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Sample records for il-18 enhances thrombospondin-1

  1. IL-18 enhances thrombospondin-1 production in human gastric cancer via JNK pathway

    SciTech Connect

    Kim, Jihye; Kim, Cherlhyun; Kim, Tae Sung; Bang, Sa Ik; Yang, Young; Park, Hyunjeong; Cho, Daeho . E-mail: cdhkor@sookmyung.ac.kr

    2006-06-16

    IL-18 is a pleiotropic cytokine that is produced by many cancer cells. A recent report suggested that IL-18 plays a key role in regulating the immune escape of melanoma and gastric cancer cells. Thrombospondin (TSP-1) is known to inhibit angiogenesis in several cancers but some studies have reported that it stimulates angiogenesis in some cancers such as gastric cancer. IL-18 and TSP-1 are related to tumor proliferation and metastasis. This study investigated the relationship between IL-18 and TSP-1 in gastric cancer. RT-PCR and ELISA showed that after the cells had been treated with IL-18, the level of TSP-1 mRNA expression and TSP-1 protein production by IL-18 increased in both a dose- and time-dependent manner. The cells were next treated with specific inhibitors in order to determine the signal pathway involved in IL-18-enhanced TSP-1 production. IL-18-enhanced TSP-1 expression was blocked by SP600125, a c-Jun N-terminal kinase (JNK) specific inhibitor. In addition, Western blot showed that IL-18 enhanced the expression of phosphorylated JNK. Overall, these results suggest that IL-18 plays a key role in TSP-1 expression involving JNK.

  2. Blockade of IL-18 signaling diminished neuropathic pain and enhanced the efficacy of morphine and buprenorphine.

    PubMed

    Pilat, Dominika; Piotrowska, Anna; Rojewska, Ewelina; Jurga, Agnieszka; Ślusarczyk, Joanna; Makuch, Wioletta; Basta-Kaim, Agnieszka; Przewlocka, Barbara; Mika, Joanna

    2016-03-01

    Currently, the low efficacy of antinociceptive drugs for the treatment of neuropathic pain is a major therapeutic problem. Here, we show the potential role of interleukin (IL)-18 signaling in this phenomenon. IL-18 is an important molecule that performs various crucial functions, including the alteration of nociceptive transmission in response to neuropathic pain. We have studied the changes in the mRNA and protein levels (qRT-PCR and Western blot analysis, respectively) of IL-18, IL-18-binding protein (IL-18BP) and the IL-18 receptor (IL-18R) over time in rats following chronic constriction injury (CCI) of the sciatic nerve. Our study demonstrated that the spinal levels of IL-18BP were slightly downregulated at days 7 and 14 in the rats subjected to CCI. In contrast, the IL-18 and IL-18R mRNA expression and protein levels were elevated in the ipsilateral spinal cord on days 2, 7 and 14. Moreover, in rats exposed to a single intrathecal administration of IL-18BP (50 and 100 ng) 7 or 14 days following CCI, symptoms of neuropathic pain were attenuated, and the analgesia pursuant to morphine and buprenorphine (0.5 and 2.5 μg) was enhanced. In summary, the restoration of the analgesic activity of morphine and buprenorphine via the blockade of IL-18 signaling suggests that increased IL-18 pathway may account for the decreased analgesic efficacy of opioids for neuropathic pain.

  3. Thrombospondin-1 Interacts with Trypanosoma cruzi Surface Calreticulin to Enhance Cellular Infection

    PubMed Central

    Johnson, Candice A.; Kleshchenko, Yulia Y.; Ikejiani, Adaeze O.; Udoko, Aniekanabasi N.; Cardenas, Tatiana C.; Pratap, Siddharth; Duquette, Mark A.; Lima, Maria F.; Lawler, Jack; Villalta, Fernando; Nde, Pius N.

    2012-01-01

    Trypanosoma cruzi causes Chagas disease, which is a neglected tropical disease that produces severe pathology and mortality. The mechanisms by which the parasite invades cells are not well elucidated. We recently reported that T. cruzi up-regulates the expression of thrombospondin-1 (TSP-1) to enhance the process of cellular invasion. Here we characterize a novel TSP-1 interaction with T. cruzi that enhances cellular infection. We show that labeled TSP-1 interacts specifically with the surface of T. cruzi trypomastigotes. We used TSP-1 to pull down interacting parasite surface proteins that were identified by mass spectrometry. We also show that full length TSP-1 and the N-terminal domain of TSP-1 (NTSP) interact with T. cruzi surface calreticulin (TcCRT) and other surface proteins. Pre-exposure of recombinant NTSP or TSP-1 to T. cruzi significantly enhances cellular infection of wild type mouse embryo fibroblasts (MEF) compared to the C-terminal domain of TSP-1, E3T3C1. In addition, blocking TcCRT with antibodies significantly inhibits the enhancement of cellular infection mediated by the TcCRT-TSP-1 interaction. Taken together, our findings indicate that TSP-1 interacts with TcCRT on the surface of T. cruzi through the NTSP domain and that this interaction enhances cellular infection. Thus surface TcCRT is a virulent factor that enhances the pathogenesis of T. cruzi infection through TSP-1, which is up-regulated by the parasite. PMID:22808206

  4. Thrombospondin-1 interacts with Trypanosoma cruzi surface calreticulin to enhance cellular infection.

    PubMed

    Johnson, Candice A; Kleshchenko, Yulia Y; Ikejiani, Adaeze O; Udoko, Aniekanabasi N; Cardenas, Tatiana C; Pratap, Siddharth; Duquette, Mark A; Lima, Maria F; Lawler, Jack; Villalta, Fernando; Nde, Pius N

    2012-01-01

    Trypanosoma cruzi causes Chagas disease, which is a neglected tropical disease that produces severe pathology and mortality. The mechanisms by which the parasite invades cells are not well elucidated. We recently reported that T. cruzi up-regulates the expression of thrombospondin-1 (TSP-1) to enhance the process of cellular invasion. Here we characterize a novel TSP-1 interaction with T. cruzi that enhances cellular infection. We show that labeled TSP-1 interacts specifically with the surface of T. cruzi trypomastigotes. We used TSP-1 to pull down interacting parasite surface proteins that were identified by mass spectrometry. We also show that full length TSP-1 and the N-terminal domain of TSP-1 (NTSP) interact with T. cruzi surface calreticulin (TcCRT) and other surface proteins. Pre-exposure of recombinant NTSP or TSP-1 to T. cruzi significantly enhances cellular infection of wild type mouse embryo fibroblasts (MEF) compared to the C-terminal domain of TSP-1, E3T3C1. In addition, blocking TcCRT with antibodies significantly inhibits the enhancement of cellular infection mediated by the TcCRT-TSP-1 interaction. Taken together, our findings indicate that TSP-1 interacts with TcCRT on the surface of T. cruzi through the NTSP domain and that this interaction enhances cellular infection. Thus surface TcCRT is a virulent factor that enhances the pathogenesis of T. cruzi infection through TSP-1, which is up-regulated by the parasite. PMID:22808206

  5. Immune enhancing effects of recombinant bovine IL-18 on foot-and-mouth disease vaccination in mice model.

    PubMed

    Shi, Xi-Ju; Wang, Bin; Wang, Ming

    2007-01-26

    Foot-and-mouth disease (FMD) is a highly contagious disease in cloven-hoofed animals and can cause a considerable socio-economic loss for affected countries. Interleukin-18 (IL-18) is a pleiotropic cytokine and plays important role in both the development of a functional immune system as well as the response of the organism to infection. In the present study, bovine IL-18 (BoIL-18), Foot-and-mouth disease virus VP1 and VP1/BoIL-18 fusion genes were cloned and expressed in pichia pastoris (P. pastoris) and subsequently immune effects were evaluated to study the immune enhancing effects of recombinant BoIL-18 (rBoIL-18) on FMD vaccination. The results showed that the genes encoding for BoIL-18, VP1 and VP1/BoIL-18 are successfully expressed in P. pastoris and the expressed recombinant VP1 (rVP1) proteins could induce both humoral and marginal cell-mediated immune responses in mice, while the co-inoculation with rBoIL-18 could markedly enhance both of immune responses, and the inoculation of the fusion product rVP1/BoIL-18 showed even more dramatic immune responses, suggesting rBoIL-18 has a potential to enhance the efficacy of vaccination against FMDV infection.

  6. Production of functional IL-18 by different subtypes of murine and human dendritic cells (DC): DC-derived IL-18 enhances IL-12-dependent Th1 development.

    PubMed

    Stoll, S; Jonuleit, H; Schmitt, E; Müller, G; Yamauchi, H; Kurimoto, M; Knop, J; Enk, A H

    1998-10-01

    IL-18 is a recently described cytokine that shares biological activities with IL-12 in driving the development of Th1-type T cells. As dendritic cells (DC) are very potent inducers of T cell proliferation and differentiation we wondered whether they utilize IL-18 as a factor driving Th1 development. We demonstrate by Northern blot and reverse transcription-PCR that various subtypes of human and murine DC as well as the DC-line XS contain IL-18 mRNA. When supernatants of either enriched Langerhans cells (LC) or bone marrow-derived DC were analyzed for production of IL-18 protein, IL-18 production was detected in an IL-18-specific ELISA. To assess whether the IL-18 protein released by DC is functional, we performed a sensitive bioassay using the IL-18-dependent stimulation of concanavalin A-stimulated T cells. Both, supernatants from bone marrow-derived DC and enriched LC induced IFN-gamma production in the T cells. This production was partially inhibitable by addition of anti-IL-18 antiserum. In a TCR-transgenic mouse system we further demonstrate that DC-derived IL-18 potentiates IL-12-dependent Th1 development. Using DC derived from IL-12 knockout animals, we show that DC-derived IL-18 by itself is not capable of inducing Th1 cell differentiation. Together the data demonstrate that subtypes of DC are able to release functional IL-18 that is able to induce IFN-gamma production and Th1 differentiation in primed T cells.

  7. Secreted Thrombospondin-1 Regulates Macrophage Interleukin-1β Production and Activation through CD47

    PubMed Central

    Stein, Erica V.; Miller, Thomas W.; Ivins-O’Keefe, Kelly; Kaur, Sukhbir; Roberts, David D.

    2016-01-01

    Thrombospondin-1 regulates inflammation by engaging several cell surface receptors and by modulating activities of other secreted factors. We have uncovered a novel role of thrombospondin-1 in modulating production and activation of the proinflammatory cytokine IL-1β by human and murine macrophages. Physiological concentrations of thrombospondin-1 limit the induction by lipopolysaccharide of IL-1β mRNA and total protein production by human macrophages. This inhibition can be explained by the ability of thrombospondin-1 to disrupt the interaction between CD47 and CD14, thereby limiting activation of NFκB/AP-1 by lipopolysaccharide. Only the CD47-binding domain of thrombospondin-1 exhibits this activity. In contrast, CD47, CD36, and integrin-binding domains of thrombospondin-1 independently enhance the inflammasome-dependent maturation of IL-1β in human THP-1 monocyte-derived macrophages. Correspondingly, mouse bone marrow-derived macrophages that lack either thrombospondin-1 or CD47 exhibit diminished induction of mature IL-1β in response to lipopolysaccharide. Lack of CD47 also limits lipopolysaccharide induction of IL-1β, NLRP3, and caspase-1 mRNAs. These data demonstrate that thrombospondin-1 exerts CD47-dependent and -independent pro-and anti-inflammatory effects on the IL-1β pathway. Therefore, thrombospondin-1 and its receptor CD47 may be useful targets for limiting the pro-inflammatory effects of lipopolysaccharide and for treating endotoxemia. PMID:26813769

  8. IL-18BP is decreased in osteoporotic women: Prevents Inflammasome mediated IL-18 activation and reduces Th17 differentiation

    PubMed Central

    Mansoori, Mohd Nizam; Shukla, Priyanka; Kakaji, Manisha; Tyagi, Abdul M; Srivastava, Kamini; Shukla, Manoj; Dixit, Manisha; Kureel, Jyoti; Gupta, Sushil; Singh, Divya

    2016-01-01

    IL-18BP is a natural antagonist of pro-inflammatory IL-18 cytokine linked to autoimmune disorders like rheumatoid arthritis. However, its role in post menopausal osteoporosis is still unknown. In this study, we investigated the role of IL-18BP on murine osteoblasts, its effect on osteoblasts-CD4+ T cells and osteoblasts-CD11b+ macrophage co-culture. mIL-18BPd enhances osteoblast differentiation and inhibits the activation of NLRP3 inflammasome and caspase-1 which process IL-18 to its active form. Using estrogen deficient mice, we also determined the effect of mIL-18BP on various immune and skeletal parameters. Ovariectomized mice treated with mIL-18BPd exhibited decrease in Th17/Treg ratio and pro-inflammatory cytokines. mIL-18BPd treatment restored trabecular microarchitecture, preserved cortical bone parameters likely attributed to an increased number of bone lining cells and reduced osteoclastogenesis. Importantly, these results were corroborated in female osteoporotic subjects where decreased serum IL-18BP levels and enhanced serum IL-18 levels were observed. Our study forms a strong basis for using humanized IL-18BP towards the treatment of postmenopausal osteoporosis. PMID:27649785

  9. IL-18BP is decreased in osteoporotic women: Prevents Inflammasome mediated IL-18 activation and reduces Th17 differentiation.

    PubMed

    Mansoori, Mohd Nizam; Shukla, Priyanka; Kakaji, Manisha; Tyagi, Abdul M; Srivastava, Kamini; Shukla, Manoj; Dixit, Manisha; Kureel, Jyoti; Gupta, Sushil; Singh, Divya

    2016-01-01

    IL-18BP is a natural antagonist of pro-inflammatory IL-18 cytokine linked to autoimmune disorders like rheumatoid arthritis. However, its role in post menopausal osteoporosis is still unknown. In this study, we investigated the role of IL-18BP on murine osteoblasts, its effect on osteoblasts-CD4+ T cells and osteoblasts-CD11b+ macrophage co-culture. mIL-18BPd enhances osteoblast differentiation and inhibits the activation of NLRP3 inflammasome and caspase-1 which process IL-18 to its active form. Using estrogen deficient mice, we also determined the effect of mIL-18BP on various immune and skeletal parameters. Ovariectomized mice treated with mIL-18BPd exhibited decrease in Th17/Treg ratio and pro-inflammatory cytokines. mIL-18BPd treatment restored trabecular microarchitecture, preserved cortical bone parameters likely attributed to an increased number of bone lining cells and reduced osteoclastogenesis. Importantly, these results were corroborated in female osteoporotic subjects where decreased serum IL-18BP levels and enhanced serum IL-18 levels were observed. Our study forms a strong basis for using humanized IL-18BP towards the treatment of postmenopausal osteoporosis. PMID:27649785

  10. Regulation of IL-18 in Helicobacter pylori Infection1

    PubMed Central

    Yamauchi, Kazuyoshi; Choi, Il-Ju; Lu, Hong; Ogiwara, Hiroaki; Graham, David Y.; Yamaoka, Yoshio

    2010-01-01

    The gastric mucosal immune response is thought to be comprised predominantly of the Th1 type; however, there are limited data regarding the role of IL-18 in Helicobacter pylori-induced inflammation. We investigated IL-18 levels in gastric mucosal biopsy specimens as well as in isolated gastric epithelial cells and lamina propria mononuclear cells. We also investigated IL-18 levels in gastric epithelial cells and the monocyte cell line THP-1 cocultured with H. pylori. In both systems, IL-18 levels were markedly enhanced in H. pylori-infected epithelial cells and monocytes. IL-18 levels in H. pylori-infected gastric mucosa were well correlated with the severity of gastric inflammation, confirming that H. pylori-induced IL-18 plays an important role in gastric injury. Virulence factors of H. pylori; the cag pathogenicity island and OipA affected IL-18 induction in different manners. Up-regulation of IL-18 mRNA/protein in epithelial cells was dependent on both virulence factors. Interestingly, up-regulation of IL-18 mRNA in monocytes was independent of both factors, whereas IL-18 protein was OipA dependent – cag pathogenicity island independent, indicating that OipA regulates IL-18 induction in monocytes at the posttranscriptional level. IL-18 levels in the gastric biopsy specimens showed similar patterns to those in lamina propria mononuclear cells with respect to virulence factors, suggesting that submucosal monocytes/macrophages are the main source of IL-18 induced by H. pylori infection. H. pylori appeared to regulate the ERK/JNK→AP-1 pathway in both cell types. In addition, OipA and its related p38 pathway may be closely involved in IL-18 induction in H. pylori-infected gastric mucosa and may contribute to gastric injury. PMID:18178861

  11. Endogenous thrombospondin-1 regulates leukocyte recruitment and activation and accelerates death from systemic candidiasis.

    PubMed

    Martin-Manso, Gema; Navarathna, Dhammika H M L P; Galli, Susana; Soto-Pantoja, David R; Kuznetsova, Svetlana A; Tsokos, Maria; Roberts, David D

    2012-01-01

    Disseminated Candida albicans infection results in high morbidity and mortality despite treatment with existing antifungal drugs. Recent studies suggest that modulating the host immune response can improve survival, but specific host targets for accomplishing this goal remain to be identified. The extracellular matrix protein thrombospondin-1 is released at sites of tissue injury and modulates several immune functions, but its role in C. albicans pathogenesis has not been investigated. Here, we show that mice lacking thrombospondin-1 have an advantage in surviving disseminated candidiasis and more efficiently clear the initial colonization from kidneys despite exhibiting fewer infiltrating leukocytes. By examining local and systemic cytokine responses to C. albicans and other standard inflammatory stimuli, we identify a crucial function of phagocytes in this enhanced resistance. Subcutaneous air pouch and systemic candidiasis models demonstrated that endogenous thrombospondin-1 enhances the early innate immune response against C. albicans and promotes activation of inflammatory macrophages (inducible nitric oxide synthase⁺, IL-6(high), TNF-α(high), IL-10(low)), release of the chemokines MIP-2, JE, MIP-1α, and RANTES, and CXCR2-driven polymorphonuclear leukocytes recruitment. However, thrombospondin-1 inhibited the phagocytic capacity of inflammatory leukocytes in vivo and in vitro, resulting in increased fungal burden in the kidney and increased mortality in wild type mice. Thus, thrombospondin-1 enhances the pathogenesis of disseminated candidiasis by creating an imbalance in the host immune response that ultimately leads to reduced phagocytic function, impaired fungal clearance, and increased mortality. Conversely, inhibitors of thrombospondin-1 may be useful drugs to improve patient recovery from disseminated candidiasis.

  12. IL-1β and IL-18 inhibition of HIV-1 replication in Jurkat cells and PBMCs.

    PubMed

    Wang, Xue; Mbondji-Wonje, Christelle; Zhao, Jiangqin; Hewlett, Indira

    2016-05-13

    HIV-1 infection-induced apoptosis is able to ensure viral replication. The death of some CD4+ T cells residing in lymphoid tissues can be induced by HIV-1 infection through caspase-1 driven pyroptosis with release of cytokine of IL-1β and IL-18. It is not well known whether IL-1β and IL-18 affect HIV-1 replication in lymphocytic cells. Using susceptible lymphocytic cell line, Jurkat cells, and primary peripheral blood mononuclear cells (PBMCs), we studied the effects of IL-1β and IL-18 on HIV-1 replication. We found that treatment with exogenous IL-1β protein (rIL-1β) and IL-18 protein (rIL-18), or expression of IL-1β and IL-18 significantly reduced HIV-1 replication. HIV-1 infection enhanced caspase-3 expression and its activation, and had no effects on caspase-1 activity. Treatment with rIL-1β and rIL-18 dramatically lowered caspase-3 activity. IL-1β and IL-18 also played roles in diminishing reactivation of viral replication from latency in J1.1 cells. These results indicate that IL-1β and IL-18 are able to inhibit HIV-1 replication, and their effects may be due to signaling through apoptosis involved in inactivation of caspase-3 activity.

  13. Epithelial-derived IL-18 regulates Th17 cell differentiation and Foxp3+ Treg cell function in the intestine

    PubMed Central

    Harrison, OJ; Srinivasan, N; Pott, J; Schiering, C; Krausgruber, T; Ilott, NE; Maloy, KJ

    2015-01-01

    Elevated levels of interleukin-18 (IL-18) are found in many chronic inflammatory disorders, including inflammatory bowel disease (IBD), and polymorphisms in the IL18R1-IL18RAP locus are associated with IBD susceptibility. IL-18 is an IL-1 family cytokine that has been proposed to promote barrier function in the intestine, but the effects of IL-18 on intestinal CD4+ T cells are poorly understood. Here, we demonstrate that IL-18R1 expression is enhanced on both effector and regulatory CD4+ T cells in the intestinal lamina propria, with Th17 cells exhibiting particularly high levels. We further show that, during steady state, intestinal epithelial cells (IEC) constitutively secrete IL-18 that acts directly on IL-18R1-expressing CD4+ T cells to limit colonic Th17 cell differentiation, in part by antagonizing IL-1R1-signalling. In addition, although IL-18R1 is not required for colonic Foxp3+ Treg cell differentiation, we found that IL-18R1 signaling was critical for Foxp3+ Treg cell mediated control of intestinal inflammation, where it promoted expression of key Treg effector molecules. Thus, IL-18 is a key epithelial-derived cytokine that differentially regulates distinct subsets of intestinal CD4+ T cells during both homeostatic and inflammatory conditions, a finding with potential implications for treatment of chronic inflammatory disorders. PMID:25736457

  14. Original insights on thrombospondin-1-related antireceptor strategies in cancer.

    PubMed

    Jeanne, Albin; Schneider, Christophe; Martiny, Laurent; Dedieu, Stéphane

    2015-01-01

    Thrombospondin-1 (TSP-1) is a large matricellular glycoprotein known to be overexpressed within tumor stroma in several cancer types. While mainly considered as an endogenous angiogenesis inhibitor, TSP-1 exhibits multifaceted functionalities in a tumor context depending both on TSP-1 concentration as well as differential receptor expression by cancer cells and on tumor-associated stromal cells. Besides, the complex modular structure of TSP-1 along with the wide variety of its soluble ligands and membrane receptors considerably increases the complexity of therapeutically targeting interactions involving TSP-1 ligation of cell-surface receptors. Despite the pleiotropic nature of TSP-1, many different antireceptor strategies have been developed giving promising results in preclinical models. However, transition to clinical trials often led to nuanced outcomes mainly due to frequent severe adverse effects. In this review, we will first expose the intricate and even sometimes opposite effects of TSP-1-related signaling on tumor progression by paying particular attention to modulation of angiogenesis and tumor immunity. Then, we will provide an overview of current developments and prospects by focusing particularly on the cell-surface molecules CD47 and CD36 that function as TSP-1 receptors; including antibody-based approaches, therapeutic gene modulation and the use of peptidomimetics. Finally, we will discuss original approaches specifically targeting TSP-1 domains, as well as innovative combination strategies with a view to producing an overall anticancer response. PMID:26578962

  15. Original insights on thrombospondin-1-related antireceptor strategies in cancer

    PubMed Central

    Jeanne, Albin; Schneider, Christophe; Martiny, Laurent; Dedieu, Stéphane

    2015-01-01

    Thrombospondin-1 (TSP-1) is a large matricellular glycoprotein known to be overexpressed within tumor stroma in several cancer types. While mainly considered as an endogenous angiogenesis inhibitor, TSP-1 exhibits multifaceted functionalities in a tumor context depending both on TSP-1 concentration as well as differential receptor expression by cancer cells and on tumor-associated stromal cells. Besides, the complex modular structure of TSP-1 along with the wide variety of its soluble ligands and membrane receptors considerably increases the complexity of therapeutically targeting interactions involving TSP-1 ligation of cell-surface receptors. Despite the pleiotropic nature of TSP-1, many different antireceptor strategies have been developed giving promising results in preclinical models. However, transition to clinical trials often led to nuanced outcomes mainly due to frequent severe adverse effects. In this review, we will first expose the intricate and even sometimes opposite effects of TSP-1-related signaling on tumor progression by paying particular attention to modulation of angiogenesis and tumor immunity. Then, we will provide an overview of current developments and prospects by focusing particularly on the cell-surface molecules CD47 and CD36 that function as TSP-1 receptors; including antibody-based approaches, therapeutic gene modulation and the use of peptidomimetics. Finally, we will discuss original approaches specifically targeting TSP-1 domains, as well as innovative combination strategies with a view to producing an overall anticancer response. PMID:26578962

  16. Original insights on thrombospondin-1-related antireceptor strategies in cancer.

    PubMed

    Jeanne, Albin; Schneider, Christophe; Martiny, Laurent; Dedieu, Stéphane

    2015-01-01

    Thrombospondin-1 (TSP-1) is a large matricellular glycoprotein known to be overexpressed within tumor stroma in several cancer types. While mainly considered as an endogenous angiogenesis inhibitor, TSP-1 exhibits multifaceted functionalities in a tumor context depending both on TSP-1 concentration as well as differential receptor expression by cancer cells and on tumor-associated stromal cells. Besides, the complex modular structure of TSP-1 along with the wide variety of its soluble ligands and membrane receptors considerably increases the complexity of therapeutically targeting interactions involving TSP-1 ligation of cell-surface receptors. Despite the pleiotropic nature of TSP-1, many different antireceptor strategies have been developed giving promising results in preclinical models. However, transition to clinical trials often led to nuanced outcomes mainly due to frequent severe adverse effects. In this review, we will first expose the intricate and even sometimes opposite effects of TSP-1-related signaling on tumor progression by paying particular attention to modulation of angiogenesis and tumor immunity. Then, we will provide an overview of current developments and prospects by focusing particularly on the cell-surface molecules CD47 and CD36 that function as TSP-1 receptors; including antibody-based approaches, therapeutic gene modulation and the use of peptidomimetics. Finally, we will discuss original approaches specifically targeting TSP-1 domains, as well as innovative combination strategies with a view to producing an overall anticancer response.

  17. Construction of an Expression System for Bioactive IL-18 and Generation of Recombinant Canine Distemper Virus Expressing IL-18

    PubMed Central

    LIU, Yuxiu; SATO, Hiroki; HAMANA, Masahiro; MOONAN, Navita Anisia; YONEDA, Misako; XIA, Xianzhu; KAI, Chieko

    2014-01-01

    ABSTRACT Interleukin 18 (IL-18) plays an important role in the T-helper-cell type 1 immune response against intracellular parasites, bacteria and viral infections. It has been widely used as an adjuvant for vaccines and as an anticancer agent. However, IL-18 protein lacks a typical signal sequence and requires cleavage into its mature active form by caspase 1. In this study, we constructed mammalian expression vectors carrying cDNA encoding mature canine IL-18 (cIL-18) or mouse IL-18 (mIL-18) fused to the human IL-2 (hIL-2) signal sequence. The expressed proIL-18 proteins were processed to their mature forms in the cells. The supernatants of cells transfected with these plasmids induced high interferon-γ production in canine peripheral blood mononuclear cells or mouse splenocytes, respectively, indicating the secretion of bioactive IL-18. Using reverse genetics, we also generated a recombinant canine distemper virus that expresses cIL-18 or mIL-18 fused to the hIL-2 signal sequence. As expected, both recombinant viruses produced mature IL-18 in the infected cells, which secreted bioactive IL-18. These results indicate that the signal sequence from hIL-2 is suitable for the secretion of mature IL-18. These recombinant viruses can also potentially be used as immunoadjuvants and agents for anticancer therapies in vivo. PMID:24898077

  18. Construction of an expression system for bioactive IL-18 and generation of recombinant canine distemper virus expressing IL-18.

    PubMed

    Liu, Yuxiu; Sato, Hiroki; Hamana, Masahiro; Moonan, Navita Anisia; Yoneda, Misako; Xia, Xianzhu; Kai, Chieko

    2014-09-01

    Interleukin 18 (IL-18) plays an important role in the T-helper-cell type 1 immune response against intracellular parasites, bacteria and viral infections. It has been widely used as an adjuvant for vaccines and as an anticancer agent. However, IL-18 protein lacks a typical signal sequence and requires cleavage into its mature active form by caspase 1. In this study, we constructed mammalian expression vectors carrying cDNA encoding mature canine IL-18 (cIL-18) or mouse IL-18 (mIL-18) fused to the human IL-2 (hIL-2) signal sequence. The expressed proIL-18 proteins were processed to their mature forms in the cells. The supernatants of cells transfected with these plasmids induced high interferon-γ production in canine peripheral blood mononuclear cells or mouse splenocytes, respectively, indicating the secretion of bioactive IL-18. Using reverse genetics, we also generated a recombinant canine distemper virus that expresses cIL-18 or mIL-18 fused to the hIL-2 signal sequence. As expected, both recombinant viruses produced mature IL-18 in the infected cells, which secreted bioactive IL-18. These results indicate that the signal sequence from hIL-2 is suitable for the secretion of mature IL-18. These recombinant viruses can also potentially be used as immunoadjuvants and agents for anticancer therapies in vivo. PMID:24898077

  19. Development of Membrane-Bound GM-CSF and IL-18 as an Effective Tumor Vaccine

    PubMed Central

    Cheng, Ta-Chun; Chuang, Chih-Hung; Kao, Chien-Han; Hsieh, Yuan-Chin; Cheng, Kuang-Hung; Wang, Jaw-Yuan; Cheng, Chiu-Min; Chen, Chien-Shu; Cheng, Tian-Lu

    2015-01-01

    The development of effective adjuvant is the key factor to boost the immunogenicity of tumor cells as a tumor vaccine. In this study, we expressed membrane-bound granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-18 (IL-18) as adjuvants in tumor cells to stimulate immune response. B7 transmembrane domain fused GM-CSF and IL-18 was successfully expressed in the cell membrane and stimulated mouse splenocyte proliferation. Co-expression of GM-CSF and IL-18 reduced tumorigenesis (P<0.05) and enhanced tumor protective efficacy (P<0.05) significantly in comparison with GM-CSF alone. These results indicated that the combination of GM-CSF andIL-18 will enhance the immunogenicity of a cell-based anti-tumor vaccine. This membrane-bound approach can be applied to other cytokines for the development of novel vaccine strategies. PMID:26186692

  20. Chlamydia trachomatis mouse pneumonitis lung infection in IL-18 and IL-12 knockout mice: IL-12 is dominant over IL-18 for protective immunity.

    PubMed Central

    Lu, H.; Yang, X.; Takeda, K.; Zhang, D.; Fan, Y.; Luo, M.; Shen, C.; Wang, S.; Akira, S.; Brunham, R. C.

    2000-01-01

    BACKGROUND: Interferon (IFN)-gamma is a key to protective immunity against a variety of intracellular bacterial infections, including Chlamydia trachomatis. Interleukin (IL)-18, a recently identified Th1 cytokine, together with IL-12 is a strong stimulator for IFN-gamma production. We investigated the relative roles of IL-18 and IL- 12 in protective immunity to C. trachomatis mouse pneumonitis (MoPn) infection using gene knockout (KO) and wild-type (WT) mice. MATERIALS AND METHODS: Mice were intranasally infected with C. trachomatis MoPn and protective immunity was assessed among groups of mice by daily body weight changes, lung growth of MoPn, and histopathological appearances at day 10 postinfection. The corresponding immune responses for each group of mice at the same postinfection time point were evaluated by measuring antigen-specific antibody isotype responses and cytokine profiles. RESULTS: Our results showed that IL-18 deficiency had little or no influence on clearance of MoPn from the lung, although KO mice exhibited slightly more severe inflammatory reactions in lung tissues, as well as reduced systemic and local IFN-gamma production, compared with WT mice. Results with IL-18 KO mice were in sharp contrast to those observed with IL-12 KO mice that showed substantially reduced clearance of MoPn from the lungs, substantial reductions of antigen-specific systemic and lung IFN-gamma production, decreased ratio of MoPn-specific immunoglobulin G (IgG)2a/IgG1, and severe pathological changes in the lung with extensive polymorphonuclear, instead of mononuclear, cell infiltration. Exogenous IL-12 or IL-18 was able to increase IFN-gamma production in IL-18 KO mice; whereas, only exogenous IL-12, but not IL-18, enhanced IFN-gamma production in IL-12 KO mice. Caspase-1 is the key protease for activation of IL-18 precursor into the bioactive form, and caspase-1 KO mice also displayed similar bacterial clearance and body weight loss to that in WT mice at early stages

  1. Thrombospondin 1 promotes synaptic formation in bone marrow-derived neuron-like cells.

    PubMed

    Huang, Yun; Lu, Mingnan; Guo, Weitao; Zeng, Rong; Wang, Bin; Wang, Huaibo

    2013-04-01

    In this study, a combination of growth factors was used to induce bone marrow mesenchymal stem cells differentiation into neuron-like cells, in a broader attempt to observe the role of thrombospondin 1 in synapse formation. Results showed that there was no significant difference in the differentiation rate of neuron-like cells between bone marrow mesenchymal stem cells with thrombospondin induction and those without. However, the cell shape was more complex and the neurites were dendritic, with unipolar, bipolar or multipolar morphologies, after induction with thrombospondin 1. The induced cells were similar in morphology to normal neurites. Immunohistochemical staining showed that the number of positive cells for postsynaptic density protein 95 and synaptophysin 1 protein was significantly increased after induction with thrombospondin 1. These findings indicate that thrombospondin 1 promotes synapse formation in neuron-like cells that are differentiated from bone marrow mesenchymal stem cells.

  2. The matricellular protein thrombospondin-1 globally regulates cardiovascular function and responses to stress via CD47.

    PubMed

    Roberts, David D; Miller, Thomas W; Rogers, Natasha M; Yao, Mingyi; Isenberg, Jeffrey S

    2012-04-01

    Matricellular proteins play diverse roles in modulating cell behavior by engaging specific cell surface receptors and interacting with extracellular matrix proteins, secreted enzymes, and growth factors. Studies of such interactions involving thrombospondin-1 have revealed several physiological functions and roles in the pathogenesis of injury responses and cancer, but the relatively mild phenotypes of mice lacking thrombospondin-1 suggested that thrombospondin-1 would not be a central player that could be exploited therapeutically. Recent research focusing on signaling through its receptor CD47, however, has uncovered more critical roles for thrombospondin-1 in acute regulation of cardiovascular dynamics, hemostasis, immunity, and mitochondrial homeostasis. Several of these functions are mediated by potent and redundant inhibition of the canonical nitric oxide pathway. Conversely, elevated tissue thrombospondin-1 levels in major chronic diseases of aging may account for the deficient nitric oxide signaling that characterizes these diseases, and experimental therapeutics targeting CD47 show promise for treating such chronic diseases as well as acute stress conditions that are associated with elevated thrombospondin-1 expression.

  3. sFRP-1 binds via its netrin-related motif to the N-module of thrombospondin-1 and blocks thrombospondin-1 stimulation of MDA-MB-231 breast carcinoma cell adhesion and migration.

    PubMed

    Martin-Manso, Gema; Calzada, Maria J; Chuman, Yoshiro; Sipes, John M; Xavier, Charles P; Wolf, Vladimir; Kuznetsova, Svetlana A; Rubin, Jeffrey S; Roberts, David D

    2011-05-15

    Secreted frizzled-related protein (sFRP)-1 is a Wnt antagonist that inhibits breast carcinoma cell motility, whereas the secreted glycoprotein thrombospondin-1 stimulates adhesion and motility of the same cells. We examined whether thrombospondin-1 and sFRP-1 interact directly or indirectly to modulate cell behavior. Thrombospondin-1 bound sFRP-1 with an apparent K(d)=48nM and the related sFRP-2 with a K(d)=95nM. Thrombospondin-1 did not bind to the more distantly related sFRP-3. The association of thrombospondin-1 and sFRP-1 is primarily mediated by the amino-terminal N-module of thrombospondin-1 and the netrin domain of sFRP-1. sFRP-1 inhibited α3β1 integrin-mediated adhesion of MDA-MB-231 breast carcinoma cells to a surface coated with thrombospondin-1 or recombinant N-module, but not adhesion of the cells on immobilized fibronectin or type I collagen. sFRP-1 also inhibited thrombospondin-1-mediated migration of MDA-MB-231 and MDA-MB-468 breast carcinoma cells. Although sFRP-2 binds similarly to thrombospondin-1, it did not inhibit thrombospondin-1-stimulated adhesion. Thus, sFRP-1 binds to thrombospondin-1 and antagonizes stimulatory effects of thrombospondin-1 on breast carcinoma cell adhesion and motility. These results demonstrate that sFRP-1 can modulate breast cancer cell responses by interacting with thrombospondin-1 in addition to its known effects on Wnt signaling.

  4. Oncolytic adenovirus co-expressing IL-12 and IL-18 improves tumor-specific immunity via differentiation of T cells expressing IL-12Rβ2 or IL-18Rα.

    PubMed

    Choi, I-K; Lee, J-S; Zhang, S-N; Park, J; Sonn, C H; Lee, K-M; Yun, C-O

    2011-09-01

    The oncolytic adenovirus (Ad) is currently being advanced as a promising antitumor remedy as it selectively replicates in tumor cells and can transfer and amplify therapeutic genes. Interleukin (IL)-12 induces a potent antitumor effect by promoting natural killer (NK) cell and cytotoxic T cell activities. IL-18 also augments cytotoxicity of NK cells and proliferation of T cells. This effect further enhances the function of IL-12 in a synergistic manner. Therefore, we investigated for the first time an effective cancer immunogene therapy of syngeneic tumors via intratumoral administration of oncolytic Ad co-expressing IL-12 and IL-18, RdB/IL-12/IL-18. Intratumoral administration of RdB/IL-12/IL-18 improved antitumor effects, as well as increased survival, in B16-F10 murine melanoma model. The ratio of T-helper type 1/2 cytokine as well as the levels of IL-12, IL-18, interferon-γ and granulocyte-macrophage colony-stimulating factor was markedly elevated in RdB/IL-12/IL-18-treated tumors. Mice injected with RdB/IL-12/IL-18 also showed enhanced cytotoxicity of tumor-specific immune cells. Consistent with these results, immense necrosis and infiltration of NK cells, as well as CD4+ and CD8+ T cells, were observed in RdB/IL-12/IL-18-treated tumor tissues. Importantly, tumors treated with RdB/IL-12/IL-18 showed an elevated number of T cells expressing IL-12Rβ2 or IL-18Rα. These results provide a new insight into therapeutic mechanisms of IL-12 plus IL-18 and provide a potential clinical cancer immunotherapeutic agent for improved antitumor immunity.

  5. Determination of the CD148-Interacting Region in Thrombospondin-1

    PubMed Central

    Jiang, Rosie; Brantley-Sieders, Dana M.; Chen, Jin; Mernaugh, Raymond L.; Takahashi, Takamune

    2016-01-01

    CD148 is a transmembrane protein tyrosine phosphatase that is expressed in multiple cell types, including vascular endothelial cells and duct epithelial cells. Previous studies have shown a prominent role of CD148 to reduce growth factor signals and suppress cell proliferation and transformation. Further, we have recently shown that thrombospondin-1 (TSP1) serves as a functionally important ligand for CD148. TSP1 has multiple structural elements and interacts with various cell surface receptors that exhibit differing effects. In order to create the CD148-specific TSP1 fragment, here we investigated the CD148-interacting region in TSP1 using a series of TSP1 fragments and biochemical and biological assays. Our results demonstrate that: 1) CD148 binds to the 1st type 1 repeat in TSP1; 2) Trimeric TSP1 fragments that contain the 1st type repeat inhibit cell proliferation in A431D cells that stably express wild-type CD148 (A431D/CD148wt cells), while they show no effects in A431D cells that lack CD148 or express a catalytically inactive form of CD148. The anti-proliferative effect of the TSP1 fragment in A431D/CD148wt cells was largely abolished by CD148 knockdown and antagonized by the 1st, but not the 2nd and 3rd, type 1 repeat fragment. Furthermore, the trimeric TSP1 fragments containing the 1st type repeat increased the catalytic activity of CD148 and reduced phospho-tyrosine contents of EGFR and ERK1/2, defined CD148 substrates. These effects were not observed in the TSP1 fragments that lack the 1st type 1 repeat. Last, we demonstrate that the trimeric TSP1 fragment containing the 1st type 1 repeat inhibits endothelial cell proliferation in culture and angiogenesis in vivo. These effects were largely abolished by CD148 knockdown or deficiency. Collectively, these findings indicate that the 1st type 1 repeat interacts with CD148, reducing growth factor signals and inhibiting epithelial or endothelial cell proliferation and angiogenesis. PMID:27149518

  6. Epithelial IL-18 Equilibrium Controls Barrier Function in Colitis

    PubMed Central

    Nowarski, Roni; Jackson, Ruaidhrí; Gagliani, Nicola; de Zoete, Marcel R.; Palm, Noah W.; Bailis, Will; Low, Jun Siong; Harman, Christian C.D.; Graham, Morven; Elinav, Eran; Flavell, Richard A.

    2016-01-01

    SUMMARY The intestinal mucosal barrier controlling the resident microbiome is dependent on a protective mucus layer generated by goblet cells, impairment of which is a hallmark of the inflammatory bowel disease Ulcerative Colitis. Here we show that IL-18 is critical in driving the pathologic breakdown of barrier integrity in a model of colitis. Deletion of Il18 or its receptor Il18r1 in intestinal epithelial cells (Δ/EC) conferred protection from colitis and mucosal damage in mice. In contrast, deletion of the IL-18 negative regulator Il18bp resulted in severe colitis associated with loss of mature goblet cells. Colitis and goblet cell loss were rescued in Il18bp−/−;Il18rΔ/EC mice, demonstrating that colitis severity is controlled at the level of IL-18 signaling in intestinal epithelial cells. IL-18 inhibited goblet cell maturation by regulating the transcriptional program instructing goblet cell development. These results inform on the mechanism of goblet cell dysfunction which underlies the pathology of Ulcerative Colitis. PMID:26638073

  7. Pneumococcal association to platelets is mediated by soluble fibrin and supported by thrombospondin-1.

    PubMed

    Niemann, Silke; Kehrel, Beate E; Heilmann, Christine; Rennemeier, Claudia; Peters, Georg; Hammerschmidt, Sven

    2009-10-01

    Platelets and coagulation are involved in bacterial colonisation of the host. Streptocococcus pneumoniae (pneumococcus) are important etiologic agents of respiratory tract infections in humans. The formation of pneumococci-platelet associations may facilitate haematogenous dissemination of pneumococci by providing an adhesive surface on damaged endothelium. However, the formation of platelet-pneumococci associations and the factors involved in this process have not been described so far. The formation of platelet-pneumococci associates was analysed and quantified using flow cytometry. Binding of pneumococci to platelets was significantly increased after activation of platelets with thrombin, while platelet activation by ADP or collagen did not promote formation of platelet-pneumococci associates. In addition to be a platelet agonist, thrombin cleaves fibrinogen, which results in the generation of fibrin. The simultaneous formation of fibrin and activation of platelets was shown to be a prerequisite for a high number of platelet-pneumococci associates. Moreover, exogenously added human thrombospondin-1 (TSP-1) significantly enhanced the association of pneumococci with activated platelets. Soluble fibrin and TSP-1 are key co-factors of platelet-pneumococci-association. Similar results were recently demonstrated for S. aureus-platelet adhesion. Consequently, we hypothesise that the described mechanism of platelet-bacteria-association might represent a general and important strategy of Gram-positive bacteria during development of invasive diseases.

  8. Neuroblastoma cells expressing mature IL-18, but not proIL-18, induce a strong and immediate antitumor immune response.

    PubMed

    Heuer, J G; Tucker-McClung, C; Hock, R A

    1999-07-01

    Retroviral constructs were designed to express the novel cytokine interleukin 18 (IL-18), also known as interferon-gamma-inducing factor, in a murine neuroblastoma cell line [neuro-2a (N-2a)] to examine the effects of IL-18 expression on tumorigenicity. N-2a cells expressing proIL-18 (N-2a/IL-18p) were as tumorigenic as parental N-2a cells, whereas N-2a cells engineered to secrete mature IL-18 (N-2a/IL-18m) were nontumorigenic. Inoculation of mice with N-2a/IL-18m generated immediate immunity to parental N-2a. N-2a/IL-18m formed tumors in mice depleted of CD4+ and CD8+ T cells, suggesting that the antitumor immune response was T cell mediated. The resulting T-helper (Th) immune response was also characterized in vitro and had a large Th1 component based on in vitro production of the cytokines IFN-gamma and granulocyte macrophage colony-stimulating factor in response to tumor cells and IL-18.

  9. Epithelial-derived IL-18 regulates Th17 cell differentiation and Foxp3⁺ Treg cell function in the intestine.

    PubMed

    Harrison, O J; Srinivasan, N; Pott, J; Schiering, C; Krausgruber, T; Ilott, N E; Maloy, K J

    2015-11-01

    Elevated levels of interleukin-18 (IL-18) are found in many chronic inflammatory disorders, including inflammatory bowel disease (IBD), and polymorphisms in the IL18R1-IL18RAP locus are associated with IBD susceptibility. IL-18 is an IL-1 family cytokine that has been proposed to promote barrier function in the intestine, but the effects of IL-18 on intestinal CD4(+) T cells are poorly understood. Here we demonstrate that IL-18R1 expression is enhanced on both effector and regulatory CD4(+) T cells in the intestinal lamina propria, with T helper type 17 (Th17) cells exhibiting particularly high levels. We further show that, during steady state, intestinal epithelial cells constitutively secrete IL-18 that acts directly on IL-18R1-expressing CD4(+) T cells to limit colonic Th17 cell differentiation, in part by antagonizing IL-1R1 signaling. In addition, although IL-18R1 is not required for colonic Foxp3(+) regulatory T (Treg) cell differentiation, we found that IL-18R1 signaling was critical for Foxp3(+) Treg cell-mediated control of intestinal inflammation, where it promoted the expression of key Treg effector molecules. Thus IL-18 is a key epithelial-derived cytokine that differentially regulates distinct subsets of intestinal CD4(+) T cells during both homeostatic and inflammatory conditions, a finding with potential implications for treatment of chronic inflammatory disorders.

  10. IL-18 Expression Results in a Recombinant Vaccinia Virus That Is Highly Attenuated and Immunogenic

    PubMed Central

    Verardi, Paulo H.; Legrand, Fatema A.; Chan, Kenneth S.; Peng, Yue; Jones, Leslie A.

    2014-01-01

    Interferon-γ (IFN-γ) is an attenuating factor for vaccinia virus (VACV), decreasing its virulence in vivo by more than a million fold. It is also a highly effective adjuvant when administered at the time of immunization with protein antigens. However, recombinant VACV (rVACV) vaccines expressing IFN-γ do not induce enhanced immune responses. It is possible that the IFN-γ expressed by rVACVs induces both an antiviral state and increased immunological clearance, thus resulting in decreased levels of antigen expression due to reduced viral replication and spread. We conjectured that delaying expression of IFN-γ would result in enhanced production of antigens by rVACVs thus resulting in increased immune responses to foreign antigens. Interleukin (IL)-18, also known as IFN-γ inducing factor, is a cytokine that induces T and NK cells to produce IFN-γ. In this study, we demonstrated that an rVACV expressing bioactive murine IL-18 replicated to low but detectable levels in vivo, unlike an rVACV expressing IFN-γ. Moreover, the rVACV expressing IL-18 was significantly attenuated in both immunocompromised and immunocompetent mice. This attenuation was dependent on IFN-γ, as IL-18 expression failed to attenuate VACV in IFN-γ knock-out mice. Cytotoxic T-cell (CTL) and anamnestic antibody responses were slightly increased in animals vaccinated with the rVACV expressing IL-18. Thus, induction of IFN-γ because of IL-18 expression resulted in an rVACV that replicated to low but detectable levels in vivo, yet elicited slightly better CTL and anamnestic humoral immune responses. PMID:24168450

  11. Distinct Effects of IL-18 on the Engraftment and Function of Human Effector CD8+ T Cells and Regulatory T Cells

    PubMed Central

    Danet-Desnoyers, Gwenn; Liu, Ronghua; Jiang, Shuguang; Albelda, Steven M.; Golovina, Tatiana; Coukos, George; Riley, James L.; Jonak, Zdenka L.; June, Carl H.

    2008-01-01

    IL-18 has pleotropic effects on the activation of T cells during antigen presentation. We investigated the effects of human IL-18 on the engraftment and function of human T cell subsets in xenograft mouse models. IL-18 enhanced the engraftment of human CD8+ effector T cells and promoted the development of xenogeneic graft versus host disease (GVHD). In marked contrast, IL-18 had reciprocal effects on the engraftment of CD4+CD25+Foxp3+ regulatory T cells (Tregs) in the xenografted mice. Adoptive transfer experiments indicated that IL-18 prevented the suppressive effects of Tregs on the development of xenogeneic GVHD. The IL-18 results were robust as they were observed in two different mouse strains. In addition, the effects of IL-18 were systemic as IL-18 promoted engraftment and persistence of human effector T cells and decreased Tregs in peripheral blood, peritoneal cavity, spleen and liver. In vitro experiments indicated that the expression of the IL-18Rα was induced on both CD4 and CD8 effector T cells and Tregs, and that the duration of expression was less sustained on Tregs. These preclinical data suggest that human IL-18 may have use as an adjuvant for immune reconstitution after cytotoxic therapies, and to augment adoptive immunotherapy, donor leukocyte infusions, and vaccine strategies. PMID:18818761

  12. AIM2 inflammasome mediates Arsenic-induced secretion of IL-1 β and IL-18.

    PubMed

    Zhang, Mingfang; Qi, Yuanlin; Li, Hui; Cui, Jiajun; Dai, Lu; Frank, Jacqueline A; Chen, Jian; Xu, Wenhua; Chen, Gang

    2016-06-01

    Chronic sterile inflammation has been implicated in the pathogenesis of many cancers, including skin cancer. Chronic arsenic exposure is closely associated with the development of skin cancer. However, there is a lack of understanding how arsenic induces chronic inflammation in the skin. Interleukin-1 family cytokines play a central role in regulating immune and inflammatory response. IL-1α, IL-1β and IL-18 are three pro-inflammatory cytokines in IL-1 family. Their secretion, especially the secretion of IL-1β and IL-18, is regulated by inflammasomes which are multi-protein complexes containing sensor proteins, adaptor protein and caspase-1. The data from current study show sub-chronic arsenic exposure activates AIM2 inflammasome which in turn activates caspase-1 and enhances the secretion of IL-1β and IL-18 in HaCaT cells and the skin of BALB/c mice. In addition, arsenic-promoted activation of AIM2 inflammasome and increase of IL-1β/IL-18 production are inhibited by PKR inhibitor in HaCaT cells or in the skin of PKR mutant mice, indicating a potential role of PKR in arsenic-induced sterile inflammation. PMID:27471628

  13. Thrombospondin-1 and CD47 signaling regulate healing of thermal injury in mice

    PubMed Central

    Soto-Pantoja, David R.; Shih, Hubert B.; Maxhimer, Justin B.; Cook, Katherine L.; Ghosh, Arunima; Isenberg, Jeffrey S.; Roberts, David D.

    2016-01-01

    More than 2.5 million Americans suffer from burn injuries annually, and burn management is a major public health problem. Treatments have been developed to manage wound injuries employing skin grafts, various dressings and topical and systemic agents. However, these often achieve limited degrees of success. We previously reported that targeting the interaction of thrombospondin-1 with its signaling receptor CD47 or deletion of the genes encoding either of these proteins in mice improves recovery from soft tissue ischemic injuries as well as tissue injuries caused by ionizing radiation. We now demonstrate that the absence of CD47 improves the rate of wound closure for a focal dermal second-degree thermal injury, whereas lack of thrombospondin-1 initially delays wound closure compared to healing in wild type mice. Doppler analysis of the wounded area showed increased blood flow in both CD47 and thrombospondin-1 null mice. Accelerated wound closure in the CD47 null mice was associated with increased fibrosis as demonstrated by a 4-fold increase in collagen fraction. Wound tissue of CD47 null mice showed increased thrombospondin-1 mRNA and protein expression and TGF-β1 mRNA levels. Activation of latent TGF-β1 was increased in thermally injured CD47-null tissue as assessed by phosphor-ylation of the TGF-β1 receptor-regulated transcription factors SMAD-2 and -3. Overall these results indicate that targeting CD47 may improve the speed of healing thermal injuries, but some level of CD47 expression may be required to limit the long term TGF-β1-dependent fibrosis of these wounds. PMID:24840925

  14. The frequency of an IL-18-associated haplotype in Africans.

    PubMed

    Thompson, Simon R; Humphries, Steve E; Thomas, Mark G; Ekong, Rosemary; Tarekegn, Ayele; Bekele, Endeshaw; Creemer, Olivia; Bradman, Neil; Veeramah, Krishna R

    2013-04-01

    Variation within the gene for the proinflammatory cytokine interleukin (IL)-18 has been associated with inter-individual differences in levels of free protein and disease risk. We investigated the frequency of function-associated IL18 gene haplotypes in an extensive sample (n=2357) of African populations from across the continent. A previously identified five tagging SNP (single-nucleotide polymorphism) haplotype (here designated hGTATA), known to be associated with lower levels of IL-18, was observed at a frequency of 27% in a British population of recent European ancestry, but was found at low frequency (<8%) or completely absent in African populations. Potentially protective variants may, as a consequence, be found at low frequency in African individuals and may confer a difference in disease risk.

  15. Dietary fat overcomes the protective activity of thrombospondin-1 signaling in the Apc(Min/+) model of colon cancer.

    PubMed

    Soto-Pantoja, D R; Sipes, J M; Martin-Manso, G; Westwood, B; Morris, N L; Ghosh, A; Emenaker, N J; Roberts, D D

    2016-01-01

    Thrombospondin 1 is a glycoprotein that regulates cellular phenotype through interactions with its cellular receptors and extracellular matrix-binding partners. Thrombospondin 1 locally regulates angiogenesis and inflammatory responses that contribute to colorectal carcinogenesis in Apc(Min/+) mice. The ability of thrombospondin 1 to regulate responses of cells and tissues to a variety of stresses suggested that loss of thrombospondin 1 may also have broader systemic effects on metabolism to modulate carcinogenesis. Apc(Min/+):Thbs1(-/-) mice exhibited decreased survival and higher tumor multiplicities in the small and large intestine relative to Apc(Min/+) mice when fed a low (5%) fat western diet. However, the protective effect of endogenous thrombospondin 1 was lost when the mice were fed a western diet containing 21% fat. Biochemical profiles of liver tissue identified systemic metabolic changes accompanying the effects of thrombospondin 1 and dietary lipid intake on tumorigenesis. A high-fat western diet differentially regulated elements of amino acid, energy and lipid metabolism in Apc(Min/+):Thbs1(-/-) mice relative to Apc(Min/+):Thbs1(+/+)mice. Metabolic changes in ketone body and tricarboxylic acid cycle intermediates indicate functional interactions between Apc and thrombospondin 1 signaling that control mitochondrial function. The cumulative diet-dependent differential changes observed in Apc(Min/+):Thbs1(-/-) versus Apc(Min/+) mice include altered amino acid and lipid metabolism, mitochondrial dysfunction, eicosanoids and ketone body formation. This metabolic profile suggests that the protective role of thrombospondin 1 to decrease adenoma formation in Apc(Min/+) mice results in part from improved mitochondrial function. PMID:27239962

  16. IL18 Gene Variants Influence the Susceptibility to Chagas Disease.

    PubMed

    Leon Rodriguez, Daniel A; Carmona, F David; Echeverría, Luis Eduardo; González, Clara Isabel; Martin, Javier

    2016-03-01

    Chagas disease is a parasitic disorder caused by the infection with the flagellated protozoan Trypanosoma cruzi. According to the World Health Organization, more than six million people are currently infected in endemic regions. Genetic factors have been proposed to influence predisposition to infection and development of severe clinical phenotypes like chronic Chagas cardiomyopathy (CCC). Interleukin 18 (IL18) encodes a proinflammatory cytokine that has been proposed to be involved in controlling T. cruzi infection. In this study, we analyzed the possible role of six IL18 gene variants (rs5744258, rs360722, rs2043055, rs187238, rs1946518 and rs360719), which cover most of the variation within the locus, in the susceptibility to infection by T. cruzi and/or CCC. In total, 1,171 individuals from a Colombian region endemic for Chagas disease, classified as seronegative (n = 595), seropositive asymptomatic (n = 175) and CCC (n = 401), were genotyped using TaqMan probes. Significant associations with T. cruzi infection were observed when comparing seronegative and seropositive individuals for rs187238 (P = 2.18E-03, OR = 0.77), rs360719 (P = 1.49E-03, OR = 0.76), rs2043055 (P = 2.52E-03, OR = 1.29), and rs1946518 (P = 0.0162, OR = 1.22). However, dependence analyses suggested that the association was mainly driven by the polymorphism rs360719. This variant is located within the promoter region of the IL18 gene, and it has been described that it creates a binding site for the transcription factor OCT-1 affecting IL-18 expression levels. In addition, no evidence of association was observed between any of the analyzed IL18 gene polymorphisms and the development of CCC. In summary, our data suggest that genetic variation within the promoter region of IL18 is directly involved in the susceptibility to infection by T. cruzi, which provides novel insight into disease pathophysiology and adds new perspectives to achieve a more effective disease control.

  17. Adjuvant effects of recombinant giant panda (Ailuropoda melanoleuca) IL-18 on the canine distemper disease vaccine in mice

    PubMed Central

    YAN, Yue; NIU, Lili; DENG, Jiabo; WANG, Qiang; YU, Jianqiu; ZHANG, Yizheng; WANG, Jianxi; CHEN, Jiao; WEI, Changhe; TAN, Xuemei

    2014-01-01

    Canine distemper virus (CDV) is a morbillivirus known to cause morbidity and mortality in a broad range of animals. Giant pandas (Ailuropoda melanoleuca), especially captive ones, are susceptible to natural infection with CDV. Interleukin-18 (IL-18) is a powerful adjuvant molecule that can enhance the development of antigen-specific immunity and vaccine efficacy. In this study, a giant panda IL-18 gene eukaryotic expression plasmid (pcAmIL-18) was constructed. Female BALB/c mice were muscularly inoculated with the plasmids pcAmIL-18, pcDNA3.1 and PBS, respectively. They were subsequently injected with an attenuated CDV vaccine for dogs, and the induced humoral and cellular responses were evaluated. The results showed that pcAmIL-18 remarkably improved the level of specific antibody, IFN-γ and IL-2 in mice sera, the T lymphocyte proliferation index and the percentage of CD4+ and CD8+ cells. These data indicated that pcAmIL-18 is a potential adjuvant that promotes specific immunity. PMID:25399820

  18. Adjuvant effects of recombinant giant panda (Ailuropoda melanoleuca) IL-18 on the canine distemper disease vaccine in mice.

    PubMed

    Yan, Yue; Niu, Lili; Deng, Jiabo; Wang, Qiang; Yu, Jianqiu; Zhang, Yizheng; Wang, Jianxi; Chen, Jiao; Wei, Changhe; Tan, Xuemei

    2015-02-01

    Canine distemper virus (CDV) is a morbillivirus known to cause morbidity and mortality in a broad range of animals. Giant pandas (Ailuropoda melanoleuca), especially captive ones, are susceptible to natural infection with CDV. Interleukin-18 (IL-18) is a powerful adjuvant molecule that can enhance the development of antigen-specific immunity and vaccine efficacy. In this study, a giant panda IL-18 gene eukaryotic expression plasmid (pcAmIL-18) was constructed. Female BALB/c mice were muscularly inoculated with the plasmids pcAmIL-18, pcDNA3.1 and PBS, respectively. They were subsequently injected with an attenuated CDV vaccine for dogs, and the induced humoral and cellular responses were evaluated. The results showed that pcAmIL-18 remarkably improved the level of specific antibody, IFN-γ and IL-2 in mice sera, the T lymphocyte proliferation index and the percentage of CD4(+) and CD8(+) cells. These data indicated that pcAmIL-18 is a potential adjuvant that promotes specific immunity.

  19. Adjuvant effects of recombinant giant panda (Ailuropoda melanoleuca) IL-18 on the canine distemper disease vaccine in mice.

    PubMed

    Yan, Yue; Niu, Lili; Deng, Jiabo; Wang, Qiang; Yu, Jianqiu; Zhang, Yizheng; Wang, Jianxi; Chen, Jiao; Wei, Changhe; Tan, Xuemei

    2015-02-01

    Canine distemper virus (CDV) is a morbillivirus known to cause morbidity and mortality in a broad range of animals. Giant pandas (Ailuropoda melanoleuca), especially captive ones, are susceptible to natural infection with CDV. Interleukin-18 (IL-18) is a powerful adjuvant molecule that can enhance the development of antigen-specific immunity and vaccine efficacy. In this study, a giant panda IL-18 gene eukaryotic expression plasmid (pcAmIL-18) was constructed. Female BALB/c mice were muscularly inoculated with the plasmids pcAmIL-18, pcDNA3.1 and PBS, respectively. They were subsequently injected with an attenuated CDV vaccine for dogs, and the induced humoral and cellular responses were evaluated. The results showed that pcAmIL-18 remarkably improved the level of specific antibody, IFN-γ and IL-2 in mice sera, the T lymphocyte proliferation index and the percentage of CD4(+) and CD8(+) cells. These data indicated that pcAmIL-18 is a potential adjuvant that promotes specific immunity. PMID:25399820

  20. Cell-type specific adhesive interactions of skeletal myoblasts with thrombospondin-1.

    PubMed Central

    Adams, J C; Lawler, J

    1994-01-01

    Thrombospondin-1 (TSP-1) is an extracellular matrix glycoprotein that may play important roles in the morphogenesis and repair of skeletal muscle. To begin to explore the role of thrombospondin-1 in this tissue, we have examined the interactions of three rodent skeletal muscle cell lines, C2C12, G8, and H9c2, with platelet TSP-1. The cells secrete thrombospondin and incorporate it into the cell layer in a distribution distinct from that of fibronectin. Myoblasts attach and spread on fibronectin- or thrombospondin-coated substrates with similar time and concentration dependencies. Whereas cells adherent on fibronectin organize actin stress fibers, cells adherent on TSP-1 display prominent membrane ruffles and lamellae that contain radial actin microspikes. Attachment to thrombospondin-1 or the 140-kDa tryptic fragment is mediated by interactions with the type 1 repeats and the carboxy-terminal globular domain. Attachment is not inhibited by heparin, GRGDSP peptide, or VTCG peptide but is inhibited by chondroitin sulphate A. Integrins of the beta 1 or alpha V subgroups do not appear to be involved in myoblast attachment to TSP-1; instead, this process depends in part on cell surface chondroitin sulphate proteoglycans. Whereas the central 70-kDa chymotryptic fragment of TSP-1 does not support myoblast attachment, the carboxy-terminal domain of TSP-1 expressed as a fusion protein in the bacterial expression vector, pGEX, supported myoblast attachment to 30% the level of intact TSP-1. Thrombospondin-4 (TSP-4) is also present in skeletal muscle and a fusion protein containing the carboxy-terminal domain of TSP-4 also supported myoblast adhesion, although this protein was less active on a molar basis than the TSP-1 fusion protein. Thus, the carboxyterminal domain of TSP-1 appears to contain a primary attachment site for myoblasts, and this activity is present in a second member of the thrombospondin family. Images PMID:7519904

  1. IL18 Gene Variants Influence the Susceptibility to Chagas Disease.

    PubMed

    Leon Rodriguez, Daniel A; Carmona, F David; Echeverría, Luis Eduardo; González, Clara Isabel; Martin, Javier

    2016-03-01

    Chagas disease is a parasitic disorder caused by the infection with the flagellated protozoan Trypanosoma cruzi. According to the World Health Organization, more than six million people are currently infected in endemic regions. Genetic factors have been proposed to influence predisposition to infection and development of severe clinical phenotypes like chronic Chagas cardiomyopathy (CCC). Interleukin 18 (IL18) encodes a proinflammatory cytokine that has been proposed to be involved in controlling T. cruzi infection. In this study, we analyzed the possible role of six IL18 gene variants (rs5744258, rs360722, rs2043055, rs187238, rs1946518 and rs360719), which cover most of the variation within the locus, in the susceptibility to infection by T. cruzi and/or CCC. In total, 1,171 individuals from a Colombian region endemic for Chagas disease, classified as seronegative (n = 595), seropositive asymptomatic (n = 175) and CCC (n = 401), were genotyped using TaqMan probes. Significant associations with T. cruzi infection were observed when comparing seronegative and seropositive individuals for rs187238 (P = 2.18E-03, OR = 0.77), rs360719 (P = 1.49E-03, OR = 0.76), rs2043055 (P = 2.52E-03, OR = 1.29), and rs1946518 (P = 0.0162, OR = 1.22). However, dependence analyses suggested that the association was mainly driven by the polymorphism rs360719. This variant is located within the promoter region of the IL18 gene, and it has been described that it creates a binding site for the transcription factor OCT-1 affecting IL-18 expression levels. In addition, no evidence of association was observed between any of the analyzed IL18 gene polymorphisms and the development of CCC. In summary, our data suggest that genetic variation within the promoter region of IL18 is directly involved in the susceptibility to infection by T. cruzi, which provides novel insight into disease pathophysiology and adds new perspectives to achieve a more effective disease control. PMID:27027876

  2. IL18 Gene Variants Influence the Susceptibility to Chagas Disease

    PubMed Central

    Leon Rodriguez, Daniel A; Carmona, F. David; Echeverría, Luis Eduardo; González, Clara Isabel; Martin, Javier

    2016-01-01

    Chagas disease is a parasitic disorder caused by the infection with the flagellated protozoan Trypanosoma cruzi. According to the World Health Organization, more than six million people are currently infected in endemic regions. Genetic factors have been proposed to influence predisposition to infection and development of severe clinical phenotypes like chronic Chagas cardiomyopathy (CCC). Interleukin 18 (IL18) encodes a proinflammatory cytokine that has been proposed to be involved in controlling T. cruzi infection. In this study, we analyzed the possible role of six IL18 gene variants (rs5744258, rs360722, rs2043055, rs187238, rs1946518 and rs360719), which cover most of the variation within the locus, in the susceptibility to infection by T. cruzi and/or CCC. In total, 1,171 individuals from a Colombian region endemic for Chagas disease, classified as seronegative (n = 595), seropositive asymptomatic (n = 175) and CCC (n = 401), were genotyped using TaqMan probes. Significant associations with T. cruzi infection were observed when comparing seronegative and seropositive individuals for rs187238 (P = 2.18E-03, OR = 0.77), rs360719 (P = 1.49E-03, OR = 0.76), rs2043055 (P = 2.52E-03, OR = 1.29), and rs1946518 (P = 0.0162, OR = 1.22). However, dependence analyses suggested that the association was mainly driven by the polymorphism rs360719. This variant is located within the promoter region of the IL18 gene, and it has been described that it creates a binding site for the transcription factor OCT-1 affecting IL-18 expression levels. In addition, no evidence of association was observed between any of the analyzed IL18 gene polymorphisms and the development of CCC. In summary, our data suggest that genetic variation within the promoter region of IL18 is directly involved in the susceptibility to infection by T. cruzi, which provides novel insight into disease pathophysiology and adds new perspectives to achieve a more effective disease control. PMID:27027876

  3. Therapeutic targeting of the thrombospondin-1 receptor CD47 to treat liver cancer.

    PubMed

    Roberts, David D; Kaur, Sukhbir; Soto-Pantoja, David R

    2015-03-01

    CD47 is a signaling receptor for the matricellular protein thrombospondin-1 and a counter-receptor for signal regulatory protein-α (SIRPα) on macrophages. Following its initial discovery in 1992 as a cell surface protein that is over-expressed by ovarian carcinoma, elevated CD47 expression has emerged as a negative prognostic factor for a variety of cancers. CD47 is also a potential therapeutic target based on the ability of CD47 blockade to cause regression of tumors in mice, and a humanized CD47 antibody has recently entered phase I clinical trials. CD47 blockade may control tumor growth by inhibiting thrombospondin-1 signaling or by preventing inhibitory SIRPα signaling in tumor-associated macrophages. A recent publication by Lee et al. (Hepatology 60:179-191, 2014) provides evidence that blocking CD47 signaling specifically depletes tumor-initiating stem cells in hepatocellular carcinoma and implicates cathepsin-S/protease-activated receptor-2 signaling in mediating this therapeutic response.

  4. Cloning and characterization of giant panda (Ailuropoda melanoleuca) IL-18 binding protein.

    PubMed

    Yan, Yue; Deng, Jiabo; Niu, Lili; Wang, Qiang; Yu, Jianqiu; Shao, Huanhuan; Cao, Qinghua; Zhang, Yizheng; Tan, Xuemei

    2016-06-01

    The giant panda (Ailuropoda melanoleuca) is an endangered species. Interleukin-18 (IL-18) plays an important role in the innate and adaptive immune responses by inducing IFN-γ. IL-18 has been implicated in the pathogenesis of various diseases. IL-18 binding protein (IL-18BP) is an intrinsic inhibitor of IL-18 that possesses higher affinity to IL-18. In this study, we cloned and characterized IL-18BP in giant panda (AmIL-18BP) from the spleen. The amino acid sequence of giant panda IL-18BP ORF shared about 65% identities with other species. To evaluate the effects of AmIL-18BP on the immune responses, we expressed the recombinant AmIL-18BP in Escherichia coli BL21 (DE3).The fusing protein PET-AmIL-18BP was purified by nickel affinity column chromatography. The biological function of purified PET-AmIL-18BP was determined on mice splenocyte by qRT-PCR. The results showed that AmIL-18BP was functional and could significantly reduce IFN-γ production in murine splenocytes. These results will facilitate the study of protecting giant panda on etiology and immunology. PMID:27234556

  5. Cloning and characterization of giant panda (Ailuropoda melanoleuca) IL-18 binding protein.

    PubMed

    Yan, Yue; Deng, Jiabo; Niu, Lili; Wang, Qiang; Yu, Jianqiu; Shao, Huanhuan; Cao, Qinghua; Zhang, Yizheng; Tan, Xuemei

    2016-06-01

    The giant panda (Ailuropoda melanoleuca) is an endangered species. Interleukin-18 (IL-18) plays an important role in the innate and adaptive immune responses by inducing IFN-γ. IL-18 has been implicated in the pathogenesis of various diseases. IL-18 binding protein (IL-18BP) is an intrinsic inhibitor of IL-18 that possesses higher affinity to IL-18. In this study, we cloned and characterized IL-18BP in giant panda (AmIL-18BP) from the spleen. The amino acid sequence of giant panda IL-18BP ORF shared about 65% identities with other species. To evaluate the effects of AmIL-18BP on the immune responses, we expressed the recombinant AmIL-18BP in Escherichia coli BL21 (DE3).The fusing protein PET-AmIL-18BP was purified by nickel affinity column chromatography. The biological function of purified PET-AmIL-18BP was determined on mice splenocyte by qRT-PCR. The results showed that AmIL-18BP was functional and could significantly reduce IFN-γ production in murine splenocytes. These results will facilitate the study of protecting giant panda on etiology and immunology.

  6. Hantavirus Infection Suppresses Thrombospondin-1 Expression in Cultured Endothelial Cells in a Strain-Specific Manner

    PubMed Central

    Khaiboullina, Svetlana F.; Morzunov, Sergey P.; St. Jeor, Stephen C.; Rizvanov, Albert A.; Lombardi, Vincent C.

    2016-01-01

    Hantavirus infection is associated with two frequently fatal diseases in humans: Hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). The pathogenesis of hantavirus infection is complex and not fully understood; however, it is believed to involve virus-induced hyperinflammatory immune responses. Thrombospondin-1 (THBS1) is a large homotrimeric protein that plays a putative role in regulating blood homeostasis. Hyperresponsiveness to inflammatory stimuli has also been associated with defects in the THBS1 gene. Our data suggest that hantavirus infection of human umbilical cord vein endothelial cells (HUVEC) suppress the accumulation of THBS1 in the extracellular matrix. Additionally, this suppression is dependent on virus replication, implying a direct mechanism of action. Our data also imply that the pathogenic Andes and Hantaan strains inhibit THBS1 expression while the non-pathogenic Prospect Hill strain showed little inhibition. These observations suggest that a dysregulation of THBS1 may contribute to the pathogenesis of hantavirus infection. PMID:27486439

  7. Thrombospondin-1 signaling through CD47 inhibits cell cycle progression and induces senescence in endothelial cells

    PubMed Central

    Gao, Qi; Chen, Kexin; Gao, Lu; Zheng, Yang; Yang, Yong-Guang

    2016-01-01

    CD47 signaling in endothelial cells has been shown to suppress angiogenesis, but little is known about the link between CD47 and endothelial senescence. Herein, we demonstrate that the thrombospondin-1 (TSP1)-CD47 signaling pathway is a major mechanism for driving endothelial cell senescence. CD47 deficiency in endothelial cells significantly improved their angiogenic function and attenuated their replicative senescence. Lack of CD47 also suppresses activation of cell cycle inhibitors and upregulates the expression of cell cycle promoters, leading to increased cell cycle progression. Furthermore, TSP1 significantly accelerates replicative senescence and associated cell cycle arrest in a CD47-dependent manner. These findings demonstrate that TSP1-CD47 signaling is an important mechanism driving endothelial cell senescence. Thus, TSP1 and CD47 provide attractive molecular targets for treatment of aging-associated cardiovascular dysfunction and diseases involving endothelial dysregulation. PMID:27607583

  8. Hantavirus Infection Suppresses Thrombospondin-1 Expression in Cultured Endothelial Cells in a Strain-Specific Manner.

    PubMed

    Khaiboullina, Svetlana F; Morzunov, Sergey P; St Jeor, Stephen C; Rizvanov, Albert A; Lombardi, Vincent C

    2016-01-01

    Hantavirus infection is associated with two frequently fatal diseases in humans: Hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). The pathogenesis of hantavirus infection is complex and not fully understood; however, it is believed to involve virus-induced hyperinflammatory immune responses. Thrombospondin-1 (THBS1) is a large homotrimeric protein that plays a putative role in regulating blood homeostasis. Hyperresponsiveness to inflammatory stimuli has also been associated with defects in the THBS1 gene. Our data suggest that hantavirus infection of human umbilical cord vein endothelial cells (HUVEC) suppress the accumulation of THBS1 in the extracellular matrix. Additionally, this suppression is dependent on virus replication, implying a direct mechanism of action. Our data also imply that the pathogenic Andes and Hantaan strains inhibit THBS1 expression while the non-pathogenic Prospect Hill strain showed little inhibition. These observations suggest that a dysregulation of THBS1 may contribute to the pathogenesis of hantavirus infection. PMID:27486439

  9. Thrombospondin-1 in differentiated thyroid cancer: Dr. Jekyll and Mr. Hyde.

    PubMed

    Ghoneim, Christelle; Soula-Rothhut, Mahdhia; Rothhut, Bernard

    2008-01-01

    Thrombospondin-1 (TSP-1) is a member of a family of five structurally related extracellular glycoproteins that plays a major role in cell-matrix and cell-cell interactions. Due to its multifunctional nature and its ability to bind to a variety of cell surface receptors and matrix proteins, TSP-1 has been identified as a potential regulator of angiogenesis and tumor progression. In this review, we summarize recent results that we obtained in our laboratory dealing with the regulation of thombospondin-1 expression by epidermal growth factor and hepatocyte growth factor. Our results show that TSP-1 can have opposite effects on cell invasion depending upon the type of differentiated thyroid carcinoma studied. PMID:18661355

  10. Expression of Pentraxin 3 and Thrombospondin 1 in Gingival Crevicular Fluid during Wound Healing after Gingivectomy in Postorthodontic Patients

    PubMed Central

    Rauten, Anne Marie; Silosi, Isabela; Stratul, Stefan Ioan; Toma, Vasilica

    2016-01-01

    Background. Wound healing is a tissue repair process after an injury, and two of its main components are inflammation and angiogenesis, in which course a cascade of mediators is involved. The aim of this research was to evaluate the involvement of Pentraxin 3 and Thrombospondin 1 in wound healing after periodontal surgery (gingivectomy) for gingival overgrowth during orthodontic treatment with or without magnification devices, by assessing their levels in GCF. Methods. From 19 patients with gingival overgrowth as a result of fixed orthodontic treatment, the overgrown gingiva was removed by gingivectomy, from one half of the mandibular arch without magnification and from the other under magnification. Pentraxin 3 and Thrombospondin 1 were determined from gingival crevicular fluid by ELISA tests. Results. Statistically significant differences (p < 0.05) and correlations between levels of the two biomarkers were analyzed. Statistically significant differences were established between levels of the two biomarkers at different time points, with significant positive correlation at the point of 24 hours. Conclusions. Within the limitations of this study, the results seem to sustain the involvement of Pentraxin 3 and Thrombospondin 1 in the processes of inflammation and angiogenesis in wound healing of patients with postorthodontic gingivectomy. The dynamics of Pentraxin 3 and Thrombospondin 1 levels could suggest a reduced inflammation and a faster angiogenesis using microsurgery. PMID:27403446

  11. Expression of Pentraxin 3 and Thrombospondin 1 in Gingival Crevicular Fluid during Wound Healing after Gingivectomy in Postorthodontic Patients.

    PubMed

    Rauten, Anne Marie; Silosi, Isabela; Stratul, Stefan Ioan; Foia, Liliana; Camen, Adrian; Toma, Vasilica; Cioloca, Daniel; Surlin, Valeriu; Surlin, Petra; Bogdan, Maria

    2016-01-01

    Background. Wound healing is a tissue repair process after an injury, and two of its main components are inflammation and angiogenesis, in which course a cascade of mediators is involved. The aim of this research was to evaluate the involvement of Pentraxin 3 and Thrombospondin 1 in wound healing after periodontal surgery (gingivectomy) for gingival overgrowth during orthodontic treatment with or without magnification devices, by assessing their levels in GCF. Methods. From 19 patients with gingival overgrowth as a result of fixed orthodontic treatment, the overgrown gingiva was removed by gingivectomy, from one half of the mandibular arch without magnification and from the other under magnification. Pentraxin 3 and Thrombospondin 1 were determined from gingival crevicular fluid by ELISA tests. Results. Statistically significant differences (p < 0.05) and correlations between levels of the two biomarkers were analyzed. Statistically significant differences were established between levels of the two biomarkers at different time points, with significant positive correlation at the point of 24 hours. Conclusions. Within the limitations of this study, the results seem to sustain the involvement of Pentraxin 3 and Thrombospondin 1 in the processes of inflammation and angiogenesis in wound healing of patients with postorthodontic gingivectomy. The dynamics of Pentraxin 3 and Thrombospondin 1 levels could suggest a reduced inflammation and a faster angiogenesis using microsurgery.

  12. Dysfunction of mitochondria and deformed gap junctions in the heart of IL-18-deficient mice.

    PubMed

    Li, Wen; Jin, Denan; Hata, Masaki; Takai, Shinji; Yamanishi, Kyosuke; Shen, Weili; El-Darawish, Yosif; Yamanishi, Hiromichi; Okamura, Haruki

    2016-08-01

    Interleukin-18 (IL-18) was discovered as an interferon-γ-inducing factor and has been regarded as a proinflammatory cytokine. However, IL-18 is ubiquitously expressed both in immune/inflammatory cells and in nonimmune cells, and its biological roles have not been sufficiently elucidated. Here, we demonstrate that IL-18-deficient [IL-18 knockout (KO)] mice have heart abnormalities that may be related to impaired autophagy. In endurance running tests, IL-18KO mice ran significantly shorter distances compared with wild-type (WT) mice. Echocardiographs indicated disability in the systolic and diastolic functions of the IL-18KO mouse heart. Immunostaining of connexin 43 showed heterogeneous localization of gap junctions in the lateral membranes of the IL-18KO cardiac myocytes. Western blotting analysis revealed decreased phosphorylated connexin 43 in the IL-18KO heart. Electron microscopy revealed unusual localization of intercalated disks, swollen or damaged mitochondria, and broad, indistinct Z-lines in the IL-18KO heart. In accordance with the morphological observation, mitochondrial respiratory function, including that of complexes I and IV, was impaired, and production of reactive oxygen species was augmented in IL-18KO hearts. Notably, levels of LC3-II were markedly lower in the IL-18KO hearts than in WT hearts. In the culture of cardiac myocytes of IL-18KO neonates, exogenous IL-18 upregulated LC3-II and increased the number of intact mitochondria with high mitochondrial membrane potential. These results indicated that IL-18 has roles apart from those as a proinflammatory cytokine in cardiac myocytes and suggested that IL-18 contributes to the homeostatic maintenance of mitochondrial function and gap-junction turnover in cardiac myocytes, possibly by upregulating autophagy.

  13. An Association Study of Interleukin 18 Receptor Genes (IL18R1 and IL18RAP) in Lumbar Disc Degeneration

    PubMed Central

    Omair, Ahmad; Lie, Benedicte Alexandra; Reikeras, Olav; Brox, Jens Ivar

    2012-01-01

    Objectives: To examine association of candidate genetic variants in structural, inflammatory, matrix modifying, vitamin D receptor genes and variants associated with osteoarthritis, with surgical candidates and surgical patients with lumbar disc degeneration (LDD), in light of their previously reported susceptibility for LDD. Methods: Genotyping of 146 Norwegian LDD patients and 188 Norwegian controls was performed for 20 single-nucleotide polymorphisms (SNPs) from collagen, aggrecan, interleukin, VDR, MMP3 and COX2 genes and 7 SNPs from osteoarthritic genes. Results: The neighboring genes IL18R1 and IL18RAP polymorphisms (rs2287037 and rs1420100), showed a statistically non-significant risk for developing LDD (OR 1.36 [95 % CI 0.99 – 1.87]; p=0.06 and OR 1.33 [95 % CI 0.98-1.81]; p=0.07). Homozygosity of these risk alleles was associated with LDD (p=0.023 and p=0.027). The non-risk alleles at these SNPs were situated on a haplotype negatively associated with LDD (p=0.008). Carriage of at least one non-risk allele at both loci also reduces the risk of developing LDD (OR 0.51 [95 % CI 0.33-0.80]; p=0.003). Conclusion: Our findings support the polygenic nature of LDD and suggest that variation in interleukin 18 receptor genes could affect the risk of severe LDD and associated low back pain. PMID:22550553

  14. Downregulation of thrombospondin-1 by DNA hypermethylation is associated with tumor progression in laryngeal squamous cell carcinoma

    PubMed Central

    Huang, Chuang; Zhou, Xiaohong; Li, Zhenhua; Liu, Hong; He, Yun; Ye, Guo; Huang, Kun

    2016-01-01

    Thrombospondin-1 (THBS-1) has been demonstrated to have a complicated role in human cancer and to exert stimulatory and inhibitory effects in different types of tumors. DNA methylation, as the most frequent mechanism for gene silencing, has been widely investigated in regards to the development of tumors. However, the expression levels and methylation status of THBS-1, and their roles in laryngeal squamous cell carcinoma (LSCC) remain to be elucidated. The present study detected downregulated THBS-1 mRNA and protein expression levels in LSCC by using reverse transcription-quantitative polymerase chain reaction (PCR) and western blotting, while decreased expression levels of THBS-1 mRNA and protein were significantly associated with lymph node metastasis and tumor-node-metastasis (TNM) stage. Furthermore, aberrant methylation of THBS-1 was frequently observed in LSCC by methylation-specific PCR, particularly in tumor tissues from lymph node metastasis or samples from cancer with advanced TNM stage. Furthermore, the current study demonstrated that downregulated expression of THBS-1 in LSCC was consistent with aberrant methylation of this gene. Treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxy-cytidine in Hep-2 cells induced demethylation of THBS-1, enhanced THBS-1 expression, and inhibited the proliferative and invasive ability of Hep-2 cells. Collectively, the results of the present study suggest that THBS-1 may exert an inhibitory effect in the development of LSCC. Aberrant methylation was an important reason for the downregulation of THBS-1 and was involved in the invasion and metastasis of LSCC. Demethylating agents may be effective candidates for the treatment of LSCC. PMID:27485791

  15. A poxvirus protein that binds to and inactivates IL-18, and inhibits NK cell response.

    PubMed

    Born, T L; Morrison, L A; Esteban, D J; VandenBos, T; Thebeau, L G; Chen, N; Spriggs, M K; Sims, J E; Buller, R M

    2000-03-15

    IL-18 induces IFN-gamma and NK cell cytotoxicity, making it a logical target for viral antagonism of host defense. We demonstrate that the ectromelia poxvirus p13 protein, bearing homology to the mammalian IL-18 binding protein, binds IL-18, and inhibits its activity in vitro. Binding of IL-18 to the viral p13 protein was compared with binding to the cellular IL-18R. The dissociation constant of p13 for murine IL-18 is 5 nM, compared with 0.2 nM for the cellular receptor heterodimer. Mice infected with a p13 deletion mutant of ectromelia virus had elevated cytotoxicity for YAC-1 tumor cell targets compared with control animals. Additionally, the p13 deletion mutant virus exhibited decreased levels of infectivity. Our data suggest that inactivation of IL-18, and subsequent impairment of NK cell cytotoxicity, may be one mechanism by which ectromelia evades the host immune response. PMID:10706717

  16. Leptin promotes breast cancer cell migration and invasion via IL-18 expression and secretion.

    PubMed

    Li, Kuangfa; Wei, Lan; Huang, Yunxiu; Wu, Yang; Su, Min; Pang, Xueli; Wang, Nian; Ji, Feihu; Zhong, Changli; Chen, Tingmei

    2016-06-01

    In recent years, crosstalk between tumor microenvironment and cancer cells have received increasing attention. Accumulating research data suggests that leptin, a key adipokine secreted from adipocytes, plays important roles in breast cancer development. In our study, the effects of leptin on polarization of tumor-associated macrophages (TAMs) and promotion of the invasiveness of tumor cells were investigated. THP1 cells were used to differentiate M2 polarization macrophages. After stimulated by leptin, we established a co-culture system of tumor cells and macrophages to evaluate the function of leptin-induced macrophages in the migration and invasion of breast cancer cells. The gene and protein expressions were analyzed and the underlying mechanisms were evaluated. Moreover, pathological human specimens, and xenografts in nude mice, were detected to strengthen the in vitro results. Leptin elevated the expression of an array of cytokines in TAMs, IL-18 was the most increased, with an activation of the NF-κB/NF-κB1 signalling pathway. Additionally, after treated with leptin, TAMs significantly promoted the migration and invasion of breast cancer cells. However, these effects of leptin were abolished by the co-incubation of Bay11‑7082, a pharmacological NF-κB inhibitor. Leptin also directly stimulated IL-18 expression in breast cancer cells, which, differently, was via the PI3K/AKT-ATF-2 signaling pathway. In vivo studies showed that malignant breast carcinoma exhibited strong higher expression of Leptin, IL-8, and TAMs markers. Xenograft tumor-bearing mouse models showed that leptin significantly increased tumor volume, enhanced lung metastases, and increased expression of IL-8 and TAM markers, which were abolished by depletion of macrophages by clophosome-clodronate liposomes (CCL). Leptin could induce IL-18 expression both in TAMs and breast cancer cells. Leptin-induced IL-18 expression was regulated via NF-κB/NF-κB1 signaling in TAMs, while via PI3K

  17. Thrombospondin-1 activation of signal-regulatory protein-α stimulates reactive oxygen species production and promotes renal ischemia reperfusion injury.

    PubMed

    Yao, Mingyi; Rogers, Natasha M; Csányi, Gábor; Rodriguez, Andres I; Ross, Mark A; St Croix, Claudette; Knupp, Heather; Novelli, Enrico M; Thomson, Angus W; Pagano, Patrick J; Isenberg, Jeffrey S

    2014-06-01

    Ischemia reperfusion injury (IRI) causes tissue and organ injury, in part, through alterations in tissue blood flow and the production of reactive oxygen species. The cell surface receptor signal-regulatory protein-α (SIRP-α) is expressed on inflammatory cells and suppresses phagocytosis, but the function of SIRP-α in IRI has not been determined. We reported previously that the matricellular protein thrombospondin-1 is upregulated in IRI. Here, we report a novel interaction between thrombospondin-1 and SIRP-α on nonphagocytic cells. In cell-free experiments, thrombospondin-1 bound SIRP-α. In vascular smooth muscle cells and renal tubular epithelial cells, treatment with thrombospondin-1 led to phosphorylation of SIRP-α and downstream activation of Src homology domain 2-containing phosphatase-1. Thrombospondin-1 also stimulated phosphorylation of p47(phox) (an organizer subunit for nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 1/2) and increased production of superoxide, both of which were abrogated by knockdown or antibody blockade of SIRP-α. In rodent aortic rings, treatment with thrombospondin-1 increased the production of superoxide and inhibited nitric oxide-mediated vasodilation in a SIRP-α-dependent manner. Renal IRI upregulated the thrombospondin-1-SIRP-α signaling axis and was associated with increased superoxide production and cell death. A SIRP-α antibody that blocks thrombospondin-1 activation of SIRP-α mitigated the effects of renal IRI, increasing blood flow, suppressing production of reactive oxygen species, and preserving cellular architecture. A role for CD47 in SIRP-α activation in these pathways is also described. Overall, these results suggest that thrombospondin-1 binding to SIRP-α on nonphagocytic cells activates NADPH oxidase, limits vasodilation, and promotes renal IRI.

  18. Targeted inhibition of IL-18 attenuates irinotecaninduced intestinal mucositis in mice

    PubMed Central

    Lima-Júnior, R C P; Freitas, H C; Wong, D V T; Wanderley, C W S; Nunes, L G; Leite, L L; Miranda, S P; Souza, M H L P; Brito, G A C; Magalhães, P J C; Teixeira, M M; Cunha, F Q; Ribeiro, R A

    2014-01-01

    Background and Purpose Intestinal mucositis is a common side-effect of irinotecan-based cancer chemotherapy regimens. This mucositis is associated with cytokine activation and NO synthesis. Production of IL-18 is up-regulated in patients suffering from inflammatory bowel disease. Therefore, we have investigated the role of IL-18 in the pathogenesis of irinotecan-induced intestinal mucositis. Experimental Approach Wild type (WT), IL-18 or caspase-1 knockout mice were treated with either saline or irinotecan (60 mg·kg−1 per 4 days, i.p.) or the IL-18 binding protein (IL-18bp, 10 mg·kg−1) before irinotecan. On day 5, diarrhoea was monitored and proximal intestinal strips were obtained for histopathology, in vitro gut contractility, myeloperoxidase (MPO) and inducible NOS (iNOS) activity, and detection of IL-18 expression. Key Results Irinotecan induced severe diarrhoea accompanied by intestinal injury (villi shortening and increased crypt depth). Additionally, irinotecan treatment increased MPO and iNOS activity, iNOS immunostaining and IL-18 expression in WT mice compared with saline treatment. The IL-18 production was associated with macrophages. In vitro, intestinal smooth muscle strips were hyperresponsive to ACh after irinotecan treatment. Increases in MPO and iNOS activity, intestinal contractility and diarrhoea were prevented in caspase-1 knockout and IL-18 knockout mice, and in IL-18bp-treated WT mice. Furthermore, the Survival of irinotecan-treated mice was increased and iNOS immunoexpression and IL-18 production prevented in IL-18 knockout mice. Conclusions and Implications Targeting IL-18 function may be a promising therapeutic approach to decreasing the severity of intestinal mucositis during irinotecan treatment regimens. PMID:24428790

  19. Global deletion of thrombospondin-1 increases cardiac and skeletal muscle capillarity and exercise capacity in mice.

    PubMed

    Malek, Moh H; Olfert, I Mark

    2009-06-01

    Thrombospondin-1 (TSP-1) is a known inhibitor of angiogenesis; however, a skeletal muscle phenotype of TSP-1 null mice has not been investigated. The purposes of this study were to compare and contrast TSP-1 null and wild-type mice by examining the following: (1) capillarity in the skeletal and cardiac muscles; (2) fibre type composition and oxidative enzyme activity in the hindlimb; and (3) the consequences of TSP-1 gene deletion for exercise capacity. In TSP-1 null mice, maximal running speed was 11% greater and time to exhaustion during submaximal endurance running was 67% greater compared with wild-type mice. Morphometric analyses revealed that TSP-1 null mice had higher (P < 0.05) capillarity in the heart and skeletal muscle than wild-type mice, whereas no differences for fibre type composition or oxidative enzyme activity were present between the two groups. Cardiac function, as measured by transthoracic echocardiography, revealed no difference in myocardial contractility but greater left ventricular end-diastolic and systolic dimensions, corresponding to an elevated heart mass in the TSP-1 null mice. The results of this study indicate that TSP-1 is an important endogenous negative regulator of angiogenesis that prevents excessive capillarization in the heart and skeletal muscles. The increased capillarity alone was sufficient to increase (P < 0.05) exercise capacity. These data demonstrate that the capillary-to-muscle interface is a critical factor that limits oxygen transport during exercise. PMID:19297388

  20. Alternative chemistries for the synthesis of thrombospondin-1 type 1 repeats.

    PubMed

    Tiefenbrunn, Theresa K; Blanco-Canosa, Juan; Dawson, Philip E

    2010-01-01

    Synthetic protein engineering has benefited from the development of diverse methods for the synthesis of functionalized peptide fragments and approaches for their subsequent assembly into full length polypeptides. Here we describe a series of synthetic approaches for the total chemical synthesis of the second type 1 repeat of thrombospondin-1 (TSR2) that vary in both the location of the ligation site and alpha-amine protecting group strategy (Boc/Fmoc) used for the synthesis of the associated peptide fragments. These syntheses illustrate that challenging peptide sequences can result from the protecting group strategy as well as from sequence-dependent factors. Importantly, we find that such challenges can be overcome by altering the chemistry used for solid phase peptide synthesis, the choice of ligation site, and the resin used as a solid support. From these studies, we have developed a robust synthetic route to the TSR2 polypeptide consisting of native chemical ligation between an N-terminal fragment synthesized by Boc-SPPS and a C-terminal fragment synthesized by Fmoc-SPPS. Finally, the folded TSR2 domain is obtained following an optimized oxidative folding protocol using an excess of oxidized glutathione. This optimized synthesis will enable the use of unnatural amino acids to probe the unusual structure and anti-angiogenic activity of this protein domain.

  1. Extensible byssus of Pinctada fucata: Ca2+-stabilized nanocavities and a thrombospondin-1 protein

    PubMed Central

    Liu, Chuang; Li, Shiguo; Huang, Jingliang; Liu, Yangjia; Jia, Ganchu; Xie, Liping; Zhang, Rongqing

    2015-01-01

    The extensible byssus is produced by the foot of bivalve animals, including the pearl oyster Pinctada fucata, and enables them to attach to hard underwater surfaces. However, the mechanism of their extensibility is not well understood. To understand this mechanism, we analyzed the ultrastructure, composition and mechanical properties of the P. fucata byssus using electron microscopy, elemental analysis, proteomics and mechanical testing. In contrast to the microstructures of Mytilus sp. byssus, the P. fucata byssus has an exterior cuticle without granules and an inner core with nanocavities. The removal of Ca2+ by ethylenediaminetetraacetic acid (EDTA) treatment expands the nanocavities and reduces the extensibility of the byssus, which is accompanied by a decrease in the β-sheet conformation of byssal proteins. Through proteomic methods, several proteins with antioxidant and anti-corrosive properties were identified as the main components of the distal byssus regions. Specifically, a protein containing thrombospondin-1 (TSP-1), which is highly expressed in the foot, is hypothesized to be responsible for byssus extensibility. Together, our findings demonstrate the importance of inorganic ions and multiple proteins for bivalve byssus extension, which could guide the future design of biomaterials for use in seawater. PMID:26446436

  2. Extensible byssus of Pinctada fucata: Ca2+-stabilized nanocavities and a thrombospondin-1 protein

    NASA Astrophysics Data System (ADS)

    Liu, Chuang; Li, Shiguo; Huang, Jingliang; Liu, Yangjia; Jia, Ganchu; Xie, Liping; Zhang, Rongqing

    2015-10-01

    The extensible byssus is produced by the foot of bivalve animals, including the pearl oyster Pinctada fucata, and enables them to attach to hard underwater surfaces. However, the mechanism of their extensibility is not well understood. To understand this mechanism, we analyzed the ultrastructure, composition and mechanical properties of the P. fucata byssus using electron microscopy, elemental analysis, proteomics and mechanical testing. In contrast to the microstructures of Mytilus sp. byssus, the P. fucata byssus has an exterior cuticle without granules and an inner core with nanocavities. The removal of Ca2+ by ethylenediaminetetraacetic acid (EDTA) treatment expands the nanocavities and reduces the extensibility of the byssus, which is accompanied by a decrease in the β-sheet conformation of byssal proteins. Through proteomic methods, several proteins with antioxidant and anti-corrosive properties were identified as the main components of the distal byssus regions. Specifically, a protein containing thrombospondin-1 (TSP-1), which is highly expressed in the foot, is hypothesized to be responsible for byssus extensibility. Together, our findings demonstrate the importance of inorganic ions and multiple proteins for bivalve byssus extension, which could guide the future design of biomaterials for use in seawater.

  3. Astrocyte-secreted thrombospondin-1 modulates synapse and spine defects in the fragile X mouse model.

    PubMed

    Cheng, Connie; Lau, Sally K M; Doering, Laurie C

    2016-01-01

    Astrocytes are key participants in various aspects of brain development and function, many of which are executed via secreted proteins. Defects in astrocyte signaling are implicated in neurodevelopmental disorders characterized by abnormal neural circuitry such as Fragile X syndrome (FXS). In animal models of FXS, the loss in expression of the Fragile X mental retardation 1 protein (FMRP) from astrocytes is associated with delayed dendrite maturation and improper synapse formation; however, the effect of astrocyte-derived factors on the development of neurons is not known. Thrombospondin-1 (TSP-1) is an important astrocyte-secreted protein that is involved in the regulation of spine development and synaptogenesis. In this study, we found that cultured astrocytes isolated from an Fmr1 knockout (Fmr1 KO) mouse model of FXS displayed a significant decrease in TSP-1 protein expression compared to the wildtype (WT) astrocytes. Correspondingly, Fmr1 KO hippocampal neurons exhibited morphological deficits in dendritic spines and alterations in excitatory synapse formation following long-term culture. All spine and synaptic abnormalities were prevented in the presence of either astrocyte-conditioned media or a feeder layer derived from FMRP-expressing astrocytes, or following the application of exogenous TSP-1. Importantly, this work demonstrates the integral role of astrocyte-secreted signals in the establishment of neuronal communication and identifies soluble TSP-1 as a potential therapeutic target for Fragile X syndrome. PMID:27485117

  4. Thrombospondin 1 Deficiency Ameliorates the Development of Adriamycin-Induced Proteinuric Kidney Disease

    PubMed Central

    Maimaitiyiming, Hasiyeti; Zhou, Qi; Wang, Shuxia

    2016-01-01

    Accumulating evidence suggests that thrombospondin 1 (TSP1) is an important player in diabetic nephropathy. However, the role of TSP1 in podocyte injury and the development of non-diabetic proteinuric kidney disease is largely unknown. In the current study, by using a well-established podocyte injury model (adriamycin-induced nephropathy mouse model), we examined the contribution of TSP1 to the development of proteinuric kidney disease. We found that TSP1 was up-regulated in the glomeruli, notably in podocytes, in adriamycin injected mice before the onset of proteinuria. ADR treatment also stimulated TSP1 expression in cultured human podocytes in vitro. Moreover, increased TSP1 mediated ADR-induced podocyte apoptosis and actin cytoskeleton disorganization. This TSP1’s effect was through a CD36-dependent mechanism and involved in the stimulation of p38MAPK pathway. Importantly, in vivo data demonstrated that TSP1 deficiency protected mice from ADR induced podocyte loss and foot process effacement. ADR induced proteinuria, glomerulosclerosis, renal macrophage infiltration and inflammation was also attenuated in TSP1 deficient mice. Taken together, these studies provide new evidence that TSP1 contributes to the development of non-diabetic proteinuric kidney disease by stimulating podocyte injury and the progression of renal inflammation. PMID:27196103

  5. Interaction of thrombospondin1 and CD36 contributes to obesity-associated podocytopathy.

    PubMed

    Cui, Wenpeng; Maimaitiyiming, Hasiyeti; Zhou, Qi; Norman, Heather; Zhou, Changcheng; Wang, Shuxia

    2015-07-01

    Obesity is associated with podocyte injury and the development of proteinuria. Elevated plasma free fatty acid is one of the characteristics of obesity and has been linked to podocyte dysfunction. However, the mechanisms remain unclear. In the current study, we examined the effect of saturated free fatty acid (FFA) on human podocyte apoptosis and function in vitro. The mechanism and its in vivo relevance were also determined. We found that FFA treatment induced human podocyte apoptosis and dysfunction, which was associated with increased expression of a matricellular protein-thrombospondin1 (TSP1). FFA stimulated TSP1 expression in podocytes at the transcriptional levels through activation of MAPK pathway. Addition of purified TSP1 to cell culture media induced podocyte apoptosis and dysfunction. Tis effect is though a TGF-β independent mechanism. Moreover, peptide treatment to block TSP1 binding to its receptor-CD36 attenuated FFA induced podocyte apoptosis, suggesting that TSP1/CD36 interaction mediates FFA-induced podocyte apoptosis. Importantly, using a diet-induced obese mouse model, in vivo data demonstrated that obesity-associated podocyte apoptosis and dysfunction were attenuated in TSP1 deficient mice as well as in CD36 deficient mice. Taken together, these studies provide novel evidence that the interaction of TSP1 with its receptor CD36 contributes to obesity--associated podocytopathy.

  6. Thrombospondin-1 and CD47 Regulation of Cardiac, Pulmonary and Vascular Responses in Health and Disease

    PubMed Central

    Rogers, Natasha M.; Sharifi-Sanjani, Maryam; Csányi, Gábor; Pagano, Patrick J.; Isenberg, Jeffrey S.

    2014-01-01

    Cardiovascular homeostasis and health is maintained through the balanced interactions of cardiac generated blood flow and cross-talk between the cellular components that comprise blood vessels. Central to this cross-talk is endothelial generated nitric oxide (NO) that stimulates relaxation of the contractile vascular smooth muscle (VSMC) layer of blood vessels. In cardiovascular disease this balanced interaction is disrupted and NO signaling lost. Work over the last several years indicates regulation of NO is much more complex than previously believed. It is now apparent the secreted protein thrombospondin-1 (TSP1), that is upregulated in cardiovascular disease and animal models of the same, on activating cell surface receptor CD47, redundantly inhibits NO production and NO signaling. This inhibitory event has implications for baseline and disease-related responses mediated by NO. Further work has identified that TSP1-CD47 signaling stimulates enzymatic reactive oxygen species (ROS) production to further limit blood flow and promote vascular disease. Herein consideration is given to the most recent discoveries in this regard which identify the TSP1-CD47 axis as a major proximate governor of cardiovascular health. PMID:24418252

  7. IL-18 cytokine levels modulate innate immune responses and cryptosporidiosis in mice.

    PubMed

    Bedi, Brahmchetna; McNair, Nina N; Förster, Irmgard; Mead, Jan R

    2015-01-01

    IL-18 is known to play a key role limiting Cryptosporidium parvum infection. In this study, we show that IL-18 depletion in SCID mice significantly exacerbates C. parvum infection, whereas, treatment with recombinant IL-18 (rIL-18), significantly decreases the parasite load, as compared to controls. Increases in serum IFN-γ levels as well as the up-regulation of the antimicrobial peptides, cathelicidin antimicrobial peptide and beta defensin 3 (Defb3) were observed in the intestinal mucosa of mice treated with rIL-18. In addition, C. parvum infection significantly increased mRNA expression levels (> 50 fold) of the alpha defensins, Defa3 and 5, respectively. Interestingly, we also found a decrease in mRNA expression of IL-33 (a recently identified cytokine in the same family as IL-18) in the small intestinal tissue from mice treated with rIL-18. In comparison, the respective genes were induced by IL-18 depletion. Our findings suggest that IL-18 can mediate its protective effects via different routes such as IFN-γ induction or by directly stimulating intestinal epithelial cells to increase antimicrobial activity.

  8. Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18.

    PubMed

    Wynn, James Lawrence; Wilson, Chris S; Hawiger, Jacek; Scumpia, Philip O; Marshall, Andrew F; Liu, Jin-Hua; Zharkikh, Irina; Wong, Hector R; Lahni, Patrick; Benjamin, John T; Plosa, Erin J; Weitkamp, Jörn-Hendrik; Sherwood, Edward R; Moldawer, Lyle L; Ungaro, Ricardo; Baker, Henry V; Lopez, M Cecilia; McElroy, Steven J; Colliou, Natacha; Mohamadzadeh, Mansour; Moore, Daniel Jensen

    2016-05-10

    Interleukin (IL)-18 is an important effector of innate and adaptive immunity, but its expression must also be tightly regulated because it can potentiate lethal systemic inflammation and death. Healthy and septic human neonates demonstrate elevated serum concentrations of IL-18 compared with adults. Thus, we determined the contribution of IL-18 to lethality and its mechanism in a murine model of neonatal sepsis. We find that IL-18-null neonatal mice are highly protected from polymicrobial sepsis, whereas replenishing IL-18 increased lethality to sepsis or endotoxemia. Increased lethality depended on IL-1 receptor 1 (IL-1R1) signaling but not adaptive immunity. In genome-wide analyses of blood mRNA from septic human neonates, expression of the IL-17 receptor emerged as a critical regulatory node. Indeed, IL-18 administration in sepsis increased IL-17A production by murine intestinal γδT cells as well as Ly6G(+) myeloid cells, and blocking IL-17A reduced IL-18-potentiated mortality to both neonatal sepsis and endotoxemia. We conclude that IL-17A is a previously unrecognized effector of IL-18-mediated injury in neonatal sepsis and that disruption of the deleterious and tissue-destructive IL-18/IL-1/IL-17A axis represents a novel therapeutic approach to improve outcomes for human neonates with sepsis.

  9. Role of IL-18 in Second-Hand Smoke–Induced Emphysema

    PubMed Central

    Kratzer, Adelheid; Salys, Jonas; Nold-Petry, Claudia; Cool, Carlyne; Zamora, Martin; Bowler, Russ; Koczulla, Andreas Rembert; Janciauskiene, Sabina; Edwards, Michael G.; Dinarello, Charles A.

    2013-01-01

    Chronic second-hand smoke (SHS) exposure comprises the main risk factor for nonsmokers to develop chronic obstructive pulmonary disease (COPD). However, the mechanisms behind the chronic inflammation and lung destruction remain incompletely understood. In this study, we show that chronic exposure of Sprague-Dawley rats to SHS results in a significant increase of proinflammatory cytokine IL-18 and chemokine (C-C motif) ligand 5 in the bronchoalveolar lavage fluid (BALF) and a significant decrease of vascular endothelial growth factor (VEGF) in the lung tissue. SHS exposure resulted in progressive alveolar airspace enlargement, cell death, pulmonary vessel loss, vessel muscularization, collagen deposition, and right ventricular hypertrophy. Alveolar macrophages displayed a foamy phenotype and a decreased expression of the natural inhibitor of IL-18, namely, IL-18 binding protein (IL-18BP). Moreover, IL-18 down-regulated the expression of VEGF receptor–1 and VEGFR receptor–2, and induced apoptosis in pulmonary microvascular endothelial cells in vitro. We also observed a trend toward increased concentrations of IL-18 in the BALF of patients with COPD. Our findings suggest that IL-18–mediated endothelial cell death may contribute to vascular destruction and disappearance in SHS-induced COPD. Moreover, IL-18 and IL-18BP are potential new targets for therapeutics. PMID:23392573

  10. IL-18 cytokine levels modulate innate immune responses and cryptosporidiosis in mice.

    PubMed

    Bedi, Brahmchetna; McNair, Nina N; Förster, Irmgard; Mead, Jan R

    2015-01-01

    IL-18 is known to play a key role limiting Cryptosporidium parvum infection. In this study, we show that IL-18 depletion in SCID mice significantly exacerbates C. parvum infection, whereas, treatment with recombinant IL-18 (rIL-18), significantly decreases the parasite load, as compared to controls. Increases in serum IFN-γ levels as well as the up-regulation of the antimicrobial peptides, cathelicidin antimicrobial peptide and beta defensin 3 (Defb3) were observed in the intestinal mucosa of mice treated with rIL-18. In addition, C. parvum infection significantly increased mRNA expression levels (> 50 fold) of the alpha defensins, Defa3 and 5, respectively. Interestingly, we also found a decrease in mRNA expression of IL-33 (a recently identified cytokine in the same family as IL-18) in the small intestinal tissue from mice treated with rIL-18. In comparison, the respective genes were induced by IL-18 depletion. Our findings suggest that IL-18 can mediate its protective effects via different routes such as IFN-γ induction or by directly stimulating intestinal epithelial cells to increase antimicrobial activity. PMID:25155632

  11. Chronic delivery of a thrombospondin-1 mimetic decreases skeletal muscle capillarity in mice.

    PubMed

    Audet, Gerald N; Fulks, Daniel; Stricker, Janelle C; Olfert, I Mark

    2013-01-01

    Angiogenesis is an essential process for normal skeletal muscle function. There is a growing body of evidence suggesting that thrombospondin-1 (TSP-1), a potent antiangiogenic protein in tumorigenesis, is an important regulator of both physiological and pathological skeletal muscle angiogenesis. We tested the hypothesis that chronic exposure to a TSP-1 mimetic (ABT-510), which targets the CD36 TSP-1 receptor, would decrease skeletal muscle capillarity as well as alter the balance between positive and negative angiogenic proteins under basal conditions. Osmotic minipumps with either ABT-510 or vehicle (5% dextrose) were implanted subcutaneously in the subscapular region of C57/BL6 mice for 14 days. When compared to the vehicle treated mice, the ABT-510 group had a 20% decrease in capillarity in the superficial region of the gastrocnemius (GA), 11% decrease in the plantaris (PLT), and a 35% decrease in the soleus (SOL). ABT-510 also decreased muscle protein expression of vascular endothelial growth factor (VEGF) in both the GA (-140%) and SOL (-62%); however there was no change in VEGF in the PLT. Serum VEGF was not altered in ABT-510 treated animals. Endogenous TSP-1 protein expression in all muscles remained unaltered. Tunnel staining revealed no difference in muscle apoptosis between ABT-510 and vehicle treated groups. These data provide evidence that the anti-angiogenic effects of TSP-1 are mediated, at least in part, via the CD36 receptor. It also suggests that under physiologic conditions the TSP-1/CD36 axis plays a role in regulating basal skeletal muscle microvessel density.

  12. Chronic Delivery of a Thrombospondin-1 Mimetic Decreases Skeletal Muscle Capillarity in Mice

    PubMed Central

    Audet, Gerald N.; Fulks, Daniel; Stricker, Janelle C.; Olfert, I. Mark

    2013-01-01

    Angiogenesis is an essential process for normal skeletal muscle function. There is a growing body of evidence suggesting that thrombospondin-1 (TSP-1), a potent antiangiogenic protein in tumorigenesis, is an important regulator of both physiological and pathological skeletal muscle angiogenesis. We tested the hypothesis that chronic exposure to a TSP-1 mimetic (ABT-510), which targets the CD36 TSP-1 receptor, would decrease skeletal muscle capillarity as well as alter the balance between positive and negative angiogenic proteins under basal conditions. Osmotic minipumps with either ABT-510 or vehicle (5% dextrose) were implanted subcutaneously in the subscapular region of C57/BL6 mice for 14 days. When compared to the vehicle treated mice, the ABT-510 group had a 20% decrease in capillarity in the superficial region of the gastrocnemius (GA), 11% decrease in the plantaris (PLT), and a 35% decrease in the soleus (SOL). ABT-510 also decreased muscle protein expression of vascular endothelial growth factor (VEGF) in both the GA (−140%) and SOL (−62%); however there was no change in VEGF in the PLT. Serum VEGF was not altered in ABT-510 treated animals. Endogenous TSP-1 protein expression in all muscles remained unaltered. Tunnel staining revealed no difference in muscle apoptosis between ABT-510 and vehicle treated groups. These data provide evidence that the anti-angiogenic effects of TSP-1 are mediated, at least in part, via the CD36 receptor. It also suggests that under physiologic conditions the TSP-1/CD36 axis plays a role in regulating basal skeletal muscle microvessel density. PMID:23405239

  13. Acute and chronic mu opioids differentially regulate thrombospondins 1 and 2 isoforms in astrocytes.

    PubMed

    Phamduong, Ellen; Rathore, Maanjot K; Crews, Nicholas R; D'Angelo, Alexander S; Leinweber, Andrew L; Kappera, Pranay; Krenning, Thomas M; Rendell, Victoria R; Belcheva, Mariana M; Coscia, Carmine J

    2014-02-19

    Chronic opioids induce synaptic plasticity, a major neuronal adaptation. Astrocyte activation in synaptogenesis may play a critical role in opioid tolerance, withdrawal, and dependence. Thrombospondins 1 and 2 (TSP1/2) are astrocyte-secreted matricellular glycoproteins that promote neurite outgrowth as well as dendritic spine and synapse formation, all of which are inhibited by chronic μ opioids. In prior studies, we discovered that the mechanism of TSP1 regulation by μ opioids in astrocytes involves crosstalk between three different classes of receptors, μ opioid receptor, EGFR and TGFβR. Moreover, TGFβ1 stimulated TSP1 expression via EGFR and ERK/MAPK activation, indicating that EGFR is a signaling hub for opioid and TGFβ1 actions. Using various selective antagonists, and inhibitors, here we compared the mechanisms of chronic opioid regulation of TSP1/2 isoform expression in vivo and in immortalized rat cortical astrocytes. TSP1/2 release from astrocytes was also monitored. Acute and chronic μ opioids, morphine, and the prototypic μ ligand, DAMGO, modulated TSP2 protein levels. TSP2 but not TSP1 protein content was up-regulated by acute (3 h) morphine or DAMGO by an ERK/MAPK dependent mechanism. Paradoxically, TSP2 protein levels were altered neither by TGFβ1 nor by astrocytic neurotrophic factors, EGF, CNTF, and BMP4. TSP1/2 immunofluorescence was increased in astrocytes subjected to scratch-wounding, suggesting TSPs may be useful markers for the "reactive" state of these cells and potentially for different types of injury. Previously, we determined that chronic morphine attenuated both neurite outgrowth and synapse formation in cocultures of primary astrocytes and neurons under similar temporal conditions that μ opioids reduced TSP1 protein levels in astrocytes. Here we found that, after the same 8 day treatment, morphine or DAMGO diminished TSP2 protein levels in astrocytes. Therefore, μ opioids may deter synaptogenesis via both TSP1/2 isoforms, but

  14. IL-27 stimulates human NK-cell effector functions and primes NK cells for IL-18 responsiveness.

    PubMed

    Ziblat, Andrea; Domaica, Carolina I; Spallanzani, Raúl G; Iraolagoitia, Ximena L Raffo; Rossi, Lucas E; Avila, Damián E; Torres, Nicolás I; Fuertes, Mercedes B; Zwirner, Norberto W

    2015-01-01

    IL-27, a member of the IL-12 family of cytokines, is produced by APCs, and displays pro- and anti-inflammatory effects. How IL-27 affects human NK cells still remains unknown. In this study, we observed that mature DCs secreted IL-27 and that blockade of IL-27R (CD130) reduced the amount of IFN-γ produced by NK cells during their coculture, showing the importance of IL-27 during DC-NK-cell crosstalk. Accordingly, human rIL-27 stimulated IFN-γ secretion by NK cells in a STAT1-dependent manner, induced upregulation of CD25 and CD69 on NK cells, and displayed a synergistic effect with IL-18. Preincubation experiments demonstrated that IL-27 primed NK cells for IL-18-induced IFN-γ secretion, which was associated with an IL-27-driven upregulation of T-bet expression. Also, IL-27 triggered NKp46-dependent NK-cell-mediated cytotoxicity against Raji, T-47D, and HCT116 cells, and IL-18 enhanced this cytotoxic response. Such NK-cell-mediated cytotoxicity involved upregulation of perforin, granule exocytosis, and TRAIL-mediated cytotoxicity but not Fas-FasL interaction. Moreover, IL-27 also potentiated Ab-dependent cell-mediated cytotoxicity against mAb-coated target cells. Taken together, IL-27 stimulates NK-cell effector functions, which might be relevant in different physiological and pathological situations. PMID:25308526

  15. An NK Cell Perforin Response Elicited via IL-18 Controls Mucosal Inflammation Kinetics during Salmonella Gut Infection

    PubMed Central

    Müller, Anna A.; Dolowschiak, Tamas; Sellin, Mikael E.; Felmy, Boas; Verbree, Carolin; Gadient, Sandra; Westermann, Alexander J.; Vogel, Jörg; LeibundGut-Landmann, Salome; Hardt, Wolf-Dietrich

    2016-01-01

    Salmonella Typhimurium (S.Tm) is a common cause of self-limiting diarrhea. The mucosal inflammation is thought to arise from a standoff between the pathogen's virulence factors and the host's mucosal innate immune defenses, particularly the mucosal NAIP/NLRC4 inflammasome. However, it had remained unclear how this switches the gut from homeostasis to inflammation. This was studied using the streptomycin mouse model. S.Tm infections in knockout mice, cytokine inhibition and –injection experiments revealed that caspase-1 (not -11) dependent IL-18 is pivotal for inducing acute inflammation. IL-18 boosted NK cell chemoattractants and enhanced the NK cells' migratory capacity, thus promoting mucosal accumulation of mature, activated NK cells. NK cell depletion and Prf-/- ablation (but not granulocyte-depletion or T-cell deficiency) delayed tissue inflammation. Our data suggest an NK cell perforin response as one limiting factor in mounting gut mucosal inflammation. Thus, IL-18-elicited NK cell perforin responses seem to be critical for coordinating mucosal inflammation during early infection, when S.Tm strongly relies on virulence factors detectable by the inflammasome. This may have broad relevance for mucosal defense against microbial pathogens. PMID:27341123

  16. An NK Cell Perforin Response Elicited via IL-18 Controls Mucosal Inflammation Kinetics during Salmonella Gut Infection.

    PubMed

    Müller, Anna A; Dolowschiak, Tamas; Sellin, Mikael E; Felmy, Boas; Verbree, Carolin; Gadient, Sandra; Westermann, Alexander J; Vogel, Jörg; LeibundGut-Landmann, Salome; Hardt, Wolf-Dietrich

    2016-06-01

    Salmonella Typhimurium (S.Tm) is a common cause of self-limiting diarrhea. The mucosal inflammation is thought to arise from a standoff between the pathogen's virulence factors and the host's mucosal innate immune defenses, particularly the mucosal NAIP/NLRC4 inflammasome. However, it had remained unclear how this switches the gut from homeostasis to inflammation. This was studied using the streptomycin mouse model. S.Tm infections in knockout mice, cytokine inhibition and -injection experiments revealed that caspase-1 (not -11) dependent IL-18 is pivotal for inducing acute inflammation. IL-18 boosted NK cell chemoattractants and enhanced the NK cells' migratory capacity, thus promoting mucosal accumulation of mature, activated NK cells. NK cell depletion and Prf-/- ablation (but not granulocyte-depletion or T-cell deficiency) delayed tissue inflammation. Our data suggest an NK cell perforin response as one limiting factor in mounting gut mucosal inflammation. Thus, IL-18-elicited NK cell perforin responses seem to be critical for coordinating mucosal inflammation during early infection, when S.Tm strongly relies on virulence factors detectable by the inflammasome. This may have broad relevance for mucosal defense against microbial pathogens. PMID:27341123

  17. Alternaria extract activates autophagy that induces IL-18 release from airway epithelial cells.

    PubMed

    Murai, Hiroki; Okazaki, Shintaro; Hayashi, Hisako; Kawakita, Akiko; Hosoki, Koa; Yasutomi, Motoko; Sur, Sanjiv; Ohshima, Yusei

    2015-09-01

    Alternaria alternata is a major outdoor allergen that causes allergic airway diseases. Alternaria extract (ALT-E) has been shown to induce airway epithelial cells to release IL-18 and thereby initiate Th2-type responses. We investigated the underlying mechanisms involved in IL-18 release from ALT-E-stimulated airway epithelial cells. Normal human bronchial epithelial cells and A549 human lung adenocarcinoma cells were stimulated with ALT-E in the presence of different inhibitors of autophagy or caspases. IL-18 levels in culture supernatants were measured by ELISA. The numbers of autophagosomes, an LC3-I to LC3-II conversion, and p62 degradation were determined by immunofluorescence staining and immunoblotting. 3-methyladenine and bafilomycin, which inhibit the formation of preautophagosomal structures and autolysosomes, respectively, suppressed ALT-E-induced IL-18 release by cells, whereas caspase 1 and 8 inhibitors did not. ALT-E-stimulation increased autophagosome formation, LC-3 conversion, and p62 degradation in airway epithelial cells. LPS-stimulation induced the LC3 conversion in A549 cells, but did not induce IL-18 release or p62 degradation. Unlike LPS, ALT-E induced airway epithelial cells to release IL-18 via an autophagy dependent, caspase 1 and 8 independent pathway. Although autophagy has been shown to negatively regulate canonical inflammasome activity in TLR-stimulated macrophages, our data indicates that this process is an unconventional mechanism of IL-18 secretion by airway epithelial cells.

  18. Hippocampal volume and depressive symptoms are linked to serum IL-18 in schizophrenia

    PubMed Central

    Piras, Fabrizio; Palladino, Ilaria; Iorio, Mariangela; Salani, Francesca; Ciaramella, Antonio; Chiapponi, Chiara; Caltagirone, Carlo; Spalletta, Gianfranco

    2015-01-01

    Objective: Since schizophrenia (SCZ) is often accompanied by hippocampal abnormalities and dysregulation of cytokine production, this study aimed to investigate the impact of the cytokine interleukin (IL)-18, whose biological system appears to be perturbed in SCZ, on brain structure and clinical severity in patients with chronic SCZ. Methods: The serum levels of IL-18, including its free bioactive form (i.e., the cytokine fraction not bound to its specific endogenous inhibitor IL-18 binding protein), were evaluated in a case-control study involving 71 individuals with SCZ diagnosis and 29 healthy controls. All participants underwent brain MRI automatic evaluation for hippocampal volume estimation. The Positive and Negative Syndrome Scale (PANSS) was administered to measure severity of symptoms in patients with SCZ. Results: Lower amounts of free IL-18 were related to smaller hippocampal volume measures in patients with SCZ. Furthermore, in line with a possible neuroprotective effect of the cytokine, higher levels of free IL-18 corresponded to lower subscores of PANSS depression in patients with SCZ. Conclusions: These findings demonstrate that the levels of circulating bioactive IL-18 are related to both hippocampal volume and severity of psychopathologic symptoms in patients with SCZ, confirming the involvement of the cytokine in SCZ pathophysiology and suggesting hippocampal-dependent and neuroprotective functions of IL-18 in this clinical context. PMID:25977936

  19. Heparan sulfate modification of the transmembrane receptor CD47 is necessary for inhibition of T cell receptor signaling by thrombospondin-1.

    PubMed

    Kaur, Sukhbir; Kuznetsova, Svetlana A; Pendrak, Michael L; Sipes, John M; Romeo, Martin J; Li, Zhuqing; Zhang, Lijuan; Roberts, David D

    2011-04-29

    Cell surface proteoglycans on T cells contribute to retroviral infection, binding of chemokines and other proteins, and are necessary for some T cell responses to the matricellular glycoprotein thrombospondin-1. The major cell surface proteoglycans expressed by primary T cells and Jurkat T cells have an apparent M(r) > 200,000 and are modified with chondroitin sulfate and heparan sulfate chains. Thrombospondin-1 bound in a heparin-inhibitable manner to this proteoglycan and to a soluble form released into the medium. Based on mass spectrometry, knockdown, and immunochemical analyses, the proteoglycan contains two major core proteins as follows: amyloid precursor-like protein-2 (APLP2, apparent M(r) 230,000) and CD47 (apparent M(r) > 250,000). CD47 is a known thrombospondin-1 receptor but was not previously reported to be a proteoglycan. This proteoglycan isoform of CD47 is widely expressed on vascular cells. Mutagenesis identified glycosaminoglycan modification of CD47 at Ser(64) and Ser(79). Inhibition of T cell receptor signaling by thrombospondin-1 was lost in CD47-deficient T cells that express the proteoglycan isoform of APLP2, indicating that binding to APLP2 is not sufficient. Inhibition of CD69 induction was restored in CD47-deficient cells by re-expressing CD47 or an S79A mutant but not by the S64A mutant. Therefore, inhibition of T cell receptor signaling by thrombospondin-1 is mediated by CD47 and requires its modification at Ser(64).

  20. IL-18 Production from the NLRP1 Inflammasome Prevents Obesity and Metabolic Syndrome.

    PubMed

    Murphy, Andrew J; Kraakman, Michael J; Kammoun, Helene L; Dragoljevic, Dragana; Lee, Man K S; Lawlor, Kate E; Wentworth, John M; Vasanthakumar, Ajithkumar; Gerlic, Motti; Whitehead, Lachlan W; DiRago, Ladina; Cengia, Louise; Lane, Rachael M; Metcalf, Donald; Vince, James E; Harrison, Leonard C; Kallies, Axel; Kile, Benjamin T; Croker, Ben A; Febbraio, Mark A; Masters, Seth L

    2016-01-12

    Interleukin-18 (IL-18) is activated by Caspase-1 in inflammasome complexes and has anti-obesity effects; however, it is not known which inflammasome regulates this process. We found that mice lacking the NLRP1 inflammasome phenocopy mice lacking IL-18, with spontaneous obesity due to intrinsic lipid accumulation. This is exacerbated when the mice are fed a high-fat diet (HFD) or a high-protein diet, but not when mice are fed a HFD with low energy density (high fiber). Furthermore, mice with an activating mutation in NLRP1, and hence increased IL-18, have decreased adiposity and are resistant to diet-induced metabolic dysfunction. Feeding these mice a HFD further increased plasma IL-18 concentrations and strikingly resulted in loss of adipose tissue mass and fatal cachexia, which could be prevented by genetic deletion of IL-18. Thus, NLRP1 is an innate immune sensor that functions in the context of metabolic stress to produce IL-18, preventing obesity and metabolic syndrome.

  1. Acetylsalicylic acid inhibits IL-18-induced cardiac fibroblast migration through the induction of RECK.

    PubMed

    Siddesha, Jalahalli M; Valente, Anthony J; Sakamuri, Siva S V P; Gardner, Jason D; Delafontaine, Patrice; Noda, Makoto; Chandrasekar, Bysani

    2014-07-01

    The pathogenesis of cardiac fibrosis and adverse remodeling is thought to involve the ROS-dependent induction of inflammatory cytokines and matrix metalloproteinases (MMPs), and the activation and migration of cardiac fibroblasts (CF). Here we investigated the role of RECK (reversion-inducing-cysteine-rich protein with Kazal motifs), a unique membrane-anchored MMP regulator, on IL-18-induced CF migration, and the effect of acetylsalicylic acid (ASA) on this response. In a Matrigel invasion assay, IL-18-induced migration of primary mouse CF was dependent on both IKK/NF-κB- and JNK/AP-1-mediated MMP9 induction and Sp1-mediated RECK suppression, mechanisms that required Nox4-dependent H(2)O(2) generation. Notably, forced expression of RECK attenuated IL-18-induced MMP9 activation and CF migration. Further, therapeutic concentrations of ASA inhibited IL-18-induced H(2)O(2) generation, MMP9 activation, RECK suppression, and CF migration. The salicylic acid moiety of ASA similarly attenuated IL-18-induced CF migration. Thus, ASA may exert potential beneficial effect in cardiac fibrosis through multiple protective mechanisms.

  2. Intratumoral delivery of encapsulated IL-12, IL-18 and TNF-alpha in a model of metastatic breast cancer.

    PubMed

    Sabel, Michael S; Su, Gang; Griffith, Kent A; Chang, Alfred E

    2010-07-01

    Intratumoral (i.t.) cytokine release through the use of poly-lactic acid microspheres (PLAM) holds tremendous potential for the immunotherapy of breast cancer as it harnesses the immunologic potential of autologous tumor in a clinically feasible and minimally toxic manner. We examined the potential of combinations of i.t. IL-12, IL-18 and TNF-alpha PLAM to generate a tumor-specific immune response and improve outcome in a model of metastatic breast cancer. Balb/c mice with established 4T1 mammary carcinomas were treated with a single injection of BSA, IL-12, IL-18 or TNF-alpha-loaded PLAM alone or in combination after spontaneous metastases occurred. Combined treatment with IL-12 and TNF-alpha PLAM was superior to all other treatments, including the triple combination of IL-12, IL-18 and TNF-alpha in ablation of the primary tumor, eradicating distant disease and enhancing survival. Simultaneous delivery of IL-12 and TNF-alpha was superior to sequential delivery of IL-12 followed by TNF-alpha, but not TNF-alpha followed by IL-12. In vivo lymphocyte depletion studies established that the effects of IL-12 alone are mediated primarily by NK cells, while the combination of IL-12 and TNF-alpha is dependent upon CD8+ T-cells. Only the combination of IL-12 and TNF-alpha results in an increase in both CD4+ and CD8+ T-cells and a reduction in CD4+CD25+ cells. While there was no change in the dendritic cell population, IL-12 and TNF-alpha resulted in a dramatic increase in DC maturation and antigen presentation. Neoadjuvant immunotherapy with simultaneous intratumoral delivery of IL-12 and TNF-alpha PLAM augments DC antigen presentation and increases cytotoxic T-cells without increasing regulatory T-cells, resulting in a T-cell based anti-tumor immune response capable of eradicating disseminated disease. The addition of IL-18 did not improve the efficacy. PMID:19802695

  3. Monoclonal antibodies to murine thrombospondin-1 and thrombospondin-2 reveal differential expression patterns in cancer and low antigen expression in normal tissues

    SciTech Connect

    Bujak, Emil; Pretto, Francesca; Ritz, Danilo; Gualandi, Laura; Wulhfard, Sarah; Neri, Dario

    2014-09-10

    There is a considerable interest for the discovery and characterization of tumor-associated antigens, which may facilitate antibody-based pharmacodelivery strategies. Thrombospondin-1 and thrombospondin-2 are homologous secreted proteins, which have previously been reported to be overexpressed during remodeling typical for wound healing and tumor progression and to possibly play a functional role in cell proliferation, migration and apoptosis. To our knowledge, a complete immunohistochemical characterization of thrombospondins levels in normal rodent tissues has not been reported so far. Using antibody phage technology, we have generated and characterized monoclonal antibodies specific to murine thrombospondin-1 and thrombospondin-2, two antigens which share 62% aminoacid identity. An immunofluorescence analysis revealed that both antigens are virtually undetectable in normal mouse tissues, except for a weak staining of heart tissue by antibodies specific to thrombospondin-1. The analysis also showed that thrombospondin-1 was strongly expressed in 5/7 human tumors xenografted in nude mice, while it was only barely detectable in 3/8 murine tumors grafted in immunocompetent mice. By contrast, a high-affinity antibody to thrombospondin-2 revealed a much lower level of expression of this antigen in cancer specimens. Our analysis resolves ambiguities related to conflicting reports on thrombosponding expression in health and disease. Based on our findings, thrombospondin-1 (and not thrombospondin-2) may be considered as a target for antibody-based pharmacodelivery strategies, in consideration of its low expression in normal tissues and its upregulation in cancer. - Highlights: • High affinity monoclonal antibodies to murine and human TSP1 and 2 were raised. • Both antigens are virtually undetectable in normal mouse tissues. • Strong positivity of human tumor xenografts for TSP1 was detected. • Study revealed much lower level of TSP2 expression in cancer specimens

  4. Inflammasome activation of IL-18 results in endothelial progenitor cell dysfunction in systemic lupus erythematosus.

    PubMed

    Kahlenberg, J Michelle; Thacker, Seth G; Berthier, Celine C; Cohen, Clemens D; Kretzler, Matthias; Kaplan, Mariana J

    2011-12-01

    Systemic lupus erythematosus (SLE) is an autoimmune disease with heterogeneous manifestations including severe organ damage and vascular dysfunction leading to premature atherosclerosis. IFN-α has been proposed to have an important role in the development of lupus and lupus-related cardiovascular disease, partly by repression of IL-1 pathways leading to impairments in vascular repair induced by endothelial progenitor cells (EPCs) and circulating angiogenic cells (CACs). Counterintuitively, SLE patients also display transcriptional upregulation of the IL-1β/IL-18 processing machinery, the inflammasome. To understand this dichotomy and its impact on SLE-related cardiovascular disease, we examined cultures of human and murine control or lupus EPC/CACs to determine the role of the inflammasome in endothelial differentiation. We show that caspase-1 inhibition improves dysfunctional SLE EPC/CAC differentiation into mature endothelial cells and blocks IFN-α-mediated repression of this differentiation, implicating inflammasome activation as a crucial downstream pathway leading to aberrant vasculogenesis. Furthermore, serum IL-18 levels are elevated in SLE and correlate with EPC/CAC dysfunction. Exogenous IL-18 inhibits endothelial differentiation in control EPC/CACs and neutralization of IL-18 in SLE EPC/CAC cultures restores their capacity to differentiate into mature endothelial cells, supporting a deleterious effect of IL-18 on vascular repair in vivo. Upregulation of the inflammasome machinery was operational in vivo, as evidenced by gene array analysis of lupus nephritis biopsies. Thus, the effects of IFN-α are complex and contribute to an elevated risk of cardiovascular disease by suppression of IL-1β pathways and by upregulation of the inflammasome machinery and potentiation of IL-18 activation.

  5. Imbalanced production of IL-18 and its antagonist in human diseases, and its implications for HIV-1 infection.

    PubMed

    Samarani, Suzanne; Allam, Ossama; Sagala, Patrick; Aldabah, Zainab; Jenabian, Mohammad-Ali; Mehraj, Vikram; Tremblay, Cécile; Routy, Jean-Pierre; Amre, Devendra; Ahmad, Ali

    2016-06-01

    IL-18 is a pleiotropic and multifunctional cytokine that belongs to the IL-1 family. It is produced as a biologically inactive precursor, which is cleaved into its active mature form mainly by caspase-1. The caspase becomes active from its inactive precursor (procaspase-1) upon assembly of an inflammasome. Because of IL-18's potential pro-inflammatory and tissue destructive effects, its biological activities are tightly controlled in the body by its naturally occurring antagonist called IL-18BP. The antagonist is produced in the body both constitutively and in response to an increased production of IL-18 as a negative feedback mechanism. Under physiological conditions, most of IL-18 in the circulation is bound with IL-18BP and is inactive. However, an imbalance in the production of IL-18 and its antagonist (an increase in the production of IL-18 with a decrease, no increase or an insufficient increase in the production of IL-18BP) has been described in many chronic inflammatory diseases in humans. The imbalance results in an increase in the concentrations of free IL-18 (unbound with its antagonist) resulting in increased biological activities of the cytokine that contribute towards pathogenesis of the disease. In this article, we provide an overview of the current biology of IL-18 and its antagonist, discuss how the imbalance occurs in HIV infections and how it contributes towards development of AIDS and other non-AIDS-associated clinical conditions occurring in HIV-infected individuals undergoing combination anti-retroviral therapy (cART). Finally, we discuss challenges facing immunotherapeutic strategies aimed at restoring balance between IL-18 and its antagonist in these patients.

  6. Inflammasome-dependent and -independent IL-18 production mediates immunity to the ISCOMATRIX adjuvant.

    PubMed

    Wilson, Nicholas S; Duewell, Peter; Yang, Becky; Li, Yun; Marsters, Scot; Koernig, Sandra; Latz, Eicke; Maraskovsky, Eugene; Morelli, Adriana Baz; Schnurr, Max; Ashkenazi, Avi

    2014-04-01

    Adjuvants are an essential component of modern vaccines and used for their ability to elicit immunity to coadministered Ags. Many adjuvants in clinical development are particulates, but how they drive innate and adaptive immune responses remains poorly understood. Studies have shown that a number of vaccine adjuvants activate inflammasome pathways in isolated APCs. However, the contribution of inflammasome activation to vaccine-mediated immunity in vivo remains controversial. In this study, we evaluated immune cell responses to the ISCOMATRIX adjuvant (IMX) in mice. Like other particulate vaccine adjuvants, IMX potently activated the NALP-3-ASC-Caspase-1 inflammasome in APCs, leading to IL-1β and IL-18 production. The IL-18R pathway, but not IL-1R, was required for early innate and subsequent cellular immune responses to a model IMX vaccine. APCs directly exposed to IMX underwent an endosome-mediated cell-death response, which we propose initiates inflammatory events locally at the injection site. Importantly, both inflammasome-related and -unrelated pathways contributed to IL-18 dependence in vivo following IMX administration. TNF-α provided a physiological priming signal for inflammasome-dependent IL-18 production by APCs, which correlated with reduced vaccine-mediated immune cell responses in TNF-α- or TNFR-deficient mice. Taken together, our findings highlight an important disconnect between the mechanisms of vaccine adjuvant action in vitro versus in vivo.

  7. Further development of the NCTC 2544 IL-18 assay to identify in vitro contact allergens.

    PubMed

    Galbiati, V; Mitjans, M; Lucchi, L; Viviani, B; Galli, C L; Marinovich, M; Corsini, E

    2011-04-01

    Several European Union legislations request the use of in vitro methods for toxicological evaluations, including sensitization, in order to increase consumer safety but also to reduce the use of animals. The EU project SENS-IT-IV addresses the need of developing predictive in vitro tests to assess contact and respiratory hypersensitivity reactions. In this context, we have recently reported the possibility to use IL-18 production in the human keratinocyte cell line NCTC 2544 to discriminate contact sensitizer from irritants and low molecular weight respiratory allergens. The aims of the present study were to further develop this assay in order to optimize experimental conditions; to develop a 96-well plate format to establish a high throughput assay; to test the performance of other available keratinocyte cell lines, and to understand the signal transduction pathway involved in p-phenylenediamine (PPD)-induced IL-18 production. If cells reach confluence at the moment of treatment, the ability to identify contact allergens is lost; therefore a careful check for the optimal cell density using PPD as reference contact allergen is critical. In our hands, a cell density of 1-2.5 × 10(5)cells/ml gave optimal stimulation. In order to develop a high throughput test, cells seeded in 96-well plate were exposed to contact allergens (2,4-dinitrochlorobenzene, p-phenylenediamine, isoeugenol, cinnamaldehyde, tetramethylthiuram disulfite, resorcinol, cinnamic alcohol and eugenol), irritants (phenol, sodium laurel sulphate, lactic acid and salicylic acid) and respiratory allergens (hexachloroplatinate, diphenylmethane diisocyanate, trimellitic anhydride). A selective increase in total (intracellular plus released) IL-18 was observed 24h later in cells treated with contact allergens, whereas no changes were observed following treatment with respiratory allergens and irritants, confirming previous results obtained in a 24-well format assay. A selective induction of IL-18 was also

  8. Cloning, protein expression and immunogenicity of HBs-murine IL-18 fusion DNA vaccine.

    PubMed

    Channarong, Sunee; Mitrevej, Ampol; Sinchaipanid, Nuttanan; Usuwantim, Kanchana; Kulkeaw, Kasem; Chaicumpa, Wanpen

    2007-12-01

    Hepatitis B is a global serious disease caused by hepatitis B virus (HBV). There is no known cure for hepatitis B. The best way to deal with the disease is by preventing with hepatitis B vaccine. However, the current protein-based vaccines made up of recombinant hepatitis B surface antigen (HBsAg) are ineffective in chronic HBV carriers and a significant number of the vaccinees do not mount the protective immune response. Novel DNA-based immunization may overcome the deficits of the protein-based immunization and may provide more effective prophylactic and therapeutic outcomes. In this study, we constructed a recombinant plasmid carrying gene encoding the HBV surface antigen (HBs) linked to DNA segment encoding full-length murine interleukin-18, i.e. pcDNA-HBs-IL-18. Immunogenicity of the DNA construct was carried out in BALB/c mice in comparison with mock, i.e. pcDNA3.1+ and vaccines comprised of pRc/CMV-HBs and pRc/CMV-HBs plus pcDNA-IL-18. All vaccinated mice revealed significant serum anti-HBs IgG response after two intramuscular injections of the vaccines at 28 day interval as compared to the level of mock. Co-administration of pRc/CMV-HBs and pcDNA-IL-18 elicited arbitrarily higher levels of anti-HBs IgG than the levels in mice immunized with pRc/CMV-HBs alone and mice that received pcDNA-HBs-IL-18 although not statistically different. Further experiments are needed to investigate the subisotypes of the IgG antibody, the kinetics of cytokine and the cell-mediated immune response. For this communication, the prototype HBs-IL-18 DNA vaccine was successfully constructed and the gene encoding murine IL-18 was successfully cloned. The latter can be co-injected with the antigen coding DNA or used as a fusion partner to the DNA for priming the immune response. The recombinant HBs and full-length IL-18 proteins have potential for other research purposes. They may be used also as standard proteins in the protein quantification assay. PMID:18402297

  9. Thrombospondin-1 as a Paradigm for the Development of Antiangiogenic Agents Endowed with Multiple Mechanisms of Action

    PubMed Central

    Rusnati, Marco; Urbinati, Chiara; Bonifacio, Silvia; Presta, Marco; Taraboletti, Giulia

    2010-01-01

    Uncontrolled neovascularization occurs in several angiogenesis-dependent diseases, including cancer. Neovascularization is tightly controlled by the balance between angiogenic growth factors and antiangiogenic agents. The various natural angiogenesis inhibitors identified so far affect neovascularization by different mechanisms of action. Thrombospondin-1 (TSP-1) is a matricellular modular glycoprotein that acts as a powerful endogenous inhibitor of angiogenesis. It acts both indirectly, by sequestering angiogenic growth factors and effectors in the extracellular environment, and directly, by inducing an antiangiogenic program in endothelial cells following engagement of specific receptors including CD36, CD47, integrins and proteoglycans (all involved in angiogenesis ). In view of its central, multifaceted role in angiogenesis, TSP-1 has served as a source of antiangiogenic tools, including TSP-1 fragments, synthetic peptides and peptidomimetics, gene therapy strategies, and agents that up-regulate TSP-1 expression. This review discusses TSP-1-based inhibitors of angiogenesis, their mechanisms of action and therapeutic potential, drawing our experience with angiogenic growth factor-interacting TSP-1 peptides, and the possibility of exploiting them to design novel antiangiogenic agents.

  10. Cyclic thrombospondin-1 mimetics: grafting of a thrombospondin sequence into circular disulfide-rich frameworks to inhibit endothelial cell migration.

    PubMed

    Chan, Lai Yue; Craik, David J; Daly, Norelle L

    2015-01-01

    Tumour formation is dependent on nutrient and oxygen supply from adjacent blood vessels. Angiogenesis inhibitors can play a vital role in controlling blood vessel formation and consequently tumour progression by inhibiting endothelial cell proliferation, sprouting and migration. The primary aim of the present study was to design cyclic thrombospondin-1 (TSP-1) mimetics using disulfide-rich frameworks for anti-angiogenesis therapies and to determine whether these peptides have better potency than the linear parent peptide. A short anti-angiogenic heptapeptide fragment from TSP-1 (GVITRIR) was incorporated into two cyclic disulfide-rich frameworks, namely MCoTI-II (Momordica cochinchinensis trypsin inhibitor-II) and SFTI-1 (sunflower trypsin inhibitor-1). The cyclic peptides were chemically synthesized and folded in oxidation buffers, before being tested in a series of in vitro evaluations. Incorporation of the bioactive heptapeptide fragment into the cyclic frameworks resulted in peptides that inhibited microvascular endothelial cell migration, and had no toxicity against normal primary human endothelial cells or cancer cells. Importantly, all of the designed cyclic TSP-1 mimetics were far more stable than the linear heptapeptide in human serum. The present study has demonstrated a novel approach to stabilize the active region of TSP-1. The anti-angiogenic activity of the native TSP-1 active fragment was maintained in the new TSP-1 mimetics and the results provide a new chemical approach for the design of TSP-1 mimetics. PMID:26464514

  11. Chemopreventive apigenin controls UVB-induced cutaneous proliferation and angiogenesis through HuR and thrombospondin-1.

    PubMed

    Tong, Xin; Mirzoeva, Salida; Veliceasa, Dorina; Bridgeman, Bryan B; Fitchev, Philip; Cornwell, Mona L; Crawford, Susan E; Pelling, Jill C; Volpert, Olga V

    2014-11-30

    Plant flavonoid apigenin prevents and inhibits UVB-induced carcinogenesis in the skin and has strong anti-proliferative and anti-angiogenic properties. Here we identify mechanisms, by which apigenin controls these oncogenic events. We show that apigenin acts, at least in part, via endogenous angiogenesis inhibitor, thrombospondin-1 (TSP1). TSP1 expression by the epidermal keratinocytes is potently inhibited by UVB. It inhibits cutaneous angiogenesis and UVB-induced carcinogenesis. We show that apigenin restores TSP1 in epidermal keratinocytes subjected to UVB and normalizes proliferation and angiogenesis in UVB-exposed skin. Importantly, reconstituting TSP1 anti-angiogenic function in UVB-irradiated skin with a short bioactive peptide mimetic representing exclusively its anti-angiogenic domain reproduced the anti-proliferative and anti-angiogenic effects of apigenin. Cox-2 and HIF-1α are important mediators of angiogenesis. Both apigenin and TSP1 peptide mimetic attenuated their induction by UVB. Finally we identified the molecular mechanism, whereby apigenin did not affect TSP1 mRNA, but increased de novo protein synthesis. Knockdown studies implicated the RNA-binding protein HuR, which controls mRNA stability and translation. Apigenin increased HuR cytoplasmic localization and physical association with TSP1 mRNA causing de novo TSP1 synthesis. HuR cytoplasmic localization was, in turn, dependent on CHK2 kinase. Together, our data provide a new mechanism, by which apigenin controls UVB-induced carcinogenesis. PMID:25526033

  12. Thrombospondin-1 deficiency causes a shift from fibroproliferative to inflammatory kidney disease and delays onset of renal failure.

    PubMed

    Zeisberg, Michael; Tampe, Björn; LeBleu, Valerie; Tampe, Desiree; Zeisberg, Elisabeth M; Kalluri, Raghu

    2014-10-01

    Thrombospondin-1 (TSP1) is a multifunctional matricellular protein known to promote progression of chronic kidney disease. To gain insight into the underlying mechanisms through which TSP1 accelerates chronic kidney disease, we compared disease progression in Col4a3 knockout (KO) mice, which develop spontaneous kidney failure, with that of Col4a3;Tsp1 double-knockout (DKO) mice. Decline of excretory renal function was significantly delayed in the absence of TSP1. Although Col4a3;Tsp1 DKO mice did progress toward end-stage renal failure, their kidneys exhibited distinct histopathological lesions, compared with creatinine level-matched Col4a3 KO mice. Although kidneys of both Col4a3 KO and Col4a3;Tsp1 DKO mice exhibited a widened tubulointerstitium, predominant lesions in Col4a3 KO kidneys were collagen deposition and fibroblast accumulation, whereas in Col4a3;Tsp1 DKO kidney inflammation was predominant, with less collagen deposition. Altered disease progression correlated with impaired activation of transforming growth factor-β1 (TGF-β1) in vivo and in vitro in the absence of TSP1. In summary, our findings suggest that TSP1 contributes to progression of chronic kidney disease by catalyzing activation of latent TGF-β1, resulting in promotion of a fibroproliferative response over an inflammatory response. Furthermore, the findings suggest that fibroproliferative and inflammatory lesions are independent entities, both of which contribute to decline of renal function.

  13. Cyclic thrombospondin-1 mimetics: grafting of a thrombospondin sequence into circular disulfide-rich frameworks to inhibit endothelial cell migration.

    PubMed

    Chan, Lai Yue; Craik, David J; Daly, Norelle L

    2015-10-13

    Tumour formation is dependent on nutrient and oxygen supply from adjacent blood vessels. Angiogenesis inhibitors can play a vital role in controlling blood vessel formation and consequently tumour progression by inhibiting endothelial cell proliferation, sprouting and migration. The primary aim of the present study was to design cyclic thrombospondin-1 (TSP-1) mimetics using disulfide-rich frameworks for anti-angiogenesis therapies and to determine whether these peptides have better potency than the linear parent peptide. A short anti-angiogenic heptapeptide fragment from TSP-1 (GVITRIR) was incorporated into two cyclic disulfide-rich frameworks, namely MCoTI-II (Momordica cochinchinensis trypsin inhibitor-II) and SFTI-1 (sunflower trypsin inhibitor-1). The cyclic peptides were chemically synthesized and folded in oxidation buffers, before being tested in a series of in vitro evaluations. Incorporation of the bioactive heptapeptide fragment into the cyclic frameworks resulted in peptides that inhibited microvascular endothelial cell migration, and had no toxicity against normal primary human endothelial cells or cancer cells. Importantly, all of the designed cyclic TSP-1 mimetics were far more stable than the linear heptapeptide in human serum. The present study has demonstrated a novel approach to stabilize the active region of TSP-1. The anti-angiogenic activity of the native TSP-1 active fragment was maintained in the new TSP-1 mimetics and the results provide a new chemical approach for the design of TSP-1 mimetics.

  14. Cyclic thrombospondin-1 mimetics: grafting of a thrombospondin sequence into circular disulfide-rich frameworks to inhibit endothelial cell migration

    PubMed Central

    Chan, Lai Yue; Craik, David J.; Daly, Norelle L.

    2015-01-01

    Tumour formation is dependent on nutrient and oxygen supply from adjacent blood vessels. Angiogenesis inhibitors can play a vital role in controlling blood vessel formation and consequently tumour progression by inhibiting endothelial cell proliferation, sprouting and migration. The primary aim of the present study was to design cyclic thrombospondin-1 (TSP-1) mimetics using disulfide-rich frameworks for anti-angiogenesis therapies and to determine whether these peptides have better potency than the linear parent peptide. A short anti-angiogenic heptapeptide fragment from TSP-1 (GVITRIR) was incorporated into two cyclic disulfide-rich frameworks, namely MCoTI-II (Momordica cochinchinensis trypsin inhibitor-II) and SFTI-1 (sunflower trypsin inhibitor-1). The cyclic peptides were chemically synthesized and folded in oxidation buffers, before being tested in a series of in vitro evaluations. Incorporation of the bioactive heptapeptide fragment into the cyclic frameworks resulted in peptides that inhibited microvascular endothelial cell migration, and had no toxicity against normal primary human endothelial cells or cancer cells. Importantly, all of the designed cyclic TSP-1 mimetics were far more stable than the linear heptapeptide in human serum. The present study has demonstrated a novel approach to stabilize the active region of TSP-1. The anti-angiogenic activity of the native TSP-1 active fragment was maintained in the new TSP-1 mimetics and the results provide a new chemical approach for the design of TSP-1 mimetics. PMID:26464514

  15. Thrombospondin-1 might be a therapeutic target to suppress RB cells by regulating the DNA double-strand breaks repair

    PubMed Central

    Zhang, Zhang; Zhang, Ping; Yang, Ying; Wu, Nandan; Xu, Lijun; Zhang, Jing; Ge, Jian; Yu, Keming; Zhuang, Jing

    2016-01-01

    Retinoblastoma (RB) arises from the retina, and its growth usually occurs under the retina and toward the vitreous. Ideal therapy should aim to inhibit the tumor and protect neural cells, increasing the patient's life span and quality of life. Previous studies have demonstrated that Thrombospondin-1 (TSP-1) is associated with neurogenesis, neovascularization and tumorigenesis. However, at present, the bioactivity of TSP-1 in retinoblastoma has not been defined. Herein, we demonstrated that TSP-1 was silenced in RB cell lines and clinical tumor samples. HDAC inhibitor, Trichostatin A (TSA), could notably transcriptionally up-regulate TSP-1 in RB cells, WERI-Rb1 cells and Y79 cells. Moreover, we found human recombinant TSP-1 (hTSP-1) could significantly inhibit the cell viability of RB cells both in vitro and in vivo. Interestingly, hTSP-1 could significantly induce the expression of γ-H2AX, a well-characterized in situ marker of DNA double-strand breaks (DSBs) in RB cells. The DNA NHEJ pathway in WERI-Rb1 cells could be significantly inhibited by hTSP-1. A mutation in Rb1 might be involved in the hTSP-1-medicated γ-H2AX increasing in WERI-Rb1 cells. Furthermore, hTSP-1 could inhibit RB cells while promoting retinal neurocyte survival in the neuronal and retinoblastoma cell co-culture system. As such, TSP-1 may become a therapeutic target for treatment of retinoblastoma. PMID:26756218

  16. Thrombospondin 1 mediates high-fat diet-induced muscle fibrosis and insulin resistance in male mice.

    PubMed

    Inoue, Mayumi; Jiang, Yibin; Barnes, Richard H; Tokunaga, Masakuni; Martinez-Santibañez, Gabriel; Geletka, Lynn; Lumeng, Carey N; Buchner, David A; Chun, Tae-Hwa

    2013-12-01

    Thrombospondin 1 (THBS1 or TSP-1) is a circulating glycoprotein highly expressed in hypertrophic visceral adipose tissues of humans and mice. High-fat diet (HFD) feeding induces the robust increase of circulating THBS1 in the early stages of HFD challenge. The loss of Thbs1 protects male mice from diet-induced weight gain and adipocyte hypertrophy. Hyperinsulinemic euglycemic clamp study has demonstrated that Thbs1-null mice are protected from HFD-induced insulin resistance. Tissue-specific glucose uptake study has revealed that the insulin-sensitive phenotype of Thbs1-null mice is mostly mediated by skeletal muscles. Further assessments of the muscle phenotype using RNA sequencing, quantitative PCR, and histological studies have demonstrated that Thbs1-null skeletal muscles are protected from the HFD-dependent induction of Col3a1 and Col6a1, coupled with a new collagen deposition. At the same time, the Thbs1-null mice display a better circadian rhythm and higher amplitude of energy expenditure with a browning phenotype in sc adipose tissues. These results suggest that THBS1, which circulates in response to a HFD, may induce insulin resistance and fibrotic tissue damage in skeletal muscles as well as the de-browning of sc adipose tissues in the early stages of a HFD challenge. Our study may shed new light on the pathogenic role played by a circulating extracellular matrix protein in the cross talk between adipose tissues and skeletal muscles during obesity progression. PMID:24140711

  17. Thrombospondin-1 might be a therapeutic target to suppress RB cells by regulating the DNA double-strand breaks repair.

    PubMed

    Chen, Pei; Yu, Na; Zhang, Zhang; Zhang, Ping; Yang, Ying; Wu, Nandan; Xu, Lijun; Zhang, Jing; Ge, Jian; Yu, Keming; Zhuang, Jing

    2016-02-01

    Retinoblastoma (RB) arises from the retina, and its growth usually occurs under the retina and toward the vitreous. Ideal therapy should aim to inhibit the tumor and protect neural cells, increasing the patient's life span and quality of life. Previous studies have demonstrated that Thrombospondin-1 (TSP-1) is associated with neurogenesis, neovascularization and tumorigenesis. However, at present, the bioactivity of TSP-1 in retinoblastoma has not been defined. Herein, we demonstrated that TSP-1 was silenced in RB cell lines and clinical tumor samples. HDAC inhibitor, Trichostatin A (TSA), could notably transcriptionally up-regulate TSP-1 in RB cells, WERI-Rb1 cells and Y79 cells. Moreover, we found human recombinant TSP-1 (hTSP-1) could significantly inhibit the cell viability of RB cells both in vitro and in vivo. Interestingly, hTSP-1 could significantly induce the expression of γ-H2AX, a well-characterized in situ marker of DNA double-strand breaks (DSBs) in RB cells. The DNA NHEJ pathway in WERI-Rb1 cells could be significantly inhibited by hTSP-1. A mutation in Rb1 might be involved in the hTSP-1-medicated γ-H2AX increasing in WERI-Rb1 cells. Furthermore, hTSP-1 could inhibit RB cells while promoting retinal neurocyte survival in the neuronal and retinoblastoma cell co-culture system. As such, TSP-1 may become a therapeutic target for treatment of retinoblastoma.

  18. Bone marrow-derived Gr1+ cells can generate a metastasis-resistant microenvironment via induced secretion of thrombospondin-1

    PubMed Central

    Catena, Raúl; Bhattacharya, Nandita; Rayes, Tina El; Wang, Suming; Choi, Hyejin; Gao, Dingcheng; Ryu, Seongho; Joshi, Natasha; Bielenberg, Diane; Lee, Sharrell B.; Haukaas, Svein A.; Gravdal, Karsten; Halvorsen, Ole J.; Akslen, Lars A.; Watnick, Randolph S.; Mittal, Vivek

    2013-01-01

    Metastatic tumors have been shown to establish permissive microenvironments for metastases via recruitment of bone marrow (BM)- derived cells. Here, we show that metastasis-incompetent tumors are also capable of generating such microenvironments. However, in these situations the otherwise pro-metastatic Gr1+ myeloid cells create a metastasis-refractory microenvironment via the induction of thrombospondin-1 (Tsp-1) by tumor-secreted prosaposin. (BM)-specific genetic deletion of Tsp-1 abolished the inhibition of metastasis, which was restored by BM transplant from Tsp-1+ donors. We also developed a 5-amino acid peptide from prosaposin as a pharmacological inducer of Tsp-1 in Gr1+ BM cells, which dramatically suppresses metastasis. These results provide mechanistic insights into why certain tumors are deficient in metastatic potential and implicate recruited Gr1+ myeloid cells as the main source of Tsp-1. The results underscore the plasticity of Gr1+ cells, which, depending on the context, promote or inhibit metastasis, and suggest that the peptide could be a potential therapeutic agent against metastatic cancer. PMID:23633432

  19. IFN-γ Production Depends on IL-12 and IL-18 Combined Action and Mediates Host Resistance to Dengue Virus Infection in a Nitric Oxide-Dependent Manner

    PubMed Central

    Cisalpino, Daniel; Amaral, Flávio A.; Souza, Patrícia R. S.; Souza, Rafael S.; Ryffel, Bernhard; Vieira, Leda Q.; Silva, Tarcília A.; Atrasheuskaya, Alena; Ignatyev, George; Sousa, Lirlândia P.; Souza, Danielle G.; Teixeira, Mauro M.

    2011-01-01

    Dengue is a mosquito-borne disease caused by one of four serotypes of Dengue virus (DENV-1–4). Severe dengue infection in humans is characterized by thrombocytopenia, increased vascular permeability, hemorrhage and shock. However, there is little information about host response to DENV infection. Here, mechanisms accounting for IFN-γ production and effector function during dengue disease were investigated in a murine model of DENV-2 infection. IFN-γ expression was greatly increased after infection of mice and its production was preceded by increase in IL-12 and IL-18 levels. In IFN-γ−/− mice, DENV-2-associated lethality, viral loads, thrombocytopenia, hemoconcentration, and liver injury were enhanced, when compared with wild type-infected mice. IL-12p40−/− and IL-18−/− infected-mice showed decreased IFN-γ production, which was accompanied by increased disease severity, higher viral loads and enhanced lethality. Blockade of IL-18 in infected IL-12p40−/− mice resulted in complete inhibition of IFN-γ production, greater DENV-2 replication, and enhanced disease manifestation, resembling the response seen in DENV-2-infected IFN-γ−/− mice. Reduced IFN-γ production was associated with diminished Nitric Oxide-synthase 2 (NOS2) expression and NOS2−/− mice had elevated lethality, more severe disease evolution and increased viral load after DENV-2 infection. Therefore, IL-12/IL-18-induced IFN-γ production and consequent NOS2 induction are of major importance to host resistance against DENV infection. PMID:22206036

  20. Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1β

    PubMed Central

    Pomerantz, Benjamin J.; Reznikov, Leonid L.; Harken, Alden H.; Dinarello, Charles A.

    2001-01-01

    The proinflammatory cytokine IL-18 was investigated for its role in human myocardial function. An ischemia/reperfusion (I/R) model of suprafused human atrial myocardium was used to assess myocardial contractile force. Addition of IL-18 binding protein (IL-18BP), the constitutive inhibitor of IL-18 activity, to the perifusate during and after I/R resulted in improved contractile function after I/R from 35% of control to 76% with IL-18BP. IL-18BP treatment also preserved intracellular tissue creatine kinase levels (by 420%). Steady-state mRNA levels for IL-18 were elevated after I/R, and the concentration of IL-18 in myocardial homogenates was increased (control, 5.8 pg/mg vs. I/R, 26 pg/mg; P < 0.01). Active IL-18 requires cleavage of its precursor form by the IL-1β-converting enzyme (caspase 1); inhibition of caspase 1 also attenuated the depression in contractile force after I/R (from 35% of control to 75.8% in treated atrial muscle; P < 0.01). Because caspase 1 also cleaves the precursor IL-1β, IL-1 receptor blockade was accomplished by using the IL-1 receptor antagonist. IL-1 receptor antagonist added to the perifusate also resulted in a reduction of ischemia-induced contractile dysfunction. These studies demonstrate that endogenous IL-18 and IL-1β play a significant role in I/R-induced human myocardial injury and that inhibition of caspase 1 reduces the processing of endogenous precursors of IL-18 and IL-1β and thereby prevents ischemia-induced myocardial dysfunction. PMID:11226333

  1. Cofactor Regulation of C5a Chemotactic Activity in Physiological Fluids. Requirement for the Vitamin D Binding Protein, Thrombospondin-1 and its Receptors

    PubMed Central

    Trujillo, Glenda; Zhang, Jianhua; Habiel, David M.; Ge, Lingyin; Ramadass, Mahalakshmi; Ghebrehiwet, Berhane; Kew, Richard R.

    2011-01-01

    Factors in physiological fluids that regulate the chemotactic activity of complement activation peptides C5a and C5a des Arg are not well understood. The vitamin D binding protein (DBP) has been shown to significantly enhance chemotaxis to C5a/C5a des Arg. More recently, platelet-derived thrombospondin-1 (TSP-1) has been shown to facilitate the augmentation of C5a-induced chemotaxis by DBP. The objective of this study was to better characterize these chemotactic cofactors and investigate the role that cell surface TSP-1 receptors CD36 and CD47 may play in this process. The chemotactic activity in C-activated normal serum, citrated plasma, DBP-depleted serum or C5 depleted serum was determined for both normal human neutrophils and U937 cell line transfected with the C5a receptor (U937-C5aR). In addition, levels of C5a des Arg, DBP and TSP-1 in these fluids were measured by RIA or ELISA. Results show that there is a clear hierarchy with C5a being the essential primary signal (DBP or TSP-1 will not function in the absence of C5a), DBP the necessary cofactor and TSP-1 a dependent tertiary factor, since it cannot function to enhance chemotaxis to C5a without DBP. Measurement of the C5a-induced intracellular calcium flux confirmed the same hierarchy observed with chemotaxis. Moreover, analysis of bronchoalveolar lavage fluid (BALF) from patients with the adult respiratory distress syndrome (ARDS) demonstrated that C5a-dependent chemotactic activity is significantly decreased after anti-DBP treatment. Finally, results show that TSP-1 utilizes cell surface receptors CD36 and CD47 to augment chemotaxis, but DBP does not bind to TSP-1, CD36 or CD47. The results clearly demonstrate that C5a/C5a des Arg needs both DBP and TSP-1 for maximal chemotactic activity and suggest that the regulation of C5a chemotactic activity in physiological fluids is more complex than previously thought. PMID:22014686

  2. Soluble IL-1RII and IL-18 are associated with incipient upper extremity soft tissue disorders.

    PubMed

    Rechardt, Martti; Shiri, Rahman; Matikainen, Sampsa; Viikari-Juntura, Eira; Karppinen, Jaro; Alenius, Harri

    2011-05-01

    Previous studies suggest a role for IL-1β in the pathophysiology of upper extremity soft tissue disorders (UESTDs). We studied the levels of interleukin-1 family members in patients with incipient UESTDs and compared them with healthy controls. In this case control study, we included 163 patients with UESTDs and symptom duration shorter than 1 month and 42 healthy controls matched for age and gender at the group level. Serum levels of cytokines IL-1α, IL-1β, IL-1Ra, IL-6, IL-8, IL-18, IL-33, TNFα and sensitized C-reactive protein as well as IL-1 family soluble receptors sIL-1RII and sST2 were assessed. We used unconditional logistic regression models to study the associations between cytokines and UESTDs. After adjustment for potential confounders, the serum levels of sIL-1RII (p<0.001) and sST2 (p=0.014) were higher in the patients than the controls. The level of IL-18 was lower in the patients than the controls (p=0.005). There were no significant differences between the patients and controls regarding the levels of IL-1α, IL-1β, IL-1Ra, IL-33, IL-6, IL-8, TNFα, or sensitized C-reactive protein. The levels of circulating sIL-1RII and IL-18 are associated with incipient UESTDs, suggesting an important role for these IL-1 family members in the early course of UESTDs. PMID:21371906

  3. Biophysical characterization, including disulfide bond assignments, of the anti-angiogenic type 1 domains of human thrombospondin-1.

    PubMed

    Huwiler, Kristin G; Vestling, Martha M; Annis, Douglas S; Mosher, Deane F

    2002-12-01

    Thrombospondin-1 (TSP1), a modular secreted glycoprotein, possesses anti-angiogenic activity both in vitro and in vivo. This activity has been localized to the thrombospondin type 1 repeats/domains (TSR). A TSP1 monomer contains three TSRs, each with a hydrophobic cluster with three conserved tryptophans (WxxWxxW), a basic cluster with two conserved arginines (RxR), and six conserved cysteines. Using the baculovirus system, we expressed TSRs of human TSP1 as either the three domains in tandem (P123) or the third domain alone (P3) and demonstrated that both P123 and P3 at nanomolar concentrations inhibit either basic fibroblast-growth-factor or sphingosine-1-phosphate induced endothelial cell migration. Far-UV circular dichroism (CD) indicated that P123 and P3 have a common global fold that is very similar to properdin, a protein with six TSRs. Near-UV CD and fluorescence quenching studies indicated the conserved tryptophans are in a structured, partially solvent-accessible, positively charged environment. N-terminal sequence and mass spectrometry analysis of trypsin-digested TSRs indicated that the RFK linker sequence between P1 and P2 is readily proteolyzed and the conserved arginines are solvent accessible. By a combination of proteolysis and mass spectrometry, the recombinant TSRs were determined to be fully disulfide bonded with a connectivity of 1-5, 2-6, and 3-4 (cysteines are numbered sequentially from N- to C-terminus). TSRs are found in numerous extracellular proteins. These TSRs share the hydrophobic and basic clusters of the TSP TSRs but some have quite different placement of cysteine residues. We propose a sorting of TSRs into six groups that reconciles our results with information about other TSRs.

  4. Structural Insight into the Role of Thrombospondin-1 Binding to Calreticulin in Calreticulin-Induced Focal Adhesion Disassembly†

    PubMed Central

    Yan, Qi; Murphy-Ullrich, Joanne E.; Song, Yuhua

    2010-01-01

    Thrombospondin-1 (TSP1) binding to calreticulin (CRT) on the cell surface stimulates association of CRT with LDL receptor-related protein (LRP1) to signal focal adhesion disassembly and engagement of cellular activities. The structural basis for this phenomenon is unknown. We studied the binding thermodynamics of the TSP1–CRT complex and the conformational changes in CRT induced by binding to TSP1 with combined binding free energy analysis, molecular dynamics simulation, and anisotropic network model restrained molecular dynamics simulation. Results showed that mutations of Lys 24 and Lys 32 in TSP1 to Ala and of amino acids 24–26 and 32–34 in CRT to Ala significantly weakened the binding of TSP1 and CRT, which is consistent with experimental results. Upon validation of the calculated binding affinity changes of the TSP1–CRT complex by mutations in key residues in TSP1 and CRT with the experimental results, we performed conformational analyses to understand the role of TSP1 binding to CRT in the induction of conformational changes in CRT. Conformational analyses showed that TSP1 binding to CRT resulted in a more “open” conformation and a significant rotational change for the CRT N-domain with respect to the CRT P-domain, which could expose the potential binding site(s) in CRT for binding to LRP1 to signal focal adhesion disassembly. Results offer structural insight into the role of TSP1 binding to CRT in CRT-induced focal adhesion disassembly. PMID:20337411

  5. Thrombospondin-1 Deficiency Causes a Shift from Fibroproliferative to Inflammatory Kidney Disease and Delays Onset of Renal Failure

    PubMed Central

    Zeisberg, Michael; Tampe, Björn; LeBleu, Valerie; Tampe, Desiree; Zeisberg, Elisabeth M.; Kalluri, Raghu

    2015-01-01

    Thrombospondin-1 (TSP1) is a multifunctional matricellular protein known to promote progression of chronic kidney disease. To gain insight into the underlying mechanisms through which TSP1 accelerates chronic kidney disease, we compared disease progression in Col4a3 knockout (KO) mice, which develop spontaneous kidney failure, with that of Col4a3;Tsp1 double-knockout (DKO) mice. Decline of excretory renal function was significantly delayed in the absence of TSP1. Although Col4a3;Tsp1 DKO mice did progress toward end-stage renal failure, their kidneys exhibited distinct histopathological lesions, compared with creatinine level–matched Col4a3 KO mice. Although kidneys of both Col4a3 KO and Col4a3;Tsp1 DKO mice exhibited a widened tubulointerstitium, predominant lesions in Col4a3 KO kidneys were collagen deposition and fibroblast accumulation, whereas in Col4a3;Tsp1 DKO kidney inflammation was predominant, with less collagen deposition. Altered disease progression correlated with impaired activation of transforming growth factor-β1 (TGF-β1) in vivo and in vitro in the absence of TSP1. In summary, our findings suggest that TSP1 contributes to progression of chronic kidney disease by catalyzing activation of latent TGF-β1, resulting in promotion of a fibroproliferative response over an inflammatory response. Furthermore, the findings suggest that fibroproliferative and inflammatory lesions are independent entities, both of which contribute to decline of renal function. PMID:25111226

  6. GTP cyclohydrolase I prevents diabetic-impaired endothelial progenitor cells and wound healing by suppressing oxidative stress/thrombospondin-1.

    PubMed

    Tie, Lu; Chen, Lu-Yuan; Chen, Dan-Dan; Xie, He-Hui; Channon, Keith M; Chen, Alex F

    2014-05-15

    Endothelial progenitor cell (EPC) dysfunction is a key contributor to diabetic refractory wounds. Endothelial nitric oxide synthase (eNOS), which critically regulates the mobilization and function of EPCs, is uncoupled in diabetes due to decreased cofactor tetrahydrobiopterin (BH4). We tested whether GTP cyclohydrolase I (GTPCH I), the rate-limiting enzyme of BH4 synthesis, preserves EPC function in type 1 diabetic mice. Type 1 diabetes was induced in wild-type (WT) and GTPCH I transgenic (Tg-GCH) mice by intraperitoneal injection of streptozotocin (STZ). EPCs were isolated from the peripheral blood and bone marrow of WT, Tg-GCH, and GTPCH I-deficient hph-1 mice. The number of EPCs was significantly lower in STZ-WT mice and hph-1 mice and was rescued in STZ Tg-GCH mice. Furthermore, GTPCH I overexpression improved impaired diabetic EPC migration and tube formation. EPCs from WT, Tg-GCH, and STZ-Tg-GCH mice were administered to diabetic excisional wounds and accelerated wound healing significantly, with a concomitant augmentation of angiogenesis. Flow cytometry measurements showed that intracellular nitric oxide (NO) levels were reduced significantly in STZ-WT and hph-1 mice, paralleled by increased superoxide anion levels; both were rescued in STZ-Tg-GCH mice. Western blot analysis revealed that thrombospondin-1 (TSP-1) was significantly upregulated in the EPCs of STZ-WT mice and hph-1 mice and suppressed in STZ-treated Tg-GCH mice. Our results demonstrate that the GTPCH I/BH4 pathway is critical to preserve EPC quantity, function, and regenerative capacity during wound healing in type 1 diabetic mice at least partly through the attenuation of superoxide and TSP-1 levels and augmentation of NO level.

  7. Leptin augments recruitment of IRF-1 and CREB to thrombospondin-1 gene promoter in vascular smooth muscle cells in vitro.

    PubMed

    Sahu, Soumyadip; Ganguly, Rituparna; Raman, Priya

    2016-08-01

    We previously reported that high pathophysiological concentrations of leptin, the adipocyte-secreted peptide, upregulate the expression of a potent proatherogenic matricellular protein, thrombospondin-1 (TSP-1), in vascular smooth muscle cells. Moreover, this regulation was found to occur at the level of transcription; however, the underlying molecular mechanisms remain unknown. The goal of the present study was to investigate the specific transcriptional mechanisms that mediate upregulation of TSP-1 expression by leptin. Primary human aortic smooth muscle cell cultures were transiently transfected with different TSP-1 gene (THBS1) promoter-linked luciferase reporter constructs, and luciferase activity in response to leptin (100 ng/ml) was assessed. We identified a long THBS1 promoter (-1270/+750) fragment with specific leptin response elements that are required for increased TSP-1 transcription by leptin. Promoter analyses, protein/DNA array and gel shift assays demonstrated activation and association of transcription factors, interferon regulatory factor-1 (IRF-1) and cAMP response element-binding protein (CREB), to the distal fragment of the THBS1 promoter in response to leptin. Supershift, chromatin immunoprecipitation, and coimmunoprecipitation assays revealed formation of a single complex between IRF-1 and CREB in response to leptin; importantly, recruitment of this complex to the THBS1 promoter mediated leptin-induced TSP-1 transcription. Finally, binding sequence decoy oligomer and site-directed mutagenesis revealed that regulatory elements for both IRF-1 (-1019 to -1016) and CREB (-1198 to -1195), specific to the distal THBS1 promoter, were required for leptin-induced TSP-1 transcription. Taken together, these findings demonstrate that leptin promotes a cooperative association between IRF-1 and CREB on the THBS1 promoter driving TSP-1 transcription in vascular smooth muscle cells. PMID:27281481

  8. Thrombospondin-1-dependent immune regulation by transforming growth factor-β2-exposed antigen-presenting cells.

    PubMed

    Mir, Fayaz Ahmad; Contreras-Ruiz, Laura; Masli, Sharmila

    2015-12-01

    An important role of transforming growth factor-β (TGF-β) in the development of regulatory T cells is well established. Although integrin-mediated activation of latent TGF-β1 is considered essential for the induction of regulatory T (Treg) cells by antigen-presenting cells (APCs), such an activation mechanism is not applicable to the TGF-β2 isoform, which lacks an integrin-binding RGD sequence in its latency-associated peptide. Mucosal and ocular tissues harbour TGF-β2-expressing APCs involved in Treg induction. The mechanisms that regulate TGF-β activation in such APCs remain unclear. In this study, we demonstrate that murine APCs exposed to TGF-β2 in the environment predominantly increase expression of TGF-β2. Such predominantly TGF-β2-expressing APCs use thrombospondin-1 (TSP-1) as an integrin-independent mechanism to activate their newly synthesized latent TGF-β2 to induce Foxp3(+) Treg cells both in vitro and in vivo. Expression of Treg induction by TGF-β2-expressing APCs is supported by a TSP-1 receptor, CD36, which facilitates activation of latent TGF-β during antigen presentation. Our results suggest that APC-derived TSP-1 is essential for the development of an adaptive regulatory immune response induced by TGF-β2-expressing APCs similar to those located at mucosal and ocular sites. These findings introduce the integrin-independent mechanism of TGF-β activation as an integral part of peripheral immune tolerance associated with TGF-β2-expressing tissues.

  9. HIF-2α-mediated induction of pulmonary thrombospondin-1 contributes to hypoxia-driven vascular remodelling and vasoconstriction

    PubMed Central

    Labrousse-Arias, David; Castillo-González, Raquel; Rogers, Natasha M.; Torres-Capelli, Mar; Barreira, Bianca; Aragonés, Julián; Cogolludo, Ángel; Isenberg, Jeffrey S.; Calzada, María J.

    2016-01-01

    Aims Hypoxic conditions stimulate pulmonary vasoconstriction and vascular remodelling, both pathognomonic changes in pulmonary arterial hypertension (PAH). The secreted protein thrombospondin-1 (TSP1) is involved in the maintenance of lung homeostasis. New work identified a role for TSP1 in promoting PAH. Nonetheless, it is largely unknown how hypoxia regulates TSP1 in the lung and whether this contributes to pathological events during PAH. Methods and results In cell and animal experiments, we found that hypoxia induces TSP1 in lungs, pulmonary artery smooth muscle cells and endothelial cells, and pulmonary fibroblasts. Using a murine model of constitutive hypoxia, gene silencing, and luciferase reporter experiments, we found that hypoxia-mediated induction of pulmonary TSP1 is a hypoxia-inducible factor (HIF)-2α-dependent process. Additionally, hypoxic tsp1−/− pulmonary fibroblasts and pulmonary artery smooth muscle cell displayed decreased migration compared with wild-type (WT) cells. Furthermore, hypoxia-mediated induction of TSP1 destabilized endothelial cell–cell interactions. This provides genetic evidence that TSP1 contributes to vascular remodelling during PAH. Expanding cell data to whole tissues, we found that, under hypoxia, pulmonary arteries (PAs) from WT mice had significantly decreased sensitivity to acetylcholine (Ach)-stimulated endothelial-dependent vasodilation. In contrast, hypoxic tsp1−/− PAs retained sensitivity to Ach, mediated in part by TSP1 regulation of pulmonary Kv channels. Translating these preclinical studies, we find in the lungs from individuals with end-stage PAH, both TSP1 and HIF-2α protein expression increased in the pulmonary vasculature compared with non-PAH controls. Conclusions These findings demonstrate that HIF-2α is clearly implicated in the TSP1 pulmonary regulation and provide new insights on its contribution to PAH-driven vascular remodelling and vasoconstriction. PMID:26503986

  10. Protection from Inflammatory Organ Damage in a Murine Model of Hemophagocytic Lymphohistiocytosis Using Treatment with IL-18 Binding Protein

    PubMed Central

    Chiossone, Laura; Audonnet, Sandra; Chetaille, Bruno; Chasson, Lionel; Farnarier, Catherine; Berda-Haddad, Yael; Jordan, Stefan; Koszinowski, Ulrich H.; Dalod, Marc; Mazodier, Karin; Novick, Daniela; Dinarello, Charles A.; Vivier, Eric; Kaplanski, Gilles

    2012-01-01

    Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition due to the association of an infectious agent with lymphocyte cytotoxicity defects, either of congenital genetic origin in children or presumably acquired in adults. In HLH patients, an excess of lymphocyte or macrophage cytokines, such as IFN-γ and TNFα is present in serum. In animal models of the disease, IFN-γ and TNF-α have been shown to play a central pathogenic role. In humans, unusually high concentrations of IL-18, an inducer of IFN-γ, and TNF-α have been reported, and are associated with an imbalance between IL-18 and its natural inhibitor IL-18 binding protein (IL-18BP) resulting in an excess of free IL-18. Here we studied whether IL-18BP could reduce disease severity in an animal model of HLH. Mouse cytomegalovirus infection in perforin-1 knock-out mice induced a lethal condition similar to human HLH characterized by cytopenia with marked inflammatory lesions in the liver and spleen as well as the presence of hemophagocytosis in bone marrow. IL-18BP treatment decreased hemophagocytosis and reversed liver as well as spleen damage. IL-18BP treatment also reduced both IFN-γ and TNF-α production by CD8+ T and NK cells, as well as Fas ligand expression on NK cell surface. These data suggest that IL-18BP is beneficial in an animal model of HLH and in combination with anti-infectious therapy may be a promising strategy to treat HLH patients. PMID:22891066

  11. Antibody and T cell responses induced in chickens immunized with avian influenza virus N1 and NP DNA vaccine with chicken IL-15 and IL-18.

    PubMed

    Lim, Kian-Lam; Jazayeri, Seyed Davoud; Yeap, Swee Keong; Mohamed Alitheen, Noorjahan Banu; Bejo, Mohd Hair; Ideris, Aini; Omar, Abdul Rahman

    2013-12-01

    We had examined the immunogenicity of a series of plasmid DNAs which include neuraminidase (NA) and nucleoprotein (NP) genes from avian influenza virus (AIV). The interleukin-15 (IL-15) and interleukin-18 (IL-18) as genetic adjuvants were used for immunization in combination with the N1 and NP AIV genes. In the first trial, 8 groups of chickens were established with 10 specific-pathogen-free (SPF) chickens per group while, in the second trial 7 SPF chickens per group were used. The overall N1 enzyme-linked immunosorbent assay (ELISA) titer in chickens immunized with the pDis/N1+pDis/IL-15 was higher compared to the chickens immunized with the pDis/N1 and this suggesting that chicken IL-15 could play a role in enhancing the humoral immune response. Besides that, the chickens that were immunized at 14-day-old (Trial 2) showed a higher N1 antibody titer compared to the chickens that were immunized at 1-day-old (Trial 1). Despite the delayed in NP antibody responses, the chickens co-administrated with IL-15 were able to induce earlier and higher antibody response compared to the pDis/NP and pDis/NP+pDis/IL-18 inoculated groups. The pDis/N1+pDis/IL-15 inoculated chickens also induced higher CD8+ T cells increase than the pDis/N1 group in both trials (P<0.05). The flow cytometry results from both trials demonstrated that the pDis/N1+pDis/IL-18 groups were able to induce CD4+ T cells higher than the pDis/N1 group (P<0.05). Meanwhile, pDis/N1+pDis/IL-18 group was able to induce CD8+ T cells higher than the pDis/N1 group (P<0.05) in Trial 2 only. In the present study, pDis/NP was not significant (P>0.05) in inducing CD4+ and CD8+ T cells when co-administered with the pDis/IL-18 in both trials in comparison to the pDis/NP. Our data suggest that the pDis/N1+pDis/IL-15 combination has the potential to be used as a DNA vaccine against AIV in chickens.

  12. Circulating levels of the interleukin (IL)-4 receptor and of IL-18 in patients with Plasmodium falciparum malaria.

    PubMed

    Perkmann, Thomas; Winkler, Heidi; Graninger, Wolfgang; Kremsner, Peter G; Winkler, Stefan

    2005-02-21

    Circulating levels of sIL-4R, IL-18 and IFN-gamma were studied by ELISA in 36 Gabonese patients with Plasmodium falciparum malaria (29 children, 7 adults). Drug induced clearance of parasitemia, studied in 22 patients with mild disease, was accompanied by a rapid decrease of sIL-4R and IFN-gamma to normal values and an increase of circulating IL-18, suggesting the downregulation of a type 2 biased immune response and a dissociated type 1 responsiveness while resolving parasitemia. Comparing subgroups with hyperparasitemia/severe anemia and mild malaria, children with severe malaria had significant higher levels of sIL-4R and IFN-gamma, whereas IL-18 levels were not statistically different. Furthermore, among those children, higher levels of circulating IL-18 correlated with a lower degree of parasitemia.

  13. IL-12 and IL-18 induce MAP kinase-dependent adhesion of T cells to extracellular matrix components.

    PubMed

    Ariel, Amiram; Novick, Daniela; Rubinstein, Menachem; Dinarello, Charles A; Lider, Ofer; Hershkoviz, Rami

    2002-07-01

    Cytokines and chemokines play an essential role in recruiting leukocytes from the circulation to the peripheral sites of inflammation by modulating cellular interactions with endothelial cell ligands and extracellular matrix (ECM). Herein, we examined regulation of T cell adhesion to ECM ligands by two major proinflammatory cytokines, interleukin (IL)-12 and IL-18. IL-12 and IL-18 induced T cell adhesion to fibronectin (FN) and hyaluronic acid at low (pM) concentrations that were mediated by specific adhesion molecules expressed on the T cell surface, namely, beta(1) integrins and CD44, respectively. The induction of adhesion by IL-12 and IL-18 was inhibited by extracellular signal-regulated kinase and p38 mitogen-activated protein kinase inhibitors (PD098059 and SB203580, respectively). In contrast, IL-12- and IL-18-induced interferon-gamma (INF-gamma) secretion from T cells was inhibited by SB203580, but not by PD098059. It is interesting that low concentrations of IL-12 and IL-18 induced T cell adhesion to FN in a synergistic manner. Thus, in addition to the regulation of late inflammatory functions such as INF-gamma production, IL-12 and IL-18, alone or in combination, regulate early inflammatory events such as T cell adhesion to inflamed sites. PMID:12101280

  14. Large-scale production of porcine mature interleukin-18 (IL-18) in silkworms using a hybrid baculovirus expression system.

    PubMed

    Muneta, Yoshihiro; Zhao, Hong Kun; Inumaru, Shigeki; Mori, Yasuyuki

    2003-02-01

    In this report, a hybrid baculovirus expression system, which means a hybrid virus of the Autographa californica nuclear polyhedrosis virus and the Bombyx mori nuclear polyhedrosis virus, was used for the large-scale production of porcine mature interleukin-18 (IL-18) in silkworms. Two recombinant hybrid baculoviruses containing cDNA of the porcine precursor IL-18 and the porcine caspase-1 were constructed and were used to infect silkworm larvae. After the co-infection of the two viruses, porcine mature IL-18 was efficiently produced in the haemolymph. The concentration of IL-18 in the haemolymph was 80-100 microg/ml, as determined by porcine IL-18 specific ELISA. This yield was twenty-times more than that of the insect cell expression system described previously. The porcine mature IL-18 produced by the silkworms strongly induced interferon-gamma (IFN-gamma) production from porcine PBMC. An insect factory system for the large-scale production of useful cytokines for livestock animals will be available in the near future. PMID:12655117

  15. NK cell-extrinsic IL-18 signaling is required for efficient NK-cell activation by vaccinia virus.

    PubMed

    Brandstadter, Joshua D; Huang, Xiaopei; Yang, Yiping

    2014-09-01

    NK cells are important for the control of vaccinia virus (VV) in vivo. Recent studies have shown that multiple pathways are required for effective activation of NK cells. These include both TLR-dependent and -independent pathways, as well as the NKG2D activating receptor that recognizes host stress-induced NKG2D ligands. However, it remains largely unknown what controls the upregulation of NKG2D ligands in response to VV infection. In this study using C57BL/6 mice, we first showed that IL-18 is critical for NK-cell activation and viral clearance. We then demonstrated that IL-18 signaling on both NK cells and DCs is required for efficient NK-cell activation upon VV infection in vitro. We further showed in vivo that efficient NK-cell activation in response to VV is dependent on DCs and IL-18 signaling in non-NK cells, suggesting an essential role for NK cell-extrinsic IL-18 signaling in NK-cell activation. Mechanistically, IL-18 signaling in DCs promotes expression of Rae-1, an NKG2D ligand. Collectively, our data reveal a previously unrecognized role for NK cell-extrinsic IL-18 signaling in NK-cell activation through upregulation of NKG2D ligands. These observations may provide insights into the design of effective NK-cell-based therapies for viral infections and cancer.

  16. IL-18 gene polymorphism in patients with visceral leishmaniasis in East Azarbaijan, Iran.

    PubMed

    Ahmadpour, Ehsan; Bazmani, Ahad; Kohansal, Mohamad Hasan; Kazemi, Abdolhasan; Babaloo, Zohre

    2016-09-01

    Visceral leishmaniasis (VL) is a parasitic disease caused by Leishmania species. According to the important role of cellular immunity against VL, this study was directed to determine the frequency of -607A/C and -137G/C genotypes on promoter region of interleukin-18 gene. The study groups included 91 patients with confirmed history of VL, 106 healthy seronegative, and 79 healthy seropositive individuals. All three groups were analyzed by amplification refractory mutation system polymerase chain reaction (ARMS-PCR). The highest rate of -607/A, and -607/C alleles was observed in seronegative individuals (66/67 %) and in the patients (72/83 %). Allele frequency of -607/C is more than -607/A allele in all groups. In position of -137, frequency of -137/G allele in all groups was more than -137/C. Statistical analysis of distribution of genotypes, did not reveal any significant difference among groups. On the basis of the results, there was no significant association between VL and polymorphism of IL-18 promoter. The results of this study showed that IL-18 gene promoter polymorphisms at positions -607 and -137 are not associated with VL in East Azerbaijan, Iran. PMID:27605823

  17. CD14 and IL18 gene polymorphisms associated with colorectal cancer subsite risks among atomic bomb survivors.

    PubMed

    Hu, Yiqun; Yoshida, Kengo; Cologne, John B; Maki, Mayumi; Morishita, Yukari; Sasaki, Keiko; Hayashi, Ikue; Ohishi, Waka; Hida, Ayumi; Kyoizumi, Seishi; Kusunoki, Yoichiro; Tokunaga, Katsushi; Nakachi, Kei; Hayashi, Tomonori

    2015-01-01

    Colorectal cancer (CRC) is a common malignancy worldwide, and chronic inflammation is a risk factor for CRC. In this study, we carried out a cohort study among the Japanese atomic bomb (A-bomb) survivor population to investigate any association between immune- and inflammation-related gene polymorphisms and CRC. We examined the effects of six single-nucleotide polymorphisms of CD14 and IL18 on relative risks (RRs) of CRC. Results showed that RRs of CRC, overall and by anatomic subsite, significantly increased with increasing radiation dose. The CD14-911A/A genotype showed statistically significant higher risks for all CRC and distal CRC compared with the other two genotypes. In addition, the IL18-137 G/G genotype showed statistically significant higher risks for proximal colon cancer compared with the other two genotypes. In phenotype-genotype analyses, the CD14-911A/A genotype presented significantly higher levels of membrane and soluble CD14 compared with the other two genotypes, and the IL18-137 G/G genotype tended to be lower levels of plasma interleukin (IL)-18 compared with the other two genotypes. These results suggest the potential involvement of a CD14-mediated inflammatory response in the development of distal CRC and an IL18-mediated inflammatory response in the development of proximal colon cancer among A-bomb survivors.

  18. Macrophage-derived IL-18 and increased fibrinogen deposition are age-related inflammatory signatures of vascular remodeling

    PubMed Central

    Rodriguez-Menocal, Luis; Faridi, Mohd Hafeez; Martinez, Laisel; Shehadeh, Lina A.; Duque, Juan C.; Wei, Yuntao; Mesa, Annia; Pena, Angela; Gupta, Vineet; Pham, Si M.

    2014-01-01

    Aging has been associated with pathological vascular remodeling and increased neointimal hyperplasia. The understanding of how aging exacerbates this process is fundamental to prevent cardiovascular complications in the elderly. This study proposes a mechanism by which aging sustains leukocyte adhesion, vascular inflammation, and increased neointimal thickness after injury. The effect of aging on vascular remodeling was assessed in the rat balloon injury model using microarray analysis, immunohistochemistry, and LINCOplex assays. The injured arteries in aging rats developed thicker neointimas than those in younger animals, and this significantly correlated with a higher number of tissue macrophages and increased vascular IL-18. Indeed, IL-18 was 23-fold more abundant in the injured vasculature of aged animals compared with young rats, while circulating levels were similar in both groups of animals. The depletion of macrophages in aged rats with clodronate liposomes ameliorated vascular accumulation of IL-18 and significantly decreased neointimal formation. IL-18 was found to inhibit apoptosis of vascular smooth muscle cells (VSMC) and macrophages, thus favoring both the formation and inflammation of the neointima. In addition, injured arteries of aged rats accumulated 18-fold more fibrinogen-γ than those of young animals. Incubation of rat peritoneal macrophages with immobilized IL-18 increased leukocyte adhesion to fibrinogen and suggested a proinflammatory positive feedback loop among macrophages, VSMC, and the deposition of fibrinogen during neointimal hyperplasia. In conclusion, our data reveal that concentration changes in vascular cytokine and fibrinogen following injury in aging rats contribute to local inflammation and postinjury neointima formation. PMID:24414074

  19. Renoprotective Effect of Lactoferrin against Chromium-Induced Acute Kidney Injury in Rats: Involvement of IL-18 and IGF-1 Inhibition

    PubMed Central

    Hegazy, Rehab; Salama, Abeer; Mansour, Dina; Hassan, Azza

    2016-01-01

    Hexavalent chromium (CrVI) is a heavy metal widely used in more than 50 industries. Nephrotoxicity is a major adverse effect of chromium poisoning. The present study investigated the potential renoprotective effect of lactoferrin (Lf) against potassium dichromate (PDC)-induced acute kidney injury (AKI) in rats. Beside, because previous studies suggest that interlukin-18 (IL-18) and insulin-like growth factor-1 (IGF-1) play important roles in promoting kidney damage, the present work aimed to evaluate the involvement of these two cytokines in PDC model of AKI and in the potential renoprotective effect of lactoferrin. Adult male albino Wistar rats were pretreated with Lf (200mg/kg/day, p.o.) or (300mg/kg/day, p.o.); the doses that are usually used in the experiment studies, for 14 days followed by a single dose of PDC (15mg/kg, s.c.). PDC caused significant increase in serum urea, creatinine, and total protein levels. This was accompanied with decreased renal glutathione content, and increased renal malondialdehyde, IL-18, IL-4, nuclear factor kappa B (NFκB), IGF-1, and the phosphorylated form of forkhead box protein O1 (FoxO1) levels. Moreover, normal expression IFN-γ mRNA and enhanced expression of TNF-α mRNA was demonstrated in renal tissues. Histopathological investigations provoked deleterious changes in the renal tissues. Tubular epithelial hyperplasia and apoptosis were demonstrated immunohistochemically by positive proliferating cell nuclear antigen (PCNA), Bax, and Caspase-3 expression, respectively. Pretreatment of rats with Lf in both doses significantly corrected all previously mentioned PDC-induced changes with no significant difference between both doses. In conclusion, the findings of the present study demonstrated the involvement of oxidative stress, inflammatory reactions, tubular hyperplasia and apoptosis in PDC-induced AKI. It suggested a role of IL-18 through stimulation of IL-4-induced inflammatory pathway, and IGF-1 through triggering FoxO1

  20. Renoprotective Effect of Lactoferrin against Chromium-Induced Acute Kidney Injury in Rats: Involvement of IL-18 and IGF-1 Inhibition.

    PubMed

    Hegazy, Rehab; Salama, Abeer; Mansour, Dina; Hassan, Azza

    2016-01-01

    Hexavalent chromium (CrVI) is a heavy metal widely used in more than 50 industries. Nephrotoxicity is a major adverse effect of chromium poisoning. The present study investigated the potential renoprotective effect of lactoferrin (Lf) against potassium dichromate (PDC)-induced acute kidney injury (AKI) in rats. Beside, because previous studies suggest that interlukin-18 (IL-18) and insulin-like growth factor-1 (IGF-1) play important roles in promoting kidney damage, the present work aimed to evaluate the involvement of these two cytokines in PDC model of AKI and in the potential renoprotective effect of lactoferrin. Adult male albino Wistar rats were pretreated with Lf (200 mg/kg/day, p.o.) or (300 mg/kg/day, p.o.); the doses that are usually used in the experiment studies, for 14 days followed by a single dose of PDC (15 mg/kg, s.c.). PDC caused significant increase in serum urea, creatinine, and total protein levels. This was accompanied with decreased renal glutathione content, and increased renal malondialdehyde, IL-18, IL-4, nuclear factor kappa B (NFκB), IGF-1, and the phosphorylated form of forkhead box protein O1 (FoxO1) levels. Moreover, normal expression IFN-γ mRNA and enhanced expression of TNF-α mRNA was demonstrated in renal tissues. Histopathological investigations provoked deleterious changes in the renal tissues. Tubular epithelial hyperplasia and apoptosis were demonstrated immunohistochemically by positive proliferating cell nuclear antigen (PCNA), Bax, and Caspase-3 expression, respectively. Pretreatment of rats with Lf in both doses significantly corrected all previously mentioned PDC-induced changes with no significant difference between both doses. In conclusion, the findings of the present study demonstrated the involvement of oxidative stress, inflammatory reactions, tubular hyperplasia and apoptosis in PDC-induced AKI. It suggested a role of IL-18 through stimulation of IL-4-induced inflammatory pathway, and IGF-1 through triggering Fox

  1. IL-18 regulates IL-1β-dependent hepatic melanoma metastasis via vascular cell adhesion molecule-1

    PubMed Central

    Vidal-Vanaclocha, Fernando; Fantuzzi, Giamila; Mendoza, Lorea; Fuentes, Angela M.; Anasagasti, Miren J.; Martín, Javier; Carrascal, Teresa; Walsh, Patrick; Reznikov, Leonid L.; Kim, Soo-Hyun; Novick, Daniela; Rubinstein, Menachem; Dinarello, Charles A.

    2000-01-01

    Proinflammatory cytokines, including IL-1β and tumor necrosis factor-α (TNF-α), promote cancer cell adhesion and liver metastases by up-regulating the expression of vascular cell adhesion molecule-1 (VCAM-1) on hepatic sinusoidal endothelium (HSE). In this study, hepatic metastasis after intrasplenically injected mouse B16 melanoma (B16M) cells was reduced 84–95% in mice with null mutations for either IL-1β or the IL-1β-converting enzyme (ICE, caspase-1) compared with wild-type mice. On day 12, 47% of wild-type mice were dead compared with 19% of either IL-1β or ICE-deficient mice. In vitro, conditioned medium from B16M cells (B16M-CM) induced the release of TNF-α and IL-1β from cultures of primary murine HSE. The effect of B16M-CM on HSE resulted in increased numbers of B16M cells adhering to HSE, which was completely abrogated by a specific inhibitor of ICE, anti-IL-18 or IL-18-binding protein. Exogenous IL-18 added to HSE also increased the number of adhering melanoma cells; however, this was not affected by IL-1 receptor blockade or TNF neutralization but rather by anti-VCAM-1. These results demonstrate a role for IL-1β and IL-18 in the development of hepatic metastases of B16M in vivo. In vitro, soluble products from B16M cells stimulate HSE to sequentially release TNF-α, IL-1β, and IL-18. The IL-18 cytokine increases expression of VCAM-1 and the adherence of melanoma cells. PMID:10639148

  2. Critical role for IL-18 in spontaneous lung inflammation caused by autophagy deficiency.

    PubMed

    Abdel Fattah, Elmoataz; Bhattacharya, Abhisek; Herron, Alan; Safdar, Zeenat; Eissa, N Tony

    2015-06-01

    Autophagy is an important component of the immune response. However, the functions of autophagy in human diseases are much less understood. We studied biological consequences of autophagy deficiency in mice lacking the essential autophagy gene Atg7 or Atg5 in myeloid cells. Surprisingly, these mice presented with spontaneous sterile lung inflammation, characterized by marked recruitment of inflammatory cells, submucosal thickening, goblet cell metaplasia, and increased collagen content. Lung inflammation was associated with increase in several proinflammatory cytokines in the bronchoalveolar lavage and in serum. This inflammation was largely driven by IL-18 as a result of constitutive inflammasome activation. Following i.p. LPS injection, autophagy-deficient mice had higher levels of proinflammatory cytokines in lungs and in serum, as well as increased mortality, than control mice. Intranasal bleomycin challenge exacerbated lung inflammation in autophagy-deficient mice and produced more severe fibrotic changes than in control mice. These results uncover a new and important role for autophagy as negative regulator of lung inflammation.

  3. [Secreted cytokines in the uterine lumina are predictive of subsequent implantation. Presence of IL18 in the uterine flushing].

    PubMed

    Ledée-Bataille, N

    2004-02-01

    The materno-foetal relationship is not simply maternal tolerance of a foreign tissue, but a series of intricate mutual cytokine interactions governing selective immune regulation and also control of the adhesion and vascularisation processes during this dialogue. There is strong evidence that locally secreted cytokines, such as interleukine 18 (IL18) control the implantation process and can cause implantation failure in case of absence or overactivation. Uterine flushing fluids may be analysed to determine the level of several cytokines. At the time of egg retrieval, the flushing procedure does not adversely affect pregnancy rates. We report a strong positive correlation between the presence of IL18 in the uterine flushing and bad implantation rates. The presence of IL18 in the lumina is the traduction of an overactivation of endometrial IL18 that should be diagnosed and treated. Moreover, endometrial biopsy could define which type of cytokinic dysregulation is implicated in repeated implantation failure and define which type of treatment need to be introduced.

  4. Serum IL-18 as biomarker in predicting long-term renal outcome among pediatric-onset systemic lupus erythematosus patients

    PubMed Central

    Wu, Chao-Yi; Yang, Huang-Yu; Yao, Tsung-Chieh; Liu, Su-Hsun; Huang, Jing-Long

    2016-01-01

    Abstract An urge of biomarker identification is needed to better monitor lupus nephritis (LN) disease activity, guide clinical treatment, and predict patient's long-term outcome. With the proinflammatory effect and its association with inflammasomes, the significance of interleukin-18 (IL-18) among pediatric-onset systemic lupus erythematous (pSLE) patient, especially, its importance in predicting long-term renal outcome was investigated. In a pSLE cohort of 96 patients with an average follow-up period of 10.39 ± 3.31 years, clinical data and laboratory workups including serum IL-18 were collected at time of disease onset and 6 months after treatment despite their initial renal status. Through Cox regression analysis, the parameters at baseline and at 6 months posttreatment were carefully analyzed. Average age of all cases was 12.74 ± 3.01 years old and 65 of them underwent renal biopsy at the time of diagnosis. Nine subjects (9.38%) progressed to end-stage renal disease (ESRD) and 2 cases (2.08%) died during follow-up. Through multivariate analysis, serum IL-18 level 6 months posttreatment was found to be the most unfavorable factor associating poor clinical outcome despite patient's initial renal status. In addition, the presentation of serum IL-18 in its correlation with SLE global disease activity as well as the presence and severity of LN were all significant (P < 0.001, P = 0.03, and P = 0.02, respectively). The histological classification of LN, however, was not associated with the level of IL-18 among the pSLE patients (P = 0.64). The role of serum IL-18 as biomarker representing global disease activity and status of renal flares among pSLE population was shown for the first time. Additionally, we have identified IL-18 at 6 months posttreatment a novel marker for long-term renal outcome prediction. PMID:27749566

  5. Expression and localization of IL-18 in the hypothalamic-pituitary-ovarian axis of non-pregnant, pregnant, and abortive rats.

    PubMed

    Wang, Yuesi; Zhang, Xiuli; Zhang, Yan; Xu, Hui; Fang, Guangli

    2011-12-01

    Cytokines present in the reproductive system play an important role both in the modulation of immune responses to infectious challenge and in the establishment and maintenance of pregnancy. Interleukin 18 (IL-18) has been regarded as an important regulator of innate and acquired immune response, but its expression and distribution in the hypothalamic-pituitary-ovarian axis remain unclear. In this paper, the expression and distribution of IL-18 in non-pregnant, pregnant, and early abortive rats were examined using an ultra-sensitive immunohistochemical streptavidin-peroxidase method, enzyme-linked immunosorbent assay, and reverse transcription-polymerase chain reaction. The results showed that IL-18 expression in the pituitary, in follicular ovaries, and in the corpus luteum of abortive rats were significantly lower than that of pregnant and non-pregnant rats. However, the staining of IL-18 in the hypothalamus, interstitial glands of the ovary, and uterus of abortive rats was strikingly stronger than those of the non-pregnant ones. IL-18 mRNA expression in rat uterus was detected in all groups, whereas IL-18 mRNA content in abortive rat uterus was significantly higher than in normal pregnant rats. Further, IL-18 in the peripheral blood serum of abortive rats was significantly lower than in same-period normal pregnant rats. The differential expression of IL-18 in early abortion suggests that IL-18 may be related to the underlying mechanisms of abortion.

  6. The Role of IL-23, IL-22, and IL-18 in Campylobacter Jejuni Infection of Conventional Infant Mice

    PubMed Central

    Heimesaat, Markus M.; Alutis, Marie E.; Grundmann, Ursula; Fischer, André; Göbel, Ulf B.; Bereswill, Stefan

    2016-01-01

    We have recently shown that, within 1 week following peroral Campylobacter jejuni infection, conventional infant mice develop self-limiting enteritis. We here investigated the role of IL-23, IL-22, and IL-18 during C. jejuni strain 81-176 infection of infant mice. The pathogen efficiently colonized the intestines of IL-18–/– mice only, but did not translocate to extra-intestinal compartments. At day 13 postinfection (p.i.), IL-22–/– mice displayed lower colonic epithelial apoptotic cell numbers as compared to wildtype mice, whereas, conversely, colonic proliferating cells increased in infected IL-22–/– and IL-18–/– mice. At day 6 p.i., increases in neutrophils, T and B lymphocytes were less pronounced in gene-deficient mice, whereas regulatory T cell numbers were lower in IL-23p19–/– and IL-22–/– as compared to wildtype mice, which was accompanied by increased colonic IL-10 levels in the latter. Until then, colonic pro-inflammatory cytokines including TNF, IFN-γ, IL-6, and MCP-1 increased in IL-23p19–/– mice, whereas IL-18–/– mice exhibited decreased cytokine levels and lower colonic numbers of T and B cell as well as of neutrophils, macrophages, and monocytes as compared to wildtype controls. In conclusion, IL-23, IL-22, and IL-18 are differentially involved in mediating C. jejuni-induced immunopathology of conventional infant mice. PMID:27429795

  7. Identification of a truncated splice variant of IL-18 receptor alpha in the human and rat, with evidence of wider evolutionary conservation

    PubMed Central

    Grattan, David R.

    2014-01-01

    Interleukin-18 (IL-18) is a pro-inflammatory cytokine which stimulates activation of the nuclear factor kappa beta (NF-κB) pathway via interaction with the IL-18 receptor. The receptor itself is formed from a dimer of two subunits, with the ligand-binding IL-18Rα subunit being encoded by the IL18R1 gene. A splice variant of murine IL18r1, which has been previously described, is formed by transcription of an unspliced intron (forming a ‘type II’ IL18r1 transcript) and is predicted to encode a receptor with a truncated intracellular domain lacking the capacity to generate downstream signalling. In order to examine the relevance of this finding to human IL-18 function, we assessed the presence of a homologous transcript by reverse transcription-polymerase chain reaction (RT-PCR) in the human and rat as another common laboratory animal. We present evidence for type II IL18R1 transcripts in both species. While the mouse and rat transcripts are predicted to encode a truncated receptor with a novel 5 amino acid C-terminal domain, the human sequence is predicted to encode a truncated protein with a novel 22 amino acid sequence bearing resemblance to the ‘Box 1’ motif of the Toll/interleukin-1 receptor (TIR) domain, in a similar fashion to the inhibitory interleukin-1 receptor 2. Given that transcripts from these three species are all formed by inclusion of homologous unspliced intronic regions, an analysis of homologous introns across a wider array of 33 species with available IL18R1 gene records was performed, which suggests similar transcripts may encode truncated type II IL-18Rα subunits in other species. This splice variant may represent a conserved evolutionary mechanism for regulating IL-18 activity. PMID:25250214

  8. Leptin and adiponectin, but not IL18, are related with insulin resistance in treated HIV-1-infected patients with lipodystrophy.

    PubMed

    Veloso, Sergi; Escoté, Xavier; Ceperuelo-Mallafré, Victòria; López-Dupla, Miguel; Peraire, Joaquim; Viladés, Consuelo; Domingo, Pere; Castro, Antoni; Olona, Montserrat; Sirvent, Joan-Josep; Leal, Manuel; Vendrell, Joan; Richart, Cristóbal; Vidal, Francesc

    2012-05-01

    Leptin, adiponectin and IL18 are adipokines related with obesity, insulin resistance and dyslipidemia in the general population. Treated HIV-1-infected patients with lipodystrophy may develop insulin resistance and proatherogenic dyslipidemia. We assessed the relationship between plasma adipokine levels, adipokine genetics, lipodystrophy and metabolic disturbances. Plasma leptin, adiponectin and IL18 levels were assessed in 446 individuals: 282 HIV-1-infected patients treated with antiretroviral drugs (132 with lipodystrophy and 150 without) and 164 uninfected controls (UC). The LEP2410A>G, LEPRQ223R, ADIPQ276G>T, ADIPOR2-Intron5A>G and IL18-607C>A polymorphisms were validated by sequencing. Leptin levels were higher in UC than in HIV-1-infected, either with or without lipodystrophy (p<0.001 for both comparisons) and were lower in patients with lipodystrophy compared with those without lipodystrophy (p=0.006). In patients with lipodystrophy, leptin had a positive correlation with insulin and with HOMA-IR. Adiponectin levels were non-significantly different in UC and HIV-1-infected patients. Patients with lipodystrophy had lower adiponectin levels than non-lipodystrophy subjects (p<0.001). In patients with lipodystrophy, adiponectin was negatively correlated with insulin, HOMA-IR and triglycerides. Plasma IL18 levels were higher in HIV-1-infected patients compared with UC (p<0.001), and no differences were found according to the presence of lipodystrophy. In patients with lipodystrophy there was a negative correlation between IL18 levels and LDLc. Genetic analyses indicated no significant associations with lipodystrophy nor with insulin resistance or with lipid abnormalities. In conclusion, HIV-1-infected patients have reduced plasma leptin levels. This reduction is magnified in patients with lipodystrophy whose adiponectin levels were lower than that of non-lipodystrophy subjects. Plasma IL18 levels are increased in infected patients irrespective of the presence of

  9. Decreased astrocytic thrombospondin-1 secretion after chronic ammonia treatment reduces the level of synaptic proteins: in vitro and in vivo studies.

    PubMed

    Jayakumar, Arumugam R; Tong, Xiao Y; Curtis, Kevin M; Ruiz-Cordero, Roberto; Shamaladevi, Nagarajarao; Abuzamel, Missa; Johnstone, Joshua; Gaidosh, Gabriel; Rama Rao, Kakulavarapu V; Norenberg, Michael D

    2014-11-01

    Chronic hepatic encephalopathy (CHE) is a major complication in patients with severe liver disease. Elevated blood and brain ammonia levels have been implicated in its pathogenesis, and astrocytes are the principal neural cells involved in this disorder. Since defective synthesis and release of astrocytic factors have been shown to impair synaptic integrity in other neurological conditions, we examined whether thrombospondin-1 (TSP-1), an astrocytic factor involved in the maintenance of synaptic integrity, is also altered in CHE. Cultured astrocytes were exposed to ammonia (NH₄Cl, 0.5-2.5 mM) for 1-10 days, and TSP-1 content was measured in cell extracts and culture media. Astrocytes exposed to ammonia exhibited a reduction in intra- and extracellular TSP-1 levels. Exposure of cultured neurons to conditioned media from ammonia-treated astrocytes showed a decrease in synaptophysin, PSD95, and synaptotagmin levels. Conditioned media from TSP-1 over-expressing astrocytes that were treated with ammonia, when added to cultured neurons, reversed the decline in synaptic proteins. Recombinant TSP-1 similarly reversed the decrease in synaptic proteins. Metformin, an agent known to increase TSP-1 synthesis in other cell types, also reversed the ammonia-induced TSP-1 reduction. Likewise, we found a significant decline in TSP-1 level in cortical astrocytes, as well as a reduction in synaptophysin content in vivo in a rat model of CHE. These findings suggest that TSP-1 may represent an important therapeutic target for CHE. Defective release of astrocytic factors may impair synaptic integrity in chronic hepatic encephalopathy. We found a reduction in the release of the astrocytic matricellular proteins thrombospondin-1 (TSP-1) in ammonia-treated astrocytes; such reduction was associated with a decrease in synaptic proteins caused by conditioned media from ammonia-treated astrocytes. Exposure of neurons to CM from ammonia-treated astrocytes, in which TSP-1 is over

  10. Extraction of RNA from archival tissues and measurement of thrombospondin-1 mRNA in normal, dysplastic, and malignant oral tissues.

    PubMed

    Macluskey, M; Baillie, R; Morrow, H; Schor, S L; Schor, A M

    2006-04-01

    Thrombospondin-1 (TSP-1) is an extracellular matrix glycoprotein implicated in the regulation of angiogenesis and tumour development. Our objectives were to ascertain the quantity and quality of RNA extracted from archival, formalin-fixed, paraffin embedded, oral tissues and their application in measuring the concentrations of TSP-1 mRNA in these tissues. We compared three techniques of isolation of RNA as well as related experimental variables. TSP-1 mRNA was measured in specimens of normal, dysplastic, and malignant oral tissues by real-time reverse transcriptase polymerase chain reaction (RT-PCR). RNA suitable for analysis by real-time RT-PCR was obtained by the three techniques tested, although the yield varied depending on the protocol used (range 0.2-3.6 microg/mm(3)). The mean (S.D.) concentrations of TSP-1 mRNA relative to 18S were 21.1 (7.2) in normal oral tissues (n=9), 11.0 (8.2) in dysplastic tissue (n=8) and 7.3 (5.3) in carcinomatous tissue (n=17). The difference between normal and carcinomatous specimens was significant (p=0.01). This reduction in expression of TSP-1 mRNA from normal to dysplasia to carcinoma may favour the angiogenic drive that accompanies the development of oral tumours.

  11. Thrombospondin-1 (TSP1) Contributes to the Development of Vascular Inflammation by Regulating Monocytic Cell Motility in Mouse Models of Abdominal Aortic Aneurysm

    PubMed Central

    Liu, Zhenjie; Morgan, Stephanie; Ren, Jun; Wang, Qiwei; Annis, Douglas S.; Mosher, Deane F.; Zhang, Jing; Sorenson, Christine M; Sheibani, Nader; Liu, Bo

    2015-01-01

    Rationale Histological examination of abdominal aortic aneurysm (AAA) tissues demonstrates extracellular matrix (ECM) destruction and infiltration of inflammatory cells. Previous work with mouse models of AAA has shown that anti-inflammatory strategies can effectively attenuate aneurysm formation. Thrombospondin-1 (TSP1) is a matricellular protein involved in the maintenance of vascular structure and homeostasis through the regulation of biological functions such as cell proliferation, apoptosis, and adhesion. Expression levels of TSP1 correlate with vascular disease conditions. Objective To use TSP1 deficient (Thbs1−/−) mice to test the hypothesis that TSP1 contributes to pathogenesis of AAAs. Methods and Results Mouse experimental AAA was induced either through perivascular treatment with calcium phosphate, intraluminal perfusion with porcine elastase, or systemic administration of Angiotensin II. Induction of AAA increased TSP1 expression in aortas of C57BL/6 or apoE−/− mice. Compared to Thbs1+/+ mice, Thbs1−/− mice developed significantly smaller aortic expansion when subjected to AAA inductions, which was associated with diminished infiltration of macrophages. Thbs1−/− monocytic cells had reduced adhesion and migratory capacity in vitro compared to wildtype counterparts. Adoptive transfer of Thbs1+/+ monocytic cells or bone marrow reconstitution rescued aneurysm development in Thbs1−/− mice. Conclusions TSP1 expression plays a significant role in regulation of migration and adhesion of mononuclear cells, contributing to vascular inflammation during AAA development. PMID:25940549

  12. Thrombospondin-1-induced smooth muscle cell chemotaxis and proliferation are dependent on transforming growth factor-β2 and hyaluronic acid synthase.

    PubMed

    Stein, Jeffrey J; Iwuchukwu, Chinenye; Maier, Kristopher G; Gahtan, Vivian

    2013-12-01

    Angioplasty causes local vascular injury, leading to the release of thrombospondin-1 (TSP-1), which stimulates vascular smooth muscle cell (VSMC) migration and proliferation, important steps in the development of intimal hyperplasia. Transforming growth factor beta 2 (TGF-β2) and hyaluronic acid synthase (HAS) are two pro-stenotic genes upregulated in VSMCs by TSP-1. We hypothesized that inhibition of TGF-β2 or HAS would inhibit TSP-1-induced VSMC migration, proliferation, and TSP-1 signaling. Our data demonstrate that Inhibition of either TGF-β2 or HAS inhibited TSP-1-induced VSMC migration and proliferation. Activation of ERK 1 was decreased by TGF-β2 inhibition and unaffected by HAS inhibition. TGF-β2 and HAS are not implicated in TSP-1-induced thbs1 expression, while they are each implicated in TSP-1-induced expression of their own gene. In summary, TSP-1-induced VSMC migration and proliferation rely on intact TGF-β2 signaling and HAS function. TSP-1 activation of ERK 1 is dependent on TGF-β2. These data further expand our understanding of the complexity of TSP-1 cellular signaling and the involvement of TGF-β2 and HAS.

  13. Slow release of growth factors and thrombospondin-1 in Choukroun's platelet-rich fibrin (PRF): a gold standard to achieve for all surgical platelet concentrates technologies.

    PubMed

    Dohan Ehrenfest, David M; de Peppo, Giuseppe M; Doglioli, Pierre; Sammartino, Gilberto

    2009-02-01

    Platelet concentrates for surgical topical applications are nowadays often used, but quantification of the long-term growth factor release from these preparations in most cases is impossible. Indeed, in most protocols, platelets are massively activated and there is no significant fibrin matrix to support growth factor release and cell migration. Choukroun's platelet-rich fibrin (PRF), a second generation platelet concentrate, is a leucocyte- and platelet-rich fibrin biomaterial. Here, we show that this dense fibrin membrane releases high quantities of three main growth factors (Transforming Growth Factor b-1 (TGFbeta-1), platelet derived growth factor AB, PDGF-AB; vascular endothelial growth factor, VEGF) and an important coagulation matricellular glycoprotein (thrombospondin-1, TSP-1) during 7 days. Moreover, the comparison between the final released amounts and the initial content of the membrane (after forcible extraction) allows us to consider that the leucocytes trapped in the fibrin matrix continue to produce high quantities of TGFbeta-1 and VEGF during the whole experimental time.

  14. Thrombospondin-1 (TSP-1) Analogs ABT-510 and ABT-898 Inhibit Prolactinoma Growth and Recover Active Pituitary Transforming Growth Factor-β1 (TGF-β1)

    PubMed Central

    Recouvreux, M. Victoria; Camilletti, M. Andrea; Rifkin, Daniel B.; Becu-Villalobos, Damasia

    2012-01-01

    Prolactinomas are the most prevalent type of secreting pituitary tumors in humans and generally respond well to a medical therapy with dopamine agonists. However, for patients exhibiting resistance to dopaminergic drugs, alternative treatments are desired. Antiangiogenic strategies might represent a potential therapy for these tumors. Thrombospondin 1 (TSP-1) is a large multifunctional glycoprotein involved in multiple biological processes including angiogenesis, apoptosis, and activation of TGF-β1. Because tumors that overexpress TSP-1 grow more slowly, have fewer metastases, and have decreased angiogenesis, TSP-1 provides a novel target for cancer treatment. ABT-510 and ABT-898 are TSP-1 synthetic analogs that mimic its antiangiogenic action. In the present study, we explored the potential effect of ABT-510 and ABT-898 on experimental prolactinomas induced by chronic diethylstilbestrol (DES) treatment in female rats. We demonstrated that a 2-wk treatment with ABT-510 and ABT-898 counteracted the increase in pituitary size and serum prolactin levels as well as the pituitary proliferation rate induced by DES. These inhibitory effects on tumor growth could be mediated by the antiangiogenic properties of the drugs. We also demonstrated that ABT-510 and ABT-898, in addition to their described antiangiogenic effects, increased active TGF-β1 level in the tumors. We postulate that the recovery of the local cytokine activation participates in the inhibition of lactotrope function. These results place these synthetic TSP-1 analogs as potential alternative or complementary treatments in dopamine agonist-resistant prolactinomas. PMID:22700773

  15. Sphingosine kinase inhibitor suppresses IL-18-induced interferon-gamma production through inhibition of p38 MAPK activation in human NK cells

    SciTech Connect

    Cheon, Soyoung; Song, Seok Bean; Jung, Minkyung; Park, Yoorim; Bang, Jung-Wook; Kim, Tae Sung; Park, Hyunjeong; Kim, Cherl-hyun; Yang, Yool-hee; Bang, Sa Ik; Cho, Daeho

    2008-09-12

    Natural killer (NK) cells play an important role in the innate immune response. Interleukin-18 (IL-18) is a well-known interferon-gamma (IFN-{gamma} inducing factor, which stimulates immune response in NK and T cells. Sphingosine kinase (SPHK) catalyzes the formation of sphingosine 1-phosphate (S1P), which acts as a second messenger to function as an anti-apoptotic factor and proliferation stimulator of immune cells. In this study, to elucidate whether SPHK is involved in IL-18-induced IFN-{gamma} production, we measured IL-18-induced IFN-{gamma} production after pre-treatment with SPHK inhibitor (SKI) in NK-92MI cells. We found that IL-18-induced IFN-{gamma} expression was blocked by SKI pre-treatment in both mRNA and protein levels. In addition, the increased IFN-{gamma} production by stimulation with IL-18 is mediated through both SPHK and p38 MAPK. To determine the upstream signals of SKI and p38 MAPK in IL-18-induced IFN-{gamma} production, phosphorylation levels of p38 MAPK was measured after SKI pre-treatment. As a result, inhibition of SPHK by SKI blocked phosphorylation of p38 MAPK, showing that SPHK activation by IL-18 is an upstream signal of p38 MAPK activation. Inhibition of SPHK by SKI also inhibited IL-18-induced IFN-{gamma} production in human primary NK cells. In conclusion, SPHK activation is an essential factor for IL-18-induced IFN-{gamma} production via p38 MAPK.

  16. Human umbilical cord blood-derived mesenchymal stem cells improve functional recovery through thrombospondin1, pantraxin3, and vascular endothelial growth factor in the ischemic rat brain.

    PubMed

    Park, Hyung Woo; Moon, Hyo-Eun; Kim, Hye-Soo R; Paek, Seung Leal; Kim, Yona; Chang, Jong Wook; Yang, Yoon Sun; Kim, KwanWoo; Oh, Wonil; Hwang, Jae Ha; Kim, Jin Wook; Kim, Dong Gyu; Paek, Sun Ha

    2015-12-01

    Cell therapy is a potential therapeutic method for cerebral ischemia, which remains a serious problem. In the search for more effective therapeutic methods, many kinds of stem cells from various tissues have been developed and tested as candidate therapeutic agents. Among them, human umbilical cord blood (hUCB)-derived mesenchymal stem cells (MSCs) are widely used for cell therapy because of their genetic flexibility. To confirm that they are effective and understand how they affect ischemic neural cells, hUCB-MSCs were directly administered ipsilaterally into an ischemic zone induced by middle cerebral artery occlusion (MCAO). We found that the neurobehavioral performance of the hUCB-MSC group was significantly improved compared with that of the vehicle-injected control group. The infarct was also remarkably smaller in the hUCB-MSC group. Additionally, hUCB-MSC transplantation resulted in a greater number of newly generated cells and angiogenic and tissue repair factors and a lower number of inflammatory events in the penumbra zone. To determine why these events occurred, hUCB-MSCs were assayed under hypoxic and normoxic conditions in vitro. The results showed that hUCB-MSCs exhibit higher expression levels of thrombospondin1, pantraxin3, and vascular endothelial growth factor under hypoxic conditions than under normoxic conditions. These results were found to be correlated with our in vivo immunofluorescent staining results. On the basis of these findings, we suggest that hUCB-MSCs may have a beneficial effect on cerebral ischemia, especially through angiogenesis, neurogenesis, and anti-inflammatory effects, and thus could be used as a therapeutic agent to treat neurological disorders such as cerebral ischemia.

  17. Syndecan-4 contributes to endothelial tubulogenesis through interactions with two motifs inside the pro-angiogenic N-terminal domain of thrombospondin-1.

    PubMed

    Nunes, Sara Santana; Outeiro-Bernstein, Marianna A Ferrari do; Juliano, Luiz; Vardiero, Francisco; Nader, Helena B; Woods, Anne; Legrand, Chantal; Morandi, Verônica

    2008-03-01

    Thrombospondin-1 (TSP-1) is an extracellular matrix protein that modulates focal adhesion in mammalian cells and exhibits dual roles in angiogenesis. In a previous work, we showed that a recombinant 18 kDa protein encompassing the N-terminal residues 1-174 of human TSP-1 (TSP18) induced tubulogenesis of human umbilical vein endothelial cells and protected them from apoptosis. Our results indicated that these effects were possibly mediated by syndecan-4 proteoglycan, since binding of TSP18 to endothelial extracts was inhibited by anti-syndecan-4 antibody. Syndecan-4 is a heparan-sulfate proteoglycan that regulates cell-matrix interactions and is the only member of its family present in focal adhesions. In this report, we demonstrate that a monoclonal antibody against syndecan-4 blocks TSP18-induced tubulogenesis. Furthermore, through 2D adhesion and 3D angiogenic assays, we demonstrate that two sequences, TSP Hep I and II, retain the major pro-angiogenic activity of TSP18. These TSP-1 motifs also compete with the fibronectin Hep II domain for binding to syndecan-4 on endothelial cell surface, indicating that they may exert their effects by interfering with the recognition of fibronectin by syndecan-4. Additionally, TSP18 and its derived peptides activate the PKC-dependent Akt-PKB signaling pathway. Blockage of PKC activation prevented HUVEC spreading when seeded on TSP18 fragment, and on TSP Hep I and TSP Hep II peptides, but not on gelatin-coated substrates. Our results identify syndecan-4 as a novel receptor for the N-terminus of TSP-1 and suggest that TSP-1 N-terminal pro-angiogenic activity is linked to its capacity of interfering with syndecan-4 functions in the course of cell adhesion. PMID:17879962

  18. Downregulation of thrombospondin-1 by DNA hypermethylation is associated with tumor progression in laryngeal squamous cell carcinoma.

    PubMed

    Huang, Chuang; Zhou, Xiaohong; Li, Zhenhua; Liu, Hong; He, Yun; Ye, Guo; Huang, Kun

    2016-09-01

    Thrombospondin‑1 (THBS‑1) has been demonstrated to have a complicated role in human cancer and to exert stimulatory and inhibitory effects in different types of tumors. DNA methylation, as the most frequent mechanism for gene silencing, has been widely investigated in regards to the development of tumors. However, the expression levels and methylation status of THBS‑1, and their roles in laryngeal squamous cell carcinoma (LSCC) remain to be elucidated. The present study detected downregulated THBS‑1 mRNA and protein expression levels in LSCC by using reverse transcription-quantitative polymerase chain reaction (PCR) and western blotting, while decreased expression levels of THBS‑1 mRNA and protein were significantly associated with lymph node metastasis and tumor‑node‑metastasis (TNM) stage. Furthermore, aberrant methylation of THBS‑1 was frequently observed in LSCC by methylation‑specific PCR, particularly in tumor tissues from lymph node metastasis or samples from cancer with advanced TNM stage. Furthermore, the current study demonstrated that downregulated expression of THBS‑1 in LSCC was consistent with aberrant methylation of this gene. Treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxy-cytidine in Hep‑2 cells induced demethylation of THBS-1, enhanced THBS‑1 expression, and inhibited the proliferative and invasive ability of Hep‑2 cells. Collectively, the results of the present study suggest that THBS‑1 may exert an inhibitory effect in the development of LSCC. Aberrant methylation was an important reason for the downregulation of THBS‑1 and was involved in the invasion and metastasis of LSCC. Demethylating agents may be effective candidates for the treatment of LSCC.

  19. Human mucosal-associated invariant T cells contribute to antiviral influenza immunity via IL-18-dependent activation.

    PubMed

    Loh, Liyen; Wang, Zhongfang; Sant, Sneha; Koutsakos, Marios; Jegaskanda, Sinthujan; Corbett, Alexandra J; Liu, Ligong; Fairlie, David P; Crowe, Jane; Rossjohn, Jamie; Xu, Jianqing; Doherty, Peter C; McCluskey, James; Kedzierska, Katherine

    2016-09-01

    Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes known to elicit potent immunity to a broad range of bacteria, mainly via the rapid production of inflammatory cytokines. Whether MAIT cells contribute to antiviral immunity is less clear. Here we asked whether MAIT cells produce cytokines/chemokines during severe human influenza virus infection. Our analysis in patients hospitalized with avian H7N9 influenza pneumonia showed that individuals who recovered had higher numbers of CD161(+)Vα7.2(+) MAIT cells in peripheral blood compared with those who succumbed, suggesting a possible protective role for this lymphocyte population. To understand the mechanism underlying MAIT cell activation during influenza, we cocultured influenza A virus (IAV)-infected human lung epithelial cells (A549) and human peripheral blood mononuclear cells in vitro, then assayed them by intracellular cytokine staining. Comparison of influenza-induced MAIT cell activation with the profile for natural killer cells (CD56(+)CD3(-)) showed robust up-regulation of IFNγ for both cell populations and granzyme B in MAIT cells, although the individual responses varied among healthy donors. However, in contrast to the requirement for cell-associated factors to promote NK cell activation, the induction of MAIT cell cytokine production was dependent on IL-18 (but not IL-12) production by IAV-exposed CD14(+) monocytes. Overall, this evidence for IAV activation via an indirect, IL-18-dependent mechanism indicates that MAIT cells are protective in influenza, and also possibly in any human disease process in which inflammation and IL-18 production occur.

  20. Human mucosal-associated invariant T cells contribute to antiviral influenza immunity via IL-18–dependent activation

    PubMed Central

    Loh, Liyen; Wang, Zhongfang; Sant, Sneha; Koutsakos, Marios; Jegaskanda, Sinthujan; Liu, Ligong; Fairlie, David P.; Crowe, Jane; Rossjohn, Jamie; Xu, Jianqing; Doherty, Peter C.; Kedzierska, Katherine

    2016-01-01

    Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes known to elicit potent immunity to a broad range of bacteria, mainly via the rapid production of inflammatory cytokines. Whether MAIT cells contribute to antiviral immunity is less clear. Here we asked whether MAIT cells produce cytokines/chemokines during severe human influenza virus infection. Our analysis in patients hospitalized with avian H7N9 influenza pneumonia showed that individuals who recovered had higher numbers of CD161+Vα7.2+ MAIT cells in peripheral blood compared with those who succumbed, suggesting a possible protective role for this lymphocyte population. To understand the mechanism underlying MAIT cell activation during influenza, we cocultured influenza A virus (IAV)-infected human lung epithelial cells (A549) and human peripheral blood mononuclear cells in vitro, then assayed them by intracellular cytokine staining. Comparison of influenza-induced MAIT cell activation with the profile for natural killer cells (CD56+CD3−) showed robust up-regulation of IFNγ for both cell populations and granzyme B in MAIT cells, although the individual responses varied among healthy donors. However, in contrast to the requirement for cell-associated factors to promote NK cell activation, the induction of MAIT cell cytokine production was dependent on IL-18 (but not IL-12) production by IAV-exposed CD14+ monocytes. Overall, this evidence for IAV activation via an indirect, IL-18–dependent mechanism indicates that MAIT cells are protective in influenza, and also possibly in any human disease process in which inflammation and IL-18 production occur. PMID:27543331

  1. Human mucosal-associated invariant T cells contribute to antiviral influenza immunity via IL-18-dependent activation.

    PubMed

    Loh, Liyen; Wang, Zhongfang; Sant, Sneha; Koutsakos, Marios; Jegaskanda, Sinthujan; Corbett, Alexandra J; Liu, Ligong; Fairlie, David P; Crowe, Jane; Rossjohn, Jamie; Xu, Jianqing; Doherty, Peter C; McCluskey, James; Kedzierska, Katherine

    2016-09-01

    Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes known to elicit potent immunity to a broad range of bacteria, mainly via the rapid production of inflammatory cytokines. Whether MAIT cells contribute to antiviral immunity is less clear. Here we asked whether MAIT cells produce cytokines/chemokines during severe human influenza virus infection. Our analysis in patients hospitalized with avian H7N9 influenza pneumonia showed that individuals who recovered had higher numbers of CD161(+)Vα7.2(+) MAIT cells in peripheral blood compared with those who succumbed, suggesting a possible protective role for this lymphocyte population. To understand the mechanism underlying MAIT cell activation during influenza, we cocultured influenza A virus (IAV)-infected human lung epithelial cells (A549) and human peripheral blood mononuclear cells in vitro, then assayed them by intracellular cytokine staining. Comparison of influenza-induced MAIT cell activation with the profile for natural killer cells (CD56(+)CD3(-)) showed robust up-regulation of IFNγ for both cell populations and granzyme B in MAIT cells, although the individual responses varied among healthy donors. However, in contrast to the requirement for cell-associated factors to promote NK cell activation, the induction of MAIT cell cytokine production was dependent on IL-18 (but not IL-12) production by IAV-exposed CD14(+) monocytes. Overall, this evidence for IAV activation via an indirect, IL-18-dependent mechanism indicates that MAIT cells are protective in influenza, and also possibly in any human disease process in which inflammation and IL-18 production occur. PMID:27543331

  2. Genetic analysis of innate immunity in Behcet’s disease identifies an association with IL-37 and IL-18RAP

    PubMed Central

    Tan, Handan; Deng, Bolin; Yu, Hongsong; Yang, Yi; Ding, Lin; Zhang, Qi; Qin, Jieying; Kijlstra, Aize; Chen, Rui; Yang, Peizeng

    2016-01-01

    Interleukin-1 (IL-1) and the IL-1 receptor (IL-1R) family play an important role in the pathogenesis of inflammatory diseases. This study aimed to investigate the association between single nucleotide polymorphisms (SNP) of IL-1 and IL-1R family genes with Vogt-Koyanagi-Harada (VKH) and Behcet’s disease (BD) in Han Chinese. The case-control study was divided into two stages and included 419 VKH cases, 1063 BD cases and 1872 healthy controls. The MassARRAY platform (Sequenom), iPLEX Gold Assay and TaqMan SNP assays were used to score genotypes of 24 SNPs. The expression of IL-37 and IL-18Rap was measured by ELISA and real-time PCR in genotyped healthy individuals. A significantly lower frequency of the AG genotype, and a higher frequency of the GG genotype and G allele of IL-37/rs3811047 were observed in BD as compared to controls. AA genotype and A allele frequency of IL-18RAP/rs2058660 was significantly decreased in BD as compared to controls. Functional studies performed in healthy controls showed that rs3811047 AG genotype carriers had a higher IL-37 gene expression in peripheral blood mononuclear cells (PBMCs) than GG carriers. GG carriers showed a higher cytokine expression as compared to AG carriers. No association was detected between the tested SNPs and VKH. PMID:27775096

  3. Chlamydial plasmid-encoded protein pORF5 induces production of IL-1β and IL-18 via NALP3 inflammasome activation and p38 MAPK pathway

    PubMed Central

    Cao, Wenjuan; Zou, Yan; Su, Shengmei; He, Zhansheng; Liu, Yan; Huang, Qiulin; Li, Zhongyu

    2015-01-01

    The pathogenesis of Chlamydia-induced inflammation is poorly understood. pORF5 is the only secreted protein encoded by Chlamydial plasmid. This study aims to investigate the effects of pORF5 on the production of interleukin-1β (IL-1β) and interleukin-18 (IL-18) and the underlying mechanisms of these effects. THP-1 (a human acute monocytic leukemia cell line) cells were stimulated by pORF5 with or without pretreatment with Natch domain, Leucine-rich repeat and PYD-containing protein 3 (NALP3) siRNA, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) siRNA, cysteine aspartate-specific protease-1 (caspase-1) specific inhibitor and p38 mitogen-activated protein kinase (p38 MAPK) inhibitor. IL-1β, IL-18 and caspase-1 expression was detected through both ELISA and qRT-PCR. NALP3 and ASC expression was detected by qRT-PCR. The expression of caspase-1 and phosphorylated-p38 MAPK was detected by western blot analysis. pORF5 induced IL-1β, IL-18, caspase-1 and NALP3 inflammasome expression in THP-1 cells. Caspase-1 inhibitor significantly reduced pORF5-induced IL-1β and IL-18 expression. The siRNAs for NALP3 inflammasome significantly reduced pORF5-induced IL-1β, IL-18 and caspase-1 expression. Furthermore, p38 MAPK inhibitor significantly reduced pORF5-induced IL-1β, IL-18, caspase-1 and NALP3 inflammasome expression. pORF5 could induce production of IL-1β and IL-18 via NALP3 inflammasome activation and p38MAPK pathway. pORF5 protein might play an important role in Chlamydia pathogenesis. This study provides a new insight into the molecular pathogenesis of Chlamydial diseases. PMID:26884953

  4. Superior protective and therapeutic effects of IL-12 and IL-18 gene-transduced dendritic neuroblastoma fusion cells on liver metastasis of murine neuroblastoma.

    PubMed

    Iinuma, Hisae; Okinaga, Kota; Fukushima, Ryoji; Inaba, Tsuyoshi; Iwasaki, Kota; Okinaga, Akira; Takahashi, Ichiro; Kaneko, Michio

    2006-03-15

    Fusion vaccine of dendritic cells (DCs) and tumor cells has the advantage of inducing an immune response against multiple tumor Ags, including unknown tumor Ags. Using the liver metastasis model of C1300 neuroblastoma cells, we assessed the protective and therapeutic effects of fusion cells transduced with the IL-12 gene and/or the IL-18 gene. Improving the fusion method by combining polyethylene glycol and electroporation increased loading efficiency. In the A/J mice vaccinated with fusion cells modified with the LacZ gene (fusion/LacZ), IFN-gamma production and CTL activity increased significantly compared with that of DCs/LacZ, C1300/LacZ, or a mixture of the two (mixture/LacZ). With the transduction of IL-12 and IL-18 genes into the fusion cells (fusion/IL-12/IL-18), the level of IFN-gamma increased more than five times that of other fusion groups. In addition, NK cell activity and CTL activity increased significantly compared with that of mixture/LacZ, fusion/LacZ, DC/LacZ, or C1300/LacZ. In the protective and therapeutic studies of fusion cell vaccine, mice vaccinated with fusion/LacZ, fusion/IL-12, fusion/IL-18, or fusion/IL-12/IL-18 showed a significant decrease in liver metastasis and a significant increase in survival compared with mice given a mixture/LacZ, DCs/LacZ, or C1300/LacZ. In particular, the mice receiving fusion/IL-12/IL-18 vaccine showed a complete protective effect and the highest therapeutic effects. The present study investigates the improved loading efficiency of fusion cells and suggests that the introduction of IL-12 and IL-18 genes can induce extremely strong protective and therapeutic effects on liver metastasis of neuroblastoma.

  5. Positive inductive effect of IL-18 on virus-specific immune responses induced by PRRSV-GP5 DNA vaccine in swine.

    PubMed

    Zhang, Xiaodong; Li, Guojiang; Gao, Lei; Mu, Lianzhi; Zhang, Lichun; Cong, Yanlong; Ding, Zhuang

    2013-04-01

    Two DNA vaccines encoding the envelope protein GP5 of porcine reproductive and respiratory syndrome virus (PRRSV) alone (pEGFP-GP5) and co-encoding GP5 and swine interleukin-18 (IL-18) proteins (pEGFP-IL18-GP5), were constructed and comparatively evaluated for their abilities to induce humoral and cellular responses in piglets. Experimental results showed that among all vaccinated groups, the live PRRSV vaccine elicited the highest titre of serum neutralizing antibody and the strongest cell-mediated immune responses, which means that the live PRRSV vaccine is still the first option for the vaccination against PRRSV. Moreover, the piglets inoculated with pEGFP-IL18-GP5 developed significantly higher IFN-γ production response, significantly increased percentages of CD4(+) and CD8(+) T-lymphocytes and significantly higher specific T-lymphocyte proliferation response than the pEGFP-GP5 inoculated pigs (P<0.05). These results demonstrated the positive inductive effect of IL-18 on the activation of cellular immune responses in swines. Therefore, in order to develop a new type vaccine for PRRS prevention and control, co-encoding of GP5 and IL-18 proteins may be a good choice.

  6. Relationship of serum levels of TNF-α, IL-6 and IL-18 and schizophrenia-like symptoms in chronic ketamine abusers

    PubMed Central

    Fan, Ni; Luo, Yayan; Xu, Ke; Zhang, Minling; Ke, Xiaoyin; Huang, Xini; Ding, Yi; Wang, Daping; Ning, Yuping; Deng, Xuefeng; He, Hongbo

    2016-01-01

    Objective Exposing to NMDAR receptor antagonists, such as ketamine, produces schizophrenia-like symptoms in humans and deteriorates symptoms in schizophrenia patients. Meanwhile, schizophrenia is associated with alterations of cytokines in the immune system. This study aims to examine the serum TNF-α, IL-6 and IL-18 levels in chronic human ketamine users as compared to healthy subjects. The correlations between the serum cytokines levels with the demographic, ketamine use characteristics and psychiatric symptoms were also assessed. Methods 155 subjects who fulfilled the criteria of ketamine dependence and 80 healthy control subjects were recruited. Serum TNF-α, IL-6 and IL-18 levels were measured using an enzyme-linked immunosorbent assay (ELISA). The psychiatric symptoms of the ketamine abusers were assessed using the Positive and Negative Syndrome Scale (PANSS). Results Serum IL-6 and IL-18 levels were significantly higher, while serum TNF-α level was significantly lower among ketamine users than among healthy controls (p < 0.05). Serum TNF-α levels showed a significant negative association with PANSS total score (r = −0.210, p < 0.01) and negative subscore (r = −0.300, p < 0.01). No significant association was found between PANSS score and serum levels of IL-6 and IL-18. Conclusions Serum levels of TNF-α, IL-6 and IL-18 were altered in chronic ketamine abusers which may play a role in schizophrenia-like symptoms in chronic ketamine abusers. PMID:26589393

  7. IL-18, but not IL-15, contributes to the IL-12-dependent induction of NK-cell effector functions by Leishmania infantum in vivo.

    PubMed

    Haeberlein, Simone; Sebald, Heidi; Bogdan, Christian; Schleicher, Ulrike

    2010-06-01

    Activation of NK cells is a hallmark of infections with intracellular pathogens. We previously showed that the protozoan parasite Leishmania infantum triggered a rapid NK-cell response in mice that required TLR9-positive myeloid DC and IL-12, but no IFN-alpha/beta. Here, we investigated whether IL-15 or IL-18 mediate the activity of IL-12 or function as independent activators of NK cells. In contrast to earlier studies that described IL-15 as crucial for NK-cell priming in response to TLR ligands, the expression of IFN-gamma, FasL, perforin and granzyme B by NK cells in L. infantum-infected mice was completely preserved in the absence of IL-15, whereas the proliferative capacity of NK cells was lower than in WT mice. IFN-gamma secretion, cytotoxicity and FasL expression of NK cells from infected IL-18(-/-) mice were significantly reduced compared with controls, but, unlike IL-12, IL-18 was not essential for NK-cell effector functions. Part of the NK-cell-stimulatory effect of IL-12 was dependent on IL-18. We conclude that IL-15 is not functioning as a universal NK-cell priming signal and that IL-18 contributes to the NK-cell response in visceral leishmaniasis. The cytokine requirements for NK-cell activation appear to differ contingent upon the infectious pathogen.

  8. Altered serum levels of TNF-α, IL-6 and IL-18 in manic, depressive, mixed state of bipolar disorder patients.

    PubMed

    Luo, Yayan; He, Hongbo; Zhang, Minling; Huang, Xini; Fan, Ni

    2016-10-30

    Bipolar disorder (BD) is associated with alterations of cytokines in the immune system. The aim of this study was to assess the serum levels of TNF-α, IL-6 and IL-18 in manic, depressive, mixed state patients of BD. The correlations between the serum cytokines levels with the demographic characteristics and the psychiatric symptoms were also assessed. We measured serum TNF-α, IL-6 and IL-18 levels using an enzyme-linked immunosorbent assay (ELISA) from 59 BD patients (37 in manic state, 12 in depressive state, 10 in mixed state) and 80 healthy control subjects. The psychotic symptoms of BD were assessed using the Hamilton Depression Scale (HAMD) and the Young Mania Rating Scale (YMRS). The results showed that serum TNF-α and IL-6 levels in manic, depressive and mixed state BD patients were significantly higher than that in controls, while serum IL-18 level was only significantly higher in depressive patients. Serum IL-6 level was significantly positively correlated with YMRS scores in manic episode as well as in mixed episode. When gender and age were added as potentially confounding covariate terms, the differences between controls and each mood state patients were still significant. Our findings provided additional evidence that elevated TNF-α, IL-6 and IL-18 pathway activities may be involved in the psychopathology of BD. Due to the lack of controlling important confounding factors, such as BMI, smoking status and alcohol use, further studies are required to confirm the roles of TNF-α, IL-6 and IL-18. PMID:27455146

  9. An isomeric mixture of novel cerebrosides isolated from Impatiens pritzellii reduces lipopolysaccharide-induced release of IL-18 from human peripheral blood mononuclear cells.

    PubMed

    Zhou, Xuefeng; Tang, Lan; Liu, Yonghong

    2009-08-01

    An isomeric mixture of two cerebrosides, soya-cerebrosides I and II, was isolated from an ethno drug, the rhizomes of Impatiens pritzellii Hook. f. var. hupehensis Hook. f., and their structures were identified by spectroscopic (NMR, MS) analysis. In order to determine the immunomodulatory activities of soya-cerebrosides I and II, the effects of the mixture of cerebrosides (MC) on cytotoxicity of human peripheral blood mononuclear cells (PBMC) and the inhibitory activities to lipopolysaccharide (LPS)-induced interleukin (IL)-18 in PBMC were studied. The MC at concentrations of 10 and 1 microM, without toxicity to PBMC in 24 h, showed obvious inhibitory activity on IL-18 secretion. Because of this effect of modulating the cellular immune response, soya-cerebrosides I and II were considered to be the active substances of this ethno drug.

  10. Genome-Wide Analysis Identifies IL-18 and FUCA2 as Novel Genes Associated with Diastolic Function in African Americans with Sickle Cell Disease

    PubMed Central

    Sysol, Justin R.; Abbasi, Taimur; Patel, Amit R.; Lang, Roberto M.; Gupta, Akash; Garcia, Joe G. N.; Gordeuk, Victor R.; Machado, Roberto F.

    2016-01-01

    Background Diastolic dysfunction is common in sickle cell disease (SCD), and is associated with an increased risk of mortality. However, the molecular pathogenesis underlying this development is poorly understood. The aim of this study was to identify a gene expression profile that is associated with diastolic function in SCD, potentially elucidating molecular mechanisms behind diastolic dysfunction development. Methods Diastolic function was measured via echocardiography in 65 patients with SCD from two independent study populations. Gene expression microarray data was compared with diastolic function in both study cohorts. Candidate genes that associated in both analyses were tested for validation in a murine SCD model. Lastly, genotyping array data from the replication cohort was used to derive cis-expression quantitative trait loci (cis-eQTLs) and genetic associations within the candidate gene regions. Results Transcriptome data from both patient cohorts implicated 7 genes associated with diastolic function, and mouse SCD myocardial expression validated 3 of these genes. Genetic associations and eQTLs were detected in 2 of the 3 genes, FUCA2 and IL18. Conclusions FUCA2 and IL18 are associated with diastolic function in SCD patients, and may be involved in the pathogenesis of the disease. Genetic polymorphisms within the FUCA2 and IL18 gene regions are also associated with diastolic function in SCD, likely by affecting expression levels of the genes. PMID:27636371

  11. IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction.

    PubMed

    Nold-Petry, Claudia A; Lo, Camden Y; Rudloff, Ina; Elgass, Kirstin D; Li, Suzhao; Gantier, Michael P; Lotz-Havla, Amelie S; Gersting, Søren W; Cho, Steven X; Lao, Jason C; Ellisdon, Andrew M; Rotter, Björn; Azam, Tania; Mangan, Niamh E; Rossello, Fernando J; Whisstock, James C; Bufler, Philip; Garlanda, Cecilia; Mantovani, Alberto; Dinarello, Charles A; Nold, Marcel F

    2015-04-01

    Interleukin 37 (IL-37) and IL-1R8 (SIGIRR or TIR8) are anti-inflammatory orphan members of the IL-1 ligand family and IL-1 receptor family, respectively. Here we demonstrate formation and function of the endogenous ligand-receptor complex IL-37-IL-1R8-IL-18Rα. The tripartite complex assembled rapidly on the surface of peripheral blood mononuclear cells upon stimulation with lipopolysaccharide. Silencing of IL-1R8 or IL-18Rα impaired the anti-inflammatory activity of IL-37. Whereas mice with transgenic expression of IL-37 (IL-37tg mice) with intact IL-1R8 were protected from endotoxemia, IL-1R8-deficient IL-37tg mice were not. Proteomic and transcriptomic investigations revealed that IL-37 used IL-1R8 to harness the anti-inflammatory properties of the signaling molecules Mer, PTEN, STAT3 and p62(dok) and to inhibit the kinases Fyn and TAK1 and the transcription factor NF-κB, as well as mitogen-activated protein kinases. Furthermore, IL-37-IL-1R8 exerted a pseudo-starvational effect on the metabolic checkpoint kinase mTOR. IL-37 thus bound to IL-18Rα and exploited IL-1R8 to activate a multifaceted intracellular anti-inflammatory program.

  12. Changes in Neuronal Excitability by Activated Microglia: Differential Na(+) Current Upregulation in Pyramid-Shaped and Bipolar Neurons by TNF-α and IL-18.

    PubMed

    Klapal, Lars; Igelhorst, Birte A; Dietzel-Meyer, Irmgard D

    2016-01-01

    Microglia are activated during pathological events in the brain and are capable of releasing various types of inflammatory cytokines. Here, we demonstrate that the addition of 5% microglia activated by 1 μg/ml lipopolysaccharides (LPS) to hippocampal cultures upregulates Na(+) current densities (INavD) of bipolar as well as pyramid-shaped neurons, thereby increasing their excitability. Deactivation of microglia by the addition of 10 ng/ml transforming growth factor-β (TGF-β) decreases INavD below control levels suggesting that the residual activated microglial cells influence neuronal excitability in control cultures. Preincubation of hippocampal cultures with 10 ng/ml tumor necrosis factor-α (TNF-α), a major cytokine released by activated microglia, upregulated INavD significantly by ~30% in bipolar cells, whereas in pyramid-shaped cells, the upregulation only reached an increase of ~14%. Incubation of the cultures with antibodies against either TNF-receptor 1 or 2 blocked the upregulation of INavD in bipolar cells, whereas in pyramid-shaped cells, increases in INavD were exclusively blocked by antibodies against TNF-receptor 2, suggesting that both cell types respond differently to TNF-α exposure. Since additional cytokines, such as interleukin-18 (IL-18), are released from activated microglia, we tested potential effects of IL-18 on INavD in both cell types. Exposure to 5-10 ng/ml IL-18 for 4 days increased INavD in both pyramid-shaped as well as bipolar neurons, albeit the dose-response curves were shifted to lower concentrations in bipolar cells. Our results suggest that by secretion of cytokines, microglial cells upregulate Na(+) current densities in bipolar and pyramid-shaped neurons to some extent differentially. Depending on the exact cytokine composition and concentration released, this could change the balance between the activity of inhibitory bipolar and excitatory pyramid-shaped cells. Since bipolar cells show a larger upregulation of

  13. Changes in Neuronal Excitability by Activated Microglia: Differential Na+ Current Upregulation in Pyramid-Shaped and Bipolar Neurons by TNF-α and IL-18

    PubMed Central

    Klapal, Lars; Igelhorst, Birte A.; Dietzel-Meyer, Irmgard D.

    2016-01-01

    Microglia are activated during pathological events in the brain and are capable of releasing various types of inflammatory cytokines. Here, we demonstrate that the addition of 5% microglia activated by 1 μg/ml lipopolysaccharides (LPS) to hippocampal cultures upregulates Na+ current densities (INavD) of bipolar as well as pyramid-shaped neurons, thereby increasing their excitability. Deactivation of microglia by the addition of 10 ng/ml transforming growth factor-β (TGF-β) decreases INavD below control levels suggesting that the residual activated microglial cells influence neuronal excitability in control cultures. Preincubation of hippocampal cultures with 10 ng/ml tumor necrosis factor-α (TNF-α), a major cytokine released by activated microglia, upregulated INavD significantly by ~30% in bipolar cells, whereas in pyramid-shaped cells, the upregulation only reached an increase of ~14%. Incubation of the cultures with antibodies against either TNF-receptor 1 or 2 blocked the upregulation of INavD in bipolar cells, whereas in pyramid-shaped cells, increases in INavD were exclusively blocked by antibodies against TNF-receptor 2, suggesting that both cell types respond differently to TNF-α exposure. Since additional cytokines, such as interleukin-18 (IL-18), are released from activated microglia, we tested potential effects of IL-18 on INavD in both cell types. Exposure to 5–10 ng/ml IL-18 for 4 days increased INavD in both pyramid-shaped as well as bipolar neurons, albeit the dose–response curves were shifted to lower concentrations in bipolar cells. Our results suggest that by secretion of cytokines, microglial cells upregulate Na+ current densities in bipolar and pyramid-shaped neurons to some extent differentially. Depending on the exact cytokine composition and concentration released, this could change the balance between the activity of inhibitory bipolar and excitatory pyramid-shaped cells. Since bipolar cells show a larger upregulation of

  14. IL-6, IL-18, sIL-2R, and TNFα proinflammatory markers in depression and schizophrenia patients who are free of overt inflammation.

    PubMed

    Al-Hakeim, Hussein Kadhem; Al-Rammahi, Duaa Abdulzahraa; Al-Dujaili, Arafat Hussein

    2015-08-15

    Major depressive disorder (MDD) and schizophrenia are associated with inflammatory processes. Studies have shown that these disorders exhibit increase in the level of one or more proinflammatory markers. However, these studies did not exclude patients with obvious inflammation (i.e., CRP>6mg/L). Therefore, a comprehensive study should include those inflammatory disorders. In the present study, the inflammatory natures of MDD and schizophrenia were investigated. To achieve this goal, serum levels of interleukin-6 (IL-6), interleukin-18 (IL-18), tumor necrosis factor alpha (TNFα), and soluble interleukin 2 receptor (sIL-2R) in depressed and schizophrenic patients were obtained and compared with those of the control group. Results showed a significant increase (p<0.05) in serum levels of IL-6, IL-18, TNFα, and sIL-2R in MDD and schizophrenic patients compared with the control group. Also patients with schizophrenia group showed higher levels of the inflammatory markers than MDD and control groups. The current study concluded that the immunological response in the MDD and schizophrenic patients groups was significantly stimulated. These disorders may be considered an inflammatory disorder because of elevated levels of proinflammatory cytokines in spite of lacking an overt inflammation. Furthermore results of this study suggested the possibility of the use of anti-inflammatory drugs as adjuvant therapy in schizophrenic and depressive disorders. PMID:25985379

  15. Interleukin (IL)-22 receptor 1 is over-expressed in primary Sjogren's syndrome and Sjögren-associated non-Hodgkin lymphomas and is regulated by IL-18.

    PubMed

    Ciccia, F; Guggino, G; Rizzo, A; Bombardieri, M; Raimondo, S; Carubbi, F; Cannizzaro, A; Sireci, G; Dieli, F; Campisi, G; Giacomelli, R; Cipriani, Paola; De Leo, G; Alessandro, R; Triolo, G

    2015-08-01

    The aim of this study was to elucidate more clearly the role of interleukin (IL)-18 in modulating the IL-22 pathway in primary Sjögren's syndrome (pSS) patients and in pSS-associated lymphomas. Minor salivary glands (MSGs) from patients with pSS and non-specific chronic sialoadenitis (nSCS), parotid glands biopsies from non-Hodgkin lymphomas (NHL) developed in pSS patients, were evaluated for IL-18, IL-22, IL-22 receptor 1 (IL-22R1), IL-22 binding protein (IL-22BP) and signal transducer and activator of transcription-3 (STAT-3) expression. MSGs IL-22R1-expressing cells were characterized by confocal microscopy and flow cytometry in pSS, nSCS and healthy controls . The effect of recombinant IL-18 and IL-22 on peripheral blood mononuclear cells (PBMCs) from pSS and nSCS was studied by flow cytometry and reverse transcription-polymerase chain reaction (RT-PCR). MSGs of pSS and NHL were characterized by an imbalance between IL-22 and IL-22BP protein expression, with IL-18 and IL-22BP being expressed in a mutually exclusive manner and IL-18 and IL-22R1 being correlated directly. Aberrant expression of IL-22R1, induced by IL-18, was observed only among tissue and circulating myeloid cells of pSS patients and macrophages of NHL tissues of pSS patients, but not nSCS. IL-22R1 expression on PBMC of pSS was functional, as its stimulation with recombinant IL-22 significantly up-regulated the expression of STAT-3, IL-17 and IL-22. An IL-18-dependent aberrant expression of IL-22R1 on cells of haematopoietic origin seems to be a specific immunological signature of patients with pSS and pSS-associated lymphomas.

  16. Interleukin (IL)-22 receptor 1 is over-expressed in primary Sjogren’s syndrome and Sjögren-associated non-Hodgkin lymphomas and is regulated by IL-18

    PubMed Central

    Ciccia, F; Guggino, G; Rizzo, A; Bombardieri, M; Raimondo, S; Carubbi, F; Cannizzaro, A; Sireci, G; Dieli, F; Campisi, G; Giacomelli, R; Cipriani, Paola; De Leo, G; Alessandro, R; Triolo, G

    2015-01-01

    The aim of this study was to elucidate more clearly the role of interleukin (IL)-18 in modulating the IL-22 pathway in primary Sjögren’s syndrome (pSS) patients and in pSS-associated lymphomas. Minor salivary glands (MSGs) from patients with pSS and non-specific chronic sialoadenitis (nSCS), parotid glands biopsies from non-Hodgkin lymphomas (NHL) developed in pSS patients, were evaluated for IL-18, IL-22, IL-22 receptor 1 (IL-22R1), IL-22 binding protein (IL-22BP) and signal transducer and activator of transcription-3 (STAT-3) expression. MSGs IL-22R1-expressing cells were characterized by confocal microscopy and flow cytometry in pSS, nSCS and healthy controls. The effect of recombinant IL-18 and IL-22 on peripheral blood mononuclear cells (PBMCs) from pSS and nSCS was studied by flow cytometry and reverse transcription–polymerase chain reaction (RT-PCR). MSGs of pSS and NHL were characterized by an imbalance between IL-22 and IL-22BP protein expression, with IL-18 and IL-22BP being expressed in a mutually exclusive manner and IL-18 and IL-22R1 being correlated directly. Aberrant expression of IL-22R1, induced by IL-18, was observed only among tissue and circulating myeloid cells of pSS patients and macrophages of NHL tissues of pSS patients, but not nSCS. IL-22R1 expression on PBMC of pSS was functional, as its stimulation with recombinant IL-22 significantly up-regulated the expression of STAT-3, IL-17 and IL-22. An IL-18-dependent aberrant expression of IL-22R1 on cells of haematopoietic origin seems to be a specific immunological signature of patients with pSS and pSS-associated lymphomas. PMID:25880879

  17. Interleukin (IL)-22 receptor 1 is over-expressed in primary Sjogren's syndrome and Sjögren-associated non-Hodgkin lymphomas and is regulated by IL-18.

    PubMed

    Ciccia, F; Guggino, G; Rizzo, A; Bombardieri, M; Raimondo, S; Carubbi, F; Cannizzaro, A; Sireci, G; Dieli, F; Campisi, G; Giacomelli, R; Cipriani, Paola; De Leo, G; Alessandro, R; Triolo, G

    2015-08-01

    The aim of this study was to elucidate more clearly the role of interleukin (IL)-18 in modulating the IL-22 pathway in primary Sjögren's syndrome (pSS) patients and in pSS-associated lymphomas. Minor salivary glands (MSGs) from patients with pSS and non-specific chronic sialoadenitis (nSCS), parotid glands biopsies from non-Hodgkin lymphomas (NHL) developed in pSS patients, were evaluated for IL-18, IL-22, IL-22 receptor 1 (IL-22R1), IL-22 binding protein (IL-22BP) and signal transducer and activator of transcription-3 (STAT-3) expression. MSGs IL-22R1-expressing cells were characterized by confocal microscopy and flow cytometry in pSS, nSCS and healthy controls . The effect of recombinant IL-18 and IL-22 on peripheral blood mononuclear cells (PBMCs) from pSS and nSCS was studied by flow cytometry and reverse transcription-polymerase chain reaction (RT-PCR). MSGs of pSS and NHL were characterized by an imbalance between IL-22 and IL-22BP protein expression, with IL-18 and IL-22BP being expressed in a mutually exclusive manner and IL-18 and IL-22R1 being correlated directly. Aberrant expression of IL-22R1, induced by IL-18, was observed only among tissue and circulating myeloid cells of pSS patients and macrophages of NHL tissues of pSS patients, but not nSCS. IL-22R1 expression on PBMC of pSS was functional, as its stimulation with recombinant IL-22 significantly up-regulated the expression of STAT-3, IL-17 and IL-22. An IL-18-dependent aberrant expression of IL-22R1 on cells of haematopoietic origin seems to be a specific immunological signature of patients with pSS and pSS-associated lymphomas. PMID:25880879

  18. Murine Macrophages Secrete Interferon γ upon Combined Stimulation with Interleukin (IL)-12 and IL-18: A Novel Pathway of Autocrine Macrophage Activation

    PubMed Central

    Munder, Markus; Mallo, Moisés; Eichmann, Klaus; Modolell, Manuel

    1998-01-01

    Interferon (IFN)-γ, a key immunoregulatory cytokine, has been thought to be produced solely by activated T cells and natural killer cells. In this study, we show that murine bone marrow– derived macrophages (BMMΦ) secrete large amounts of IFN-γ upon appropriate stimulation. Although interleukin (IL)-12 and IL-18 alone induce low levels of IFN-γ mRNA transcripts, the combined stimulation of BMMΦ with both cytokines leads to the efficient production of IFN-γ protein. The macrophage-derived IFN-γ is biologically active as shown by induction of inducible nitric oxide synthase as well as upregulation of CD40 in macrophages. Our findings uncover a novel pathway of autocrine macrophage activation by demonstrating that the macrophage is not only a key cell type responding to IFN-γ but also a potent IFN-γ–producing cell. PMID:9625771

  19. DNA vaccine (P1-2A-3C-pCDNA) co-administered with Bovine IL-18 gives protective immune response against Foot and Mouth Disease in cattle.

    PubMed

    Kotla, Sivareddy; Sanghratna Vishanath, Bahire; H J, Dechamma; K, Ganesh; V V S, Suryanarayana; Reddy, G R

    2016-09-25

    Foot-and-mouth disease (FMD) is a highly contagious disease of cloven-hoofed animals causing considerable economic loss in the affected countries. Presently used tissue culture inactivated vaccine protects the vaccinated animals for a short duration. DNA vaccines along with appropriate adjutants is one of the approach for the development of alternative vaccine. In the present study, we constructed P1-2A-3CpCDNA (containing P1-2A-3C coding sequences of FMDV Asia-1 Ind 63/72) and bovine IL-18 pCDNA plasmids and evaluated in cattle. Four groups of calves each group containing six calves were vaccinated with 200μg of plasmid DNA vaccine P1-2A-3CpCDNA, P1-2A-3CpCDNA+ bIL-18pCDNA and inactivated vaccine respectively where as fourth group was unvaccinated. P1-2A-3CpCDNA+bIL-18pCDNA vaccinated animals have shown higher levels of neutralizing antibodies and specific T-cell proliferation responses. Higher levels of CD4(+) and CD8(+) cells were observed in these animals. Similarly, IL-18 adjuvanted group has shown increased Th1 and Th2 cytokine responses. All the vaccinated animals were challenged with cattle adapted FMD homologous Asia1 virus two weeks after the booster dose. IL18 co administered DNA vaccine construct has protected four out of six animals challenged with homologous virus. PMID:27599937

  20. Endogenous conversion of ω-6 to ω-3 polyunsaturated fatty acids in fat-1 mice attenuated intestinal polyposis by either inhibiting COX-2/β-catenin signaling or activating 15-PGDH/IL-18.

    PubMed

    Han, Young-Min; Park, Jong-Min; Cha, Ji-Young; Jeong, Migyeong; Go, Eun-Jin; Hahm, Ki Baik

    2016-05-01

    Omega-3 polyunsaturated fatty acids (ω-3PUFAs) have inhibitory effects in various preclinical cancer models, but their effects in intestinal polyposis have never been examined. As attempts have been made to use nutritional intervention to counteract colon cancer development, in this study we evaluated the effects of ω-3 PUFAs on intestinal polyposis in the Apc(Min/+) mouse model. The experimental groups included wild-type C56BL/6 mice, Apc(Min/+) mice, fat-1 transgenic mice expressing an n-3 desaturase to enable ω-3 PUFA synthesis, and Apc(Min/+) × fat-1 double-transgenic mice; all mice were 20 weeks of age. Small intestines were collected for gross and pathologic evaluation, including assessment of polyp number and size, followed by immunohistochemical staining and Western blotting. After administration of various concentrations of ω-3 PUFAs, PUFA levels were measured in small intestine tissue by GC/MS/MS analysis to compare with PUFA synthesis of between C57BL6 and fat-1mice. As a result, ω-3 PUFAs significantly attenuated Apc mutation-induced intestinal polyposis accompanied with significant inhibition of Wnt/β-catenin signaling, COX-2 and PGE2, but induced significant levels of 15-PGDH. In addition, significant induction of the inflammasome-related substrates as IL-1β and IL-18 and activation of caspase-1 was observed in Apc(Min/+) × fat-1 mice. Administration of at least 3 g/60 kg ω-3 PUFAs was equivalent to ω-3 PUFAs produced in fat-1 mice and resulted in significant increase in the expression of IL-1β, caspase-3 and IL-18, as seen in Apc(Min/+) × fat-1 mice. We conclude that ω-3PUFAs can prevent intestinal polyp formation by inhibition of Wnt/β-catenin signaling, but increased levels of 15-PGDH and IL-18.

  1. Genetic characterization of interleukins (IL-1α, IL-1β, IL-2, IL-4, IL-8, IL-10, IL-12A, IL-12B, IL-15 and IL-18) with relevant biological roles in lagomorphs

    PubMed Central

    Neves, Fabiana; Abrantes, Joana; Almeida, Tereza; de Matos, Ana Lemos; Costa, Paulo P

    2015-01-01

    ILs, as essential innate immune modulators, are involved in an array of biological processes. In the European rabbit (Oryctolagus cuniculus) IL-1α, IL-1β, IL-2, IL-4, IL-8, IL-10, IL-12A, IL-12B, IL-15 and IL-18 have been implicated in inflammatory processes and in the immune response against rabbit hemorrhagic disease virus and myxoma virus infections. In this study we characterized these ILs in six Lagomorpha species (European rabbit, pygmy rabbit, two cottontail rabbit species, European brown hare and American pika). Overall, these ILs are conserved between lagomorphs, including in their exon/intron structure. Most differences were observed between leporids and American pika. Indeed, when comparing both, some relevant differences were observed in American pika, such as the location of the stop codon in IL-1α and IL-2, the existence of a different transcript in IL8 and the number of cysteine residues in IL-1β. Changes at N-glycosylation motifs were also detected in IL-1, IL-10, IL-12B and IL-15. IL-1α is the protein that presents the highest evolutionary distances, which is in contrast to IL-12A where the distances between lagomorphs are the lowest. For all these ILs, sequences of human and European rabbit are more closely related than between human and mouse or European rabbit and mouse. PMID:26395994

  2. Genetic characterization of interleukins (IL-1α, IL-1β, IL-2, IL-4, IL-8, IL-10, IL-12A, IL-12B, IL-15 and IL-18) with relevant biological roles in lagomorphs.

    PubMed

    Neves, Fabiana; Abrantes, Joana; Almeida, Tereza; de Matos, Ana Lemos; Costa, Paulo P; Esteves, Pedro J

    2015-11-01

    ILs, as essential innate immune modulators, are involved in an array of biological processes. In the European rabbit (Oryctolagus cuniculus) IL-1α, IL-1β, IL-2, IL-4, IL-8, IL-10, IL-12A, IL-12B, IL-15 and IL-18 have been implicated in inflammatory processes and in the immune response against rabbit hemorrhagic disease virus and myxoma virus infections. In this study we characterized these ILs in six Lagomorpha species (European rabbit, pygmy rabbit, two cottontail rabbit species, European brown hare and American pika). Overall, these ILs are conserved between lagomorphs, including in their exon/intron structure. Most differences were observed between leporids and American pika. Indeed, when comparing both, some relevant differences were observed in American pika, such as the location of the stop codon in IL-1α and IL-2, the existence of a different transcript in IL8 and the number of cysteine residues in IL-1β. Changes at N-glycosylation motifs were also detected in IL-1, IL-10, IL-12B and IL-15. IL-1α is the protein that presents the highest evolutionary distances, which is in contrast to IL-12A where the distances between lagomorphs are the lowest. For all these ILs, sequences of human and European rabbit are more closely related than between human and mouse or European rabbit and mouse. PMID:26395994

  3. Ehrlichia chaffeensis induces monocyte inflammatory responses through MyD88, ERK, and NF-κB but not through TRIF, interleukin-1 receptor 1 (IL-1R1)/IL-18R1, or toll-like receptors.

    PubMed

    Miura, Koshiro; Matsuo, Junji; Rahman, M Akhlakur; Kumagai, Yumi; Li, Xin; Rikihisa, Yasuko

    2011-12-01

    Human monocytic ehrlichiosis, an influenza-like illness accompanied by signs of hepatitis, is caused by infection of monocytes/macrophages with a lipopolysaccharide-deficient bacterium, Ehrlichia chaffeensis. The E. chaffeensis strain Wakulla induces diffuse hepatitis with neutrophil infiltration in mice with severe combined immunodeficiency, which is accompanied by strong CXCL2 (mouse functional homolog of interleukin-8 [IL-8]) and tumor necrosis factor alpha (TNF-α) expression in the liver. In this study, we found that expression of IL-1β, CXCL2, and TNF-α was induced by strain Wakulla in mouse bone marrow-derived macrophages; this expression was dependent on MyD88, but not on TRIF, TLR2/4, IL-1R1/IL-18R1, or endosome acidification. When the human leukemia cell line THP-1 was exposed to E. chaffeensis, significant upregulation of IL-8, IL-1β, and TNF-α mRNA and extracellular regulated kinase 2 (ERK2) activation were detected. U0126 (inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 [MEK1/2] upstream of ERK), manumycin A (Ras inhibitor), BAY43-9006 (Raf-1 inhibitor), and NS-50 (inhibitor of NF-κB nuclear translocation) inhibited the cytokine gene expression. A luciferase reporter assay using HEK293 cells, which lack Toll-like receptors (TLRs), showed activation of both the IL-8 promoter and NF-κB by E. chaffeensis. Activation of the IL-8 promoter in transfected HEK293 cells was inhibited by manumycin A, BAY43-9006, U0126, and transfection with a dominant-negative Ras mutant. These results indicate that the E. chaffeensis Wakulla strain can induce inflammatory responses through MyD88-dependent NF-κB and ERK pathways, without the involvement of TRIF and TLRs.

  4. Anthocyanins from black soybean seed coat enhance wound healing.

    PubMed

    Xu, Lianji; Choi, Tae Hyun; Kim, Sukwha; Kim, Sang-Hyon; Chang, Hyuk Won; Choe, Misun; Kwon, Sun Young; Hur, Ji An; Shin, Sung Chul; Chung, Jong Il; Kang, Dawon; Zhang, Duo

    2013-10-01

    Anthocyanins are known to have antioxidant and antiinflammatory effects. We hypothesized that anthocyanins would enhance wound healing in Sprague-Dawley rats. The purpose of this study was to evaluate our hypothesis and investigate the mechanism of wound healing enhancement. The cytoprotective effect of an immortalized epidermal keratinocyte cell line (HaCaT) and human neonatal dermal fibroblasts in response to various concentrations of anthocyanins was determined. Vascular endothelial growth factor (VEGF) and thrombospondin 1 (TSP1) of HaCaT were measured by Western blot analysis. Anthocyanins were applied to the wounds in rats, and the healing ratio was calculated. Tissue VEGF, TSP1, CD31, nuclear factor-κB, and phosphorylation of IκBα were measured. The viability of the HaCaT cell line and human neonatal dermal fibroblasts increased under cytotoxicity by H2O2 in the anthocyanin-treated groups. The VEGF in the anthocyanin-treated groups increased, whereas TSP1 decreased. Wounds in the experimental groups healed faster, and VEGF and CD31 increased in the experimental groups, whereas TSP1 decreased. Anthocyanins inhibited the translocation of nuclear factor-κB (p65) from cytosol to nucleus and also prevented the phosphorylation of IκBα. Anthocyanins enhance wound healing through a cytoprotective effect, enhancement of angiogenesis, and an antiinflammatory effect.

  5. A Role for Syndecan-1 in Coupling Fascin Spike Formation by Thrombospondin-1

    PubMed Central

    Adams, Josephine C.; Kureishy, Nina; Taylor, Amanda L.

    2001-01-01

    An important role of cell matrix adhesion receptors is to mediate transmembrane coupling between extracellular matrix attachment, actin reorganization, and cell spreading. Thrombospondin (TSP)-1 is a modulatory component of matrix expressed during development, immune response, or wound repair. Cell adhesion to TSP-1 involves formation of biochemically distinct matrix contacts based on stable fascin spikes. The cell surface adhesion receptors required have not been identified. We report here that antibody clustering of syndecan-1 proteoglycan specifically transduces organization of cortical actin and fascin bundles in several cell types. Transfection of COS-7 cells with syndecan-1 is sufficient to stimulate cell spreading, fascin spike assembly, and extensive protrusive lateral ruffling on TSP-1 or on syndecan-1 antibody. The underlying molecular mechanism depends on glycosaminoglycan (GAG) modification of the syndecan-1 core protein at residues S45 or S47 for cell membrane spreading and on the VC2 region of the cytoplasmic domain for spreading and fascin spike formation. Expression of the VC2 deletion mutant or GAG-negative syndecan-1 showed that syndecan-1 is necessary in spreading and fascin spike formation by C2C12 cells on TSP-1. These results establish a novel role for syndecan-1 protein in coupling a physiological matrix ligand to formation of a specific matrix contact structure. PMID:11257118

  6. Thrombospondin-1, -2 and -5 have differential effects on vascular smooth muscle cell physiology

    SciTech Connect

    Helkin, Alex; Maier, Kristopher G.; Gahtan, Vivian

    2015-09-04

    Introduction: The thrombospondins (TSPs) are matricellular proteins that exert multifunctional effects by binding cytokines, cell-surface receptors and other proteins. TSPs play important roles in vascular pathobiology and are all expressed in arterial lesions. The differential effects of TSP-1, -2, and -5 represent a gap in knowledge in vascular smooth muscle cell (VSMC) physiology. Our objective is to determine if structural differences of the TSPs imparted different effects on VSMC functions critical to the formation of neointimal hyperplasia. We hypothesize that TSP-1 and -2 induce similar patterns of migration, proliferation and gene expression, while the effects of TSP-5 are different. Methods: Human aortic VSMC chemotaxis was tested for TSP-2 and TSP-5 (1–40 μg/mL), and compared to TSP-1 and serum-free media (SFM) using a modified Boyden chamber. Next, VSMCs were exposed to TSP-1, TSP-2 or TSP-5 (0.2–40 μg/mL). Proliferation was assessed by MTS assay. Finally, VSMCs were exposed to TSP-1, TSP-2, TSP-5 or SFM for 3, 6 or 24 h. Quantitative real-time PCR was performed on 96 genes using a microfluidic card. Statistical analysis was performed by ANOVA or t-test, with p < 0.05 being significant. Results: TSP-1, TSP-2 and TSP-5 at 20 μg/mL all induce chemotaxis 3.1 fold compared to serum-free media. TSP-1 and TSP-2 induced proliferation 53% and 54% respectively, whereas TSP-5 did not. In the gene analysis, overall, cardiovascular system development and function is the canonical pathway most influenced by TSP treatment, and includes multiple growth factors, cytokines and proteases implicated in cellular migration, proliferation, vasculogenesis, apoptosis and inflammation pathways. Conclusions and relevance: The results of this study indicate TSP-1, -2, and -5 play active roles in VSMC physiology and gene expression. Similarly to TSP-1, VSMC chemotaxis to TSP-2 and -5 is dose-dependent. TSP-1 and -2 induces VSMC proliferation, but TSP-5 does not, likely due conservation of N-terminal domains in TSP-1 and -2. In addition, TSP-1, -2 and -5 significantly affect VSMC gene expression; however, little overlap exists in the specific genes altered. This study further delineates TSP-1, -2 and -5's contributions to processes related to VSMC physiology. - Highlights: • We examined the effects of three different thrombospondins on smooth muscle cells. • Thrombospondins −1, −2, −5 all increase smooth muscle cell migration. • Thrombospondins −1 and −2, but not −5, increase smooth muscle cell proliferation. • All three thrombospondins exhibit temporally distinct patterns of gene expression. • Thrombospondins −1 and −2 display distinct patterns of gene expression.

  7. Enhanced immune response of MAIT cells in tuberculous pleural effusions depends on cytokine signaling

    PubMed Central

    Jiang, Jing; Chen, Xinchun; An, Hongjuan; Yang, Bingfen; Zhang, Fuping; Cheng, Xiaoxing

    2016-01-01

    The functions of MAIT cells at the site of Mycobacterium tuberculosis infection in humans are still largely unknown. In this study, the phenotypes and immune response of MAIT cells from tuberculous pleural effusions and peripheral blood were investigated. MAIT cells in tuberculous pleural effusions had greatly enhanced IFN-γ, IL-17F and granzyme B response compared with those in peripheral blood. The level of IFN-γ response in MAIT cells from tuberculous pleural effusions was inversely correlated with the extent of tuberculosis infection (p = 0.0006). To determine whether cytokines drive the immune responses of MAIT cells at the site of tuberculosis infection, the role of IL-1β, IL-2, IL-7, IL-12, IL-15 and IL-18 was investigated. Blockade of IL-2, IL-12 or IL-18 led to significantly reduced production of IFN-γ and/or granzyme B in MAIT cells from tuberculous pleural effusions. Majority of IL-2-producing cells (94.50%) in tuberculous pleural effusions had phenotype of CD3+CD4+, and most IL-12p40-producing cells (91.39%) were CD14+ cells. MAIT cells had significantly elevated expression of γc receptor which correlated with enhanced immune responses of MAIT cells. It is concluded that MAIT cells from tuberculous pleural effusions exhibited highly elevated immune response to Mtb antigens, which are controlled by cytokines produced by innate/adaptive immune cells. PMID:27586092

  8. Enhanced immune response of MAIT cells in tuberculous pleural effusions depends on cytokine signaling.

    PubMed

    Jiang, Jing; Chen, Xinchun; An, Hongjuan; Yang, Bingfen; Zhang, Fuping; Cheng, Xiaoxing

    2016-01-01

    The functions of MAIT cells at the site of Mycobacterium tuberculosis infection in humans are still largely unknown. In this study, the phenotypes and immune response of MAIT cells from tuberculous pleural effusions and peripheral blood were investigated. MAIT cells in tuberculous pleural effusions had greatly enhanced IFN-γ, IL-17F and granzyme B response compared with those in peripheral blood. The level of IFN-γ response in MAIT cells from tuberculous pleural effusions was inversely correlated with the extent of tuberculosis infection (p = 0.0006). To determine whether cytokines drive the immune responses of MAIT cells at the site of tuberculosis infection, the role of IL-1β, IL-2, IL-7, IL-12, IL-15 and IL-18 was investigated. Blockade of IL-2, IL-12 or IL-18 led to significantly reduced production of IFN-γ and/or granzyme B in MAIT cells from tuberculous pleural effusions. Majority of IL-2-producing cells (94.50%) in tuberculous pleural effusions had phenotype of CD3(+)CD4(+), and most IL-12p40-producing cells (91.39%) were CD14(+) cells. MAIT cells had significantly elevated expression of γc receptor which correlated with enhanced immune responses of MAIT cells. It is concluded that MAIT cells from tuberculous pleural effusions exhibited highly elevated immune response to Mtb antigens, which are controlled by cytokines produced by innate/adaptive immune cells. PMID:27586092

  9. Neutrophil Extracellular Trap-Associated Protein Activation of the NLRP3 Inflammasome Is Enhanced in Lupus Macrophages

    PubMed Central

    Kahlenberg, J. Michelle; Carmona-Rivera, Carmelo; Smith, Carolyne K.; Kaplan, Mariana J.

    2012-01-01

    Neutrophil extracellular traps (NETs) represent an important defense mechanism against microorganisms. Clearance of NETs is impaired in a subset of patients with systemic lupus erythematosus (SLE), while NETosis is increased in neutrophils and, particularly, in low-density granulocytes derived from lupus patients. NETs are toxic to the endothelium, expose immunostimulatory molecules, activate plasmacytoid dendritic cells and may participate in organ damage through incompletely characterized pathways. In order to better understand the role of NETs in fostering dysregulated inflammation, we examined inflammasome activation in response to NETs or to LL-37, an antibacterial protein externalized on the NETs. Both NETs and LL-37 activate caspase-1, the central enzyme of the inflammasome, in both human and murine macrophages, resulting in release of active IL-1β and IL-18. LL-37 activation of the NLRP3 inflammasome utilizes P2×7 receptor-mediated potassium efflux. NET and LL-37-mediated activation of the inflammasome is enhanced in macrophages derived from lupus patients. In turn, IL-18 is able to stimulate NETosis in human neutrophils. These results suggest that enhanced formation of NETs in lupus patients can lead to increased inflammasome activation in adjacent macrophages. This leads to release of inflammatory cytokines which further stimulate NETosis, resulting in a feed-forward inflammatory loop that could potentially lead to disease flares and/or organ damage. PMID:23267025

  10. Neutrophil extracellular trap-associated protein activation of the NLRP3 inflammasome is enhanced in lupus macrophages.

    PubMed

    Kahlenberg, J Michelle; Carmona-Rivera, Carmelo; Smith, Carolyne K; Kaplan, Mariana J

    2013-02-01

    Neutrophil extracellular traps (NETs) represent an important defense mechanism against microorganisms. Clearance of NETs is impaired in a subset of patients with systemic lupus erythematosus, and NETosis is increased in neutrophils and, particularly, in low-density granulocytes derived from lupus patients. NETs are toxic to the endothelium, expose immunostimulatory molecules, activate plasmacytoid dendritic cells, and may participate in organ damage through incompletely characterized pathways. To better understand the role of NETs in fostering dysregulated inflammation, we examined inflammasome activation in response to NETs or to LL-37, an antibacterial protein externalized on NETs. Both NETs and LL-37 activate caspase-1, the central enzyme of the inflammasome, in both human and murine macrophages, resulting in release of active IL-1β and IL-18. LL-37 activation of the NLRP3 inflammasome utilizes P2X7 receptor-mediated potassium efflux. NET and LL-37-mediated activation of the inflammasome is enhanced in macrophages derived from lupus patients. In turn, IL-18 is able to stimulate NETosis in human neutrophils. These results suggest that enhanced formation of NETs in lupus patients can lead to increased inflammasome activation in adjacent macrophages. This leads to release of inflammatory cytokines that further stimulate NETosis, resulting in a feed-forward inflammatory loop that could potentially lead to disease flares and/or organ damage.

  11. 76 FR 76744 - Prospective Grant of Exclusive License: Use of Agents Targeting Thrombospondin-1 and CD47 To...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-08

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health Prospective Grant of Exclusive License: Use of Agents... Radiotherapy in Cancer Patients AGENCY: National Institutes of Health, Public Health Service, HHS....

  12. Elevated postinjury thrombospondin 1-CD47 triggering aids differentiation of patients' defective inflammatory CD1a+dendritic cells.

    PubMed

    Bandyopadhyay, Gautam; Bandyopadhyay, Sanjukta; Bankey, Paul E; Miller-Graziano, Carol L

    2014-11-01

    A subset of Pts develops dysfunctional MO to inflammatory DC differentiation and immunosuppression. MDDC, a newly described DC subset, is pivotal in initiating antibacterial responses. Endogenous proteins are known to alter MO to MDDC differentiation. In particular, trauma-elevated TSP-1, a protein that is known to affect MO functions, could trigger MDDC differentiation defects. We hypothesized that TSP-1-deranged differentiation of inflammatory CD1a(+)MDDC would negatively alter activation of immune functions, thereby increasing the risk of postinjury infections. Post-trauma increased TSP-1 levels in patients' plasma and MO correlated with two distinct MDDC differentiation dysfunctions: the previously described decreased CD1a(+)DC yields but also, development of an immunoincompetent CD1a(+)MDDC. The Pts' development of Dysf DC correlated to increased infectious complications. TSP-1 triggered its inhibitory receptor, CD47, activating an inhibitory phosphatase, SHP-1. Increased pSHP-1, decreased antigen processing, and depressed T cell stimulation characterized Pt Dysf DC. TSP-1 mimics added during Cnt MDDC differentiation depressed CD1a(+)DC yields but more importantly, also induced defective CD1a(+)MDDC, reproducing Pts' MDDC differentiation dysfunctions. CD47 triggering during Cnt MDDC differentiation increased SHP-1 activation, inhibiting IL-4-induced STAT-6 activation (critical for CD1a(+)MDDC differentiation). SHP-1 inhibition during MDDC differentiation in the presence of TSP-1 mimics restored pSTAT-6 levels and CD1a(+)MDDC immunogenicity. Thus, postinjury-elevated TSP-1 can decrease CD1a(+)DC yields but more critically, also induces SHP-1 hyperactivity, deviating MDDC differentiation to defective CD1a(+) inflammatory MDDCs by inhibiting STAT-6. PMID:25001859

  13. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia.

    PubMed

    Romee, Rizwan; Rosario, Maximillian; Berrien-Elliott, Melissa M; Wagner, Julia A; Jewell, Brea A; Schappe, Timothy; Leong, Jeffrey W; Abdel-Latif, Sara; Schneider, Stephanie E; Willey, Sarah; Neal, Carly C; Yu, Liyang; Oh, Stephen T; Lee, Yi-Shan; Mulder, Arend; Claas, Frans; Cooper, Megan A; Fehniger, Todd A

    2016-09-21

    Natural killer (NK) cells are an emerging cellular immunotherapy for patients with acute myeloid leukemia (AML); however, the best approach to maximize NK cell antileukemia potential is unclear. Cytokine-induced memory-like NK cells differentiate after a brief preactivation with interleukin-12 (IL-12), IL-15, and IL-18 and exhibit enhanced responses to cytokine or activating receptor restimulation for weeks to months after preactivation. We hypothesized that memory-like NK cells exhibit enhanced antileukemia functionality. We demonstrated that human memory-like NK cells have enhanced interferon-γ production and cytotoxicity against leukemia cell lines or primary human AML blasts in vitro. Using mass cytometry, we found that memory-like NK cell functional responses were triggered against primary AML blasts, regardless of killer cell immunoglobulin-like receptor (KIR) to KIR-ligand interactions. In addition, multidimensional analyses identified distinct phenotypes of control and memory-like NK cells from the same individuals. Human memory-like NK cells xenografted into mice substantially reduced AML burden in vivo and improved overall survival. In the context of a first-in-human phase 1 clinical trial, adoptively transferred memory-like NK cells proliferated and expanded in AML patients and demonstrated robust responses against leukemia targets. Clinical responses were observed in five of nine evaluable patients, including four complete remissions. Thus, harnessing cytokine-induced memory-like NK cell responses represents a promising translational immunotherapy approach for patients with AML.

  14. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia.

    PubMed

    Romee, Rizwan; Rosario, Maximillian; Berrien-Elliott, Melissa M; Wagner, Julia A; Jewell, Brea A; Schappe, Timothy; Leong, Jeffrey W; Abdel-Latif, Sara; Schneider, Stephanie E; Willey, Sarah; Neal, Carly C; Yu, Liyang; Oh, Stephen T; Lee, Yi-Shan; Mulder, Arend; Claas, Frans; Cooper, Megan A; Fehniger, Todd A

    2016-09-21

    Natural killer (NK) cells are an emerging cellular immunotherapy for patients with acute myeloid leukemia (AML); however, the best approach to maximize NK cell antileukemia potential is unclear. Cytokine-induced memory-like NK cells differentiate after a brief preactivation with interleukin-12 (IL-12), IL-15, and IL-18 and exhibit enhanced responses to cytokine or activating receptor restimulation for weeks to months after preactivation. We hypothesized that memory-like NK cells exhibit enhanced antileukemia functionality. We demonstrated that human memory-like NK cells have enhanced interferon-γ production and cytotoxicity against leukemia cell lines or primary human AML blasts in vitro. Using mass cytometry, we found that memory-like NK cell functional responses were triggered against primary AML blasts, regardless of killer cell immunoglobulin-like receptor (KIR) to KIR-ligand interactions. In addition, multidimensional analyses identified distinct phenotypes of control and memory-like NK cells from the same individuals. Human memory-like NK cells xenografted into mice substantially reduced AML burden in vivo and improved overall survival. In the context of a first-in-human phase 1 clinical trial, adoptively transferred memory-like NK cells proliferated and expanded in AML patients and demonstrated robust responses against leukemia targets. Clinical responses were observed in five of nine evaluable patients, including four complete remissions. Thus, harnessing cytokine-induced memory-like NK cell responses represents a promising translational immunotherapy approach for patients with AML. PMID:27655849

  15. Moral Enhancement

    PubMed Central

    Douglas, Thomas

    2008-01-01

    Opponents of biomedical enhancement often claim that, even if such enhancement would benefit the enhanced, it would harm others. But this objection looks unpersuasive when the enhancement in question is a moral enhancement — an enhancement that will expectably leave the enhanced person with morally better motives than she had previously. In this article I (1) describe one type of psychological alteration that would plausibly qualify as a moral enhancement, (2) argue that we will, in the medium-term future, probably be able to induce such alterations via biomedical intervention, and (3) defend future engagement in such moral enhancements against possible objections. My aim is to present this kind of moral enhancement as a counter-example to the view that biomedical enhancement is always morally impermissible. PMID:19132138

  16. Dendritic cell-derived thrombospondin-1 is critical for the generation of the ocular surface Th17 response to desiccating stress

    PubMed Central

    Gandhi, Niral B.; Su, Zhitao; Zhang, Xiaobo; Volpe, Eugene A.; Pelegrino, Flavia S. A.; Rahman, Salman A.; Li, De-Quan; Pflugfelder, Stephen C.; de Paiva, Cintia S.

    2013-01-01

    TSP-1 is a physiologic activator of TGF-β, a critical induction factor for Th17-mediated immunity. The purpose of this study was to investigate the role of TSP-1 in the induction of the Th17 ocular surface response to DS. TSP-1KO and WT mice were subjected to DS5 and DS10), and parameters of ocular surface disease, including corneal barrier function, conjunctival CD4+ T cell infiltration, and GC density, were evaluated. TSP-1KO mice subjected to DS had less corneal barrier disruption, reduced loss of PAS+ GC, and decreased CD4+ T cell infiltration in the conjunctiva. In contrast to WT, TSP-1KO mice failed to up-regulate MMP-3 and MMP-9 mRNA transcripts in the cornea and IL-17A mRNA transcripts in the conjunctiva. RAG-1KO recipients of adoptively transferred CD4+ T cells isolated from TSP-1KO mice subjected to DS5 showed milder dry-eye phenotype and less conjunctival inflammation than recipients of CD4+ T cells from DS5 WT control. Reconstitution of TSP-1KO mice with WT DCs prior to DS reversed the resistance of the TSP-1KO to DS-induced immunopathology. In conclusion, DC-derived TSP-1 is critical for generating the Th17 ocular surface response to DS. PMID:23983225

  17. Opposite regulation of thrombospondin-1 and corticotropin-induced secreted protein/thrombospondin-2 expression by adrenocorticotropic hormone in adrenocortical cells.

    PubMed

    Lafeuillade, B; Pellerin, S; Keramidas, M; Danik, M; Chambaz, E M; Feige, J J

    1996-04-01

    Corticotropin-induced secreted protein (CISP) is a trimeric glycoprotein secreted by primary cultures of bovine adrenortical cells in response to adrenocorticotropic hormone (ACTH). This protein was recently purified in our laboratory, and its N-terminal amino-acid sequence revealed a significant similarity with thrombospondin-2 (TSP2). We report here the nucleotide sequence of a 386 bp RT-PCR fragment specific for CISP. The deduced protein sequence shares 84% identity with the N-terminal portion of mature human TSP2, suggesting that CISP is its bovine counterpart. Northern analysis of adrenocortical cell RNA using the above cDNA fragment as a probe revealed a 6.0 kb CISP/TSP2 mRNA whose abundance was increased nearly fivefold following a 24 h cell treatment with 10(-7) M ACTH. Under the same conditions, the expression of TSP1 mRNA was reduced by tenfold. The protein levels of TSP1 and CISP/TSP2 varied accordingly with their respective mRNA levels, as shown by immunoprecipitation and immunofluorescence experiments. Taken together, these data show that ACTH induces a dramatic shift in the pattern of adrenocortical cell thrombospondin expression from TSP1 to CISP/TSP2. This observation suggests that these two members of the thrombospondin family exert distinct biological functions in the adrenal cortex. This hypothesis is further supported by the observation that anti-CISP antibodies inhibit the maintenance of the morphological changes of bovine adrenocortical cells induced by ACTH, whereas anti-TSP1 antibodies do not. PMID:8698834

  18. The N-terminal domain of thrombospondin-1: a key for the dual effect of TSP-1 in angiogenesis and cancer progression?

    PubMed

    Morandi, Verônica

    2009-01-01

    The data presented in this article suggest that intact TSP-1 may act, in normal vessel homeostasis, as an angiostatic factor favoring vessel quiescence, or even vessel regression, but this activity would be largely impaired in the presence of an excess of angiogenic stimuli and proteases. The fact that the N-terminal domain of TSP-1 (heparin-binding domain or HBD) is recognized by a plethora of cell receptors, all of them engaged in proangiogenic responses, strongly suggests that the proteolytic cleavage of HBD may be relevant in certain pathophysiological conditions. PMID:19219378

  19. Autophagy deficiency in macrophages enhances NLRP3 inflammasome activity and chronic lung disease following silica exposure.

    PubMed

    Jessop, Forrest; Hamilton, Raymond F; Rhoderick, Joseph F; Shaw, Pamela K; Holian, Andrij

    2016-10-15

    Autophagy is an important metabolic mechanism that can promote cellular survival following injury. The specific contribution of autophagy to silica-induced inflammation and disease is not known. The objective of these studies was to determine the effects of silica exposure on the autophagic pathway in macrophages, as well as the general contribution of autophagy in macrophages to inflammation and disease. Silica exposure enhanced autophagic activity in vitro in Bone Marrow derived Macrophages and in vivo in Alveolar Macrophages isolated from silica-exposed mice. Impairment of autophagy in myeloid cells in vivo using Atg5(fl/fl)LysM-Cre(+) mice resulted in enhanced cytotoxicity and inflammation after silica exposure compared to littermate controls, including elevated IL-18 and the alarmin HMGB1 in the whole lavage fluid. Autophagy deficiency caused some spontaneous inflammation and disease. Greater silica-induced acute inflammation in Atg5(fl/fl)LysM-Cre(+) mice correlated with increased fibrosis and chronic lung disease. These studies demonstrate a critical role for autophagy in suppressing silica-induced cytotoxicity and inflammation in disease development. Furthermore, this data highlights the importance of basal autophagy in macrophages and other myeloid cells in maintaining lung homeostasis.

  20. Autophagy deficiency in macrophages enhances NLRP3 inflammasome activity and chronic lung disease following silica exposure.

    PubMed

    Jessop, Forrest; Hamilton, Raymond F; Rhoderick, Joseph F; Shaw, Pamela K; Holian, Andrij

    2016-10-15

    Autophagy is an important metabolic mechanism that can promote cellular survival following injury. The specific contribution of autophagy to silica-induced inflammation and disease is not known. The objective of these studies was to determine the effects of silica exposure on the autophagic pathway in macrophages, as well as the general contribution of autophagy in macrophages to inflammation and disease. Silica exposure enhanced autophagic activity in vitro in Bone Marrow derived Macrophages and in vivo in Alveolar Macrophages isolated from silica-exposed mice. Impairment of autophagy in myeloid cells in vivo using Atg5(fl/fl)LysM-Cre(+) mice resulted in enhanced cytotoxicity and inflammation after silica exposure compared to littermate controls, including elevated IL-18 and the alarmin HMGB1 in the whole lavage fluid. Autophagy deficiency caused some spontaneous inflammation and disease. Greater silica-induced acute inflammation in Atg5(fl/fl)LysM-Cre(+) mice correlated with increased fibrosis and chronic lung disease. These studies demonstrate a critical role for autophagy in suppressing silica-induced cytotoxicity and inflammation in disease development. Furthermore, this data highlights the importance of basal autophagy in macrophages and other myeloid cells in maintaining lung homeostasis. PMID:27594529

  1. Amphotericin B stimulates γδ T and NK cells, and enhances protection from Salmonella infection.

    PubMed

    Hedges, Jodi F; Mitchell, Angela M; Jones, Kerri; Kimmel, Emily; Ramstead, Andrew G; Snyder, Deann T; Jutila, Mark A

    2015-08-01

    Amphotericin B (AmB) is a commonly used antifungal drug, with well-documented effects on cellular immune responses. We determined that AmB-stimulated γδ T-cell activation and proliferation in vitro at very low concentrations. AmB also enhanced IFN-γ production by NK cells in combination with IL-18. AmB had a greater effect on IFN-γ production in cells isolated from very young animals. Although innate immunostimulatory aspects of AmB have been defined, AmB has not been extensively applied in non-fungal infection settings. Given that γδ T cells are increased and activated in Salmonella infection in cattle, we assessed the effects of AmB in protection from Salmonella enterocolitis in calves. One injection of AmB, at approximately one-tenth of the concentration used in human patients to counter fungal infection, or saline control, was delivered intravenously to calves prior to infection with Salmonella. This single injection caused no adverse effects, reduced disease symptoms from Salmonella enterocolitis and significantly reduced Salmonella bacteria shed in feces of infected animals. Our findings suggest that AmB may be an inexpensive and readily available prophylactic approach for the prevention of bacterial infection in calves.

  2. Biocatalyst Enhancement

    EPA Science Inventory

    The increasing availability of enzyme collections has assisted attempts by pharmaceutical producers to adopt green chemistry approaches to manufacturing. A joint effort between an enzyme producer and a pharmaceutical manufacturer has been enhanced over the past three years by ena...

  3. Enhancing Opportunities.

    ERIC Educational Resources Information Center

    Meyers, Michelle J.

    1994-01-01

    Hispanics can enhance their professional career by finding jobs with corporations that offer to pay for graduate tuition. This opportunity has positively influenced the careers of many Hispanics and has proven advantageous for corporations as well by increasing the knowledge and skills of their employees. (LP)

  4. Interleukin-18 activates skeletal muscle AMPK and reduces weight gain and insulin resistance in mice.

    PubMed

    Lindegaard, Birgitte; Matthews, Vance B; Brandt, Claus; Hojman, Pernille; Allen, Tamara L; Estevez, Emma; Watt, Matthew J; Bruce, Clinton R; Mortensen, Ole H; Syberg, Susanne; Rudnicka, Caroline; Abildgaard, Julie; Pilegaard, Henriette; Hidalgo, Juan; Ditlevsen, Susanne; Alsted, Thomas J; Madsen, Andreas N; Pedersen, Bente K; Febbraio, Mark A

    2013-09-01

    Circulating interleukin (IL)-18 is elevated in obesity, but paradoxically causes hypophagia. We hypothesized that IL-18 may attenuate high-fat diet (HFD)-induced insulin resistance by activating AMP-activated protein kinase (AMPK). We studied mice with a global deletion of the α-isoform of the IL-18 receptor (IL-18R(-/-)) fed a standard chow or HFD. We next performed gain-of-function experiments in skeletal muscle, in vitro, ex vivo, and in vivo. We show that IL-18 is implicated in metabolic homeostasis, inflammation, and insulin resistance via mechanisms involving the activation of AMPK in skeletal muscle. IL-18R(-/-) mice display increased weight gain, ectopic lipid deposition, inflammation, and reduced AMPK signaling in skeletal muscle. Treating myotubes or skeletal muscle strips with IL-18 activated AMPK and increased fat oxidation. Moreover, in vivo electroporation of IL-18 into skeletal muscle activated AMPK and concomitantly inhibited HFD-induced weight gain. In summary, IL-18 enhances AMPK signaling and lipid oxidation in skeletal muscle implicating IL-18 in metabolic homeostasis.

  5. Enhancing bioremediation

    SciTech Connect

    Koenigsberg, S.

    1997-02-01

    Oxygen is often the limiting factor in aerobic bioremediation. Without adequate oxygen, contaminant degradation will either cease or proceed by highly inefficient anaerobic processes. Researchers at Regenesis Bioremediation Products recently develope a technology to combat this problem, Oxygen Release Compound (ORC) a unique formulation of magnesium peroxide release oxygen slowly when hydrated. ORC is idea for supporting bioremediation of underground storage tank releases. ORC treatment represents a low intensity approach to remediation - simple, passive, low-cost, long term enhancement of a natural attenuation. 1 fig.

  6. EDITORIAL: Enhancing nanolithography Enhancing nanolithography

    NASA Astrophysics Data System (ADS)

    Demming, Anna

    2012-01-01

    Lithography was invented in late 18th century Bavaria by an ambitious young playwright named Alois Senefelder. Senefelder experimented with stone, wax, water and ink in the hope of finding a way of reproducing text so that he might financially gain from a wider distribution of his already successful scripts. His discovery not only facilitated the profitability of his plays, but also provided the world with an affordable printing press that would ultimately democratize the dissemination of art, knowledge and literature. Since Senefelder, experiments in lithography have continued with a range of innovations including the use of electron beams and UV that allow increasingly higher-resolution features [1, 2]. Applications for this have now breached the limits of paper printing into the realms of semiconductor and microelectronic mechanical systems technology. In this issue, researchers demonstrate a technique for fabricating periodic features in poly(3,4-ethylene dioxythiophene)-poly(styrenesulfonate) (PEDOT-PSS) [3]. Their method combines field enhancements from silica nanospheres with laser-interference lithography to provide a means of patterning a polymer that has the potential to open the market of low-end, high-volume microelectronics. Laser-interference lithography has already been used successfully in patterning. Researchers in Korea used laser-interference lithography to generate stamps for imprinting a two-dimensional photonic crystal structure into green light emitting diodes (LEDs) [4]. The imprinted patterns comprised depressions 100 nm deep and 180 nm wide with a periodicity of 295 nm. In comparison with unpatterned LEDs, the intensity of photoluminescence was enhanced by a factor of seven in the LEDs that had the photonic crystal structures imprinted in them. The potential of exploiting field enhancements around nanostructures for new technologies has also attracted a great deal of attention. Researchers in the USA and Australia have used the field

  7. How aluminum adjuvants could promote and enhance non-target IgE synthesis in a genetically-vulnerable sub-population.

    PubMed

    Terhune, Todd D; Deth, Richard C

    2013-01-01

    Aluminum-containing adjuvants increase the effectiveness of vaccination, but their ability to augment immune responsiveness also carries the risk of eliciting non-target responses, especially in genetically susceptible individuals. This study reviews the relevant actions of aluminum adjuvants and sources of genetic risk that can combine to adversely affect a vulnerable sub-population. Aluminum adjuvants promote oxidative stress and increase inflammasome activity, leading to the release of IL-1β, IL-18, and IL-33, but not the important regulatory cytokine IL-12. In addition, they stimulate macrophages to produce PGE₂, which also has a role in regulating immune responses. This aluminum-induced cytokine context leads to a T(H)2 immune response, characterized by the further release of IL-3, IL-4, IL-5, IL-9, IL-13, and IgE-potentiating factors such as sCD23. Genetic variants in cytokine genes, such as IL-4, IL-13, IL-33, and IL-18 influence the response to vaccines in children and are also associated with atopy. These genetic factors may therefore define a genetically-vulnerable sub-population, children with a family history of atopy, who may experience an exaggerated T(H)2 immune response to aluminum-containing vaccines. IL-4, sCD23, and IgE are common factors for both atopy and the immune-stimulating properties of aluminum adjuvants. IL-4 is critical in the production of IgE and total IgE up-regulation. IL-4 has also been reported to induce the production of sCD23 and trigger resting sIgM+, sIgD+ B-cells to switch to sIgE+ B-cells, making them targets for IgE-potentiating factors. Further, the actions of IgE-potentiating factors on sIgE+ B-cells are polyclonal and unrestricted, triggering their differentiation into IgE-forming plasma cells. These actions provide a mechanism for aluminum-adjuvant promotion and enhancement of non-target IgE in a genetically vulnerable sub-population. Identification of these individuals may decrease the risk of adverse events

  8. rAdinbitor, a disintegrin from Agkistrodon halys brevicaudus stejneger, inhibits tumorigenicity of hepatocarcinoma via enhanced anti-angiogenesis and immunocompetence.

    PubMed

    Sun, Ming-Zhong; Cui, Yanhua; Guo, Chunmei; Zhao, Baochang; Liu, Shuqing

    2015-09-01

    Adinbitor is a disintegrin previously obtained from Agkistrodon halys brevicaudus stejneger by our group. Here, we investigated the in vitro and in vivo anti-tumor activities of recombinant Adinbitor (rAdinbitor). rAdinbitor stimulation can inhibit the in vitro proliferation, migration and invasion capacities of murine hepatocarcinoma H22 and Hca-F cells. The administrations of rAdinbitor either by gavage or intraperitoneal injection suppress the tumor malignancy and prolong the survival rate and time of H22-transplanted mice. The number and size of formed blood vessels decreased dramatically in tumorous tissues in that the expression levels of vascular endothelial growth factor (VEGF) and cluster of differentiation 34 (CD34) were significantly decreased in responding to rAdinbitor treatment. The protein levels of IL-18 and IgG increased significantly in the serum of H22-transplanted tumor mice with rAdinbitor treatment. rAdinbitor shows in vitro and in vivo anti-tumor effects as an angiogenesis inhibitor and immunocompetence enhancer. PMID:26133656

  9. Can stock enhancement enhance stocks?

    NASA Astrophysics Data System (ADS)

    Støttrup, J. G.; Sparrevohn, C. R.

    2007-02-01

    Successful stock enhancement or restocking requires a thorough understanding of the ecological processes that provide a potential for stocking within different ecosystems, i.e. determine which factors define the potential for stocking, such as population dynamics, economic cost-benefits, fisheries management and socio-economic impacts. Stocking is not simply a question of aquaculture logistics (i.e. the ability to produce a sufficient number of fry relative to the magnitude of the natural recruitment within the system), nor should it be a new outlet for aquaculture production. Quantitative targets should be set and the expected performance of the stocking tested. Potential loopholes, such as post-release mortality and habitat requirements related to the release, should be examined and resolved. If properly managed, stocking may lead to an increase in population, contribute to the local fishery and/or lead to an increase in the spawning stock biomass. The criteria for stocking are discussed in this paper using examples from flatfish and cod stocking programmes within specific ecosystems.

  10. Cognitive Enhancement and Education

    ERIC Educational Resources Information Center

    Buchanan, Allen

    2011-01-01

    Cognitive enhancement--augmenting normal cognitive capacities--is not new. Literacy, numeracy, computers, and the practices of science are all cognitive enhancements. Science is now making new cognitive enhancements possible. Biomedical cognitive enhancements (BCEs) include the administration of drugs, implants of genetically engineered or…

  11. [Study of the polymorphism R353Q in the coagulation factor VII gene and the N700S in the thrombospondin-1 gene in young patients with acute myocardial infarction].

    PubMed

    Valades-Mejía, María Guadalupe; Domínguez-López, María Lilia; Aceves-Chimal, José Luis; Miranda, Alfredo Leaños; Majluf-Cruz, Abraham; Isordia-Salas, Irma

    2014-01-01

    Antecedentes: el infarto agudo de miocardio es la principal causa de morbilidad y mortalidad en el mundo, y resulta de la combinación de factores modificables y genéticos. Se ha propuesto que el polimorfismo R353Q en el gen del factor VII de la coagulación representa un factor protector en contra del infarto agudo de miocardio, mientras que el polimorfismo N700S en el gen de la trombospondina-1 (TSP- 1) incrementa el riesgo; sin embargo, los resultados aún suscitan controversia. Objetivo: determinar la posible asociación de los polimorfismos R353Q y del N700S con el infarto agudo de miocardio en pacientes mexicanos menores de 45 años. Material y métodos: estudio de casos y controles que incluyó 252 pacientes con diagnóstico de infarto agudo de miocardio y 252 individuos aparentemente sanos sin antecedentes de enfermedad coronaria, pareados por edad y sexo. Los polimorfismos R353Q N700S se determinaron en todos los participantes por medio de PCR-RFLP. Resultados: no se observó diferencia estadística en la distribución genotípica del polimorfismo R353Q del FVII entre los grupos con infarto agudo de miocardio y el grupo control (p = 0.06). Se encontró una distribución genotípica similar del polimorfismo N700S en ambos grupos (p = 0.50). Se identificaron como factores de riesgo independiente para infarto agudo de miocardio: hipertensión arterial, diabetes mellitus, antecedentes heredofamiliares para enfermedad coronaria y dislipidemia. Conclusiones: los polimorfismos R353Q y N700S no representan un factor protector o de riesgo, respectivamente, para infarto agudo de miocardio en pacientes jóvenes mexicanos. Palabras clave: factor VII de la coagulación, trombospondina-1, infarto agudo de miocardio, polimorfismo.

  12. Interleukin 18 augments growth ability via NF-κB and p38/ATF2 pathways by targeting cyclin B1, cyclin B2, cyclin A2, and Bcl-2 in BRL-3A rat liver cells.

    PubMed

    Zhang, Jihong; Pan, Cuiyun; Xu, Tiantian; Niu, Zhipeng; Ma, Chengkai; Xu, Cunshuan

    2015-05-25

    Interleukin 18 (IL-18) is a pleiotropic cytokine and capable of stimulating proliferation of certain cell types. Nonetheless, its effect on normal liver cells cultured remains unclear. In the present study, we discovered that IL-18 expression level was remarkably elevated at 3.3 and 8.6h after synchronized BRL-3A rat liver cells (G0 phase) re-entering the cell cycle. In addition, recombinant rat IL-18 (rrIL-18) at dosages 5-10 ng/ml increased the cell viability compared to untreated cells (with medium only) at 24 and 48 h (P<0.05). At the same time, the percentage of BrdU-labeling cells was also significantly increased (P<0.01). On the other hand, knockdown of IL-18 expression with short interference RNA (siRNA), the cell viability began to decline at 24h and significantly decreased compared to negative control (NC) at 48 and 72 h after transfection (P<0.05). Meanwhile, the number of cells in division phase (G2/M) was reduced in parallel. Further, after treatment with rrIL-18 (5 ng/ml), IL-18 and its receptor subunit IL-18Rα increased both at mRNA and protein levels. Moreover, the expression levels of adaptor molecule MyD88, transcription factor NF-κB and its downstream targets cyclin B1 and cyclin B2 were remarkably enhanced in BRL-3A cells stimulated by rrIL-18. Furthermore, transcription factor ATF2 and its targeted genes cyclin A2, Bcl-2 were also markedly increased after treatment with rrIL-18. These results demonstrated that IL-18 can augment cell proliferation via NF-κB and p38/ATF2 pathway by targeting cyclin B1, cyclin B2, cyclin A2 and Bcl-2 in BRL-3A rat liver cells.

  13. Enhancement and Civic Virtue

    PubMed Central

    Jefferson, Will; Douglas, Thomas; Kahane, Guy; Savulescu, Julian

    2014-01-01

    Opponents of biomedical enhancement frequently adopt what Allen Buchanan has called the Personal Goods Assumption. On this assumption, the benefits of biomedical enhancement will accrue primarily to those individuals who undergo enhancements, not to wider society. Buchanan has argued that biomedical enhancements might in fact have substantial social benefits by increasing productivity. We outline another way in which enhancements might benefit wider society: by augmenting civic virtue and thus improving the functioning of our political communities. We thus directly confront critics of biomedical enhancement who argue that it will lead to a loss of social cohesion and a breakdown in political life. PMID:24882886

  14. Acute experimental changes in mood state regulate immune function in relation to central opioid neurotransmission: a model of human CNS-peripheral inflammatory interaction.

    PubMed

    Prossin, A R; Koch, A E; Campbell, P L; Barichello, T; Zalcman, S S; Zubieta, J-K

    2016-02-01

    Although evidence shows depressed moods enhance risk for somatic diseases, molecular mechanisms underlying enhanced somatic susceptibility are ill-defined. Knowledge of these molecular mechanisms will inform development of treatment and prevention strategies across comorbid depressive and somatic illnesses. Existing evidence suggests that interleukin-18 (IL-18; an IL-1 family cytokine) is elevated in depression and implicated in pathophysiology underlying comorbid medical illnesses. We previously identified strong associations between baseline IL-18 and μ-opioid receptor availability in major depressive disorder (MDD) volunteers. Combined with the evidence in animal models, we hypothesized that experimental mood induction would change IL-18, the extent proportional to opioid neurotransmitter release. Using the Velten technique in a [(11)C]carfentanil positron emission tomography neuroimaging study, we examined the impact of experimentally induced mood (sad, neutral) on plasma IL-18 and relationships with concurrent changes in the central opioid neurotransmission in 28 volunteers (healthy, MDD). Results showed mood induction impacted IL-18 (F2,25=12.2, P<0.001), sadness increasing IL-18 (T27=2.6, P=0.01) and neutral mood reducing IL-18 (T27=-4.1, P<0.001). In depressed volunteers, changes in IL-18 were more pronounced (F2,25=3.6, P=0.03) and linearly proportional to sadness-induced μ-opioid activation (left ventral pallidum, bilateral anterior cingulate cortices, right hypothalamus and bilateral amygdala). These data demonstrate that dynamic changes of a pro-inflammatory IL-1 superfamily cytokine, IL-18, and its relationship to μ-opioid neurotransmission in response to experimentally induced sadness. Further testing is warranted to delineate the role of neuroimmune interactions involving IL-18 in enhancing susceptibility to medical illness (that is, diabetes, heart disease and persistent pain states) in depressed individuals. PMID:26283642

  15. Acute experimental changes in mood state regulate immune function in relation to central opioid neurotransmission: a model of human CNS-peripheral inflammatory interaction

    PubMed Central

    Prossin, A R; Koch, A E; Campbell, P L; Barichello, T; Zalcman, S S; Zubieta, J-K

    2016-01-01

    Although evidence shows depressed moods enhance risk for somatic diseases, molecular mechanisms underlying enhanced somatic susceptibility are ill-defined. Knowledge of these molecular mechanisms will inform development of treatment and prevention strategies across comorbid depressive and somatic illnesses. Existing evidence suggests that interleukin-18 (IL-18; an IL-1 family cytokine) is elevated in depression and implicated in pathophysiology underlying comorbid medical illnesses. We previously identified strong associations between baseline IL-18 and μ-opioid receptor availability in major depressive disorder (MDD) volunteers. Combined with the evidence in animal models, we hypothesized that experimental mood induction would change IL-18, the extent proportional to opioid neurotransmitter release. Using the Velten technique in a [11C]carfentanil positron emission tomography neuroimaging study, we examined the impact of experimentally induced mood (sad, neutral) on plasma IL-18 and relationships with concurrent changes in the central opioid neurotransmission in 28 volunteers (healthy, MDD). Results showed mood induction impacted IL-18 (F2,25=12.2, P<0.001), sadness increasing IL-18 (T27=2.6, P=0.01) and neutral mood reducing IL-18 (T27=−4.1, P<0.001). In depressed volunteers, changes in IL-18 were more pronounced (F2,25=3.6, P=0.03) and linearly proportional to sadness-induced μ-opioid activation (left ventral pallidum, bilateral anterior cingulate cortices, right hypothalamus and bilateral amygdala). These data demonstrate that dynamic changes of a pro-inflammatory IL-1 superfamily cytokine, IL-18, and its relationship to μ-opioid neurotransmission in response to experimentally induced sadness. Further testing is warranted to delineate the role of neuroimmune interactions involving IL-18 in enhancing susceptibility to medical illness (that is, diabetes, heart disease and persistent pain states) in depressed individuals. PMID:26283642

  16. Chemical penetration enhancers.

    PubMed

    Newton, Stephen J

    2013-01-01

    Chemical penetration enhancers are utilized in topical preparations as a method for enhancing permeation of drugs across the skin. In particular, they are utilized for transdermal delivery of medications in an attempt to produce a systemic response, to avoid first-pass metabolism, and to decrease the gastrointestinal transit time observed with oral medications. A review of the selection of chemical penetration enhancers, their mechanism of action, the most common chemical penetration enhancers in each class, and alternatives will be discussed in detail.

  17. The proinflammatory cytokine interleukin-18 alters multiple signaling pathways to inhibit natural killer cell death

    USGS Publications Warehouse

    Hodge, D.L.; Subleski, J.J.; Reynolds, D.A.; Buschman, M.D.; Schill, W.B.; Burkett, M.W.; Malyguine, A.M.; Young, H.A.

    2006-01-01

    The proinflammatory cytokine, interleukin-18 (IL-18), is a natural killer (NK) cell activator that induces NK cell cytotoxicity and interferon-?? (IFN-??) expression. In this report, we define a novel role for IL-18 as an NK cell protective agent. Specifically, IL-18 prevents NK cell death initiated by different and distinct stress mechanisms. IL-18 reduces NK cell self-destruction during NK-targeted cell killing, and in the presence of staurosporin, a potent apoptotic inducer, IL-18 reduces caspase-3 activity. The critical regulatory step in this process is downstream of the mitochondrion and involves reduced cleavage and activation of caspase-9 and caspase-3. The ability of IL-18 to regulate cell survival is not limited to a caspase death pathway in that IL-18 augments tumor necrosis factor (TNF) signaling, resulting in increased and prolonged mRNA expression of c-apoptosis inhibitor 2 (cIAP2), a prosurvival factor and caspase-3 inhibitor, and TNF receptor-associated factor 1 (TRAF1), a prosurvival protein. The cumulative effects of IL-18 define a novel role for this cytokine as a molecular survival switch that functions to both decrease cell death through inhibition of the mitochondrial apoptotic pathway and enhance TNF induction of prosurvival factors. ?? Mary Ann Liebert, Inc.

  18. Smart Image Enhancement Process

    NASA Technical Reports Server (NTRS)

    Jobson, Daniel J. (Inventor); Rahman, Zia-ur (Inventor); Woodell, Glenn A. (Inventor)

    2012-01-01

    Contrast and lightness measures are used to first classify the image as being one of non-turbid and turbid. If turbid, the original image is enhanced to generate a first enhanced image. If non-turbid, the original image is classified in terms of a merged contrast/lightness score based on the contrast and lightness measures. The non-turbid image is enhanced to generate a second enhanced image when a poor contrast/lightness score is associated therewith. When the second enhanced image has a poor contrast/lightness score associated therewith, this image is enhanced to generate a third enhanced image. A sharpness measure is computed for one image that is selected from (i) the non-turbid image, (ii) the first enhanced image, (iii) the second enhanced image when a good contrast/lightness score is associated therewith, and (iv) the third enhanced image. If the selected image is not-sharp, it is sharpened to generate a sharpened image. The final image is selected from the selected image and the sharpened image.

  19. Suboptimization of developmental enhancers.

    PubMed

    Farley, Emma K; Olson, Katrina M; Zhang, Wei; Brandt, Alexander J; Rokhsar, Daniel S; Levine, Michael S

    2015-10-16

    Transcriptional enhancers direct precise on-off patterns of gene expression during development. To explore the basis for this precision, we conducted a high-throughput analysis of the Otx-a enhancer, which mediates expression in the neural plate of Ciona embryos in response to fibroblast growth factor (FGF) signaling and a localized GATA determinant. We provide evidence that enhancer specificity depends on submaximal recognition motifs having reduced binding affinities ("suboptimization"). Native GATA and ETS (FGF) binding sites contain imperfect matches to consensus motifs. Perfect matches mediate robust but ectopic patterns of gene expression. The native sites are not arranged at optimal intervals, and subtle changes in their spacing alter enhancer activity. Multiple tiers of enhancer suboptimization produce specific, but weak, patterns of expression, and we suggest that clusters of weak enhancers, including certain "superenhancers," circumvent this trade-off in specificity and activity. PMID:26472909

  20. Credit Enhancement Overview Guide

    SciTech Connect

    Financing Solutions Working Group

    2014-01-01

    Provides considerations for state and local policymakers and energy efficiency program administrators designing and implementing successful credit enhancement strategies for residential and commercial buildings.

  1. Enhancing Drug Court Success

    ERIC Educational Resources Information Center

    Deschenes, Elizabeth Piper; Ireland, Connie; Kleinpeter, Christine B.

    2009-01-01

    This study evaluates the impact of enhanced drug court services in a large county in Southern California. These enhanced services, including specialty counseling groups, educational/employment resources, and increased Residential Treatment (RT) beds, were designed to increase program retention and successful completion (graduation) of drug court.…

  2. Enhanced oil recovery update

    SciTech Connect

    Smith, R.V

    1989-03-01

    Technology continues to grow in the realm of enhanced oil recovery. Since 1950 several processes have proven economic for oil recovery. Others are still in their infancy and must be custom designed for each reservoir. This paper gives a general overview of these processes. The author focuses on the latest technology and the outlook for enhanced oil recovery operations.

  3. Enhancing Individual Readiness.

    ERIC Educational Resources Information Center

    1997

    This document contains three papers from a symposium on enhancing individual readiness through human resource development (HRD). "Secondary School Administrator's Perception of Enhancing Self-Worth through Service" (Thomas Li-Ping Tang, Emily James Weatherford) presents results of a study to examine secondary school administrators' endorsement of…

  4. Electrostatic precipitator efficiency enhancement

    SciTech Connect

    Polizzotti, D.M.; Steelhammer, J.C.

    1983-05-24

    Method for enhancing the removal of particles from a particleladen gas stream utilizing an electrostatic precipitator, which comprises treating the gas with morpholine or derivatives thereof. Treated particles are found to also have desirable flow characteristics. Particularly effective compositions for the purpose comprise a combination of the morpholine, or derivative thereof, with an electrostatic precipitator efficiency enhancer, and in particular an alkanolamine.

  5. Should we enhance animals?

    PubMed Central

    Chan, Sarah

    2012-01-01

    Much bioethical discussion has been devoted to the subject of human enhancement through various technological means such as genetic modification. Although many of the same technologies could be, indeed in many cases already have been, applied to non-human animals, there has been very little consideration of the concept of “animal enhancement”, at least not in those specific terms. This paper addresses the notion of animal enhancement and the ethical issues surrounding it. A definition of animal enhancement is proposed that provides a framework within which to consider these issues; and it is argued that if human enhancement can be considered to be a moral obligation, so too can animal enhancement. PMID:19880704

  6. EDITORIAL: Nano-enhanced! Nano-enhanced!

    NASA Astrophysics Data System (ADS)

    Demming, Anna

    2010-08-01

    In the early 19th century, a series of engineering and scientific breakthroughs by Nicolas Léonard Sadi Carnot, James Watt and many others led to the foundations of thermodynamics and a new pedigree of mechanical designs that reset the standards of engineering efficiency. The result was the industrial revolution. In optical- and electronics- based nanotechnology research, a similarly subtle bargain is being made; we cannot alter the fact that systems have a finite response to external excitations, but what we can do is enhance that response. The promising attributes of ZnO have long been recognised; its large band gap and high exciton binding energy lend it to a number of applications from laser diodes, LEDs, optical waveguides and switches, and acousto-optic applications to sun cream. When this material is grown into nanowires and nanorods, the material gains a whole new dimension, as quantum confinement effects come into play. Discovery of the enhanced radiative recombination, which has potential for exploitation in many optical and opto-electronic applications, drove intensive research into investigating these structures and into finding methods to synthesise them with optimised properties. This research revealed further subtleties in the properties of these materials. One example is the work by researchers in the US reporting synthesis procedures that produced a yield—defined as the weight ratio of ZnO nanowires to the original graphite flakes—of 200%, and which also demonstrated, through photoluminescence analysis of nanowires grown on graphite flakes and substrates, that graphite induces oxygen vacancies during annealing, which enhances the deep-level to near-band-edge emission ratio [1]. Other one-dimensional materials that provide field emission enhancements include carbon nanotubes, and work has been performed to find ways of optimising the emission efficiency from these structures, such as through control of the emitter density [2]. One of the

  7. Hierarchical image enhancement

    NASA Astrophysics Data System (ADS)

    Qi, Wei; Han, Jing; Zhang, Yi; Bai, Lian-fa

    2016-05-01

    Image enhancement is an important technique in computer vision. In this paper, we propose a hierarchical image enhancement approach based on the structure layer and texture layer. In the structure layer, we propose a structure-based method based on GMM, which better exploits structure details with fewer noise. In the texture layer, we present a structure-filtering method to filter unwanted texture with keeping completeness of detected salient structure. Next, we introduce a structure constraint prior to integrate them, leading to an improved enhancement result. Extensive experiments demonstrate that the proposed approach achieves higher quality results than previous approaches.

  8. LIGNITE FUEL ENHANCEMENT

    SciTech Connect

    Charles Bullinger

    2005-07-07

    This 4th quarterly Technical Progress Report for the Lignite Fuel Enhancement Project summarizes activities from April 1st through June 30th of 2005. It also summarizes the subsequent purchasing activity and dryer/process construction.

  9. LIGNITE FUEL ENHANCEMENT

    SciTech Connect

    Charles Bullinger

    2005-06-07

    This 3rd quarterly Technical Progress Report for the Lignite Fuel Enhancement Project summarizes activities from January 1st through March 31st of 2005. It also summarizes the subsequent purchasing activity and final dryer/process design.

  10. CD47 regulates renal tubular epithelial cell self-renewal and proliferation following renal ischemia reperfusion.

    PubMed

    Rogers, Natasha M; Zhang, Zheng J; Wang, Jiao-Jing; Thomson, Angus W; Isenberg, Jeffrey S

    2016-08-01

    Defects in renal tubular epithelial cell repair contribute to renal ischemia reperfusion injury, cause acute kidney damage, and promote chronic renal disease. The matricellular protein thrombospondin-1 and its receptor CD47 are involved in experimental renal ischemia reperfusion injury, although the role of this interaction in renal recovery is unknown. We found upregulation of self-renewal genes (transcription factors Oct4, Sox2, Klf4 and cMyc) in the kidney of CD47(-/-) mice after ischemia reperfusion injury. Wild-type animals had minimal self-renewal gene expression, both before and after injury. Suggestive of cell autonomy, CD47(-/-) renal tubular epithelial cells were found to increase expression of the self-renewal genes. This correlated with enhanced proliferative capacity compared with cells from wild-type mice. Exogenous thrombospondin-1 inhibited self-renewal gene expression in renal tubular epithelial cells from wild-type but not CD47(-/-) mice, and this was associated with decreased proliferation. Treatment of renal tubular epithelial cells with a CD47 blocking antibody or CD47-targeting small interfering RNA increased expression of some self-renewal transcription factors and promoted cell proliferation. In a syngeneic kidney transplant model, treatment with a CD47 blocking antibody increased self-renewal transcription factor expression, decreased tissue damage, and improved renal function compared with that in control mice. Thus, thrombospondin-1 via CD47 inhibits renal tubular epithelial cell recovery after ischemia reperfusion injury through inhibition of proliferation/self-renewal.

  11. Enhanced metabolite generation

    DOEpatents

    Chidambaram, Devicharan

    2012-03-27

    The present invention relates to the enhanced production of metabolites by a process whereby a carbon source is oxidized with a fermentative microbe in a compartment having a portal. An electron acceptor is added to the compartment to assist the microbe in the removal of excess electrons. The electron acceptor accepts electrons from the microbe after oxidation of the carbon source. Other transfers of electrons can take place to enhance the production of the metabolite, such as acids, biofuels or brewed beverages.

  12. Resonance enhanced tunneling

    NASA Astrophysics Data System (ADS)

    Matsumoto, S.; Yoshimura, M.

    2000-12-01

    Time evolution of tunneling in thermal medium is examined using the real-time semiclassical formalism previously developed. Effect of anharmonic terms in the potential well is shown to give a new mechanism of resonance enhanced tunneling. If the friction from environment is small enough, this mechanism may give a very large enhancement for the tunneling rate. The case of the asymmetric wine bottle potential is worked out in detail.

  13. MORAL ENHANCEMENT AND FREEDOM

    PubMed Central

    Harris, John

    2011-01-01

    This paper identifies human enhancement as one of the most significant areas of bioethical interest in the last twenty years. It discusses in more detail one area, namely moral enhancement, which is generating significant contemporary interest. The author argues that so far from being susceptible to new forms of high tech manipulation, either genetic, chemical, surgical or neurological, the only reliable methods of moral enhancement, either now or for the foreseeable future, are either those that have been in human and animal use for millennia, namely socialization, education and parental supervision or those high tech methods that are general in their application. By that is meant those forms of cognitive enhancement that operate across a wide range of cognitive abilities and do not target specifically ‘ethical’ capacities. The paper analyses the work of some of the leading contemporary advocates of moral enhancement and finds that in so far as they identify moral qualities or moral emotions for enhancement they have little prospect of success. PMID:21133978

  14. Altered expression of antiviral cytokine mRNAs associated with cyclophosphamide’s enhancement of viral oncolysis

    PubMed Central

    Wakimoto, H; Fulci, G; Timinski, E; Chiocca, E Antonio

    2010-01-01

    Oncolytic viruses (OVs) are being used as anticancer agents in preclinical and clinical trials. Propagation of OVs inside infected tumors is critical to their efficacy and is mediated by the productive generation of progeny OVs within infected tumor cells. In turn, this progeny can spread the infection to other tumor cells in successive rounds of oncolysis. Previously, we had found that, in rats, cyclophosphamide (CPA) pretreatment increased infection of brain tumors by an intra-arterially administered herpessimplex virus type 1 OV, because it inhibited activation of complement responses, mediated by innate IgM. We also have previously shown that other pharmacologic inhibitors of complement, such as cobra venom factor (CVF), allowed for increased infection. However, in these studies, further inhibition of complement responses by CVF did not result in additional infection of brain tumor cells or in propagation of OV to surrounding tumor cells. In this study, we sought to determine if CPA did lead to increased infection/propagation from initially infected tumor cells. Unlike our results with CVF, we find that CPA administration does result in a time-dependent increase in infection of tumor cells, suggestive of increased propagation, in both syngeneic and athymic models of brain tumors. This increase was due to increased survival of OV within infected tumors and brain surrounding tumors. CPA’s effect was not due to a direct enhancement of viral replication in tumor cells, rather was associated with its immunosuppressive effects. RT-PCR analysis revealed that CPA administration resulted in impaired mRNA production by peripheral blood mono-nuclear cells (PBMCs) of several cytokines (interferons α/β, interferon γ, TNFα, IL-15, and IL-18) with anti-HSV function. These findings suggest that the CPA-mediated facilitation of OV intraneoplastic propagation is associated with a general decrease of antiviral cytokines mRNAs in PBMCs. These findings not only suggest a

  15. Interleukin-18 produced by bone marrow-derived stromal cells supports T-cell acute leukaemia progression

    PubMed Central

    Uzan, Benjamin; Poglio, Sandrine; Gerby, Bastien; Wu, Ching-Lien; Gross, Julia; Armstrong, Florence; Calvo, Julien; Cahu, Xavier; Deswarte, Caroline; Dumont, Florent; Passaro, Diana; Besnard-Guérin, Corinne; Leblanc, Thierry; Baruchel, André; Landman-Parker, Judith; Ballerini, Paola; Baud, Véronique; Ghysdael, Jacques; Baleydier, Frédéric; Porteu, Francoise; Pflumio, Francoise

    2014-01-01

    Development of novel therapies is critical for T-cell acute leukaemia (T-ALL). Here, we investigated the effect of inhibiting the MAPK/MEK/ERK pathway on T-ALL cell growth. Unexpectedly, MEK inhibitors (MEKi) enhanced growth of 70% of human T-ALL cell samples cultured on stromal cells independently of NOTCH activation and maintained their ability to propagate in vivo. Similar results were obtained when T-ALL cells were cultured with ERK1/2-knockdown stromal cells or with conditioned medium from MEKi-treated stromal cells. Microarray analysis identified interleukin 18 (IL-18) as transcriptionally up-regulated in MEKi-treated MS5 cells. Recombinant IL-18 promoted T-ALL growth in vitro, whereas the loss of function of IL-18 receptor in T-ALL blast cells decreased blast proliferation in vitro and in NSG mice. The NFKB pathway that is downstream to IL-18R was activated by IL-18 in blast cells. IL-18 circulating levels were increased in T-ALL-xenografted mice and also in T-ALL patients in comparison with controls. This study uncovers a novel role of the pro-inflammatory cytokine IL-18 and outlines the microenvironment involvement in human T-ALL development. PMID:24778454

  16. Human nature and enhancement.

    PubMed

    Buchanan, Allen

    2009-03-01

    Appeals to the idea of human nature are frequent in the voluminous literature on the ethics of enhancing human beings through biotechnology. Two chief concerns about the impact of enhancements on human nature have been voiced. The first is that enhancement may alter or destroy human nature. The second is that if enhancement alters or destroys human nature, this will undercut our ability to ascertain the good because, for us, the good is determined by our nature. The first concern assumes that altering or destroying human nature is in itself a bad thing. The second concern assumes that human nature provides a standard without which we cannot make coherent, defensible judgments about what is good. I will argue (1) that there is nothing wrong, per se, with altering or destroying human nature, because, on a plausible understanding of what human nature is, it contains bad as well as good characteristics and there is no reason to believe that eliminating some of the bad would so imperil the good as to make the elimination of the bad impermissible, and (2) that altering or destroying human nature need not result in the loss of our ability to make judgments about the good, because we possess a conception of the good by which we can and do evaluate human nature. I will argue that appeals to human nature tend to obscure rather than illuminate the debate over the ethics of enhancement and can be eliminated in favor of more cogent considerations.

  17. Mechanisms of memory enhancement.

    PubMed

    Stern, Sarah A; Alberini, Cristina M

    2013-01-01

    The ongoing quest for memory enhancement is one that grows necessary as the global population increasingly ages. The extraordinary progress that has been made in the past few decades elucidating the underlying mechanisms of how long-term memories are formed has provided insight into how memories might also be enhanced. Capitalizing on this knowledge, it has been postulated that targeting many of the same mechanisms, including CREB activation, AMPA/NMDA receptor trafficking, neuromodulation (e.g., via dopamine, adrenaline, cortisol, or acetylcholine) and metabolic processes (e.g., via glucose and insulin) may all lead to the enhancement of memory. These and other mechanisms and/or approaches have been tested via genetic or pharmacological methods in animal models, and several have been investigated in humans as well. In addition, a number of behavioral methods, including exercise and reconsolidation, may also serve to strengthen and enhance memories. By utilizing this information and continuing to investigate these promising avenues, memory enhancement may indeed be achieved in the future.

  18. Deletion of A44L, A46R and C12L Vaccinia Virus Genes from the MVA Genome Improved the Vector Immunogenicity by Modifying the Innate Immune Response Generating Enhanced and Optimized Specific T-Cell Responses.

    PubMed

    Holgado, María Pía; Falivene, Juliana; Maeto, Cynthia; Amigo, Micaela; Pascutti, María Fernanda; Vecchione, María Belén; Bruttomesso, Andrea; Calamante, Gabriela; Del Médico-Zajac, María Paula; Gherardi, María Magdalena

    2016-01-01

    MVA is an attenuated vector that still retains immunomodulatory genes. We have previously reported its optimization after deleting the C12L gene, coding for the IL-18 binding-protein. Here, we analyzed the immunogenicity of MVA vectors harboring the simultaneous deletion of A44L, related to steroid synthesis and A46R, a TLR-signaling inhibitor (MVAΔA44L-A46R); or also including a deletion of C12L (MVAΔC12L/ΔA44L-A46R). The absence of biological activities of the deleted genes in the MVA vectors was demonstrated. Adaptive T-cell responses against VACV epitopes, evaluated in spleen and draining lymph-nodes of C57Bl/6 mice at acute/memory phases, were of higher magnitude in those animals that received deleted MVAs compared to MVAwt. MVAΔC12L/ΔA44L-A46R generated cellular specific memory responses of higher quality characterized by bifunctionality (CD107a/b⁺/IFN-γ⁺) and proliferation capacity. Deletion of selected genes from MVA generated innate immune responses with higher levels of determining cytokines related to T-cell response generation, such as IL-12, IFN-γ, as well as IL-1β and IFN-β. This study describes for the first time that simultaneous deletion of the A44L, A46R and C12L genes from MVA improved its immunogenicity by enhancing the host adaptive and innate immune responses, suggesting that this approach comprises an appropriate strategy to increase the MVA vaccine potential. PMID:27223301

  19. Deletion of A44L, A46R and C12L Vaccinia Virus Genes from the MVA Genome Improved the Vector Immunogenicity by Modifying the Innate Immune Response Generating Enhanced and Optimized Specific T-Cell Responses

    PubMed Central

    Holgado, María Pía; Falivene, Juliana; Maeto, Cynthia; Amigo, Micaela; Pascutti, María Fernanda; Vecchione, María Belén; Bruttomesso, Andrea; Calamante, Gabriela; del Médico-Zajac, María Paula; Gherardi, María Magdalena

    2016-01-01

    MVA is an attenuated vector that still retains immunomodulatory genes. We have previously reported its optimization after deleting the C12L gene, coding for the IL-18 binding-protein. Here, we analyzed the immunogenicity of MVA vectors harboring the simultaneous deletion of A44L, related to steroid synthesis and A46R, a TLR-signaling inhibitor (MVAΔA44L-A46R); or also including a deletion of C12L (MVAΔC12L/ΔA44L-A46R). The absence of biological activities of the deleted genes in the MVA vectors was demonstrated. Adaptive T-cell responses against VACV epitopes, evaluated in spleen and draining lymph-nodes of C57Bl/6 mice at acute/memory phases, were of higher magnitude in those animals that received deleted MVAs compared to MVAwt. MVAΔC12L/ΔA44L-A46R generated cellular specific memory responses of higher quality characterized by bifunctionality (CD107a/b+/IFN-γ+) and proliferation capacity. Deletion of selected genes from MVA generated innate immune responses with higher levels of determining cytokines related to T-cell response generation, such as IL-12, IFN-γ, as well as IL-1β and IFN-β. This study describes for the first time that simultaneous deletion of the A44L, A46R and C12L genes from MVA improved its immunogenicity by enhancing the host adaptive and innate immune responses, suggesting that this approach comprises an appropriate strategy to increase the MVA vaccine potential. PMID:27223301

  20. Surface Enhanced Quantum Control

    NASA Astrophysics Data System (ADS)

    Rangan, Chitra

    2013-05-01

    Miniaturization of quantum technologies have led to physics that require the marriage of atomic physics and nanomaterials science. Some of the resulting areas of research are hybrid quantum devices, single-molecule spectroscopies, table-top intense field generators, etc. I will present an area of research that I dub ``Surface-enhanced quantum control'' that is an exciting way of controlling light and nanomatter. By combining the electromagnetic enhancement properties of plasmonic nanomaterials with the modification of the atomic properties, we can achieve an unprecedented level of control over quantum dynamics. I will present examples of surface-enhanced state purification, in which quantum states near metal nanostructures can be rapidly purified by the application of a weak near-resonant control field. We gratefully acknowledge support from the NSERC Discovery Grant Program and the NSERC Strategic Network for Bioplasmonic Systems.

  1. Rituals enhance consumption.

    PubMed

    Vohs, Kathleen D; Wang, Yajin; Gino, Francesca; Norton, Michael I

    2013-09-01

    Four experiments tested the novel hypothesis that ritualistic behavior potentiates and enhances ensuing consumption--an effect found for chocolates, lemonade, and even carrots. Experiment 1 showed that participants who engaged in ritualized behavior, compared with those who did not, evaluated chocolate as more flavorful, valuable, and deserving of behavioral savoring. Experiment 2 demonstrated that random gestures do not boost consumption as much as ritualistic gestures do. It further showed that a delay between a ritual and the opportunity to consume heightens enjoyment, which attests to the idea that ritual behavior stimulates goal-directed action (to consume). Experiment 3 found that performing a ritual oneself enhances consumption more than watching someone else perform the same ritual, suggesting that personal involvement is crucial for the benefits of rituals to emerge. Finally, Experiment 4 provided direct evidence of the underlying process: Rituals enhance the enjoyment of consumption because of the greater involvement in the experience that they prompt.

  2. Biomedical enhancements as justice.

    PubMed

    Nam, Jeesoo

    2015-02-01

    Biomedical enhancements, the applications of medical technology to make better those who are neither ill nor deficient, have made great strides in the past few decades. Using Amartya Sen's capability approach as my framework, I argue in this article that far from being simply permissible, we have a prima facie moral obligation to use these new developments for the end goal of promoting social justice. In terms of both range and magnitude, the use of biomedical enhancements will mark a radical advance in how we compensate the most disadvantaged members of society.

  3. Inflammasome-regulated Cytokines Are Critical Mediators of Acute Lung Injury

    PubMed Central

    Dolinay, Tamás; Kim, Young Sam; Howrylak, Judie; Hunninghake, Gary M.; Fredenburgh, Laura; Massaro, Anthony F.; Rogers, Angela; Gazourian, Lee; Nakahira, Kiichi; Haspel, Jeffrey A.; Landazury, Roberto; Eppanapally, Sabitha; Christie, Jason D.; Meyer, Nuala J.; Ware, Lorraine B.; Christiani, David C.; Ryter, Stefan W.; Baron, Rebecca M.

    2012-01-01

    Rationale: Despite advances in clinical management, there are currently no reliable diagnostic and therapeutic targets for acute respiratory distress syndrome (ARDS). The inflammasome/caspase-1 pathway regulates the maturation and secretion of proinflammatory cytokines (e.g., IL-18). IL-18 is associated with injury in animal models of systemic inflammation. Objectives: We sought to determine the contribution of the inflammasome pathway in experimental acute lung injury and human ARDS. Methods: We performed comprehensive gene expression profiling on peripheral blood from patients with critical illness. Gene expression changes were assessed using real-time polymerase chain reaction, and IL-18 levels were measured in the plasma of the critically ill patients. Wild-type mice or mice genetically deficient in IL-18 or caspase-1 were mechanically ventilated using moderate tidal volume (12 ml/kg). Lung injury parameters were assessed in lung tissue, serum, and bronchoalveolar lavage fluid. Measurements and Main Results: In mice, mechanical ventilation enhanced IL-18 levels in the lung, serum, and bronchoalveolar lavage fluid. IL-18–neutralizing antibody treatment, or genetic deletion of IL-18 or caspase-1, reduced lung injury in response to mechanical ventilation. In human patients with ARDS, inflammasome-related mRNA transcripts (CASP1, IL1B, and IL18) were increased in peripheral blood. In samples from four clinical centers, IL-18 was elevated in the plasma of patients with ARDS (sepsis or trauma-induced ARDS) and served as a novel biomarker of intensive care unit morbidity and mortality. Conclusions: The inflammasome pathway and its downstream cytokines play critical roles in ARDS development. PMID:22461369

  4. Role of Chitinase 3-Like-1 in Interleukin-18-Induced Pulmonary Type 1, Type 2, and Type 17 Inflammation; Alveolar Destruction; and Airway Fibrosis in the Murine Lung.

    PubMed

    Kang, Min-Jong; Yoon, Chang Min; Nam, Milang; Kim, Do-Hyun; Choi, Je-Min; Lee, Chun Geun; Elias, Jack A

    2015-12-01

    Chitinase 3-like 1 (Chi3l1), which is also called YKL-40 in humans and BRP-39 in mice, is the prototypic chitinase-like protein. Recent studies have highlighted its impressive ability to regulate the nature of tissue inflammation and the magnitude of tissue injury and fibroproliferative repair. This can be appreciated in studies that highlight its induction after cigarette smoke exposure, during which it inhibits alveolar destruction and the genesis of pulmonary emphysema. IL-18 is also known to be induced and activated by cigarette smoke, and, in murine models, the IL-18 pathway has been shown to be necessary and sufficient to generate chronic obstructive pulmonary disease-like inflammation, fibrosis, and tissue destruction. However, the relationship between Chi3l1 and IL-18 has not been defined. To address this issue we characterized the expression of Chi3l1/BRP-39 in control and lung-targeted IL-18 transgenic mice. We also characterized the effects of transgenic IL-18 in mice with wild-type and null Chi3l1 loci. The former studies demonstrated that IL-18 is a potent stimulator of Chi3l1/BRP-39 and that this stimulation is mediated via IFN-γ-, IL-13-, and IL-17A-dependent mechanisms. The latter studies demonstrated that, in the absence of Chi3l1/BRP-39, IL-18 induced type 2 and type 17 inflammation and fibrotic airway remodeling were significantly ameliorated, whereas type 1 inflammation, emphysematous alveolar destruction, and the expression of cytotoxic T lymphocyte perforin, granzyme, and retinoic acid early transcript 1 expression were enhanced. These studies demonstrate that IL-18 is a potent stimulator of Chi3l1 and that Chi3l1 is an important mediator of IL-18-induced inflammatory, fibrotic, alveolar remodeling, and cytotoxic responses.

  5. Association between Interleukin-18 Polymorphisms and Hepatocellular Carcinoma Occurrence and Clinical Progression.

    PubMed

    Lau, Hon-Kit; Hsieh, Ming-Ju; Yang, Shun-Fa; Wang, Hsiang-Ling; Kuo, Wu-Hsien; Lee, Hsiang-Lin; Yeh, Chao-Bin

    2016-01-01

    We investigated the association between interleukin-18 (IL-18) polymorphisms and the susceptibility and clinicopathological state of hepatocellular carcinoma (HCC). In total, 901 participants, including 559 healthy controls and 342 patients with HCC, were recruited. The allelic discrimination of -607A/C (rs1946518) and -137G/C (rs187238) polymorphisms of IL-18 was assessed through real-time polymerase chain reaction by performing the TaqMan assay. The IL-18 -137G/C polymorphism but not the -607A/C polymorphism showed a significant association with the risk of HCC. Participants carrying the IL-18 -137 polymorphism with heterozygous G/C and homozygous CC genotypes showed a 1.987-fold increase (95% CI = 1.301-3.032; p = 0.001) in the risk of HCC compared with those homozygous for wild-type G/G. The 342 patients with HCC carrying the IL-18 -137G/C polymorphism were positive for hepatitis B virus (HBV) infection with an adjusted odds ratio of 1.668. Moreover, the 142 HBV positive patients with HCC and the IL-18 -137 polymorphism were positive for at least one C genotype and showed significant vascular invasion (p = 0.018). Furthermore, the level of α-fetoprotein was high in the patients carrying the IL-18 -137 polymorphism with GC+CC alleles (p = 0.011). In conclusion, the IL-18 -137G/C polymorphism with a GC+CC genotype could be a factor that increases the risk of HCC. Furthermore, the correlation between the IL-18 -137G/C polymorphism and HCC-related HBV infection is a risk factor for vascular invasion and has a synergistic effect that can further enhance HCC prognosis.

  6. Association between Interleukin-18 Polymorphisms and Hepatocellular Carcinoma Occurrence and Clinical Progression.

    PubMed

    Lau, Hon-Kit; Hsieh, Ming-Ju; Yang, Shun-Fa; Wang, Hsiang-Ling; Kuo, Wu-Hsien; Lee, Hsiang-Lin; Yeh, Chao-Bin

    2016-01-01

    We investigated the association between interleukin-18 (IL-18) polymorphisms and the susceptibility and clinicopathological state of hepatocellular carcinoma (HCC). In total, 901 participants, including 559 healthy controls and 342 patients with HCC, were recruited. The allelic discrimination of -607A/C (rs1946518) and -137G/C (rs187238) polymorphisms of IL-18 was assessed through real-time polymerase chain reaction by performing the TaqMan assay. The IL-18 -137G/C polymorphism but not the -607A/C polymorphism showed a significant association with the risk of HCC. Participants carrying the IL-18 -137 polymorphism with heterozygous G/C and homozygous CC genotypes showed a 1.987-fold increase (95% CI = 1.301-3.032; p = 0.001) in the risk of HCC compared with those homozygous for wild-type G/G. The 342 patients with HCC carrying the IL-18 -137G/C polymorphism were positive for hepatitis B virus (HBV) infection with an adjusted odds ratio of 1.668. Moreover, the 142 HBV positive patients with HCC and the IL-18 -137 polymorphism were positive for at least one C genotype and showed significant vascular invasion (p = 0.018). Furthermore, the level of α-fetoprotein was high in the patients carrying the IL-18 -137 polymorphism with GC+CC alleles (p = 0.011). In conclusion, the IL-18 -137G/C polymorphism with a GC+CC genotype could be a factor that increases the risk of HCC. Furthermore, the correlation between the IL-18 -137G/C polymorphism and HCC-related HBV infection is a risk factor for vascular invasion and has a synergistic effect that can further enhance HCC prognosis. PMID:27429592

  7. Measuring and Enhancing Creativity

    ERIC Educational Resources Information Center

    Mahboub, Kamyar C.; Portillo, Margaret B.; Liu, Yinhui; Chandraratna, Susantha

    2004-01-01

    The purpose of this study was to assess ways by which creativity may be enhanced in a design-oriented course. In order to demonstrate the validity of the approach, a statistically based study was employed. Additionally, the experiment was replicated in two design-oriented fields at the University of Kentucky. These fields were civil engineering…

  8. Investigations into Character Enhancement.

    ERIC Educational Resources Information Center

    Hartoonian, H. Michael

    2001-01-01

    Presents six different investigations of character enhancement that attempts to answer three questions: (1) who are you; (2) what is your destination; and (3) who is your captain? Intends to build relationships among ideas such as perspective taking, seeing and making connections with the other, and understanding more about ethical development.…

  9. Teaching to Enhance Research

    ERIC Educational Resources Information Center

    Harland, Tony

    2016-01-01

    In this paper, I present a conceptual argument for "teaching-led research" in which university lecturers construct courses that directly and positively influence their research, while at the same time, safeguard and enhance the student experience. A research-pedagogy for higher education considers the link between teaching and research,…

  10. Enhancing Employee Skills.

    ERIC Educational Resources Information Center

    1999

    This document contains four symposium papers on enhancing employee skills. "The Effect of Study Skills Training Intervention on United States Air Force Aeromedical Apprentices" (John C. Griffith) demonstrates how study skills intervention resulted in a significant increase in the end-of-course scores of a sample of 90 randomly selected Air Force…

  11. Enhancing Workgroup Performance.

    ERIC Educational Resources Information Center

    1998

    This document contains four papers from a symposium on enhancing workgroup performance in human resource development (HRD). "Formation of Cross-Cultural Global Teams: Making Informed Choices on Team Composition" (Robert L. Dilworth) describes how a mixed class of U.S. and international students identified their cultural and learning styles and…

  12. Cognition-Enhancing Drugs

    PubMed Central

    Mehlman, Maxwell J

    2004-01-01

    New drugs that enhance cognition in cognitively healthy individuals present difficult public policy challenges. While their use is not inherently unethical, steps must be taken to ensure that they are safe, that they are widely available to promote equality of opportunity, and that individuals are free to decide whether or not to use them. PMID:15330974

  13. Graphically Enhanced Science Notebooks

    ERIC Educational Resources Information Center

    Minogue, James; Wiebe, Eric; Madden, Lauren; Bedward, John; Carter, Mike

    2010-01-01

    A common mode of communication in the elementary classroom is the science notebook. In this article, the authors outline the ways in which "graphically enhanced science notebooks" can help engage students in complete and robust inquiry. Central to this approach is deliberate attention to the efficient and effective use of student-generated…

  14. Competence Enhancement Behavior Management

    ERIC Educational Resources Information Center

    Farmer, Thomas W.; Goforth, Jennifer B.; Hives, Jacqueline; Aaron, Annie; Jackson, Frances; Sgammato, Adrienne

    2006-01-01

    Competence Enhancement Behavior Management is presented as a framework for supporting students with challenging behaviors in general education classrooms. This approach emphasizes classroom management and discipline strategies that (a) help to build positive relations with students, (b) communicate to students that they are important, and (c)…

  15. Does Powerpoint enhance learning?

    PubMed

    Penciner, Rick

    2013-03-01

    The ubiquitous nature of PowerPoint begs the question, does PowerPoint enhance learning? This narrative explores the evidence for the effectiveness of PowerPoint and multimedia presentations in learning and information processing. Practical recommendations are provided for presentations.

  16. Music Enhances Learning.

    ERIC Educational Resources Information Center

    Campabello, Nicolette; De Carlo, Mary Jane; O'Neil, Jean; Vacek, Mary Jill

    An action research project implemented musical strategies to affect and enhance student recall and memory. The target population was three suburban elementary schools near a major midwestern city: (1) a kindergarten classroom contained 32-38 students; (2) a second grade classroom contained 23 students and five Individualized Education Program…

  17. Piezoelectrically Enhanced Photocathodes

    NASA Technical Reports Server (NTRS)

    Beach, Robert A.; Nikzad, Shouleh; Bell, Lloyd Douglas; Strittmatter, Robert

    2011-01-01

    Doping of photocathodes with materials that have large piezoelectric coefficients has been proposed as an alternative means of increasing the desired photoemission of electrons. Treating cathode materials to increase emission of electrons is called "activation" in the art. It has been common practice to activate photocathodes by depositing thin layers of suitable metals (usually, cesium). Because cesium is unstable in air, fabrication of cesiated photocathodes and devices that contain them must be performed in sealed tubes under vacuum. It is difficult and costly to perform fabrication processes in enclosed, evacuated spaces. The proposed piezoelectrically enhanced photocathodes would have electron-emission properties similar to those of cesiated photocathodes but would be stable in air, and therefore could be fabricated more easily and at lower cost. Candidate photocathodes include nitrides of elements in column III of the periodic table . especially compounds of the general formula Al(x)Ga(1.x)N (where 0< or = x < or =.1). These compounds have high piezoelectric coefficients and are suitable for obtaining response to ultraviolet light. Fabrication of a photocathode according to the proposal would include inducement of strain in cathode layers during growth of the layers on a substrate. The strain would be induced by exploiting structural mismatches among the various constituent materials of the cathode. Because of the piezoelectric effect in this material, the strain would give rise to strong electric fields that, in turn, would give rise to a high concentration of charge near the surface. Examples of devices in which piezoelectrically enhanced photocathodes could be used include microchannel plates, electron- bombarded charge-coupled devices, image tubes, and night-vision goggles. Piezoelectrically enhanced photocathode materials could also be used in making highly efficient monolithic photodetectors. Highly efficient and stable piezoelectrically enhanced

  18. Tea enhances insulin activity.

    PubMed

    Anderson, Richard A; Polansky, Marilyn M

    2002-11-20

    The most widely known health benefits of tea relate to the polyphenols as the principal active ingredients in protection against oxidative damage and in antibacterial, antiviral, anticarcinogenic, and antimutagenic activities, but polyphenols in tea may also increase insulin activity. The objective of this study was to determine the insulin-enhancing properties of tea and its components. Tea, as normally consumed, was shown to increase insulin activity >15-fold in vitro in an epididymal fat cell assay. Black, green, and oolong teas but not herbal teas, which are not teas in the traditional sense because they do not contain leaves of Camellia senensis, were all shown to increase insulin activity. High-performance liquid chromatography fractionation of tea extracts utilizing a Waters SymmetryPrep C18 column showed that the majority of the insulin-potentiating activity for green and oolong teas was due to epigallocatechin gallate. For black tea, the activity was present in several regions of the chromatogram corresponding to, in addition to epigallocatechin gallate, tannins, theaflavins, and other undefined compounds. Several known compounds found in tea were shown to enhance insulin with the greatest activity due to epigallocatechin gallate followed by epicatechin gallate, tannins, and theaflavins. Caffeine, catechin, and epicatechin displayed insignificant insulin-enhancing activities. Addition of lemon to the tea did not affect the insulin-potentiating activity. Addition of 5 g of 2% milk per cup decreased the insulin-potentiating activity one-third, and addition of 50 g of milk per cup decreased the insulin-potentiating activity approximately 90%. Nondairy creamers and soy milk also decreased the insulin-enhancing activity. These data demonstrate that tea contains in vitro insulin-enhancing activity and the predominant active ingredient is epigallocatechin gallate. PMID:12428980

  19. Surface-enhanced spectroscopy

    NASA Astrophysics Data System (ADS)

    Moskovits, Martin

    1985-07-01

    In 1978 it was discovered, largely through the work of Fleischmann, Van Duyne, Creighton, and their coworkers that molecules adsorbed on specially prepared silver surfaces produce a Raman spectrum that is at times a millionfold more intense than expected. This effect was dubbed surface-enhanced Raman scattering (SERS). Since then the effect has been demonstrated with many molecules and with a number of metals, including Cu, Ag, Au, Li, Na, K, In, Pt, and Rh. In addition, related phenomena such as surface-enhanced second-harmonic generation, four-wave mixing, absorption, and fluorescence have been observed. Although not all fine points of the enhancement mechanism have been clarified, the majority view is that the largest contributor to the intensity amplification results from the electric field enhancement that occurs in the vicinity of small, interacting metal particles that are illuminated with light resonant or near resonant with the localized surface-plasmon frequency of the metal structure. Small in this context is gauged in relation to the wavelength of light. The special preparations required to produce the effect, which include among other techniques electrochemical oxidation-reduction cycling, deposition of metal on very cold substrates, and the generation of metal-island films and colloids, is now understood to be necessary as a means of producing surfaces with appropriate electromagnetic resonances that may couple to electromagnetic fields either by generating rough films (as in the case of the former two examples) or by placing small metal particles in close proximity to one another (as in the case of the latter two). For molecules chemisorbed on SERS-active surface there exists a "chemical enhancement" in addition to the electromagnetic effect. Although difficult to measure accurately, the magnitude of this effect rarely exceeds a factor of 10 and is best thought to arise from the modification of the Raman polarizability tensor of the adsorbate

  20. Enhanced coalbed methane recovery

    SciTech Connect

    Mazzotti, M.; Pini, R.; Storti, G.

    2009-01-15

    The recovery of coalbed methane can be enhanced by injecting CO{sub 2} in the coal seam at supercritical conditions. Through an in situ adsorption/desorption process the displaced methane is produced and the adsorbed CO{sub 2} is permanently stored. This is called enhanced coalbed methane recovery (ECBM) and it is a technique under investigation as a possible approach to the geological storage of CO{sub 2} in a carbon dioxide capture and storage system. This work reviews the state of the art on fundamental and practical aspects of the technology and summarizes the results of ECBM field tests. These prove the feasibility of ECBM recovery and highlight substantial opportunities for interdisciplinary research at the interface between earth sciences and chemical engineering.

  1. Superposition Enhanced Nested Sampling

    NASA Astrophysics Data System (ADS)

    Martiniani, Stefano; Stevenson, Jacob D.; Wales, David J.; Frenkel, Daan

    2014-07-01

    The theoretical analysis of many problems in physics, astronomy, and applied mathematics requires an efficient numerical exploration of multimodal parameter spaces that exhibit broken ergodicity. Monte Carlo methods are widely used to deal with these classes of problems, but such simulations suffer from a ubiquitous sampling problem: The probability of sampling a particular state is proportional to its entropic weight. Devising an algorithm capable of sampling efficiently the full phase space is a long-standing problem. Here, we report a new hybrid method for the exploration of multimodal parameter spaces exhibiting broken ergodicity. Superposition enhanced nested sampling combines the strengths of global optimization with the unbiased or athermal sampling of nested sampling, greatly enhancing its efficiency with no additional parameters. We report extensive tests of this new approach for atomic clusters that are known to have energy landscapes for which conventional sampling schemes suffer from broken ergodicity. We also introduce a novel parallelization algorithm for nested sampling.

  2. Enhanced Microfluidic Electromagnetic Measurements

    NASA Technical Reports Server (NTRS)

    Giovangrandi, Laurent (Inventor); Ricco, Antonio J. (Inventor); Kovacs, Gregory (Inventor)

    2015-01-01

    Techniques for enhanced microfluidic impedance spectroscopy include causing a core fluid to flow into a channel between two sheath flows of one or more sheath fluids different from the core fluid. Flow in the channel is laminar. A dielectric constant of a fluid constituting either sheath flow is much less than a dielectric constant of the core fluid. Electrical impedance is measured in the channel between at least a first pair of electrodes. In some embodiments, enhanced optical measurements include causing a core fluid to flow into a channel between two sheath flows of one or more sheath fluids different from the core fluid. An optical index of refraction of a fluid constituting either sheath flow is much less than an optical index of refraction of the core fluid. An optical property is measured in the channel.

  3. Enhanced magnetocaloric effect material

    DOEpatents

    Lewis, Laura J. H.

    2006-07-18

    A magnetocaloric effect heterostructure having a core layer of a magnetostructural material with a giant magnetocaloric effect having a magnetic transition temperature equal to or greater than 150 K, and a constricting material layer coated on at least one surface of the magnetocaloric material core layer. The constricting material layer may enhance the magnetocaloric effect by restriction of volume changes of the core layer during application of a magnetic field to the heterostructure. A magnetocaloric effect heterostructure powder comprising a plurality of core particles of a magnetostructural material with a giant magnetocaloric effect having a magnetic transition temperature equal to or greater than 150 K, wherein each of the core particles is encapsulated within a coating of a constricting material is also disclosed. A method for enhancing the magnetocaloric effect within a giant magnetocaloric material including the step of coating a surface of the magnetocaloric material with a constricting material is disclosed.

  4. Image enhancement by holography.

    NASA Technical Reports Server (NTRS)

    Stroke, G. W.

    1973-01-01

    The speed of the holographic image deblurring method has recently been further enhanced by a new speed in the realization of the powerful holographic image-deblurring filter. The filter makes it possible to carry out the deblurring, in the optical computer used, in times of the order of one second. The experimental achievements using the holographic image-enhancement method are illustrated with examples ranging from out-of-focus or motion-blurred photographs, including 'amateur' photos recorded on Polaroid film, to the sharpening of the best available electron micrographs of viruses. Images recorded with X-rays, notably from rocket-borne photos of the sun, and out-of-focus photographs from cameras in NASA satellites have been similarly deblurred.

  5. Enhancing genetic virtue.

    PubMed

    Walker, Mark

    2009-09-01

    The Genetic Virtue Project (GVP) is a proposed interdisciplinary effort between philosophers, psychologists and geneticists to discover and enhance human ethics using biotechnology genetic correlates of virtuous behavior. The empirical plausibility that virtues have biological correlates is based on the claims that (a) virtues are a subset of personality, specifically, personality traits conceived of as "enduring behaviors," and (b) that there is ample evidence that personality traits have a genetic basis. The moral necessity to use the GVP for moral enhancement is based on the claims that we should eliminate evil (as understood generically, not religiously), as some evil is a function of human nature. The GVP is defended against several ethical and political criticisms.

  6. Digital Enhancement Of Pneumothoraces

    NASA Astrophysics Data System (ADS)

    Cocklin, M.; Kaye, G.; Kerr, I.; Lams, P.

    1982-11-01

    If a patient presents with symptoms indicative of a pneumothorax it is improbable that it would not be detected in a chest radiograph. However, detection on the radiograph can be difficult and a small pneumothorax may be missed when there is no clinical suspicion of its presence. This report presents some methods by which the characteristic pneumothorax edge may be enhanced by digital image processing. Various examples are given.

  7. Lignite Fuel Enhancement

    SciTech Connect

    Charles Bullinger

    2006-02-03

    This 6th quarterly Technical Progress Report for the Lignite Fuel Enhancement Project summarizes activities from October 1st through December 31st of 2005. It also summarizes the subsequent purchasing activity and dryer/process construction. Hypothesis remains the same. We will be able to dry lignite an increment to benefit the performance of and reduce emissions from a coal burning electric power generating station.

  8. Enhanced Rescue Lift Capability

    NASA Technical Reports Server (NTRS)

    Young, Larry A.

    2007-01-01

    The evolving and ever-increasing demands of emergency response and disaster relief support provided by rotorcraft dictate, among other things, the development of enhanced rescue lift capability for these platforms. This preliminary analysis is first-order in nature but provides considerable insight into some of the challenges inherent in trying to effect rescue using a unique form of robotic rescue device deployed and operated from rotary-wing aerial platforms.

  9. [About moral enhancement].

    PubMed

    Goffi, Jean-Yves

    2015-01-01

    First, a short summary of the moral enhancement debate is drawn up. Then an argument first put forward by J. Harris is explored: this argument is directly related to I. Perrson's and J. Savulescu's conception of moral life. To conclude, it is suggested that they advocate a naïve idea of technology, conceived as a neutral means for value loaded ends. PMID:26238765

  10. Enhanced airglow at Titan

    NASA Astrophysics Data System (ADS)

    Royer, Emilie; Esposito, Larry; Wahlund, Jan-Erik

    2016-06-01

    The Cassini Ultraviolet Imaging Spectrograph (UVIS) instrument made thousand of observations of Titan since its arrival in the Saturnian system in 2004, but only few of them have been analyzed yet. Using the imaging capability of UVIS combined to a big data analytics approach, we have been able to uncover an unexpected pattern in this observations: on several occasions the Titan airglow exhibits an enhanced brightness by approximately a factor of 2, generally combined with a lower altitude of the airglow emission peak. These events typically last from 10 to 30 minutes and are followed and preceded by an airglow of regular and expected level of brightness and altitude. Observations made by the Cassini Plasma Spectrometer (CAPS) instrument onboard Cassini allowed us to correlate the enhanced airglow observed on T-32 with an electron burst. The timing of the burst and the level of energetic electrons (1 keV) observed by CAPS correspond to a brighter and lower than typical airglow displayed on the UVIS data. Furthermore, during T-32 Titan was inside the Saturn's magnetosheath and thus more subject to bombardment by energetic particles. However, our analysis demonstrates that the presence of Titan inside the magnetosheath is not a necessary condition for the production of an enhanced airglow, as we detected other similar events while Titan was within Saturn's magnetosphere. The study presented here aims to a better understanding of the interactions of Titan's upper atmosphere with its direct environment.

  11. Sleep for cognitive enhancement

    PubMed Central

    Diekelmann, Susanne

    2014-01-01

    Sleep is essential for effective cognitive functioning. Loosing even a few hours of sleep can have detrimental effects on a wide variety of cognitive processes such as attention, language, reasoning, decision making, learning and memory. While sleep is necessary to ensure normal healthy cognitive functioning, it can also enhance performance beyond the boundaries of the normal condition. This article discusses the enhancing potential of sleep, mainly focusing on the domain of learning and memory. Sleep is known to facilitate the consolidation of memories learned before sleep as well as the acquisition of new memories to be learned after sleep. According to a widely held model this beneficial effect of sleep relies on the neuronal reactivation of memories during sleep that is associated with sleep-specific brain oscillations (slow oscillations, spindles, ripples) as well as a characteristic neurotransmitter milieu. Recent research indicates that memory processing during sleep can be boosted by (i) cueing memory reactivation during sleep; (ii) stimulating sleep-specific brain oscillations; and (iii) targeting specific neurotransmitter systems pharmacologically. Olfactory and auditory cues can be used, for example, to increase reactivation of associated memories during post-learning sleep. Intensifying neocortical slow oscillations (the hallmark of slow wave sleep (SWS)) by electrical or auditory stimulation and modulating specific neurotransmitters such as noradrenaline and glutamate likewise facilitates memory processing during sleep. With this evidence in mind, this article concludes by discussing different methodological caveats and ethical issues that should be considered when thinking about using sleep for cognitive enhancement in everyday applications. PMID:24765066

  12. Enhancement and Obsolescence: Avoiding an "Enhanced Rat Race".

    PubMed

    Sparrow, Robert

    2015-09-01

    A claim about continuing technological progress plays an essential, if unacknowledged, role in the philosophical literature on "human enhancement." I argue that-should it eventuate-continuous improvement in enhancement technologies may prove more bane than benefit. A rapid increase in the power of available enhancements would mean that each cohort of enhanced individuals will find itself in danger of being outcompeted by the next in competition for important social goods-a situation I characterize as an "enhanced rat race." Rather than risk the chance of being rendered technologically and socially obsolete by the time one is in one's early 20s, it may be rational to prefer that a wide range of enhancements that would generate positional disadvantages that outweigh their absolute advantages be prohibited altogether. The danger of an enhanced rat race therefore constitutes a novel argument in favor of abandoning the pursuit of certain sorts of enhancements. PMID:26412737

  13. Metamaterials enhancing optical forces

    NASA Astrophysics Data System (ADS)

    Ginis, Vincent; Tassin, Philippe; Soukoulis, Costas M.; Veretennicoff, Irina

    2014-05-01

    The interaction between light and matter involves not only an energy transfer, but also the transfer of linear momentum. In everyday life applications this linear momentum of light is too small to play any significant role. However, in nanoscale dimensions, the associated optical forces start to play an increasingly important role. These forces are, e.g., large enough for exiting experiments in the fields of cavity-optomechanics, laser cooling and optical trapping of small particles. Recently, it has been suggested that optical gradient forces can also be employed for all-optical actuation in micro- and nanophotonic systems. The typical setup consists of two slab waveguides positioned in each others vicinity such that they are coupled through the interaction of the evanescent tails. Although the gradient forces between these waveguides can be enhanced considerably using electromagnetic resonators or slow-light techniques, the resulting displacements remain relatively small. In this contribution, we present an alternative approach to enhance optical gradient forces between waveguides using a combination of transformation optics and metamaterials. Our design starts from the observation that gradient forces exponentially decay with the separation distance between the waveguides. Therefore, we employ transformation optics to annihilate the apparent distance for light between the waveguides. Analytical calculations confirm that the resulting forces indeed increase when such an annihilating cladding is inserted. Subsequently, we discuss the metamaterial implementation of this annihilating medium. Such lensing media automatically translate into anisotropic metamaterials with negative components in the permittivity and permeability tensors. Our full-wave numerical simulations show that the overall amplification is highly limited by the loss-tangent of the metamaterial cladding. However, as this cladding only needs to operate in the near-field for a specific polarization

  14. Cell Growth Enhancement

    NASA Technical Reports Server (NTRS)

    1992-01-01

    Exogene Corporation uses advanced technologies to enhance production of bio-processed substances like proteins, antibiotics and amino acids. Among them are genetic modification and a genetic switch. They originated in research for Jet Propulsion Laboratory. Extensive experiments in cell growth through production of hemoglobin to improve oxygen supply to cells were performed. By improving efficiency of oxygen use by cells, major operational expenses can be reduced. Greater product yields result in decreased raw material costs and more efficient use of equipment. A broad range of applications is cited.

  15. Optical waveguide enhanced photovoltaics.

    PubMed

    Rühle, Sven; Greenwald, Shlomit; Koren, Elad; Zaban, Arie

    2008-12-22

    Enhanced light to electric power conversion efficiency of photovoltaic cells with a low absorbance was achieved using waveguide integration. We present a proof of concept using a very thin dye-sensitized solar cell which absorbed only a small fraction of the light at normal incidence. The glass substrate in conjunction with the solar cells reflecting back contact formed a planar waveguide, which lead to more than four times higher conversion efficiency compared to conventional illumination at normal incidence. This illumination concept leads to a new type of multi-junction PV systems based on enforced spectral splitting along the waveguide.

  16. Plasma enhanced microwave joining

    SciTech Connect

    Yiin, T.; Barmatz, M.; Sayir, A.

    1995-12-31

    A new method for plasma enhanced microwave joining of high purity (99.8%) alumina has been developed. The controlled application of a plasma between the adjoining surfaces of two rods initially heats the microwave-low-absorbing alumina rods to temperatures high enough for them to absorb microwave energy efficiently. With this technology, the adjacent surfaces of alumina rods can be melted and welded together in less than three minutes using approximately 400 watts of microwave energy. Four point bending tests measured fracture strengths of up to 130 MPa at the joined interface. Optical and SEM micrographs indicated that exaggerated grain growth prevailed for all joints studied.

  17. Enhanced by Frost

    NASA Technical Reports Server (NTRS)

    2005-01-01

    30 September 2005 This Mars Global Surveyor (MGS) Mars Orbiter Camera (MOC) image shows outcrops of south polar layered terrain. Their appearance in this July 2005 springtime image is enhanced by bright patches of carbon dioxide frost. The frost is left over from the previous southern winter season; by summer, the frost would be gone.

    Location near: 84.6oS, 203.5oW Image width: width: 3 km (1.9 mi) Illumination from: upper left Season: Southern Spring

  18. Cognitive diversity and moral enhancement.

    PubMed

    Gyngell, Chris; Easteal, Simon

    2015-01-01

    One debate in contemporary bioethics centers on whether the development of cognitive enhancement technologies (CETs) will hasten the need for moral enhancement. In this article we provide a new argument in favor of pursuing these enhancement technologies together. The widespread availability of CETs will likely increase population-level cognitive diversity. Different people will choose to enhance different aspects of their cognition, and some won't enhance themselves at all. Although this has the potential to be beneficial for society, it could also result in harms as people become more different from one another. Aspects of our moral psychology make it difficult for people to cooperate and coordinate actions with those who are very different from themselves. These moral failings could be targeted by moral enhancement technologies, which may improve cooperation among individuals. Moral enhancement technologies will therefore help society maximize the benefits, and reduce the costs, associated with widespread access to cognitive enhancements.

  19. Computer enhancement of radiographs

    NASA Technical Reports Server (NTRS)

    Dekaney, A.; Keane, J.; Desautels, J.

    1973-01-01

    Examination of three relevant noise processes and the image degradation associated with Marshall Space Flight Center's (MSFC) X-ray/scanning system was conducted for application to computer enhancement of radiographs using MSFC's digital filtering techniques. Graininess of type M, R single coat and R double coat X-ray films was quantified as a function of density level using root-mean-square (RMS) granularity. Quantum mottle (including film grain) was quantified as a function of the above film types, exposure level, specimen material and thickness, and film density using RMS granularity and power spectral density (PSD). For various neutral-density levels the scanning device used in digital conversion of radiographs was examined for noise characteristics which were quantified by RMS granularity and PSD. Image degradation of the entire pre-enhancement system (MG-150 X-ray device; film; and optronics scanner) was measured using edge targets to generate modulation transfer functions (MTF). The four parameters were examined as a function of scanning aperture sizes of approximately 12.5 25 and 50 microns.

  20. Telemetry-Enhancing Scripts

    NASA Technical Reports Server (NTRS)

    Maimone, Mark W.

    2009-01-01

    Scripts Providing a Cool Kit of Telemetry Enhancing Tools (SPACKLE) is a set of software tools that fill gaps in capabilities of other software used in processing downlinked data in the Mars Exploration Rovers (MER) flight and test-bed operations. SPACKLE tools have helped to accelerate the automatic processing and interpretation of MER mission data, enabling non-experts to understand and/or use MER query and data product command simulation software tools more effectively. SPACKLE has greatly accelerated some operations and provides new capabilities. The tools of SPACKLE are written, variously, in Perl or the C or C++ language. They perform a variety of search and shortcut functions that include the following: Generating text-only, Event Report-annotated, and Web-enhanced views of command sequences; Labeling integer enumerations with their symbolic meanings in text messages and engineering channels; Systematic detecting of corruption within data products; Generating text-only displays of data-product catalogs including downlink status; Validating and labeling of commands related to data products; Performing of convenient searches of detailed engineering data spanning multiple Martian solar days; Generating tables of initial conditions pertaining to engineering, health, and accountability data; Simplified construction and simulation of command sequences; and Fast time format conversions and sorting.

  1. Surfactant-enhanced bioremediation

    SciTech Connect

    Churchill, P.F.; Dudley, R.J.; Churchill, S.A.

    1995-12-31

    This study was undertaken to examine the effect of three structurally related, non-ionic surfactants, Triton X-45, Triton X-100 and Triton X-165, as well as the oleophilic fertilizer, Inipol EAP 22, on the rate of biodegradation of phenanthrene by pure bacterial cultures. Each surfactant dramatically increased the apparent aqueous solubility of phenanthrene. Model studies were conducted to investigate the ability of these surfactants to enhance the rate of transport and uptake of polycyclic aromatic hydrocarbons into bacterial cells, and to assess the impact that increasing the aqueous solubility of hydrocarbons has on their rate of biodegradation. The results indicate that increasing the apparent aqueous solubility of hydrocarbons can lead to enhanced biodegradation rates by two Pseudomonas saccharophila strains. However, the experiments also suggest that some surfactants can inhibit aromatic hydrocarbon biodegradation by certain bacteria. The data also support the hypothesis that surface-active components present in the oleophilic fertilizer formulation, Inipol EAP 22, may have significantly contributed to the positive results reported in tests of remedial agent impact on bioremediation, which was used as a supplemental clean-up technology on Exxon Valdez crude oil-contaminated Alaskan beaches.

  2. Direct vs. Indirect Moral Enhancement.

    PubMed

    Schaefer, G Owen

    2015-09-01

    Moral enhancement is an ostensibly laudable project. Who wouldn't want people to become more moral? Still, the project's approach is crucial. We can distinguish between two approaches for moral enhancement: direct and indirect. Direct moral enhancements aim at bringing about particular ideas, motives or behaviors. Indirect moral enhancements, by contrast, aim at making people more reliably produce the morally correct ideas, motives or behaviors without committing to the content of those ideas, motives and/or actions. I will argue, on Millian grounds, that the value of disagreement puts serious pressure on proposals for relatively widespread direct moral enhancement. A more acceptable path would be to focus instead on indirect moral enhancements while staying neutral, for the most part, on a wide range of substantive moral claims. I will outline what such indirect moral enhancement might look like, and why we should expect it to lead to general moral improvement.

  3. Digitally Enhanced Heterodyne Interferometry

    NASA Technical Reports Server (NTRS)

    Shaddock, Daniel; Ware, Brent; Lay, Oliver; Dubovitsky, Serge

    2010-01-01

    Spurious interference limits the performance of many interferometric measurements. Digitally enhanced interferometry (DEI) improves measurement sensitivity by augmenting conventional heterodyne interferometry with pseudo-random noise (PRN) code phase modulation. DEI effectively changes the measurement problem from one of hardware (optics, electronics), which may deteriorate over time, to one of software (modulation, digital signal processing), which does not. DEI isolates interferometric signals based on their delay. Interferometric signals are effectively time-tagged by phase-modulating the laser source with a PRN code. DEI improves measurement sensitivity by exploiting the autocorrelation properties of the PRN to isolate only the signal of interest and reject spurious interference. The properties of the PRN code determine the degree of isolation.

  4. Photon enhanced thermionic emission

    SciTech Connect

    Schwede, Jared; Melosh, Nicholas; Shen, Zhixun

    2014-10-07

    Photon Enhanced Thermionic Emission (PETE) is exploited to provide improved efficiency for radiant energy conversion. A hot (greater than 200.degree. C.) semiconductor cathode is illuminated such that it emits electrons. Because the cathode is hot, significantly more electrons are emitted than would be emitted from a room temperature (or colder) cathode under the same illumination conditions. As a result of this increased electron emission, the energy conversion efficiency can be significantly increased relative to a conventional photovoltaic device. In PETE, the cathode electrons can be (and typically are) thermalized with respect to the cathode. As a result, PETE does not rely on emission of non-thermalized electrons, and is significantly easier to implement than hot-carrier emission approaches.

  5. Plant performance enhancement program

    SciTech Connect

    Munchausen, J.H.

    1995-09-01

    The Plant Performance Enhancement Program (P{sup 2}EP), an initiative of the Electric Power Research Institute (EPRI), responds to strong industry incentives to improve nuclear plant thermal efficiency and electrical output. Launched by EPRI`s Nuclear Power Division, P{sup 2}EP operates within the purview of the Plant Support Engineering (PSE) Program, with day-to-day activities conducted out of the P{sup 2}EP office headquartered at EPRI`s facility in Charlotte, North Carolina. This alignment is consistent with EPFU`s strategic targets in support of industry goals, keeping P{sup 2}EP`s mission in clear focus: Helping utility thermal performance engineers improve the heat rate of nuclear power plants, thereby increasing unit average capacity and reducing plant operations and maintenance costs per kilowatt-hour.

  6. Structure Size Enhanced Histogram

    NASA Astrophysics Data System (ADS)

    Wesarg, Stefan; Kirschner, Matthias

    Direct volume visualization requires the definition of transfer functions (TFs) for the assignment of opacity and color. Multi-dimensional TFs are based on at least two image properties, and are specified by means of 2D histograms. In this work we propose a new type of a 2D histogram which combines gray value with information about the size of the structures. This structure size enhanced (SSE) histogram is an intuitive approach for representing anatomical features. Clinicians — the users we are focusing on — are much more familiar with selecting features by their size than by their gradient magnitude value. As a proof of concept, we employ the SSE histogram for the definition of two-dimensional TFs for the visualization of 3D MRI and CT image data.

  7. Global Enhanced Vegetation Index

    NASA Technical Reports Server (NTRS)

    2002-01-01

    By carefully measuring the wavelengths and intensity of visible and near-infrared light reflected by the land surface back up into space, the Moderate-resolution Imaging Spectroradiometer (MODIS) Team can quantify the concentrations of green leaf vegetation around the world. The above MODIS Enhanced Vegetation Index (EVI) map shows the density of plant growth over the entire globe. Very low values of EVI (white and brown areas) correspond to barren areas of rock, sand, or snow. Moderate values (light greens) represent shrub and grassland, while high values indicate temperate and tropical rainforests (dark greens). The MODIS EVI gives scientists a new tool for monitoring major fluctuations in vegetation and understanding how they affect, and are affected by, regional climate trends. For more information, read NASA Unveils Spectacular Suite of New Global Data Products from MODIS. Image courtesy MODIS Land Group/Vegetation Indices, Alfredo Huete, Principal Investigator, and Kamel Didan, University of Arizona

  8. Cavity enhanced atomic magnetometry

    PubMed Central

    Crepaz, Herbert; Ley, Li Yuan; Dumke, Rainer

    2015-01-01

    Atom sensing based on Faraday rotation is an indispensable method for precision measurements, universally suitable for both hot and cold atomic systems. Here we demonstrate an all-optical magnetometer where the optical cell for Faraday rotation spectroscopy is augmented with a low finesse cavity. Unlike in previous experiments, where specifically designed multipass cells had been employed, our scheme allows to use conventional, spherical vapour cells. Spherical shaped cells have the advantage that they can be effectively coated inside with a spin relaxation suppressing layer providing long spin coherence times without addition of a buffer gas. Cavity enhancement shows in an increase in optical polarization rotation and sensitivity compared to single-pass configurations. PMID:26481853

  9. Plasmonic enhanced ultrafast switch.

    SciTech Connect

    Subramania,Ganapathi Subramanian; Reno, John Louis; Passmore, Brandon Scott; Harris, Tom.; Shaner, Eric Arthur; Barrick, Todd A.

    2009-09-01

    Ultrafast electronic switches fabricated from defective material have been used for several decades in order to produce picosecond electrical transients and TeraHertz radiation. Due to the ultrashort recombination time in the photoconductor materials used, these switches are inefficient and are ultimately limited by the amount of optical power that can be applied to the switch before self-destruction. The goal of this work is to create ultrafast (sub-picosecond response) photoconductive switches on GaAs that are enhanced through plasmonic coupling structures. Here, the plasmonic coupler primarily plays the role of being a radiation condenser which will cause carriers to be generated adjacent to metallic electrodes where they can more efficiently be collected.

  10. Delta launcher enhanced

    NASA Astrophysics Data System (ADS)

    1987-08-01

    The next-generation, 'Delta II' version of the Delta expendable launch vehicle will be able to launch over 4000 lbs into geosynchronous transfer orbit (GTO), as required by the USAF's Navstar GPS; the current Delta 3920 configuration can loft only 2800 lbs into GEO. Three distinct growth configurations of the Delta II are planned: the 6925, whose booster propellant tanks will be extended by 12 ft; the 7925, whose improved booster engine will increase nozzle expansion ratio from 8:1 to 12:1; and the 'enhanced ' Delta II, with stretched graphite-epoxy solid rocket motor cases. In this final form, Delta II will boost 4010 lbs into GTO, or 11,110 lbs into LEO.

  11. Enhancing multiple disciplinary teamwork.

    PubMed

    Weaver, Terri E

    2008-01-01

    Multiple disciplinary research provides an opportunity to bring together investigators across disciplines to provide new views and develop innovative approaches to important questions. Through this shared experience, novel paradigms are formed, original frameworks are developed, and new language is generated. Integral to the successful construction of effective cross-disciplinary teams is the recognition of antecedent factors that affect the development of the team such as intrapersonal, social, physical environmental, organizational, and institutional influences. Team functioning is enhanced with well-developed behavioral, affective, interpersonal, and intellectual processes. Outcomes of effective multiple disciplinary research teams include novel ideas, integrative models, new training programs, institutional change, and innovative policies that can also influence the degree to which antecedents and processes contribute to team performance. Ongoing evaluation of team functioning and achievement of designated outcomes ensures the continued development of the multiple disciplinary team and confirmation of this approach as important to the advancement of science.

  12. Enhanced oil recovery system

    DOEpatents

    Goldsberry, Fred L.

    1989-01-01

    All energy resources available from a geopressured geothermal reservoir are used for the production of pipeline quality gas using a high pressure separator/heat exchanger and a membrane separator, and recovering waste gas from both the membrane separator and a low pressure separator in tandem with the high pressure separator for use in enhanced oil recovery, or in powering a gas engine and turbine set. Liquid hydrocarbons are skimmed off the top of geothermal brine in the low pressure separator. High pressure brine from the geothermal well is used to drive a turbine/generator set before recovering waste gas in the first separator. Another turbine/generator set is provided in a supercritical binary power plant that uses propane as a working fluid in a closed cycle, and uses exhaust heat from the combustion engine and geothermal energy of the brine in the separator/heat exchanger to heat the propane.

  13. Enhanced Geothermal Systems

    SciTech Connect

    Jeanloz, R.; Stone, H.

    2013-12-31

    DOE, through the Geothermal Technologies Office (GTO) within the Office of Energy Efficiency and Renewable Energy, requested this study, identifying a focus on: i) assessment of technologies and approaches for subsurface imaging and characterization so as to be able to validate EGS opportunities, and ii) assessment of approaches toward creating sites for EGS, including science and engineering to enhance permeability and increase the recovery factor. Two days of briefings provided in-depth discussion of a wide range of themes and challenges in EGS, and represented perspectives from industry, government laboratories and university researchers. JASON also contacted colleagues from universities, government labs and industry in further conversations to learn the state of the field and potential technologies relevant to EGS.

  14. Teacher Enhancement Institute

    NASA Technical Reports Server (NTRS)

    Marshall-Bradley, Tina

    1994-01-01

    During the 1980's, a period of intense concern over educational quality in the United States, few indicators of U.S. student achievement garnered the interest of policy makers and pundits as successfully as the results of international testing in mathematics and science. This concern was so great that as a part of the Goals 2000 initiative, President George Bush indicated that 'By the year 2000, U.S. students should be first in the world in mathematics and science.' The Clinton Administration is placing a major emphasis, not only on rigorous academic standards and creating a new system for assessing students' progress, but also including professional development as a major focus. The argument being that teachers need more sustained, intensive training to prepare them to teach to higher standards. Executive order 12821 mandates that national laboratories 'assist in the mathematics and science education of our Nation's students, teachers, parents and the public by establishing programs at their agency to provide for training elementary and secondary school teachers to improve their knowledge of mathematics and science'. These and other issues led to the development of ideas for a project that addresses the need for excellence in mathematics, science and technology instruction. In response to these initiatives the NASA/LaRC Teacher Enhancement Institute was proposed. The TEI incorporated systemic reform perspectives, enhanced content knowledge for teachers, and teacher preparation. Emphasis was also placed on recruiting those educators who teach in impoverished urban school districts with at-risk student populations who have been traditionally under represented in science, mathematics, technology and engineering. Participants in the Teacher Enhancement Institute were 37 teachers from grades K-8, teaching in Region 2 in the state of Virginia, as well as 2 preservice teachers from Norfolk State University and one teacher from Dublin, Virginia, where a Science

  15. An integrated statistical model for enhanced murine cardiomyocyte differentiation via optimized engagement of 3D extracellular matrices

    PubMed Central

    Jung, Jangwook P.; Hu, Dongjian; Domian, Ibrahim J.; Ogle, Brenda M.

    2015-01-01

    The extracellular matrix (ECM) impacts stem cell differentiation, but identifying formulations supportive of differentiation is challenging in 3D models. Prior efforts involving combinatorial ECM arrays seemed intuitively advantageous. We propose an alternative that suggests reducing sample size and technological burden can be beneficial and accessible when coupled to design of experiments approaches. We predict optimized ECM formulations could augment differentiation of cardiomyocytes derived in vitro. We employed native chemical ligation to polymerize 3D poly (ethylene glycol) hydrogels under mild conditions while entrapping various combinations of ECM and murine induced pluripotent stem cells. Systematic optimization for cardiomyocyte differentiation yielded a predicted solution of 61%, 24%, and 15% of collagen type I, laminin-111, and fibronectin, respectively. This solution was confirmed by increased numbers of cardiac troponin T, α-myosin heavy chain and α-sarcomeric actinin-expressing cells relative to suboptimum solutions. Cardiomyocytes of composites exhibited connexin43 expression, appropriate contractile kinetics and intracellular calcium handling. Further, adding a modulator of adhesion, thrombospondin-1, abrogated cardiomyocyte differentiation. Thus, the integrated biomaterial platform statistically identified an ECM formulation best supportive of cardiomyocyte differentiation. In future, this formulation could be coupled with biochemical stimulation to improve functional maturation of cardiomyocytes derived in vitro or transplanted in vivo. PMID:26687770

  16. Lignite Fuel Enhancement

    SciTech Connect

    Charles Bullinger; Nenad Sarunac

    2010-03-31

    Pulverized coal power plants which fire lignites and other low-rank high-moisture coals generally operate with reduced efficiencies and increased stack emissions due to the impacts of high fuel moisture on stack heat loss and pulverizer and fan power. A process that uses plant waste heat sources to evaporate a portion of the fuel moisture from the lignite feedstock in a moving bed fluidized bed dryer (FBD) was developed in the U.S. by a team led by Great River Energy (GRE). The demonstration was conducted with Department of Energy (DOE) funding under DOE Award Number DE-FC26-04NT41763. The objectives of GRE's Lignite Fuel Enhancement project were to demonstrate reduction in lignite moisture content by using heat rejected from the power plant, apply technology at full scale at Coal Creek Station (CCS), and commercialize it. The Coal Creek Project has involved several stages, beginning with lignite drying tests in a laboratory-scale FBD at the Energy Research Center (ERC) and development of theoretical models for predicting dryer performance. Using results from these early stage research efforts, GRE built a 2 ton/hour pilot-scale dryer, and a 75 ton/hour prototype drying system at Coal Creek Station. Operated over a range of drying conditions, the results from the pilot-scale and prototype-scale dryers confirmed the performance of the basic dryer design concept and provided the knowledge base needed to scale the process up to commercial size. Phase 2 of the GRE's Lignite Fuel Enhancement project included design, construction and integration of a full-scale commercial coal drying system (four FBDs per unit) with Coal Creek Units 1 and 2 heat sources and coal handling system. Two series of controlled tests were conducted at Coal Creek Unit 1 with wet and dried lignite to determine effect of dried lignite on unit performance and emissions. Wet lignite was fired during the first, wet baseline, test series conducted in September 2009. The second test series was performed

  17. Enhanced preliminary assessment

    SciTech Connect

    Not Available

    1992-02-01

    An Enhanced Preliminary Assessment was conducted at Fort Benjamin Harrison (FBH) Indiana, which is located approximately 12 miles from downtown Indianapolis in Lawrence Township, Marion County. FBH contains 2,501 acres, of which approximately 1,069 acres is covered by woodlands. Activities at FBH include administration, training, housing, and support. Sensitive environments at FBH include wetlands, habitat areas for the endangered Indiana bat, endangered plants, and historically and archeologically significant areas. FBH is a U.S. Army Soldier Support Center under the jurisdiction of the U.S. Army Training and Doctrine Command (TRADOC). Based on information obtained during and subsequent to a site visit (15 through 18 October 1991), 36 types of Areas Requiring Environmental Evaluation (AREEs) were identified and grouped by the following categories: Facility Operations; Maintenance/Fueling Operations; Water Treatment Operations; Training Areas; Hazardous Materials Storage/Waste Handling Areas; Sanitary Wastewater Treatment Plants; Storage Tanks; Landfills/Incinerators; Medical Facilities; Burn Pit Areas; Spill Areas; Ammunition Storage; Coal Storage; and Facility-wide AREEs. This report presents a summary of findings for each AREE and recommendations for further action.

  18. Enhanced Design Alternative IV

    SciTech Connect

    N. E. Kramer

    1999-05-18

    This report evaluates Enhanced Design Alternative (EDA) IV as part of the second phase of the License Application Design Selection (LADS) effort. The EDA IV concept was compared to the VA reference design using criteria from the ''Design Input Request for LADS Phase II EDA Evaluations'' (CRWMS M&O 1999b) and (CRWMS M&O 1999f). Briefly, the EDA IV concept arranges the waste packages close together in an emplacement configuration known as ''line load''. Continuous pre-closure ventilation keeps the waste packages from exceeding the 350 C cladding and 200 C (4.3.13) drift wall temperature limits. This EDA concept keeps relatively high, uniform emplacement drift temperatures (post-closure) to drive water away from the repository and thus dry out the pillars between emplacement drifts. The waste package is shielded to permit human access to emplacement drifts and includes an integral filler inside the package to reduce the amount of water that can contact the waste form. Closure of the repository is desired 50 years after first waste is emplaced. Both backfill and a drip shields will be emplaced at closure to improve post-closure performance.

  19. Enhanced Micellar Catalysis LDRD.

    SciTech Connect

    Betty, Rita G.; Tucker, Mark D; Taggart, Gretchen; Kinnan, Mark K.; Glen, Crystal Chanea; Rivera, Danielle; Sanchez, Andres; Alam, Todd Michael

    2012-12-01

    The primary goals of the Enhanced Micellar Catalysis project were to gain an understanding of the micellar environment of DF-200, or similar liquid CBW surfactant-based decontaminants, as well as characterize the aerosolized DF-200 droplet distribution and droplet chemistry under baseline ITW rotary atomization conditions. Micellar characterization of limited surfactant solutions was performed externally through the collection and measurement of Small Angle X-Ray Scattering (SAXS) images and Cryo-Transmission Electron Microscopy (cryo-TEM) images. Micellar characterization was performed externally at the University of Minnesotas Characterization Facility Center, and at the Argonne National Laboratory Advanced Photon Source facility. A micellar diffusion study was conducted internally at Sandia to measure diffusion constants of surfactants over a concentration range, to estimate the effective micelle diameter, to determine the impact of individual components to the micellar environment in solution, and the impact of combined components to surfactant phase behavior. Aerosolized DF-200 sprays were characterized for particle size and distribution and limited chemical composition. Evaporation rates of aerosolized DF-200 sprays were estimated under a set of baseline ITW nozzle test system parameters.

  20. Enhanced target factor analysis.

    PubMed

    Rostami, Akram; Abdollahi, Hamid; Maeder, Marcel

    2016-03-10

    Target testing or target factor analysis, TFA, is a well-established soft analysis method. TFA answers the question whether an independent target test vector measured at the same wavelengths as the collection of spectra in a data matrix can be excluded as the spectrum of one of the components in the system under investigation. Essentially, TFA cannot positively prove that a particular test spectrum is the true spectrum of one of the components, it can, only reject a spectrum. However, TFA will not reject, or in other words TFA will accept, many spectra which cannot be component spectra. Enhanced Target Factor Analysis, ETFA addresses the above problem. Compared with traditional TFA, ETFA results in a significantly narrower range of positive results, i.e. the chance of a false positive test result is dramatically reduced. ETFA is based on feasibility testing as described in Refs. [16-19]. The method has been tested and validated with computer generated and real data sets.

  1. Enhanced membrane gas separations

    SciTech Connect

    Prasad, R.

    1993-07-13

    An improved membrane gas separation process is described comprising: (a) passing a feed gas stream to the non-permeate side of a membrane system adapted for the passage of purge gas on the permeate side thereof, and for the passage of the feed gas stream in a counter current flow pattern relative to the flow of purge gas on the permeate side thereof, said membrane system being capable of selectively permeating a fast permeating component from said feed gas, at a feed gas pressure at or above atmospheric pressure; (b) passing purge gas to the permeate side of the membrane system in counter current flow to the flow of said feed gas stream in order to facilitate carrying away of said fast permeating component from the surface of the membrane and maintaining the driving force for removal of the fast permeating component through the membrane from the feed gas stream, said permeate side of the membrane being maintained at a subatmospheric pressure within the range of from about 0.1 to about 5 psia by vacuum pump means; (c) recovering a product gas stream from the non-permeate side of the membrane; and (d) discharging purge gas and the fast permeating component that has permeated the membrane from the permeate side of the membrane, whereby the vacuum conditions maintained on the permeate side of the membrane by said vacuum pump means enhance the efficiency of the gas separation operation, thereby reducing the overall energy requirements thereof.

  2. Enhancing chemical reactions

    DOEpatents

    Morrey, John R.

    1978-01-01

    Methods of enhancing selected chemical reactions. The population of a selected high vibrational energy state of a reactant molecule is increased substantially above its population at thermal equilibrium by directing onto the molecule a beam of radiant energy from a laser having a combination of frequency and intensity selected to pump the selected energy state, and the reaction is carried out with the temperature, pressure, and concentrations of reactants maintained at a combination of values selected to optimize the reaction in preference to thermal degradation by transforming the absorbed energy into translational motion. The reaction temperature is selected to optimize the reaction. Typically a laser and a frequency doubler emit radiant energy at frequencies of .nu. and 2.nu. into an optical dye within an optical cavity capable of being tuned to a wanted frequency .delta. or a parametric oscillator comprising a non-centrosymmetric crystal having two indices of refraction, to emit radiant energy at the frequencies of .nu., 2.nu., and .delta. (and, with a parametric oscillator, also at 2.nu.-.delta.). Each unwanted frequency is filtered out, and each desired frequency is focused to the desired radiation flux within a reaction chamber and is reflected repeatedly through the chamber while reactants are fed into the chamber and reaction products are removed therefrom.

  3. Waste water filtration enhancement

    SciTech Connect

    Martin, H.L.

    1989-01-01

    Removal of submicron particles from process solutions and waste water is now economically achievable using a new Tyvek{reg sign} media in conventional filtration equipment. This new product greatly enhances filtration and allows use of the much improved filter aids and polymers which were recently developed. It has reduced operating costs and ensures a clean effluent discharge to the environment. This significant technical development is especially important to those who discharge to a small stream with low 7Q10 flow and must soon routinely pass the Toxicity tests that are being required by many States for NPDES permit renewal. The Savannah River Plant produces special nuclear materials for the US Government. Aluminum forming and metal finishing operations in M-Area, that manufacture fuel and target assemblies for the nuclear reactors, discharge to a waste water treatment facility using BAT hydroxide precipitation and filtration. The new Tyvek{reg sign} media and filter aids have achieved 55% less solids in the filtrate discharged to Tims Branch Creek, 15% less hazardous waste (dry filter cake), 150%-370% more filtration capacity, 74% lower materials purchase cost, 10% lower total M-Area manufacturing cost, and have improved safety. Performance with the improved polymers is now being evaluated.

  4. Enhancing young people's awareness.

    PubMed

    Doan Thi Tien

    1995-01-01

    The role of the Vietnam Youth Union (21 million members) is to educate the youth aged 14-28 years about the movement at the grassroots level. Since 1995, it has been entrusted with information, education, and communication (IEC) activities (implemented through the Educational Center for Population, Health, and Development) concerning family planning, the environment, human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). Mass media, direct communication, Youth Union leading staff, Youth Union cultural and arts activities, and advertisement have been used. 16 newspapers and magazines, a radio program, and a TV program disseminate information for the group. 1000 motivators' groups, 1370 Youth Clubs, and Youth Villages at the commune level work to enhance awareness and to change biased attitudes and habits. Leading staff speak at conferences and seminars that are attended by target groups. Art troupes perform at special local events; plays are organized and videos are shown. The HIV/AIDS information and prevention campaign is of great importance because research findings indicate that many young people believe that only prostitutes and drug addicts can be infected, and that condoms are bad and only for use with prostitutes. There are about 2300 persons infected with HIV in 14 provinces, mostly in the south and central regions. 131 are reported to have developed AIDS. PMID:12320323

  5. Enhanced local tomography

    DOEpatents

    Katsevich, Alexander J.; Ramm, Alexander G.

    1996-01-01

    Local tomography is enhanced to determine the location and value of a discontinuity between a first internal density of an object and a second density of a region within the object. A beam of radiation is directed in a predetermined pattern through the region of the object containing the discontinuity. Relative attenuation data of the beam is determined within the predetermined pattern having a first data component that includes attenuation data through the region. In a first method for evaluating the value of the discontinuity, the relative attenuation data is inputted to a local tomography function .function..sub..LAMBDA. to define the location S of the density discontinuity. The asymptotic behavior of .function..sub..LAMBDA. is determined in a neighborhood of S, and the value for the discontinuity is estimated from the asymptotic behavior of .function..sub..LAMBDA.. In a second method for evaluating the value of the discontinuity, a gradient value for a mollified local tomography function .gradient..function..sub..LAMBDA..epsilon. (x.sub.ij) is determined along the discontinuity; and the value of the jump of the density across the discontinuity curve (or surface) S is estimated from the gradient values.

  6. Backside configured surface plasmonic enhancement

    SciTech Connect

    Gu, Guiru; Lu, Xuejun; Vaillancourt, Jarrod

    2014-03-31

    In this work, we fabricated, measured and compared the quantum dots infrared photodetector enhancement by the top- and backside- configured plasmonic structures. The backside configured plasmonic structure can provide much higher device performance enhancement. Furthermore, the excitation of the surface plasmonic waves by the top- and backside- configured plasmonic structures was analyzed. Detailed simulation results of the electric field at different wavelength from top illumination and backside illumination were provided. The stronger electric field from the backside illumination attributed to the higher enhancement.

  7. Cognitive Enhancement: Treating or Cheating?

    PubMed

    Whetstine, Leslie M

    2015-09-01

    In this article I provide an overview of the moral and medical questions surrounding the use of cognitive enhancers. This discussion will be framed in light of 4 key considerations: (1) is there a difference between therapy and enhancement? (2) How safe are these interventions? (3) Is the use of nootropics cheating? (4) Would enhancers create a further divide of social inequality where only the very wealthy have access to them?

  8. Performance-enhancing supplements.

    PubMed

    Pecci, M A; Lombardo, J A

    2000-11-01

    Supplements that are marketed as ergogenic aids have achieved widespread use in the United States. In image-conscious society, these agents are not only being consumed by athletes, but also by those looking for a quick fix to enhance their appearance. Many assume that the performance claims made by the manufacturers are based on actual data, and that these agents must be safe because they are sold to the general public. Unfortunately, in most cases these assumptions are false. Creatine has become very popular, particularly among college and high school athletes. Studies within the last 5 years have shown that creatine does seem to have certain ergogenic benefits in a laboratory setting. It is not currently known whether these benefits actually can be transferred to the playing field. Although creatine has not consistently been shown to cause any major side effects, there is some question regarding creatine's effect on the kidneys, particularly with long-term use. Also, the safety of supplementation in children and adolescents has not been examined at all; its use in this population should be discouraged until there are more data. Androstenedione is an agent that has received a large amount of popular press in the last year, and this has led to an surge in its usage. It is believed to exert its ergogenic effects through conversion to testosterone. But what limited data are available suggest that at the recommended dosage, it does not cause any measurable change in testosterone levels, or provide any ergogenic benefit in inexperienced weight lifters. Also, it has yet to be determined whether androstenedione causes any of the side effects often attributed to use of the illegal anabolic steroids. Its mechanism of action suggests it has the potential to cause many of these negative effects. Studies are just beginning to appear in the literature, and certainly more data need to be gathered before androstenedione supplementation can be recommended for use as an ergogenic

  9. Lignite Fuel Enhancement

    SciTech Connect

    Charles Bullinger

    2007-03-31

    This 11th quarterly Technical Progress Report for the Lignite Fuel Enhancement Project summarizes activities from January 1st through March 31st of 2007. It summarizes the completion of the Prototype testing activity and initial full-scale dryer design, Budget Period 2 activity during that time period. The Design Team completed process design and layouts of air, water, and coal systems. Heyl-Patterson completed dryer drawings and has sent RFPs to several fabricators for build and assembly. Several meetings were held with Barr engineers to finalize arrangement of the drying, air jig, and coal handling systems. Honeywell held meetings do discuss the control system logic and hardware location. By the end of March we had processed nearly 300,000 tons of lignite through the dryer. Outage preparation maintenance activities on a coal transfer hopper restricted operation of the dryer in February and March. The Outage began March 17th. We will not dry coal again until early May when the Outage on Unit No.2 completes. The Budget Period 1 (Phase 1) final report was submitted this quarter. Comments were received from NETL and are being reviewed. The Phase 2 Project Management Plan was submitted to NETL in January 2007. This deliverable also included the Financing Plan. An application for R&D 100 award was submitted in February. The project received an award from the Minnesota Professional Engineering Society's Seven Wonders of Engineering Award and Minnesota ACEC Grand Award in January. To further summarize, the focus this quarter has been on finalizing commercial design and the layout of four dryers behind each Unit. The modification to the coal handling facilities at Coal Creek and incorporation of air jigs to further beneficiate the segregated material the dryers will reject 20 to 30 % of the mercury and sulfur is segregated however this modification will recover the carbon in that stream.

  10. Enhancers, enhancers - from their discovery to today's universe of transcription enhancers.

    PubMed

    Schaffner, Walter

    2015-04-01

    Transcriptional enhancers are short (200-1500 base pairs) DNA segments that are able to dramatically boost transcription from the promoter of a target gene. Originally discovered in simian virus 40 (SV40), a small DNA virus, transcription enhancers were soon also found in immunoglobulin genes and other cellular genes as key determinants of cell-type-specific gene expression. Enhancers can exert their effect over long distances of thousands, even hundreds of thousands of base pairs, either from upstream, downstream, or from within a transcription unit. The number of enhancers in eukaryotic genomes correlates with the complexity of the organism; a typical mammalian gene is likely controlled by several enhancers to fine-tune its expression at different developmental stages, in different cell types and in response to different signaling cues. Here, I provide a personal account of how enhancers were discovered more than 30 years ago, and also address the amazing development of the field since then.

  11. Plasmon Enhanced Photoemission

    SciTech Connect

    Polyakov, Aleksandr

    2012-05-08

    this work, the structure consisted of rectangular nano-grooves (NGs) arranged in a subwavelength grating on a metal surface is presented that provides a dramatic increase in the metal’s absorption, field localization, and field enhancement. When light is polarized perpendicular to the orientation of the grooves a standing SPP wave is excited along the vertical walls in the NGs, that act as Fabry-Perot resonators. By adjusting the geometry of the NGs and the period of the subwavelength grating the resonance can be fine tuned to a desired position, for example, the laser fundamental wavelength, anywhere from the UV to the near infrared (NIR). Two types of gratings are presented: (a) a gold grating with period of 600 nm, and (b) an aluminum-gold grating with a period of 100 nm; both with resonance at 720 nm. In each case, strong on-resonance absorption was observed, with over 98% for grating (b). Unlike the grating-coupled SPP waves, where the angle is well defined by the momentum matching condition, the resonant NGs allow coupling to the standing modes at a range of angles of incidence, referred to as the angular bandwidth. A new model for the on-resonance absorption based on the ensamble action of the NGs is presented that serves as the basis for a design of an NG grating with an ultrawide spectral as well as angular bandwidth. For sample (b), the angular bandwidth is 80 degrees, corresponding to an opening angle of 160 degrees. The photoemission enhancement for such a grating was measured to be seven orders of magnitude for a four-photon photoemission. This is an incredible result demonstrating the power of the plasmonic grating presented, which is an efficient light trapper and field enhancer for a non-linear processes. These results demonstrate that the metal photocathode prepared with a NG grating on the metal surface will provide sufficient pulse charge driven by a 1 μJ 15fs pulsed laser at 800 nm for the optimum FEL operation.

  12. Enhancing Motivation in Physical Education

    ERIC Educational Resources Information Center

    Alderman, Brandon L.; Beighle, Aaron; Pangrazi, Robert P.

    2006-01-01

    Increasing motivation towards physical activity through quality physical education has recently gained considerable attention. Several investigators have outlined specific models or theories to illustrate how motivation can be enhanced in physical education. Enhancing a youngster's perceived physical competence, promoting intrinsic motivation…

  13. Enhancing Self Esteem. Second Edition.

    ERIC Educational Resources Information Center

    Frey, Diane; Carlock, C. Jesse

    This book takes the theory of self-esteem and translates that theory into practice. It presents a systematic approach to enhancing self-esteem, suggesting a specific sequence and phase-wise progression of enhancing self-esteem. Cognitive, emotional, and behavioral aspects of individuals are all incorporated into the theory and practice outlined in…

  14. Performance-enhancing drug use.

    PubMed

    Green, Gary A

    2009-09-01

    According to Gary Green, MD, everyone who deals with athletes is a "stakeholder" in the issue of performance-enhancing drugs and can influence athletes in a positive or negative role. In this issue of ORTHOPEDICS, Dr Green shares his thoughts on testing, prevention, and education of performance-enhancing drug use.

  15. Resolution Enhancement of Multilook Imagery

    SciTech Connect

    Galbraith, Amy E.

    2004-07-01

    This dissertation studies the feasibility of enhancing the spatial resolution of multi-look remotely-sensed imagery using an iterative resolution enhancement algorithm known as Projection Onto Convex Sets (POCS). A multi-angle satellite image modeling tool is implemented, and simulated multi-look imagery is formed to test the resolution enhancement algorithm. Experiments are done to determine the optimal con guration and number of multi-angle low-resolution images needed for a quantitative improvement in the spatial resolution of the high-resolution estimate. The important topic of aliasing is examined in the context of the POCS resolution enhancement algorithm performance. In addition, the extension of the method to multispectral sensor images is discussed and an example is shown using multispectral confocal fluorescence imaging microscope data. Finally, the remote sensing issues of atmospheric path radiance and directional reflectance variations are explored to determine their effect on the resolution enhancement performance.

  16. The Misfortunes of Moral Enhancement.

    PubMed

    Azevedo, Marco Antonio

    2016-10-01

    In Unfit for the Future, Ingmar Persson and Julian Savulescu present a sophisticated argument in defense of the imperative of moral enhancement. They claim that without moral enhancement, the future of humanity is seriously compromised. The possibility of ultimate harm, caused by a dreadful terrorist attack or by a final unpreventable escalation of the present environmental crisis aggravated by the availability of cognitive enhancement, makes moral enhancement a top priority. It may be considered optimistic to think that our present moral capabilities can be successfully improved by means of moral education, moral persuasion, and fear of punishment. So, without moral enhancement, drastic restrictions on human freedom would become the only alternative to prevent those dramatic potential outcomes. In this article, I will try to show that we still have reason to be less pessimistic and that Persson & Savulescu's arguments are fortunately unconvincing.

  17. The Misfortunes of Moral Enhancement.

    PubMed

    Azevedo, Marco Antonio

    2016-10-01

    In Unfit for the Future, Ingmar Persson and Julian Savulescu present a sophisticated argument in defense of the imperative of moral enhancement. They claim that without moral enhancement, the future of humanity is seriously compromised. The possibility of ultimate harm, caused by a dreadful terrorist attack or by a final unpreventable escalation of the present environmental crisis aggravated by the availability of cognitive enhancement, makes moral enhancement a top priority. It may be considered optimistic to think that our present moral capabilities can be successfully improved by means of moral education, moral persuasion, and fear of punishment. So, without moral enhancement, drastic restrictions on human freedom would become the only alternative to prevent those dramatic potential outcomes. In this article, I will try to show that we still have reason to be less pessimistic and that Persson & Savulescu's arguments are fortunately unconvincing. PMID:27473409

  18. Lignite Fuel Enhancement

    SciTech Connect

    Charles Bullinger

    2006-04-03

    This 7th quarterly Technical Progress Report for the Lignite Fuel Enhancement Project summarizes activities from January 1st through March 31st of 2006. It also summarizes the subsequent purchasing activity, dryer/process construction, and testing. The Design Team began conferencing again as construction completed and the testing program began. Primary focus this quarter was construction/installation completion. Phase 1 extension recommendation, and subsequent new project estimate, Forms 424 and 4600 were accepted by DOE headquarters. DOE will complete the application and amended contract. All major mechanical equipment was run, checked out, and tested this quarter. All water, air, and coal flow loops were run and tested. The system was run on January 30th, shut down to adjust equipment timing in the control system on the 31st, and run to 75 ton//hour on February 1st. It ran for seven to eight hours per day until March 20th when ''pairs'' testing ( 24 hour running) began. ''Pairs'' involves comparative testing of unit performance with seven ''wet'' pulverizers versus six ''wet'' and one ''dry''. During the interim, more operators were brought up to speed on system operation and control was shifted to the main Unit No.2 Control Room. The system is run now from the Unit control board operator and an equipment operator checks the system during regular rounds or when an alarm needs verification. The flawless start-up is unprecedented in the industry and credit should be made to the diligence and tenacity of Coal Creek maintenance/checkout staff. Great River Energy and Headwaters did not meet to discuss the Commercialization Plan this quarter. The next meeting is pending data from the drying system. Discussions with Basin Electric, Otter Tail, and Dairyland continue and confidentiality secured as we promote dryers in their stations. Lighting and fire protection were completed in January. Invoices No.12 through No.20 are completed and forwarded following preliminary

  19. Enhanced Elliptic Grid Generation

    NASA Technical Reports Server (NTRS)

    Kaul, Upender K.

    2007-01-01

    An enhanced method of elliptic grid generation has been invented. Whereas prior methods require user input of certain grid parameters, this method provides for these parameters to be determined automatically. "Elliptic grid generation" signifies generation of generalized curvilinear coordinate grids through solution of elliptic partial differential equations (PDEs). Usually, such grids are fitted to bounding bodies and used in numerical solution of other PDEs like those of fluid flow, heat flow, and electromagnetics. Such a grid is smooth and has continuous first and second derivatives (and possibly also continuous higher-order derivatives), grid lines are appropriately stretched or clustered, and grid lines are orthogonal or nearly so over most of the grid domain. The source terms in the grid-generating PDEs (hereafter called "defining" PDEs) make it possible for the grid to satisfy requirements for clustering and orthogonality properties in the vicinity of specific surfaces in three dimensions or in the vicinity of specific lines in two dimensions. The grid parameters in question are decay parameters that appear in the source terms of the inhomogeneous defining PDEs. The decay parameters are characteristic lengths in exponential- decay factors that express how the influences of the boundaries decrease with distance from the boundaries. These terms govern the rates at which distance between adjacent grid lines change with distance from nearby boundaries. Heretofore, users have arbitrarily specified decay parameters. However, the characteristic lengths are coupled with the strengths of the source terms, such that arbitrary specification could lead to conflicts among parameter values. Moreover, the manual insertion of decay parameters is cumbersome for static grids and infeasible for dynamically changing grids. In the present method, manual insertion and user specification of decay parameters are neither required nor allowed. Instead, the decay parameters are

  20. Utilizing scattering to further enhance integrating cavity-enhanced spectroscopy

    NASA Astrophysics Data System (ADS)

    Bixler, Joel N.; Winkler, Chase A.; Hokr, Brett H.; Mason, John D.; Yakovlev, Vladislav V.

    2016-01-01

    Spectroscopic optical characterization and identification of molecular structures and complex systems would greatly benefit from new technologies capable of analyzing molecular species in small quantities with maximum sensitivity and specificity. Integrating cavity-enhanced spectroscopy has recently been shown as a viable tool for achieving this goal. This technique could greatly benefit from methods for further enhancing the desired spectroscopic signal, allowing for lower detection limits. Here, we present a simple method to further enhance fluorescence signal generated inside an integrating cavity by introducing additional scattering to the sample of interest.

  1. Environmental engineering education enhancement

    NASA Astrophysics Data System (ADS)

    Caporali, E.

    2012-04-01

    Since higher education plays a central role in the development of both human beings and modern societies, enhancing social, cultural and economic development, active citizenship, ethical values and expertises for a sustainable growth, environment respectful, the European Commission promotes a wide range of programmes. Among the EC programmes, the TEMPUS - Trans European Mobility Programme for University Studies, with the support of the DG EAC of the European Commission, has contributed to many aspects of general interest for higher education. Curricula harmonization, LifeLong Learning Programme development, ICT use, quality assessment, accreditation, innovation learning methods, growth of networks of institutions trusting each other, are the focused aspects. Such a solid cooperation framework is surely among the main outcomes of the TEMPUS Projects leaded by the University of Firenze UNIFI (Italy), DEREC - Development of Environment and Resources Engineering Curriculum (2005-2008), and its spin-off DEREL - Development of Environment and Resources Engineering Learning (2010-2013), and VICES - Videoconferencing Educational Services (2009-2012). DEREC and DEREL TEMPUS projects, through the co-operation of Universities in Italy, Austria, Germany, Greece, Macedonia, Albania and Serbia, are aimed at the development of first and second level curricula in "Environment and Resources Engineering" at the Ss. Cyril and Methodius University - UKIM Skopje (MK). In the DEREC Project the conditions for offering a joint degree title in the field of Environmental Engineering between UNIFI and UKIM Skopje were fulfilled and a shared educational programme leading to the mutual recognition of degree titles was defined. The DEREL project, as logical continuation of DEREC, is aimed to introduce a new, up-to-date, postgraduate second level curriculum in Environment and Resources Engineering at UKIM Skopje, University of Novi Sad (RS) and Polytechnic University of Tirana (AL). following

  2. Excitation enhancement and extraction enhancement with photonic crystals

    SciTech Connect

    Shapira, Ofer; Soljacic, Marin; Zhen, Bo; Chua, Song-Liang; Lee, Jeongwon; Joannopoulos, John

    2015-03-03

    Disclosed herein is a system for stimulating emission from at least one an emitter, such as a quantum dot or organic molecule, on the surface of a photonic crystal comprising a patterned dielectric substrate. Embodiments of this system include a laser or other source that illuminates the emitter and the photonic crystal, which is characterized by an energy band structure exhibiting a Fano resonance, from a first angle so as to stimulate the emission from the emitter at a second angle. The coupling between the photonic crystal and the emitter may result in spectral and angular enhancement of the emission through excitation and extraction enhancement. These enhancement mechanisms also reduce the emitter's lasing threshold. For instance, these enhancement mechanisms enable lasing of a 100 nm thick layer of diluted organic molecules solution with reduced threshold intensity. This reduction in lasing threshold enables more efficient organic light emitting devices and more sensitive molecular sensing.

  3. Resolution enhancement in tilted coordinates

    NASA Astrophysics Data System (ADS)

    Hariri Naghadeh, Diako; Keith Morley, Christopher

    2016-11-01

    Deconvolution is applied to remove source wavelet effects from seismograms. The results are resolution enhancement that enables detection of thin layers. Following enhancement of resolution, low frequency and high angle reflectors, particularly at great depth, appear as low amplitude and semi-invisible reflectors that are difficult to track and pick. A new approach to enhance resolution is introduced that estimates a derivative using continuous wavelet transform in tilted coordinates. The results are compared with sparse spike deconvolution, curvelet deconvolution and inverse quality filtering in wavelet domain. The positive consequence of the new method is to increase sampling of high dip features by changing the coordinate system from Cartesian to tilted. To compare those methods a complex data set was chosen that includes high angle faults and chaotic mass transport complex. Image enhancement using curvelet deconvolution shows a chaotic system as a non-chaotic one. The results show that sparse spike deconvolution and inverse quality filtering in wavelet domain are able to enhance resolution more than curvelet deconvolution especially at great depth but it is impossible to follow steep dip reflectors after resolution enhancement using these methods, especially when their apparent dips are more than 45°. By estimating derivatives in a continuous wavelet transform from tilted data sets similar resolution enhancement as the other deconvolution methods is achieved but additionally steep dipping reflectors are imaged much better than others. Subtracted results of the enhanced resolution data set using new method and the other introduced methods show that steeply dipping reflectors are highlighted as a particular ability of the new method. The results show that high frequency recovery in Cartesian co-ordinate is accompanied by inability to image steeply dipping reflectors especially at great depths. Conversely recovery of high frequency data and imaging of the data

  4. WEATHERABILITY OF ENHANCED DEGRADABLE PLASTICS

    EPA Science Inventory

    The main objective of this study was to assess the performance and the asociated variability of several selected enhanced degradable plastic materials under a variety of different exposure conditions. Other objectives were to identify the major products formed during degradation ...

  5. Geothermal Permeability Enhancement - Final Report

    SciTech Connect

    Joe Beall; Mark Walters

    2009-06-30

    The overall objective is to apply known permeability enhancement techniques to reduce the number of wells needed and demonstrate the applicability of the techniques to other undeveloped or under-developed fields. The Enhanced Geothermal System (EGS) concept presented in this project enhances energy extraction from reduced permeability zones in the super-heated, vapor-dominated Aidlin Field of the The Geysers geothermal reservoir. Numerous geothermal reservoirs worldwide, over a wide temperature range, contain zones of low permeability which limit the development potential and the efficient recovery of heat from these reservoirs. Low permeability results from poorly connected fractures or the lack of fractures. The Enhanced Geothermal System concept presented here expands these technologies by applying and evaluating them in a systematic, integrated program.

  6. Ultrasonic enhancement of battery diffusion.

    PubMed

    Hilton, R; Dornbusch, D; Branson, K; Tekeei, A; Suppes, G J

    2014-03-01

    It has been demonstrated that sonic energy can be harnessed to enhance convection in Galvanic cells during cyclic voltammetry; however, the practical value of this approach is limited due to the lack of open volumes for convection patterns to develop in most batteries. This study evaluates the ability of ultrasonic waves to enhance diffusion in membrane separators commonly used in sandwich-architecture batteries. Studies include the measuring of open-circuit performance curves to interpret performances in terms of reductions in concentration overpotentials. The use of a 40 kHz sonicator bath can consistently increase the voltage of the battery and reduce overpotential losses up to 30%. This work demonstrates and quantifies battery enhancement due to enhanced diffusion made possible with ultrasonic energy.

  7. Platelets enhance neutrophil transendothelial migration

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Platelets are increasingly recognized as important mediators of inflammation in addition to thrombosis. While platelets have been shown to promote neutrophil (PMN) adhesion to endothelium in various inflammatory models, it is unclear whether platelets enhance neutrophil transmigration across inflame...

  8. IN SITU ENHANCED SOURCE REMOVAL

    EPA Science Inventory

    This html report describes and compares the performance of in situ technologies designed to accelerate the removal of organic contaminants from unconsolidated soils and aquifers. The research was conducted through the Enhanced Source Removal (ESR) Program within the Subsurface Pr...

  9. Moderate eugenics and human enhancement.

    PubMed

    Selgelid, Michael J

    2014-02-01

    Though the reputation of eugenics has been tarnished by history, eugenics per se is not necessarily a bad thing. Many advocate a liberal new eugenics--where individuals are free to choose whether or not to employ genetic technologies for reproductive purposes. Though genetic interventions aimed at the prevention of severe genetic disorders may be morally and socially acceptable, reproductive liberty in the context of enhancement may conflict with equality. Enhancement could also have adverse effects on utility. The enhancement debate requires a shift in focus. What the equality and/or utility costs of enhancement will be is an empirical question. Rather than philosophical speculation, more social science research is needed to address it. Philosophers, meanwhile, should address head-on the question of how to strike a balance between liberty, equality, and utility in cases of conflict (in the context of genetics).

  10. Cognitive enhancers for anxiety disorders.

    PubMed

    Hofmann, Stefan G; Smits, Jasper A J; Asnaani, Anu; Gutner, Cassidy A; Otto, Michael W

    2011-08-01

    Cognitive-behavioral therapy is an effective intervention for anxiety disorders. However, a significant number of people do not respond or only show partial response even after an adequate course of the treatment. Recent research has shown that the efficacy of the intervention can be improved by the use of cognitive enhancers that augment the core learning processes of cognitive-behavior therapy. This manuscript provides a review of the current state of cognitive enhancers for the treatment of anxiety disorders.

  11. Chemically enhanced in situ recovery

    SciTech Connect

    Sale, T.; Pitts, M.; Wyatt, K.

    1996-08-01

    Chemically enhanced recovery is a promising alternative to current technologies for management of subsurface releases of organic liquids. Through the inclusion of surfactants, solvents, polymers, and/or alkaline agents to a waterflood, the transport of targeted organic compounds can be increased and rates of recovery enhanced. By far, the vast majority of work done in the field of chemically enhanced recovery has been at a laboratory scale. The following text focuses on chemically enhanced recovery from a field application perspective with emphasis given to chlorinated solvents in a low permeability setting. While chlorinated solvents are emphasized, issues discussed are also relevant to organic liquids less dense than water such as petroleum products. Topics reviewed include: (1) Description of technology; (2) General technology considerations; (3) Low permeability media considerations; (4) Cost and reliability considerations; (5) Commercial availability; and (6) Case histories. Through this paper an appreciation is developed of both the potential and limitations of chemically enhanced recovery. Excluded from the scope of this paper is the in situ destruction of organic compounds through processes such as chemical or biological oxidation, chemically enhanced recovery of inorganic compounds, and ex situ soil treatment processes. 11 refs., 2 figs., 1 tab.

  12. Moral enhancement requires multiple virtues.

    PubMed

    Hughes, James J

    2015-01-01

    Some of the debates around the concept of moral enhancement have focused on whether the improvement of a single trait, such as empathy or intelligence, would be a good in general, or in all circumstances. All virtue theories, however, both secular and religious, have articulated multiple virtues that temper and inform one another in the development of a mature moral character. The project of moral enhancement requires a reengagement with virtue ethics and contemporary moral psychology to develop an empirically grounded model of the virtues and a fuller model of character development. Each of these virtues may be manipulable with electronic, psychopharmaceutical, and genetic interventions. A set of interdependent virtues is proposed, along with some of the research pointing to ways such virtues could be enhanced.

  13. Sexual dimorphism and human enhancement.

    PubMed

    Casal, Paula

    2013-12-01

    Robert Sparrow argues that because of women's longer life expectancy philosophers who advocate the genetic modification of human beings to enhance welfare rather than merely supply therapy are committed to favouring the selection of only female embryos, an implication he deems sufficiently implausible to discredit their position. If Sparrow's argument succeeds, then philosophers who advocate biomedical moral enhancement also seem vulnerable to a similar charge because of men's greater propensity for various forms of harmful wrongdoing. This paper argues there are various flaws in Sparrow's argument that render it unsuccessful. The paper also examines whether dimorphism reduction is a more desirable outcome than male elimination, thereby further illustrating the difficulties besetting the distinction between therapy and enhancement.

  14. Moral enhancement requires multiple virtues.

    PubMed

    Hughes, James J

    2015-01-01

    Some of the debates around the concept of moral enhancement have focused on whether the improvement of a single trait, such as empathy or intelligence, would be a good in general, or in all circumstances. All virtue theories, however, both secular and religious, have articulated multiple virtues that temper and inform one another in the development of a mature moral character. The project of moral enhancement requires a reengagement with virtue ethics and contemporary moral psychology to develop an empirically grounded model of the virtues and a fuller model of character development. Each of these virtues may be manipulable with electronic, psychopharmaceutical, and genetic interventions. A set of interdependent virtues is proposed, along with some of the research pointing to ways such virtues could be enhanced. PMID:25473861

  15. Piezoelectric enhancement under negative pressure

    PubMed Central

    Kvasov, Alexander; McGilly, Leo J.; Wang, Jin; Shi, Zhiyong; Sandu, Cosmin S.; Sluka, Tomas; Tagantsev, Alexander K.; Setter, Nava

    2016-01-01

    Enhancement of ferroelectric properties, both spontaneous polarization and Curie temperature under negative pressure had been predicted in the past from first principles and recently confirmed experimentally. In contrast, piezoelectric properties are expected to increase by positive pressure, through polarization rotation. Here we investigate the piezoelectric response of the classical PbTiO3, Pb(Zr,Ti)O3 and BaTiO3 perovskite ferroelectrics under negative pressure from first principles and find significant enhancement. Piezoelectric response is then tested experimentally on free-standing PbTiO3 and Pb(Zr,Ti)O3 nanowires under self-sustained negative pressure, confirming the theoretical prediction. Numerical simulations verify that negative pressure in nanowires is the origin of the enhanced electromechanical properties. The results may be useful in the development of highly performing piezoelectrics, including lead-free ones. PMID:27396411

  16. Piezoelectric enhancement under negative pressure.

    PubMed

    Kvasov, Alexander; McGilly, Leo J; Wang, Jin; Shi, Zhiyong; Sandu, Cosmin S; Sluka, Tomas; Tagantsev, Alexander K; Setter, Nava

    2016-01-01

    Enhancement of ferroelectric properties, both spontaneous polarization and Curie temperature under negative pressure had been predicted in the past from first principles and recently confirmed experimentally. In contrast, piezoelectric properties are expected to increase by positive pressure, through polarization rotation. Here we investigate the piezoelectric response of the classical PbTiO3, Pb(Zr,Ti)O3 and BaTiO3 perovskite ferroelectrics under negative pressure from first principles and find significant enhancement. Piezoelectric response is then tested experimentally on free-standing PbTiO3 and Pb(Zr,Ti)O3 nanowires under self-sustained negative pressure, confirming the theoretical prediction. Numerical simulations verify that negative pressure in nanowires is the origin of the enhanced electromechanical properties. The results may be useful in the development of highly performing piezoelectrics, including lead-free ones. PMID:27396411

  17. Piezoelectric enhancement under negative pressure.

    PubMed

    Kvasov, Alexander; McGilly, Leo J; Wang, Jin; Shi, Zhiyong; Sandu, Cosmin S; Sluka, Tomas; Tagantsev, Alexander K; Setter, Nava

    2016-07-11

    Enhancement of ferroelectric properties, both spontaneous polarization and Curie temperature under negative pressure had been predicted in the past from first principles and recently confirmed experimentally. In contrast, piezoelectric properties are expected to increase by positive pressure, through polarization rotation. Here we investigate the piezoelectric response of the classical PbTiO3, Pb(Zr,Ti)O3 and BaTiO3 perovskite ferroelectrics under negative pressure from first principles and find significant enhancement. Piezoelectric response is then tested experimentally on free-standing PbTiO3 and Pb(Zr,Ti)O3 nanowires under self-sustained negative pressure, confirming the theoretical prediction. Numerical simulations verify that negative pressure in nanowires is the origin of the enhanced electromechanical properties. The results may be useful in the development of highly performing piezoelectrics, including lead-free ones.

  18. Human enhancement: The new eugenics.

    PubMed

    Vizcarrondo, Felipe E

    2014-08-01

    Supporters of human enhancement through genetic and other reproductive technologies claim that the new liberal eugenics, based on science and individual consent differs from the old eugenics which was unscientific and coercive. Supporters claim it is the parent's moral obligation to produce the best children possible. At this time, a defective gene that is identified in an unborn child cannot be repaired. To prevent the manifestation of the undesirable trait the unborn child is destroyed. The arguments in support of human enhancement are based on an ethic of consequence that could allow for nearly any means as long as the desired end is reached. Medical enhancement may affect the parent-child family unit; the parents' love for the child may be conditioned on the expected results. The new eugenics, although based on science, continues to pursue the same goal as the old eugenics, the development of a superior individual and the elimination of those considered inferior.

  19. Piezoelectric enhancement under negative pressure

    NASA Astrophysics Data System (ADS)

    Kvasov, Alexander; McGilly, Leo J.; Wang, Jin; Shi, Zhiyong; Sandu, Cosmin S.; Sluka, Tomas; Tagantsev, Alexander K.; Setter, Nava

    2016-07-01

    Enhancement of ferroelectric properties, both spontaneous polarization and Curie temperature under negative pressure had been predicted in the past from first principles and recently confirmed experimentally. In contrast, piezoelectric properties are expected to increase by positive pressure, through polarization rotation. Here we investigate the piezoelectric response of the classical PbTiO3, Pb(Zr,Ti)O3 and BaTiO3 perovskite ferroelectrics under negative pressure from first principles and find significant enhancement. Piezoelectric response is then tested experimentally on free-standing PbTiO3 and Pb(Zr,Ti)O3 nanowires under self-sustained negative pressure, confirming the theoretical prediction. Numerical simulations verify that negative pressure in nanowires is the origin of the enhanced electromechanical properties. The results may be useful in the development of highly performing piezoelectrics, including lead-free ones.

  20. Human enhancement: The new eugenics

    PubMed Central

    Vizcarrondo, Felipe E.

    2014-01-01

    Supporters of human enhancement through genetic and other reproductive technologies claim that the new liberal eugenics, based on science and individual consent differs from the old eugenics which was unscientific and coercive. Supporters claim it is the parent's moral obligation to produce the best children possible. At this time, a defective gene that is identified in an unborn child cannot be repaired. To prevent the manifestation of the undesirable trait the unborn child is destroyed. The arguments in support of human enhancement are based on an ethic of consequence that could allow for nearly any means as long as the desired end is reached. Medical enhancement may affect the parent–child family unit; the parents’ love for the child may be conditioned on the expected results. The new eugenics, although based on science, continues to pursue the same goal as the old eugenics, the development of a superior individual and the elimination of those considered inferior. PMID:25249705

  1. Directionally enhanced probe for side-illumination Tip enhanced spectroscopy

    NASA Astrophysics Data System (ADS)

    Shen, Hongming; Lu, Guowei; Cao, Zhengmin; He, Yingbo; Cheng, Yuqing; Li, Jiafang; Li, Zhi-Yuan; Gong, Qihuang

    2016-10-01

    We demonstrate a high-performance apertureless near-field probe made of a tapered metal tip with a set of periodic shallow grooves near the apex. The spontaneous emission from a single emitter near the tip is investigated systematically for the side-illumination tip enhanced spectroscopy (TES). In contrast with the bare tapered metal tip in conventional side-illumination TES, the corrugated probe not only enhances strongly local excitation field but also concentrates the emission directivity, which leads to high collection efficiency and signal-to-noise ratio. In particular, we propose an asymmetric TES tip based on two coupling nanorods with different length at the apex to realize unidirectional enhanced emission rate from a single emitter. Interestingly, we find that the radiation pattern is sensitive to the emission wavelength and the emitter positions respective to the apex, which can result in an increase of signal-to-noise ratio by suppressing undesired signal. The proposed asymmetrical corrugated probe opens up a broad range of practical applications, e.g. increasing the detection efficiency of tip enhanced spectroscopy at the single-molecule level.

  2. Plasmon enhancement of luminescence upconversion.

    PubMed

    Park, Wounjhang; Lu, Dawei; Ahn, Sungmo

    2015-05-21

    Frequency conversion has always been an important topic in optics. Nonlinear optics has traditionally focused on frequency conversion based on nonlinear susceptibility but with the recent development of upconversion nanomaterials, luminescence upconversion has begun to receive renewed attention. While upconversion nanomaterials open doors to a wide range of new opportunities, they remain too inefficient for most applications. Incorporating plasmonic nanostructures provides a promising pathway to highly efficient upconversion. Naturally, a plethora of theoretical and experimental studies have been published in recent years, reporting enhancements up to several hundred. It is however difficult to make meaningful comparisons since the plasmonic fields are highly sensitive to the local geometry and excitation condition. Also, many luminescence upconversion processes involve multiple steps via different physical mechanisms and the overall output is often determined by a delicate interplay among them. This review is aimed at offering a comprehensive framework for plasmon enhanced luminescence upconversion. We first present quantum electrodynamics descriptions for all the processes involved in luminescence upconversion, which include absorption, emission, energy transfer and nonradiative transitions. We then present a bird's eye view of published works on plasmon enhanced upconversion, followed by more detailed discussion on comparable classes of nanostructures, the effects of spacer layers and local heating, and the dynamics of the plasmon enhanced upconversion process. Plasmon enhanced upconversion is a challenging and exciting field from the fundamental scientific perspective and also from technological standpoints. It offers an excellent system to study how optical processes are affected by the local photonic environment. This type of research is particularly timely as the plasmonics is placing heavier emphasis on nonlinearity. At the same time, efficient upconversion

  3. Biological enhancement of hydrocarbon extraction

    DOEpatents

    Brigmon, Robin L.; Berry, Christopher J.

    2009-01-06

    A method of microbial enhanced oil recovery for recovering oil from an oil-bearing rock formation is provided. The methodology uses a consortium of bacteria including a mixture of surfactant producing bacteria and non-surfactant enzyme producing bacteria which may release hydrocarbons from bitumen containing sands. The described bioprocess can work with existing petroleum recovery protocols. The consortium microorganisms are also useful for treatment of above oil sands, ground waste tailings, subsurface oil recovery, and similar materials to enhance remediation and/or recovery of additional hydrocarbons from the materials.

  4. Power enhanced frequency conversion system

    NASA Technical Reports Server (NTRS)

    Sanders, Steven (Inventor); Lang, Robert J. (Inventor); Waarts, Robert G. (Inventor)

    2001-01-01

    A frequency conversion system includes at least one source providing a first near-IR wavelength output including a gain medium for providing high power amplification, such as double clad fiber amplifier, a double clad fiber laser or a semiconductor tapered amplifier to enhance the power output level of the near-IR wavelength output. The NFM device may be a difference frequency mixing (DFM) device or an optical parametric oscillation (OPO) device. Pump powers are gain enhanced by the addition of a rare earth amplifier or oscillator, or a Ra-man/Brillouin amplifier or oscillator between the high power source and the NFM device.

  5. Enhanced coagulation for arsenic removal

    SciTech Connect

    Cheng, R.C.; Liang, S.; Wang, H.C.; Beuhler, M.D. )

    1994-09-01

    The possible use of enhanced coagulation for arsenic removal was examined at the facilities of a California utility in 1992 and 1993. The tests were conducted at bench, pilot, and demonstration scales, with two source waters. Alum and ferric chloride, with cationic polymer, were investigated at various influence arsenic concentrations. The investigators concluded that for the source waters tested, enhanced coagulation could be effective for arsenic removal and that less ferric chloride than alum, on a weight basis, is needed to achieve the same removal.

  6. Plasmon-enhanced UV photocatalysis

    SciTech Connect

    Honda, Mitsuhiro; Saito, Yuika Kawata, Satoshi; Kumamoto, Yasuaki; Taguchi, Atsushi

    2014-02-10

    We report plasmonic nanoparticle enhanced photocatalysis on titanium dioxide (TiO{sub 2}) in the deep-UV range. Aluminum (Al) nanoparticles fabricated on TiO{sub 2} film increases the reaction rate of photocatalysis by factors as high as 14 under UV irradiation in the range of 260–340 nm. The reaction efficiency has been determined by measuring the decolorization rate of methylene blue applied on the TiO{sub 2} substrate. The enhancement of photocatalysis shows particle size and excitation wavelength dependence, which can be explained by the surface plasmon resonance of Al nanoparticles.

  7. Sorption enhanced CO2 methanation.

    PubMed

    Borgschulte, Andreas; Gallandat, Noris; Probst, Benjamin; Suter, Riccardo; Callini, Elsa; Ferri, Davide; Arroyo, Yadira; Erni, Rolf; Geerlings, Hans; Züttel, Andreas

    2013-06-28

    The transformation from the fatuous consumption of fossil energy towards a sustainable energy circle is most easily marketable by not changing the underlying energy carrier but generating it from renewable energy. Hydrocarbons can be principally produced from renewable hydrogen and carbon dioxide collected by biomass. However, research is needed to increase the energetic and economic efficiency of the process. We demonstrate the enhancement of CO2 methanation by sorption enhanced catalysis. The preparation and catalytic activity of sorption catalysts based on Ni particles in zeolites is reported. The functioning of the sorption catalysis is discussed together with the determination of the reaction mechanism, providing implications for new ways in catalysis. PMID:23673365

  8. Enhanced image capture through fusion

    NASA Technical Reports Server (NTRS)

    Burt, Peter J.; Hanna, Keith; Kolczynski, Raymond J.

    1993-01-01

    Image fusion may be used to combine images from different sensors, such as IR and visible cameras, to obtain a single composite with extended information content. Fusion may also be used to combine multiple images from a given sensor to form a composite image in which information of interest is enhanced. We present a general method for performing image fusion and show that this method is effective for diverse fusion applications. We suggest that fusion may provide a powerful tool for enhanced image capture with broad utility in image processing and computer vision.

  9. Temporal resolution enhancement from motion

    NASA Astrophysics Data System (ADS)

    Rollason, M. P.; Watson, G. H.; Strens, M. J. A.

    2009-09-01

    We describe progress in the third year of the EMRS DTC TEP theme project entitled "Temporal Resolution Enhancement from Motion". The aim is to develop algorithms that combine evidence over time from a sequence of images in order to improve spatial resolution and reduce unwanted artefacts. Years one and two of this project developed and demonstrated an efficient algorithm that provided good resolution enhancement of a scene viewed in the far field (approximately flat) [1]. This paper reports a new algorithm which is applicable to a three dimensional scene where substantial depth variation causes parallax within the imagery. The new algorithm is demonstrated using airborne infra-red imagery.

  10. Lift enhancement in flying snakes

    NASA Astrophysics Data System (ADS)

    Krishnan, Anush; Socha, John; Vlachos, Pavlos; Barba, Lorena

    2013-11-01

    Flying snakes use a unique method of aerial locomotion: they jump from tree branches, flatten their bodies and undulate through the air to produce a glide. The shape of their body cross-section during the glide plays an important role in generating lift. We present a computational investigation of the aerodynamics of the cross-sectional shape. We performed two-dimensional simulations of incompressible flow past the anatomically correct cross-section of the species Chrysopelea paradisi, which show that a significant enhancement in lift appears at an angle of attack of 35 degrees, for Reynolds numbers 2000 and above. Previous experiments on physical models also demonstrated an increased lift and at the same angle of attack. The simulations point to the lift enhancement arising from the early separation of the boundary layer on the dorsal surface of the snake profile, without stall. The separated shear layer rolls up and interacts with secondary vorticity in the near-wake, inducing the primary vortex to remain closer to the body and thus cause enhanced suction, resulting in higher lift. In physical experiments, the flow is inherently 3-D due to fluid instabilities, and it is intriguing that the enhanced lift also appears in the two-dimensional simulations.

  11. Communication Enhancement: Principles and Practices.

    ERIC Educational Resources Information Center

    Shane, Howard

    1988-01-01

    A physician discusses the work of the Communications Enhancement Clinic at Children's Hospital-Boston in providing assistance to children with severe speech problems. He describes the process of evaluating and matching a child's strengths and weaknesses to available technology, including educational software, speech or print output devices, and…

  12. Managing to enhance soil health

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Healthy soils are critical for meeting current and future societal demands. Management strategies that protect the soil against erosion, build soil organic matter and promote nutrient cycling are ways to enhance soil health. Keeping soils covered and judicious use of agrochemicals are akin to us “hu...

  13. Engage, Enhance, and Extend Learning!

    ERIC Educational Resources Information Center

    Keren-Kolb, Liz

    2013-01-01

    Educators often say that technology is more than a gimmick or add-on, and that it should engage, enhance, or extend learning in ways that traditional tools do not. Yet they seldom stop to define these terms, and they can be confusing, especially for teachers and preservice teachers. Recently, while collaborating on an English language arts and…

  14. 10 Suggestions for Enhancing Lecturing

    ERIC Educational Resources Information Center

    Heitzmann, Ray

    2010-01-01

    Criticism of the lecture method remains a staple of discussion and writing in academia--and most of the time it's deserved! Those interested in improving this aspect of their teaching might wish to consider some or all of the following suggestions for enhancing lectures. These include: (1) Lectures must start with a "grabber"; (2) Lectures must be…

  15. Enhancing hydrogen spillover and storage

    DOEpatents

    Yang, Ralph T.; Li, Yingwel; Lachawiec, Jr., Anthony J.

    2011-05-31

    Methods for enhancing hydrogen spillover and storage are disclosed. One embodiment of the method includes doping a hydrogen receptor with metal particles, and exposing the hydrogen receptor to ultrasonification as doping occurs. Another embodiment of the method includes doping a hydrogen receptor with metal particles, and exposing the doped hydrogen receptor to a plasma treatment.

  16. Enhancing hydrogen spillover and storage

    DOEpatents

    Yang, Ralph T; Li, Yingwei; Lachawiec, Jr., Anthony J

    2013-02-12

    Methods for enhancing hydrogen spillover and storage are disclosed. One embodiment of the method includes doping a hydrogen receptor with metal particles, and exposing the hydrogen receptor to ultrasonication as doping occurs. Another embodiment of the method includes doping a hydrogen receptor with metal particles, and exposing the doped hydrogen receptor to a plasma treatment.

  17. Centers for Enhancement of Education.

    ERIC Educational Resources Information Center

    Biggerstaff, Ed

    The Center for Enhancement of Education organizes seven specialized centers within the School of Education and Human Services to provide faculty and students with the opportunity for research, development, and public service activities that complement and supplement classroom teaching. Each of the seven centers stresses one of the following…

  18. Alumina-Enhanced Thermal Barrier

    NASA Technical Reports Server (NTRS)

    Smith, Marnell; Leiser, Dan; Goldstein, Howard

    1989-01-01

    Rigid, fibrous ceramic tile material called "alumina-enhanced thermal barrier" (AETB) extends temperature capability of insulating materials. Material has obvious potential for terrestrial use in kilns, furnaces, heat engines, and other applications in which light weight and high operating temperature are specified. Three kinds of ceramic fibers are blended, molded, and sintered to make refractory tiles.

  19. Key Issue: Enhancing Teacher Leadership

    ERIC Educational Resources Information Center

    National Comprehensive Center for Teacher Quality, 2007

    2007-01-01

    "Teachers are leaders when they function in professional communities to affect student learning; contribute to school improvement; inspire excellence in practice; and empower stakeholders to participate in educational improvement" (Childs-Bowen, Moller, & Scrivner, 2000, p. 28). Enhancing teacher leadership can help schools and districts reach the…

  20. Germplasm enhancement for RWA resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Our contribution to this annual newsletter is a summary of research accomplishments in the past year in germplasm enhancement for RWA resistance in barley at the USDA-ARS, Wheat, Peanut and Other Field Crops Research Unit, Stillwater, OK. RWA is a serious pest of barley in the intermountain regions...

  1. Germplasm enhancement for RWA resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Our contribution to this annual newsletter is a summary of research accomplishments in the past year in germplasm enhancement for RWA resistance in barley at the USDA-ARS Wheat, Peanut and Other Field Crops Research Unit, Stillwater, OK. Russian wheat aphid (RWA) is a serious pest of barley in the ...

  2. Enhancing What Students Can Do

    ERIC Educational Resources Information Center

    Poel, Elissa Wolfe

    2007-01-01

    The Human Function Model, as described in the University of Kentucky Assistive Technology Project, places assistive technology in its proper perspective, as an external support that can enhance an individual's ability to function within the environment. The National Assistive Technology Research Institute groups assistive technology and related…

  3. Enhancing Instruction through Software Infusion.

    ERIC Educational Resources Information Center

    Sia, Archie P.

    The presence of the computer in the classroom is no longer considered an oddity; it has become an ordinary resource for teachers to use for the enhancement of instruction. This paper presents an examination of software infusion, i.e., the use of computer software to enrich instruction in an academic curriculum. The process occurs when a chosen…

  4. Forensics: Enhancing Civic Literacy & Democracy

    ERIC Educational Resources Information Center

    Briscoe, Shawn F.

    2009-01-01

    Forensics--interpretation, speech, and debate--can and should be a meaningful part of every school's curriculum. To put it simply, the course of study, alongside cocurricular competition, promotes civic education and enhances the standard curriculum by helping students explore myriad topics from multiple angles and find the truth in each,…

  5. Innovative Solution to Video Enhancement

    NASA Technical Reports Server (NTRS)

    2001-01-01

    Through a licensing agreement, Intergraph Government Solutions adapted a technology originally developed at NASA's Marshall Space Flight Center for enhanced video imaging by developing its Video Analyst(TM) System. Marshall's scientists developed the Video Image Stabilization and Registration (VISAR) technology to help FBI agents analyze video footage of the deadly 1996 Olympic Summer Games bombing in Atlanta, Georgia. VISAR technology enhanced nighttime videotapes made with hand-held camcorders, revealing important details about the explosion. Intergraph's Video Analyst System is a simple, effective, and affordable tool for video enhancement and analysis. The benefits associated with the Video Analyst System include support of full-resolution digital video, frame-by-frame analysis, and the ability to store analog video in digital format. Up to 12 hours of digital video can be stored and maintained for reliable footage analysis. The system also includes state-of-the-art features such as stabilization, image enhancement, and convolution to help improve the visibility of subjects in the video without altering underlying footage. Adaptable to many uses, Intergraph#s Video Analyst System meets the stringent demands of the law enforcement industry in the areas of surveillance, crime scene footage, sting operations, and dash-mounted video cameras.

  6. CPS Science Laboratory Enhancement Project

    SciTech Connect

    James, Chandra

    2011-11-30

    The lab enhancement initiative was designed to support early implementation efforts of new policy to promote safe learning environments and school labs called the Chemical Safety and Hygiene Plan (CSHP). These efforts included comprehensive inventories and chemical removals at all Chicago Public High Schools, conducted by environmental health and safety consultants, and the development of professional development resources for teachers.

  7. Biosurfactant and enhanced oil recovery

    DOEpatents

    McInerney, Michael J.; Jenneman, Gary E.; Knapp, Roy M.; Menzie, Donald E.

    1985-06-11

    A pure culture of Bacillus licheniformis strain JF-2 (ATCC No. 39307) and a process for using said culture and the surfactant lichenysin produced thereby for the enhancement of oil recovery from subterranean formations. Lichenysin is an effective surfactant over a wide range of temperatures, pH's, salt and calcium concentrations.

  8. Enhancements to PVM's BEOLIN architecture

    NASA Technical Reports Server (NTRS)

    Springer, Paul L.

    2005-01-01

    .4.3 of PVM had previously been enhanced by the addition of a new architecture, BEOLIN, which allowed a PVM user to abstract a Beowulf class computer with a private network to appear as a single system, visible to the outside world, which could spawn tasks on different internal nodes.

  9. Enhancing Author's Voice through Scripting

    ERIC Educational Resources Information Center

    Young, Chase J.; Rasinski, Timothy V.

    2011-01-01

    The authors suggest using scripting as a strategy to mentor and enhance author's voice in writing. Through gradual release, students use authentic literature as a model for writing with voice. The authors also propose possible extensions for independent practice, integration across content areas, and tips for evaluation.

  10. Who Benefits from Pension Enhancements?

    ERIC Educational Resources Information Center

    Koedel, Cory; Ni, Shawn; Podgursky, Michael

    2014-01-01

    During the late 1990s public pension funds across the United States accrued large actuarial surpluses. The seemingly flush conditions of the pension funds led legislators in most states to substantially improve retirement benefits for public workers, including teachers. In this study we examine the benefit enhancements to the teacher pension…

  11. Effectiveness of Enhanced Safety Management

    SciTech Connect

    Waterfall, K.W. )

    1988-01-01

    This paper discusses the development of an Enhanced Safety Management (ESM) campaign to improve safety and reduce risk in oil and gas exploration. The essentials of ESM are summarized by the author. The paper addresses the method developed to implement ESM and how the control of process designs to control operations minimizes the risk of a major accident.

  12. Immunologic Function and Molecular Insight of Recombinant Interleukin-18.

    PubMed

    Saetang, Jirakrit; Puseenam, Aekkachai; Roongsawang, Niran; Voravuthikunchai, Supayang Piyawan; Sangkhathat, Surasak; Tipmanee, Varomyalin

    2016-01-01

    In recent years, cytokine-mediated therapy has emerged as further advance alternative in cancer therapy. Interleukin-18 (IL-18) has exhibited interesting anti-cancer properties especially when combined with IL-12. We engineered IL-18 in order to improve its activity using single point mutagenesis. IL-18 mutants were constructed according to binding residues and polarity which we tried to increase polarity in M33Q and M60Q, enhanced cationicity in E6K, and flexibility in T63A. All IL-18 proteins were expressed in Pichia pastoris, purified, and then measured the activity by treating with the NK-92MI cell line to evaluate interferon-γ (IFN-γ) stimulation. The E6K and T63A mutant forms showed higher activity with respect to native proteins at the concentration of 200 ng mL-1 by inducing the expression of IFN-γ, about factors of 9 and 4, respectively. Meanwhile, M33Q and M60Q had no significant activity to induce IFN-γ. Interestingly, the combination of E6K and T63A mutations could synergize the induction activity of IL-18 to be 16 times at 200 ng mL-1. Furthermore, molecular dynamics studies have elucidated the effect due to mutation on conformation of the binding site of IL-18. The results turn out that E6K provides structural perseverance against mutation, while M33Q and M60Q promote vivid overall change in protein conformation, especially at the binding site. For T63A, mutation yields small difference in structure but clearly increases structural flexibility. However, a small structural change was observed when T63A was combined with E6K. Our research resulted in a novel version of IL-18 which could be a new key candidate for cytokine-mediated therapy. PMID:27483370

  13. Immunologic Function and Molecular Insight of Recombinant Interleukin-18

    PubMed Central

    Saetang, Jirakrit; Puseenam, Aekkachai; Roongsawang, Niran; Voravuthikunchai, Supayang Piyawan; Sangkhathat, Surasak

    2016-01-01

    In recent years, cytokine-mediated therapy has emerged as further advance alternative in cancer therapy. Interleukin-18 (IL-18) has exhibited interesting anti-cancer properties especially when combined with IL-12. We engineered IL-18 in order to improve its activity using single point mutagenesis. IL-18 mutants were constructed according to binding residues and polarity which we tried to increase polarity in M33Q and M60Q, enhanced cationicity in E6K, and flexibility in T63A. All IL-18 proteins were expressed in Pichia pastoris, purified, and then measured the activity by treating with the NK-92MI cell line to evaluate interferon-γ (IFN-γ) stimulation. The E6K and T63A mutant forms showed higher activity with respect to native proteins at the concentration of 200 ng mL-1 by inducing the expression of IFN-γ, about factors of 9 and 4, respectively. Meanwhile, M33Q and M60Q had no significant activity to induce IFN-γ. Interestingly, the combination of E6K and T63A mutations could synergize the induction activity of IL-18 to be 16 times at 200 ng mL-1. Furthermore, molecular dynamics studies have elucidated the effect due to mutation on conformation of the binding site of IL-18. The results turn out that E6K provides structural perseverance against mutation, while M33Q and M60Q promote vivid overall change in protein conformation, especially at the binding site. For T63A, mutation yields small difference in structure but clearly increases structural flexibility. However, a small structural change was observed when T63A was combined with E6K. Our research resulted in a novel version of IL-18 which could be a new key candidate for cytokine-mediated therapy. PMID:27483370

  14. Image enhancement method for fingerprint recognition system.

    PubMed

    Li, Shunshan; Wei, Min; Tang, Haiying; Zhuang, Tiange; Buonocore, Michael

    2005-01-01

    Image enhancement plays an important role in Fingerprint Recognition System. In this paper fingerprint image enhancement method, a refined Gabor filter, is presented. This enhancement method can connect the ridge breaks, ensures the maximal gray values located at the ridge center and has the ability to compensate for the nonlinear deformations. The result shows it can improve the performance of image enhancement.

  15. Blob-enhanced reconstruction technique

    NASA Astrophysics Data System (ADS)

    Castrillo, Giusy; Cafiero, Gioacchino; Discetti, Stefano; Astarita, Tommaso

    2016-09-01

    A method to enhance the quality of the tomographic reconstruction and, consequently, the 3D velocity measurement accuracy, is presented. The technique is based on integrating information on the objects to be reconstructed within the algebraic reconstruction process. A first guess intensity distribution is produced with a standard algebraic method, then the distribution is rebuilt as a sum of Gaussian blobs, based on location, intensity and size of agglomerates of light intensity surrounding local maxima. The blobs substitution regularizes the particle shape allowing a reduction of the particles discretization errors and of their elongation in the depth direction. The performances of the blob-enhanced reconstruction technique (BERT) are assessed with a 3D synthetic experiment. The results have been compared with those obtained by applying the standard camera simultaneous multiplicative reconstruction technique (CSMART) to the same volume. Several blob-enhanced reconstruction processes, both substituting the blobs at the end of the CSMART algorithm and during the iterations (i.e. using the blob-enhanced reconstruction as predictor for the following iterations), have been tested. The results confirm the enhancement in the velocity measurements accuracy, demonstrating a reduction of the bias error due to the ghost particles. The improvement is more remarkable at the largest tested seeding densities. Additionally, using the blobs distributions as a predictor enables further improvement of the convergence of the reconstruction algorithm, with the improvement being more considerable when substituting the blobs more than once during the process. The BERT process is also applied to multi resolution (MR) CSMART reconstructions, permitting simultaneously to achieve remarkable improvements in the flow field measurements and to benefit from the reduction in computational time due to the MR approach. Finally, BERT is also tested on experimental data, obtaining an increase of the

  16. Enhancing who? Enhancing what? Ethics, bioethics, and transhumanism.

    PubMed

    Koch, Tom

    2010-12-01

    Transhumanists advance a "posthuman" condition in which technological and genetic enhancements will transform humankind. They are joined in this goal by bioethicists arguing for genetic selection as a means of "enhancing evolution," improving if not also the species then at least the potential lives of future individuals. The argument of both, this paper argues, is a new riff on the old eugenics tune. As ever, it is done in the name of science and its presumed knowledge base. As ever, the result is destructive rather than instructive, bad faith promoted as high ideal. The paper concludes with the argument that species advancement is possible but in a manner thoroughly distinct from that advanced by either of these groups.

  17. Enhanced functional integration of human photoreceptor precursors into human and rodent retina in an ex vivo retinal explant model system.

    PubMed

    Yanai, Anat; Laver, Christopher R J; Gregory-Evans, Cheryl Y; Liu, Ran R; Gregory-Evans, Kevin

    2015-06-01

    Retinal disease is the major cause of irreversible blindness in developed countries. Transplantation of photoreceptor precursor cells (PPCs) derived from human embryonic stem cells (hESCs) is a promising and widely applicable approach for the treatment of these blinding conditions. Previously, it has been shown that after transplantation into the degenerating retina, the percentage of PPCs that undergo functional integration is low. The factors that inhibit PPC engraftment remain largely unknown, in part, because so many adverse factors could be at play during in vivo experiments. To advance our knowledge in overcoming potential adverse effects and optimize PPC transplantation, we have developed a novel ex vivo system. Harvested neural retina was placed directly on top of cultured retinal pigment epithelial (RPE) cells from a number of different sources. To mimic PPC transplantation into the subretinal space, hESC-derived PPCs were inserted between the retinal explant and underlying RPE. Explants cocultured with hESC-derived RPE maintained normal gross morphology and viability for up to 2 weeks, whereas the explants cultured on ARPE19 and RPE-J failed by 7 days. Furthermore, the proportion of PPCs expressing ribbon synapse-specific proteins BASSOON and RIBEYE was significantly higher when cocultured with hESC-derived RPE (20% and 10%, respectively), than when cocultured with ARPE19 (only 6% and 2%, respectively). In the presence of the synaptogenic factor thrombospondin-1 (TSP-1), the proportion of BASSOON-positive and RIBEYE-positive PPCs cocultured with hESC-derived RPE increased to ∼30% and 15%, respectively. These data demonstrate the utility of an ex vivo model system to define factors, such as TSP-1, which could influence integration efficiency in future in vivo experiments in models of retinal degeneration.

  18. Fertility-enhancing hysteroscopic surgery.

    PubMed

    Cela, Vito; Litta, Pietro; Franchini, Mario; Sergiampietri, Claudia; Simi, Giovanna; Freschi, Letizia; Artini, Paolo G; Papini, Francesca

    2016-04-01

    Anatomical uterine element and functional components play a fundamental role in the enhancing of fertility are the major actors. Uterine pathologies, including congenital or acquired lesions, have been reported in 21 to 47% of patients undergoing in vitro fertilization cycles. Hysteroscopy is an important procedure in the study of one of the most important element of fertility: the uterus, even if its use in the world of infertility is discussed. There are many studies on safety and feasibility of the procedure and on patient compliance, but there is no consensus on its systemic use. This study, thanks to the wide literature about the use of hysteroscopic surgery to enhance fertility in most of the congenital and acquired problems affecting women in fertility age, allows defining that diagnostic and operative hysteroscopy is a rapid and safety technology to improve fertility. PMID:26928416

  19. Nonhereditary enhancement of progeny growth

    NASA Technical Reports Server (NTRS)

    Khan, Amir S.; Fiorotto, Marta L.; Hill, Leigh-Anne; Malone, P. Brandon; Cummings, Kathleen K.; Parghi, Deena; Schwartz, Robert J.; Smith, Roy G.; Draghia-Akli, Ruxandra

    2002-01-01

    The im electroporated injection of a protease-resistant GH-releasing hormone cDNA into rat dams at 16 d gestation resulted in enhanced long-term growth of the F(1) offspring. The offspring were significantly heavier by 2 wk of age, and the difference was sustained to 10 wk of age. Consistent with their augmented growth, the plasma IGF-I concentration of the F(1) progeny was increased significantly. The pituitary gland of the offspring was significantly heavier and contained an increased number of somatotrophs and PRL-secreting cells, which is indicative of modification of cell lineage differentiation. These unique findings demonstrate that enhanced GH-releasing hormone expression in pregnant dams can result in intergenerational growth promotion by altering development of the pituitary gland in the offspring.

  20. Enhancing Research Papers in Astronomy

    NASA Astrophysics Data System (ADS)

    Kroffe, Kerry; McCann, G.

    2013-01-01

    XML-based production of journal articles, combined with real-time transformations, now make it possible to develop new enhancements to the reading experience and to the content of the article itself. Papers from AAS journals are now available in ‘Article Evolution’ HTML format, providing both familiar and new functionality that improves the reading experience. This poster will outline the roadmap for the development of ‘Article Evolution’ functionality and ask for input to help shape future enhancements that meet the needs of the astronomy community. Two of the ongoing developments described are ’semantic enrichment’ of articles and adoption of ORCID (Open Researcher and Contributor ID). Both of these have exciting possibilities at an article level within ‘Article Evolution’ but will also impact widely on third party services, such as linking and discovery of research papers.

  1. Biosurfactant-enhanced soil bioremediation

    SciTech Connect

    Kosaric, N.; Lu, G.; Velikonja, J.

    1995-12-01

    Bioremediation of soil contaminated with organic chemicals is a viable alternative method for clean-up and remedy of hazardous waste sites. The final objective in this approach is to convert the parent toxicant into a readily biodegradable product which is harmless to human health and/or the environment. Biodegradation of hydrocarbons in soil can also efficiently be enhanced by addition or in-situ production of biosufactants. It was generally observed that the degradation time was shortened and particularly the adaptation time for the microbes. More data from our laboratories showed that chlorinated aromatic compounds, such as 2,4-dichlorophenol, a herbicide Metolachlor, as well as naphthalene are degraded faster and more completely when selected biosurfactants are added to the soil. More recent data demonstrated an enhanced biodegradation of heavy hydrocarbons in petrochemical sludges, and in contaminated oil when biosurfactants were present or were added prior to the biodegradation process.

  2. Ras enhances Myc protein stability.

    PubMed

    Sears, R; Leone, G; DeGregori, J; Nevins, J R

    1999-02-01

    Various experiments have demonstrated a collaborative action of Myc and Ras, both in normal cell growth control as well as during oncogenesis. We now show that Ras enhances the accumulation of Myc activity by stabilizing the Myc protein. Whereas Myc has a very short half-life when produced in the absence of mitogenic signals, due to degradation by the 26S proteasome, the half-life of Myc increases markedly in growth-stimulated cells. This stabilization is dependent on the Ras/Raf/MAPK pathway and is not augmented by proteasome inhibition, suggesting that Ras inhibits the proteasome-dependent degradation of Myc. We propose that one aspect of Myc-Ras collaboration is an ability of Ras to enhance the accumulation of transcriptionally active Myc protein.

  3. Mixing enhancement using axial flow

    NASA Technical Reports Server (NTRS)

    Papamoschou, Dimitri (Inventor)

    2003-01-01

    A method and an apparatus for enhancing fluid mixing. The method comprises the following: (a) configuring a duct to have an effective outer wall, an effective inner wall, a cross-sectional shape, a first cross-sectional area and an exit area, the first cross-sectional area and the exit area being different in size; (b) generating a first flow at the first cross-sectional area, the first flow having a total pressure and a speed equal to or greater than a local speed of sound; and (c) generating a positive streamwise pressure gradient in a second flow in proximity of the exit area. The second flow results from the first flow. Fluid mixing is enhanced downstream from the duct exit area.

  4. Resolution enhanced sound detecting apparatus

    NASA Technical Reports Server (NTRS)

    Kendall, J. M. (Inventor)

    1979-01-01

    An apparatus is described for enhancing the resolution of a sound detector of the type which includes an acoustic mirror for focusing sound from an object onto a microphone to enable the determination of the location from which the sound arises. The enhancement apparatus includes an enclosure which surrounds the space between the mirror and microphone, and contains a gas heavier than air, such as Freon, through which sound moves slower and therefore with a shorter wavelength than in air, so that a mirror of given size has greater resolving power. An acoustically transparent front wall of the enclosure which lies forward of the mirror, can include a pair of thin sheets with pressured air between them, to form an end of the region of heavy gas into a concave shape.

  5. Three Fresh Exposures, Enhanced Color

    NASA Technical Reports Server (NTRS)

    2004-01-01

    This enhanced-color panoramic camera image from the Mars Exploration Rover Opportunity features three holes created by the rock abrasion tool between sols 143 and 148 (June 18 and June 23, 2004) inside 'Endurance Crater.' The enhanced image makes the red colors a little redder and blue colors a little bluer, allowing viewers to see differences too subtle to be seen without the exaggeration. When compared with an approximately true color image, the tailings from the rock abrasion tool and the interior of the abraded holes are more prominent in this view. Being able to discriminate color variations helps scientists determine rocks' compositional differences and texture variations. This image was created using the 753-, 535- and 432-nanometer filters.

  6. Method for enhanced oil recovery

    DOEpatents

    Comberiati, Joseph R.; Locke, Charles D.; Kamath, Krishna I.

    1980-01-01

    The present invention is directed to an improved method for enhanced recovery of oil from relatively "cold" reservoirs by carbon dioxide flooding. In oil reservoirs at a temperature less than the critical temperature of 87.7.degree. F. and at a pore pressure greater than the saturation pressure of carbon dioxide at the temperature of the reservoir, the carbon dioxide remains in the liquid state which does not satisfactorily mix with the oil. However, applicants have found that carbon dioxide can be vaporized in situ in the reservoir by selectively reducing the pore pressure in the reservoir to a value less than the particular saturated vapor pressure so as to greatly enhance the mixing of the carbon dioxide with the oil.

  7. Quantum-Enhanced Machine Learning

    NASA Astrophysics Data System (ADS)

    Dunjko, Vedran; Taylor, Jacob M.; Briegel, Hans J.

    2016-09-01

    The emerging field of quantum machine learning has the potential to substantially aid in the problems and scope of artificial intelligence. This is only enhanced by recent successes in the field of classical machine learning. In this work we propose an approach for the systematic treatment of machine learning, from the perspective of quantum information. Our approach is general and covers all three main branches of machine learning: supervised, unsupervised, and reinforcement learning. While quantum improvements in supervised and unsupervised learning have been reported, reinforcement learning has received much less attention. Within our approach, we tackle the problem of quantum enhancements in reinforcement learning as well, and propose a systematic scheme for providing improvements. As an example, we show that quadratic improvements in learning efficiency, and exponential improvements in performance over limited time periods, can be obtained for a broad class of learning problems.

  8. Enhancing Soundtracks From Old Movies

    NASA Technical Reports Server (NTRS)

    Frazer, Robert E.

    1992-01-01

    Proposed system enhances soundtracks of old movies. Signal on optical soundtrack of film digitized and processed to reduce noise and improve quality; timing signals added, and signal recorded on compact disk. Digital comparator and voltage-controlled oscillator synchronizes speed of film-drive motor and compact disk motor. Frame-coded detector reads binary frame-identifying marks on film. Digital comparator generates error signal if marks on film do not match those on compact disk.

  9. Preactivated thiomers: permeation enhancing properties.

    PubMed

    Wang, Xueqing; Iqbal, Javed; Rahmat, Deni; Bernkop-Schnürch, Andreas

    2012-11-15

    The study was aimed to prepare a series of poly(acrylic acid)-cysteine-2-mercaptonicotinic acid conjugates (preactivated thiomers) and to evaluate the influence of molecular mass or degree of preactivation with 2-mercaptonicotinic acid (2MNA) on their permeation enhancing properties. Preactivated thiomers with different molecular mass and different degree of preactivation were synthesized and categorized on the basis of their molecular mass and degree of preactivation as PAA(100)-Cys-2MNA (h), PAA(250)-Cys-2MNA (h), PAA(450)-Cys-2MNA (h), PAA(450)-Cys-2MNA (m) and PAA(450)-Cys-2MNA (l). In vitro permeation studies, the permeation enhancement ability for preactivated thiomers was ranked as PAA(450)-Cys-2MNA (h)>PAA(250)-Cys-2MNA (h)>PAA(100)-Cys-2MNA (h) on both Caco-2 cell monolayers and rat intestinal mucosa. Comparing the influence of degree of preactivation with 2MNA on permeation enhancement, the following order PAA(450)-Cys-2MNA (h)>PAA(450)-Cys-2MNA (m)≈PAA(450)-Cys-2MNA (l) on Caco-2 cell monolayers and PAA(450)-Cys-2MNA (m)>PAA(450)-Cys-2MNA (h)>PAA(450)-Cys-2MNA (l) on intestinal mucosa was observed. The P(app) of sodium fluorescein was 5.08-fold improved on Caco-2 cell monolayers for PAA(450)-Cys-2MNA (h) and 2.46-fold improved on intestinal mucosa for PAA(450)-Cys-2MNA (m), respectively, in comparison to sodium fluorescein in buffer only. These results indicated that preactivated thiomers could be considered as a promising macromolecular permeation enhancing polymer for non-invasive drug administration.

  10. Closing thoughts for cognitive enhancement.

    PubMed

    Kantak, Kathleen M; Wettstein, Joseph G

    2015-01-01

    The wide-ranging field of cognition enhancing research along with its ethics as it stands today is summarized. In the forefront are potentially novel drugs and non-pharmacological treatments for cognitive impairment across many different psychiatric and neurologic indications. Today's research will bring new drugs to patients tomorrow, and tomorrow's research will bring new molecular targets to clinical development that should be cognitive domain-specific. There is the likelihood that special populations may be better treated and that personalized medicine for cognitive impairment could become a reality. It is conceivable that with the current research effort, cognition enhancing drugs will become available to wide-ranging populations of people with neuropsychiatric illness and to those that are healthy. In some cultures, there is a push in society to be more intelligent or have more cognitive prowess. Thus, the ethical use of cognitive enhancing drugs should be an area of debate and communication. Neuroethics is a growing field and it intends to bring together key contributors such as physicians, disease experts, regulatory officials, and policy makers to discuss how such medicines can or should be made available. Together with this, one has to consider the possibility that no single medicine or technology will have a great impact on cognition and, therefore, combination therapy of drugs plus other approaches like exercise or transcranial direct-current stimulation may be the path forward. This is another area of scientific inquiry and debate, and the results should be fruitful and helpful to patients. The science of cognition is advancing at a rapid rate, and communication of its progress along with the development of rational and ethical policies for use of cognitive enhancers will be beneficial.

  11. CARE 3, Version 4 enhancements

    NASA Technical Reports Server (NTRS)

    Bryant, L. A.; Stiffler, J. J.

    1985-01-01

    The enhancements and error corrections to CARE III Version 4 are listed. All changes to Version 4 with the exception of the internal redundancy model were implemented in Version 5. Version 4 is the first public release version for execution on the CDC Cyber 170 series computers. Version 5 is the second release version and it is written in ANSI standard FORTRAN 77 for execution on the DEC VAX 11/700 series computers and many others.

  12. Technology Education Professional Enhancement Project

    NASA Technical Reports Server (NTRS)

    Hughes, Thomas A., Jr.

    1996-01-01

    The two goals of this project are: the use of integrative field of aerospace technology to enhance the content and instruction delivered by math, science, and technology teachers through the development of a new publication entitled NASA Technology Today, and to develop a rationale and structure for the study of technology, which establishes the foundation for developing technology education standards and programs of the future.

  13. Enhancing Centrifugal Separation With Electrophoresis

    NASA Technical Reports Server (NTRS)

    Herrmann, F. T.

    1986-01-01

    Separation of biological cells by coil-planet centrifuge enhanced by electrophoresis. By itself, coil-planet centrifuge offers relatively gentle method of separating cells under low centrifugal force in physiological medium that keeps cells alive. With addition of voltage gradient to separation column of centrifuge, separation still gentle but faster and more complete. Since separation apparatus contains no rotary seal, probability of leakage, contamination, corrosion, and short circuits reduced.

  14. Enhanced heat transfer using nanofluids

    DOEpatents

    Choi, Stephen U. S.; Eastman, Jeffrey A.

    2001-01-01

    This invention is directed to a method of and apparatus for enhancing heat transfer in fluids such as deionized water. ethylene glycol, or oil by dispersing nanocrystalline particles of substances such as copper, copper oxide, aluminum oxide, or the like in the fluids. Nanocrystalline particles are produced and dispersed in the fluid by heating the substance to be dispersed in a vacuum while passing a thin film of the fluid near the heated substance. The fluid is cooled to control its vapor pressure.

  15. Photodetector with enhanced light absorption

    DOEpatents

    Kane, James

    1985-01-01

    A photodetector including a light transmissive electrically conducting layer having a textured surface with a semiconductor body thereon. This layer traps incident light thereby enhancing the absorption of light by the semiconductor body. A photodetector comprising a textured light transmissive electrically conducting layer of SnO.sub.2 and a body of hydrogenated amorphous silicon has a conversion efficiency about fifty percent greater than that of comparative cells. The invention also includes a method of fabricating the photodetector of the invention.

  16. Chemical enhancement of surface deposition

    DOEpatents

    Patch, Keith D.; Morgan, Dean T.

    1997-07-29

    A method and apparatus for increasing the deposition of ions onto a surface, such as the adsorption of uranium ions on the detecting surface of a radionuclide detector. The method includes the step of exposing the surface to a complexing agent, such as a phosphate ion solution, which has an affinity for the dissolved species to be deposited on the surface. This provides, for example, enhanced sensitivity of the radionuclide detector.

  17. Chemical enhancement of surface deposition

    DOEpatents

    Patch, K.D.; Morgan, D.T.

    1997-07-29

    A method and apparatus are disclosed for increasing the deposition of ions onto a surface, such as the adsorption of uranium ions on the detecting surface of a radionuclide detector. The method includes the step of exposing the surface to a complexing agent, such as a phosphate ion solution, which has an affinity for the dissolved species to be deposited on the surface. This provides, for example, enhanced sensitivity of the radionuclide detector. 16 figs.

  18. The Likelihood of Cognitive Enhancement

    PubMed Central

    Lynch, Gary; Palmer, Linda C.; Gall, Christine M.

    2011-01-01

    Whether drugs that enhance cognition in healthy individuals will appear in the near future has become a topic of considerable interest. We address this possibility using a three variable system (psychological effect, neurobiological mechanism, efficiency vs. capabilities) for classifying candidates. Ritalin and modafinil, two currently available compounds, operate on primary psychological states that in turn affect cognitive operations (attention, memory), but there is little evidence that these effects translate into improvements in complex cognitive processing. A second category of potential enhancers includes agents that improve memory encoding, generally without large changes in primary psychological states. Unfortunately, there is little information on how these compounds affect cognitive performance in standard psychological tests. Recent experiments have identified a number of sites at which memory drugs could, in principle, manipulate the cell biological systems underlying the learning-related long-term potentiation (LTP) effect; this may explain the remarkable diversity of memory promoting compounds. Indeed, many of these agents are known to have positive effects on LTP. A possible third category of enhancement drugs directed specifically at integrated cognitive operations is nearly empty. From a neurobiological perspective, two plausible candidate classes have emerged that both target the fast excitatory transmission responsible for communication within cortical networks. One acts on nicotinic receptors (alpha7, alpha4) that regulate release of the neurotransmitter glutamate while the other (‘ampakines’) allosterically modulates the glutamate receptors mediating the post-synaptic response (EPSCs). Brain imaging in primates has shown that ampakines expand cortical networks engaged by a complex task; coupled with behavioral data, these findings provide evidence for the possibility of generating new cognitive capabilities. Finally, we suggest that

  19. How rotational vortices enhance transfers

    NASA Astrophysics Data System (ADS)

    Griffani, D.; Rognon, P.; Metzger, B.; Einav, I.

    2013-09-01

    Inspired by recent observations of granular flow, we examine how rotational vortices contribute to heat or mass transfer enhancement in a fluid. We use a tracer method to simulate both diffusion and advection in systems of differing intrinsic diffusivities D0, vortex sizes R, vortex rotation frequencies f, and vortex lifetimes ℓ. The results reveal that these systems exhibit an effective diffusive behavior, characterized by an effective diffusivity Deff. A striking finding is the existence of two regimes, dichotomised by the Péclet number Pe = R2f/D0. When the Péclet number is less than one, there is no transfer enhancement, Deff = D0. For higher values, vortices produce some transfer enhancement with a corresponding power law Deff/D0 ≈ Pen. The power n ranges from a lower bound of 0.5 for stationary vortices of lifetime infinity, to an upper bound of 1 for vortices of lifetimes shorter than half a rotation. This difference is attributed to two different internal mechanisms involving the coupling of diffusion and advection. These results could provide new insights on the transfer properties of fluid systems comprising rotational vortices, such as granular materials, suspensions, foams, and emulsions, as well as low Reynolds number stirred flows.

  20. Enhancement classification of galaxy images

    NASA Astrophysics Data System (ADS)

    Jenkinson, John

    With the advent of astronomical imaging technology developments, and the increased capacity of digital storage, the production of photographic atlases of the night sky have begun to generate volumes of data which need to be processed autonomously. As part of the Tonantzintla Digital Sky Survey construction, the present work involves software development for the digital image processing of astronomical images, in particular operations that preface feature extraction and classification. Recognition of galaxies in these images is the primary objective of the present work. Many galaxy images have poor resolution or contain faint galaxy features, resulting in the misclassification of galaxies. An enhancement of these images by the method of the Heap transform is proposed, and experimental results are provided which demonstrate the image enhancement to improve the presence of faint galaxy features thereby improving classification accuracy. The feature extraction was performed using morphological features that have been widely used in previous automated galaxy investigations. Principal component analysis was applied to the original and enhanced data sets for a performance comparison between the original and reduced features spaces. Classification was performed by the Support Vector Machine learning algorithm.

  1. Dispersion-Enhanced Laser Gyroscope

    NASA Technical Reports Server (NTRS)

    Smith, David D.; Chang, Hongrok; Arissian, L.; Diels, J. C.

    2008-01-01

    We analyze the effect of a highly dispersive element placed inside a modulated optical cavity on the frequency and amplitude of the output modulation to determine the conditions for enhanced gyroscopic sensitivities. The element is treated as both a phase and amplitude filter, and the time-dependence of the cavity field is considered. Both atomic gases (two-level and multi-level) and optical resonators (single and coupled) are considered and compared as dispersive elements. We find that it is possible to simultaneously enhance the gyro scale factor sensitivity and suppress the dead band by using an element with anomalous dispersion that has greater loss at the carrier frequency than at the side-band frequencies, i.e., an element that simultaneously pushes and intensifies the perturbed cavity modes, e.g. a two-level absorber or an under-coupled optical resonator. The sensitivity enhancement is inversely proportional to the effective group index, becoming infinite at a group index of zero. However, the number of round trips required to reach a steady-state also becomes infinite when the group index is zero (or two). For even larger dispersions a steady-state cannot be achieved, and nonlinear dynamic effects such as bistability and periodic oscillations are predicted in the gyro response.

  2. [Lower is better: ENHANCE affair].

    PubMed

    Scardi, Sabino; Umari, Paolo; D'Agata, Bianca Maria

    2008-06-01

    Ezetimibe lowers the intestinal absorption of cholesterol, being complementary to the effects of statin. To check its efficacy in lowering the carotid intima-media thickness, in 2002 a multicenter international trial called ENHANCE was started, in order to assess by ultrasound the regression of atherosclerotic plaques. The protocol tested the use of simvastatin 80 mg + placebo versus simvastatin 80 mg + ezetimibe 10 mg in 720 randomized patients. Both drugs were well tolerated. Combination therapy was associated with a larger reduction in LDL cholesterol, but there were no differences in the intima-media thickness measured at three sites in the carotid arteries, nor differences in cardiovascular events between the two groups in the trial. These results provoked disappointment of sponsors (Merck, Schering Plough) who, although the results of the trial were available since march 2007, delayed official communication of about 18 months. This led to speculations and rumors among media, American Government, cardiologic scientific associations, and consequences in the Ezetimibe market and at Wall Street. In particular, the American College of Cardiology didn't accept the communication of ENHANCE results to the Late Breaking Trial Session of the Chicago congress, diverting it to another secondary forum. In conclusion, the experience of the ENHANCE trial suggests to pharmaceutical companies, researchers, clinicians, scientific companies and media a deep meditation in order to avoid in the future similar problems in the management of results of medical research.

  3. Cyclosporine A enhances platelet aggregation.

    PubMed

    Grace, A A; Barradas, M A; Mikhailidis, D P; Jeremy, J Y; Moorhead, J F; Sweny, P; Dandona, P

    1987-12-01

    In view of the reported increase in thromboembolic episodes following cyclosporine A (CyA) therapy, the effect of this drug on platelet aggregation and thromboxane A2 release was investigated. The addition of CyA, at therapeutic concentrations to platelet rich plasma from normal subjects in vitro was found to increase aggregation in response to adrenaline, collagen and ADP. Ingestion of CyA by healthy volunteers was also associated with enhanced platelet aggregation. The CyA-mediated enhancement of aggregation was further enhanced by the addition in vitro of therapeutic concentrations of heparin. Platelets from renal allograft recipients treated with CyA also showed hyperaggregability and increased thromboxane A2 release, which were most marked at "peak" plasma CyA concentration and less so at "trough" concentrations. Platelet hyperaggregability in renal allograft patients on long-term CyA therapy tended to revert towards normal following the replacement of CyA with azathioprine. Hypertensive patients with renal allografts on nifedipine therapy had normal platelet function and thromboxane release in spite of CyA therapy. These observations suggest that CyA-mediated platelet activation may contribute to the pathogenesis of the thromboembolic phenomena associated with the use of this drug. The increased release of thromboxane A2 (a vasoconstrictor) may also play a role in mediating CyA-related nephrotoxicity.

  4. Threshold enhancement of diphoton resonances

    NASA Astrophysics Data System (ADS)

    Bharucha, Aoife; Djouadi, Abdelhak; Goudelis, Andreas

    2016-10-01

    We revisit a mechanism to enhance the decay width of (pseudo-)scalar resonances to photon pairs when the process is mediated by loops of charged fermions produced near threshold. Motivated by the recent LHC data, indicating the presence of an excess in the diphoton spectrum at approximately 750 GeV, we illustrate this threshold enhancement mechanism in the case of a 750 GeV pseudoscalar boson A with a two-photon decay mediated by a charged and uncolored fermion having a mass at the 1/2MA threshold and a small decay width, < 1 MeV. The implications of such a threshold enhancement are discussed in two explicit scenarios: i) the Minimal Supersymmetric Standard Model in which the A state is produced via the top quark mediated gluon fusion process and decays into photons predominantly through loops of charginos with masses close to 1/2MA and ii) a two Higgs doublet model in which A is again produced by gluon fusion but decays into photons through loops of vector-like charged heavy leptons. In both these scenarios, while the mass of the charged fermion has to be adjusted to be extremely close to half of the A resonance mass, the small total widths are naturally obtained if only suppressed three-body decay channels occur. Finally, the implications of some of these scenarios for dark matter are discussed.

  5. Enhanced vision meets pilot assistance

    NASA Astrophysics Data System (ADS)

    Hecker, Peter; Doehler, Hans-Ullrich; Suikat, Reiner

    1999-07-01

    As presented in previous contributions within SPIE's Enhanced and Synthetic Vision Conferences, DLR's Institute of Flight Guidance is involved in the design, development and testing of enhanced vision systems for flight guidance applications. The combination of forward looking imaging sensors (such as DaimlerChrysler's HiVision millimeter wave radar), terrain data stored in on-board databases plus information transmitted from ground or on-board other aircraft via data link is used to give the air crew an improved situational awareness. This helps pilots to handle critical tasks, such as landing approaches and taxiing especially under adverse weather conditions. The research and development of this system was mostly funded by a national research program from mid of 1996 to mid of 1999. On one hand this paper will give a general overview about the project and the lessons learned. Results of flight tests carried out recently will be shown as well as brief looks into evaluation tests on-board an Airbus A-340 full flight simulator performed mid of 1998 at the Flight Simulation Center Berlin. On the other hand an outlook will be presented, which shows enhanced vision systems as a major player in the theater of pilot assistance systems as they are under development at DLR's Institute of Flight Guidance in close cooperation with the University of the Federal Armed Forces in Munich, Germany.

  6. Polyphosphate enhances fibrin clot structure

    PubMed Central

    Smith, Stephanie A.

    2008-01-01

    Polyphosphate, a linear polymer of inorganic phosphate, is present in platelet dense granules and is secreted on platelet activation. We recently reported that polyphosphate is a potent hemostatic regulator, serving to activate the contact pathway of blood clotting and accelerate factor V activation. Because polyphosphate did not alter thrombin clotting times, it appeared to exert all its procoagulant actions upstream of thrombin. We now report that polyphosphate enhances fibrin clot structure in a calcium-dependent manner. Fibrin clots formed in the presence of polyphosphate had up to 3-fold higher turbidity, had higher mass-length ratios, and exhibited thicker fibers in scanning electron micrographs. The ability of polyphosphate to enhance fibrin clot turbidity was independent of factor XIIIa activity. When plasmin or a combination of plasminogen and tissue plasminogen activators were included in clotting reactions, fibrin clots formed in the presence of polyphosphate exhibited prolonged clot lysis times. Release of polyphosphate from activated platelets or infectious microorganisms may play an important role in modulating fibrin clot structure and increasing its resistance to fibrinolysis. Polyphosphate may also be useful in enhancing the structure of surgical fibrin sealants. PMID:18544683

  7. Enhanced Jumping-Droplet Departure.

    PubMed

    Kim, Moon-Kyung; Cha, Hyeongyun; Birbarah, Patrick; Chavan, Shreyas; Zhong, Chen; Xu, Yuehan; Miljkovic, Nenad

    2015-12-15

    Water vapor condensation on superhydrophobic surfaces has received much attention in recent years because of its ability to shed water droplets at length scales 3 decades smaller than the capillary length (∼1 mm) via coalescence-induced droplet jumping. Jumping-droplet condensation has been demonstrated to enhance heat transfer, anti-icing, and self-cleaning efficiency and is governed by the theoretical inertial-capillary scaled jumping speed (U). When two droplets coalesce, the experimentally measured jumping speed (Uexp) is fundamentally limited by the internal fluid dynamics during the coalescence process (Uexp < 0.23U). Here, we theoretically and experimentally demonstrate multidroplet (>2) coalescence as an avenue to break the two-droplet speed limit. Using side-view and top-view high-speed imaging to study more than 1000 jumping events on a copper oxide nanostructured superhydrophobic surface, we verify that droplet jumping occurs as a result of three fundamentally different mechanisms: (1) coalescence between two droplets, (2) coalescence among more than two droplets (multidroplet), and (3) coalescence between one or more droplets on the surface and a returning droplet that has already departed (multihop). We measured droplet-jumping speeds for a wide range of droplet radii (5-50 μm) and demonstrated that while the two-droplet capillary-to-inertial energy conversion mechanism is not identical to that of multidroplet jumping, speeds above the theoretical two-droplet limit (>0.23U) can be achieved. However, we discovered that multihop coalescence resulted in drastically reduced jumping speeds (≪0.23U) due to adverse momentum contributions from returning droplets. To quantify the impact of enhanced jumping speed on heat-transfer performance, we developed a condensation critical heat flux model to show that modest jumping speed enhancements of 50% using multidroplet jumping can enhance performance by up to 40%. Our results provide a starting point for the

  8. Integrating diverse datasets improves developmental enhancer prediction.

    PubMed

    Erwin, Genevieve D; Oksenberg, Nir; Truty, Rebecca M; Kostka, Dennis; Murphy, Karl K; Ahituv, Nadav; Pollard, Katherine S; Capra, John A

    2014-06-01

    Gene-regulatory enhancers have been identified using various approaches, including evolutionary conservation, regulatory protein binding, chromatin modifications, and DNA sequence motifs. To integrate these different approaches, we developed EnhancerFinder, a two-step method for distinguishing developmental enhancers from the genomic background and then predicting their tissue specificity. EnhancerFinder uses a multiple kernel learning approach to integrate DNA sequence motifs, evolutionary patterns, and diverse functional genomics datasets from a variety of cell types. In contrast with prediction approaches that define enhancers based on histone marks or p300 sites from a single cell line, we trained EnhancerFinder on hundreds of experimentally verified human developmental enhancers from the VISTA Enhancer Browser. We comprehensively evaluated EnhancerFinder using cross validation and found that our integrative method improves the identification of enhancers over approaches that consider a single type of data, such as sequence motifs, evolutionary conservation, or the binding of enhancer-associated proteins. We find that VISTA enhancers active in embryonic heart are easier to identify than enhancers active in several other embryonic tissues, likely due to their uniquely high GC content. We applied EnhancerFinder to the entire human genome and predicted 84,301 developmental enhancers and their tissue specificity. These predictions provide specific functional annotations for large amounts of human non-coding DNA, and are significantly enriched near genes with annotated roles in their predicted tissues and lead SNPs from genome-wide association studies. We demonstrate the utility of EnhancerFinder predictions through in vivo validation of novel embryonic gene regulatory enhancers from three developmental transcription factor loci. Our genome-wide developmental enhancer predictions are freely available as a UCSC Genome Browser track, which we hope will enable

  9. Freshwater aspects of anadromous salmonid enhancement

    USGS Publications Warehouse

    Gould, Rowan W.

    1982-01-01

    Freshwater enhancement of anadromous salmonid populations has been practiced in the United States and Canada since the late 1800's. Reduction of natural spawning habitat and increasing fishing pressure make artificial enhancement a possible alternative to declining populations. Enhancement of anadromous salmonids involved improvement of the natural environment and reducing natural mortality. Methods of enhancement include fishways, spawning and rearing channels, stream rehabilitation, lake fertilization, environmental management, and artificial propagation techniques. Five Pacific salmon species and steelhead trout are commonly enhanced, primarily in watershed entering the Pacific Ocean and Great Lakes. Enhancement efforts contribute heavily to a commercial and sport industry realizing over $1.5 billion.

  10. Polycarboxylates Enhance Beetle Antifreeze Protein Activity

    PubMed Central

    Amornwittawat, Natapol; Wang, Sen; Duman, John G.; Wen, Xin

    2008-01-01

    Summary Antifreeze proteins (AFPs) lower the noncolligative freezing point of water in the presence of ice below the ice melting point. The temperature difference between the melting point and the noncolligative freezing point is termed thermal hysteresis (TH). The magnitude of the TH depends on the specific activity and the concentration of AFP, and the concentration of enhancers in the solution. Known enhancers are certain low molecular mass molecules and proteins. Here, we investigated a series of polycarboxylates that enhance the TH activity of an AFP from the beetle Dendroides canadensis (DAFP) using differential scanning calorimetry (DSC). Triethylenetetramine-N,N,N′,N″,N‴,N‴-hexaacetate, the most efficient enhancer identified in this work, can increase the TH of DAFP by nearly 1.5 fold over than that of the published best enhancer, citrate. The Zn2+ coordinated carboxylate results in loss of the enhancement ability of the carboxylate on antifreeze activity. There is not an additional increase in TH when a weaker enhancer is added to a stronger enhancer solution. These observations suggest that the more carboxylate groups per enhancer molecule the better the efficiency of the enhancer and that the freedom of motion of these molecules is necessary for them to serve as enhancers for AFP. The hydroxyl groups in the enhancer molecules can also positively affect their TH enhancement efficiency, though not as strongly as carboxylate groups. Mechanisms are discussed. PMID:18620083

  11. Gasdynamic enhancement of nonpremixed combustion

    SciTech Connect

    Marble, F.E.

    1994-12-31

    To promote efficient performance of very high speed air-breathing propulsion systems, the combustor Mach number must be of the order of six for a flight Mach number of 18. Because of this high gas speed through the combustor, mixing rates of hydrogen fuel with air must be very rapid in order to allow a combustor of reasonable length. It is proposed to enhance the rate of mixing and combustion of hydrogen and air, and thereby reduce combustor length, through the introduction of streamwise vorticity generated by the interaction of a weak oblique shock wave with the density gradient between air and a cylindrical jet of hydrogen. Because of the high Mach number flow in the combustor, the oblique shock traverses the jet at a small angle with respect to the free stream direction, and the principle of slender body theory allows one conceptually to replace the three-dimensional steady flow with a two-dimensional unsteady flow. As a consequence, two-dimensional time-dependent computational studies and an extensive experimental shock tube investigation were employed to assess mixing rates for the steady flow in the combustor. The results indicated that under realistic conditions, adequate mixing could be accomplished within 1 ms, a rate that was technologically interesting. Encouraged by these experiments, a ``practical`` injector, utilizing shock-enhanced mixing, was designed for a combustor having a free stream Mach number of 6.0. A detailed aerodynamic and mixing investigation was carried out in the Mach 6 High Reynolds Number Tunnel at the NASA-Langley Research Center. The results confirmed both the details and the overall effectiveness of the shock-enhanced mixing concept.

  12. Permeability enhancement by shock cooling

    NASA Astrophysics Data System (ADS)

    Griffiths, Luke; Heap, Michael; Reuschlé, Thierry; Baud, Patrick; Schmittbuhl, Jean

    2015-04-01

    The permeability of an efficient reservoir, e.g. a geothermal reservoir, should be sufficient to permit the circulation of fluids. Generally speaking, permeability decreases over the life cycle of the geothermal system. As a result, is usually necessary to artificially maintain and enhance the natural permeability of these systems. One of the methods of enhancement -- studied here -- is thermal stimulation (injecting cold water at low pressure). This goal of this method is to encourage new thermal cracks within the reservoir host rocks, thereby increasing reservoir permeability. To investigate the development of thermal microcracking in the laboratory we selected two granites: a fine-grained (Garibaldi Grey granite, grain size = 0.5 mm) and a course-grained granite (Lanhelin granite, grain size = 2 mm). Both granites have an initial porosity of about 1%. Our samples were heated to a range of temperatures (100-1000 °C) and were either cooled slowly (1 °C/min) or shock cooled (100 °C/s). A systematic microstructural (2D crack area density, using standard stereological techniques, and 3D BET specific surface area measurements) and rock physical property (porosity, P-wave velocity, uniaxial compressive strength, and permeability) analysis was undertaken to understand the influence of slow and shock cooling on our reservoir granites. Microstructurally, we observe that the 2D crack surface area per unit volume and the specific surface area increase as a result of thermal stressing, and, for the same maximum temperature, crack surface area is higher in the shock cooled samples. This observation is echoed by our rock physical property measurements: we see greater changes for the shock cooled samples. We can conclude that shock cooling is an extremely efficient method of generating thermal microcracks and modifying rock physical properties. Our study highlights that thermal treatments are likely to be an efficient method for the "matrix" permeability enhancement of

  13. Enhanced radiation resistant fiber optics

    DOEpatents

    Lyons, Peter B.; Looney, Larry D.

    1993-01-01

    A process for producing an optical fiber having enhanced radiation resitance is provided, the process including maintaining an optical fiber within a hydrogen-containing atmosphere for sufficient time to yield a hydrogen-permeated optical fiber having an elevated internal hydrogen concentration, and irradiating the hydrogen-permeated optical fiber at a time while the optical fiber has an elevated internal hydrogen concentration with a source of ionizing radiation. The radiation source is typically a cobalt-60 source and the fiber is pre-irradiated with a dose level up to about 1000 kilorads of radiation.

  14. Enhanced radiation resistant fiber optics

    DOEpatents

    Lyons, P.B.; Looney, L.D.

    1993-11-30

    A process for producing an optical fiber having enhanced radiation resistance is provided, the process including maintaining an optical fiber within a hydrogen-containing atmosphere for sufficient time to yield a hydrogen-permeated optical fiber having an elevated internal hydrogen concentration, and irradiating the hydrogen-permeated optical fiber at a time while the optical fiber has an elevated internal hydrogen concentration with a source of ionizing radiation. The radiation source is typically a cobalt-60 source and the fiber is pre-irradiated with a dose level up to about 1000 kilorads of radiation. 4 figures.

  15. Enhancement of polyisoprene latex production

    NASA Technical Reports Server (NTRS)

    Bauman, Albert J. (Inventor)

    1979-01-01

    Production of high molecular weight polyisoprene latex is enhanced by administering to plants, particularly Guayule Plants, an amine containing at least one two-carbon chain substituent and preferably substituted trialkylamine of the general structure: ##STR1## where R.sub.4, R.sub.5 and R.sub.6 are alkyl, preferably ethyl and at least one of R.sub.4, R.sub.5 and R.sub.6 is preferably an electron withdrawing group substituted aryloxy or arylthio ethyl group.

  16. Privacy-enhanced electronic mail

    NASA Astrophysics Data System (ADS)

    Bishop, Matt

    1990-06-01

    The security of electronic mail sent through the Internet may be described in exactly three words: there is none. The Privacy and Security Research Group has recommended implementing mechanisms designed to provide security enhancements. The first set of mechanisms provides a protocol to provide privacy, integrity, and authentication for electronic mail; the second provides a certificate-based key management infrastructure to support key distribution throughout the internet, to support the first set of mechanisms. These mechanisms are described, as well as the reasons behind their selection and how these mechanisms can be used to provide some measure of security in the exchange of electronic mail.

  17. Intralymphatic immunization enhances DNA vaccination

    NASA Astrophysics Data System (ADS)

    Maloy, Kevin J.; Erdmann, Iris; Basch, Veronique; Sierro, Sophie; Kramps, Thomas A.; Zinkernagel, Rolf M.; Oehen, Stefan; Kündig, Thomas M.

    2001-03-01

    Although DNA vaccines have been shown to elicit potent immune responses in animal models, initial clinical trials in humans have been disappointing, highlighting a need to optimize their immunogenicity. Naked DNA vaccines are usually administered either i.m. or intradermally. The current study shows that immunization with naked DNA by direct injection into a peripheral lymph node enhances immunogenicity by 100- to 1,000-fold, inducing strong and biologically relevant CD8+ cytotoxic T lymphocyte responses. Because injection directly into a lymph node is a rapid and easy procedure in humans, these results have important clinical implications for DNA vaccination.

  18. Nutritional Supplements to Enhance Recovery

    NASA Astrophysics Data System (ADS)

    Ziegenfuss, Tim N.; Landis, Jamie; Greenwood, Mike

    The ability to recover from intense exercise often separates good athletes from great ones. In the past, "recovery" often simply included rest, physical modalities (e.g., massage, hydration therapy) and meeting basic nutritional needs for fluid and energy intake. Today, athletes have a number of additional options to help them recover from high intensity training, one of which includes the judicious use of dietary supplements. This chapter briefly reviews nutritional strategies that have a strong theoretical background for enhancing rehydration/electrolyte balance, replenishing energy reserves, minimizing oxidative damage, and stimulating muscle repair.

  19. Enhanced Master Controller Unit Tester

    NASA Technical Reports Server (NTRS)

    Benson, Patricia; Johnson, Yvette; Johnson, Brian; Williams, Philip; Burton, Geoffrey; McCoy, Anthony

    2007-01-01

    The Enhanced Master Controller Unit Tester (EMUT) software is a tool for development and testing of software for a master controller (MC) flight computer. The primary function of the EMUT software is to simulate interfaces between the MC computer and external analog and digital circuitry (including other computers) in a rack of equipment to be used in scientific experiments. The simulations span the range of nominal, off-nominal, and erroneous operational conditions, enabling the testing of MC software before all the equipment becomes available.

  20. Enhancing professionalism at GPU Nuclear

    SciTech Connect

    Coe, R.P. )

    1992-01-01

    Late in 1988, GPU Nuclear embarked on a major program aimed at enhancing professionalism at its Oyster Creek and Three Mile Island nuclear generating stations. The program was also to include its corporate headquarters in Parsippany, New Jersey. The overall program was to take several directions, including on-site degree programs, a sabbatical leave-type program for personnel to finish college degrees, advanced technical training for licensed staff, career progression for senior reactor operators, and expanded teamwork and leadership training for control room crew. The largest portion of this initiative was the development and delivery of professionalism training to the nearly 2,000 people at both nuclear generating sites.

  1. Computer Program Helps Enhance Images

    NASA Technical Reports Server (NTRS)

    Stanfill, Daniel F., IV

    1994-01-01

    Pixel Pusher is Macintosh application program for viewing and performing minor enhancements on imagery. Works with color images digitized to 8 bits. Reads image files in JPL's two primary image formats VICAR and PDS as well as in Macintosh PICT format. VICAR (NPO-18076) handles array of image-processing capabilities used for variety of applications, including processing of biomedical images, cartography, imaging of Earth resources, and geological exploration. Pixel Pusher also imports color lookup tables in VICAR format for viewing images in pseudocolor (256 colors). Written in Symantec's Think C.

  2. Feedback enhanced plasma spray tool

    DOEpatents

    Gevelber, Michael Alan; Wroblewski, Donald Edward; Fincke, James Russell; Swank, William David; Haggard, Delon C.; Bewley, Randy Lee

    2005-11-22

    An improved automatic feedback control scheme enhances plasma spraying of powdered material through reduction of process variability and providing better ability to engineer coating structure. The present inventors discovered that controlling centroid position of the spatial distribution along with other output parameters, such as particle temperature, particle velocity, and molten mass flux rate, vastly increases control over the sprayed coating structure, including vertical and horizontal cracks, voids, and porosity. It also allows improved control over graded layers or compositionally varying layers of material, reduces variations, including variation in coating thickness, and allows increasing deposition rate. Various measurement and system control schemes are provided.

  3. Elastic mismatch enhances cell motility

    NASA Astrophysics Data System (ADS)

    Bresler, Yony; Palmieri, Benoit; Grant, Martin

    In recent years, the study of physics phenomena in cancer has drawn considerable attention. In cancer metastasis, a soft cancer cell leaves the tumor, and must pass through the endothelium before reaching the bloodstream. Using a phase-field model we have shown that the elasticity mismatch between cells alone is sufficient to enhance the motility of thesofter cancer cell by means of bursty migration, in agreement with experiment. We will present further characterization of these behaviour, as well as new possible applications for this model.

  4. Enhancing the crisis management briefing.

    PubMed

    Clark, Daniel W; Volkmann, Peter

    2005-01-01

    The Crisis Management Briefing (CMB) is a powerful and versatile crisis intervention tool, effective within a wide variety of populations, settings, and critical incidents. Initially proposed by Everly (2000), the CMB uniquely fills the factual information void following a critical incident. Additionally, a CMB provides essential information on effective coping strategies and available helping resources, tailored to the specific incident(s). The authors expand on the original CMB construct using their combined field experience, offering recommendations on team composition, strategic planning factors, using CISDs vs. CMBs, and specific enhancements for the four phases. They conclude with examples of specific interventions across a variety of events to illustrate their recommendations.

  5. Enhanced thermopower of gated silicene

    NASA Astrophysics Data System (ADS)

    Yan, Yonghong; Wu, Haifei; Jiang, Feng; Zhao, Hui

    2013-11-01

    We theoretically investigate the thermopower of silicene systems in an external electric field perpendicular to the silicene sheet. In the absence of the field, we estimate that the thermopower of pure silicene is of order ˜80 μV/K. When a finite field is applied, a comparatively big band gap is opened and the thermopower is thus enhanced by several times as compared with the case without the field. The effect of disorder is also studied, and we find only minimal difference.

  6. Helium and Enhanced Image of the Sun

    NASA Video Gallery

    This video blinks between an image in Helium and an enhanced image. The original image is from AIA on SDO and the enhanced image was created at the LM Solar and Astrophysics Laboratory (LMSAL) by D...

  7. ATAMM enhancement and multiprocessor performance evaluation

    NASA Technical Reports Server (NTRS)

    Stoughton, John W.; Mielke, Roland R.; Som, Sukhamoy; Obando, Rodrigo; Malekpour, Mahyar R.; Jones, Robert L., III; Mandala, Brij Mohan V.

    1991-01-01

    ATAMM (Algorithm To Architecture Mapping Model) enhancement and multiprocessor performance evaluation is discussed. The following topics are included: the ATAMM model; ATAMM enhancement; ADM (Advanced Development Model) implementation of ATAMM; and ATAMM support tools.

  8. DENdb: database of integrated human enhancers.

    PubMed

    Ashoor, Haitham; Kleftogiannis, Dimitrios; Radovanovic, Aleksandar; Bajic, Vladimir B

    2015-01-01

    Enhancers are cis-acting DNA regulatory regions that play a key role in distal control of transcriptional activities. Identification of enhancers, coupled with a comprehensive functional analysis of their properties, could improve our understanding of complex gene transcription mechanisms and gene regulation processes in general. We developed DENdb, a centralized on-line repository of predicted enhancers derived from multiple human cell-lines. DENdb integrates enhancers predicted by five different methods generating an enriched catalogue of putative enhancers for each of the analysed cell-lines. DENdb provides information about the overlap of enhancers with DNase I hypersensitive regions, ChIP-seq regions of a number of transcription factors and transcription factor binding motifs, means to explore enhancer interactions with DNA using several chromatin interaction assays and enhancer neighbouring genes. DENdb is designed as a relational database that facilitates fast and efficient searching, browsing and visualization of information. Database URL: http://www.cbrc.kaust.edu.sa/dendb/. PMID:26342387

  9. Cross-talk between interferon-gamma and interleukin-18 in melanogenesis.

    PubMed

    Zhou, Jia; Ling, Jingjing; Wang, Yong; Shang, Jing; Ping, Fengfeng

    2016-10-01

    Skin is the largest organ in our body and strategically placed to provide a metabolically active biological barrier against a range of noxious stressors. A lot of inflammatory cytokines, which are increased after ultraviolet (UV) irradiation produced by keratinocytes or other immunocytes, are closely related to pigmentary changes, including interleukin-18 (IL-18) and interferon-γ (IFN-γ). In this study, the effect of cross-talk between IL-18 and IFN-γ on melanogenesis was investigated. Treatment with IL-18 resulted in a dose-dependent increase of melanogenesis, while IFN-γ made an opposite effect. This influence of IL-18 and IFN-γ was mediated by regulations of microphthalmia-associated transcription factor (MITF) and its downstream enzymatic cascade expressions. Furthermore, IFN-γ inhibited basal and IL-18-induced melanogenesis. IFN-γ increased signal transducer and activator of transcription-1 (STAT-1) phosphorylation to play its position in regulating melanin pigmentation, and its inhibitory effect could be prevented by Janus Kinase 1 (JAK 1) inhibitor. IFN-γ could inhibit melanogenesis by decreasing melanocyte dendrite formation. In addition, IFN-γ inhibited the expressions of Rab Pases to suppress the mature and transport of melanosomes. IL-18 could rapidly induce Akt and PTEN phosphorylation and p65 expression in B16F10 cells. When treatment with IL-18 and IFN-γ together, the phosphorylation level of Protein Kinase B (Akt) and phosphatase and tensin homolog deleted on chromosome ten (PTEN) and expression of p65 NF-κB were inhibited, compared with treated with IL-18 only. Our studies indicated that IFN-γ could directly induce B16F10 cells apoptosis in vitro. Furthermore, we demonstrated that IFN-γ markedly up-regulated IL-18 binding protein (BP) production in normal human foreskin-derived epidermal keratinocytes in dose-dependent manner. UVB irradiation induced protease-activated receptor-2 (PAR-2) expression in NHEK, IFN-γ could inhibit this

  10. Cross-talk between interferon-gamma and interleukin-18 in melanogenesis.

    PubMed

    Zhou, Jia; Ling, Jingjing; Wang, Yong; Shang, Jing; Ping, Fengfeng

    2016-10-01

    Skin is the largest organ in our body and strategically placed to provide a metabolically active biological barrier against a range of noxious stressors. A lot of inflammatory cytokines, which are increased after ultraviolet (UV) irradiation produced by keratinocytes or other immunocytes, are closely related to pigmentary changes, including interleukin-18 (IL-18) and interferon-γ (IFN-γ). In this study, the effect of cross-talk between IL-18 and IFN-γ on melanogenesis was investigated. Treatment with IL-18 resulted in a dose-dependent increase of melanogenesis, while IFN-γ made an opposite effect. This influence of IL-18 and IFN-γ was mediated by regulations of microphthalmia-associated transcription factor (MITF) and its downstream enzymatic cascade expressions. Furthermore, IFN-γ inhibited basal and IL-18-induced melanogenesis. IFN-γ increased signal transducer and activator of transcription-1 (STAT-1) phosphorylation to play its position in regulating melanin pigmentation, and its inhibitory effect could be prevented by Janus Kinase 1 (JAK 1) inhibitor. IFN-γ could inhibit melanogenesis by decreasing melanocyte dendrite formation. In addition, IFN-γ inhibited the expressions of Rab Pases to suppress the mature and transport of melanosomes. IL-18 could rapidly induce Akt and PTEN phosphorylation and p65 expression in B16F10 cells. When treatment with IL-18 and IFN-γ together, the phosphorylation level of Protein Kinase B (Akt) and phosphatase and tensin homolog deleted on chromosome ten (PTEN) and expression of p65 NF-κB were inhibited, compared with treated with IL-18 only. Our studies indicated that IFN-γ could directly induce B16F10 cells apoptosis in vitro. Furthermore, we demonstrated that IFN-γ markedly up-regulated IL-18 binding protein (BP) production in normal human foreskin-derived epidermal keratinocytes in dose-dependent manner. UVB irradiation induced protease-activated receptor-2 (PAR-2) expression in NHEK, IFN-γ could inhibit this

  11. Textual Enhancement of Input: Issues and Possibilities

    ERIC Educational Resources Information Center

    Han, ZhaoHong; Park, Eun Sung; Combs, Charles

    2008-01-01

    The input enhancement hypothesis proposed by Sharwood Smith (1991, 1993) has stimulated considerable research over the last 15 years. This article reviews the research on textual enhancement of input (TE), an area where the majority of input enhancement studies have aggregated. Methodological idiosyncrasies are the norm of this body of research.…

  12. Transcriptional enhancer from milk protein genes

    DOEpatents

    Casperson, Gerald F.; Schmidhauser, Christian T.; Bissell, Mina J.

    1999-01-01

    The invention relates to novel enhancer nucleotide sequences which stimulate transcription of heterologous DNA in cells in culture. The enhancers are derived from major milk protein genes by the process of deletion mapping and functional analysis. The invention also relates to expression vectors containing the novel enhancers.

  13. Real-time digital image enhancement

    NASA Technical Reports Server (NTRS)

    Woods, R. E.; Gonzalez, R. C.

    1981-01-01

    A programmable system for enhancing monocular and stereographic images at video rates is presented. The system provides both automatic and interactive enhancement modes based on histogram modification and intensity mapping techniques. Experimental results which illustrate enhancement capabilities under a variety of scene types and conditions are described.

  14. RTU Comparison Calculator Enhancement Plan

    SciTech Connect

    Miller, James D.; Wang, Weimin; Katipamula, Srinivas

    2015-07-01

    Over the past two years, Department of Energy’s Building Technologies Office (BTO) has been investigating ways to increase the operating efficiency of the packaged rooftop units (RTUs) in the field. First, by issuing a challenge to the RTU manufactures to increase the integrated energy efficiency ratio (IEER) by 60% over the existing ASHRAE 90.1-2010 standard. Second, by evaluating the performance of an advanced RTU controller that reduces the energy consumption by over 40%. BTO has previously also funded development of a RTU comparison calculator (RTUCC). RTUCC is a web-based tool that provides the user a way to compare energy and cost savings for two units with different efficiencies. However, the RTUCC currently cannot compare savings associated with either the RTU Challenge unit or the advanced RTU controls retrofit. Therefore, BTO has asked PNNL to enhance the tool so building owners can compare energy and savings associated with this new class of products. This document provides the details of the enhancements that are required to support estimating energy savings from use of RTU challenge units or advanced controls on existing RTUs.

  15. Chromophore-enhanced bacterial photothermolysis

    NASA Astrophysics Data System (ADS)

    Huckleby, Jana K.; Morton, Rebecca J.; Bartels, Kenneth E.

    1999-06-01

    The use of chromophore dyes to enhance the bactericidal effect of laser energy was studied as a means to optimize laser treatment for the decontamination of wound. Using an in vitro study, various concentrations of indocyanine green (ICG), carbon black, and fluorescein were mixed with a suspension of bacteria and plated on tryptic soy agar. Plates were exposed to a laser beam of 10-15 watts for times ranging from 0 to 180 seconds, incubated overnight, and colony counts were performed. Bacteria not mixed with chromophore were used as controls. Six bacterial strains encompassing a range of bacterial types were used: Staphylococcus aureau, Streptococcus pyogenes, Escherichia coli, Pseudomonas aeruginosa, Bacillus cereus spore suspensions, and Clostridium perfringens. Laser treatment alone had no effect on any of the bacteria. Significant killing of gram-positive bacteria, including spores of Bacillus cereus, was observed only with the use of ICG and diode laser energy. No effect was observed using any of the chromophores on the gram-negative bacteria. The results of this study indicate that successful killing of gram-positive bacteria can be achieved using ICG combined with appropriate laser energy and wavelength. Efforts to enhance the susceptibility of gram-negative bacteria to photothermolysis by laser energy were unsuccessful.

  16. Thermal Enhanced Vapor Extraction System

    SciTech Connect

    Phelan, J.M.

    1992-01-01

    At some landfills, hazardous wastes were placed into disposal pits with other waste oils. Volatile organic wastes, such as cleaning solvents, when combined with oil are much more difficult to remove from the soils because the oil makes the volatile organic chemical evaporate much slower. The typical vacuum extraction remediation method could become a lengthy campaign. Since all chemicals evaporate faster when they are heated, if the contaminated soil could be heated, the chemicals would be easier to remove from the soil. By using heating techniques developed by the Oil and Gas Industry to enhance the removal of oil and gas resources from the soil, the problem of removing contamination from the soils could be solved. The Thermal Enhanced Vapor Extraction System (TEVES) demonstration will combine vacuum vapor extraction technology with powerline frequency soil heating and radiofrequency soil heating to accelerate the soil decontamination process. The premise that soil heating technology can actually reduce the costs of soil decontamination is complicated by the high capital costs of the soil heating equipment and the cost of electrode installation. By performing this field demonstration, Sandia will be able to collect the information needed to see if this new technology will improve the decontamination of soils.

  17. Thermal Enhanced Vapor Extraction System

    SciTech Connect

    Phelan, J.M.

    1992-12-31

    At some landfills, hazardous wastes were placed into disposal pits with other waste oils. Volatile organic wastes, such as cleaning solvents, when combined with oil are much more difficult to remove from the soils because the oil makes the volatile organic chemical evaporate much slower. The typical vacuum extraction remediation method could become a lengthy campaign. Since all chemicals evaporate faster when they are heated, if the contaminated soil could be heated, the chemicals would be easier to remove from the soil. By using heating techniques developed by the Oil and Gas Industry to enhance the removal of oil and gas resources from the soil, the problem of removing contamination from the soils could be solved. The Thermal Enhanced Vapor Extraction System (TEVES) demonstration will combine vacuum vapor extraction technology with powerline frequency soil heating and radiofrequency soil heating to accelerate the soil decontamination process. The premise that soil heating technology can actually reduce the costs of soil decontamination is complicated by the high capital costs of the soil heating equipment and the cost of electrode installation. By performing this field demonstration, Sandia will be able to collect the information needed to see if this new technology will improve the decontamination of soils.

  18. Electrokinetic Microstrirring to Enhance Immunoassays

    NASA Astrophysics Data System (ADS)

    Feldman, Hope; Sigurdson, Marin; Meinhart, Carl

    2006-11-01

    Electrokinetic microstirring is used to improve the sensitivity of microfluidic heterogeneous immuno-sensors by enhancing the transport in diffusion-limited reactions. The AC electrokinetic force, Electrothermal Flow, is exploited to create a circular stirring fluid motion, thereby providing more binding opportunities between suspended and wall-immobilized molecules. This process can significantly reduce test times, important for both field-portable biosensors and for lab-based assays. A 2-D numerical simulation model is used to predict the effect of electrothermal flow on a heterogeneous immunoassay resulting from an AC potential applied to two parallel electrodes. The binding is increased by a factor of 7 for an applied voltage of 10 Vrms. The effect was investigated experimentally using a high affinity biotin-streptavidin reaction. Microstirred reaction rates were compared with passive reactions. The measurements show on average an order of magnitude increase in binding between immobilized biotin and fluorescently-labeled streptavidin after 5 minutes. Therefore, this technique shows significant promise for reducing incubation time and enhancing the sensitivity of immunoassays.

  19. Defense mutualisms enhance plant diversification.

    PubMed

    Weber, Marjorie G; Agrawal, Anurag A

    2014-11-18

    The ability of plants to form mutualistic relationships with animal defenders has long been suspected to influence their evolutionary success, both by decreasing extinction risk and by increasing opportunity for speciation through an expanded realized niche. Nonetheless, the hypothesis that defense mutualisms consistently enhance plant diversification across lineages has not been well tested due to a lack of phenotypic and phylogenetic information. Using a global analysis, we show that the >100 vascular plant families in which species have evolved extrafloral nectaries (EFNs), sugar-secreting organs that recruit arthropod mutualists, have twofold higher diversification rates than families that lack species with EFNs. Zooming in on six distantly related plant clades, trait-dependent diversification models confirmed the tendency for lineages with EFNs to display increased rates of diversification. These results were consistent across methodological approaches. Inference using reversible-jump Markov chain Monte Carlo (MCMC) to model the placement and number of rate shifts revealed that high net diversification rates in EFN clades were driven by an increased number of positive rate shifts following EFN evolution compared with sister clades, suggesting that EFNs may be indirect facilitators of diversification. Our replicated analysis indicates that defense mutualisms put lineages on a path toward increased diversification rates within and between clades, and is concordant with the hypothesis that mutualistic interactions with animals can have an impact on deep macroevolutionary patterns and enhance plant diversity.

  20. Potential MCNP enhancements for NCT

    SciTech Connect

    Estes, G.P.; Taylor, W.M.

    1992-12-01

    MCNP a Monte Carlo radiation transport code, is currently widely used in the medical community for a variety of purposes including treatment planning, diagnostics, beam design, tomographic studies, and radiation protection. This is particularly true in the Neutron Capture Therapy (NCT) community. The current widespread medical use of MCNP after its general public distribution in about 1980 attests to the code`s general versatility and usefulness, particularly since its development to date has not been influenced by medical applications. This paper discusses enhancements to MCNP that could be implemented at Los Alamos for the benefit of the NCT community. These enhancements generally fall into two categories, namely those that have already been developed to some extent but are not yet publicly available, and those that seem both needed based on our current understanding of NCT goals, and achievable based on our working knowledge of the MCNP code. MCNP is a general, coupled neutron/photon/electron Monte Carlo code developed and maintained by the Radiation Transport Group at Los Alamos. It has been used extensively for radiation shielding studies, reactor analysis, detector design, physics experiment interpretation, oil and gas well logging, radiation protection studies, accelerator design, etc. over the years. MCNP is a three-dimensional geometry, continuous energy physics code capable of modeling complex geometries, specifying material regions such as organs by the intersections of analytical surfaces.

  1. Enhanced modeling features within TREETOPS

    NASA Technical Reports Server (NTRS)

    Vandervoort, R. J.; Kumar, Manoj N.

    1989-01-01

    The original motivation for TREETOPS was to build a generic multi-body simulation and remove the burden of writing multi-body equations from the engineers. The motivation of the enhancement was twofold: (1) to extend the menu of built-in features (sensors, actuators, constraints, etc.) that did not require user code; and (2) to extend the control system design capabilities by linking with other government funded software (NASTRAN and MATLAB). These enhancements also serve to bridge the gap between structures and control groups. It is common on large space programs for the structures groups to build hi-fidelity models of the structure using NASTRAN and for the controls group to build lower order models because they lack the tools to incorporate the former into their analysis. Now the controls engineers can accept the hi-fidelity NASTRAN models into TREETOPS, add sensors and actuators, perform model reduction and couple the result directly into MATLAB to perform their design. The controller can then be imported directly into TREETOPS for non-linear, time-history simulation.

  2. RTU Comparison Calculator Enhancement Plan

    SciTech Connect

    Miller, James D.; Wang, Weimin; Katipamula, Srinivas

    2014-03-31

    Over the past two years, Department of Energy’s Building Technologies Office (BTO) has been investigating ways to increase the operating efficiency of the packaged rooftop units (RTUs) in the field. First, by issuing a challenge to the RTU manufactures to increase the integrated energy efficiency ratio (IEER) by 60% over the existing ASHRAE 90.1-2010 standard. Second, by evaluating the performance of an advanced RTU controller that reduces the energy consumption by over 40%. BTO has previously also funded development of a RTU comparison calculator (RTUCC). RTUCC is a web-based tool that provides the user a way to compare energy and cost savings for two units with different efficiencies. However, the RTUCC currently cannot compare savings associated with either the RTU Challenge unit or the advanced RTU controls retrofit. Therefore, BTO has asked PNNL to enhance the tool so building owners can compare energy and savings associated with this new class of products. This document provides the details of the enhancements that are required to support estimating energy savings from use of RTU challenge units or advanced controls on existing RTUs.

  3. Psychopharmacological enhancement: a conceptual framework

    PubMed Central

    2012-01-01

    The availability of a range of new psychotropic agents raises the possibility that these will be used for enhancement purposes (smart pills, happy pills, and pep pills). The enhancement debate soon raises questions in philosophy of medicine and psychiatry (eg, what is a disorder?), and this debate in turn raises fundament questions in philosophy of language, science, and ethics. In this paper, a naturalistic conceptual framework is proposed for addressing these issues. This framework begins by contrasting classical and critical concepts of categories, and then puts forward an integrative position that is based on cognitive-affective research. This position can in turn be used to consider the debate between pharmacological Calvinism (which may adopt a moral metaphor of disorder) and psychotropic utopianism (which may emphasize a medical metaphor of disorder). I argue that psychiatric treatment of serious psychiatric disorders is justified, and that psychotropics are an acceptable kind of intervention. The use of psychotropics for sub-threshold phenomena requires a judicious weighing of the relevant facts (which are often sparse) and values. PMID:22244084

  4. Defense mutualisms enhance plant diversification

    PubMed Central

    Weber, Marjorie G.; Agrawal, Anurag A.

    2014-01-01

    The ability of plants to form mutualistic relationships with animal defenders has long been suspected to influence their evolutionary success, both by decreasing extinction risk and by increasing opportunity for speciation through an expanded realized niche. Nonetheless, the hypothesis that defense mutualisms consistently enhance plant diversification across lineages has not been well tested due to a lack of phenotypic and phylogenetic information. Using a global analysis, we show that the >100 vascular plant families in which species have evolved extrafloral nectaries (EFNs), sugar-secreting organs that recruit arthropod mutualists, have twofold higher diversification rates than families that lack species with EFNs. Zooming in on six distantly related plant clades, trait-dependent diversification models confirmed the tendency for lineages with EFNs to display increased rates of diversification. These results were consistent across methodological approaches. Inference using reversible-jump Markov chain Monte Carlo (MCMC) to model the placement and number of rate shifts revealed that high net diversification rates in EFN clades were driven by an increased number of positive rate shifts following EFN evolution compared with sister clades, suggesting that EFNs may be indirect facilitators of diversification. Our replicated analysis indicates that defense mutualisms put lineages on a path toward increased diversification rates within and between clades, and is concordant with the hypothesis that mutualistic interactions with animals can have an impact on deep macroevolutionary patterns and enhance plant diversity. PMID:25349406

  5. Resolution-enhanced Mapping Spectrometer

    NASA Technical Reports Server (NTRS)

    Kumer, J. B.; Aubrun, J. N.; Rosenberg, W. J.; Roche, A. E.

    1993-01-01

    A familiar mapping spectrometer implementation utilizes two dimensional detector arrays with spectral dispersion along one direction and spatial along the other. Spectral images are formed by spatially scanning across the scene (i.e., push-broom scanning). For imaging grating and prism spectrometers, the slit is perpendicular to the spatial scan direction. For spectrometers utilizing linearly variable focal-plane-mounted filters the spatial scan direction is perpendicular to the direction of spectral variation. These spectrometers share the common limitation that the number of spectral resolution elements is given by the number of pixels along the spectral (or dispersive) direction. Resolution enhancement by first passing the light input to the spectrometer through a scanned etalon or Michelson is discussed. Thus, while a detector element is scanned through a spatial resolution element of the scene, it is also temporally sampled. The analysis for all the pixels in the dispersive direction is addressed. Several specific examples are discussed. The alternate use of a Michelson for the same enhancement purpose is also discussed. Suitable for weight constrained deep space missions, hardware systems were developed including actuators, sensor, and electronics such that low-resolution etalons with performance required for implementation would weigh less than one pound.

  6. Cavity-Enhanced Ultrafast Spectroscopy

    NASA Astrophysics Data System (ADS)

    Allison, Thomas

    2016-05-01

    Ultrafast optical spectroscopy methods, such as transient absorption spectroscopy and 2D-spectroscopy, are widely used across many disciplines. However, these techniques are typically restricted to optically thick samples, such as solids and liquid solutions. Using a frequency comb laser and optical cavities, we present a new technique for performing ultrafast optical spectroscopy with high sensitivity, enabling work in dilute gas-phase molecular beams. Resonantly enhancing the probe pulses, we demonstrate transient absorption measurements with a detection limit of ΔOD = 2 ×10-10 (1 ×10-9 /√{Hz}). Resonantly enhancing the pump pulses allows us to produce a high excitation fraction at high repetition-rate, so that signals can be recorded from samples with optical densities as low as OD 10-8 , or column densities < 1010 molecules/ cm2. To our knowledge, this represents a 5,000-fold improvement of the state-of-the-art. This work was supported by the National Science Foundation under Grant Number 1404296.

  7. Transcriptional enhancers in ascidian development.

    PubMed

    Wang, Wei; Christiaen, Lionel

    2012-01-01

    The study of cis-regulatory DNAs that control developmental gene expression is integral to the modeling of comprehensive genomic regulatory networks for embryogenesis. Ascidian embryos provide a unique opportunity for the analysis of cis-regulatory DNAs with cellular resolution in the context of a simple but typical chordate body plan. Here, we review landmark studies that have laid the foundations for the study of transcriptional enhancers, among other cis-regulatory DNAs, and their roles in ascidian development. The studies using ascidians of the Ciona genus have capitalized on a unique electroporation technique that permits the simultaneous transfection of hundreds of fertilized eggs, which develop rapidly and express transgenes with little mosaicism. Current studies using the ascidian embryo benefit from extensively annotated genomic resources to characterize transcript models in silico. The search for functional noncoding sequences can be guided by bioinformatic analyses combining evolutionary conservation, gene coexpression, and combinations of overrepresented short-sequence motifs. The power of the transient transfection assays has allowed thorough dissection of numerous cis-regulatory modules, which provided insights into the functional constraints that shape enhancer architecture and diversification. Future studies will benefit from pioneering stable transgenic lines and the analysis of chromatin states. Whole genome expression, functional and DNA binding data are being integrated into comprehensive genomic regulatory network models of early ascidian cell specification with a single-cell resolution that is unique among chordate model systems.

  8. Enhanced flue gas conditioning study

    SciTech Connect

    Miller, S.J.; Laudal, D.L.

    1991-11-01

    Many electrostatic precipitators (ESPS) do not achieve acceptable particulate removal efficiencies because of high-resistivity ash. One method to improve ESP performance is to employ chemical conditioning agents to reduce fly ash resistivity. Widely used agents include sulfur trioxide (SO[sub 3]) and ammonia, which are sometimes used simultaneously. For some fly ashes, that have a low affinity for SO[sub 3], conditioning with SO[sub 3] alone is not adequate to reduce resistivity without excessive amounts of SO[sub 3] exiting the stack. In such cases, the use of ammonia in addition to SO[sub 3] may reduce the amount of required SO[sub 3] and prevent the emission of excess SO[sub 3] out of the stack. The general objective of the work was to test enhanced flue gas conditioning methods to improve the performance of ESPS. Specific objectives were to (1) verify the relationship between the required SO[sub 3] injection rates to maintain the desired fly ash resistivity and temperature for four coals, (2) verify that dual conditioning with both ammonia and SO[sub 3] promotes SO[sub 3] utilization and allows for resistivity modification with moderate SO[sub 3] injection rates, and (3) verify the effectiveness and practicality of an enhanced flue gas conditioning (EFGC) method. The EFGC method is a proprietary development of Wahlco, Inc.

  9. Enhancement of confinement in tokamaks

    SciTech Connect

    Furth, H.P.

    1986-05-01

    A plausible interpretation of the experimental evidence is that energy confinement in tokamaks is governed by two separate considerations: (1) the need for resistive MHD kink-stability, which limits the permissible range of current profiles - and therefore normally also the range of temperature profiles; and (2) the presence of strongly anomalous microscopic energy transport near the plasma edge, which calibrates the amplitude of the global temperature profile, thus determining the energy confinement time tau/sub E/. Correspondingly, there are two main paths towards the enhancement of tokamak confinement: (1) Configurational optimization, to increase the MHD-stable energy content of the plasma core, can evidently be pursued by varying the cross-sectional shape of the plasma and/or finding stable radial profiles with central q-values substantially below unity - but crossing from ''first'' to ''second'' stability within the peak-pressure region would have the greatest ultimate potential. (2) Suppression of edge turbulence, so as to improve the heat insulation in the outer plasma shell, can be pursued by various local stabilizing techniques, such as use of a poloidal divertor. The present confinement model and initial TFTR pellet-injection results suggest that the introduction of a super-high-density region within the plasma core should be particularly valuable for enhancing ntau/subE/. In D-T operation, a centrally peaked plasma pressure profile could possibly lend itself to alpha-particle-driven entry into the second-stability regime.

  10. Enhanced Video-Oculography System

    NASA Technical Reports Server (NTRS)

    Moore, Steven T.; MacDougall, Hamish G.

    2009-01-01

    A previously developed video-oculography system has been enhanced for use in measuring vestibulo-ocular reflexes of a human subject in a centrifuge, motor vehicle, or other setting. The system as previously developed included a lightweight digital video camera mounted on goggles. The left eye was illuminated by an infrared light-emitting diode via a dichroic mirror, and the camera captured images of the left eye in infrared light. To extract eye-movement data, the digitized video images were processed by software running in a laptop computer. Eye movements were calibrated by having the subject view a target pattern, fixed with respect to the subject s head, generated by a goggle-mounted laser with a diffraction grating. The system as enhanced includes a second camera for imaging the scene from the subject s perspective, and two inertial measurement units (IMUs) for measuring linear accelerations and rates of rotation for computing head movements. One IMU is mounted on the goggles, the other on the centrifuge or vehicle frame. All eye-movement and head-motion data are time-stamped. In addition, the subject s point of regard is superimposed on each scene image to enable analysis of patterns of gaze in real time.

  11. Optical antenna enhanced spontaneous emission

    PubMed Central

    Eggleston, Michael S.; Messer, Kevin; Zhang, Liming; Yablonovitch, Eli; Wu, Ming C.

    2015-01-01

    Atoms and molecules are too small to act as efficient antennas for their own emission wavelengths. By providing an external optical antenna, the balance can be shifted; spontaneous emission could become faster than stimulated emission, which is handicapped by practically achievable pump intensities. In our experiments, InGaAsP nanorods emitting at ∼200 THz optical frequency show a spontaneous emission intensity enhancement of 35× corresponding to a spontaneous emission rate speedup ∼115×, for antenna gap spacing, d = 40 nm. Classical antenna theory predicts ∼2,500× spontaneous emission speedup at d ∼ 10 nm, proportional to 1/d2. Unfortunately, at d < 10 nm, antenna efficiency drops below 50%, owing to optical spreading resistance, exacerbated by the anomalous skin effect (electron surface collisions). Quantum dipole oscillations in the emitter excited state produce an optical ac equivalent circuit current, Io = qω|xo|/d, feeding the antenna-enhanced spontaneous emission, where q|xo| is the dipole matrix element. Despite the quantum-mechanical origin of the drive current, antenna theory makes no reference to the Purcell effect nor to local density of states models. Moreover, plasmonic effects are minor at 200 THz, producing only a small shift of antenna resonance frequency. PMID:25624503

  12. Plasmonic enhancement of ultraviolet fluorescence

    NASA Astrophysics Data System (ADS)

    Jiao, Xiaojin

    Plasmonics relates to the interaction between electromagnetic radiation and conduction electrons at metallic interfaces or in metallic nanostructures. Surface plasmons are collective electron oscillations at a metal surface, which can be manipulated by shape, texture and material composition. Plasmonic applications cover a broad spectrum from visible to near infrared, including biosensing, nanolithography, spectroscopy, optoelectronics, photovoltaics and so on. However, there remains a gap in this activity in the ultraviolet (UV, < 400 nm), where significant opportunity exists for both fundamental and application research. Motivating factors in the study of UV Plasmonics are the direct access to biomolecular resonances and native fluorescence, resonant Raman scattering interactions, and the potential for exerting control over photochemical reactions. This dissertation aims to fill in the gap of Plasmonics in the UV with efforts of design, fabrication and characterization of aluminium (Al) and magnesium (Mg) nanostructures for the application of label-free bimolecular detection via native UV fluorescence. The first contribution of this dissertation addresses the design of Al nanostructures in the context of UV fluorescence enhancement. A design method that combines analytical analysis with numerical simulation has been developed. Performance of three canonical plasmonic structures---the dipole antenna, bullseye nanoaperture and nanoaperture array---has been compared. The optimal geometrical parameters have been determined. A novel design of a compound bullseye structure has been proposed and numerically analyzed for the purpose of compensating for the large Stokes shift typical of UV fluorescence. Second, UV lifetime modification of diffusing molecules by Al nanoapertures has been experimentally demonstrated for the first time. Lifetime reductions of ~3.5x have been observed for the high quantum yield (QY) laser dye p-terphenyl in a 60 nm diameter aperture with 50

  13. Approach to intensely enhancing neck nodes

    PubMed Central

    Karandikar, Amit; Gummalla, Krishna Mohan; Loke, Siu Cheng; Goh, Julian; Tan, Tiong Yong

    2016-01-01

    Cervical node evaluation is one of the most common problems encountered by a radiologist. Here, we present a pictorial review of intensely enhancing neck nodes. While enhancement in a cervical node is a common radiologic finding on contrast-enhanced computed tomography scan, only few conditions cause intense enhancement in cervical nodes. We discuss the common causes of intensely enhancing neck nodes along with pertinent radiologic features and key differentiating points that aid radiologists in reaching a diagnosis. In addition, we discuss certain potential non-nodal mimics, which need to be excluded. PMID:26782154

  14. NORMAL HUMAN VARIATION: REFOCUSSING THE ENHANCEMENT DEBATE

    PubMed Central

    Kahane, Guy; Savulescu, Julian

    2015-01-01

    This article draws attention to several common mistakes in thinking about biomedical enhancement, mistakes that are made even by some supporters of enhancement. We illustrate these mistakes by examining objections that John Harris has recently raised against the use of pharmacological interventions to directly modulate moral decision-making. We then apply these lessons to other influential figures in the debate about enhancement. One upshot of our argument is that many considerations presented as powerful objections to enhancement are really strong considerations in favour of biomedical enhancement, just in a different direction. Another upshot is that it is unfortunate that much of the current debate focuses on interventions that will radically transform normal human capacities. Such interventions are unlikely to be available in the near future, and may not even be feasible. But our argument shows that the enhancement project can still have a radical impact on human life even if biomedical enhancement operated entirely within the normal human range. PMID:23906367

  15. Hydrodynamic enhanced dielectrophoretic particle trapping

    DOEpatents

    Miles, Robin R.

    2003-12-09

    Hydrodynamic enhanced dielectrophoretic particle trapping carried out by introducing a side stream into the main stream to squeeze the fluid containing particles close to the electrodes producing the dielelectrophoretic forces. The region of most effective or the strongest forces in the manipulating fields of the electrodes producing the dielectrophoretic forces is close to the electrodes, within 100 .mu.m from the electrodes. The particle trapping arrangement uses a series of electrodes with an AC field placed between pairs of electrodes, which causes trapping of particles along the edges of the electrodes. By forcing an incoming flow stream containing cells and DNA, for example, close to the electrodes using another flow stream improves the efficiency of the DNA trapping.

  16. Quantum-enhanced absorption refrigerators

    NASA Astrophysics Data System (ADS)

    Correa, Luis A.; Palao, José P.; Alonso, Daniel; Adesso, Gerardo

    2014-02-01

    Thermodynamics is a branch of science blessed by an unparalleled combination of generality of scope and formal simplicity. Based on few natural assumptions together with the four laws, it sets the boundaries between possible and impossible in macroscopic aggregates of matter. This triggered groundbreaking achievements in physics, chemistry and engineering over the last two centuries. Close analogues of those fundamental laws are now being established at the level of individual quantum systems, thus placing limits on the operation of quantum-mechanical devices. Here we study quantum absorption refrigerators, which are driven by heat rather than external work. We establish thermodynamic performance bounds for these machines and investigate their quantum origin. We also show how those bounds may be pushed beyond what is classically achievable, by suitably tailoring the environmental fluctuations via quantum reservoir engineering techniques. Such superefficient quantum-enhanced cooling realises a promising step towards the technological exploitation of autonomous quantum refrigerators.

  17. Enhanced High Resolution RBS System

    NASA Astrophysics Data System (ADS)

    Pollock, Thomas J.; Hass, James A.; Klody, George M.

    2011-06-01

    Improvements in full spectrum resolution with the second NEC high resolution RBS system are summarized. Results for 50 Å TiN/HfO films on Si yielding energy resolution on the order of 1 keV are also presented. Detector enhancements include improved pulse processing electronics, upgraded shielding for the MCP/RAE detector, and reduced noise generated from pumping. Energy resolution measurements on spectra front edge coupled with calculations using 0.4mStr solid angle show that beam energy spread at 400 KeV from the Pelletron® accelerator is less than 100 eV. To improve user throughput, magnet control has been added to the automatic data collection. Depth profiles derived from experimental data are discussed. For the thin films profiled, depth resolutions were on the Angstrom level with the non-linear energy/channel conversions ranging from 100 to 200 eV.

  18. Enhanced NIF neutron activation diagnostics

    SciTech Connect

    Yeamans, C. B.; Bleuel, D. L.; Bernstein, L. A.

    2012-10-15

    The NIF neutron activation diagnostic suite relies on removable activation samples, leading to operational inefficiencies and a fundamental lower limit on the half-life of the activated product that can be observed. A neutron diagnostic system measuring activation of permanently installed samples could remove these limitations and significantly enhance overall neutron diagnostic capabilities. The physics and engineering aspects of two proposed systems are considered: one measuring the {sup 89}Zr/{sup 89m}Zr isomer ratio in the existing Zr activation medium and the other using potassium zirconate as the activation medium. Both proposed systems could improve the signal-to-noise ratio of the current system by at least a factor of 5 and would allow independent measurement of fusion core velocity and fuel areal density.

  19. Enhancing the US Power Infrastructure

    SciTech Connect

    Charles Alexander

    2010-05-31

    The primary motivation for this set of research activities was to develop a foundation in several aspects of power in order to position Cleveland State University to lead a multiuniversity effort to secure funding for enhanced power system projects and to be able to eventually secure a NASA Space Power Systems Center status through the competitive bidding process. This was accomplished by focusing on these major project areas, (1) the design of the next generation nuclear-electric power generation system, (2) the design of a distributed, fault-tolerant, and modular power system, and (3) the development of the dynamics and control of active magnetic bearings for flywheel energy storage without using conventional sensors.

  20. Feature enhancement and phonological acquisition.

    PubMed

    Yavas, M

    1997-01-01

    Distinctive features have been part of clinical work in phonological assessment and therapy. In almost all studies the set of features used was the Chomsky and Halle system. Stevens and Keyser (1989) offer a new look at distinctive features from the dimension of perceptual saliency, and account for the markedness relationship between segments. This paper explores to what extent it is possible to account for the substitution patterns in child phonologies based on the concepts of feature hierarchy, enhancement, and perceptual saliency as proposed by Stevens and Keyser. Concentrating on the consonantal substitutions in normal and disordered child speech, an attempt is made to distinguish between normal and unusual/idiosyncratic processes. Implications for assessment are discussed. PMID:21271756

  1. Enhanced NIF neutron activation diagnostics.

    PubMed

    Yeamans, C B; Bleuel, D L; Bernstein, L A

    2012-10-01

    The NIF neutron activation diagnostic suite relies on removable activation samples, leading to operational inefficiencies and a fundamental lower limit on the half-life of the activated product that can be observed. A neutron diagnostic system measuring activation of permanently installed samples could remove these limitations and significantly enhance overall neutron diagnostic capabilities. The physics and engineering aspects of two proposed systems are considered: one measuring the (89)Zr/(89 m)Zr isomer ratio in the existing Zr activation medium and the other using potassium zirconate as the activation medium. Both proposed systems could improve the signal-to-noise ratio of the current system by at least a factor of 5 and would allow independent measurement of fusion core velocity and fuel areal density.

  2. Quantum-enhanced absorption refrigerators.

    PubMed

    Correa, Luis A; Palao, José P; Alonso, Daniel; Adesso, Gerardo

    2014-01-01

    Thermodynamics is a branch of science blessed by an unparalleled combination of generality of scope and formal simplicity. Based on few natural assumptions together with the four laws, it sets the boundaries between possible and impossible in macroscopic aggregates of matter. This triggered groundbreaking achievements in physics, chemistry and engineering over the last two centuries. Close analogues of those fundamental laws are now being established at the level of individual quantum systems, thus placing limits on the operation of quantum-mechanical devices. Here we study quantum absorption refrigerators, which are driven by heat rather than external work. We establish thermodynamic performance bounds for these machines and investigate their quantum origin. We also show how those bounds may be pushed beyond what is classically achievable, by suitably tailoring the environmental fluctuations via quantum reservoir engineering techniques. Such superefficient quantum-enhanced cooling realises a promising step towards the technological exploitation of autonomous quantum refrigerators. PMID:24492860

  3. Shale Oil Value Enhancement Research

    SciTech Connect

    James W. Bunger

    2006-11-30

    Raw kerogen oil is rich in heteroatom-containing compounds. Heteroatoms, N, S & O, are undesirable as components of a refinery feedstock, but are the basis for product value in agrochemicals, pharmaceuticals, surfactants, solvents, polymers, and a host of industrial materials. An economically viable, technologically feasible process scheme was developed in this research that promises to enhance the economics of oil shale development, both in the US and elsewhere in the world, in particular Estonia. Products will compete in existing markets for products now manufactured by costly synthesis routes. A premium petroleum refinery feedstock is also produced. The technology is now ready for pilot plant engineering studies and is likely to play an important role in developing a US oil shale industry.

  4. Atomic force microscope: Enhanced sensitivity

    SciTech Connect

    Davis, D.T.

    1995-06-01

    Atomic force microscopes (AFMs) are a recent development representing the state of the art in measuring ultrafine surface features. Applications are found in such fields of research as biology, microfabrication, material studies, and surface chemistry. Fiber-optic interferometer techniques developed at LLNL offer the potential of improving the vertical resolution of these instruments by up to 2 orders of magnitude. We are attempting to replace the current AFM measurement scheme, which consists of an optical beam deflection approach, with our fiber-optic interferometer scheme, a much more sensitive displacement measurement technique. In performing this research, we hope to accomplish two important goals; (1) to enhance the sensitivity of the AFM, and (2) to achieve important improvements in our fiber-optic interferometer technology.

  5. Unrequited: neurochemical enhancement of love.

    PubMed

    Bamford, Rebecca

    2015-07-01

    I raise several concerns with Earp and colleagues' analysis of enhancement through neurochemical modulation of love as a key issue in contemporary neuroethics. These include: (i) strengthening their deflation of medicalization concerns by showing how the objection that love should be left outside of the scope of medicine would directly undermine the goal of medicine; (ii) developing stronger analysis of the social and political concerns relevant to neurochemical modulation of love, by exploring and suggesting possible counters to ways in which 'wellbeing' may be used as a tool of oppression; (iii) providing reasons to support a broad need for ecological investigation of, and indeed ecological education concerning, neurotechnology; (iv) suggesting ways in which philosophy, and the humanities more broadly, remain directly relevant to responding effectively to issues in contemporary neuroethics.

  6. Teacher Enhancement and Preparation Programs

    NASA Technical Reports Server (NTRS)

    1995-01-01

    These two programs provide opportunities for K-12 teachers of mathematics, science, and technology to spend two weeks at a NASA center learning about aeronautics and space. Participants are selected by peer review from a contracting agent that assists NASA in administering the program. Each teacher receives a stipend that covers the cost of travel, housing, meals, and graduate credit. NEWMAST provides for approximately 100 secondary teachers, and NEWTEST is a program designed to meet the needs of approximately 125 elementary teachers each summer. Teachers are provided with a wide variety of experiences including research laboratory observations, presentations, and 'shadowships'. Individual and team projects are used to enhance the participants knowledge of space and aeronautics and to motivate the teachers to incorporate the summer workshop activities into their classrooms.

  7. Image enhancement for pattern recognition

    NASA Astrophysics Data System (ADS)

    Huynh, Quyen Q.; Neretti, Nicola; Intrator, Nathan; Dobeck, Gerald J.

    1998-09-01

    We investigate various image enhancement techniques geared towards a specific detector. Our database consists of side- scan sonar images collected at the Naval Surface Warfare Center (NSWC), and the detector we use has proven to have excellent results on these data. We start by investigating various wavelet and wavelet packet denoising methods. Other methods we consider are based on more common filters (Gaussian and DOG filters). In wavelet based denoising we try different approaches, combining techniques that have been successfully used in signal and image denoising. We notice that the performance is mostly affected by the choice of the scale levels to which shrinkage is applied. We demonstrate that wavelet denoising can significantly improve detection performance while keeping low false alarm rates.

  8. Enhancing AFLOW Visualization using Jmol

    NASA Astrophysics Data System (ADS)

    Lanasa, Jacob; New, Elizabeth; Stefek, Patrik; Honaker, Brigette; Hanson, Robert; Aflow Collaboration

    The AFLOW library is a database of theoretical solid-state structures and calculated properties created using high-throughput ab initio calculations. Jmol is a Java-based program capable of visualizing and analyzing complex molecular structures and energy landscapes. In collaboration with the AFLOW consortium, our goal is the enhancement of the AFLOWLIB database through the extension of Jmol's capabilities in the area of materials science. Modifications made to Jmol include the ability to read and visualize AFLOW binary alloy data files, the ability to extract from these files information using Jmol scripting macros that can be utilized in the creation of interactive web-based convex hull graphs, the capability to identify and classify local atomic environments by symmetry, and the ability to search one or more related crystal structures for atomic environments using a novel extension of inorganic polyhedron-based SMILES strings

  9. Enhanced NIF neutron activation diagnosticsa)

    NASA Astrophysics Data System (ADS)

    Yeamans, C. B.; Bleuel, D. L.; Bernstein, L. A.

    2012-10-01

    The NIF neutron activation diagnostic suite relies on removable activation samples, leading to operational inefficiencies and a fundamental lower limit on the half-life of the activated product that can be observed. A neutron diagnostic system measuring activation of permanently installed samples could remove these limitations and significantly enhance overall neutron diagnostic capabilities. The physics and engineering aspects of two proposed systems are considered: one measuring the 89Zr/89mZr isomer ratio in the existing Zr activation medium and the other using potassium zirconate as the activation medium. Both proposed systems could improve the signal-to-noise ratio of the current system by at least a factor of 5 and would allow independent measurement of fusion core velocity and fuel areal density.

  10. Simulator for enhanced ATAMM multiprocessing

    NASA Technical Reports Server (NTRS)

    Andrews, Asa M.; Jones, Robert L.; Hayes, Paul J.; Benz, Harry F.

    1991-01-01

    A simulator is introduced which follows the rules of the enhanced Algorithm to Architecture Mapping Model (ATAMM) multiprocessing strategy. ATAMM is a method for embedding an algorithm into a multiprocessing system in addition to providing system performance prediction capabilities. A discussion of the inner workings of the Architecture Design and Assessment System (ADAS) hosted simulator is introduced to illustrate how the simulator follows the ATAMM rule set. A sample 5-node algorithm graph is given as an example to illustrate: (1) entering of a graph into the simulator and how to run the graph using a graph entry tool; (2) how to analyze the data; and (3) a comparison of the simulation results with the predicted results from ATAMM.

  11. Does groundwater enhance evaporative cooling?

    NASA Astrophysics Data System (ADS)

    Rouholahnejad, E.

    2015-12-01

    Evaporation is a key process in land-climate interactions, not only because it directly regulates the hydrological cycle, but also because it contributes to the Earth's energy balance. Due to its feedbacks on large-scale water processes and its impact on the dynamics of the atmosphere, it has been considered as a driver of droughts and heatwaves1-3. While evaporation from ocean surfaces is likely to increase with rising temperatures, it is unclear whether evapotranspiration from land surfaces could similarly increase, due to possible limitations imposed by soil moisture and vegetation physiology4. Observations suggest that groundwater (hereafter GW) has an important role in hydrological budgets and soil moisture variability in many regions, supplying moisture for evapotranspiration during dry seasons5, 6. Although modeling studies suggest that GW is often close enough to the surface to interact with the atmosphere7, 8, the soil water storage is often underestimated by land surface models. This is most likely due to neglecting the lateral movement of water from topographically higher altitudes to valley bottoms and its convergence close to the land surface, as well as the upward movement of water in the capillary fringe.The focus of this study is to understand where and when GW may significantly enhance the availability of soil water for evapotranspiration. We also quantified the potential contribution of GW to evapotranspiration in the areas where GW is a major supply. We used the global network of eddy covariance observations9 (FLUXNET) along with global modeled GW depth10 and GLEAM ET model estimates11 to address the current gap in modelling ET due to neglecting GW supply. Having identified areas where GW is tightly coupled with the atmosphere through evaporation processes, the study provides the basis to examine the "air conditioning effect" of GW and test the idea if GW enhances evaporation to the extent that leads to a cooler temperatures and wetter climates.

  12. Enhanced Luminescence of Lanthanides: Determination of Europium by Enhanced Luminescence

    NASA Astrophysics Data System (ADS)

    Jenkins, Amanda L.; Murray, George M.

    1998-02-01

    An experiment has been developed to teach the principles of molecular luminescence spectroscopy. This laboratory experiment is designed for upper-level undergraduates as a less toxic alternative to current fluorescence experiments. It combines elements of physical and inorganic as well as analytical chemistry. The experiment can be performed on a variety of rudimentary fluorescence instrumentation and still give good analytical figures of merit. The object of the experiment is to measure the luminescent enhancement that is achieved when a lanthanide such as Eu(III) or Tb(III) is complexed with appropriate organic ligands, in this case 2,6 pyridinedicarboxylic acid. The importance of pH on metal ion coordination is also explored via luminescence intensity. This approach provides several advantages over current luminescence experiments. These advantages include limited toxicity and flammability of the chemicals involved, a large luminescence linear dynamic range, and low detection limits (parts per trillion). These low detection limits, achieved using modest equipment, allow the determination of the europium concentration in a variety of samples, such as tap water. The narrow lanthanide luminescent bands also permit incorporation of qualitative analysis of a mixture of lanthanides.

  13. Self-Enhancement: Food for Thought.

    PubMed

    Sedikides, Constantine; Gregg, Aiden P

    2008-03-01

    Self-enhancement denotes a class of psychological phenomena that involve taking a tendentiously positive view of oneself. We distinguish between four levels of self-enhancement-an observed effect, an ongoing process, a personality trait, and an underlying motive-and then use these distinctions to organize the wealth of relevant research. Furthermore, to render these distinctions intuitive, we draw an extended analogy between self-enhancement and the phenomenon of eating. Among the topics we address are (a) manifestations of self-enhancement, both obvious and subtle, and rival interpretations; (b) experimentally documented dynamics of affirming and threatening the ego; and (c) primacy of self-enhancement, considered alongside other intrapsychic phenomena, and across different cultures. Self-enhancement, like eating, is a fundamental part of human nature.

  14. Tip-Enhanced Raman Spectroscopy (TERS)

    NASA Astrophysics Data System (ADS)

    Pettinger, Bruno

    Tip-enhanced Raman spectroscopy is a vibrational spectroscopy with hitherto unprecedented sensitivity and spatial resolution. Since the enhancement is mainly provided by the near-field excited at the apex of a suitable tip, TERS appears to be a widely applicable spectroscopy and microscopy tool, in contrast to its parents, surface-enhanced Raman spectroscopy (SERS) and scanning near-field optical microscopy (SNOM). TER scattering has been observed for a number of molecules adsorbed at various substrates, including single-crystalline metal surfaces, showing thereby a more than million-fold enhancement of the Raman scattering. It is important to note that the field-enhancement provides, beyond TERS, promising avenues for applications to other optical techniques, such as tip-enhanced CARS, two-photon fluorescence and infrared scattering-type near-field microscopy.

  15. An evaluative conservative case for biomedical enhancement.

    PubMed

    Danaher, John

    2016-09-01

    It is widely believed that a conservative moral outlook is opposed to biomedical forms of human enhancement. In this paper, I argue that this widespread belief is incorrect. Using Cohen's evaluative conservatism as my starting point, I argue that there are strong conservative reasons to prioritise the development of biomedical enhancements. In particular, I suggest that biomedical enhancement may be essential if we are to maintain our current evaluative equilibrium (ie, the set of values that undergird and permeate our current political, economic and personal lives) against the threats to that equilibrium posed by external, non-biomedical forms of enhancement. I defend this view against modest conservatives who insist that biomedical enhancements pose a greater risk to our current evaluative equilibrium, and against those who see no principled distinction between the forms of human enhancement.

  16. An evaluative conservative case for biomedical enhancement.

    PubMed

    Danaher, John

    2016-09-01

    It is widely believed that a conservative moral outlook is opposed to biomedical forms of human enhancement. In this paper, I argue that this widespread belief is incorrect. Using Cohen's evaluative conservatism as my starting point, I argue that there are strong conservative reasons to prioritise the development of biomedical enhancements. In particular, I suggest that biomedical enhancement may be essential if we are to maintain our current evaluative equilibrium (ie, the set of values that undergird and permeate our current political, economic and personal lives) against the threats to that equilibrium posed by external, non-biomedical forms of enhancement. I defend this view against modest conservatives who insist that biomedical enhancements pose a greater risk to our current evaluative equilibrium, and against those who see no principled distinction between the forms of human enhancement. PMID:27354246

  17. A Thomistic appraisal of human enhancement technologies.

    PubMed

    Eberl, Jason T

    2014-08-01

    Debate concerning human enhancement often revolves around the question of whether there is a common "nature" that all human beings share and which is unwarrantedly violated by enhancing one's capabilities beyond the "species-typical" norm. I explicate Thomas Aquinas's influential theory of human nature, noting certain key traits commonly shared among human beings that define each as a "person" who possesses inviolable moral status. Understanding the specific qualities that define the nature of human persons, which includes self-conscious awareness, capacity for intellective thought, and volitional autonomy, informs the ethical assessment of various forms of enhancement. Some forms of cognitive and physical enhancement may be desirable from the perspective of what constitutes the "flourishing" of human persons in our fundamental nature; while other forms of enhancement, such as emotive or so-called "moral" enhancement, run the risk of detracting from human flourishing when evaluated from the virtue-theoretic perspective Aquinas promotes.

  18. Plasmon-enhanced optical sensors: a review.

    PubMed

    Li, Ming; Cushing, Scott K; Wu, Nianqiang

    2015-01-21

    Surface plasmon resonance (SPR) has found extensive applications in chemi-sensors and biosensors. Plasmons play different roles in different types of optical sensors. SPR transduces a signal in a colorimetric sensor through shifts in the spectral position and intensity in response to external stimuli. SPR can also concentrate the incident electromagnetic field in a nanostructure, modulating fluorescence emission and enabling plasmon-enhanced fluorescence to be used for ultrasensitive detection. Furthermore, plasmons have been extensively used for amplifying a Raman signal in a surface-enhanced Raman scattering sensor. This paper presents a review of recent research progress in plasmon-enhanced optical sensing, giving emphasis on the physical basis of plasmon-enhanced sensors and how these principles guide the design of sensors. In particular, this paper discusses the design strategies for nanomaterials and nanostructures to plasmonically enhance optical sensing signals, also highlighting the applications of plasmon-enhanced optical sensors in healthcare, homeland security, food safety and environmental monitoring.

  19. Enhanced potentiometry by metallic nanoparticles.

    PubMed

    Noyhouzer, T; Valdinger, I; Mandler, D

    2013-09-01

    Measuring the oxidation-reduction potential (Eh) requires an interface that is not selective toward specific species but exchanges electrons with all redox couples in the solution. Sluggish electron transfer (ET) kinetics with the species will not reflect the "true" Eh of the solution. Here, we present a novel approach by which adsorbed metal nanoparticles (NPs) are used for enhancing ET exchange rates between redox species and electrode surface and therefore affect significantly the measurement of the open circuit potential (OCP) and cyclic voltammetry (CV). The OCP and CV of various organic and inorganic species such as l-dopa, dopac, iron(II), and iodide are measured by bare stainless steel and by stainless steel modified by either Pt or Au NPs. We study the effect of the surface coverage of the stainless steel surface by NPs on the electrochemical response. Moreover, the stainless steel electrode was modified simultaneously by Au and Pt nanoparticles. This improved concurrently the stainless steel response (CV and potentiometry) toward two different species; l-dopa, which shows fast electron transfer on Pt, and catechol, which exhibits fast electron transfer on Au. We believe that this approach could be a first step toward developing a superior electrode for measuring the "true" Eh of complex aquatic systems.

  20. Holographic enhanced remote sensing system

    NASA Technical Reports Server (NTRS)

    Iavecchia, Helene P.; Gaynor, Edwin S.; Huff, Lloyd; Rhodes, William T.; Rothenheber, Edward H.

    1990-01-01

    The Holographic Enhanced Remote Sensing System (HERSS) consists of three primary subsystems: (1) an Image Acquisition System (IAS); (2) a Digital Image Processing System (DIPS); and (3) a Holographic Generation System (HGS) which multiply exposes a thermoplastic recording medium with sequential 2-D depth slices that are displayed on a Spatial Light Modulator (SLM). Full-parallax holograms were successfully generated by superimposing SLM images onto the thermoplastic and photopolymer. An improved HGS configuration utilizes the phase conjugate recording configuration, the 3-SLM-stacking technique, and the photopolymer. The holographic volume size is currently limited to the physical size of the SLM. A larger-format SLM is necessary to meet the desired 6 inch holographic volume. A photopolymer with an increased photospeed is required to ultimately meet a display update rate of less than 30 seconds. It is projected that the latter two technology developments will occur in the near future. While the IAS and DIPS subsystems were unable to meet NASA goals, an alternative technology is now available to perform the IAS/DIPS functions. Specifically, a laser range scanner can be utilized to build the HGS numerical database of the objects at the remote work site.

  1. Microbial enhanced oil recovery research

    SciTech Connect

    Sharma, M.M.; Georgiou, G.

    1990-01-01

    The objective of this work is to develop an engineering framework for the exploitation of microorganisms to enhance oil recovery. Specific goals include: (1) investigation of the mechanisms of microbially induced oil mobilization; (2) the production, isolation, chemical characterization and study of the physical properties of microbially produced surfactants; (3) model studies in sandstone cores for the characterization of the interactions between growing microbially cultures and oil reservoirs; (4) development of simulators for MEOR; and (5) design of operational strategies for the sequential injection of microorganisms and nutrient in reservoirs are: (1) systematic discussion of the mechanisms important in MEOR processes; (2) Measurement of the growth characteristics of Bacillus Licheniformis under various conditions of pH, temperature and salt concentration for both aerobic and anaerobic growth.; (3) measurement of interfacial tension reducing ability of the biosurfactant under different conditions of pH and salt concentration; (4) development of some preliminary methods to concentrate and characterize the biosurfactant; (5) development of a compositional numerical simulator for MEOR processes; and (6) Measurement of the lowest interfacial tension (IFT) value reported for biosurfactants to date. Demonstration of the fact that the low IFT values required for oil recovery can be attained with biosurfactants.

  2. Enhanced decision making through neuroscience

    NASA Astrophysics Data System (ADS)

    Szu, Harold; Jung, TP; Makeig, Scott

    2012-06-01

    We propose to enhance the decision making of pilot, co-pilot teams, over a range of vehicle platforms, with the aid of neuroscience. The goal is to optimize this collaborative decision making interplay in time-critical, stressful situations. We will research and measure human facial expressions, personality typing, and brainwave measurements to help answer questions related to optimum decision-making in group situations. Further, we propose to examine the nature of intuition in this decision making process. The brainwave measurements will be facilitated by a University of California, San Diego (UCSD) developed wireless Electroencephalography (EEG) sensing cap. We propose to measure brainwaves covering the whole head area with an electrode density of N=256, and yet keep within the limiting wireless bandwidth capability of m=32 readouts. This is possible because solving Independent Component Analysis (ICA) and finding the hidden brainwave sources allow us to concentrate selective measurements with an organized sparse source -->s sensing matrix [Φs], rather than the traditional purely random compressive sensing (CS) matrix[Φ].

  3. Enhanced Model for Fast Ignition

    SciTech Connect

    Mason, Rodney J.

    2010-10-12

    Laser Fusion is a prime candidate for alternate energy production, capable of serving a major portion of the nation's energy needs, once fusion fuel can be readily ignited. Fast Ignition may well speed achievement of this goal, by reducing net demands on laser pulse energy and timing precision. However, Fast Ignition has presented a major challenge to modeling. This project has enhanced the computer code ePLAS for the simulation of the many specialized phenomena, which arise with Fast Ignition. The improved code has helped researchers to understand better the consequences of laser absorption, energy transport, and laser target hydrodynamics. ePLAS uses efficient implicit methods to acquire solutions for the electromagnetic fields that govern the accelerations of electrons and ions in targets. In many cases, the code implements fluid modeling for these components. These combined features, "implicitness and fluid modeling," can greatly facilitate calculations, permitting the rapid scoping and evaluation of experiments. ePLAS can be used on PCs, Macs and Linux machines, providing researchers and students with rapid results. This project has improved the treatment of electromagnetics, hydrodynamics, and atomic physics in the code. It has simplified output graphics, and provided new input that avoids the need for source code access by users. The improved code can now aid university, business and national laboratory users in pursuit of an early path to success with Fast Ignition.

  4. Irradiation enhancement of biomass conversion

    NASA Astrophysics Data System (ADS)

    Smith, G. S.; Kiesling, H. E.; Galyean, M. L.; Bader, J. R.

    The vast supply of cellulosic agricultural residues and industrial by-products that is produced each year is a prospective resource of biomass suitable for conversion to useful products such as feedstock for the chemicals industry and feedstuffs for the livestock industry. Conversions of such biomass is poor at present, and utilization is inefficient, because of physio-chemical barriers to biological degradation and (or) anti-quality components such as toxicants that restrict biological usages. Improvements in biodegradability of ligno-cellulosic materials have been accomplished by gamma-ray and electron-beam irradiation at intermediate dosage (˜ 50 Mrad; .5 MGy); but applications of the technology have been hampered by questionable interpretations of results. Recent research with organic wastes such as sewage sludge and straw suggests opportunity for important applications of irradiation technology in enhancement of biomass conversion. Data from experiments using irradiated straw as feed for ruminants are presented and discussed in relation to research on prospective usage of sewage products as feed for ruminants. Findings are discussed in regard to prospective applications in industrial fermentation processes. Possible usage of irradiation technology for destruction of toxicants in exotic plants is considered in regard to prospective new feedstuffs.

  5. Ultrasound enhanced thrombolysis: Clinical evidence

    NASA Astrophysics Data System (ADS)

    Alexandrov, Andrei V.

    2005-04-01

    Phase II CLOTBUST randomized clinical trial (Houston, Barcelona, Edmonton, Calgary) evaluated patients with acute ischemic stroke due to intracranial occlusion and treated with intravenous tissue plasminogen activator (TPA) within 3 h of symptom onset. Randomization: monitoring with pulsed wave 2 MHz transcranial Doppler (TCD) (Target) or placebo monitoring (Control). Safety: symptomatic bleeding to the brain (sICH). Primary end-point: complete recanalization on TCD or dramatic clinical recovery by the total NIHSS score <3, or improvement by >10 NIHSS points within 2 hours after TPA bolus. All projected 126 patients were randomized 1:1 to target (median NIHSS 16) or control (NIHSS 17). sICH: 4.8% Target, 4.8% Controls. Primary end-point was achieved by 31 (49%, Target) versus 19 (30%, Control), p<0.03. At 3 months, 22 (42% Target) and 14 (29% Control) patients achieved favorable outcomes. Continuous TCD monitoring of intracranial occlusion safely augments TPA-induced arterial recanalization, and 2 MHz diagnostic ultrasound has a positive biological activity that aids systemic thrombolytic therapy. For the first time in clinical medicine, the CLOTBUST trial provides the evidence that ultrasound enhances thrombolytic activity of a drug in humans thereby confirming intense multi-disciplinary experimental research conducted worldwide for the past 30 years.

  6. Facebook enhances antidepressant pharmacotherapy effects.

    PubMed

    Mota Pereira, Jorge

    2014-01-01

    Treatment-resistant major depressive disorder (TR-MDD) is a complex condition, with very low remission rates. In recent years some studies have been conducted on the implementation of cognitive behavioral therapy and psychodynamic psychotherapy interventions via the Internet to MDD patients, and results have been promising. However, there have been no studies in patients with TR-MDD nor with the use of Facebook with the psychiatrist as "friend." 60 TR-MDD patients were randomized to one of three groups: Facebook group with psychiatrist as "friend," Facebook group without psychiatrist as "friend," and control group (no Facebook use). Both Facebook groups spent at least 1 hour/day on Facebook, 7 days/week, during the 3 months. All patients maintained their usual pharmacotherapy. All participants were evaluated at baseline and at 1, 2, and 3 months for depressive symptoms using HAD17 and BDI-II. Results show that both Facebook groups had a decrease on HADM17 and BDI-II scores as well as higher remission and response rates than the control group, with better results if the psychiatrist was a "friend" on Facebook. Therefore, in TR-MDD, Facebook can be used as an effective enhancement therapy, adjuvant to pharmacological therapy with regular consultations, especially if the psychiatrist is the patient's online "friend."

  7. Enhanced safeguards via solution monitoring

    SciTech Connect

    Burr, T.; Wangen, L.

    1996-09-01

    Solution monitoring is defined as the essentially continuous monitoring of solution level, density, and temperature in all tanks in the process that contain, or could contain, safeguards-significant quantities of nuclear material. This report describes some of the enhancements that solution monitoring could make to international safeguards. The focus is on the quantifiable benefits of solution monitoring, but qualitatively, solution monitoring can be viewed as a form of surveillance. Quantitatively, solution monitoring can in some cases improve diversion detection probability. For example, the authors show that under certain assumptions, solution monitoring can be used to reduce the standard deviation of the annual material balance, {sigma}{sub MB}, from approximately 17 kg to approximately 4 kg. Such reduction in {sigma}{sub MB} will not always be possible, as they discuss. However, in all cases, solution monitoring would provide assurance that the measurement error models are adequate so that one has confidence in his estimate of {sigma}{sub MB}. Some of the results in this report were generated using data that were simulated with prototype solution monitoring software that they are developing. An accompanying document describes that software.

  8. Enhanced Eryptosis Following Gramicidin Exposure

    PubMed Central

    Malik, Abaid; Bissinger, Rosi; Liu, Guoxing; Liu, Guilai; Lang, Florian

    2015-01-01

    The peptide antibiotic and ionophore gramicidin has previously been shown to trigger apoptosis of nucleated cells. In analogy to apoptosis, the suicidal death of erythrocytes or eryptosis involves cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include oxidative stress, increase of cytosolic Ca2+ activity ([Ca2+]i), and ceramide. The present study explored, whether gramicidin triggers eryptosis. To this end phosphatidylserine exposure at the cell surface was estimated from annexin V binding, cell volume from forward scatter, red blood cell distribution width (RDW) from electronic particle counting, reactive oxidant species (ROS) from 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) fluorescence, [Ca2+]i from Fluo3- and Fluo4 fluorescence, and ceramide abundance from binding of specific antibodies. As a result, a 24 h exposure of human erythrocytes to gramicidin significantly increased the percentage of annexin-V-binding cells (≥1 µg/mL), forward scatter (≥0.5 µg/mL) and hemolysis. Gramicidin enhanced ROS activity, [Ca2+]i and ceramide abundance at the erythrocyte surface. The stimulation of annexin-V-binding by gramicidin was significantly blunted but not abolished by removal of extracellular Ca2+. In conclusion, gramicidin stimulates phospholipid scrambling of the erythrocyte cell membrane, an effect at least partially due to induction of oxidative stress, increase of [Ca2+]i and up-regulation of ceramide abundance. Despite increase of [Ca2+]i, gramicidin increases cell volume and slightly reduces RWD. PMID:25915718

  9. Facebook Enhances Antidepressant Pharmacotherapy Effects

    PubMed Central

    Mota Pereira, Jorge

    2014-01-01

    Treatment-resistant major depressive disorder (TR-MDD) is a complex condition, with very low remission rates. In recent years some studies have been conducted on the implementation of cognitive behavioral therapy and psychodynamic psychotherapy interventions via the Internet to MDD patients, and results have been promising. However, there have been no studies in patients with TR-MDD nor with the use of Facebook with the psychiatrist as “friend.” 60 TR-MDD patients were randomized to one of three groups: Facebook group with psychiatrist as “friend,” Facebook group without psychiatrist as “friend,” and control group (no Facebook use). Both Facebook groups spent at least 1 hour/day on Facebook, 7 days/week, during the 3 months. All patients maintained their usual pharmacotherapy. All participants were evaluated at baseline and at 1, 2, and 3 months for depressive symptoms using HAD17 and BDI-II. Results show that both Facebook groups had a decrease on HADM17 and BDI-II scores as well as higher remission and response rates than the control group, with better results if the psychiatrist was a “friend” on Facebook. Therefore, in TR-MDD, Facebook can be used as an effective enhancement therapy, adjuvant to pharmacological therapy with regular consultations, especially if the psychiatrist is the patient's online “friend.” PMID:24574930

  10. Advanced integrated enhanced vision systems

    NASA Astrophysics Data System (ADS)

    Kerr, J. R.; Luk, Chiu H.; Hammerstrom, Dan; Pavel, Misha

    2003-09-01

    In anticipation of its ultimate role in transport, business and rotary wing aircraft, we clarify the role of Enhanced Vision Systems (EVS): how the output data will be utilized, appropriate architecture for total avionics integration, pilot and control interfaces, and operational utilization. Ground-map (database) correlation is critical, and we suggest that "synthetic vision" is simply a subset of the monitor/guidance interface issue. The core of integrated EVS is its sensor processor. In order to approximate optimal, Bayesian multi-sensor fusion and ground correlation functionality in real time, we are developing a neural net approach utilizing human visual pathway and self-organizing, associative-engine processing. In addition to EVS/SVS imagery, outputs will include sensor-based navigation and attitude signals as well as hazard detection. A system architecture is described, encompassing an all-weather sensor suite; advanced processing technology; intertial, GPS and other avionics inputs; and pilot and machine interfaces. Issues of total-system accuracy and integrity are addressed, as well as flight operational aspects relating to both civil certification and military applications in IMC.

  11. Enhanced eryptosis following gramicidin exposure.

    PubMed

    Malik, Abaid; Bissinger, Rosi; Liu, Guoxing; Liu, Guilai; Lang, Florian

    2015-04-23

    The peptide antibiotic and ionophore gramicidin has previously been shown to trigger apoptosis of nucleated cells. In analogy to apoptosis, the suicidal death of erythrocytes or eryptosis involves cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include oxidative stress, increase of cytosolic Ca2+ activity ([Ca2+]i), and ceramide. The present study explored, whether gramicidin triggers eryptosis. To this end phosphatidylserine exposure at the cell surface was estimated from annexin V binding, cell volume from forward scatter, red blood cell distribution width (RDW) from electronic particle counting, reactive oxidant species (ROS) from 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) fluorescence, [Ca2+]i from Fluo3- and Fluo4 fluorescence, and ceramide abundance from binding of specific antibodies. As a result, a 24 h exposure of human erythrocytes to gramicidin significantly increased the percentage of annexin-V-binding cells (≥1 µg/mL), forward scatter (≥0.5 µg/mL) and hemolysis. Gramicidin enhanced ROS activity, [Ca2+]i and ceramide abundance at the erythrocyte surface. The stimulation of annexin-V-binding by gramicidin was significantly blunted but not abolished by removal of extracellular Ca2+. In conclusion, gramicidin stimulates phospholipid scrambling of the erythrocyte cell membrane, an effect at least partially due to induction of oxidative stress, increase of [Ca2+]i and up-regulation of ceramide abundance. Despite increase of [Ca2+]i, gramicidin increases cell volume and slightly reduces RWD.

  12. Facebook enhances antidepressant pharmacotherapy effects.

    PubMed

    Mota Pereira, Jorge

    2014-01-01

    Treatment-resistant major depressive disorder (TR-MDD) is a complex condition, with very low remission rates. In recent years some studies have been conducted on the implementation of cognitive behavioral therapy and psychodynamic psychotherapy interventions via the Internet to MDD patients, and results have been promising. However, there have been no studies in patients with TR-MDD nor with the use of Facebook with the psychiatrist as "friend." 60 TR-MDD patients were randomized to one of three groups: Facebook group with psychiatrist as "friend," Facebook group without psychiatrist as "friend," and control group (no Facebook use). Both Facebook groups spent at least 1 hour/day on Facebook, 7 days/week, during the 3 months. All patients maintained their usual pharmacotherapy. All participants were evaluated at baseline and at 1, 2, and 3 months for depressive symptoms using HAD17 and BDI-II. Results show that both Facebook groups had a decrease on HADM17 and BDI-II scores as well as higher remission and response rates than the control group, with better results if the psychiatrist was a "friend" on Facebook. Therefore, in TR-MDD, Facebook can be used as an effective enhancement therapy, adjuvant to pharmacological therapy with regular consultations, especially if the psychiatrist is the patient's online "friend." PMID:24574930

  13. Inhomogeneous thermal conductivity enhances thermoelectric cooling

    NASA Astrophysics Data System (ADS)

    Lu, Tingyu; Zhou, Jun; Li, Nianbei; Yang, Ronggui; Li, Baowen

    2014-12-01

    We theoretically investigate the enhancement of thermoelectric cooling performance in thermoelectric refrigerators made of materials with inhomogeneous thermal conductivity, beyond the usual practice of enhancing thermoelectric figure of merit (ZT) of materials. The dissipation of the Joule heat in such thermoelectric refrigerators is asymmetric which can give rise to better thermoelectric cooling performance. Although the thermoelectric figure of merit and the coefficient-of-performance are slightly enhanced, both the maximum cooling power and the maximum cooling temperature difference can be enhanced significantly. This finding can be used to increase the heat absorption at the cold end. We further find that the asymmetric dissipation of Joule heat leads to thermal rectification.

  14. Optical nanogap matrices for plasmonic enhancement applications

    NASA Astrophysics Data System (ADS)

    Bauman, Stephen J.; Debu, Desalegn T.; Hill, Avery M.; Novak, Eric C.; Natelson, Douglas; Herzog, Joseph B.

    2014-09-01

    Plasmonic structures can be used to enhance electromagnetic radiation, and nanoscale (<5 nm) gaps can increase this enhancement even further. Fabrication of these desired structures involves using a relatively new, previously developed self-aligned process to overcome typical electron beam lithography resolution limits. The resulting nanogap structures have been shown to exhibit enhanced optical emission. This technique enables the fabrication of a large-area two-dimensional matrix of such nanostructures which could prove useful for photovoltaics, plasmonically enhanced Raman spectroscopy, biosensing, and other optoelectronic applications. Computational electromagnetic simulations of the structures will prove useful for predicting behavior upon interaction with light and for experimental comparison.

  15. On the argument that enhancement is "cheating".

    PubMed

    Schermer, M

    2008-02-01

    One frequently used argument in the discussion on human enhancement is that enhancement is a form of cheating. This argument is well-known in relation to doping in sports, but recently it has also been used with regard to cognitive enhancement in the context of education and exams. This paper analyses the enhancement-is-cheating argument by comparing sports and education, and by evaluating how the argument can be interpreted in both contexts. If cheating is understood as breaking the rules in order to gain an unfair advantage over others, it can be argued that some enhancements are a form of cheating. This problem of cheating is, however, relatively easy to remedy by either changing the rules, or by instituting controls and sanctions. This does not, therefore, constitute a categorical objection to enhancement. A further analysis of the intuitions behind the enhancement-is-cheating argument, however, shows that if sports and education are understood as "practices", with their own internal goods and standards of excellence, some potential problems of enhancement can be articulated. These concern the internal goods and standards of excellence that are characteristic of specific practices. Seen from this perspective, the important question is how enhancement technologies might be embedded in specific practices--or how they might corrode them.

  16. Factors affecting enhanced video quality preferences

    PubMed Central

    Satgunam, PremNandhini; Woods, Russell L; Bronstad, P Matthew; Peli, Eli

    2013-01-01

    The development of video quality metrics requires methods for measuring perceived video quality. Most such metrics are designed and tested using databases of images degraded by compression and scored using opinion ratings. We studied video quality preferences for enhanced images of normally-sighted participants using the method of paired comparisons with a thorough statistical analysis. Participants (n=40) made pair-wise comparisons of high definition (HD) video clips enhanced at four different levels using a commercially available enhancement device. Perceptual scales were computed with binary logistic regression to estimate preferences for each level and to provide statistical inference of the differences among levels and the impact of other variables. While moderate preference for enhanced videos was found, two unexpected effects were also uncovered: (1) Participants could be broadly classified into two groups: those who preferred enhancement ("Sharp") and those who disliked enhancement ("Smooth"). (2) Enhancement preferences depended on video content, particularly for human faces to be enhanced less. The results suggest that algorithms to evaluate image quality (at least for enhancement) may need to be adjusted or applied differentially based on video content and viewer preferences. The possible impact of similar effects on image quality of compressed video needs to be evaluated. PMID:24107400

  17. Enhancing Ocean Research Data Access

    NASA Astrophysics Data System (ADS)

    Chandler, Cynthia; Groman, Robert; Shepherd, Adam; Allison, Molly; Arko, Robert; Chen, Yu; Fox, Peter; Glover, David; Hitzler, Pascal; Leadbetter, Adam; Narock, Thomas; West, Patrick; Wiebe, Peter

    2014-05-01

    The Biological and Chemical Oceanography Data Management Office (BCO-DMO) works in partnership with ocean science investigators to publish data from research projects funded by the Biological and Chemical Oceanography Sections and the Office of Polar Programs Antarctic Organisms & Ecosystems Program at the U.S. National Science Foundation. Since 2006, researchers have been contributing data to the BCO-DMO data system, and it has developed into a rich repository of data from ocean, coastal and Great Lakes research programs. While the ultimate goal of the BCO-DMO is to ensure preservation of NSF funded project data and to provide open access to those data, achievement of those goals is attained through a series of related phases that benefits from active collaboration and cooperation with a large community of research scientists as well as curators of data and information at complementary data repositories. The BCO-DMO is just one of many intermediate data management centers created to facilitate long-term preservation of data and improve access to ocean research data. Through partnerships with other data management professionals and active involvement in local and global initiatives, BCO-DMO staff members are working to enhance access to ocean research data available from the online BCO-DMO data system. Continuing efforts in use of controlled vocabulary terms, development of ontology design patterns and publication of content as Linked Open Data are contributing to improved discovery and availability of BCO-DMO curated data and increased interoperability of related content available from distributed repositories. We will demonstrate how Semantic Web technologies (e.g. RDF/XML, SKOS, OWL and SPARQL) have been integrated into BCO-DMO data access and delivery systems to better serve the ocean research community and to contribute to an expanding global knowledge network.

  18. Robotically enhanced rubber hand illusion.

    PubMed

    Arata, Jumpei; Hattori, Masashi; Ichikawa, Shohei; Sakaguchi, Masamichi

    2014-01-01

    The rubber hand illusion is a well-known multisensory illusion. In brief, watching a rubber hand being stroked by a paintbrush while one's own unseen hand is synchronously stroked causes the rubber hand to be attributed to one's own body and to "feel like it's my hand." The rubber hand illusion is thought to be triggered by the synchronized tactile stimulation of both the subject's hand and the fake hand. To extend the conventional rubber hand illusion, we introduce robotic technology in the form of a master-slave telemanipulator. The developed one degree-of-freedom master-slave system consists of an exoskeleton master equipped with an optical encoder that is worn on the subject's index finger and a motor-actuated index finger on the rubber hand, which allows the subject to perform unilateral telemanipulation. The moving rubber hand illusion has been studied by several researchers in the past with mechanically connected rigs between the subject's body and the fake limb. The robotic instruments let us investigate the moving rubber hand illusion with less constraints, thus behaving closer to the classic rubber hand illusion. In addition, the temporal delay between the body and the fake limb can be precisely manipulated. The experimental results revealed that the robotic instruments significantly enhance the rubber hand illusion. The time delay is significantly correlated with the effect of the multisensory illusion, and the effect significantly decreased at time delays over 100 ms. These findings can potentially contribute to the investigations of neural mechanisms in the field of neuroscience and of master-slave systems in the field of robotics.

  19. Enhanced absorption cycle computer model

    NASA Astrophysics Data System (ADS)

    Grossman, G.; Wilk, M.

    1993-09-01

    Absorption heat pumps have received renewed and increasing attention in the past two decades. The rising cost of electricity has made the particular features of this heat-powered cycle attractive for both residential and industrial applications. Solar-powered absorption chillers, gas-fired domestic heat pumps, and waste-heat-powered industrial temperature boosters are a few of the applications recently subjected to intensive research and development. The absorption heat pump research community has begun to search for both advanced cycles in various multistage configurations and new working fluid combinations with potential for enhanced performance and reliability. The development of working absorption systems has created a need for reliable and effective system simulations. A computer code has been developed for simulation of absorption systems at steady state in a flexible and modular form, making it possible to investigate various cycle configurations with different working fluids. The code is based on unit subroutines containing the governing equations for the system's components and property subroutines containing thermodynamic properties of the working fluids. The user conveys to the computer an image of his cycle by specifying the different subunits and their interconnections. Based on this information, the program calculates the temperature, flow rate, concentration, pressure, and vapor fraction at each state point in the system, and the heat duty at each unit, from which the coefficient of performance (COP) may be determined. This report describes the code and its operation, including improvements introduced into the present version. Simulation results are described for LiBr-H2O triple-effect cycles, LiCl-H2O solar-powered open absorption cycles, and NH3-H2O single-effect and generator-absorber heat exchange cycles. An appendix contains the user's manual.

  20. Electronic enhancement of tear secretion

    NASA Astrophysics Data System (ADS)

    Brinton, Mark; Lim Chung, Jae; Kossler, Andrea; Kook, Koung Hoon; Loudin, Jim; Franke, Manfred; Palanker, Daniel

    2016-02-01

    Objective. To study electrical stimulation of the lacrimal gland and afferent nerves for enhanced tear secretion, as a potential treatment for dry eye disease. We investigate the response pathways and electrical parameters to safely maximize tear secretion. Approach. We evaluated the tear response to electrical stimulation of the lacrimal gland and afferent nerves in isofluorane-anesthetized rabbits. In acute studies, electrical stimulation was performed using bipolar platinum foil electrodes, implanted beneath the inferior lacrimal gland, and a monopolar electrode placed near the afferent ethmoid nerve. Wireless microstimulators with bipolar electrodes were implanted beneath the lacrimal gland for chronic studies. To identify the response pathways, we applied various pharmacological inhibitors. To optimize the stimulus, we measured tear secretion rate (Schirmer test) as a function of pulse amplitude (1.5-12 mA), duration (0.1-1 ms) and repetition rate (10-100 Hz). Main results. Stimulation of the lacrimal gland increased tear secretion by engaging efferent parasympathetic nerves. Tearing increased with stimulation amplitude, pulse duration and repetition rate, up to 70 Hz. Stimulation with 3 mA, 500 μs pulses at 70 Hz provided a 4.5 mm (125%) increase in Schirmer score. Modulating duty cycle further increased tearing up to 57%, compared to continuous stimulation in chronically implanted animals (36%). Ethmoid (afferent) nerve stimulation increased tearing similar to gland stimulation (3.6 mm) via a reflex pathway. In animals with chronically implanted stimulators, a nearly 6 mm increase (57%) was achieved with 12-fold less charge density per pulse (0.06-0.3 μC mm-2 with 170-680 μs pulses) than the damage threshold (3.5 μC mm-2 with 1 ms pulses). Significance. Electrical stimulation of the lacrimal gland or afferent nerves may be used as a treatment for dry eye disease. Clinical trials should validate this approach in patients with aqueous tear deficiency, and

  1. The Nox1/4 Dual Inhibitor GKT137831 or Nox4 Knockdown Inhibits Angiotensin-II-Induced Adult Mouse Cardiac Fibroblast Proliferation and Migration. AT1 Physically Associates With Nox4.

    PubMed

    Somanna, Naveen K; Valente, Anthony J; Krenz, Maike; Fay, William P; Delafontaine, Patrice; Chandrasekar, Bysani

    2016-05-01

    Both oxidative stress and inflammation contribute to chronic hypertension-induced myocardial fibrosis and adverse cardiac remodeling. Here we investigated whether angiotensin (Ang)-II-induced fibroblast proliferation and migration are NADPH oxidase (Nox) 4/ROS and IL-18 dependent. Our results show that the potent induction of mouse cardiac fibroblast (CF) proliferation and migration by Ang-II is markedly attenuated by Nox4 knockdown and the Nox inhibitor DPI. Further, Nox4 knockdown and DPI pre-treatment attenuated Ang-II-induced IL-18, IL-18Rα and collagen expression, and MMP9 and LOX activation. While neutralization of IL-18 blunted Ang-II-induced CF proliferation and migration, knockdown of MMP9 attenuated CF migration. The antioxidant NAC and the cell-permeable SOD mimetics Tempol, MnTBAP, and MnTMPyP attenuated oxidative stress and inhibited CF proliferation and migration. The Nox1/Nox4 dual inhibitor GKT137831 also blunted Ang-II-induced H2 O2 production and CF proliferation and migration. Further, AT1 bound Nox4, and Ang-II enhanced their physical association. Notably, GKT137831 attenuated the AT1/Nox4 interaction. These results indicate that Ang-II induces CF proliferation and migration in part via Nox4/ROS-dependent IL-18 induction and MMP9 activation, and may involve AT1/Nox4 physical association. Thus, either (i) neutralizing IL-18, (ii) blocking AT1/Nox4 interaction or (iii) use of the Nox1/Nox4 inhibitor GKT137831 may have therapeutic potential in chronic hypertension-induced adverse cardiac remodeling.

  2. Unsuccessful Retrieval Attempts Enhance Subsequent Learning

    ERIC Educational Resources Information Center

    Kornell, Nate; Hays, Matthew Jensen; Bjork, Robert A.

    2009-01-01

    Taking tests enhances learning. But what happens when one cannot answer a test question--does an unsuccessful retrieval attempt impede future learning or enhance it? The authors examined this question using materials that ensured that retrieval attempts would be unsuccessful. In Experiments 1 and 2, participants were asked fictional…

  3. Sensor fusion method for machine performance enhancement

    SciTech Connect

    Mou, J.I.; King, C.; Hillaire, R.; Jones, S.; Furness, R.

    1998-03-01

    A sensor fusion methodology was developed to uniquely integrate pre-process, process-intermittent, and post-process measurement and analysis technology to cost-effectively enhance the accuracy and capability of computer-controlled manufacturing equipment. Empirical models and computational algorithms were also developed to model, assess, and then enhance the machine performance.

  4. Arousal-Enhanced Location Memory for Pictures

    ERIC Educational Resources Information Center

    Mather, Mara; Nesmith, Kathryn

    2008-01-01

    Four experiments revealed arousal-enhanced location memory for pictures. After an incidental encoding task, participants were more likely to remember the locations of positive and negative arousing pictures than the locations of non-arousing pictures, indicating better binding of location to picture. This arousal-enhanced binding effect did not…

  5. Nanoparticle Based Surface-Enhanced Raman Spectroscopy

    SciTech Connect

    Talley, C E; Huser, T R; Hollars, C W; Jusinski, L; Laurence, T; Lane, S M

    2005-01-03

    Surface-enhanced Raman scattering is a powerful tool for the investigation of biological samples. Following a brief introduction to Raman and surface-enhanced Raman scattering, several examples of biophotonic applications of SERS are discussed. The concept of nanoparticle based sensors using SERS is introduced and the development of these sensors is discussed.

  6. Enhancing Engineering Education through Engineering Management

    ERIC Educational Resources Information Center

    Pence, Kenneth R.; Rowe, Christopher J.

    2012-01-01

    Engineering Management courses are added to a traditional engineering curriculum to enhance the value of an undergraduate's engineering degree. A four-year engineering degree often leaves graduates lacking in business and management acumen. Engineering management education covers topics enhancing the value of new graduates by teaching management…

  7. Online Faculty Satisfaction and Quality Enhancement Initiatives

    ERIC Educational Resources Information Center

    Satterlee, Anita G.

    2010-01-01

    The purpose of this paper is to examine possible effects of an institution's quality enhancement initiatives on the job satisfaction of online faculty. Quality enhancement initiatives are a normal part of the accreditation process and faculty shoulder some of the responsibility for success of those initiatives. Therefore, it is imperative that…

  8. Surface-Enhanced Second-Harmonic Generation

    SciTech Connect

    Chen, C. K.; de Castro, A. R.B.; Shen, Y. R.

    1981-01-12

    Second harmonic generation at a silver-air interface was enhanced due to surface roughness by a factor of 10⁴. The local field enhancement is believed to be responsible for the effect. An unusually broad luminescence background extending far beyond the antiStokes side of the second harmonic was also observed.

  9. Enhancing critical current density of cuprate superconductors

    DOEpatents

    Chaudhari, Praveen

    2015-06-16

    The present invention concerns the enhancement of critical current densities in cuprate superconductors. Such enhancement of critical current densities include using wave function symmetry and restricting movement of Abrikosov (A) vortices, Josephson (J) vortices, or Abrikosov-Josephson (A-J) vortices by using the half integer vortices associated with d-wave symmetry present in the grain boundary.

  10. Animal Behaviour: Friendship Enhances Trust in Chimpanzees.

    PubMed

    Silk, Joan

    2016-01-25

    Individuals that participate in exchanges with delayed rewards can be exploited if their partners don't reciprocate. In humans, friendships are built on trust, and trust enhances cooperation. New evidence suggests that close social bonds also enhance trust in chimpanzees.

  11. Learning To Make Music Enhances Spatial Reasoning.

    ERIC Educational Resources Information Center

    Hetland, Lois

    2000-01-01

    Examines whether active instruction in music enhances preschool and elementary school student performance on spatial tasks. Reports that music enhances the spatial-temporal performance of children during and up to two years following the instruction and that the effect is moderate and consistent. Includes references. (CMK)

  12. Digital enhancement of flow field images

    NASA Technical Reports Server (NTRS)

    Kudlinski, Robert A.; Park, Stephen K.

    1988-01-01

    Most photographs of experimentally generated fluid flow fields have inherently poor photographic quality, specifically low contrast. Thus, there is a need to establish a process for quickly and accurately enhancing these photographs to provide improved versions for physical interpretation, analysis, and publication. A sequence of digital image processing techniques which have been demonstrated to effectively enhance such photographs is described.

  13. Conceptual and practical problems of moral enhancement.

    PubMed

    Beck, Birgit

    2015-05-01

    Recently, the debate on human enhancement has shifted from familiar topics like cognitive enhancement and mood enhancement to a new and - to no one's surprise - controversial subject, namely moral enhancement. Some proponents from the transhumanist camp allude to the 'urgent need' of improving the moral conduct of humankind in the face of ever growing technological progress and the substantial dangers entailed in this enterprise. Other thinkers express more sceptical views about this proposal. As the debate has revealed so far, there is no shared opinion among philosophers (or scientists) about the meaning, prospects, and ethical evaluation of moral enhancement. In this article I will address several conceptual and practical problems of this issue, in order to encourage discussion about the prospects of (thinking about) moral enhancement in the future. My assumption is that (i) for the short term, there is little chance of arriving at an agreement on the proper understanding of morality and the appropriateness of one single (meta-)ethical theory; (ii) apart from this, there are further philosophical puzzles loosely referred to in the debate which add to theoretical confusion; and (iii) even if these conceptual problems could be solved, there are still practical problems to be smoothed out if moral enhancement is ever to gain relevance apart from merely theoretical interest. My tentative conclusion, therefore, will be that moral enhancement is not very likely to be made sense of - let alone realized - in the medium-term future.

  14. Doping explosive materials for neutron radiographic enhancement.

    NASA Technical Reports Server (NTRS)

    Golliher, K. G.

    1971-01-01

    Discussion of studies relating to the selection of doping materials of high neutron absorption usable for enhancing the neutron radiographic imaging of explosive mixtures, without interfering with the proper chemical reaction of the explosives. The results of the studies show that gadolinium oxide is an excellent material for doping explosive mixtures to enhance the neutron radiographic image.

  15. Open Educational Practices for Curriculum Enhancement

    ERIC Educational Resources Information Center

    Armellini, Alejandro; Nie, Ming

    2013-01-01

    Open educational resources (OER) and open educational practices (OEP) are relatively new areas in educational research. How OER and OEP can help practitioners enhance curricula is one of a number of under-researched topics. This article aims to enable practitioners to identify and implement appropriate open practices to enhance higher education…

  16. Enhancing Vocabulary Development in Multiple Classroom Contexts.

    ERIC Educational Resources Information Center

    Harmon, Janis M.; Staton, Denise G.

    1999-01-01

    Describes ways teachers can enhance students' vocabulary development through multiple contexts available in typical middle school classroom settings. Addresses questions about vocabulary learning and offers suggestions for enhancing vocabulary with narrative and expository texts that involve multiple classroom contexts. Considers the Vocab-o-gram…

  17. Conceptual and practical problems of moral enhancement.

    PubMed

    Beck, Birgit

    2015-05-01

    Recently, the debate on human enhancement has shifted from familiar topics like cognitive enhancement and mood enhancement to a new and - to no one's surprise - controversial subject, namely moral enhancement. Some proponents from the transhumanist camp allude to the 'urgent need' of improving the moral conduct of humankind in the face of ever growing technological progress and the substantial dangers entailed in this enterprise. Other thinkers express more sceptical views about this proposal. As the debate has revealed so far, there is no shared opinion among philosophers (or scientists) about the meaning, prospects, and ethical evaluation of moral enhancement. In this article I will address several conceptual and practical problems of this issue, in order to encourage discussion about the prospects of (thinking about) moral enhancement in the future. My assumption is that (i) for the short term, there is little chance of arriving at an agreement on the proper understanding of morality and the appropriateness of one single (meta-)ethical theory; (ii) apart from this, there are further philosophical puzzles loosely referred to in the debate which add to theoretical confusion; and (iii) even if these conceptual problems could be solved, there are still practical problems to be smoothed out if moral enhancement is ever to gain relevance apart from merely theoretical interest. My tentative conclusion, therefore, will be that moral enhancement is not very likely to be made sense of - let alone realized - in the medium-term future. PMID:24654942

  18. College Enhancement Strategies and Socioeconomic Inequality

    ERIC Educational Resources Information Center

    Wolniak, Gregory C.; Wells, Ryan S.; Engberg, Mark E.; Manly, Catherine A.

    2016-01-01

    The study provides new information on the relationships between students' socioeconomic backgrounds, utilization of college enhancement strategies, and subsequent 4-year college enrollment. Enhancement strategies represent student behaviors used to bolster the competitiveness of a college application, such as Advanced Placement exams and a variety…

  19. Surfactant and process for enhanced oil recovery

    SciTech Connect

    Stapp, P. R.

    1985-03-12

    A novel surfactant is formed by reacting maleic anhydride with a polynuclear aromatic compound having a molecular weight of at least 155. A novel surfactant system useful in enhanced oil recovery containing the above surfactant is also provided. In addition, an improved process for the enhanced recovery of oil is provided utilizing the novel surfactant system.

  20. Bandwidth enhancement of dielectric resonator antennas

    NASA Technical Reports Server (NTRS)

    Lee, Richard Q.; Simons, Rainee N.

    1993-01-01

    An experimental investigation of bandwidth enhancement of dielectric resonator antennas (DRA) using parasitic elements is reported. Substantial bandwidth enhancement for the HE(sub 11delta) mode of the stacked geometry and for the HE(sub 13delta) mode of the coplanar collinear geometry was demonstrated. Excellent radiation patterns for the HE(sub 11delta) mode were also recorded.