIS)

    Sudmann, R.H.

    1983-01-01

    For five decades, health physicists have discussed the thickness, area, significance of radioactive contamination and the exposures to various portions of the skin. Concern about instances of skin contamination extend beyond the resultant organ dose simply because it is a recognizable and quantifiable event. As such, there is a tendency for management and regulatory agencies to use it as a trend indicator. The final result is a score card similar to the list of OSHA reportable accidents. In fact, the skin contamination incidence rate has a somewhat different meaning to the health physicist, to the manager, and to the regulator. The question must then be asked, What is the true significance of skin contamination, Is it the resultant skin dose, Is it an indicator of loss of control, Is it both or neither. In order to answer these questions, Rockwell Hanford Operations began analysis of the previous five years records of skin contamination cases. Since by policy each incidence of skin contamination is documented, a large percentage of the 425 records analyzed were of low level activity (less than 100 dpm/cm 2 ) on the extremeties, primarily hands and fingers. Most of these cases were readily decontaminated with soap and water. Individual elements studied included: detection/monitoring methods and limits; impact of type of operation on the incidence rate; causes of and methods for reduction of the incidence rate; reporting and documentation; and dose assessment. Results of the study indicate that skin contamination rarely presents a beta dose problem because it is normally highly localized on the extremeties. Only in unusual cases does it represent a potential for internal deposition. Thus, the real importance of skin contamination incidence is as an indicator of deteriorating conditions and should be reviewed by health physicists, managers and regulators as such

  6. Madecassoside Inhibits Melanin Synthesis by Blocking Ultraviolet-Induced Inflammation

    Directory of Open Access Journals (Sweden)

    Eunsun Jung

    2013-12-01

    Full Text Available Madecassoside (MA, a pentacyclic triterpene isolated from Centella asitica (L., is used as a therapeutic agent in wound healing and also as an anti-inflammatory and anti-aging agent. However, the involvement of MA in skin-pigmentation has not been reported. This study was conducted to investigate the effects of MA on ultraviolet (UV-induced melanogenesis and mechanisms in a co-culture system of keratinocytes and melanocytes. MA significantly inhibited UVR-induced melanin synthesis and melanosome transfer in the co-culture system. These effects were further demonstrated by the MA-induced inhibition of protease-activated receptor-2 expression and its signaling pathway, cyclooxygenase-2, prostaglandin E2 and prostaglandin F2 alpha in keratinocytes. The clinical efficacy of MA was confirmed on artificially tanned human skin. MA significantly reduced UV-induced melanin index at 8 weeks after topical application. Overall, the study demonstrated significant benefits of MA use in the inhibition of hyperpigmentation caused by UV irradiation.

  7. Inhibition of ethylene production by cobaltous ion

    International Nuclear Information System (INIS)

    Lau, O.L; Yang, S.F.

    1976-01-01

    The effect of Co 2+ on ethylene production by mung bean (Phaseolus aureus Roxb.) and by apple tissues was studied. Co 2+ , depending on concentrations applied, effectively inhibited ethylene production by both tissues. It also strongly inhibited the ethylene production induced by IAA, kinetin, IAA plus kinetin, Ca 2+ , kinetin plus Ca 2+ , or Cu 2+ treatments in mung bean hypocotyl segments. While Co 2+ greatly inhibited ethylene production, it had little effect on the respiration of apple tissue, indicating that Co 2+ does not exert its inhibitory effect as a general metabolic inhibitor. Ni 2+ , which belongs to the same group as Co 2+ in the periodic table, also markedly curtailed both the basal and the induced ethylene production by apple and mung bean hypocotyl tissues. In a system in which kinetin and Ca 2+ were applied together, kinetin greatly enhanced Ca 2+ uptake, thus enhancing ethylene production. Co 2+ , however, slightly inhibited the uptake of Ca 2+ but appreciably inhibited ethylene production, either in the presence or in the absence of kinetin. Tracer experiments using apple tissue indicated that Co 2+ strongly inhibited the in vivo conversion of L-[U-- 14 C]methionine to 14 C-ethylene. These data suggested that Co 2+ inhibited ethylene production by inhibiting the conversion of methionine to ethylene, a common step which is required for ethylene formation by higher plants. Co 2+ is known to promote elongation, leaf expansion, and hook opening in excised plant parts in response to applied auxins or cytokinins.Since ethylene is known to inhibit those growth phenomena, it is suggested that Co 2+ exerts its promotive effect, at least in part, by inhibiting ethylene formation

  8. Carotid endarterectomy significantly improves postoperative laryngeal sensitivity.

    Science.gov (United States)

    Hammer, Georg Philipp; Tomazic, Peter Valentin; Vasicek, Sarah; Graupp, Matthias; Gugatschka, Markus; Baumann, Anneliese; Konstantiniuk, Peter; Koter, Stephan Herwig

    2016-11-01

    Iatrogenic injury of the vagus nerve or its branches during carotid endarterectomy (CEA) can result in globus sensation, dysphagia, and even vocal fold immobility. Knowledge of morphologic and functional laryngopharyngeal outcomes after CEA is poor. The present study was performed to determine potential iatrogenic damage to the laryngeal innervation after CEA. An area of particular interest was the supraglottic sensory threshold, which was examined by Fiberoptic Endoscopic Evaluation of Swallowing With Sensory Testing (FEESST; Pentax Medical Company, Montvale, NJ), a validated and safe method for the determination of the motor and sensory components of swallowing. FEESST was used preoperatively in 32 patients scheduled to undergo CEA and twice postoperatively to examine the motor and sensory components of swallowing. In this endolaryngeal examination, laryngopharyngeal sensory thresholds (in mm Hg) were defined as normal at 6.0 mm Hg APP, with a value >10.0 mm Hg APP indicating abolished laryngeal adductor reflex. Acoustic voice parameters were also analyzed for further functional changes of the larynx. The mean ± standard deviation preoperative FEESST measures showed no significant differences (P = .065) between the operated-on side (6.73 ± 1.73 mm Hg) and the opposite side (5.83 ± 1.68 mm Hg). At 2 days postoperatively, the threshold increased (P = .001) to 7.62 ± 1.98 mm Hg on the operated-on side. A laryngopharyngeal mucosal hematoma on the operated side was endoscopically detectable in eight patients (30.8%); in these patients, we found a markedly elevated (P = .021) measure of 9.50 ± 0.93 mm Hg. On the opposite (nonoperated-on) side of the laryngopharynx, the thresholds remained at the same level as preoperatively over all assessments (P >.05), whereas the differences between the operated and nonoperated-on sides and the hematoma and nonhematoma groups were highly significant (P = .004 and P = .001, respectively). Surprisingly, the

  9. Prognostic significance of erythropoietin in pancreatic adenocarcinoma.

    Directory of Open Access Journals (Sweden)

    Thilo Welsch

    Full Text Available BACKGROUND: Erythropoietin (Epo administration has been reported to have tumor-promoting effects in anemic cancer patients. We investigated the prognostic impact of endogenous Epo in patients with pancreatic ductal adenocarcinoma (PDAC. METHODOLOGY: The clinico-pathological relevance of hemoglobin (Hb, n = 150, serum Epo (sEpo, n = 87 and tissue expression of Epo/Epo receptor (EpoR, n = 104 was analyzed in patients with PDAC. Epo/EpoR expression, signaling, growth, invasion and chemoresistance were studied in Epo-exposed PDAC cell lines. RESULTS: Compared to donors, median preoperative Hb levels were reduced by 15% in both chronic pancreatitis (CP, p<0.05 and PDAC (p<0.001, reaching anemic grade in one third of patients. While inversely correlating to Hb (r = -0.46, 95% of sEPO values lay within the normal range. The individual levels of compensation were adequate in CP (observed to predicted ratio, O/P = 0.99 but not in PDAC (O/P = 0.85. Strikingly, lower sEPO values yielding inadequate Epo responses were prominent in non-metastatic M0-patients, whereas these parameters were restored in metastatic M1-group (8 vs. 13 mU/mL; O/P = 0.82 vs. 0.96; p<0.01--although Hb levels and the prevalence of anemia were comparable. Higher sEpo values (upper quartile ≥ 16 mU/ml were not significantly different in M0 (20% and M1 (30% groups, but were an independent prognostic factor for shorter survival (HR 2.20, 10 vs. 17 months, p<0.05. The pattern of Epo expression in pancreas and liver suggested ectopic release of Epo by capillaries/vasa vasorum and hepatocytes, regulated by but not emanating from tumor cells. Epo could initiate PI3K/Akt signaling via EpoR in PDAC cells but failed to alter their functions, probably due to co-expression of the soluble EpoR isoform, known to antagonize Epo. CONCLUSION/SIGNIFICANCE: Higher sEPO levels counteract anemia but worsen outcome in PDAC patients. Further trials are required to clarify how overcoming a sEPO threshold

  10. Inhibition of neutral sphingomyelinase decreases elevated levels of inducible nitric oxide synthase and apoptotic cell death in ocular hypertensive rats

    Energy Technology Data Exchange (ETDEWEB)

    Aslan, Mutay, E-mail: mutayaslan@akdeniz.edu.tr [Department of Medical Biochemistry, Akdeniz University Faculty of Medicine, Antalya (Turkey); Basaranlar, Goksun [Department of Biophysics, Akdeniz University Faculty of Medicine, Antalya (Turkey); Unal, Mustafa [Department of Ophthalmology, Akdeniz University Faculty of Medicine, Antalya (Turkey); Ciftcioglu, Akif [Department of Pathology, Akdeniz University Faculty of Medicine, Antalya (Turkey); Derin, Narin [Department of Biophysics, Akdeniz University Faculty of Medicine, Antalya (Turkey); Mutus, Bulent [Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario (Canada)

    2014-11-01

    Endoplasmic reticulum (ER) stress and excessive nitric oxide production via induction of inducible nitric oxide synthase (NOS2) have been implicated in the pathogenesis of neuronal retinal cell death in ocular hypertension. Neutral sphingomyelinase (N-SMase)/ceramide pathway can regulate NOS2 expression, hence this study determined the role of selective neutral sphingomyelinase (N-SMase) inhibition on retinal NOS2 levels, ER stress, apoptosis and visual evoked potentials (VEPs) in a rat model of elevated intraocular pressure (EIOP). NOS2 expression and retinal protein nitration were significantly greater in EIOP and significantly decreased with N-SMase inhibition. A significant increase was observed in retinal ER stress markers pPERK, CHOP and GRP78 in EIOP, which were not significantly altered by N-SMase inhibition. Retinal TUNEL staining showed increased apoptosis in all EIOP groups; however N-SMase inhibition significantly decreased the percent of apoptotic cells in EIOP. Caspase-3, -8 and -9 activities were significantly increased in EIOP and returned to baseline levels following N-SMase inhibition. Latencies of all VEP components were significantly prolonged in EIOP and shortened following N-SMase inhibition. Data confirm the role of nitrative injury in EIOP and highlight the protective effect of N-SMase inhibition in EIOP via down-regulation of NOS2 levels and nitrative stress. - Highlights: • Inhibition of N-SMase decreases NOS2 levels in ocular hypertension. • Inhibition of N-SMase decreases protein nitration in ocular hypertension. • Inhibition of N-SMase decreases caspase activation in ocular hypertension. • Inhibition of N-SMase decreases apoptosis in ocular hypertension.

  11. Significance of blood examination in radiation workers

    International Nuclear Information System (INIS)

    Mori, Hirofumi; Nakamura, Shinobu; Ando, Atsushi; Kojima, Kazuhiko; Kikuta, Yoko.

    1978-01-01

    Blood examination made for the past 3 years revealed that the influences of chronic exposure of extremely small amounts of radiation (an average of 5 mrem/day) on peripheral blood are not detected. However, the blood examination, which is prescribed at least twice a year by law, is for determining whether or not the results of blood examination are within a normal range. Therefore, even though influences of a large amount of radiation are detected, it has little significance as a monitoring of chronic exposure of extremely small amounts of radiation. If the blood examination is used as a monitoring method for detecting exposure, it is important to compare the results with the previous ones in the same individuals. It is also necessary to increase the number of examinations and to study the blood more in detail. However, before that, the standard of the evaluation should be more defined because of its obscurity. The present blood examination is useful in managing the health generally. However, it is not good as a monitoring for chronic exposure of the extremely small amounts of radiation. Therefore, a routine biological method to be able to monitor radiation more precisely, is required. (Namekawa, K.)

  12. Making lasting memories: Remembering the significant

    Science.gov (United States)

    McGaugh, James L.

    2013-01-01

    Although forgetting is the common fate of most of our experiences, much evidence indicates that emotional arousal enhances the storage of memories, thus serving to create, selectively, lasting memories of our more important experiences. The neurobiological systems mediating emotional arousal and memory are very closely linked. The adrenal stress hormones epinephrine and corticosterone released by emotional arousal regulate the consolidation of long-term memory. The amygdala plays a critical role in mediating these stress hormone influences. The release of norepinephrine in the amygdala and the activation of noradrenergic receptors are essential for stress hormone-induced memory enhancement. The findings of both animal and human studies provide compelling evidence that stress-induced activation of the amygdala and its interactions with other brain regions involved in processing memory play a critical role in ensuring that emotionally significant experiences are well-remembered. Recent research has determined that some human subjects have highly superior autobiographic memory of their daily experiences and that there are structural differences in the brains of these subjects compared with the brains of subjects who do not have such memory. Understanding of neurobiological bases of such exceptional memory may provide additional insights into the processes underlying the selectivity of memory. PMID:23754441

  13. PROMPT Ia SUPERNOVAE ARE SIGNIFICANTLY DELAYED

    International Nuclear Information System (INIS)

    Raskin, Cody; Scannapieco, Evan; Rhoads, James; Della Valle, Massimo

    2009-01-01

    The time delay between the formation of a population of stars and the onset of type Ia supernovae (SNe Ia) sets important limits on the masses and nature of SN Ia progenitors. Here, we use a new observational technique to measure this time delay by comparing the spatial distributions of SNe Ia to their local environments. Previous work attempted such analyses encompassing the entire host of each SN Ia, yielding inconclusive results. Our approach confines the analysis only to the relevant portions of the hosts, allowing us to show that even so-called prompt SNe Ia that trace star formation on cosmic timescales exhibit a significant delay time of 200-500 million years. This implies that either the majority of Ia companion stars have main-sequence masses less than 3 M sun , or that most SNe Ia arise from double white dwarf binaries. Our results are also consistent with a SNe Ia rate that traces the white dwarf formation rate, scaled by a fixed efficiency factor.

  14. Clinical significance of anaplasia in childhood rhabdomyosarcoma.

    Science.gov (United States)

    Sidhom, Iman; El Nadi, Enas; Taha, Hala; Elkinaai, Naglaa; Zaghloul, Mohamed S; Younes, Alaa; Labib, Rania; Sabry, Mohamed

    2015-06-01

    The presence of anaplastic features has been known to correlate with poor clinical outcome in various pediatric malignancies, including Wilms tumor and medulloblastoma but not in rhabdomyosarcoma. Aim was to study the frequency of anaplasia at presentation in childhood rhabdomyosarcoma and its relationship to clinical and pathological characteristics as well as to outcome. Anaplasia was retrospectively assessed in 105 consecutive pediatric rhabdomyosarcoma patients who were registered at the Children's Cancer Hospital in Egypt (CCHE) during the period from July 2007 till the end of May 2010. Anaplasia was diagnosed in 18 patients (17.1%), focal in 10 (9.5%) and diffuse in 8 (7.6%). The distribution of anaplasia was found to be more common in older patients having age⩾10 years. Also it was more likely to occur in the high risk group and in tumors with unfavorable histology (alveolar subtype), and stage IV. The 3-year failure free survival rates for patients with and without anaplasia were 27.8±10.6% and 53.4±5.8%, respectively (p=0.014) and the 3-year overall survival rates were 35.3±11.6% and 61±6%, respectively (p=0.019). The frequency of anaplasia in pediatric patients with rhabdomyosarcoma in our study was 17.1%. The presence of anaplasia had statistically significant worse clinical outcome. Copyright © 2015 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  15. Clinical significance of anaplasia in childhood rhabdomyosarcoma

    International Nuclear Information System (INIS)

    Sidhom, I.; El Nadi, E.; Taha, H.; Elkinaai, N.; Zaghloul, M.S.; Younes, A.; Labib, R.; Sabry, M.

    2015-01-01

    Background: The presence of anaplastic features has been known to correlate with poor clinical outcome in various pediatric malignancies, including Wilms tumor and medulloblastoma but not in rhabdomyosarcoma. Aim: Aim was to study the frequency of anaplasia at presentation in childhood rhabdomyosarcoma and its relationship to clinical and pathological characteristics as well as to outcome. Patients and Methods: Anaplasia was retrospectively assessed in 105 consecutive pediatric rhabdomyosarcoma patients who were registered at the Children’s Cancer Hospital in Egypt (CCHE) during the period from July 2007 till the end of May 2010. Results: Anaplasia was diagnosed in 18 patients (17.1%), focal in 10 (9.5%) and diffuse in 8 (7.6%). The distribution of anaplasia was found to be more common in older patients having age P 10 years. Also it was more likely to occur in the high risk group and in tumors with unfavorable histology (alveolar subtype), and stage IV. The 3-year failure free survival rates for patients with and without anaplasia were 27.8 ± 10.6% and 53.4 ± 5.8%, respectively (p = 0.014) and the 3-year overall survival rates were 35.3 ± 11.6% and 61 ± 6%, respectively (p = 0.019). Conclusions: The frequency of anaplasia in pediatric patients with rhabdomyosarcoma in our study was 17.1%. The presence of anaplasia had statistically significant worse clinical outcome

  16. Traditional Indian spices and their health significance.

    Science.gov (United States)

    Krishnaswamy, Kamala

    2008-01-01

    India has been recognized all over the world for spices and medicinal plants. Both exhibit a wide range of physiological and pharmacological properties. Current biomedical efforts are focused on their scientific merits, to provide science-based evidence for the traditional uses and to develop either functional foods or nutraceuticals. The Indian traditional medical systems use turmeric for wound healing, rheumatic disorders, gastrointestinal symptoms, deworming, rhinitis and as a cosmetic. Studies in India have explored its anti-inflammatory, cholekinetic and anti-oxidant potentials with the recent investigations focusing on its preventive effect on precarcinogenic, anti-inflammatory and anti atherosclerotic effects in biological systems both under in vitro and in vivo conditions in animals and humans. Both turmeric and curcumin were found to increase detoxifying enzymes, prevent DNA damage, improve DNA repair, decrease mutations and tumour formation and exhibit antioxidative potential in animals. Limited clinical studies suggest that turmeric can significantly impact excretion of mutagens in urine in smokers and regress precancerous palatal lesions. It reduces DNA adducts and micronuclei in oral epithelial cells. It prevents formation of nitroso compounds both in vivo and in vitro. It delays induced cataract in diabetes and reduces hyperlipidemia in obese rats. Recently several molecular targets have been identified for therapeutic / preventive effects of turmeric. Fenugreek seeds, a rich source of soluble fiber used in Indian cuisine reduces blood glucose and lipids and can be used as a food adjuvant in diabetes. Similarly garlic, onions, and ginger have been found to modulate favourably the process of carcinogenesis.

  17. The measure and significance of Bateman's principles.

    Science.gov (United States)

    Collet, Julie M; Dean, Rebecca F; Worley, Kirsty; Richardson, David S; Pizzari, Tommaso

    2014-05-07

    Bateman's principles explain sex roles and sexual dimorphism through sex-specific variance in mating success, reproductive success and their relationships within sexes (Bateman gradients). Empirical tests of these principles, however, have come under intense scrutiny. Here, we experimentally show that in replicate groups of red junglefowl, Gallus gallus, mating and reproductive successes were more variable in males than in females, resulting in a steeper male Bateman gradient, consistent with Bateman's principles. However, we use novel quantitative techniques to reveal that current methods typically overestimate Bateman's principles because they (i) infer mating success indirectly from offspring parentage, and thus miss matings that fail to result in fertilization, and (ii) measure Bateman gradients through the univariate regression of reproductive over mating success, without considering the substantial influence of other components of male reproductive success, namely female fecundity and paternity share. We also find a significant female Bateman gradient but show that this likely emerges as spurious consequences of male preference for fecund females, emphasizing the need for experimental approaches to establish the causal relationship between reproductive and mating success. While providing qualitative support for Bateman's principles, our study demonstrates how current approaches can generate a misleading view of sex differences and roles.

  18. Significance and popularity in music production

    Science.gov (United States)

    Gravino, Pietro; Servedio, Vito D. P.; Tria, Francesca; Loreto, Vittorio

    2017-01-01

    Creative industries constantly strive for fame and popularity. Though highly desirable, popularity is not the only achievement artistic creations might ever acquire. Leaving a longstanding mark in the global production and influencing future works is an even more important achievement, usually acknowledged by experts and scholars. ‘Significant’ or ‘influential’ works are not always well known to the public or have sometimes been long forgotten by the vast majority. In this paper, we focus on the duality between what is successful and what is significant in the musical context. To this end, we consider a user-generated set of tags collected through an online music platform, whose evolving co-occurrence network mirrors the growing conceptual space underlying music production. We define a set of general metrics aiming at characterizing music albums throughout history, and their relationships with the overall musical production. We show how these metrics allow to classify albums according to their current popularity or their belonging to expert-made lists of important albums. In this way, we provide the scientific community and the public at large with quantitative tools to tell apart popular albums from culturally or aesthetically relevant artworks. The generality of the methodology presented here lends itself to be used in all those fields where innovation and creativity are in play. PMID:28791169

  19. CT diagnostic significance of tuboovarian abscess

    International Nuclear Information System (INIS)

    Du Tieqiao; Dong Jie; Xu Quanying; An Haiqin; Sang Chunyu

    2006-01-01

    Objective: To analyze computed tomographic (CT) imaging features of tuboovarian abscess as well as to discuss CT diagnostic significance. Methods: Ten patients with tuboovarian abscess were performed CT enhancing scans. Results: Ten patients manifested thick-walled, cystic-solid complex adnexal mass and indistinct margins on CT imaging. Internal thick septations and layered enhancement of the mass border on CT contrast images were common. Associated findings of CT included thickening of' the uterosacral ligaments in 9 of 10 patients, increased attenuation of the presacral and perirectal fat secondary to edema in 9 patients, serpiginous structure corresponding to a dilated, pus-filled fallopian tube in 6 patients and fluid-filled within uterine cavity in 4 patients. On CT scans, the inflammatory infiltration of adnexal abscesses involved pelvic structure included adhesion with borders of uterus in 9 patients, adhesion with rectal or sigmoid in 4 patients and pelvic wall or bowel loop in 3 patients. Two cases with peritoneal thicken showed ascites on CT images and right adnexal tuboovarian abscess in 2 patients were associated with appendicitis. Conclusion: CT can reveal pelvic adjacent organs involvement or adhesion and inflammatory infihration of pelvic floor soft-tissues or fascial planes except showing cystic solid complex mass of adnexal location so that indicating characteristics and the extent of the suspected pelvic inflammatory diseases. CT can be valuable in difficult cases of gynecologic infective diseases. (authors)

  20. Clinical significance of perceptible fetal motion.

    Science.gov (United States)

    Rayburn, W F

    1980-09-15

    The monitoring of fetal activity during the last trimester of pregnancy has been proposed to be useful in assessing fetal welfare. The maternal perception of fetal activity was tested among 82 patients using real-time ultrasonography. All perceived fetal movements were visualized on the scanner and involved motion of the lower limbs. Conversely, 82% of all visualized motions of fetal limbs were perceived by the patients. All combined motions of fetal trunk with limbs were preceived by the patients and described as strong movements, whereas clusters of isolated, weak motions of the fetal limbs were less accurately perceived (56% accuracy). The number of fetal movements perceived during the 15-minute test period was significantly (p fetal motion was present (44 of 45 cases) than when it was absent (five of 10 cases). These findings reveal that perceived fetal motion is: (1) reliable; (2) related to the strength of lower limb motion; (3) increased with ruptured amniotic membranes; and (4) reassuring if considered to be active.

  1. Evolutionary significance of ageing in the wild.

    Science.gov (United States)

    Kowald, Axel; Kirkwood, Thomas B L

    2015-11-01

    Human lifespan has risen dramatically over the last 150 years, leading to a significant increase in the fraction of aged people in the population. Until recently it was believed that this contrasted strongly with the situation in wild populations of animals, where the likelihood of encountering demonstrably senescent individuals was believed to be negligible. Over the recent years, however, a series of field studies has appeared that shows ageing can also be observed for many species in the wild. We discuss here the relevance of this finding for the different evolutionary theories of ageing, since it has been claimed that ageing in the wild is incompatible with the so-called non-adaptive (non-programmed) theories, i.e. those in which ageing is presumed not to offer a direct selection benefit. We show that a certain proportion of aged individuals in the population is fully compatible with the antagonistic pleiotropy and the disposable soma theories, while it is difficult to reconcile with the mutation accumulation theory. We also quantify the costs of ageing using life history data from recent field studies and a range of possible metrics. We discuss the merits and problems of the different metrics and also introduce a new metric, yearly death toll, that aims directly at quantifying the deaths caused by the ageing process. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Significant and Basic Innovations in Urban Planning

    Science.gov (United States)

    Kolyasnikov, V. A.

    2017-11-01

    The article considers the development features of the innovative urban planning in the USSR and Russia in XVIII - XX centuries. Innovative urban planning is defined as an activity on innovations creation and their implementation to obtain a socio-economic, political, environmental or other effect. In the course of urban development history this activity represents a cyclic wave process in which there are phases of rise and fall. The study of cyclic waves in the development of innovative urban planning uses the concept of basic and epochal innovations selection. This concept was developed by scientists for the study of cyclic wave processes in economics. Its adaptation to the conditions of innovative urban planning development allows one to introduce the concept of “basic innovation” and “significant innovation” in the theory and practice of settlement formation and their systems as well as to identify opportunities to highlight these innovations in the history of Russian urban planning. From these positions, six innovation waves committed to the urban development over the past 300 years are being investigated. The observed basic innovations in the domestic urban area show that urban development is a vital area for ensuring the country’s geopolitical security. Basic innovations are translated in time and modernized under new conditions of urban planning development. In this regard, we can predict the development of four basic innovations in post-Soviet Russia.

  3. Death, Catastrophe, and the Significance of Tragedy

    Directory of Open Access Journals (Sweden)

    Jennifer Ballengee

    2014-05-01

    Full Text Available This NANO note will examine the tension between representation, memorial, and the catastrophe of death that emerges in the space of tragedy, as the problem arises in two quite different works: Oedipus at Colonus, a fairly typical fifth-century Greek tragedy, and Falling Man, Don DeLillo’s novel that, in its attempt to address the events of 9/11, reflects in form and subject matter many of Aristotle’s terms of tragic representation. It is not the intent of this note to engage with the recent proliferation of work in “performance theory.” Rather than being concerned with an imagined exchange between audience and actor, this study examines how the supplementary relationship of gesture and speech in tragedy disrupts the public/private distinction, and how this articulation effects and enables the public memorialization of death. Thus, this paper will consider the representation of death as an event whose catastrophic, and somewhat mysterious, collision of the public and the private lends it its tragic significance.

  4. Medical Significance of Microorganisms in Spacecraft Environment

    Science.gov (United States)

    Pierson, Duane L.; Ott, C. Mark

    2007-01-01

    Microorganisms can spoil food supplies, contaminate drinking water, release noxious volatile compounds, initiate allergic responses, contaminate the environment, and cause infectious diseases. International acceptability limits have been established for bacterial and fungal contaminants in air and on surfaces, and environmental monitoring is conducted to ensure compliance. Allowable levels of microorganism in water and food have also been established. Environmental monitoring of the space shuttle, the Mir, and the ISS have allowed for some general conclusions. Generally, the bacteria found in air and on interior surfaces are largely of human origin such as Staphylococcus spp., Micrococcus spp. Common environmental genera such as Bacillus spp. are the most commonly isolated bacteria from all spacecraft. Yeast species associated with humans such as Candida spp. are commonly found. Aspergillus spp., Penicillium spp., and Cladosporium spp. are the most commonly isolated filamentous fungi. Microbial levels in the environment differ significantly depending upon humidity levels, condensate accumulation, and availability of carbon sources. However, human "normal flora" of bacteria and fungi can result in serious, life-threatening diseases if human immunity is compromised. Disease incidence is expected to increase as mission duration increases.

  5. [The significance of meat quality in marketing].

    Science.gov (United States)

    Kallweit, E

    1994-07-01

    Food quality in general and meat quality in particular are not only evaluated by means of objective quality traits but the entire production process is gaining more attention by the modern consumer. Due to this development quality programs were developed to define the majority of the processes in all production and marketing steps which are again linked by contracts. Not all of these items are quality relevant, but are concessions to ethic principles (animal welfare etc.). This is demonstrated by the example of Scharrel-pork production. The price differentiation at the pork market is still influenced predominantly by quantitative carcass traits. On the European market quality programs still are of minor significance. Premiums which are paid for high quality standards are more or less compensated by higher production costs and lower lean meat percentages, which must be expected in stress susceptible strains. The high efforts to establish quality programs, however, help to improve the quality level in general, and secure the market shares for local producers.

  6. Magnolol inhibits migration of vascular smooth muscle cells via cytoskeletal remodeling pathway to attenuate neointima formation

    International Nuclear Information System (INIS)

    Karki, Rajendra; Kim, Seong-Bin; Kim, Dong-Wook

    2013-01-01

    Background: Increased proliferation and migration of vascular smooth muscle cells (VSMCs) contribute importantly to the formation of both atherosclerotic and restenotic lesions. The objective of this study was to investigate the effect of magnolol on VSMC migration. Methods: The proteolytic activity of matrix metalloproteinases (MMPs) in tumor necrosis factor alpha (TNF-α) stimulated VSMCs was performed by gelatin zymography. VSMC migration was assessed by wound healing and Boyden chamber methods. Collagen induced VSMC adhesion was determined by spectrofluorimeter and stress fibers formation was evaluated by fluorescence microscope. The expression of signaling molecules involved in stress fibers formation was determined by western blot. The phosphorylation of myosin light chain (MLC20) was determined by urea-glycerol polyacrylamide gel electrophoresis. Immunohistochemistry was performed to determine the expression of β1-integrin and collagen type I in the injured carotid arteries of rats on day 35 after vascular injury. Results: VSMC migration was strongly inhibited by magnolol without affecting MMPs expression. Also, magnolol inhibited β1-integrin expression, FAK phosphorylation and RhoA and Cdc42 activation to inhibit the collagen induced stress fibers formation. Moreover, magnolol inhibited the phosphorylation of MLC20. Our in vivo results showed that magnolol inhibited β1-integrin expression, collagen type I deposition and FAK phosphorylation in injured carotid arteries without affecting MMP-2 activity. Conclusions: Magnolol inhibited VSMC migration via inhibition of cytoskeletal remodeling pathway to attenuate neointima formation. General significance: This study provides a rationale for further evaluation of magnolol for the management of atherosclerosis and restenosis. - Highlights: • Magnolol strongly inhibited migration of VSMCs. • Magnolol inhibited stress fibers formation. • MLC20 phosphorylation was also inhibited by magnolol. • Anti

  7. Magnolol inhibits migration of vascular smooth muscle cells via cytoskeletal remodeling pathway to attenuate neointima formation

    Energy Technology Data Exchange (ETDEWEB)

    Karki, Rajendra [Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri-Kansas City (United States); Department of Oriental Medicine Resources, Mokpo National University (Korea, Republic of); Kim, Seong-Bin [Jeollanamdo Development Institute for Korean Traditional Medicine, Jangheung gun, Jeollanamdo (Korea, Republic of); Kim, Dong-Wook, E-mail: dbkim@mokpo.ac.kr [Department of Oriental Medicine Resources, Mokpo National University (Korea, Republic of)

    2013-12-10

    Background: Increased proliferation and migration of vascular smooth muscle cells (VSMCs) contribute importantly to the formation of both atherosclerotic and restenotic lesions. The objective of this study was to investigate the effect of magnolol on VSMC migration. Methods: The proteolytic activity of matrix metalloproteinases (MMPs) in tumor necrosis factor alpha (TNF-α) stimulated VSMCs was performed by gelatin zymography. VSMC migration was assessed by wound healing and Boyden chamber methods. Collagen induced VSMC adhesion was determined by spectrofluorimeter and stress fibers formation was evaluated by fluorescence microscope. The expression of signaling molecules involved in stress fibers formation was determined by western blot. The phosphorylation of myosin light chain (MLC20) was determined by urea-glycerol polyacrylamide gel electrophoresis. Immunohistochemistry was performed to determine the expression of β1-integrin and collagen type I in the injured carotid arteries of rats on day 35 after vascular injury. Results: VSMC migration was strongly inhibited by magnolol without affecting MMPs expression. Also, magnolol inhibited β1-integrin expression, FAK phosphorylation and RhoA and Cdc42 activation to inhibit the collagen induced stress fibers formation. Moreover, magnolol inhibited the phosphorylation of MLC20. Our in vivo results showed that magnolol inhibited β1-integrin expression, collagen type I deposition and FAK phosphorylation in injured carotid arteries without affecting MMP-2 activity. Conclusions: Magnolol inhibited VSMC migration via inhibition of cytoskeletal remodeling pathway to attenuate neointima formation. General significance: This study provides a rationale for further evaluation of magnolol for the management of atherosclerosis and restenosis. - Highlights: • Magnolol strongly inhibited migration of VSMCs. • Magnolol inhibited stress fibers formation. • MLC20 phosphorylation was also inhibited by magnolol. • Anti

  8. Radiological significance of thorium processing in manufacturing

    International Nuclear Information System (INIS)

    Davis, M.W.

    1985-01-01

    The study of thorium processing in manufacturing comprised monitoring programs at a plant where thorium dioxide was in use and another where the use of thorium nitrate had been discontinued. The measurements of the solubility in simulated lung fluid proved that both materials belonged in the Y Class with dissolution half-times greater than 500 days. Bioassay measurements of 20 subjects from both facilities proved that in vitro monitoring methods, urine, feces, hair and nails analysis were not sufficient indicators of thorium uptake. In vivo monitoring by phoswich and large sodium iodide detectors were proven to be good methods of determining thorium lung burdens. The thoron in breath technique was shown to have a lower limit of sensitivity than lung counting, however, due to lack of information regarding the thoron escape rate from the thorium particles in the lungs the method is not as accurate as lung counting. Two subjects at the thorium dioxide facility had lung burdens of 21+- 16 Bq and 29+- 24 Bq Th 232 and one at the thorium nitrate facility had a lung burden of 37+- 13 Bq. Improvements in the procedures and use of a glove box were among the recommendations to reduce the inhalation of thorium by workers at the thorium dioxide facility. Decontamination of several rooms at the thorium nitrate facility and sealing of the walls and floors were recommended in order to reduce the escape of thoron gas into the room air. The risk to non Atomic Radiation Workers was primarily due to thoron daughters in air while gamma radiation and thorium in air were less important. Conversely, at the thorium dioxide facility the inhalation of thorium in air was the most significant exposure pathway

  9. Psoriasis causes significant economic burden to patients.

    Science.gov (United States)

    Mustonen, A; Mattila, K; Leino, M; Koulu, L; Tuominen, R

    2014-06-01

    Psoriasis results in expenses to patients from many cost sources. Psoriasis treatments may result in considerable time and traveling costs, yet many studies fail to account for these costs. The objective of this study was to evaluate the multidimensional economic burden of psoriasis to patients. The study was based on 232 Finnish patients with psoriasis or psoriatic arthritis visiting a tertiary level dermatological clinic during a 1-year study period between October 1, 2009 and September 30, 2010. The data were based on a patient questionnaire, clinical data from the medical records and reimbursement data from the Finnish Social Insurance Institution. Item costs were based on true costs charged from the patients and all time cost estimates were based on the Human Capital Approach method. 199 patients with psoriasis and 33 with psoriatic arthritis were included in the study. Total costs were higher for patients receiving traditional systemic medications or phototherapy than those not receiving such treatment. Travel costs and travel time costs accounted for more than 60% of the costs of phototherapy. Skin care at home was time consuming and thus caused significant burden to patients. The majority of the visit costs arose from hospital visits and only a small proportion were attributed to visiting primary health care providers. Visit charges and other patient co-payments were estimated to play a minor role in the total cost of psoriasis incurred by patients, while travel costs and lost time comprised the majority of the costs, which should not be omitted in future studies regarding costs of treatments.

  10. Significance of venous anastomosis in fingertip replantation.

    Science.gov (United States)

    Hattori, Yasunori; Doi, Kazuteru; Ikeda, Keisuke; Abe, Yukio; Dhawan, Vikas

    2003-03-01

    Adequate venous outflow is the most important factor for successful fingertip replantation. The authors have attempted venous anastomosis in all cases of fingertip replantation to overcome postoperative congestion. In this article, the significance of venous repair for fingertip replantation is described from the authors' results of 64 complete fingertip amputations in 55 consecutive patients, which were replanted from January of 1996 to June of 2001. The overall survival rate was 86 percent. Of the 44 replantations in zone I, 37 survived, and the success rate was 84 percent. Of the 20 replantations in zone II, 18 survived, and the success rate was 90 percent. Venous anastomosis was attempted in all cases, but it was possible in 39 zone I and in all zone II replantations. For arterial repair, vein grafts were necessary in 17 of the 44 zone I and in one of the 20 zone II replantations; for venous repair, they were necessary in six zone I replantations and one zone II replantation. Postoperative vascular complications occurred in 15 replantations. There were five cases of arterial thrombosis and 10 cases of venous congestion. Venous congestion occurred in nine zone I and one zone II replantations. In five of these 10 replantations, venous anastomosis was not possible. In another five replantations, venous outflow was established at the time of surgery, but occlusion occurred subsequently. Except for the five failures resulting from arterial thrombosis, successful venous repair was possible in 49 of 59 replantations (83 percent). Despite the demand for skillful microsurgical technique and longer operation time, the authors' results using venous anastomosis in successful fingertip replantations are encouraging. By performing venous anastomosis, external bleeding can be avoided and a higher survival rate can be achieved. Venous anastomosis for fingertip replantation is a reliable and worthwhile procedure.

  11. Clinical significance of autoantibodies in autoimmune hepatitis.

    Science.gov (United States)

    Liberal, Rodrigo; Mieli-Vergani, Giorgina; Vergani, Diego

    2013-10-01

    The accurate diagnosis and classification of autoimmune hepatitis (AIH) rely upon the detection of characteristic autoantibodies. Positivity for anti-nuclear (ANA) and/or anti-smooth muscle (SMA) autoantibodies defines AIH type 1 (AIH-1), whereas anti-liver kidney microsomal type 1 (anti-LKM1) and/or anti-liver cytosol type 1 (anti-LC1) define AIH type 2 (AIH-2). ANA and SMA, and less commonly anti-LKM1, have also been detected in de-novo autoimmune hepatitis developing after liver transplantation, a condition that may affect patients transplanted for non-autoimmune liver disease. The diagnostic autoantibodies associated with AIH-1 are also detected in the paediatric AIH/sclerosing cholangitis overlap syndrome, referred to as autoimmune sclerosing cholangitis (ASC). ASC, like adult primary sclerosing cholangitis, is often associated with atypical perinuclear anti-neutrophil cytoplasmic autoantibodies (p-ANCA), although p-ANCA are also detected in other autoimmune liver diseases. These associations highlight the necessity for simple and prompt diagnostic autoantibody testing, and the requirement for the accurate interpretation of the results of the tests in the clinical context. Fine-mapping of antigenic autoantibody targets has facilitated the development of rapid molecular assays that have the potential to revolutionise the field if properly standardised and when used in combination with classical immunofluorescence. Despite their diagnostic significance, the pathogenic role of the various autoantibodies and the mechanisms by which they can potentially inflict damage onto the liver cell remain a topic for further research. Copyright © 2013 Elsevier Ltd. All rights reserved.

  12. The significance of routines in nursing practice.

    Science.gov (United States)

    Rytterström, Patrik; Unosson, Mitra; Arman, Maria

    2011-12-01

    The aim of this study was to illuminate the significance of routines in nursing practice. Clinical nursing is performed under the guidance of routines to varying degrees. In the nursing literature, routine is described as having both negative and positive aspects, but use of the term is inconsistent, and empirical evidence is sparse. In the research on organisational routines, a distinction is made between routine as a rule and routine as action. A qualitative design using a phenomenological-hermeneutic approach. Data collection from three focus groups focused on nurses' experience of routines. Seventeen individual interviews from a previous study focusing on caring culture were also analysed in a secondary qualitative analysis. All participants were employed as 'qualified nursing pool' nurses. Routines are experienced as pragmatic, obstructive and meaningful. The aim of the pragmatic routine was to ensure that daily working life works; this routine is practised more on the basis of rational arguments and obvious intentions. The obstructive routine had negative consequences for nursing practice and was described as nursing losing its humanity and violating the patient's integrity. The meaningful routine involved becoming one with the routine and for the nurses, it felt right and meaningful to adapt to it. Routines become meaningful when the individual action is in harmony with the cultural pattern on which the nursing work is based. Instead of letting contemporary practice passively become routine, routines can be assessed and developed using research and theoretical underpinnings as a starting point for nursing practice. Leaders have a special responsibility to develop and support meaningful routines. One approach could be to let wards examine their routines from a patient perspective on the basis of the themes of pragmatic, meaningful and obstructive routine. © 2010 Blackwell Publishing Ltd.

  13. Comparative in vitro inhibition of urinary tract pathogens by single- and multi-strain probiotics.

    Science.gov (United States)

    Chapman, C M C; Gibson, G R; Todd, S; Rowland, I

    2013-09-01

    Multi-species probiotic preparations have been suggested as having a wide spectrum of application, although few studies have compared their efficacy with that of individual component strains at equal concentrations. We therefore tested the ability of 4 single probiotics and 4 probiotic mixtures to inhibit the urinary tract pathogens Escherichia coli NCTC 9001 and Enterococcus faecalis NCTC 00775. We used an agar spot test to test the ability of viable cells to inhibit pathogens, while a broth inhibition assay was used to assess inhibition by cell-free probiotic supernatants in both pH-neutralised and non-neutralised forms. In the agar spot test, all probiotic treatments showed inhibition, L. acidophilus was the most inhibitory single strain against E. faecalis, L. fermentum the most inhibitory against E. coli. A commercially available mixture of 14 strains (Bio-Kult(®)) was the most effective mixture, against E. faecalis, the 3-lactobacillus mixture the most inhibitory against E. coli. Mixtures were not significantly more inhibitory than single strains. In the broth inhibition assays, all probiotic supernatants inhibited both pathogens when pH was not controlled, with only 2 treatments causing inhibition at a neutral pH. Both viable cells of probiotics and supernatants of probiotic cultures were able to inhibit growth of two urinary tract pathogens. Probiotic mixtures prevented the growth of urinary tract pathogens but were not significantly more inhibitory than single strains. Probiotics appear to produce metabolites that are inhibitory towards urinary tract pathogens. Probiotics display potential to reduce the incidence of urinary tract infections via inhibition of colonisation.

  14. Selenium inhibits the phytotoxicity of mercury in garlic (Allium sativum)

    International Nuclear Information System (INIS)

    Zhao, Jiating; Gao, Yuxi; Li, Yu-Feng; Hu, Yi; Peng, Xiaomin; Dong, Yuanxing; Li, Bai; Chen, Chunying; Chai, Zhifang

    2013-01-01

    To investigate the influence of selenium on mercury phytotoxicity, the levels of selenium and mercury were analyzed with inductively coupled plasma-mass spectrometry (ICP-MS) in garlic tissues upon exposure to different dosages of inorganic mercury (Hg 2+ ) and selenite (SeO 3 2− ) or selenate (SeO 4 2− ). The distributions of selenium and mercury were examined with micro-synchrotron radiation X-ray fluorescence (μ-SRXRF), and the mercury speciation was investigated with micro-X-ray absorption near edge structure (μ-XANES). The results show that Se at higher exposure levels (>1 mg/L of SeO 3 2− or SeO 4 2− ) would significantly inhibit the absorption and transportation of Hg when Hg 2+ levels are higher than 1 mg/L in culture media. SeO 3 2− and SeO 4 2− were found to be equally effective in reducing Hg accumulation in garlic. The inhibition of Hg uptake by Se correlates well with the influence of Se on Hg phytotoxicity as indicated by the growth inhibition factor. Elemental imaging using μ-SRXRF also shows that Se could inhibit the accumulation and translocation of Hg in garlic. μ-XANES analysis shows that Hg is mainly present in the forms of Hg–S bonding as Hg(GSH) 2 and Hg(Met) 2 . Se exposure elicited decrease of Hg–S bonding in the form of Hg(GSH) 2 , together with Se-mediated alteration of Hg absorption, transportation and accumulation, may account for attenuated Hg phytotoxicity by Se in garlic. -- Highlights: ► Hg phytotoxicity can be mitigated by Se supplement in garlic growth. ► Se can inhibit the accumulation and transportation of Hg in garlic tissues. ► Localization and speciation of Hg in garlic can be modified by Se

  15. Gradient microfluidics enables rapid bacterial growth inhibition testing.

    Science.gov (United States)

    Li, Bing; Qiu, Yong; Glidle, Andrew; McIlvenna, David; Luo, Qian; Cooper, Jon; Shi, Han-Chang; Yin, Huabing

    2014-03-18

    Bacterial growth inhibition tests have become a standard measure of the adverse effects of inhibitors for a wide range of applications, such as toxicity testing in the medical and environmental sciences. However, conventional well-plate formats for these tests are laborious and provide limited information (often being restricted to an end-point assay). In this study, we have developed a microfluidic system that enables fast quantification of the effect of an inhibitor on bacteria growth and survival, within a single experiment. This format offers a unique combination of advantages, including long-term continuous flow culture, generation of concentration gradients, and single cell morphology tracking. Using Escherichia coli and the inhibitor amoxicillin as one model system, we show excellent agreement between an on-chip single cell-based assay and conventional methods to obtain quantitative measures of antibiotic inhibition (for example, minimum inhibition concentration). Furthermore, we show that our methods can provide additional information, over and above that of the standard well-plate assay, including kinetic information on growth inhibition and measurements of bacterial morphological dynamics over a wide range of inhibitor concentrations. Finally, using a second model system, we show that this chip-based systems does not require the bacteria to be labeled and is well suited for the study of naturally occurring species. We illustrate this using Nitrosomonas europaea, an environmentally important bacteria, and show that the chip system can lead to a significant reduction in the period required for growth and inhibition measurements (<4 days, compared to weeks in a culture flask).

  16. Inhibition of herpes simplex virus replication by tobacco extracts.

    Science.gov (United States)

    Hirsch, J M; Svennerholm, B; Vahlne, A

    1984-05-01

    Herpes simplex virus type 1 (HSV-1) has been associated with the genesis of leukoplakias, epithelial atypia, and oral cancer. Tobacco habits, such as snuff dipping, are also definitely correlated with this type of lesion. The normal cytolytic HSV-1 infection can, after in vitro inactivation, transform cells. Extracts of snuff were prepared and assayed for their ability to inhibit HSV-1 replication. Plaque formation assays of HSV-1 in the presence of snuff extract showed that a reduced number of plaques was formed. Different batches of one brand of snuff were tested for inhibition of herpes simplex virus (HSV) production. More than 99% inhibition of 24-hr HSV production was obtained with undiluted batches. The 1:5 dilutions of snuff had an inhibitory effect of 85% and 1:25 dilutions, 39%. In agreement, the attachment of the virus to the host cell and penetration of the virus to the cell nuclei were found to be inhibited as was the synthesis of viral DNA. Nicotine had an inhibitory effect, while aromatic additions to snuff were found to have no major inhibitory effect on HSV replication. Snuff extracts were prepared from different brands of snuff reported to contain high and low quantities of tobacco-specific N-nitrosamines. Brands with reported high levels of tobacco-specific N-nitrosamines had significantly greater ability to inhibit HSV replication. In conclusion, this study has shown that extracts of snuff have inhibitory effects on the production of cytolytic HSV-1 infections. A chronic snuff dipper keeps tobacco in the mouth for the major part of the day. Thus, virus shed in the oral cavity in connection with a reactivated latent HSV-1 infection has great possibilities of being affected by snuff or derivatives of snuff. It is suggested that an interaction between tobacco products and HSV-1 might be involved in the development of dysplastic lesions in the oral cavity.

  17. Regulation of spatial selectivity by crossover inhibition.

    Science.gov (United States)

    Cafaro, Jon; Rieke, Fred

    2013-04-10

    Signals throughout the nervous system diverge into parallel excitatory and inhibitory pathways that later converge on downstream neurons to control their spike output. Converging excitatory and inhibitory synaptic inputs can exhibit a variety of temporal relationships. A common motif is feedforward inhibition, in which an increase (decrease) in excitatory input precedes a corresponding increase (decrease) in inhibitory input. The delay of inhibitory input relative to excitatory input originates from an extra synapse in the circuit shaping inhibitory input. Another common motif is push-pull or "crossover" inhibition, in which increases (decreases) in excitatory input occur together with decreases (increases) in inhibitory input. Primate On midget ganglion cells receive primarily feedforward inhibition and On parasol cells receive primarily crossover inhibition; this difference provides an opportunity to study how each motif shapes the light responses of cell types that play a key role in visual perception. For full-field stimuli, feedforward inhibition abbreviated and attenuated responses of On midget cells, while crossover inhibition, though plentiful, had surprisingly little impact on the responses of On parasol cells. Spatially structured stimuli, however, could cause excitatory and inhibitory inputs to On parasol cells to increase together, adopting a temporal relation very much like that for feedforward inhibition. In this case, inhibitory inputs substantially abbreviated a cell's spike output. Thus inhibitory input shapes the temporal stimulus selectivity of both midget and parasol ganglion cells, but its impact on responses of parasol cells depends strongly on the spatial structure of the light inputs.

  18. Fear inhibition in high trait anxiety.

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    Merel Kindt

    Full Text Available Trait anxiety is recognized as an individual risk factor for the development of anxiety disorders but the neurobiological mechanisms remain unknown. Here we test whether trait anxiety is associated with impaired fear inhibition utilizing the AX+/BX- conditional discrimination procedure that allows for the independent evaluation of startle fear potentiation and inhibition of fear. Sixty undergraduate students participated in the study--High Trait Anxious: n = 28 and Low Trait Anxious: n = 32. We replicated earlier findings that a transfer of conditioned inhibition for startle responses requires contingency awareness. However, contrary to the fear inhibition hypothesis, our data suggest that high trait anxious individuals show a normal fear inhibition of conditioned startle responding. Only at the cognitive level the high trait anxious individuals showed evidence for impaired inhibitory learning of the threat cue. Together with other findings where impaired fear inhibition was only observed in those PTSD patients who were either high on hyperarousal symptoms or with current anxiety symptoms, we question whether impaired fear inhibition is a biomarker for the development of anxiety disorders.

  19. Prognostic Significance of Signet Ring Gastric Cancer

    Science.gov (United States)

    Taghavi, Sharven; Jayarajan, Senthil N.; Davey, Adam; Willis, Alliric I.

    2012-01-01

    Purpose Studies in Asia have questioned the dictum that signet ring cell carcinoma (SRC) has a worse prognosis than other forms of gastric cancer. Our study determined differences in presentation and outcomes between SRC and gastric adenocarcinoma (AC) in the United States. Patients and Methods The National Cancer Institute Surveillance, Epidemiology, and End Results database was reviewed for SRC and AC from 2004 to 2007. Results We reviewed 10,246 cases of patients with gastric cancer, including 2,666 of SRC and 7,580 of AC. SRC presented in younger patients (61.9 v 68.7 years; P < .001) and less often in men (52.7% v 68.7%; P < .001). SRC patients were more frequently black (11.3% v 10.9%), Asian (16.4% v 13.2%), American Indian/Alaska Native (0.9% v 0.8%), or Hispanic (23.3% v 14.0%; P < .001). SRC was more likely to be stage T3-4 (45.8% v 33.3%), have lymph node spread (59.7% v 51.8%), and distant metastases (40.2% v 37.6%; P < .001). SRC was more likely to be found in the lower (30.7% v 24.2%) and middle stomach (30.6% v 20.7%; P < .001). Median survival was not different between the two (AC, 14.0 months v SRC, 13.0 months; P = .073). Multivariable analyses demonstrated SRC was not associated with mortality (hazard ratio [HR], 1.05; 95% CI, 0.96 to 1.11; P = .150). Mortality was associated with age (HR, 1.01; 95% CI, 1.01 to 1.02; P < .001), black race (HR, 1.10; 95% CI, 1.01 to 1.20; P = .026), and tumor grade. Variables associated with lower mortality risk included Asian race (HR, 0.83; 95% CI, 0.77 to 0.91; P < .001) and surgery (HR, 0.37; 95% CI, 0.34 to 0.39; P < .001). Conclusion In the United States, SRC significantly differs from AC in extent of disease at presentation. However, when adjusted for stage, SRC does not portend a worse prognosis. PMID:22927530

  20. Biological significance of soluble IL-2 receptor

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    Calogero Caruso

    1993-01-01

    Full Text Available A NUMBER of receptors for growth factors and differentiation antigens have been found to be secreted or released by cells. Following mononuclear cell (MNC activation and interleukin-2 receptor (IL-2R expression, a soluble form of the Alpha;-chain of IL-2R (sIL-2R is released. The sIL-2R has been shown to be present in the culture supernatants of activated MNCs as well as in normal sera and, in higher amounts, in sera from subjects affected by several diseases including neoplastic, infectious and autoimmune ones, and in sera from transplanted patients suffering allograft rejection. The blood sIL-2R levels depend on the number of producing cells and the number of molecules per cell, so that sIL-2R blood values may represent an index of the number and the functional state of producing cells, both normal and neoplastic. Thus, monitoring of the immune system, mostly T-cells and haematological malignancies might be targets for the measurement of sIL-2R. Since many conditions may influence sIL-2R production, little diagnostic use may result from these measurements. However, since blood sIL-2R levels may correlate with disease progression and/or response to therapy, their measurement may be a useful index of activity and extent of disease. The precise biological role of the soluble form of the IL-2R is still a matter of debate. However, we know that increased sIL-2R levels may be observed in association with several immunological abnormalities and that sIL-2R is able to bind IL-2. It is conceivable then that in these conditions the excess sIL-2R released in vivo by activated lymphoid cells or by neoplastic cells may somehow regulate IL-2-dependent processes. On the other hand, it cannot exclude that sIL-2R is a by-product without biological significance. Finally, it is puzzling that in many conditions in which an increase of blood sIL-2R values has been observed, MNCs display a decreased in vitro capacity to produce sIL-2R. These seemingly contrasting

  1. Zinc-finger antiviral protein inhibits XMRV infection.

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    Xinlu Wang

    Full Text Available BACKGROUND: The zinc-finger antiviral protein (ZAP is a host factor that specifically inhibits the replication of certain viruses, including Moloney murine leukemia virus (MoMLV, HIV-1, and certain alphaviruses and filoviruses. ZAP binds to specific viral mRNAs and recruits cellular mRNA degradation machinery to degrade the target RNA. The common features of ZAP-responsive RNA sequences remain elusive and thus whether a virus is susceptible to ZAP can only be determined experimentally. Xenotropic murine leukemia virus-related virus (XMRV is a recently identified γ-retrovirus that was originally thought to be involved in prostate cancer and chronic fatigue syndrome but recently proved to be a laboratory artefact. Nonetheless, XMRV as a new retrovirus has been extensively studied. Since XMRV and MoMLV share only 67.9% sequence identity in the 3'UTRs, which is the target sequence of ZAP in MoMLV, whether XMRV is susceptible to ZAP remains to be determined. FINDINGS: We constructed an XMRV-luc vector, in which the coding sequences of Gag-Pol and part of Env were replaced with luciferase-coding sequence. Overexpression of ZAP potently inhibited the expression of XMRV-luc in a ZAP expression-level-dependent manner, while downregulation of endogenous ZAP rendered cells more sensitive to infection. Furthermore, ZAP inhibited the spreading of replication-competent XMRV. Consistent with the previously reported mechanisms by which ZAP inhibits viral infection, ZAP significantly inhibited the accumulation of XMRV-luc mRNA in the cytoplasm. The ZAP-responsive element in XMRV mRNA was mapped to the 3'UTR. CONCLUSIONS: ZAP inhibits XMRV replication by preventing the accumulation of viral mRNA in the cytoplasm. Documentation of ZAP inhibiting XMRV helps to broaden the spectrum of ZAP's antiviral activity. Comparison of the target sequences of ZAP in XMRV and MoMLV helps to better understand the features of ZAP-responsive elements.

  2. Inhibition of thromboxane synthase induces lung cancer cell death via increasing the nuclear p27

    International Nuclear Information System (INIS)

    Leung, Kin Chung; Hsin, Michael K.Y.; Chan, Joey S.Y.; Yip, Johnson H.Y.; Li, Mingyue; Leung, Billy C.S.; Mok, Tony S.K.; Warner, Timothy D.; Underwood, Malcolm J.; Chen, George G.

    2009-01-01

    The role of thromboxane in lung carcinogenesis is not clearly known, though thromboxane B2 (TXB 2 ) level is increased and antagonists of thromboxane receptors or TXA2 can induce apoptosis of lung cancer cells. p27, an atypical tumor suppressor, is normally sequestered in the nucleus. The increased nuclear p27 may result in apoptosis of tumor cells. We hypothesize that the inhibition of thromboxane synthase (TXS) induces the death of lung cancer cells and that such inhibition is associated with the nuclear p27 level. Our experiment showed that the inhibition of TXS significantly induced the death or apoptosis in lung cancer cells. The activity of TXS was increased in lung cancer. The nuclear p27 was remarkably reduced in lung cancer tissues. The inhibition of TXS caused the cell death and apoptosis of lung cancer cells, likely via the elevation of the nuclear p27 since the TXS inhibition promoted the nuclear p27 level and the inhibition of p27 by its siRNA recovered the cell death induced by TXS inhibition. Collectively, lung cancer cells produce high levels of TXB 2 but their nuclear p27 is markedly reduced. The inhibition of TXS results in the p27-related induction of cell death in lung cancer cells.

  3. Inhibition of thromboxane synthase induces lung cancer cell death via increasing the nuclear p27

    Energy Technology Data Exchange (ETDEWEB)

    Leung, Kin Chung; Hsin, Michael K.Y.; Chan, Joey S.Y.; Yip, Johnson H.Y.; Li, Mingyue; Leung, Billy C.S. [Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories (Hong Kong); Mok, Tony S.K. [Department of Clinical Oncology, The Chinese University of Hong Kong, Shatin, New Territories (Hong Kong); Warner, Timothy D. [The William Harvey Research Institute, Queen Mary University of London, London (United Kingdom); Underwood, Malcolm J. [Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories (Hong Kong); Chen, George G., E-mail: gchen@cuhk.edu.hk [Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories (Hong Kong)

    2009-10-15

    The role of thromboxane in lung carcinogenesis is not clearly known, though thromboxane B2 (TXB{sub 2}) level is increased and antagonists of thromboxane receptors or TXA2 can induce apoptosis of lung cancer cells. p27, an atypical tumor suppressor, is normally sequestered in the nucleus. The increased nuclear p27 may result in apoptosis of tumor cells. We hypothesize that the inhibition of thromboxane synthase (TXS) induces the death of lung cancer cells and that such inhibition is associated with the nuclear p27 level. Our experiment showed that the inhibition of TXS significantly induced the death or apoptosis in lung cancer cells. The activity of TXS was increased in lung cancer. The nuclear p27 was remarkably reduced in lung cancer tissues. The inhibition of TXS caused the cell death and apoptosis of lung cancer cells, likely via the elevation of the nuclear p27 since the TXS inhibition promoted the nuclear p27 level and the inhibition of p27 by its siRNA recovered the cell death induced by TXS inhibition. Collectively, lung cancer cells produce high levels of TXB{sub 2} but their nuclear p27 is markedly reduced. The inhibition of TXS results in the p27-related induction of cell death in lung cancer cells.

  4. Use of bacillus subtilis strains to inhibit postharvest pathogenic fungi; Attivita` antagonista di alcuni ceppi di bacillus subtilis nei confronti di funghi patogeni

    Energy Technology Data Exchange (ETDEWEB)

    Arras, G.; Gambella, F.; Demontis, S.; Petretto, A.

    1995-09-01

    An isolate (87) of the bacillus subtilis strains isolated from cold stored citrus fruit 13 proved to inhibit the growth in vitro of the penicillium italicum used in the experiment (from 50.6% to 92.2%) and to inhibit botrytis cinerea (from 65.3% to 95.9%). A further test, superimposing on plates containing PDA strains Nos. 13, 173, and 160, totally inhibited the fungi. Tested in vivo on artificially bruised oranges, they significantly inhibited two fungi.

  5. Significance of NTM infections in Croatia

    Directory of Open Access Journals (Sweden)

    V Katalinic-Jankovic

    2015-01-01

    laboratory are sent to the National Reference Laboratory for identification. NTM strains have been systematically recorded and reported since 1982. In the last decade, two retrospective analyses were done to assess the clinical relevance of different NTM species and the burden of pulmonary NTM disease. Over the past decade, a 30-fold increase in overall NTM isolation rates and a 4-fold increase in PNTM incidence were observed. Mycobacterium xenopi was the most frequently seen causative agent of pulmonary NTM disease, but the degree of clinical relevance (i.e., percentage of patients meeting the diagnosis criteria, per species was higher for isolates of MAC (66.5% and M. kansasii (57.2%. Only about 30% of the M. xenopi isolates represented true disease. Further, interesting regional differences were observed. Clinically relevant NTM isolates were significantly more often found in the coastal region of Croatia, and the average annual incidence of the PNTM was twice as high in coastal compared with the continental region. The overall burden of PNTM in Croatia is still low compared with tuberculosis. This can, in part, explain the observed lack of knowledge of NTM infections among respiratory specialists. Since these pathogens are increasingly common worldwide, especially in countries where the incidence of tuberculosis is declining, a constant rising of awareness and knowledge is necessary.

  6. Advanced Glycation End Products Inhibit the Proliferation of Human Umbilical Vein Endothelial Cells by Inhibiting Cathepsin D

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    Yuan Li

    2017-02-01

    Full Text Available We aimed to investigate the effect of advanced glycation end products (AGEs on the proliferation and migration ability of human umbilical vein endothelial cells (HUVECs. Cell proliferation was detected by methyl thiazolyl tetrazolium (MTT assay, real-time cell analyzer and 5-Ethynyl-2′-deoxyuridine (EdU staining. Cell migration was detected by wound-healing and transwell assay. AGEs significantly inhibited the proliferation and migration of HUVECs in a time-and dose-dependent way. Western blotting revealed that AGEs dramatically increased the expression of microtubule-associated protein 1 light chain 3 (LC3 II/I and p62. Immunofluorescence of p62 and acridine orange staining revealed that AGEs significantly increased the expression of p62 and the accumulation of autophagic vacuoles, respectively. Chloroquine (CQ could further promote the expression of LC3 II/I and p62, increase the accumulation of autophagic vacuoles and promote cell injury induced by AGEs. In addition, AGEs reduced cathepsin D (CTSD expression in a time-dependent way. Overexpression of wild-type CTSD significantly decreased the ratio of LC 3 II/I as well as p62 accumulation induced by AGEs, but overexpression of catalytically inactive mutant CTSD had no such effects. Only overexpression of wild-type CTSD could restore the proliferation of HUVECs inhibited by AGEs. However, overexpression of both wild-type CTSD and catalytically inactive mutant CTSD could promote the migration of HUVECs inhibited by AGEs. Collectively, our study found that AGEs inhibited the proliferation and migration in HUVECs and promoted autophagic flux, which in turn played a protective role against AGEs-induced cell injury. CTSD, in need of its catalytic activity, may promote proliferation in AGEs-treated HUVECs independent of the autophagy-lysosome pathway. Meanwhile, CTSD could improve the migration of AGEs-treated HUVECs regardless of its enzymatic activity.

  7. Advanced Glycation End Products Inhibit the Proliferation of Human Umbilical Vein Endothelial Cells by Inhibiting Cathepsin D.

    Science.gov (United States)

    Li, Yuan; Chang, Ye; Ye, Ning; Dai, Dongxue; Chen, Yintao; Zhang, Naijin; Sun, Guozhe; Sun, Yingxian

    2017-02-17

    We aimed to investigate the effect of advanced glycation end products (AGEs) on the proliferation and migration ability of human umbilical vein endothelial cells (HUVECs). Cell proliferation was detected by methyl thiazolyl tetrazolium (MTT) assay, real-time cell analyzer and 5-Ethynyl-2'-deoxyuridine (EdU) staining. Cell migration was detected by wound-healing and transwell assay. AGEs significantly inhibited the proliferation and migration of HUVECs in a time-and dose-dependent way. Western blotting revealed that AGEs dramatically increased the expression of microtubule-associated protein 1 light chain 3 (LC3) II/I and p62. Immunofluorescence of p62 and acridine orange staining revealed that AGEs significantly increased the expression of p62 and the accumulation of autophagic vacuoles, respectively. Chloroquine (CQ) could further promote the expression of LC3 II/I and p62, increase the accumulation of autophagic vacuoles and promote cell injury induced by AGEs. In addition, AGEs reduced cathepsin D (CTSD) expression in a time-dependent way. Overexpression of wild-type CTSD significantly decreased the ratio of LC 3 II/I as well as p62 accumulation induced by AGEs, but overexpression of catalytically inactive mutant CTSD had no such effects. Only overexpression of wild-type CTSD could restore the proliferation of HUVECs inhibited by AGEs. However, overexpression of both wild-type CTSD and catalytically inactive mutant CTSD could promote the migration of HUVECs inhibited by AGEs. Collectively, our study found that AGEs inhibited the proliferation and migration in HUVECs and promoted autophagic flux, which in turn played a protective role against AGEs-induced cell injury. CTSD, in need of its catalytic activity, may promote proliferation in AGEs-treated HUVECs independent of the autophagy-lysosome pathway. Meanwhile, CTSD could improve the migration of AGEs-treated HUVECs regardless of its enzymatic activity.

  8. Heparin octasaccharide decoy liposomes inhibit replication of multiple viruses

    Science.gov (United States)

    Hendricks, Gabriel L.; Velazquez, Lourdes; Pham, Serena; Qaisar, Natasha; Delaney, James C.; Viswanathan, Karthik; Albers, Leila; Comolli, James C.; Shriver, Zachary; Knipe, David M.; Kurt-Jones, Evelyn A.; Fygenson, Deborah K.; Trevejo, Jose M.

    2016-01-01

    Heparan sulfate (HS) is a ubiquitous glycosaminoglycan that serves as a cellular attachment site for a number of significant human pathogens, including respiratory syncytial virus (RSV), human parainfluenza virus 3 (hPIV3), and herpes simplex virus (HSV). Decoy receptors can target pathogens by binding to the receptor pocket on viral attachment proteins, acting as ‘molecular sinks’ and preventing the pathogen from binding to susceptible host cells. Decoy receptors functionalized with HS could bind to pathogens and prevent infection, so we generated decoy liposomes displaying HS-octasaccharide (HS-octa). These decoy liposomes significantly inhibited RSV, hPIV3, and HSV infectivity in vitro to a greater degree than the original HS-octa building block. The degree of inhibition correlated with the density of HS-octa displayed on the liposome surface. Decoy liposomes with HS-octa inhibited infection of viruses to a greater extent than either full-length heparin or HS-octa alone. Decoy liposomes were effective when added prior to infection or following the initial infection of cells in vitro. By targeting the well-conserved receptor-binding sites of HS-binding viruses, decoy liposomes functionalized with HS-octa are a promising therapeutic antiviral agent and illustrate the utility of the liposome delivery platform. PMID:25637710

  9. Inhibition of sortase A by chalcone prevents Listeria monocytogenes infection.

    Science.gov (United States)

    Li, Hongen; Chen, Yutao; Zhang, Bing; Niu, Xiaodi; Song, Meng; Luo, Zhaoqing; Lu, Gejin; Liu, Bowen; Zhao, Xiaoran; Wang, Jianfeng; Deng, Xuming

    2016-04-15

    The critical role of sortase A in gram-positive bacterial pathogenicity makes this protein a good potential target for antimicrobial therapy. In this study, we report for the first time the crystal structure of Listeria monocytogenes sortase A and identify the active sites that mediate its transpeptidase activity. We also used a sortase A (SrtA) enzyme activity inhibition assay, simulation, and isothermal titration calorimetry analysis to discover that chalcone, an agent with little anti-L. monocytogenes activity, could significantly inhibit sortase A activity with an IC50 of 28.41 ± 5.34 μM by occupying the active site of SrtA. The addition of chalcone to a co-culture of L. monocytogenes and Caco-2 cells significantly inhibited bacterial entry into the cells and L. monocytogenes-mediated cytotoxicity. Additionally, chalcone treatment decreased the mortality of infected mice, the bacterial burden in target organs, and the pathological damage to L. monocytogenes-infected mice. In conclusion, these findings suggest that chalcone is a promising candidate for the development of treatment against L. monocytogenes infection. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. In vivo antimicrobial inhibition of Punica granatum extracts as mouthwash

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    Dhifaf M. Al-Obaidi

    2017-12-01

    Full Text Available Background — Complex polysaccharides have been detected and characterized in Punica granatum or pomegranate constituents who may act as fungal and bacterial inhibitor as well as an anti-inflammatory effect. However, limited studies were reported on using pomegranate extracts as an anti-bacterial mouthwash. Objectives — To determine the effect of Punica granatum (pomegranate extract on microbial activity of some bacterial genus isolated from the mouth. Material and Methods — This study included preparation of three different concentrations of Punica granatum methanolic extract of 25%, 50%, and 75%. The inhibition activity of these extracts was tested on different strains such as Sm, Sa, Ec, Kp, Sg and Sf. Results — Results exhibited an effective inhibition of pomegranate extracts against most of the tested strains which were isolated from patients' mouths. The 50% and 75% concentrations of methanolic extract exhibited significant inhibition against four tested strains compared to mouthwash (P≤0.05, while the 25% concentration was less effective than the other concentrations and its antibacterial effect was non-significant in comparison with the mouthwash. Conclusions — This study indicates the inhibitory effectiveness of Punica granatum extracts of high percentage on microbial activity of some bacterial genus isolated from patients’ mouths and suggests the possibility prepare a mouthwash from pomegranate extract.

  11. ATF3 represses PPARγ expression and inhibits adipocyte differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Jang, Min-Kyung; Jung, Myeong Ho, E-mail: jung0603@pusan.ac.kr

    2014-11-07

    Highlights: • ATF3 decrease the expression of PPARγ and its target gene in 3T3-L1 adipocytes. • ATF3 represses the promoter activity of PPARγ2 gene. • ATF/CRE (−1537/−1530) is critical for ATF3-mediated downregulation of PPARγ. • ATF3 binds to the promoter region containing the ATF/CRE. • ER stress inhibits adipocyte differentiation through downregulation of PPARγ by ATF3. - Abstract: Activating transcription factor 3 (ATF3) is a stress-adaptive transcription factor that mediates cellular stress response signaling. We previously reported that ATF3 represses CCAAT/enhancer binding protein α (C/EBPα) expression and inhibits 3T3-L1 adipocyte differentiation. In this study, we explored potential role of ATF3 in negatively regulating peroxisome proliferator activated receptor-γ (PPARγ). ATF3 decreased the expression of PPARγ and its target gene in 3T3-L1 adipocytes. ATF3 also repressed the activity of −2.6 Kb promoter of mouse PPARγ2. Overexpression of PPARγ significantly prevented the ATF3-mediated inhibition of 3T3-L1 differentiation. Transfection studies with 5′ deleted-reporters showed that ATF3 repressed the activity of −2037 bp promoter, whereas it did not affect the activity of −1458 bp promoter, suggesting that ATF3 responsive element is located between the −2037 and −1458. An electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrated that ATF3 binds to ATF/CRE site (5′-TGACGTTT-3′) between −1537 and −1530. Mutation of the ATF/CRE site abrogated ATF3-mediated transrepression of the PPARγ2 promoter. Treatment with thapsigargin, endoplasmic reticulum (ER) stress inducer, increased ATF3 expression, whereas it decreased PPARγ expression. ATF3 knockdown significantly blocked the thapsigargin-mediated downregulation of PPARγ expression. Furthermore, overexpression of PPARγ prevented inhibition of 3T3-L1 differentiation by thapsigargin. Collectively, these results suggest that ATF3-mediated

  12. Increased oxidative stress mediates the antitumor effect of PARP inhibition in ovarian cancer

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    Dong Hou

    2018-07-01

    Full Text Available PARP inhibitors have been widely tested in clinical trials, especially for the treatment of breast cancer and ovarian cancer, and were shown to be highly successful. Because PARP primarily functions in sensing and repairing DNA strand breaks, the therapeutic effect of PARP inhibition is generally believed to be attributed to impaired DNA repair. We here report that oxidative stress is also increased by PARP inhibition and mediates the antitumor effect. We showed that PARP1 is highly expressed in specimens of high grade serous ovarian carcinoma and its activity is required for unperturbed proliferation of ovarian cancer cells. Inhibition or depletion of PARP leads to not only an increase in DNA damage, but also an elevation in the levels of reactive oxygen species (ROS. Importantly, antioxidant N-acetylcysteine (NAC significantly attenuated the induction of DNA damage and the perturbation of proliferation by PARP inhibition or depletion. We further showed that NADPH oxidases 1 and 4 were significantly upregulated by PARP inhibition and were partially responsible for the induction of oxidative stress. Depletion of NOX1 and NOX4 partially rescued the growth inhibition of PARP1-deficient tumor xenografts. Our findings suggest that in addition to compromising the repair of DNA damage, PARP inhibition or depletion may exert extra antitumor effect by elevating oxidative stress in ovarian cancer cells. Keywords: PARP1, Oxidative stress, NADPH oxidases, Ovarian cancer

  13. Inhibition of histamine and eicosanoid release from dispersed human lung cells in vitro by quinotolast.

    Science.gov (United States)

    Okayama, Y; Hiroi, J; Lau, L C; Church, M K

    1995-12-01

    We have examined the effects of a new anti-allergic drug, quinotolast [sodium 5-(4-oxo-1-phenoxy-4H-quinolizine-3-carboxamido) yetrazolate monohydrate], in inhibiting the release of histamine and the generation of leukotriene (LT) C4 and prostaglandin (PG) D2 from dispersed human lung cells and compared this with those of its active metabolite in the rat, hydroxy quinotolast, and reference drugs, tranilast and sodium cromoglycate (SCG). Quinotolast in the concentration range of 1-100 micrograms/ml inhibited histamine and LTC4 release in a concentration-dependent manner. The inhibitory effect of quinotolast on histamine release from dispersed lung cells was largely independent of the preincubation period, no tachyphylaxis being observed. Hydroxy quinotolast and tranilast showed a weak inhibition of histamine release only when the drugs were added to the cells simultaneously with anti-IgE challenge. Quinotolast, 100 micrograms/ml, and SCG, 1 mM, significantly inhibited PGD2 and LTC4 release. Quinotolast inhibited PGD2 release by 100% and LTC4 release by 54%, whereas SCG inhibited PDG2 release by 33% and LTC4 release by 100%. No cross-tachyphylaxis between quinotolast and SCG was observed. The results demonstrated that quinotolast showed a significant inhibition of inflammatory mediators from human dispersed lung cells, suggesting that quinotolast is a good candidate for a clinical anti-allergic drug.

  14. Relationship between self-reported childhood behavioral inhibition and lifetime anxiety disorders in a clinical sample.

    Science.gov (United States)

    Gladstone, Gemma L; Parker, Gordon B; Mitchell, Phillip B; Wilhelm, Kay A; Malhi, Gin S

    2005-01-01

    To examine the association between an early inhibited temperament and lifetime anxiety disorders, we studied a sample of patients with major depression who were not selected on the basis of comorbid axis I anxiety disorders. One-hundred eighty-nine adults (range = 17-68 years) referred to a tertiary depression unit underwent structured diagnostic interviews for depression and anxiety and completed two self-report measures of behavioral inhibition, the retrospective measure of behavioural inhibition (RMBI) [Gladstone and Parker, 2005] and the adult measure of behavioural inhibition (AMBI) [Gladstone and Parker, 2005]. Patients' scores were classified into "low," "moderate," or "high" inhibition. While groups did not differ in terms of depression severity, there were differences across groups in clinically diagnosed nonmelancholic status and age of onset of first episode. Those reporting a high degree of childhood inhibition were significantly more likely to qualify for a diagnosis of social phobia, and this association was independent of their scores on the AMBI. Findings are discussed in light of the existing risk-factor literature and support the hypothesis that an early inhibited temperament may be a significant precursor to later anxiety, especially social anxiety disorder. Copyright 2005 Wiley-Liss, Inc.

  15. Probing inhibitory effects of nanocrystalline cellulose: inhibition versus surface charge

    Science.gov (United States)

    Male, Keith B.; Leung, Alfred C. W.; Montes, Johnny; Kamen, Amine; Luong, John H. T.

    2012-02-01

    NCC derived from different biomass sources was probed for its plausible cytotoxicity by electric cell-substrate impedance sensing (ECIS). Two different cell lines, Spodoptera frugiperda Sf9 insect cells and Chinese hamster lung fibroblast V79, were exposed to NCC and their spreading and viability were monitored and quantified by ECIS. Based on the 50%-inhibition concentration (ECIS50), none of the NCC produced was judged to have any significant cytotoxicity on these two cell lines. However, NCC derived from flax exhibited the most pronounced inhibition on Sf9 compared to hemp and cellulose powder. NCCs from flax and hemp pre-treated with pectate lyase were also less inhibitory than NCCs prepared from untreated flax and hemp. Results also suggested a correlation between the inhibitory effect and the carboxylic acid contents on the NCC.

  16. A new calcineurin inhibition domain in Cabin1

    International Nuclear Information System (INIS)

    Jang, Hyonchol; Cho, Eun-Jung; Youn, Hong-Duk

    2007-01-01

    Calcineurin (CN), a calcium-activated phosphatase, plays a critical role in various biological processes including T cell activation. Cabin1, a calcineurin binding protein 1, has been shown to bind directly to CN using its C-terminal region and inhibit CN activity. However, no increase in CN activity has been found in Cabin1ΔC T cells, which produce a truncated Cabin1 lacking the C-terminal CN binding region. Here, we report that Cabin1 has additional CN binding domain in its 701-900 amino acid residues. Cabin1 (701-900) blocked both CN-mediated dephosphorylation and nuclear import of NFAT and thus inhibited IL-2 production in response to PMA/ionomycin stimulation. This fact may explain why Cabin1ΔC mice previously showed no significant defect in CN-mediated signaling pathway

  17. Metalloproteinase inhibition prevents acute respiratory distress syndrome.

    Science.gov (United States)

    Carney, D E; McCann, U G; Schiller, H J; Gatto, L A; Steinberg, J; Picone, A L; Nieman, G F

    2001-08-01

    The acute respiratory distress syndrome (ARDS) occurs in patients with clearly identifiable risk factors, and its treatment remains merely supportive. We postulated that patients at risk for ARDS can be protected against lung injury by a prophylactic treatment strategy that targets neutrophil-derived proteases. We hypothesized that a chemically modified tetracycline 3 (COL-3), a potent inhibitor of neutrophil matrix metalloproteinases (MMPs) and neutrophil elastase (NE) with minimal toxicity, would prevent ARDS in our porcine endotoxin-induced ARDS model. Yorkshire pigs were anesthetized, intubated, surgically instrumented for hemodynamic monitoring, and randomized into three groups: (1) control (n = 4), surgical instrumentation only; (2) lipopolysaccharide (LPS) (n = 4), infusion of Escherichia coli lipopolysaccharide at 100 microg/kg; and (3) COL-3 + LPS (n = 5), ingestion of COL-3 (100 mg/kg) 12 h before LPS infusion. All animals were monitored for 6 h following LPS or sham LPS infusion. Serial bronchoalveolar lavage (BAL) samples were analyzed for MMP concentration by gelatin zymography. Lung tissue was fixed for morphometric assessment at necropsy. LPS infusion was marked by significant (P decrement in arterial oxygen partial pressure (P(a)O(2)) (LPS = 66 +/- 15 mm Hg, Control = 263 +/- 25 mm Hg) 6 h following LPS or sham LPS infusion, respectively. Pretreatment with COL-3 reduced the above pathophysiological changes 6 h following LPS infusion (P(plat) = 18.5 +/- 1.7 mm Hg, P(a)O(2) = 199 +/- 35 mm Hg; P = NS vs control). MMP-9 and MMP-2 concentration in BAL fluid was significantly increased between 2 and 4 h post-LPS infusion; COL-3 reduced the increase in MMP-9 and MMP-2 concentration at all time periods. Morphometrically LPS caused a significant sequestration of neutrophils and monocytes into pulmonary tissue. Pretreatment with COL-3 ameliorated this response. The wet/dry lung weight ratio was significantly greater (P single prophylactic treatment with COL

  18. In vitro evaluation of single- and multi-strain probiotics: Inter-species inhibition between probiotic strains, and inhibition of pathogens.

    Science.gov (United States)

    Chapman, C M C; Gibson, G R; Rowland, I

    2012-08-01

    Many studies comparing the effects of single- and multi-strain probiotics on pathogen inhibition compare treatments with different concentrations. They also do not examine the possibility of inhibition between probiotic strains with a mixture. We tested the ability of 14 single-species probiotics to inhibit each other using a cross-streak assay, and agar spot test. We then tested the ability of 15 single-species probiotics and 5 probiotic mixtures to inhibit Clostridium difficile, Escherichia coli and S. typhimurium, using the agar spot test. Testing was done with mixtures created in two ways: one group contained component species incubated together, the other group of mixtures was made using component species which had been incubated separately, equalised to equal optical density, and then mixed in equal volumes. Inhibition was observed for all combinations of probiotics, suggesting that when used as such there may be inhibition between probiotics, potentially reducing efficacy of the mixture. Significant inter-species variation was seen against each pathogen. When single species were tested against mixtures, the multi-species preparations displayed significantly (p probiotic species will inhibit each other when incubated together in vitro, in many cases a probiotic mixture was more effective at inhibiting pathogens than its component species when tested at approximately equal concentrations of biomass. This suggests that using a probiotic mixture might be more effective at reducing gastrointestinal infections, and that creating a mixture using species with different effects against different pathogens may have a broader spectrum of action that a single provided by a single strain. Copyright © 2012 Elsevier Ltd. All rights reserved.

  19. Should we stop thinking about inhibition? Searching for individual and age differences in inhibition ability.

    Science.gov (United States)

    Rey-Mermet, Alodie; Gade, Miriam; Oberauer, Klaus

    2018-04-01

    Inhibition is often conceptualized as a unitary construct reflecting the ability to ignore and suppress irrelevant information. At the same time, it has been subdivided into inhibition of prepotent responses (i.e., the ability to stop dominant responses) and resistance to distracter interference (i.e., the ability to ignore distracting information). The present study investigated the unity and diversity of inhibition as a psychometric construct, and tested the hypothesis of an inhibition deficit in older age. We measured inhibition in young and old adults with 11 established laboratory tasks: antisaccade, stop-signal, color Stroop, number Stroop, arrow flanker, letter flanker, Simon, global-local, positive and negative compatibility tasks, and n-2 repetition costs in task switching. In both age groups, the inhibition measures from individual tasks had good reliabilities, but correlated only weakly among each other. Structural equation modeling identified a 2-factor model with factors for inhibition of prepotent responses and resistance to distracter interference. Older adults scored worse in the inhibition of prepotent response, but better in the resistance to distracter interference. However, the model had low explanatory power. Together, these findings call into question inhibition as a psychometric construct and the hypothesis of an inhibition deficit in older age. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

  20. Inhibition of urinary calculi -- a spectroscopic study

    Science.gov (United States)

    Manciu, Felicia; Govani, Jayesh; Durrer, William; Reza, Layra; Pinales, Luis

    2008-10-01

    Although a considerable number of investigations have already been undertaken and many causes such as life habits, metabolic disorders, and genetic factors have been noted as sources that accelerate calculi depositions and aggregations, there are still plenty of unanswered questions regarding efficient inhibition and treatment mechanisms. Thus, in an attempt to acquire more insights, we propose here a detailed scientific study of kidney stone formation and growth inhibition based on a traditional medicine approach with Rotula Aquatica Lour (RAL) herbal extracts. A simplified single diffusion gel growth technique was used for synthesizing the samples for the present study. The unexpected Zn presence in the sample with RAL inhibitor, as revealed by XPS measurements, explains the inhibition process and the dramatic reflectance of the incident light observed in the infrared transmission studies. Raman data demonstrate potential binding of the inhibitor with the oxygen of the kidney stone. Photoluminescence results corroborate to provide additional evidence of Zn-related inhibition.

  1. Exogenously triggered response inhibition in developmental stuttering.

    Science.gov (United States)

    Eggers, Kurt; De Nil, Luc F; Van den Bergh, Bea R H

    2018-06-01

    The purpose of the present study was to examine relations between children's exogenously triggered response inhibition and stuttering. Participants were 18 children who stutter (CWS; mean age = 9;01 years) and 18 children who not stutter (CWNS; mean age = 9;01 years). Participants were matched on age (±3 months) and gender. Response inhibition was assessed by a stop signal task (Verbruggen, Logan, & Stevens, 2008). Results suggest that CWS, compared to CWNS, perform comparable to CWNS in a task where response control is externally triggered. Our findings seem to indicate that previous questionnaire-based findings (Eggers, De Nil, & Van den Bergh, 2010) of a decreased efficiency of response inhibition cannot be generalized to all types of response inhibition. Copyright © 2018 Elsevier Inc. All rights reserved.

  2. Hypnotic suggestibility, cognitive inhibition, and dissociation.

    Science.gov (United States)

    Dienes, Zoltán; Brown, Elizabeth; Hutton, Sam; Kirsch, Irving; Mazzoni, Giuliana; Wright, Daniel B

    2009-12-01

    We examined two potential correlates of hypnotic suggestibility: dissociation and cognitive inhibition. Dissociation is the foundation of two of the major theories of hypnosis and other theories commonly postulate that hypnotic responding is a result of attentional abilities (including inhibition). Participants were administered the Waterloo-Stanford Group Scale of Hypnotic Susceptibility, Form C. Under the guise of an unrelated study, 180 of these participants also completed: a version of the Dissociative Experiences Scale that is normally distributed in non-clinical populations; a latent inhibition task, a spatial negative priming task, and a memory task designed to measure negative priming. The data ruled out even moderate correlations between hypnotic suggestibility and all the measures of dissociation and cognitive inhibition overall, though they also indicated gender differences. The results are a challenge for existing theories of hypnosis.

  3. Corrosion inhibition by lithium zinc phosphate pigment

    International Nuclear Information System (INIS)

    Alibakhshi, E.; Ghasemi, E.; Mahdavian, M.

    2013-01-01

    Highlights: •Synthesis of lithium zinc phosphate (LZP) by chemical co-precipitation method. •Corrosion inhibition activity of pigments compare with zinc phosphate (ZP). •LZP showed superior corrosion inhibition effect in EIS measurements. •Evaluation of adhesion strength and dispersion stability. -- Abstract: Lithium zinc phosphate (LZP) has been synthesized through a co-precipitation process and characterized by XRD and IR spectroscopy. The inhibitive performances of this pigment for corrosion of mild steel have been discussed in comparison with the zinc phosphate (ZP) in the pigment extract solution by means of EIS and in the epoxy coating by means of salt spray. The EIS and salt spray results revealed the superior corrosion inhibitive effect of LZP compared to ZP. Moreover, adhesion strength and dispersion stability of the pigmented epoxy coating showed the advantage of LZP compared to ZP

  4. Partial inhibition of in vitro pollen germination by simulated solar ultraviolet-B radiation

    International Nuclear Information System (INIS)

    Flint, S.D.; Caldwell, M.M.

    1984-01-01

    Pollen from four temperate-latitude taxa were treated with UV radiation in a portion of the UV-B (280-320 nm) waveband during in vitro germination. Inhibition of germination was noted in this pollen compared to samples treated identically except for the exclusion of the UV-B portion of the spectrum. Levels similar to maximum solar UV-B found in temperate-latitude areas failed to inhibit pollen germination significantly, while levels similar to maximum solar UV-B found in equatorial alpine locations caused partial inhibition of germination in three of the four taxa examined

  5. IN VITRO ANTIOXIDANT AND α-AMYLASE INHIBITION ACTIVITIES OF PANCHSAKAR CHURNA

    Directory of Open Access Journals (Sweden)

    Ashok Kumar B.S.

    2013-12-01

    Full Text Available Panchsakar Churna is the composition of Cassia angustifolia, Terminalia chebula, Zingiber officinale, Foeniculum vulgare and Saindhava lavana. Aqueous extract of churna was used to investigate antioxidant activity by ferrous ion chelating assay and ferric reducing power and alpha amylase inhibition activity by dinitrosalicylic acid method (DNSA. Aqueous extract of churna showed maximum ferrous chelating activity - 42.01 and ferric reducing power - 1.5 and 83.33 % of inhibition protein denaturation at 1000 µg/ml. Panchsakar churna showed significant antioxidant and alpha amylase inhibition activities.

  6. Transmitters and pathways mediating inhibition of spinal itch-signaling neurons by scratching and other counterstimuli.

    Directory of Open Access Journals (Sweden)

    Tasuku Akiyama

    Full Text Available Scratching relieves itch, but the underlying neural mechanisms are poorly understood. We presently investigated a role for the inhibitory neurotransmitters GABA and glycine in scratch-evoked inhibition of spinal itch-signaling neurons in a mouse model of chronic dry skin itch. Superficial dorsal horn neurons ipsilateral to hindpaw dry skin treatment exhibited a high level of spontaneous firing that was significantly attenuated by cutaneous scratching, pinch and noxious heat. Scratch-evoked inhibition was nearly abolished by spinal delivery of the glycine antagonist, strychnine, and was markedly attenuated by respective GABA(A and GABA(B antagonists bicuculline and saclofen. Scratch-evoked inhibition was also significantly attenuated (but not abolished by interruption of the upper cervical spinal cord, indicating the involvement of both segmental and suprasegmental circuits that engage glycine- and GABA-mediated inhibition of spinal itch-signaling neurons by noxious counterstimuli.

  7. Effects of Afternoon Nap Deprivation on Adult Habitual Nappers’ Inhibition Functions

    Directory of Open Access Journals (Sweden)

    Qingwei Chen

    2018-01-01

    Full Text Available Multiple studies have established the effects of afternoon naps on cognition. However, relatively few studies have investigated the domain of executive functions. Moreover, the effects of napping on inhibition are far from conclusive. The present study employed adult habitual nappers to investigate the effects of afternoon nap deprivation on response-based inhibition assessed by a Go/No-go task and stimulus-based inhibition assessed by a Flanker task and on alertness assessed by a psychomotor vigilance test (PVT and the Karolinska Sleepiness Scale (KSS. The results showed that afternoon nap deprivation significantly decreased participants’ accuracy and reaction speed for the Go/No-go task but not for the Flanker task. In addition, participants’ alertness was significantly impaired after nap deprivation in terms of increased subjective sleepiness and worse PVT performance. Task-specific effects of napping on inhibition were demonstrated. The implications of the results are discussed.

  8. Ginger extract inhibits LPS induced macrophage activation and function

    Directory of Open Access Journals (Sweden)

    Bruch David

    2008-01-01

    Full Text Available Abstract Background Macrophages play a dual role in host defence. They act as the first line of defence by mounting an inflammatory response to antigen exposure and also act as antigen presenting cells and initiate the adaptive immune response. They are also the primary infiltrating cells at the site of inflammation. Inhibition of macrophage activation is one of the possible approaches towards modulating inflammation. Both conventional and alternative approaches are being studied in this regard. Ginger, an herbal product with broad anti inflammatory actions, is used as an alternative medicine in a number of inflammatory conditions like rheumatic disorders. In the present study we examined the effect of ginger extract on macrophage activation in the presence of LPS stimulation. Methods Murine peritoneal macrophages were stimulated by LPS in presence or absence of ginger extract and production of proinflammatory cytokines and chemokines were observed. We also studied the effect of ginger extract on the LPS induced expression of MHC II, B7.1, B7.2 and CD40 molecules. We also studied the antigen presenting function of ginger extract treated macrophages by primary mixed lymphocyte reaction. Results We observed that ginger extract inhibited IL-12, TNF-α, IL-1β (pro inflammatory cytokines and RANTES, MCP-1 (pro inflammatory chemokines production in LPS stimulated macrophages. Ginger extract also down regulated the expression of B7.1, B7.2 and MHC class II molecules. In addition ginger extract negatively affected the antigen presenting function of macrophages and we observed a significant reduction in T cell proliferation in response to allostimulation, when ginger extract treated macrophages were used as APCs. A significant decrease in IFN-γ and IL-2 production by T cells in response to allostimulation was also observed. Conclusion In conclusion ginger extract inhibits macrophage activation and APC function and indirectly inhibits T cell activation.

  9. PARP-1 inhibition alleviates diabetic cardiac complications in experimental animals.

    Science.gov (United States)

    Zakaria, Esraa M; El-Bassossy, Hany M; El-Maraghy, Nabila N; Ahmed, Ahmed F; Ali, Abdelmoneim A

    2016-11-15

    Cardiovascular complications are the major causes of mortality among diabetic population. Poly(ADP-ribose) polymerase-1 enzyme (PARP-1) is activated by oxidative stress leading to cellular damage. We investigated the implication of PARP-1 in diabetic cardiac complications. Type 2 diabetes was induced in rats by high fructose-high fat diet and low streptozotocin dose. PARP inhibitor 4-aminobenzamide (4-AB) was administered daily for ten weeks after diabetes induction. At the end of study, surface ECG, blood pressure and vascular reactivity were studied. PARP-1 activity, reduced glutathione (GSH) and nitrite contents were assessed in heart muscle. Fasting glucose, fructosamine, insulin, and tumor necrosis factor alpha (TNF-α) levels were measured in serum. Finally, histological examination and collagen deposition detection in rat ventricular and aortic sections were carried out. Hearts isolated from diabetic animals showed increased PARP-1 enzyme activity compared to control animals while significantly reduced by 4-AB administration. PARP-1 inhibition by 4-AB alleviated cardiac ischemia in diabetic animals as indicated by ECG changes. PARP-1 inhibition also reduced cardiac inflammation in diabetic animals as evidenced by histopathological changes. In addition, 4-AB administration improved the elevated blood pressure and the associated exaggerated vascular contractility, endothelial destruction and vascular inflammation seen in diabetic animals. Moreover, PARP-1 inhibition decreased serum levels of TNF-α and cardiac nitrite but increased cardiac GSH contents in diabetic animals. However, PARP-1 inhibition did not significantly affect the developed hyperglycemia. Our findings prove that PARP-1 enzyme plays an important role in diabetic cardiac complications through combining inflammation, oxidative stress, and fibrosis mechanisms. Copyright © 2016. Published by Elsevier B.V.

  10. Salmonella infection inhibits intestinal biotin transport: cellular and molecular mechanisms.

    Science.gov (United States)

    Ghosal, Abhisek; Jellbauer, Stefan; Kapadia, Rubina; Raffatellu, Manuela; Said, Hamid M

    2015-07-15

    Infection with the nontyphoidal Salmonella is a common cause of food-borne disease that leads to acute gastroenteritis/diarrhea. Severe/prolonged cases of Salmonella infection could also impact host nutritional status, but little is known about its effect on intestinal absorption of vitamins, including biotin. We examined the effect of Salmonella enterica serovar Typhimurium (S. typhimurium) infection on intestinal biotin uptake using in vivo (streptomycin-pretreated mice) and in vitro [mouse (YAMC) and human (NCM460) colonic epithelial cells, and human intestinal epithelial Caco-2 cells] models. The results showed that infecting mice with wild-type S. typhimurium, but not with its nonpathogenic isogenic invA spiB mutant, leads to a significant inhibition in jejunal/colonic biotin uptake and in level of expression of the biotin transporter, sodium-dependent multivitamin transporter. In contrast, infecting YAMC, NCM460, and Caco-2 cells with S. typhimurium did not affect biotin uptake. These findings suggest that the effect of S. typhimurium infection is indirect and is likely mediated by proinflammatory cytokines, the levels of which were markedly induced in the intestine of S. typhimurium-infected mice. Consistent with this hypothesis, exposure of NCM460 cells to the proinflammatory cytokines TNF-α and IFN-γ led to a significant inhibition of biotin uptake, sodium-dependent multivitamin transporter expression, and activity of the SLC5A6 promoter. The latter effects appear to be mediated, at least in part, via the NF-κB signaling pathway. These results demonstrate that S. typhimurium infection inhibits intestinal biotin uptake, and that the inhibition is mediated via the action of proinflammatory cytokines.

  11. Human milk glycoconjugates that inhibit pathogens.

    Science.gov (United States)

    Newburg, D S

    1999-02-01

    Breast-fed infants have lower incidence of diarrhea, respiratory disease, and otitis media. The protection by human milk has long been attributed to the presence of secretory IgA. However, human milk contains large numbers and amounts of complex carbohydrates, including glycoproteins, glycolipids, glycosaminoglycans, mucins, and especially oligosaccharides. The oligosaccharides comprise the third most abundant solid constituent of human milk, and contain a myriad of structures. Complex carbohydrate moieties of glycoconjugates and oligosaccharides are synthesized by the many glycosyltransferases in the mammary gland; those with homology to cell surface glycoconjugate pathogen receptors may inhibit pathogen binding, thereby protecting the nursing infant. Several examples are reviewed: A fucosyloligosaccharide inhibits the diarrheagenic effect of stable toxin of Escherichia coli. A different fucosyloligosaccharide inhibits infection by Campylobacter jejuni. Binding of Streptococcus pneumoniae and of enteropathogenic E. coli to their respective receptors is inhibited by human milk oligosaccharides. The 46-kD glycoprotein, lactadherin, inhibits rotavirus binding and infectivity. Low levels of lactadherin in human milk are associated with a higher incidence of symptomatic rotavirus in breast-fed infants. A mannosylated glycopeptide inhibits binding by enterohemorrhagic E. coli. A glycosaminoglycan inhibits binding of gp120 to CD4, the first step in HIV infection. Human milk mucin inhibits binding by S-fimbriated E. coli. The ganglioside, GM1, reduces diarrhea production by cholera toxin and labile toxin of E. coli. The neutral glycosphingolipid, Gb3, binds to Shigatoxin. Thus, many complex carbohydrates of human milk may be novel antipathogenic agents, and the milk glycoconjugates and oligosaccharides may be a major source of protection for breastfeeding infants.

  12. Inhibition in the Human Auditory Cortex.

    Directory of Open Access Journals (Sweden)

    Koji Inui

    Full Text Available Despite their indispensable roles in sensory processing, little is known about inhibitory interneurons in humans. Inhibitory postsynaptic potentials cannot be recorded non-invasively, at least in a pure form, in humans. We herein sought to clarify whether prepulse inhibition (PPI in the auditory cortex reflected inhibition via interneurons using magnetoencephalography. An abrupt increase in sound pressure by 10 dB in a continuous sound was used to evoke the test response, and PPI was observed by inserting a weak (5 dB increase for 1 ms prepulse. The time course of the inhibition evaluated by prepulses presented at 10-800 ms before the test stimulus showed at least two temporally distinct inhibitions peaking at approximately 20-60 and 600 ms that presumably reflected IPSPs by fast spiking, parvalbumin-positive cells and somatostatin-positive, Martinotti cells, respectively. In another experiment, we confirmed that the degree of the inhibition depended on the strength of the prepulse, but not on the amplitude of the prepulse-evoked cortical response, indicating that the prepulse-evoked excitatory response and prepulse-evoked inhibition reflected activation in two different pathways. Although many diseases such as schizophrenia may involve deficits in the inhibitory system, we do not have appropriate methods to evaluate them; therefore, the easy and non-invasive method described herein may be clinically useful.

  13. Role of Proteasome-Dependent Protein Degradation in Long-Term Operant Memory in "Aplysia"

    Science.gov (United States)

    Lyons, Lisa C.; Gardner, Jacob S.; Gandour, Catherine E.; Krishnan, Harini C.

    2017-01-01

    We investigated the in vivo role of protein degradation during intermediate (ITM) and long-term memory (LTM) in "Aplysia" using an operant learning paradigm. The proteasome inhibitor MG-132 inhibited the induction and molecular consolidation of LTM with no effect on ITM. Remarkably, maintenance of steady-state protein levels through…

  14. Repression of protein translation and mTOR signaling by proteasome inhibitor in colon cancer cells

    International Nuclear Information System (INIS)

    Wu, William Ka Kei; Volta, Viviana; Cho, Chi Hin; Wu, Ya Chun; Li, Hai Tao; Yu, Le; Li, Zhi Jie; Sung, Joseph Jao Yiu

    2009-01-01

    Protein homeostasis relies on a balance between protein synthesis and protein degradation. The ubiquitin-proteasome system is a major catabolic pathway for protein degradation. In this respect, proteasome inhibition has been used therapeutically for the treatment of cancer. Whether inhibition of protein degradation by proteasome inhibitor can repress protein translation via a negative feedback mechanism, however, is unknown. In this study, proteasome inhibitor MG-132 lowered the proliferation of colon cancer cells HT-29 and SW1116. In this connection, MG-132 reduced the phosphorylation of mammalian target of rapamycin (mTOR) at Ser2448 and Ser2481 and the phosphorylation of its downstream targets 4E-BP1 and p70/p85 S6 kinases. Further analysis revealed that MG-132 inhibited protein translation as evidenced by the reductions of 35 S-methionine incorporation and polysomes/80S ratio. Knockdown of raptor, a structural component of mTOR complex 1, mimicked the anti-proliferative effect of MG-132. To conclude, we demonstrate that the inhibition of protein degradation by proteasome inhibitor represses mTOR signaling and protein translation in colon cancer cells.

  15. Beyond Behavioral Inhibition: A Computer Avatar Task Designed to Assess Behavioral Inhibition Extends to Harm Avoidance

    Directory of Open Access Journals (Sweden)

    Michael Todd Allen

    2017-09-01

    Full Text Available Personality factors such as behavioral inhibition (BI, a temperamental tendency for avoidance in the face of unfamiliar situations, have been identified as risk factors for anxiety disorders. Personality factors are generally identified through self-report inventories. However, this tendency to avoid may affect the accuracy of these self-report inventories. Previously, a computer based task was developed in which the participant guides an on-screen “avatar” through a series of onscreen events; performance on the task could accurately predict participants’ BI, measured by a standard paper and pencil questionnaire (Adult Measure of Behavioral Inhibition, or AMBI. Here, we sought to replicate this finding as well as compare performance on the avatar task to another measure related to BI, the harm avoidance (HA scale of the Tridimensional Personality Questionnaire (TPQ. The TPQ includes HA scales as well as scales assessing reward dependence (RD, novelty seeking (NS and persistence. One hundred and one undergraduates voluntarily completed the avatar task and the paper and pencil inventories in a counter-balanced order. Scores on the avatar task were strongly correlated with BI assessed via the AMBI questionnaire, which replicates prior findings. Females exhibited higher HA scores than males, but did not differ on scores on the avatar task. There was a strong positive relationship between scores on the avatar task and HA scores. One aspect of HA, fear of uncertainty was found to moderately mediate the relationship between AMBI scores and avatar scores. NS had a strong negative relationship with scores on the avatar task, but there was no significant relationship between RD and scores on the avatar task. These findings indicate the effectiveness of the avatar task as a behavioral alternative to self-report measures to assess avoidance. In addition, the use of computer based behavioral tasks are a viable alternative to paper and pencil self

  16. Evidence of gender differences in the ability to inhibit brain activation elicited by food stimulation

    OpenAIRE

    Wang, Gene-Jack; Volkow, Nora D.; Telang, Frank; Jayne, Millard; Ma, Yeming; Pradhan, Kith; Zhu, Wei; Wong, Christopher T.; Thanos, Panayotis K.; Geliebter, Allan; Biegon, Anat; Fowler, Joanna S.

    2009-01-01

    Although impaired inhibitory control is linked to a broad spectrum of health problems, including obesity, the brain mechanism(s) underlying voluntary control of hunger are not well understood. We assessed the brain circuits involved in voluntary inhibition of hunger during food stimulation in 23 fasted men and women using PET and 2-deoxy-2[18F]fluoro-D-glucose (18FDG). In men, but not in women, food stimulation with inhibition significantly decreased activation in amygdala, hippocampus, insul...

  17. Bioengineered Hydrogel to Inhibit Post-Traumatic Central Nervous System Scarring

    Science.gov (United States)

    2016-10-01

    AWARD NUMBER: W81XWH-14-1-0586 TITLE: Bioengineered Hydrogel to Inhibit Post-Traumatic Central Nervous System Scarring PRINCIPAL...Hydrogel to Inhibit Post-Traumatic Central Nervous System Scarring 5a. CONTRACT NUMBER W81XWH-14-1-0586 5b. GRANT NUMBER W81XWH- 14-1-0586 5c...barriers that prevent the optimal delivery of biologics and cells to the injured nervous system . A significant problem is the formation of scar tissue

  18. Inhibition of B16-BL6 melanoma growth in mice by methionine-enkephalin.

    Science.gov (United States)

    Murgo, A J

    1985-08-01

    The antitumor effect of methionine-enkephalin [( Met]enkephalin) was demonstrated in C57BL/6J mice inoculated with B16-BL6 melanoma cells. Local subcutaneous tumor growth was inhibited with a 50-micrograms dose daily for 7 or 14 days. The antitumor effect of [Met]enkephalin was inhibited by the administration of the opioid receptor antagonist naloxone. Naloxone alone had no significant effect on tumor growth.

  19. Enantioselective inhibition of carprofen towards UDP-glucuronosyltransferase (UGT) 2B7.

    Science.gov (United States)

    Fang, Zhong-Ze; Wang, Haina; Cao, Yun-Feng; Sun, Dong-Xue; Wang, Li-Xuan; Hong, Mo; Huang, Ting; Chen, Jian-Xing; Zeng, Jia

    2015-03-01

    UDP-glucuronosyltransferases (UGTs)-catalyzed glucuronidation conjugation reaction plays an important role in the elimination of many important clinical drugs and endogenous substances. The present study aims to investigate the enantioselective inhibition of carprofen towards UGT isoforms. In vitro a recombinant UGT isoforms-catalyzed 4-methylumbelliferone (4-MU) glucuronidation incubation mixture was used to screen the inhibition potential of (R)-carprofen and (S)-carprofen towards multiple UGT isoforms. The results showed that (S)-carprofen exhibited stronger inhibition potential than (R)-carprofen towards UGT2B7. However, no significant difference was observed for the inhibition of (R)-carprofen and (S)-carprofen towards other UGT isoforms. Furthermore, the inhibition kinetic behavior was compared for the inhibition of (S)-carprofen and (R)-carprofen towards UGT2B7. A Lineweaver-Burk plot showed that both (S)-carprofen and (R)-carprofen exhibited competitive inhibition towards UGT2B7-catalyzed 4-MU glucuronidation. The inhibition kinetic parameter (Ki ) was calculated to be 7.0 μM and 31.1 μM for (S)-carprofen and (R)-carprofen, respectively. Based on the standard for drug-drug interaction, the threshold for (S)-carprofen and (R)-carprofen to induce a drug-drug interaction is 0.7 μM and 3.1 μM, respectively. In conclusion, enantioselective inhibition of carprofen towards UDP-glucuronosyltransferase (UGT) 2B7 was demonstrated in the present study. Using the in vitro inhibition kinetic parameter, the concentration threshold of (S)-carprofen and (R)-carprofen to possibly induce the drug-drug interaction was obtained. Therefore, clinical monitoring of the plasma concentration of (S)-carprofen is more important than (R)-carprofen to avoid a possible drug-drug interaction between carprofen and the drugs mainly undergoing UGT2B7-catalyzed metabolism. © 2014 Wiley Periodicals, Inc.

  20. Curcumin inhibits amygdaloid kindled seizures in rats.

    Science.gov (United States)

    DU, Peng; Li, Xin; Lin, Hao-Jie; Peng, Wei-Feng; Liu, Jian-Ying; Ma, Yu; Fan, Wei; Wang, Xin

    2009-06-20

    Curcumin can reduce the severity of seizures induced by kainate acid (KA), but the role of curcumin in amygdaloid kindled models is still unknown. This study aimed to explore the effect of curcumin on the development of kindling in amygdaloid kindled rats. With an amygdaloid kindled Sprague-Dawley (SD) rat model and an electrophysiological method, different doses of curcumin (10 mgxkg(-1)xd(-1) and 30 mgxkg(-1)xd(-1) as low dose groups, 100 mgxkg(-1)xd(-1) and 300 mgxkg(-1)xd(-1) as high dose groups) were administrated intraperitoneally during the whole kindling days, by comparison with the course of kindling, afterdischarge (AD) thresholds and the number of ADs to reach the stages of class I to V seizures in the rats between control and experimental groups. One-way or two-way ANOVA and Fisher's least significant difference post hoc test were used for statistical analyses. Curcumin (both 100 mgxkg(-1)xd(-1) and 300 mgxkg(-1)xd(-1)) significantly inhibited the behavioral seizure development in the (19.80 +/- 2.25) and (21.70 +/- 2.21) stimulations respectively required to reach the kindled state. Rats treated with 100 mgxkg(-1)xd(-1) curcumin 30 minutes before kindling stimulation showed an obvious increase in the stimulation current intensity required to evoke AD from (703.3 +/- 85.9) microA to (960.0 +/- 116.5) microA during the progression to class V seizures. Rats treated with 300 mgxkg(-1)xd(-1) curcumin showed a significant increase in the stimulation current intensity required to evoke AD from (735.0 +/- 65.2) microA to (867.0 +/- 93.4) microA during the progression to class V seizures. Rats treated with 300 mgxkg(-1)xd(-1) curcumin required much more evoked ADs to reach the stage of class both IV (as (199.83 +/- 12.47) seconds) and V seizures (as (210.66 +/- 10.68) seconds). Rats treated with 100 mgxkg(-1)xd(-1) curcumin required much more evoked ADs to reach the stage of class V seizures (as (219.56 +/- 18.24) seconds). Our study suggests that curcumin has

  1. Resveratrol inhibits PDGF receptor mitogenic signaling in mesangial cells: role of PTP1B

    Science.gov (United States)

    Venkatesan, Balachandar; Ghosh-Choudhury, Nandini; Das, Falguni; Mahimainathan, Lenin; Kamat, Amrita; Kasinath, Balakuntalam S.; Abboud, Hanna E.; Choudhury, Goutam Ghosh

    2008-01-01

    Mesangioproliferative glomerulonephritis is associated with overactive PDGF receptor signal transduction. We show that the phytoalexin resveratrol dose dependently inhibits PDGF-induced DNA synthesis in mesangial cells with an IC50 of 10 μM without inducing apoptosis. Remarkably, the increased SIRT1 deacetylase activity induced by resveratrol was not necessary for this inhibitory effect. Resveratrol significantly blocked PDGF-stimulated c-Src and Akt kinase activation, resulting in reduced cyclin D1 expression and attenuated pRb phosphorylation and cyclin-dependent kinase-2 (CDK2) activity. Furthermore, resveratrol inhibited PDGFR phosphorylation at the PI 3 kinase and Grb-2 binding sites tyrosine-751 and tyrosine-716, respectively. This deficiency in PDGFR phosphorylation resulted in significant inhibition of PI 3 kinase and Erk1/2 MAPK activity. Interestingly, resveratrol increased the activity of protein tyrosine phosphatase PTP1B, which dephosphorylates PDGF-stimulated phosphorylation at tyrosine-751 and tyrosine-716 on PDGFR with concomitant reduction in Akt and Erk1/2 kinase activity. PTP1B significantly inhibited PDGF-induced DNA synthesis without inducing apoptosis. These results for the first time provide evidence that the stilbene resveratrol targets PTP1B to inhibit PDGFR mitogenic signaling.—Venkatesan, B., Ghosh-Choudhury, N., Das, F., Mahimainathan, L., Kamat, A., Kasinath, B. S., Abboud, H. E., Choudhury, G. G. Resveratrol inhibits PDGF receptor mitogenic signaling in mesangial cells: role of PTP1B. PMID:18567737

  2. Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition

    Science.gov (United States)

    Hubers, Scott A.; Brown, Nancy J.

    2016-01-01

    Heart failure affects approximately 5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the FDA approved the first of a new class of drugs for the treatment of heart failure; valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses two of the pathophysiologic mechanisms of heart failure - activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared to enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacologic properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension. PMID:26976916

  3. Characterization of acetylcholinesterase-inhibition by itopride.

    Science.gov (United States)

    Iwanaga, Y; Kimura, T; Miyashita, N; Morikawa, K; Nagata, O; Itoh, Z; Kondo, Y

    1994-11-01

    Itopride is a gastroprokinetic benzamide derivative. This agent inhibited both electric eel acetylcholinesterase (AChE) and horse serum butyrylcholinesterase (BuChE). The IC50 of itopride with AChE (2.04 +/- 0.27 microM) was, however, 100-fold less than that with BuChE, whereas in the case of neostigmine with AChE (11.3 +/- 3.4 nM), it was 10-fold less. The recovery of AChE activity inhibited by 10(-7) M neostigmine was partial, but that inhibited by up to 3 x 10(-5) M itopride was complete when the reaction mixture was subjected to ultrafiltration. Double reciprocal plots of the experimental data showed that both Km and Vmax were affected by itopride, suggesting that the inhibition is a "mixed" type, although primarily being an uncompetitive one. The inhibitory effect of itopride on cholinesterase (ChE) activity in guinea pig gastrointestine was much weaker than that on pure AChE. However, in the presence of a low dose of diisopropyl fluorophosphate, just enough to inhibit BuChE but not AChE, the IC50s of itopride against ChE activities were found to be about 0.5 microM. In conclusion, itopride exerts reversible and a "mixed" type of inhibition preferably against AChE. The IC50 of itopride for electric eel and guinea pig gastrointestinal AChE inhibition was 200 times and 50 times as large as that of neostigmine, respectively.

  4. Arctigenin, a phenylpropanoid dibenzylbutyrolactone lignan, inhibits type I-IV allergic inflammation and pro-inflammatory enzymes.

    Science.gov (United States)

    Lee, Ji Yun; Kim, Chang Jong

    2010-06-01

    We previously reported that arctigenin, a phenylpropanoid dibenzylbutyrolactone lignan isolated from Forsythia koreana, exhibits anti-inflammatory, antioxidant, and analgesic effects in animal models. In addition, arctigenin inhibited eosinophil peroxidase and activated myeloperoxidase in inflamed tissues. In this study, we tested the effects of arctigenin on type I-IV allergic inflammation and pro-inflammatory enzymes in vitro and in vivo. Arctigenin significantly inhibited the heterologous passive cutaneous anaphylaxis induced by ovalbumin in mice at 15 mg/kg, p.o., and compound 48/80-induced histamine release from rat peritoneal mast cells at 10 microM. Arctigenin (15 mg/kg, p.o.) significantly inhibited reversed cutaneous anaphylaxis. Further, arctigenin (15 mg/kg, p.o.) significantly inhibited the Arthus reaction to sheep's red blood cells, decreasing the hemolysis titer, the hemagglutination titer, and the plaque-forming cell number for SRBCs. In addition, arctigenin significantly inhibited delayed type hypersensitivity at 15 mg/kg, p.o. and the formation of rosette-forming cells at 45 mg/kg, p.o. Contact dermatitis induced by picrylchloride and dinitrofluorobenzene was significantly (p arctigenin (0.3 mg/ear). Furthermore, arctigenin dose-dependently inhibited pro-inflammatory enzymes, such as cyclooxygenase-1 and 2, 5-lipoxygenase, phospholipase A2, and phosphodiesterase. Our results show that arctigenin significantly inhibited B- and T-cell mediated allergic inflammation as well as pro-inflammatory enzymes.

  5. The kampo medicine Daikenchuto inhibits peritoneal fibrosis in mice.

    Science.gov (United States)

    Kitamura, Mineaki; Nishino, Tomoya; Obata, Yoko; Oka, Satoru; Abe, Shinichi; Muta, Kumiko; Ozono, Yoshiyuki; Koji, Takehiko; Kohno, Shigeru

    2015-01-01

    Long-term peritoneal dialysis therapy causes inflammation and histological changes in the peritoneal membrane. Inflammation generally activates fibroblasts and results in fibroblast-myofibroblast differentiation. Heat-shock protein 47 (HSP 47), a collagen-specific molecular chaperone, is localized in myofibroblasts and is involved in the progression of peritoneal fibrosis. Daikenchuto (DKT), a Kampo medicine, is used to prevent postoperative colon adhesion. It inhibits inflammation and HSP 47 expression in the gastrointestinal tract. We examined the effect of DKT on chlorhexidine gluconate (CG)-induced peritoneal fibrosis in mice injected with 0.1% CG dissolved in 15% ethanol. DKT was dissolved in the drinking water. Histological changes were assessed using Masson trichrome staining. Cells expressing α-smooth muscle actin (α-SMA), HSP 47, phospho-Smad 2/3, F4/80, and monocyte chemotactic protein-1 were examined immunohistochemically. Compared with the control group, the peritoneal tissues of the CG group were markedly thickened, and the number of cells expressing α-SMA, HSP 47, phospho-Smad 2/3, F4/80, and monocyte chemotactic protein-1 was significantly increased. However, these changes were inhibited in the DKT-treated group. These results indicate that DKT can prevent peritoneal fibrosis by inhibiting inflammation and HSP 47 expression.

  6. Puerarin Alleviates Neuropathic Pain by Inhibiting Neuroinflammation in Spinal Cord

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    Ming Liu

    2014-01-01

    Full Text Available Neuropathic pain responds poorly to drug treatments, and partial relief is achieved in only about half of the patients. Puerarin, the main constituent of Puerariae Lobatae Radix, has been used extensively in China to treat hypertension and tumor. The current study examined the effects of puerarin on neuropathic pain using two most commonly used animal models: chronic constriction injury (CCI and diabetic neuropathy. We found that consecutive intrathecal administration of puerarin (4–100 nM for 7 days inhibited the mechanical and thermal nociceptive response induced by CCI and diabetes without interfering with the normal pain response. Meanwhile, in both models puerarin inhibited the activation of microglia and astroglia in the spinal dorsal horn. Puerarin also reduced the upregulated levels of nuclear factor-κB (NF-κB and other proinflammatory cytokines, such as IL-6, IL-1β, and TNF-α, in the spinal cord. In summary, puerarin alleviated CCI- and diabetes-induced neuropathic pain, and its effectiveness might be due to the inhibition of neuroinflammation in the spinal cord. The anti-inflammation effect of puerarin might be related to the suppression of spinal NF-κB activation and/or cytokines upregulation. We conclude that puerarin has a significant effect on alleviating neuropathic pain and thus may serve as a therapeutic approach for neuropathic pain.

  7. Inhibition of coronary blood flow by a vascular waterfall mechanism.

    Science.gov (United States)

    Downey, J M; Kirk, E S

    1975-06-01

    The mechanism whereby systole inhibits coronary blood flow was examined. A branch of the left coronary artery was maximally dilated with an adenosine infusion, and the pressure-flow relationship was obtained for beating and arrested states. The pressure-flow curve for the arrested state was shifted toward higher pressures and in the range of pressures above peak ventricular pressure was linear and parallel to that for the arrested state. Below this range the curve for the beating state converged toward that for the arrested state and was convex to the pressure axis. These results were compared with a model of the coronary vasculature that consisted of numerous parallel channels, each responding to local intramyocardial pressure by forming vascular waterfalls. When intramyocardial pressure in the model was assigned values from zero at the epicardium to peak ventricular pressure at the endocardium, pressure-flow curves similar to the experimental ones resulted. Thus, we conclude that systole inhibits coronary perfusion by the formation of vascular waterfalls and that the intramyocardial pressures responsible for this inhibition do not significantly exceed peak ventricular pressure.

  8. IL-17 inhibits chondrogenic differentiation of human mesenchymal stem cells.

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    Masahiro Kondo

    Full Text Available OBJECTIVE: Mesenchymal stem cells (MSCs can differentiate into cells of mesenchymal lineages, such as osteoblasts and chondrocytes. Here we investigated the effects of IL-17, a key cytokine in chronic inflammation, on chondrogenic differentiation of human MSCs. METHODS: Human bone marrow MSCs were pellet cultured in chondrogenic induction medium containing TGF-β3. Chondrogenic differentiation was detected by cartilage matrix accumulation and chondrogenic marker gene expression. RESULTS: Over-expression of cartilage matrix and chondrogenic marker genes was noted in chondrogenic cultures, but was inhibited by IL-17 in a dose-dependent manner. Expression and phosphorylation of SOX9, the master transcription factor for chondrogenesis, were induced within 2 days and phosphorylated SOX9 was stably maintained until day 21. IL-17 did not alter total SOX9 expression, but significantly suppressed SOX9 phosphorylation in a dose-dependent manner. At day 7, IL-17 also suppressed the activity of cAMP-dependent protein kinase A (PKA, which is known to phosphorylate SOX9. H89, a selective PKA inhibitor, also suppressed SOX9 phosphorylation, expression of chondrogenic markers and cartilage matrix, and also decreased chondrogenesis. CONCLUSIONS: IL-17 inhibited chondrogenesis of human MSCs through the suppression of PKA activity and SOX9 phosphorylation. These results suggest that chondrogenic differentiation of MSCs can be inhibited by a mechanism triggered by IL-17 under chronic inflammation.

  9. Vardenafil inhibiting parasympathetic function of tracheal smooth muscle.

    Science.gov (United States)

    Lee, Fei-Peng; Chao, Pin-Zhir; Wang, Hsing-Won

    2018-07-01

    Levitra, a phosphodiesterase-5 (PDE5) inhibitor, is the trade name of vardenafil. Nowadays, it is applied to treatment of erectile dysfunction. PDE5 inhibitors are employed to induce dilatation of the vascular smooth muscle. The effect of Levitra on impotency is well known; however, its effect on the tracheal smooth muscle has rarely been explored. When administered for sexual symptoms via oral intake or inhalation, Levitra might affect the trachea. This study assessed the effects of Levitra on isolated rat tracheal smooth muscle by examining its effect on resting tension of tracheal smooth muscle, contraction caused by 10 -6  M methacholine as a parasympathetic mimetic, and electrically induced tracheal smooth muscle contractions. The results showed that adding methacholine to the incubation medium caused the trachea to contract in a dose-dependent manner. Addition of Levitra at doses of 10 -5  M or above elicited a significant relaxation response to 10 -6  M methacholine-induced contraction. Levitra could inhibit electrical field stimulation-induced spike contraction. It alone had minimal effect on the basal tension of the trachea as the concentration increased. High concentrations of Levitra could inhibit parasympathetic function of the trachea. Levitra when administered via oral intake might reduce asthma attacks in impotent patients because it might inhibit parasympathetic function and reduce methacholine-induced contraction of the tracheal smooth muscle. Copyright © 2018. Published by Elsevier Taiwan LLC.

  10. Recombinant human prion protein inhibits prion propagation in vitro.

    Science.gov (United States)

    Yuan, Jue; Zhan, Yi-An; Abskharon, Romany; Xiao, Xiangzhu; Martinez, Manuel Camacho; Zhou, Xiaochen; Kneale, Geoff; Mikol, Jacqueline; Lehmann, Sylvain; Surewicz, Witold K; Castilla, Joaquín; Steyaert, Jan; Zhang, Shulin; Kong, Qingzhong; Petersen, Robert B; Wohlkonig, Alexandre; Zou, Wen-Quan

    2013-10-09

    Prion diseases are associated with the conformational conversion of the cellular prion protein (PrP(C)) into the pathological scrapie isoform (PrP(Sc)) in the brain. Both the in vivo and in vitro conversion of PrP(C) into PrP(Sc) is significantly inhibited by differences in amino acid sequence between the two molecules. Using protein misfolding cyclic amplification (PMCA), we now report that the recombinant full-length human PrP (rHuPrP23-231) (that is unglycosylated and lacks the glycophosphatidylinositol anchor) is a strong inhibitor of human prion propagation. Furthermore, rHuPrP23-231 also inhibits mouse prion propagation in a scrapie-infected mouse cell line. Notably, it binds to PrP(Sc), but not PrP(C), suggesting that the inhibitory effect of recombinant PrP results from blocking the interaction of brain PrP(C) with PrP(Sc). Our findings suggest a new avenue for treating prion diseases, in which a patient's own unglycosylated and anchorless PrP is used to inhibit PrP(Sc) propagation without inducing immune response side effects.

  11. DBR1 siRNA inhibition of HIV-1 replication

    Directory of Open Access Journals (Sweden)

    Naidu Yathi

    2005-10-01

    Full Text Available Abstract Background HIV-1 and all retroviruses are related to retroelements of simpler organisms such as the yeast Ty elements. Recent work has suggested that the yeast retroelement Ty1 replicates via an unexpected RNA lariat intermediate in cDNA synthesis. The putative genomic RNA lariat intermediate is formed by a 2'-5' phosphodiester bond, like that found in pre-mRNA intron lariats and it facilitates the minus-strand template switch during cDNA synthesis. We hypothesized that HIV-1 might also form a genomic RNA lariat and therefore that siRNA-mediated inhibition of expression of the human RNA lariat de-branching enzyme (DBR1 expression would specifically inhibit HIV-1 replication. Results We designed three short interfering RNA (siRNA molecules targeting DBR1, which were capable of reducing DBR1 mRNA expression by 80% and did not significantly affect cell viability. We assessed HIV-1 replication in the presence of DBR1 siRNA and found that DBR1 knockdown led to decreases in viral cDNA and protein production. These effects could be reversed by cotransfection of a DBR1 cDNA indicating that the inhibition of HIV-1 replication was a specific effect of DBR1 underexpression. Conclusion These data suggest that DBR1 function may be needed to debranch a putative HIV-1 genomic RNA lariat prior to completion of reverse transcription.

  12. Inhibition of fatty acid metabolism reduces human myeloma cells proliferation.

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    José Manuel Tirado-Vélez

    Full Text Available Multiple myeloma is a haematological malignancy characterized by the clonal proliferation of plasma cells. It has been proposed that targeting cancer cell metabolism would provide a new selective anticancer therapeutic strategy. In this work, we tested the hypothesis that inhibition of β-oxidation and de novo fatty acid synthesis would reduce cell proliferation in human myeloma cells. We evaluated the effect of etomoxir and orlistat on fatty acid metabolism, glucose metabolism, cell cycle distribution, proliferation, cell death and expression of G1/S phase regulatory proteins in myeloma cells. Etomoxir and orlistat inhibited β-oxidation and de novo fatty acid synthesis respectively in myeloma cells, without altering significantly glucose metabolism. These effects were associated with reduced cell viability and cell cycle arrest in G0/G1. Specifically, etomoxir and orlistat reduced by 40-70% myeloma cells proliferation. The combination of etomoxir and orlistat resulted in an additive inhibitory effect on cell proliferation. Orlistat induced apoptosis and sensitized RPMI-8226 cells to apoptosis induction by bortezomib, whereas apoptosis was not altered by etomoxir. Finally, the inhibitory effect of both drugs on cell proliferation was associated with reduced p21 protein levels and phosphorylation levels of retinoblastoma protein. In conclusion, inhibition of fatty acid metabolism represents a potential therapeutic approach to treat human multiple myeloma.

  13. Viologen-Phosphorus Dendrimers Inhibit α-Synuclein Fibrillation.

    Science.gov (United States)

    Milowska, Katarzyna; Grochowina, Justyna; Katir, Nadia; El Kadib, Abdelkrim; Majoral, Jean-Pierre; Bryszewska, Maria; Gabryelak, Teresa

    2013-03-04

    Inhibition of α-synuclein (ASN) fibril formation is a potential therapeutic strategy in Parkinson's disease and other synucleinopathies. The aim of this study was to examine the role of viologen-phosphorus dendrimers in the α-synuclein fibrillation process and to assess the structural changes in α-synuclein under the influence of dendrimers. ASN interactions with phosphonate and pegylated surface-reactive viologen-phosphorus dendrimers were examined by measuring the zeta potential, which allowed determining the number of dendrimer molecules that bind to the ASN molecule. The fibrillation kinetics and the structural changes were examined using ThT fluorescence and CD spectroscopy. Depending on the concentration of the used dendrimer and the nature of the reactive groups located on the surface, ASN fibrillation kinetics can be significantly reduced, and even, in the specific case of phosphonate dendrimers, the fibrillation can be totally inhibited at low concentrations. The presented results indicate that viologen-phosphorus dendrimers are able to inhibit ASN fibril formation and may be used as fibrillar regulating agents in neurodegenerative disorders.

  14. Mini-review: Inhibition of biofouling by marine microorganisms.

    Science.gov (United States)

    Dobretsov, Sergey; Abed, Raeid M M; Teplitski, Max

    2013-01-01

    Any natural or artificial substratum exposed to seawater is quickly fouled by marine microorganisms and later by macrofouling species. Microfouling organisms on the surface of a substratum form heterogenic biofilms, which are composed of multiple species of heterotrophic bacteria, cyanobacteria, diatoms, protozoa and fungi. Biofilms on artificial structures create serious problems for industries worldwide, with effects including an increase in drag force and metal corrosion as well as a reduction in heat transfer efficiency. Additionally, microorganisms produce chemical compounds that may induce or inhibit settlement and growth of other fouling organisms. Since the last review by the first author on inhibition of biofouling by marine microbes in 2006, significant progress has been made in the field. Several antimicrobial, antialgal and antilarval compounds have been isolated from heterotrophic marine bacteria, cyanobacteria and fungi. Some of these compounds have multiple bioactivities. Microorganisms are able to disrupt biofilms by inhibition of bacterial signalling and production of enzymes that degrade bacterial signals and polymers. Epibiotic microorganisms associated with marine algae and invertebrates have a high antifouling (AF) potential, which can be used to solve biofouling problems in industry. However, more information about the production of AF compounds by marine microorganisms in situ and their mechanisms of action needs to be obtained. This review focuses on the AF activity of marine heterotrophic bacteria, cyanobacteria and fungi and covers publications from 2006 up to the end of 2012.

  15. Puerarin alleviates neuropathic pain by inhibiting neuroinflammation in spinal cord.

    Science.gov (United States)

    Liu, Ming; Liao, Kaijun; Yu, Changxi; Li, Xuejun; Liu, Suhuan; Yang, Shuyu

    2014-01-01

    Neuropathic pain responds poorly to drug treatments, and partial relief is achieved in only about half of the patients. Puerarin, the main constituent of Puerariae Lobatae Radix, has been used extensively in China to treat hypertension and tumor. The current study examined the effects of puerarin on neuropathic pain using two most commonly used animal models: chronic constriction injury (CCI) and diabetic neuropathy. We found that consecutive intrathecal administration of puerarin (4-100 nM) for 7 days inhibited the mechanical and thermal nociceptive response induced by CCI and diabetes without interfering with the normal pain response. Meanwhile, in both models puerarin inhibited the activation of microglia and astroglia in the spinal dorsal horn. Puerarin also reduced the upregulated levels of nuclear factor-κB (NF-κB) and other proinflammatory cytokines, such as IL-6, IL-1β, and TNF-α, in the spinal cord. In summary, puerarin alleviated CCI- and diabetes-induced neuropathic pain, and its effectiveness might be due to the inhibition of neuroinflammation in the spinal cord. The anti-inflammation effect of puerarin might be related to the suppression of spinal NF-κB activation and/or cytokines upregulation. We conclude that puerarin has a significant effect on alleviating neuropathic pain and thus may serve as a therapeutic approach for neuropathic pain.

  16. Radiosensitization by histone deacetylase inhibition in an osteosarcoma mouse model

    International Nuclear Information System (INIS)

    Blattmann, C.; University Children's Hospital of Heidelberg; Thiemann, M.; Stenzinger, A.

    2013-01-01

    Background: Osteosarcomas (OS) are highly malignant and radioresistant tumors. Histone deacetylase inhibitors (HDACi) constitute a novel class of anticancer agents. We sought to investigate the effect of combined treatment with suberoylanilide hydroxamic acid (SAHA) and radiotherapy in OS in vivo. Methods: Clonogenic survival of human OS cell lines as well as tumor growth delay of OS xenografts were tested after treatment with either vehicle, radiotherapy (XRT), SAHA, or XRT and SAHA. Tumor proliferation, necrosis, microvascular density, apoptosis, and p53/p21 were monitored by immunohistochemistry. The CD95 pathway was performed by flow cytometry, caspase (3/7/8) activity measurements, and functional inhibition of CD95 death signaling. Results: Combined treatment with SAHA and XRT markedly reduced the surviving fraction of OS cells as compared to XRT alone. Likewise, dual therapy significantly inhibited OS tumor growth in vivo as compared to XRT alone, reflected by reduced tumor proliferation, impaired angiogenesis, and increased apoptosis. Addition of HDACi to XRT led to elevated p53, p21, CD95, and CD95L expression. Inhibition of CD95 signaling reduced HDACi- and XRT-induced apoptosis. Conclusion: Our data show that HDACi increases the radiosensitivity of osteosarcoma cells at least in part via ligand-induced apoptosis. HDACi thus emerge as potentially useful treatment components of OS. (orig.)

  17. Anandamide inhibits adhesion and migration of breast cancer cells

    International Nuclear Information System (INIS)

    Grimaldi, Claudia; Pisanti, Simona; Laezza, Chiara; Malfitano, Anna Maria; Santoro, Antonietta; Vitale, Mario; Caruso, Maria Gabriella; Notarnicola, Maria; Iacuzzo, Irma; Portella, Giuseppe; Di Marzo, Vincenzo; Bifulco, Maurizio

    2006-01-01

    The endocannabinoid system regulates cell proliferation in human breast cancer cells. We reasoned that stimulation of cannabinoid CB 1 receptors could induce a non-invasive phenotype in breast mtastatic cells. In a model of metastatic spreading in vivo, the metabolically stable anandamide analogue, 2-methyl-2'-F-anandamide (Met-F-AEA), significantly reduced the number and dimension of metastatic nodes, this effect being antagonized by the selective CB 1 antagonist SR141716A. In MDA-MB-231 cells, a highly invasive human breast cancer cell line, and in TSA-E1 cells, a murine breast cancer cell line, Met-F-AEA inhibited adhesion and migration on type IV collagen in vitro without modifying integrin expression: both these effects were antagonized by SR141716A. In order to understand the molecular mechanism involved in these processes, we analyzed the phosphorylation of FAK and Src, two tyrosine kinases involved in migration and adhesion. In Met-F-AEA-treated cells, we observed a decreased tyrosine phosphorylation of both FAK and Src, this effect being attenuated by SR141716A. We propose that CB 1 receptor agonists inhibit tumor cell invasion and metastasis by modulating FAK phosphorylation, and that CB 1 receptor activation might represent a novel therapeutic strategy to slow down the growth of breast carcinoma and to inhibit its metastatic diffusion in vivo

  18. Inhibition of matrix metalloproteinase-2 by PARP inhibitors

    International Nuclear Information System (INIS)

    Nicolescu, Adrian C.; Holt, Andrew; Kandasamy, Arulmozhi D.; Pacher, Pal; Schulz, Richard

    2009-01-01

    Matrix metalloproteinase-2 (MMP-2), a ubiquitously expressed zinc-dependent endopeptidase, and poly(ADP-ribosyl) polymerase (PARP), a nuclear enzyme regulating DNA repair, are activated by nitroxidative stress associated with various pathologies. As MMP-2 plays a detrimental role in heart injuries resulting from enhanced nitroxidative stress, where PARP and MMP inhibitors are beneficial, we hypothesized that PARP inhibitors may affect MMP-2 activity. Using substrate degradation assays to determine MMP-2 activity we found that four PARP inhibitors (3-AB, PJ-34, 5-AIQ, and EB-47) inhibited 64 kDa MMP-2 in a concentration-dependent manner. The IC 50 values of PJ-34 and 5-AIQ were in the high micromolar range and comparable to those of known MMP-2 inhibitors doxycycline, minocycline or o-phenanthroline, whereas those for 3-AB and EB-47 were in the millimolar range. Co-incubation of PARP inhibitors with doxycycline showed an additive inhibition of MMP-2 that was significant for 3-AB alone. These data demonstrate that the protective effects of some PARP inhibitors may include inhibition of MMP-2 activity.

  19. Inhibition of matrix metalloproteinase-2 by PARP inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Nicolescu, Adrian C.; Holt, Andrew; Kandasamy, Arulmozhi D. [Departments of Pharmacology and Pediatrics, Cardiovascular Research Centre, University of Alberta, Edmonton, Alta., Canada T6G 2S2 (Canada); Pacher, Pal [National Institutes of Health, NIAAA, Laboratory of Physiologic Studies, Bethesda, MD (United States); Schulz, Richard, E-mail: richard.schulz@ualberta.ca [Departments of Pharmacology and Pediatrics, Cardiovascular Research Centre, University of Alberta, Edmonton, Alta., Canada T6G 2S2 (Canada)

    2009-10-02

    Matrix metalloproteinase-2 (MMP-2), a ubiquitously expressed zinc-dependent endopeptidase, and poly(ADP-ribosyl) polymerase (PARP), a nuclear enzyme regulating DNA repair, are activated by nitroxidative stress associated with various pathologies. As MMP-2 plays a detrimental role in heart injuries resulting from enhanced nitroxidative stress, where PARP and MMP inhibitors are beneficial, we hypothesized that PARP inhibitors may affect MMP-2 activity. Using substrate degradation assays to determine MMP-2 activity we found that four PARP inhibitors (3-AB, PJ-34, 5-AIQ, and EB-47) inhibited 64 kDa MMP-2 in a concentration-dependent manner. The IC{sub 50} values of PJ-34 and 5-AIQ were in the high micromolar range and comparable to those of known MMP-2 inhibitors doxycycline, minocycline or o-phenanthroline, whereas those for 3-AB and EB-47 were in the millimolar range. Co-incubation of PARP inhibitors with doxycycline showed an additive inhibition of MMP-2 that was significant for 3-AB alone. These data demonstrate that the protective effects of some PARP inhibitors may include inhibition of MMP-2 activity.

  20. Radiosensitization by histone deacetylase inhibition in an osteosarcoma mouse model

    Energy Technology Data Exchange (ETDEWEB)

    Blattmann, C. [Olgahospital, Stuttgart (Germany). Paediatrie 5; University Children' s Hospital of Heidelberg (Germany). Dept. of Pediatric Oncology, Hematology and Immunology; Thiemann, M. [German Cancer Research Center (DKFZ), Heidelberg (Germany). Dept. of Radiotherapy, Molecular- and Translational Radiation Oncology; Stenzinger, A. [Heidelberg Univ. (Germany). Inst. of Pathology; and others

    2013-11-15

    Background: Osteosarcomas (OS) are highly malignant and radioresistant tumors. Histone deacetylase inhibitors (HDACi) constitute a novel class of anticancer agents. We sought to investigate the effect of combined treatment with suberoylanilide hydroxamic acid (SAHA) and radiotherapy in OS in vivo. Methods: Clonogenic survival of human OS cell lines as well as tumor growth delay of OS xenografts were tested after treatment with either vehicle, radiotherapy (XRT), SAHA, or XRT and SAHA. Tumor proliferation, necrosis, microvascular density, apoptosis, and p53/p21 were monitored by immunohistochemistry. The CD95 pathway was performed by flow cytometry, caspase (3/7/8) activity measurements, and functional inhibition of CD95 death signaling. Results: Combined treatment with SAHA and XRT markedly reduced the surviving fraction of OS cells as compared to XRT alone. Likewise, dual therapy significantly inhibited OS tumor growth in vivo as compared to XRT alone, reflected by reduced tumor proliferation, impaired angiogenesis, and increased apoptosis. Addition of HDACi to XRT led to elevated p53, p21, CD95, and CD95L expression. Inhibition of CD95 signaling reduced HDACi- and XRT-induced apoptosis. Conclusion: Our data show that HDACi increases the radiosensitivity of osteosarcoma cells at least in part via ligand-induced apoptosis. HDACi thus emerge as potentially useful treatment components of OS. (orig.)

  1. Antioxidant Activity and Acetylcholinesterase Inhibition of Grape Skin Anthocyanin (GSA

    Directory of Open Access Journals (Sweden)

    Mehnaz Pervin

    2014-07-01

    Full Text Available We aimed to investigate the antioxidant and acetylcholinesterase inhibitory activities of the anthocyanin rich extract of grape skin. Grape skin anthocyanin (GSA neutralized free radicals in different test systems, such as 2,-2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid (ABTS and 2,2-diphenyl-1-picrylhydrazyl (DPPH assays, to form complexes with Fe2+ preventing 2,2'-azobis(2-amidinopropane dihydrochloride (AAPH-induced erythrocyte hemolysis and oxidative DNA damage. Moreover, GSA decreased reactive oxygen species (ROS generation in isolated mitochondria thus inhibiting 2',-7'-dichlorofluorescin (DCFH oxidation. In an in vivo study, female BALB/c mice were administered GSA, at 12.5, 25, and 50 mg per kg per day orally for 30 consecutive days. Herein, we demonstrate that GSA administration significantly elevated the level of antioxidant enzymes in mice sera, livers, and brains. Furthermore, GSA inhibited acetylcholinesterase (AChE in the in vitro assay with an IC50 value of 363.61 µg/mL. Therefore, GSA could be an excellent source of antioxidants and its inhibition of cholinesterase is of interest with regard to neurodegenerative disorders such as Alzheimer’s disease.

  2. Mycotoxicogenic fungal inhibition by innovative cheese cover with aromatic plants.

    Science.gov (United States)

    Moro, Armando; Librán, Celia M; Berruga, M Isabel; Zalacain, Amaya; Carmona, Manuel

    2013-03-30

    The use of aromatic plants and their extracts with antimicrobial properties may be compromised in the case of cheese, as some type of fungal starter is needed during its production. Penicillium verrucosum is considered a common cheese spoiler. The aim of this study was to evaluate the innovative use of certain aromatic plants as natural cheese covers in order to prevent mycotoxicogenic fungal growth (P. verrucosum). A collection of 12 essential oils (EOs) was obtained from various aromatic plants by solvent-free microwave extraction technology, and volatile characterisation of the EOs was carried out by gas chromatography/mass spectrometry. The most effective EOs against P. verrucosum were obtained from Anethum graveolens, Hyssopus officinalis and Chamaemelum nobile, yielding 50% inhibition of fungal growth at concentration values lower than 0.02 µL mL⁻¹. All EOs showed high volatile heterogeneity, with α-phellandrene, pinocamphone, isopinocamphone, α-pinene, camphene, 1,8-cineole, carvacrol and trans-anethole being found to be statistically significant in the antifungal model. The use of these aromatic plants as natural covers on cheese can satisfactorily inhibit the growth of some mycotoxicogenic fungal spoilers. Among the volatile compounds present, α- and β-phellandrene were confirmed as the most relevant in the inhibition. © 2012 Society of Chemical Industry.

  3. Homocysteine inhibits hepatocyte proliferation via endoplasmic reticulum stress.

    Directory of Open Access Journals (Sweden)

    Xue Yu

    Full Text Available Homocysteine is an independent risk factor for coronary, cerebral, and peripheral vascular diseases. Recent studies have shown that levels of homocysteine are elevated in patients with impaired hepatic function, but the precise role of homocysteine in the development of hepatic dysfunction is unclear. In this study, we examined the effect of homocysteine on hepatocyte proliferation in vitro. Our results demonstrated that homocysteine inhibited hepatocyte proliferation by up-regulating protein levels of p53 as well as mRNA and protein levels of p21(Cip1 in primary cultured hepatocytes. Homocysteine induced cell growth arrest in p53-positive hepatocarcinoma cell line HepG2, but not in p53-null hepatocarcinoma cell line Hep3B. A p53 inhibitor pifithrin-α inhibited the expression of p21(Cip1 and attenuated homocysteine-induced cell growth arrest. Homocysteine induced TRB3 expression via endoplasmic reticulum stress pathway, resulting in Akt dephosphorylation. Knock-down of endogenous TRB3 significantly suppressed the inhibitory effect of homocysteine on cell proliferation and the phosphorylation of Akt. LiCl reversed homocysteine-mediated cell growth arrest by inhibiting TRB3-mediated Akt dephosphorylation. These results demonstrate that both TRB3 and p21(Cip1 are critical molecules in the homocysteine signaling cascade and provide a mechanistic explanation for impairment of liver regeneration in hyperhomocysteinemia.

  4. CYTOTOXIC, α-CHYMOTRYPSIN AND UREASE INHIBITION ACTIVITIES OF THE PLANT Heliotropium dasycarpum L.

    Science.gov (United States)

    Ghaffari, Muhammad Abuzar; Chaudhary, Bashir Ahmed; Uzair, Muhammad; Ashfaq, Khuram

    2016-01-01

    The aim of this study was to investigate Cytotoxic, α-Chymotrypsin and Urease inhibition activities of the plant Heliotropium dasycarpum . Dichloromethane and methanol extracts of the plant were evaluated for cytotoxic, α-Chymotrypsin and Urease inhibition by using in vivo Brine Shrimp lethality bioassay and in vitro enzymatic inhibition assays respectively. The methanol extract of the plant exhibited significant cytotoxic activity. Out of 30 brine shrimp larvae, 2 (6%), 26 (86%) and 28 (93%) larvae were survived at concentration of 1000μg/ml, 100μg/ml and 10μg/ml respectively with LD50; 215.837. Similarly 21 (70%), 25 (83%), 29 (96%) larvae were survived of dichloromethane plant extract with LD50; 6170.64. The methanol and dichloromethane extract exhibited 10.50±0.18% and 41.51±0.15% α-chymotrypsin enzyme inhibition respectively with IC 50 values of greater than 500 μmol. The methanol extract showed 24.39±0.21% Urease enzyme inhibition with IC 50 values of greater than 400 μmol While dichloromethane extract has 11.46±0.09% enzyme inhibition with IC 50 values of greater than 500 μmol. The results clearly indicated that Heliotropium dasycarpum has cytotoxic potential and enzyme inhibition properties. Further study is needed to screen out antitumor and anti-ulcerative agents.

  5. Inhibition of human UDP-glucuronosyltransferase enzymes by lapatinib, pazopanib, regorafenib and sorafenib: Implications for hyperbilirubinemia.

    Science.gov (United States)

    Miners, John O; Chau, Nuy; Rowland, Andrew; Burns, Kushari; McKinnon, Ross A; Mackenzie, Peter I; Tucker, Geoffrey T; Knights, Kathleen M; Kichenadasse, Ganessan

    2017-04-01

    Kinase inhibitors (KIs) are a rapidly expanding class of drugs used primarily for the treatment of cancer. Data relating to the inhibition of UDP-glucuronosyltransferase (UGT) enzymes by KIs is sparse. However, lapatinib (LAP), pazopanib (PAZ), regorafenib (REG) and sorafenib (SOR) have been implicated in the development of hyperbilirubinemia in patients. This study aimed to characterise the role of UGT1A1 inhibition in hyperbilirubinemia and assess the broader potential of these drugs to perpetrate drug-drug interactions arising from UGT enzyme inhibition. Twelve recombinant human UGTs from subfamilies 1A and 2B were screened for inhibition by LAP, PAZ, REG and SOR. IC 50 values for the inhibition of all UGT1A enzymes, except UGT1A3 and UGT1A4, by the four KIs were enzyme identified to date. In vitro-in vivo extrapolation indicates that inhibition of UGT1A1 contributes significantly to the hyperbilirubinemia observed in patients treated with REG and SOR, but not with LAP and PAZ. Inhibition of other UGT1A1 substrates in vivo is likely. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. The Effects of Kaempferol-Inhibited Autophagy on Osteoclast Formation.

    Science.gov (United States)

    Kim, Chang-Ju; Shin, Sang-Hun; Kim, Bok-Joo; Kim, Chul-Hoon; Kim, Jung-Han; Kang, Hae-Mi; Park, Bong-Soo; Kim, In-Ryoung

    2018-01-02

    Kaempferol, a flavonoid compound, is derived from the rhizome of Kaempferia galanga L ., which is used in traditional medicine in Asia. Autophagy has pleiotropic functions that are involved in cell growth, survival, nutrient supply under starvation, defense against pathogens, and antigen presentation. There are many studies dealing with the inhibitory effects of natural flavonoids in bone resorption. However, no studies have explained the relationship between the autophagic and inhibitory processes of osteoclastogenesis by natural flavonoids. The present study was undertaken to investigate the inhibitory effects of osteoclastogenesis through the autophagy inhibition process stimulated by kaempferol in murin macrophage (RAW 264.7) cells. The cytotoxic effect of Kaempferol was investigated by MTT assay. The osteoclast differentiation and autophagic process were confirmed via tartrate-resistant acid phosphatase (TRAP) staining, pit formation assay, western blot, and real-time PCR. Kaempferol controlled the expression of autophagy-related factors and in particular, it strongly inhibited the expression of p62/SQSTM1. In the western blot and real time-PCR analysis, when autophagy was suppressed with the application of 3-Methyladenine (3-MA) only, osteoclast and apoptosis related factors were not significantly affected. However, we found that after cells were treated with kaempferol, these factors inhibited autophagy and activated apoptosis. Therefore, we presume that kaempferol-inhibited autophagy activated apoptosis by degradation of p62/SQSTM1. Further study of the p62/SQSTM1 gene as a target in the autophagy mechanism, may help to delineate the potential role of kaempferol in the treatment of bone metabolism disorders.

  7. Essential oil of Curcuma longa inhibits Streptococcus mutans biofilm formation.

    Science.gov (United States)

    Lee, Kwang-Hee; Kim, Beom-Su; Keum, Ki-Suk; Yu, Hyeon-Hee; Kim, Young-Hoi; Chang, Byoung-Soo; Ra, Ji-Young; Moon, Hae-Dalma; Seo, Bo-Ra; Choi, Na-Young; You, Yong-Ouk

    2011-01-01

    Curcuma longa (C. longa) has been used as a spice in foods and as an antimicrobial in Oriental medicine. In this study, we evaluated the inhibitory effects of an essential oil isolated from C. longa on the cariogenic properties of Streptococcus mutans (S. mutans), which is an important bacterium in dental plaque and dental caries formation. First, the inhibitory effects of C. longa essential oil on the growth and acid production of S. mutans were tested. Next, the effect of C. longa essential oil on adhesion to saliva-coated hydroxyapatite beads (S-HAs) was investigated. C. longa essential oil inhibited the growth and acid production of S. mutans at concentrations from 0.5 to 4 mg/mL. The essential oil also exhibited significant inhibition of S. mutans adherence to S-HAs at concentrations higher than 0.5 mg/mL. S. mutans biofilm formation was determined by scanning electron microscopy (SEM) and safranin staining. The essential oil of C. longa inhibited the formation of S. mutans biofilms at concentrations higher than 0.5 mg/mL. The components of C. longa essential oil were then analyzed by GC and GC-MS, and the major components were α-turmerone (35.59%), germacrone (19.02%), α-zingiberene (8.74%), αr-turmerone (6.31%), trans-β-elemenone (5.65%), curlone (5.45%), and β-sesquiphellandrene (4.73%). These results suggest that C. longa may inhibit the cariogenic properties of S. mutans. © 2011 Institute of Food Technologists®

  8. BET bromodomain inhibition of MYC-amplified medulloblastoma.

    Science.gov (United States)

    Bandopadhayay, Pratiti; Bergthold, Guillaume; Nguyen, Brian; Schubert, Simone; Gholamin, Sharareh; Tang, Yujie; Bolin, Sara; Schumacher, Steven E; Zeid, Rhamy; Masoud, Sabran; Yu, Furong; Vue, Nujsaubnusi; Gibson, William J; Paolella, Brenton R; Mitra, Siddhartha S; Cheshier, Samuel H; Qi, Jun; Liu, Kun-Wei; Wechsler-Reya, Robert; Weiss, William A; Swartling, Fredrik J; Kieran, Mark W; Bradner, James E; Beroukhim, Rameen; Cho, Yoon-Jae

    2014-02-15

    MYC-amplified medulloblastomas are highly lethal tumors. Bromodomain and extraterminal (BET) bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here, we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma. We evaluated the effects of genetic and pharmacologic inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and genetically engineered mouse model (GEMM)-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC or MYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed the in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice. Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed downregulation of MYC expression and confirmed the inhibition of MYC-associated transcriptional targets. The exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged the survival of orthotopic xenograft models of MYC-amplified medulloblastoma (P < 0.001). Xenografts harvested from mice after five doses of JQ1 had reduced the expression of MYC mRNA and a reduced proliferative index. JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma. ©2013 AACR

  9. 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

  10. Aspartate inhibits Staphylococcus aureus biofilm formation.

    Science.gov (United States)

    Yang, Hang; Wang, Mengyue; Yu, Junping; Wei, Hongping

    2015-04-01

    Biofilm formation renders Staphylococcus aureus highly resistant to conventional antibiotics and host defenses. Four D-amino acids (D-Leu, D-Met, D-Trp and D-Tyr) have been reported to be able to inhibit biofilm formation and disassemble established S. aureus biofilms. We report here for the first time that both D- and L-isoforms of aspartate (Asp) inhibited S. aureus biofilm formation on tissue culture plates. Similar biofilm inhibition effects were also observed against other staphylococcal strains, including S. saprophyticus, S. equorum, S. chromogenes and S. haemolyticus. It was found that Asp at high concentrations (>10 mM) inhibited the growth of planktonic N315 cells, but at subinhibitory concentrations decreased the cellular metabolic activity without influencing cell growth. The decreased cellular metabolic activity might be the reason for the production of less protein and DNA in the matrix of the biofilms formed in the presence of Asp. However, varied inhibition efficacies of Asp were observed for biofilms formed by clinical staphylococcal isolates. There might be mechanisms other than decreasing the metabolic activity, e.g. the biofilm phenotypes, affecting biofilm formation in the presence of Asp. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  11. Terbinafine inhibits gap junctional intercellular communication

    International Nuclear Information System (INIS)

    Lee, Ju Yeun; Yoon, Sei Mee; Choi, Eun Ju; Lee, Jinu

    2016-01-01

    Terbinafine is an antifungal agent that selectively inhibits fungal sterol synthesis by blocking squalene epoxidase. We evaluated the effect of terbinafine on gap junctional intercellular communication (GJIC). Fluorescence recovery after photobleaching (FRAP) and I-YFP GJIC assays revealed that terbinafine inhibits GJIC in a reversible and dose-dependent manner in FRT-Cx43 and LN215 cells. Treatment with terbinafine did not affect Cx43 phosphorylation status or intracellular Ca 2+ concentration, well-known action mechanisms of various GJIC blockers. While a structurally related chemical, naftifine, attenuated GJIC, epigallocatechin gallate, another potent squalene epoxidase inhibitor with a different structure, did not. These results suggest that terbinafine inhibits GJIC with a so far unknown mechanism of action. - Highlights: • In vitro pharmacological studies were performed on FRT-Cx43 and LN215 cells. • Terbinafine inhibits gap junctional intercellular communication in both cell lines. • The inhibitory effect of terbinafine is reversible and dose-dependent. • Treatment of terbinafine does not alter Cx43 phosphorylation or cytosolic Ca 2+ concentration. • Inhibition of squalene epoxidase is not involved in this new effect of terbinafine.

  12. Terbinafine inhibits gap junctional intercellular communication

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Ju Yeun, E-mail: whitewndus@naver.com [College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983 (Korea, Republic of); Yoon, Sei Mee, E-mail: sei_mee@naver.com [College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983 (Korea, Republic of); Department of Integrated OMICS for Biomedical Sciences, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-749 (Korea, Republic of); Choi, Eun Ju, E-mail: yureas@naver.com [College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983 (Korea, Republic of); Lee, Jinu, E-mail: jinulee@yonsei.ac.kr [College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983 (Korea, Republic of)

    2016-09-15

    Terbinafine is an antifungal agent that selectively inhibits fungal sterol synthesis by blocking squalene epoxidase. We evaluated the effect of terbinafine on gap junctional intercellular communication (GJIC). Fluorescence recovery after photobleaching (FRAP) and I-YFP GJIC assays revealed that terbinafine inhibits GJIC in a reversible and dose-dependent manner in FRT-Cx43 and LN215 cells. Treatment with terbinafine did not affect Cx43 phosphorylation status or intracellular Ca{sup 2+} concentration, well-known action mechanisms of various GJIC blockers. While a structurally related chemical, naftifine, attenuated GJIC, epigallocatechin gallate, another potent squalene epoxidase inhibitor with a different structure, did not. These results suggest that terbinafine inhibits GJIC with a so far unknown mechanism of action. - Highlights: • In vitro pharmacological studies were performed on FRT-Cx43 and LN215 cells. • Terbinafine inhibits gap junctional intercellular communication in both cell lines. • The inhibitory effect of terbinafine is reversible and dose-dependent. • Treatment of terbinafine does not alter Cx43 phosphorylation or cytosolic Ca{sup 2+} concentration. • Inhibition of squalene epoxidase is not involved in this new effect of terbinafine.

  13. Environmental "Omics" of International Space Station: Insights, Significance, and Consequences

    Science.gov (United States)

    Venkateswaran, Kasthuri

    2016-07-01

    detected. The nine-erythromycin sensitive S. aureus strains exhibited spontaneous mutation when rifampin was tested. Some of the S. aureus strains tolerated gentamycin and tobramycin but cefazolin, cefoxitin, ciprofloxacin and oxacillin inhibited the growth of the S. aureus. Whole genome sequencing (WGS) of 21 ISS strains, exhibiting resistance to various antibiotics, was carried out. The antibiotic resistant genes deduced from the WGS were compared with the resistomes generated directly from the gene pool of the environmental samples. Using a targeted amplification panel consisting of over 500 antimicrobial resistance genes, we were able to confirm the results of the phenotypic assays. Specifically, the presence of multiple β-lactamase genes was observed. The class A β-lactamase genes, tem-1 (ampicillin-resistance) and ctx-M-14 (cefotaxime conferring gene), were found in multiple sites of ISS. In addition, presence of mecA gene (penicillin clusters) was confirmed in several sampling locations from both ISS flights. Finally, the existence of the ermA gene (erythromycin) was established. These results suggest widespread and consistent distribution of multiple antibiotic resistance genes throughout the ISS. The resistome data generated via molecular methods will be extremely important in determining the microbial significance to the crew health and the ISS maintenance. These data sets will be placed in the NASA GeneLab bioinformatics environment - consisting of a database, computational tools, and improved methods - that would subsequently be made open to the scientific research community to encourage innovation.

  14. Dietary change: what are the responses and roles of significant others?

    Science.gov (United States)

    Paisley, Judy; Beanlands, Heather; Goldman, Joanne; Evers, Susan; Chappell, Janet

    2008-01-01

    This study examined the impact of one person's dietary change on the experiences of a significant other with whom they regularly shared meals. Qualitative constant comparison approach using semistructured interviews. Community-based. Forty-two participants were recruited using a stratified purposive sampling strategy. Verbatim transcripts were analyzed using NUD*IST, version 4.0 software (Qualitative Solutions and Research, Melbourne, Australia, 1997) and manual coding. Most dietary changers had modified their diets in response to a disease diagnosis (eg, cardiovascular disease, diabetes, cancer, hypoglycemia, acquired immunodeficiency syndrome (AIDS), ulcer, allergies). Others had changed their diets for personal reasons (eg, weight loss, vegetarian diets). The dietary changes included dietary fat reduction, conversion to vegetarian or vegan diets, restriction of total kilocalorie intake, and elimination or reduction of specific food items. Significant others described a range of emotional responses to the dietary change, including cooperation, encouragement, skepticism, and anger. Significant others' descriptions of the roles that they played in the dietary change were positive (enabling), neutral (neither enabling nor inhibiting), or negative (inhibiting). Most significant others played positive roles; few played neutral or negative roles. Understanding dietary change from the perspective of significant others can enable nutrition professionals to develop strategies to promote dietary modifications as a shared activity.

  15. Anterior cingulate cortex surface area relates to behavioral inhibition in adolescents with and without heavy prenatal alcohol exposure.

    Science.gov (United States)

    Migliorini, Robyn; Moore, Eileen M; Glass, Leila; Infante, M Alejandra; Tapert, Susan F; Jones, Kenneth Lyons; Mattson, Sarah N; Riley, Edward P

    2015-10-01

    Prenatal alcohol exposure is associated with behavioral disinhibition, yet the brain structure correlates of this deficit have not been determined with sufficient detail. We examined the hypothesis that the structure of the anterior cingulate cortex (ACC) relates to inhibition performance in youth with histories of heavy prenatal alcohol exposure (AE, n = 32) and non-exposed controls (CON, n = 21). Adolescents (12-17 years) underwent structural magnetic resonance imaging yielding measures of gray matter volume, surface area, and thickness across four ACC subregions. A subset of subjects were administered the NEPSY-II Inhibition subtest. MANCOVA was utilized to test for group differences in ACC and inhibition performance and multiple linear regression was used to probe ACC-inhibition relationships. ACC surface area was significantly smaller in AE, though this effect was primarily driven by reduced right caudal ACC (rcACC). AE also performed significantly worse on inhibition speed but not on inhibition accuracy. Regression analyses with the rcACC revealed a significant group × ACC interaction. A smaller rcACC surface area was associated with slower inhibition completion time for AE but was not significantly associated with inhibition in CON. After accounting for processing speed, smaller rcACC surface area was associated with worse (i.e., slower) inhibition regardless of group. Examining processing speed independently, a decrease in rcACC surface area was associated with faster processing speed for CON but not significantly associated with processing speed in AE. Results support the theory that caudal ACC may monitor reaction time in addition to inhibition and highlight the possibility of delayed ACC neurodevelopment in prenatal alcohol exposure. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Inhibition of food stimulated acid secretion by misoprostol, an orally active synthetic E1 analogue prostaglandin.

    OpenAIRE

    Ramage, J K; Denton, A; Williams, J G

    1985-01-01

    The effect of 200 micrograms misoprostol (a synthetic prostaglandin E1 analogue) on food stimulated intragastric acidity has been monitored over a 9 h period in 16 normal volunteers. Misoprostol caused a significant inhibition of intragastric acidity for 2 h post-dosing, but no significant effect was seen thereafter on either basal or food stimulated acidity.

  17. Bcl6 promotes osteoblastogenesis through Stat1 inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Fujie, Atsuhiro; Funayama, Atsushi; Miyauchi, Yoshiteru [Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Sato, Yuiko [Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Department of Musculoskeletal Reconstruction and Regeneration Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Kobayashi, Tami [Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Department of Integrated Bone Metabolism and Immunology, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Kanagawa, Hiroya; Katsuyama, Eri; Hao, Wu; Tando, Toshimi; Watanabe, Ryuichi [Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Morita, Mayu [Department of Dentistry and Oral Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Miyamoto, Kana; Kanaji, Arihiko; Morioka, Hideo; Matsumoto, Morio; Toyama, Yoshiaki [Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Miyamoto, Takeshi, E-mail: miyamoto@z5.keio.jp [Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Department of Integrated Bone Metabolism and Immunology, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan)

    2015-02-13

    Bone mass is tightly controlled by a balance between osteoclast and osteoblast activities. Although these cell types mature via different pathways, some factors reportedly regulate differentiation of both. Here, in a search for factors governing osteoblastogenesis but also expressed in osteoclasts to control both cell types by one molecule, we identified B cell lymphoma 6 (Bcl6) as one of those factors and show that it promotes osteoblast differentiation. Bcl6 was previously shown to negatively regulate osteoclastogenesis. We report that lack of Bcl6 results in significant inhibition of osteoblastogensis in vivo and in vitro and in defects in secondary ossification center formation in vivo. Signal transducer and activator of transcription 1 (Stat1) reportedly attenuates osteoblast differentiation by inhibiting nuclear translocation of runt-related transcription factor 2 (Runx2), which is essential for osteoblast differentiation. We found that lack of Bcl6 resulted in significant elevation of Stat1 mRNA and protein expression in osteoblasts and showed that Stat1 is a direct target of Bcl6 using a chromatin immune-precipitation assay. Mice lacking both Bcl6 and Stat1 (DKO) exhibited significant rescue of bone mass and osteoblastic parameters as well as partial rescue of secondary ossification center formation compared with Bcl6-deficient mice in vivo. Altered osteoblastogenesis in Bcl6-deficient cells was also restored in DKO in vitro. Thus, Bcl6 plays crucial roles in regulating both osteoblast activation and osteoclast inhibition. - Highlights: • Bcl6 is required for osteoblast differentiation. • Bcl6{sup −/−} mice exhibited altered osteoblastogenesis and reduced bone mass in vivo and in vitro. • We identified Stat1 as a direct target of Bcl6 in osteoblasts. • Bcl6 and Stat1 doubly deficient mice exhibited rescued bone phenotypes compared with Bcl6{sup −/−} mice.

  18. Inhibition of SIRT1 combined with gemcitabine therapy for pancreatic carcinoma

    Directory of Open Access Journals (Sweden)

    Gong DJ

    2013-07-01

    Full Text Available Dao-Jun Gong,1 Jia-Min Zhang,1 Min Yu,1 Bo Zhuang,1 Qing-Qu Guo21Department of Hepatobiliary-Pancreatic Surgery, Jinhua Hospital of Zhejiang University, Jinhua, People's Republic of China; 2Department of Surgery, Second Affiliated Hospital of Zhejiang University College of Medicine, Hangzhou, People's Republic of ChinaBackground: Pancreatic carcinoma possesses one of the highest lethality rates, highest drug-resistance, and highest incidence rates. The objective of this research was to enhance the efficacy and drug-resistance for pancreatic carcinoma by using inhibition of SIRT1 combined with gemcitabine therapy methods.Methods: Three pancreatic carcinoma cells (PANC-1 cells, BxPC-3 cells, and SW1990 cells received treatment with physiological saline, inhibition of SIRT1, gemcitabine, and combination therapy with inhibition of SIRT1 and gemcitabine in vitro; then BxPC-3 pancreatic cancer xenogeneic mice also received treatment with physiological saline, inhibition of SIRT1, gemcitabine, and combination therapy with inhibition of SIRT1 and gemcitabine in vivo.Results: The cleaved poly ADP ribose polymerase (PARP-1 effect of drug in pancreatic carcinoma cells was significantly different (P < 0.05 and the efficacy in descending order was the combination therapy with inhibition of SIRT1 and gemcitabine, inhibition of SIRT1, and gemcitabine. The BxPC-3 pancreatic cancer xenogeneic mice model received treatment with physiological saline, inhibition of SIRT1, gemcitabine, and combination therapy with inhibition of SIRT1 and gemcitabine in vivo and the results showed that the tumor volumes decreased and the survival rate within 45 days increased according to the order of the given drugs and the difference was significant (P < 0.05.Conclusion: Combination therapy with inhibition of SIRT1 and gemcitabine could improve efficacy and survival time in a BxPC-3 pancreatic cancer xenogeneic mice model, compared with single inhibition of SIRT1, or single

  19. Occult pneumothoraces in Chinese patients with significant blunt chest trauma: radiological classification and proposed clinical significance.

    Science.gov (United States)

    Lee, Ryan K L; Graham, Colin A; Yeung, Janice H H; Ahuja, Anil T; Rainer, Timothy H

    2012-12-01

    An occult pneumothorax (OP) is a pneumothorax not seen on a supine chest X-ray (CXR) but detected on abdominal or thoracic computed tomography (CT) scanning. With the increasing use of CT in the management of significantly injured trauma patients, more OPs are being detected. The aim of this study was to classify OPs diagnosed on thoracic CT (TCT) and correlate them with their clinical significance. Retrospective analysis of prospectively collected trauma registry data. Total 36 (N=36) consecutive significantly injured trauma patients admitted through the emergency department (ED) who sustained blunt chest trauma and underwent TCT between 1 January 2007 and 31 December 2008 were included. OP was defined as the identification (by a consultant radiologist) of a pneumothorax on TCT that had not been detected on supine CXR. OPs were classified by laterality (unilateral/bilateral) and location (apical, basal, non apical/basal). The size of pneumothoraces, severity of injury [including number of associated thoracic injuries and injury severity score (ISS)], length of hospital stay and mortality were compared between groups. The need for tube thoracostomy and clinical outcome were also analysed. Patients with bilateral OPs (N=8) had significantly more associated thoracic injuries (median: 2 vs. 1, p=0.01), higher ISS (median: 35 vs. 23, p=0.02) and longer hospital stay (median: 20 days vs. 11 days, p=0.01) than those with a unilateral OP (N=28). Basal OPs (N=7) were significantly larger than apical (N=10) and non-apical/basal Ops (N=11). Basal OPs were associated with significantly more associated thoracic injuries (median: 2 vs. 1, p=0.01), higher ISS (median: 35 vs. 25, p=0.04) and longer hospital stays (median: 23 days vs. 17 days, p=0.02) than apical Ops, which had higher ISS (median: 35 vs. 25, p=0.04) and longer hospital stays (median: 23 days vs. 15 days, p=0.02) than non-apical/basal OPs. Non-apical/basal OPs were associated with more related injuries (median: 2

  20. Silver-Palladium Surfaces Inhibit Biofilm Formation

    DEFF Research Database (Denmark)

    Chiang, Wen-Chi; Schroll, Casper; Hilbert, Lisbeth Rischel

    2009-01-01

    Undesired biofilm formation is a major concern in many areas. In the present study, we investigated biofilm-inhibiting properties of a silver-palladium surface that kills bacteria by generating microelectric fields and electrochemical redox processes. For evaluation of the biofilm inhibition...... efficacy and study of the biofilm inhibition mechanism, the silver-sensitive Escherichia coli J53 and the silver-resistant E. coli J53[pMG101] strains were used as model organisms, and batch and flow chamber setups were used as model systems. In the case of the silver-sensitive strain, the silver......-palladium surfaces killed the bacteria and prevented biofilm formation under conditions of low or high bacterial load. In the case of the silver-resistant strain, the silver-palladium surfaces killed surface-associated bacteria and prevented biofilm formation under conditions of low bacterial load, whereas under...

  1. Inhibition of melanogenesis by Xanthium strumarium L.

    Science.gov (United States)

    Li, Hailan; Min, Young Sil; Park, Kyoung-Chan; Kim, Dong-Seok

    2012-01-01

    Xanthium strumarium L. (Asteraceae) is traditionally used in Korea to treat skin diseases. In this study, we investigated the effects of a X. strumarium stem extract on melanin synthesis. It inhibited melanin synthesis in a concentration-dependent manner, but it did not directly inhibit tyrosinase, the rate-limiting melanogenic enzyme, and instead downregulated microphthalmia-associated transcription factor (MITF) and tyrosinase expression. MITF, the master regulator of pigmentation, is a target of the Wnt signaling pathway, which includes glycogen synthase kinase 3β (GSK3β) and β-catenin. Hence, the influence of X. strumarium stem extract on GSK3β and β-catenin was further investigated. X. strumarium induced GSK3β phosphorylation (inactivation), but the level of β-catenin did not change. Moreover, a specific GSK3β inhibitor restored X. strumarium-induced melanin reduction. Hence, we suggest that X. strumarium inhibits melanin synthesis through downregulation of tyrosinase via GSK3β phosphorylation.

  2. Mapuche Herbal Medicine Inhibits Blood Platelet Aggregation

    Directory of Open Access Journals (Sweden)

    Susan Skanderup Falkenberg

    2012-01-01

    Full Text Available 12 plant species traditionally used by the Mapuche people in Chile to treat wounds and inflammations have been evaluated for their direct blood platelet inhibition. Seven of the 12 tested plant species showed platelet inhibitory effect in sheep blood, and four of these were also able to inhibit the ADP- (5.0 μM and collagen- (2.0 μg/mL induced aggregations in human blood. These four species in respective extracts (in brackets were Blechnum chilense (MeOH, Luma apiculata (H2O, Amomyrtus luma (DCM : MeOH 1 : 1 and Cestrum parqui (DCM : MeOH 1 : 1. The platelet aggregating inhibitory effects of A. luma (DCM : MeOH 1 : 1, and L. apiculata (H2O were substantial and confirmed by inhibition of platelet surface activation markers.

  3. Distractor inhibition: Evidence from lateralized readiness potentials.

    Science.gov (United States)

    Pramme, Lisa; Dierolf, Angelika M; Naumann, Ewald; Frings, Christian

    2015-08-01

    The present study investigated distractor inhibition on the level of stimulus representation. In a sequential distractor-to-distractor priming task participants had to respond to target letters flanked by distractor digits. Reaction time and stimulus-locked lateralized readiness potentials (S-LRPs) of probe responses were measured. Distractor-target onset asynchrony was varied. For RTs responses to probe targets were faster in the case of prime-distractor repetition compared to distractor changes indicating distractor inhibition. Benefits in RTs and the latency of S-LRP onsets for distractor repetition were also modulated by distractor-target onset asynchrony. For S-LRPs distractor inhibition was only present with a simultaneous onset of distractors and target. The results confirm previous results indicating inhibitory mechanisms of object-based selective attention on the level of distractor representations. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Terbinafine inhibits gap junctional intercellular communication.

    Science.gov (United States)

    Lee, Ju Yeun; Yoon, Sei Mee; Choi, Eun Ju; Lee, Jinu

    2016-09-15

    Terbinafine is an antifungal agent that selectively inhibits fungal sterol synthesis by blocking squalene epoxidase. We evaluated the effect of terbinafine on gap junctional intercellular communication (GJIC). Fluorescence recovery after photobleaching (FRAP) and I-YFP GJIC assays revealed that terbinafine inhibits GJIC in a reversible and dose-dependent manner in FRT-Cx43 and LN215 cells. Treatment with terbinafine did not affect Cx43 phosphorylation status or intracellular Ca(2+) concentration, well-known action mechanisms of various GJIC blockers. While a structurally related chemical, naftifine, attenuated GJIC, epigallocatechin gallate, another potent squalene epoxidase inhibitor with a different structure, did not. These results suggest that terbinafine inhibits GJIC with a so far unknown mechanism of action. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Inhibition of aluminum corrosion using Opuntia extract

    International Nuclear Information System (INIS)

    El-Etre, A.Y.

    2003-01-01

    The inhibitive action of the mucilage extracted from the modified stems of prickly pears, toward acid corrosion of aluminum, is tested using weight loss, thermometry, hydrogen evolution and polarization techniques. It was found that the extract acts as a good corrosion inhibitor for aluminum corrosion in 2.0 M HCl solution. The inhibition action of the extract was discussed in view of Langmuir adsorption isotherm. It was found that the adsorption of the extract on aluminum surface is a spontaneous process. The inhibition efficiency (IE) increases as the extract concentration is increased. The effect of temperature on the IE was studied. It was found that the presence of extract increases the activation energy of the corrosion reaction. Moreover, the thermodynamic parameters of the adsorption process were calculated. It was found also that the Opuntia extract provides a good protection to aluminum against pitting corrosion in chloride ion containing solutions

  6. Mapuche herbal medicine inhibits blood platelet aggregation.

    Science.gov (United States)

    Falkenberg, Susan Skanderup; Tarnow, Inge; Guzman, Alfonso; Mølgaard, Per; Simonsen, Henrik Toft

    2012-01-01

    12 plant species traditionally used by the Mapuche people in Chile to treat wounds and inflammations have been evaluated for their direct blood platelet inhibition. Seven of the 12 tested plant species showed platelet inhibitory effect in sheep blood, and four of these were also able to inhibit the ADP- (5.0 μM) and collagen- (2.0 μg/mL) induced aggregations in human blood. These four species in respective extracts (in brackets) were Blechnum chilense (MeOH), Luma apiculata (H(2)O), Amomyrtus luma (DCM : MeOH 1 : 1) and Cestrum parqui (DCM : MeOH 1 : 1). The platelet aggregating inhibitory effects of A. luma (DCM : MeOH 1 : 1), and L. apiculata (H(2)O) were substantial and confirmed by inhibition of platelet surface activation markers.

  7. Inhibition of eating behavior: negative cognitive effects of dieting.

    Science.gov (United States)

    Hart, K E; Chiovari, P

    1998-06-01

    This study tested the hypothesis that dieters would score higher than nondieters in terms of food rumination. Two hundred and thirty one college undergraduates completed the Eating Obsessive-Compulsiveness Scale (EOCS) and responded to a questionnaire that inquired about dieting status. Subjects also completed measures that tapped neuroticism and social desirability. Results showed that current dieters were significantly more obsessed with thoughts of eating and food than were nondieters. Neither dieting status nor EOCS scale scores were related to neuroticism or social desirability. These results are consistent with previous theory and research suggesting that inhibition of appetitive behaviors can have negative cognitive effects. Moreover, they indicate a potential target for therapeutic intervention.

  8. Progesterone inhibits epithelial-to-mesenchymal transition in endometrial cancer.

    Directory of Open Access Journals (Sweden)

    Paul H van der Horst

    Full Text Available BACKGROUND: Every year approximately 74,000 women die of endometrial cancer, mainly due to recurrent or metastatic disease. The presence of tumor infiltrating lymphocytes (TILs as well as progesterone receptor (PR positivity has been correlated with improved prognosis. This study describes two mechanisms by which progesterone inhibits metastatic spread of endometrial cancer: by stimulating T-cell infiltration and by inhibiting epithelial-to-mesenchymal cell transition (EMT. METHODOLOGY AND PRINCIPAL FINDINGS: Paraffin sections from patients with (n = 9 or without (n = 9 progressive endometrial cancer (recurrent or metastatic disease were assessed for the presence of CD4+ (helper, CD8+ (cytotoxic and Foxp3+ (regulatory T-lymphocytes and PR expression. Progressive disease was observed to be associated with significant loss of TILs and loss of PR expression. Frozen tumor samples, used for genome-wide expression analysis, showed significant regulation of pathways involved in immunesurveillance, EMT and metastasis. For a number of genes, such as CXCL14, DKK1, DKK4, PEG10 and WIF1, quantitive RT-PCR was performed to verify up- or downregulation in progressive disease. To corroborate the role of progesterone in regulating invasion, Ishikawa (IK endometrial cancer cell lines stably transfected with PRA (IKPRA, PRB (IKPRB and PRA+PRB (IKPRAB were cultured in presence/absence of progesterone (MPA and used for genome-wide expression analysis, Boyden- and wound healing migration assays, and IHC for known EMT markers. IKPRB and IKPRAB cell lines showed MPA induced inhibition of migration and loss of the mesenchymal marker vimentin at the invasive front of the wound healing assay. Furthermore, pathway analysis of significantly MPA regulated genes showed significant down regulation of important pathways involved in EMT, immunesuppression and metastasis: such as IL6-, TGF-β and Wnt/β-catenin signaling. CONCLUSION: Intact progesterone signaling in non

  9. Dark chocolate inhibits platelet aggregation in healthy volunteers.

    Science.gov (United States)

    Innes, Andrew J; Kennedy, Gwen; McLaren, Margaret; Bancroft, Anne J; Belch, Jill J F

    2003-08-01

    Cardiovascular disease is a leading cause of death in the UK. The flavonoids found in cocoa may produce a cardio-protective role for chocolate with a high cocoa content. Thirty healthy volunteers were randomised to receive 100 g of white, milk or dark chocolate, and assessments of platelet function were undertaken on venous blood samples before and after chocolate consumption. White and milk chocolate had no significant effect on platelets. However dark chocolate inhibited collagen-induced platelet aggregation in platelet rich plasma. In the future dark chocolate may have a role in prevention of cardiovascular and thromboembolic diseases.

  10. Bisubstrate inhibition: Theory and application to N-acetyltransferases.

    Science.gov (United States)

    Yu, Michael; Magalhães, Maria L B; Cook, Paul F; Blanchard, John S

    2006-12-12

    Bisubstrate inhibitors represent a potentially powerful group of compounds that have found significant therapeutic utility. Although these compounds have been synthesized and tested against a number of enzymes that catalyze sequential bireactant reactions, the detailed theory for predicting the expected patterns of inhibition against the two substrates for various bireactant kinetic mechanisms has, heretofore, not been presented. We have derived the rate equations for all likely sequential bireactant mechanisms and provide two examples in which bisubstrate inhibitors allow the kinetic mechanism to be determined. Bisubstrate inhibitor kinetics is a powerful diagnostic for the determination of kinetic mechanisms.

  11. Increased GABA(A) inhibition of the RVLM after hindlimb unloading in rats

    Science.gov (United States)

    Moffitt, Julia A.; Heesch, Cheryl M.; Hasser, Eileen M.

    2002-01-01

    Attenuated baroreflex-mediated increases in renal sympathetic nerve activity (RSNA) in hindlimb unloaded (HU) rats apparently are due to changes within the central nervous system. We hypothesized that GABA(A) receptor-mediated inhibition of the rostral ventrolateral medulla (RVLM) is increased after hindlimb unloading. Responses to bilateral microinjection of the GABA(A) antagonist (-)-bicuculline methiodide (BIC) into the RVLM were examined before and during caudal ventrolateral medulla (CVLM) inhibition in Inactin-anesthetized control and HU rats. Increases in mean arterial pressure (MAP), heart rate (HR), and RSNA in response to BIC in the RVLM were significantly enhanced in HU rats. Responses to bilateral CVLM blockade were not different. When remaining GABA(A) inhibition in the RVLM was blocked by BIC during CVLM inhibition, the additional increases in MAP and RSNA were significantly greater in HU rats. These data indicate that GABA(A) receptor-mediated inhibition of RVLM neurons is augmented after hindlimb unloading. Effects of input from the CVLM were unaltered. Thus, after cardiovascular deconditioning in rodents, the attenuated increase in sympathetic nerve activity in response to hypotension is associated with greater GABA(A) receptor-mediated inhibition of RVLM neurons originating at least in part from sources other than the CVLM.

  12. Thienoquinolins exert diuresis by strongly inhibiting UT-A urea transporters

    Science.gov (United States)

    Ren, Huiwen; Wang, Yanhua; Xing, Yongning; Ran, Jianhua; Liu, Ming; Lei, Tianluo; Zhou, Hong; Li, Runtao; Sands, Jeff M.

    2014-01-01

    Urea transporters (UT) play an important role in the urine concentration mechanism by mediating intrarenal urea recycling, suggesting that UT inhibitors could have therapeutic use as a novel class of diuretic. Recently, we found a thienoquinolin UT inhibitor, PU-14, that exhibited diuretic activity. The purpose of this study was to identify more potent UT inhibitors that strongly inhibit UT-A isoforms in the inner medullary collecting duct (IMCD). Efficient thienoquinolin UT inhibitors were identified by structure-activity relationship analysis. Urea transport inhibition activity was assayed in perfused rat terminal IMCDs. Diuretic activity of the compound was determined in rats and mice using metabolic cages. The results show that the compound PU-48 exhibited potent UT-A inhibition activity. The inhibition was 69.5% with an IC50 of 0.32 μM. PU-48 significantly inhibited urea transport in perfused rat terminal IMCDs. PU-48 caused significant diuresis in UT-B null mice, which indicates that UT-A is the target of PU-48. The diuresis caused by PU-48 did not change blood Na+, K+, or Cl− levels or nonurea solute excretion in rats and mice. No toxicity was detected in cells or animals treated with PU-48. The results indicate that thienoquinolin UT inhibitors induce a diuresis by inhibiting UT-A in the IMCD. This suggests that they may have the potential to be developed as a novel class of diuretics with fewer side effects than classical diuretics. PMID:25298523

  13. Comparison the Executive Functions of Inhibition and Problem Solving in Adolescents with and Without Substance Abuse

    Directory of Open Access Journals (Sweden)

    Tahereh masoomi mofrad

    2015-03-01

    Full Text Available Executive functions are self-regulated functions and show the ability to inhibition, self-changing, planning, organization, using the working memory, solving problems and targeting for homework and school activities. This study compares the executive functions of inhibition and problem solving in adolescents with and without substance abuse. In this causal-comparative study, 15 adolescents with substance abuse and 15 normal adolescents were selected which matched each other with the same age, sex and education. The research tools were Wisconsin Card, was used for assessing the inhibition executive functions, and Heppner and Petersen Questionnaires for problem solving. The results showed that there were statistically significant differences between groups between average score of inhibition executive functions and solving problem (except trend– avoid component. There were not statistically significant differences in the average score of inhibition executive functions and solving problem according to age, sex and education. It is concluded that the drug addicts are weaker than those without substance abuse based on the inhibition executive function and problem solving. These findings can be used for the prevention program.

  14. Oridonin inhibits breast cancer growth and metastasis through blocking the Notch signaling

    Directory of Open Access Journals (Sweden)

    Shixin Xia

    2017-05-01

    Full Text Available Background: Oridonin is a diterpenoid isolated from Rabdosia rubescens with potent anticancer activity. The aim of our study is to investigate the role of oridonin to inhibit growth and metastasis of human breast cancer cells. Methods: The effect of oridonin on proliferation was evaluated by MTT assay, cell migration and invasion were evaluated by transwell migration and invasion assays in human breast cancer cells. The inhibitive effect of oridonin in vivo was determined by using xenografted nude mice. In addition, the expression of Notch receptors (Notch 1–4 was detected by western blot. Results: Oridonin inhibited human breast cancer cells in vitro and in vivo. In addition, oridonin significantly induced human breast cancer cells apoptosis. Furthermore, the oridonin treatment not only inhibited cancer cell migration and invasion, but more significantly, decreased the expression of Notch 1-4 protein. Conclusion: Our results suggest that the inhibitive effect of oridonin is likely to be driven by the inhibition of Notch signaling pathway and the resulting increased apoptosis.

  15. Luteolin suppresses angiogenesis and vasculogenic mimicry formation through inhibiting Notch1-VEGF signaling in gastric cancer.

    Science.gov (United States)

    Zang, Mingde; Hu, Lei; Zhang, Baogui; Zhu, Zhenglun; Li, Jianfang; Zhu, Zhenggang; Yan, Min; Liu, Bingya

    2017-08-26

    Gastric cancer is a great threat to the health of the people worldwide and lacks effective therapeutic regimens. Luteolin is one of Chinese herbs and presents in many fruits and green plants. In our previous study, we observed that luteolin inhibited cell migration and promoted cell apoptosis in gastric cancer. In the present study, luteolin significantly inhibited tube formation of human umbilical vein endothelial cells (HUVECs) through decreasing cell migration and proliferation of HUVECs in a dose-dependent manner. Vasculogenic mimicry (VM) tubes formed by gastric cancer cells were also inhibited with luteolin treatment. To explore how luteolin inhibited tubes formation, ELISA assay for VEGF was performed. Both of the VEGF secretion from Hs-746T cells and HUVECs were significantly decreased subsequent to luteolin treatment. In addition, cell migration was increased with the interaction between gastric cancer cells and HUVECs in co-culture assays. However, the promoting effects were abolished subsequent to luteolin treatment. Furthermore, luteolin inhibited VEGF secretion through suppressing Notch1 expression in gastric cancer. Overexpression of Notch1 in gastric cancer cells partially rescued the effects on cell migration, proliferation, HUVECs tube formation, and VM formation induced by luteolin treatment. In conclusion, luteolin inhibits angiogenesis and VM formation in gastric cancer through suppressing VEGF secretion dependent on Notch1 expression. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Comparable cortical activation with inferior performance in women during a novel cognitive inhibition task.

    Science.gov (United States)

    Halari, R; Kumari, V

    2005-03-07

    Men are hypothesised to perform better than women at tasks requiring cognitive inhibition. The present study applied whole-brain functional magnetic resonance imaging to investigate the neural correlates of cognitive inhibition using a novel task, requiring detection of numbers decreasing in numerical order, in relation to sex. The study involved 19 young healthy subjects (9 men, 10 women). Behavioural sex differences favouring men were found on the inhibition, but not on the automatization (i.e. detection of numbers increasing in numerical order), condition of the task. Significant areas of activation associated with cognitive inhibition included the right inferior prefrontal and bilateral dorsolateral prefrontal cortices, left inferior and superior parietal lobes, and bilateral temporal regions across men and women. No brain region was significantly differently activated in men and women. Our findings demonstrate that (a) cognitive inhibition is dependent on intact processes within frontal and parietal regions, and (b) women show inferior cognitive inhibition despite of comparable activation to men in relevant regions. Equated behavioural performance may elicit sex differences in brain activation.

  17. Product inhibition of enzymatic hydrolysis of cellulose: are we running the reactions all wrong?

    DEFF Research Database (Denmark)

    Meyer, Anne S.

    2012-01-01

    cellobiose and glucose. The reported KI for glucose on the T. reesei cellulases and -glucosidase varies from 0.04 to 5 g/L. The type of inhibition is debated, and probably varies for different -glucosidases, but with a required goal of sufficient glucose concentration to support ethanol concentrations....... This is because the currently used Trichoderma reesei derived cellulases, i.e. exoglucanases (mainly the cellobiohydrolases Cel7A and Cel6A), endo-1,4--glucanases, and now boosted with -glucosidase and other enzymes, now considered the “industry standard” enzymes, are significantly inhibited by the products...... of minimum ∼5–6% v/v, the glucose product concentrations exceed the critical limit for product inhibition. Hence, regardless of the recent progress in enzyme development for cellulose hydrolysis, the glucose product inhibition remains an issue, which is exacerbated as the reaction progresses, especially...

  18. Inhibition of alloxan diabetes by low dose {gamma}-irradiation before alloxan administration

    Energy Technology Data Exchange (ETDEWEB)

    Yamaoka, Kiyonori [Central Research Inst. of Electric Power Industry, Komae, Tokyo (Japan). Komae Research Lab.; Takehara, Yoshiki; Yoshioka, Tamotsu; Utsumi, Kozo

    1994-10-01

    We evaluated the inhibitory effects of whole body {sup 60}Co-{gamma} irradiation at a single low dose on alloxan-induced hyperglycemia in rats. (1) In rats that received alloxan, SOD activity in pancreas significantly decreased, but the decrease was inhibited by irradiation at a dose of 0.5 Gy. (2) Similarly, plasma peroxide, pancreatic peroxide, and blood glucose increased. However, the increase in pancreatic peroxide was inhibited by irradiation at a dose of 0.5 or 1.0 Gy and the increase in blood glucose by irradiation at 0.5 Gy. (3) After alloxan administration, degranulation was observed in cells, but this was inhibited by irradiation at 0.5 Gy. These results suggest that alloxan diabetes was inhibited by the increase of SOD activity in pancreas after low dose irradiation at 0.5 Gy. (author).

  19. Inhibition of Orobanche crenata seed germination and radicle growth by allelochemicals identified in cereals.

    Science.gov (United States)

    Fernández-Aparicio, Mónica; Cimmino, Alessio; Evidente, Antonio; Rubiales, Diego

    2013-10-16

    Orobanche crenata is a parasitic weed that causes severe yield losses in important grain and forage legume crops. Cereals have been reported to inhibit O. crenata parasitism when grown intercropped with susceptible legumes, but the responsible metabolites have not been identified. A number of metabolites have been reported in cereals that have allelopathic properties against weeds, pests, and pathogens. We tested the effect of several allelochemicals identified in cereals on O. crenata seed germination and radicle development. We found that 2-benzoxazolinone, its derivative 6-chloroacetyl-2-benzoxazolinone, and scopoletin significantly inhibited O. crenata seed germination. Benzoxazolinones, l-tryptophan, and coumalic acid caused the stronger inhibition of radicle growth. Also, other metabolites reduced radicle length, this inhibition being dose-dependent. Only scopoletin caused cell necrotic-like darkening in the young radicles. Prospects for their application to parasitic weed management are discussed.

  20. Formation and Inhibition of Nε-(Carboxymethyllysine in Saccharide-Lysine Model Systems during Microwave Heating

    Directory of Open Access Journals (Sweden)

    Bing Li

    2012-10-01

    Full Text Available  Nε-(carboxymethyl lysine (CML is the most abundant advanced glycation end product (AGE, and frequently selected as an AGEs marker in laboratory studies. In this paper, the formation and inhibition of Nε-(carboxymethyllysine in saccharide-lysine model systems during microwave heating have been studied. The microwave heating treatment significantly promoted the formation of CML during Maillard reactions, which was related to the reaction temperature, time and type of saccharide. The order of CML formation for different saccharides was lactose > glucose > sucrose. Then, the inhibition ef