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Sample records for inhibitor r-125489 demonstrates

  1. Neuraminidase inhibitor R-125489 - A promising drug for treating influenza virus: Steered molecular dynamics approach

    Energy Technology Data Exchange (ETDEWEB)

    Mai, Binh Khanh [Institute for Computational Science and Technology, 6 Quarter, Linh Trung Ward, Thu Duc District, Ho Chi Minh City (Viet Nam); Li, Mai Suan, E-mail: masli@ifpan.edu.pl [Institute of Physics, Polish Academy of Sciences, Al. Lotnikow 32/46, 02-668 Warsaw (Poland)

    2011-07-08

    Highlights: {yields} We study binding affinity of R-125489 and its prodrug CS-8958 to neuraminidase of pathogenic influenza viruses by molecular dynamics simulations. {yields} It is shown that, in agreement with experiments, R-125489 binds to neuraminidase more tightly than CS-8958. {yields} We predict that R-125489 can be used to treat not only wild-type but also tamiflu-resistant N294S, H274Y variants of A/H5N1 virus. {yields} The high correlation between theoretical and experimental data implies that SMD is a very promising tool for drug design. -- Abstract: Two neuraminidase inhibitors, oseltamivir and zanamivir, are important drug treatments for influenza. Oseltamivir-resistant mutants of the influenza virus A/H1N1 and A/H5N1 have emerged, necessitating the development of new long-acting antiviral agents. One such agent is a new neuraminidase inhibitor R-125489 and its prodrug CS-8958. An atomic level understanding of the nature of this antiviral agents binding is still missing. We address this gap in our knowledge by applying steered molecular dynamics (SMD) simulations to different subtypes of seasonal and highly pathogenic influenza viruses. We show that, in agreement with experiments, R-125489 binds to neuraminidase more tightly than CS-8958. Based on results obtained by SMD and the molecular mechanics-Poisson-Boltzmann surface area method, we predict that R-125489 can be used to treat not only wild-type but also tamiflu-resistant N294S, H274Y variants of A/H5N1 virus as its binding affinity does not vary much across these systems. The high correlation level between theoretically determined rupture forces and experimental data on binding energies for the large number of systems studied here implies that SMD is a promising tool for drug design.

  2. Neuraminidase inhibitor R-125489 - A promising drug for treating influenza virus: Steered molecular dynamics approach

    International Nuclear Information System (INIS)

    Mai, Binh Khanh; Li, Mai Suan

    2011-01-01

    Highlights: → We study binding affinity of R-125489 and its prodrug CS-8958 to neuraminidase of pathogenic influenza viruses by molecular dynamics simulations. → It is shown that, in agreement with experiments, R-125489 binds to neuraminidase more tightly than CS-8958. → We predict that R-125489 can be used to treat not only wild-type but also tamiflu-resistant N294S, H274Y variants of A/H5N1 virus. → The high correlation between theoretical and experimental data implies that SMD is a very promising tool for drug design. -- Abstract: Two neuraminidase inhibitors, oseltamivir and zanamivir, are important drug treatments for influenza. Oseltamivir-resistant mutants of the influenza virus A/H1N1 and A/H5N1 have emerged, necessitating the development of new long-acting antiviral agents. One such agent is a new neuraminidase inhibitor R-125489 and its prodrug CS-8958. An atomic level understanding of the nature of this antiviral agents binding is still missing. We address this gap in our knowledge by applying steered molecular dynamics (SMD) simulations to different subtypes of seasonal and highly pathogenic influenza viruses. We show that, in agreement with experiments, R-125489 binds to neuraminidase more tightly than CS-8958. Based on results obtained by SMD and the molecular mechanics-Poisson-Boltzmann surface area method, we predict that R-125489 can be used to treat not only wild-type but also tamiflu-resistant N294S, H274Y variants of A/H5N1 virus as its binding affinity does not vary much across these systems. The high correlation level between theoretically determined rupture forces and experimental data on binding energies for the large number of systems studied here implies that SMD is a promising tool for drug design.

  3. Inhibitors

    Science.gov (United States)

    ... JM, and the Hemophilia Inhibitor Research Study Investigators. Validation of Nijmegen-Bethesda assay modifications to allow inhibitor ... webinars on blood disorders Language: English (US) Español (Spanish) File Formats Help: How do I view different ...

  4. Rigid amphipathic fusion inhibitors demonstrate antiviral activity against African swine fever virus.

    Science.gov (United States)

    Hakobyan, Astghik; Galindo, Inmaculada; Nañez, Almudena; Arabyan, Erik; Karalyan, Zaven; Chistov, Alexey A; Streshnev, Philipp P; Korshun, Vladimir A; Alonso, Covadonga; Zakaryan, Hovakim

    2018-01-01

    Rigid amphipathic fusion inhibitors (RAFIs) are a family of nucleoside derivatives that inhibit the infectivity of several enveloped viruses by interacting with virion envelope lipids and inhibiting fusion between viral and cellular membranes. Here we tested the antiviral activity of two RAFIs, 5-(Perylen-3-ylethynyl)-arabino-uridine (aUY11) and 5-(Perylen-3-ylethynyl)uracil-1-acetic acid (cm1UY11) against African swine fever virus (ASFV), for which no effective vaccine is available. Both compounds displayed a potent, dose-dependent inhibitory effect on ASFV infection in Vero cells. The major antiviral effect was observed when aUY11 and cm1UY11 were added at early stages of infection and maintained during the complete viral cycle. Furthermore, virucidal assay revealed a significant extracellular anti-ASFV activity for both compounds. We also found decrease in the synthesis of early and late viral proteins in Vero cells treated with cm1UY11. Finally, the inhibitory effect of aUY11 and cm1UY11 on ASFV infection in porcine alveolar macrophages was confirmed. Overall, our study has identified novel anti-ASFV compounds with potential for future therapeutic developments.

  5. Inhibitors of bacterial N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) and demonstration of in vitro antimicrobial activity.

    Science.gov (United States)

    Gillner, Danuta; Armoush, Nicola; Holz, Richard C; Becker, Daniel P

    2009-11-15

    The dapE-encoded N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) is a critical bacterial enzyme for the construction of the bacterial cell wall. A screen biased toward compounds containing zinc-binding groups (ZBG's) including thiols, carboxylic acids, boronic acids, phosphonates and hydroxamates has delivered a number of micromolar inhibitors of DapE from Haemophilus influenzae, including the low micromolar inhibitor L-captopril (IC(50)=3.3 microM, K(i)=1.8 microM). In vitro antimicrobial activity was demonstrated for L-captopril against Escherichia coli.

  6. The Bruton Tyrosine Kinase (BTK) Inhibitor Acalabrutinib Demonstrates Potent On-Target Effects and Efficacy in Two Mouse Models of Chronic Lymphocytic Leukemia

    DEFF Research Database (Denmark)

    Herman, Sarah E M; Montraveta, Arnau; Niemann, Carsten U

    2017-01-01

    into the drinking water.Results: Utilizing biochemical assays, we demonstrate that acalabrutinib is a highly selective BTK inhibitor as compared with ibrutinib. In the human CLL NSG xenograft model, treatment with acalabrutinib demonstrated on-target effects, including decreased phosphorylation of PLCγ2, ERK......). In two complementary mouse models of CLL, acalabrutinib significantly reduced tumor burden and increased survival compared with vehicle treatment. Overall, acalabrutinib showed increased BTK selectivity compared with ibrutinib while demonstrating significant antitumor efficacy in vivo on par...... with ibrutinib. Clin Cancer Res; 23(11); 2831-41. ©2016 AACR....

  7. New small molecule inhibitors of UPR activation demonstrate that PERK, but not IRE1α signaling is essential for promoting adaptation and survival to hypoxia

    International Nuclear Information System (INIS)

    Cojocari, Dan; Vellanki, Ravi N.; Sit, Brandon; Uehling, David; Koritzinsky, Marianne; Wouters, Bradly G.

    2013-01-01

    Background and purpose: The unfolded protein response (UPR) is activated in response to hypoxia-induced stress in the endoplasmic reticulum (ER) and consists of three distinct signaling arms. Here we explore the potential of targeting two of these arms with new potent small-molecule inhibitors designed against IRE1α and PERK. Methods: We utilized shRNAs and small-molecule inhibitors of IRE1α (4μ8c) and PERK (GSK-compound 39). XBP1 splicing and DNAJB9 mRNA was measured by qPCR and was used to monitor IRE1α activity. PERK activity was monitored by immunoblotting eIF2α phosphorylation and qPCR of DDIT3 mRNA. Hypoxia tolerance was measured using proliferation and clonogenic cell survival assays of cells exposed to mild or severe hypoxia in the presence of the inhibitors. Results: Using knockdown experiments we show that PERK is essential for survival of KP4 cells while knockdown of IRE1α dramatically decreases the proliferation and survival of HCT116 during hypoxia. Further, we show that in response to both hypoxia and other ER stress-inducing agents both 4μ8c and the PERK inhibitor are selective and potent inhibitors of IRE1α and PERK activation, respectively. However, despite potent inhibition of IRE1α activation, 4μ8c had no effect on cell proliferation or clonogenic survival of cells exposed to hypoxia. This was in contrast to the inactivation of PERK signaling with the PERK inhibitor, which reduced tolerance to hypoxia and other ER stress inducing agents. Conclusions: Our results demonstrate that IRE1α but not its splicing activity is important for hypoxic cell survival. The PERK signaling arm is uniquely important for promoting adaptation and survival during hypoxia-induced ER stress and should be the focus of future therapeutic efforts

  8. Fanca-/- hematopoietic stem cells demonstrate a mobilization defect which can be overcome by administration of the Rac inhibitor NSC23766.

    Science.gov (United States)

    Milsom, Michael D; Lee, Andrew W; Zheng, Yi; Cancelas, Jose A

    2009-07-01

    Fanconi anemia is a severe bone marrow failure syndrome resulting from inactivating mutations of Fanconi anemia pathway genes. Gene and cell therapy trials using hematopoietic stem cells and progenitors have been hampered by poor mobilization of HSC to peripheral blood in response to G-CSF. Using a murine model of Fanconi anemia (Fanca(-/-) mice), we found that the Fanca deficiency was associated with a profound defect in hematopoietic stem cells and progenitors mobilization in response to G-CSF in absence of bone marrow failure, which correlates with the findings of clinical trials in Fanconi anemia patients. This mobilization defect was overcome by co-administration of the Rac inhibitor NSC23766, suggesting that Rac signaling is implicated in the retention of Fanca(-/-) hematopoietic stem cells and progenitors in the bone marrow. In view of these data, we propose that targeting Rac signaling may enhance G-CSF-induced HSC mobilization in Fanconi anemia.

  9. Mitochondrial genome-knockout cells demonstrate a dual mechanism of action for the electron transport complex I inhibitor mycothiazole.

    Science.gov (United States)

    Meyer, Kirsten J; Singh, A Jonathan; Cameron, Alanna; Tan, An S; Leahy, Dora C; O'Sullivan, David; Joshi, Praneta; La Flamme, Anne C; Northcote, Peter T; Berridge, Michael V; Miller, John H

    2012-04-01

    Mycothiazole, a polyketide metabolite isolated from the marine sponge Cacospongia mycofijiensis, is a potent inhibitor of metabolic activity and mitochondrial electron transport chain complex I in sensitive cells, but other cells are relatively insensitive to the drug. Sensitive cell lines (IC(50) 0.36-13.8 nM) include HeLa, P815, RAW 264.7, MDCK, HeLa S3, 143B, 4T1, B16, and CD4/CD8 T cells. Insensitive cell lines (IC(50) 12.2-26.5 μM) include HL-60, LN18, and Jurkat. Thus, there is a 34,000-fold difference in sensitivity between HeLa and HL-60 cells. Some sensitive cell lines show a biphasic response, suggesting more than one mechanism of action. Mitochondrial genome-knockout ρ(0) cell lines are insensitive to mycothiazole, supporting a conditional mitochondrial site of action. Mycothiazole is cytostatic rather than cytotoxic in sensitive cells, has a long lag period of about 12 h, and unlike the complex I inhibitor, rotenone, does not cause G(2)/M cell cycle arrest. Mycothiazole decreases, rather than increases the levels of reactive oxygen species after 24 h. It is concluded that the cytostatic inhibitory effects of mycothiazole on mitochondrial electron transport function in sensitive cell lines may depend on a pre-activation step that is absent in insensitive cell lines with intact mitochondria, and that a second lower-affinity cytotoxic target may also be involved in the metabolic and growth inhibition of cells.

  10. Focal Adhesion Kinase Inhibitors in Combination with Erlotinib Demonstrate Enhanced Anti-Tumor Activity in Non-Small Cell Lung Cancer.

    Directory of Open Access Journals (Sweden)

    Grant A Howe

    Full Text Available Blockade of epidermal growth factor receptor (EGFR activity has been a primary therapeutic target for non-small cell lung cancers (NSCLC. As patients with wild-type EGFR have demonstrated only modest benefit from EGFR tyrosine kinase inhibitors (TKIs, there is a need for additional therapeutic approaches in patients with wild-type EGFR. As a key component of downstream integrin signalling and known receptor cross-talk with EGFR, we hypothesized that targeting focal adhesion kinase (FAK activity, which has also been shown to correlate with aggressive stage in NSCLC, would lead to enhanced activity of EGFR TKIs. As such, EGFR TKI-resistant NSCLC cells (A549, H1299, H1975 were treated with the EGFR TKI erlotinib and FAK inhibitors (PF-573,228 or PF-562,271 both as single agents and in combination. We determined cell viability, apoptosis and 3-dimensional growth in vitro and assessed tumor growth in vivo. Treatment of EGFR TKI-resistant NSCLC cells with FAK inhibitor alone effectively inhibited cell viability in all cell lines tested; however, its use in combination with the EGFR TKI erlotinib was more effective at reducing cell viability than either treatment alone when tested in both 2- and 3-dimensional assays in vitro, with enhanced benefit seen in A549 cells. This increased efficacy may be due in part to the observed inhibition of Akt phosphorylation when the drugs were used in combination, where again A549 cells demonstrated the most inhibition following treatment with the drug combination. Combining erlotinib with FAK inhibitor was also potent in vivo as evidenced by reduced tumor growth in the A549 mouse xenograft model. We further ascertained that the enhanced sensitivity was irrespective of the LKB1 mutational status. In summary, we demonstrate the effectiveness of combining erlotinib and FAK inhibitors for use in known EGFR wild-type, EGFR TKI resistant cells, with the potential that a subset of cell types, which includes A549, could be

  11. Leiomyoma Cells in 3-Dimensional Cultures Demonstrate an Attenuated Response to Fasudil, a Rho-Kinase Inhibitor, When Compared to 2-Dimensional Cultures

    Science.gov (United States)

    Malik, Minnie; Britten, Joy; Segars, James

    2014-01-01

    Uterine leiomyomata are common benign tumors in women of reproductive age and demonstrate an attenuated response to mechanical signaling that involves Rho and integrins. To further characterize the impairment in Rho signaling, we studied the effect of Rho-kinase inhibitor, fasudil, on extracellular matrix production, in 2-dimensional (2D) and 3-dimensional (3D) cultures of leiomyoma and myometrial cells. Leiomyoma 2D cultures demonstrated a rapid decrease in gene transcripts and protein for fibronectin, procollagen 1A, and versican. In 3D cultures, fibronectin and procollagen 1A proteins demonstrated increased levels at lower concentrations of fasudil, followed by a concentration-dependent decrease. Versican protein increased up to 3-fold, whereas fibromodulin demonstrated a significant decrease of 1.92-fold. Myometrial 2D or 3D cultures demonstrated a decrease in all proteins after 72 hours of treatment. The 3D leiomyoma cultures demonstrated a significant increase in active RhoA, followed by a concentration-dependent decrease at higher concentrations. A concentration-dependent increase in phospho-extracellular regulated signal kinase and proapoptotic protein Bax was observed in 3D leiomyoma cultures. Fasudil relaxed the contraction of the 3D collagen gels caused by myometrium and leiomyoma cell growth. These findings indicate that the altered state of Rho signaling in leiomyoma was more clearly observed in 3D cultures. The results also suggest that fasudil may have clinical applicability for treatment of uterine leiomyoma. PMID:25084783

  12. Statins: 3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors demonstrate anti-atherosclerotic character due to their antioxidant capacity

    Digital Repository Service at National Institute of Oceanography (India)

    Puttananjaiah, M.H.; Dhale, M.A.; Gaonkar, V.; Keni, S.

    inhibitors (commonly known as statins) are widely used in cardiovascular disease prevention to lower the cholesterol. The antioxidant activity of HMG-CoA reductase inhibitors was studied by lipid peroxidation inhibition assay, DPPH, and hydroxyl radical...

  13. Identification of an imidazopyridine scaffold to generate potent and selective TYK2 inhibitors that demonstrate activity in an in vivo psoriasis model.

    Science.gov (United States)

    Liang, Jun; Van Abbema, Anne; Balazs, Mercedesz; Barrett, Kathy; Berezhkovsky, Leo; Blair, Wade S; Chang, Christine; Delarosa, Donnie; DeVoss, Jason; Driscoll, Jim; Eigenbrot, Charles; Goodacre, Simon; Ghilardi, Nico; MacLeod, Calum; Johnson, Adam; Bir Kohli, Pawan; Lai, Yingjie; Lin, Zhonghua; Mantik, Priscilla; Menghrajani, Kapil; Nguyen, Hieu; Peng, Ivan; Sambrone, Amy; Shia, Steven; Smith, Jan; Sohn, Sue; Tsui, Vickie; Ultsch, Mark; Williams, Karen; Wu, Lawren C; Yang, Wenqian; Zhang, Birong; Magnuson, Steven

    2017-09-15

    Herein we report identification of an imidazopyridine class of potent and selective TYK2 inhibitors, exemplified by prototype 6, through constraint of the rotatable amide bond connecting the pyridine and aryl rings of compound 1. Further optimization led to generation of compound 30 that potently inhibits the TYK2 enzyme and the IL-23 pathway in cells, exhibits selectivity against cellular JAK2 activity, and has good pharmacokinetic properties. In mice, compound 30 demonstrated dose-dependent reduction of IL-17 production in a PK/PD model as well as in an imiquimod-induced psoriasis model. In this efficacy model, the IL-17 decrease was accompanied by a reduction of ear thickness indicating the potential of TYK2 inhibition as a therapeutic approach for psoriasis patients. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. CDK4/6 dual inhibitor abemaciclib demonstrates compelling preclinical activity against esophageal adenocarcinoma: a novel therapeutic option for a deadly disease.

    Science.gov (United States)

    Kosovec, Juliann E; Zaidi, Ali H; Omstead, Ashten N; Matsui, Daisuke; Biedka, Mark J; Cox, Erin J; Campbell, Patrick T; Biederman, Robert W W; Kelly, Ronan J; Jobe, Blair A

    2017-11-21

    Esophageal adenocarcinoma (EAC) is a deadly disease with limited therapeutic options. In the present study, we determined the preclinical efficacy of CDK4/6 inhibitor abemaciclib for treatment of EAC. In vitro , apoptosis, proliferation, and pathway regulation were evaluated in OE19, OE33, and FLO1 EAC cell lines. In vivo , esophagojejunostomy was performed on rats to induce EAC. At 36 weeks post-surgery, MRI and endoscopic biopsy established baseline tumor volume and molecular correlates, respectively. Next, the study animals were randomized to 26mg/kg intraperitoneal abemaciclib treatment or vehicle control for 28 days. Pre and post treatment MRIs, histopathology, and qRT-PCR were utilized to determine response. Our results demonstrated treatment with abemaciclib lead to increased apoptosis, and decreased proliferation in OE19 (p=0.185), OE33 (p=0.048), and FLO1 (p=0.043) with anticipated downstream molecular inhibition. In vivo , 78.9% of treatment animals demonstrated >20% tumor volume decrease (placebo 0%). Mean tumor volume changed in the treatment arm by -65.5% (placebo +133.5%) (p<0.01), and prevalence changed by -37.5% (placebo +16.7%) (p<0.01). Pre vs post treatment qRT-PCR demonstrated significant inhibition of all downstream molecular correlates. Overall our findings suggest potent antitumor efficacy of abemaciclib against EAC with evident molecular pathway inhibition and reasonable safety, establishing the rationale for future clinical development.

  15. A preclinical orthotopic model for glioblastoma recapitulates key features of human tumors and demonstrates sensitivity to a combination of MEK and PI3K pathway inhibitors.

    Science.gov (United States)

    El Meskini, Rajaa; Iacovelli, Anthony J; Kulaga, Alan; Gumprecht, Michelle; Martin, Philip L; Baran, Maureen; Householder, Deborah B; Van Dyke, Terry; Weaver Ohler, Zoë

    2015-01-01

    Current therapies for glioblastoma multiforme (GBM), the highest grade malignant brain tumor, are mostly ineffective, and better preclinical model systems are needed to increase the successful translation of drug discovery efforts into the clinic. Previous work describes a genetically engineered mouse (GEM) model that contains perturbations in the most frequently dysregulated networks in GBM (driven by RB, KRAS and/or PI3K signaling and PTEN) that induce development of Grade IV astrocytoma with properties of the human disease. Here, we developed and characterized an orthotopic mouse model derived from the GEM that retains the features of the GEM model in an immunocompetent background; however, this model is also tractable and efficient for preclinical evaluation of candidate therapeutic regimens. Orthotopic brain tumors are highly proliferative, invasive and vascular, and express histology markers characteristic of human GBM. Primary tumor cells were examined for sensitivity to chemotherapeutics and targeted drugs. PI3K and MAPK pathway inhibitors, when used as single agents, inhibited cell proliferation but did not result in significant apoptosis. However, in combination, these inhibitors resulted in a substantial increase in cell death. Moreover, these findings translated into the in vivo orthotopic model: PI3K or MAPK inhibitor treatment regimens resulted in incomplete pathway suppression and feedback loops, whereas dual treatment delayed tumor growth through increased apoptosis and decreased tumor cell proliferation. Analysis of downstream pathway components revealed a cooperative effect on target downregulation. These concordant results, together with the morphologic similarities to the human GBM disease characteristics of the model, validate it as a new platform for the evaluation of GBM treatment. © 2015. Published by The Company of Biologists Ltd.

  16. A preclinical orthotopic model for glioblastoma recapitulates key features of human tumors and demonstrates sensitivity to a combination of MEK and PI3K pathway inhibitors

    Directory of Open Access Journals (Sweden)

    Rajaa El Meskini

    2015-01-01

    Full Text Available Current therapies for glioblastoma multiforme (GBM, the highest grade malignant brain tumor, are mostly ineffective, and better preclinical model systems are needed to increase the successful translation of drug discovery efforts into the clinic. Previous work describes a genetically engineered mouse (GEM model that contains perturbations in the most frequently dysregulated networks in GBM (driven by RB, KRAS and/or PI3K signaling and PTEN that induce development of Grade IV astrocytoma with properties of the human disease. Here, we developed and characterized an orthotopic mouse model derived from the GEM that retains the features of the GEM model in an immunocompetent background; however, this model is also tractable and efficient for preclinical evaluation of candidate therapeutic regimens. Orthotopic brain tumors are highly proliferative, invasive and vascular, and express histology markers characteristic of human GBM. Primary tumor cells were examined for sensitivity to chemotherapeutics and targeted drugs. PI3K and MAPK pathway inhibitors, when used as single agents, inhibited cell proliferation but did not result in significant apoptosis. However, in combination, these inhibitors resulted in a substantial increase in cell death. Moreover, these findings translated into the in vivo orthotopic model: PI3K or MAPK inhibitor treatment regimens resulted in incomplete pathway suppression and feedback loops, whereas dual treatment delayed tumor growth through increased apoptosis and decreased tumor cell proliferation. Analysis of downstream pathway components revealed a cooperative effect on target downregulation. These concordant results, together with the morphologic similarities to the human GBM disease characteristics of the model, validate it as a new platform for the evaluation of GBM treatment.

  17. First demonstration of cerebrospinal fluid and plasma A beta lowering with oral administration of a beta-site amyloid precursor protein-cleaving enzyme 1 inhibitor in nonhuman primates.

    Science.gov (United States)

    Sankaranarayanan, Sethu; Holahan, Marie A; Colussi, Dennis; Crouthamel, Ming-Chih; Devanarayan, Viswanath; Ellis, Joan; Espeseth, Amy; Gates, Adam T; Graham, Samuel L; Gregro, Allison R; Hazuda, Daria; Hochman, Jerome H; Holloway, Katharine; Jin, Lixia; Kahana, Jason; Lai, Ming-tain; Lineberger, Janet; McGaughey, Georgia; Moore, Keith P; Nantermet, Philippe; Pietrak, Beth; Price, Eric A; Rajapakse, Hemaka; Stauffer, Shaun; Steinbeiser, Melissa A; Seabrook, Guy; Selnick, Harold G; Shi, Xiao-Ping; Stanton, Matthew G; Swestock, John; Tugusheva, Katherine; Tyler, Keala X; Vacca, Joseph P; Wong, Jacky; Wu, Guoxin; Xu, Min; Cook, Jacquelynn J; Simon, Adam J

    2009-01-01

    beta-Site amyloid precursor protein (APP)-cleaving enzyme (BACE) 1 cleavage of amyloid precursor protein is an essential step in the generation of the potentially neurotoxic and amyloidogenic A beta 42 peptides in Alzheimer's disease. Although previous mouse studies have shown brain A beta lowering after BACE1 inhibition, extension of such studies to nonhuman primates or man was precluded by poor potency, brain penetration, and pharmacokinetics of available inhibitors. In this study, a novel tertiary carbinamine BACE1 inhibitor, tertiary carbinamine (TC)-1, was assessed in a unique cisterna magna ported rhesus monkey model, where the temporal dynamics of A beta in cerebrospinal fluid (CSF) and plasma could be evaluated. TC-1, a potent inhibitor (IC(50) approximately 0.4 nM), has excellent passive membrane permeability, low susceptibility to P-glycoprotein transport, and lowered brain A beta levels in a mouse model. Intravenous infusion of TC-1 led to a significant but transient lowering of CSF and plasma A beta levels in conscious rhesus monkeys because it underwent CYP3A4-mediated metabolism. Oral codosing of TC-1 with ritonavir, a potent CYP3A4 inhibitor, twice daily over 3.5 days in rhesus monkeys led to sustained plasma TC-1 exposure and a significant and sustained reduction in CSF sAPP beta, A beta 40, A beta 42, and plasma A beta 40 levels. CSF A beta 42 lowering showed an EC(50) of approximately 20 nM with respect to the CSF [TC-1] levels, demonstrating excellent concordance with its potency in a cell-based assay. These results demonstrate the first in vivo proof of concept of CSF A beta lowering after oral administration of a BACE1 inhibitor in a nonhuman primate.

  18. Fanca−/− hematopoietic stem cells demonstrate a mobilization defect which can be overcome by administration of the Rac inhibitor NSC23766

    Science.gov (United States)

    Milsom, Michael D.; Lee, Andrew W.; Zheng, Yi; Cancelas, Jose A.

    2009-01-01

    Fanconi anemia is a severe bone marrow failure syndrome resulting from inactivating mutations of Fanconi anemia pathway genes. Gene and cell therapy trials using hematopoietic stem cells and progenitors have been hampered by poor mobilization of HSC to peripheral blood in response to G-CSF. Using a murine model of Fanconi anemia (Fanca−/− mice), we found that the Fanca deficiency was associated with a profound defect in hematopoietic stem cells and progenitors mobilization in response to G-CSF in absence of bone marrow failure, which correlates with the findings of clinical trials in Fanconi anemia patients. This mobilization defect was overcome by co-administration of the Rac inhibitor NSC23766, suggesting that Rac signaling is implicated in the retention of Fanca−/− hematopoietic stem cells and progenitors in the bone marrow. In view of these data, we propose that targeting Rac signaling may enhance G-CSF-induced HSC mobilization in Fanconi anemia. PMID:19491337

  19. Proteomic demonstration of the recurrent presence of inter-alpha-inhibitor H4 heavy-chain during aspergillosis induced in an animal model.

    Science.gov (United States)

    Desoubeaux, Guillaume; Jourdan, Marie-Lise; Valera, Lionel; Jardin, Bénédicte; Hem, Sonia; Caille, Agnès; Cormier, Bénédicte; Marchand-Adam, Sylvain; Bailly, Éric; Diot, Patrice; Chandenier, Jacques

    2014-05-01

    Invasive pulmonary aspergillosis remains a matter of great concern in oncology/haematology, intensive care units and organ transplantation departments. Despite the availability of various diagnostic tools with attractive features, new markers of infection are required for better medical care. We therefore looked for potential pulmonary biomarkers of aspergillosis, by carrying out two-dimensional (2D) gel electrophoresis comparing the proteomes of bronchial-alveolar lavage fluids (BALF) from infected rats and from control rats presenting non-specific inflammation, both immunocompromised. A bioinformatic analysis of the 2D-maps revealed significant differences in the abundance of 20 protein spots (ANOVA P-valuevalue0.8). One of these proteins, identified by mass spectrometry, was considered of potential interest: inter-alpha-inhibitor H4 heavy-chain (ITIH4), characterised for the first time in this infectious context. Western blotting confirmed its overabundance in all infected BALF, particularly at early stages of murine aspergillosis. Further investigations were carried on rat serum, and confirmed that ITIH4 levels increased during experimental aspergillosis. Preliminary results in human samples strengthened this trend. To our knowledge, this is the first description of the involvement of ITIH4 in aspergillosis. Copyright © 2013 Elsevier GmbH. All rights reserved.

  20. A cheap, simple high throughput method for screening native Helicobacter pylori urease inhibitors using a recombinant Escherichia coli, its validation and demonstration of Pistacia atlantica methanolic extract effectivity and specificity.

    Science.gov (United States)

    Amar, Natalie; Peretz, Avi; Gerchman, Yoram

    2017-02-01

    Helicobacter pylori is the most frequent and persistent bacterial infection worldwide, and a risk factor for active gastritis, peptic ulcers, mucosa-associated lymphoid tissue lymphoma, and gastric cancer. Although combined antibiotics treatment is effective cases of antibiotic resistance are reported at an alarming rate. The H. pylori urease enzyme is essential for the bacteria establishment in the gastric mucosa, resulting urease inhibitors being sought after as effective and specific anti- H. pylori treatment. To-date, screening assays are based mostly on the analog plant urease enzyme but difference in properties of the plant and bacterial enzymes hamper these efforts. We have developed a screening assay based on recombinant Escherichia coli expressing native H. pylori urease, and validated this assay using thiourea and a methanolic extract of Pistacia atlantica. The assay demonstrated the thiourea and the extract to be potent urease inhibitors, with the extract having strong bacteriostatic activity against clinical isolates of H. pylori, including such with antibiotic resistance. The extract was also found to be neutral toward common probiotic bacteria, supporting its specificity and compatibility with digestive system desired microflora and suggesting it could be a good source for anti-H. pylori compounds. The assay has proven to be cheap, simple and native alternative to the plant enzyme based assay and could allow for high throughput screening for new urease inhibitors and could expedite screening and development of novel, better H. pylori remedies helping us to combat this infection. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Measurement of dabigatran: previously demonstrated Hemoclot® Thrombin Inhibitor assay reagent instability on Sysmex CS-2100i is no longer an issue

    DEFF Research Database (Denmark)

    Comuth, Willemijn; Faaborg, Louise; Henriksen, Linda Østervig

    2017-01-01

    hours. Since the reagent composition was unchanged, the increased stability could be due to changed logistics by the supplier, with stock and transfer closer by. Previously demonstrated HTI reagent instability is no longer an issue at our laboratory. The reliability of results of clinical studies...

  2. A novel pyrazolo[1,5-a]pyrimidine is a potent inhibitor of cyclin-dependent protein kinases 1, 2, and 9, which demonstrates antitumor effects in human tumor xenografts following oral administration.

    Science.gov (United States)

    Heathcote, Dean A; Patel, Hetal; Kroll, Sebastian H B; Hazel, Pascale; Periyasamy, Manikandan; Alikian, Mary; Kanneganti, Seshu K; Jogalekar, Ashutosh S; Scheiper, Bodo; Barbazanges, Marion; Blum, Andreas; Brackow, Jan; Siwicka, Alekasandra; Pace, Robert D M; Fuchter, Matthew J; Snyder, James P; Liotta, Dennis C; Freemont, Paul S; Aboagye, Eric O; Coombes, R Charles; Barrett, Anthony G M; Ali, Simak

    2010-12-23

    Cyclin-dependent protein kinases (CDKs) are central to the appropriate regulation of cell proliferation, apoptosis, and gene expression. Abnormalities in CDK activity and regulation are common features of cancer, making CDK family members attractive targets for the development of anticancer drugs. Here, we report the identification of a pyrazolo[1,5-a]pyrimidine derived compound, 4k (BS-194), as a selective and potent CDK inhibitor, which inhibits CDK2, CDK1, CDK5, CDK7, and CDK9 (IC₅₀= 3, 30, 30, 250, and 90 nmol/L, respectively). Cell-based studies showed inhibition of the phosphorylation of CDK substrates, Rb and the RNA polymerase II C-terminal domain, down-regulation of cyclins A, E, and D1, and cell cycle block in the S and G₂/M phases. Consistent with these findings, 4k demonstrated potent antiproliferative activity in 60 cancer cell lines tested (mean GI₅₀= 280 nmol/L). Pharmacokinetic studies showed that 4k is orally bioavailable, with an elimination half-life of 178 min following oral dosing in mice. When administered at a concentration of 25 mg/kg orally, 4k inhibited human tumor xenografts and suppressed CDK substrate phosphorylation. These findings identify 4k as a novel, potent CDK selective inhibitor with potential for oral delivery in cancer patients.

  3. Syk inhibitors.

    Science.gov (United States)

    Chihara, Kazuyasu; Kimura, Yukihiro; Honjo, Chisato; Takeuchi, Kenji; Sada, Kiyonao

    2013-01-01

    Non-receptor type of protein-tyrosine kinase Syk (spleen tyrosine kinase) was isolated in University of Fukui in 1991. Syk is most highly expressed by haemopoietic cells and known to play crucial roles in the signal transduction through various immunoreceptors of the adaptive immune response. However, recent reports demonstrate that Syk also mediates other biological functions, such as innate immune response, osteoclast maturation, platelet activation and cellular adhesion. Moreover, ectopic expression of Syk by epigenetic changes is reported to cause retinoblastoma. Because of its critical roles on the cellular functions, the development of Syk inhibitors for clinical use has been desired. Although many candidate compounds were produced, none of them had progressed to clinical trials. However, novel Syk inhibitors were finally developed and its usefulness has been evaluated in the treatment of allergic rhinitis, rheumatoid arthritis and idiopathic thrombocytopenic purpura. In this review, we will summarize the history, structure and function of Syk, and then the novel Syk inhibitors and their current status. In addition, we will introduce our research focused on the functions of Syk on Dectin-1-mediated mast cell activation.

  4. Postnatal changes of gene expression for tissue inhibitors of metalloproteinase-1 and -2 and cystatins S and C, in rat submandibular gland demonstrated by quantitative reverse transcription-polymerase chain reaction.

    Science.gov (United States)

    Nishiura, T; Abe, K

    1999-01-01

    The rat submandibular gland is not fully developed at birth and definitive differentiation takes place postnatally. The steady-state mRNA expression for the four proteinase inhibitor molecules, tissue inhibitors of metalloproteinase (TIMP)-1 and -2, and cystatins S and C, and for a housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (G3PDH), in rat submandibular glands was measured by quantitative competitive reverse transcription-polymerase chain reaction (RT-PCR) at different stages of postnatal development. The gene-expression patterns of TIMP-1 and -2 relative to G3PDH were similar to each other. The TIMP-2 and cystatin C genes were more highly expressed than those of TIMP-1 and cystatin S at all stages. Moreover, the gene expressions of TIMP-1 and -2, and of cystatins S and C, were predominant between 1 and 7, and 7 and 12 weeks of age, respectively, and coincided developmentally with the regression of terminal tubule cells and the differentiation of granular convoluted tubule cells, respectively. Quantitative competitive RT-PCR allowed accurate measurement of small changes in the steady-state concentrations of these proteinase-inhibitor mRNA molecules.

  5. Tested Demonstrations.

    Science.gov (United States)

    Gilbert, George L.

    1983-01-01

    An apparatus is described in which effects of pressure, volume, and temperature changes on a gas can be observed simultaneously. Includes use of the apparatus in demonstrating Boyle's, Gay-Lussac's, and Charles' Laws, attractive forces, Dalton's Law of Partial pressures, and in illustrating measurable vapor pressures of liquids and some solids.…

  6. Tested Demonstrations.

    Science.gov (United States)

    Gilbert, George L., Ed.

    1987-01-01

    Describes two demonstrations to illustrate characteristics of substances. Outlines a method to detect the changes in pH levels during the electrolysis of water. Uses water pistols, one filled with methane gas and the other filled with water, to illustrate the differences in these two substances. (TW)

  7. JAK inhibitors in autoinflammation.

    Science.gov (United States)

    Hoffman, Hal M; Broderick, Lori

    2018-06-11

    Interferonopathies are a subset of autoinflammatory disorders with a prominent type I IFN gene signature. Treatment of these patients has been challenging, given the lack of response to common autoinflammatory therapeutics including IL-1 and TNF blockade. JAK inhibitors (Jakinibs) are a family of small-molecule inhibitors that target the JAK/STAT signaling pathway and have shown clinical efficacy, with FDA and European Medicines Agency (EMA) approval for arthritic and myeloproliferative syndromes. Sanchez and colleagues repurposed baricitinib to establish a significant role for JAK inhibition as a novel therapy for patients with interferonopathies, demonstrating the power of translational rare disease research with lifesaving effects.

  8. [Syk inhibitors].

    Science.gov (United States)

    Kimura, Yukihiro; Chihara, Kazuyasu; Takeuchi, Kenji; Sada, Kiyonao

    2013-07-01

    Non-receptor type of protein-tyrosine kinase Syk (spleen tyrosine kinase) was isolated in the University of Fukui in 1991. Syk is known to be essential for the various physiological functions, especially in hematopoietic lineage cells. Moreover, ectopic expression of Syk by epigenetic changes is reported to cause retinoblastoma. Recently, novel Syk inhibitors were developed and its usefulness has been evaluated in the treatment of allergic rhinitis, rheumatoid arthritis, and idiopathic thrombocytopenic purpura. In this review, we will summarize the history, structure, and function of Syk, and then describe the novel Syk inhibitors and their current status. Furthermore, we will introduce our findings of the adaptor protein 3BP2 (c-Abl SH3 domain-binding protein-2), as a novel target of Syk.

  9. Human small cell lung cancer NYH cells selected for resistance to the bisdioxopiperazine topoisomerase II catalytic inhibitor ICRF-187 demonstrate a functional R162Q mutation in the Walker A consensus ATP binding domain of the alpha isoform

    DEFF Research Database (Denmark)

    Wessel, I; Jensen, L H; Jensen, P B

    1999-01-01

    in expression of the beta isoform. Sequencing of the entire topoisomerase IIalpha cDNA from NYH/187 cells demonstrated a homozygous G-->A point mutation at nucleotide 485, leading to a R162Q conversion in the Walker A consensus ATP binding site (residues 161-165 in the alpha isoform), this being the first drug......-selected mutation described at this site. Western blotting after incubation with ICRF-187 showed no depletion of the alpha isoform in NYH/187 cells in contrast to wild-type (wt) cells, whereas equal depletion of the beta isoform was observed in the two sublines. Alkaline elution assay demonstrated a lack...... of inhibition of etoposide-induced DNA single-stranded breaks in NYH/187 cells, whereas this inhibition was readily apparent in NYH cells. Site-directed mutagenesis in human topoisomerase IIalpha introduced into a yeast Saccharomyces cerevisiae strain with a temperature-conditional yeast TOP2 mutant...

  10. Discovery of natural mouse serum derived HIV-1 entry inhibitor(s).

    Science.gov (United States)

    Wei, M; Chen, Y; Xi, J; Ru, S; Ji, M; Zhang, D; Fang, Q; Tang, B

    Among rationally designed human immunodeficiency virus 1 (HIV-1) inhibitors, diverse natural factors have showed as potent anti-HIV activity in human blood. We have discovered that the boiled supernatant of healthy mouse serum could suppress HIV-1 entry, and exhibited reduced inhibitory activity after trypsin digestion. Further analysis demonstrated that only the fraction containing 10-25 K proteins could inhibit HIV-1 mediated cell-cell fusion. These results suggest that the 10-25 K protein(s) is novel natural HIV-1 entry inhibitor(s). Our findings provide important information about novel natural HIV entry inhibitors in mouse serum.

  11. Azidoblebbistatin, a photoreactive myosin inhibitor

    Science.gov (United States)

    Képiró, Miklós; Várkuti, Boglárka H.; Bodor, Andrea; Hegyi, György; Drahos, László; Kovács, Mihály; Málnási-Csizmadia, András

    2012-01-01

    Photoreactive compounds are important tools in life sciences that allow precisely timed covalent crosslinking of ligands and targets. Using a unique technique we have synthesized azidoblebbistatin, which is a derivative of blebbistatin, the most widely used myosin inhibitor. Without UV irradiation azidoblebbistatin exhibits identical inhibitory properties to those of blebbistatin. Using UV irradiation, azidoblebbistatin can be covalently crosslinked to myosin, which greatly enhances its in vitro and in vivo effectiveness. Photo-crosslinking also eliminates limitations associated with the relatively low myosin affinity and water solubility of blebbistatin. The wavelength used for photo-crosslinking is not toxic for cells and tissues, which confers a great advantage in in vivo tests. Because the crosslink results in an irreversible association of the inhibitor to myosin and the irradiation eliminates the residual activity of unbound inhibitor molecules, azidoblebbistatin has a great potential to become a highly effective tool in both structural studies of actomyosin contractility and the investigation of cellular and physiological functions of myosin II. We used azidoblebbistatin to identify previously unknown low-affinity targets of the inhibitor (EC50 ≥ 50 μM) in Dictyostelium discoideum, while the strongest interactant was found to be myosin II (EC50 = 5 μM). Our results demonstrate that azidoblebbistatin, and potentially other azidated drugs, can become highly useful tools for the identification of strong- and weak-binding cellular targets and the determination of the apparent binding affinities in in vivo conditions. PMID:22647605

  12. Biodiesel Mass Transit Demonstration

    Science.gov (United States)

    2010-04-01

    The Biodiesel Mass Transit Demonstration report is intended for mass transit decision makers and fleet managers considering biodiesel use. This is the final report for the demonstration project implemented by the National Biodiesel Board under a gran...

  13. Authoring Effective Demonstrations

    National Research Council Canada - National Science Library

    Fu, Dan; Jensen, Randy; Salas, Eduardo; Rosen, Michael A; Ramachandran, Sowmya; Upshaw, Christin L; Hinkelman, Elizabeth; Lampton, Don

    2007-01-01

    ... or human role-players for each training event. We report our ongoing efforts to (1) research the nature and purpose of demonstration, articulating guidelines for effective demonstration within a training context, and (2...

  14. Comparing Demonstratives in Kwa

    African Journals Online (AJOL)

    This paper is a comparative study of demonstrative forms in three K wa languages, ... relative distance from the deictic centre, such as English this and that, here and there. ... Mostly, the referents of demonstratives are 'activated' or at least.

  15. Polarized Light Corridor Demonstrations.

    Science.gov (United States)

    Davies, G. R.

    1990-01-01

    Eleven demonstrations of light polarization are presented. Each includes a brief description of the apparatus and the effect demonstrated. Illustrated are strain patterns, reflection, scattering, the Faraday Effect, interference, double refraction, the polarizing microscope, and optical activity. (CW)

  16. Pathophysiological significance and therapeutic applications of snake venom protease inhibitors.

    Science.gov (United States)

    Thakur, Rupamoni; Mukherjee, Ashis K

    2017-06-01

    Protease inhibitors are important constituents of snake venom and play important roles in the pathophysiology of snakebite. Recently, research on snake venom protease inhibitors has provided valuable information to decipher the molecular details of various biological processes and offer insight for the development of some therapeutically important molecules from snake venom. The process of blood coagulation and fibrinolysis, in addition to affecting platelet function, are well known as the major targets of several snake venom protease inhibitors. This review summarizes the structure-functional aspects of snake venom protease inhibitors that have been described to date. Because diverse biological functions have been demonstrated by protease inhibitors, a comparative overview of their pharmacological and pathophysiological properties is also highlighted. In addition, since most snake venom protease inhibitors are non-toxic on their own, this review evaluates the different roles of individual protease inhibitors that could lead to the identification of drug candidates and diagnostic molecules. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Strategy Guideline: Demonstration Home

    Energy Technology Data Exchange (ETDEWEB)

    Savage, C.; Hunt, A.

    2012-12-01

    This guideline will provide a general overview of the different kinds of demonstration home projects, a basic understanding of the different roles and responsibilities involved in the successful completion of a demonstration home, and an introduction into some of the lessons learned from actual demonstration home projects. Also, this guideline will specifically look at the communication methods employed during demonstration home projects. And lastly, we will focus on how to best create a communication plan for including an energy efficient message in a demonstration home project and carry that message to successful completion.

  18. Strategy Guideline. Demonstration Home

    Energy Technology Data Exchange (ETDEWEB)

    Hunt, A.; Savage, C.

    2012-12-01

    This guideline will provide a general overview of the different kinds of demonstration home projects, a basic understanding of the different roles and responsibilities involved in the successful completion of a demonstration home, and an introduction into some of the lessons learned from actual demonstration home projects. Also, this guideline will specifically look at the communication methods employed during demonstration home projects. And lastly, we will focus on how to best create a communication plan for including an energy efficient message in a demonstration home project and carry that message to successful completion.

  19. Manufacturing Demonstration Facility (MDF)

    Data.gov (United States)

    Federal Laboratory Consortium — The U.S. Department of Energy Manufacturing Demonstration Facility (MDF) at Oak Ridge National Laboratory (ORNL) provides a collaborative, shared infrastructure to...

  20. Monoamine Oxidase Inhibitors (MAOIs)

    Science.gov (United States)

    ... health-medications/index.shtml. Accessed May 16, 2016. Hirsch M, et al. Monoamine oxidase inhibitors (MAOIs) for ... www.uptodate.com/home. Accessed May 16, 2016. Hirsch M, et al. Discontinuing antidepressant medications in adults. ...

  1. Innovative technology demonstration

    International Nuclear Information System (INIS)

    Anderson, D.B.; Luttrell, S.P.; Hartley, J.N.; Hinchee, R.

    1992-04-01

    The Innovative Technology Demonstration (ITD) program at Tinker Air Force Base (TAFB), Oklahoma City, Oklahoma, will demonstrate the overall utility and effectiveness of innovative technologies for site characterization, monitoring, and remediation of selected contaminated test sites. The current demonstration test sites include a CERCLA site on the NPL list, located under a building (Building 3001) that houses a large active industrial complex used for rebuilding military aircraft, and a site beneath and surrounding an abandoned underground tank vault used for storage of jet fuels and solvents. The site under Building 3001 (the NW Test Site) is contaminated with TCE and Cr +6 ; the site with the fuel storage vault (the SW Tanks Site) is contaminated with fuels, BTEX and TCE. These sites and others have been identified for cleanup under the Air Force's Installation Restoration Program (IRP). This document describes the demonstrations that have been conducted or are planned for the TAFB

  2. Laser Communications Relay Demonstration

    Data.gov (United States)

    National Aeronautics and Space Administration — LCRD is a minimum two year flight demonstration in geosynchronous Earth orbit to advance optical communications technology toward infusion into Deep Space and Near...

  3. Spacecraft Fire Safety Demonstration

    Data.gov (United States)

    National Aeronautics and Space Administration — The objective of the Spacecraft Fire Safety Demonstration project is to develop and conduct large-scale fire safety experiments on an International Space Station...

  4. Education Payload Operation - Demonstrations

    Science.gov (United States)

    Keil, Matthew

    2009-01-01

    Education Payload Operation - Demonstrations (EPO-Demos) are recorded video education demonstrations performed on the International Space Station (ISS) by crewmembers using hardware already onboard the ISS. EPO-Demos are videotaped, edited, and used to enhance existing NASA education resources and programs for educators and students in grades K-12. EPO-Demos are designed to support the NASA mission to inspire the next generation of explorers.

  5. Buried Waste Integrated Demonstration

    International Nuclear Information System (INIS)

    1994-03-01

    The Buried Waste Integrated Demonstration (BWID) supports the applied research, development, demonstration, and evaluation of a suite of advanced technologies that offer promising solutions to the problems associated with the remediation of buried waste. BWID addresses the difficult remediation problems associated with DOE complex-wide buried waste, particularly transuranic (TRU) contaminated buried waste. BWID has implemented a systems approach to the development and demonstration of technologies that will characterize, retrieve, treat, and dispose of DOE buried wastes. This approach encompasses the entire remediation process from characterization to post-monitoring. The development and demonstration of the technology is predicated on how a technology fits into the total remediation process. To address all of these technological issues, BWID has enlisted scientific expertise of individuals and groups from within the DOE Complex, as well as experts from universities and private industry. The BWID mission is to support development and demonstration of a suite of technologies that, when integrated with commercially-available technologies, forms a comprehensive, remediation system for the effective and efficient remediation of buried waste throughout the DOE Complex. BWID will evaluate and validate demonstrated technologies and transfer this information and equipment to private industry to support the Office of Environmental Restoration (ER), Office of Waste Management (WM), and Office of Facility Transition (FT) remediation planning and implementation activities

  6. SGLT2 inhibitors.

    Science.gov (United States)

    Dardi, I; Kouvatsos, T; Jabbour, S A

    2016-02-01

    Diabetes mellitus is a serious health issue and an economic burden, rising in epidemic proportions over the last few decades worldwide. Although several treatment options are available, only half of the global diabetic population achieves the recommended or individualized glycemic targets. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents with a novel insulin-independent action. SGLT2 is a transporter found in the proximal renal tubules, responsible for the reabsorption of most of the glucose filtered by the kidney. Inhibition of SGLT2 lowers the blood glucose level by promoting the urinary excretion of excess glucose. Due to their insulin-independent action, SGLT2 inhibitors can be used with any degree of beta-cell dysfunction or insulin resistance, related to a very low risk of hypoglycemia. In addition to improving glycemic control, SGLT2 inhibitors have been associated with a reduction in weight and blood pressure when used as monotherapy or in combination with other antidiabetic agents in patients with type 2 diabetes mellitus (T2DM). Treatment with SGLT2 inhibitors is usually well tolerated; however, they have been associated with an increased incidence of urinary tract and genital infections, although these infections are usually mild and easy to treat. SGLT2 inhibitors are a promising new option in the armamentarium of drugs for patients with T2DM. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Aromatase inhibitors in pediatrics.

    Science.gov (United States)

    Wit, Jan M; Hero, Matti; Nunez, Susan B

    2011-10-25

    Aromatase, an enzyme located in the endoplasmic reticulum of estrogen-producing cells, catalyzes the rate-limiting step in the conversion of androgens to estrogens in many tissues. The clinical features of patients with defects in CYP19A1, the gene encoding aromatase, have revealed a major role for this enzyme in epiphyseal plate closure, which has promoted interest in the use of inhibitors of aromatase to improve adult height. The availability of the selective aromatase inhibitors letrozole and anastrozole--currently approved as adjuvant therapy for breast cancer--have stimulated off-label use of aromatase inhibitors in pediatrics for the following conditions: hyperestrogenism, such as aromatase excess syndrome, Peutz-Jeghers syndrome, McCune-Albright syndrome and functional follicular ovarian cysts; hyperandrogenism, for example, testotoxicosis (also known as familial male-limited precocious puberty) and congenital adrenal hyperplasia; pubertal gynecomastia; and short stature and/or pubertal delay in boys. Current data suggest that aromatase inhibitors are probably effective in the treatment of patients with aromatase excess syndrome or testotoxicosis, partially effective in Peutz-Jeghers and McCune-Albright syndrome, but probably ineffective in gynecomastia. Insufficient data are available in patients with congenital adrenal hyperplasia or functional ovarian cysts. Although aromatase inhibitors appear effective in increasing adult height of boys with short stature and/or pubertal delay, safety concerns, including vertebral deformities, a decrease in serum HDL cholesterol levels and increase of erythrocytosis, are reasons for caution.

  8. Learning From Demonstration?

    DEFF Research Database (Denmark)

    Koch, Christian; Bertelsen, Niels Haldor

    2014-01-01

    Demonstration projects are often used in the building sector to provide a basis for using new processes and/or products. The climate change agenda implies that construction is not only required to deliver value for the customer, cost reductions and efficiency but also sustainable buildings....... This paper reports on an early demonstration project, the Building of a passive house dormitory in the Central Region of Denmark in 2006-2009. The project was supposed to deliver value, lean design, prefabrication, quality in sustainability, certification according to German standards for passive houses......, and micro combined heat and power using hydrogen. Using sociological and business economic theories of innovation, the paper discusses how early movers of innovation tend to obtain only partial success when demonstrating their products and often feel obstructed by minor details. The empirical work...

  9. Solar renovation demonstration projects

    Energy Technology Data Exchange (ETDEWEB)

    Bruun Joergensen, O [ed.

    1998-10-01

    In the framework of the IEA SHC Programme, a Task on building renovation was initiated, `Task 20, Solar Energy in Building Renovation`. In a part of the task, Subtask C `Design of Solar Renovation Projects`, different solar renovation demonstration projects were developed. The objective of Subtask C was to demonstrate the application of advanced solar renovation concepts on real buildings. This report documents 16 different solar renovation demonstration projects including the design processes of the projects. The projects include the renovation of houses, schools, laboratories, and factories. Several solar techniques were used: building integrated solar collectors, glazed balconies, ventilated solar walls, transparent insulation, second skin facades, daylight elements and photovoltaic systems. These techniques are used in several simple as well as more complex system designs. (au)

  10. Biodenitrification demonstration test report

    International Nuclear Information System (INIS)

    Benear, A.K.; Murray, S.J.; Lahoda, E.J.; Leslie, J.W.; Patton, J.B.; Menako, C.R.

    1987-08-01

    A two-column biodenitrification (BDN) facility was constructed at the Feed Materials Production Center (FMPC) in 1985 and 1986 to test the feasibility of biological treatment for industrial nitrate-bearing waste water generated at FMPC. This demonstration facility comprises one-half of the proposed four-column production facility. A demonstration test was conducted over a four month period in 1987. The results indicate the proposed BDN production facility can process FMPC industrial wastewater in a continuous manner while maintaining an effluent that will consistently meet the proposed NPDES limits for combined nitrate nitrogen (NO 3 -N) and nitrite nitrogen (NO 2 -N). The proposed NPDES limits are 62 kg/day average and 124 kg/day maximum. These limits were proportioned to determine that the two-column demonstration facility should meet the limits of 31 kg/day average and 62 kg/day maximum

  11. Distributed picture compilation demonstration

    Science.gov (United States)

    Alexander, Richard; Anderson, John; Leal, Jeff; Mullin, David; Nicholson, David; Watson, Graham

    2004-08-01

    A physical demonstration of distributed surveillance and tracking is described. The demonstration environment is an outdoor car park overlooked by a system of four rooftop cameras. The cameras extract moving objects from the scene, and these objects are tracked in a decentralized way, over a real communication network, using the information form of the standard Kalman filter. Each node therefore has timely access to the complete global picture and because there is no single point of failure in the system, it is robust. The demonstration system and its main components are described here, with an emphasis on some of the lessons we have learned as a result of applying a corpus of distributed data fusion theory and algorithms in practice. Initial results are presented and future plans to scale up the network are also outlined.

  12. Photovoltaic demonstration projects

    Energy Technology Data Exchange (ETDEWEB)

    Gillett, W B; Hacker, R J; Kaut, W [eds.

    1991-01-01

    This book, the proceedings of the fourth PV-Contractors' Meeting organized by the Commission of the European Communities, Directorate-General for Energy, held at Brussels on 21 and 22 November 1989, provides an overview of the photovoltaic demonstration projects which have been supported in the framework of the Energy Demonstration Program since 1983. It includes reports by each of the contractors who submitted proposals in 1983, 1984, 1985 and 1986, describing progress with their projects. Summaries of the discussions held at the meeting, which included contractors whose projects were submitted in 1987, are also presented. The different technologies which are being demonstrated concern the modules, the cabling of the array, structure design, storage strategy and power conditioning. The various applications include desalination, communications, dairy farms, water pumping, and warning systems. Papers have been processed separately for inclusion on the data base.

  13. Electric vehicle demonstration

    Energy Technology Data Exchange (ETDEWEB)

    Ouellet, M. [National Centre for Advanced Transportation, Saint-Jerome, PQ (Canada)

    2010-07-01

    The desirable characteristics of Canadian projects that demonstrate vehicle use in real-world operation and the appropriate mechanism to collect and disseminate the monitoring data were discussed in this presentation. The scope of the project was on passenger cars and light duty trucks operating in plug-in electric vehicle (PHEV) or battery electric vehicle modes. The presentation also discussed the funding, stakeholders involved, Canadian travel pattern analysis, regulatory framework, current and recent electric vehicle demonstration projects, and project guidelines. It was concluded that some demonstration project activities may have been duplicated as communication between the proponents was insufficient. It was recommended that data monitoring using automatic data logging with minimum reliance on logbooks and other user entry should be emphasized. figs.

  14. Innovative technology demonstrations

    International Nuclear Information System (INIS)

    Anderson, D.B.; Luttrell, S.P.; Hartley, J.N.

    1992-08-01

    Environmental Management Operations (EMO) is conducting an Innovative Technology Demonstration Program for Tinker Air Force Base (TAFB). Several innovative technologies are being demonstrated to address specific problems associated with remediating two contaminated test sites at the base. Cone penetrometer testing (CPT) is a form of testing that can rapidly characterize a site. This technology was selected to evaluate its applicability in the tight clay soils and consolidated sandstone sediments found at TAFB. Directionally drilled horizontal wells was selected as a method that may be effective in accessing contamination beneath Building 3001 without disrupting the mission of the building, and in enhancing the extraction of contamination both in ground water and in soil. A soil gas extraction (SGE) demonstration, also known as soil vapor extraction, will evaluate the effectiveness of SGE in remediating fuels and TCE contamination contained in the tight clay soil formations surrounding the abandoned underground fuel storage vault located at the SW Tanks Site. In situ sensors have recently received much acclaim as a technology that can be effective in remediating hazardous waste sites. Sensors can be useful for determining real-time, in situ contaminant concentrations during the remediation process for performance monitoring and in providing feedback for controlling the remediation process. Following the SGE demonstration, the SGE system and SW Tanks test site will be modified to demonstrate bioremediation as an effective means of degrading the remaining contaminants in situ. The bioremediation demonstration will evaluate a bioventing process in which the naturally occurring consortium of soil bacteria will be stimulated to aerobically degrade soil contaminants, including fuel and TCE, in situ

  15. Innovative technology demonstrations

    International Nuclear Information System (INIS)

    Anderson, D.B.; Hartley, J.N.; Luttrell, S.P.

    1992-04-01

    Currently, several innovative technologies are being demonstrated at Tinker Air Force Base (TAFB) to address specific problems associated with remediating two contaminated test sites at the base. Cone penetrometer testing (CPT) is a form of testing that can rapidly characterize a site. This technology was selected to evaluate its applicability in the tight clay soils and consolidated sandstone sediments found at TAFB. Directionally drilled horizontal wells have been successfully installed at the US Department of Energy's (DOE) Savannah River Site to test new methods of in situ remediation of soils and ground water. This emerging technology was selected as a method that may be effective in accessing contamination beneath Building 3001 without disrupting the mission of the building, and in enhancing the extraction of contamination both in ground water and in soil. A soil gas extraction (SGE) demonstration, also known as soil vapor extraction, will evaluate the effectiveness of SGE in remediating fuels and TCE contamination contained in the tight clay soil formations surrounding the abandoned underground fuel storage vault located at the SW Tanks Site. In situ sensors have recently received much acclaim as a technology that can be effective in remediating hazardous waste sites. Sensors can be useful for determining real-time, in situ contaminant concentrations during the remediation process for performance monitoring and in providing feedback for controlling the remediation process. A demonstration of two in situ sensor systems capable of providing real-time data on contamination levels will be conducted and evaluated concurrently with the SGE demonstration activities. Following the SGE demonstration, the SGE system and SW Tanks test site will be modified to demonstrate bioremediation as an effective means of degrading the remaining contaminants in situ

  16. Gigashot Optical Laser Demonstrator

    Energy Technology Data Exchange (ETDEWEB)

    Deri, R. J. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    2015-10-13

    The Gigashot Optical Laser Demonstrator (GOLD) project has demonstrated a novel optical amplifier for high energy pulsed lasers operating at high repetition rates. The amplifier stores enough pump energy to support >10 J of laser output, and employs conduction cooling for thermal management to avoid the need for expensive and bulky high-pressure helium subsystems. A prototype amplifier was fabricated, pumped with diode light at 885 nm, and characterized. Experimental results show that the amplifier provides sufficient small-signal gain and sufficiently low wavefront and birefringence impairments to prove useful in laser systems, at repetition rates up to 60 Hz.

  17. Photovoltaic demonstration projects 2

    Energy Technology Data Exchange (ETDEWEB)

    Gillett, W B; Hacker, R J [Halcrow (William) and Partners, Swindon (UK); Kaut, W [eds.

    1989-01-01

    This book, the proceedings of the third Photovoltaic Contractors' Meeting organised by the Commission of the European Communities, Directorate-General for Energy provides an overview of the photovoltaic demonstration projects which have been supported by the Energy Directorate of the Commission of the European Communities since 1983. It includes reports by each of the contractors who submitted proposals in 1983, 1984 and 1985, describing progress with their projects. The different technologies which are being demonstrated concern the modules, the cabling of the array, structure design, storage strategy and power conditioning. The various applications include powering of houses, villages, recreation centres, water desalination, communications, dairy farms, water pumping and warning systems. (author).

  18. 2-Aminobenzimidazoles as potent Aurora kinase inhibitors.

    Science.gov (United States)

    Zhong, Min; Bui, Minna; Shen, Wang; Baskaran, Subramanian; Allen, Darin A; Elling, Robert A; Flanagan, W Michael; Fung, Amy D; Hanan, Emily J; Harris, Shannon O; Heumann, Stacey A; Hoch, Ute; Ivy, Sheryl N; Jacobs, Jeffrey W; Lam, Stuart; Lee, Heman; McDowell, Robert S; Oslob, Johan D; Purkey, Hans E; Romanowski, Michael J; Silverman, Jeffrey A; Tangonan, Bradley T; Taverna, Pietro; Yang, Wenjin; Yoburn, Josh C; Yu, Chul H; Zimmerman, Kristin M; O'Brien, Tom; Lew, Willard

    2009-09-01

    This Letter describes the discovery and key structure-activity relationship (SAR) of a series of 2-aminobenzimidazoles as potent Aurora kinase inhibitors. 2-Aminobenzimidazole serves as a bioisostere of the biaryl urea residue of SNS-314 (1c), which is a potent Aurora kinase inhibitor and entered clinical testing in patients with solid tumors. Compared to SNS-314, this series of compounds offers better aqueous solubility while retaining comparable in vitro potency in biochemical and cell-based assays; in particular, 6m has also demonstrated a comparable mouse iv PK profile to SNS-314.

  19. Inseparable Phone Books Demonstration

    Science.gov (United States)

    Balta, Nuri; Çetin, Ali

    2017-01-01

    This study is aimed at first introducing a well-known discrepant event; inseparable phone books and second, turning it into an experiment for high school or middle school students. This discrepant event could be used especially to indicate how friction force can be effective in producing an unexpected result. Demonstration, discussion, explanation…

  20. PHARUS ASAR demonstrator

    NARCIS (Netherlands)

    Smith, A.J.E.; Bree, R.J.P. van; Calkoen, C.J.; Dekker, R.J.; Otten, M.P.G.; Rossum, W.L. van

    2001-01-01

    PHARUS is a polarimetric phased array C-band Synthetic Aperture Radar (SAR), designed and built for airborne use. Advanced SAR (ASAR) data in image and alternating polarization mode have been simulated with PHARUS to demonstrate the use of Envisat for a number of typical SAR applications that are

  1. Demonstrating the Gas Laws.

    Science.gov (United States)

    Holko, David A.

    1982-01-01

    Presents a complete computer program demonstrating the relationship between volume/pressure for Boyle's Law, volume/temperature for Charles' Law, and volume/moles of gas for Avagadro's Law. The programing reinforces students' application of gas laws and equates a simulated moving piston to theoretical values derived using the ideal gas law.…

  2. Astronomy LITE Demonstrations

    Science.gov (United States)

    Brecher, Kenneth

    2006-12-01

    Project LITE (Light Inquiry Through Experiments) is a materials, software, and curriculum development project. It focuses on light, optics, color and visual perception. According to two recent surveys of college astronomy faculty members, these are among the topics most often included in the large introductory astronomy courses. The project has aimed largely at the design and implementation of hands-on experiences for students. However, it has also included the development of lecture demonstrations that employ novel light sources and materials. In this presentation, we will show some of our new lecture demonstrations concerning geometrical and physical optics, fluorescence, phosphorescence and polarization. We have developed over 200 Flash and Java applets that can be used either by teachers in lecture settings or by students at home. They are all posted on the web at http://lite.bu.edu. For either purpose they can be downloaded directly to the user's computer or run off line. In lecture demonstrations, some of these applets can be used to control the light emitted by video projectors to produce physical effects in materials (e.g. fluorescence). Other applets can be used, for example, to demonstrate that the human percept of color does not have a simple relationship with the physical frequency of the stimulating source of light. Project LITE is supported by Grant #DUE-0125992 from the NSF Division of Undergraduate Education.

  3. A Magnetic Circuit Demonstration.

    Science.gov (United States)

    Vanderkooy, John; Lowe, June

    1995-01-01

    Presents a demonstration designed to illustrate Faraday's, Ampere's, and Lenz's laws and to reinforce the concepts through the analysis of a two-loop magnetic circuit. Can be made dramatic and challenging for sophisticated students but is suitable for an introductory course in electricity and magnetism. (JRH)

  4. Cathepsin D inhibitors

    Directory of Open Access Journals (Sweden)

    M. Gacko

    2007-11-01

    Full Text Available Inhibitors of cathepsin D belong to chemical compounds that estrify carboxyl groups of the Asp33 and Asp231residues of its catalytic site, penta-peptides containing statin, i.e. the amino acid similar in structure to the tetraedric indirectproduct, and polypeptides found in the spare organs of many plants and forming permanent noncovalent complexes withcathepsin. Cathepsin D activity is also inhibited by alpha2-macroglobulin and antibodies directed against this enzyme.Methods used to determine the activity and concentration of these inhibitors and their analytical, preparative and therapeuticapplications are discussed.

  5. A cyclic peptidic serine protease inhibitor

    DEFF Research Database (Denmark)

    Zhao, Baoyu; Xu, Peng; Jiang, Longguang

    2014-01-01

    Peptides are attracting increasing interest as protease inhibitors. Here, we demonstrate a new inhibitory mechanism and a new type of exosite interactions for a phage-displayed peptide library-derived competitive inhibitor, mupain-1 (CPAYSRYLDC), of the serine protease murine urokinase...... pocket, its carbonyl group aligning improperly relative to Ser195 and the oxyanion hole, explaining why the peptide is an inhibitor rather than a substrate. Substitution of the P1 Arg with novel unnatural Arg analogues with aliphatic or aromatic ring structures led to an increased affinity, depending......, in spite of a less favorable binding entropy and loss of a polar interaction. We conclude that increased flexibility of the peptide allows more favorable exosite interactions, which, in combination with the use of novel Arg analogues as P1 residues, can be used to manipulate the affinity and specificity...

  6. SGLT2 Inhibitors and the Diabetic Kidney.

    Science.gov (United States)

    Fioretto, Paola; Zambon, Alberto; Rossato, Marco; Busetto, Luca; Vettor, Roberto

    2016-08-01

    Diabetic nephropathy (DN) is the most common cause of end-stage renal disease worldwide. Blood glucose and blood pressure control reduce the risk of developing this complication; however, once DN is established, it is only possible to slow progression. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, the most recent glucose-lowering oral agents, may have the potential to exert nephroprotection not only through improving glycemic control but also through glucose-independent effects, such as blood pressure-lowering and direct renal effects. It is important to consider, however, that in patients with impaired renal function, given their mode of action, SGLT2 inhibitors are less effective in lowering blood glucose. In patients with high cardiovascular risk, the SGLT2 inhibitor empagliflozin lowered the rate of cardiovascular events, especially cardiovascular death, and substantially reduced important renal outcomes. Such benefits on DN could derive from effects beyond glycemia. Glomerular hyperfiltration is a potential risk factor for DN. In addition to the activation of the renin-angiotensin-aldosterone system, renal tubular factors, including SGLT2, contribute to glomerular hyperfiltration in diabetes. SGLT2 inhibitors reduce sodium reabsorption in the proximal tubule, causing, through tubuloglomerular feedback, afferent arteriole vasoconstriction and reduction in hyperfiltration. Experimental studies showed that SGLT2 inhibitors reduced hyperfiltration and decreased inflammatory and fibrotic responses of proximal tubular cells. SGLT2 inhibitors reduced glomerular hyperfiltration in patients with type 1 diabetes, and in patients with type 2 diabetes, they caused transient acute reductions in glomerular filtration rate, followed by a progressive recovery and stabilization of renal function. Interestingly, recent studies consistently demonstrated a reduction in albuminuria. Although these data are promising, only dedicated renal outcome trials will clarify whether

  7. Remote monitoring demonstration

    International Nuclear Information System (INIS)

    Caskey, Susan; Olsen, John

    2006-01-01

    The recently upgraded remote monitoring system at the Joyo Experimental Reactor uses a DCM-14 camera module and GEMINI software. The final data is compatible both with the IAEA-approved GARS review software and the ALIS software that was used for this demonstration. Features of the remote monitoring upgrade emphasized compatibility with IAEA practice. This presentation gives particular attention to the selection process for meeting network security considerations at the O'arai site. The Joyo system is different from the NNCA's ACPF system, in that it emphasizes use of IAEA standard camera technology and data acquisition and transmission software. In the demonstration itself, a temporary virtual private network (VPN) between the meeting room and the server at Sandia in Albuquerque allowed attendees to observe data stored from routine transmissions from the Joyo Fresh Fuel Storage to Sandia. Image files from a fuel movement earlier in the month showed Joyo workers and IAEA inspectors carrying out a transfer. (author)

  8. Commercial incineration demonstration

    International Nuclear Information System (INIS)

    Borduin, L.C.; Neuls, A.S.

    1981-01-01

    Low-level radioactive wastes (LLW) generated by nuclear utilities presently are shipped to commercial burial grounds for disposal. Substantially increasing shipping and disposal charges have sparked renewed industry interest in incineration and other advanced volume reduction techniques as potential cost-saving measures. Repeated inquiries from industry sources regarding LLW applicability of the Los Alamos controlled-air incineration (CAI) design led DOE to initiate this commercial demonstration program in FY-1980. The selected program approach to achieving CAI demonstration at a utility site is a DOE sponsored joint effort involving Los Alamos, a nuclear utility, and a liaison subcontractor. Required development tasks and responsibilities of the particpants are described. Target date for project completion is the end of FY-1985

  9. Photovoltaic demonstration projects

    Energy Technology Data Exchange (ETDEWEB)

    Kaut, W [Commission of the European Communities, Brussels (Belgium); Gillett, W B; Hacker, R J [Halcrow Gilbert Associates Ltd., Swindon (GB)

    1992-12-31

    This publication, comprising the proceedings of the fifth contractor`s meeting organized by the Commission of the European Communities, Directorate-General for Energy, provides an overview of the photovoltaic demonstration projects which have been supported in the framework of the energy demonstration programme since 1983. It includes reports by each of the contractors who submitted proposals in 1987 and 1988, describing progress within their projects. Projects accepted from earlier calls for proposals and not yet completed were reviewed by a rapporteur and are discussed in the summary section. The results of the performance monitoring of all projects and the lessons drawn from the practical experience of the projects are also presented in the summaries and conclusions. Contractors whose projects were submitted in 1989 were also present at the meeting and contributed to the reported discussions. This proceeding is divided into four sessions (General, Housing, technical presentations, other applications) and 24 papers are offered.

  10. AVNG system demonstration

    Energy Technology Data Exchange (ETDEWEB)

    Thron, Jonathan Louis [Los Alamos National Laboratory; Mac Arthur, Duncan W [Los Alamos National Laboratory; Kondratov, Sergey [VNIIEF; Livke, Alexander [VNIIEF; Razinkov, Sergey [VNIIEF

    2010-01-01

    An attribute measurement system (AMS) measures a number of unclassified attributes of potentially classified material. By only displaying these unclassified results as red or green lights, the AMS protects potentially classified information while still generating confidence in the measurement result. The AVNG implementation that we describe is an AMS built by RFNC - VNIIEF in Sarov, Russia. To provide additional confidence, the AVNG was designed with two modes of operation. In the secure mode, potentially classified measurements can be made with only the simple red light/green light display. In the open mode, known unclassified material can be measured with complete display of the information collected from the radiation detectors. The AVNG demonstration, which occurred in Sarov, Russia in June 2009 for a joint US/Russian audience, included exercising both modes of AVNG operation using a number of multi-kg plutonium sources. In addition to describing the demonstration, we will show photographs and/or video taken of AVNG operation.

  11. Antares: preliminary demonstrator results

    International Nuclear Information System (INIS)

    Kouchner, A.

    2000-05-01

    The ANTARES collaboration is building an undersea neutrino telescope off Toulon (Mediterranean sea) with effective area ∼ 0.1 km 2 . An extensive study of the site properties has been achieved together with software analysis in order to optimize the performance of the detector. Results are summarized here. An instrumented line, linked to shore for first time via an electro-optical cable, has been immersed late 1999. The preliminary results of this demonstrator line are reported. (author)

  12. The Majorana Demonstrator

    Energy Technology Data Exchange (ETDEWEB)

    Aguayo, Estanislao; Fast, James E.; Hoppe, Eric W.; Keillor, Martin E.; Kephart, Jeremy D.; Kouzes, Richard T.; LaFerriere, Brian D.; Merriman, Jason H.; Orrell, John L.; Overman, Nicole R.; Avignone, Frank T.; Back, Henning O.; Combs, Dustin C.; Leviner, L.; Young, A.; Barabash, Alexander S.; Konovalov, S.; Vanyushin, I.; Yumatov, Vladimir; Bergevin, M.; Chan, Yuen-Dat; Detwiler, Jason A.; Loach, J. C.; Martin, R. D.; Poon, Alan; Prior, Gersende; Vetter, Kai; Bertrand, F.; Cooper, R. J.; Radford, D. C.; Varner, R. L.; Yu, Chang-Hong; Boswell, M.; Elliott, S.; Gehman, Victor M.; Hime, Andrew; Kidd, M. F.; LaRoque, B. H.; Rielage, Keith; Ronquest, M. C.; Steele, David; Brudanin, V.; Egorov, Viatcheslav; Gusey, K.; Kochetov, Oleg; Shirchenko, M.; Timkin, V.; Yakushev, E.; Busch, Matthew; Esterline, James H.; Tornow, Werner; Christofferson, Cabot-Ann; Horton, Mark; Howard, S.; Sobolev, V.; Collar, J. I.; Fields, N.; Creswick, R.; Doe, Peter J.; Johnson, R. A.; Knecht, A.; Leon, Jonathan D.; Marino, Michael G.; Miller, M. L.; Robertson, R. G. H.; Schubert, Alexis G.; Wolfe, B. A.; Efremenko, Yuri; Ejiri, H.; Hazama, R.; Nomachi, Masaharu; Shima, T.; Finnerty, P.; Fraenkle, Florian; Giovanetti, G. K.; Green, M.; Henning, Reyco; Howe, M. A.; MacMullin, S.; Phillips, D.; Snavely, Kyle J.; Strain, J.; Vorren, Kris R.; Guiseppe, Vincente; Keller, C.; Mei, Dong-Ming; Perumpilly, Gopakumar; Thomas, K.; Zhang, C.; Hallin, A. L.; Keeter, K.; Mizouni, Leila; Wilkerson, J. F.

    2011-09-03

    A brief review of the history and neutrino physics of double beta decay is given. A description of the MAJORANA DEMONSTRATOR research and development program, including background reduction techniques, is presented in some detail. The application of point contact (PC) detectors to the experiment is discussed, including the effectiveness of pulse shape analysis. The predicted sensitivity of a PC detector array enriched to 86% to 76Ge is given.

  13. IGCC technology and demonstration

    Energy Technology Data Exchange (ETDEWEB)

    Palonen, J [A. Ahlstrom Corporation, Karhula (Finland). Hans Ahlstrom Lab.; Lundqvist, R G [A. Ahlstrom Corporation, Helsinki (Finland); Staahl, K [Sydkraft AB, Malmoe (Sweden)

    1997-12-31

    Future energy production will be performed by advanced technologies that are more efficient, more environmentally friendly and less expensive than current technologies. Integrated gasification combined cycle (IGCC) power plants have been proposed as one of these systems. Utilising biofuels in future energy production will also be emphasised since this lowers substantially carbon dioxide emissions into the atmosphere due to the fact that biomass is a renewable form of energy. Combining advanced technology and biomass utilisation is for this reason something that should and will be encouraged. A. Ahlstrom Corporation of Finland and Sydkraft AB of Sweden have as one part of company strategies adopted this approach for the future. The companies have joined their resources in developing a biomass-based IGCC system with the gasification part based on pressurised circulating fluidized-bed technology. With this kind of technology electrical efficiency can be substantially increased compared to conventional power plants. As a first concrete step, a decision has been made to build a demonstration plant. This plant, located in Vaernamo, Sweden, has already been built and is now in commissioning and demonstration stage. The system comprises a fuel drying plant, a pressurised CFB gasifier with gas cooling and cleaning, a gas turbine, a waste heat recovery unit and a steam turbine. The plant is the first in the world where the integration of a pressurised gasifier with a gas turbine will be realised utilising a low calorific gas produced from biomass. The capacity of the Vaernamo plant is 6 MW of electricity and 9 MW of district heating. Technology development is in progress for design of plants of sizes from 20 to 120 MWe. The paper describes the Bioflow IGCC system, the Vaernamo demonstration plant and experiences from the commissioning and demonstration stages. (orig.)

  14. IGCC technology and demonstration

    Energy Technology Data Exchange (ETDEWEB)

    Palonen, J. [A. Ahlstrom Corporation, Karhula (Finland). Hans Ahlstrom Lab.; Lundqvist, R.G. [A. Ahlstrom Corporation, Helsinki (Finland); Staahl, K. [Sydkraft AB, Malmoe (Sweden)

    1996-12-31

    Future energy production will be performed by advanced technologies that are more efficient, more environmentally friendly and less expensive than current technologies. Integrated gasification combined cycle (IGCC) power plants have been proposed as one of these systems. Utilising biofuels in future energy production will also be emphasised since this lowers substantially carbon dioxide emissions into the atmosphere due to the fact that biomass is a renewable form of energy. Combining advanced technology and biomass utilisation is for this reason something that should and will be encouraged. A. Ahlstrom Corporation of Finland and Sydkraft AB of Sweden have as one part of company strategies adopted this approach for the future. The companies have joined their resources in developing a biomass-based IGCC system with the gasification part based on pressurised circulating fluidized-bed technology. With this kind of technology electrical efficiency can be substantially increased compared to conventional power plants. As a first concrete step, a decision has been made to build a demonstration plant. This plant, located in Vaernamo, Sweden, has already been built and is now in commissioning and demonstration stage. The system comprises a fuel drying plant, a pressurised CFB gasifier with gas cooling and cleaning, a gas turbine, a waste heat recovery unit and a steam turbine. The plant is the first in the world where the integration of a pressurised gasifier with a gas turbine will be realised utilising a low calorific gas produced from biomass. The capacity of the Vaernamo plant is 6 MW of electricity and 9 MW of district heating. Technology development is in progress for design of plants of sizes from 20 to 120 MWe. The paper describes the Bioflow IGCC system, the Vaernamo demonstration plant and experiences from the commissioning and demonstration stages. (orig.)

  15. Lunar Water Resource Demonstration

    Science.gov (United States)

    Muscatello, Anthony C.

    2008-01-01

    In cooperation with the Canadian Space Agency, the Northern Centre for Advanced Technology, Inc., the Carnegie-Mellon University, JPL, and NEPTEC, NASA has undertaken the In-Situ Resource Utilization (ISRU) project called RESOLVE. This project is a ground demonstration of a system that would be sent to explore permanently shadowed polar lunar craters, drill into the regolith, determine what volatiles are present, and quantify them in addition to recovering oxygen by hydrogen reduction. The Lunar Prospector has determined these craters contain enhanced hydrogen concentrations averaging about 0.1%. If the hydrogen is in the form of water, the water concentration would be around 1%, which would translate into billions of tons of water on the Moon, a tremendous resource. The Lunar Water Resource Demonstration (LWRD) is a part of RESOLVE designed to capture lunar water and hydrogen and quantify them as a backup to gas chromatography analysis. This presentation will briefly review the design of LWRD and some of the results of testing the subsystem. RESOLVE is to be integrated with the Scarab rover from CMIJ and the whole system demonstrated on Mauna Kea on Hawaii in November 2008. The implications of lunar water for Mars exploration are two-fold: 1) RESOLVE and LWRD could be used in a similar fashion on Mars to locate and quantify water resources, and 2) electrolysis of lunar water could provide large amounts of liquid oxygen in LEO, leading to lower costs for travel to Mars, in addition to being very useful at lunar outposts.

  16. Waste and Disposal: Demonstration

    International Nuclear Information System (INIS)

    Neerdael, B.; Buyens, M.; De Bruyn, D.; Volckaert, G.

    2002-01-01

    Within the Belgian R and D programme on geological disposal, demonstration experiments have become increasingly important. In this contribution to the scientific report 2001, an overview is given of SCK-CEN's activities and achievements in the field of large-scale demonstration experiments. In 2001, main emphasis was on the PRACLAY project, which is a large-scale experiment to demonstrate the construction and the operation of a gallery for the disposal of HLW in a clay formation. The PRACLAY experiment will contribute to enhance understanding of water flow and mass transport in dense clay-based materials as well as to improve the design of the reference disposal concept. In the context of PRACLAY, a surface experiment (OPHELIE) has been developed to prepare and to complement PRACLAY-related experimental work in the HADES Underground Research Laboratory. In 2001, efforts were focussed on the operation of the OPHELIE mock-up. SCK-CEN also contributed to the SELFRAC roject which studies the self-healing of fractures in a clay formation

  17. Transglutaminase inhibitor from milk

    NARCIS (Netherlands)

    Jong, G.A.H. de; Wijngaards, G.; Koppelman, S.J.

    2003-01-01

    Cross-linking experiments of skimmed bovine milk with bacterial transglutaminase isolated from Streptoverticillium mobaraense showed only some degree of formation of high-molecular-weight casein polymers. Studies on the nature of this phenomenon revealed that bovine milk contains an inhibitor of

  18. Inhibitors of histone demethylases

    DEFF Research Database (Denmark)

    Lohse, Brian; Kristensen, Jesper L; Kristensen, Line H

    2011-01-01

    Methylated lysines are important epigenetic marks. The enzymes involved in demethylation have recently been discovered and found to be involved in cancer development and progression. Despite the relative recent discovery of these enzymes a number of inhibitors have already appeared. Most of the i...

  19. Demonstration of HITEX

    International Nuclear Information System (INIS)

    Morrison, H.D.; Woodall, K.B.

    1993-01-01

    A model reactor for HITEX successfully demonstrated the concept of high-temperature isotopic exchange in a closed loop simulating the conditions for fusion fuel cleanup. The catalyst of platinum on alumina pellets provided a surface area large enough to operate the reactor at 400 degrees celsius with flow rates up to 2 L/min. A 15-L tank containing a mixture of 4% CD 4 in H 2 was depleted in deuterium within 75 minutes down to 100 ppm HD above the natural concentration of HD in the make-up hydrogen stream. The application to tritium removal from tritiated impurities in a hydrogen stream will work as well or better

  20. Visual Electricity Demonstrator

    Science.gov (United States)

    Lincoln, James

    2017-09-01

    The Visual Electricity Demonstrator (VED) is a linear diode array that serves as a dynamic alternative to an ammeter. A string of 48 red light-emitting diodes (LEDs) blink one after another to create the illusion of a moving current. Having the current represented visually builds an intuitive and qualitative understanding about what is happening in a circuit. In this article, I describe several activities for this device and explain how using this technology in the classroom can enhance the understanding and appreciation of physics.

  1. Exploration Medical System Demonstration

    Science.gov (United States)

    Rubin, D. A.; Watkins, S. D.

    2014-01-01

    BACKGROUND: Exploration class missions will present significant new challenges and hazards to the health of the astronauts. Regardless of the intended destination, beyond low Earth orbit a greater degree of crew autonomy will be required to diagnose medical conditions, develop treatment plans, and implement procedures due to limited communications with ground-based personnel. SCOPE: The Exploration Medical System Demonstration (EMSD) project will act as a test bed on the International Space Station (ISS) to demonstrate to crew and ground personnel that an end-to-end medical system can assist clinician and non-clinician crew members in optimizing medical care delivery and data management during an exploration mission. Challenges facing exploration mission medical care include limited resources, inability to evacuate to Earth during many mission phases, and potential rendering of medical care by non-clinicians. This system demonstrates the integration of medical devices and informatics tools for managing evidence and decision making and can be designed to assist crewmembers in nominal, non-emergent situations and in emergent situations when they may be suffering from performance decrements due to environmental, physiological or other factors. PROJECT OBJECTIVES: The objectives of the EMSD project are to: a. Reduce or eliminate the time required of an on-orbit crew and ground personnel to access, transfer, and manipulate medical data. b. Demonstrate that the on-orbit crew has the ability to access medical data/information via an intuitive and crew-friendly solution to aid in the treatment of a medical condition. c. Develop a common data management framework that can be ubiquitously used to automate repetitive data collection, management, and communications tasks for all activities pertaining to crew health and life sciences. d. Ensure crew access to medical data during periods of restricted ground communication. e. Develop a common data management framework that

  2. Commercial incineration demonstration

    International Nuclear Information System (INIS)

    Vavruska, J.S.; Borduin, L.C.

    1982-01-01

    Low-level radioactive wastes (LLW) generated by nuclear utilities presently are shipped to commercial burial grounds for disposal. Increasing transportation and disposal costs have caused industry to consider incineration as a cost-effective means of volume reduction of combustible LLW. Repeated inquiries from the nuclear industry regarding the applicability of the Los Alamos controlled air incineration (CAI) design led the DOE to initiate a commercial demonstration program in FY-1980. Development studies and results in support of this program involving ion exchange resin incineration and fission/activation product distributions within the Los Alamos CAI are described

  3. Demonstration tokamak power plant

    International Nuclear Information System (INIS)

    Abdou, M.; Baker, C.; Brooks, J.; Ehst, D.; Mattas, R.; Smith, D.L.; DeFreece, D.; Morgan, G.D.; Trachsel, C.

    1983-01-01

    A conceptual design for a tokamak demonstration power plant (DEMO) was developed. A large part of the study focused on examining the key issues and identifying the R and D needs for: (1) current drive for steady-state operation, (2) impurity control and exhaust, (3) tritium breeding blanket, and (4) reactor configuration and maintenance. Impurity control and exhaust will not be covered in this paper but is discussed in another paper in these proceedings, entitled Key Issues of FED/INTOR Impurity Control System

  4. Predicting DPP-IV inhibitors with machine learning approaches

    Science.gov (United States)

    Cai, Jie; Li, Chanjuan; Liu, Zhihong; Du, Jiewen; Ye, Jiming; Gu, Qiong; Xu, Jun

    2017-04-01

    Dipeptidyl peptidase IV (DPP-IV) is a promising Type 2 diabetes mellitus (T2DM) drug target. DPP-IV inhibitors prolong the action of glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), improve glucose homeostasis without weight gain, edema, and hypoglycemia. However, the marketed DPP-IV inhibitors have adverse effects such as nasopharyngitis, headache, nausea, hypersensitivity, skin reactions and pancreatitis. Therefore, it is still expected for novel DPP-IV inhibitors with minimal adverse effects. The scaffolds of existing DPP-IV inhibitors are structurally diversified. This makes it difficult to build virtual screening models based upon the known DPP-IV inhibitor libraries using conventional QSAR approaches. In this paper, we report a new strategy to predict DPP-IV inhibitors with machine learning approaches involving naïve Bayesian (NB) and recursive partitioning (RP) methods. We built 247 machine learning models based on 1307 known DPP-IV inhibitors with optimized molecular properties and topological fingerprints as descriptors. The overall predictive accuracies of the optimized models were greater than 80%. An external test set, composed of 65 recently reported compounds, was employed to validate the optimized models. The results demonstrated that both NB and RP models have a good predictive ability based on different combinations of descriptors. Twenty "good" and twenty "bad" structural fragments for DPP-IV inhibitors can also be derived from these models for inspiring the new DPP-IV inhibitor scaffold design.

  5. Inhibitory Effects of Respiration Inhibitors on Aflatoxin Production

    Directory of Open Access Journals (Sweden)

    Shohei Sakuda

    2014-03-01

    Full Text Available Aflatoxin production inhibitors, which do not inhibit the growth of aflatoxigenic fungi, may be used to control aflatoxin without incurring a rapid spread of resistant strains. A respiration inhibitor that inhibits aflatoxin production was identified during a screening process for natural, aflatoxin-production inhibitors. This prompted us to evaluate respiration inhibitors as potential aflatoxin control agents. The inhibitory activities of four natural inhibitors, seven synthetic miticides, and nine synthetic fungicides were evaluated on aflatoxin production in Aspergillus parasiticus. All of the natural inhibitors (rotenone, siccanin, aptenin A5, and antimycin A inhibited fungal aflatoxin production with IC50 values around 10 µM. Among the synthetic miticides, pyridaben, fluacrypyrim, and tolfenpyrad exhibited strong inhibitory activities with IC50 values less than 0.2 µM, whereas cyflumetofen did not show significant inhibitory activity. Of the synthetic fungicides, boscalid, pyribencarb, azoxystrobin, pyraclostrobin, and kresoxim-methyl demonstrated strong inhibitory activities, with IC50 values less than 0.5 µM. Fungal growth was not significantly affected by any of the inhibitors tested at concentrations used. There was no correlation observed between the targets of respiration inhibitors (complexes I, II, and III and their IC50 values for aflatoxin-production inhibitory activity. This study suggests that respiration inhibitors, including commonly used pesticides, are useful for aflatoxin control.

  6. Inhibitory Effects of Respiration Inhibitors on Aflatoxin Production

    Science.gov (United States)

    Sakuda, Shohei; Prabowo, Diyan Febri; Takagi, Keiko; Shiomi, Kazuro; Mori, Mihoko; Ōmura, Satoshi; Nagasawa, Hiromichi

    2014-01-01

    Aflatoxin production inhibitors, which do not inhibit the growth of aflatoxigenic fungi, may be used to control aflatoxin without incurring a rapid spread of resistant strains. A respiration inhibitor that inhibits aflatoxin production was identified during a screening process for natural, aflatoxin-production inhibitors. This prompted us to evaluate respiration inhibitors as potential aflatoxin control agents. The inhibitory activities of four natural inhibitors, seven synthetic miticides, and nine synthetic fungicides were evaluated on aflatoxin production in Aspergillus parasiticus. All of the natural inhibitors (rotenone, siccanin, aptenin A5, and antimycin A) inhibited fungal aflatoxin production with IC50 values around 10 µM. Among the synthetic miticides, pyridaben, fluacrypyrim, and tolfenpyrad exhibited strong inhibitory activities with IC50 values less than 0.2 µM, whereas cyflumetofen did not show significant inhibitory activity. Of the synthetic fungicides, boscalid, pyribencarb, azoxystrobin, pyraclostrobin, and kresoxim-methyl demonstrated strong inhibitory activities, with IC50 values less than 0.5 µM. Fungal growth was not significantly affected by any of the inhibitors tested at concentrations used. There was no correlation observed between the targets of respiration inhibitors (complexes I, II, and III) and their IC50 values for aflatoxin-production inhibitory activity. This study suggests that respiration inhibitors, including commonly used pesticides, are useful for aflatoxin control. PMID:24674936

  7. Smart Grid Demonstration Project

    Energy Technology Data Exchange (ETDEWEB)

    Miller, Craig [National Rural Electric Cooperative Association, Arlington, VA (United States); Carroll, Paul [National Rural Electric Cooperative Association, Arlington, VA (United States); Bell, Abigail [National Rural Electric Cooperative Association, Arlington, VA (United States)

    2015-03-11

    The National Rural Electric Cooperative Association (NRECA) organized the NRECA-U.S. Department of Energy (DOE) Smart Grid Demonstration Project (DE-OE0000222) to install and study a broad range of advanced smart grid technologies in a demonstration that spanned 23 electric cooperatives in 12 states. More than 205,444 pieces of electronic equipment and more than 100,000 minor items (bracket, labels, mounting hardware, fiber optic cable, etc.) were installed to upgrade and enhance the efficiency, reliability, and resiliency of the power networks at the participating co-ops. The objective of this project was to build a path for other electric utilities, and particularly electrical cooperatives, to adopt emerging smart grid technology when it can improve utility operations, thus advancing the co-ops’ familiarity and comfort with such technology. Specifically, the project executed multiple subprojects employing a range of emerging smart grid technologies to test their cost-effectiveness and, where the technology demonstrated value, provided case studies that will enable other electric utilities—particularly electric cooperatives— to use these technologies. NRECA structured the project according to the following three areas: Demonstration of smart grid technology; Advancement of standards to enable the interoperability of components; and Improvement of grid cyber security. We termed these three areas Technology Deployment Study, Interoperability, and Cyber Security. Although the deployment of technology and studying the demonstration projects at coops accounted for the largest portion of the project budget by far, we see our accomplishments in each of the areas as critical to advancing the smart grid. All project deliverables have been published. Technology Deployment Study: The deliverable was a set of 11 single-topic technical reports in areas related to the listed technologies. Each of these reports has already been submitted to DOE, distributed to co-ops, and

  8. Electrodynamic Dust Shield Demonstrator

    Science.gov (United States)

    Stankie, Charles G.

    2013-01-01

    The objective of the project was to design and manufacture a device to demonstrate a new technology developed by NASA's Electrostatics and Surface Physics Laboratory. The technology itself is a system which uses magnetic principles to remove regolith dust from its surface. This project was to create an enclosure that will be used to demonstrate the effectiveness of the invention to The Office of the Chief Technologist. ONE of the most important challenges of space exploration is actually caused by something very small and seemingly insignificant. Dust in space, most notably on the moon and Mars, has caused many unforeseen issues. Dirt and dust on Earth, while a nuisance, can be easily cleaned and kept at bay. However, there is considerably less weathering and erosion in space. As a result, the microscopic particles are extremely rough and abrasive. They are also electrostatically charged, so they cling to everything they make contact with. This was first noted to be a major problem during the Apollo missions. Dust would stick to the spacesuits, and could not be wiped off as predicted. Dust was brought back into the spacecraft, and was even inhaled by astronauts. This is a major health hazard. Atmospheric storms and other events can also cause dust to coat surfaces of spacecraft. This can cause abrasive damage to the craft. The coating can also reduce the effectiveness of thermal insulation and solar panels.' A group of engineers at Kennedy Space Center's Electrostatics and Surface Physics Laboratory have developed a new technology, called the Electrodynamic Dust Shield, to help alleviate these problems. It is based off of the electric curtain concept developed at NASA in 1967. "The EDS is an active dust mitigation technology that uses traveling electric fields to transport electrostatically charged dust particles along surfaces. To generate the traveling electric fields, the EDS consists of a multilayer dielectric coating with an embedded thin electrode grid

  9. Fuel Cell Demonstration Program

    Energy Technology Data Exchange (ETDEWEB)

    Gerald Brun

    2006-09-15

    In an effort to promote clean energy projects and aid in the commercialization of new fuel cell technologies the Long Island Power Authority (LIPA) initiated a Fuel Cell Demonstration Program in 1999 with six month deployments of Proton Exchange Membrane (PEM) non-commercial Beta model systems at partnering sites throughout Long Island. These projects facilitated significant developments in the technology, providing operating experience that allowed the manufacturer to produce fuel cells that were half the size of the Beta units and suitable for outdoor installations. In 2001, LIPA embarked on a large-scale effort to identify and develop measures that could improve the reliability and performance of future fuel cell technologies for electric utility applications and the concept to establish a fuel cell farm (Farm) of 75 units was developed. By the end of October of 2001, 75 Lorax 2.0 fuel cells had been installed at the West Babylon substation on Long Island, making it the first fuel cell demonstration of its kind and size anywhere in the world at the time. Designed to help LIPA study the feasibility of using fuel cells to operate in parallel with LIPA's electric grid system, the Farm operated 120 fuel cells over its lifetime of over 3 years including 3 generations of Plug Power fuel cells (Lorax 2.0, Lorax 3.0, Lorax 4.5). Of these 120 fuel cells, 20 Lorax 3.0 units operated under this Award from June 2002 to September 2004. In parallel with the operation of the Farm, LIPA recruited government and commercial/industrial customers to demonstrate fuel cells as on-site distributed generation. From December 2002 to February 2005, 17 fuel cells were tested and monitored at various customer sites throughout Long Island. The 37 fuel cells operated under this Award produced a total of 712,635 kWh. As fuel cell technology became more mature, performance improvements included a 1% increase in system efficiency. Including equipment, design, fuel, maintenance

  10. Fusion-power demonstration

    International Nuclear Information System (INIS)

    Henning, C.D.; Logan, B.G.; Carlson, G.A.; Neef, W.S.; Moir, R.W.; Campbell, R.B.; Botwin, R.; Clarkson, I.R.; Carpenter, T.J.

    1983-01-01

    As a satellite to the MARS (Mirror Advanced Reactor Study) a smaller, near-term device has been scoped, called the FPD (Fusion Power Demonstration). Envisioned as the next logical step toward a power reactor, it would advance the mirror fusion program beyond MFTF-B and provide an intermediate step toward commercial fusion power. Breakeven net electric power capability would be the goal such that no net utility power would be required to sustain the operation. A phased implementation is envisioned, with a deuterium checkout first to verify the plasma systems before significant neutron activation has occurred. Major tritium-related facilities would be installed with the second phase to produce sufficient fusion power to supply the recirculating power to maintain the neutral beams, ECRH, magnets and other auxiliary equipment

  11. Spent fuel pyroprocessing demonstration

    International Nuclear Information System (INIS)

    McFarlane, L.F.; Lineberry, M.J.

    1995-01-01

    A major element of the shutdown of the US liquid metal reactor development program is managing the sodium-bonded spent metallic fuel from the Experimental Breeder Reactor-II to meet US environmental laws. Argonne National Laboratory has refurbished and equipped an existing hot cell facility for treating the spent fuel by a high-temperature electrochemical process commonly called pyroprocessing. Four products will be produced for storage and disposal. Two high-level waste forms will be produced and qualified for disposal of the fission and activation products. Uranium and transuranium alloys will be produced for storage pending a decision by the US Department of Energy on the fate of its plutonium and enriched uranium. Together these activities will demonstrate a unique electrochemical treatment technology for spent nuclear fuel. This technology potentially has significant economic and technical advantages over either conventional reprocessing or direct disposal as a high-level waste option

  12. Industrial demonstration trials

    International Nuclear Information System (INIS)

    Gelee, M.; Fabre, C.; Villepoix, R. de; Fra, J.; Le Foulgoc, L.; Morel, Y.; Querite, P.; Roques, R.

    1975-01-01

    Prototypes of the plant components, meeting the specifications set by the process and built by industrial firms in collaboration with the supervisor and the C.E.A., are subjected to trial runs on the UF 6 test bench of the Pierrelatte testing zone. These items of equipment (diffuser, compressor, exchanger) are placed in an industrial operation context very similar to that of an enrichment plant. Their performance is measured within a broad region around the working point and their reliability observed over periods up to several tens of thousands of hours. Between 1969 and 1973 six industrial demonstration test benches have been built, marking the stages in the technical preparation of the 1973 file on the basis of which the decision of building was taken by Eurodif [fr

  13. Fusion Power Demonstration III

    International Nuclear Information System (INIS)

    Lee, J.D.

    1985-07-01

    This is the third in the series of reports covering the Fusion Power Demonstration (FPD) design study. This volume considers the FPD-III configuration that incorporates an octopole end plug. As compared with the quadrupole end-plugged designs of FPD-I and FPD-II, this octopole configuration reduces the number of end cell magnets and shortens the minimum ignition length of the central cell. The end-cell plasma length is also reduced, which in turn reduces the size and cost of the end cell magnets and shielding. As a contiuation in the series of documents covering the FPD, this report does not stand alone as a design description of FPD-III. Design details of FPD-III subsystems that do not differ significantly from those of the FPD-II configuration are not duplicated in this report

  14. TPA device for demonstration

    International Nuclear Information System (INIS)

    1980-02-01

    The TPA (torus plasma for amature) is a small race-trac type device made by the technical service division to demonstrate basic properties of plasma such as electron temperature, conductivity, effect of helical field for toroidal drift, and shape of plasma in mirror and cusp magnetic field in linear section. The plasmas are produced by RF discharge (-500W) and/or DC discharge (-30 mA) within glass discharge tube. Where major radius is 50 cm, length of linear section is 50 cm, toroidal magnetic field is 200 gauss. The device has been designed to be compact with only 100 V power source (-3.2 KW for the case without helical field) and to be full automatic sequence of operation. (author)

  15. Fusion power demonstration

    International Nuclear Information System (INIS)

    Henning, C.D.; Logan, B.G.

    1983-01-01

    As a satellite to the MARS (Mirror Advanced Reactor Study) a smaller, near-term device has been scoped, called the FPD (Fusion Power Demonstration). Envisioned as the next logical step toward a power reactor, it would advance the mirror fusion program beyond MFTF-B and provide an intermediate step toward commercial fusion power. Breakeven net electric power capability would be the goal such that no net utility power would be required to sustain the operation. A phased implementation is envisioned, with a deuterium checkout first to verify the plasma systems before significant neutron activation has occurred. Major tritium-related facilities would be installed with the second phase to produce sufficient fusion power to supply the recirculating power to maintain the neutral beams, ECRH, magnets and other auxiliary equipment

  16. Dynamic wall demonstration project

    Energy Technology Data Exchange (ETDEWEB)

    Nakatsui, L.; Mayhew, W.

    1990-12-01

    The dynamic wall concept is a ventilation strategy that can be applied to a single family dwelling. With suitable construction, outside air can be admitted through the exterior walls of the house to the interior space to function as ventilation air. The construction and performance monitoring of a demonstration house built to test the dynamic wall concept in Sherwood Park, Alberta, is described. The project had the objectives of demonstrating and assessing the construction methods; determining the cost-effectiveness of the concept in Alberta; analyzing the operation of the dynamic wall system; and determining how other components and systems in the house interact with the dynamic wall. The exterior wall construction consisted of vinyl siding, spun-bonded polyolefin-backed (SBPO) rigid fiberglass sheathing, 38 mm by 89 mm framing, fiberglass batt insulation and 12.7 mm drywall. The mechanical system was designed to operate in the dynamic (negative pressure) mode, however flexibility was provided to allow operation in the static (balanced pressure) mode to permit monitoring of the walls as if they were in a conventional house. The house was monitored by an extensive computerized monitoring system. Dynamic wall operation was dependent on pressure and temperature differentials between indoor and outdoor as well as wind speed and direction. The degree of heat gain was found to be ca 74% of the indoor-outdoor temperature differential. Temperature of incoming dynamic air was significantly affected by solar radiation and measurement of indoor air pollutants found no significant levels. 4 refs., 34 figs., 11 tabs.

  17. ROS inhibitor N-acetyl-L-cysteine antagonizes the activity of proteasome inhibitors.

    Science.gov (United States)

    Halasi, Marianna; Wang, Ming; Chavan, Tanmay S; Gaponenko, Vadim; Hay, Nissim; Gartel, Andrei L

    2013-09-01

    NAC (N-acetyl-L-cysteine) is commonly used to identify and test ROS (reactive oxygen species) inducers, and to inhibit ROS. In the present study, we identified inhibition of proteasome inhibitors as a novel activity of NAC. Both NAC and catalase, another known scavenger of ROS, similarly inhibited ROS levels and apoptosis associated with H₂O₂. However, only NAC, and not catalase or another ROS scavenger Trolox, was able to prevent effects linked to proteasome inhibition, such as protein stabilization, apoptosis and accumulation of ubiquitin conjugates. These observations suggest that NAC has a dual activity as an inhibitor of ROS and proteasome inhibitors. Recently, NAC was used as a ROS inhibitor to functionally characterize a novel anticancer compound, piperlongumine, leading to its description as a ROS inducer. In contrast, our own experiments showed that this compound depicts features of proteasome inhibitors including suppression of FOXM1 (Forkhead box protein M1), stabilization of cellular proteins, induction of ROS-independent apoptosis and enhanced accumulation of ubiquitin conjugates. In addition, NAC, but not catalase or Trolox, interfered with the activity of piperlongumine, further supporting that piperlongumine is a proteasome inhibitor. Most importantly, we showed that NAC, but not other ROS scavengers, directly binds to proteasome inhibitors. To our knowledge, NAC is the first known compound that directly interacts with and antagonizes the activity of proteasome inhibitors. Taken together, the findings of the present study suggest that, as a result of the dual nature of NAC, data interpretation might not be straightforward when NAC is utilized as an antioxidant to demonstrate ROS involvement in drug-induced apoptosis.

  18. Identification of fermentation inhibitors in wood hydrolyzates and removal of inhibitors by ion exchange and liquid-liquid extraction

    Science.gov (United States)

    Luo, Caidian

    1998-12-01

    aliphatic acids has been identified in the wood hydrolyzate studied. They are potential fermentation inhibitors probably similar to acetic acid. Ethyl acetate extraction has also been demonstrated to be a possible method to remove fermentation inhibitors from hydrolyzates. (Abstract shortened by UMI.)

  19. Acid corrosion inhibitor

    Energy Technology Data Exchange (ETDEWEB)

    Chen, N G

    1964-04-28

    An acid corrosion inhibitor is prepared by a 2-stage vacuum evaporation of effluents obtained from the ammonia columns of the coking oven plant. The effluent, leaving a scrubber in which the phenols are removed at a temperature of 98$C, passes through a quartz filter and flows into a heated chamber in which it is used for preheating a solution circulating through a vacuum unit, maintaining the temperature of the solution at 55$ to 60$C. The effluent enters a large tank in which it is boiled at 55$ to 60$C under 635 to 640 mm Hg pressure. Double evaporation of this solution yields a very effective acid corrosion inhibitor. Its corrosion-preventing effect is 97.9% compared with 90.1% for thiourea and 88.5% for urotropin under identical conditions.

  20. Benzoylurea Chitin Synthesis Inhibitors.

    Science.gov (United States)

    Sun, Ranfeng; Liu, Chunjuan; Zhang, Hao; Wang, Qingmin

    2015-08-12

    Benzoylurea chitin synthesis inhibitors are widely used in integrated pest management (IPM) and insecticide resistance management (IRM) programs due to their low toxicity to mammals and predatory insects. In the past decades, a large number of benzoylurea derivatives have been synthesized, and 15 benzoylurea chitin synthesis inhibitors have been commercialized. This review focuses on the history of commercial benzolyphenylureas (BPUs), synthetic methods, structure-activity relationships (SAR), action mechanism research, environmental behaviors, and ecotoxicology. Furthermore, their disadvantages of high risk to aquatic invertebrates and crustaceans are pointed out. Finally, we propose that the para-substituents at anilide of benzoylphenylureas should be the functional groups, and bipartite model BPU analogues are discussed in an attempt to provide new insight for future development of BPUs.

  1. A Demonstration of Lusail

    KAUST Repository

    Mansour, Essam; Abdelaziz, Ibrahim; Ouzzani, Mourad; Aboulnaga, Ashraf; Kalnis, Panos

    2017-01-01

    There has been a proliferation of datasets available as interlinked RDF data accessible through SPARQL endpoints. This has led to the emergence of various applications in life science, distributed social networks, and Internet of Things that need to integrate data from multiple endpoints. We will demonstrate Lusail; a system that supports the need of emerging applications to access tens to hundreds of geo-distributed datasets. Lusail is a geo-distributed graph engine for querying linked RDF data. Lusail delivers outstanding performance using (i) a novel locality-aware query decomposition technique that minimizes the intermediate data to be accessed by the subqueries, and (ii) selectivityawareness and parallel query execution to reduce network latency and to increase parallelism. During the demo, the audience will be able to query actually deployed RDF endpoints as well as large synthetic and real benchmarks that we have deployed in the public cloud. The demo will also show that Lusail outperforms state-of-the-art systems by orders of magnitude in terms of scalability and response time.

  2. A Demonstration of Lusail

    KAUST Repository

    Mansour, Essam

    2017-05-10

    There has been a proliferation of datasets available as interlinked RDF data accessible through SPARQL endpoints. This has led to the emergence of various applications in life science, distributed social networks, and Internet of Things that need to integrate data from multiple endpoints. We will demonstrate Lusail; a system that supports the need of emerging applications to access tens to hundreds of geo-distributed datasets. Lusail is a geo-distributed graph engine for querying linked RDF data. Lusail delivers outstanding performance using (i) a novel locality-aware query decomposition technique that minimizes the intermediate data to be accessed by the subqueries, and (ii) selectivityawareness and parallel query execution to reduce network latency and to increase parallelism. During the demo, the audience will be able to query actually deployed RDF endpoints as well as large synthetic and real benchmarks that we have deployed in the public cloud. The demo will also show that Lusail outperforms state-of-the-art systems by orders of magnitude in terms of scalability and response time.

  3. Demonstration exercise 'Cavtat 09'

    International Nuclear Information System (INIS)

    Trut, D.

    2009-01-01

    The demonstration exercise is to show a terrorist attack in urban area resulting in a certain number of injured people. On 7th April 2009 a terrorist group HAL 9000 is in Cavtat and set up an explosive devices with chemical reagents in several spots with intention to activate them and cause great number of victims. On the same day, in area of the Cavtat Croatia Hotel, which is hosting the world CBMTS Congress, Cavtat Police Station notice several masked persons, in escapement. Hotel personnel alerted the County 112 Center about noticed devices placed by chlorine dioxide tanks, for water conditioning. Intervention police came to block entrance to this area and evacuate hotel's guests and congress members. An explosion and fire occurs from where the position of water-conditioning plant and chlorine dioxide tank. The 112 Center alarms fire-fighters for fight fire and decontamination action and HAZMAT Civil Support Team from Georgia (participated the congress). In the meantime, guests have been instructed not to leave their rooms and to hermetically close doors and windows with available material to keep away potential toxic fume. Decision makers form the County Protection and Rescue Headquarters monitors the situation till the end of alert for the population in the area of Cavtat.(author)

  4. Tidd PFBC demonstration project

    Energy Technology Data Exchange (ETDEWEB)

    Marrocco, M. [American Electric Power, Columbus, OH (United States)

    1997-12-31

    The Tidd project was one of the first joint government-industry ventures to be approved by the US Department of Energy (DOE) in its Clean Coal Technology Program. In March 1987, DOE signed an agreement with the Ohio Power Company, a subsidiary of American Electric Power, to refurbish the then-idle Tidd plant on the banks of the Ohio River with advanced pressurized fluidized bed technology. Testing ended after 49 months of operation, 100 individual tests, and the generation of more than 500,000 megawatt-hours of electricity. The demonstration plant has met its objectives. The project showed that more than 95 percent of sulfur dioxide pollutants could be removed inside the advanced boiler using the advanced combustion technology, giving future power plants an attractive alternative to expensive, add-on scrubber technology. In addition to its sulfur removal effectiveness, the plant`s sustained periods of steady-state operation boosted its availability significantly above design projections, heightening confidence that pressurized fluidized bed technology will be a reliable, baseload technology for future power plants. The technology also controlled the release of nitrogen oxides to levels well below the allowable limits set by federal air quality standards. It also produced a dry waste product that is much easier to handle than wastes from conventional power plants and will likely have commercial value when produced by future power plants.

  5. Kinesthetic Transverse Wave Demonstration

    Science.gov (United States)

    Pantidos, Panagiotis; Patapis, Stamatis

    2005-09-01

    This is a variation on the String and Sticky Tape demonstration "The Wave Game," suggested by Ron Edge. A group of students stand side by side, each one holding a card chest high with both hands. The teacher cues the first student to begin raising and lowering his card. When he starts lowering his card, the next student begins to raise his. As succeeding students move their cards up and down, a wave such as that shown in the figure is produced. To facilitate the process, students' motions were synchronized with the ticks of a metronome (without such synchronization it was nearly impossible to generate a satisfactory wave). Our waves typically had a frequency of about 1 Hz and a wavelength of around 3 m. We videotaped the activity so that the students could analyze the motions. The (17-year-old) students had not received any prior instruction regarding wave motion and did not know beforehand the nature of the exercise they were about to carry out. During the activity they were asked what a transverse wave is. Most of them quickly realized, without teacher input, that while the wave propagated horizontally, the only motion of the transmitting medium (them) was vertical. They located the equilibrium points of the oscillations, the crests and troughs of the waves, and identified the wavelength. The teacher defined for them the period of the oscillations of the motion of a card to be the total time for one cycle. The students measured this time and then several asserted that it was the same as the wave period. Knowing the length of the waves and the number of waves per second, the next step can easily be to find the wave speed.

  6. Cyclooxygenase-2 inhibitors and knee prosthesis surgery

    OpenAIRE

    Meunier, Andreas

    2008-01-01

    Adverse effects of cyclooxygenase (COX) inhibitors on bone healing have previously been demonstrated in diaphyseal fracture models in animals. In spite of that, they are widely used as postoperative analgesics in orthopaedic surgery. After joint replacement, a bone repair process starts at the interface between bone and cement. If this process is disturbed, the prosthesis may never become rigidly fixed to the bone, leading to migration and with time loosening. This thesis investigates the eff...

  7. PARP Inhibitors in Ovarian Cancer.

    Science.gov (United States)

    Mittica, Gloria; Ghisoni, Eleonora; Giannone, Gaia; Genta, Sofia; Aglietta, Massimo; Sapino, Anna; Valabrega, Giorgio

    2018-03-05

    Treatment of Epithelial Ovarian Cancer (EOC), historically based on surgery and platinum doublet chemotherapy, is associated with high risk of relapse and poor prognosis for recurrent disease. In this landscape, the innovative treatment with PARP inhibitors (PARPis) demonstrated an outstanding activity in EOC, and is currently changing clinical practice in BRCA mutant patients. To highlight the mechanism of action, pharmacokinetics, clinical activity, indications and current strategies of development of Olaparib, Niraparib, Rucaparib, Talazoparib and Veliparib, the 5 most relevant PARPis. We performed a review on Pubmed using 'ovarian cancer' and the name of each PARPi (PARP inhibitor) discussed in the review as Medical Subject Headings (MeSH) keywords. The same search was performed on "clinicaltrial.gov" to identify ongoing clinical trials and on "google.com/patents" and "uspto.gov" for recent patents exploring PARPIs in ovarian cancer. Olaparib, Niraparib and Rucaparib are already approved for treatment of recurrent EOC and their indications are partially overlapping. Talazoparib and Veliparib are promising PARPis, but currently under investigation in early phase trials. Several studies are evaluating PARPis in monotherapy or in associations, in a wide range of settings (i.e. first line, neoadjuvant, platinum-sensitive and resistant disease). PARPis are valuable options in patients with recurrent ovarian cancer with promising activity in different stages of this disease. Further studies are required to better define optimal clinical settings, predictors of response beyond BRCA mutations and strategies to overcome secondary resistance of PARPis therapy in EOC. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  8. DGAT inhibitors for obesity.

    Science.gov (United States)

    Matsuda, Daisuke; Tomoda, Hiroshi

    2007-10-01

    Obesity is characterized by the accumulation of triacylglycerol in adipocytes. Diacylglycerol acyltransferase (DGAT) catalyzes the final reaction of triacylgycerol synthesis. Two isozymes of DGAT, DGAT1 and DGAT2, have been reported. Increased DGAT2 activity has a role in steatosis, while DGAT1 plays a role in very (V)LDL synthesis; increased plasma VLDL concentrations may promote obesity and thus DGAT1 is considered a potential therapeutic target of inhibition for obesity control. Several DGAT inhibitors of natural and synthetic origin have been reported, and their future prospect as anti-obesity drugs is discussed in this review.

  9. Pulmonary Toxicity of Cholinesterase Inhibitors

    National Research Council Canada - National Science Library

    Hilmas, Corey; Adler, Michael; Baskin, Steven I; Gupta, Ramesh C

    2006-01-01

    .... Whereas nerve agents were produced primarily for military deployment, other cholinesterase inhibitors were used for treating conditions such as myasthenia gravis and as pretreaunents for nerve agent exposure...

  10. Raltegravir: first in class HIV integrase inhibitor

    Directory of Open Access Journals (Sweden)

    Zelalem Temesgen

    2008-06-01

    Full Text Available Zelalem Temesgen1, Dawd S Siraj21Mayo Clinic, Rochester, MN, USA; 2East Carolina University Greenville, NC, USAAbstract: On October 16, 2007, the US Food and Drug Administration (FDA approved raltegravir for treatment of human immunodeficiency virus (HIV-1 infection in combination with other antiretroviral agents in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. Raltegravir is first in a novel class of antiretroviral drugs known as integrase inhibitors. It has demonstrated potent anti HIV activity in both antiretroviral treatment-naïve and experienced patients. The most common adverse events reported with raltegravir during phase 2 and 3 clinical trials were diarrhea, nausea, and headache. Laboratory abnormalities include mild elevations in liver transaminases and creatine phosphokinase.Keywords: raltegravir, HIV, antiretroviral agents, integrase inhibitors

  11. Small molecule inhibitors of anthrax edema factor.

    Science.gov (United States)

    Jiao, Guan-Sheng; Kim, Seongjin; Moayeri, Mahtab; Thai, April; Cregar-Hernandez, Lynne; McKasson, Linda; O'Malley, Sean; Leppla, Stephen H; Johnson, Alan T

    2018-01-15

    Anthrax is a highly lethal disease caused by the Gram-(+) bacteria Bacillus anthracis. Edema toxin (ET) is a major contributor to the pathogenesis of disease in humans exposed to B. anthracis. ET is a bipartite toxin composed of two proteins secreted by the vegetative bacteria, edema factor (EF) and protective antigen (PA). Our work towards identifying a small molecule inhibitor of anthrax edema factor is the subject of this letter. First we demonstrate that the small molecule probe 5'-Fluorosulfonylbenzoyl 5'-adenosine (FSBA) reacts irreversibly with EF and blocks enzymatic activity. We then show that the adenosine portion of FSBA can be replaced to provide more drug-like molecules which are up to 1000-fold more potent against EF relative to FSBA, display low cross reactivity when tested against a panel of kinases, and are nanomolar inhibitors of EF in a cell-based assay of cAMP production. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Novel nonpeptidic inhibitors of peptide deformylase.

    Science.gov (United States)

    Jayasekera, M M; Kendall, A; Shammas, R; Dermyer, M; Tomala, M; Shapiro, M A; Holler, T P

    2000-09-15

    A novel series of nonpeptidic compounds structurally related to the known anticholesteremic thyropropic acid were found to inhibit Escherichia coli peptide deformylase (PDF), with IC50 values in the low-micromolar range. Kinetic analysis of [4-(4-hydroxyphenoxy)-3,5-diiodophenyl]acetic acid reveals competitive inhibition, with a Ki value of 0.66 +/- 0.007 microM. A structure-activity relationship study demonstrates that the carboxylate is required for activity, while the distal phenolic function can be methylated without significant effect. Either decreasing the number of iodine atoms on the molecule to one or increasing the number of iodine atoms to four results in the loss of an order of magnitude in potency. These compounds are the first nonpeptidic inhibitors disclosed and represent a template from which better inhibitors might be designed.

  13. Information Integration Technology Demonstration (IITD)

    National Research Council Canada - National Science Library

    Loe, Richard

    2001-01-01

    The objectives of the Information Integration Technology Demonstration (IITD) were to investigate, design a software architecture and demonstrate a capability to display intelligence data from multiple disciplines...

  14. A novel class of small molecule inhibitors of HDAC6.

    Science.gov (United States)

    Inks, Elizabeth S; Josey, Benjamin J; Jesinkey, Sean R; Chou, C James

    2012-02-17

    Histone deacetylases (HDACs) are a family of enzymes that play significant roles in numerous biological processes and diseases. HDACs are best known for their repressive influence on gene transcription through histone deacetylation. Mapping of nonhistone acetylated proteins and acetylation-modifying enzymes involved in various cellular pathways has shown protein acetylation/deacetylation also plays key roles in a variety of cellular processes including RNA splicing, nuclear transport, and cytoskeletal remodeling. Studies of HDACs have accelerated due to the availability of small molecule HDAC inhibitors, most of which contain a canonical hydroxamic acid or benzamide that chelates the metal catalytic site. To increase the pool of unique and novel HDAC inhibitor pharmacophores, a pharmacological active compound screen was performed. Several unique HDAC inhibitor pharmacophores were identified in vitro. One class of novel HDAC inhibitors, with a central naphthoquinone structure, displayed a selective inhibition profile against HDAC6. Here we present the results of a unique class of HDAC6 inhibitors identified using this compound library screen. In addition, we demonstrated that treatment of human acute myeloid leukemia cell line MV4-11 with the selective HDAC6 inhibitors decreases levels of mutant FLT-3 and constitutively active STAT5 and attenuates Erk phosphorylation, all of which are associated with the inhibitor's selective toxicity against leukemia.

  15. A novel method for screening the glutathione transferase inhibitors

    Directory of Open Access Journals (Sweden)

    Węgrzyn Grzegorz

    2009-03-01

    Full Text Available Abstract Background Glutathione transferases (GSTs belong to the family of Phase II detoxification enzymes. GSTs catalyze the conjugation of glutathione to different endogenous and exogenous electrophilic compounds. Over-expression of GSTs was demonstrated in a number of different human cancer cells. It has been found that the resistance to many anticancer chemotherapeutics is directly correlated with the over-expression of GSTs. Therefore, it appears to be important to find new GST inhibitors to prevent the resistance of cells to anticancer drugs. In order to search for glutathione transferase (GST inhibitors, a novel method was designed. Results Our results showed that two fragments of GST, named F1 peptide (GYWKIKGLV and F2 peptide (KWRNKKFELGLEFPNL, can significantly inhibit the GST activity. When these two fragments were compared with several known potent GST inhibitors, the order of inhibition efficiency (measured in reactions with 2,4-dinitrochlorobenzene (CDNB and glutathione as substrates was determined as follows: tannic acid > cibacron blue > F2 peptide > hematin > F1 peptide > ethacrynic acid. Moreover, the F1 peptide appeared to be a noncompetitive inhibitor of the GST-catalyzed reaction, while the F2 peptide was determined as a competitive inhibitor of this reaction. Conclusion It appears that the F2 peptide can be used as a new potent specific GST inhibitor. It is proposed that the novel method, described in this report, might be useful for screening the inhibitors of not only GST but also other enzymes.

  16. Biological abatement of cellulase inhibitors

    Science.gov (United States)

    Bio-abatement uses a fungus to metabolize and remove fermentation inhibitors. To determine whether bio-abatement could alleviate enzyme inhibitor effects observed in biomass liquors after pretreatment, corn stover at 10% (w/v) solids was pretreated with either dilute acid or liquid hot water. The ...

  17. Proteinaceous alpha-araylase inhibitors

    DEFF Research Database (Denmark)

    Svensson, Birte; Fukuda, Kenji; Nielsen, P.K.

    2004-01-01

    -amylase inhibitors belong to seven different protein structural families, most of which also contain evolutionary related proteins without inhibitory activity. Two families include bifunctional inhibitors acting both on alpha-amylases and proteases. High-resolution structures are available of target alpha...

  18. Corrosion inhibitors. Manufacture and technology

    International Nuclear Information System (INIS)

    Ranney, M.W.

    1976-01-01

    Detailed information is presented relating to corrosion inhibitors. Areas covered include: cooling water, boilers and water supply plants; oil well and refinery operations; fuel and lubricant additives for automotive use; hydraulic fluids and machine tool lubes; grease compositions; metal surface treatments and coatings; and general processes for corrosion inhibitors

  19. AZT as a telomerase inhibitor

    International Nuclear Information System (INIS)

    Gomez, Daniel E.; Armando, Romina G.; Alonso, Daniel F.

    2012-01-01

    Telomerase is a highly specialized reverse transcriptase (RT) and the maintenance of telomeric length is determined by this specific enzyme. The human holoenzyme telomerase is a ribonucleoprotein composed by a catalytic subunit, hTERT, an RNA component, hTR, and a group of associated proteins. Telomerase is normally expressed in embryonic cells and is repressed during adulthood. The enzyme is reexpressed in around 85% of solid tumors. This observation makes it a potential target for developing drugs that could be developed for therapeutic purposes. The identification of the hTERT as a functional catalytic RT prompted studies of inhibiting telomerase with the HIV RT inhibitor azidothymidine (AZT). Previously, we have demonstrated that AZT binds preferentially to telomeres, inhibits telomerase and enhances tumor cell senescence, and apoptosis after AZT treatment in breast mammary adenocarcinoma cells. Since then, several studies have considered AZT for telomerase inhibition and have led to potential clinical strategies for anticancer therapy. This review covers present thinking of the inhibition of telomerase by AZT and future treatment protocols using the drug.

  20. Proton pump inhibitors and gastroenteritis

    International Nuclear Information System (INIS)

    Hassing, Robert-Jan; Verbon, Annelies; Visser, Herman de; Hofman, Albert; Stricker, Bruno H.

    2016-01-01

    An association between proton pump inhibitor (PPI) therapy and bacterial gastroenteritis has been suggested as well as contradicted. The aim of this study was to examine the association between the use of PPIs and occurrence of bacterial gastroenteritis in the prospective Rotterdam Study. The Rotterdam Study is a population-based cohort study among 14,926 subjects aged 45 years and older with up to 24 years of follow-up. Analyses were performed with a generalized estimating equations method in participants who handed-in a diagnostic stool sample. Furthermore, a nested case–control analysis was performed using the total cohort as a reference group. A bacterial microorganism was isolated in 125 samples, whereas 1174 samples were culture negative. In the generalized estimating equations analysis, we found that participants with a bacterial gastroenteritis were more likely than controls to be current users of PPIs (adjusted OR 1.94; 95 % CI 1.15–3.25). Different sensitivity analyses did not change this result. A considerably higher effect was observed (adjusted OR 6.14; 95 % CI 3.81–9.91), using the total cohort as a reference in a nested case–control analysis. Current PPI therapy is associated with an increased risk of bacterial gastroenteritis. However, by reducing the risk of selection and information bias in our study design, we demonstrated that the effect is lower than previously assumed.

  1. Novel targeted therapeutics: inhibitors of MDM2, ALK and PARP

    Directory of Open Access Journals (Sweden)

    Hsueh Chung-Tsen

    2011-04-01

    Full Text Available Abstract We reviewed preclinical data and clinical development of MDM2 (murine double minute 2, ALK (anaplastic lymphoma kinase and PARP (poly [ADP-ribose] polymerase inhibitors. MDM2 binds to p53, and promotes degradation of p53 through ubiquitin-proteasome degradation. JNJ-26854165 and RO5045337 are 2 small-molecule inhibitors of MDM2 in clinical development. ALK is a transmembrane protein and a member of the insulin receptor tyrosine kinases. EML4-ALK fusion gene is identified in approximately 3-13% of non-small cell lung cancer (NSCLC. Early-phase clinical studies with Crizotinib, an ALK inhibitor, in NSCLC harboring EML4-ALK have demonstrated promising activity with high response rate and prolonged progression-free survival. PARPs are a family of nuclear enzymes that regulates the repair of DNA single-strand breaks through the base excision repair pathway. Randomized phase II study has shown adding PARP-1 inhibitor BSI-201 to cytotoxic chemotherapy improves clinical outcome in patients with triple-negative breast cancer. Olaparib, another oral small-molecule PARP inhibitor, demonstrated encouraging single-agent activity in patients with advanced breast or ovarian cancer. There are 5 other PARP inhibitors currently under active clinical investigation.

  2. Microarray-based screening of heat shock protein inhibitors.

    Science.gov (United States)

    Schax, Emilia; Walter, Johanna-Gabriela; Märzhäuser, Helene; Stahl, Frank; Scheper, Thomas; Agard, David A; Eichner, Simone; Kirschning, Andreas; Zeilinger, Carsten

    2014-06-20

    Based on the importance of heat shock proteins (HSPs) in diseases such as cancer, Alzheimer's disease or malaria, inhibitors of these chaperons are needed. Today's state-of-the-art techniques to identify HSP inhibitors are performed in microplate format, requiring large amounts of proteins and potential inhibitors. In contrast, we have developed a miniaturized protein microarray-based assay to identify novel inhibitors, allowing analysis with 300 pmol of protein. The assay is based on competitive binding of fluorescence-labeled ATP and potential inhibitors to the ATP-binding site of HSP. Therefore, the developed microarray enables the parallel analysis of different ATP-binding proteins on a single microarray. We have demonstrated the possibility of multiplexing by immobilizing full-length human HSP90α and HtpG of Helicobacter pylori on microarrays. Fluorescence-labeled ATP was competed by novel geldanamycin/reblastatin derivatives with IC50 values in the range of 0.5 nM to 4 μM and Z(*)-factors between 0.60 and 0.96. Our results demonstrate the potential of a target-oriented multiplexed protein microarray to identify novel inhibitors for different members of the HSP90 family. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. Buried Waste Integrated Demonstration lessons learned: 1993 technology demonstrations

    International Nuclear Information System (INIS)

    Kostelnik, K.M.; Owens, K.J.

    1994-01-01

    An integrated technology demonstration was conducted by the Buried Waste Integrated Demonstration (BWID) at the Idaho National Engineering Laboratory Cold Test Pit in the summer of 1993. This program and demonstration was sponsored by the US Department of Energy Office of Technology Development. The demonstration included six technologies representing a synergistic system for the characterization and retrieval of a buried hazardous waste site. The integrated technology demonstration proved very successful and a summary of the technical accomplishments is presented. Upon completion of the integrated technology demonstration, cognizant program personnel participated in a lessons learned exercise. This exercise was conducted at the Simplot Decision Support Center at Idaho State University and lessons learned activity captured additional information relative to the integration of technologies for demonstration purposes. This information will be used by BWID to enhance program planning and strengthen future technology demonstrations

  4. A novel small molecule inhibitor of hepatitis C virus entry.

    Directory of Open Access Journals (Sweden)

    Carl J Baldick

    Full Text Available Small molecule inhibitors of hepatitis C virus (HCV are being developed to complement or replace treatments with pegylated interferons and ribavirin, which have poor response rates and significant side effects. Resistance to these inhibitors emerges rapidly in the clinic, suggesting that successful therapy will involve combination therapy with multiple inhibitors of different targets. The entry process of HCV into hepatocytes represents another series of potential targets for therapeutic intervention, involving viral structural proteins that have not been extensively explored due to experimental limitations. To discover HCV entry inhibitors, we utilized HCV pseudoparticles (HCVpp incorporating E1-E2 envelope proteins from a genotype 1b clinical isolate. Screening of a small molecule library identified a potent HCV-specific triazine inhibitor, EI-1. A series of HCVpp with E1-E2 sequences from various HCV isolates was used to show activity against all genotype 1a and 1b HCVpp tested, with median EC50 values of 0.134 and 0.027 µM, respectively. Time-of-addition experiments demonstrated a block in HCVpp entry, downstream of initial attachment to the cell surface, and prior to or concomitant with bafilomycin inhibition of endosomal acidification. EI-1 was equally active against cell-culture adapted HCV (HCVcc, blocking both cell-free entry and cell-to-cell transmission of virus. HCVcc with high-level resistance to EI-1 was selected by sequential passage in the presence of inhibitor, and resistance was shown to be conferred by changes to residue 719 in the carboxy-terminal transmembrane anchor region of E2, implicating this envelope protein in EI-1 susceptibility. Combinations of EI-1 with interferon, or inhibitors of NS3 or NS5A, resulted in additive to synergistic activity. These results suggest that inhibitors of HCV entry could be added to replication inhibitors and interferons already in development.

  5. Recent advances in botulinum neurotoxin inhibitor development.

    Science.gov (United States)

    Kiris, Erkan; Burnett, James C; Kane, Christopher D; Bavari, Sina

    2014-01-01

    Botulinum neurotoxins (BoNTs) are endopeptidases that target motor neurons and block acetylcholine neurotransmitter release. This action results in the muscle paralysis that defines the disease botulism. To date, there are no FDA-approved therapeutics to treat BoNT-mediated paralysis after intoxication of the motor neuron. Importantly, the rationale for pursuing treatments to counter these toxins is driven by their potential misuse. Current drug discovery efforts have mainly focused on small molecules, peptides, and peptidomimetics that can directly and competitively inhibit BoNT light chain proteolytic activity. Although this is a rational approach, direct inhibition of the Zn(2+) metalloprotease activity has been elusive as demonstrated by the dearth of candidates undergoing clinical evaluation. Therefore, broadening the scope of viable targets beyond that of active site protease inhibitors represents an additional strategy that could move the field closer to the clinic. Here we review the rationale, and discuss the outcomes of earlier approaches and highlight potential new targets for BoNT inhibition. These include BoNT uptake and processing inhibitors, enzymatic inhibitors, and modulators of neuronal processes associated with toxin clearance, neurotransmitter potentiation, and other pathways geared towards neuronal recovery and repair.

  6. Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor.

    Science.gov (United States)

    Honma, Daisuke; Kanno, Osamu; Watanabe, Jun; Kinoshita, Junzo; Hirasawa, Makoto; Nosaka, Emi; Shiroishi, Machiko; Takizawa, Takeshi; Yasumatsu, Isao; Horiuchi, Takao; Nakao, Akira; Suzuki, Keisuke; Yamasaki, Tomonori; Nakajima, Katsuyoshi; Hayakawa, Miho; Yamazaki, Takanori; Yadav, Ajay Singh; Adachi, Nobuaki

    2017-10-01

    Polycomb repressive complex 2 (PRC2) methylates histone H3 lysine 27 and represses gene expression to regulate cell proliferation and differentiation. Enhancer of zeste homolog 2 (EZH2) or its close homolog EZH1 functions as a catalytic subunit of PRC2, so there are two PRC2 complexes containing either EZH2 or EZH1. Tumorigenic functions of EZH2 and its synthetic lethality with some subunits of SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes have been observed. However, little is known about the function of EZH1 in tumorigenesis. Herein, we developed novel, orally bioavailable EZH1/2 dual inhibitors that strongly and selectively inhibited methyltransferase activity of both EZH2 and EZH1. EZH1/2 dual inhibitors suppressed trimethylation of histone H3 lysine 27 in cells more than EZH2 selective inhibitors. They also showed greater antitumor efficacy than EZH2 selective inhibitor in vitro and in vivo against diffuse large B-cell lymphoma cells harboring gain-of-function mutation in EZH2. A hematological cancer panel assay indicated that EZH1/2 dual inhibitor has efficacy against some lymphomas, multiple myeloma, and leukemia with fusion genes such as MLL-AF9, MLL-AF4, and AML1-ETO. A solid cancer panel assay demonstrated that some cancer cell lines are sensitive to EZH1/2 dual inhibitor in vitro and in vivo. No clear correlation was detected between sensitivity to EZH1/2 dual inhibitor and SWI/SNF mutations, with a few exceptions. Severe toxicity was not seen in rats treated with EZH1/2 dual inhibitor for 14 days at drug levels higher than those used in the antitumor study. Our results indicate the possibility of EZH1/2 dual inhibitors for clinical applications. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  7. Integrated Ground Operations Demonstration Units

    Data.gov (United States)

    National Aeronautics and Space Administration — The overall goal of the AES Integrated Ground Operations Demonstration Units (IGODU) project is to demonstrate cost efficient cryogenic operations on a relevant...

  8. Cargo Data Management Demonstration System

    Science.gov (United States)

    1974-02-01

    Delays in receipt and creation of cargo documents are a problem in international trade. The work described demonstrates some of the advantages and capabilities of a computer-based cargo data management system. A demonstration system for data manageme...

  9. Teleoperation for learning by demonstration

    DEFF Research Database (Denmark)

    Kukliński, Kamil; Fischer, Kerstin; Marhenke, Ilka

    2014-01-01

    Learning by demonstration is a useful technique to augment a robot's behavioral inventory, and teleoperation allows lay users to demonstrate novel behaviors intuitively to the robot. In this paper, we compare two modes of teleoperation of an industrial robot, the demonstration by means of a data...... glove and by means of a control object (peg). Experiments with 16 lay users, performing assembly task on the Cranfield benchmark objects, show that the control peg leads to more success, more efficient demonstration and fewer errors....

  10. Helicopter detection and classification demonstrator

    NARCIS (Netherlands)

    Koersel, A.C. van

    2000-01-01

    A technology demonstrator that detects and classifies different helicopter types automatically, was developed at TNO-FEL. The demonstrator is based on a PC, which receives its acoustic input from an all-weather microphone. The demonstrator uses commercial off-the-shelf hardware to digitize the

  11. [ACE inhibitors and the kidney].

    Science.gov (United States)

    Hörl, W H

    1996-01-01

    Treatment with ACE inhibitors results in kidney protection due to reduction of systemic blood pressure, intraglomerular pressure, an antiproliferative effect, reduction of proteinuria and a lipid-lowering effect in proteinuric patients (secondary due to reduction of protein excretion). Elderly patients with diabetes melitus, coronary heart disease or peripheral vascular occlusion are at risk for deterioration of kidney function due to a high frequency of renal artery stenosis in these patients. In patients with renal insufficiency dose reduction of ACE inhibitors is necessary (exception: fosinopril) but more important is the risk for development of hyperkalemia. Patients at risk for renal artery stenosis and patients pretreated with diuretics should receive a low ACE inhibitor dosage initially ("start low - go slow"). For compliance reasons once daily ACE inhibitor dosage is recommended.

  12. Cardiovascular effects of sodium glucose cotransporter 2 inhibitors

    Directory of Open Access Journals (Sweden)

    Santos Cavaiola T

    2018-04-01

    Full Text Available Tricia Santos Cavaiola, Jeremy Pettus Division of Endocrinology and Metabolism, University of California San Diego, San Diego, CA, USA Abstract: As the first cardiovascular (CV outcome trial of a glucose-lowering agent to demonstrate a reduction in the risk of CV events in patients with type 2 diabetes mellitus (T2DM, the EMPAgliflozin Removal of Excess Glucose: Cardiovascular OUTCOME Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME® trial, which investigated the sodium glucose cotransporter 2 (SGLT2 inhibitor empagliflozin, has generated great interest among health care professionals. CV outcomes data for another SGLT2 inhibitor, canagliflozin, have been published recently in the CANagliflozin CardioVascular Assessment Study (CANVAS Program, as have CV data from the retrospective real-world study Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors (CVD-REAL, which compared SGLT2 inhibitors with other classes of glucose-lowering drugs. This review discusses the results of these three studies and, with a focus on EMPA-REG OUTCOME, examines the possible mechanisms by which SGLT2 inhibitors may reduce CV risk in patients with T2DM. Keywords: canagliflozin, cardiovascular outcomes, dapagliflozin, empagliflozin, mechanisms, sodium glucose cotransporter 2 inhibitors

  13. Synthesis and Application of Pyrrolidone-containing Shale Inhibitors

    Science.gov (United States)

    Liu, Yonggui; Hou, Jie; Zhang, Yang; Yan, Jing; Song, Tao; Xu, Yongjun

    2018-03-01

    New generation polyamine inhibitors are amino-terminated polyethers with excellent inhibiting capabilities; they play a key role in borehole stabilization and reservoir protection. However, polyamine inhibitors are limited by their poor thermal stability, which can be attributed to the presence of ether bonds in their molecular structures. We propose a three-step synthesis approach fora novel pyrrolidone-containing polyamine inhibitor (DYNP) by introducing N-vinyl-2-pyrrolidone (NVP) on divinyloxyethane. This polyamine inhibitor exhibits an optimized molecular structure and has enhanced heat resistance. Characterizations by infrared (IR) spectroscopy and evaluation tests demonstrate several advantages of DYNP inhibitors, including excellent inhibiting capability (superior to similar materials such as polyamines), improved heat resistance (reasonable stability at temperatures up to 240°C), and good compatibility with both fresh water and salt water drilling fluids. These can be attributed to the presence of considerable amounts of amino groups in the repeating unit of DYNP molecules. The DYNP inhibitor was applied in over 20 boreholes in tight oil blocks in Daqing Oilfield to relieve hydration of formations with high shale contents. For instance, drilling in the 2033.5m horizontal section of Dragon 2 borehole was smooth, with a borehole diameter expansion ratio below 10%.

  14. Inhibition of matrix metalloproteinase-2 by PARP inhibitors

    International Nuclear Information System (INIS)

    Nicolescu, Adrian C.; Holt, Andrew; Kandasamy, Arulmozhi D.; Pacher, Pal; Schulz, Richard

    2009-01-01

    Matrix metalloproteinase-2 (MMP-2), a ubiquitously expressed zinc-dependent endopeptidase, and poly(ADP-ribosyl) polymerase (PARP), a nuclear enzyme regulating DNA repair, are activated by nitroxidative stress associated with various pathologies. As MMP-2 plays a detrimental role in heart injuries resulting from enhanced nitroxidative stress, where PARP and MMP inhibitors are beneficial, we hypothesized that PARP inhibitors may affect MMP-2 activity. Using substrate degradation assays to determine MMP-2 activity we found that four PARP inhibitors (3-AB, PJ-34, 5-AIQ, and EB-47) inhibited 64 kDa MMP-2 in a concentration-dependent manner. The IC 50 values of PJ-34 and 5-AIQ were in the high micromolar range and comparable to those of known MMP-2 inhibitors doxycycline, minocycline or o-phenanthroline, whereas those for 3-AB and EB-47 were in the millimolar range. Co-incubation of PARP inhibitors with doxycycline showed an additive inhibition of MMP-2 that was significant for 3-AB alone. These data demonstrate that the protective effects of some PARP inhibitors may include inhibition of MMP-2 activity.

  15. Inhibition of matrix metalloproteinase-2 by PARP inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Nicolescu, Adrian C.; Holt, Andrew; Kandasamy, Arulmozhi D. [Departments of Pharmacology and Pediatrics, Cardiovascular Research Centre, University of Alberta, Edmonton, Alta., Canada T6G 2S2 (Canada); Pacher, Pal [National Institutes of Health, NIAAA, Laboratory of Physiologic Studies, Bethesda, MD (United States); Schulz, Richard, E-mail: richard.schulz@ualberta.ca [Departments of Pharmacology and Pediatrics, Cardiovascular Research Centre, University of Alberta, Edmonton, Alta., Canada T6G 2S2 (Canada)

    2009-10-02

    Matrix metalloproteinase-2 (MMP-2), a ubiquitously expressed zinc-dependent endopeptidase, and poly(ADP-ribosyl) polymerase (PARP), a nuclear enzyme regulating DNA repair, are activated by nitroxidative stress associated with various pathologies. As MMP-2 plays a detrimental role in heart injuries resulting from enhanced nitroxidative stress, where PARP and MMP inhibitors are beneficial, we hypothesized that PARP inhibitors may affect MMP-2 activity. Using substrate degradation assays to determine MMP-2 activity we found that four PARP inhibitors (3-AB, PJ-34, 5-AIQ, and EB-47) inhibited 64 kDa MMP-2 in a concentration-dependent manner. The IC{sub 50} values of PJ-34 and 5-AIQ were in the high micromolar range and comparable to those of known MMP-2 inhibitors doxycycline, minocycline or o-phenanthroline, whereas those for 3-AB and EB-47 were in the millimolar range. Co-incubation of PARP inhibitors with doxycycline showed an additive inhibition of MMP-2 that was significant for 3-AB alone. These data demonstrate that the protective effects of some PARP inhibitors may include inhibition of MMP-2 activity.

  16. The cardiovascular safety trials of DPP-4 inhibitors, GLP-1 agonists, and SGLT2 inhibitors.

    Science.gov (United States)

    Secrest, Matthew H; Udell, Jacob A; Filion, Kristian B

    2017-04-01

    In this paper, we review the results of large, double-blind, placebo-controlled randomized trials mandated by the US Food and Drug Administration to examine the cardiovascular safety of newly-approved antihyperglycemic agents in patients with type 2 diabetes. The cardiovascular effects of dipeptidyl peptidase-4 (DPP-4) inhibitors remain controversial: while these drugs did not reduce or increase the risk of primary, pre-specified composite cardiovascular outcomes, one DPP-4 inhibitor (saxagliptin) increased the risk of hospitalization for heart failure in the overall population; another (alogliptin) demonstrated inconsistent effects on heart failure hospitalization across subgroups of patients, and a third (sitagliptin) demonstrated no effect on heart failure. Evidence for cardiovascular benefits of glucagon-like peptide-1 (GLP-1) agonists has been similarly heterogeneous, with liraglutide and semaglutide reducing the risk of composite cardiovascular outcomes, but lixisenatide having no reduction or increase in cardiovascular risk. The effect of GLP-1 agonists on retinopathy remains a potential concern. In the only completed trial to date to assess a sodium-glucose cotransporter-2 (SGLT2) inhibitor, empagliflozin reduced the risk of composite cardiovascular endpoints, predominantly through its impact on cardiovascular mortality and heart failure hospitalization. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Biochemical Importance of Glycosylation of Plasminogen Activator Inhibitor-1

    DEFF Research Database (Denmark)

    Gils, Ann; Pedersen, Katrine Egelund; Skottrup, Peter Durand

    2003-01-01

    The serpin plasminogen activator inhibitor-1 (PAI-1) is a potential target for anti-thrombotic and anti-cancer therapy. PAI-1 has 3 potential sites for N-linked glycosylation. We demonstrate here that PAI-1 expressed recombinantly or naturally by human cell lines display a heterogeneous glycosyla...

  18. Optics Demonstrations Using Cylindrical Lenses

    Science.gov (United States)

    Ivanov, Dragia; Nikolov, Stefan

    2015-01-01

    In this paper we consider the main properties of cylindrical lenses and propose several demonstrational experiments that can be performed with them. Specifically we use simple glasses full of water to demonstrate some basic geometrical optics principles and phenomena. We also present some less standard experiments that can be performed with such…

  19. A Comprehensive General Chemistry Demonstration

    Science.gov (United States)

    Sweeder, Ryan D.; Jeffery, Kathleen A.

    2013-01-01

    This article describes the use of a comprehensive demonstration suitable for a high school or first-year undergraduate introductory chemistry class. The demonstration involves placing a burning candle in a container adjacent to a beaker containing a basic solution with indicator. After adding a lid, the candle will extinguish and the produced…

  20. Offsite demonstrations for MWLID technologies

    International Nuclear Information System (INIS)

    Williams, C.; Gruebel, R.

    1995-01-01

    The goal of the Offsite Demonstration Project for Mixed Waste Landfill Integrated Demonstration (MWLID)-developed environmental site characterization and remediation technologies is to facilitate the transfer, use, and commercialization of these technologies to the public and private sector. The meet this goal, the project identified environmental restoration needs of mixed waste and/or hazardous waste landfill owners (Native American, municipal, DOE, and DoD); documenting potential demonstration sites and the contaminants present at each site; assessing the environmental regulations that would effect demonstration activities; and evaluating site suitability for demonstrating MWLID technologies at the tribal and municipal sites identified. Eighteen landfill sites within a 40.2-km radius of Sandia National Laboratories are listed on the CERCLIS Site/Event Listing for the state of New Mexico. Seventeen are not located within DOE or DoD facilities and are potential offsite MWLID technology demonstration sites. Two of the seventeen CERCLIS sites, one on Native American land and one on municipal land, were evaluated and identified as potential candidates for off-site demonstrations of MWLID-developed technologies. Contaminants potentially present on site include chromium waste, household/commercial hazardous waste, volatile organic compounds, and petroleum products. MWLID characterization technologies applicable to these sites include Magnetometer Towed Array, Cross-borehole Electromagnetic Imaging, SitePlanner trademark/PLUME, Hybrid Directional Drilling, Seamist trademark/Vadose Zone Monitoring, Stripping Analyses, and x-ray Fluorescence Spectroscopy for Heavy Metals

  1. Metal corrosion inhibitors and ecology

    International Nuclear Information System (INIS)

    Krasts, H.; Svarce, J.; Berge, B.

    1999-01-01

    The use of metal corrosion inhibitors in water is one of the cheapest method to protect metals against corrosion. However, the used inhibitors can come to surface water in the course of time and can become as source of environmental pollution. It is important to co-ordinate amount of substances in the elaborated inhibitors not only with demands for metal protection, but also with demands for quality of surface water and drinking water according to normative statements: 3.5 mg/l (as PO 4 ) for hexametaphosphate, tripolyphosphate and phosphonate; 40 mg/l (as SiO 2 for silicate, up to 1 mg/l for CU 2+ ; up to 5 mg/l for Zn 2+ ; up to 1 mg/l for B; up to 0.5 mg/l for Mo 2+ . The examples of the elaborated inhibitors are given. Many organic substances can be used as corrosion inhibitors, but there is shortage of standard methods for their analysis in water in Latvia. Removing of salt's deposits from boilers needs elaboration of a separate normative statement for dispersing waste water which content chloride at high concentration and heavy metals. (authors)

  2. Notional Airspace Operations Demonstration Plan

    Science.gov (United States)

    Trongale, Nicholas A.

    2006-01-01

    The airspace operations demonstration (AOD) is intended to show that the Access 5 Step 1 functional requirements can be met. The demonstration will occur in two phases. The initial on-range phase will be carried out in restricted airspace to demonstrate the cooperative collision avoidance (CCA) functional requirements and to provide risk-reduction for the AOD by allowing the test team to rehearse some elements of the demonstration mission. The CCA system to be used in these flights is based on Automatic Dependent Surveillance-Broadcast (ADS-B) which is a commercially-available system by which airplanes constantly broadcast their current position and altitude to other aircraft and ground resources over a dedicated radio datalink. The final phase will occur in the national airspace (NAS) and will be the formal demonstration of the remainder of the proposed functional requirements. The general objectives of the AOD are as follows: (1) Demonstrate that the UAS can aviate in the NAS (2) Demonstrate that the UAS can navigate in the NAS (3) Demonstrate that the UAS can communicate with the NAS (4) Demonstrate that the UAS can perform selected collision avoidance functions in the NAS (5) Demonstrate that the UAS can evaluate and avoid weather conflicts in the NAS (6) Demonstrate that the UAS can provide adequate command and control in the NAS In addition to the stated objectives, there are a number of goals for the flight demonstration. The demo can be accomplished successfully without achieving these goals, but these goals are to be used as a guideline for preparing for the mission. The goals are: (1) Mission duration of at least 24 hours (2) Loiter over heavy traffic to evaluate the data block issue identified during the Access 5 Airspace Operations Simulations (3) Document the contingency management process and lessons learned (4) Document the coordination process for Ground Control Stations (GCS) handoff (5) Document lessons learned regarding the process of flying in

  3. Demonstration of Cauchy: Understanding Algebraic

    Directory of Open Access Journals (Sweden)

    T.L. Costa

    2012-11-01

    Full Text Available ABSTRACT: In this study we present some considerations about the End of Course Work undergraduate Full Degree in Mathematics / UFMT, drafted in 2011, and by taking title "A story about Cauchy and Euler's theorem on polyhedra" that gave birth to our research project Master of Education, begun in 2012, on the approaches of Euler's theorem on polyhedra in mathematics textbooks. At work in 2011 presented some considerations about the history of Euler's theorem for polyhedra which focus the demonstration presented by Cauchy (1789-1857, who tries to generalize it, relying on assumptions not observable in Euclidean geometry. Therefore, we seek the accessible literature on the history of mathematics; relate some aspects of the demonstration Cauchy with historical events on the development of mathematics in the nineteenth century, which allowed the acceptance of such a demonstration by mathematicians of his time.Keywords: History of Mathematics. Euler's Theorem on Polyhedra. Demonstration of Cauchy.

  4. CT Demonstration of Caput Medusae

    Science.gov (United States)

    Weber, Edward C.; Vilensky, Joel A.

    2009-01-01

    Maximum intensity and volume rendered CT displays of caput medusae are provided to demonstrate both the anatomy and physiology of this portosystemic shunt associated with portal hypertension. (Contains 2 figures.)

  5. Fuel Gas Demonstration Plant Program. Volume I. Demonstration plant

    Energy Technology Data Exchange (ETDEWEB)

    1979-01-01

    The objective of this project is for Babcock Contractors Inc. (BCI) to provide process designs, and gasifier retort design for a fuel gas demonstration plant for Erie Mining Company at Hoyt Lake, Minnesota. The fuel gas produced will be used to supplement natural gas and fuel oil for iron ore pellet induration. The fuel gas demonstration plant will consist of five stirred, two-stage fixed-bed gasifier retorts capable of handling caking and non-caking coals, and provisions for the installation of a sixth retort. The process and unit design has been based on operation with caking coals; however, the retorts have been designed for easy conversion to handle non-caking coals. The demonstration unit has been designed to provide for expansion to a commercial plant (described in Commercial Plant Package) in an economical manner.

  6. Positron emitter labeled enzyme inhibitors

    International Nuclear Information System (INIS)

    Fowler, J.S.; MacGregor, R.R.; Wolf, A.P.; Langstrom, B.

    1990-01-01

    This invention involves a new strategy for imagining and mapping enzyme activity in the living human and animal body using positron emitter-labeled suicide enzyme inactivators or inhibitors which become covalently bound to the enzyme as a result of enzymatic catalysis. Two such suicide inactivators for monoamine oxidase have been labeled with carbon-11 and used to map the enzyme subtypes in the living human and animal body using PET. By using positron emission tomography to image the distribution of radioactivity produced by the body penetrating radiation emitted by carbon-11, a map of functionally active monoamine oxidase activity is obtained. Clorgyline and L-deprenyl are suicide enzyme inhibitors and irreversibly inhibit monoamine oxidase. When these inhibitors are labeled with carbon-11 they provide selective probes for monoamine oxidase localization and reactivity in vivo using positron emission tomography

  7. ROCK inhibitors in ocular disease

    Directory of Open Access Journals (Sweden)

    Eva Halasz

    2016-12-01

    Full Text Available Rho kinases (ROCKs have a crucial role in actin-cytoskeletal reorganization and thus are involved in broad aspects of cell motility, from smooth muscle contraction to neurite outgrowth. The first marketed ROCK inhibitor, called fasudil, has been used safely for treatment of cerebral vasospasm since 1995 in Japan. During the succeeding decades ROCK inhibitors have been applied in many pathological conditions from central nervous system disorders to cardiovascular disease as potential therapeutic agents or experimental tools to help understand the underlying (pathomechanisms. In 2014, a fasudil derivate named ripasudil was accepted for clinical use in glaucoma and ocular hypertension. Since ROCK kinases are widely expressed in ocular tissues, they have been implicated in the pathology of many ocular conditions such as corneal dysfunction, glaucoma, cataract, diabetic retinopathy, age-related macular degeneration, and retinal detachment. This paper aims to provide an overview of the most recent status/application of ROCK inhibitors in the field of eye disease.

  8. Imidazopyridine derivatives as potent and selective Polo-like kinase (PLK) inhibitors.

    Science.gov (United States)

    Sato, Yoshiyuki; Onozaki, Yu; Sugimoto, Tetsuya; Kurihara, Hideki; Kamijo, Kaori; Kadowaki, Chie; Tsujino, Toshiaki; Watanabe, Akiko; Otsuki, Sachie; Mitsuya, Morihiro; Iida, Masato; Haze, Kyosuke; Machida, Takumitsu; Nakatsuru, Yoko; Komatani, Hideya; Kotani, Hidehito; Iwasawa, Yoshikazu

    2009-08-15

    A novel class of imidazopyridine derivatives was designed as PLK1 inhibitors. Extensive SAR studies supported by molecular modeling afforded a highly potent and selective compound 36. Compound 36 demonstrated good antitumor efficacy in xenograft nude rat model.

  9. Characterization of inhibitor(s) of β-glucuronidase enzyme activity in GUS-transgenic wheat

    KAUST Repository

    Ramadan, Ahmed M Ali; Eissa, Hala F.; El-Domyati, Fotouh M.; Saleh, Osama Mesilhy; Ibrahim, Nasser E.; Salama, M. I.; Mahfouz, Magdy M.; Bahieldin, Ahmed M.

    2011-01-01

    The uidA gene, encoding for β-glucuronidase (GUS), is the most frequently used reporter gene in plants. As a reporter enzyme, GUS can be assayed both qualitatively and quantitatively. In wheat, there are numerous reports of failure in detecting GUS enzyme activity in tissues of transgenic plants, while other reports have suggested presence of β-glucuronidase inhibitor(s) in wheat tissues. In the present study, we show that the β-glucuronidase enzyme activity is not only tissue-specific but also genotype-dependent. Our data demonstrate that the glucuronic acid could be the candidate inhibitor for β-glucuronidase enzyme activity in wheat leaves and roots. It should be noted that the assays to detect β-glucuronidase enzyme activity in wheat should be interpreted carefully. Based on the data of our present study, we recommend studying the chemical pathways, the unintended effects and the possible loss-of-function of any candidate transgene prior to transformation experiments. © 2011 Springer Science+Business Media B.V.

  10. Characterization of inhibitor(s) of β-glucuronidase enzyme activity in GUS-transgenic wheat

    KAUST Repository

    Ramadan, Ahmed M Ali

    2011-06-26

    The uidA gene, encoding for β-glucuronidase (GUS), is the most frequently used reporter gene in plants. As a reporter enzyme, GUS can be assayed both qualitatively and quantitatively. In wheat, there are numerous reports of failure in detecting GUS enzyme activity in tissues of transgenic plants, while other reports have suggested presence of β-glucuronidase inhibitor(s) in wheat tissues. In the present study, we show that the β-glucuronidase enzyme activity is not only tissue-specific but also genotype-dependent. Our data demonstrate that the glucuronic acid could be the candidate inhibitor for β-glucuronidase enzyme activity in wheat leaves and roots. It should be noted that the assays to detect β-glucuronidase enzyme activity in wheat should be interpreted carefully. Based on the data of our present study, we recommend studying the chemical pathways, the unintended effects and the possible loss-of-function of any candidate transgene prior to transformation experiments. © 2011 Springer Science+Business Media B.V.

  11. A bioavailable cathepsin S nitrile inhibitor abrogates tumor development.

    Science.gov (United States)

    Wilkinson, Richard D A; Young, Andrew; Burden, Roberta E; Williams, Rich; Scott, Christopher J

    2016-04-21

    Cathepsin S has been implicated in a variety of malignancies with genetic ablation studies demonstrating a key role in tumor invasion and neo-angiogenesis. Thus, the application of cathepsin S inhibitors may have clinical utility in the treatment of cancer. In this investigation, we applied a cell-permeable dipeptidyl nitrile inhibitor of cathepsin S, originally developed to target cathepsin S in inflammatory diseases, in both in vitro and in vivo tumor models. Validation of cathepsin S selectivity was carried out by assaying fluorogenic substrate turnover using recombinant cathepsin protease. Complete kinetic analysis was carried out and true K i values calculated. Abrogation of tumour invasion using murine MC38 and human MCF7 cell lines were carried out in vitro using a transwell migration assay. Effect on endothelial tube formation was evaluated using primary HUVEC cells. The effect of inhibitor in vivo on MC38 and MCF7 tumor progression was evaluated using cells propagated in C57BL/6 and BALB/c mice respectively. Subsequent immunohistochemical staining of proliferation (Ki67) and apoptosis (TUNEL) was carried out on MCF7 tumors. We confirmed that this inhibitor was able to selectively target cathepsin S over family members K, V, L and B. The inhibitor also significantly reduced MC38 and MCF7 cell invasion and furthermore, significantly reduced HUVEC endothelial tubule formation in vitro. In vivo analysis revealed that the compound could significantly reduce tumor volume in murine MC38 syngeneic and MCF7 xenograft models. Immunohistochemical analysis of MCF7 tumors revealed cathepsin S inhibitor treatment significantly reduced proliferation and increased apoptosis. In summary, these results highlight the characterisation of this nitrile cathepsin S inhibitor using in vitro and in vivo tumor models, presenting a compound which may be used to further dissect the role of cathepsin S in cancer progression and may hold therapeutic potential.

  12. Buried Waste Integrated Demonstration Plan

    International Nuclear Information System (INIS)

    Kostelnik, K.M.

    1991-12-01

    This document presents the plan of activities for the Buried Waste Integrated Demonstration (BWID) program which supports the environmental restoration (ER) objectives of the Department of Energy (DOE) Complex. Discussed in this plan are the objectives, organization, roles and responsibilities, and the process for implementing and managing BWID. BWID is hosted at the Idaho National Engineering Laboratory (INEL), but involves participants from throughout the DOE Complex, private industry, universities, and the international community. These participants will support, demonstrate, and evaluate a suite of advanced technologies representing a comprehensive remediation system for the effective and efficient remediation of buried waste. The processes for identifying technological needs, screening candidate technologies for applicability and maturity, selecting appropriate technologies for demonstration, field demonstrating, evaluation of results and transferring technologies to environmental restoration programs are also presented. This document further describes the elements of project planning and control that apply to BWID. It addresses the management processes, operating procedures, programmatic and technical objectives, and schedules. Key functions in support of each demonstration such as regulatory coordination, safety analyses, risk evaluations, facility requirements, and data management are presented

  13. Auditory demonstrations simulating Mayan architecture

    Science.gov (United States)

    Lubman, David

    2005-09-01

    Fascination with the ancient temples and ball court at Chichen Itza provide rich opportunities for science education. Children of all ages are delighted to learn that the sound of handclaps scattered from long temple staircases are transformed into bird chirps. Their engagement in such seemingly magical phenomena provides magic moments for teaching acoustical principals, including the picket-fence effect (PFE). PFE transforms impulsive sounds scattered from spatially periodic structures into tonal sounds. PFE is demonstrated with a computer possessing a sound card and a simple sound editing program. The inverse relationship between tonal frequency and the time interval between periodic impulses is easily demonstrated. The number of impulses needed to produce an audible tone is easily demonstrated and compared with the number of steps on the staircase. Transformation of audible tones into downward-gliding chirps is simulated by monotonically increasing the time between impulses. The Great Ball Court also provides opportunities for acoustical demonstration. Observers clapping their hands while standing between the long, tall, and parallel walls of the playing field marvel at the profound flutter echo heard for about 1.5 s. The flutter echo sonogram demonstrates the speed of sound and frequency-selective atmospheric attenuation.

  14. Demonstration of reliability centered maintenance

    International Nuclear Information System (INIS)

    Schwan, C.A.; Morgan, T.A.

    1991-04-01

    Reliability centered maintenance (RCM) is an approach to preventive maintenance planning and evaluation that has been used successfully by other industries, most notably the airlines and military. Now EPRI is demonstrating RCM in the commercial nuclear power industry. Just completed are large-scale, two-year demonstrations at Rochester Gas ampersand Electric (Ginna Nuclear Power Station) and Southern California Edison (San Onofre Nuclear Generating Station). Both demonstrations were begun in the spring of 1988. At each plant, RCM was performed on 12 to 21 major systems. Both demonstrations determined that RCM is an appropriate means to optimize a PM program and improve nuclear plant preventive maintenance on a large scale. Such favorable results had been suggested by three earlier EPRI pilot studies at Florida Power ampersand Light, Duke Power, and Southern California Edison. EPRI selected the Ginna and San Onofre sites because, together, they represent a broad range of utility and plant size, plant organization, plant age, and histories of availability and reliability. Significant steps in each demonstration included: selecting and prioritizing plant systems for RCM evaluation; performing the RCM evaluation steps on selected systems; evaluating the RCM recommendations by a multi-disciplinary task force; implementing the RCM recommendations; establishing a system to track and verify the RCM benefits; and establishing procedures to update the RCM bases and recommendations with time (a living program). 7 refs., 1 tab

  15. Demonstration of blind quantum computing.

    Science.gov (United States)

    Barz, Stefanie; Kashefi, Elham; Broadbent, Anne; Fitzsimons, Joseph F; Zeilinger, Anton; Walther, Philip

    2012-01-20

    Quantum computers, besides offering substantial computational speedups, are also expected to preserve the privacy of a computation. We present an experimental demonstration of blind quantum computing in which the input, computation, and output all remain unknown to the computer. We exploit the conceptual framework of measurement-based quantum computation that enables a client to delegate a computation to a quantum server. Various blind delegated computations, including one- and two-qubit gates and the Deutsch and Grover quantum algorithms, are demonstrated. The client only needs to be able to prepare and transmit individual photonic qubits. Our demonstration is crucial for unconditionally secure quantum cloud computing and might become a key ingredient for real-life applications, especially when considering the challenges of making powerful quantum computers widely available.

  16. Savannah River Plant incinerator demonstration

    International Nuclear Information System (INIS)

    Lewandowski, K.E.

    1983-01-01

    A full-scale incineration process was demonstrated at the Savannah River Laboratory (SRL) using nonradioactive waste. From October 1981 through September 1982, 15,700 kilograms of solid waste and 5.7 m 3 of solvent were incinerated. Emissions of off-gas components (NO/sub x/, SO 2 , CO, and particulates) were well below South Carolina state standards. Volume reductions of 20:1 for solid waste and 7:1 for Purex solvent/lime slurry were achieved. The process has been relocated and upgraded by the Savannah River Plant to accept low-level beta-gamma combustibles. During a two-year demonstration, the facility will incinerate slightly radioactive ( 3 ) solvent and suspect level (< 1 mR/h at 0.0254 meter) solid wastes. This demonstration will begin in early 1984

  17. SGLT2 Inhibitors as a Therapeutic Option for Diabetic Nephropathy

    Directory of Open Access Journals (Sweden)

    Daiji Kawanami

    2017-05-01

    Full Text Available Diabetic nephropathy (DN is a major cause of end-stage renal disease (ESRD worldwide. Glycemic and blood pressure (BP control are important but not sufficient to attenuate the incidence and progression of DN. Sodium–glucose cotransporter (SGLT 2 inhibitors are a new class of glucose-lowering agent suggested to exert renoprotective effects in glucose lowering-dependent and independent fashions. Experimental studies have shown that SGLT2 inhibitors attenuate DN in animal models of both type 1 diabetes (T1D and type 2 diabetes (T2D, indicating a potential renoprotective effect beyond glucose reduction. Renoprotection by SGLT2 inhibitors has been demonstrated in T2D patients with a high cardiovascular risk in randomized controlled trials (RCTs. These favorable effects of SGLT2 inhibitors are explained by several potential mechanisms, including the attenuation of glomerular hyperfiltration, inflammation and oxidative stress. In this review article, we discuss the renoprotective effects of SGLT2 inhibitors by integrating experimental findings with the available clinical data.

  18. Cardiovascular effects of sodium glucose cotransporter 2 inhibitors

    Science.gov (United States)

    Cavaiola, Tricia Santos; Pettus, Jeremy

    2018-01-01

    As the first cardiovascular (CV) outcome trial of a glucose-lowering agent to demonstrate a reduction in the risk of CV events in patients with type 2 diabetes mellitus (T2DM), the EMPAgliflozin Removal of Excess Glucose: Cardiovascular OUTCOME Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME®) trial, which investigated the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin, has generated great interest among health care professionals. CV outcomes data for another SGLT2 inhibitor, canagliflozin, have been published recently in the CANagliflozin CardioVascular Assessment Study (CANVAS) Program, as have CV data from the retrospective real-world study Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors (CVD-REAL), which compared SGLT2 inhibitors with other classes of glucose-lowering drugs. This review discusses the results of these three studies and, with a focus on EMPA-REG OUTCOME, examines the possible mechanisms by which SGLT2 inhibitors may reduce CV risk in patients with T2DM. PMID:29695924

  19. SGLT2 Inhibitors as a Therapeutic Option for Diabetic Nephropathy.

    Science.gov (United States)

    Kawanami, Daiji; Matoba, Keiichiro; Takeda, Yusuke; Nagai, Yosuke; Akamine, Tomoyo; Yokota, Tamotsu; Sango, Kazunori; Utsunomiya, Kazunori

    2017-05-18

    Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD) worldwide. Glycemic and blood pressure (BP) control are important but not sufficient to attenuate the incidence and progression of DN. Sodium-glucose cotransporter (SGLT) 2 inhibitors are a new class of glucose-lowering agent suggested to exert renoprotective effects in glucose lowering-dependent and independent fashions. Experimental studies have shown that SGLT2 inhibitors attenuate DN in animal models of both type 1 diabetes (T1D) and type 2 diabetes (T2D), indicating a potential renoprotective effect beyond glucose reduction. Renoprotection by SGLT2 inhibitors has been demonstrated in T2D patients with a high cardiovascular risk in randomized controlled trials (RCTs). These favorable effects of SGLT2 inhibitors are explained by several potential mechanisms, including the attenuation of glomerular hyperfiltration, inflammation and oxidative stress. In this review article, we discuss the renoprotective effects of SGLT2 inhibitors by integrating experimental findings with the available clinical data.

  20. Structural Principles in the Development of Cyclic Peptidic Enzyme Inhibitors

    Science.gov (United States)

    Xu, Peng; Andreasen, Peter A.; Huang, Mingdong

    2017-01-01

    This review summarizes our studies in the development of small cyclic peptides for specifically modulating enzyme activity. Serine proteases share highly similar active sites but perform diverse physiological and pathological functions. From a phage-display peptide library, we isolated two mono-cyclic peptides, upain-1 (CSWRGLENHRMC) and mupain-1 (CPAYSRYLDC), which inhibit the activity of human and murine urokinase-type plasminogen activators (huPA and muPA) with Ki values in the micromolar or sub-micromolar range, respectively. The following affinity maturations significantly enhanced the potencies of the two peptides, 10-fold and >250-fold for upain-1 and mupain-1, respectively. The most potent muPA inhibitor has a potency (Ki = 2 nM) and specificity comparable to mono-clonal antibodies. Furthermore, we also found an unusual feature of mupain-1 that its inhibitory potency can be enhanced by increasing the flexibility, which challenges the traditional viewpoint that higher rigidity leading to higher affinity. Moreover, by changing a few key residues, we converted mupain-1 from a uPA inhibitor to inhibitors of other serine proteases, including plasma kallikrein (PK) and coagulation factor XIa (fXIa). PK and fXIa inhibitors showed Ki values in the low nanomolar range and high specificity. Our studies demonstrate the versatility of small cyclic peptides to engineer inhibitory potency against serine proteases and to provide a new strategy for generating peptide inhibitors of serine proteases. PMID:29104489

  1. HTCC: Broad Range Inhibitor of Coronavirus Entry.

    Directory of Open Access Journals (Sweden)

    Aleksandra Milewska

    Full Text Available To date, six human coronaviruses have been known, all of which are associated with respiratory infections in humans. With the exception of the highly pathogenic SARS and MERS coronaviruses, human coronaviruses (HCoV-NL63, HCoV-OC43, HCoV-229E, and HCoV-HKU1 circulate worldwide and typically cause the common cold. In most cases, infection with these viruses does not lead to severe disease, although acute infections in infants, the elderly, and immunocompromised patients may progress to severe disease requiring hospitalization. Importantly, no drugs against human coronaviruses exist, and only supportive therapy is available. Previously, we proposed the cationically modified chitosan, N-(2-hydroxypropyl-3-trimethylammonium chitosan chloride (HTCC, and its hydrophobically-modified derivative (HM-HTCC as potent inhibitors of the coronavirus HCoV-NL63. Here, we show that HTCC inhibits interaction of a virus with its receptor and thus blocks the entry. Further, we demonstrate that HTCC polymers with different degrees of substitution act as effective inhibitors of all low-pathogenic human coronaviruses.

  2. Lonafarnib is a potential inhibitor for neovascularization.

    Directory of Open Access Journals (Sweden)

    Linlin Sun

    Full Text Available Atherosclerosis is a common cardiovascular disease that involves the build-up of plaque on the inner walls of the arteries. Intraplaque neovacularization has been shown to be essential in the pathogenesis of atherosclerosis. Previous studies showed that small-molecule compounds targeting farnesyl transferase have the ability to prevent atherosclerosis in apolipoprotein E-deficient mice, but the underlying mechanism remains to be elucidated. In this study, we found that lonafarnib, a specific inhibitor of farnesyl transferase, elicits inhibitory effect on vascular endothelial capillary assembly in vitro in a dose-dependent manner. In addition, we showed that lonafarnib treatment led to a dose-dependent decrease in scratch wound closure in vitro, whereas it had little effect on endothelial cell proliferation. These data indicate that lonafarnib inhibits neovascularization via directly targeting endothelial cells and disturbing their motility. Moreover, we demonstrated that pharmacological inhibition of farnesyl transferase by lonafarnib significantly impaired centrosome reorientation toward the leading edge of endothelial cells. Mechanistically, we found that the catalytic β subunit of farnesyl transferase associated with a cytoskeletal protein important for the establishment and maintenance of cell polarity. Additionally, we showed that lonafarnib remarkably inhibited the expression of the cytoskeletal protein and interrupted its interaction with farnesyl transferase. Our findings thus offer novel mechanistic insight into the protective effect of farnesyl transferase inhibitors on atherosclerosis and provide encouraging evidence for the potential use of this group of agents in inhibiting plaque neovascularization.

  3. Biological abatement of cellulase inhibitors.

    Science.gov (United States)

    Cao, Guangli; Ximenes, Eduardo; Nichols, Nancy N; Zhang, Leyu; Ladisch, Michael

    2013-10-01

    Removal of enzyme inhibitors released during lignocellulose pretreatment is essential for economically feasible biofuel production. We tested bio-abatement to mitigate enzyme inhibitor effects observed in corn stover liquors after pretreatment with either dilute acid or liquid hot water at 10% (w/v) solids. Bio-abatement of liquors was followed by enzymatic hydrolysis of cellulose. To distinguish between inhibitor effects on enzymes and recalcitrance of the substrate, pretreated corn stover solids were removed and replaced with 1% (w/v) Solka Floc. Cellulose conversion in the presence of bio-abated liquors from dilute acid pretreatment was 8.6% (0.1x enzyme) and 16% (1x enzyme) higher than control (non-abated) samples. In the presence of bio-abated liquor from liquid hot water pretreated corn stover, 10% (0.1x enzyme) and 13% (1x enzyme) higher cellulose conversion was obtained compared to control. Bio-abatement yielded improved enzyme hydrolysis in the same range as that obtained using a chemical (overliming) method for mitigating inhibitors. Copyright © 2013 Elsevier Ltd. All rights reserved.

  4. Phosphodiesterase inhibitors in clinical urology.

    Science.gov (United States)

    Ückert, Stefan; Kuczyk, Markus A; Oelke, Matthias

    2013-05-01

    To date, benign diseases of the male and female lower urinary and genital tract, such as erectile dysfunction, bladder overactivity, lower urinary tract symptomatology secondary to benign prostatic hyperplasia and symptoms of female sexual dysfunction (including arousal and orgasmic disorders), can be therapeutically approached by influencing the function of the smooth musculature of the respective tissues. The use of isoenzyme-selective phosphodiesterase (PDE) inhibitors is considered a great opportunity to treat various diseases of the human urogenital tract. PDE inhibitors, in particular the PDE5 (cyclic GMP PDE) inhibitors avanafil, lodenafil, sildenafil, tadalafil, udenafil and vardenafil, are regarded as efficacious, having a fast onset of drug action and an improved effect-to-adverse event ratio, combining a high response rate with the advantage of an on-demand intake. The purpose of this review is to summarize recent as well as potential future indications, namely, erectile dysfunction, Peyronie's disease, overactive bladder, urinary stone disease, lower urinary tract symptomatology secondary to benign prostatic hyperplasia and premature ejaculation, for the use of PDE inhibitors in clinical urology.

  5. Inhibitors of mTOR

    NARCIS (Netherlands)

    Klümpen, Heinz-Josef; Beijnen, Jos H.; Gurney, Howard; Schellens, Jan H. M.

    2010-01-01

    Inhibitors of mammalian target of rapamycin (mTOR) have been approved for the treatment of renal cell carcinoma and appear to have a role in the treatment of other malignancies. The primary objective of this drug review is to provide pharmacokinetic and dynamic properties of the commonly used drugs

  6. Retroviral proteinases and their inhibitors

    Czech Academy of Sciences Publication Activity Database

    Sedláček, Juraj

    2000-01-01

    Roč. 3, 3,4 (2000), s. 23-24 [ Proteolytic enzymes and their inhibitors in physiology and pathogenesis. 14.09.2000, Plzen] Institutional research plan: CEZ:AV0Z5052915 Subject RIV: EB - Genetics ; Molecular Biology

  7. Monoamine depletion by reuptake inhibitors

    Directory of Open Access Journals (Sweden)

    Hinz M

    2011-10-01

    Full Text Available Marty Hinz1, Alvin Stein2, Thomas Uncini31Clinical Research, NeuroResearch Clinics Inc, Cape Coral, FL; 2Stein Orthopedic Associates, Plantation, FL; 3DBS Labs Inc, Duluth, MN, USABackground: Disagreement exists regarding the etiology of cessation of the observed clinical results with administration of reuptake inhibitors. Traditionally, when drug effects wane, it is known as tachyphylaxis. With reuptake inhibitors, the placebo effect is significantly greater than the drug effect in the treatment of depression and attention deficit hyperactivity disorder, leading some to assert that waning of drug effects is placebo relapse, not tachyphylaxis.Methods: Two groups were retrospectively evaluated. Group 1 was composed of subjects with depression and Group 2 was composed of bariatric subjects treated with reuptake inhibitors for appetite suppression.Results: In Group 1, 200 subjects with depression were treated with citalopram 20 mg per day. A total of 46.5% (n = 93 achieved relief of symptoms (Hamilton-D rating score ≤ 7, of whom 37 (39.8% of whom experienced recurrence of depression symptoms, at which point an amino acid precursor formula was started. Within 1–5 days, 97.3% (n = 36 experienced relief of depression symptoms. In Group 2, 220 subjects were treated with phentermine 30 mg in the morning and citalopram 20 mg at 4 pm. In this group, 90.0% (n = 198 achieved adequate appetite suppression. The appetite suppression ceased in all 198 subjects within 4–48 days. Administration of an amino acid precursor formula restored appetite suppression in 98.5% (n = 195 of subjects within 1–5 days.Conclusion: Reuptake inhibitors do not increase the total number of monoamine molecules in the central nervous system. Their mechanism of action facilitates redistribution of monoamines from one place to another. In the process, conditions are induced that facilitate depletion of monoamines. The "reuptake inhibitor monoamine depletion theory" of this paper

  8. Demonstrating Fermat's Principle in Optics

    Science.gov (United States)

    Paleiov, Orr; Pupko, Ofir; Lipson, S. G.

    2011-01-01

    We demonstrate Fermat's principle in optics by a simple experiment using reflection from an arbitrarily shaped one-dimensional reflector. We investigated a range of possible light paths from a lamp to a fixed slit by reflection in a curved reflector and showed by direct measurement that the paths along which light is concentrated have either…

  9. Some Field Demonstrations in India

    Indian Academy of Sciences (India)

    First page Back Continue Last page Graphics. Some Field Demonstrations in India. 2x150kVAR STATCOM at M/s Hindusthan Latex, Trivandrum. 250kVAR, 800V dc, 2-level STATCOM (Installed at Peekey Steels, Calicut). 250kVAR,800V dc, UPQC at CDAC, Trivandrum. REFERENCE: Website www. cdac.gov.in.

  10. Flexible-Rotor Balancing Demonstration

    Science.gov (United States)

    Giordano, J.; Zorzi, E.

    1986-01-01

    Report describes method for balancing high-speed rotors at relatively low speeds and discusses demonstration of method on laboratory test rig. Method ensures rotor brought up to speeds well over 20,000 r/min smoothly, without excessive vibration amplitude at critical speeds or at operating speed.

  11. A Demonstration and a Souvenir

    Science.gov (United States)

    Lentz, Randy

    1978-01-01

    Describes an activity using interchangeable, preset tool holders to provide a demonstration for parents or students attending a school's open house session that produces a small souvenir (an aluminum mini-chalice) for them. A procedure sheet for the school's individual lathe and specification diagrams for making the cup are provided. (TA)

  12. NDT performance demonstration in Spain

    International Nuclear Information System (INIS)

    Bollini, G.J.

    1994-01-01

    The experience obtained from the in-service inspection of reactor pressure vessels (RPV) of Spanish nuclear power plants and the participation in several international programs, such as PISC, has shown the need for a performance demonstration, not only for the ultrasonic inspection techniques of RPV, but also for other ISI non-destructive techniques as in the case of eddy current inspection of steam generator tubing. Section XI of the ASME Code, which is applied in Spain for ISI, has incorporated recently the Appendix VIII for performance demonstration of ultrasonic inspection techniques. As a direct consequence of this, a Spanish project for performance demonstration of ultrasonic inspection techniques has been launched recently, which includes the manufacturing of full-scale mock-ups of nozzle to vessel welds, reactor vessel welds, wrought austenitic piping welds and ferritic piping welds of PWR and BWR nuclear power plants from different suppliers. This considerable technical effort will let the different Spanish organizations which are part of the project to participate and colaborate with similar international projects and in particular with a European initiative for performance demonstration. (Author)

  13. SunJammer Technology Demonstration

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Sunjammer Project is a NASA funded contract to L?Garde Inc. to fly a solar sail demonstration for a period of approximately one year. L?Garde is also partnered...

  14. The buried waste integrated demonstration

    International Nuclear Information System (INIS)

    Kostelnik, K.M.

    1991-01-01

    There are numerous locations throughout the Department of Energy (DOE) Complex where wastes have been buried in the ground or stored for future disposal. Much of this buried waste is contaminated with hazardous and radioactive materials. An extensive research program has been initiated at the Idaho National Engineering Laboratory (INEL) to develop and demonstrate advanced remediation techniques for DOE Complex buried waste. The purpose of the Buried Waste Integrated Demonstration (BWID), is to develop a scientifically sound and deployable remediation system consisting of advanced technologies which address the buried waste characteristics of the DOE Complex. This comprehensive remediation system win include technologies for the entire remediation cycle (cradle-to-grave). Technologies developed and demonstrated within the BWID will be transferred to the DOE Complex sites with buried waste, to private industry, and to universities. Multidirectional technology transfer is encouraged by the BWID. Identification and evaluation of plausible technological solutions are an ongoing activity of the BWID. A number of technologies are currently under development throughout the DOE Complex, private industry, and universities. Technology integration mechanisms have been established by BWID to facilitate collaborative research and demonstration of applicable remedial technologies for buried waste. Successful completion of the BWID will result in the development of a proven and deployable system at the INEL and other DOE Complex buried waste sites, thereby supporting the DOE Complex's environmental restoration objectives

  15. E/Z MAS demonstration

    International Nuclear Information System (INIS)

    Boor, M.G.; Hurford, J.M.; Landry, R.P.; Martinez, B.J.; Solem, A.M.; Whiteson, R.; Zardecki, A.

    1998-01-01

    Los Alamos National Laboratory has developed E/Z MAS, a new generation nuclear material accountability application based on the latest technology and designed for facilities required to track nuclear materials with a simple-to-use interface. E/Z MAS is based on years of experience spent developing nuclear material accounting systems. E/Z MAS uses a modern relational database with a web server and enables users on a classified local area network to interact with the database with web browsers. The E/Z MAS Demonstration poster session demonstrates the E/Z MAS functions required by an operational nuclear facility to track material as it enters and leaves a facility and to account for the material as it moves through a process. The generation of internal facility reports and external reports for the Russian Federal system will be demonstrated. Bar-code readers will be used to demonstrate the ability of EZ MAS to automate certain functions, such as physical inventories at facilities

  16. US GCFR demonstration plant design

    International Nuclear Information System (INIS)

    Hunt, P.S.; Snyder, H.J.

    1980-05-01

    A general description of the US GCFR demonstration plant conceptual design is given to provide a context for more detailed papers to follow. The parameters selected for use in the design are presented and the basis for parameter selection is discussed. Nuclear steam supply system (NSSS) and balance of plant (BOP) component arrangements and systems are briefly discussed

  17. Satellite Demonstration: The Videodisc Technology.

    Science.gov (United States)

    Propp, George; And Others

    1979-01-01

    Originally part of a symposium on educational media for the deaf, the paper describes a satellite demonstration of video disc materials. It is explained that a panel of deaf individuals in Washington, D.C. and another in Nebraska came into direct two-way communication for the first time, and video disc materials were broadcast via the satellite.…

  18. DOE's annealing prototype demonstration projects

    International Nuclear Information System (INIS)

    Warren, J.; Nakos, J.; Rochau, G.

    1997-01-01

    One of the challenges U.S. utilities face in addressing technical issues associated with the aging of nuclear power plants is the long-term effect of plant operation on reactor pressure vessels (RPVs). As a nuclear plant operates, its RPV is exposed to neutrons. For certain plants, this neutron exposure can cause embrittlement of some of the RPV welds which can shorten the useful life of the RPV. This RPV embrittlement issue has the potential to affect the continued operation of a number of operating U.S. pressurized water reactor (PWR) plants. However, RPV material properties affected by long-term irradiation are recoverable through a thermal annealing treatment of the RPV. Although a dozen Russian-designed RPVs and several U.S. military vessels have been successfully annealed, U.S. utilities have stated that a successful annealing demonstration of a U.S. RPV is a prerequisite for annealing a licensed U.S. nuclear power plant. In May 1995, the Department of Energy's Sandia National Laboratories awarded two cost-shared contracts to evaluate the feasibility of annealing U.S. licensed plants by conducting an anneal of an installed RPV using two different heating technologies. The contracts were awarded to the American Society of Mechanical Engineers (ASME) Center for Research and Technology Development (CRTD) and MPR Associates (MPR). The ASME team completed its annealing prototype demonstration in July 1996, using an indirect gas furnace at the uncompleted Public Service of Indiana's Marble Hill nuclear power plant. The MPR team's annealing prototype demonstration was scheduled to be completed in early 1997, using a direct heat electrical furnace at the uncompleted Consumers Power Company's nuclear power plant at Midland, Michigan. This paper describes the Department's annealing prototype demonstration goals and objectives; the tasks, deliverables, and results to date for each annealing prototype demonstration; and the remaining annealing technology challenges

  19. Irvine Smart Grid Demonstration, a Regional Smart Grid Demonstration Project

    Energy Technology Data Exchange (ETDEWEB)

    Yinger, Robert [Southern California Edison Company, Rosemead, CA (United States); Irwin, Mark [Southern California Edison Company, Rosemead, CA (United States)

    2015-12-29

    ISGD was a comprehensive demonstration that spanned the electricity delivery system and extended into customer homes. The project used phasor measurement technology to enable substation-level situational awareness, and demonstrated SCE’s next-generation substation automation system. It extended beyond the substation to evaluate the latest generation of distribution automation technologies, including looped 12-kV distribution circuit topology using URCIs. The project team used DVVC capabilities to demonstrate CVR. In customer homes, the project evaluated HAN devices such as smart appliances, programmable communicating thermostats, and home energy management components. The homes were also equipped with energy storage, solar PV systems, and a number of energy efficiency measures (EEMs). The team used one block of homes to evaluate strategies and technologies for achieving ZNE. A home achieves ZNE when it produces at least as much renewable energy as the amount of energy it consumes annually. The project also assessed the impact of device-specific demand response (DR), as well as load management capabilities involving energy storage devices and plug-in electric vehicle charging equipment. In addition, the ISGD project sought to better understand the impact of ZNE homes on the electric grid. ISGD’s SENet enabled end-to-end interoperability between multiple vendors’ systems and devices, while also providing a level of cybersecurity that is essential to smart grid development and adoption across the nation. The ISGD project includes a series of sub-projects grouped into four logical technology domains: Smart Energy Customer Solutions, Next-Generation Distribution System, Interoperability and Cybersecurity, and Workforce of the Future. Section 2.3 provides a more detailed overview of these domains.

  20. Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

    Science.gov (United States)

    Serotonin and norepinephrine reuptake inhibitors (SNRIs) Antidepressant SNRIs help relieve depression symptoms, such as irritability and sadness, ... effects they may cause. By Mayo Clinic Staff Serotonin and norepinephrine reuptake inhibitors (SNRIs) are a class ...

  1. Contemporary protease inhibitors and cardiovascular risk

    DEFF Research Database (Denmark)

    Lundgren, Jens; Mocroft, Amanda; Ryom, Lene

    2018-01-01

    PURPOSE OF REVIEW: To review the evidence linking use of HIV protease inhibitors with excess risk of cardiovascular disease (CVD) in HIV+ populations. RECENT FINDINGS: For the two contemporary most frequently used protease inhibitors, darunavir and atazanavir [both pharmacologically boosted...

  2. Incineration demonstration at Savannah River

    International Nuclear Information System (INIS)

    Lewandowski, K.E.; Becker, G.W.; Mersman, K.E.; Roberson, W.A.

    1983-01-01

    A full-scale incineration process for Savannah River Plant (SRP) low level beta-gamma combustible waste was demonstrated at the Savannah River Laboratory (SRL) using nonradioactive wastes. From October 1981 through September 1982, 15,700 kilograms of solid waste and 5.7 m 3 of solvent were incinerated. Emissions of off-gas components (NO/sub x/, SO 2 , CO, and particulates) were well below South Carolina state standards. Volume reductions of 20:1 for solid waste and 7:1 for Purex solvent/lime slurry were achieved. Presently, the process is being upgraded by SRP to accept radioactive wastes. During a two-year SRP demonstration, the facility will be used to incinerate slightly radioactive ( 3 ) solvent and suspect level (<1 mR/hr at 0.0254 meter) solid wastes

  3. Plasma hearth process demonstration project

    International Nuclear Information System (INIS)

    Geimer, R.M.; Gillins, R.L.

    1995-01-01

    The Plasma Hearth Process (PHP) demonstration project is one of the key technology projects in the US Department of Energy (DOE) Office of Technology Development Mixed Waste Focus Area. The PHP is a high temperature thermal treatment process using a plasma arc torch in a stationary, refractory lined chamber that destroys organics and stabilizes the residuals in a nonleaching, vitrified waste form, greatly improving the disposability of the waste. This paper describes the PHP system and summarizes test results to date, including volume reduction, destruction and removal efficiencies for organic wastes, and emission characteristics. Tests performed so far demonstrate that the PHP adresses DOE mixed waste final waste form requirements and US Environmental Protection Agency Toxicity Characteristic Leaching Procedure requirements

  4. Actinide Separation Demonstration Facility, Tarapur

    International Nuclear Information System (INIS)

    Vishwaraj, I.

    2017-01-01

    Partitioning of minor actinide from high level waste could have a substantial impact in lowering the radio toxicity associated with high level waste as well as it will reduce the burden on geological repository. In Indian context, the partitioned minor actinide could be routed into the fast breeder reactor systems scheduled for commissioning in the near period. The technological breakthrough in solvent development has catalyzed the partitioning programme in India, leading to the setting up and hot commissioning of the Actinide Separation Demonstration Facility (ASDF) at BARC, Tarapur. The engineering scale Actinide Separation Demonstration Facility (ASDF) has been retrofitted in an available radiological hot cell situated adjacent to the Advanced Vitrification Facility (AVS). This location advantage ensures an uninterrupted supply of high-level waste and facilitates the vitrification of the high-level waste after separation of minor actinides

  5. Efficacy of c-Met inhibitor for advanced prostate cancer

    International Nuclear Information System (INIS)

    Tu, William H; Zhu, Chunfang; Clark, Curtis; Christensen, James G; Sun, Zijie

    2010-01-01

    Aberrant expression of HGF/SF and its receptor, c-Met, often correlates with advanced prostate cancer. Our previous study showed that expression of c-Met in prostate cancer cells was increased after attenuation of androgen receptor (AR) signalling. This suggested that current androgen ablation therapy for prostate cancer activates c-Met expression and may contribute to development of more aggressive, castration resistant prostate cancer (CRPC). Therefore, we directly assessed the efficacy of c-Met inhibition during androgen ablation on the growth and progression of prostate cancer. We tested two c-Met small molecule inhibitors, PHA-665752 and PF-2341066, for anti-proliferative activity by MTS assay and cell proliferation assay on human prostate cancer cell lines with different levels of androgen sensitivity. We also used renal subcapsular and castrated orthotopic xenograft mouse models to assess the effect of the inhibitors on prostate tumor formation and progression. We demonstrated a dose-dependent inhibitory effect of PHA-665752 and PF-2341066 on the proliferation of human prostate cancer cells and the phosphorylation of c-Met. The effect on cell proliferation was stronger in androgen insensitive cells. The c-Met inhibitor, PF-2341066, significantly reduced growth of prostate tumor cells in the renal subcapsular mouse model and the castrated orthotopic mouse model. The effect on cell proliferation was greater following castration. The c-Met inhibitors demonstrated anti-proliferative efficacy when combined with androgen ablation therapy for advanced prostate cancer

  6. Coumarins as cholinesterase inhibitors: A review.

    Science.gov (United States)

    de Souza, Luana G; Rennã, Magdalena N; Figueroa-Villar, Jose D

    2016-07-25

    The first report in literature of the isolation of coumarin was in the year 1820. After this report, other papers were published demonstrating the isolation and synthesis of coumarin and analogues. These compounds have been studying along the years for several different pathologies. One of these pathologies was Alzheimer's disease (AD), being the main cause of dementia in the contemporary world. There are two hypotheses to explain the pathogenesis mechanism and disease symptoms, then having the "amyloid hypothesis" and the "cholinergic hypothesis". Some drugs for AD are based on the theory of "cholinergic hypothesis", which objective is to increase the concentration of ACh in the synaptic cleft by the inhibition of cholinesterases. Over the last twenty years, many studies with coumarins compounds were reported as cholinesterases inhibitors. The aim of the present review is to discuss the studies and development of new compounds for AD treatment. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  7. Earth Science Capability Demonstration Project

    Science.gov (United States)

    Cobleigh, Brent

    2006-01-01

    A viewgraph presentation reviewing the Earth Science Capability Demonstration Project is shown. The contents include: 1) ESCD Project; 2) Available Flight Assets; 3) Ikhana Procurement; 4) GCS Layout; 5) Baseline Predator B Architecture; 6) Ikhana Architecture; 7) UAV Capability Assessment; 8) The Big Picture; 9) NASA/NOAA UAV Demo (5/05 to 9/05); 10) NASA/USFS Western States Fire Mission (8/06); and 11) Suborbital Telepresence.

  8. Mixed Waste Landfill Integrated Demonstration

    International Nuclear Information System (INIS)

    1994-02-01

    The mission of the Mixed Waste Landfill Integrated Demonstration (MWLID) is to demonstrate, in contaminated sites, new technologies for clean-up of chemical and mixed waste landfills that are representative of many sites throughout the DOE Complex and the nation. When implemented, these new technologies promise to characterize and remediate the contaminated landfill sites across the country that resulted from past waste disposal practices. Characterization and remediation technologies are aimed at making clean-up less expensive, safer, and more effective than current techniques. This will be done by emphasizing in-situ technologies. Most important, MWLID's success will be shared with other Federal, state, and local governments, and private companies that face the important task of waste site remediation. MWLID will demonstrate technologies at two existing landfills. Sandia National Laboratories' Chemical Waste Landfill received hazardous (chemical) waste from the Laboratory from 1962 to 1985, and the Mixed-Waste Landfill received hazardous and radioactive wastes (mixed wastes) over a twenty-nine year period (1959-1988) from various Sandia nuclear research programs. Both landfills are now closed. Originally, however, the sites were selected because of Albuquerque's and climate and the thick layer of alluvial deposits that overlay groundwater approximately 480 feet below the landfills. This thick layer of ''dry'' soils, gravel, and clays promised to be a natural barrier between the landfills and groundwater

  9. Salt decontamination demonstration test results

    International Nuclear Information System (INIS)

    Snell, E.B.; Heng, C.J.

    1983-06-01

    The Salt Decontamination Demonstration confirmed that the precipitation process could be used for large-scale decontamination of radioactive waste sale solution. Although a number of refinements are necessary to safely process the long-term requirement of 5 million gallons of waste salt solution per year, there were no observations to suggest that any fundamentals of the process require re-evaluation. Major accomplishments were: (1) 518,000 gallons of decontaminated filtrate were produced from 427,000 gallons of waste salt solution from tank 24H. The demonstration goal was to produce a minimum of 200,000 gallons of decontaminated salt solution; (2) cesium activity in the filtrate was reduced by a factor of 43,000 below the cesium activity in the tank 24 solution. This decontamination factor (DF) exceeded the demonstration goal of a DF greater than 10,000; (3) average strontium-90 activity in the filtrate was reduced by a factor of 26 to less than 10 3 d/m/ml versus a goal of less than 10 4 d/m/ml; and (4) the concentrated precipitate was washed to a final sodium ion concentration of 0.15 M, well below the 0.225 M upper limit for DWPF feed. These accomplishments were achieved on schedule and without incident. Total radiation exposure to personnel was less than 350 mrem and resulted primarily from sampling precipitate slurry inside tank 48. 3 references, 6 figures, 2 tables

  10. Aerospace Communications Security Technologies Demonstrated

    Science.gov (United States)

    Griner, James H.; Martzaklis, Konstantinos S.

    2003-01-01

    In light of the events of September 11, 2001, NASA senior management requested an investigation of technologies and concepts to enhance aviation security. The investigation was to focus on near-term technologies that could be demonstrated within 90 days and implemented in less than 2 years. In response to this request, an internal NASA Glenn Research Center Communications, Navigation, and Surveillance Aviation Security Tiger Team was assembled. The 2-year plan developed by the team included an investigation of multiple aviation security concepts, multiple aircraft platforms, and extensively leveraged datalink communications technologies. It incorporated industry partners from NASA's Graphical Weather-in-the-Cockpit research, which is within NASA's Aviation Safety Program. Two concepts from the plan were selected for demonstration: remote "black box," and cockpit/cabin surveillance. The remote "black box" concept involves real-time downlinking of aircraft parameters for remote monitoring and archiving of aircraft data, which would assure access to the data following the loss or inaccessibility of an aircraft. The cockpit/cabin surveillance concept involves remote audio and/or visual surveillance of cockpit and cabin activity, which would allow immediate response to any security breach and would serve as a possible deterrent to such breaches. The datalink selected for the demonstrations was VDL Mode 2 (VHF digital link), the first digital datalink for air-ground communications designed for aircraft use. VDL Mode 2 is beginning to be implemented through the deployment of ground stations and aircraft avionics installations, with the goal of being operational in 2 years. The first demonstration was performed December 3, 2001, onboard the LearJet 25 at Glenn. NASA worked with Honeywell, Inc., for the broadcast VDL Mode 2 datalink capability and with actual Boeing 757 aircraft data. This demonstration used a cockpitmounted camera for video surveillance and a coupling to

  11. Reduction rules for reset/inhibitor nets

    NARCIS (Netherlands)

    Verbeek, H.M.W.; Wynn, M.T.; Aalst, van der W.M.P.; Hofstede, ter A.H.M.

    2010-01-01

    Reset/inhibitor nets are Petri nets extended with reset arcs and inhibitor arcs. These extensions can be used to model cancellation and blocking. A reset arc allows a transition to remove all tokens from a certain place when the transition fires. An inhibitor arc can stop a transition from being

  12. Allosteric small-molecule kinase inhibitors

    DEFF Research Database (Denmark)

    Wu, Peng; Clausen, Mads Hartvig; Nielsen, Thomas E.

    2015-01-01

    current barriers of kinase inhibitors, including poor selectivity and emergence of drug resistance. In spite of the small number of identified allosteric inhibitors in comparison with that of inhibitors targeting the ATP pocket, encouraging results, such as the FDA-approval of the first small...

  13. Exploration Medical System Demonstration Project

    Science.gov (United States)

    Chin, D. A.; McGrath, T. L.; Reyna, B.; Watkins, S. D.

    2011-01-01

    A near-Earth Asteroid (NEA) mission will present significant new challenges including hazards to crew health created by exploring a beyond low earth orbit destination, traversing the terrain of asteroid surfaces, and the effects of variable gravity environments. Limited communications with ground-based personnel for diagnosis and consultation of medical events require increased crew autonomy when diagnosing conditions, creating treatment plans, and executing procedures. Scope: The Exploration Medical System Demonstration (EMSD) project will be a test bed on the International Space Station (ISS) to show an end-to-end medical system assisting the Crew Medical Officers (CMO) in optimizing medical care delivery and medical data management during a mission. NEA medical care challenges include resource and resupply constraints limiting the extent to which medical conditions can be treated, inability to evacuate to Earth during many mission phases, and rendering of medical care by a non-clinician. The system demonstrates the integration of medical technologies and medical informatics tools for managing evidence and decision making. Project Objectives: The objectives of the EMSD project are to: a) Reduce and possibly eliminate the time required for a crewmember and ground personnel to manage medical data from one application to another. b) Demonstrate crewmember's ability to access medical data/information via a software solution to assist/aid in the treatment of a medical condition. c) Develop a common data management architecture that can be ubiquitously used to automate repetitive data collection, management, and communications tasks for all crew health and life sciences activities. d) Develop a common data management architecture that allows for scalability, extensibility, and interoperability of data sources and data users. e) Lower total cost of ownership for development and sustainment of peripheral hardware and software that use EMSD for data management f) Provide

  14. AAEC builds synroc demonstration plant

    International Nuclear Information System (INIS)

    O'Hagan, R.

    1986-01-01

    A demonstration plant to test the feasibility of an Australian-developed method of immobilising radioactive waste is being built at the Australian Atomic Energy Commission's Lucas Heights Research Laboratories. The plant will operate as if radioactive waste was actually being processed, but non-radioactive elements of a similar composition will be used. The process involves the simulated waste being mixed into a slurry with the main SYNROC ingredients and then converted to a powder. The powder is moved about the plant in bellows-type containers by robots

  15. Charge sniffer for electrostatics demonstrations

    Science.gov (United States)

    Dinca, Mihai P.

    2011-02-01

    An electronic electroscope with a special design for demonstrations and experiments on static electricity is described. It operates as an electric charge sniffer by detecting slightly charged objects when they are brought to the front of its sensing electrode. The sniffer has the advantage of combining high directional sensitivity with a logarithmic bar display. It allows for the identification of electric charge polarity during charge separation by friction, peeling, electrostatic induction, batteries, or secondary coils of power transformers. Other experiments in electrostatics, such as observing the electric field of an oscillating dipole and the distance dependence of the electric field generated by simple charge configurations, are also described.

  16. Dynamic Underground Stripping Demonstration Project

    International Nuclear Information System (INIS)

    Aines, R.; Newmark, R.; McConachie, W.; Rice, D.; Ramirez, A.; Siegel, W.; Buettner, M.; Daily, W.; Krauter, P.; Folsom, E.; Boegel, A.J.; Bishop, D.; udel, K.

    1992-03-01

    LLNL is collaborating with the UC Berkeley College of Engineering to develop and demonstrate a system of thermal remediation and underground imaging techniques for use in rapid cleanup of localized underground spills. Called ''Dynamic Stripping'' to reflect the rapid and controllable nature of the process, it will combine steam injection, direct electrical heating, and tomographic geophysical imaging in a cleanup of the LLNL gasoline spill. In the first 8 months of the project, a Clean Site engineering test was conducted to prove the field application of the techniques before moving to the contaminated site in FY 92

  17. Improved Potency of Indole-Based NorA Efflux Pump Inhibitors: From Serendipity toward Rational Design and Development.

    Science.gov (United States)

    Buonerba, Federica; Lepri, Susan; Goracci, Laura; Schindler, Bryan D; Seo, Susan M; Kaatz, Glenn W; Cruciani, Gabriele

    2017-01-12

    The NorA efflux pump is a potential drug target for reversal of resistance to selected antibacterial agents, and recently we described indole-based inhibitor candidates. Herein we report a second class of inhibitors derived from them but with significant differences in shape and size. In particular, compounds 13 and 14 are very potent inhibitors in that they demonstrated the lowest IC 50 values (2 μM) ever observed among all indole-based compounds we have evaluated.

  18. Flambeau River Biofuels Demonstration Plant

    Energy Technology Data Exchange (ETDEWEB)

    Byrne, Robert J. [Flambeau River Biofuels, Inc., Park Falls, WI (United States)

    2012-07-30

    Flambeau River BioFuels, Inc. (FRB) proposed to construct a demonstration biomass-to-liquids (BTL) biorefinery in Park Falls, Wisconsin. The biorefinery was to be co-located at the existing pulp and paper mill, Flambeau River Papers, and when in full operation would both generate renewable energy – making Flambeau River Papers the first pulp and paper mill in North America to be nearly fossil fuel free – and produce liquid fuels from abundant and renewable lignocellulosic biomass. The biorefinery would serve to validate the thermochemical pathway and economic models for BTL production using forest residuals and wood waste, providing a basis for proliferating BTL conversion technologies throughout the United States. It was a project goal to create a compelling new business model for the pulp and paper industry, and support the nation’s goal for increasing renewable fuels production and reducing its dependence on foreign oil. FRB planned to replicate this facility at other paper mills after this first demonstration scale plant was operational and had proven technical and economic feasibility.

  19. Parker Hybrid Hydraulic Drivetrain Demonstration

    Energy Technology Data Exchange (ETDEWEB)

    Collett, Raymond [Parker-Hannifin Corporation, Cleveland, OH (United States); Howland, James [Parker-Hannifin Corporation, Cleveland, OH (United States); Venkiteswaran, Prasad [National Energy Technology Lab. (NETL), Morgantown, WV (United States)

    2014-03-31

    This report examines the benefits of Parker Hannifin hydraulic hybrid brake energy recovery systems used in commercial applications for vocational purposes. A detailed background on the problem statement being addressed as well as the solution set specific for parcel delivery will be provided. Objectives of the demonstration performed in high start & stop applications included opportunities in fuel usage reduction, emissions reduction, vehicle productivity, and vehicle maintenance. Completed findings during the demonstration period and parallel investigations with NREL, CALSTART, along with a literature review will be provided herein on this research area. Lastly, results identified in the study by third parties validated the savings potential in fuel reduction of on average of 19% to 52% over the baseline in terms of mpg (Lammert, 2014, p11), Parker data for parcel delivery vehicles in the field parallels this at a range of 35% - 50%, emissions reduction of 17.4% lower CO2 per mile and 30.4% lower NOx per mile (Gallo, 2014, p15), with maintenance improvement in the areas of brake and starter replacement, while leaving room for further study in the area of productivity in terms of specific metrics that can be applied and studied.

  20. Reactor-vessel-sectioning demonstration

    International Nuclear Information System (INIS)

    Lundgren, R.A.

    1981-09-01

    A technical demonstration was successfully completed of simulated reactor vessel sectioning using the combined techniques of air arc gouging and flame cutting. A 4-ft x 3-ft x 9-in. thick sample was fabricated of A36 carbon steel to simulate a reactor vessel wall. A 1/4-in. layer of stainless steel (SS) was tungsten inert gas (TIG)-welded to the carbon steel. Several techniques were considered to section the simulated reactor vessel; air arc gouging was selected to penetrate the stainless steel, and flame cutting was selected to sever the carbon steel. Three sectioning operations were demonstrated. For all three, the operating parameters were the same; but the position of the sample was varied. For the first cut, the sample was placed in a horizontal position, and it was successfully severed from the SS side. For the second cut, the sample was turned over and cut from the carbon steel side. Cutting from the carbon steel side has the advantages of cost reduction

  1. Stabilization versus inhibition of TAFIa by competitive inhibitors in vitro

    NARCIS (Netherlands)

    Walker, J.B.; Hughes, B.; James, I.; Haddock, P.; Kluft, C.; Bajzar, L.

    2003-01-01

    Two competitive inhibitors of TAFIa (activated thrombin-activable fibrinolysis inhibitor), 2-guanidinoethyl-mercaptosuccinic acid and potato tuber carboxypeptidase inhibitor, variably affect fibrinolysis of clotted human plasma. Depending on their concentration, the inhibitors shortened, prolonged,

  2. Checkpoint inhibitors in endometrial cancer: preclinical rationale and clinical activity.

    Science.gov (United States)

    Mittica, Gloria; Ghisoni, Eleonora; Giannone, Gaia; Aglietta, Massimo; Genta, Sofia; Valabrega, Giorgio

    2017-10-27

    Treatment of advanced and recurrent endometrial cancer (EC) is still an unmet need for oncologists and gynecologic oncologists. The Cancer Genome Atlas Research Network (TCGA) recently provided a new genomic classification, dividing EC in four subgroups. Two types of EC, the polymerase epsilon (POLE)-ultra-mutated and the microsatellite instability-hyper-mutated (MSI-H), are characterized by a high mutation rate providing the rationale for a potential activity of checkpoint inhibitors. We analyzed all available evidence supporting the role of tumor microenvironment (TME) in EC development and the therapeutic implications offered by immune checkpoint inhibitors in this setting. We performed a review on Pubmed with Mesh keywords 'endometrial cancer' and the name of each checkpoint inhibitor discussed in the article. The same search was operated on clinicaltrial.gov to identify ongoing clinical trials exploring PD-1/PD-L1 and CTLA-4 axis in EC, particularly focusing on POLE-ultra-muted and MSI-H cancer types. POLE-ultra-mutated and MSI-H ECs showed an active TME expressing high number of neo-antigens and an elevated amount of tumor infiltrating lymphocytes (TILs). Preliminary results from a phase-1 clinical trial (KEYNOTE-028) demonstrated antitumor activity of Pembrolizumab in EC. Moreover, both Pembrolizumab and Nivolumab reported durable clinical responses in POLE-ultra-mutated patients. Immune checkpoint inhibitors are an attractive option in POLE-ultra-mutated and MSI-H ECs. Future investigations in these subgroups include combinations of checkpoints inhibitors with chemotherapy and small tyrosine kinase inhibitors (TKIs) to enhance a more robust intra-tumoral immune response.

  3. Identification by shape-based virtual screening and evaluation of new tyrosinase inhibitors

    Directory of Open Access Journals (Sweden)

    Qi Li

    2018-01-01

    Full Text Available Targeting tyrosinase is considered to be an effective way to control the production of melanin. Tyrosinase inhibitor is anticipated to provide new therapy to prevent skin pigmentation, melanoma and neurodegenerative diseases. Herein, we report our results in identifying new tyrosinase inhibitors. The shape-based virtual screening was performed to discover new tyrosinase inhibitors. Thirteen potential hits derived from virtual screening were tested by biological determinations. Compound 5186-0429 exhibited the most potent inhibitory activity. It dose-dependently inhibited the activity of tyrosinase, with the IC50 values 6.2 ± 2.0 µM and 10.3 ± 5.4 µM on tyrosine and L-Dopa formation, respectively. The kinetic study of 5186-0429 demonstrated that this compound acted as a competitive inhibitor. We believe the discoveries here could serve as a good starting point for further design of potent tyrosinase inhibitor.

  4. Energy 2007. Research, development, demonstration; Energi 07. Forskning, udvikling, demonstration

    Energy Technology Data Exchange (ETDEWEB)

    Byriel, I.P.; Justesen, Helle; Beck, A.; Borup Jensen, J.; Rosenfeldt Jakobsen, Kl; Jacobsen, Steen Hartvig (eds.)

    2007-08-10

    Danish energy research is in an exciting and challenging situation. Rising oil prices, unstable energy supply, climate policy responsibilities and globalization have brought development of new environmentally friendly and more efficient energy technologies into focus. Promising international markets for newly developed energy technologies are emerging, and at the same time well established Danish positions of strength are challenged by new strong actors on the global market. The Danish government has set to work on its vision of an appreciable strengthening of public energy research funding through the recent law on the energy technological development and demonstration programme EUDP and the realization of globalization funds. The interaction between basic and applied research must be kept intact. In this report the various Danish energy research programmes administered by Energinet.dk, Danish Energy Authority, Danish Energy Association, Danish Council for Strategic Research's Programme Commission on Energy and Environment and Danish National Advanced Technology Foundation, coordinate their annual reports for the first time. The aim of Energy 2007 is to give the reader an idea of how the energy research programmes collaborate on solving the major energy technology challenges - also in an international context. (BA)

  5. Biochemical Importance of Glycosylation of Plasminogen Activator Inhibitor-1

    DEFF Research Database (Denmark)

    Gils, Ann; Pedersen, Katrine Egelund; Skottrup, Peter

    2003-01-01

    The serpin plasminogen activator inhibitor-1 (PAI-1) is a potential target for anti-thrombotic and anti-cancer therapy. PAI-1 has 3 potential sites for N-linked glycosylation. We demonstrate here that PAI-1 expressed recombinantly or naturally by human cell lines display a heterogeneous glycosyla......The serpin plasminogen activator inhibitor-1 (PAI-1) is a potential target for anti-thrombotic and anti-cancer therapy. PAI-1 has 3 potential sites for N-linked glycosylation. We demonstrate here that PAI-1 expressed recombinantly or naturally by human cell lines display a heterogeneous...... with the glycosylation sites could be excluded as explanation for the differential reactivity. The latency transition of non-glycosylated, but not of glycosylated PAI-1, was strongly accelerated by a non-ionic detergent. The different biochemical properties of glycosylated and non-glycosylated PAI-1 depended...

  6. The Liquid Argon Purity Demonstrator

    Energy Technology Data Exchange (ETDEWEB)

    Adamowski, M.; Carls, B.; Dvorak, E.; Hahn, A.; Jaskierny, W.; Johnson, C.; Jostlein, H.; Kendziora, C.; Lockwitz, S.; Pahlka, B.; Plunkett, R.; Pordes, S.; Rebel, B.; Schmitt, R.; Stancari, M.; Tope, T.; Voirin, E.; Yang, T.

    2014-07-01

    The Liquid Argon Purity Demonstrator was an R&D test stand designed to determine if electron drift lifetimes adequate for large neutrino detectors could be achieved without first evacuating the cryostat. We describe here the cryogenic system, its operations, and the apparatus used to determine the contaminant levels in the argon and to measure the electron drift lifetime. The liquid purity obtained by this system was facilitated by a gaseous argon purge. Additionally, gaseous impurities from the ullage were prevented from entering the liquid at the gas-liquid interface by condensing the gas and filtering the resulting liquid before returning to the cryostat. The measured electron drift lifetime in this test was greater than 6 ms, sustained over several periods of many weeks. Measurements of the temperature profile in the argon, to assess convective flow and boiling, were also made and are compared to simulation.

  7. Prototypical Rod Consolidation Demonstration Project

    International Nuclear Information System (INIS)

    1993-05-01

    The objective of Phase 3 of the Prototypical Rod consolidation Demonstration Project (PRCDP) was to procure, fabricate, assemble, and test the Prototypical Rod consolidation System as described in the NUS Phase 2 Final Design Report. This effort required providing the materials, components, and fabricated parts which makes up all of the system equipment. In addition, it included the assembly, installation, and setup of this equipment at the Cold Test Facility. During the Phase 3 effort the system was tested on a component, subsystem, and system level. This volume 1, discusses the PRCDP Phase 3 Test Program that was conducted by the HALLIBURTON NUS Environmental Corporation under contract AC07-86ID12651 with the United States Department of Energy. This document, Volume 1, Book 2 discusses the following topics: Fuel Rod Extraction System Test Results and Analysis Reports and Clamping Table Test Results and Analysis Reports

  8. Prototypical Rod Consolidation Demonstration Project

    International Nuclear Information System (INIS)

    1993-05-01

    The objective of Phase 3 of the Prototypical Rod consolidation Demonstration Project (PRCDP) was to procure, fabricate, assemble, and test the Prototypical Rod consolidation System as described in the NUS Phase 2 Final Design Report. This effort required providing the materials, components, and fabricated parts which makes up all of the system equipment. In addition, it included the assembly, installation, and setup of this equipment at the Cold Test Facility. During the Phase 3 effort the system was tested on a component, subsystem, and system level. This volume 1, discusses the PRCDP Phase 3 Test Program that was conducted by the HALLIBURTON NUS Environmental Corporation under contract AC07-86ID12651 with the United States Department of Energy. This document, Volume 1, Book 1 discusses the following topics: the background of the project; test program description; summary of tests and test results; problem evaluation; functional requirements confirmation; recommendations; and completed test documentation for tests performed in Phase 3

  9. Prototypical Rod Consolidation Demonstration Project

    International Nuclear Information System (INIS)

    1993-05-01

    The objective of Phase III of the Prototypical Rod Consolidation Demonstration Project (PRCDP) was to procure, fabricate, assemble, and test the Prototypical Rod Consolidation System as described in the NUS Phase II Final Design Report. This effort required providing the materials, components, and fabricated parts which makes up all of the system equipment. In addition, it included the assembly, installation, and setup of this equipment at the Cold Test Facility. During the Phase III effort the system was tested on a component, subsystem, and system level. Volume IV provides the Operating and Maintenance Manual for the Prototypical Rod Consolidation System that was installed at the Cold Test Facility. This document, Book 1 of Volume IV, discusses: Process overview functional descriptions; Control system descriptions; Support system descriptions; Maintenance system descriptions; and Process equipment descriptions

  10. Demonstration of creep during filtration

    DEFF Research Database (Denmark)

    Christensen, Morten Lykkegaard; Bugge, Thomas Vistisen; Kirchheiner, Anders Løvenbalk

    The classical filtration theory assumes a unique relationship between the local filter cake porosity and the local effective pressure. For a number of compressible materials, it has however been observed that during the consolidation stage this may not be the case. It has been found...... that the production of filtrate also depends on the characteristic time for the filter cake solids to deform. This is formulated in the Terzaghi-Voigt model in which a secondary consolidation is introduced. The secondary consolidation may be visualized by plots of the relative cake deformation (U) v.s. the square...... root of time. Even more clearly it is demonstrated by plotting the liquid pressure at the cake piston interface v.s. the relative deformation (to be shown). The phenomenon of a secondary consolidation processes is in short called creep. Provided that the secondary consolidation rate is of the same...

  11. Prototypical Rod Consolidation Demonstration Project

    International Nuclear Information System (INIS)

    1993-05-01

    The objective of Phase 3 of the Prototypical Rod consolidation Demonstration Project (PRCDP) was to procure, fabricate, assemble, and test the Prototypical Rod consolidation System as described in the NUS Phase 2 Final Design Report. This effort required providing the materials, components, and fabricated parts which makes up all of the system equipment. In addition, it included the assembly, installation, and setup of this equipment at the Cold Test Facility. During the Phase 3 effort the system was tested on a component, subsystem, and system level. This volume 1, discusses the PRCDP Phase 3 Test Program that was conducted by the HALLIBURTON NUS Environmental Corporation under contract AC07-86ID12651 with the United States Department of Energy. This document, Volume 1, Book 9 discusses the following topics: Integrated System Normal Operations Test Results and Analysis Report; Integrated System Off-Normal Operations Test Results and Analysis Report; and Integrated System Maintenance Operations Test Results and Analysis Report

  12. Clean Coal Diesel Demonstration Project

    Energy Technology Data Exchange (ETDEWEB)

    Robert Wilson

    2006-10-31

    A Clean Coal Diesel project was undertaken to demonstrate a new Clean Coal Technology that offers technical, economic and environmental advantages over conventional power generating methods. This innovative technology (developed to the prototype stage in an earlier DOE project completed in 1992) enables utilization of pre-processed clean coal fuel in large-bore, medium-speed, diesel engines. The diesel engines are conventional modern engines in many respects, except they are specially fitted with hardened parts to be compatible with the traces of abrasive ash in the coal-slurry fuel. Industrial and Municipal power generating applications in the 10 to 100 megawatt size range are the target applications. There are hundreds of such reciprocating engine power-plants operating throughout the world today on natural gas and/or heavy fuel oil.

  13. Alderney 5 complex demonstration project

    Energy Technology Data Exchange (ETDEWEB)

    Stewart, D. [High Performance Energy Systems, Halifax, NS (Canada)

    2008-07-01

    The Halifax Regional Municipality (HRM) is the largest municipality in Atlantic Canada. This presentation described the flagship facility and the energy efficiency retrofit of five HRM-owned buildings called the Alderney 5 complex. The 5 objectives of the demonstration project involved a district-scale cooling project; replacement of chillers with harbour cooling; and replacement of a high exergy system with a low exergy system. Synergies and challenges of the project were also identified. The presentation also referred to borehole thermal energy storage; existing Halifax Harbour cooling; Halifax Harbour temperatures; cold energy geothermal borehole field; and the benefits of advanced concentric boreholes. A project update and progress to date were also provided. The Alderney 5 project represents the first concentric borehole technology for use to store and retrieve cold energy. tabs., figs.

  14. Prototypical Rod Consolidation Demonstration Project

    International Nuclear Information System (INIS)

    1993-05-01

    The objective of Phase 3 of the Prototypical Rod consolidation Demonstration Project (PRCDP) was to procure, fabricate, assemble, and test the Prototypical Rod consolidation System as described in the NUS Phase 2 Final Design Report. This effort required providing the materials, components, and fabricated parts which makes up all of the system equipment. In addition, it included the assembly, installation, and setup of this equipment at the Cold Test Facility. During the Phase 3 effort the system was tested on a component, subsystem, and system level. This volume 1, discusses the PRCDP Phase 3 Test Program that was conducted by the HALLIBURTON NUS Environmental Corporation under contract AC07-86ID12651 with the United States Department of Energy. This document, Volume 1, Book 8 discusses Control System SOT Tests Results and Analysis Report. This is a continuation of Book 7

  15. Deep Space Habitat Concept Demonstrator

    Science.gov (United States)

    Bookout, Paul S.; Smitherman, David

    2015-01-01

    This project will develop, integrate, test, and evaluate Habitation Systems that will be utilized as technology testbeds and will advance NASA's understanding of alternative deep space mission architectures, requirements, and operations concepts. Rapid prototyping and existing hardware will be utilized to develop full-scale habitat demonstrators. FY 2014 focused on the development of a large volume Space Launch System (SLS) class habitat (Skylab Gen 2) based on the SLS hydrogen tank components. Similar to the original Skylab, a tank section of the SLS rocket can be outfitted with a deep space habitat configuration and launched as a payload on an SLS rocket. This concept can be used to support extended stay at the Lunar Distant Retrograde Orbit to support the Asteroid Retrieval Mission and provide a habitat suitable for human missions to Mars.

  16. Navy fuel cell demonstration project.

    Energy Technology Data Exchange (ETDEWEB)

    Black, Billy D.; Akhil, Abbas Ali

    2008-08-01

    This is the final report on a field evaluation by the Department of the Navy of twenty 5-kW PEM fuel cells carried out during 2004 and 2005 at five Navy sites located in New York, California, and Hawaii. The key objective of the effort was to obtain an engineering assessment of their military applications. Particular issues of interest were fuel cell cost, performance, reliability, and the readiness of commercial fuel cells for use as a standalone (grid-independent) power option. Two corollary objectives of the demonstration were to promote technological advances and to improve fuel performance and reliability. From a cost perspective, the capital cost of PEM fuel cells at this stage of their development is high compared to other power generation technologies. Sandia National Laboratories technical recommendation to the Navy is to remain involved in evaluating successive generations of this technology, particularly in locations with greater environmental extremes, and it encourages their increased use by the Navy.

  17. Prototypical Rod Construction Demonstration Project

    International Nuclear Information System (INIS)

    1993-05-01

    The objective of Phase 3 of the Prototypical Rod consolidation Demonstration Project (PRCDP) was to procure, fabricate, assemble, and test the Prototypical Rod consolidation System as described in the NUS Phase 2 Final Design Report. This effort required providing the materials, components, and fabricated parts which makes up all of the system equipment. In addition, it included the assembly, installation, and setup of this equipment at the Cold Test Facility. During the Phase 3 effort the system was tested on a component, subsystem, and system level. This volume 1, discusses the PRCDP Phase 3 Test Program that was conducted by the HALLIBURTON NUS Environmental Corporation under contract AC07-86ID12651 with the United States Department of Energy. This document, Volume 1, Book 3 discusses the following topics: Downender Test Results and Analysis Report; NFBC Canister Upender Test Results and Analysis Report; Fuel Assembly Handling Fixture Test Results and Analysis Report; and Fuel Canister Upender Test Results and Analysis Report

  18. Prototypical Rod Consolidation Demonstration Project

    International Nuclear Information System (INIS)

    1993-05-01

    The objective of Phase III of the Prototypical Rod Consolidation Demonstration Project (PRCDP) was to procure, fabricate, assemble, and test the Prototypical Rod Consolidation System as described in the NUS Phase II Final Design Report. This effort required providing the materials, components, and fabricated parts which makes up all of the system equipment. In addition, it included the assembly, installation, and setup of this equipment at the Cold Test Facility. During the Phase III effort the system was tested on a component, subsystem, and system level. Volume IV provides the Operating and Maintenance Manual for the Prototypical Rod Consolidation System that was installed at the Cold Test Facility. This document, Book 4 of Volume IV, discusses: Off-normal operating and recovery procedures; Emergency response procedures; Troubleshooting procedures; and Preventive maintenance procedures

  19. Reactor-vessel-sectioning demonstration

    International Nuclear Information System (INIS)

    Lundgren, R.A.

    1981-07-01

    A successful technical demonstration of simulated reactor vessel sectioning was completed using the combined techniques of air arc gouging and flame cutting. A 4-ft x 3-ft x 9-in. thick sample was fabricated of A36 carbon steel to simulate a reactor vessel wall. A 1/4-in layer of stainless steel (SS) was tungsten inert gas (TIG)-welded to the carbon steel. Several techniques were considered to section the simulated reactor vessel: an air arc gouger was chosen to penetrate the stainless steel, and flame cutting was selected to sever the carbon steel. After the simulated vessel was successfully cut from the SS side, another cut was made, starting from the carbon steel side. This cut was also successful. Cutting from the carbon steel side has the advantages of cost reduction since the air arc gouging step is eliminated and contamination controlled because the molten metal is blown inward

  20. Performance Demonstration Program Management Plan

    International Nuclear Information System (INIS)

    2005-01-01

    To demonstrate compliance with the Waste Isolation Pilot Plant (WIPP) waste characterization program, each testing and analytical facility performing waste characterization activities participates in the Performance Demonstration Program (PDP). The PDP serves as a quality control check against expected results and provides information about the quality of data generated in the characterization of waste destined for WIPP. Single blind audit samples are prepared and distributed by an independent organization to each of the facilities participating in the PDP. There are three elements within the PDP: analysis of simulated headspace gases, analysis of solids for Resource Conservation and Recovery Act (RCRA) constituents, and analysis for transuranic (TRU) radionuclides using nondestructive assay (NDA) techniques. Because the analysis for TRU radionuclides using NDA techniques involves both the counting of drums and standard waste boxes, four PDP plans are required to describe the activities of the three PDP elements. In accordance with these PDP plans, the reviewing and approving authority for PDP results and for the overall program is the CBFO PDP Appointee. The CBFO PDP Appointee is responsible for ensuring the implementation of each of these plans by concurring with the designation of the Program Coordinator and by providing technical oversight and coordination for the program. The Program Coordinator will designate the PDP Manager, who will coordinate the three elements of the PDP. The purpose of this management plan is to identify how the requirements applicable to the PDP are implemented during the management and coordination of PDP activities. The other participants in the program (organizations that perform site implementation and activities under CBFO contracts or interoffice work orders) are not covered under this management plan. Those activities are governed by the organization's quality assurance (QA) program and procedures or as otherwise directed by CBFO.

  1. Potent selective nonpeptidic inhibitors of human lung tryptase

    Science.gov (United States)

    Burgess, Laurence E.; Newhouse, Bradley J.; Ibrahim, Prabha; Rizzi, James; Kashem, Mohammed A.; Hartman, Ann; Brandhuber, Barbara J.; Wright, Clifford D.; Thomson, David S.; Vigers, Guy P. A.; Koch, Kevin

    1999-01-01

    Human lung tryptase, a homotetrameric serine protease unique to mast cell secretory granules, has been implicated in the pathogenesis of asthma. A hypothesis that tethered symmetrical inhibitors might bridge two adjacent active sites was explored via a rationally designed series of bisbenzamidines. These compounds demonstrated a remarkable distanced-defined structure–activity relationship against human tryptase with one series possessing subnanomolar potencies. Additional evidence supporting the concept of active-site bridging is also presented. PMID:10411878

  2. Potent selective nonpeptidic inhibitors of human lung tryptase

    OpenAIRE

    Burgess, Laurence E.; Newhouse, Bradley J.; Ibrahim, Prabha; Rizzi, James; Kashem, Mohammed A.; Hartman, Ann; Brandhuber, Barbara J.; Wright, Clifford D.; Thomson, David S.; Vigers, Guy P. A.; Koch, Kevin

    1999-01-01

    Human lung tryptase, a homotetrameric serine protease unique to mast cell secretory granules, has been implicated in the pathogenesis of asthma. A hypothesis that tethered symmetrical inhibitors might bridge two adjacent active sites was explored via a rationally designed series of bisbenzamidines. These compounds demonstrated a remarkable distanced-defined structure–activity relationship against human tryptase with one series possessing subnanomolar potencies. Additional evidence supporting ...

  3. Clinical use of PI3K inhibitors in B-cell lymphoid malignancies: today and tomorrow.

    Science.gov (United States)

    Greenwell, I B; Flowers, C R; Blum, K A; Cohen, J B

    2017-03-01

    PI3K inhibitors are an important new therapeutic option for the treatment of relapsed and refractory B-cell lymphoid malignancies. Idelalisib is a PI3Kδ inhibitor that has been approved for the treatment of lymphoma and chronic lymphocytic leukemia in the relapsed/refractory setting, and several other PI3K inhibitors are being developed targeting other isoforms of the PI3K enzyme, which results in distinct toxicities and variable efficacy in the clinical setting. Areas covered: We provide a general overview of PI3K inhibitors, recommended applications, and the mechanism and management of toxicities. We further review trials, ongoing and completed, leading to the approval of idelalisib as well other PI3K inhibitors currently in development. Articles were obtained from PubMed, and abstracts were searched for the past 5 years from the websites for ASCO, ASH, EHA, and ICML/Lugano. Expert commentary: PI3K inhibitors provide an important and powerful pharmacologic tool in the armamentarium against hematologic malignancies, especially for relapsed/refractory B-cell lymphoid malignancies. Unique toxicities are associated with inhibition of different isoforms of the PI3K enzyme, as demonstrated with the infectious and autoimmune toxicities associated with the PI3Kδ inhibitor, idelalisib. Due to these unique toxicities, PI3K inhibitors should only be used in formally approved combinations and settings.

  4. Demonstration of Data Interactive Publications

    Science.gov (United States)

    Domenico, B.; Weber, J.

    2012-04-01

    This is a demonstration version of the talk given in session ESSI2.4 "Full lifecycle of data." For some years now, the authors have developed examples of online documents that allowed the reader to interact directly with datasets, but there were limitations that restricted the interaction to specific desktop analysis and display tools that were not generally available to all readers of the documents. Recent advances in web service technology and related standards are making it possible to develop systems for publishing online documents that enable readers to access, analyze, and display the data discussed in the publication from the perspective and in the manner from which the author wants it to be represented. By clicking on embedded links, the reader accesses not only the usual textual information in a publication, but also data residing on a local or remote web server as well as a set of processing tools for analyzing and displaying the data. With the option of having the analysis and display processing provided on the server (or in the cloud), there are now a broader set of possibilities on the client side where the reader can interact with the data via a thin web client, a rich desktop application, or a mobile platform "app." The presentation will outline the architecture of data interactive publications along with illustrative examples.

  5. Demonstration poloidal coil test facility

    International Nuclear Information System (INIS)

    Sato, Masahiko; Kawano, Katumi; Tada, Eisuke

    1989-01-01

    A new compact cryogenic cold compressor was developed by Japan Atomic Energy Research Institute (JAERI) in collaboration with Isikawajima-Harima Heavy Industries Co., Ltd. (IHI) in order to produce the supercritical helium below 4.2 K for Demonstration Poloidal Coils (DPC) which are forced-flow cooled type superconducting pulse coils. This compressor is one of key components for DPC test facility. The cold compressor reduces pressure in liquid helium bath, which contains liquid helium of around 3,000 l, down to 0.5 atm efficiently. Consequently, supercritical helium down to 3.5 K is produced and supplied to the DPC coils. A centrifugal compressor with dynamic gas bearing is selected as a compressor mechanism to realize high adiabatic efficiency and large flow rate. In this performance tests, the compressor was operated for 220 h at saturated condition from 0.5 to 1.0 atm without any failure. High adiabatic efficiency (more than 60 %) is achieved with wide flow range (25-65 g/s) and the design value is fully satisfied. The compressor can rotate up to 80,000 rpm at maximum then the coil supply temperature of supercritical helium is 3.5 K. (author)

  6. Demonstration of superconducting micromachined cavities

    Energy Technology Data Exchange (ETDEWEB)

    Brecht, T., E-mail: teresa.brecht@yale.edu; Reagor, M.; Chu, Y.; Pfaff, W.; Wang, C.; Frunzio, L.; Devoret, M. H.; Schoelkopf, R. J. [Department of Applied Physics, Yale University, New Haven, Connecticut 06511 (United States)

    2015-11-09

    Superconducting enclosures will be key components of scalable quantum computing devices based on circuit quantum electrodynamics. Within a densely integrated device, they can protect qubits from noise and serve as quantum memory units. Whether constructed by machining bulk pieces of metal or microfabricating wafers, 3D enclosures are typically assembled from two or more parts. The resulting seams potentially dissipate crossing currents and limit performance. In this letter, we present measured quality factors of superconducting cavity resonators of several materials, dimensions, and seam locations. We observe that superconducting indium can be a low-loss RF conductor and form low-loss seams. Leveraging this, we create a superconducting micromachined resonator with indium that has a quality factor of two million, despite a greatly reduced mode volume. Inter-layer coupling to this type of resonator is achieved by an aperture located under a planar transmission line. The described techniques demonstrate a proof-of-principle for multilayer microwave integrated quantum circuits for scalable quantum computing.

  7. Prototypical Rod Consolidation Demonstration Project

    International Nuclear Information System (INIS)

    1993-05-01

    The objective of Phase 3 of the Prototypical Rod consolidation Demonstration Project (PRCDP) was to procure, fabricate, assemble, and test the Prototypical Rod consolidation System as described in the NUS Phase 2 Final Design Report. This effort required providing the materials, components, and fabricated parts which makes up all of the system equipment. In addition, it included the assembly, installation, and setup of this equipment at the Cold Test Facility. During the Phase 3 effort the system was tested on a component, subsystem, and system level. This volume 1, discusses the PRCDP Phase 3 Test Program that was conducted by the HALLIBURTON NUS Environmental Corporation under contract AC07-86ID12651 with the United States Department of Energy. This document, Volume 1, Book 4 discusses the following topics: Rod Compaction/Loading System Test Results and Analysis Report; Waste Collection System Test Results and Analysis Report; Waste Container Transfer Fixture Test Results and Analysis Report; Staging and Cutting Table Test Results and Analysis Report; and Upper Cutting System Test Results and Analysis Report

  8. Dynamic underground stripping demonstration project

    International Nuclear Information System (INIS)

    Newmark, R.L.

    1992-04-01

    LLNL is collaborating with the UC Berkeley College of Engineering to develop and demonstrate a system of thermal remediation techniques for rapid cleanup of localized underground spills. Called dynamic stripping to reflect the rapid and controllable nature of the process, it will combine steam injection, direct electrical heating, and tomographic geophysical imaging in a cleanup of the LLNL gasoline spill. In the first eight months of the project, a Clean Site engineering test was conducted to prove the field application of the techniques. Tests then began on the contaminated site in FY 1992. This report describes the work at the Clean Site, including design and performance criteria, test results, interpretations, and conclusions. We fielded 'a wide range of new designs and techniques, some successful and some not. In this document, we focus on results and performance, lessons learned, and design and operational changes recommended for work at the contaminated site. Each section focuses on a different aspect of the work and can be considered a self-contained contribution

  9. Prototypical Rod Consolidation Demonstration Project

    International Nuclear Information System (INIS)

    1993-05-01

    The objective of Phase 3 of the Prototypical Rod consolidation Demonstration Project (PRCDP) was to procure, fabricate, assemble, and test the Prototypical Rod consolidation System as described in the NUS Phase 2 Final Design Report. This effort required providing the materials, components, and fabricated parts which makes up all of the system equipment. In addition, it included the assembly, installation, and setup of this equipment at the Cold Test Facility. During the Phase 3 effort the system was tested on a component, subsystem, and system level. This volume 1, discusses the PRCDP Phase 3 Test Program that was conducted by the HALLIBURTON NUS Environmental Corporation under contract AC07-86ID12651 with the United States Department of Energy. This document, Volume 1, Book 5 discusses the following topics: Lower Cutting System Test Results and Analysis Report; NFBC Loading System Test Results and Analysis Report; Robotic Bridge Transporter Test Results and Analysis Report; RM-10A Remotec Manipulator Test Results and Analysis Report; and Manipulator Transporter Test Results and Analysis Report

  10. Ionosphere Waves Service - A demonstration

    Science.gov (United States)

    Crespon, François

    2013-04-01

    In the frame of the FP7 POPDAT project the Ionosphere Waves Service was developed by ionosphere experts to answer several questions: How make the old ionosphere missions more valuable? How provide scientific community with a new insight on wave processes that take place in the ionosphere? The answer is a unique data mining service accessing a collection of topical catalogues that characterize a huge number of Atmospheric Gravity Waves, Travelling Ionosphere Disturbances and Whistlers events. The Ionosphere Waves Service regroups databases of specific events extracted by experts from a ten of ionosphere missions which end users can access by applying specific searches and by using statistical analysis modules for their domain of interest. The scientific applications covered by the IWS are relative to earthquake precursors, ionosphere climatology, geomagnetic storms, troposphere-ionosphere energy transfer, and trans-ionosphere link perturbations. In this presentation we propose to detail the service design, the hardware and software architecture, and the service functions. The service interface and capabilities will be the focus of a demonstration in order to help potential end-users for their first access to the Ionosphere Waves Service portal. This work is made with the support of FP7 grant # 263240.

  11. Histone Deacetylase Inhibitors Prolong Cardiac Repolarization through Transcriptional Mechanisms.

    Science.gov (United States)

    Spence, Stan; Deurinck, Mark; Ju, Haisong; Traebert, Martin; McLean, LeeAnne; Marlowe, Jennifer; Emotte, Corinne; Tritto, Elaine; Tseng, Min; Shultz, Michael; Friedrichs, Gregory S

    2016-09-01

    Histone deacetylase (HDAC) inhibitors are an emerging class of anticancer agents that modify gene expression by altering the acetylation status of lysine residues of histone proteins, thereby inducing transcription, cell cycle arrest, differentiation, and cell death or apoptosis of cancer cells. In the clinical setting, treatment with HDAC inhibitors has been associated with delayed cardiac repolarization and in rare instances a lethal ventricular tachyarrhythmia known as torsades de pointes. The mechanism(s) of HDAC inhibitor-induced effects on cardiac repolarization is unknown. We demonstrate that administration of structurally diverse HDAC inhibitors to dogs causes delayed but persistent increases in the heart rate corrected QT interval (QTc), an in vivo measure of cardiac repolarization, at timepoints far removed from the Tmax for parent drug and metabolites. Transcriptional profiling of ventricular myocardium from dogs treated with various HDAC inhibitors demonstrated effects on genes involved in protein trafficking, scaffolding and insertion of various ion channels into the cell membrane as well as genes for specific ion channel subunits involved in cardiac repolarization. Extensive in vitro ion channel profiling of various structural classes of HDAC inhibitors (and their major metabolites) by binding and acute patch clamp assays failed to show any consistent correlations with direct ion channel blockade. Drug-induced rescue of an intracellular trafficking-deficient mutant potassium ion channel, hERG (G601S), and decreased maturation (glycosylation) of wild-type hERG expressed by CHO cells in vitro correlated with prolongation of QTc intervals observed in vivo The results suggest that HDAC inhibitor-induced prolongation of cardiac repolarization may be mediated in part by transcriptional changes of genes required for ion channel trafficking and localization to the sarcolemma. These data have broad implications for the development of these drug classes and

  12. Zinc oxide nanoparticles as novel alpha-amylase inhibitors

    Science.gov (United States)

    Dhobale, Sandip; Thite, Trupti; Laware, S. L.; Rode, C. V.; Koppikar, Soumya J.; Ghanekar, Ruchika-Kaul; Kale, S. N.

    2008-11-01

    Amylase inhibitors, also known as starch blockers, contain substances that prevent dietary starches from being absorbed by the body via inhibiting breakdown of complex sugars to simpler ones. In this sense, these materials are projected as having potential applications in diabetes control. In this context, we report on zinc oxide nanoparticles as possible alpha-amylase inhibitors. Zinc oxide nanoparticles have been synthesized using soft-chemistry approach and 1-thioglycerol was used as a surfactant to yield polycrystalline nanoparticles of size ˜18 nm, stabilized in wurtzite structure. Conjugation study and structural characterization have been done using x-ray diffraction technique, Fourier transform infrared spectroscopy, UV-visible spectroscopy, and transmission electron microscopy. Cytotoxicity studies on human fibrosarcoma (HT-1080) and skin carcinoma (A-431) cell lines as well as mouse primary fibroblast cells demonstrate that up to a dose of 20 μg/ml, ZnO nanoparticles are nontoxic to the cells. We report for the first time the alpha-amylase inhibitory activity of ZnO nanoparticles wherein an optimum dose of 20 μg/ml was sufficient to exhibit 49% glucose inhibition at neutral pH and 35 °C temperature. This inhibitory activity was similar to that obtained with acarbose (a standard alpha-amylase inhibitor), thereby projecting ZnO nanoparticles as novel alpha-amylase inhibitors.

  13. Bcl-XL represents a druggable molecular vulnerability during aurora B inhibitor-mediated polyploidization.

    Science.gov (United States)

    Shah, O Jameel; Lin, Xiaoyu; Li, Leiming; Huang, Xiaoli; Li, Junling; Anderson, Mark G; Tang, Hua; Rodriguez, Luis E; Warder, Scott E; McLoughlin, Shaun; Chen, Jun; Palma, Joann; Glaser, Keith B; Donawho, Cherrie K; Fesik, Stephen W; Shen, Yu

    2010-07-13

    Aurora kinase B inhibitors induce apoptosis secondary to polyploidization and have entered clinical trials as an emerging class of neocytotoxic chemotherapeutics. We demonstrate here that polyploidization neutralizes Mcl-1 function, rendering cancer cells exquisitely dependent on Bcl-XL/-2. This "addiction" can be exploited therapeutically by combining aurora kinase inhibitors and the orally bioavailable BH3 mimetic, ABT-263, which inhibits Bcl-XL, Bcl-2, and Bcl-w. The combination of ABT-263 with aurora B inhibitors produces a synergistic loss of viability in a range of cell lines of divergent tumor origin and exhibits more sustained tumor growth inhibition in vivo compared with aurora B inhibitor monotherapy. These data demonstrate that Bcl-XL/-2 is necessary to support viability during polyploidization in a variety of tumor models and represents a druggable molecular vulnerability with potential therapeutic utility.

  14. Histone deacetylase inhibitors (HDACIs): multitargeted anticancer agents.

    Science.gov (United States)

    Ververis, Katherine; Hiong, Alison; Karagiannis, Tom C; Licciardi, Paul V

    2013-01-01

    Histone deacetylase (HDAC) inhibitors are an emerging class of therapeutics with potential as anticancer drugs. The rationale for developing HDAC inhibitors (and other chromatin-modifying agents) as anticancer therapies arose from the understanding that in addition to genetic mutations, epigenetic changes such as dysregulation of HDAC enzymes can alter phenotype and gene expression, disturb homeostasis, and contribute to neoplastic growth. The family of HDAC inhibitors is large and diverse. It includes a range of naturally occurring and synthetic compounds that differ in terms of structure, function, and specificity. HDAC inhibitors have multiple cell type-specific effects in vitro and in vivo, such as growth arrest, cell differentiation, and apoptosis in malignant cells. HDAC inhibitors have the potential to be used as monotherapies or in combination with other anticancer therapies. Currently, there are two HDAC inhibitors that have received approval from the US FDA for the treatment of cutaneous T-cell lymphoma: vorinostat (suberoylanilide hydroxamic acid, Zolinza) and depsipeptide (romidepsin, Istodax). More recently, depsipeptide has also gained FDA approval for the treatment of peripheral T-cell lymphoma. Many more clinical trials assessing the effects of various HDAC inhibitors on hematological and solid malignancies are currently being conducted. Despite the proven anticancer effects of particular HDAC inhibitors against certain cancers, many aspects of HDAC enzymes and HDAC inhibitors are still not fully understood. Increasing our understanding of the effects of HDAC inhibitors, their targets and mechanisms of action will be critical for the advancement of these drugs, especially to facilitate the rational design of HDAC inhibitors that are effective as antineoplastic agents. This review will discuss the use of HDAC inhibitors as multitargeted therapies for malignancy. Further, we outline the pharmacology and mechanisms of action of HDAC inhibitors while

  15. Magnetic Launch Assist Demonstration Test

    Science.gov (United States)

    2001-01-01

    This image shows a 1/9 subscale model vehicle clearing the Magnetic Launch Assist System, formerly referred to as the Magnetic Levitation (MagLev), test track during a demonstration test conducted at the Marshall Space Flight Center (MSFC). Engineers at MSFC have developed and tested Magnetic Launch Assist technologies. To launch spacecraft into orbit, a Magnetic Launch Assist System would use magnetic fields to levitate and accelerate a vehicle along a track at very high speeds. Similar to high-speed trains and roller coasters that use high-strength magnets to lift and propel a vehicle a couple of inches above a guideway, a launch-assist system would electromagnetically drive a space vehicle along the track. A full-scale, operational track would be about 1.5-miles long and capable of accelerating a vehicle to 600 mph in 9.5 seconds. This track is an advanced linear induction motor. Induction motors are common in fans, power drills, and sewing machines. Instead of spinning in a circular motion to turn a shaft or gears, a linear induction motor produces thrust in a straight line. Mounted on concrete pedestals, the track is 100-feet long, about 2-feet wide and about 1.5-feet high. The major advantages of launch assist for NASA launch vehicles is that it reduces the weight of the take-off, the landing gear, the wing size, and less propellant resulting in significant cost savings. The US Navy and the British MOD (Ministry of Defense) are planning to use magnetic launch assist for their next generation aircraft carriers as the aircraft launch system. The US Army is considering using this technology for launching target drones for anti-aircraft training.

  16. Coal ash artificial reef demonstration

    International Nuclear Information System (INIS)

    Livingston, R.J.; Brendel, G.F.; Bruzek, D.A.

    1991-01-01

    This experimental project evaluated the use of coal ash to construct artificial reefs. An artificial reef consisting of approximately 33 tons of cement-stabilized coal ash blocks was constructed in approximately 20 feet of water in the Gulf of Mexico approximately 9.3 miles west of Cedar Key, Florida. The project objectives were: (1) demonstrate that a durable coal ash/cement block can be manufactured by commercial block-making machines for use in artificial reefs, and (2) evaluate the possibility that a physically stable and environmentally acceptable coal ash/cement block reef can be constructed as a means of expanding recreational and commercial fisheries. The reef was constructed in February 1988 and biological surveys were made at monthly intervals from May 1988 to April 1989. The project provided information regarding: Development of an optimum design mix, block production and reef construction, chemical composition of block leachate, biological colonization of the reef, potential concentration of metals in the food web associated with the reef, acute bioassays (96-hour LC 50 ). The Cedar Key reef was found to be a habitat that was associated with a relatively rich assemblage of plants and animals. The reef did not appear to be a major source of heavy metals to species at various levels of biological organization. GAI Consultants, Inc (GAI) of Monroeville, Pennsylvania was the prime consultant for the project. The biological monitoring surveys and evaluations were performed by Environmental Planning and Analysis, Inc. of Tallahassee, Florida. The chemical analyses of biological organisms and bioassay elutriates were performed by Savannah Laboratories of Tallahassee, Florida. Florida Power Corporation of St. Petersburg, Florida sponsored the project and supplied ash from their Crystal River Energy Complex

  17. Calcineurin-inhibitor pain syndrome.

    Science.gov (United States)

    Prommer, Eric

    2012-07-01

    There has been increased recognition of calcineurin, a phosphoprotein serine/threonine phosphatase enzyme, in the regulation of many physiologic systems. Calcineurin mediates activation of lymphocytes, which play a role in immune response. Widely distributed in the central nervous system, calcinuerin also plays an important role in sensory neural function, via its role in the regulation of newly discovered 2-pore potassium channels, which greatly influence neuronal resting membrane potentials. Calcinuerin inhibition is the mechanism of action of immunomodulatory drugs such as cyclosporine and tacrolimus, which are widely used in transplantation medicine to prevent rejection. While important for immunosuppression, the use of calcineurin inhibitors has been associated with the development of a new pain syndrome called the calcineurin pain syndrome, which appears to be an untoward complication of the interruption of the physiologic function of calcineurin. This is a narrative review focusing on the epidemiology, pathophysiology, characterization of a newly recognized pain syndrome associated with the use of calcineurin inhibitors. The use of immunosuppressants however is associated with several well-known toxicities to which the calcineurin pain syndrome can be added. The development of this syndrome most likely involves altered nociceptive processing due to the effect of calcineurin inhibition on neuronal firing, as well as effects of calcineurin on vascular tone. The most striking aspect of the treatment of this syndrome is the response to calcium channel blockers, which suggest that the effects of calcineurin inhibition on vascular tone play an important role in the development of the calcineurin pain syndrome. The calcineurin syndrome is a newly recognized complication associated with the use of calcineurin inhibitors. There is no standard therapy at this time but anecdotal reports suggest the effectiveness of calcium channel blockers.

  18. Crystallization inhibitors for amorphous oxides

    International Nuclear Information System (INIS)

    Reznitskij, L.A.; Filippova, S.E.

    1993-01-01

    Data for the last 10 years, in which experimental results of studying the temperature stabilization of x-ray amorphous oxides (including R 3 Fe 5 O 12 R-rare earths, ZrO 2 , In 2 O 3 , Sc 2 O 3 ) and their solid solution are presented, are generalized. Processes of amorphous oxide crystallization with the production of simple oxides, solid solutions and chemical compounds with different polyhedral structure, are investigated. Energy and crystallochemical criteria for selecting the doping inhibitor-components stabilizing the amorphous state are ascertained, temperatures and enthalpies of amorpous oxide crystallization are determined, examination of certain provisions of iso,orphous miscibility theory is conducted

  19. Inhibitors of plant hormone transport

    Czech Academy of Sciences Publication Activity Database

    Klíma, Petr; Laňková, Martina; Zažímalová, Eva

    2016-01-01

    Roč. 253, č. 6 (2016), s. 1391-1404 ISSN 0033-183X R&D Projects: GA MŠk(CZ) LD15088 Institutional support: RVO:61389030 Keywords : polar auxin transport * acid-binding protein * gnom arf-gef * equilibrative nucleoside transporter * efflux carrier polarity * plasma-membrane-protein * cultured tobacco cells * arabidopsis-thaliana * gravitropic response * brefeldin-a * Plant hormones * Transport * Inhibitors * Auxin * Cytokinins * Strigolactones * Abscisic acid * Cell biology Subject RIV: ED - Physiology Impact factor: 2.870, year: 2016

  20. Prostatic-Like Syndrome in a Woman with Chronic Lymphocytic Leukemia: Sequential Kinase Inhibitor Therapy

    Directory of Open Access Journals (Sweden)

    Diego Velasco-Rodríguez

    2017-01-01

    Full Text Available Chronic lymphocytic leukemia (CLL is an incurable lymphoproliferative disorder with a heterogeneous genetic and clinical course. Two kinase inhibitors, ibrutinib and idelalisib, have demonstrated achievement of complete and durable remissions in relapse/refractory genetically unselected CLL patients. We present a case of relapsed CLL with extensive disease and hourglass deformity of urinary bladder as a result of the compression of two extraperitoneal paravesical soft tissue bulky masses, with excellent response to sequential kinase inhibitor therapy.

  1. Oligopeptidase B from Serratia proteamaculans. III. Inhibition analysis. Specific interactions with metalloproteinase inhibitors.

    Science.gov (United States)

    Mikhailova, A G; Khairullin, R F; Kolomijtseva, G Ya; Rumsh, L D

    2012-03-01

    Inhibition of the novel oligopeptidase B from Serratia proteamaculans (PSP) by basic pancreatic trypsin inhibitor, Zn2+ ions, and o- and m-phenanthroline was investigated. A pronounced effect of calcium ions on the interaction of PSP with inhibitors was demonstrated. Inversion voltamperometry and atomic absorption spectrometry revealed no zinc ions in the PSP molecule. Hydrophobic nature of the enzyme inhibition by o- and m-phenanthroline was established.

  2. Laura: Soybean variety lacking Kunitz trypsin inhibitor

    Directory of Open Access Journals (Sweden)

    Srebrić Mirjana

    2010-01-01

    Full Text Available Grain of conventional soybean varieties requires heat processing to break down trypsin inhibitor's activity before using as food or animal feed. At the same time, protein denaturation and other qualitative changes occur in soybean grain, especially if the temperature of heating is not controlled. Two types of trypsin inhibitor were found in soybean grain the Kunitz trypsin inhibitor and the Bowman-Birk inhibitor. Mature grain of soybean Laura is lacking Kunitz trypsin inhibitor. Grain yield of variety Laura is equal to high yielding varieties from the maturity group I, where it belongs. Lacking of Kunitz-trypsin inhibitor makes soybean grain suitable for direct feeding in adult non ruminant animals without previous thermal processing. Grain of variety Laura can be processed for a shorter period of time than conventional soybeans. This way we save energy, and preserve valuable nutritional composition of soybean grain, which is of interest in industrial processing.

  3. Vanadium Compounds as PTP Inhibitors

    Directory of Open Access Journals (Sweden)

    Elsa Irving

    2017-12-01

    Full Text Available Phosphotyrosine signaling is regulated by the opposing actions of protein tyrosine kinases (PTKs and protein tyrosine phosphatases (PTPs. Here we discuss the potential of vanadium derivatives as PTP enzyme inhibitors and metallotherapeutics. We describe how vanadate in the V oxidized state is thought to inhibit PTPs, thus acting as a pan-inhibitor of this enzyme superfamily. We discuss recent developments in the biological and biochemical actions of more complex vanadium derivatives, including decavanadate and in particular the growing number of oxidovanadium compounds with organic ligands. Pre-clinical studies involving these compounds are discussed in the anti-diabetic and anti-cancer contexts. Although in many cases PTP inhibition has been implicated, it is also clear that many such compounds have further biochemical effects in cells. There also remain concerns surrounding off-target toxicities and long-term use of vanadium compounds in vivo in humans, hindering their progress through clinical trials. Despite these current misgivings, interest in these chemicals continues and many believe they could still have therapeutic potential. If so, we argue that this field would benefit from greater focus on improving the delivery and tissue targeting of vanadium compounds in order to minimize off-target toxicities. This may then harness their full therapeutic potential.

  4. Proton pump inhibitors and osteoporosis

    DEFF Research Database (Denmark)

    Andersen, Bjarne Nesgaard; Johansen, Per Birger; Abrahamsen, Bo

    2016-01-01

    PURPOSE OF REVIEW: The purpose of the review is to provide an update on recent advances in the evidence based on proton pump inhibitors (PPI) as a possible cause of osteoporosis and osteoporotic fractures. This review focuses, in particular, on new studies published in the last 18 months and a di......PURPOSE OF REVIEW: The purpose of the review is to provide an update on recent advances in the evidence based on proton pump inhibitors (PPI) as a possible cause of osteoporosis and osteoporotic fractures. This review focuses, in particular, on new studies published in the last 18 months...... and a discussion of these findings and how this has influenced our understanding of this association, the clinical impact and the underlying pathophysiology. RECENT FINDINGS: New studies have further strengthened existing evidence linking use of PPIs to osteoporosis. Short-term use does not appear to pose a lower...... risk than long-term use. There is a continued lack of conclusive studies identifying the pathogenesis. Direct effects on calcium absorption or on osteoblast or osteoclast action cannot at present plausibly explain the mechanism. SUMMARY: The use of PPIs is a risk factor for development of osteoporosis...

  5. Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors.

    Directory of Open Access Journals (Sweden)

    Christina Gavegnano

    2017-12-01

    Full Text Available Despite advances in the treatment of HIV infection with ART, elucidating strategies to overcome HIV persistence, including blockade of viral reservoir establishment, maintenance, and expansion, remains a challenge. T cell homeostasis is a major driver of HIV persistence. Cytokines involved in regulating homeostasis of memory T cells, the major hub of the HIV reservoir, trigger the Jak-STAT pathway. We evaluated the ability of tofacitinib and ruxolitinib, two FDA-approved Jak inhibitors, to block seeding and maintenance of the HIV reservoir in vitro. We provide direct demonstration for involvement of the Jak-STAT pathway in HIV persistence in vivo, ex vivo, and in vitro; pSTAT5 strongly correlates with increased levels of integrated viral DNA in vivo, and in vitro Jak inhibitors reduce the frequency of CD4+ T cells harboring integrated HIV DNA. We show that Jak inhibitors block viral production from infected cells, inhibit γ-C receptor cytokine (IL-15-induced viral reactivation from latent stores thereby preventing transmission of infectious particles to bystander activated T cells. These results show that dysregulation of the Jak-STAT pathway is associated with viral persistence in vivo, and that Jak inhibitors target key events downstream of γ-C cytokine (IL-2, IL-7 and IL-15 ligation to their receptors, impacting the magnitude of the HIV reservoir in all memory CD4 T cell subsets in vitro and ex vivo. Jak inhibitors represent a therapeutic modality to prevent key events of T cell activation that regulate HIV persistence and together, specific, potent blockade of these events may be integrated to future curative strategies.

  6. Developing selective histone deacetylases (HDACs) inhibitors through ebselen and analogs.

    Science.gov (United States)

    Wang, Yuren; Wallach, Jason; Duane, Stephanie; Wang, Yuan; Wu, Jianghong; Wang, Jeffrey; Adejare, Adeboye; Ma, Haiching

    2017-01-01

    Histone deacetylases (HDACs) are key regulators of gene expression in cells and have been investigated as important therapeutic targets for cancer and other diseases. Different subtypes of HDACs appear to play disparate roles in the cells and are associated with specific diseases. Therefore, substantial effort has been made to develop subtype-selective HDAC inhibitors. In an effort to discover existing scaffolds with HDAC inhibitory activity, we screened a drug library approved by the US Food and Drug Administration and a National Institutes of Health Clinical Collection compound library in HDAC enzymatic assays. Ebselen, a clinical safe compound, was identified as a weak inhibitor of several HDACs, including HDAC1, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, and HDAC9 with half maximal inhibitory concentrations approximately single digit of µM. Two ebselen analogs, ebselen oxide and ebsulfur (a diselenide analog of ebselen), also inhibited these HDACs, however with improved potencies on HDAC8. Benzisothiazol, the core structure of ebsulfur, specifically inhibited HDAC6 at a single digit of µM but had no inhibition on other HDACs. Further efforts on structure-activity relationship based on the core structure of ebsulfur led to the discovery of a novel class of potent and selective HDAC6 inhibitors with RBC-2008 as the lead compound with single-digit nM potency. This class of histone deacetylase inhibitor features a novel pharmacophore with an ebsulfur scaffold selectively targeting HDAC6. Consistent with its inhibition on HDAC6, RBC-2008 significantly increased the acetylation levels of α-tubulin in PC-3 cells. Furthermore, treatment with these compounds led to cell death of multiple tumor cell lines in a dose-dependent manner. These results demonstrated that ebselen and ebsulfur analogs are inhibitors of HDACs, supporting further preclinical development of this class of compounds for potential therapeutic applications.

  7. Genipin-Cross-Linked Chitosan Nerve Conduits Containing TNF-α Inhibitors for Peripheral Nerve Repair.

    Science.gov (United States)

    Zhang, Li; Zhao, Weijia; Niu, Changmei; Zhou, Yujie; Shi, Haiyan; Wang, Yalin; Yang, Yumin; Tang, Xin

    2018-07-01

    Tissue engineered nerve grafts (TENGs) are considered a promising alternative to autologous nerve grafting, which is considered the "gold standard" clinical strategy for peripheral nerve repair. Here, we immobilized tumor necrosis factor-α (TNF-α) inhibitors onto a nerve conduit, which was introduced into a chitosan (CS) matrix scaffold utilizing genipin (GP) as the crosslinking agent, to fabricate CS-GP-TNF-α inhibitor nerve conduits. The in vitro release kinetics of TNF-α inhibitors from the CS-GP-TNF-α inhibitor nerve conduits were investigated using high-performance liquid chromatography. The in vivo continuous release profile of the TNF-α inhibitors released from the CS-GP-TNF-α inhibitor nerve conduits was measured using an enzyme-linked immunosorbent assay over 14 days. We found that the amount of TNF-α inhibitors released decreased with time after the bridging of the sciatic nerve defects in rats. Moreover, 4 and 12 weeks after surgery, histological analyses and functional evaluations were carried out to assess the influence of the TENG on regeneration. Immunochemistry performed 4 weeks after grafting to assess early regeneration outcomes revealed that the TENG strikingly promoted axonal outgrowth. Twelve weeks after grafting, the TENG accelerated myelin sheath formation, as well as functional restoration. In general, the regenerative outcomes following TENG more closely paralleled findings observed with autologous grafting than the use of the CS matrix scaffold. Collectively, our data indicate that the CS-GP-TNF-α inhibitor nerve conduits comprised an elaborate system for sustained release of TNF-α inhibitors in vitro, while studies in vivo demonstrated that the TENG could accelerate regenerating axonal outgrowth and functional restoration. The introduction of CS-GP-TNF-α-inhibitor nerve conduits into a scaffold may contribute to an efficient and adaptive immune microenvironment that can be used to facilitate peripheral nerve repair.

  8. Impact of sodium–glucose cotransporter 2 inhibitors on blood pressure

    Directory of Open Access Journals (Sweden)

    Reed JW

    2016-10-01

    Full Text Available James W Reed Morehouse School of Medicine, Atlanta, GA, USA Abstract: SGLT2 inhibitors are glucose-lowering agents used to treat type 2 diabetes mellitus (T2DM. These agents target the kidney to promote urinary glucose excretion, resulting in improved blood glucose control. SGLT2-inhibitor therapy is also associated with weight loss and blood pressure (BP lowering. Hypertension is a common comorbidity in patients with T2DM, and is associated with excess morbidity and mortality. This review summarizes data on the effect of SGLT2 inhibitors marketed in the US (namely canagliflozin, dapagliflozin, or empagliflozin on BP in patients with T2DM. Boolean searches were conducted that included terms related to BP or hypertension with terms for SGLT2 inhibitors, canagliflozin, dapagliflozin, or empagliflozin using PubMed, Google, and Google Scholar. Data from numerous randomized controlled trials of SGLT2 inhibitors in patients with T2DM demonstrated clinically relevant reductions in both systolic and diastolic BP, assessed via seated office measurements and 24-hour ambulatory BP monitoring. Observed BP lowering was not associated with compensatory increases in heart rate. Circadian BP rhythm was also maintained. The mechanism of SGLT2 inhibitor-associated BP reduction is not fully understood, but is assumed to be related to osmotic diuresis and natriuresis. Other factors that may also contribute to BP reduction include SGLT2 inhibitor-associated decreases in body weight and reduced arterial stiffness. Local inhibition of the renin–angiotensin–aldosterone system secondary to increased delivery of sodium to the juxtaglomerular apparatus during SGLT2 inhibition has also been postulated. Although SGLT2 inhibitors are not indicated as BP-lowering agents, the modest decreases in systolic and diastolic BP observed with SGLT2 inhibitors may provide an extra clinical advantage for the majority of patients with T2DM, in addition to improving blood glucose

  9. PD-1/PD-L1 Inhibitors for Immuno-oncology: From Antibodies to Small Molecules.

    Science.gov (United States)

    Geng, Qiaohong; Jiao, Peifu; Jin, Peng; Su, Gaoxing; Dong, Jinlong; Yan, Bing

    2018-02-12

    The recent regulatory approvals of immune checkpoint protein inhibitors, such as ipilimumab, pembrolizumab, nivolumab, atezolizumab, durvalumab, and avelumab ushered a new era in cancer therapy. These inhibitors do not attack tumor cells directly but instead mobilize the immune system to re-recognize and eradicate tumors, which endows them with unique advantages including durable clinical responses and substantial clinical benefits. PD-1/PD-L1 inhibitors, a pillar of immune checkpoint protein inhibitors, have demonstrated unprecedented clinical efficacy in more than 20 cancer types. Besides monoclonal antibodies, diverse PD- 1/PD-L1 inhibiting candidates, such as peptides, small molecules have formed a powerful collection of weapons to fight cancer. The goal of this review is to summarize and discuss the current PD-1/PD-L1 inhibitors including candidates under clinical development, their molecular interactions with PD-1 or PD-L1, the disclosed structureactivity relationships of peptides and small molecules as inhibitors. Current PD-1/PD-L1 inhibitors under clinical development are exclusively dominated by antibodies. The molecular interactions of therapeutic antibodies with PD-1 or PD-L1 have been gradually elucidated for the design of novel inhibitors. Various peptides and traditional small molecules have been investigated in preclinical model to discover novel PD-1/PD-L1 inhibitors. Peptides and small molecules may play an important role in immuno-oncology because they may bind to multiple immune checkpoint proteins via rational design, opening opportunity for a new generation of novel PD-1/PD-L1 inhibitors. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  10. A Forceful Demonstration by FORS

    Science.gov (United States)

    1998-09-01

    .). In addition, detailed computer software was provided to prepare the complex astronomical observations with FORS in advance and to monitor the instrument performance by quality checks of the scientific data accumulated. In return for building FORS for the community of European astrophysicists, the scientists in the three institutions of the FORS Consortium have received a certain amount of Guaranteed Observing Time at the VLT. This time will be used for various research projects concerned, among others, with minor bodies in the outer solar system, stars at late stages of their evolution and the clouds of gas they eject, as well as galaxies and quasars at very large distances, thereby permitting a look-back towards the early epoch of the universe. First tests of FORS1 at the VLT UT1: a great success After careful preparation, the FORS consortium has now started the so-called commissioning of the instrument. This comprises the thorough verification of the specified instrument properties at the telescope, checking the correct functioning under software control from the Paranal control room and, at the end of this process, a demonstration that the instrument fulfills its scientific purpose as planned. While performing these tests, the commissioning team at Paranal were able to obtain images of various astronomical objects, some of which are shown here. Two of these were obtained on the night of "FORS First Light". The photos demonstrate some of the impressive posibilities with this new instrument. They are based on observations with the FORS standard resolution collimator (field size 6.8 x 6.8 armin = 2048 x 2048 pixels; 1 pixel = 0.20 arcsec). Spiral galaxy NGC 1288 ESO PR Photo 37a/98 ESO PR Photo 37a/98 [Preview - JPEG: 800 x 908 pix - 224k] [High-Res - JPEG: 3000 x 3406 pix - 1.5Mb] A colour image of spiral galaxy NGC 1288, obtained on the night of "FORS First Light". The first photo shows a reproduction of a colour composite image of the beautiful spiral galaxy NGC

  11. Small Molecule Inhibitors That Selectively Block Dengue Virus Methyltransferase*

    Science.gov (United States)

    Lim, Siew Pheng; Sonntag, Louis Sebastian; Noble, Christian; Nilar, Shahul H.; Ng, Ru Hui; Zou, Gang; Monaghan, Paul; Chung, Ka Yan; Dong, Hongping; Liu, Boping; Bodenreider, Christophe; Lee, Gladys; Ding, Mei; Chan, Wai Ling; Wang, Gang; Jian, Yap Li; Chao, Alexander Theodore; Lescar, Julien; Yin, Zheng; Vedananda, T. R.; Keller, Thomas H.; Shi, Pei-Yong

    2011-01-01

    Crystal structure analysis of Flavivirus methyltransferases uncovered a flavivirus-conserved cavity located next to the binding site for its cofactor, S-adenosyl-methionine (SAM). Chemical derivatization of S-adenosyl-homocysteine (SAH), the product inhibitor of the methylation reaction, with substituents that extend into the identified cavity, generated inhibitors that showed improved and selective activity against dengue virus methyltransferase (MTase), but not related human enzymes. Crystal structure of dengue virus MTase with a bound SAH derivative revealed that its N6-substituent bound in this cavity and induced conformation changes in residues lining the pocket. These findings demonstrate that one of the major hurdles for the development of methyltransferase-based therapeutics, namely selectivity for disease-related methyltransferases, can be overcome. PMID:21147775

  12. TYROSINE KINASE INHIBITORS AND PREGNANCY

    Directory of Open Access Journals (Sweden)

    Elisabetta Abruzzese

    2014-04-01

    Full Text Available The management of patients with chronic myeloid leukemia (CML during pregnancy has became recently a matter of continuous debate.  The introduction of the Tyrosine Kinase Inhibitors (TKIs in clinical practice has dramatically changed the prognosis of CML patients.  Patients diagnosed in chronic phase can reasonably expect many years of excellent disease control and good quality of life, as well as a normal life expectancy.  This fact has come the necessity to address issues relating to fertility and pregnancy. Physicians are not infrequently being asked for advice regarding the need for, and or the appropriateness of, stopping treatment in order to conceive. In this report we will review the data published in terms of fertility, conception, pregnancy, pregnancy outcome and illness control for all the approved TKIs, as well as suggest how to manage a planned and/or unplanned pregnancy.

  13. Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis.

    Science.gov (United States)

    Robertson, Lindsay; Kesteven, Patrick; McCaslin, James E

    2015-06-30

    11 randomised controlled trials of 27,945 participants. Three studies tested oral DTIs (two dabigatran and one ximelagatran), while eight tested oral factor Xa inhibitors (four rivaroxaban, two apixaban and two edoxaban). We deemed all included studies to be of high methodological quality and low risk of bias. The quality of the evidence was graded as high as the outcomes were direct and effect estimates were consistent and precise, as reflected in the narrow CIs around the ORs. Meta-analysis of three studies (7596 participants) comparing oral DTIs with standard anticoagulation groups showed no difference in the rate of recurrent VTE (OR 1.09; 95% CI 0.80 to 1.49), recurrent DVT (OR 1.08; 95% CI 0.74 to 1.58), fatal PE (OR 1.00; 95% CI 0.27 to 3.70), non-fatal PE (OR 1.12; 95% CI 0.66 to 1.90) or all-cause mortality (OR 0.82; 95% CI 0.60 to 1.13). However, oral DTIs were associated with reduced bleeding (OR 0.68; 95% CI 0.47 to 0.98). Meta-analysis of eight studies (16,356 participants) comparing oral factor Xa inhibitors with standard anticoagulation demonstrated a similar rate of recurrent VTE between the two treatments (OR 0.89; 95% CI 0.73 to 1.07). Oral factor Xa inhibitors were associated with a lower rate of recurrent DVT (OR 0.75; 95% CI 0.57 to 0.98). However, this was a weak association, heavily dependent on one study. The rate of fatal (OR 1.20; 95% CI 0.71 to 2.03), non-fatal PE (OR 0.94; 95% CI 0.68 to 1.28) and all-cause mortality (OR 0.90; 95% CI 0.65 to 1.23) was similar between the two treatment groups. Oral factor Xa inhibitors were also associated with reduced bleeding (OR 0.57; 95% CI 0.43 to 0.76). None of the included studies measured post-thrombotic syndrome or health-related quality of life. NOACs such as DTIs and factor Xa inhibitors may be an effective and safe alternative to conventional anticoagulation treatment for acute DVT.

  14. PTP1B inhibitor promotes endothelial cell motility by activating the DOCK180/Rac1 pathway.

    Science.gov (United States)

    Wang, Yuan; Yan, Feng; Ye, Qing; Wu, Xiao; Jiang, Fan

    2016-04-07

    Promoting endothelial cell (EC) migration is important not only for therapeutic angiogenesis, but also for accelerating re-endothelialization after vessel injury. Several recent studies have shown that inhibition of protein tyrosine phosphatase 1B (PTP1B) may promote EC migration and angiogenesis by enhancing the vascular endothelial growth factor receptor-2 (VEGFR2) signalling. In the present study, we demonstrated that PTP1B inhibitor could promote EC adhesion, spreading and migration, which were abolished by the inhibitor of Rac1 but not RhoA GTPase. PTP1B inhibitor significantly increased phosphorylation of p130Cas, and the interactions among p130Cas, Crk and DOCK180; whereas the phosphorylation levels of focal adhesion kinase, Src, paxillin, or Vav2 were unchanged. Gene silencing of DOCK180, but not Vav2, abrogated the effects of PTP1B inhibitor on EC motility. The effects of PTP1B inhibitor on EC motility and p130Cas/DOCK180 activation persisted in the presence of the VEGFR2 antagonist. In conclusion, we suggest that stimulation of the DOCK180 pathway represents an alternative mechanism of PTP1B inhibitor-stimulated EC motility, which does not require concomitant VEGFR2 activation as a prerequisite. Therefore, PTP1B inhibitor may be a useful therapeutic strategy for promoting EC migration in cardiovascular patients in which the VEGF/VEGFR functions are compromised.

  15. Interaction of HIV-1 reverse transcriptase ribonuclease H with an acylhydrazone inhibitor.

    Science.gov (United States)

    Gong, Qingguo; Menon, Lakshmi; Ilina, Tatiana; Miller, Lena G; Ahn, Jinwoo; Parniak, Michael A; Ishima, Rieko

    2011-01-01

    HIV-1 reverse transcriptase is a bifunctional enzyme, having both DNA polymerase (RNA- and DNA-dependent) and ribonuclease H activities. HIV-1 reverse transcriptase has been an exceptionally important target for antiretroviral therapeutic development, and nearly half of the current clinically used antiretrovirals target reverse transcriptase DNA polymerase. However, no inhibitors of reverse transcriptase ribonuclease H are on the market or in preclinical development. Several drug-like small molecule inhibitors of reverse transcriptase ribonuclease H have been described, but little structural information is available about the interactions between reverse transcriptase ribonuclease H and inhibitors that exhibit antiviral activity. In this report, we describe NMR studies of the interaction of a new ribonuclease H inhibitor, BHMP07, with a catalytically active HIV-1 reverse transcriptase ribonuclease H domain fragment. We carried out solution NMR experiments to identify the interaction interface of BHMP07 with the ribonuclease H domain fragment. Chemical shift changes of backbone amide signals at different BHMP07 concentrations clearly demonstrate that BHMP07 mainly recognizes the substrate handle region in the ribonuclease H fragment. Using ribonuclease H inhibition assays and reverse transcriptase mutants, the binding specificity of BHMP07 was compared with another inhibitor, dihydroxy benzoyl naphthyl hydrazone. Our results provide a structural characterization of the ribonuclease H inhibitor interaction and are likely to be useful for further improvements of the inhibitors. © 2010 John Wiley & Sons A/S.

  16. Synergistic efficacy in human ovarian cancer cells by histone deacetylase inhibitor TSA and proteasome inhibitor PS-341.

    Science.gov (United States)

    Fang, Yong; Hu, Yi; Wu, Peng; Wang, Beibei; Tian, Yuan; Xia, Xi; Zhang, Qinghua; Chen, Tong; Jiang, Xuefeng; Ma, Quanfu; Xu, Gang; Wang, Shixuan; Zhou, Jianfeng; Ma, Ding; Meng, Li

    2011-05-01

    Histone deacetylase inhibitors and proteasome inhibitor are all emerging as new classes of anticancer agents. We chose TSA and PS-341 to identify whether they have a synergistic efficacy on human ovarian cancer cells. After incubated with 500 nM TSA or/and 40 nM PS-341, we found that combined groups resulted in a striking increase of apoptosis and G2/M blocking rates, no matter in A2780, cisplatin-sensitive ovarian cancer cell line OV2008 or its resistant variant C13*. This demonstrated that TSA interacted synergistically with PS-341, which raised the possibility that combined the two drugs may represent a novel strategy in ovarian cancer.

  17. Discovery and SAR of hydantoin TACE inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Wensheng; Guo, Zhuyan; Orth, Peter; Madison, Vincent; Chen, Lei; Dai, Chaoyang; Feltz, Robert J.; Girijavallabhan, Vinay M.; Kim, Seong Heon; Kozlowski, Joseph A.; Lavey, Brian J.; Li, Dansu; Lundell, Daniel; Niu, Xiaoda; Piwinski, John J.; Popovici-Muller, Janeta; Rizvi, Razia; Rosner, Kristin E.; Shankar, Bandarpalle B.; Shih, Neng-Yang; Siddiqui, M.A.; Sun, J.; Tong, L.; Umland, S.; Wong, M.K.; Yang, D.Y.; Zhou, G. (Merck)

    2010-09-03

    We disclose inhibitors of TNF-{alpha} converting enzyme (TACE) designed around a hydantoin zinc binding moiety. Crystal structures of inhibitors bound to TACE revealed monodentate coordination of the hydantoin to the zinc. SAR, X-ray, and modeling designs are described. To our knowledge, these are the first reported X-ray structures of TACE with a hydantoin zinc ligand.

  18. Does plasminogen activator inhibitor-1 drive lymphangiogenesis?

    DEFF Research Database (Denmark)

    Bruyère, Françoise; Melen-Lamalle, Laurence; Blacher, Silvia

    2010-01-01

    The purpose of this study is to explore the function of plasminogen activator inhibitor-1 (PAI-1) during pathological lymphangiogenesis. PAI-1, the main physiological inhibitor of plasminogen activators is involved in pathological angiogenesis at least by controlling extracellular proteolysis and...

  19. Electrochemical Behaviour of Environmentally Friendly Inhibitor of ...

    African Journals Online (AJOL)

    Electrochemical Behaviour of Environmentally Friendly Inhibitor of Aloe Secundiflora Extract in Corrosion Control of Carbon Steel in Soft Water Media. ... The investigation was performed at different inhibitor concentrations under static and dynamic conditions using a Rotating Disk Electrode (RDE). The impedance and ...

  20. Efflux inhibitor suppresses Streptococcus mutans virulence properties.

    Science.gov (United States)

    Zeng, Huihui; Liu, Jia; Ling, Junqi

    2017-04-01

    It is well established that efflux pumps play important roles in bacterial pathogenicity and efflux inhibitors (EIs) have been proved to be effective in suppressing bacterial virulence properties. However, little is known regarding the EI of Streptococcus mutans, a well-known caries-inducing bacterium. In this study, we identified the EI of S. mutans through ethidium bromide efflux assay and investigated how EI affected S. mutans virulence regarding the cariogenicity and stress response. Results indicated that reserpine, the identified EI, suppressed acid tolerance, mutacin production and transformation efficiency of S. mutans, and modified biofilm architecture and extracellular polysaccharide distribution. Suppressed glycosyltransferase activity was also noted after reserpine exposure. The data from quantitative real-time-PCR demonstrated that reserpine significantly altered the expression profile of quorum-sensing and virulence-associated genes. These findings suggest that reserpine represents a promising adjunct anticariogenic agent in that it suppresses virulence properties of S. mutans. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  1. Reverse transcriptase inhibitors as potential colorectal microbicides.

    Science.gov (United States)

    Herrera, Carolina; Cranage, Martin; McGowan, Ian; Anton, Peter; Shattock, Robin J

    2009-05-01

    We investigated whether reverse transcriptase (RT) inhibitors (RTI) can be combined to inhibit human immunodeficiency virus type 1 (HIV-1) infection of colorectal tissue ex vivo as part of a strategy to develop an effective rectal microbicide. The nucleotide RTI (NRTI) PMPA (tenofovir) and two nonnucleoside RTI (NNRTI), UC-781 and TMC120 (dapivirine), were evaluated. Each compound inhibited the replication of the HIV isolates tested in TZM-bl cells, peripheral blood mononuclear cells, and colorectal explants. Dual combinations of the three compounds, either NRTI-NNRTI or NNRTI-NNRTI combinations, were more active than any of the individual compounds in both cellular and tissue models. Combinations were key to inhibiting infection by NRTI- and NNRTI-resistant isolates in all models tested. Moreover, we found that the replication capacities of HIV-1 isolates in colorectal explants were affected by single point mutations in RT that confer resistance to RTI. These data demonstrate that colorectal explants can be used to screen compounds for potential efficacy as part of a combination microbicide and to determine the mucosal fitness of RTI-resistant isolates. These findings may have important implications for the rational design of effective rectal microbicides.

  2. Histone deacetylase inhibitors (HDACIs: multitargeted anticancer agents

    Directory of Open Access Journals (Sweden)

    Ververis K

    2013-02-01

    Full Text Available Katherine Ververis,1 Alison Hiong,1 Tom C Karagiannis,1,* Paul V Licciardi2,*1Epigenomic Medicine, Alfred Medical Research and Education Precinct, 2Allergy and Immune Disorders, Murdoch Childrens Research Institute, Melbourne, VIC, Australia*These authors contributed equally to this workAbstract: Histone deacetylase (HDAC inhibitors are an emerging class of therapeutics with potential as anticancer drugs. The rationale for developing HDAC inhibitors (and other chromatin-modifying agents as anticancer therapies arose from the understanding that in addition to genetic mutations, epigenetic changes such as dysregulation of HDAC enzymes can alter phenotype and gene expression, disturb homeostasis, and contribute to neoplastic growth. The family of HDAC inhibitors is large and diverse. It includes a range of naturally occurring and synthetic compounds that differ in terms of structure, function, and specificity. HDAC inhibitors have multiple cell type-specific effects in vitro and in vivo, such as growth arrest, cell differentiation, and apoptosis in malignant cells. HDAC inhibitors have the potential to be used as monotherapies or in combination with other anticancer therapies. Currently, there are two HDAC inhibitors that have received approval from the US FDA for the treatment of cutaneous T-cell lymphoma: vorinostat (suberoylanilide hydroxamic acid, Zolinza and depsipeptide (romidepsin, Istodax. More recently, depsipeptide has also gained FDA approval for the treatment of peripheral T-cell lymphoma. Many more clinical trials assessing the effects of various HDAC inhibitors on hematological and solid malignancies are currently being conducted. Despite the proven anticancer effects of particular HDAC inhibitors against certain cancers, many aspects of HDAC enzymes and HDAC inhibitors are still not fully understood. Increasing our understanding of the effects of HDAC inhibitors, their targets and mechanisms of action will be critical for the

  3. Potential physiological role of plant glycosidase inhibitors

    DEFF Research Database (Denmark)

    Bellincampi, D.; Carmadella, L.; Delcour, J.A.

    2004-01-01

    Carbohydrate-active enzymes including glycosidases, transglycosidases, glycosyltransferases, polysaccharide lyases and carbohydrate esterases are responsible for the enzymatic processing of carbohydrates in plants. A number of carbohydrate-active enzymes are produced by microbial pathogens...... and insects responsible of severe crop losses. Plants have evolved proteinaceous inhibitors to modulate the activity of several of these enzymes. The continuing discovery of new inhibitors indicates that this research area is still unexplored and may lead to new exciting developments. To date, the role...... of the inhibitors is not completely understood. Here we review recent results obtained on the best characterised inhibitors, pointing to their possible biological role in vivo. Results recently obtained with plant transformation technology indicate that this class of inhibitors has potential biotechnological...

  4. Histone deacetylase inhibitors improve the replication of oncolytic herpes simplex virus in breast cancer cells.

    Directory of Open Access Journals (Sweden)

    James J Cody

    Full Text Available New therapies are needed for metastatic breast cancer patients. Oncolytic herpes simplex virus (oHSV is an exciting therapy being developed for use against aggressive tumors and established metastases. Although oHSV have been demonstrated safe in clinical trials, a lack of sufficient potency has slowed the clinical application of this approach. We utilized histone deacetylase (HDAC inhibitors, which have been noted to impair the innate antiviral response and improve gene transcription from viral vectors, to enhance the replication of oHSV in breast cancer cells. A panel of chemically diverse HDAC inhibitors were tested at three different doses (LD50 for their ability to modulate the replication of oHSV in breast cancer cells. Several of the tested HDAC inhibitors enhanced oHSV replication at low multiplicity of infection (MOI following pre-treatment of the metastatic breast cancer cell line MDA-MB-231 and the oHSV-resistant cell line 4T1, but not in the normal breast epithelial cell line MCF10A. Inhibitors of class I HDACs, including pan-selective compounds, were more effective for increasing oHSV replication compared to inhibitors that selectively target class II HDACs. These studies demonstrate that select HDAC inhibitors increase oHSV replication in breast cancer cells and provides support for pre-clinical evaluation of this combination strategy.

  5. Didactic demonstrations of superfluidity and superconductivity phenomena

    International Nuclear Information System (INIS)

    Aniola-Jedrzejak, L.; Lewicki, A.; Pilipowicz, A.; Tarnawski, Z.; Bialek, H.

    1980-01-01

    In order to demonstrate to students phenomena of superfluidity and superconductivity a special helium cryostat has been constructed. The demonstrated effects, construction of the cryostat and the method of demonstration are described. (author)

  6. High-throughput screening assay of hepatitis C virus helicase inhibitors using fluorescence-quenching phenomenon

    International Nuclear Information System (INIS)

    Tani, Hidenori; Akimitsu, Nobuyoshi; Fujita, Osamu; Matsuda, Yasuyoshi; Miyata, Ryo; Tsuneda, Satoshi; Igarashi, Masayuki; Sekiguchi, Yuji; Noda, Naohiro

    2009-01-01

    We have developed a novel high-throughput screening assay of hepatitis C virus (HCV) nonstructural protein 3 (NS3) helicase inhibitors using the fluorescence-quenching phenomenon via photoinduced electron transfer between fluorescent dyes and guanine bases. We prepared double-stranded DNA (dsDNA) with a 5'-fluorescent-dye (BODIPY FL)-labeled strand hybridized with a complementary strand, the 3'-end of which has guanine bases. When dsDNA is unwound by helicase, the dye emits fluorescence owing to its release from the guanine bases. Our results demonstrate that this assay is suitable for quantitative assay of HCV NS3 helicase activity and useful for high-throughput screening for inhibitors. Furthermore, we applied this assay to the screening for NS3 helicase inhibitors from cell extracts of microorganisms, and found several cell extracts containing potential inhibitors.

  7. New generation LDHI with an improved environmental profile[Low dosage hydrate inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Fu, Bob; Houston, Christopher; Spratt, Tony

    2005-07-01

    A new generation of low dosage hydrate inhibitors has been developed. These inhibitors are specially designed and synthesized in the laboratory in order to achieve a high level of performance as hydrate inhibitors and to improve their environmental profiles. These new inhibitors have been extensively evaluated in the laboratory using high pressure rocking cells. They function like anti-agglomerants by preventing the formation of large hydrate crystals or agglomerates. The resulting hydrate crystals are extremely tiny and finely dispersed in the hydrocarbon stream. In addition to controlling the hydrate crystal growth, these novel molecules demonstrate the ability to extend the induction time to onset of hydrate formation. When compared to the previous generations, the improved performance as well as the favorable environmental characteristics further expand the window for LDHI applications in the fields. (Author)

  8. Fatty Amides from Crude Rice Bran Oil as Green Corrosion Inhibitors

    Directory of Open Access Journals (Sweden)

    E. Reyes-Dorantes

    2017-01-01

    Full Text Available Due to its high oil content, this research proposes the use of an agroindustrial byproduct (rice bran as a sustainable option for the synthesis of corrosion inhibitors. From the crude rice bran oil, the synthesis of fatty amide-type corrosion inhibitors was carried out. The corrosion inhibitory capacity of the fatty amides was evaluated on an API X-70 steel using electrochemical techniques such as real-time corrosion monitoring and potentiodynamic polarization curves. As a corrosive medium, a CO2-saturated solution (3.5% NaCl was used at three temperatures (30, 50, and 70°C and different concentrations of inhibitor (0, 5, 10, 25, 50, and 100 ppm. The results demonstrate that the sustainable use of agroindustrial byproducts is a good alternative to the synthesis of environmentally friendly inhibitors with high corrosion inhibition efficiencies.

  9. Inhibitor Risk Stratification and Individualized Treatment in Patients With Nonsevere Hemophilia A: A Single-Institution Practice Audit.

    Science.gov (United States)

    Sun, Haowei Linda; Chan, Stella; Yenson, Paul; Jackson, Shannon

    2018-03-01

    Inhibitor risk in nonsevere hemophilia A increases with cumulative factor VIII (FVIII) exposure days and high-risk mutations. A standardized approach to minimize inhibitor risk is warranted. Following establishment of a systematic approach to reduce inhibitor risk in nonsevere hemophilia, we evaluated the uptake of these strategies into clinical practice. All adult males with nonsevere hemophilia A followed by British Columbia Adult Hemophilia Program from 2004 to 2016 were included in this retrospective audit. Quality-of-care indicators on inhibitor prevention were examined. Of 108 patients, 18 patients had high-risk FVIII mutations for inhibitor development. Rates of FVIII genotyping and 1-deamino-8-d-arginine-vasopressin (DDAVP) testing in mild patients without contraindications were both over 90%, although DDAVP was used for surgical prophylaxis in only 70% of procedures. Inhibitor testing and clinic visits occurred at a median interval of 22 months. Over 80% of patients with high-risk mutations had documentation and education on their inhibitor risk. Our practice audit demonstrated a high level of recognition and patient education of individual inhibitor risk. Impact of our standardized approach on the incidence of inhibitor development is yet to be determined.

  10. Sertraline demonstrates fungicidal activity in vitro for Coccidioides immitis

    Directory of Open Access Journals (Sweden)

    Simon Paul

    2016-07-01

    Full Text Available Coccidioidomycosis causes substantial morbidity in endemic areas. Disseminated coccidioidomycosis is an AIDS defining condition and treatment often requires lifelong antifungal therapy. Sertraline, a widely used serotonin-reuptake inhibitor anti-depressant, has demonstrated activity against Candida and Cryptococcus sp. both in vitro and in vivo. To evaluate if sertraline has activity against Coccidioides, the minimal inhibitory concentration (MIC and minimal fungicidal concentration (MFC of sertraline for four clinical isolates of C. immitis were determined. Sertraline was observed to have an MIC range of 4–8 µg/ml and MFC also of 4–8 µg/ml for Coccidioides. These MIC and MFC results for C. immitis are similar to those reported for Cryptococcus sp. suggesting sertraline may potentially have utility for the treatment of coccidioidomycosis.

  11. The Wonders of Phosphodiesterase‑5 Inhibitors: A Majestic History

    African Journals Online (AJOL)

    A milestone in drug discovery was the selective inhibitors of. PDE‑5 that ... the pharmacotherapeutics of PDE‑5 inhibitors and the majestic history that led to their discovery. ..... including HIV protease inhibitors, ketoconazole, itraconazole,.

  12. Impact of sodium–glucose cotransporter 2 inhibitors on blood pressure

    Science.gov (United States)

    Reed, James W

    2016-01-01

    SGLT2 inhibitors are glucose-lowering agents used to treat type 2 diabetes mellitus (T2DM). These agents target the kidney to promote urinary glucose excretion, resulting in improved blood glucose control. SGLT2-inhibitor therapy is also associated with weight loss and blood pressure (BP) lowering. Hypertension is a common comorbidity in patients with T2DM, and is associated with excess morbidity and mortality. This review summarizes data on the effect of SGLT2 inhibitors marketed in the US (namely canagliflozin, dapagliflozin, or empagliflozin) on BP in patients with T2DM. Boolean searches were conducted that included terms related to BP or hypertension with terms for SGLT2 inhibitors, canagliflozin, dapagliflozin, or empagliflozin using PubMed, Google, and Google Scholar. Data from numerous randomized controlled trials of SGLT2 inhibitors in patients with T2DM demonstrated clinically relevant reductions in both systolic and diastolic BP, assessed via seated office measurements and 24-hour ambulatory BP monitoring. Observed BP lowering was not associated with compensatory increases in heart rate. Circadian BP rhythm was also maintained. The mechanism of SGLT2 inhibitor-associated BP reduction is not fully understood, but is assumed to be related to osmotic diuresis and natriuresis. Other factors that may also contribute to BP reduction include SGLT2 inhibitor-associated decreases in body weight and reduced arterial stiffness. Local inhibition of the renin–angiotensin–aldosterone system secondary to increased delivery of sodium to the juxtaglomerular apparatus during SGLT2 inhibition has also been postulated. Although SGLT2 inhibitors are not indicated as BP-lowering agents, the modest decreases in systolic and diastolic BP observed with SGLT2 inhibitors may provide an extra clinical advantage for the majority of patients with T2DM, in addition to improving blood glucose control. PMID:27822054

  13. Structure-Based Design of Potent and Selective 3-Phosphoinositide-Dependent Kinase-1 (PDK1) Inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Medina, Jesus R.; Becker, Christopher J.; Blackledge, Charles W.; Duquenne, Celine; Feng, Yanhong; Grant, Seth W.; Heerding, Dirk; Li, William H.; Miller, William H.; Romeril, Stuart P.; Scherzer, Daryl; Shu, Arthur; Bobko, Mark A.; Chadderton, Antony R.; Dumble, Melissa; Gardiner, Christine M.; Gilbert, Seth; Liu, Qi; Rabindran, Sridhar K.; Sudakin, Valery; Xiang, Hong; Brady, Pat G.; Campobasso, Nino; Ward, Paris; Axten, Jeffrey M. (GSKPA)

    2014-10-02

    Phosphoinositide-dependent protein kinase-1(PDK1) is a master regulator of the AGC family of kinases and an integral component of the PI3K/AKT/mTOR pathway. As this pathway is among the most commonly deregulated across all cancers, a selective inhibitor of PDK1 might have utility as an anticancer agent. Herein we describe our lead optimization of compound 1 toward highly potent and selective PDK1 inhibitors via a structure-based design strategy. The most potent and selective inhibitors demonstrated submicromolar activity as measured by inhibition of phosphorylation of PDK1 substrates as well as antiproliferative activity against a subset of AML cell lines. In addition, reduction of phosphorylation of PDK1 substrates was demonstrated in vivo in mice bearing OCl-AML2 xenografts. These observations demonstrate the utility of these molecules as tools to further delineate the biology of PDK1 and the potential pharmacological uses of a PDK1 inhibitor.

  14. Developing selective histone deacetylases (HDACs inhibitors through ebselen and analogs

    Directory of Open Access Journals (Sweden)

    Wang Y

    2017-05-01

    cell death of multiple tumor cell lines in a dose-dependent manner. These results demonstrated that ebselen and ebsulfur analogs are inhibitors of HDACs, supporting further preclinical development of this class of compounds for potential therapeutic applications. Keywords: HDAC, inhibitor, ebselen, RBC-2008, screening, compound library, drug discovery

  15. Squash inhibitor family of serine proteinases

    International Nuclear Information System (INIS)

    Otlewski, J.; Krowarsch, D.

    1996-01-01

    Squash inhibitors of serine proteinases form an uniform family of small proteins. They are built of 27-33 amino-acid residues and cross-linked with three disulfide bridges. The reactive site peptide bond (P1-P1') is between residue 5 (Lys, Arg or Leu) and 6 (always Ile). High resolution X-ray structures are available for two squash inhibitors complexed with trypsin. NMR solution structures have also been determined for free inhibitors. The major structural motif is a distorted, triple-stranded antiparallel beta-sheet. A similar folding motif has been recently found in a number of proteins, including: conotoxins from fish-hunting snails, carboxypeptidase inhibitor from potato, kalata B1 polypeptide, and in some growth factors (e.g. nerve growth factor, transforming growth factor β2, platelet-derived growth factor). Squash inhibitors are highly stable and rigid proteins. They inhibit a number of serine proteinases: trypsin, plasmin, kallikrein, blood clotting factors: X a and XII a , cathepsin G. The inhibition spectrum can be much broadened if specific amino-acid substitutions are introduced, especially at residues which contact proteinase. Squash inhibitors inhibit proteinases via the standard mechanism. According to the mechanism, inhibitors are substrates which exhibit at neutral pH a high k cat /K m index for hydrolysis and resynthesis of the reactive site, and a low value of the hydrolysis constant. (author)

  16. Histone Deacetylase Inhibitors as Anticancer Drugs.

    Science.gov (United States)

    Eckschlager, Tomas; Plch, Johana; Stiborova, Marie; Hrabeta, Jan

    2017-07-01

    Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC) and histone acetyltransferases (HAT). HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities.

  17. Histone Deacetylase Inhibitors as Anticancer Drugs

    Directory of Open Access Journals (Sweden)

    Tomas Eckschlager

    2017-07-01

    Full Text Available Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC and histone acetyltransferases (HAT. HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities.

  18. Discovery and Characterization of Novel Nonsubstrate and Substrate NAMPT Inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Wilsbacher, Julie L.; Cheng, Min; Cheng, Dong; Trammell, Samuel A.J.; Shi, Yan; Guo, Jun; Koeniger, Stormy L.; Kovar, Peter J.; He, Yupeng; Selvaraju, Sujatha; Heyman, H. Robin; Sorensen, Bryan K.; Clark, Richard F.; Hansen, T. Matthew; Longenecker, Kenton L.; Raich, Diana; Korepanova, Alla V.; Cepa, Steven; Towne, Danli L.; Abraham, Vivek C.; Tang, Hua; Richardson, Paul L.; McLoughlin, Shaun M.; Badagnani, Ilaria; Curtin, Michael L.; Michaelides, Michael R.; Maag, David; Buchanan, F. Gregory; Chiang, Gary G.; Gao, Wenqing; Rosenberg, Saul H.; Brenner, Charles; Tse, Chris (AbbVie)

    2017-05-03

    Cancer cells are highly reliant on NAD+-dependent processes, including glucose metabolism, calcium signaling, DNA repair, and regulation of gene expression. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ salvage from nicotinamide, has been investigated as a target for anticancer therapy. Known NAMPT inhibitors with potent cell activity are composed of a nitrogen-containing aromatic group, which is phosphoribosylated by the enzyme. Here, we identified two novel types of NAM-competitive NAMPT inhibitors, only one of which contains a modifiable, aromatic nitrogen that could be a phosphoribosyl acceptor. Both types of compound effectively deplete cellular NAD+, and subsequently ATP, and produce cell death when NAMPT is inhibited in cultured cells for more than 48 hours. Careful characterization of the kinetics of NAMPT inhibition in vivo allowed us to optimize dosing to produce sufficient NAD+ depletion over time that resulted in efficacy in an HCT116 xenograft model. Our data demonstrate that direct phosphoribosylation of competitive inhibitors by the NAMPT enzyme is not required for potent in vitro cellular activity or in vivo antitumor efficacy. Mol Cancer Ther; 16(7); 1236–45.

  19. Immune checkpoint inhibitors for nonsmall cell lung cancer treatment

    Directory of Open Access Journals (Sweden)

    Yuh-Min Chen

    2017-01-01

    Full Text Available Immune checkpoint inhibition with blocking antibodies that target cytotoxic T-lymphocyte antigen-4 (CTLA-4 and the programmed cell death protein 1 (PD-1 pathway [PD-1/programmed death-ligand 1 (PD-L1] have demonstrated promise in a variety of malignancies. While ipilimumab has been approved as a CTLA-4 blocking antibody by the US Food and Drug Administration for the treatment of advanced melanoma, it is still not approved for lung cancer treatment. In contrast, nivolumab and pembrolizumab, both PD-1 blocking antibodies, have been approved for second-line treatment of nonsmall cell lung cancer in 2015 because of their high potency and long-lasting effects in some patient subgroups. Other PD-1 and PD-L1 monoclonal antibodies are also in active development phase. Treatment with such immune checkpoint inhibitors is associated with a unique pattern of immune-related adverse events or side effects. Combination approaches involving CTLA-4 and PD-1/PD-L1 blockade or checkpoint inhibitors with chemotherapy or radiotherapy are being investigated to determine whether they may enhance the efficacy of treatment. Despite many challenges ahead, immunotherapy with checkpoint inhibitors has already become a new and important treatment modality for lung cancer in the last decade following the discovery of targeted therapy.

  20. PCSK9 Inhibitors: Treating the Right Patients in Daily Practice.

    Science.gov (United States)

    King, Peta; Nicholls, Stephen J

    2017-08-01

    Monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) have emerged as a novel approach to low-density lipoprotein cholesterol (LDL-C) lowering. The potential role of PCSK9 inhibitors in clinical practice will be reviewed. Clinical trials have demonstrated that PCSK9 inhibitors produce robust LDL-C lowering when administered either as monotherapy or in combination with statins. This provides the opportunity to achieve effective lipid lowering in familial hypercholesterolemia, patients with either established atherosclerotic cardiovascular disease or high risk primary prevention and an important opportunity to treat patients with statin intolerance. The findings from plaque imaging and patients with established atherosclerotic cardiovascular disease suggest that PCSK9 inhibition has favorable outcomes beyond improving lipid profiles, which has the opportunity to expand their use. PCSK9 inhibitors represent a new approach to achieving effective cardiovascular risk reduction in a broader number of patients. How these agents will be taken up in clinical practice remains to be determined.

  1. Reverse transcriptase inhibitors as microbicides.

    Science.gov (United States)

    Lewi, Paul; Heeres, Jan; Ariën, Kevin; Venkatraj, Muthusamy; Joossens, Jurgen; Van der Veken, Pieter; Augustyns, Koen; Vanham, Guido

    2012-01-01

    The CAPRISA 004 study in South Africa has accelerated the development of vaginal and rectal microbicides containing antiretrovirals that target specific enzymes in the reproduction cycle of HIV, especially reverse transcriptase inhibitors (RTI). In this review we discuss the potential relevance of HIV-1 RTIs as microbicides, focusing in the nucleotide RTI tenofovir and six classes of nonnucleoside RTIs (including dapivirine, UC781, urea and thiourea PETTs, DABOs and a pyrimidinedione). Although tenofovir and dapivirine appear to be most advanced in clinical trials as potential microbicides, several issues remain unresolved, e.g., the importance of nonhuman primates as a "gatekeeper" for clinical trials, the emergence and spread of drug-resistant mutants, the combination of microbicides that target different phases of viral reproduction and the accessibility to microbicides in low-income countries. Thus, here we discuss the latest research on RTI as microbicides in the light of the continuing spread of the HIV pandemic from the point of view of medicinal chemistry, virological, and pharmaceutical studies.

  2. ALK inhibitors, a pharmaceutical perspective

    Directory of Open Access Journals (Sweden)

    Arturo eGalvani

    2012-02-01

    Full Text Available In 2007, the ALK tyrosine kinase, already known to be translocated and activated in Anaplastic Large Cell Lymphoma, and a few other rare cancers, was described as a potential therapeutic target for a subset of non small-cell lung cancer (NSCLC patients. Clinical proof of concept, culminating in the recent approval by the FDA of the Pfizer drug Xalkori (crizotinib, formerly known as PF-02341066 followed in record time. The drug was approved together with a companion diagnostic, the Vysis ALK Break Apart FISH Probe Kit (Abbott Molecular, Inc. for detection of eligible patients. This remarkable example of the coming of age of personalized medicine in cancer therapy is hopefully only an auspice of things to come in this rapidly developing field. Perhaps unsurprisingly, however, the appearance of clinical acquired resistance to crizotinib has already been observed early on in clinical testing, with the identification of several ALK secondary point mutations which diminish drug efficacy, and which open the way for development of second-generation inhibitors. It is also emerging that acquired resistance to crizotinib may also occur through ALK-independent mechanisms, which still need to be elucidated in detail.

  3. SGLT2 Inhibitors May Predispose to Ketoacidosis.

    Science.gov (United States)

    Taylor, Simeon I; Blau, Jenny E; Rother, Kristina I

    2015-08-01

    Sodium glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic drugs that increase urinary excretion of glucose, thereby improving glycemic control and promoting weight loss. Since approval of the first-in-class drug in 2013, data have emerged suggesting that these drugs increase the risk of diabetic ketoacidosis. In May 2015, the Food and Drug Administration issued a warning that SGLT2 inhibitors may lead to ketoacidosis. Using PubMed and Google, we conducted Boolean searches including terms related to ketone bodies or ketoacidosis with terms for SGLT2 inhibitors or phlorizin. Priority was assigned to publications that shed light on molecular mechanisms whereby SGLT2 inhibitors could affect ketone body metabolism. SGLT2 inhibitors trigger multiple mechanisms that could predispose to diabetic ketoacidosis. When SGLT2 inhibitors are combined with insulin, it is often necessary to decrease the insulin dose to avoid hypoglycemia. The lower dose of insulin may be insufficient to suppress lipolysis and ketogenesis. Furthermore, SGLT2 is expressed in pancreatic α-cells, and SGLT2 inhibitors promote glucagon secretion. Finally, phlorizin, a nonselective inhibitor of SGLT family transporters decreases urinary excretion of ketone bodies. A decrease in the renal clearance of ketone bodies could also increase the plasma ketone body levels. Based on the physiology of SGLT2 and the pharmacology of SGLT2 inhibitors, there are several biologically plausible mechanisms whereby this class of drugs has the potential to increase the risk of developing diabetic ketoacidosis. Future research should be directed toward identifying which patients are at greatest risk for this side effect and also to optimizing pharmacotherapy to minimize the risk to patients.

  4. Ocular Toxicity Profile of ST-162 and ST-168 as Novel Bifunctional MEK/PI3K Inhibitors.

    Science.gov (United States)

    Smith, Andrew; Pawar, Mercy; Van Dort, Marcian E; Galbán, Stefanie; Welton, Amanda R; Thurber, Greg M; Ross, Brian D; Besirli, Cagri G

    2018-04-30

    ST-162 and ST-168 are small-molecule bifunctional inhibitors of MEK and PI3K signaling pathways that are being developed as novel antitumor agents. Previous small-molecule and biologic MEK inhibitors demonstrated ocular toxicity events that were dose limiting in clinical studies. We evaluated in vitro and in vivo ocular toxicity profiles of ST-162 and ST-168. Photoreceptor cell line 661W and adult retinal pigment epithelium cell line ARPE-19 were treated with increasing concentrations of bifunctional inhibitors. Western blots, cell viability, and caspase activity assays were performed to evaluate MEK and PI3K inhibition and dose-dependent in vitro toxicity, and compared with monotherapy. In vivo toxicity profile was assessed by intravitreal injection of ST-162 and ST-168 in Dutch-Belted rabbits, followed by ocular examination and histological analysis of enucleated eyes. Retinal cell lines treated with ST-162 or ST-168 exhibited dose-dependent inhibition of MEK and PI3K signaling. Compared with inhibition by monotherapies and their combinations, bifunctional inhibitors demonstrated reduced cell death and caspase activity. In vivo, both bifunctional inhibitors exhibited a more favorable toxicity profile when compared with MEK inhibitor PD0325901. Novel MEK and PI3K bifunctional inhibitors ST-162 and ST-168 demonstrate favorable in vitro and in vivo ocular toxicity profiles, supporting their further development as potential therapeutic agents targeting multiple aggressive tumors.

  5. Enzyme structure and interaction with inhibitors

    International Nuclear Information System (INIS)

    London, R.E.

    1983-01-01

    This article reviews some of the results of studies on the 13 C-labeled enzyme dihydrofolate reductase (DHFR). Nuclear magnetic resonance (NMR) techniques are used in combination with isotopic labeling to learn about the structure and dynamics of this enzyme. 13 C-labeling is used for the purpose of studying enzyme/substrate and enzyme/inhibitor interactions. A second set of studies with DHFR was designed to investigate the basis for the high affinity between the inhibitor methotrexate and DHFR. The label was placed on the inhibitor, rather than the enzyme

  6. An Updated Review of Tyrosinase Inhibitors

    Directory of Open Access Journals (Sweden)

    Te-Sheng Chang

    2009-05-01

    Full Text Available Tyrosinase is a multifunctional, glycosylated, and copper-containing oxidase, which catalyzes the first two steps in mammalian melanogenesis and is responsible for enzymatic browning reactions in damaged fruits during post-harvest handling and processing. Neither hyperpigmentation in human skin nor enzymatic browning in fruits are desirable. These phenomena have encouraged researchers to seek new potent tyrosinase inhibitors for use in foods and cosmetics. This article surveys tyrosinase inhibitors newly discovered from natural and synthetic sources. The inhibitory strength is compared with that of a standard inhibitor, kojic acid, and their inhibitory mechanisms are discussed.

  7. Application of chemical arrays in screening elastase inhibitors.

    Science.gov (United States)

    Gao, Feng; Du, Guan-Hua

    2006-06-01

    Protein chip technology provides a new and useful tool for high-throughput screening of drugs because of its high performance and low sample consumption. In order to screen elastase inhibitors on a large scale, we designed a composite microarray integrating enzyme chip containing chemical arrays on glass slides to screen for enzymatic inhibitors. The composite microarray includes an active proteinase film, screened chemical arrays distributed on the film, and substrate microarrays to demonstrate change of color. The detection principle is that elastase hydrolyzes synthetic colorless substrates and turns them into yellow products. Because yellow is difficult to detect, bromochlorophenol blue (BPB) was added into substrate solutions to facilitate the detection process. After the enzyme had catalyzed reactions for 2 h, effects of samples on enzymatic activity could be determined by detecting color change of the spots. When chemical samples inhibited enzymatic activity, substrates were blue instead of yellow products. If the enzyme retained its activity, the yellow color of the products combined with blue of BPB to make the spots green. Chromogenic differences demonstrated whether chemicals inhibited enzymatic activity or not. In this assay, 11,680 compounds were screened, and two valuable chemical hits were identified, which demonstrates that this assay is effective, sensitive and applicable for high-throughput screening (HTS).

  8. Efficacy of the JAK2 inhibitor INCB16562 in a murine model of MPLW515L-induced thrombocytosis and myelofibrosis

    OpenAIRE

    Koppikar, Priya; Abdel-Wahab, Omar; Hedvat, Cyrus; Marubayashi, Sachie; Patel, Jay; Goel, Aviva; Kucine, Nicole; Gardner, Jeffrey R.; Combs, Andrew P.; Vaddi, Kris; Haley, Patrick J.; Burn, Timothy C.; Rupar, Mark; Bromberg, Jacqueline F.; Heaney, Mark L.

    2010-01-01

    The discovery of JAK2 and MPL mutations in patients with myeloproliferative neoplasms (MPNs) provided important insight into the genetic basis of these disorders and led to the development of JAK2 kinase inhibitors for MPN therapy. Although recent studies have shown that JAK2 kinase inhibitors demonstrate efficacy in a JAK2V617F murine bone marrow transplantation model, the effects of JAK2 inhibitors on MPLW515L-mediated myeloproliferation have not been investigated. In this report, we descri...

  9. Tea Contains Potent Inhibitors of Tyrosine Phosphatase PTP1B

    OpenAIRE

    Ma, Junfeng; Li, Zhe; Xing, Shu; Ho, Wanting Tina; Fu, Xueqi; Zhao, Zhizhuang Joe

    2011-01-01

    Tea is widely consumed all over the world. Studies have demonstrated the role of tea in prevention and treatment of various chronic diseases including diabetes and obesity, but the underlying mechanism is unclear. PTP1B is a widely expressed tyrosine phosphatase which has been defined as a target for therapeutic drug development to treat diabetes and obesity. In screening for inhibitors of PTP1B, we found that aqueous extracts of teas exhibited potent PTP1B inhibitory effects with an IC50 val...

  10. Transient protective effect of caspase inhibitors in RCS rat.

    Science.gov (United States)

    Perche, O; Doly, M; Ranchon-Cole, I

    2008-03-01

    In most retinal degenerations in humans and in animal models, photoreceptor cells die by apoptosis. Although the biochemical features are similar in all apoptotic cells, different molecular events lead the cell to death. In the present study we used a rat model of inherited retinal degeneration, the RCS rats, to investigate the involvement of the proteases, caspases and/or calpains, in photoreceptor apoptosis. In the first experiments, rats were untreated or injected intravitreally at post natal day 27 (P27) with the large broad spectrum caspase inhibitor, ZVAD, the calpain inhibitor, MuhPhe, or with the vehicle, DMSO. Retinal status was evaluated at P35 and P42 by electroretinography, morphometry and apoptotic nuclei detection. DMSO and MuhPhe had no effect on RCS retinas as evidenced by equivalent loss of function and equivalent number of apoptotic cells than in untreated group. ZVAD transiently reduced apoptotic cells and preserved photoreceptor function at P35 but not at P42. These results suggest that caspases but not calpains are involved in retinal degeneration in the RCS. In the second experiments, RCS rats were injected twice at P27 and P35 with ZVAD or DMSO. Although ZVAD-treated retinas were preserved at P35 compared to the DMSO controls, the second injection of ZVAD did not extend the preserving effect to P42. Moreover, a single injection of ZVAD at P35 had no preserving effect at P42. All these data taken together suggest that caspases do not play a pivotal role after P35. In a fourth set of experiments, we used specific caspase inhibitors to elucidate which caspase was activated. The caspase-1/4 inhibitor (YVAD) or the caspase-3/7 inhibitor (DEVD) were injected intravitreally at P27 and retinal status was evaluated at P35 and P42. Electroretinograms and apoptotic nuclei detection demonstrated that YVAD and DEVD preserved photoreceptors at P35 but not at P42. These results suggest that both caspase-1/4 and caspase-3/7 play a major role in the apoptotic

  11. Strategies for discontinuation of proton pump inhibitors

    DEFF Research Database (Denmark)

    Haastrup, Peter; Paulsen, Maja S; Begtrup, Luise M

    2014-01-01

    PURPOSE: Proton pump inhibitors (PPIs) are considered to be overprescribed. Consensus on how to attempt discontinuation is, however, lacking. We therefore conducted a systematic review of clinical studies on discontinuation of PPIs. METHODS: Systematic review based on clinical studies investigating...

  12. Predicting the Performance of Organic Corrosion Inhibitors

    Directory of Open Access Journals (Sweden)

    David A. Winkler

    2017-12-01

    Full Text Available The withdrawal of effective but toxic corrosion inhibitors has provided an impetus for the discovery of new, benign organic compounds to fill that role. Concurrently, developments in the high-throughput synthesis of organic compounds, the establishment of large libraries of available chemicals, accelerated corrosion inhibition testing technologies, and the increased capability of machine learning methods have made discovery of new corrosion inhibitors much faster and cheaper than it used to be. We summarize these technical developments in the corrosion inhibition field and describe how data-driven machine learning methods can generate models linking molecular properties to corrosion inhibition that can be used to predict the performance of materials not yet synthesized or tested. We briefly summarize the literature on quantitative structure–property relationships models of small organic molecule corrosion inhibitors. The success of these models provides a paradigm for rapid discovery of novel, effective corrosion inhibitors for a range of metals and alloys in diverse environments.

  13. Novel diamide-based inhibitors of IMPDH.

    Science.gov (United States)

    Gu, Henry H; Iwanowicz, Edwin J; Guo, Junqing; Watterson, Scott H; Shen, Zhongqi; Pitts, William J; Dhar, T G Murali; Fleener, Catherine A; Rouleau, Katherine; Sherbina, N Z; Witmer, Mark; Tredup, Jeffrey; Hollenbaugh, Diane

    2002-05-06

    A series of novel amide-based small molecule inhibitors of inosine monophosphate dehydrogenase is described. The synthesis and the structure-activity relationships (SARs) derived from in vitro studies are presented.

  14. Synthesis and Characterization of Novel Acyl-Glycine Inhibitors of GlyT2.

    Science.gov (United States)

    Mostyn, Shannon N; Carland, Jane E; Shimmon, Susan; Ryan, Renae M; Rawling, Tristan; Vandenberg, Robert J

    2017-09-20

    It has been demonstrated previously that the endogenous compound N-arachidonyl-glycine inhibits the glycine transporter GlyT2, stimulates glycinergic neurotransmission, and provides analgesia in animal models of neuropathic and inflammatory pain. However, it is a relatively weak inhibitor with an IC 50 of 9 μM and is subject to oxidation via cyclooxygenase, limiting its therapeutic value. In this paper we describe the synthesis and testing of a novel series of monounsaturated C18 and C16 acyl-glycine molecules as inhibitors of the glycine transporter GlyT2. We demonstrate that they are up to 28 fold more potent that N-arachidonyl-glycine with no activity at the closely related GlyT1 transporter at concentrations up to 30 μM. This novel class of compounds show considerable promise as a first generation of GlyT2 transport inhibitors.

  15. Beyond gastric acid reduction: Proton pump inhibitors induce heme oxygenase-1 in gastric and endothelial cells

    International Nuclear Information System (INIS)

    Becker, Jan C.; Grosser, Nina; Waltke, Christian; Schulz, Stephanie; Erdmann, Kati; Domschke, Wolfram; Schroeder, Henning; Pohle, Thorsten

    2006-01-01

    Proton pump inhibitors (PPIs) have been demonstrated to prevent gastric mucosal injury by mechanisms independent of acid inhibition. Here we demonstrate that both omeprazole and lansoprazole protect human gastric epithelial and endothelial cells against oxidative stress. This effect was abrogated in the presence of the heme oxygenase-1 (HO-1) inhibitor ZnBG. Exposure to either PPI resulted in a strong induction of HO-1 expression on mRNA and protein level, and led to an increased activity of this enzyme. Expression of cyclooxygenase isoforms 1 and 2 remained unaffected, and COX-inhibitors did not antagonize HO-1 induction by PPIs. Our results suggest that the antioxidant defense protein HO-1 is a target of PPIs in both endothelial and gastric epithelial cells. HO-1 induction might account for the gastroprotective effects of PPIs independently of acid inhibition, especially in NSAID gastropathy. Moreover, our findings provide additional perspectives for a possible but yet unexplored use of PPIs in vasoprotection

  16. Beyond gastric acid reduction: Proton pump inhibitors induce heme oxygenase-1 in gastric and endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Becker, Jan C [Department of Medicine B, University of Muenster, 48149 Muenster (Germany); Grosser, Nina [Department of Pharmacology and Toxicology, School of Pharmacy, Martin Luther University, Halle-Wittenberg, 06099 Halle (Saale) (Germany); Waltke, Christian [Department of Medicine B, University of Muenster, 48149 Muenster (Germany); Schulz, Stephanie [Department of Pharmacology and Toxicology, School of Pharmacy, Martin Luther University, Halle-Wittenberg, 06099 Halle (Saale) (Germany); Erdmann, Kati [Department of Pharmacology and Toxicology, School of Pharmacy, Martin Luther University, Halle-Wittenberg, 06099 Halle (Saale) (Germany); Domschke, Wolfram [Department of Medicine B, University of Muenster, 48149 Muenster (Germany); Schroeder, Henning [Department of Pharmacology and Toxicology, School of Pharmacy, Martin Luther University, Halle-Wittenberg, 06099 Halle (Saale) (Germany); Pohle, Thorsten [Department of Medicine B, University of Muenster, 48149 Muenster (Germany)

    2006-07-07

    Proton pump inhibitors (PPIs) have been demonstrated to prevent gastric mucosal injury by mechanisms independent of acid inhibition. Here we demonstrate that both omeprazole and lansoprazole protect human gastric epithelial and endothelial cells against oxidative stress. This effect was abrogated in the presence of the heme oxygenase-1 (HO-1) inhibitor ZnBG. Exposure to either PPI resulted in a strong induction of HO-1 expression on mRNA and protein level, and led to an increased activity of this enzyme. Expression of cyclooxygenase isoforms 1 and 2 remained unaffected, and COX-inhibitors did not antagonize HO-1 induction by PPIs. Our results suggest that the antioxidant defense protein HO-1 is a target of PPIs in both endothelial and gastric epithelial cells. HO-1 induction might account for the gastroprotective effects of PPIs independently of acid inhibition, especially in NSAID gastropathy. Moreover, our findings provide additional perspectives for a possible but yet unexplored use of PPIs in vasoprotection.

  17. Checkpoint inhibitors in cancer immunotherapy: Cross reactivity of a CTLA-4 antibody and IDO-inhibitor L-1MT in pigs

    DEFF Research Database (Denmark)

    Al-Shatrawi, Zina Adil; Frøsig, Thomas Mørch; Jungersen, Gregers

    a non-specific activation of porcine T cells. This will be further investigated to provide the basis for in vivo studies investigating checkpoint inhibitor blockade in combination with other cancer immunotherapies. Eventually our goal is to establish pigs as an alternative large animal model......Blockade of checkpoint inhibitors has recently shown very convincing results in the treatment of cancer. One key target is CTLA-4, which has been demonstrated to be a potent negative regulator of lymphocyte activation. The treatment with the FDA-approved fully human CTLA-4 monoclonal antibody...... Ipilimumab increases anticancer T-cell reactivity and overall survival of metastatic cancer patients. Indole-amine 2,3-dioxygenase (IDO) is another checkpoint inhibitor which suppresses T-cell immunity by the depletion of tryptophan in the T-cell microenvironment, and also inhibition of IDO by L-1...

  18. Monoamine Oxidase B Inhibitors in Parkinson's Disease.

    Science.gov (United States)

    Dezsi, Livia; Vecsei, Laszlo

    2017-01-01

    Parkinson's disease (PD) is a neurodegenerative disorder with a prevalence increasing with age. Oxidative stress and glutamate toxicity are involved in its pathomechanism. There are still many unmet needs of PD patients, including the alleviation of motor fluctuations and dyskinesias, and the development of therapies with neuroprotective potential. To give an overview of the pharmacological properties, the efficacy and safety of the monoamine oxidase B (MAO-B) inhibitors in the treatment of PD, with special focus on the results of randomized clinical trials. A literature search was conducted in PubMed for 'PD treatment', 'MAO-B inhibitors', 'selegiline', 'rasagiline', 'safinamide' and 'clinical trials' with 'MAO-B inhibitors' in 'Parkinson' disease'. MAO-B inhibitors have a favorable pharmacokinetic profile, improve the dopamine deficient state and may have neuroprotective properties. Safinamide exhibits an anti-glutamatergic effect as well. When applied as monotherapy, MAO-B inhibitors provide a modest, but significant improvement of motor function and delay the need for levodopa. Rasagiline and safinamide were proven safe and effective when added to a dopamine agonist in early PD. As add-on to levodopa, MAO-B inhibitors significantly reduced off-time and were comparable in efficacy to COMT inhibitors. Improvements were achieved as regards certain non-motor symptoms as well. Due to the efficacy shown in clinical trials and their favorable side-effect profile, MAO-B inhibitors are valuable drugs in the treatment of PD. They are recommended as monotherapy in the early stages of the disease and as add-on therapy to levodopa in advanced PD. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. The effect of chemical anti-inhibitors on fibrinolytic enzymes and inhibitors

    DEFF Research Database (Denmark)

    Sidelmann, Johannes Jakobsen; Jespersen, J; Kluft, C

    1997-01-01

    proteases. We studied the influence of chemical anti-inhibitors (chloramine T, flufenamate, sodium lauryl sulfate, and methylamine) on fibrinolytic serine proteases and fibrinolytic enzyme inhibitors using the physiological substrate fibrin as plasmin substrate. Low concentrations of chloramine T (0.01 mmol......%) and plasminogen activators (apparent recovery > 200%). Sodium lauryl sulfate eliminates the major fibrinolytic enzyme inhibitors, but increases the activity of plasmin (apparent recovery > 200%) and plasminogen activator, urokinase type (apparent recovery 130%). Methylamine affects only plasmin inhibition. We...

  20. Anti-fibrinolytic and anti-microbial activities of a serine protease inhibitor from honeybee (Apis cerana) venom.

    Science.gov (United States)

    Yang, Jie; Lee, Kwang Sik; Kim, Bo Yeon; Choi, Yong Soo; Yoon, Hyung Joo; Jia, Jingming; Jin, Byung Rae

    2017-10-01

    Bee venom contains a variety of peptide constituents, including low-molecular-weight protease inhibitors. While the putative low-molecular-weight serine protease inhibitor Api m 6 containing a trypsin inhibitor-like cysteine-rich domain was identified from honeybee (Apis mellifera) venom, no anti-fibrinolytic or anti-microbial roles for this inhibitor have been elucidated. In this study, we identified an Asiatic honeybee (A. cerana) venom serine protease inhibitor (AcVSPI) that was shown to act as a microbial serine protease inhibitor and plasmin inhibitor. AcVSPI was found to consist of a trypsin inhibitor-like domain that displays ten cysteine residues. Interestingly, the AcVSPI peptide sequence exhibited high similarity to the putative low-molecular-weight serine protease inhibitor Api m 6, which suggests that AcVSPI is an allergen Api m 6-like peptide. Recombinant AcVSPI was expressed in baculovirus-infected insect cells, and it demonstrated inhibitory activity against trypsin, but not chymotrypsin. Additionally, AcVSPI has inhibitory effects against plasmin and microbial serine proteases; however, it does not have any detectable inhibitory effects on thrombin or elastase. Consistent with these inhibitory effects, AcVSPI inhibited the plasmin-mediated degradation of fibrin to fibrin degradation products. AcVSPI also bound to bacterial and fungal surfaces and exhibited anti-microbial activity against fungi as well as gram-positive and gram-negative bacteria. These findings demonstrate the anti-fibrinolytic and anti-microbial roles of AcVSPI as a serine protease inhibitor. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Prodrugs of herpes simplex thymidine kinase inhibitors.

    Science.gov (United States)

    Yanachkova, Milka; Xu, Wei-Chu; Dvoskin, Sofya; Dix, Edward J; Yanachkov, Ivan B; Focher, Federico; Savi, Lida; Sanchez, M Dulfary; Foster, Timothy P; Wright, George E

    2015-04-01

    Because guanine-based herpes simplex virus thymidine kinase inhibitors are not orally available, we synthesized various 6-deoxy prodrugs of these compounds and evaluated them with regard to solubility in water, oral bioavailability, and efficacy to prevent herpes simplex virus-1 reactivation from latency in a mouse model. Organic synthesis was used to prepare compounds, High Performance Liquid Chromatography (HPLC) to analyze hydrolytic conversion, Mass Spectrometry (MS) to measure oral bioavailability, and mouse latent infection and induced reactivation to evaluate the efficacy of a specific prodrug. Aqueous solubilities of prodrugs were improved, oxidation of prodrugs by animal cytosols occurred in vitro, and oral absorption of the optimal prodrug sacrovir™ (6-deoxy-mCF3PG) in the presence of the aqueous adjuvant Soluplus® and conversion to active compound N(2)-[3-(trifluoromethyl)pheny])guanine (mCF3PG) were accomplished in mice. Treatment of herpes simplex virus-1 latent mice with sacrovir™ in 1% Soluplus in drinking water significantly suppressed herpes simplex virus-1 reactivation and viral genomic replication. Ad libitum oral delivery of sacrovir™ was effective in suppressing herpes simplex virus-1 reactivation in ocularly infected latent mice as measured by the numbers of mice shedding infectious virus at the ocular surface, numbers of trigeminal ganglia positive for infectious virus, number of corneas that had detectable infectious virus, and herpes simplex virus-1 genome copy numbers in trigeminal ganglia following reactivation. These results demonstrate the statistically significant effect of the prodrug on suppressing herpes simplex virus-1 reactivation in vivo. © The Author(s) 2015.

  2. Development of Radiosensitizer using farnesyltransferase inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Lim, Jong Seok; Choe, Yong Kyung; Han, Mi Young; Kim, Kwang Dong [Korea Research Institute of Bioscience and Biotechnology, Taejon (Korea)

    1999-03-01

    We selected some compounds that were reported to have an activity of farneyltransferase inhibitor and tested the hypothesis that they might be used to radiosensitize cells transformed by ras oncogenes. The inhibition of ras processing using some, but not all, inhibitors resulted in higher levels of cell death after {gamma}-irradiation and increased radiosensitivity in H-ras-transformed NIH3T3 cells and MCF-10A human tumor cells. They did not induce additional cell death in control cells that doe not have ras mutation. Furthermore, the treatment of inhibitors alone induced a weak G0/G1 block, whereas inhibitors in combination with {gamma}-irradiation induced an additional enrichment in the G2/M phase of the cell cycle that typically represents irradiation-induced growth arrest. At present, the underling mechanism by which the farnesylltransferase inhibitors exert radiosensitizing effect is not known. In summary, our results suggest and lead to the possibility that some of farnesylation inhibitors may prove clinically useful not only as antitumor agents, but also radiosensitizers of tumors whose growth is dependent on ras function. (author). 15 refs., 10 figs., 4 tabs.

  3. Natural inhibitors of tumor-associated proteases

    International Nuclear Information System (INIS)

    Magdolen, U.; Krol, J.; Sato, S.; Schmitt, M.; Magdolen, V.; Krueger, A.; Mueller, M.M.; Sperl, S.

    2002-01-01

    The turnover and remodelling of extracellular matrix (ECM) is an essential part of many normal biological processes including development, morphogenesis, and wound healing. ECM turnover also occurs in severe pathological situations like artherosclerosis, fibrosis, tumor invasion and metastasis. The major proteases involved in this turnover are serine proteases (especially the urokinase-type plasminogen activator/plasmin system), matrix metalloproteases (a family of about 20 zinc-dependent endopeptidases including collagenases, gelatinases, stromelysins, and membrane-type metalloproteases), and cysteine proteases. In vivo, the activity of these proteases is tightly regulated in the extracellular space by zymogen activation and/or controlled inhibition. In the present review, we give an overview on the structure and biochemical properties of important tumor-associated protease inhibitors such as plasminogen activator inhibitor type 1 and type 2 (PAI-1, PAI-2), tissue inhibitors of metalloproteinases (TIMP-1, -2, -3, and -4), and the cysteine protease inhibitor cystatin C. Interestingly, some of these inhibitors of tumor-associated proteases display multiple functions which rather promote than inhibit tumor progression, when the presence of inhibitors in the tumor tissue is not balanced. (author)

  4. Emerging Corrosion Inhibitors for Interfacial Coating

    Directory of Open Access Journals (Sweden)

    Mona Taghavikish

    2017-12-01

    Full Text Available Corrosion is a deterioration of a metal due to reaction with environment. The use of corrosion inhibitors is one of the most effective ways of protecting metal surfaces against corrosion. Their effectiveness is related to the chemical composition, their molecular structures and affinities for adsorption on the metal surface. This review focuses on the potential of ionic liquid, polyionic liquid (PIL and graphene as promising corrosion inhibitors in emerging coatings due to their remarkable properties and various embedment or fabrication strategies. The review begins with a precise description of the synthesis, characterization and structure-property-performance relationship of such inhibitors for anti-corrosion coatings. It establishes a platform for the formation of new generation of PIL based coatings and shows that PIL corrosion inhibitors with various heteroatoms in different form can be employed for corrosion protection with higher barrier properties and protection of metal surface. However, such study is still in its infancy and there is significant scope to further develop new structures of PIL based corrosion inhibitors and coatings and study their behaviour in protection of metals. Besides, it is identified that the combination of ionic liquid, PIL and graphene could possibly contribute to the development of the ultimate corrosion inhibitor based coating.

  5. Developing HIV-1 Protease Inhibitors through Stereospecific Reactions in Protein Crystals.

    Science.gov (United States)

    Olajuyigbe, Folasade M; Demitri, Nicola; De Zorzi, Rita; Geremia, Silvano

    2016-10-31

    Protease inhibitors are key components in the chemotherapy of HIV infection. However, the appearance of viral mutants routinely compromises their clinical efficacy, creating a constant need for new and more potent inhibitors. Recently, a new class of epoxide-based inhibitors of HIV-1 protease was investigated and the configuration of the epoxide carbons was demonstrated to play a crucial role in determining the binding affinity. Here we report the comparison between three crystal structures at near-atomic resolution of HIV-1 protease in complex with the epoxide-based inhibitor, revealing an in-situ epoxide ring opening triggered by a pH change in the mother solution of the crystal. Increased pH in the crystal allows a stereospecific nucleophile attack of an ammonia molecule onto an epoxide carbon, with formation of a new inhibitor containing amino-alcohol functions. The described experiments open a pathway for the development of new stereospecific protease inhibitors from a reactive lead compound.

  6. Developing HIV-1 Protease Inhibitors through Stereospecific Reactions in Protein Crystals

    Directory of Open Access Journals (Sweden)

    Folasade M. Olajuyigbe

    2016-10-01

    Full Text Available Protease inhibitors are key components in the chemotherapy of HIV infection. However, the appearance of viral mutants routinely compromises their clinical efficacy, creating a constant need for new and more potent inhibitors. Recently, a new class of epoxide-based inhibitors of HIV-1 protease was investigated and the configuration of the epoxide carbons was demonstrated to play a crucial role in determining the binding affinity. Here we report the comparison between three crystal structures at near-atomic resolution of HIV-1 protease in complex with the epoxide-based inhibitor, revealing an in-situ epoxide ring opening triggered by a pH change in the mother solution of the crystal. Increased pH in the crystal allows a stereospecific nucleophile attack of an ammonia molecule onto an epoxide carbon, with formation of a new inhibitor containing amino-alcohol functions. The described experiments open a pathway for the development of new stereospecific protease inhibitors from a reactive lead compound.

  7. SGLT2 inhibitors in the pipeline for the treatment of diabetes mellitus in Japan.

    Science.gov (United States)

    Ito, Hiroyuki; Shinozaki, Masahiro; Nishio, Shinya; Abe, Mariko

    2016-10-01

    Sodium glucose cotransporter 2 (SGLT2) inhibitors have been available for the treatment of type 2 diabetes (T2DM) in Japan since April 2014. The prescription rate in Japan is low in comparison to Western countries. We summarize the results obtained from the phase 3 clinical trials and clinical studies involving Japanese T2DM patients. We also discuss the current situation and the future prospects of SGLT2 inhibitors in Japan. Unexpected adverse events, such as cerebral infarction and diabetic ketoacidosis have been reported from clinics shortly after the initiation of SGLT2 inhibitor treatment. However, the reductions in blood glucose levels and body weight have been demonstrated in phase 3 trials using 6 types of SGLT2 inhibitors, while observational studies of Japanese T2DM patients, which were performed in the clinical setting, showed that the incidence of adverse drug reactions, such as severe hypoglycemia, was low. SGLT2 inhibitors are also considered to be effective for treating Japanese patients with T2DM. When prescribing SGLT2 inhibitors, it is necessary to ensure that they are used appropriately because the Japanese T2DM patient population has a high proportion of elderly individuals and a high incidence of cerebrovascular disease.

  8. Reverse zymography alone does not confirm presence of a protease inhibitor.

    Science.gov (United States)

    Dutta, Sangita; Bhattacharyya, Debasish

    2013-03-01

    Reverse zymography is applied for identification and semi-quantification of protease inhibitors that are of protein in nature. However, a protein that shows band in reverse zymography against a protease used for digestion of the gel need not be an inhibitor; it might be resistant to degradation by the protease. We demonstrate that in reverse zymography, avidin, streptavidin and the leaf extract of Catharanthus roseus behave like inhibitors of proteases like papain, ficin, bromelain extracts from pineapple leaf, stem and fruit and trypsin. Still, they do not act as inhibitors of those proteases when enzyme assays were done in solution. In reverse zymography, the extract of pineapple crown leaf shows two major inhibitor bands against its own proteases. Identification of these proteins from sequences derived from MALDI TOF MS analysis indicated that they are fruit and stem bromelains. Avidin, streptavidin and bromelains are 'kinetically stable proteins' that are usually resistant to proteolysis. Thus, it is recommended that identification of an inhibitor of a protease by reverse zymography should be supported by independent assay methods for confirmation.

  9. Modulation of the epithelial sodium channel (ENaC by bacterial metalloproteases and protease inhibitors.

    Directory of Open Access Journals (Sweden)

    Michael B Butterworth

    Full Text Available The serralysin family of metalloproteases is associated with the virulence of multiple gram-negative human pathogens, including Pseudomonas aeruginosa and Serratia marcescens. The serralysin proteases share highly conserved catalytic domains and show evolutionary similarity to the mammalian matrix metalloproteases. Our previous studies demonstrated that alkaline protease (AP from Pseudomonas aeruginosa is capable of activating the epithelial sodium channel (ENaC, leading to an increase in sodium absorption in airway epithelia. The serralysin proteases are often co-expressed with endogenous, intracellular or periplasmic inhibitors, which putatively protect the bacterium from unwanted or unregulated protease activities. To evaluate the potential use of these small protein inhibitors in regulating the serralysin induced activation of ENaC, proteases from Pseudomonas aeruginosa and Serratia marcescens were purified for characterization along with a high affinity inhibitor from Pseudomonas. Both proteases showed activity against in vitro substrates and could be blocked by near stoichiometric concentrations of the inhibitor. In addition, both proteases were capable of activating ENaC when added to the apical surfaces of multiple epithelial cells with similar slow activation kinetics. The high-affinity periplasmic inhibitor from Pseudomonas effectively blocked this activation. These data suggest that multiple metalloproteases are capable of activating ENaC. Further, the endogenous, periplasmic bacterial inhibitors may be useful for modulating the downstream effects of the serralysin virulence factors under physiological conditions.

  10. Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Aβ Levels Mediated by Brain Shuttle Transport

    Directory of Open Access Journals (Sweden)

    Nadine Ruderisch

    2017-10-01

    Full Text Available Therapeutic approaches to fight Alzheimer's disease include anti-Amyloidβ (Aβ antibodies and secretase inhibitors. However, the blood-brain barrier (BBB limits the brain exposure of biologics and the chemical space for small molecules to be BBB permeable. The Brain Shuttle (BS technology is capable of shuttling large molecules into the brain. This allows for new types of therapeutic modalities engineered for optimal efficacy on the molecular target in the brain independent of brain penetrating properties. To this end, we designed BACE1 peptide inhibitors with varying lipid modifications with single-digit picomolar cellular potency. Secondly, we generated active-exosite peptides with structurally confirmed dual binding mode and improved potency. When fused to the BS via sortase coupling, these BACE1 inhibitors significantly reduced brain Aβ levels in mice after intravenous administration. In plasma, both BS and non-BS BACE1 inhibitor peptides induced a significant time- and dose-dependent decrease of Aβ. Our results demonstrate that the BS is essential for BACE1 peptide inhibitors to be efficacious in the brain and active-exosite design of BACE1 peptide inhibitors together with lipid modification may be of therapeutic relevance.

  11. Effect of kinase inhibitors on the therapeutic properties of monoclonal antibodies.

    Science.gov (United States)

    Duong, Minh Ngoc; Matera, Eva-Laure; Mathé, Doriane; Evesque, Anne; Valsesia-Wittmann, Sandrine; Clémenceau, Béatrice; Dumontet, Charles

    2015-01-01

    Targeted therapies of malignancies currently consist of therapeutic monoclonal antibodies and small molecule kinase inhibitors. The combination of these novel agents raises the issue of potential antagonisms. We evaluated the potential effect of 4 kinase inhibitors, including the Bruton tyrosine kinase inhibitor ibrutinib, and 3 PI3K inhibitors idelalisib, NVP-BEZ235 and LY294002, on the effects of the 3 monoclonal antibodies, rituximab and obinutuzumab (directed against CD20) and trastuzumab (directed against HER2). We found that ibrutinib potently inhibits antibody-dependent cell-mediated cytotoxicity exerted by all antibodies, with a 50% inhibitory concentration of 0.2 microM for trastuzumab, 0.5 microM for rituximab and 2 microM for obinutuzumab, suggesting a lesser effect in combination with obinutuzumab than with rituximab. The 4 kinase inhibitors were found to inhibit phagocytosis by fresh human neutrophils, as well as antibody-dependent cellular phagocytosis induced by the 3 antibodies. Conversely co-administration of ibrutinib with rituximab, obinutuzumab or trastuzumab did not demonstrate any inhibitory effect of ibrutinib in vivo in murine xenograft models. In conclusion, some kinase inhibitors, in particular, ibrutinib, are likely to exert inhibitory effects on innate immune cells. However, these effects do not compromise the antitumor activity of monoclonal antibodies in vivo in the models that were evaluated.

  12. Perchlorate Removal, Destruction, and Field Monitoring Demonstration

    National Research Council Canada - National Science Library

    Coppola, Edward N; Davis, Andrea

    2006-01-01

    The objectives of this demonstration were to evaluate and demonstrate a complete perchlorate ion exchange process for groundwater that included a unique, regenerable, perchlorate-selective ion exchange resin...

  13. HTI retrieval demonstration project execution plan

    International Nuclear Information System (INIS)

    Ellingson, D.R.

    1997-01-01

    This plan describes the process for demonstrating the retrieval of difficult Hanford tank waste forms utilizing commercial technologies and the private sector to conduct the operations. The demonstration is to be conducted in Tank 241-C-106

  14. Introduction to Methods Demonstrations for Authentication

    International Nuclear Information System (INIS)

    Kouzes, Richard T.; Hansen, Randy R.; Pitts, W. K.

    2002-01-01

    During the Trilateral Initiative Technical Workshop on Authentication and Certification, PNNL will demonstrate some authentication technologies. This paper briefly describes the motivation for these demonstrations and provide background on them

  15. Using Daily Horoscopes To Demonstrate Expectancy Confirmation.

    Science.gov (United States)

    Munro, Geoffrey D.; Munro, James E.

    2000-01-01

    Describes a classroom demonstration that uses daily horoscopes to show the effect that expectation can have on judgment. Addresses the preparation, procedure, and results of the demonstration, and student evaluations. States that the demonstration appears to be effective for teaching students about expectancy confirmation. (CMK)

  16. 40 CFR 117.14 - Demonstration projects.

    Science.gov (United States)

    2010-07-01

    ... 40 Protection of Environment 21 2010-07-01 2010-07-01 false Demonstration projects. 117.14 Section... DETERMINATION OF REPORTABLE QUANTITIES FOR HAZARDOUS SUBSTANCES Applicability § 117.14 Demonstration projects... research or demonstration projects relating to the prevention, control, or abatement of hazardous substance...

  17. Cone penetrometer demonstration standard startup review checklist

    International Nuclear Information System (INIS)

    KRIEG, S.A.

    1998-01-01

    Startup readiness for the Cone Penetrometer Demonstration in AX Tank Farm will be verified through the application of a Standard Startup Review Checklist. This is a listing of those items essential to demonstrating readiness to start the Cone Penetrometer Demonstration in AX Tank Farm

  18. Elucidating the structural basis for differing enzyme inhibitor potency by cryo-EM.

    Science.gov (United States)

    Rawson, Shaun; Bisson, Claudine; Hurdiss, Daniel L; Fazal, Asif; McPhillie, Martin J; Sedelnikova, Svetlana E; Baker, Patrick J; Rice, David W; Muench, Stephen P

    2018-02-20

    Histidine biosynthesis is an essential process in plants and microorganisms, making it an attractive target for the development of herbicides and antibacterial agents. Imidazoleglycerol-phosphate dehydratase (IGPD), a key enzyme within this pathway, has been biochemically characterized in both Saccharomyces cerevisiae ( Sc_ IGPD) and Arabidopsis thaliana ( At_ IGPD). The plant enzyme, having been the focus of in-depth structural analysis as part of an inhibitor development program, has revealed details about the reaction mechanism of IGPD, whereas the yeast enzyme has proven intractable to crystallography studies. The structure-activity relationship of potent triazole-phosphonate inhibitors of IGPD has been determined in both homologs, revealing that the lead inhibitor (C348) is an order of magnitude more potent against Sc_ IGPD than At_ IGPD; however, the molecular basis of this difference has not been established. Here we have used single-particle electron microscopy (EM) to study structural differences between the At and Sc_ IGPD homologs, which could influence the difference in inhibitor potency. The resulting EM maps at ∼3 Å are sufficient to de novo build the protein structure and identify the inhibitor binding site, which has been validated against the crystal structure of the At_ IGPD/C348 complex. The structure of Sc _IGPD reveals that a 24-amino acid insertion forms an extended loop region on the enzyme surface that lies adjacent to the active site, forming interactions with the substrate/inhibitor binding loop that may influence inhibitor potency. Overall, this study provides insights into the IGPD family and demonstrates the power of using an EM approach to study inhibitor binding. Copyright © 2018 the Author(s). Published by PNAS.

  19. Potential role of recombinant secretory leucoprotease inhibitor in the prevention of neutrophil mediated matrix degradation.

    Science.gov (United States)

    Llewellyn-Jones, C G; Lomas, D A; Stockley, R A

    1994-06-01

    Neutrophil elastase is able to degrade connective tissue matrices and is thought to be involved in the pathogenesis of destructive lung diseases. The ability of recombinant secretory leucoprotease inhibitor (rSLPI) to inhibit neutrophil mediated degradation of fibronectin in vitro is demonstrated and its efficacy compared with native alpha-1-proteinase inhibitor (n alpha 1-PI), recombinant alpha-1-proteinase inhibitor (r alpha 1-PI), and the chemical elastase inhibitor ICI 200,355. When preincubated with neutrophils both rSLPI and r alpha 1-PI were effective inhibitors of fibronectin degradation although n alpha 1-PI and ICI 200,355 were less effective. Recombinant SLPI was the most effective inhibitor when the cells were allowed to adhere to fibronectin before the addition of the inhibitors. Preincubation of rSLPI (0.1 mumol/l) with the fibronectin plate resulted in almost total inhibition of fibronectin degradation (reduced to 3.3 (SE 0.9)% of control). Pretreating the fibronectin plate with 1 mumol/l rSLPI, r alpha 1-PI and ICI 200,355 followed by thorough washing before the addition of cells resulted in no inhibition of fibronectin degradation with r alpha 1-PI and the ICI inhibitor, but rSLPI retained its inhibitory effect. This effect could be reduced by adding rSLPI in high pH buffer or 2 mol/1 NaCl. It is postulated that rSLPI binds to fibronectin to form a protective layer which prevents its degradation by neutrophil elastase. It may prove to be the most useful therapeutic agent in the prevention of neutrophil mediated lung damage.

  20. Apyrase inhibitors enhance the ability of diverse fungicides to inhibit the growth of different plant-pathogenic fungi.

    Science.gov (United States)

    Kumar Tripathy, Manas; Weeraratne, Gayani; Clark, Greg; Roux, Stanley J

    2017-09-01

    A previous study has demonstrated that the treatment of Arabidopsis plants with chemical inhibitors of apyrase enzymes increases their sensitivity to herbicides. In this study, we found that the addition of the same or related apyrase inhibitors could potentiate the ability of different fungicides to inhibit the growth of five different pathogenic fungi in plate growth assays. The growth of all five fungi was partially inhibited by three commonly used fungicides: copper octanoate, myclobutanil and propiconazole. However, when these fungicides were individually tested in combination with any one of four different apyrase inhibitors (AI.1, AI.10, AI.13 or AI.15), their potency to inhibit the growth of five fungal pathogens was increased significantly relative to their application alone. The apyrase inhibitors were most effective in potentiating the ability of copper octanoate to inhibit fungal growth, and least effective in combination with propiconazole. Among the five pathogens assayed, that most sensitive to the fungicide-potentiating effects of the inhibitors was Sclerotinia sclerotiorum. Overall, among the 60 treatment combinations tested (five pathogens, four apyrase inhibitors, three fungicides), the addition of apyrase inhibitors increased significantly the sensitivity of fungi to the fungicide treatments in 53 of the combinations. Consistent with their predicted mode of action, inhibitors AI.1, AI.10 and AI.13 each increased the level of propiconazole retained in one of the fungi, suggesting that they could partially block the ability of efflux transporters to remove propiconazole from these fungi. © 2016 BSPP AND JOHN WILEY & SONS LTD.

  1. Inactivation of proteinaceous protease inhibitors of soybeans by isolated fungi

    NARCIS (Netherlands)

    Meijer, M.M.T.; Spekking, W.T.J.; Sijtsma, L.; Bont, de J.A.M.

    1995-01-01

    Proteinaceous protease inhibitors, Kunitz Soybean Trypsin Inhibitor (KSTI) and Bowman Birk Inhibitor (BBI), in legume seeds reduce the digestibility of proteins in feed of monogastric animals. Enzymatic inactivation of these inhibitors will increase the nutritional value of the feed. The aim of this

  2. Contribution of murine innate serum inhibitors toward interference within influenza virus immune assays.

    Science.gov (United States)

    Cwach, Kevin T; Sandbulte, Heather R; Klonoski, Joshua M; Huber, Victor C

    2012-03-01

    Prior to detection of an antibody response toward influenza viruses using the hemagglutination inhibition assay (HAI), sera are routinely treated to inactivate innate inhibitors using both heat inactivation (56°C) and recombinant neuraminidase [receptor-destroying enzyme (RDE)]. We revisited the contributions of innate serum inhibitors toward interference with influenza viruses in immune assays, using murine sera, with emphasis on the interactions with influenza A viruses of the H3N2 subtype. We used individual serum treatments: 56°C alone, RDE alone, or RDE + 56°C, to treat sera prior to evaluation within HAI, microneutralization, and macrophage uptake assays. Our data demonstrate that inhibitors present within untreated murine sera interfere with the HAI assay in a manner that is different from that seen for the microneutralization assay. Specifically, the γ class inhibitor α(2) -Macroglobulin (A2-M) can inhibit H3N2 viruses within the HAI assay, but not in the microneutralization assay. Based on these findings, we used a macrophage uptake assay to demonstrate that these inhibitors can increase uptake by macrophages when the influenza viruses express an HA from a 1968 H3N2 virus isolate, but not a 1997 H3N2 isolate. The practice of treating sera to inactivate innate inhibitors of influenza viruses prior to evaluation within immune assays has allowed us to effectively detect influenza virus-specific antibodies for decades. However, this practice has yielded an under-appreciation for the contribution of innate serum inhibitors toward host immune responses against these viruses, including contributions toward neutralization and macrophage uptake. © 2011 Blackwell Publishing Ltd.

  3. New benzothiazole/thiazole-containing hydroxamic acids as potent histone deacetylase inhibitors and antitumor agents

    DEFF Research Database (Denmark)

    Thanh Tung, Truong; Oanh, Dao Thi Kim; Dung, Phan Thi Phuong

    2013-01-01

    Results from clinical studies have demonstrated that inhibitors of histone deacetylase (HDAC) enzymes possess promise for the treatment of several types of cancer. Zolinza(®) (widely known as SAHA) has been approved by the FDA for the treatment of T-cell lymphoma. As a continuity of our ongoing...

  4. Down-regulation of Notch-1 by γ-secretase inhibitor suppress the ...

    African Journals Online (AJOL)

    Notch-1 signaling is crucial for stem cell maintenance and in a variety of tissues. Previous research has demonstrated that Notch-1 activity plays a key role in prostate tumorigenesis. However, the function of Notch-1 signaling in tumorigenesis can be either oncogene or suppressor gene. In our paper, γ- secretase inhibitor ...

  5. Ace inhibitors and cardiovascular regulation : the importance of autocrine and paracrine mechanisms

    NARCIS (Netherlands)

    Wijngaarden, Jan van

    1992-01-01

    As demonstrated in a large number of clinical studies, angiotensin converting enzyme (ACE) inhibitors are of great value for the treatment of cardiovascular disorders. Although the clinical merits of these drugs are now well recognized, their mechanism of action is not yet completely understood. The

  6. Bowman-Birk inhibitor affects pathways associated with energy metabolism in Drosophila melanogaster

    Science.gov (United States)

    Bowman-Birk inhibitor (BBI) is toxic when fed to certain insects, including the fruit fly, Drosophila melanogaster. Dietary BBI has been demonstrated to slow growth and increase insect mortality by inhibiting the digestive enzymes trypsin and chymotrypsin, resulting in a reduced supply of amino acid...

  7. Discovery of potent inhibitors of soluble epoxide hydrolase by combinatorial library design and structure-based virtual screening.

    Science.gov (United States)

    Xing, Li; McDonald, Joseph J; Kolodziej, Steve A; Kurumbail, Ravi G; Williams, Jennifer M; Warren, Chad J; O'Neal, Janet M; Skepner, Jill E; Roberds, Steven L

    2011-03-10

    Structure-based virtual screening was applied to design combinatorial libraries to discover novel and potent soluble epoxide hydrolase (sEH) inhibitors. X-ray crystal structures revealed unique interactions for a benzoxazole template in addition to the conserved hydrogen bonds with the catalytic machinery of sEH. By exploitation of the favorable binding elements, two iterations of library design based on amide coupling were employed, guided principally by the docking results of the enumerated virtual products. Biological screening of the libraries demonstrated as high as 90% hit rate, of which over two dozen compounds were single digit nanomolar sEH inhibitors by IC(50) determination. In total the library design and synthesis produced more than 300 submicromolar sEH inhibitors. In cellular systems consistent activities were demonstrated with biochemical measurements. The SAR understanding of the benzoxazole template provides valuable insights into discovery of novel sEH inhibitors as therapeutic agents.

  8. Combined effects of EGFR tyrosine kinase inhibitors and vATPase inhibitors in NSCLC cells

    Energy Technology Data Exchange (ETDEWEB)

    Jin, Hyeon-Ok [KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Hong, Sung-Eun [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Kim, Chang Soon [Department of Microbiological Engineering, Kon-Kuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143–701 (Korea, Republic of); Park, Jin-Ah; Kim, Jin-Hee; Kim, Ji-Young; Kim, Bora [KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Chang, Yoon Hwan; Hong, Seok-Il; Hong, Young Jun [Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Park, In-Chul, E-mail: parkic@kirams.re.kr [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Lee, Jin Kyung, E-mail: jklee@kirams.re.kr [KIRAMS Radiation Biobank, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of); Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul, 139–706 (Korea, Republic of)

    2015-08-15

    Despite excellent initial clinical responses of non-small cell lung cancer (NSCLC) patients to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), many patients eventually develop resistance. According to a recent report, vacuolar H + ATPase (vATPase) is overexpressed and is associated with chemotherapy drug resistance in NSCLC. We investigated the combined effects of EGFR TKIs and vATPase inhibitors and their underlying mechanisms in the regulation of NSCLC cell death. We found that combined treatment with EGFR TKIs (erlotinib, gefitinib, or lapatinib) and vATPase inhibitors (bafilomycin A1 or concanamycin A) enhanced synergistic cell death compared to treatments with each drug alone. Treatment with bafilomycin A1 or concanamycin A led to the induction of Bnip3 expression in an Hif-1α dependent manner. Knock-down of Hif-1α or Bnip3 by siRNA further enhanced cell death induced by bafilomycin A1, suggesting that Hif-1α/Bnip3 induction promoted resistance to cell death induced by the vATPase inhibitors. EGFR TKIs suppressed Hif-1α and Bnip3 expression induced by the vATPase inhibitors, suggesting that they enhanced the sensitivity of the cells to these inhibitors by decreasing Hif-1α/Bnip3 expression. Taken together, we conclude that EGFR TKIs enhance the sensitivity of NSCLC cells to vATPase inhibitors by decreasing Hif-1α/Bnip3 expression. We suggest that combined treatment with EGFR TKIs and vATPase inhibitors is potentially effective for the treatment of NSCLC. - Highlights: • Co-treatment with EGFR TKIs and vATPase inhibitors induces synergistic cell death • EGFR TKIs enhance cell sensitivity to vATPase inhibitors via Hif-1α downregulation • Co-treatment of these inhibitors is potentially effective for the treatment of NSCLC.

  9. Screening of protein kinase inhibitors identifies PKC inhibitors as inhibitors of osteoclastic acid secretion and bone resorption

    Directory of Open Access Journals (Sweden)

    Boutin Jean A

    2010-10-01

    Full Text Available Abstract Background Bone resorption is initiated by osteoclastic acidification of the resorption lacunae. This process is mediated by secretion of protons through the V-ATPase and chloride through the chloride antiporter ClC-7. To shed light on the intracellular signalling controlling extracellular acidification, we screened a protein kinase inhibitor library in human osteoclasts. Methods Human osteoclasts were generated from CD14+ monocytes. The effect of different kinase inhibitors on lysosomal acidification in human osteoclasts was investigated using acridine orange for different incubation times (45 minutes, 4 and 24 hours. The inhibitors were tested in an acid influx assay using microsomes isolated from human osteoclasts. Bone resorption by human osteoclasts on bone slices was measured by calcium release. Cell viability was measured using AlamarBlue. Results Of the 51 compounds investigated only few inhibitors were positive in both acidification and resorption assays. Rottlerin, GF109203X, Hypericin and Ro31-8220 inhibited acid influx in microsomes and bone resorption, while Sphingosine and Palmitoyl-DL-carnitine-Cl showed low levels of inhibition. Rottlerin inhibited lysosomal acidification in human osteoclasts potently. Conclusions In conclusion, a group of inhibitors all indicated to inhibit PKC reduced acidification in human osteoclasts, and thereby bone resorption, indicating that acid secretion by osteoclasts may be specifically regulated by PKC in osteoclasts.

  10. Scaffold-hopping from xanthines to tricyclic guanines: A case study of dipeptidyl peptidase 4 (DPP4) inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Pissarnitski, Dmitri A.; Zhao, Zhiqiang; Cole, David; Wu, Wen-Lian; Domalski, Martin; Clader, John W.; Scapin, Giovanna; Voigt, Johannes; Soriano, Aileen; Kelly, Theresa; Powles, Mary Ann; Yao, Zuliang; Burnett, Duane A. (Merck)

    2016-11-01

    Molecular modeling of unbound tricyclic guanine scaffolds indicated that they can serve as effective bioisosteric replacements of xanthines. This notion was further confirmed by a combination of X-ray crystallography and SAR studies, indicating that tricyclic guanine DPP4 inhibitors mimic the binding mode of xanthine inhibitors, exemplified by linagliptin. Realization of the bioisosteric relationship between these scaffolds potentially will lead to a wider application of cyclic guanines as xanthine replacements in drug discovery programs for a variety of biological targets. Newly designed DPP4 inhibitors achieved sub-nanomolar potency range and demonstrated oral activity in vivo in mouse glucose tolerance test.

  11. The performance of a surface-applied corrosion inhibitor for the carbon steel in saturated Ca(OH)2 solutions

    International Nuclear Information System (INIS)

    Zheng, Haibing; Li, Weihua; Ma, Fubin; Kong, Qinglin

    2014-01-01

    In the present work, the performance of an amino alcohol based surface applied inhibitor was studied by the electrochemical techniques in saturated Ca(OH) 2 solutions. The surface morphology of the carbon steel was observed by scanning electron microscope, and the energy diffraction spectrum was also tested. Results showed that the inhibitor used in this work demonstrated obvious inhibition efficiency on the carbon steel in saturated Ca(OH) 2 solutions. The inhibition mechanism of the inhibitor lies in the quick adsorption of the active component on carbon steel surface

  12. Human HDAC isoform selectivity achieved via exploitation of the acetate release channel with structurally unique small molecule inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Whitehead, Lewis; Dobler, Markus R.; Radetich, Branko; Zhu, Yanyi; Atadja, Peter W.; Claiborne, Tavina; Grob, Jonathan E.; McRiner, Andrew; Pancost, Margaret R.; Patnaik, Anup; Shao, Wenlin; Shultz, Michael; Tichkule, Ritesh; Tommasi, Ruben A.; Vash, Brian; Wang, Ping; Stams, Travis (Novartis)

    2013-11-20

    Herein we report the discovery of a family of novel yet simple, amino-acid derived class I HDAC inhibitors that demonstrate isoform selectivity via access to the internal acetate release channel. Isoform selectivity criteria is discussed on the basis of X-ray crystallography and molecular modeling of these novel inhibitors bound to HDAC8, potentially revealing insights into the mechanism of enzymatic function through novel structural features revealed at the atomic level.

  13. Inhibitor chymotrypsynowy nasion wiechliny łąkowej (Poa pratensis [Chymotrypsin inhibitor from Poa pratensis seeds

    Directory of Open Access Journals (Sweden)

    I. Lorenc-Kubis

    2015-01-01

    Full Text Available A chymotrypsin inhibitor was isolated from Poa pratensis seeds. The inhibitor showed also antytriptic activity. It is a termostable protein, soluble in water, sodium chloride, but insoluble in 5% trichloracetic acid and 0.15 M sulphosalicylic acid.

  14. Structural basis for decreased induction of class IB PI3-kinases expression by MIF inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Abhay Kumar [Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis MO USA; Pantouris, Georgios [Department of Pharmacology, Yale University School of Medicine, New Haven CT USA; Borosch, Sebastian [Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Aachen Germany; Rojanasthien, Siripong [Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis MO USA; Cho, Thomas Yoonsang [Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis MO USA

    2016-09-13

    Macrophage migration inhibitory factor (MIF) is a master regulator of proinflammatory cytokines and plays pathological roles when not properly regulated in rheumatoid arthritis, lupus, atherosclerosis, asthma and cancer. Unlike canonical cytokines, MIF has vestigial keto-enol tautomerase activity. Most of the current MIF inhibitors were screened for the inhibition of this enzymatic activity. However, only some of the enzymatic inhibitors inhibit receptor-mediated biological functions of MIF, such as cell recruitment, through an unknown molecular mechanism. The goal of this study was to understand the molecular basis underlying the pharmacological inhibition of biological functions of MIF. Here, we demonstrate how the structural changes caused upon inhibitor binding translate into the alteration of MIF-induced downstream signalling. Macrophage migration inhibitory factor activates phosphoinositide 3-kinases (PI3Ks) that play a pivotal role in immune cell recruitment in health and disease. There are several different PI3K isoforms, but little is known about how they respond to MIF. We demonstrate that MIF up-regulates the expression of Class IB PI3Ks in leucocytes. We also demonstrate that MIF tautomerase active site inhibitors down-regulate the expression of Class IB PI3Ks as well as leucocyte recruitment in vitro and in vivo. Finally, based on our MIF:inhibitor complex crystal structures, we hypothesize that the reduction in Class IB PI3K expression occurs because of the displacement of Pro1 towards the second loop of MIF upon inhibitor binding, which results in increased flexibility of the loop 2 and sub-optimal MIF binding to its receptors. These results will provide molecular insights for fine-tuning the biological functions of MIF.

  15. How to Demonstrate Microgravity in your Classroom

    Science.gov (United States)

    DeLombard, Richard; Hall, Nancy Rabel

    2013-01-01

    Learn why zero gravity is a misnomer and learn how to demonstrate microgravity to students and the general public. In this session, a short theory segment will explain and reinforce these concepts so that you may explain to others. Session participants will also see simple equipment that demonstrates microgravity during the session and can just as well be done in the classroom or museum exhibit hall. The hands-on demonstration devices range from a leaky water bottle to an electronic drop tower with an on-board camera. The session will also include demonstration techniques for Physics, Forces & Motion, and orbits. This material is useful for middle school forces and motions instruction, high school physics instruction, public demonstrations at conferences & school open houses, travelling museum exhibits, fixed museum exhibits, and independent student projects or experiments. These activities also connect the terrestrial demonstration with planetary & moon motion, comet trajectory, and more.

  16. Phenyl thiazolyl urea and carbamate derivatives as new inhibitors of bacterial cell-wall biosynthesis.

    Science.gov (United States)

    Francisco, Gerardo D; Li, Zhong; Albright, J Donald; Eudy, Nancy H; Katz, Alan H; Petersen, Peter J; Labthavikul, Pornpen; Singh, Guy; Yang, Youjun; Rasmussen, Beth A; Lin, Yang-I; Mansour, Tarek S

    2004-01-05

    Over 50 phenyl thiazolyl urea and carbamate derivatives were synthesized for evaluation as new inhibitors of bacterial cell-wall biosynthesis. Many of them demonstrated good activity against MurA and MurB and gram-positive bacteria including MRSA, VRE and PRSP. 3,4-Difluorophenyl 5-cyanothiazolylurea (3p) with clog P of 2.64 demonstrated antibacterial activity against both gram-positive and gram-negative bacteria.

  17. SGLT2 inhibitors: are they safe?

    Science.gov (United States)

    Filippas-Ntekouan, Sebastian; Filippatos, Theodosios D; Elisaf, Moses S

    2018-01-01

    Sodium-glucose linked transporter type 2 (SGLT2) inhibitors are a relatively new class of antidiabetic drugs with positive cardiovascular and kidney effects. The aim of this review is to present the safety issues associated with SGLT2 inhibitors. Urogenital infections are the most frequently encountered adverse events, although tend to be mild to moderate and are easily manageable with standard treatment. Although no increased acute kidney injury risk was evident in the major trials, the mechanism of action of these drugs requires caution when they are administered in patients with extracellular volume depletion or with drugs affecting renal hemodynamics. Canagliflozin raised the risk of amputations and the rate of fractures in the CANVAS trial, although more data are necessary before drawing definite conclusions. The risk of euglycemic diabetic ketoacidosis seems to be minimal when the drugs are prescribed properly. Regarding other adverse events, SGLT2 inhibitors do not increase the risk of hypoglycemia even when co-administered with insulin, but a decrease in the dose of sulphonylureas may be needed. The available data do not point to a causative role of SGLT2 inhibitors on malignancy risk, however, these drugs should be used with caution in patients with known hematuria or history of bladder cancer. SGLT2 inhibitors seem to be safe and effective in the treatment of diabetes but more studies are required to assess their long-term safety.

  18. Aromatase inhibitors and breast cancer prevention.

    Science.gov (United States)

    Litton, Jennifer Keating; Arun, Banu K; Brown, Powel H; Hortobagyi, Gabriel N

    2012-02-01

    Endocrine therapy with selective estrogen receptor modulators (SERMs) has been the mainstay of breast cancer prevention trials to date. The aromatase inhibitors, which inhibit the final chemical conversion of androgens to estrogens, have shown increased disease-free survival benefit over tamoxifen in patients with primary hormone receptor-positive breast cancer, as well as reducing the risk of developing contralateral breast cancers. The aromatase inhibitors are being actively evaluated as prevention agents for women with a history of ductal carcinoma in situ as well as for women who are considered to be at high risk for developing primary invasive breast cancer. This review evaluates the available prevention data, as evidenced by the decrease in contralateral breast cancers, when aromatase inhibitors are used in the adjuvant setting, as well as the emerging data of the aromatase inhibitors specifically tested in the prevention setting for women at high risk. Exemestane is a viable option for breast cancer prevention. We continue to await further follow-up on exemestane as well as other aromatase inhibitors in the prevention setting for women at high risk of developing breast cancer or with a history of ductal carcinoma in situ.

  19. Janus kinase inhibitors: jackpot or potluck?

    Directory of Open Access Journals (Sweden)

    Pavithran Keechilat

    2012-06-01

    Full Text Available The reports of a unique mutation in the Janus kinase-2 gene (JAK2 in polycythemia vera by several independent groups in 2005 quickly spurred the development of the Janus kinase inhibitors. In one of the great victories of translational research in recent times, the first smallmolecule Janus kinase inhibitor ruxolitinib entered a phase I trial in 2007. With the approval of ruxolitinib by the US Federal Drug Administration in November 2011 for high-risk and intermediate-2 risk myelofibrosis, a change in paradigm has occurred in the management of a subset of myeloproliferative neoplasms (MPN: primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Whereas the current evidence for ruxolitinib only covers high-risk and intermediate-2 risk myelofibrosis, inhibitors with greater potency are likely to offer better disease control and survival advantage in patients belonging to these categories, and possibly to the low-risk and intermediate-1 risk categories of MPN as well. But use of the Janus kinase inhibitors also probably has certain disadvantages, such as toxicity, resistance, withdrawal phenomenon, non-reversal of histology, and an implausible goal of disease clone eradication, some of which could offset the gains. In spite of this, Janus kinase inhibitors are here to stay, and for use in more than just myeloproliferative neoplasms.

  20. The mixed waste landfill integrated demonstration

    International Nuclear Information System (INIS)

    Burford, T.D.; Williams, C.V.

    1994-01-01

    The Mixed Waste Landfill Integrated Demonstration (MWLID) focuses on ''in-situ'' characterization, monitoring, remediation, and containment of landfills in arid environments that contain hazardous and mixed waste. The MWLID mission is to assess, demonstrate, and transfer technologies and systems that lead to faster, better, cheaper, and safer cleanup. Most important, the demonstrated technologies will be evaluated against the baseline of conventional technologies and systems. The comparison will include the cost, efficiency, risk, and feasibility of using these innovative technologies at other sites

  1. Challenging demonstrations in the physics classroom

    International Nuclear Information System (INIS)

    Raz, E.

    2004-01-01

    Full Text: We consider the role of classroom demonstrations in improving students understanding of physics lectures and suggest criteria to decide whether a given demonstration will be pedagogically useful. In the light of these considerations, we performed two series of related experiments before groups of high-school students. We shall perform one of them with active participation from the audience. We shall also show some challenging demonstrations performed in the final stages of the Israeli Physics Olympiad for high-school students

  2. In silico panning for a non-competitive peptide inhibitor

    Directory of Open Access Journals (Sweden)

    Ikebukuro Kazunori

    2007-01-01

    Full Text Available Abstract Background Peptide ligands have tremendous therapeutic potential as efficacious drugs. Currently, more than 40 peptides are available in the market for a drug. However, since costly and time-consuming synthesis procedures represent a problem for high-throughput screening, novel procedures to reduce the time and labor involved in screening peptide ligands are required. We propose the novel approach of 'in silico panning' which consists of a two-stage screening, involving affinity selection by docking simulation and evolution of the peptide ligand using genetic algorithms (GAs. In silico panning was successfully applied to the selection of peptide inhibitor for water-soluble quinoprotein glucose dehydrogenase (PQQGDH. Results The evolution of peptide ligands for a target enzyme was achieved by combining a docking simulation with evolution of the peptide ligand using genetic algorithms (GAs, which mimic Darwinian evolution. Designation of the target area as next to the substrate-binding site of the enzyme in the docking simulation enabled the selection of a non-competitive inhibitor. In all, four rounds of selection were carried out on the computer; the distribution of the docking energy decreased gradually for each generation and improvements in the docking energy were observed over the four rounds of selection. One of the top three selected peptides with the lowest docking energy, 'SERG' showed an inhibitory effect with Ki value of 20 μM. PQQGDH activity, in terms of the Vmax value, was 3-fold lower than that of the wild-type enzyme in the presence of this peptide. The mechanism of the SERG blockage of the enzyme was identified as non-competitive inhibition. We confirmed the specific binding of the peptide, and its equilibrium dissociation constant (KD value was calculated as 60 μM by surface plasmon resonance (SPR analysis. Conclusion We demonstrate an effective methodology of in silico panning for the selection of a non

  3. Test and Demonstration Assets of New Mexico

    Energy Technology Data Exchange (ETDEWEB)

    None

    2008-03-31

    This document was developed by the Arrowhead Center of New Mexico State University as part of the National Security Preparedness Project (NSPP), funded by a DOE/NNSA grant. The NSPP has three primary components: business incubation, workforce development, and technology demonstration and validation. The document contains a survey of test and demonstration assets in New Mexico available for external users such as small businesses with security technologies under development. Demonstration and validation of national security technologies created by incubator sources, as well as other sources, are critical phases of technology development. The NSPP will support the utilization of an integrated demonstration and validation environment.

  4. A Novel System for Identification of Inhibitors of Rift Valley Fever Virus Replication

    Directory of Open Access Journals (Sweden)

    Mary E. Piper

    2010-03-01

    Full Text Available Rift Valley fever virus (RVFV is a human and livestock pathogen endemic to sub-Saharan Africa. We have developed a T7-dependent system for the efficient production of RVFV-like particles (RVF-VLPs based on the virulent ZH-501 strain of RVFV. The RVF-VLPs are capable of performing a single round of infection, allowing for the study of viral replication, assembly, and infectivity. We demonstrate that these RVF-VLPs are antigenically indistinguishable from authentic RVFV and respond similarly to a wide array of known and previously unknown chemical inhibitors. This system should be useful for screening for small molecule inhibitors of RVFV replication.

  5. A novel system for identification of inhibitors of rift valley Fever virus replication.

    Science.gov (United States)

    Piper, Mary E; Gerrard, Sonja R

    2010-03-01

    Rift Valley fever virus (RVFV) is a human and livestock pathogen endemic to sub-Saharan Africa. We have developed a T7-dependent system for the efficient production of RVFV-like particles (RVF-VLPs) based on the virulent ZH-501 strain of RVFV. The RVF-VLPs are capable of performing a single round of infection, allowing for the study of viral replication, assembly, and infectivity. We demonstrate that these RVF-VLPs are antigenically indistinguishable from authentic RVFV and respond similarly to a wide array of known and previously unknown chemical inhibitors. This system should be useful for screening for small molecule inhibitors of RVFV replication.

  6. Effects of selective phosphodiesterases-4 inhibitors on learning and memory: a review of recent research.

    Science.gov (United States)

    Peng, Sheng; Sun, Haiyan; Zhang, Xiaoqing; Liu, Gongjian; Wang, Guanglei

    2014-09-01

    Phosphodiesterase-4 (PDE-4) regulates the intracellular level of cyclic adenosine monophosphate. Recent studies demonstrated that PDE-4 inhibitors can counteract deficits in long-term memory caused by aging or increased expression of mutant forms of human amyloid precursor proteins, and can influence the process of memory function and cognitive enhancement. Therapeutics, such as ketamine, a drug used in clinical anesthesia, can also cause memory deficits as adverse effects. Targeting PDE-4 with selective inhibitors may offer a novel therapeutic strategy to prevent, slow the progress, and, eventually, treat memory deficits.

  7. Permanganate-assisted removal of PCR inhibitors during the DNA Chelex extraction from stained denim samples.

    Science.gov (United States)

    Pîrlea, Sorina; Puiu, Mihaela; Răducan, Adina; Oancea, Dumitru

    2017-03-01

    In this study, it was demonstrated that the DNA Chelex extraction combined with the permanganate assisted-oxidation is highly efficient in removing the PCR inhibitors often found in clothing materials, such as phthalocyanine. The extraction assays were conducted in saliva, blood and epithelial cells samples mixed with three oxidation-resistant dye copper(II) α-phthalocyanine, copper(II) β-phthalocyanine and tetrasulfonated copper(II) β-phthalocyanine. After DNA amplification, all samples were able to provide full DNA profiles. The permanganate/Chelex system was tested further on denim-stained samples and displayed the same ability to remove the PCR inhibitors from the commercial textile materials.

  8. Identification of novel bacterial histidine biosynthesis inhibitors using docking, ensemble rescoring, and whole-cell assays

    DEFF Research Database (Denmark)

    Henriksen, Signe Teuber; Liu, J.; Estiu, G.

    2010-01-01

    histidine biosynthesis pathway, which is predicted to be essential for bacterial biomass productions. Virtual screening of a library of similar to 10(6) compounds identified 49 potential inhibitors of three enzymes of this pathway. Eighteen representative compounds were directly tested on three S. aureus......-and two Escherichia coli strains in standard disk inhibition assays. Thirteen compounds are inhibitors of some or all of the S. aureus strains, while 14 compounds weakly inhibit growth in one or both E. coli strains. The high hit rate obtained from a fast virtual screen demonstrates the applicability...

  9. [A novel dipeptidyl peptidase IV inhibitors developed through scaffold hopping and drug splicing strategy].

    Science.gov (United States)

    Wang, Shan-Chun; Zeng, Li-Li; Ding, Yu-Yang; Zeng, Shao-Gao; Song, Hong-Rui; Hu, Wen-Hui; Xie, Hui

    2014-01-01

    Though all the marketed drugs of dipeptidyl peptidase IV inhibitors are structurally different, their inherent correlation is worthy of further investigation. Herein we rapidly discovered a novel DPP-IV inhibitor 8g (IC50 = 4.9 nmol.L-1) which exhibits as good activity and selectivity as the market drugs through scaffold hopping and drug splicing strategies based on alogliptin and linagliptin. This study demonstrated that the employment of classic medicinal chemistry strategy to the marketed drugs with specific target is an efficient approach to discover novel bioactive molecules.

  10. Safety of C1-Esterase Inhibitor in Acute and Prophylactic Therapy of Hereditary Angioedema

    DEFF Research Database (Denmark)

    Busse, Paula; Bygum, Anette; Edelman, Jonathan

    2014-01-01

    BACKGROUND: The plasma-derived, pasteurized C1-inhibitor (C1-INH) concentrate, Berinert has a 4-decade history of use in hereditary angioedema (HAE), with a substantial literature base that demonstrates safety and efficacy. Thromboembolic events have rarely been reported with C1-INH products......, typically with off-label use or at supratherapeutic doses. OBJECTIVES: Active surveillance of safety and clinical usage patterns of pasteurized C1-inhibitor concentrate and the more recent pasteurized, nanofiltered C1-INH, with a particular interest in thromboembolic events. METHODS: A registry...

  11. SGLT-2 Inhibitors and Cardiovascular Risk

    DEFF Research Database (Denmark)

    Cavender, Matthew A; Norhammar, Anna; Birkeland, Kåre I

    2018-01-01

    BACKGROUND: Prior studies found patients treated with sodium-glucose co-transporter-2 inhibitors (SGLT-2i) had lower rates of death and heart failure (HF). Whether the benefits of SGLT-2i vary based upon the presence of cardiovascular disease (CVD) is unknown. OBJECTIVES: This study sought...... to determine the association between initiation of SGLT-2i therapy and HF or death in patients with and without CVD. METHODS: The CVD-REAL (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors) study was a multinational, observational study in which adults with type 2 diabetes...... evidence regarding the benefit of SGLT-2i in patients without established CVD. (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors [CVD-REAL]; NCT02993614)....

  12. Tidd PFBC Demonstration Project, A DOE Assessment

    Energy Technology Data Exchange (ETDEWEB)

    National Energy Technology Laboratory

    2001-08-31

    The Clean Coal Technology (CCT) Demonstration Program is a government and industry co-funded technology development effort to demonstrate a new generation of innovative coal utilization processes. One goal of the program is to furnish the energy marketplace with a variety of energy efficient, environmentally superior coal-based technologies. Demonstration projects seek to establish the commercial feasibility of the most promising coal technologies that have proceeded beyond the proof-of-concept stage. This report is a post-project assessment of the DOE CCT Demonstration Program, the Tidd PFBC Demonstration Project. A major objective of the CCT Program is to provide the technical data necessary for the private sector to proceed confidently with the commercial replication of the demonstrated technologies. An essential element of meeting this goal is the dissemination of results from the demonstration projects. This post-project assessment (PPA) report is an independent DOE appraisal of the successes that the completed project had in achieving its objectives and aiding in the commercialization of the demonstrated technology. The report also provides an assessment of the expected technical, environmental, and economic performance of the commercial version of the technology, as well as an analysis of the commercial market.

  13. OVERVIEW OF USEPA'S ARSENIC TECHNOLOGY DEMONSTRATION PROGRAM

    Science.gov (United States)

    This presentation provides a summary on the Arsenic Treatment Technology Demonstration Program. The information includes the history and the current status of the demonstration projects on both round 1 and round 2 including some photos of the treatment systems. The presentation m...

  14. The Simplest Demonstration on Acoustic Beats

    Science.gov (United States)

    Ganci, Alessio; Ganci, Salvatore

    2015-01-01

    The classical demonstration experiment on acoustic beats using two signal generators and a dual trace oscilloscope is an important ingredient in teaching the subject. This short laboratory note aims to point out what may be the simplest demonstrative experiment on acoustic beats to carry out in a classroom without employing any lab apparatus.

  15. Status of IFR fuel cycle demonstration

    International Nuclear Information System (INIS)

    Lineberry, M.J.; Phipps, R.D.; McFarlane, H.F.

    1993-01-01

    The next major step in Argonne's Integral Fast Reactor (IFR) Program is demonstration of the pyroprocess fuel cycle, in conjunction with continued operation of EBR-II. The Fuel Cycle Facility (FCF) is being readied for this mission. This paper will address the status of facility systems and process equipment, the initial startup experience, and plans for the demonstration program

  16. Professor's Page: Do Demonstration Lessons Work?

    Science.gov (United States)

    Clarke, Doug

    2011-01-01

    As part of a large research and professional development project funded by the Catholic Education Office Melbourne (CEOM), called "Contemporary Teaching and Learning of Mathematics," the ACU team has been leading demonstration lessons. There is certainly not universal agreement on the worth of demonstration lessons in the mathematics…

  17. Buried Waste Integrated Demonstration Strategy Plan

    International Nuclear Information System (INIS)

    Kostelnik, K.M.

    1993-02-01

    The Buried Waste Integrated Demonstration (BWID) supports the applied research, development, demonstration, and evaluation of a suite of advanced technologies that form a comprehensive remediation system for the effective and efficient remediation of buried waste. These efforts are identified and coordinated in support of the US Department of Energy (DOE), Environmental Restoration and Waste Management (ERWM) needs and objectives. The present focus of BWID is to support retrieval and ex situ treatment configuration options. Future activities will explore and support containment and stabilization efforts in addition to the retrieval/ex situ treatment options. Long and short term strategies of the BWID are provided. Processes for identifying technological needs, screening candidate technologies for BWID applicability, researching technical issues, field demonstrating technologies, evaluating demonstration results to determine each technology's threshold of capability, and commercializing successfully demonstrated technologies for implementation for environmental restoration also are presented in this report

  18. Buried waste integrated demonstration technology integration process

    International Nuclear Information System (INIS)

    Ferguson, J.S.; Ferguson, J.E.

    1992-04-01

    A Technology integration Process was developed for the Idaho National Energy Laboratories (INEL) Buried Waste Integrated Demonstration (BWID) Program to facilitate the transfer of technology and knowledge from industry, universities, and other Federal agencies into the BWID; to successfully transfer demonstrated technology and knowledge from the BWID to industry, universities, and other Federal agencies; and to share demonstrated technologies and knowledge between Integrated Demonstrations and other Department of Energy (DOE) spread throughout the DOE Complex. This document also details specific methods and tools for integrating and transferring technologies into or out of the BWID program. The document provides background on the BWID program and technology development needs, demonstrates the direction of technology transfer, illustrates current processes for this transfer, and lists points of contact for prospective participants in the BWID technology transfer efforts. The Technology Integration Process was prepared to ensure compliance with the requirements of DOE's Office of Technology Development (OTD)

  19. Comparison of Clot-based, Chromogenic, and Fluorescence Assays for Measurement of Factor VIII Inhibitors in the U.S. Hemophilia Inhibitor Research Study

    Science.gov (United States)

    Miller, Connie H.; Rice, Anne S.; Boylan, Brian; Shapiro, Amy D.; Lentz, Steven R.; Wicklund, Brian M.; Kelly, Fiona M.; Soucie, J. Michael

    2015-01-01

    Summary Background Detection and validation of inhibitors (antibodies) to hemophilia treatment products are important for clinical care, evaluation of product safety, and assessment of population trends. Methods Centralized monitoring for factor VIII (FVIII) inhibitors was conducted for patients in the Hemophilia Inhibitor Research Study using a previously reported modified Nijmegen-Bethesda clotting assay (NBA), a chromogenic Bethesda assay (CBA), and a novel fluorescence immunoassay (FLI). Results NBA and CBA were performed on 1005 specimens and FLI on 272 specimens. CBA was negative on 880/883 specimens (99.7%) with Nijmegen-Bethesda units (NBU)NBA and negative CBA, 58.1% were FLI-negative, 12.9% had evidence of lupus anticoagulant, and 35.5% had non-time-dependent inhibition. CBA and FLI were positive on 72.4% and 100% of 1.0–1.9 NBU specimens and 43.1% and 50.0% of 0.5–0.9 NBU specimens. FLI detected antibodies in 98.0% of CBA-positive and 81.6% of NBA-positive specimens (P=0.004). Among 21 new inhibitors detected by NBA, 5 (23.8%) with 0.7–1.3 NBU did not react in CBA or FLI. Among previously positive patients with 0.5–1.9 NBU, 7/25 (28%) were not CBA or FLI positive. FLI was positive on 36/169 NBU-negative specimens (21.3%). Conclusions FVIII specificity could not be demonstrated by CBA or FLI for 26% of inhibitors of 0.5–1.9 NBU; such results must be interpreted with caution. Low titer inhibitors detected in clot-based assays should always be repeated, with consideration given to evaluating their reactivity with FVIII using more specific assays. PMID:23601690

  20. The activity of non-specific esterase in the thyroid epithelial cells of the guinea pig as influenced by various inhibitors and activators. A histochemical study

    DEFF Research Database (Denmark)

    Kirkeby, S

    1976-01-01

    The action of various inhibitors and activators upon esterase activity in the thyroid epithelial cells is demonstrated. The agents used were triorthocresylphosphate (TOCP), parachloromercuribenzoate (PCMB), Arsanillic acid, p-nitrophenyl dimethyl carbamate and bis p-nitrophenyl phosphate. TOCP wa...

  1. New halogenated phenylcoumarins as tyrosinase inhibitors.

    Science.gov (United States)

    Matos, Maria João; Santana, Lourdes; Uriarte, Eugenio; Delogu, Giovanna; Corda, Marcella; Fadda, Maria Benedetta; Era, Benedetta; Fais, Antonella

    2011-06-01

    With the aim to find out structural features for the tyrosinase inhibitory activity, in the present communication we report the synthesis and pharmacological evaluation of a new series of phenylcoumarin derivatives with different number of hydroxyl or ether groups and bromo substituent in the scaffold. The synthesized compounds 5-12 were evaluated as mushroom tyrosinase inhibitors showing, two of them, lower IC(50) than the umbelliferone. Compound 12 (IC(50)=215 μM) is the best tyrosinase inhibitor of this series. Copyright © 2011 Elsevier Ltd. All rights reserved.

  2. Green inhibitors. Rare Earth based systems

    International Nuclear Information System (INIS)

    Aballe, A.; Bethencourt, M.; Botana, F.J.; Perez, J.; Rodriguez, M.A.; Marcos, M.

    1997-01-01

    Lanthanum, Cerium and Samarium chlorides have been investigated as uniform and pitting corrosion inhibitors of AISI 434 and AISI 304 stainless steels and AA 5083 Al-Mg alloy in 3.5% Na Cl aerated aqueous solutions. Their inhibitor power was evaluated by using electrochemical techniques such as Linear and Cyclic Polarisation. In each case, the highest protection degree was found in the solution dropped with 500 ppm of CeCl 3 . Similar results were obtained for additions of 500 ppm of LaCl 3 . Scanning Electron Microscopy and Energy Dispersive Spectroscopy allowed us to confirm the cathodic nature of the inhibition process. (Author) 27 refs

  3. Development of Matrix Metalloproteinase-2 Inhibitors for Cardioprotection

    Directory of Open Access Journals (Sweden)

    Péter Bencsik

    2018-04-01

    Full Text Available The objective of our present study is to develop novel inhibitors for MMP-2 for acute cardioprotection. In a series of pilot studies, novel substituted carboxylic acid derivatives were synthesized based on imidazole and thiazole scaffolds and then tested in a screeening cascade for MMP inhibition. We found that the MMP-inhibiting effects of imidazole and thiazole carboxylic acid-based compounds are superior in efficacy in comparison to the conventional hydroxamic acid derivatives of the same molecules. Based on these results, a 568-membered focused library of imidazole and thiazole compounds was generated in silico and then the library members were docked to the 3D model of MMP-2 followed by an in vitro medium throughput screening (MTS based on a fluorescent assay employing MMP-2 catalytic domain. Altogether 45 compounds showed a docking score of >70, from which 30 compounds were successfully synthesized. Based on the MMP-2 inhibitory tests using gelatin zymography, 7 compounds were then selected and tested in neonatal rat cardiac myocytes subjected to simulated I/R injury. Six compounds showed significant cardio-cytoprotecion and the most effective compound (MMPI-1154 significantly decreased infarct size when applied at 1 μM in an ex vivo model for acute myocardial infarction. This is the first demonstration that imidazole and thiazole carboxylic acid-based compounds are more efficacious MMP-2 inhibitor than their hydroxamic acid derivatives. MMPI-1154 is a promising novel cardio-cytoprotective imidazole-carboxylic acid MMP-2 inhibitor lead candidate for the treatment of acute myocardial infarction.

  4. Development of Matrix Metalloproteinase-2 Inhibitors for Cardioprotection

    Science.gov (United States)

    Bencsik, Péter; Kupai, Krisztina; Görbe, Anikó; Kenyeres, Éva; Varga, Zoltán V.; Pálóczi, János; Gáspár, Renáta; Kovács, László; Weber, Lutz; Takács, Ferenc; Hajdú, István; Fabó, Gabriella; Cseh, Sándor; Barna, László; Csont, Tamás; Csonka, Csaba; Dormán, György; Ferdinandy, Péter

    2018-01-01

    The objective of our present study is to develop novel inhibitors for MMP-2 for acute cardioprotection. In a series of pilot studies, novel substituted carboxylic acid derivatives were synthesized based on imidazole and thiazole scaffolds and then tested in a screeening cascade for MMP inhibition. We found that the MMP-inhibiting effects of imidazole and thiazole carboxylic acid-based compounds are superior in efficacy in comparison to the conventional hydroxamic acid derivatives of the same molecules. Based on these results, a 568-membered focused library of imidazole and thiazole compounds was generated in silico and then the library members were docked to the 3D model of MMP-2 followed by an in vitro medium throughput screening (MTS) based on a fluorescent assay employing MMP-2 catalytic domain. Altogether 45 compounds showed a docking score of >70, from which 30 compounds were successfully synthesized. Based on the MMP-2 inhibitory tests using gelatin zymography, 7 compounds were then selected and tested in neonatal rat cardiac myocytes subjected to simulated I/R injury. Six compounds showed significant cardio-cytoprotecion and the most effective compound (MMPI-1154) significantly decreased infarct size when applied at 1 μM in an ex vivo model for acute myocardial infarction. This is the first demonstration that imidazole and thiazole carboxylic acid-based compounds are more efficacious MMP-2 inhibitor than their hydroxamic acid derivatives. MMPI-1154 is a promising novel cardio-cytoprotective imidazole-carboxylic acid MMP-2 inhibitor lead candidate for the treatment of acute myocardial infarction. PMID:29674965

  5. Phenolic Amides Are Potent Inhibitors of De Novo Nucleotide Biosynthesis.

    Science.gov (United States)

    Pisithkul, Tippapha; Jacobson, Tyler B; O'Brien, Thomas J; Stevenson, David M; Amador-Noguez, Daniel

    2015-09-01

    An outstanding challenge toward efficient production of biofuels and value-added chemicals from plant biomass is the impact that lignocellulose-derived inhibitors have on microbial fermentations. Elucidating the mechanisms that underlie their toxicity is critical for developing strategies to overcome them. Here, using Escherichia coli as a model system, we investigated the metabolic effects and toxicity mechanisms of feruloyl amide and coumaroyl amide, the predominant phenolic compounds in ammonia-pretreated biomass hydrolysates. Using metabolomics, isotope tracers, and biochemical assays, we showed that these two phenolic amides act as potent and fast-acting inhibitors of purine and pyrimidine biosynthetic pathways. Feruloyl or coumaroyl amide exposure leads to (i) a rapid buildup of 5-phosphoribosyl-1-pyrophosphate (PRPP), a key precursor in nucleotide biosynthesis, (ii) a rapid decrease in the levels of pyrimidine biosynthetic intermediates, and (iii) a long-term generalized decrease in nucleotide and deoxynucleotide levels. Tracer experiments using (13)C-labeled sugars and [(15)N]ammonia demonstrated that carbon and nitrogen fluxes into nucleotides and deoxynucleotides are inhibited by these phenolic amides. We found that these effects are mediated via direct inhibition of glutamine amidotransferases that participate in nucleotide biosynthetic pathways. In particular, feruloyl amide is a competitive inhibitor of glutamine PRPP amidotransferase (PurF), which catalyzes the first committed step in de novo purine biosynthesis. Finally, external nucleoside supplementation prevents phenolic amide-mediated growth inhibition by allowing nucleotide biosynthesis via salvage pathways. The results presented here will help in the development of strategies to overcome toxicity of phenolic compounds and facilitate engineering of more efficient microbial producers of biofuels and chemicals. Copyright © 2015, Pisithkul et al.

  6. Phenolic Amides Are Potent Inhibitors of De Novo Nucleotide Biosynthesis

    Science.gov (United States)

    Pisithkul, Tippapha; Jacobson, Tyler B.; O'Brien, Thomas J.; Stevenson, David M.

    2015-01-01

    An outstanding challenge toward efficient production of biofuels and value-added chemicals from plant biomass is the impact that lignocellulose-derived inhibitors have on microbial fermentations. Elucidating the mechanisms that underlie their toxicity is critical for developing strategies to overcome them. Here, using Escherichia coli as a model system, we investigated the metabolic effects and toxicity mechanisms of feruloyl amide and coumaroyl amide, the predominant phenolic compounds in ammonia-pretreated biomass hydrolysates. Using metabolomics, isotope tracers, and biochemical assays, we showed that these two phenolic amides act as potent and fast-acting inhibitors of purine and pyrimidine biosynthetic pathways. Feruloyl or coumaroyl amide exposure leads to (i) a rapid buildup of 5-phosphoribosyl-1-pyrophosphate (PRPP), a key precursor in nucleotide biosynthesis, (ii) a rapid decrease in the levels of pyrimidine biosynthetic intermediates, and (iii) a long-term generalized decrease in nucleotide and deoxynucleotide levels. Tracer experiments using 13C-labeled sugars and [15N]ammonia demonstrated that carbon and nitrogen fluxes into nucleotides and deoxynucleotides are inhibited by these phenolic amides. We found that these effects are mediated via direct inhibition of glutamine amidotransferases that participate in nucleotide biosynthetic pathways. In particular, feruloyl amide is a competitive inhibitor of glutamine PRPP amidotransferase (PurF), which catalyzes the first committed step in de novo purine biosynthesis. Finally, external nucleoside supplementation prevents phenolic amide-mediated growth inhibition by allowing nucleotide biosynthesis via salvage pathways. The results presented here will help in the development of strategies to overcome toxicity of phenolic compounds and facilitate engineering of more efficient microbial producers of biofuels and chemicals. PMID:26070680

  7. A high throughput screening assay for identifying glycation inhibitors on MALDI-TOF target.

    Science.gov (United States)

    Zhang, Qiuting; Tu, Zongcai; Wang, Hui; Fan, Liangliang; Huang, Xiaoqin; Xiao, Hui

    2015-03-01

    The Maillard reaction plays an important role in the food industry, however, the deleterious effects generated by the advanced glycation end-products (AGEs) have been well recognized. Many efforts have been made to seek new AGE inhibitors, in particular those natural ones without adverse effect. We have developed a rapid, mass spectrometry based, on-plate screening assay for novel AGE inhibitors. The glycation reaction, inhibition feedback as well as the subsequent MALDI mass spectrometric analysis occurred on one single MALDI plate. At 1:10 M ratio of peptide to sugar, as little as 4h incubation time allowed the screening test to be ready for analysis. DSP, inhibition and IC50 were calculated to evaluate selected inhibitors and resulting inhibition efficiencies were consistent with available references. We demonstrated that this method provide a potential high throughput screening assay to analyze and identify the anti-glycation agents. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. Selective small-chemical inhibitors of protein arginine methyltransferase 5 with anti-lung cancer activity.

    Directory of Open Access Journals (Sweden)

    Gui-Mei Kong

    Full Text Available Protein arginine methyltransferase 5 (PRMT5 plays critical roles in a wide variety of biological processes, including tumorigenesis. By screening a library of small chemical compounds, we identified eight compounds that selectively inhibit the PRMT5 enzymatic activity, with IC50 values ranging from 0.1 to 6 μM. Molecular docking simulation and site-directed mutagenesis indicated that identified compounds target the substrate-binding site in PRMT5. Treatment of lung cancer cells with identified inhibitors led to inhibition of the symmetrical arginine methylation of SmD3 and histones and the cellular proliferation. Oral administration of the inhibitor demonstrated antitumor activity in a lung tumor xenograft model. Thus, identified PRMT5-specific small-molecule inhibitors would help elucidate the biological roles of PRMT5 and serve as lead compounds for future drug development.

  9. Secretory leukocyte protease inhibitor protein regulates the penetrance of frontotemporal lobar degeneration in progranulin mutation carriers.

    Science.gov (United States)

    Ghidoni, Roberta; Flocco, Rosa; Paterlini, Anna; Glionna, Michela; Caruana, Loredana; Tonoli, Elisa; Binetti, Giuliano; Benussi, Luisa

    2014-01-01

    The discovery that mutations in the gene encoding for progranulin (GRN) cause frontotemporal lobar degeneration (FTLD) and other neurodegenerative diseases leading to dementia has brought renewed interest in progranulin and its functions in the central nervous system. Full length progranulin is preserved from cleavage by secretory leukocyte protease inhibitor (SLPI), one of the smallest serine protease inhibitor circulating in plasma. Herein, we investigated the relationship between circulating SLPI and progranulin in affected and unaffected subjects belonging to 26 Italian pedigrees carrying GRN null mutations. In GRN null mutation carriers, we demonstrated: i) an increase of circulating SLPI levels in affected subjects; ii) an age-related upregulation of the serine-protease inhibitor in response to lifetime progranulin shortage; and iii) a delay in the age of onset in subjects with the highest SLPI protein levels. The study of SLPI and its relation to progranulin suggests the existence of unexpected molecular players in progranulin-associated neurodegeneration.

  10. Condensed Tannins from Longan Bark as Inhibitor of Tyrosinase: Structure, Activity, and Mechanism.

    Science.gov (United States)

    Chai, Wei-Ming; Huang, Qian; Lin, Mei-Zhen; Ou-Yang, Chong; Huang, Wen-Yang; Wang, Ying-Xia; Xu, Kai-Li; Feng, Hui-Ling

    2018-01-31

    In this study, the content, structure, antityrosinase activity, and mechanism of longan bark condensed tannins were evaluated. The findings obtained from mass spectrometry demonstrated that longan bark condensed tannins were mixtures of procyanidins, propelargonidins, prodelphinidins, and their acyl derivatives (galloyl and p-hydroxybenzoate). The enzyme analysis indicated that these mixtures were efficient, reversible, and mixed (competitive is dominant) inhibitor of tyrosinase. What's more, the mixtures showed good inhibitions on proliferation, intracellular enzyme activity and melanogenesis of mouse melanoma cells (B 16 ). From molecular docking, the results showed the interactions between inhibitors and tyrosinase were driven by hydrogen bond, electrostatic, and hydrophobic interactions. In addition, high levels of total phenolic and extractable condensed tannins suggested that longan bark might be a good source of tyrosinase inhibitor. This study would offer theoretical basis for the development of longan bark condensed tannins as novel food preservatives and medicines of skin diseases.

  11. Discovery of a Parenteral Small Molecule Coagulation Factor XIa Inhibitor Clinical Candidate (BMS-962212).

    Science.gov (United States)

    Pinto, Donald J P; Orwat, Michael J; Smith, Leon M; Quan, Mimi L; Lam, Patrick Y S; Rossi, Karen A; Apedo, Atsu; Bozarth, Jeffrey M; Wu, Yiming; Zheng, Joanna J; Xin, Baomin; Toussaint, Nathalie; Stetsko, Paul; Gudmundsson, Olafur; Maxwell, Brad; Crain, Earl J; Wong, Pancras C; Lou, Zhen; Harper, Timothy W; Chacko, Silvi A; Myers, Joseph E; Sheriff, Steven; Zhang, Huiping; Hou, Xiaoping; Mathur, Arvind; Seiffert, Dietmar A; Wexler, Ruth R; Luettgen, Joseph M; Ewing, William R

    2017-12-14

    Factor XIa (FXIa) is a blood coagulation enzyme that is involved in the amplification of thrombin generation. Mounting evidence suggests that direct inhibition of FXIa can block pathologic thrombus formation while preserving normal hemostasis. Preclinical studies using a variety of approaches to reduce FXIa activity, including direct inhibitors of FXIa, have demonstrated good antithrombotic efficacy without increasing bleeding. On the basis of this potential, we targeted our efforts at identifying potent inhibitors of FXIa with a focus on discovering an acute antithrombotic agent for use in a hospital setting. Herein we describe the discovery of a potent FXIa clinical candidate, 55 (FXIa K i = 0.7 nM), with excellent preclinical efficacy in thrombosis models and aqueous solubility suitable for intravenous administration. BMS-962212 is a reversible, direct, and highly selective small molecule inhibitor of FXIa.

  12. Roles of secretory leukocyte protease inhibitor amniotic membrane in oral wound healing

    Directory of Open Access Journals (Sweden)

    Elly Munadziroh

    2006-12-01

    Full Text Available Secretory Leukocyte Protease Inhibitor (SLPI is serine protease inhibitor. Secretory Leukocyte Protease Inhibitor is a protein found in secretions such as whole saliva, seminal fluid, cervical mucus, synovial fluid, breast milk, tears, and cerebral spinal fluid, as in secretions from the nose and bronchi, amniotic fluid and amniotic membrane etc. These findings demonstrate that SLPI function as a potent anti protease, anti inflammatory, bactericidal, antifungal, tissue repair, extra cellular synthesis. Impaired healing states are characterized by excessive proteolysis and often bacterial infection, leading to the hypothesis that SLPI may have a role in the process. The objectives of this article are to investigate the role of SLPI in oral inflammation and how it contributes to tissue repair in oral mucosa. The oral wound healing responses are impaired in the SLPI sufficient mice and matrix synthesis and collagen deposition are delayed. This study indicated that SLPI is a povital factor necessary for optimal wound healing.

  13. The in vitro screening of aromatic amides as potential inhibitors of poly (ADP-ribose) polymerase

    International Nuclear Information System (INIS)

    Brown, D.M.; Horsman, M.R.; Lee, W.W.; Brown, J.M.

    1984-01-01

    It is now well established that the chromosomal enzyme poly (ADP-ribose) polymerase (ADPRP) is involved in the repair of DNA damage caused by ionizing radiation and alkylating agents, although the mechanisms involved are still not clear. ADPRP inhibitors include thymidine, nicotinamides, benzamides and methyl xanthines. The authors have demonstrated that these compounds are effective inhibitors of X-ray-induced potentially lethal damage repair (PLDR). More recently, they have shown that the cytotoxicity of the bifunctional alkylating L-phenylalanine mustard (L-PAM) was enhanced in vitro and in vivo by 3-aminobenzamide, nicotinamide and caffeine, although in the latter case pharmacokinetic changes could have contributed to the enhanced killing. The authors have examined a series of substituted carbocyclic and heterocyclic aromatic amides as potential inhibitors of ADPRP. The effect of these compounds on ADPRP activity in vitro as well as their effect on the repair of X-ray and alkylation damage in vitro are presented

  14. An ibuprofen-antagonized plasmin inhibitor released by human endothelial cells.

    Science.gov (United States)

    Rockwell, W B; Ehrlich, H P

    1991-02-01

    Serum-free culture medium harvested from endothelial cell monolayer cultures derived from human scars and dermis was examined for inhibition of fibrinolysis using a fibrin plate assay. Human cultured fibroblasts and smooth muscle cells did not produce any detectable inhibitory activity. The inhibitor is spontaneously released from the cultured endothelial cells over time. In the fibrin plate assay of plasmin-induced fibrinolysis, one nonsteroidal antiinflammatory (NSAI) drug, ibuprofen, was demonstrated to antagonize the inhibition of fibrinolysis. The antagonistic activity of ibuprofen appears unrelated to its NSAI drug activity because other NSAI drugs such as indomethacin and tolmetin have minimal antagonistic activity. Heating the cultured endothelial cells to 42 degrees C stimulates greater release of the inhibitor in a shorter period of time. This plasmin inhibitor, which is produced by endothelial cells, may contribute to postburn vascular occlusion, leading to secondary progressive necrosis in burn-traumatized patients.

  15. Phosphodiesterase type 5 inhibitors increase Herceptin transport and treatment efficacy in mouse metastatic brain tumor models.

    Directory of Open Access Journals (Sweden)

    Jinwei Hu

    2010-04-01

    Full Text Available Chemotherapeutic drugs and newly developed therapeutic monoclonal antibodies are adequately delivered to most solid and systemic tumors. However, drug delivery into primary brain tumors and metastases is impeded by the blood-brain tumor barrier (BTB, significantly limiting drug use in brain cancer treatment.We examined the effect of phosphodiesterase 5 (PDE5 inhibitors in nude mice on drug delivery to intracranially implanted human lung and breast tumors as the most common primary tumors forming brain metastases, and studied underlying mechanisms of drug transport. In vitro assays demonstrated that PDE5 inhibitors enhanced the uptake of [(14C]dextran and trastuzumab (Herceptin, a humanized monoclonal antibody against HER2/neu by cultured mouse brain endothelial cells (MBEC. The mechanism of drug delivery was examined using inhibitors for caveolae-mediated endocytosis, macropinocytosis and coated pit/clathrin endocytosis. Inhibitor analysis strongly implicated caveolae and macropinocytosis endocytic pathways involvement in the PDE5 inhibitor-enhanced Herceptin uptake by MBEC. Oral administration of PDE5 inhibitor, vardenafil, to mice with HER2-positive intracranial lung tumors led to an increased tumor permeability to high molecular weight [(14C]dextran (2.6-fold increase and to Herceptin (2-fold increase. Survival time of intracranial lung cancer-bearing mice treated with Herceptin in combination with vardenafil was significantly increased as compared to the untreated, vardenafil- or Herceptin-treated mice (p0.05.These findings suggest that PDE5 inhibitors may effectively modulate BTB permeability, and enhance delivery and therapeutic efficacy of monoclonal antibodies in hard-to-treat brain metastases from different primary tumors that had metastasized to the brain.

  16. The COX-2 inhibitor meloxicam prevents pregnancy when administered as an emergency contraceptive to nonhuman primates.

    Science.gov (United States)

    McCann, Nicole C; Lynch, Terrie J; Kim, Soon Ok; Duffy, Diane M

    2013-12-01

    Cyclooxygenase-2 (COX-2) inhibitors reduce prostaglandin synthesis and disrupt essential reproductive processes. Ultrasound studies in women demonstrated that oral COX-2 inhibitors can delay or prevent follicle collapse associated with ovulation. The goal of this study was to determine if oral administration of a COX-2 inhibitor can inhibit reproductive function with sufficient efficacy to prevent pregnancy in primates. The COX-2 inhibitor meloxicam (or vehicle) was administered orally to proven fertile female cynomolgus macaques using one emergency contraceptive model and three monthly contraceptive models. In the emergency contraceptive model, females were bred with a proven fertile male once 2±1 days before ovulation, returned to the females' home cage, and then received 5 days of meloxicam treatment. In the monthly contraceptive models, females were co-caged for breeding with a proven fertile male for a total of 5 days beginning 2±1 days before ovulation. Animals received meloxicam treatment (1) cycle days 5-22, or (2) every day, or (3) each day of the 5-day breeding period. Female were then assessed for pregnancy. The pregnancy rate with meloxicam administration using the emergency contraception model was 6.5%, significantly lower than the pregnancy rate of 33.3% when vehicle without meloxicam was administered. Pregnancy rates with the three monthly contraceptive models (75%-100%) were not consistent with preventing pregnancy. Oral COX-2 inhibitor administration can prevent pregnancy after a single instance of breeding in primates. While meloxicam may be ineffective for regular contraception, pharmacological inhibition of COX-2 may be an effective method of emergency contraception for women. COX-2 inhibitors can interfere with ovulation, but the contraceptive efficacy of drugs of this class has not been directly tested. This study, conducted in nonhuman primates, is the first to suggest that a COX-2 inhibitor may be effective as an emergency contraceptive.

  17. Preoperative renin-angiotensin system inhibitors protect renal function in aging patients undergoing cardiac surgery.

    Science.gov (United States)

    Barodka, Viachaslau; Silvestry, Scott; Zhao, Ning; Jiao, Xiangyin; Whellan, David J; Diehl, James; Sun, Jian-Zhong

    2011-05-15

    Renal failure (RF) represents a major postoperative complication for elderly patients undergoing cardiac surgery. This observational cohort study examines effects of preoperative use of renin-angiotensin system (RAS) inhibitors on postoperative renal failure in aging patients undergoing cardiac surgery. We retrospectively analyzed a cohort of 1287 patients who underwent cardiac surgery at this institution (2003-2007). The patients included were ≥65 years old, scheduled for elective cardiac surgery, and without preexisting RF (defined by the criteria of the Society of Thoracic Surgeons as described in Method). Of all patients evaluated, 346 patients met the inclusion criteria and were divided into two groups: using (n = 122) or not using (n = 224) preoperative RAS inhibitors. A comparison of the two groups showed no significant differences in baseline parameters, including creatinine clearance, body mass index, history of diabetes and smoking, preoperative medicines (except that more patients with RAS inhibitors had a history of hypertension or congestive heart failure, fewer RAS inhibitor patients had chronic lung disease), in intraoperative perfusion and aortic cross-clamp time, and in postoperative complications and 30-d mortality. Multivariate logistic regression analysis demonstrated, however, that preoperative RAS inhibitors significantly and independently reduced the incidence of postoperative RF in the patients undergoing cardiac surgery compared with those not taking RAS inhibitors: 1.6% versus 7.6%, yielding an odds ratio of 0.19 (95 % CI 0.04-0.84, P = 0.029). Preoperative RAS inhibitors may have significant renoprotective effects for aging patients undergoing elective cardiac surgery. Copyright © 2011 Elsevier Inc. All rights reserved.

  18. PI3K inhibitors as new cancer therapeutics: implications for clinical trial design

    Directory of Open Access Journals (Sweden)

    Massacesi C

    2016-01-01

    Full Text Available Cristian Massacesi,1 Emmanuelle Di Tomaso,2 Patrick Urban,3 Caroline Germa,4 Cornelia Quadt,5 Lucia Trandafir,1 Paola Aimone,3 Nathalie Fretault,1 Bharani Dharan,4 Ranjana Tavorath,4 Samit Hirawat4 1Novartis Oncology, Paris, France; 2Novartis Institutes for BioMedical Research Inc, Cambridge, MA, USA; 3Novartis Pharma AG, Basel, Switzerland; 4Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 5Novartis Pharmaceuticals KK, Tokyo, Japan Abstract: The PI3K–AKT–mTOR pathway is frequently activated in cancer. PI3K inhibitors, including the pan-PI3K inhibitor buparlisib (BKM120 and the PI3Kα-selective inhibitor alpelisib (BYL719, currently in clinical development by Novartis Oncology, may therefore be effective as anticancer agents. Early clinical studies with PI3K inhibitors have demonstrated preliminary antitumor activity and acceptable safety profiles. However, a number of unanswered questions regarding PI3K inhibition in cancer remain, including: what is the best approach for different tumor types, and which biomarkers will accurately identify the patient populations most likely to benefit from specific PI3K inhibitors? This review summarizes the strategies being employed by Novartis Oncology to help maximize the benefits of clinical studies with buparlisib and alpelisib, including stratification according to PI3K pathway activation status, selective enrollment/target enrichment (where patients with PI3K pathway-activated tumors are specifically recruited, nonselective enrollment with mandatory tissue collection, and enrollment of patients who have progressed on previous targeted agents, such as mTOR inhibitors or endocrine therapy. An overview of Novartis-sponsored and Novartis-supported trials that are utilizing these approaches in a range of cancer types, including breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, lymphoma, and glioblastoma multiforme, is also described. Keywords: PI3K

  19. Identification of small molecule inhibitors of Pseudomonas aeruginosa exoenzyme S using a yeast phenotypic screen.

    Directory of Open Access Journals (Sweden)

    Anthony Arnoldo

    2008-02-01

    Full Text Available Pseudomonas aeruginosa is an opportunistic human pathogen that is a key factor in the mortality of cystic fibrosis patients, and infection represents an increased threat for human health worldwide. Because resistance of Pseudomonas aeruginosa to antibiotics is increasing, new inhibitors of pharmacologically validated targets of this bacterium are needed. Here we demonstrate that a cell-based yeast phenotypic assay, combined with a large-scale inhibitor screen, identified small molecule inhibitors that can suppress the toxicity caused by heterologous expression of selected Pseudomonas aeruginosa ORFs. We identified the first small molecule inhibitor of Exoenzyme S (ExoS, a toxin involved in Type III secretion. We show that this inhibitor, exosin, modulates ExoS ADP-ribosyltransferase activity in vitro, suggesting the inhibition is direct. Moreover, exosin and two of its analogues display a significant protective effect against Pseudomonas infection in vivo. Furthermore, because the assay was performed in yeast, we were able to demonstrate that several yeast homologues of the known human ExoS targets are likely ADP-ribosylated by the toxin. For example, using an in vitro enzymatic assay, we demonstrate that yeast Ras2p is directly modified by ExoS. Lastly, by surveying a collection of yeast deletion mutants, we identified Bmh1p, a yeast homologue of the human FAS, as an ExoS cofactor, revealing that portions of the bacterial toxin mode of action are conserved from yeast to human. Taken together, our integrated cell-based, chemical-genetic approach demonstrates that such screens can augment traditional drug screening approaches and facilitate the discovery of new compounds against a broad range of human pathogens.

  20. Marketing Plan for Demonstration and Validation Assets

    Energy Technology Data Exchange (ETDEWEB)

    None, None

    2008-05-30

    The National Security Preparedness Project (NSPP), is to be sustained by various programs, including technology demonstration and evaluation (DEMVAL). This project assists companies in developing technologies under the National Security Technology Incubator program (NSTI) through demonstration and validation of technologies applicable to national security created by incubators and other sources. The NSPP also will support the creation of an integrated demonstration and validation environment. This report documents the DEMVAL marketing and visibility plan, which will focus on collecting information about, and expanding the visibility of, DEMVAL assets serving businesses with national security technology applications in southern New Mexico.

  1. Transportable Vitrification System Demonstration on Mixed Waste

    International Nuclear Information System (INIS)

    Zamecnik, J.R.; Whitehouse, J.C.; Wilson, C.N.; Van Ryn, F.R.

    1998-01-01

    This paper describes preliminary results from the first demonstration of the Transportable Vitrification System (TVS) on actual mixed waste. The TVS is a fully integrated, transportable system for the treatment of mixed and low-level radioactive wastes. The demonstration was conducted at Oak Ridge's East Tennessee Technology Park (ETTP), formerly known as the K-25 site. The purpose of the demonstration was to show that mixed wastes could be vitrified safely on a 'field' scale using joule-heated melter technology and obtain information on system performance, waste form durability, air emissions, and costs

  2. Prototype scale demonstration of CECE detritiation

    International Nuclear Information System (INIS)

    Sadhankar Ramesh; Cobanoglu, Macit

    2004-01-01

    AECL has developed and demonstrated the Combined Electrolysis and Catalytic Exchange (CECE) Process for detritiation of heavy water. Although CECE has been the subject of pilot-scale demonstrations by various organizations, AECL is the first to demonstrate this technology in an industrial prototype plant. AECL designed, built and operated a CECE demonstration facility under CAN/CSA N286 Quality Assurance Program. The facility was licensed by the Canadian nuclear regulator. This was a two-fold demonstration of the CECE technology - for upgrading (removal of light water) and for detritiation of heavy water. In 1998 June, AECL began operating the facility in upgrading mode. The design feed rate ranged up to 25 Mg/a for 95 mol% D 2 O feed water. After 18 months of operation in upgrading mode, the facility was reconfigured and operated for an additional 9 months from 2000 August in detritiation mode. Design capacity for detritiation was 5 Mg/a with a detritiation factor (DF) of 100. However, significantly higher DFs, up to 56 000, were demonstrated. Highlights of the detritiation demonstration were: Proven robustness of AECL's proprietary wetproofed catalyst for Liquid Phase Catalytic Exchange; Demonstration of a trickle-bed-recombiner for stoichiometric combination of deuterium and oxygen; Demonstration of electrolysis of highly tritiated heavy water; High process availability and controllability was demonstrated by a long interrupted run; Low emissions; Demonstration of high DF - up to 56 000 - a significant advantage of the CECE process over other approaches to detritiation; Validation of AECL's simulation code for the CECE process over a range of DFs from 100 to 50 000. Apart from the technology, AECL has expertise in all aspects of setting up a new detritiation facility including design, engineering, safety assessment, licensing support, project management and training. AECL is also the engineering and design contractor for a tritium removal facility that is under

  3. Preclinical rationale for PI3K/Akt/mTOR pathway inhibitors as therapy for epidermal growth factor receptor inhibitor-resistant non-small-cell lung cancer.

    Science.gov (United States)

    Gadgeel, Shirish M; Wozniak, Antoinette

    2013-07-01

    Mutations in the epidermal growth factor receptor gene (EGFR) are frequently observed in non-small-cell lung cancer (NSCLC), occurring in about 40% to 60% of never-smokers and in about 17% of patients with adenocarcinomas. EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have transformed therapy for patients with EGFR-mutant NSCLC and have proved superior to chemotherapy as first-line treatment for this patient group. Despite these benefits, there are currently 2 key challenges associated with EGFR inhibitor therapy for patients with NSCLC. First, only 85% to 90% of patients with the EGFR mutation derive clinical benefit from EGFR TKIs, with the remainder demonstrating innate resistance to therapy. Second, acquired resistance to EGFR TKIs inevitably occurs in patients who initially respond to therapy, with a median duration of response of about 10 months. Mutant EGFR activates various subcellular signaling cascades, including the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, which demonstrates maintained activity in a variety of TKI-resistant cancers. Given the fundamental role of the PI3K/Akt/mTOR pathway in tumor oncogenesis, proliferation, and survival, PI3K pathway inhibitors have emerged as a possible solution to the problem of EGFR TKI resistance. However resistance to EGFR TKIs is associated with considerable heterogeneity and complexity. Preclinical experiments investigating these phenomena suggest that in some patients, PI3K inhibitors will have to be paired with other targeted agents if they are to be effective. This review discusses the preclinical data supporting PI3K/Akt/mTOR pathway inhibitor combinations in EGFR TKI-resistant NSCLC from the perspective of the various agents currently being investigated in clinical trials. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. Synergistic apoptosis induction in leukemic cells by the phosphatase inhibitor salubrinal and proteasome inhibitors.

    Directory of Open Access Journals (Sweden)

    Hannes C A Drexler

    Full Text Available Cells adapt to endoplasmic reticulum (ER-stress by arresting global protein synthesis while simultaneously activating specific transcription factors and their downstream targets. These processes are mediated in part by the phosphorylation-dependent inactivation of the translation initiation factor eIF2alpha. Following restoration of homeostasis protein synthesis is resumed when the serine/threonine-protein phosphatase PP1 dephosphorylates and reactivates eIF2alpha. Proteasome inhibitors, used to treat multiple myeloma patients evoke ER-stress and apoptosis by blocking the ER-associated degradation of misfolded proteins (ERAD, however, the role of eIF2alpha phosphorylation in leukemic cells under conditions of proteasome inhibitor-mediated ER stress is currently unclear.Bcr-Abl-positive and negative leukemic cell lines were used to investigate the functional implications of PP1-related phosphatase activities on eIF2alpha phosphorylation in proteasome inhibitor-mediated ER stress and apoptosis. Rather unexpectedly, salubrinal, a recently identified PP1 inhibitor capable to protect against ER stress in various model systems, strongly synergized with proteasome inhibitors to augment apoptotic death of different leukemic cell lines. Salubrinal treatment did not affect the phosphorlyation status of eIF2alpha. Furthermore, the proapoptotic effect of salubrinal occurred independently from the chemical nature of the proteasome inhibitor, was recapitulated by a second unrelated phosphatase inhibitor and was unaffected by overexpression of a dominant negative eIF2alpha S51A variant that can not be phosphorylated. Salubrinal further aggravated ER-stress and proteotoxicity inflicted by the proteasome inhibitors on the leukemic cells since characteristic ER stress responses, such as ATF4 and CHOP synthesis, XBP1 splicing, activation of MAP kinases and eventually apoptosis were efficiently abrogated by the translational inhibitor cycloheximide.Although PP1

  5. PDE5 Inhibitors As Potential Tools In The Treatment Of Cystic Fibrosis

    Directory of Open Access Journals (Sweden)

    Sabrina eNoel

    2012-09-01

    Full Text Available Despite great advances in the understanding of the genetics and pathophysiology of cystic fibrosis (CF, there is still no cure for the disease. Using phosphodiesterase type 5 (PDE5 inhibitors, we and others have provided evidence of rescued F508del-CFTR trafficking and corrected deficient chloride transport activity. Studies using PDE5 inhibitors in mice homozygous for the clinically relevant F508del mutation have been conducted with the aim of restoring F508del-CFTR protein function. We demonstrated, by measuring transepithelial nasal potential difference in F508del mice following intraperitoneal injection of sildenafil, vardenafil or taladafil at clinical doses are able to restore the decreased CFTR-dependent chloride transport across the nasal mucosa. Moreover, vardenafil, but not sildenafil, stimulates chloride transport through the normal CFTR protein. We developed a specific nebulizer setup for mice, with which we demonstrated, through a single inhalation of PDE5 inhibitors, local activation of CFTR protein in CF. Significant potential advantages of inhalation drug therapy over oral or intravenous routes include rapid onset of pharmacological action, reduced systemic secondary effects and reduced effective drug doses compared to the drug delivered orally; this underlines the relevance and impact of our work for translational science. More recently, we analyzed the bronchoalveolar lavage of CF and wild-type mice for cell infiltrates and expression of pro-inflammatory cytokines and chemokines; we found that the CFTR activating effect of vardenafil, selected as a representative long-lasting PDE5 inhibitor, breaks the vicious circle of lung inflammation which plays a major role in morbi-mortality in CF. Our data highlight the potential use of PDE5 inhibitors in CF. Therapeutic approaches using clinically approved PDE5 inhibitors to address F508del-CFTR defects could speed up the development of new therapies for CF.

  6. Improved Peak Capacity for Capillary Electrophoretic Separations of Enzyme Inhibitors with Activity-Based Detection Using Magnetic Bead Microreactors

    Science.gov (United States)

    Yan, Xiaoyan; Gilman, S. Douglass

    2010-01-01

    A technique for separating and detecting enzyme inhibitors was developed using capillary electrophoresis with an enzyme microreactor. The on-column enzyme microreactor was constructed using NdFeB magnet(s) to immobilize alkaline phosphatase-coated superparamagnetic beads (2.8 μm diameter) inside a capillary before the detection window. Enzyme inhibition assays were performed by injecting a plug of inhibitor into a capillary filled with the substrate, AttoPhos. Product generated in the enzyme microreactor was detected by laser-induced fluorescence. Inhibitor zones electrophoresed through the capillary, passed through the enzyme microreactor, and were observed as negative peaks due to decreased product formation. The goal of this study was to improve peak capacities for inhibitor separations relative to previous work, which combined continuous engagement electrophoretically mediated microanalysis (EMMA) and transient engagement EMMA to study enzyme inhibition. The effects of electric field strength, bead injection time and inhibitor concentrations on peak capacity and peak width were investigated. Peak capacities were increased to ≥20 under optimal conditions of electric field strength and bead injection time for inhibition assays with arsenate and theophylline. Five reversible inhibitors of alkaline phosphatase (theophylline, vanadate, arsenate, L-tryptophan and tungstate) were separated and detected to demonstrate the ability of this technique to analyze complex inhibitor mixtures. PMID:20024913

  7. Synergistic Inhibition of Carbon Steel Corrosion by Inhibitor-Blends in Chloride-Containing Simulated Cooling Water

    Energy Technology Data Exchange (ETDEWEB)

    Shaban, Abdul; Felhosi, Ilona [Hungarian Academy of Sciences, Budapest (Hungary); Vastag, Gyongyi [University of Novi Sad, Novi Sad (Serbia)

    2017-06-15

    The objective of this work was to develop efficient synergistic inhibitor combinations comprising sodium nitrite (NaNO{sub 2}) and an inhibitor-blend code named (SN-50), keeping in view of their application in industrial cooling water systems. The electrochemical characteristics of the carbon steel working electrode in simulated cooling water (SCW), without and with the addition of different combinations of the inhibitors, were investigated using electrochemical impedance spectroscopy (EIS), open circuit potential (OCP). The electrode surface changes were followed by visual characterization methods. It was demonstrated in this study that all the combinations of the inhibitors exhibited synergistic benefit and higher inhibition efficiencies than did either of the individual inhibitors. The addition of SN-50 inhibitor to the SCW shifted the OCP to more anodic values and increased the polarization resistance (R{sub p}) values of carbon steel at all applied concentrations. The higher the applied sodium nitrite concentration (in the protection concentration range), the higher the obtained R{sub p} values and the inhibition efficiency improved by increasing the inhibitor concentration.

  8. Optimal Classes of Chemotherapeutic Agents Sensitized by Specific Small-Molecule Inhibitors of Akt In Vitro and In Vivo

    Directory of Open Access Journals (Sweden)

    Yan Shi

    2005-11-01

    Full Text Available Akt is a serine/threonine kinase that transduces survival signals from survival/growth factors. Deregulation and signal imbalance in cancer cells make them prone to apoptosis. Upregulation or activation of Akt to aid the survival of cancer cells is a common theme in human malignancies. We have developed small-molecule Akt inhibitors that are potent and specific. These Akt inhibitors can inhibit Akt activity and block phosphorylation by Akt on multiple downstream targets in cells. Synergy in apoptosis induction was observed when Akt inhibitors were combined with doxorubicin or camptothecin. Akt inhibitor-induced enhancement of topoisomerase inhibitor cytotoxicity was also evident in long-term cell survival assay. Synergy with paclitaxel in apoptosis induction was evident in cells pretreated with paclitaxel, and enhancement of tumor delay by paclitaxel was demonstrated through cotreatment with Akt inhibitor Compound A (A-443654. Combination with other classes of chemotherapeutic agents did not yield any enhancement of cytotoxicity. These findings provide important guidance in selecting appropriate classes of chemotherapeutic agents for combination with Akt inhibitors in cancer treatment.

  9. Caspase-1 inhibitor regulates humoral responses in experimental autoimmune myasthenia gravis via IL-6- dependent inhibiton of STAT3.

    Science.gov (United States)

    Wang, Cong-Cong; Zhang, Min; Li, Heng; Li, Xiao-Li; Yue, Long-Tao; Zhang, Peng; Liu, Ru-Tao; Chen, Hui; Li, Yan-Bin; Duan, Rui-Sheng

    2017-08-24

    We have previously demonstrated that Cysteinyl aspartate-specific proteinase-1 (caspase-1) inhibitor ameliorates experimental autoimmune myasthenia gravis (EAMG) by inhibited cellular immune response, via suppressing DC IL-1 β, CD4 + T and γdT cells IL-17 pathways. In this study, we investigated the effect of caspase-1 inhibitor on humoral immune response of EAMG and further explore the underlying mechanisms. An animal model of MG was induced by region 97-116 of the rat AChR α subunit (R97-116 peptide) in Lewis rats. Rats were treated with caspase-1 inhibitor Ac-YVAD-cmk intraperitoneally (i.p.) every second day from day 13 after the first immunization. Flow cytometry, western blot, immunofluorescence, and enzyme-linked immunosorbent assay (ELISA) were performed to evaluate the neuroprotective effect of caspase-1 inhibitor on humoral immune response of EAMG. The results showed that caspase-1 inhibitor reduced the relative affinity of anti-R97-116 IgG, suppressed germinal center response, decreased follicular helper T cells, and increased follicular regulatory T cells and regulatory B cells. In addition, we found that caspase-1 inhibitor inhibited humoral immunity response in EAMG rats via suppressing IL-6-STAT3-Bcl-6 pathways. These results suggest that caspase-1 inhibitor ameliorates EAMG by regulating humoral immune response, thus providing new insights into the development of myasthenia gravis and other autoimmune diseases therapies. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. A dual-specificity isoform of the protein kinase inhibitor PKI produced by alternate gene splicing.

    Science.gov (United States)

    Kumar, Priyadarsini; Walsh, Donal A

    2002-03-15

    We have previously shown that the protein kinase inhibitor beta (PKIbeta) form of the cAMP-dependent protein kinase inhibitor exists in multiple isoforms, some of which are specific inhibitors of the cAMP-dependent protein kinase, whereas others also inhibit the cGMP-dependent enzyme [Kumar, Van Patten and Walsh (1997), J. Biol. Chem. 272, 20011-20020]. We have now demonstrated that the switch from a cAMP-dependent protein kinase (PKA)-specific inhibitor to one with dual specificity arises as a consequence of alternate gene splicing. We have confirmed using bacterially produced pure protein that a single inhibitor species has dual specificity for both PKA and cGMP-dependent protein kinase (PKG), inhibiting each with very high and closely similar inhibitory potencies. The gene splicing converted a protein with 70 amino acids into one of 109 amino acids, and did not change the inhibitory potency to PKA, but changed it from a protein that had no detectable PKG inhibitory activity to one that now inhibited PKG in the nanomolar range.

  11. Identification of Inhibitors in Lignocellulosic Slurries and Determination of Their Effect on Hydrocarbon-Producing Microorganisms

    Directory of Open Access Journals (Sweden)

    Shihui Yang

    2018-04-01

    Full Text Available The aim of this work was to identify inhibitors in pretreated lignocellulosic slurries, evaluate high-throughput screening strategies, and investigate the impact of inhibitors on potential hydrocarbon-producing microorganisms. Compounds present in slurries that could inhibit microbial growth were identified through a detailed analysis of saccharified slurries by applying a combination of approaches of high-performance liquid chromatography, GC-MS, LC-DAD-MS, and ICP-MS. Several high-throughput assays were then evaluated to generate toxicity profiles. Our results demonstrated that Bioscreen C was useful for analyzing bacterial toxicity but not for yeast. AlamarBlue reduction assay can be a useful high-throughput assay for both bacterial and yeast strains as long as medium components do not interfere with fluorescence measurements. In addition, this work identified two major inhibitors (furfural and ammonium acetate for three potential hydrocarbon-producing bacterial species that include Escherichia coli, Cupriavidus necator, and Rhodococcus opacus PD630, which are also the primary inhibitors for ethanologens. This study was strived to establish a pipeline to quantify inhibitory compounds in biomass slurries and high-throughput approaches to investigate the effect of inhibitors on microbial biocatalysts, which can be applied for various biomass slurries or hydrolyzates generated through different pretreatment and enzymatic hydrolysis processes or different microbial candidates.

  12. PEGylated DX-1000: Pharmacokinetics and Antineoplastic Activity of a Specific Plasmin Inhibitor

    Directory of Open Access Journals (Sweden)

    Laetitia Devy

    2007-11-01

    Full Text Available Novel inhibitors of the urokinase-mediated plasminogen (plg activation system are potentially of great clinical benefit as anticancer treatments. Using phage display, we identified DX-1000 a tissue factor pathway inhibitor-derived Kunitz domain protein which is a specific high-affinity inhibitor of plasmin (pin (Ki = 99 pM. When tested in vitro, DX-1000 blocks plasminmediated pro-matrix metal loproteinase-9 (proMMP-9 activation on cells and dose-dependently inhibits tube formation, while not significantly affecting hemostasis and coagulation. However, this low-molecular weight protein inhibitor (~ 7 kDa exhibits rapid plasma clearance in mice and rabbits, limiting its potential clinical use in chronic diseases. After site-specific PEGylation, DX-1000 retains its activity and exhibits a decreased plasma clearance. This PEGylated derivative is effective in vitro, as well as potent in inhibiting tumor growth of green fluorescent protein (GFP-labeled MDA-MB-231 cells. 4PEG-DX-1000 treatment causes a significant reduction of urokinase-type plasminogen activator (uPA and plasminogen expressions, a reduction of tumor proliferation, and vascularization. 4PEG-DX-1000 treatment significantly decreases the level of active mitogenactivated protein kinase (MAPK in the primary tumors and reduces metastasis incidence. Together, our results demonstrate the potential value of plasmin inhibitors as therapeutic agents for blocking breast cancer growth and metastasis.

  13. The renal effects of SGLT2 inhibitors and a mini-review of the literature.

    Science.gov (United States)

    Andrianesis, Vasileios; Glykofridi, Spyridoula; Doupis, John

    2016-12-01

    Sodium-glucose linked transporter 2 (SGLT2) inhibitors are a new and promising class of antidiabetic agents which target renal tubular glucose reabsorption. Their action is based on the blockage of SGLT2 sodium-glucose cotransporters that are located at the luminal membrane of tubular cells of the proximal convoluted tubule, inducing glucosuria. It has been proven that they significantly reduce glycated hemoglobin (HbA1c), along with fasting and postprandial plasma glucose in patients with type 2 diabetes mellitus (T2DM). The glucosuria-induced caloric loss as well as the osmotic diuresis significantly decrease body weight and blood pressure, respectively. Given that SGLT2 inhibitors do not interfere with insulin action and secretion, their efficacy is sustained despite the progressive β-cell failure in T2DM. They are well tolerated, with a low risk of hypoglycemia. Their most frequent adverse events are minor: genital and urinal tract infections. Recently, it was demonstrated that empagliflozin presents a significant cardioprotective effect. Although the SGLT2 inhibitors' efficacy is affected by renal function, new data have been presented that some SGLT2 inhibitors, even in mild and moderate renal impairment, induce significant HbA1c reduction. Moreover, recent data indicate that SGLT2 inhibition has a beneficial renoprotective effect. The role of this review paper is to explore the current evidence on the renal effects of SGLT2 inhibitors.

  14. SGLT2 inhibitors: a promising new therapeutic option for treatment of type 2 diabetes mellitus.

    Science.gov (United States)

    Misra, Monika

    2013-03-01

    Hyperglycemia is an important pathogenic component in the development of microvascular and macrovascular complications in type 2 diabetes mellitus. Inhibition of renal tubular glucose reabsorption that leads to glycosuria has been proposed as a new mechanism to attain normoglycemia and thus prevent and diminish these complications. Sodium glucose cotransporter 2 (SGLT2) has a key role in reabsorption of glucose in kidney. Competitive inhibitors of SGLT2 have been discovered and a few of them have also been advanced in clinical trials for the treatment of diabetes. To discuss the therapeutic potential of SGLT2 inhibitors currently in clinical development. A number of preclinical and clinical studies of SGLT2 inhibitors have demonstrated a good safety profile and beneficial effects in lowering plasma glucose levels, diminishing glucotoxicity, improving glycemic control and reducing weight in diabetes. Of all the SGLT2 inhibitors, dapagliflozin is a relatively advanced compound with regards to clinical development. SGLT2 inhibitors are emerging as a promising therapeutic option for the treatment of diabetes. Their unique mechanism of action offers them the potential to be used in combination with other oral anti-diabetic drugs as well as with insulin. © 2012 The Author. JPP © 2012 Royal Pharmaceutical Society.

  15. MEK inhibition potentiates the activity of Hsp90 inhibitor 17-AAG against pancreatic cancer cells.

    Science.gov (United States)

    Zhang, Tao; Li, Yanyan; Zhu, Zhenkun; Gu, Mancang; Newman, Bryan; Sun, Duxin

    2010-10-04

    The Ras/Raf/MEK/ERK signaling has been implicated in uncontrolled cell proliferation and tumor progression in pancreatic cancer. The purpose of this study is to evaluate the antitumor activity of MEK inhibitor U0126 in combination with Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) in pancreatic cancer cells. Western blotting showed that 17-AAG caused a 2- to 3-fold transient activation of MEK/ERK signaling in pancreatic cancer cells. The activation sustained for 6 h before phospho-ERK (p-ERK) destabilization. The selective MEK inhibitor U0126 completely abolished 17-AAG induced ERK1/2 activation and resulted in more than 80% of phospho-ERK degradation after only 15 min treatment. Moreover, U0126 had complementary effect on 17-AAG regulated oncogenic and cell cycle related proteins. Although 17-AAG downregulated cyclin D1, cyclin E, CDK4 and CDK6, it led to cyclin A and CDK2 accumulation, which was reversed by the addition of U0126. Antiproliferation assay showed that combination of U0126 and 17-AAG resulted in synergistic cytotoxic effect. More importantly, 17-AAG alone only exhibited moderate inhibition of cell migration in vitro, while addition of U0126 dramatically enhanced the inhibitory effect by 2- to 5-fold. Taken together, these data demonstrate that MEK inhibitor U0126 potentiates the activity of Hsp90 inhibitor 17-AAG against pancreatic cancer cells. The combination of Hsp90 and MEK inhibition could provide a promising avenue for the treatment of pancreatic cancer.

  16. Structure-Based Design and Synthesis of Potent and Selective Matrix Metalloproteinase 13 Inhibitors.

    Science.gov (United States)

    Choi, Jun Yong; Fuerst, Rita; Knapinska, Anna M; Taylor, Alexander B; Smith, Lyndsay; Cao, Xiaohang; Hart, P John; Fields, Gregg B; Roush, William R

    2017-07-13

    We describe the use of comparative structural analysis and structure-guided molecular design to develop potent and selective inhibitors (10d and (S)-17b) of matrix metalloproteinase 13 (MMP-13). We applied a three-step process, starting with a comparative analysis of the X-ray crystallographic structure of compound 5 in complex with MMP-13 with published structures of known MMP-13·inhibitor complexes followed by molecular design and synthesis of potent but nonselective zinc-chelating MMP inhibitors (e.g., 10a and 10b). After demonstrating that the pharmacophores of the chelating inhibitors (S)-10a, (R)-10a, and 10b were binding within the MMP-13 active site, the Zn 2+ chelating unit was replaced with nonchelating polar residues that bridged over the Zn 2+ binding site and reached into a solvent accessible area. After two rounds of structural optimization, these design approaches led to small molecule MMP-13 inhibitors 10d and (S)-17b, which bind within the substrate-binding site of MMP-13 and surround the catalytically active Zn 2+ ion without chelating to the metal. These compounds exhibit at least 500-fold selectivity versus other MMPs.

  17. Postexposure protection of macaques from vaginal SHIV infection by topical integrase inhibitors.

    Science.gov (United States)

    Dobard, Charles; Sharma, Sunita; Parikh, Urvi M; West, Rolieria; Taylor, Andrew; Martin, Amy; Pau, Chou-Pong; Hanson, Debra L; Lipscomb, Jonathan; Smith, James; Novembre, Francis; Hazuda, Daria; Garcia-Lerma, J Gerardo; Heneine, Walid

    2014-03-12

    Coitally delivered microbicide gels containing antiretroviral drugs are important for HIV prevention. However, to date, microbicides have contained entry or reverse transcriptase inhibitors that block early steps in virus infection and thus need to be given as a preexposure dose that interferes with sexual practices and may limit compliance. Integrase inhibitors block late steps after virus infection and therefore are more suitable for post-coital dosing. We first determined the kinetics of strand transfer in vitro and confirmed that integration begins about 6 hours after infection. We then used a repeat-challenge macaque model to assess efficacy of vaginal gels containing integrase strand transfer inhibitors when applied before or after simian/human immunodeficiency virus (SHIV) challenge. We showed that gel containing the strand transfer inhibitor L-870812 protected two of three macaques when applied 30 min before SHIV challenge. We next evaluated the efficacy of 1% raltegravir gel and demonstrated its ability to protect macaques when applied 3 hours after SHIV exposure (five of six protected; P infections showed no evidence of drug resistance in plasma or vaginal secretions despite continued gel dosing after infection. We documented rapid vaginal absorption reflecting a short pharmacological lag time and noted that vaginal, but not plasma, virus load was substantially reduced in the breakthrough infection after raltegravir gel treatment. We provide a proof of concept that topically applied integrase inhibitors protect against vaginal SHIV infection when administered shortly before or 3 hours after virus exposure.

  18. Molecular Mechanism of Selectivity among G Protein-Coupled Receptor Kinase 2 Inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Thal, David M.; Yeow, Raymond Y.; Schoenau, Christian; Huber, Jochen; Tesmer, John J.G. (Sanofi); (Michigan)

    2012-07-11

    G protein-coupled receptors (GPCRs) are key regulators of cell physiology and control processes ranging from glucose homeostasis to contractility of the heart. A major mechanism for the desensitization of activated GPCRs is their phosphorylation by GPCR kinases (GRKs). Overexpression of GRK2 is strongly linked to heart failure, and GRK2 has long been considered a pharmaceutical target for the treatment of cardiovascular disease. Several lead compounds developed by Takeda Pharmaceuticals show high selectivity for GRK2 and therapeutic potential for the treatment of heart failure. To understand how these drugs achieve their selectivity, we determined crystal structures of the bovine GRK2-G{beta}{gamma} complex in the presence of two of these inhibitors. Comparison with the apoGRK2-G{beta}{gamma} structure demonstrates that the compounds bind in the kinase active site in a manner similar to that of the AGC kinase inhibitor balanol. Both balanol and the Takeda compounds induce a slight closure of the kinase domain, the degree of which correlates with the potencies of the inhibitors. Based on our crystal structures and homology modeling, we identified five amino acids surrounding the inhibitor binding site that we hypothesized could contribute to inhibitor selectivity. However, our results indicate that these residues are not major determinants of selectivity among GRK subfamilies. Rather, selectivity is achieved by the stabilization of a unique inactive conformation of the GRK2 kinase domain.

  19. Promiscuity and selectivity of small-molecule inhibitors across TAM receptor tyrosine kinases in pediatric leukemia.

    Science.gov (United States)

    Liu, Mao-Hua; Chen, Shi-Bing; Yu, Juan; Liu, Cheng-Jun; Zhang, Xiao-Jing

    2017-08-01

    The TAM receptor tyrosine kinase family member Mer has been recognized as an attractive therapeutic target for pediatric leukemia. Beside Mer the family contains other two kinases, namely, Tyro3 and Axl, which are highly homologues with Mer and thus most existing small-molecule inhibitors show moderate or high promiscuity across the three kinases. Here, the structural basis and energetic property of selective binding of small-molecule inhibitors to the three kinases were investigated at molecular level. It is found that the selectivity is primarily determined by the size, shape and configuration of kinase's ATP-binding site; the Mer and Axl possess a small, closed active pocket as compared to the bulky, open pocket of Tyro3. The location and conformation of active-site residues of Mer and Axl are highly consistent, suggesting that small-molecule inhibitors generally have a low Mer-over-Axl selectivity and a high Mer-over-Tyro3 selectivity. We demonstrated that the difference in ATP binding potency to the three kinases is also responsible for inhibitor selectivity. We also found that the long-range interactions and allosteric effect arising from rest of the kinase's active site can indirectly influence inhibitor binding and selectivity. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. 2017 SmartWay Logistics Tool Demonstration

    Science.gov (United States)

    This EPA presentation provides information on the SmartWay Logistics Carrier Tool: its background and development, participation in the program, application process, emission metrics, tool demonstration, data collection, and schedule for 2017.

  1. Edison Demonstration of Smallsat Networks (EDSN)

    Data.gov (United States)

    National Aeronautics and Space Administration — NASA's Edison Demonstration of SmallSat Networks (EDSN) mission will launch and deploy a group of eight cubesats into a loose formation approximately 250 miles (400...

  2. Reliability demonstration of imaging surveillance systems

    International Nuclear Information System (INIS)

    Sheridan, T.F.; Henderson, J.T.; MacDiarmid, P.R.

    1979-01-01

    Security surveillance systems which employ closed circuit television are being deployed with increasing frequency for the protection of property and other valuable assets. A need exists to demonstrate the reliability of such systems before their installation to assure that the deployed systems will operate when needed with only the scheduled amount of maintenance and support costs. An approach to the reliability demonstration of imaging surveillance systems which employ closed circuit television is described. Failure definitions based on industry television standards and imaging alarm assessment criteria for surveillance systems are discussed. Test methods which allow 24 hour a day operation without the need for numerous test scenarios, test personnel and elaborate test facilities are presented. Existing reliability demonstration standards are shown to apply which obviate the need for elaborate statistical tests. The demonstration methods employed are shown to have applications in other types of imaging surveillance systems besides closed circuit television

  3. Status of the Majorana Demonstrator experiment

    Science.gov (United States)

    Martin, R. D.; Abgrall, N.; Aguayo, E.; Avignone, F. T., III; Barabash, A. S.; Bertrand, F. E.; Boswell, M.; Brudanin, V.; Busch, M.; Caldwell, A. S.; Chan, Y.-D.; Christofferson, C. D.; Combs, D. C.; Detwiler, J. A.; Doe, P. J.; Efremenko, Yu.; Egorov, V.; Ejiri, H.; Elliott, S. R.; Esterline, J.; Fast, J. E.; Finnerty, P.; Fraenkle, F. M.; Galindo-Uribarri, A.; Giovanetti, G. K.; Goett, J.; Green, M. P.; Gruszko, J.; Guiseppe, V. E.; Gusev, K.; Hallin, A. L.; Hazama, R.; Hegai, A.; Henning, R.; Hoppe, E. W.; Howard, S.; Howe, M. A.; Keeter, K. J.; Kidd, M. F.; Kochetov, O.; Konovalov, S. I.; Kouzes, R. T.; LaFerriere, B. D.; Leon, J.; Leviner, L. E.; Loach, J. C.; MacMullin, J.; MacMullin, S.; Mertens, S.; Mizouni, L.; Nomachi, M.; Orrell, J. L.; O'Shaughnessy, C.; Overman, N. R.; Phillips, D. G., II; Poon, A. W. P.; Pushkin, K.; Radford, D. C.; Rielage, K.; Robertson, R. G. H.; Romero-Romero, E.; Ronquest, M. C.; Schubert, A. G.; Shanks, B.; Shima, T.; Shirchenko, M.; Snavely, K. J.; Snyder, N.; Soin, A.; Suriano, A. M.; Thompson, J.; Timkin, V.; Tornow, W.; Varner, R. L.; Vasilyev, S.; Vetter, K.; Vorren, K.; White, B. R.; Wilkerson, J. F.; Xu, W.; Yakushev, E.; Young, A. R.; Yu, C.-H.; Yumatov, V.

    2014-06-01

    The Majorana Demonstrator neutrinoless double beta-decay experiment is currently under construction at the Sanford Underground Research Facility in South Dakota, USA. An overview and status of the experiment are given.

  4. Classroom Demonstrations in Materials Science/Engineering.

    Science.gov (United States)

    Hirschhorn, J. S.; And Others

    Examples are given of demonstrations used at the University of Wisconsin in a materials science course for nontechnical students. Topics include crystal models, thermal properties, light, and corrosion. (MLH)

  5. Lessons Learned from Microgrid Demonstrations Worldwide

    Energy Technology Data Exchange (ETDEWEB)

    Marnay, Chris [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Zhou, Nan [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Qu, Min [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Romankiewicz, John [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

    2012-01-31

    The survey leads to policy recommendations for starting a microgrid demonstration program and overall development of microgrid and distributed energy. Additionally, specific recommendations have been made for China specifically.

  6. Keys to Successful EPIQ Business Demonstrator Implementation

    NARCIS (Netherlands)

    Shoikova, Elena; Denishev, Vladislav

    2009-01-01

    Shoikova, E., & Denishev, V. (2009). Keys to Successful EPIQ Business Demonstrator Implementation. Paper presented at the 'Open workshop of TENCompetence - Rethinking Learning and Employment at a Time of Economic Uncertainty-event'. November, 19, 2009, Manchester, United Kingdom: TENCompetence.

  7. CALDERON COKEMAKING PROCESS/DEMONSTRATION PROJECT

    International Nuclear Information System (INIS)

    Albert Calderon

    1998-01-01

    This project deals with the demonstration of a coking process using proprietary technology of Calderon, with the following objectives geared to facilitate commercialization: (1) making coke of such quality as to be suitable for use in hard-driving, large blast furnaces; (2) providing proof that such process is continuous and environmentally closed to prevent emissions; (3) demonstrating that high-coking-pressure (non-traditional) coal blends which cannot be safely charged into conventional by-product coke ovens can be used in the Calderon process; and (4) demonstrating that coke can be produced economically, at a level competitive with coke imports. The activities of the past quarter were focused on the following: Conducting bench-scale tests to produce coke and acceptable tar from the process to satisfy Koppers, a prospective stakeholder; Consolidation of the project team players to execute the full size commercial cokemaking reactor demonstration; and Progress made in advancing the design of the full size commercial cokemaking reactor

  8. Medicare Demonstration Projects and Evaluation Reports

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Centers for Medicare and Medicaid Services (CMS) conducts and sponsors a number of innovative demonstration projects to test and measure the effect of potential...

  9. Hybrid Life Support System Technology Demonstrations

    Science.gov (United States)

    Morrow, R. C.; Wetzel, J. P.; Richter, R. C.

    2018-02-01

    Demonstration of plant-based hybrid life support technologies in deep space will validate the function of these technologies for long duration missions, such as Mars transit, while providing dietary variety to improve habitability.

  10. Nuclear Systems (NS): Technology Demonstration Unit (TDU)

    Data.gov (United States)

    National Aeronautics and Space Administration — The Nuclear Systems Project demonstrates nuclear power technology readiness to support the goals of NASA's Space Technology Mission Directorate. To this end, the...

  11. Radioactive waste incineration system cold demonstration test

    Energy Technology Data Exchange (ETDEWEB)

    Hozumi, Masahiro; Takaoku, Yoshinobu; Koyama, Shigeru; Nagae, Madoka; Seike, Yasuhiko; Yamanaka, Yasuhiro; Shibata, Kenji; Manabe, Kyoichi

    1984-12-01

    To demonstrate Waste Incineration System (WIS) which our company has been licensed by Combustion Engineering Inc., USA we installed a demonstration test plant in our Hiratsuka Research Laboratory and started the demonstration test on January 1984. One of the characteristics of this system is to be able to process many kinds of wastes with only one system, and to get high volume reduction factors. In our test plant, we processed paper, cloth, wood, polyethylene sheets as the samples of solid combustible wastes and spent ion exchange resins with incineration and processed condensed liquid wastes with spray drying. We have got good performances and enough Decontamination Factor (DF) data for the dust control equipment. In this paper, we introduce this demonstration test plant and report the test results up to date. (author).

  12. Demonstration and Deployment Strategy Workshop: Summary

    Energy Technology Data Exchange (ETDEWEB)

    none,

    2014-05-01

    This report is based on the proceedings of the U.S. Department of Energy Bioenergy Technologies Office Demonstration and Deployment Strategy Workshop, held on March 12–13, 2014, at Argonne National Laboratory.

  13. Discovery and characterization of small molecule Rac1 inhibitors.

    Science.gov (United States)

    Arnst, Jamie L; Hein, Ashley L; Taylor, Margaret A; Palermo, Nick Y; Contreras, Jacob I; Sonawane, Yogesh A; Wahl, Andrew O; Ouellette, Michel M; Natarajan, Amarnath; Yan, Ying

    2017-05-23

    Aberrant activation of Rho GTPase Rac1 has been observed in various tumor types, including pancreatic cancer. Rac1 activates multiple signaling pathways that lead to uncontrolled proliferation, invasion and metastasis. Thus, inhibition of Rac1 activity is a viable therapeutic strategy for proliferative disorders such as cancer. Here we identified small molecule inhibitors that target the nucleotide-binding site of Rac1 through in silico screening. Follow up in vitro studies demonstrated that two compounds blocked active Rac1 from binding to its effector PAK1. Fluorescence polarization studies indicate that these compounds target the nucleotide-binding site of Rac1. In cells, both compounds blocked Rac1 binding to its effector PAK1 following EGF-induced Rac1 activation in a dose-dependent manner, while showing no inhibition of the closely related Cdc42 and RhoA activity. Furthermore, functional studies indicate that both compounds reduced cell proliferation and migration in a dose-dependent manner in multiple pancreatic cancer cell lines. Additionally, the two compounds suppressed the clonogenic survival of pancreatic cancer cells, while they had no effect on the survival of normal pancreatic ductal cells. These compounds do not share the core structure of the known Rac1 inhibitors and could serve as additional lead compounds to target pancreatic cancers with high Rac1 activity.

  14. A review on cholinesterase inhibitors for Alzheimer's disease.

    Science.gov (United States)

    Anand, Preet; Singh, Baldev

    2013-04-01

    Alzheimer's disease (AD), a progressive neurodegenerative disorder, is characterized by the deficits in the cholinergic system and deposition of beta amyloid (Aβ) in the form of neurofibrillary tangles and amyloid plaques. Since the cholinergic system plays an important role in the regulation of learning and memory processes, it has been targetted for the design of anti-Alzheimer's drugs. Cholinesterase inhibitors enhance cholinergic transmission directly by inhibiting the enzyme acetylcholinesterase (AChE) which hydrolyses acetylcholine. Furthermore, it has been also demonstrated that both acetylcholinesterase and butrylcholinesterase (BuChE) play an important role in Aβ-aggregation during the early stages of senile plaque formation. Therefore, AChE and BuChE inhibition have been documented as critical targets for the effective management of AD by an increase in the availability of acetylcholine in the brain regions and decrease in the Aβ deposition. This review discusses the different classes of cholinesterase inhibitors including tacrine, donepezil, rivastigmine, galantamine, xanthostigmine, para-aminobenzoic acid, coumarin, flavonoid, and pyrrolo-isoxazole analogues developed for the treatment of AD.

  15. The evolving field of kinase inhibitors in thyroid cancer.

    Science.gov (United States)

    Marotta, V; Sciammarella, C; Vitale, M; Colao, A; Faggiano, A

    2015-01-01

    Most of the genetic events implicated in the pathogenesis of thyroid cancer (TC) involve genes with kinase activity. Thus, kinase inhibitors (KIs) are very relevant in this field. KIs are considered the most suitable treatment for patients with iodine-refractory differentiated TC; these patients comprise the subgroup with the poorer prognosis. To date, only sorafenib has been approved for this indication, but promising results have been reported with several other KIs. In particular, lenvatinib has demonstrated excellent efficacy, with both progression-free survival and objective tumour response being better than with sorafenib. Despite being considered to be well tolerated, both sorafenib and lenvatinib have shown a remarkable toxicity, which has led to dose reductions in the majority of patients and to treatment discontinuation in a significant proportion of cases. The role of KIs in differentiated TC may be revolutionised by the finding that selumetinib may restore a clinical response to radioactive iodine (RAI). Vandetanib and cabozantinib have been approved for the treatment of advanced, progressive medullary TC (MTC). Nevertheless, the toxicity of both compounds suggests their selective use in those patients with strong disease progression. Treatment with the mTOR-inhibitor everolimus, alone or in combination with somatostatin analogues, should be studied in metastatic MTC patients with slow progression of disease, these representing the vast majority of patients. KIs did not significantly impact on the clinical features of anaplastic TC (ATC). Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  16. Cox-2 inhibitors and the risk of cardiovascular thrombotic events.

    LENUS (Irish Health Repository)

    Khan, M

    2012-04-01

    In 1971, Vane showed that the analgesic action of traditional NSAIDs relies on inhibition of the cyclo-oxygenase (COX) enzyme, which in turn results in reduced synthesis of proalgesic prostaglandins. Two decades later COX was shown to exist as two distinct isoforms. The constitutive isoform COX-1, supports the beneficial homeostatic functions whereas the inducible isoform, COX-2 becomes up regulated by inflammatory mediators and its products cause many of the symptoms of inflammatory diseases such as rheumatoid and osteoarthritis. Despite the benefits of NSAIDs for acute and chronic pain one of the most clinically significant and well characterized adverse effect is on GI mucosa. The search for NSAIDs with less gastrointestinal toxicity led to the introduction of the selective cyclo-oxygenase-2 (COX-2) inhibitors. The COX-2 selective (COX-1 sparing) inhibitors are associated with reduced GI mucosal damage as demonstrated in several trials. In light of the overwhelming and sometimes contradictory information for patients and physicians regarding the safety of COX-2 agents this article will summarize the available evidence regarding cardiovascular (CV) safety data and contemporary recommendations for prescribing of COX-2-selective NSAIDs.

  17. Space Internet-Embedded Web Technologies Demonstration

    Science.gov (United States)

    Foltz, David A.

    2001-01-01

    The NASA Glenn Research Center recently demonstrated the ability to securely command and control space-based assets by using the Internet and standard Internet Protocols (IP). This is a significant accomplishment because future NASA missions will benefit by using Internet standards-based protocols. The benefits include reduced mission costs and increased mission efficiency. The Internet-Based Space Command and Control System Architecture demonstrated at the NASA Inspection 2000 event proved that this communications architecture is viable for future NASA missions.

  18. Some simple demonstration experiments involving homopolar motors

    OpenAIRE

    Stewart, Seán M.

    2007-01-01

    The ready availability of very strong permanent magnets in the form of rare-earth magnetic alloys such as neodymium-iron-boron has lead to renewed interest in one of the oldest types of electric motors - the homopolar motor. The ease with which a demonstration homopolar motor can now be built and operated when neodymium magnets are used is quite remarkable. In this paper some simple homopolar motors employing neodymium magnets suitable for demonstrational purposes are described and discussed....

  19. Some simple demonstration experiments involving homopolar motors

    OpenAIRE

    Stewart,Seán M.

    2007-01-01

    The ready availability of very strong permanent magnets in the form of rare-earth magnetic alloys such as neodymium-iron-boron has lead to renewed interest in one of the oldest types of electric motors - the homopolar motor. The ease with which a demonstration homopolar motor can now be built and operated when neodymium magnets are used is quite remarkable. In this paper some simple homopolar motors employing neodymium magnets suitable for demonstrational purposes are described and discussed.

  20. Postirradiation examination of ORR demonstration elements

    International Nuclear Information System (INIS)

    Snelgrove, J.L.; Copeland, G.L.; Hofman, G.L.

    1991-01-01

    Postirradiation examinations of selected U 3 Si 2 fuel elements fabricated by B and W, CERCA, and NUKEM and irradiated during the whole core demonstration in the Oak Ridge Research Reactor are nearing completion. The results of all tests have shown the demonstration fuel elements, produced under production-line conditions, to have performed in the excellent manner expected from earlier tests of miniature fuel plates and full-sized elements. (orig.)

  1. Structural Characterization of LRRK2 Inhibitors

    NARCIS (Netherlands)

    Gilsbach, Bernd K; Messias, Ana C; Ito, Genta; Sattler, Michael; Alessi, Dario R; Wittinghofer, Alfred; Kortholt, Arjan

    2015-01-01

    Kinase inhibition is considered to be an important therapeutic target for LRRK2 mediated Parkinson's disease (PD). Many LRRK2 kinase inhibitors have been reported but have yet to be optimized in order to qualify as drug candidates for the treatment of the disease. In order to start a

  2. Rational Design of Rho Protein Inhibitors

    National Research Council Canada - National Science Library

    Rojas, Rafael J

    2006-01-01

    ... nucleotide exchange factors (RhoGEFs). We have developed a high throughput screening strategy identify novel inhibitors of Rho activation are currently following up on several compounds which appear to selectively inhibit Rho activation. These compounds may form the basis of future drug development strategies for the treatment of metastatic breast cancer.

  3. Rational Design of Rho Protein Inhibitors

    National Research Council Canada - National Science Library

    Rojas, Rafael J

    2005-01-01

    ... nucleotide exchange factors (RhoGEFs). We have developed a high throughput screening strategy identify novel inhibitors of Rho activation are currently following up on several compounds which appear to selectively inhibit Rho activation. These compounds may form the basis of future drug development strategies for the treatment of metastatic breast cancer.

  4. [Mechanisms and efficacy of SGLT2 inhibitors].

    Science.gov (United States)

    Shiba, Teruo

    2015-03-01

    SGLT2 is a low affinity, high capacity glucose co-transporter, almost exclusively expressed in the kidney cortex. Inhibition of SGLT2 has been shown to increase the daily 50g or more urinary glucose excretion, as compared to placebo, leading to a reduction in blood glucose levels and indicated only for the treatment of type 2 diabetes. In Japan 6 species of SGLT2 inhibitors have already been sold and reported to results in a decrease of FPG by 14.4 to 45.8 (mg/dL), in a reduction of HbA1c by 0.35 to 1.24% and in loss of body weight by 1.29 to 2.50(kg). There is less effect of the SGLT2 inhibitor in diabetic subjects with renal impairment and the reduction in HbA1c and FPG will be approximately half of the average in those with 30 ≤ eGFR ≤ 59. The position of SGLT2 inhibitors would be considered as the drug administered in combination or add-on therapy when the young obese type 2 diabetics without renal impairment has not yet reached to the glycemic target with other drugs although in AACE consensus statement of 2013, it has been shelved for inexperienced use with respect to the positioning of the SGLT2 inhibitors.

  5. Th17 Inhibitors in Active Psoriatic Arthritis

    DEFF Research Database (Denmark)

    Naik, Girish S; Ming, Wai K; Magodoro, Itai M

    2018-01-01

    BACKGROUND: Several biologics targeting the Th17 pathway have been developed for the treatment of psoriatic arthritis (PsA), a disabling disease with moderate response and an increased incidence of serious infections to first-line biologics (TNF-α antagonists). Th17 inhibitors could replace TNF-α...

  6. Vildagliptin: the first innovative DDP-4 inhibitor

    Directory of Open Access Journals (Sweden)

    Edvin Villkhauer

    2010-09-01

    Full Text Available A review of the main stages of investigation undertaken by Novartis Pharmaceuticals in search of a new molecule for the treatment of type 2 diabetesmellitus, dipeptidyl peptidase-4 (DPP-4 inhibitor (Vildaglyptin. The data on specificity and selectivity of the action of this molecule are presentedalong with the results of its comparison with another agent of this group (sitagliptin.

  7. Curcumin derivatives as HIV-1 protease inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Sui, Z.; Li, J.; Craik, C.S.; Ortiz de Montellano, P.R. [Univ. of California, San Francisco, CA (United States)

    1993-12-31

    Curcumin, a non-toxic natural compound from Curcuma longa, has been found to be an HIV-1 protease inhibitor. Some of its derivatives were synthesized and their inhibitory activity against the HIV-1 protease was tested. Curcumin analogues containing boron enhanced the inhibitory activity. At least of the the synthesized compounds irreversibly inhibits the HIV-1 protease.

  8. Dissolution properties of cerium dibutylphosphate corrosion inhibitors

    NARCIS (Netherlands)

    Soestbergen, van M.; Erich, S.J.F.; Huinink, H.P.; Adan, O.C.G.

    2013-01-01

    The corrosion inhibitor cerium dibutylphosphate, Ce(dbp)3, prevents corrosion by cerium and dbp deposition at the alkaline cathode and acidic anode respectively. The pH dependent Ce(dbp)3 solubility seems to play an essential role in the inhibition degree. We found that Ce(dbp)3 scarcely dissolves

  9. SEARCH OF NEW SYNTHETIC INHIBITORS OF TYROSINASE

    Directory of Open Access Journals (Sweden)

    Yu. Shesterenko

    2017-11-01

    Full Text Available Melanin pigmentation of skin plays the most important role in the protection of organism against UV-irradiation, but the excessive accumulation of melanin brings to toxic melanodermia, melasma, lentigo and other skin lesions. Tyrosinase is the key enzyme of skin melanin pigment biosynthesis. In spite of certain progress in investigation of natural and synthetic tyrosinase inhibitors, actuality of such studies is of a high level, because the existing inhibitors are in some cases unstable, expensive, toxic, requires complex methods of synthesis or isolation from natural sources. The aim of the work is screening of new tyrosinase inhibitors, using the enzyme, isolated from Agaricus bisporus. Tyrosinase was isolated from Agaricus bisporus mushrooms by a modified method. It was found, that the introduction of polyethylene glycol 4000 in the extraction process promotes 3-fold reduction of polyphenol content, which leads to increase purity of enzyme with an increase in its activity by 25%. A search for new tyrosinase inhibitors among a wide range of compounds, including derivatives of 3-chloro-1,4-naphthoquinone, isatin, 3-hydroxy-2-naphthoic acid, etc was conducted. The studied substances did not displayed inhibitory effect at concentration of 0,1-0,5 mmol/dm3.

  10. Peptide aldehyde inhibitors of bacterial peptide deformylases.

    Science.gov (United States)

    Durand, D J; Gordon Green, B; O'Connell, J F; Grant, S K

    1999-07-15

    Bacterial peptide deformylases (PDF, EC 3.5.1.27) are metalloenzymes that cleave the N-formyl groups from N-blocked methionine polypeptides. Peptide aldehydes containing a methional or norleucinal inhibited recombinant peptide deformylase from gram-negative Escherichia coli and gram-positive Bacillus subtilis. The most potent inhibitor was calpeptin, N-CBZ-Leu-norleucinal, which was a competitive inhibitor of the zinc-containing metalloenzymes, E. coli and B. subtilis PDF with Ki values of 26.0 and 55.6 microM, respectively. Cobalt-substituted E. coli and B. subtilis deformylases were also inhibited by these aldehydes with Ki values for calpeptin of 9.5 and 12.4 microM, respectively. Distinct spectral changes were observed upon binding of calpeptin to the Co(II)-deformylases, consistent with the noncovalent binding of the inhibitor rather than the formation of a covalent complex. In contrast, the chelator 1,10-phenanthroline caused the time-dependent inhibition of B. subtilis Co(II)-PDF activity with the loss of the active site metal. The fact that calpeptin was nearly equipotent against deformylases from both gram-negative and gram-positive bacterial sources lends further support to the idea that a single deformylase inhibitor might have broad-spectrum antibacterial activity. Copyright 1999 Academic Press.

  11. Immune checkpoint inhibitors for metastatic bladder cancer.

    Science.gov (United States)

    Massari, Francesco; Di Nunno, Vincenzo; Cubelli, Marta; Santoni, Matteo; Fiorentino, Michelangelo; Montironi, Rodolfo; Cheng, Liang; Lopez-Beltran, Anto; Battelli, Nicola; Ardizzoni, Andrea

    2018-03-01

    Chemotherapy has represented the standard therapy for unresectable or metastatic urothelial carcinoma for more than 20 years. The growing knowledge of the interaction between tumour and immune system has led to the advent of new classes of drugs, the immune-checkpoints inhibitors, which are intended to change the current scenario. To date, immunotherapy is able to improve the overall responses and survival. Moreover, thanks to its safety profile immune-checkpoint inhibitors could be proposed also to patients unfit for standard chemotherapy. No doubts that these agents have started a revolution expected for years, but despite this encouraging results it appears clear that not all subjects respond to these agents and requiring the development of reliable predictive response factors able to isolate patients who can more benefit from these treatments as well as new strategies aimed to improve immunotherapy clinical outcome. In this review we describe the active or ongoing clinical trials involving Programmed Death Ligand 1 (PD-L1), Programmed Death receptor 1 (PD-1) and Cytotoxic-T Lymphocyte Antigen 4 (CTLA 4) inhibitors in urothelial carcinoma focusing our attention on the developing new immune-agents and combination strategies with immune-checkpoint inhibitors. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Current and Novel Inhibitors of HIV Protease

    Czech Academy of Sciences Publication Activity Database

    Pokorná, Jana; Machala, L.; Řezáčová, Pavlína; Konvalinka, Jan

    2009-01-01

    Roč. 1, č. 3 (2009), s. 1209-1239 ISSN 1999-4915 R&D Projects: GA MŠk 1M0508 Grant - others:GA AV ČR(CZ) IAAX00320901 Program:IA Institutional research plan: CEZ:AV0Z40550506 Keywords : HIV protease * protease inhibitor * HAART Subject RIV: CE - Biochemistry

  13. Proton pump inhibitors affect the gut microbiome

    NARCIS (Netherlands)

    Imhann, Floris; Bonder, Marc Jan; Vich Vila, Arnau; Fu, Jingyuan; Mujagic, Zlatan; Vork, Lisa; Feenstra, Ettje T.; Jankipersadsing, Soesma A; Cenit, Maria Carmen; Harmsen, Hermie J M; Dijkstra, Gerard; Franke, Lude; Xavier, Ramnik J; Jonkers, Daisy; Wijmenga, Cisca; Weersma, Rinse K; Zhernakova, Alexandra

    BACKGROUND AND AIMS: Proton pump inhibitors (PPIs) are among the top 10 most widely used drugs in the world. PPI use has been associated with an increased risk of enteric infections, most notably Clostridium difficile. The gut microbiome plays an important role in enteric infections, by resisting or

  14. Pharmacological caspase inhibitors: Research towards therapeutic perspectives

    Czech Academy of Sciences Publication Activity Database

    Kudělová, J.; Fleischmannová, J.; Adamová, E.; Matalová, Eva

    2015-01-01

    Roč. 66, č. 4 (2015), s. 473-482 ISSN 0867-5910 R&D Projects: GA ČR(CZ) GA14-28254S Institutional support: RVO:68081715 Keywords : caspase * caspase inhibitor * apoptosis Subject RIV: CB - Analytical Chemistry, Separation Impact factor: 2.804, year: 2015

  15. Pharmacological caspase inhibitors: Research towards therapeutic perspectives

    Czech Academy of Sciences Publication Activity Database

    Kudělová, J.; Fleischmannová, Jana; Adamová, Eva; Matalová, Eva

    2015-01-01

    Roč. 66, č. 4 (2015), s. 473-482 ISSN 0867-5910 R&D Projects: GA ČR GB14-37368G Institutional support: RVO:67985904 Keywords : caspase * caspase inhibitor * apoptosis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.804, year: 2015

  16. Discovery of inhibitors of bacterial histidine kinases

    NARCIS (Netherlands)

    Velikova, N.R.

    2014-01-01

    Discovery of Inhibitors of Bacterial Histidine Kinases Summary

    The thesis is on novel antibacterial drug discovery (http://youtu.be/NRMWOGgeysM). Using structure-based and fragment-based drug discovery approach, we have identified small-molecule histidine-kinase

  17. Novel peptide-based protease inhibitors

    DEFF Research Database (Denmark)

    Roodbeen, Renée

    of novel peptide-based protease inhibitors, efforts were made towards improved methods for peptide synthesis. The coupling of Fmoc-amino acids onto N-methylated peptidyl resins was investigated. These couplings can be low yielding and the effect of the use of microwave heating combined with the coupling...

  18. Oestrogen, testosterone, cytotoxin and cholinesterase inhibitor ...

    African Journals Online (AJOL)

    Oestrogen, testosterone, cytotoxin and cholinesterase inhibitor removal during reclamation of sewage to drinking water. ... Risks associated with sewage effluent and reclaimed sewage should be closely monitored; therefore water at the Gammams Sewage Treatment Plant (GSTP) inlet and outlet, as well as reclaimed water ...

  19. Guidance manual for conducting technology demonstration activities

    Energy Technology Data Exchange (ETDEWEB)

    Jolley, Robert L.; Morris, Michael I.; Singh, Suman P.N.

    1991-12-01

    This demonstration guidance manual has been prepared to assist Martin Marietta Energy Systems, Inc. (Energy Systems), staff in conducting demonstrations. It is prepared in checklist style to facilitate its use and assumes that Energy Systems personnel have project management responsibility. In addition to a detailed step-by-step listing of procedural considerations, a general checklist, logic flow diagram, and several examples of necessary plans are included to assist the user in developing an understanding of the many complex activities required to manage technology demonstrations. Demonstrations are pilot-scale applications of often innovative technologies to determine the commercial viability of the technologies to perform their designed function. Demonstrations are generally conducted on well-defined problems for which existing technologies or processes are less than satisfactory in terms of effectiveness, cost, and/or regulatory compliance. Critically important issues in demonstration management include, but are not limited to, such factors as communications with line and matrix management and with the US Department of Energy (DOE) and Energy Systems staff responsible for management oversight, budgetary and schedule requirements, regulatory compliance, and safety.

  20. Guidance manual for conducting technology demonstration activities

    International Nuclear Information System (INIS)

    Jolley, R.L.; Morris, M.I.; Singh, S.P.N.

    1991-12-01

    This demonstration guidance manual has been prepared to assist Martin Marietta Energy Systems, Inc. (Energy Systems), staff in conducting demonstrations. It is prepared in checklist style to facilitate its use and assumes that Energy Systems personnel have project management responsibility. In addition to a detailed step-by-step listing of procedural considerations, a general checklist, logic flow diagram, and several examples of necessary plans are included to assist the user in developing an understanding of the many complex activities required to manage technology demonstrations. Demonstrations are pilot-scale applications of often innovative technologies to determine the commercial viability of the technologies to perform their designed function. Demonstrations are generally conducted on well-defined problems for which existing technologies or processes are less than satisfactory in terms of effectiveness, cost, and/or regulatory compliance. Critically important issues in demonstration management include, but are not limited to, such factors as communications with line and matrix management and with the US Department of Energy (DOE) and Energy Systems staff responsible for management oversight, budgetary and schedule requirements, regulatory compliance, and safety

  1. Discovery of Dengue Virus NS4B Inhibitors

    Science.gov (United States)

    Wang, Qing-Yin; Dong, Hongping; Zou, Bin; Karuna, Ratna; Wan, Kah Fei; Zou, Jing; Susila, Agatha; Yip, Andy; Shan, Chao; Yeo, Kim Long; Xu, Haoying; Ding, Mei; Chan, Wai Ling; Gu, Feng; Seah, Peck Gee; Liu, Wei; Lakshminarayana, Suresh B.; Kang, CongBao; Lescar, Julien; Blasco, Francesca; Smith, Paul W.

    2015-01-01

    ABSTRACT The four serotypes of dengue virus (DENV-1 to -4) represent the most prevalent mosquito-borne viral pathogens in humans. No clinically approved vaccine or antiviral is currently available for DENV. Here we report a spiropyrazolopyridone compound that potently inhibits DENV both in vitro and in vivo. The inhibitor was identified through screening of a 1.8-million-compound library by using a DENV-2 replicon assay. The compound selectively inhibits DENV-2 and -3 (50% effective concentration [EC50], 10 to 80 nM) but not DENV-1 and -4 (EC50, >20 μM). Resistance analysis showed that a mutation at amino acid 63 of DENV-2 NS4B (a nonenzymatic transmembrane protein and a component of the viral replication complex) could confer resistance to compound inhibition. Genetic studies demonstrate that variations at amino acid 63 of viral NS4B are responsible for the selective inhibition of DENV-2 and -3. Medicinal chemistry improved the physicochemical properties of the initial “hit” (compound 1), leading to compound 14a, which has good in vivo pharmacokinetics. Treatment of DENV-2-infected AG129 mice with compound 14a suppressed viremia, even when the treatment started after viral infection. The results have proven the concept that inhibitors of NS4B could potentially be developed for clinical treatment of DENV infection. Compound 14a represents a potential preclinical candidate for treatment of DENV-2- and -3-infected patients. IMPORTANCE Dengue virus (DENV) threatens up to 2.5 billion people and is now spreading in many regions in the world where it was not previously endemic. While there are several promising vaccine candidates in clinical trials, approved vaccines or antivirals are not yet available. Here we describe the identification and characterization of a spiropyrazolopyridone as a novel inhibitor of DENV by targeting the viral NS4B protein. The compound potently inhibits two of the four serotypes of DENV (DENV-2 and -3) both in vitro and in vivo. Our

  2. Discovery of DNA Topoisomerase I Inhibitors with Low-Cytotoxicity Based on Virtual Screening from Natural Products

    Directory of Open Access Journals (Sweden)

    Lan-Ting Xin

    2017-07-01

    Full Text Available Currently, DNA topoisomerase I (Topo I inhibitors constitute a family of antitumor agents with demonstrated clinical effects on human malignancies. However, the clinical uses of these agents have been greatly limited due to their severe toxic effects. Therefore, it is urgent to find and develop novel low toxic Topo I inhibitors. In recent years, during our ongoing research on natural antitumor products, a collection of low cytotoxic or non-cytotoxic compounds with various structures were identified from marine invertebrates, plants, and their symbiotic microorganisms. In the present study, new Topo I inhibitors were discovered from low cytotoxic and non-cytotoxic natural products by virtual screening with docking simulations in combination with bioassay test. In total, eight potent Topo I inhibitors were found from 138 low cytotoxic or non-cytotoxic compounds from coral-derived fungi and plants. All of these Topo I inhibitors demonstrated activities against Topo I-mediated relaxation of supercoiled DNA at the concentrations of 5–100 µM. Notably, the flavonoids showed higher Topo I inhibitory activities than other compounds. These newly discovered Topo I inhibitors exhibited structurally diverse and could be considered as a good starting point for the development of new antitumor lead compounds.

  3. Dry eye syndrome in aromatase inhibitor users.

    Science.gov (United States)

    Turaka, Kiran; Nottage, Jennifer M; Hammersmith, Kristin M; Nagra, Parveen K; Rapuano, Christopher J

    2013-04-01

    Aromatase inhibitors are frequently used as an adjuvant therapy in the treatment of breast cancer. We observed that several patients taking aromatase inhibitors presented with severe dry eye symptoms, and we investigated whether there is a relationship between aromatase inhibitors and dry eyes in these patients. Retrospective chart review. Forty-one women. A computerized search of health records was performed to identify patients using anastrazole, letrozole and exemestane seen by the Cornea Service from August 2008 to March 2011. The results were compared with age-matched controls. Ocular surface changes among aromatase inhibitors users. Of the 41 women, 39 were Caucasians. Thirty-nine patients had breast cancer (95%), one patient had ovarian cancer (2.5%) and one had an unknown primary cancer. Mean age was 68 ± 11.3 years (range 47-95). Most common presenting symptoms were blurred vision in 28 (68%) patients, irritation/foreign body sensation in 12 (29%) patients, redness in 9 (22%) patients, tearing in 6 (22%) patients and photosensitivity in 2 (5%) patients. Mean Schirmer's test measurement was 11 ± 5.8 mm (range 0.5-20 mm). Blepharitis was noted in 68 of 82 eyes (73%), decreased or poor tear function in 24 eyes (29%), conjunctival injection in 18 eyes (22%) and superficial punctate keratitis in 12 eyes (29%). Among an age-matched population (45-95 years), dry eye syndrome was found in only 9.5% of patients. Because the prevalence of ocular surface disease signs and symptoms appears to be higher in study group than control patients, aromatase inhibitors might be a contributing factor to the dry eye symptoms. © 2012 The Authors. Clinical and Experimental Ophthalmology © 2012 Royal Australian and New Zealand College of Ophthalmologists.

  4. RENAL SAFETY OF PROTON PUMP INHIBITORS

    Directory of Open Access Journals (Sweden)

    A. I. Dyadyk

    2017-01-01

    Full Text Available Proton pump inhibitors are a widely used in clinical practice, and are taken by millions of patients around the world for a long time. While proton pump inhibitors are well-tolerated class of drugs, the number of publications has been raised about adverse renal effects, specially their association with acute tubulointerstitial nephritis. It is one of the leading causes of acute renal injury and have catastrophic long-term consequences called chronic kidney disease. In this review, we consider epidemiology, pathogenesis, diagnostic criteria (including biopsy and morphological pattern, clinical manifestations and treatment of proton pump inhibitors-induced acute tubulointerstitial nephritis. A subclinical course without classical manifestations of a cell-mediated hypersensitivity reaction (fever, skin rash, eosinophilia, arthralgia is characteristic of acute tubulointerstitial nephritis. Increased serum creatinine, decreased glomerular filtration rate, electrolyte disorders, pathological changes in urine tests are not highly specific indicators, but allow to suspect the development of acute tubulointerstitial nephritis. The “gold” standard of diagnosis is the intravital morphological examination of the kidney tissue. Timely diagnosis and immediate discontinuation of the potentially causative drug is the mainstay of therapy and the first necessary step in the early management of suspected or biopsy-proven drug-induced acute tubulointerstitial nephritis. The usage of proton pump inhibitors should be performed only on strict indications with optimal duration of treatment and careful monitoring of kidney function. Multiple comorbidities (older age, heart failure, diabetes, cirrhosis, chronic kidney disease, hypovolemia increase potential nephrotoxicity. Awareness of this iatrogenic complication will improve diagnosis of proton pump inhibitors-induced acute tubulointerstitial nephritis by multidisciplinary specialists and increase the possibility

  5. Cost of care of haemophilia with inhibitors.

    Science.gov (United States)

    Di Minno, M N D; Di Minno, G; Di Capua, M; Cerbone, A M; Coppola, A

    2010-01-01

    In Western countries, the treatment of patients with inhibitors is presently the most challenging and serious issue in haemophilia management, direct costs of clotting factor concentrates accounting for >98% of the highest economic burden absorbed for the healthcare of patients in this setting. Being designed to address questions of resource allocation and effectiveness, decision models are the golden standard to reliably assess the overall economic implications of haemophilia with inhibitors in terms of mortality, bleeding-related morbidity, and severity of arthropathy. However, presently, most data analyses stem from retrospective short-term evaluations, that only allow for the analysis of direct health costs. In the setting of chronic diseases, the cost-utility analysis, that takes into account the beneficial effects of a given treatment/healthcare intervention in terms of health-related quality of life, is likely to be the most appropriate approach. To calculate net benefits, the quality adjusted life year, that significantly reflects such health gain, has to be compared with specific economic impacts. Differences in data sources, in medical practice and/or in healthcare systems and costs, imply that most current pharmacoeconomic analyses are confined to a narrow healthcare payer perspective. Long-term/lifetime prospective or observational studies, devoted to a careful definition of when to start a treatment; of regimens (dose and type of product) to employ, and of inhibitor population (children/adults, low-responding/high responding inhibitors) to study, are thus urgently needed to allow for newer insights, based on reliable data sources into resource allocation, effectiveness and cost-utility analysis in the treatment of haemophiliacs with inhibitors.

  6. Orbital Express fluid transfer demonstration system

    Science.gov (United States)

    Rotenberger, Scott; SooHoo, David; Abraham, Gabriel

    2008-04-01

    Propellant resupply of orbiting spacecraft is no longer in the realm of high risk development. The recently concluded Orbital Express (OE) mission included a fluid transfer demonstration that operated the hardware and control logic in space, bringing the Technology Readiness Level to a solid TRL 7 (demonstration of a system prototype in an operational environment). Orbital Express (funded by the Defense Advanced Research Projects Agency, DARPA) was launched aboard an Atlas-V rocket on March 9th, 2007. The mission had the objective of demonstrating technologies needed for routine servicing of spacecraft, namely autonomous rendezvous and docking, propellant resupply, and orbital replacement unit transfer. The demonstration system used two spacecraft. A servicing vehicle (ASTRO) performed multiple dockings with the client (NextSat) spacecraft, and performed a variety of propellant transfers in addition to exchanges of a battery and computer. The fluid transfer and propulsion system onboard ASTRO, in addition to providing the six degree-of-freedom (6 DOF) thruster system for rendezvous and docking, demonstrated autonomous transfer of monopropellant hydrazine to or from the NextSat spacecraft 15 times while on orbit. The fluid transfer system aboard the NextSat vehicle was designed to simulate a variety of client systems, including both blowdown pressurization and pressure regulated propulsion systems. The fluid transfer demonstrations started with a low level of autonomy, where ground controllers were allowed to review the status of the demonstration at numerous points before authorizing the next steps to be performed. The final transfers were performed at a full autonomy level where the ground authorized the start of a transfer sequence and then monitored data as the transfer proceeded. The major steps of a fluid transfer included the following: mate of the coupling, leak check of the coupling, venting of the coupling, priming of the coupling, fluid transfer, gauging

  7. Identification of halosalicylamide derivatives as a novel class of allosteric inhibitors of HCV NS5B polymerase.

    Science.gov (United States)

    Liu, Yaya; Donner, Pamela L; Pratt, John K; Jiang, Wen W; Ng, Teresa; Gracias, Vijaya; Baumeister, Steve; Wiedeman, Paul E; Traphagen, Linda; Warrior, Usha; Maring, Clarence; Kati, Warren M; Djuric, Stevan W; Molla, Akhteruzzaman

    2008-06-01

    Halosalicylamide derivatives were identified from high-throughput screening as potent inhibitors of HCV NS5B polymerase. The subsequent structure and activity relationship revealed the absolute requirement of the salicylamide moiety for optimum activity. Methylation of either the hydroxyl group or the amide group of the salicylamide moiety abolished the activity while the substitutions on both phenyl rings are acceptable. The halosalicylamide derivatives were shown to be non-competitive with respect to elongation nucleotide and demonstrated broad genotype activity against genotype 1-3 HCV NS5B polymerases. Inhibitor competition studies indicated an additive binding mode to the initiation pocket that is occupied by the thiadiazine class of compounds and an additive binding mode to the elongation pocket that is occupied by diketoacids, but a mutually exclusive binding mode with respect to the allosteric thumb pocket that is occupied by the benzimidazole class of inhibitors. Therefore, halosalicylamides represent a novel class of allosteric inhibitors of HCV NS5B polymerase.

  8. Synthesis and Biological Evaluation of Novel Jatrorrhizine Derivatives with Amino Groups Linked at the 3-Position as Inhibitors of Acetylcholinesterase

    Directory of Open Access Journals (Sweden)

    Xiaofei Jiang

    2017-01-01

    Full Text Available Jatrorrhizine was considered as one of the active constituents of Coptis chinensis Franch. Herein, jatrorrhizine derivatives with substituted amino groups linked at the 3-position were designed, synthesized, and biologically evaluated as inhibitors of acetylcholinesterase. Jatrorrhizine derivatives inhibited the activity of acetylcholinesterase (AChE to a greater extent than the lead compound jatrorrhizine. All these jatrorrhizine derivatives were proved to be potent inhibitors of acetylcholinesterase (AChE with submicromolar IC50 values, but less sensitive to butyrylcholinesterase (BuChE, which suggests that these jatrorrhizine derivatives are selective for AChE/BuChE. Compound 3g gave the most potent inhibitor activity for AChE (IC50 = 0.301 μM, which is greater than the lead compound jatrorrhizine. All these results demonstrated that these jatrorrhizine derivatives are potential inhibitors for AChE.

  9. Amide proton exchange rates of a bound pepsin inhibitor determined by isotope-edited proton NMR experiments

    International Nuclear Information System (INIS)

    Fesik, S.W.; Luly, J.R.; Stein, H.H.; BaMaung, N.

    1987-01-01

    From a series of isotope-edited proton NMR spectra, amide proton exchange rates were measured at 20 C, 30 C, and 40 0 C for a tightly bound 15 N-labeled tripeptide inhibitor of porcine pepsin (IC50 = 1.7 X 10(-) M). Markedly different NH exchange rates were observed for the three amide protons of the bound inhibitor. The P1 NH exchanged much more slowly than the P2 NH and P3 NH. These results are discussed in terms of the relative solvent accessibility in the active site and the role of the NH protons of the inhibitor for hydrogen bonding to the enzyme. In this study a useful approach is demonstrated for obtaining NH exchange rates on ligands bound to biomacromolecules, the knowledge of which could be of potential utility in the design of therapeutically useful nonpeptide enzyme inhibitors from peptide leads

  10. Cediranib, a pan-VEGFR inhibitor, and olaparib, a PARP inhibitor, in combination therapy for high grade serous ovarian cancer.

    Science.gov (United States)

    Ivy, S Percy; Liu, Joyce F; Lee, Jung-Min; Matulonis, Ursula A; Kohn, Elise C

    2016-01-01

    An estimated 22,000 women are diagnosed annually with ovarian cancer in the United States. Initially chemo-sensitive, recurrent disease ultimately becomes chemoresistant and may kill ~14,000 women annually. Molecularly targeted therapy with cediranib (AZD2171), a vascular endothelial growth factor receptor (VEGFR)-1, 2, and 3 signaling blocker, and olaparib (AZD2281), a poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, administered orally in combination has shown anti-tumor activity in the treatment of high grade serous ovarian cancer (HGSOC). This combination has the potential to change the treatment of HGSOC. Preclinical and clinical studies of single agent cediranib and olaparib or their combination are reviewed. Data are presented from peer-reviewed published manuscripts, completed and ongoing early phase clinical trials registered in ClinicalTrials.gov, National Cancer Institute-sponsored clinical trials, and related recent abstracts. Advances in the treatment of HGSOC that improve progression-free and overall survival have proven elusive despite examination of molecularly targeted therapy. HGSOC patients with deleterious germline or somatic mutations in BRCA1 or BRCA2 (BRCAm) are most responsive to PARP inhibitors (PARPi). PARPi combined with angiogenesis inhibition improved anti-cancer response and duration in both BRCAm and BRCA wild type HGSOC patients, compared to olaparib single agent treatment, demonstrating therapeutic chemical and contextual synthetic lethality.

  11. Launch Vehicle Demonstrator Using Shuttle Assets

    Science.gov (United States)

    Threet, Grady E., Jr.; Creech, Dennis M.; Philips, Alan D.; Water, Eric D.

    2011-01-01

    The Marshall Space Flight Center Advanced Concepts Office (ACO) has the leading role for NASA s preliminary conceptual launch vehicle design and performance analysis. Over the past several years the ACO Earth-to-Orbit Team has evaluated thousands of launch vehicle concept variations for a multitude of studies including agency-wide efforts such as the Exploration Systems Architecture Study (ESAS), Constellation, Heavy Lift Launch Vehicle (HLLV), Heavy Lift Propulsion Technology (HLPT), Human Exploration Framework Team (HEFT), and Space Launch System (SLS). NASA plans to continue human space exploration and space station utilization. Launch vehicles used for heavy lift cargo and crew will be needed. One of the current leading concepts for future heavy lift capability is an inline one and a half stage concept using solid rocket boosters (SRB) and based on current Shuttle technology and elements. Potentially, the quickest and most cost-effective path towards an operational vehicle of this configuration is to make use of a demonstrator vehicle fabricated from existing shuttle assets and relying upon the existing STS launch infrastructure. Such a demonstrator would yield valuable proof-of-concept data and would provide a working test platform allowing for validated systems integration. Using shuttle hardware such as existing RS-25D engines and partial MPS, propellant tanks derived from the External Tank (ET) design and tooling, and four-segment SRB s could reduce the associated upfront development costs and schedule when compared to a concept that would rely on new propulsion technology and engine designs. There are potentially several other additional benefits to this demonstrator concept. Since a concept of this type would be based on man-rated flight proven hardware components, this demonstrator has the potential to evolve into the first iteration of heavy lift crew or cargo and serve as a baseline for block upgrades. This vehicle could also serve as a demonstration

  12. Single-molecule supercoil-relaxation assay as a screening tool to determine the mechanism and efficacy of human topoisomerase IB inhibitors

    Science.gov (United States)

    Seol, Yeonee; Zhang, Hongliang; Agama, Keli; Lorence, Nicholas; Pommier, Yves; Neuman, Keir C.

    2015-01-01

    Human nuclear type IB topoisomerase (Top1) inhibitors are widely used and powerful anti-cancer agents. In this study, we introduce and validate a single-molecule supercoil relaxation assay as a molecular pharmacology tool for characterizing therapeutically relevant Top1 inhibitors. Using this assay, we determined the effects on Top1 supercoil relaxation activity of four Top1 inhibitors; three clinically relevant: camptothecin, LMP-400, LMP-776 (both indenoisoquinoline derivatives), and one natural product in preclinical development, lamellarin-D. Our results demonstrate that Top1 inhibitors have two distinct effects on Top1 activity: a decrease in supercoil relaxation rate and an increase in religation inhibition. The type and magnitude of the inhibition mode depend both on the specific inhibitor and on the topology of the DNA substrate. In general, the efficacy of inhibition is significantly higher with supercoiled than with relaxed DNA substrates. Comparing single-molecule inhibition with cell growth inhibition (IC50) measurements showed a correlation between the binding time of the Top1 inhibitors and their cytotoxic efficacy, independent of the mode of inhibition. This study demonstrates that the single-molecule supercoil relaxation assay is a sensitive method to elucidate the detailed mechanisms of Top1 inhibitors and is relevant for the cellular efficacy of Top1 inhibitors. PMID:26351326

  13. Accelerated reliability demonstration under competing failure modes

    International Nuclear Information System (INIS)

    Luo, Wei; Zhang, Chun-hua; Chen, Xun; Tan, Yuan-yuan

    2015-01-01

    The conventional reliability demonstration tests are difficult to apply to products with competing failure modes due to the complexity of the lifetime models. This paper develops a testing methodology based on the reliability target allocation for reliability demonstration under competing failure modes at accelerated conditions. The specified reliability at mission time and the risk caused by sampling of the reliability target for products are allocated for each failure mode. The risk caused by degradation measurement fitting of the target for a product involving performance degradation is equally allocated to each degradation failure mode. According to the allocated targets, the accelerated life reliability demonstration test (ALRDT) plans for the failure modes are designed. The accelerated degradation reliability demonstration test plans and the associated ALRDT plans for the degradation failure modes are also designed. Next, the test plan and the decision rules for the products are designed. Additionally, the effects of the discreteness of sample size and accepted number of failures for failure modes on the actual risks caused by sampling for the products are investigated. - Highlights: • Accelerated reliability demonstration under competing failure modes is studied. • The method is based on the reliability target allocation involving the risks. • The test plan for the products is based on the plans for all the failure modes. • Both failure mode and degradation failure modes are considered. • The error of actual risks caused by sampling for the products is small enough

  14. Decision support software technology demonstration plan

    Energy Technology Data Exchange (ETDEWEB)

    SULLIVAN,T.; ARMSTRONG,A.

    1998-09-01

    The performance evaluation of innovative and alternative environmental technologies is an integral part of the US Environmental Protection Agency's (EPA) mission. Early efforts focused on evaluating technologies that supported the implementation of the Clean Air and Clean Water Acts. In 1986 the Agency began to demonstrate and evaluate the cost and performance of remediation and monitoring technologies under the Superfund Innovative Technology Evaluation (SITE) program (in response to the mandate in the Superfund Amendments and Reauthorization Act of 1986 (SARA)). In 1990, the US Technology Policy was announced. This policy placed a renewed emphasis on making the best use of technology in achieving the national goals of improved quality of life for all Americans, continued economic growth, and national security. In the spirit of the technology policy, the Agency began to direct a portion of its resources toward the promotion, recognition, acceptance, and use of US-developed innovative environmental technologies both domestically and abroad. Decision Support Software (DSS) packages integrate environmental data and simulation models into a framework for making site characterization, monitoring, and cleanup decisions. To limit the scope which will be addressed in this demonstration, three endpoints have been selected for evaluation: Visualization; Sample Optimization; and Cost/Benefit Analysis. Five topics are covered in this report: the objectives of the demonstration; the elements of the demonstration plan; an overview of the Site Characterization and Monitoring Technology Pilot; an overview of the technology verification process; and the purpose of this demonstration plan.

  15. Cytogenetic study of Ascaris trypsin inhibitor in cultured human ...

    Indian Academy of Sciences (India)

    2009-04-01

    Apr 1, 2009 ... Although the physical and chemical properties of Ascaris trypsin inhibitors ... male of Ascaris suum according to the method of Pudles and. Rola (1967). ..... inhibitor isolated from Ascaris resulted in the appearance of dominant ...

  16. SGLT2 inhibitors: molecular design and potential differences in effect.

    Science.gov (United States)

    Isaji, Masayuki

    2011-03-01

    The physiological and pathological handling of glucose via sodium-glucose cotransporter-2 (SGLT2) in the kidneys has been evolving, and SGLT2 inhibitors have been focused upon as a novel drug for treating diabetes. SGLT2 inhibitors enhance renal glucose excretion by inhibiting renal glucose reabsorption. Consequently, SGLT2 inhibitors reduce plasma glucose insulin independently and improve insulin resistance in diabetes. To date, various SGLT2 inhibitors have been developed and evaluated in clinical studies. The potency and positioning of SGLT2 inhibitors as an antidiabetic drug are dependent on their characteristic profile, which induces selectivity, efficacy, pharmacokinetics, and safety. This profile decides which SGLT2 inhibitors can be expected for application of the theoretical concept of reducing renal glucose reabsorption for the treatment of diabetes. I review the structure and advancing profile of various SGLT2 inhibitors, comparing their similarities and differences, and discuss the expected SGLT2 inhibitors for an emerging category of antidiabetic drugs.

  17. Environmental life cycle analysis of potato sprout inhibitors

    NARCIS (Netherlands)

    Kerstholt, R.P.V.; Ree, C.M.; Moll, H.C.

    Potato sprout inhibitors are generally applied to suppress sprouting during winter storage. This study presents the compared environmental profiles of the two sprout inhibitors available on the Dutch market: A traditional chemical product with isopropyl-3-chlorophenylcarbamate (CIPC) and

  18. [Inhibitors of proteolytic enzymes under abiotic stresses in plants (review)].

    Science.gov (United States)

    Mosolov, V V; Valueva, T A

    2011-01-01

    Data on the role of proteolytic enzyme inhibitors in plant adaptation to various unfavorable environmental abiotic factors--water deficiency, salinization of soil, extreme temperatures, etc.--and also probable functions of proteinases inhibitors in natural plant senescense are considered.

  19. Identification and Characterization of Roseltide, a Knottin-type Neutrophil Elastase Inhibitor Derived from Hibiscus sabdariffa

    Science.gov (United States)

    Loo, Shining; Kam, Antony; Xiao, Tianshu; Nguyen, Giang K. T.; Liu, Chuan Fa; Tam, James P.

    2016-01-01

    Plant knottins are of therapeutic interest due to their high metabolic stability and inhibitory activity against proteinases involved in human diseases. The only knottin-type proteinase inhibitor against porcine pancreatic elastase was first identified from the squash family in 1989. Here, we report the identification and characterization of a knottin-type human neutrophil elastase inhibitor from Hibiscus sabdariffa of the Malvaceae family. Combining proteomic and transcriptomic methods, we identified a panel of novel cysteine-rich peptides, roseltides (rT1-rT8), which range from 27 to 39 residues with six conserved cysteine residues. The 27-residue roseltide rT1 contains a cysteine spacing and amino acid sequence that is different from the squash knottin-type elastase inhibitor. NMR analysis demonstrated that roseltide rT1 adopts a cystine-knot fold. Transcriptome analyses suggested that roseltides are bioprocessed by asparagine endopeptidases from a three-domain precursor. The cystine-knot structure of roseltide rT1 confers its high resistance against degradation by endopeptidases, 0.2 N HCl, and human serum. Roseltide rT1 was shown to inhibit human neutrophil elastase using enzymatic and pull-down assays. Additionally, roseltide rT1 ameliorates neutrophil elastase-stimulated cAMP accumulation in vitro. Taken together, our findings demonstrate that roseltide rT1 is a novel knottin-type neutrophil elastase inhibitor with therapeutic potential for neutrophil elastase associated diseases. PMID:27991569

  20. Proton Pump Inhibitors in Gastroesophageal Reflux Disease: Friend or Foe.

    Science.gov (United States)

    Gyawali, C Prakash

    2017-09-01

    Proton pump inhibitor (PPI) use in gastroesophageal reflux disease (GERD) has been redefined, in light of recent advances highlighting GERD phenotypes that respond to PPIs, and fresh revelations of potential risks of long-term PPI therapy. Erosive esophagitis predicts excellent response to PPI therapy, but non-erosive reflux disease (NERD) with abnormal reflux parameters on ambulatory reflux monitoring also demonstrates a similar response. In contrast, response is suboptimal in the absence of abnormal reflux parameters. In this setting, if an alternate appropriate indication for PPI therapy does not coexist, risks may outweigh benefits of PPI therapy. Adverse events from long-term PPI therapy continue to be reported, most based on association rather than cause-and-effect. Appropriate indications need to be established before embarking on long-term PPI therapy. Future research will define true risks of long-term PPI therapy, and develop alternate management options for acid peptic diseases.

  1. Advances of Immune Checkpoint Inhibitors in Tumor Immunotherapy

    Science.gov (United States)

    Guo, Qiao

    2018-01-01

    Immune checkpoints are cell surface molecules that can fine-tune the immune responses, they are crucial for modulating the duration and amplitude of immune reactions while maintaining self-tolerance in order to minimize autoimmune responses. Numerous studies have demonstrated that tumors cells can directly express immune-checkpoint molecules, or induce many inhibitory molecules expression in the tumor microenvironment to inhibit the anti-tumor immunity. Releasing these brakes has emerged as an exciting strategy to cure cancer. In the past few years, clinical trials with therapeutic antibodies targeting to the checkpoint molecules CTLA-4 and PD-1 have rekindled the hope for cancer immunotherapy. In contrast to the conventional treatment, checkpoint inhibitors induce broad and durable antitumor responses. In the future, treatment may involve combination therapy to target different checkpoint molecules and stages of the adaptive immune responses. In this review, we summarized the recent advances of the study and development of other checkpoint molecules in tumor immunotherapy.

  2. Kynurenine-3-monooxygenase: a review of structure, mechanism, and inhibitors.

    Science.gov (United States)

    Smith, Jason R; Jamie, Joanne F; Guillemin, Gilles J

    2016-02-01

    Kynurenine monooxygenase (KMO) is an enzyme of the kynurenine (Kyn) pathway (KP), which is the major catabolic route of tryptophan. Kyn represents a branch point of the KP, being converted into the neurotoxin 3-hydroxykynurenine via KMO, neuroprotectant kynurenic acid, and anthranilic acid. As a result of this branch point, KMO is an attractive drug target for several neurodegenerative and/or neuroinflammatory diseases, especially Huntington's (HD), Alzheimer's (AD), and Parkinson's (PD) diseases. Although a neurological target, administration of KMO inhibitors in the periphery has demonstrated promising pharmacological results. In light of a recent crystal structure release and reports of preclinical candidates, here we provide a concise yet comprehensive update on the current state of research into the enzymology of KMO and related drug discovery efforts, highlighting areas where further work is required. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Tissue inhibitor of metalloproteinases-1 in breast cancer

    DEFF Research Database (Denmark)

    Würtz, Sidse Ørnbjerg; Rasmussen, Anne-Sofie Schrohl; Sørensen, Nanna Møller

    2005-01-01

    Whether patients diagnosed with primary breast cancer are offered adjuvant systemic therapy following surgical removal of the tumor is based on prognosis. Prognosis is estimated in every patient using established prognostic variables. Unfortunately, when using the currently available prognostic...... parameters a significant proportion of patients are over-treated. Thus, in order to improve stratification of breast cancer patients, additional prognostic factors need to be identified. Tissue inhibitor of metalloproteinases-1 (TIMP-1) is one of the promising candidates for new prognostic markers in breast...... cancer, as a number of studies have demonstrated an association between high tumor-tissue levels of TIMP-1 mRNA as well as TIMP-1 protein and a poor prognosis of breast cancer patients. TIMP-1 is a member of the TIMP family, currently comprising four members (TIMP-1-4), and its main function...

  4. Loop Group Parakeet Virtual Cable Concept Demonstrator

    Science.gov (United States)

    Dowsett, T.; McNeill, T. C.; Reynolds, A. B.; Blair, W. D.

    2002-07-01

    The Parakeet Virtual Cable (PVC) concept demonstrator uses the Ethernet Local Area Network (LAN) laid for the Battle Command Support System (BCSS) to connect the Parakeet DVT(DA) (voice terminal) to the Parakeet multiplexer. This currently requires pairs of PVC interface units to be installed for each DVT(DA) . To reduce the cost of a PVC installation, the concept of a Loop Group Parakeet Virtual Cable (LGPVC) was proposed. This device was designed to replace the up to 30 PVC boxes and the multiplexer at the multiplexer side of a PVC installation. While the demonstrator is largely complete, testing has revealed an incomplete understanding of how to emulate the proprietary handshaking occurring between the circuit switch and the multiplexer. The LGPVC concept cannot yet be demonstrated.

  5. Background Model for the Majorana Demonstrator

    Science.gov (United States)

    Cuesta, C.; Abgrall, N.; Aguayo, E.; Avignone, F. T.; Barabash, A. S.; Bertrand, F. E.; Boswell, M.; Brudanin, V.; Busch, M.; Byram, D.; Caldwell, A. S.; Chan, Y.-D.; Christofferson, C. D.; Combs, D. C.; Detwiler, J. A.; Doe, P. J.; Efremenko, Yu.; Egorov, V.; Ejiri, H.; Elliott, S. R.; Fast, J. E.; Finnerty, P.; Fraenkle, F. M.; Galindo-Uribarri, A.; Giovanetti, G. K.; Goett, J.; Green, M. P.; Gruszko, J.; Guiseppe, V. E.; Gusev, K.; Hallin, A. L.; Hazama, R.; Hegai, A.; Henning, R.; Hoppe, E. W.; Howard, S.; Howe, M. A.; Keeter, K. J.; Kidd, M. F.; Kochetov, O.; Konovalov, S. I.; Kouzes, R. T.; LaFerriere, B. D.; Leon, J.; Leviner, L. E.; Loach, J. C.; MacMullin, J.; MacMullin, S.; Martin, R. D.; Meijer, S.; Mertens, S.; Nomachi, M.; Orrell, J. L.; O'Shaughnessy, C.; Overman, N. R.; Phillips, D. G.; Poon, A. W. P.; Pushkin, K.; Radford, D. C.; Rager, J.; Rielage, K.; Robertson, R. G. H.; Romero-Romero, E.; Ronquest, M. C.; Schubert, A. G.; Shanks, B.; Shima, T.; Shirchenko, M.; Snavely, K. J.; Snyder, N.; Suriano, A. M.; Thompson, J.; Timkin, V.; Tornow, W.; Trimble, J. E.; Varner, R. L.; Vasilyev, S.; Vetter, K.; Vorren, K.; White, B. R.; Wilkerson, J. F.; Wiseman, C.; Xu, W.; Yakushev, E.; Young, A. R.; Yu, C.-H.; Yumatov, V.

    The Majorana Collaboration is constructing a system containing 40 kg of HPGe detectors to demonstrate the feasibility and potential of a future tonne-scale experiment capable of probing the neutrino mass scale in the inverted-hierarchy region. To realize this, a major goal of the Majorana Demonstrator is to demonstrate a path forward to achieving a background rate at or below 1 cnt/(ROI-t-y) in the 4 keV region of interest around the Q-value at 2039 keV. This goal is pursued through a combination of a significant reduction of radioactive impurities in construction materials with analytical methods for background rejection, for example using powerful pulse shape analysis techniques profiting from the p-type point contact HPGe detectors technology. The effectiveness of these methods is assessed using simulations of the different background components whose purity levels are constrained from radioassay measurements.

  6. Manufacturing Demonstration Facility: Low Temperature Materials Synthesis

    International Nuclear Information System (INIS)

    Graham, David E.; Moon, Ji-Won; Armstrong, Beth L.; Datskos, Panos G.; Duty, Chad E.; Gresback, Ryan; Ivanov, Ilia N.; Jacobs, Christopher B.; Jellison, Gerald Earle; Jang, Gyoung Gug; Joshi, Pooran C.; Jung, Hyunsung; Meyer, Harry M.; Phelps, Tommy

    2015-01-01

    The Manufacturing Demonstration Facility (MDF) low temperature materials synthesis project was established to demonstrate a scalable and sustainable process to produce nanoparticles (NPs) for advanced manufacturing. Previous methods to chemically synthesize NPs typically required expensive, high-purity inorganic chemical reagents, organic solvents and high temperatures. These processes were typically applied at small laboratory scales at yields sufficient for NP characterization, but insufficient to support roll-to-roll processing efforts or device fabrication. The new NanoFermentation processes described here operated at a low temperature (~60 C) in low-cost, aqueous media using bacteria that produce extracellular NPs with controlled size and elemental stoichiometry. Up-scaling activities successfully demonstrated high NP yields and quality in a 900-L pilot-scale reactor, establishing this NanoFermentation process as a competitive biomanufacturing strategy to produce NPs for advanced manufacturing of power electronics, solid-state lighting and sensors.

  7. Optimizing Probability of Detection Point Estimate Demonstration

    Science.gov (United States)

    Koshti, Ajay M.

    2017-01-01

    Probability of detection (POD) analysis is used in assessing reliably detectable flaw size in nondestructive evaluation (NDE). MIL-HDBK-18231and associated mh18232POD software gives most common methods of POD analysis. Real flaws such as cracks and crack-like flaws are desired to be detected using these NDE methods. A reliably detectable crack size is required for safe life analysis of fracture critical parts. The paper provides discussion on optimizing probability of detection (POD) demonstration experiments using Point Estimate Method. POD Point estimate method is used by NASA for qualifying special NDE procedures. The point estimate method uses binomial distribution for probability density. Normally, a set of 29 flaws of same size within some tolerance are used in the demonstration. The optimization is performed to provide acceptable value for probability of passing demonstration (PPD) and achieving acceptable value for probability of false (POF) calls while keeping the flaw sizes in the set as small as possible.

  8. Manufacturing Demonstration Facility: Low Temperature Materials Synthesis

    Energy Technology Data Exchange (ETDEWEB)

    Graham, David E. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Moon, Ji-Won [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Armstrong, Beth L. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Datskos, Panos G. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Duty, Chad E. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Gresback, Ryan [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Ivanov, Ilia N. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Jacobs, Christopher B. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Jellison, Gerald Earle [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Jang, Gyoung Gug [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Joshi, Pooran C. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Jung, Hyunsung [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Meyer, III, Harry M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Phelps, Tommy [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2015-06-30

    The Manufacturing Demonstration Facility (MDF) low temperature materials synthesis project was established to demonstrate a scalable and sustainable process to produce nanoparticles (NPs) for advanced manufacturing. Previous methods to chemically synthesize NPs typically required expensive, high-purity inorganic chemical reagents, organic solvents and high temperatures. These processes were typically applied at small laboratory scales at yields sufficient for NP characterization, but insufficient to support roll-to-roll processing efforts or device fabrication. The new NanoFermentation processes described here operated at a low temperature (~60 C) in low-cost, aqueous media using bacteria that produce extracellular NPs with controlled size and elemental stoichiometry. Up-scaling activities successfully demonstrated high NP yields and quality in a 900-L pilot-scale reactor, establishing this NanoFermentation process as a competitive biomanufacturing strategy to produce NPs for advanced manufacturing of power electronics, solid-state lighting and sensors.

  9. Supercompaction/grouting demonstration project: Final report

    International Nuclear Information System (INIS)

    1987-01-01

    The purpose of this supercompaction demonstration project was to allow Martin Marietta Energy Systems, Inc. (The Company), to obtain cost analysis and performance information on volume reduction and waste encapsulation of solid, low-level contaminated waste (SLW). Ultimately, this information will be used to help define a waste disposal process for SLW that is acceptable to regulatory agencies and the US Department of Energy, Oak Ridge Operations (DOE/ORO). The technical objectives of the demonstration project were: (1) to obtain detailed performance data on each of the compacted barrels; (2) evaluate operating performance problems that may have occurred; (3) describe in detail the compaction and encapsulation process; and (4) to obtain operating cost data for the performance of this demonstration

  10. Prototypical Consolidation Demonstration Project: Final report

    International Nuclear Information System (INIS)

    Gili, J.A.; Poston, V.K.

    1993-11-01

    This is the final report of the Prototypical Consolidation Demonstration Project, which was funded by the US Department of Energy's Office of Civilian Radioactive Waste Management. The project had two objectives: (a) to develop and demonstrate a prototype of production-scale equipment for the dry, horizontal consolidation and packaging of spent nuclear fuel rods from commercial boiling water reactor and pressurized water reactor fuel assemblies, and (b) to report the development and demonstration results to the US Department of Energy, Idaho Operations Office. This report summarizes the activities and conclusions of the project management contractor, EG ampersand G Idaho, Inc., and the fabrication and testing contractor, NUS Corporation (NUS). The report also presents EG ampersand G Idaho's assessments of the equipment and procedures developed by NUS

  11. Final report for the cryogenic retrieval demonstration

    International Nuclear Information System (INIS)

    Valentich, D.J.; Yokuda, E.L.

    1992-09-01

    This report documents a demonstration of a proposed buried transuranic waste retrieval concept that uses cryogenic ground freezing and remote excavation. At the Idaho National Engineering Laboratory (INEL), there are over 8 million ft 3 of intermingled soil and transuranic (TRU) wastes in shallow land burial, and retrieval of the material is one of the options being considered by the Buried Waste Integrated Demonstration for the Environmental Restoration program. Cryogenically freezing contaminated soil and buried waste has been proposed as a way to greatly reduce or eliminate the climate the threat of contamination spread during retrieval activities. In support of this idea, a demonstration of an innovative ground freezing and retrieval technology was performed at the INEL. This initial demonstration was held near the Radioactive Waste Management Complex at a ''cold test pit'' that was built in 1988 as a test bed for the demonstration of retrieval contamination control technologies. This pit is not contaminated with any radioactive or hazardous wastes. Barrels and boxes filled with metals, plastics, tools, paper, cloth, etc. configured in the same manner as expected in contaminated pits and trenches are buried at the cold test pit. After design, fabrication, and shop testing, Sonsub mobilized to the field in early July 1992 to perform the field demonstration. It was planned to freeze and extract four pits, each 9 x 9 x 10 ft. Each pit represented a different configuration of buried waste (stacked boxes, stacked barrels, random dumped barrels and boxes, and random dumped barrels). Sonsub's proposed technology consisted of driving a series of freeze pipes into the soil and waste, using liquid nitrogen to freeze the mass, and extracting the soil and debris using a series of remote operated, bridge crane mounted tools. In conjunction with the freezing and removal activities, temperature and moisture measurements, and air monitoring were performed

  12. Test Plan for the overburden removal demonstration

    International Nuclear Information System (INIS)

    Rice, P.; Thompson, D.; Winberg, M.; Skaggs, J.

    1993-06-01

    The removal of soil overburdens from contaminated pits and trenches involves using equipment that will remove a small layer of soil from 3 to 6 in. at any time. As a layer of soil is removed, overburden characterization techniques perform surveys to a depth that exceeds each overburden removal layer to ensure that the removed soil will be free of contamination. It is generally expected that no contamination will be found in the soil overburden, which was brought in after the waste was put in place. It is anticipated that some containers in the waste zone have lost their integrity, and the waste leakage from those containers has migrated by gravity downward into the waste zone. To maintain a safe work environment, this method of overburden removal should allow safe preparation of a pit or trench for final remediation. To demonstrate the soil overburden techniques, the Buried Waste Integrated Demonstration Program has contracted vendor services to provide equipment and techniques demonstrating soil overburden removal technology. The demonstration will include tests that will evaluate equipment performance and techniques for removal of overburden soil, control of contamination spread, and dust control. To evaluate the performance of these techniques, air particulate samples, physical measurements of the excavation soil cuts, maneuverability measurements, and time versus volume (rate) of soil removal data will be collected during removal operations. To provide a medium for sample evaluation, the overburden will be spiked at specific locations and depths with rare earth tracers. This test plan will be describe the objectives of the demonstration, data quality objectives, methods to be used to operate the equipment and use the techniques in the test area, and methods to be used in collecting data during the demonstration

  13. Final report for the cryogenic retrieval demonstration

    Energy Technology Data Exchange (ETDEWEB)

    Valentich, D.J.; Yokuda, E.L.

    1992-09-01

    This report documents a demonstration of a proposed buried transuranic waste retrieval concept that uses cryogenic ground freezing and remote excavation. At the Idaho National Engineering Laboratory (INEL), there are over 8 million ft{sup 3} of intermingled soil and transuranic (TRU) wastes in shallow land burial, and retrieval of the material is one of the options being considered by the Buried Waste Integrated Demonstration for the Environmental Restoration program. Cryogenically freezing contaminated soil and buried waste has been proposed as a way to greatly reduce or eliminate the climate the threat of contamination spread during retrieval activities. In support of this idea, a demonstration of an innovative ground freezing and retrieval technology was performed at the INEL. This initial demonstration was held near the Radioactive Waste Management Complex at a ``cold test pit`` that was built in 1988 as a test bed for the demonstration of retrieval contamination control technologies. This pit is not contaminated with any radioactive or hazardous wastes. Barrels and boxes filled with metals, plastics, tools, paper, cloth, etc. configured in the same manner as expected in contaminated pits and trenches are buried at the cold test pit. After design, fabrication, and shop testing, Sonsub mobilized to the field in early July 1992 to perform the field demonstration. It was planned to freeze and extract four pits, each 9 {times} 9 {times} 10 ft. Each pit represented a different configuration of buried waste (stacked boxes, stacked barrels, random dumped barrels and boxes, and random dumped barrels). Sonsub`s proposed technology consisted of driving a series of freeze pipes into the soil and waste, using liquid nitrogen to freeze the mass, and extracting the soil and debris using a series of remote operated, bridge crane mounted tools. In conjunction with the freezing and removal activities, temperature and moisture measurements, and air monitoring were performed.

  14. Final report for the cryogenic retrieval demonstration

    Energy Technology Data Exchange (ETDEWEB)

    Valentich, D.J.; Yokuda, E.L.

    1992-09-01

    This report documents a demonstration of a proposed buried transuranic waste retrieval concept that uses cryogenic ground freezing and remote excavation. At the Idaho National Engineering Laboratory (INEL), there are over 8 million ft[sup 3] of intermingled soil and transuranic (TRU) wastes in shallow land burial, and retrieval of the material is one of the options being considered by the Buried Waste Integrated Demonstration for the Environmental Restoration program. Cryogenically freezing contaminated soil and buried waste has been proposed as a way to greatly reduce or eliminate the climate the threat of contamination spread during retrieval activities. In support of this idea, a demonstration of an innovative ground freezing and retrieval technology was performed at the INEL. This initial demonstration was held near the Radioactive Waste Management Complex at a cold test pit'' that was built in 1988 as a test bed for the demonstration of retrieval contamination control technologies. This pit is not contaminated with any radioactive or hazardous wastes. Barrels and boxes filled with metals, plastics, tools, paper, cloth, etc. configured in the same manner as expected in contaminated pits and trenches are buried at the cold test pit. After design, fabrication, and shop testing, Sonsub mobilized to the field in early July 1992 to perform the field demonstration. It was planned to freeze and extract four pits, each 9 [times] 9 [times] 10 ft. Each pit represented a different configuration of buried waste (stacked boxes, stacked barrels, random dumped barrels and boxes, and random dumped barrels). Sonsub's proposed technology consisted of driving a series of freeze pipes into the soil and waste, using liquid nitrogen to freeze the mass, and extracting the soil and debris using a series of remote operated, bridge crane mounted tools. In conjunction with the freezing and removal activities, temperature and moisture measurements, and air monitoring were

  15. Demonstrating Lenz's Law with Recycled Materials

    Science.gov (United States)

    Saraiva, Carlos

    2006-03-01

    A number of interesting demonstrations of induced electric currents and of Lenz's law have been described in this journal.1-5 In this paper, a simple version of an experiment that was described6 by Léon Foucault in 1855 is presented. Foucault placed a rotating copper disk between the poles of an electromagnet. When the electromagnet was off, the disk rotated almost without friction, but when the electromagnet was turned on, the disk stopped almost immediately. Nice discussions of this sort of magnetic braking may be found in a number of textbooks.7 Here I describe how to do the demonstration quite simply using recycled materials.

  16. Duodenal diverticula demonstrated by barium examination

    Energy Technology Data Exchange (ETDEWEB)

    Christiansen, T.; Thommesen, P.

    An investigation for biliary tract calculi and food-stimulated gastro-oesophageal reflux was carried out in 37 patients with duodenal diverticula demonstrated by barium examination. Sixty per cent of the diverticula were located in the descending part of the duodenum. Biliary tract calculi were demonstrated in 38 per cent and food-stimulated gastro-oesophageal reflux in 81 per cent of the patients. The detection of a duodenal diverticulum should result in a supplementary investigation for gallstones and gastrooesophageal reflux and its sequelae.

  17. Demonstration of safety for geologic disposal

    International Nuclear Information System (INIS)

    Taylor, E.C.; Ramspott, L.D.; Sprecher, W.M.

    1994-01-01

    The US Department of Energy (DOE) is developing a nuclear waste management system that will accept high-level radioactive waste, transport it, store it, and ultimately emplace it in a deep geologic repository. The key activity now is determining whether Yucca Mountain, Nevada is suitable as a site for the repository. If so, the crucial technological advance will be the demonstration that disposal of nuclear waste will be safe for thousands of years after closure. This paper assesses the impact of regulatory developments, legal developments, and scientific developments on such a demonstration

  18. Buried Waste Integrated Demonstration stakeholder involvement model

    International Nuclear Information System (INIS)

    Kaupanger, R.M.; Kostelnik, K.M.; Milam, L.M.

    1994-04-01

    The Buried Waste Integrated Demonstration (BWID) is a program funded by the US Department of Energy (DOE) Office of Technology Development. BWID supports the applied research, development, demonstration, and evaluation of a suite of advanced technologies that together form a comprehensive remediation system for the effective and efficient remediation of buried waste. Stakeholder participation in the DOE Environmental Management decision-making process is critical to remediation efforts. Appropriate mechanisms for communication with the public, private sector, regulators, elected officials, and others are being aggressively pursued by BWID to permit informed participation. This document summarizes public outreach efforts during FY-93 and presents a strategy for expanded stakeholder involvement during FY-94

  19. Evaluation of rubber modified asphalt demonstration projects

    Energy Technology Data Exchange (ETDEWEB)

    1994-01-01

    As part of the Ontario Government's medium-term scrap tire management strategy, 11 rubber modified asphalt demonstration projects were funded or completed, with 13 additional projects from small to large (1,500-65,000 passenger tire equivalents) approved for the 1993 paving season. This report presents the results of an August to November 1993 study of the 11 demonstration projects. The evaluation included a description of the technology; technical review of the projects; economic analysis; review of the environmental literature; environmental review of the projects; comparison of the projects with similar ones in other jurisdictions; and recommendations. Detailed information on asphalt technology is included in an appendix.

  20. Representativeness elements of an hybrid reactor demonstrator

    International Nuclear Information System (INIS)

    Kerdraon, D.; Billebaud, A.; Brissot, R.; David, S.; Giorni, A.; Heuer, D.; Loiseaux, J.M.; Meplan, O.

    2000-11-01

    This document deals with the quantification of the minimum thermal power level for a demonstrator and the definition of the physical criteria which define the representative character of a demonstrator towards a power reactor. Solutions allowing to keep an acceptable flow in an industrial core, have also been studied. The document is divided in three parts: the representativeness elements, the considered solutions and the characterization of the neutrons flows at the interfaces and the dose rates at the outer surface of the vessel. (A.L.B.)

  1. Environmental management technology demonstration and commercialization

    International Nuclear Information System (INIS)

    Daly, D.J.; Erickson, T.A.; Groenewold, G.H.

    1995-01-01

    The Energy ampersand Environmental Research Center (EERC), a contract-supported organization focused on technology research, development, demonstration, and commercialization (RDD ampersand C), is entering its second year of a Cooperative Agreement with the U.S. Department of Energy (DOE) Morgantown Energy Technology Center (METC) to facilitate the development, demonstration, and commercialization of innovative environmental management (EM) technologies in support of the activities of DOE's Office of Environmental Science and Technology (EM-50) under DOE's EM Program. This paper reviews the concept and approach of the program under the METC-EERC EM Cooperative Agreement and profiles the role the program is playing in the commercialization of five EM technologies

  2. Hanford radiochemical site decommissioning demonstration program

    International Nuclear Information System (INIS)

    Nelson, D.C.

    1971-01-01

    A program is proposed for the innovation, development, and demonstration of technologies necessary to decommission the Hanford radiochemical plant area to the extent that the sites can have unrestricted public access. The five tasks selected for development and demonstration of restoration techniques were restoration of a burial ground, decommissioning of a separations plant, restoration of a separations plant waste interim storage tank farm, restoration of a liquid disposal area, and disposal of large contaminated equipment. Process development requirements are tabulated and discussed. A proposed schedule and estimated costs are given

  3. Platelets retain high levels of active plasminogen activator inhibitor 1.

    Directory of Open Access Journals (Sweden)

    Helén Brogren

    Full Text Available The vascular fibrinolytic system is crucial for spontaneous lysis of blood clots. Plasminogen activator inhibitor 1 (PAI-1, the principal inhibitor of the key fibrinolytic enzyme tissue-type plasminogen activator (tPA, is present in platelets at high concentrations. However, the majority of PAI-1 stored in platelets has been considered to be inactive. Our recent finding (Brogren H, et al. Blood 2004 that PAI-1 de novo synthesized in platelets remained active for over 24 h, suggested that PAI-1 stored in the α-granules might be active to a larger extent than previously reported. To re-evaluate this issue, we performed experiments where the fraction of active PAI-1 was estimated by analyzing the tPA-PAI-1 complex formation. In these experiments platelets were lysed with Triton X-100 in the presence of serial dilutions of tPA and subsequently the tPA-PAI-1 complex was evaluated by Western blot. Also, using a non-immunologic assay, tPA was labeled with (125I, and (125I-tPA and (125I-tPA-PAI-1 was quantified by scintigraphy. Interestingly, both methods demonstrated that the majority (>50% of platelet PAI-1 is active. Further analyses suggested that pre-analytical procedures used in previous studies (sonication or freezing/thawing may have substantially reduced the activity of platelet PAI-1, which has lead to an underestimation of the proportion of active PAI-1. Our in vitro results are more compatible with the role of PAI-1 in clot stabilization as demonstrated in physiological and pathophysiological studies.

  4. Monamine oxidase inhibitors: current and emerging agents for Parkinson disease.

    Science.gov (United States)

    Fernandez, Hubert H; Chen, Jack J

    2007-01-01

    Monoamine oxidase type B (MAO-B) is the predominant isoform responsible for the metabolic breakdown of dopamine in the brain. Selective inhibition of brain MAO-B results in elevation of synaptosomal dopamine concentrations. Data have been reported regarding the selective MAO-B inhibitors, rasagiline and selegiline, for the symptomatic treatment of Parkinson disease (PD). Selegiline has demonstrated efficacy as monotherapy in patients with early PD (Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism study), but evidence of selegiline efficacy as adjunctive treatment in levodopa-treated PD patients with motor fluctuations is equivocal. A new formulation of selegiline (Zydis selegiline) has been evaluated in 2 small, placebo-controlled studies as adjunctive therapy to levodopa. The Zydis formulation allows pregastric absorption of selegiline, minimizing first-pass metabolism, and thereby increasing selegiline bioavailability and reducing the concentration of amphetamine metabolites. Rasagiline is a selective, second-generation, irreversible MAO-B inhibitor, with at least 5 times the potency of selegiline in vitro and in animal models. Rasagiline has demonstrated efficacy in 1 large, randomized, double-blind, placebo-controlled trial (TVP-1012 in Early Monotherapy for Parkinson's Disease Outpatients) as initial monotherapy in patients with early PD, and in 2 large, controlled trials (Parkinson's Rasagiline: Efficacy and Safety in the Treatment of "Off," Lasting Effect in Adjunct Therapy With Rasagiline Given Once Daily) as adjunctive treatment in levodopa-treated PD patients with motor fluctuations. Unlike selegiline, rasagiline is an aminoindan derivative with no amphetamine metabolites. A randomized clinical trial is underway to confirm preclinical and preliminary clinical data suggesting rasagiline has disease-modifying effects.

  5. Cellular growth kinetics distinguish a cyclophilin inhibitor from an HSP90 inhibitor as a selective inhibitor of hepatitis C virus.

    Directory of Open Access Journals (Sweden)

    Rudolf K F Beran

    Full Text Available During antiviral drug discovery, it is critical to distinguish molecules that selectively interrupt viral replication from those that reduce virus replication by adversely affecting host cell viability. In this report we investigate the selectivity of inhibitors of the host chaperone proteins cyclophilin A (CypA and heat-shock protein 90 (HSP90 which have each been reported to inhibit replication of hepatitis C virus (HCV. By comparing the toxicity of the HSP90 inhibitor, 17-(Allylamino-17-demethoxygeldanamycin (17-AAG to two known cytostatic compounds, colchicine and gemcitabine, we provide evidence that 17-AAG exerts its antiviral effects indirectly through slowing cell growth. In contrast, a cyclophilin inhibitor, cyclosporin A (CsA, exhibited selective antiviral activity without slowing cell proliferation. Furthermore, we observed that 17-AAG had little antiviral effect in a non-dividing cell-culture model of HCV replication, while CsA reduced HCV titer by more than two orders of magnitude in the same model. The assays we describe here are useful for discriminating selective antivirals from compounds that indirectly affect virus replication by reducing host cell viability or slowing cell growth.

  6. Demonstrating sustainable energy: A review-based model of sustainable energy demonstration projects

    NARCIS (Netherlands)

    Bossink, Bart

    2017-01-01

    This article develops a model of sustainable energy demonstration projects, based on a review of 229 scientific publications on demonstrations in renewable and sustainable energy. The model addresses the basic organizational characteristics (aim, cooperative form, and physical location) and learning

  7. Understanding Engagement: Science Demonstrations and Emotional Energy

    Science.gov (United States)

    Milne, Catherine; Otieno, Tracey

    2007-01-01

    Although beloved of some chemists and physicists, science demonstrations have been criticized for stifling inquiry and assisting teachers to maintain a power differential between themselves and students in the classroom. This interpretive study reports the unexpected positive learning outcomes for urban science students in two chemistry classes…

  8. Demonstration Experiments with a Stirling Engine.

    Science.gov (United States)

    Deacon, Christopher G.; And Others

    1994-01-01

    Describes an investigation with the primary purpose of allowing students to generate and interpret a pressure/volume diagram of a Stirling engine. Explains how the Stirling engine can be used to demonstrate the principles of operation of a refrigerator and a heat pump. (DDR)

  9. The UK commercial demonstration fast reactor design

    International Nuclear Information System (INIS)

    Holmes, J.A.G.

    1987-01-01

    The paper on the UK Commercial Demonstration Fast Reactor design was presented to the seminar on 'European Commercial Fast Reactor Programme, London 1987. The design is discussed under the topic headings:- primary circuit, intermediate heat exchangers and pumps, fuel and core, refuelling, steam generators, and nuclear island layout. (U.K.)

  10. SMES: Redefining the path to commercial demonstration

    Energy Technology Data Exchange (ETDEWEB)

    Bingham, W.G. [Bechtel, San Francisco, CA (United States); Lighthipe, R.W. [San Diego Gas & Electric, San Diego, CA (United States)

    1994-12-31

    SMES (Superconducting Magnetic Energy Storage) is an emerging technology offering tremendous potential benefits to the utility industry. San Diego Gas & Electric (SDG&E) and Bechtel are leading a team of companies and national laboratories working towards design and construction of the world`s first demonstration facility for large, commercial SMES for enhancing transmission stability in the Southwestern United States.

  11. Computed tomography demonstration of a hypothalamic metastasis

    International Nuclear Information System (INIS)

    Chakeres, D.W.

    1983-01-01

    This case report describes a patient who presented with panhypopituitarism secondary to hypothalamic metastasis. A primary hypothalamic abnormality was suggested by computed tomographic (CT) demonstration of a small enhancing circular mass centered within the hypothalamus. Sellar radiographs and cerebral angiography were normal. (orig.)

  12. Computed tomography demonstration of a hypothalamic metastasis

    Energy Technology Data Exchange (ETDEWEB)

    Chakeres, D.W.

    1983-05-01

    This case report describes a patient who presented with panhypopituitarism secondary to hypothalamic metastasis. A primary hypothalamic abnormality was suggested by computed tomographic (CT) demonstration of a small enhancing circular mass centered within the hypothalamus. Sellar radiographs and cerebral angiography were normal.

  13. Laboratory information system data demonstrate successful ...

    African Journals Online (AJOL)

    The National Health Laboratory Service (NHLS) performs the PCR tests for the public health sector and stores test data in a corporate data warehouse (CDW). Objectives. To demonstrate the utility of laboratory data for monitoring trends in EID coverage and early vertical transmission rates and to describe the scale-up of the ...

  14. Kaolinitic clay-based grouting demonstration

    International Nuclear Information System (INIS)

    McCloskey, A.L.; Barry, C.J.; Wilmoth, R.

    1997-01-01

    An innovative Kaolinitic Clay-Based Grouting Demonstration was performed under the Mine Waste Technology Program (MWTP), funded by the U.S. Environmental Protection Agency (EPA) and jointly administered by the EPA and the U.S. Department of Energy (DOE). The objective of the technology was to demonstrate the effectiveness of kaolinitic clay-based grouting in reducing/eliminating infiltration of surface and shallow groundwater through fractured bedrock into underground mine workings. In 1993, the Mike Horse Mine was selected as a demonstration site for the field implementation and evaluation of the grouting technology. The mine portal discharge ranged between 114 to 454 liters per minute (30 to 120 gpm) of water containing iron, zinc, manganese, and cadmium at levels exceeding the National Drinking Water Maximum Contaminant Levels. The grout formulation was designed by the developer Morrison Knudsen Corporation/Spetstamponazhgeologia (MK/STG), in May 1994. Grout injection was performed by Hayward Baker, Inc. under the directive of MSE Technology Applications, Inc. (MSE-TA) during fall of 1994. The grout was injected into directionally-drilled grout holes to form a grout curtain at the project site. Post grout observations suggest the grout was successful in reducing the infiltration of the surface and shallow groundwater from entering the underground mine workings. The proceeding paper describes the demonstration and technology used to form the subsurface barrier in the fracture system

  15. Technology Tips: Building Interactive Demonstrations with Sage

    Science.gov (United States)

    Murray, Maura

    2013-01-01

    Sage is an open-source software package that can be used in many different areas of mathematics, ranging from algebra to calculus and beyond. One of the most exciting pedagogical features of Sage (http://www.sagemath.org) is its ability to create interacts--interactive examples that can be used in a classroom demonstration or by students in a…

  16. A Demonstration of Approach and Avoidance Conflicts

    Science.gov (United States)

    Terry, W. Scott

    2010-01-01

    Choosing between 2 unpleasant alternatives (Would you rather be less intelligent or less attractive?) is more difficult than choosing between two desirable options (Would you rather be more intelligent or more attractive?). Here I describe a classroom demonstration of avoidance-avoidance conflicts. Students make a series of approach-approach and…

  17. SMES: Redefining the path to commerical demonstration

    Science.gov (United States)

    Bingham, W. G.; Lighthipe, R. W.

    1995-01-01

    SMES (Superconducting Magnetic Energy Storage) is an emerging technology offering tremendous potential benefits to the utility industry. San Diego Gas & Electric (SDG&E) and Bechtel are leading a team of companies and national laboratories working towards design and construction of the world's first demonstration facility for large, commercial SMES for enhancing transmission stability in the Southwestern United States.

  18. SMES: Redefining the path to commercial demonstration

    International Nuclear Information System (INIS)

    Bingham, W.G.; Lighthipe, R.W.

    1994-01-01

    SMES (Superconducting Magnetic Energy Storage) is an emerging technology offering tremendous potential benefits to the utility industry. San Diego Gas ampersand Electric (SDG ampersand E) and Bechtel are leading a team of companies and national laboratories working towards design and construction of the world's first demonstration facility for large, commercial SMES for enhancing transmission stability in the Southwestern United States

  19. Experiments to Demonstrate Piezoelectric and Pyroelectric Effects

    Science.gov (United States)

    Erhart, Jirí

    2013-01-01

    Piezoelectric and pyroelectric materials are used in many current applications. The purpose of this paper is to explain the basic properties of pyroelectric and piezoelectric effects and demonstrate them in simple experiments. Pyroelectricity is presented on lead zirconium titanate (PZT) ceramics as an electric charge generated by the temperature…

  20. Demonstration model of LEP bending magnet

    CERN Multimedia

    CERN PhotoLab

    1981-01-01

    To save iron and raise the flux density, the LEP bending magnet laminations were separated by spacers and the space between the laminations was filled with concrete. This is a demonstration model, part of it with the spaced laminations only, the other part filled with concrete.