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Sample records for model systems inhibition

  1. Ordering kinetics in model systems with inhibited interfacial adsorption

    DEFF Research Database (Denmark)

    Willart, J.-F.; Mouritsen, Ole G.; Naudts, J.

    1992-01-01

    . The results are related to experimental work on ordering processes in orientational glasses. It is suggested that the experimental observation of very slow ordering kinetics in, e.g., glassy crystals of cyanoadamantane may be a consequence of low-temperature activated processes which ultimately lead......The ordering kinetics in two-dimensional Ising-like spin moels with inhibited interfacial adsorption are studied by computer-simulation calculations. The inhibited interfacial adsorption is modeled by a particular interfacial adsorption condition on the structure of the domain wall between......, of the algebraic growth law, R(t)∼Atn, whereas the growth exponent, n, remains close to the value n=1/2 predicted by the classical Lifshitz-Allen-Cahn growth law for systems with nonconserved order parameter. At very low temperatures there is, however, an effective crossover to a much slower algebraic growth...

  2. Kinetic models for nitrogen inhibition in ANAMMOX and nitrification process on deammonification system at room temperature.

    Science.gov (United States)

    De Prá, Marina C; Kunz, Airton; Bortoli, Marcelo; Scussiato, Lucas A; Coldebella, Arlei; Vanotti, Matias; Soares, Hugo M

    2016-02-01

    In this study were fitted the best kinetic model for nitrogen removal inhibition by ammonium and/or nitrite in three different nitrogen removal systems operated at 25 °C: a nitrifying system (NF) containing only ammonia oxidizing bacteria (AOB), an ANAMMOX system (AMX) containing only ANAMMOX bacteria, and a deammonification system (DMX) containing both AOB and ANAMMOX bacteria. NF system showed inhibition by ammonium and was best described by Andrews model. The AMX system showed a strong inhibition by nitrite and Edwards model presented a best system representation. For DMX system, the increased substrate concentration (until 1060 mg NH3-N/L) tested was not limiting for the ammonia consumption rate and the Monod model was the best model to describe this process. The AOB and ANAMMOX sludges combined in the DMX system displayed a better activity, substrate affinity and excellent substrate tolerance than in nitrifying and ANAMMOX process. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Formation and Inhibition of Nε-(Carboxymethyllysine in Saccharide-Lysine Model Systems during Microwave Heating

    Directory of Open Access Journals (Sweden)

    Bing Li

    2012-10-01

    Full Text Available  Nε-(carboxymethyl lysine (CML is the most abundant advanced glycation end product (AGE, and frequently selected as an AGEs marker in laboratory studies. In this paper, the formation and inhibition of Nε-(carboxymethyllysine in saccharide-lysine model systems during microwave heating have been studied. The microwave heating treatment significantly promoted the formation of CML during Maillard reactions, which was related to the reaction temperature, time and type of saccharide. The order of CML formation for different saccharides was lactose > glucose > sucrose. Then, the inhibition effect on CML by five inhibitors was further examined. According to the results, ascorbic acid and tocopherol did not affect inhibition of CML, in contrast, thiamin, rutin and quercetin inhibited CML formation, and the inhibitory effects were concentration dependent.

  4. A Systems Biology Framework for Modeling Metabolic Enzyme Inhibition of Mycobacterium Tuberculosis

    Science.gov (United States)

    2009-09-15

    parameters, and group IV included those that, by definition , were directly determined once the other parameters were defined. During the sensitivity...III parameters were assumed to be related to the parameters of the first two groups; and group IV parameters are, by definition , determined once the...population growth model are described below. sAMS inhibition model sAMS inhibits the enzyme salicyl -AMP ligase (MbtA; encoded by the gene Rv2384) that

  5. Systemic EP4 Inhibition Increases Adhesion Formation in a Murine Model of Flexor Tendon Repair.

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    Michael B Geary

    Full Text Available Flexor tendon injuries are a common clinical problem, and repairs are frequently complicated by post-operative adhesions forming between the tendon and surrounding soft tissue. Prostaglandin E2 and the EP4 receptor have been implicated in this process following tendon injury; thus, we hypothesized that inhibiting EP4 after tendon injury would attenuate adhesion formation. A model of flexor tendon laceration and repair was utilized in C57BL/6J female mice to evaluate the effects of EP4 inhibition on adhesion formation and matrix deposition during flexor tendon repair. Systemic EP4 antagonist or vehicle control was given by intraperitoneal injection during the late proliferative phase of healing, and outcomes were analyzed for range of motion, biomechanics, histology, and genetic changes. Repairs treated with an EP4 antagonist demonstrated significant decreases in range of motion with increased resistance to gliding within the first three weeks after injury, suggesting greater adhesion formation. Histologic analysis of the repair site revealed a more robust granulation zone in the EP4 antagonist treated repairs, with early polarization for type III collagen by picrosirius red staining, findings consistent with functional outcomes. RT-PCR analysis demonstrated accelerated peaks in F4/80 and type III collagen (Col3a1 expression in the antagonist group, along with decreases in type I collagen (Col1a1. Mmp9 expression was significantly increased after discontinuing the antagonist, consistent with its role in mediating adhesion formation. Mmp2, which contributes to repair site remodeling, increases steadily between 10 and 28 days post-repair in the EP4 antagonist group, consistent with the increased matrix and granulation zones requiring remodeling in these repairs. These findings suggest that systemic EP4 antagonism leads to increased adhesion formation and matrix deposition during flexor tendon healing. Counter to our hypothesis that EP4 antagonism

  6. Vanadium(V) complexes in enzyme systems: aqueous chemistry, inhibition and molecular modeling in inhibitor design.

    Science.gov (United States)

    Bhattacharyya, S; Tracey, A S

    2001-05-01

    Vanadate in aqueous solution is known to influence a number of enzyme-catalyzed reactions. Such effects are well known to carry over to living systems where numerous responses to the influence of vanadium have been well-documented; perhaps the most studied being the insulin-mimetic effect. Studies of the aqueous chemistry of vanadate provide an insight into the mechanisms by which vanadate affects enzyme systems and suggests methods for the elucidation of specific types of responses. Studies of the corresponding enzymes provide complementary information that suggests model vanadate systems be studied and provides clues as to functional groups that might be utilized in the development of selective enzyme inhibition. The insulin-mimetic effect is thought by many workers to originate in the effectiveness of vanadium as an inhibitor of protein tyrosine phosphatase (PTPase) activity. One, or more PTPases regulate the phosphotyrosine levels of the insulin receptor kinase domain. Appropriate ligands allow modification of the reactivity and function of vanadate. For instance, although the complex, ((CH(3))(2)NO)(2)V(O)OH, is not quite as good an inhibitor of PTPase activity as is vanadate, it is much more effective in cell cultures for increasing glucose transport and glycogen synthesis. Studies of the chemistry of this complex provide an explanation of the efficacy of this compound as a PTPase inhibitor that is supported by computer modeling studies. Computer calculations using X-ray data of known PTPases as a basis for homology modeling then suggests functionality that needs to be addressed in developing selective PTPase inhibitors.

  7. Combined targeting of Raf and Mek synergistically inhibits tumorigenesis in triple negative breast cancer model systems.

    Science.gov (United States)

    Nagaria, Teddy S; Shi, Changnian; Leduc, Charles; Hoskin, Victoria; Sikdar, Soma; Sangrar, Waheed; Greer, Peter A

    2017-10-06

    Aberrant Ras-MAPK signaling from receptor tyrosine kinases (RTKs), including epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2), is a hallmark of triple negative breast cancer (TNBC); thus providing rationale for targeting the Ras-MAPK pathway. Components of this EGFR/HER2-Ras-Raf-Mek-Erk pathway were co-targeted in the MDA-MB-231 and MDA-MB-468 human TNBC cell lines, and in vitro effects on signaling and cytotoxicity, as well as in vivo effects on xenograft tumor growth and metastasis were assessed. The dual EGFR/HER2 inhibitor lapatinib (LPN) displayed greater cytotoxic potency and MAPK signaling inhibition than the EGFR inhibitor erlotinib, suggesting both EGFR and HER2 contribute to MAPK signaling in this TNBC model. The Raf inhibitor sorafenib (SFN) or the Mek inhibitor U0126 suppressed MAPK signaling to a greater extent than LPN; which correlated with greater cytotoxic potency of SFN, but not U0126. However, U0126 potentiated the cytotoxic efficacy of LPN and SFN in an additive and synergistic manner, respectively. This in-series Raf-Mek co-targeting synergy was recapitulated in orthotopic mouse xenografts, where SFN and the Mek inhibitor selumitinib (AZD6244) inhibited primary tumor growth and pulmonary metastasis. Raf and Mek co-inhibition exhibits synergy in TNBC models and represent a promising combination therapy for this aggressive breast cancer type.

  8. A systems biology framework for modeling metabolic enzyme inhibition of Mycobacterium tuberculosis

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    Reifman Jaques

    2009-09-01

    Full Text Available Abstract Background Because metabolism is fundamental in sustaining microbial life, drugs that target pathogen-specific metabolic enzymes and pathways can be very effective. In particular, the metabolic challenges faced by intracellular pathogens, such as Mycobacterium tuberculosis, residing in the infected host provide novel opportunities for therapeutic intervention. Results We developed a mathematical framework to simulate the effects on the growth of a pathogen when enzymes in its metabolic pathways are inhibited. Combining detailed models of enzyme kinetics, a complete metabolic network description as modeled by flux balance analysis, and a dynamic cell population growth model, we quantitatively modeled and predicted the dose-response of the 3-nitropropionate inhibitor on the growth of M. tuberculosis in a medium whose carbon source was restricted to fatty acids, and that of the 5'-O-(N-salicylsulfamoyl adenosine inhibitor in a medium with low-iron concentration. Conclusion The predicted results quantitatively reproduced the experimentally measured dose-response curves, ranging over three orders of magnitude in inhibitor concentration. Thus, by allowing for detailed specifications of the underlying enzymatic kinetics, metabolic reactions/constraints, and growth media, our model captured the essential chemical and biological factors that determine the effects of drug inhibition on in vitro growth of M. tuberculosis cells.

  9. Combined Inhibition of C5 and CD14 Attenuates Systemic Inflammation in a Piglet Model of Meconium Aspiration Syndrome.

    Science.gov (United States)

    Thomas, Anub Mathew; Schjalm, Camilla; Nilsson, Per H; Lindenskov, Paal H H; Rørtveit, Runa; Solberg, Rønnaug; Saugstad, Ola Didrik; Berglund, Magnus M; Strömberg, Patrik; Lau, Corinna; Espevik, Terje; Jansen, Johan Høgset; Castellheim, Albert; Mollnes, Tom Eirik; Barratt-Due, Andreas

    2018-02-27

    Meconium aspiration syndrome (MAS) is a severe lung condition affecting newborns and it can lead to a systemic inflammatory response. We previously documented complement activation and cytokine release in a piglet MAS model. Additionally, we showed ex vivo that meconium-induced inflammation was dependent on complement and Toll-like receptors. To assess the efficacy of the combined inhibition of complement (C5) and CD14 on systemic inflammation induced in a forceful piglet MAS model. Thirty piglets were randomly allocated to a treatment group receiving the C5-inhibitor SOBI002 and anti-CD14 (n = 15) and a nontreated control group (n = 15). MAS was induced by intratracheal meconium instillation, and the piglets were observed for 5 h. Complement, cytokines, and myeloperoxidase (MPO) were measured by ELISA. SOBI002 ablated C5 activity and the formation of the terminal complement complex in vivo. The combined inhibition attenuated the inflammasome cytokines IL-1β and IL-6 by 60 (p = 0.029) and 44% (p = 0.01), respectively, and also MPO activity in the bronchoalveolar fluid by 42% (p = 0.017). Ex vivo experiments in human blood revealed that the combined regimen attenuated meconium-induced MPO release by 64% (p = 0.008), but there was only a negligible effect with single inhibition, indicating a synergic cross-talk between the key molecules C5 and CD14. Combined inhibition of C5 and CD14 attenuates meconium-induced inflammation in vivo and this could become a future therapeutic regimen for MAS. © 2018 The Author(s) Published by S. Karger AG, Basel.

  10. Egg white hydrolysate inhibits oxidation in mayonnaise and a model system.

    Science.gov (United States)

    Kobayashi, Hideaki; Sasahara, Ryou; Yoda, Shoichi; Kotake-Nara, Eiichi

    2017-06-01

    The flavor deterioration of mayonnaise is induced by iron, which is released from egg yolk phosvitin under acidic conditions and promotes lipid oxidation. To prevent oxidative deterioration, natural components, rather than synthetic chemicals such as ethylenediaminetetraacetic acid have been required by consumers. In the present study, we evaluated the inhibitory effects of three egg white components with the same amino acid composition, namely egg white protein, hydrolysate, and the amino acid mixture, on lipid oxidation in mayonnaise and an acidic egg yolk solution as a model system. We found that the hydrolysate had the strongest inhibitory effect on lipid oxidation among the three components. The mechanism underlying the antioxidant effect was associated with Fe 2+ -chelating activity. Thus, egg white hydrolysate may have the potential as natural inhibitors of lipid oxidation in mayonnaise.

  11. Faox enzymes inhibited Maillard reaction development during storage both in protein glucose model system and low lactose UHT milk.

    Science.gov (United States)

    Troise, Antonio Dario; Dathan, Nina A; Fiore, Alberto; Roviello, Giovanni; Di Fiore, Anna; Caira, Simonetta; Cuollo, Marina; De Simone, Giuseppina; Fogliano, Vincenzo; Monti, Simona M

    2014-02-01

    Fructosamines, also known as Amadori products, are formed by the condensation of glucose with the amino group of amino acids or proteins. These compounds are precursors of advanced glycation end products (AGEs) that can be formed either endogenously during aging and diabetes, and exogenously in heat-processed food. The negative effects of dietary AGEs on human health as well as their negative impact on the quality of dairy products have been widely described, therefore specific tools able to prevent the formation of glycation products are needed. Two fructosamine oxidase enzymes isolated from Aspergillus sp. namely, Faox I and Faox II catalyze the oxidative deglycation of Amadori products representing a potential tool for inhibiting the Maillard reaction in dairy products. In this paper, the ability of recombinant Faox I and II in limiting the formation of carboxy-methyl lysine (CML) and protein-bound hydroxymethyl furfurol (b-HMF) in a commercial UHT low lactose milk and a beta-lactoglobulin (β-LG) glucose model system was investigated. Results show a consistent reduction of CML and b-HMF under all conditions. Faox effects were particularly evident on b-HMF formation in low lactose commercial milk. Peptide analysis of the β-LG glucose system identified some peptides, derived from cyanogen bromide hydrolysis, as suitable candidates to monitor Faox action in milk-based products. All in all data suggested that non-enzymatic reactions in dairy products might be strongly reduced by implementing Faox enzymes.

  12. Inhibition of melanosome transfer from melanocytes to keratinocytes by lectins and neoglycoproteins in an in vitro model system.

    Science.gov (United States)

    Minwalla, L; Zhao, Y; Cornelius, J; Babcock, G F; Wickett, R R; Le Poole, I C; Boissy, R E

    2001-06-01

    We propose that some of the critical molecules involved in the transfer of melanosomes from melanocytes to keratinocytes include plasma membrane lectins and their glycoconjugates. To investigate this mechanism, co-cultures of human melanocytes and keratinocytes derived from neonatal foreskins were established. The process of melanosome transfer was assessed by two experimental procedures. The first involved labeling melanocyte cultures with the fluorochrome CFDA. Labeled melanocytes were subsequently co-cultured with keratinocytes, and the transfer of fluorochrome assessed visually by confocal microscopy and quantitatively by flow cytometry. The second investigative approach involved co-culturing melanocytes with keratinocytes, and processing the co-cultures after 3 days for electron microscopy to quantitate the numbers of melanosomes in keratinocytes. Results from these experimental approaches indicate significant transfer of dye or melanosomes from melanocytes to keratinocytes that increased with time of co-culturing. Using these model systems, we subsequently tested a battery of lectins and neoglycoproteins for their effect in melanosome transfer. Addition of these selected molecules to co-cultures inhibited transfer of fluorochrome by approximately 15-44% as assessed by flow cytometry, and of melanosomes by 67-93% as assessed by electron microscopy. Therefore, our results suggest the roles of selected lectins and glycoproteins in melanosome transfer to keratinocytes in the skin.

  13. The Inhibition of Maillard Browning by Different Concentrations of Rosmarinic Acid and Epigallocatechin-3-Gallate in Model, Bakery, and Fruit Systems.

    Science.gov (United States)

    Favreau-Farhadi, Nicole; Pecukonis, Lauren; Barrett, Ann

    2015-10-01

    Rosmarinic acid and Epigallocatechin gallate concentrations were studied as natural inhibitors of Maillard browning in glucose/glycine model systems, and in bakery rolls and applesauce. The concentrations of the inhibitors were varied to determine the highest level of inhibition without a pro-oxidant/browning effect. UV absorbance and gas chromatography/mass spec (GC/MS) with solid phase microextraction (SPME) sampling was used to study browning in the model systems. Hunter L*, a*, b* was used to analyze the color change results of the inhibitors on applesauce and bakery rolls. It was determined that a 1.0% solution of either antioxidant in the glucose/glycine system produced the greatest inhibition and a synergistic effect was not apparent when the two were combined. Inhibition of browning and a lack of synergy between the antioxidants were also determined in food systems consisting of applesauce and bakery rolls. GC/MS analysis of the model system revealed a high level of pyrazine formation in no-inhibitor control samples and the absence of pyrazines in inhibitor-containing samples. Natural browning inhibitors, that is Rosmarinic acid and Epigallocatechin gallate, can be added to food items to inhibit browning over a prolonged period of storage in order to increase product shelf stability. The concentrations of the inhibitors require optimization since a pro-oxidant effect and increased browning will occur at high levels. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

  14. Optimal Decision Making in Neural Inhibition Models

    Science.gov (United States)

    van Ravenzwaaij, Don; van der Maas, Han L. J.; Wagenmakers, Eric-Jan

    2012-01-01

    In their influential "Psychological Review" article, Bogacz, Brown, Moehlis, Holmes, and Cohen (2006) discussed optimal decision making as accomplished by the drift diffusion model (DDM). The authors showed that neural inhibition models, such as the leaky competing accumulator model (LCA) and the feedforward inhibition model (FFI), can mimic the…

  15. Optimal decision making in neural inhibition models

    NARCIS (Netherlands)

    van Ravenzwaaij, D.; van der Maas, H.L.J.; Wagenmakers, E.-J.

    2012-01-01

    In their influential Psychological Review article, Bogacz, Brown, Moehlis, Holmes, and Cohen (2006) discussed optimal decision making as accomplished by the drift diffusion model (DDM). The authors showed that neural inhibition models, such as the leaky competing accumulator model (LCA) and the

  16. Membrane fusion activity of Semliki forest virus in a liposomal model system : Specific inhibition by Zn2+ ions

    NARCIS (Netherlands)

    Corver, J; Snippe, H; Kraaijeveld, C; Wilschut, J

    1997-01-01

    Semliki Forest virus (SFV) has been shown previously to fuse efficiently with cholesterol-and sphingolipid-containing liposomal model membranes in a low-pH-dependent manner. Several steps can be distinguished in this process, including low-pH-induced irreversible binding of the virus to the

  17. Single systemic administration of Ag85B of mycobacteria DNA inhibits allergic airway inflammation in a mouse model of asthma

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    Karamatsu K

    2012-12-01

    Full Text Available Katsuo Karamatsu,1,2 Kazuhiro Matsuo,3 Hiroyasu Inada,4 Yusuke Tsujimura,1 Yumiko Shiogama,1,2 Akihiro Matsubara,1,2 Mitsuo Kawano,5 Yasuhiro Yasutomi1,21Laboratory of Immunoregulation and Vaccine Research, Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Tsukuba, 2Division of Immunoregulation, Department of Molecular and Experimental Medicine, Mie University Graduate School of Medicine, Tsu, 3Department of Research and Development, Japan BCG Laboratory, Tokyo, 4Department of Pathology, Suzuka University of Medical Science, Suzuka, 5Department of Microbiology and Molecular Genetics, Mie University Graduate School of Medicine, Tsu, JapanAbstract: The immune responses of T-helper (Th and T-regulatory cells are thought to play a crucial role in the pathogenesis of allergic airway inflammation observed in asthma. The correction of immune response by these cells should be considered in the prevention and treatment of asthma. Native antigen 85B (Ag85B of mycobacteria, which cross-reacts among mycobacteria species, may play an important biological role in host–pathogen interaction since it elicits various immune responses by activation of Th cells. The current study investigated the antiallergic inflammatory effects of DNA administration of Ag85B from Mycobacterium kansasii in a mouse model of asthma. Immunization of BALB/c mice with alum-adsorbed ovalbumin followed by aspiration with aerosolized ovalbumin resulted in the development of allergic airway inflammation. Administration of Ag85B DNA before the aerosolized ovalbumin challenge protected the mice from subsequent induction of allergic airway inflammation. Serum and bronchoalveolar lavage immunoglobulin E levels, extent of eosinophil infiltration, and levels of Th2-type cytokines in Ag85B DNA-administered mice were significantly lower than those in control plasmid-immunized mice, and levels of Th1- and T-regulatory-type cytokines were enhanced by Ag85B

  18. Inhibition in speed and concentration tests: The Poisson inhibition model

    NARCIS (Netherlands)

    Smit, J.C.; Ven, A.H.G.S. van der

    1995-01-01

    A new model is presented to account for the reaction time fluctuations in concentration tests. The model is a natural generalization of an earlier model, the so-called Poisson-Erlang model, published by Pieters & van der Ven (1982). First, a description is given of the type of tasks for which the

  19. Evaluation of fish models of soluble epoxide hydrolase inhibition.

    OpenAIRE

    Newman, J W; Denton, D L; Morisseau, C; Koger, C S; Wheelock, C E; Hinton, D E; Hammock, B D

    2001-01-01

    Substituted ureas and carbamates are mechanistic inhibitors of the soluble epoxide hydrolase (sEH). We screened a set of chemicals containing these functionalities in larval fathead minnow (Pimphales promelas) and embryo/larval golden medaka (Oryzias latipes) models to evaluate the utility of these systems for investigating sEH inhibition in vivo. Both fathead minnow and medaka sEHs were functionally similar to the tested mammalian orthologs (murine and human) with respect to substrate hydrol...

  20. Inhibition of 2-Amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP) Formation by Alkoxy Radical Scavenging of Flavonoids and Their Quantitative Structure-Activity Relationship in a Model System.

    Science.gov (United States)

    Yu, Chundi; Shao, Zeping; Liu, Bing; Zhang, Yan; Wang, Shuo

    2016-08-01

    The inhibitory effect of 10 flavonoids on the formation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in a creatinine-phenylalanine model system was investigated through electronic spin resonance and a quantitative structure-activity relationship. Alkoxy radicals were observed during the heating process, providing evidence for a radical pathway in the formation of PhIP. The alkoxy radical scavenging capability of the flavonoids was proportional to their inhibition of PhIP formation (IC50 ). We deduced that flavonoid inhibition of PhIP generation occurs via scavenging of alkoxy radicals during the heating process. Multiple linear regression and partial least squares models were used to elucidate the relationship between PhIP inhibition activity and structure characteristics of the flavonoids. The lipo-hydro partition coefficient and molecular fractional polar surface area of the flavonoids were found to be predictive of the inhibition effect. © 2016 Institute of Food Technologists®

  1. Evaluation of fish models of soluble epoxide hydrolase inhibition.

    Science.gov (United States)

    Newman, J W; Denton, D L; Morisseau, C; Koger, C S; Wheelock, C E; Hinton, D E; Hammock, B D

    2001-01-01

    Substituted ureas and carbamates are mechanistic inhibitors of the soluble epoxide hydrolase (sEH). We screened a set of chemicals containing these functionalities in larval fathead minnow (Pimphales promelas) and embryo/larval golden medaka (Oryzias latipes) models to evaluate the utility of these systems for investigating sEH inhibition in vivo. Both fathead minnow and medaka sEHs were functionally similar to the tested mammalian orthologs (murine and human) with respect to substrate hydrolysis and inhibitor susceptibility. Low lethality was observed in either larval or embryonic fish exposed to diuron [N-(3,4-dichlorophenyl), N'-dimethyl urea], desmethyl diuron [N-(3,4-dichlorophenyl), N'-methyl urea], or siduron [N-(1-methylcyclohexyl), N'-phenyl urea]. Dose-dependent inhibition of sEH was a sublethal effect of substituted urea exposure with the potency of siduron diuron = diuron, differing from the observed in vitro sEH inhibition potency of siduron > desmethyl diuron > diuron. Further, siduron exposure synergized the toxicity of trans-stilbene oxide in fathead minnows. Medaka embryos exposed to diuron, desmethyl diuron, or siduron displayed dose-dependent delays in hatch, and elevated concentrations of diuron and desmethyl diuron produced developmental toxicity. The dose-dependent toxicity and in vivo sEH inhibition correlated, suggesting a potential, albeit undefined, relationship between these factors. Additionally, the observed inversion of in vitro to in vivo potency suggests that these fish models may provide tools for investigating the in vivo stability of in vitro inhibitors while screening for untoward effects. PMID:11171526

  2. An antisense peptide nucleic acid against Pseudomonas aeruginosa inhibiting bacterial-induced inflammatory responses in the cystic fibrosis IB3-1 cellular model system

    DEFF Research Database (Denmark)

    Montagner, Giulia; Bezzerri, Valentino; Cabrini, Giulio

    2017-01-01

    of the essential acpP gene of P. aeruginosa, and previously shown to inhibit bacterial growth, concomitantly also strongly inhibits induced up-regulation of the pro-inflammatory markers IL-8, IL-6, G-CSF, IFN-γ, IP-10, MCP-1 and TNF-α in IB3-1 cystic fibrosis cells infected by P. aeruginosa PAO1. Remarkably...... are significant considering the key role of this protein in the cystic fibrosis inflammatory process exacerbated by P. aeruginosa infection....

  3. Inhibition of bcl-2 and cox-2 Protein Expression after Local Application of a New Carmustine-Loaded Clinoptilolite-Based Delivery System in a Chemically Induced Skin Cancer Model in Mice

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    Cristina Mihaela Ghiciuc

    2017-11-01

    Full Text Available Our research has focused on in vitro and in vivo evaluations of a new Carmustine (BCNU-loaded clinoptilolite-based delivery system. Two clinoptilolite ionic forms—hydrogen form (HCLI and sodium form (NaCLI—were prepared, allowing a loading degree of about 5–6 mg BCNU/g of zeolite matrix due to the dual porous feature of clinoptilolite. Clinoptilolite-based delivery systems released 35.23% of the load in 12 h for the BCNU@HCLI system and only 10.82% for the BCNU@NaCLI system. The BCNU@HCLI system was chosen to develop gel and cream semisolid dosage forms. The cream (C_BCNU@HCLI released 29.6% of the loaded BCNU after 12 h in the Nylon synthetic membrane test and 31.6% in the collagen membrane test, higher by comparison to the gel. The new cream was evaluated in vivo in a chemically induced model of skin cancer in mice. Quantitative immunohistochemistry analysis showed stronger inhibition of B-cell lymphoma-2 (bcl-2 and cyclooxygenase 2 (cox-2 protein expression, known markers for cancer survival and aggressiveness, after the treatment with C_BCNU@HCLI by comparison to all the control treatment types, including an off-label magistral formula commercially available Carmustine cream as reference, bringing evidence that a clinoptilolite-based delivery systems could be used as a cancer drug carriers and controlled release systems (skin-targeted topical delivery systems.

  4. Loss Aversion and Inhibition in Dynamical Models of Multialternative Choice

    Science.gov (United States)

    Usher, Marius; McClelland, James L.

    2004-01-01

    The roles of loss aversion and inhibition among alternatives are examined in models of the similarity, compromise, and attraction effects that arise in choices among 3 alternatives differing on 2 attributes. R. M. Roe, J. R. Busemeyer, and J. T. Townsend (2001) have proposed a linear model in which effects previously attributed to loss aversion…

  5. Mathematical models for sleep-wake dynamics: comparison of the two-process model and a mutual inhibition neuronal model.

    Directory of Open Access Journals (Sweden)

    Anne C Skeldon

    Full Text Available Sleep is essential for the maintenance of the brain and the body, yet many features of sleep are poorly understood and mathematical models are an important tool for probing proposed biological mechanisms. The most well-known mathematical model of sleep regulation, the two-process model, models the sleep-wake cycle by two oscillators: a circadian oscillator and a homeostatic oscillator. An alternative, more recent, model considers the mutual inhibition of sleep promoting neurons and the ascending arousal system regulated by homeostatic and circadian processes. Here we show there are fundamental similarities between these two models. The implications are illustrated with two important sleep-wake phenomena. Firstly, we show that in the two-process model, transitions between different numbers of daily sleep episodes can be classified as grazing bifurcations. This provides the theoretical underpinning for numerical results showing that the sleep patterns of many mammals can be explained by the mutual inhibition model. Secondly, we show that when sleep deprivation disrupts the sleep-wake cycle, ostensibly different measures of sleepiness in the two models are closely related. The demonstration of the mathematical similarities of the two models is valuable because not only does it allow some features of the two-process model to be interpreted physiologically but it also means that knowledge gained from study of the two-process model can be used to inform understanding of the behaviour of the mutual inhibition model. This is important because the mutual inhibition model and its extensions are increasingly being used as a tool to understand a diverse range of sleep-wake phenomena such as the design of optimal shift-patterns, yet the values it uses for parameters associated with the circadian and homeostatic processes are very different from those that have been experimentally measured in the context of the two-process model.

  6. A QSAR Model for Thyroperoxidase Inhibition and Screening ...

    Science.gov (United States)

    Thyroid hormones (THs) are critical modulators of a wide range of biological processes from neurodevelopment to metabolism. Well regulated levels of THs are critical during development and even moderate changes in maternal or fetal TH levels produce irreversible neurological deficits in children. The enzyme thyroperoxidase (TPO) plays a key role in the synthesis of THs. Inhibition of TPO by xenobiotics leads to decreased TH synthesis and, depending on the degree of synthesis inhibition, may result in adverse developmental outcomes. Recently, a high-throughput screening assay for TPO inhibition (AUR-TPO) was developed and used to screen the ToxCast Phase I and II chemicals. In the present study, we used the results from the AUR-TPO screening to develop a Quantitative Structure-Activity Relationship (QSAR) model for TPO inhibition in Leadscope®. The training set consisted of 898 discrete organic chemicals: 134 positive and 764 negative for TPO inhibition. A 10 times two-fold 50% cross-validation of the model was performed, yielding a balanced accuracy of 78.7% within its defined applicability domain. More recently, an additional ~800 chemicals from the US EPA Endocrine Disruption Screening Program (EDSP21) were screened using the AUR-TPO assay. This data was used for external validation of the QSAR model, demonstrating a balanced accuracy of 85.7% within its applicability domain. Overall, the cross- and external validations indicate a model with a high predictiv

  7. Solidago canadensis L essential oil vapor effectively inhibits Botrytis cinerea growth and preserves postharvest quality of strawberry as a food model system

    Directory of Open Access Journals (Sweden)

    Shumin Liu

    2016-08-01

    Full Text Available This study investigated the anti-fungal properties of Solidago canadensis L essential oil (SCLEO against Botrytis cinerea in vitro, and its ability to control gray mold and maintain quality in strawberry fruits. SCLEO exhibited dose-dependent antifungal activity against B. cinerea and profoundly altered mycelial morphology, cellular ultrastructure, and membrane permeability as evaluated by scanning electron microscopy, transmission electron microscopy, and fluorescence microscopy. SCLEO vapor at 0.1 mL/L maintained higher sensory acceptance and reduced decay of fresh strawberry fruit, and also reduced gray mold in artificially inoculated fruit. SCLEO treatment did not however, stimulate phenylalanin ammonia-lyase (PAL, polyphenol oxidase (POD, or chitinase (CHI, enzymes related to disease resistance. This suggests that SCLEO reduces gray mold by direct inhibition of pathogen growth. SCLEO vapor may provide a new and effective strategy for controlling postharvest disease and maintaining quality in strawberries.

  8. Solidago canadensis L. Essential Oil Vapor Effectively Inhibits Botrytis cinerea Growth and Preserves Postharvest Quality of Strawberry as a Food Model System.

    Science.gov (United States)

    Liu, Shumin; Shao, Xingfeng; Wei, Yanzhen; Li, Yonghua; Xu, Feng; Wang, Hongfei

    2016-01-01

    This study investigated the anti-fungal properties of Solidago canadensis L. essential oil (SCLEO) against Botrytis cinerea in vitro, and its ability to control gray mold and maintain quality in strawberry fruits. SCLEO exhibited dose-dependent antifungal activity against B. cinerea and profoundly altered mycelial morphology, cellular ultrastructure, and membrane permeability as evaluated by scanning electron microscopy, transmission electron microscopy, and fluorescence microscopy. SCLEO vapor at 0.1 mL/L maintained higher sensory acceptance and reduced decay of fresh strawberry fruit, and also reduced gray mold in artificially inoculated fruit. SCLEO treatment did not, however, stimulate phenylalanin ammonia-lyase, polyphenol oxidase, or chitinase, enzymes related to disease resistance. This suggests that SCLEO reduces gray mold by direct inhibition of pathogen growth. SCLEO vapor may provide a new and effective strategy for controlling postharvest disease and maintaining quality in strawberries.

  9. Task Inhibition and Response Inhibition in Older versus Younger Adults: A Diffusion Model Analysis

    Directory of Open Access Journals (Sweden)

    Stefanie Schuch

    2016-11-01

    Full Text Available Differences in inhibitory ability between older (64-79 years, N=24 and younger adults (18-26 years, N =24 were investigated using a diffusion model analysis. Participants performed a task-switching paradigm that allows assessing n-2 task repetition costs, reflecting inhibitory control on the level of tasks, as well as n-1 response-repetition costs, reflecting inhibitory control on the level of responses. N-2 task repetition costs were of similar size in both age groups. Diffusion model analysis revealed that for both younger and older adults, drift rate parameters were smaller in the inhibition condition relative to the control condition, consistent with the idea that persisting task inhibition slows down response selection. Moreover, there was preliminary evidence for task inhibition effects in threshold separation and non-decision time in the older, but not the younger adults, suggesting that older adults might apply different strategies when dealing with persisting task inhibition. N-1 response-repetition costs in mean RT tended to be larger in older than younger adults, but in mean error rates were larger in younger than older adults. Diffusion-model analysis revealed longer non-decision times in response repetitions than response switches in both age groups, consistent with the idea that motor processes take longer in response repetitions than response switches due to persisting response inhibition of a previously executed response. The data also revealed age-related differences in overall performance: Older adults responded more slowly and more accurately than young adults, which was reflected by a higher threshold separation parameter in diffusion model analysis. Moreover, older adults showed larger non-decision times and higher variability in non-decision time than young adults, possibly reflecting slower and more variable motor processes. In contrast, overall drift rate did not differ between older and younger adults. Taken together

  10. Polymeric Materials For Scale Inhibition In Cooling Water Systems

    Directory of Open Access Journals (Sweden)

    Najwa S.Majeed

    2013-04-01

    Full Text Available Calcium carbonate deposition is generally predominant in cooling water-circulating system. For the control of calcium carbonate scale formation two types of polymeric scale inhibitors were used Polyamino polyether methylene phosphonate  (PAPEMPand polyacrylaminde(PAA.Model of cooling tower system have been built up in laboratory scale. Experiments were carried out using different inhibitor concentrations(0.5,1,1.5,2,3ppm ,at water temperature of  40oC and flow rate of 150 l/hr. It was found that Polyamino polyether methylene phosphonate    more effective than polyacryle amide'  as scale inhibitor in all used concentrations and the best inhibition efficiency (95% was at (2.5ppm of Polyamino polyether methylene phosphonate  and (85% with poly acryle amide at concentrations of (3 ppm. The performance of the polymeric scale inhibitors was compared with a method used to control heavy calcium carbonate scale forming by the deposition of sufficiently thin protective calcium carbonate scale using sulfuric acid and depending on Ryznar stability index controlling method. 

  11. Statin therapy inhibits remyelination in the central nervous system

    DEFF Research Database (Denmark)

    Miron, Veronique E; Zehntner, Simone P; Kuhlmann, Tanja

    2009-01-01

    Remyelination of lesions in the central nervous system contributes to neural repair following clinical relapses in multiple sclerosis. Remyelination is initiated by recruitment and differentiation of oligodendrocyte progenitor cells (OPCs) into myelinating oligodendrocytes. Simvastatin, a blood...... that OPCs were maintained in an immature state (Olig2(strong)/Nkx2.2(weak)). NogoA+ oligodendrocyte numbers were decreased during all simvastatin treatment regimens. Our findings suggest that simvastatin inhibits central nervous system remyelination by blocking progenitor differentiation, indicating...... the need to monitor effects of systemic immunotherapies that can access the central nervous system on brain tissue-repair processes....

  12. Inhibition factors and Kinetic model for ammonium inhibition on the anammox process of the SNAD biofilm.

    Science.gov (United States)

    Zheng, Zhaoming; Li, Jun; Ma, Jing; Du, Jia; Wang, Fan; Bian, Wei; Zhang, Yanzhuo; Zhao, Baihang

    2017-03-01

    The aim of the present work was to evaluate the anaerobic ammonium oxidation (anammox) activity of simultaneous partial nitrification, anammox and denitrification (SNAD) biofilm with different substrate concentrations and pH values. Kaldnes rings taken from the SNAD biofilm reactor were incubated in batch tests to determine the anammox activity. Haldane model was applied to investigate the ammonium inhibition on anammox process. As for nitrite inhibition, the NH 4 + -N removal rate of anammox process remained 87.4% of the maximum rate with the NO 2 - -N concentration of 100mg/L. Based on the results of Haldane model, no obvious difference in kinetic coefficients was observed under high or low free ammonia (FA) conditions, indicating that ammonium rather than FA was the true inhibitor for anammox process of SNAD biofilm. With the pH value of 7.0, the r max , Ks and K I of ammonium were 0.209kg NO 2 - -N/kg VSS/day, 9.5mg/L and 422mg/L, respectively. The suitable pH ranges for anammox process were 5.0 to 9.0. These results indicate that the SNAD biofilm performs excellent tolerance to adverse conditions. Copyright © 2016. Published by Elsevier B.V.

  13. Modeling the effects of cell cycle M-phase transcriptional inhibition on circadian oscillation.

    Directory of Open Access Journals (Sweden)

    Bin Kang

    2008-03-01

    Full Text Available Circadian clocks are endogenous time-keeping systems that temporally organize biological processes. Gating of cell cycle events by a circadian clock is a universal observation that is currently considered a mechanism serving to protect DNA from diurnal exposure to ultraviolet radiation or other mutagens. In this study, we put forward another possibility: that such gating helps to insulate the circadian clock from perturbations induced by transcriptional inhibition during the M phase of the cell cycle. We introduced a periodic pulse of transcriptional inhibition into a previously published mammalian circadian model and simulated the behavior of the modified model under both constant darkness and light-dark cycle conditions. The simulation results under constant darkness indicated that periodic transcriptional inhibition could entrain/lock the circadian clock just as a light-dark cycle does. At equilibrium states, a transcriptional inhibition pulse of certain periods was always locked close to certain circadian phases where inhibition on Per and Bmal1 mRNA synthesis was most balanced. In a light-dark cycle condition, inhibitions imposed at different parts of a circadian period induced different degrees of perturbation to the circadian clock. When imposed at the middle- or late-night phase, the transcriptional inhibition cycle induced the least perturbations to the circadian clock. The late-night time window of least perturbation overlapped with the experimentally observed time window, where mitosis is most frequent. This supports our hypothesis that the circadian clock gates the cell cycle M phase to certain circadian phases to minimize perturbations induced by the latter. This study reveals the hidden effects of the cell division cycle on the circadian clock and, together with the current picture of genome stability maintenance by circadian gating of cell cycle, provides a more comprehensive understanding of the phenomenon of circading gating of

  14. Behavioral inhibition system (BIS), Behavioral activation system (BAS) and schizophrenia : Relationship with psychopathology and physiology

    NARCIS (Netherlands)

    Scholten, Marion R. M.; van Honk, Jack; Aleman, Andre; Kahn, Rene S.

    2006-01-01

    Objective: The Behavioral Inhibition System (BIS) and the Behavioral Activation System (BAS) have been conceptualized as two neural motivational systems that regulate sensitivity to punishment (BIS) and reward (BAS). Imbalance in BIS and BAS levels has been reported to be related to various forms of

  15. Modeling of System Families

    National Research Council Canada - National Science Library

    Feiler, Peter

    2007-01-01

    .... The Society of Automotive Engineers (SAE) Architecture Analysis & Design Language (AADL) is an industry-standard, architecture-modeling notation specifically designed to support a component- based approach to modeling embedded systems...

  16. Modelling Railway Interlocking Systems

    DEFF Research Database (Denmark)

    Lindegaard, Morten Peter; Viuf, P.; Haxthausen, Anne Elisabeth

    2000-01-01

    In this report we present a model of interlocking systems, and describe how the model may be validated by simulation. Station topologies are modelled by graphs in which the nodes denote track segments, and the edges denote connectivity for train traÆc. Points and signals are modelled by annotatio...

  17. Models of synchronized hippocampal bursts in the presence of inhibition. I. Single population events.

    Science.gov (United States)

    Traub, R D; Miles, R; Wong, R K

    1987-10-01

    1. We constructed model networks with 520 or 1,020 cells intended to represent the CA3 region of the hippocampus. Model neurons were simulated in enough detail to reproduce intrinsic bursting and the electrotonic flow of currents along dendritic cables. Neurons exerted either excitatory or inhibitory postsynaptic actions on other cells. The network models were simulated with different levels of excitatory and inhibitory synaptic strengths in order to study epileptic and other interesting collective behaviors in the system. 2. Excitatory synapses between neurons in the network were powerful enough so that burst firing in a presynaptic neuron would evoke bursting in its connected cells. Since orthodromic or antidromic stimulation evokes both a fast and a slow phase of inhibition, two types of inhibitory cells were simulated. The properties of these inhibitory cells were modeled to resemble those of two types of inhibitory cells characterized by dual intracellular recordings in the slice preparation. 3. With fast inhibition totally blocked, a stimulus to a single cell lead to a synchronized population burst. Thus the principles of our epileptic synchronization model, developed earlier, apply even when slow inhibitory postsynaptic potentials (IPSPs) are present, as apparently occurs in the epileptic hippocampal slice. The model performs in this way because bursting can propagate through several generations in the network before slow inhibition builds up enough to block burst propagation. This can occur, however, only if connectivity is sufficiently large. With very low connection densities, slow IPSPs will prevent the development of full synchronization. 4. We performed multiple simulations in which the fast inhibitory conductance strength was kept fixed at various levels while the strength of the excitatory synapses was varied. In each simulation, we stimulated either one or four cells. For each level of inhibition, the peak number of cells bursting depended

  18. Bioaccumulation of the synthetic dye Basic Violet 3 and heavy metals in single and binary systems by Candida tropicalis grown in a sugarcane bagasse extract medium: Modelling optimal conditions using response surface methodology (RSM) and inhibition kinetics

    International Nuclear Information System (INIS)

    Das, Devlina; Charumathi, D.; Das, Nilanjana

    2011-01-01

    Single and binary effects of dye Basic Violet 3 and heavy metals, 'namely', Pb(II) and Cd(II), were investigated for their role in dye and heavy metal bioaccumulation by Candida tropicalis that was grown in a sugarcane bagasse extract medium containing 8 g/L, 16 g/L or 24 g/L of sugar. The optimum pH was found to be 4.0 in the single system and 5.0 in the binary system. A central composite design was successfully used to analyse the experimental results. Four numerical correlations that were fitted to a second order quadratic equation were used to estimate optimum combinations predicted by response surface methodology. In the dye-Pb(II) binary system, C. tropicalis was capable of bioaccumulating 49.5% of the dye and 49.6% of the Pb(II), in comparison to 15.9% of the dye and 55.5% of the Cd(II) in the dye-Cd(II) binary system. In these two systems, the pollutants were dispersed at minimum working concentration levels. Competitive inhibition was observed in both the single and binary systems, which was suggested by an increase in the saturation constant, K s , and a simultaneous decrease in the specific growth rate that was calculated from Lineweaver-Burk plots. Atomic force microscopy images demonstrated changes in yeast cell morphology by exposure to these contaminants in the dye-Pb(II) binary system grown in a bioaccumulation medium.

  19. Effect and Modeling of Glucose Inhibition and In Situ Glucose Removal During Enzymatic Hydrolysis of Pretreated Wheat Straw

    DEFF Research Database (Denmark)

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

    2010-01-01

    The enzymatic hydrolysis of lignocellulosic biomass is known to be product-inhibited by glucose. In this study, the effects on cellulolytic glucose yields of glucose inhibition and in situ glucose removal were examined and modeled during extended treatment of heat-pretreated wheat straw with the ......The enzymatic hydrolysis of lignocellulosic biomass is known to be product-inhibited by glucose. In this study, the effects on cellulolytic glucose yields of glucose inhibition and in situ glucose removal were examined and modeled during extended treatment of heat-pretreated wheat straw...... with the cellulolytic enzyme system, Celluclast (R) 1.5 L, from Trichoderma reesei, supplemented with a beta-glucosidase, Novozym (R) 188, from Aspergillus niger. Addition of glucose (0-40 g/L) significantly decreased the enzyme-catalyzed glucose formation rates and final glucose yields, in a dose-dependent manner......-Menten inhibition models without great significance of the inhibition mechanism. Moreover, the experimental in situ removal of glucose could be simulated by a Michaelis-Menten inhibition model. The data provide an important base for design of novel reactors and operating regimes which include continuous product...

  20. RSMASS system model development

    International Nuclear Information System (INIS)

    Marshall, A.C.; Gallup, D.R.

    1998-01-01

    RSMASS system mass models have been used for more than a decade to make rapid estimates of space reactor power system masses. This paper reviews the evolution of the RSMASS models and summarizes present capabilities. RSMASS has evolved from a simple model used to make rough estimates of space reactor and shield masses to a versatile space reactor power system model. RSMASS uses unique reactor and shield models that permit rapid mass optimization calculations for a variety of space reactor power and propulsion systems. The RSMASS-D upgrade of the original model includes algorithms for the balance of the power system, a number of reactor and shield modeling improvements, and an automatic mass optimization scheme. The RSMASS-D suite of codes cover a very broad range of reactor and power conversion system options as well as propulsion and bimodal reactor systems. Reactor choices include in-core and ex-core thermionic reactors, liquid metal cooled reactors, particle bed reactors, and prismatic configuration reactors. Power conversion options include thermoelectric, thermionic, Stirling, Brayton, and Rankine approaches. Program output includes all major component masses and dimensions, efficiencies, and a description of the design parameters for a mass optimized system. In the past, RSMASS has been used as an aid to identify and select promising concepts for space power applications. The RSMASS modeling approach has been demonstrated to be a valuable tool for guiding optimization of the power system design; consequently, the model is useful during system design and development as well as during the selection process. An improved in-core thermionic reactor system model RSMASS-T is now under development. The current development of the RSMASS-T code represents the next evolutionary stage of the RSMASS models. RSMASS-T includes many modeling improvements and is planned to be more user-friendly. RSMASS-T will be released as a fully documented, certified code at the end of

  1. Modeling Pharmacological Inhibition of Mast Cell Degranulation as a Therapy for Insulinoma

    Directory of Open Access Journals (Sweden)

    Laura Soucek

    2011-11-01

    Full Text Available Myc, a pleiotropic transcription factor that is deregulated and/or overexpressed in most human cancers, instructs multiple extracellular programs that are required to sustain the complex microenvironment needed for tumor maintenance, including remodeling of tumor stroma, angiogenesis, and inflammation. We previously showed in a model of pancreatic β-cell tumorigenesis that acute Myc activation in vivo triggers rapid recruitment of mast cells to the tumor site and that this is absolutely required for angiogenesis and macroscopic tumor expansion. More-over, systemic inhibition of mast cell degranulation with sodium cromoglycate induced death of tumor and endothelial cells in established tumors. Hence, mast cells are required both to establish and to maintain the tumors. Whereas this intimates that selective inhibition of mast cell function could be therapeutically efficacious, cromoglycate is not a practical drug for systemic delivery in humans, and no other systemic inhibitor of mast cell degranulation has hitherto been available. PCI-32765 is a novel inhibitor of Bruton tyrosine kinase (Btk that blocks mast cell degranulation and is currently in clinical trial as a therapy for B-cell non–Hodgkin lymphoma. Here, we show that systemic treatment of insulinoma-bearing mice with PCI-32765 efficiently inhibits Btk, blocks mast cell degranulation, and triggers collapse of tumor vasculature and tumor regression. These data reinforce the notion that mast cell function is required for maintenance of certain tumor types and indicate that the Btk inhibitor PCI-32765 may be useful in treating such diseases.

  2. Systemic resilience model

    International Nuclear Information System (INIS)

    Lundberg, Jonas; Johansson, Björn JE

    2015-01-01

    It has been realized that resilience as a concept involves several contradictory definitions, both for instance resilience as agile adjustment and as robust resistance to situations. Our analysis of resilience concepts and models suggest that beyond simplistic definitions, it is possible to draw up a systemic resilience model (SyRes) that maintains these opposing characteristics without contradiction. We outline six functions in a systemic model, drawing primarily on resilience engineering, and disaster response: anticipation, monitoring, response, recovery, learning, and self-monitoring. The model consists of four areas: Event-based constraints, Functional Dependencies, Adaptive Capacity and Strategy. The paper describes dependencies between constraints, functions and strategies. We argue that models such as SyRes should be useful both for envisioning new resilience methods and metrics, as well as for engineering and evaluating resilient systems. - Highlights: • The SyRes model resolves contradictions between previous resilience definitions. • SyRes is a core model for envisioning and evaluating resilience metrics and models. • SyRes describes six functions in a systemic model. • They are anticipation, monitoring, response, recovery, learning, self-monitoring. • The model describes dependencies between constraints, functions and strategies

  3. Thermodynamic modeling of complex systems

    DEFF Research Database (Denmark)

    Liang, Xiaodong

    . Contrary to earlier theories, the oil is not only present on the surface, but also in great volumes both in the water column and on the seafloor, which indicates that we do not know enough about how oil behaves in water and interacts with it. Sonar detection is one of the most important and necessary...... after an oil spill. Engineering thermodynamics could be applied in the state-of-the-art sonar products through advanced artificial technology, if the speed of sound, solubility and density of oil-seawater systems could be satisfactorily modelled. The addition of methanol or glycols into unprocessed well...... streams during subsea pipelines is necessary to inhibit gas hydrate formation, and the offshore reservoirs often mean complicated temperature and pressure conditions. Accurate description of the phase behavior and thermalphysical properties of complex systems containing petroleum fluids and polar...

  4. Selected System Models

    Science.gov (United States)

    Schmidt-Eisenlohr, F.; Puñal, O.; Klagges, K.; Kirsche, M.

    Apart from the general issue of modeling the channel, the PHY and the MAC of wireless networks, there are specific modeling assumptions that are considered for different systems. In this chapter we consider three specific wireless standards and highlight modeling options for them. These are IEEE 802.11 (as example for wireless local area networks), IEEE 802.16 (as example for wireless metropolitan networks) and IEEE 802.15 (as example for body area networks). Each section on these three systems discusses also at the end a set of model implementations that are available today.

  5. Inhibition of GLO1 in Glioblastoma Multiforme Increases DNA-AGEs, Stimulates RAGE Expression, and Inhibits Brain Tumor Growth in Orthotopic Mouse Models

    Directory of Open Access Journals (Sweden)

    Rahul Jandial

    2018-01-01

    Full Text Available Cancers that exhibit the Warburg effect may elevate expression of glyoxylase 1 (GLO1 to detoxify the toxic glycolytic byproduct methylglyoxal (MG and inhibit the formation of pro-apoptotic advanced glycation endproducts (AGEs. Inhibition of GLO1 in cancers that up-regulate glycolysis has been proposed as a therapeutic targeting strategy, but this approach has not been evaluated for glioblastoma multiforme (GBM, the most aggressive and difficult to treat malignancy of the brain. Elevated GLO1 expression in GBM was established in patient tumors and cell lines using bioinformatics tools and biochemical approaches. GLO1 inhibition in GBM cell lines and in an orthotopic xenograft GBM mouse model was examined using both small molecule and short hairpin RNA (shRNA approaches. Inhibition of GLO1 with S-(p-bromobenzyl glutathione dicyclopentyl ester (p-BrBzGSH(Cp2 increased levels of the DNA-AGE N2-1-(carboxyethyl-2′-deoxyguanosine (CEdG, a surrogate biomarker for nuclear MG exposure; substantially elevated expression of the immunoglobulin-like receptor for AGEs (RAGE; and induced apoptosis in GBM cell lines. Targeting GLO1 with shRNA similarly increased CEdG levels and RAGE expression, and was cytotoxic to glioma cells. Mice bearing orthotopic GBM xenografts treated systemically with p-BrBzGSH(Cp2 exhibited tumor regression without significant off-target effects suggesting that GLO1 inhibition may have value in the therapeutic management of these drug-resistant tumors.

  6. Modeling cellular systems

    CERN Document Server

    Matthäus, Franziska; Pahle, Jürgen

    2017-01-01

    This contributed volume comprises research articles and reviews on topics connected to the mathematical modeling of cellular systems. These contributions cover signaling pathways, stochastic effects, cell motility and mechanics, pattern formation processes, as well as multi-scale approaches. All authors attended the workshop on "Modeling Cellular Systems" which took place in Heidelberg in October 2014. The target audience primarily comprises researchers and experts in the field, but the book may also be beneficial for graduate students.

  7. Determination of inhibition in the enzymatic hydrolysis of cellobiose using hybrid neural modeling

    Directory of Open Access Journals (Sweden)

    F. C. Corazza

    2005-03-01

    Full Text Available Neural networks and hybrid models were used to study substrate and product inhibition observed in the enzymatic hydrolysis of cellobiose at 40ºC, 50ºC and 55ºC, pH 4.8, using cellobiose solutions with or without the addition of exogenous glucose. Firstly, the initial velocity method and nonlinear fitting with StatisticaÒ were used to determine the kinetic parameters for either the uncompetitive or the competitive substrate inhibition model at a negligible product concentration and cellobiose from 0.4 to 2.0 g/L. Secondly, for six different models of substrate and product inhibitions and data for low to high cellobiose conversions in a batch reactor, neural networks were used for fitting the product inhibition parameter to the mass balance equations derived for each model. The two models found to be best were: 1 noncompetitive inhibition by substrate and competitive by product and 2 uncompetitive inhibition by substrate and competitive by product; however, these models’ correlation coefficients were quite close. To distinguish between them, hybrid models consisting of neural networks and first principle equations were used to select the best inhibition model based on the smallest norm observed, and the model with noncompetitive inhibition by substrate and competitive inhibition by product was shown to be the best predictor of cellobiose hydrolysis reactor behavior.

  8. A digital wireless system for closed-loop inhibition of nociceptive signals

    Science.gov (United States)

    Zuo, Chao; Yang, Xiaofei; Wang, Yang; Hagains, Christopher E.; Li, Ai-Ling; Peng, Yuan B.; Chiao, J.-C.

    2012-10-01

    Neurostimulation of the spinal cord or brain has been used to inhibit nociceptive signals in pain management applications. Nevertheless, most of the current neurostimulation models are based on open-loop system designs. There is a lack of closed-loop systems for neurostimulation in research with small freely-moving animals and in future clinical applications. Based on our previously developed analog wireless system for closed-loop neurostimulation, a digital wireless system with real-time feedback between recorder and stimulator modules has been developed to achieve multi-channel communication. The wireless system includes a wearable recording module, a wearable stimulation module and a transceiver connected to a computer for real-time and off-line data processing, display and storage. To validate our system, wide dynamic range neurons in the spinal cord dorsal horn have been recorded from anesthetized rats in response to graded mechanical stimuli (brush, pressure and pinch) applied in the hind paw. The identified nociceptive signals were used to automatically trigger electrical stimulation at the periaqueductal gray in real time to inhibit their own activities by the closed-loop design. Our digital wireless closed-loop system has provided a simplified and efficient method for further study of pain processing in freely-moving animals and potential clinical application in patients. Groups 1, 2 and 3 contributed equally to this project.

  9. Systemic administration of erythropoietin inhibits retinopathy in RCS rats.

    Directory of Open Access Journals (Sweden)

    Weiyong Shen

    Full Text Available OBJECTIVE: Royal College of Surgeons (RCS rats develop vasculopathy as photoreceptors degenerate. The aim of this study was to examine the effect of erythropoietin (EPO on retinopathy in RCS rats. METHODS: Fluorescein angiography was used to monitor retinal vascular changes over time. Changes in retinal glia and vasculature were studied by immunostaining. To study the effects of EPO on retinal pathology, EPO (5000 IU/kg was injected intraperitoneally in 14 week old normal and RCS rats twice a week for 4 weeks. Changes in the retinal vasculature, glia and microglia, photoreceptor apoptosis, differential expression of p75 neurotrophin receptor (p75NTR, pro-neurotrophin 3 (pro-NT3, tumour necrosis factor-α (TNFα, pigment epithelium derived factor (PEDF and vascular endothelial growth factor-A (VEGF-A, the production of CD34(+ cells and mobilization of CD34(+/VEGF-R2(+ cells as well as recruitment of CD34(+ cells into the retina were examined after EPO treatment. RESULTS: RCS rats developed progressive capillary dropout and subretinal neovascularization which were accompanied by retinal gliosis. Systemic administration of EPO stabilized the retinal vasculature and inhibited the development of focal vascular lesions. Further studies showed that EPO modulated retinal gliosis, attenuated photoreceptor apoptosis and p75NTR and pro-NT3 upregulation, promoted the infiltration of ramified microglia and stimulated VEGF-A expression but had little effect on TNFα and PEDF expression. EPO stimulated the production of red and white blood cells and CD34(+ cells along with effective mobilization of CD34(+/VEGF-R2(+ cells. Immunofluorescence study demonstrated that EPO enhanced the recruitment of CD34+ cells into the retina. CONCLUSIONS: Our results suggest that EPO has therapeutic potentials in treatment of neuronal and vascular pathology in retinal disease. The protective effects of EPO on photoreceptors and the retinal vasculature may involve multiple

  10. Modelling of wastewater systems

    DEFF Research Database (Denmark)

    Bechmann, Henrik

    Oxygen Demand) flux and SS flux in the inlet to the WWTP. COD is measured by means of a UV absorption sensor while SS is measured by a turbidity sensor. These models include a description of the deposit of COD and SS amounts, respectively, in the sewer system, and the models can thus be used to quantify......In this thesis, models of pollution fluxes in the inlet to 2 Danish wastewater treatment plants (WWTPs) as well as of suspended solids (SS) concentrations in the aeration tanks of an alternating WWTP and in the effluent from the aeration tanks are developed. The latter model is furthermore used...... to analyze and quantify the effect of the Aeration Tank Settling (ATS) operating mode, which is used during rain events. Furthermore, the model is used to propose a control algorithm for the phase lengths during ATS operation. The models are mainly formulated as state space model in continuous time...

  11. Modeling Complex Systems

    CERN Document Server

    Boccara, Nino

    2010-01-01

    Modeling Complex Systems, 2nd Edition, explores the process of modeling complex systems, providing examples from such diverse fields as ecology, epidemiology, sociology, seismology, and economics. It illustrates how models of complex systems are built and provides indispensable mathematical tools for studying their dynamics. This vital introductory text is useful for advanced undergraduate students in various scientific disciplines, and serves as an important reference book for graduate students and young researchers. This enhanced second edition includes: . -recent research results and bibliographic references -extra footnotes which provide biographical information on cited scientists who have made significant contributions to the field -new and improved worked-out examples to aid a student’s comprehension of the content -exercises to challenge the reader and complement the material Nino Boccara is also the author of Essentials of Mathematica: With Applications to Mathematics and Physics (Springer, 2007).

  12. A Kinetic Modelling of Enzyme Inhibitions in the Central Metabolism of Yeast Cells

    Science.gov (United States)

    Kasbawati; Kalondeng, A.; Aris, N.; Erawaty, N.; Azis, M. I.

    2018-03-01

    Metabolic regulation plays an important role in the metabolic engineering of a cellular process. It is conducted to improve the productivity of a microbial process by identifying the important regulatory nodes of a metabolic pathway such as fermentation pathway. Regulation of enzymes involved in a particular pathway can be held to improve the productivity of the system. In the central metabolism of yeast cell, some enzymes are known as regulating enzymes that can be inhibited to increase the production of ethanol. In this research we study the kinetic modelling of the enzymes in the central pathway of yeast metabolism by taking into consideration the enzyme inhibition effects to the ethanol production. The existence of positive steady state solution and the stability of the system are also analysed to study the property and dynamical behaviour of the system. One stable steady state of the system is produced if some conditions are fulfilled. The conditions concern to the restriction of the maximum reactions of the enzymes in the pyruvate and acetaldehyde branch points. There exists a certain time of fermentation reaction at which a maximum and a minimum ethanol productions are attained after regulating the system. Optimal ethanol concentration is also produced for a certain initial concentration of inhibitor.

  13. Modeling Complex Systems

    International Nuclear Information System (INIS)

    Schreckenberg, M

    2004-01-01

    This book by Nino Boccara presents a compilation of model systems commonly termed as 'complex'. It starts with a definition of the systems under consideration and how to build up a model to describe the complex dynamics. The subsequent chapters are devoted to various categories of mean-field type models (differential and recurrence equations, chaos) and of agent-based models (cellular automata, networks and power-law distributions). Each chapter is supplemented by a number of exercises and their solutions. The table of contents looks a little arbitrary but the author took the most prominent model systems investigated over the years (and up until now there has been no unified theory covering the various aspects of complex dynamics). The model systems are explained by looking at a number of applications in various fields. The book is written as a textbook for interested students as well as serving as a comprehensive reference for experts. It is an ideal source for topics to be presented in a lecture on dynamics of complex systems. This is the first book on this 'wide' topic and I have long awaited such a book (in fact I planned to write it myself but this is much better than I could ever have written it!). Only section 6 on cellular automata is a little too limited to the author's point of view and one would have expected more about the famous Domany-Kinzel model (and more accurate citation!). In my opinion this is one of the best textbooks published during the last decade and even experts can learn a lot from it. Hopefully there will be an actualization after, say, five years since this field is growing so quickly. The price is too high for students but this, unfortunately, is the normal case today. Nevertheless I think it will be a great success! (book review)

  14. Modeling the earth system

    Energy Technology Data Exchange (ETDEWEB)

    Ojima, D. [ed.

    1992-12-31

    The 1990 Global Change Institute (GCI) on Earth System Modeling is the third of a series organized by the Office for Interdisciplinary Earth Studies to look in depth at particular issues critical to developing a better understanding of the earth system. The 1990 GCI on Earth System Modeling was organized around three themes: defining critical gaps in the knowledge of the earth system, developing simplified working models, and validating comprehensive system models. This book is divided into three sections that reflect these themes. Each section begins with a set of background papers offering a brief tutorial on the subject, followed by working group reports developed during the institute. These reports summarize the joint ideas and recommendations of the participants and bring to bear the interdisciplinary perspective that imbued the institute. Since the conclusion of the 1990 Global Change Institute, research programs, nationally and internationally, have moved forward to implement a number of the recommendations made at the institute, and many of the participants have maintained collegial interactions to develop research projects addressing the needs identified during the two weeks in Snowmass.

  15. Method for widespread microRNA-155 inhibition prolongs survival in ALS-model mice

    Science.gov (United States)

    Koval, Erica D.; Shaner, Carey; Zhang, Peter; du Maine, Xavier; Fischer, Kimberlee; Tay, Jia; Chau, B. Nelson; Wu, Gregory F.; Miller, Timothy M.

    2013-01-01

    microRNAs (miRNAs) are dysregulated in a variety of disease states, suggesting that this newly discovered class of gene expression repressors may be viable therapeutic targets. A microarray of miRNA changes in ALS-model superoxide dismutase 1 (SOD1)G93A rodents identified 12 miRNAs as significantly changed. Six miRNAs tested in human ALS tissues were confirmed increased. Specifically, miR-155 was increased 5-fold in mice and 2-fold in human spinal cords. To test miRNA inhibition in the central nervous system (CNS) as a potential novel therapeutic, we developed oligonucleotide-based miRNA inhibitors (anti-miRs) that could inhibit miRNAs throughout the CNS and in the periphery. Anti-miR-155 caused global derepression of targets in peritoneal macrophages and, following intraventricular delivery, demonstrated widespread functional distribution in the brain and spinal cord. After treating SOD1G93A mice with anti-miR-155, we significantly extended survival by 10 days and disease duration by 15 days (38%) while a scrambled control anti-miR did not significantly improve survival or disease duration. Therefore, antisense oligonucleotides may be used to successfully inhibit miRNAs throughout the brain and spinal cord, and miR-155 is a promising new therapeutic target for human ALS. PMID:23740943

  16. Chronic ethanol exposure inhibits distraction osteogenesis in a mouse model: Role of the TNF signaling axis

    International Nuclear Information System (INIS)

    Wahl, Elizabeth C.; Aronson, James; Liu, Lichu; Liu, Zhendong; Perrien, Daniel S.; Skinner, Robert A.; Badger, Thomas M.; Ronis, Martin J.J.; Lumpkin, Charles K.

    2007-01-01

    Tumor necrosis factor-alpha (TNF-α) is an inflammatory cytokine that modulates osteoblastogenesis. In addition, the demonstrated inhibitory effects of chronic ethanol exposure on direct bone formation in rats are hypothetically mediated by TNF-α signaling. The effects in mice are unreported. Therefore, we hypothesized that in mice (1) administration of a soluble TNF receptor 1 derivative (sTNF-R1) would protect direct bone formation during chronic ethanol exposure, and (2) administration of recombinant mouse TNF-α (rmTNF-α) to ethanol naive mice would inhibit direct bone formation. We utilized a unique model of limb lengthening (distraction osteogenesis, DO) combined with liquid diets to measure chronic ethanol's effects on direct bone formation. Chronic ethanol exposure resulted in increased marrow TNF, IL-1, and CYP 2E1 RNA levels in ethanol-treated vs. control mice, while no significant weight differences were noted. Systemic administration of sTNF-R1 during DO (8.0 mg/kg/2 days) to chronic ethanol-exposed mice resulted in enhanced direct bone formation as measured radiologically and histologically. Systemic rmTNF-α (10 μg/kg/day) administration decreased direct bone formation measures, while no significant weight differences were noted. We conclude that chronic ethanol-associated inhibition of direct bone formation is mediated to a significant extent by the TNF signaling axis in a mouse model

  17. Alpha 1 Antitrypsin Inhibits Dendritic Cell Activation and Attenuates Nephritis in a Mouse Model of Lupus.

    Directory of Open Access Journals (Sweden)

    Ahmed S Elshikha

    Full Text Available Systemic lupus erythematosus (SLE is an autoimmune disorder with a worldwide distribution and considerable mortality and morbidity. Although the pathogenesis of this disease remains elusive, over-reactive dendritic cells (DCs play a critical role in the disease development. It has been shown that human alpha-1 antitrypsin (hAAT has protective effects in type 1 diabetes and rheumatoid arthritis mouse models. In the present study, we tested the effect of AAT on DC differentiation and functions, as well as its protective effect in a lupus-prone mouse model. We showed that hAAT treatment significantly inhibited LPS (TLR4 agonist and CpG (TLR9 agonist -induced bone-marrow (BM-derived conventional and plasmacytoid DC (cDC and pDC activation and reduced the production of inflammatory cytokines including IFN-I, TNF-α and IL-1β. In MRL/lpr mice, hAAT treatment significantly reduced BM-derived DC differentiation, serum autoantibody levels, and importantly attenuated renal pathology. Our results for the first time demonstrate that hAAT inhibits DC activation and function, and it also attenuates autoimmunity and renal damage in the MRL/lpr lupus model. These results imply that hAAT has a therapeutic potential for the treatment of SLE in humans.

  18. QSAR Models for Thyroperoxidase Inhibition and Screening of U.S. and EU Chemical Inventories

    DEFF Research Database (Denmark)

    Abildgaard Rosenberg, Sine; D. Watt, Eric; Judson, Richard S.

    2017-01-01

    of QSAR2 identified the ten most discriminating structural features for TPO inhibition and non-inhibition, respectively. Both models were used to screen 72,524 REACH substances and 32,197 U.S. EPA substances, and QSAR2 with the expanded training set had an approximately 10% larger coverages compared...... developed two global quantitative structure-activity relationship (QSAR) models for TPO inhibition in vitro. Rigorous cross- and blinded external validations demonstrated that the first model, QSAR1, built from a training set of 877 chemicals, was robust and highly predictive with balanced accuracies of 80......Thyroperoxidase (TPO) is the enzyme that synthesizes thyroid hormones (THs). TPO inhibition by chemicals can result in decreased TH levels and developmental neurotoxicity, and therefore identification of TPO inhibition is of high relevance in safety evaluation of chemicals. In the present study, we...

  19. Radiosensitization by histone deacetylase inhibition in an osteosarcoma mouse model

    Energy Technology Data Exchange (ETDEWEB)

    Blattmann, C. [Olgahospital, Stuttgart (Germany). Paediatrie 5; University Children' s Hospital of Heidelberg (Germany). Dept. of Pediatric Oncology, Hematology and Immunology; Thiemann, M. [German Cancer Research Center (DKFZ), Heidelberg (Germany). Dept. of Radiotherapy, Molecular- and Translational Radiation Oncology; Stenzinger, A. [Heidelberg Univ. (Germany). Inst. of Pathology; and others

    2013-11-15

    Background: Osteosarcomas (OS) are highly malignant and radioresistant tumors. Histone deacetylase inhibitors (HDACi) constitute a novel class of anticancer agents. We sought to investigate the effect of combined treatment with suberoylanilide hydroxamic acid (SAHA) and radiotherapy in OS in vivo. Methods: Clonogenic survival of human OS cell lines as well as tumor growth delay of OS xenografts were tested after treatment with either vehicle, radiotherapy (XRT), SAHA, or XRT and SAHA. Tumor proliferation, necrosis, microvascular density, apoptosis, and p53/p21 were monitored by immunohistochemistry. The CD95 pathway was performed by flow cytometry, caspase (3/7/8) activity measurements, and functional inhibition of CD95 death signaling. Results: Combined treatment with SAHA and XRT markedly reduced the surviving fraction of OS cells as compared to XRT alone. Likewise, dual therapy significantly inhibited OS tumor growth in vivo as compared to XRT alone, reflected by reduced tumor proliferation, impaired angiogenesis, and increased apoptosis. Addition of HDACi to XRT led to elevated p53, p21, CD95, and CD95L expression. Inhibition of CD95 signaling reduced HDACi- and XRT-induced apoptosis. Conclusion: Our data show that HDACi increases the radiosensitivity of osteosarcoma cells at least in part via ligand-induced apoptosis. HDACi thus emerge as potentially useful treatment components of OS. (orig.)

  20. Information Systems Efficiency Model

    Directory of Open Access Journals (Sweden)

    Milos Koch

    2017-07-01

    Full Text Available This contribution discusses the basic concept of creating a new model for the efficiency and effectiveness assessment of company information systems. The present trends in this field are taken into account, and the attributes are retained of measuring the optimal solutions for a company’s ICT (the implementation, functionality, service, innovations, safety, relationships, costs, etc.. The proposal of a new model of assessment comes from our experience with formerly implemented and employed methods, methods which we have modified in time and adapted to companies’ needs but also to the necessaries of our research that has been done through the ZEFIS portal. The most noteworthy of them is the HOS method that we have discussed in a number of forums. Its main feature is the fact that it respects the complexity of an information system in correlation with the balanced state of its individual parts.

  1. Phospho-aspirin (MDC-22) inhibits breast cancer in preclinical animal models: an effect mediated by EGFR inhibition, p53 acetylation and oxidative stress

    International Nuclear Information System (INIS)

    Huang, Liqun; Wong, Chi C; Mackenzie, Gerardo G; Sun, Yu; Cheng, Ka Wing; Vrankova, Kvetoslava; Alston, Ninche; Ouyang, Nengtai; Rigas, Basil

    2014-01-01

    The anticancer properties of aspirin are restricted by its gastrointestinal toxicity and its limited efficacy. Therefore, we synthesized phospho-aspirin (PA-2; MDC-22), a novel derivative of aspirin, and evaluated its chemotherapeutic and chemopreventive efficacy in preclinical models of triple negative breast cancer (TNBC). Efficacy of PA-2 was evaluated in human breast cancer cells in vitro, and in orthotopic and subcutaneous TNBC xenografts in nude mice. Mechanistic studies were also carried out to elucidate the mechanism of action of PA-2. PA-2 inhibited the growth of TNBC cells in vitro more potently than aspirin. Treatment of established subcutaneous TNBC xenografts (MDA-MB-231 and BT-20) with PA-2 induced a strong growth inhibitory effect, resulting in tumor stasis (79% and 90% inhibition, respectively). PA-2, but not aspirin, significantly prevented the development of orthotopic MDA-MB-231 xenografts (62% inhibition). Mechanistically, PA-2: 1) inhibited the activation of epidermal growth factor receptor (EGFR) and suppressed its downstream signaling cascades, including PI3K/AKT/mTOR and STAT3; 2) induced acetylation of p53 at multiple lysine residues and enhanced its DNA binding activity, leading to cell cycle arrest; and 3) induced oxidative stress by suppressing the thioredoxin system, consequently inhibiting the activation of the redox sensitive transcription factor NF-κB. These molecular alterations were observed in vitro and in vivo, demonstrating their relevance to the anticancer effect of PA-2. Our findings demonstrate that PA-2 possesses potent chemotherapeutic efficacy against TNBC, and is also effective in its chemoprevention, warranting further evaluation as an anticancer agent

  2. Antioxidants Inhibit Formation of 3-Monochloropropane-1,2-diol Esters in Model Reactions.

    Science.gov (United States)

    Li, Chang; Jia, Hanbing; Shen, Mingyue; Wang, Yuting; Nie, Shaoping; Chen, Yi; Zhou, Yongqiang; Wang, Yuanxing; Xie, Mingyong

    2015-11-11

    The capacities of six antioxidants to inhibit the formation of 3-monochloropropane-1,2 diol (3-MCPD) esters were examined in this study. Inhibitory capacities of the antioxidants were investigated both in chemical models containing the precursors (tripalmitoyl glycerol, 1,2-dipalmitoyl-sn-glycerol, monopalmitoyl glycerol, and sodium chloride) of 3-MCPD esters and in oil models (rapeseed oil and sodium chloride). Six antioxidants, butylated hydroxytoluene (BHT), butylated hydroxy anisole (BHA), tert-butyl hydroquinone (TBHQ), propyl gallate (PG), L-ascorbyl palmitate (AP), and α-tocopherol (VE), were found to exhibit inhibiting capacities on 3-MCPD ester formation both in chemical models and in oil models. TBHQ provided the highest inhibitory capacity both in chemical models and in oil models; 44% of 3-MCPD ester formation was inhibited in the presence of TBHQ (66 mg/kg of oil) after heating of rapeseed oil at 230 °C for 30 min, followed by PG and AP. BHT, BHA, and VE appeared to have weaker inhibitory abilities in both models. VE exhibited the lowest inhibition rate; 22% of 3-MCPD esters were inhibited in the presence of VE (172 mg/kg of oil) after heating of rapeseed oil at 230 °C for 30 min. In addition, the inhibition rates of PG and VE decreased dramatically with an increase in temperature or heating time. The results suggested that some antioxidants, such as TBHQ, PG, and AP, could be the potential inhibitors of 3-MCPD esters in practice.

  3. Inhibition of Dermatophilus congolensis infection in a mouse model by antibiotic-producing staphylococci.

    OpenAIRE

    Noble, W. C.; Lloyd, D. H.; Appiah, S. N.

    1980-01-01

    In an acute model of skin infection with Dermatophilus congolensis in the mouse, lesions can be prevented by simultaneous application of staphylococci which produce antibiotics; non-producer staphylococci fail to inhibit lesion formation.

  4. Inhibition of Dermatophilus congolensis infection in a mouse model by antibiotic-producing staphylococci.

    Science.gov (United States)

    Noble, W C; Lloyd, D H; Appiah, S N

    1980-12-01

    In an acute model of skin infection with Dermatophilus congolensis in the mouse, lesions can be prevented by simultaneous application of staphylococci which produce antibiotics; non-producer staphylococci fail to inhibit lesion formation.

  5. Vagus nerve stimulation inhibits trigeminal nociception in a rodent model of episodic migraine

    Directory of Open Access Journals (Sweden)

    Jordan L. Hawkins

    2017-12-01

    Conclusion:. Our findings demonstrate that nVNS inhibits mechanical nociception and represses expression of proteins associated with peripheral and central sensitization of trigeminal neurons in a novel rodent model of episodic migraine.

  6. Niflumic Acid Inhibits Goblet Cell Degranulation in a Guinea Pig Asthma Model

    Directory of Open Access Journals (Sweden)

    Mitsuko Kondo

    2012-01-01

    Conclusions: NFA inhibited the secretory response of mucus granules in an asthma model, suggesting that CLCA may be associated with goblet cell degranulation and that CLCA inhibitors may be useful for the treatment of hypersecretion in asthma.

  7. In vitro inflammation inhibition model based on semi-continuous toll-like receptor biosensing.

    Directory of Open Access Journals (Sweden)

    Jin-Woo Jeon

    Full Text Available A chemical inhibition model of inflammation is proposed by semi-continuous monitoring the density of toll-like receptor 1 (TLR1 expressed on mammalian cells following bacterial infection to investigate an in vivo-mimicked drug screening system. The inflammation was induced by adding bacterial lysate (e.g., Pseudomonas aeruginosa to a mammalian cell culture (e.g., A549 cell line. The TLR1 density on the same cells was immunochemically monitored up to three cycles under optimized cyclic bacterial stimulation-and-restoration conditions. The assay was carried out by adopting a cell-compatible immunoanalytical procedure and signal generation method. Signal intensity relative to the background control obtained without stimulation was employed to plot the standard curve for inflammation. To suppress the inflammatory response, sodium salicylate, which inhibits nuclear factor-κB activity, was used to prepare the standard curve for anti-inflammation. Such measurement of differential TLR densities was used as a biosensing approach discriminating the anti-inflammatory substance from the non-effector, which was simulated by using caffeic acid phenethyl ester and acetaminophen as the two components, respectively. As the same cells exposed to repetitive bacterial stimulation were semi-continuously monitored, the efficacy and toxicity of the inhibitors may further be determined regarding persistency against time. Therefore, this semi-continuous biosensing model could be appropriate as a substitute for animal-based experimentation during drug screening prior to pre-clinical tests.

  8. Cannabinoids inhibit fibrogenesis in diffuse systemic sclerosis fibroblasts.

    Science.gov (United States)

    Garcia-Gonzalez, Estrella; Selvi, Enrico; Balistreri, Epifania; Lorenzini, Sauro; Maggio, Roberta; Natale, Maria-Rita; Capecchi, Pier-Leopoldo; Lazzerini, Pietro-Enea; Bardelli, Marco; Laghi-Pasini, Franco; Galeazzi, Mauro

    2009-09-01

    It has been demonstrated that the endocannabinoid system is up-regulated in pathologic fibrosis and that modulation of the cannabinoid receptors might limit the progression of uncontrolled fibrogenesis. The aim of this study was to investigate whether the synthetic cannabinoid receptor agonist WIN55,212-2 could modulate fibrogenesis in an in vitro model of dcSSc. The expression of cannabinoid receptors CB1 and CB2 was assessed in dcSSc fibroblasts and healthy control fibroblasts. To investigate the effect of WIN55,212-2 on dcSSc fibrogenesis, we studied type I collagen, profibrotic cytokines, fibroblast transdifferentiation into myofibroblasts, apoptotic processes and activation of the extracellular signal-related kinase 1/2 pathway prior to and after the treatment with the synthetic cannabinoid at increasing concentrations. Both CB1 and CB2 receptors were over-expressed in dcSSc fibroblasts compared with healthy controls. WIN55,212-2 caused a reduction in extracellular matrix deposition and counteracted several behavioural abnormalities of scleroderma fibroblasts including transdifferentiation into myofibroblasts and resistance to apoptosis. The anti-fibrogenic effect of WIN55,212-2 was not reverted by selective cannabinoid antagonists. Our preliminary findings suggest that cannabinoids are provided with an anti-fibrotic activity, thereby possibly representing a new class of agents targeting fibrosis diseases.

  9. A practical kinetic model that considers endproduct inhibition in anaerobic digestion processes by including the equilibrium constant.

    Science.gov (United States)

    Hoh, C Y; Cord-Ruwisch, R

    1996-09-05

    The classical Michaelis-Menten model is widely used as the basis for modeling of a number of biological systems. As the model does not consider the inhibitory effect of endproducts that accumulate in virtually all bioprocesses, it is often modified to prevent the overestimation of reaction rates when products have accumulated. Traditional approaches of model modification use the inclusion of irreversible, competitive, and noncompetitive inhibition factors. This article demonstrates that these inhibition factors are insufficient to predict product inhibition of reactions that are close the dynamic equilibrium. All models investigated were found to violate thermodynamic laws as they predicted positive reaction rates for reactions that were endergonic due to high endproduct concentrations. For modeling of biological processes that operate close to the dynamic equilibrium (e.g., anaerobic processes), it is critical to prevent the prediction of positive reaction rates when the reaction has already reached the dynamic equilibrium. This can be achieved by using a reversible kinetic model. However, the major drawback of the reversible kinetic model is the large number of empirical parameters it requires. These parameters are difficult to determine and prone to experimental error. For this reason, the reversible model is not practical in the modeling of biological processes.This article uses the fundamentals of steady-state kinetics and thermodynamics to establish an equation for the reversible kinetic model that is of practical use in bio-process modeling. The behavior of this equilibrium-based model is compared with Michaelis-Menten-based models that use traditional inhibition factors. The equilibrium-based model did not require any empirical inhibition factor to correctly predict when reaction rates must be zero due to the free energy change being zero. For highly exergonic reactions, the equilibrium-based model did not deviate significantly from the Michaelis

  10. Positional isomerism markedly affects the growth inhibition of colon cancer cells by NOSH-aspirin: COX inhibition and modeling.

    Science.gov (United States)

    Vannini, Federica; Chattopadhyay, Mitali; Kodela, Ravinder; Rao, Praveen P N; Kashfi, Khosrow

    2015-12-01

    We recently reported the synthesis of NOSH-aspirin, a novel hybrid that releases both nitric oxide (NO) and hydrogen sulfide (H2S). In NOSH-aspirin, the two moieties that release NO and H2S are covalently linked at the 1, 2 positions of acetyl salicylic acid, i.e. ortho-NOSH-aspirin (o-NOSH-aspirin). In the present study, we compared the effects of the positional isomers of NOSH-ASA (o-NOSH-aspirin, m-NOSH-aspirin and p-NOSH-aspirin) to that of aspirin on growth of HT-29 and HCT 15 colon cancer cells, belonging to the same histological subtype, but with different expression of cyclooxygenase (COX) enzymes; HT-29 express both COX-1 and COX-2, whereas HCT 15 is COX-null. We also analyzed the effect of these compounds on proliferation and apoptosis in HT-29 cells. Since the parent compound aspirin, inhibits both COX-1 and COX-2, we also evaluated the effects of these compounds on COX-1 and COX-2 enzyme activities and also performed modeling of the interactions between the positional isomers of NOSH-aspirin and COX-1 and COX-2 enzymes. We observed that the three positional isomers of NOSH aspirin inhibited the growth of both colon cancer cell lines with IC50s in the nano-molar range. In particular in HT-29 cells the IC50s for growth inhibition were: o-NOSH-ASA, 0.04±0.011 µM; m-NOSH-ASA, 0.24±0.11 µM; p-NOSH-ASA, 0.46±0.17 µM; and in HCT 15 cells the IC50s for o-NOSH-ASA, m-NOSH-ASA, and p-NOSH-ASA were 0.062 ±0.006 µM, 0.092±0.004 µM, and 0.37±0.04 µM, respectively. The IC50 for aspirin in both cell lines was >5mM at 24h. The reduction of cell growth appeared to be mediated through inhibition of proliferation, and induction of apoptosis. All 3 positional isomers of NOSH-aspirin preferentially inhibited COX-1 over COX-2. These results suggest that the three positional isomers of NOSH-aspirin have the same biological actions, but that o-NOSH-ASA displayed the strongest anti-neoplastic potential. Copyright © 2015 The Authors. Published by Elsevier B.V. All

  11. Ovulation inhibition by estetrol in an in vivo model

    DEFF Research Database (Denmark)

    Bennink, H.J.T.C.; Skouby, S.; Bouchard, P.

    2008-01-01

    : Regularly cycling female rats were treated orally twice daily for four consecutive days, starting on the day of estrus, with E4 (0.03, 0.1, 0.3, 1.0 or 3.0 mg/kg), EE (0.0003, 0.001, 0.003, 0.01 or 0.03 mg/kg) or vehicle control (eight animals per group). In a second experiment conducted under the same....... The effect is dose-dependent. The relative potency of E-4 is about 18 times less compared to that of EE. We conclude that based on these data, combined with available pharmacological and clinical data on the safety and efficacy of E-4, the human fetal estrogenic steroid estetrol is a potential candidate...... experimental protocol, 2.0 mg/kg of E4 was administered as a single daily dose or as a dose of 1.0 mg/kg twice daily. In both studies, the primary end point was the number of ovulated oocytes in the genital tract. Results: Estetrol at the twice daily dose of 0.3 mg/kg and above inhibited ovulation. This effect...

  12. Modeling tandem AAG8-MEK inhibition in melanoma cells

    International Nuclear Information System (INIS)

    Sun, Bing; Kawahara, Masahiro; Nagamune, Teruyuki

    2014-01-01

    Drug resistance presents a challenge to the treatment of cancer patients, especially for melanomas, most of which are caused by the hyperactivation of MAPK signaling pathway. Innate or acquired drug-resistant relapse calls for the investigation of the resistant mechanisms and new anti-cancer drugs to provide implications for the ultimate goal of curative therapy. Aging-associated gene 8 (AAG8, encoded by the SIGMAR1 gene) is a chaperone protein profoundly elaborated in neurology. However, roles of AAG8 in carcinogenesis remain unclear. Herein, we discover AAG8 antagonists as new MEK inhibitors in melanoma cells and propose a novel drug combination strategy for melanoma therapy by presenting the experimental evidences. We report that specific antagonism of AAG8, efficiently suppresses melanoma cell growth and migration through, at least in part, the inactivation of the RAS-CRAF-MEK signaling pathway. We further demonstrate that melanoma cells that are resistant to AAG8 antagonist harbor refractory CRAF-MEK activity. MEK acts as a central mediator for anti-cancer effects and also for the resistance mechanism, leading to our proposal of tandem AAG8-MEK inhibition in melanoma cells. Combination of AAG8 antagonist and very low concentration of a MEK inhibitor synergistically restricts the growth of drug-resistant cells. These data collectively pinpoint AAG8 as a potential target and delineate a promising drug combination strategy for melanoma therapy

  13. Neonicotinoid insecticides inhibit cholinergic neurotransmission in a molluscan (Lymnaea stagnalis) nervous system.

    Science.gov (United States)

    Vehovszky, Á; Farkas, A; Ács, A; Stoliar, O; Székács, A; Mörtl, M; Győri, J

    2015-10-01

    Neonicotinoids are highly potent and selective systemic insecticides, but their widespread use also has a growing impact on non-target animals and contaminates the environment, including surface waters. We tested the neonicotinoid insecticides commercially available in Hungary (acetamiprid, Mospilan; imidacloprid, Kohinor; thiamethoxam, Actara; clothianidin, Apacs; thiacloprid, Calypso) on cholinergic synapses that exist between the VD4 and RPeD1 neurons in the central nervous system of the pond snail Lymnaea stagnalis. In the concentration range used (0.01-1 mg/ml), neither chemical acted as an acetylcholine (ACh) agonist; instead, both displayed antagonist activity, inhibiting the cholinergic excitatory components of the VD4-RPeD1 connection. Thiacloprid (0.01 mg/ml) blocked almost 90% of excitatory postsynaptic potentials (EPSPs), while the less effective thiamethoxam (0.1 mg/ml) reduced the synaptic responses by about 15%. The ACh-evoked membrane responses of the RPeD1 neuron were similarly inhibited by the neonicotinoids, confirming that the same ACh receptor (AChR) target was involved. We conclude that neonicotinoids act on nicotinergic acetylcholine receptors (nAChRs) in the snail CNS. This has been established previously in the insect CNS; however, our data indicate differences in the background mechanism or the nAChR binding site in the snail. Here, we provide the first results concerning neonicotinoid-related toxic effects on the neuronal connections in the molluscan nervous system. Aquatic animals, including molluscs, are at direct risk while facing contaminated surface waters, and snails may provide a suitable model for further studies of the behavioral/neuronal consequences of intoxication by neonicotinoids. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. Ac2-26 Mimetic Peptide of Annexin A1 Inhibits Local and Systemic Inflammatory Processes Induced by Bothrops moojeni Venom and the Lys-49 Phospholipase A2 in a Rat Model.

    Directory of Open Access Journals (Sweden)

    Bruna Stuqui

    Full Text Available Annexin A1 (AnxA1 is an endogenous glucocorticoid regulated protein that modulates anti-inflammatory process and its therapeutic potential has recently been recognized in a range of systemic inflammatory disorders. The effect of the N-terminal peptide Ac2-26 of AnxA1 on the toxic activities of Bothrops moojeni crude venom (CV and its myotoxin II (MjTX-II were evaluated using a peritonitis rat model. Peritonitis was induced by the intraperitoneal injection of either CV or MjTX-II, a Lys-49 phospholipase A2. Fifteen minutes after the injection, the rats were treated with either Ac2-26 or PBS. Four hours later, the CV and MjTX-II-induced peritonitis were characterized by neutrophilia (in the peritoneal exudate, blood and mesentery and increased number of mesenteric degranulated mast cells and macrophages. At 24 hours post-injection, the local inflammatory response was attenuated in the CV-induced peritonitis while the MjTX-II group exhibited neutrophilia (peritoneal exudates and blood. Ac2-26 treatment prevented the influx of neutrophils in MjTX-II-induced peritonitis and diminished the proportion of mesenteric degranulated mast cells and macrophages in CV-induced peritonitis. Additionally, CV and MjTX-II promoted increased levels of IL-1β and IL-6 in the peritoneal exudates which were significantly reduced after Ac2-26 treatment. At 4 and 24 hours, the endogenous expression of AnxA1 was upregulated in the mesenteric neutrophils (CV and MjTX-II groups and mast cells (CV group. In the kidneys, CV and MjTX-II administrations were associated with an increased number of macrophages and morphological alterations in the juxtamedullary nephrons in proximal and distal tubules. Ac2-26 promoted significant recovery of the juxtamedullary structures, decreased the number of macrophages and diminished the AnxA1 in epithelial cells from distal tubules and renal capsules. Our results show that Ac2-26 treatment significantly attenuates local and systemic

  15. BRAF inhibition improves tumor recognition by the immune system

    DEFF Research Database (Denmark)

    Donia, Marco; Fagone, Paolo; Nicoletti, Ferdinando

    2012-01-01

    to be poorly efficient. By characterizing the immunological interactions between T cells and cancer cells in clinical material as well as the influence of the FDA-approved BRAF inhibitor vemurafenib on the immune system, we aimed at unraveling new strategies to expand the efficacy of adoptive T-cell transfer...

  16. Magnolol inhibits the inflammatory response in mouse mammary epithelial cells and a mouse mastitis model.

    Science.gov (United States)

    Wei, Wang; Dejie, Liang; Xiaojing, Song; Tiancheng, Wang; Yongguo, Cao; Zhengtao, Yang; Naisheng, Zhang

    2015-02-01

    Mastitis comprises an inflammation of the mammary gland, which is almost always linked with bacterial infection. The treatment of mastitis concerns antimicrobial substances, but not very successful. On the other hand, anti-inflammatory therapy with Chinese traditional medicine becomes an effective way for treating mastitis. Magnolol is a polyphenolic binaphthalene compound extracted from the stem bark of Magnolia sp., which has been shown to exert a potential for anti-inflammatory activity. The purpose of this study was to investigate the protective effects of magnolol on inflammation in lipopolysaccharide (LPS)-induced mastitis mouse model in vivo and the mechanism of this protective effects in LPS-stimulated mouse mammary epithelial cells (MMECs) in vitro. The damage of tissues was determined by histopathology and myeloperoxidase (MPO) assay. The expression of pro-inflammatory cytokines was determined by enzyme-linked immunosorbent assay (ELISA). Nuclear factor-kappa B (NF-κB), inhibitory kappa B (IκBα) protein, p38, extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and Toll-like receptor 4 (TLR4) were determined by Western blot. The results showed that magnolol significantly inhibit the LPS-induced TNF-α, IL-6, and IL-1β production both in vivo and vitro. Magnolol declined the phosphorylation of IκBα, p65, p38, ERK, and JNK in LPS-stimulated MMECs. Furthermore, magnolol inhibited the expression of TLR4 in LPS-stimulated MMECs. In vivo study, it was also observed that magnolol attenuated the damage of mastitis tissues in the mouse models. These findings demonstrated that magnolol attenuate LPS-stimulated inflammatory response by suppressing TLR4/NF-κB/mitogen-activated protein kinase (MAPK) signaling system. Thereby, magnolol may be a therapeutic agent against mastitis.

  17. Modeling and estimating system availability

    International Nuclear Information System (INIS)

    Gaver, D.P.; Chu, B.B.

    1976-11-01

    Mathematical models to infer the availability of various types of more or less complicated systems are described. The analyses presented are probabilistic in nature and consist of three parts: a presentation of various analytic models for availability; a means of deriving approximate probability limits on system availability; and a means of statistical inference of system availability from sparse data, using a jackknife procedure. Various low-order redundant systems are used as examples, but extension to more complex systems is not difficult

  18. Inhibition of the classical pathway of the complement system by saliva of Amblyomma cajennense (Acari: Ixodidae).

    Science.gov (United States)

    Franco, Paula F; Silva, Naylene C S; Fazito do Vale, Vladimir; Abreu, Jéssica F; Santos, Vânia C; Gontijo, Nelder F; Valenzuela, Jesus G; Pereira, Marcos H; Sant'Anna, Mauricio R V; Gomes, Alessandra P S; Araujo, Ricardo N

    2016-05-01

    Inhibition of the complement system during and after haematophagy is of utmost importance for tick success in feeding and tick development. The role of such inhibition is to minimise damage to the intestinal epithelium as well as avoiding inflammation and opsonisation of salivary molecules at the bite site. Despite its importance, the salivary anti-complement activity has been characterised only in species belonging to the Ixodes ricinus complex which saliva is able to inhibit the alternative and lectin pathways. Little is known about this activity in other species of the Ixodidae family. Thus, the aim of this study was to describe the inhibition of the classical pathway of the complement system by the saliva of Amblyomma cajennense at different stages of the haematophagy. The A. cajennense saliva and salivary gland extract (SGE) were able to inhibit the complement classical pathway through haemolytic assays with higher activity observed when saliva was used. The anti-complement activity is present in the salivary glands of starving females and also in females throughout the whole feeding process, with significant higher activity soon after tick detachment. The SGE activity from both females fed on mice or horses had no significant correlation (p > 0.05) with tick body weight. The pH found in the intestinal lumen of A. cajennense was 8.04 ± 0.08 and haemolytic assays performed at pH 8.0 showed activation of the classical pathway similarly to what occurs at pH 7.4. Consequently, inhibition could be necessary to protect the tick enterocytes. Indeed, the inhibition observed by SGE was higher in pH 8.0 in comparison to pH 7.4 reinforcing the role of saliva in protecting the intestinal cells. Further studies should be carried out in order to identify the inhibitor molecule and characterise its inhibition mechanism. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Inhibition of CYP1 by berberine, palmatine, and jatrorrhizine: Selectivity, kinetic characterization, and molecular modeling

    Energy Technology Data Exchange (ETDEWEB)

    Lo, Sheng-Nan [National Research Institute of Chinese Medicine, Taipei 112, Taiwan, ROC (China); Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan, ROC (China); Chang, Yu-Ping; Tsai, Keng-Chang [National Research Institute of Chinese Medicine, Taipei 112, Taiwan, ROC (China); Chang, Chia-Yu [National Research Institute of Chinese Medicine, Taipei 112, Taiwan, ROC (China); Institute of Medical Sciences, Taipei Medical University, Taipei 101, Taiwan, ROC (China); Wu, Tian-Shung [Department of Chemistry, National Chung-Kung University, Tainan 701, Taiwan, ROC (China); Ueng, Yune-Fang, E-mail: ueng@nricm.edu.tw [National Research Institute of Chinese Medicine, Taipei 112, Taiwan, ROC (China); Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan, ROC (China); Institute of Medical Sciences, Taipei Medical University, Taipei 101, Taiwan, ROC (China)

    2013-11-01

    Cytochrome P450 (P450, CYP) 1 family plays a primary role in the detoxification and bioactivation of polycyclic aromatic hydrocarbons. Human CYP1A1, CYP1A2, and CYP1B1 exhibit differential substrate specificity and tissue distribution. Berberine, palmatine, and jatrorrhizine are protoberberine alkaloids present in several medicinal herbs, such as Coptis chinensis (Huang-Lian) and goldenseal. These protoberberines inhibited CYP1A1.1- and CYP1B1.1-catalyzed 7-ethoxyresorufin O-deethylation (EROD) activities, whereas CYP1A2.1 activity was barely affected. Kinetic analysis revealed that berberine noncompetitively inhibited EROD activities of CYP1A1.1 and CYP1B1.1, whereas palmatine and jatrorrhizine caused either competitive or mixed type of inhibition. Among protoberberines, berberine caused the most potent and selective inhibitory effect on CYP1B1.1 with the least K{sub i} value of 44 ± 16 nM. Berberine also potently inhibited CYP1B1.1 activities toward 7-ethoxycoumarin and 7-methoxyresorufin, whereas the inhibition of benzo(a)pyrene hydroxylation activity was less pronounced. Berberine inhibited the polymorphic variants, CYP1B1.3 (V432L) and CYP1B1.4 (N453S), with IC{sub 50} values comparable to that for CYP1B1.1 inhibition. Berberine-mediated inhibition was abolished by a mutation of Asn228 to Thr in CYP1B1.1, whereas the inhibition was enhanced by a reversal mutation of Thr223 to Asn in CYP1A2.1. This result in conjugation with the molecular modeling revealed the crucial role of hydrogen-bonding interaction of Asn228 on CYP1B1.1 with the methoxy moiety of berberine. These findings demonstrate that berberine causes a selective CYP1B1-inhibition, in which Asn228 appears to be crucial. The inhibitory effects of berberine on CYP1B1 activities toward structurally diverse substrates can be different. - Highlights: • Berberine preferentially inhibited CYP1B1 activity. • Berberine caused similar inhibitory effects on CYP1B1.1, CYP1B1.3 and CYP1B1.4. • Asn228 in CYP

  20. Oral Administration of Escin Inhibits Acute Inflammation and Reduces Intestinal Mucosal Injury in Animal Models

    OpenAIRE

    Li, Minmin; Lu, Chengwen; Zhang, Leiming; Zhang, Jianqiao; Du, Yuan; Duan, Sijin; Wang, Tian; Fu, Fenghua

    2015-01-01

    The present study aimed to investigate the effects of oral administration of escin on acute inflammation and intestinal mucosal injury in animal models. The effects of escin on carrageenan-induced paw edema in a rat model of acute inflammation, cecal ligation and puncture (CLP) induced intestinal mucosal injury in a mouse model, were observed. It was shown that oral administration of escin inhibits carrageenan-induced paw edema and decreases the production of prostaglandin E2 (PGE2) and cyclo...

  1. Bothrops asper metalloproteinase BaP1 is inhibited by alpha(2)-macroglobulin and mouse serum and does not induce systemic hemorrhage or coagulopathy.

    Science.gov (United States)

    Escalante, Teresa; Rucavado, Alexandra; Kamiguti, Aura S; Theakston, R David G; Gutiérrez, José María

    2004-02-01

    The ability of the P-I metalloproteinase BaP1, isolated from the venom of the snake Bothrops asper, to induce systemic bleeding, thrombocytopenia and defibrinogenation was assessed in an experimental mouse model. Intravenous administration of BaP1 caused neither systemic bleeding nor any evidence of pathology in lungs, kidneys, liver, heart and brain. Moreover, there were no alterations in the whole blood clotting time or in platelet numbers. In addition, BaP1 did not inhibit collagen-induced platelet aggregation in vitro. Proteolytic and hemorrhagic activities of BaP1 were readily inhibited by the plasma proteinase inhibitor, alpha(2)-macroglobulin, and normal mouse serum also inhibited hemorrhage. Such inhibition may explain why BaP1 induces multiple local tissue-damaging effects, but is largely devoid of systemic toxicity.

  2. Cannabidiol, among other cannabinoid drugs, modulates prepulse inhibition of startle in the SHR animal model: implications for schizophrenia pharmacotherapy

    Directory of Open Access Journals (Sweden)

    Fernanda Fiel Peres

    2016-09-01

    Full Text Available Schizophrenia is a severe psychiatric disorder that involves positive, negative and cognitive symptoms. Prepulse inhibition of startle reflex (PPI is a paradigm that assesses the sensorimotor gating functioning and is impaired in schizophrenia patients as well as in animal models of this disorder. Recent data point to the participation of the endocannabinoid system in the pathophysiology and pharmacotherapy of schizophrenia. Here, we focus on the effects of cannabinoid drugs on the PPI deficit of animal models of schizophrenia, with greater focus on the SHR (Spontaneously Hypertensive Rats strain, and on the future prospects resulting from these findings.

  3. Cyclooxygenase-2 inhibition blocks M2 macrophage differentiation and suppresses metastasis in murine breast cancer model.

    Directory of Open Access Journals (Sweden)

    Yi-Rang Na

    Full Text Available Tumor cells are often associated with abundant macrophages that resemble the alternatively activated M2 subset. Tumor-associated macrophages (TAMs inhibit anti-tumor immune responses and promote metastasis. Cyclooxygenase-2 (COX-2 inhibition is known to prevent breast cancer metastasis. This study hypothesized that COX-2 inhibition affects TAM characteristics potentially relevant to tumor cell metastasis. We found that the specific COX-2 inhibitor, etodolac, inhibited human M2 macrophage differentiation, as determined by decreased CD14 and CD163 expressions and increased TNFα production. Several key metastasis-related mediators, such as vascular endothelial growth factor-A, vascular endothelial growth factor-C, and matrix metalloproteinase-9, were inhibited in the presence of etodolac as compared to untreated M2 macrophages. Murine bone marrow derived M2 macrophages also showed enhanced surface MHCII IA/IE and CD80, CD86 expressions together with enhanced TNFα expressions with etodolac treatment during differentiation. Using a BALB/c breast cancer model, we found that etodolac significantly reduced lung metastasis, possibly due to macrophages expressing increased IA/IE and TNFα, but decreased M2 macrophage-related genes expressions (Ym1, TGFβ. In conclusion, COX-2 inhibition caused loss of the M2 macrophage characteristics of TAMs and may assist prevention of breast cancer metastasis.

  4. Modelling of reverberation enhancement systems

    OpenAIRE

    ROUCH , Jeremy; Schmich , Isabelle; Galland , Marie-Annick

    2012-01-01

    International audience; Electroacoustic enhancement systems are increasingly specified by acoustic consultants to address the requests for a multi-purpose use of performance halls. However, there is still a lack of simple models to predict the effect induced by these systems on the acoustic field. Two models are introduced to establish the impulse responses of a room equipped with a reverberation enhancement system. These models are based on passive impulse responses according to the modified...

  5. MODELLING OF MATERIAL FLOW SYSTEMS

    OpenAIRE

    PÉTER TELEK

    2012-01-01

    Material flow systems are in generally very complex processes. During design, building and operation of complex systems there are many different problems. If these complex processes can be described in a simple model, the tasks will be clearer, better adaptable and easier solvable. As the material flow systems are very different, so using models is a very important aid to create uniform methods and solutions. This paper shows the details of the application possibilities of modelling in the ma...

  6. Dynamic Modeling of ALS Systems

    Science.gov (United States)

    Jones, Harry

    2002-01-01

    The purpose of dynamic modeling and simulation of Advanced Life Support (ALS) systems is to help design them. Static steady state systems analysis provides basic information and is necessary to guide dynamic modeling, but static analysis is not sufficient to design and compare systems. ALS systems must respond to external input variations and internal off-nominal behavior. Buffer sizing, resupply scheduling, failure response, and control system design are aspects of dynamic system design. We develop two dynamic mass flow models and use them in simulations to evaluate systems issues, optimize designs, and make system design trades. One model is of nitrogen leakage in the space station, the other is of a waste processor failure in a regenerative life support system. Most systems analyses are concerned with optimizing the cost/benefit of a system at its nominal steady-state operating point. ALS analysis must go beyond the static steady state to include dynamic system design. All life support systems exhibit behavior that varies over time. ALS systems must respond to equipment operating cycles, repair schedules, and occasional off-nominal behavior or malfunctions. Biological components, such as bioreactors, composters, and food plant growth chambers, usually have operating cycles or other complex time behavior. Buffer sizes, material stocks, and resupply rates determine dynamic system behavior and directly affect system mass and cost. Dynamic simulation is needed to avoid the extremes of costly over-design of buffers and material reserves or system failure due to insufficient buffers and lack of stored material.

  7. Modeling soft interface dominated systems

    NARCIS (Netherlands)

    Lamorgese, A.; Mauri, R.; Sagis, L.M.C.

    2017-01-01

    The two main continuum frameworks used for modeling the dynamics of soft multiphase systems are the Gibbs dividing surface model, and the diffuse interface model. In the former the interface is modeled as a two dimensional surface, and excess properties such as a surface density, or surface energy

  8. Validation of systems biology models

    NARCIS (Netherlands)

    Hasdemir, D.

    2015-01-01

    The paradigm shift from qualitative to quantitative analysis of biological systems brought a substantial number of modeling approaches to the stage of molecular biology research. These include but certainly are not limited to nonlinear kinetic models, static network models and models obtained by the

  9. Hilar somatostatin interneuron loss reduces dentate gyrus inhibition in a mouse model of temporal lobe epilepsy.

    Science.gov (United States)

    Hofmann, Gabrielle; Balgooyen, Laura; Mattis, Joanna; Deisseroth, Karl; Buckmaster, Paul S

    2016-06-01

    In patients with temporal lobe epilepsy, seizures usually start in the hippocampus, and dentate granule cells are hyperexcitable. Somatostatin interneurons are a major subpopulation of inhibitory neurons in the dentate gyrus, and many are lost in patients and animal models. However, surviving somatostatin interneurons sprout axon collaterals and form new synapses, so the net effect on granule cell inhibition remains unclear. The present study uses optogenetics to activate hilar somatostatin interneurons and measure the inhibitory effect on dentate gyrus perforant path-evoked local field potential responses in a mouse model of temporal lobe epilepsy. In controls, light activation of hilar somatostatin interneurons inhibited evoked responses up to 40%. Epileptic pilocarpine-treated mice exhibited loss of hilar somatostatin interneurons and less light-induced inhibition of evoked responses. These findings suggest that severe epilepsy-related loss of hilar somatostatin interneurons can overwhelm the surviving interneurons' capacity to compensate by sprouting axon collaterals. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

  10. From Numeric Models to Granular System Modeling

    Directory of Open Access Journals (Sweden)

    Witold Pedrycz

    2015-03-01

    To make this study self-contained, we briefly recall the key concepts of granular computing and demonstrate how this conceptual framework and its algorithmic fundamentals give rise to granular models. We discuss several representative formal setups used in describing and processing information granules including fuzzy sets, rough sets, and interval calculus. Key architectures of models dwell upon relationships among information granules. We demonstrate how information granularity and its optimization can be regarded as an important design asset to be exploited in system modeling and giving rise to granular models. With this regard, an important category of rule-based models along with their granular enrichments is studied in detail.

  11. Phenylmethimazole inhibits production of proinflammatory mediators and is protective in an experimental model of endotoxic shock*.

    Science.gov (United States)

    Benavides, Uruguaysito; Gonzalez-Murguiondo, Mariana; Harii, Norikazu; Lewis, Christopher J; Schwartz, Anthony L; Giuliani, Cesidio; Napolitano, Giorgio; Dagia, Nilesh M; Malgor, Ramiro; McCall, Kelly D; Kohn, Leonard D

    2012-03-01

    One form of sepsis, or endotoxic shock, is a hyperactivated systemic response caused by excessive expression of proinflammatory mediators, which results from Gram-negative bacterial lipopolysaccharide-stimulated Toll-like receptor-4 signaling. This lipopolysaccharide signaling is known to consist of a MyD88-dependent nuclear factor-κB-mediated pathway that results in production of proinflammatory mediators (tumor necrosis factor-α, interleukin-6, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, inducible nitric oxide synthase, cyclooxygenase-2) and a MyD88-independent interferon regulatory factor-mediated pathway that regulates production of Type 1 interferon-inducible proteins (interferon γ-induced protein-10, monocyte chemotactic protein-1). In prior studies, phenylmethimazole markedly decreased virally induced Toll-like receptor-3 expression and signaling and significantly suppressed murine colitis in an experimental model wherein lipopolysaccharide is known to play an important role. In this study, we probed the hypothesis that phenylmethimazole inhibits lipopolysaccharide-mediated Toll-like receptor-4 signaling and is efficacious in attenuating inflammatory changes and improving survival in an in vivo murine model of endotoxic shock. Experimental animal model. University laboratory. Male C57BL/6J mice weighing 18-22 g. Phenylmethimazole (1 mg/kg) was administered intraperitoneally to mice before a lethal lipopolysaccharide challenge (25 mg/kg). RAW264.7 mouse macrophage cells were pretreated with phenylmethimazole followed by lipopolysaccharide stimulation. : Macroscopic observations revealed that phenylmethimazole was significantly protective in controlling clinical manifestations of endotoxic shock and death under conditions wherein flunixin of meglumine and prednisolone were marginally effective. A combination of enzyme-linked immunosorbent assay, Northern blot, reverse transcriptase-polymerase chain reaction, immunohistochemistry

  12. Coastal Modeling System Advanced Topics

    Science.gov (United States)

    2012-06-18

    22 June 2012 - Day 5  Debugging and Problem solving  Model Calibration  Post-processing Coastal and Hydraulics Laboratory Focus of...Efficiently: • The setup process is fast and without wasted time or effort 3 Coastal and Hydraulics Laboratory 4 Coastal Modeling System (CMS) What...is the CMS? Integrated wave, current, and morphology change model in the Surface- water Modeling System (SMS). Why CMS? Operational at 10

  13. Stabilization of natural colors and nutraceuticals: Inhibition of anthocyanin degradation in model beverages using polyphenols.

    Science.gov (United States)

    Chung, Cheryl; Rojanasasithara, Thananunt; Mutilangi, William; McClements, David Julian

    2016-12-01

    Anthocyanins are widely used as natural colorants in foods, but they are highly susceptible to chemical degradation during storage leading to color fading. This study examined the potential of natural quillaja saponin and polyphenols (vanillin, epigallocatechin gallate, green tea extract, and protocatechualdehyde) at inhibiting color fading of anthocyanins in model beverages. The purple carrot anthocyanin (0.025%) in model beverages (citric acid, pH 3.0) containing l-ascorbic acid (0.050%) degraded with a first-order reaction rate during storage (40°C/7days in light). The addition of polyphenols (0.2%) delayed color fading, with the most notable improvement observed with green tea extract addition. The half-life for anthocyanin color fading increased from 2.9 to 6.7days with green tea extract. Fluorescence quenching measurements showed that the green tea extract contained components that interacted with anthocyanins probably through hydrophobic interactions. Overall, this study provides valuable information about enhancing the stability of anthocyanins in beverage systems using polyphenols. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Oral Administration of Escin Inhibits Acute Inflammation and Reduces Intestinal Mucosal Injury in Animal Models

    Directory of Open Access Journals (Sweden)

    Minmin Li

    2015-01-01

    Full Text Available The present study aimed to investigate the effects of oral administration of escin on acute inflammation and intestinal mucosal injury in animal models. The effects of escin on carrageenan-induced paw edema in a rat model of acute inflammation, cecal ligation and puncture (CLP induced intestinal mucosal injury in a mouse model, were observed. It was shown that oral administration of escin inhibits carrageenan-induced paw edema and decreases the production of prostaglandin E2 (PGE2 and cyclooxygenase- (COX- 2. In CLP model, low dose of escin ameliorates endotoxin induced liver injury and intestinal mucosal injury and increases the expression of tight junction protein claudin-5 in mice. These findings suggest that escin effectively inhibits acute inflammation and reduces intestinal mucosal injury in animal models.

  15. Oral Administration of Escin Inhibits Acute Inflammation and Reduces Intestinal Mucosal Injury in Animal Models.

    Science.gov (United States)

    Li, Minmin; Lu, Chengwen; Zhang, Leiming; Zhang, Jianqiao; Du, Yuan; Duan, Sijin; Wang, Tian; Fu, Fenghua

    2015-01-01

    The present study aimed to investigate the effects of oral administration of escin on acute inflammation and intestinal mucosal injury in animal models. The effects of escin on carrageenan-induced paw edema in a rat model of acute inflammation, cecal ligation and puncture (CLP) induced intestinal mucosal injury in a mouse model, were observed. It was shown that oral administration of escin inhibits carrageenan-induced paw edema and decreases the production of prostaglandin E2 (PGE2) and cyclooxygenase- (COX-) 2. In CLP model, low dose of escin ameliorates endotoxin induced liver injury and intestinal mucosal injury and increases the expression of tight junction protein claudin-5 in mice. These findings suggest that escin effectively inhibits acute inflammation and reduces intestinal mucosal injury in animal models.

  16. Safeguards system effectiveness modeling

    International Nuclear Information System (INIS)

    Bennett, H.A.; Boozer, D.D.; Chapman, L.D.; Daniel, S.L.; Engi, D.; Hulme, B.L.; Varnado, G.B.

    1976-01-01

    A general methodology for the comparative evaluation of physical protection system effectiveness at nuclear facilities is presently under development. The approach is applicable to problems of sabotage or theft at fuel cycle facilities. The overall methodology and the primary analytic techniques used to assess system effectiveness are briefly outlined

  17. Safeguards system effectiveness modeling

    International Nuclear Information System (INIS)

    Bennett, H.A.; Boozer, D.D.; Chapman, L.D.; Daniel, S.L.; Engi, D.; Hulme, B.L.; Varnado, G.B.

    1976-01-01

    A general methodology for the comparative evaluation of physical protection system effectiveness at nuclear facilities is presently under development. The approach is applicable to problems of sabotage or theft at fuel cycle facilities. In this paper, the overall methodology and the primary analytic techniques used to assess system effectiveness are briefly outlined

  18. Are US utility standby rates inhibiting diffusion of customer-owned generating systems?

    International Nuclear Information System (INIS)

    Jackson, Jerry

    2007-01-01

    New, small-scale electric generation technologies permit utility customers to generate some of their own electric power and to utilize waste heat for space heating and other applications at the building site. This combined heat and power (CHP) characteristic can provide significant energy-cost savings. However, most current US utility regulations leave CHP standby rate specification largely to utility discretion resulting in claims by CHP advocates that excessive standby rates are significantly reducing CHP-related savings and inhibiting CHP diffusion. The impacts of standby rates on the adoption of CHP are difficult to determine; however, because of the characteristically slow nature of new technology diffusion. This study develops an agent-based microsimulation model of CHP technology choice using cellular automata to represent new technology information dispersion and knowledge acquisition. Applying the model as an n-factorial experiment quantifies the impacts of standby rates on CHP technologies under alternative diffusion paths. Analysis of a sample utility indicates that, regardless of the likely diffusion process, reducing standby rates to reflect the cost of serving a large number of small, spatially clustered CHP systems significantly increases the adoption of these technologies

  19. Inhibition of bacterial oxidation of ferrous iron by lead nitrate in sulfate-rich systems

    Science.gov (United States)

    Wang, Hongmei; Gong, Linfeng; Cravotta,, Charles A.; Yang, Xiaofen; Tuovinen, Olli H.; Dong, Hailiang; Fu, Xiang

    2013-01-01

    Inhibition of bacterial oxidation of ferrous iron (Fe(II)) by Pb(NO3)2 was investigated with a mixed culture of Acidithiobacillus ferrooxidans. The culture was incubated at 30 °C in ferrous-sulfate medium amended with 0–24.2 mM Pb(II) added as Pb(NO3)2. Anglesite (PbSO4) precipitated immediately upon Pb addition and was the only solid phase detected in the abiotic controls. Both anglesite and jarosite (KFe3(SO4)2(OH)6) were detected in inoculated cultures. Precipitation of anglesite maintained dissolved Pb concentrations at 16.9–17.6 μM regardless of the concentrations of Pb(NO3)2 added. Fe(II) oxidation was suppressed by 24.2 mM Pb(NO3)2 addition even when anglesite was removed before inoculation. Experiments with 0–48 mM KNO3 demonstrated that bacterial Fe(II) oxidation decreased as nitrate concentration increased. Therefore, inhibition of Fe(II) oxidation at 24.2 mM Pb(NO3)2 addition resulted from nitrate toxicity instead of Pb addition. Geochemical modeling that considered the initial precipitation of anglesite to equilibrium followed by progressive oxidation of Fe(II) and the precipitation of jarosite and an amorphous iron hydroxide phase, without allowing plumbojarosite to precipitate were consistent with the experimental time-series data on Fe(II) oxidation under biotic conditions. Anglesite precipitation in mine tailings and other sulfate-rich systems maintains dissolved Pb concentrations below the toxicity threshold of A. ferrooxidans.

  20. Inhibition of vicariously learned fear in children using positive modeling and prior exposure.

    Science.gov (United States)

    Askew, Chris; Reynolds, Gemma; Fielding-Smith, Sarah; Field, Andy P

    2016-02-01

    One of the challenges to conditioning models of fear acquisition is to explain how different individuals can experience similar learning events and only some of them subsequently develop fear. Understanding factors moderating the impact of learning events on fear acquisition is key to understanding the etiology and prevention of fear in childhood. This study investigates these moderators in the context of vicarious (observational) learning. Two experiments tested predictions that the acquisition or inhibition of fear via vicarious learning is driven by associative learning mechanisms similar to direct conditioning. In Experiment 1, 3 groups of children aged 7 to 9 years received 1 of 3 inhibitive information interventions-psychoeducation, factual information, or no information (control)-prior to taking part in a vicarious fear learning procedure. In Experiment 2, 3 groups of children aged 7 to 10 years received 1 of 3 observational learning interventions-positive modeling (immunization), observational familiarity (latent inhibition), or no prevention (control)-before vicarious fear learning. Results indicated that observationally delivered manipulations inhibited vicarious fear learning, while preventions presented via written information did not. These findings confirm that vicarious learning shares some of the characteristics of direct conditioning and can explain why not all individuals will develop fear following a vicarious learning event. They also suggest that the modality of inhibitive learning is important and should match the fear learning pathway for increased chances of inhibition. Finally, the results demonstrate that positive modeling is likely to be a particularly effective method for preventing fear-related observational learning in children. (c) 2016 APA, all rights reserved).

  1. Pharmacological activation/inhibition of the cannabinoid system affects alcohol withdrawal-induced neuronal hypersensitivity to excitotoxic insults.

    Directory of Open Access Journals (Sweden)

    Marina Rubio

    Full Text Available Cessation of chronic ethanol consumption can increase the sensitivity of the brain to excitotoxic damages. Cannabinoids have been proposed as neuroprotectants in different models of neuronal injury, but their effect have never been investigated in a context of excitotoxicity after alcohol cessation. Here we examined the effects of the pharmacological activation/inhibition of the endocannabinoid system in an in vitro model of chronic ethanol exposure and withdrawal followed by an excitotoxic challenge. Ethanol withdrawal increased N-methyl-D-aspartate (NMDA-evoked neuronal death, probably by altering the ratio between GluN2A and GluN2B NMDA receptor subunits. The stimulation of the endocannabinoid system with the cannabinoid agonist HU-210 decreased NMDA-induced neuronal death exclusively in ethanol-withdrawn neurons. This neuroprotection could be explained by a decrease in NMDA-stimulated calcium influx after the administration of HU-210, found exclusively in ethanol-withdrawn neurons. By contrast, the inhibition of the cannabinoid system with the CB1 receptor antagonist rimonabant (SR141716 during ethanol withdrawal increased death of ethanol-withdrawn neurons without any modification of NMDA-stimulated calcium influx. Moreover, chronic administration of rimonabant increased NMDA-stimulated toxicity not only in withdrawn neurons, but also in control neurons. In summary, we show for the first time that the stimulation of the endocannabinoid system is protective against the hyperexcitability developed during alcohol withdrawal. By contrast, the blockade of the endocannabinoid system is highly counterproductive during alcohol withdrawal.

  2. A Systems Chemical Biology Study of Malate Synthase and Isocitrate Lyase Inhibition in Mycobacterium tuberculosis During Active and NRP Growth

    Science.gov (United States)

    May, Elebeoba E.; Leitão, Andrei; Tropsha, Alexander; Oprea, Tudor I.

    2013-01-01

    The ability of Mycobacterium tuberculosis (Mtb) to survive in low oxygen environments enables the bacterium to persist in a latent state within host tissues. In vitro studies of Mtb growth have identified changes in isocitrate lyase (ICL) and malate synthase (MS) that enable bacterial persistent under low oxygen and other environmentally limiting conditions. Systems chemical biology (SCB) enables us to evaluate the effects of small molecule inhibitors not only on the reaction catalyzed by malate synthase and isocitrate lyase, but the effect on the complete tricarboxylic acid cycle (TCA) by taking into account complex network relationships within that system. To study the kinetic consequences of inhibition on persistent bacilli, we implement a systems-chemical biology (SCB) platform and perform a chemistry-centric analysis of key metabolic pathways believed to impact Mtb latency. We explore consequences of disrupting the function of malate synthase (MS) and isocitrate lyase (ICL) during aerobic and hypoxic non-replicating persistence (NRP) growth by using the SCB method to identify small molecules that inhibit the function of MS and ICL, and simulating the metabolic consequence of the disruption. Results indicate variations in target and non-target reaction steps, clear differences in the normal and low oxygen models, as well as dosage dependent response. Simulation results from singular and combined enzyme inhibition strategies suggest ICL may be the more effective target for chemotherapeutic treatment against Mtb growing in a microenvironment where oxygen is slowly depleted, which may favor persistence. PMID:24121675

  3. Inhibition of bacterial foodborne pathogens by the lactoperoxidase system in combination with monolaurin.

    Science.gov (United States)

    McLay, J C; Kennedy, M J; Orourke, A L; Elliot, R M; Simmonds, R S

    2002-02-25

    The lactoperoxidase system (LPS) and monolaurin (ML) are potential natural antimicrobial agents for use in foods. The LPS is considered to have greatest activity against Gram-negative bacteria while ML is usually considered to have greatest activity against Gram-positive bacteria. An LPS-ML combination system (utilizing lactoperoxidase (LPX) in the range 5-200 mg kg(-1) and ML in the range 50-1,000 ppm) inhibited growth of Escherichia coli O157:H7 and Staphylococcus aureus. Growth of S. aureus was inhibited more strongly in broth than in milk, in milk than in ground beef A similar pattern was observed for E. coli O157:H7, though enhanced inhibition by LPS-ML systems over that obtained in comparable LPS only systems was not observed in ground beef The inhibitory action of the LPS in combination with other lipids was also examined, with progressively weaker inhibition observed in combinations including palmitoleic acid, monopalmitolein, lauric acid, caprylic acid, and sodium lauryl sulphate.

  4. Sensitivity of Gray's Behavioral Inhibition System in clinically anxious and non-anxious children and adolescents

    NARCIS (Netherlands)

    Vervoort, Leentje; Wolters, Lidewij H.; Hogendoorn, Sanne M.; de Haan, Else; Boer, Frits; Prins, Pier J. M.

    2010-01-01

    The child version of the Carver and White (1994) BIS/BAS-scales (Muris et al., 2005) was used to assess sensitivity of the Behavioral Inhibition and the Behavioral Activation System in clinically anxious and non-anxious youth (n = 175, ages 8-18 years, 70 boys). Results supported the hypothesis that

  5. Validation of Inhibition Effect in the Cellulose Hydrolysis: a Dynamic Modelling Approach

    DEFF Research Database (Denmark)

    Morales Rodriguez, Ricardo; Tsai, Chien-Tai; Meyer, Anne S.

    2011-01-01

    Enzymatic hydrolysis is one of the main steps in the processing of bioethanol from lignocellulosic raw materials. However, complete understanding of the underlying phenomena is still under development. Hence, this study has focused on validation of the inhibition effects in the cellulosic biomass...... for parameter estimation (calibration) and validation purposes. The model predictions using calibrated parameters have shown good agreement with the validation data sets, which provides credibility to the model structure and the parameter values....

  6. Mechanical Systems, Classical Models

    CERN Document Server

    Teodorescu, Petre P

    2007-01-01

    All phenomena in nature are characterized by motion; this is an essential property of matter, having infinitely many aspects. Motion can be mechanical, physical, chemical or biological, leading to various sciences of nature, mechanics being one of them. Mechanics deals with the objective laws of mechanical motion of bodies, the simplest form of motion. In the study of a science of nature mathematics plays an important role. Mechanics is the first science of nature which was expressed in terms of mathematics by considering various mathematical models, associated to phenomena of the surrounding nature. Thus, its development was influenced by the use of a strong mathematical tool; on the other hand, we must observe that mechanics also influenced the introduction and the development of many mathematical notions. In this respect, the guideline of the present book is precisely the mathematical model of mechanics. A special accent is put on the solving methodology as well as on the mathematical tools used; vectors, ...

  7. Stochastic Modelling of Energy Systems

    DEFF Research Database (Denmark)

    Andersen, Klaus Kaae

    2001-01-01

    In this thesis dynamic models of typical components in Danish heating systems are considered. Emphasis is made on describing and evaluating mathematical methods for identification of such models, and on presentation of component models for practical applications. The thesis consists of seven...... of component models, such as e.g. heat exchanger and valve models, adequate for system simulations. Furthermore, the thesis demonstrates and discusses the advantages and disadvantages of using statistical methods in conjunction with physical knowledge in establishing adequate component models of heating...... research papers (case studies) together with a summary report. Each case study takes it's starting point in typical heating system components and both, the applied mathematical modelling methods and the application aspects, are considered. The summary report gives an introduction to the scope...

  8. A Loudness Model for Time-Varying Sounds Incorporating Binaural Inhibition

    Directory of Open Access Journals (Sweden)

    Brian C. J. Moore

    2016-12-01

    Full Text Available This article describes a model of loudness for time-varying sounds that incorporates the concept of binaural inhibition, namely, that the signal applied to one ear can reduce the internal response to a signal at the other ear. For each ear, the model includes the following: a filter to allow for the effects of transfer of sound through the outer and middle ear; a short-term spectral analysis with greater frequency resolution at low than at high frequencies; calculation of an excitation pattern, representing the magnitudes of the outputs of the auditory filters as a function of center frequency; application of a compressive nonlinearity to the output of each auditory filter; and smoothing over time of the resulting instantaneous specific loudness pattern using an averaging process resembling an automatic gain control. The resulting short-term specific loudness patterns are used to calculate broadly tuned binaural inhibition functions, the amount of inhibition depending on the relative short-term specific loudness at the two ears. The inhibited specific loudness patterns are summed across frequency to give an estimate of the short-term loudness for each ear. The overall short-term loudness is calculated as the sum of the short-term loudness values for the two ears. The long-term loudness for each ear is calculated by smoothing the short-term loudness for that ear, again by a process resembling automatic gain control, and the overall loudness impression is obtained by summing the long-term loudness across ears. The predictions of the model are more accurate than those of an earlier model that did not incorporate binaural inhibition.

  9. Roles of abscisic acid and auxin in shoot-supplied ammonium inhibition of root system development

    OpenAIRE

    Li, Baohai; Li, Qing; Kronzucker, Herbert J; Shi, Weiming

    2011-01-01

    A plastic root system is a prerequisite for successful plant acclimation to variable environments. The normally functioning root system is the result of a complex interaction of root-borne signals and shoot-derived regulators. We recently demonstrated that AUX1, a well-studied component of auxin transport, mediates shoot-supplied ammonium (SSA) inhibition of lateral root (LR) formation in Arabidopsis. By contrast, the response did not involve ABA pathways, via which several other abiotic stre...

  10. Kynurenine-3-monooxygenase inhibition prevents multiple organ failure in rodent models of acute pancreatitis.

    Science.gov (United States)

    Mole, Damian J; Webster, Scott P; Uings, Iain; Zheng, Xiaozhong; Binnie, Margaret; Wilson, Kris; Hutchinson, Jonathan P; Mirguet, Olivier; Walker, Ann; Beaufils, Benjamin; Ancellin, Nicolas; Trottet, Lionel; Bénéton, Véronique; Mowat, Christopher G; Wilkinson, Martin; Rowland, Paul; Haslam, Carl; McBride, Andrew; Homer, Natalie Z M; Baily, James E; Sharp, Matthew G F; Garden, O James; Hughes, Jeremy; Howie, Sarah E M; Holmes, Duncan S; Liddle, John; Iredale, John P

    2016-02-01

    Acute pancreatitis (AP) is a common and devastating inflammatory condition of the pancreas that is considered to be a paradigm of sterile inflammation leading to systemic multiple organ dysfunction syndrome (MODS) and death. Acute mortality from AP-MODS exceeds 20% (ref. 3), and the lifespans of those who survive the initial episode are typically shorter than those of the general population. There are no specific therapies available to protect individuals from AP-MODS. Here we show that kynurenine-3-monooxygenase (KMO), a key enzyme of tryptophan metabolism, is central to the pathogenesis of AP-MODS. We created a mouse strain that is deficient for Kmo (encoding KMO) and that has a robust biochemical phenotype that protects against extrapancreatic tissue injury to the lung, kidney and liver in experimental AP-MODS. A medicinal chemistry strategy based on modifications of the kynurenine substrate led to the discovery of the oxazolidinone GSK180 as a potent and specific inhibitor of KMO. The binding mode of the inhibitor in the active site was confirmed by X-ray co-crystallography at 3.2 Å resolution. Treatment with GSK180 resulted in rapid changes in the levels of kynurenine pathway metabolites in vivo, and it afforded therapeutic protection against MODS in a rat model of AP. Our findings establish KMO inhibition as a novel therapeutic strategy in the treatment of AP-MODS, and they open up a new area for drug discovery in critical illness.

  11. Model Reduction of Hybrid Systems

    DEFF Research Database (Denmark)

    Shaker, Hamid Reza

    for model reduction of switched systems is based on the switching generalized gramians. The reduced order switched system is guaranteed to be stable for all switching signal in this method. This framework uses stability conditions which are based on switching quadratic Lyapunov functions which are less...... conservative than the stability conditions based on common quadratic Lyapunov functions. The stability conditions which are used for this method are very useful in model reduction and design problems because they have slack variables in the conditions. Similar conditions for a class of switched nonlinear......High-Technological solutions of today are characterized by complex dynamical models. A lot of these models have inherent hybrid/switching structure. Hybrid/switched systems are powerful models for distributed embedded systems design where discrete controls are applied to continuous processes...

  12. Distribution system modeling and analysis

    CERN Document Server

    Kersting, William H

    2001-01-01

    For decades, distribution engineers did not have the sophisticated tools developed for analyzing transmission systems-often they had only their instincts. Things have changed, and we now have computer programs that allow engineers to simulate, analyze, and optimize distribution systems. Powerful as these programs are, however, without a real understanding of the operating characteristics of a distribution system, engineers using the programs can easily make serious errors in their designs and operating procedures. Distribution System Modeling and Analysis helps prevent those errors. It gives readers a basic understanding of the modeling and operating characteristics of the major components of a distribution system. One by one, the author develops and analyzes each component as a stand-alone element, then puts them all together to analyze a distribution system comprising the various shunt and series devices for power-flow and short-circuit studies. He includes the derivation of all models and includes many num...

  13. Inhibition of corrosion of carbon steel by heptane sulphonic acid – Zn2+ system

    Directory of Open Access Journals (Sweden)

    C. MARY ANBARAS

    2012-03-01

    Full Text Available Corrosion inhibition of carbon steel in dam water by sodium heptane sulphonate (SHS and zinc ion system was investigated using weight loss and potentiodynamic polarization methods. Results of weight loss method indicated that inhibition efficiency (IE increased as the inhibitor concentration increased. A synergistic effect existed between SHS and Zn2+. The influence of sodium potassium tartrate (SPT on the IE of the SHS-Zn2+ system was evaluated. As the immersion period increased, the IE decreased. Polarization study revealed that SHS-Zn2+ system functioned as a cathodic inhibitor. AC impedance spectra revealed that a protective film was formed on the metal surface. The nature of the metal surface was analyzed by FTIR spectra, SEM and AFM analyses.

  14. Hydronic distribution system computer model

    Energy Technology Data Exchange (ETDEWEB)

    Andrews, J.W.; Strasser, J.J.

    1994-10-01

    A computer model of a hot-water boiler and its associated hydronic thermal distribution loop has been developed at Brookhaven National Laboratory (BNL). It is intended to be incorporated as a submodel in a comprehensive model of residential-scale thermal distribution systems developed at Lawrence Berkeley. This will give the combined model the capability of modeling forced-air and hydronic distribution systems in the same house using the same supporting software. This report describes the development of the BNL hydronics model, initial results and internal consistency checks, and its intended relationship to the LBL model. A method of interacting with the LBL model that does not require physical integration of the two codes is described. This will provide capability now, with reduced up-front cost, as long as the number of runs required is not large.

  15. Central inhibition of initiation of swallowing by systemic administration of diazepam and baclofen in anaesthetized rats.

    Science.gov (United States)

    Tsujimura, Takanori; Sakai, Shogo; Suzuki, Taku; Ujihara, Izumi; Tsuji, Kojun; Magara, Jin; Canning, Brendan J; Inoue, Makoto

    2017-05-01

    Dysphagia is caused not only by neurological and/or structural damage but also by medication. We hypothesized memantine, dextromethorphan, diazepam, and baclofen, all commonly used drugs with central sites of action, may regulate swallowing function. Swallows were evoked by upper airway (UA)/pharyngeal distension, punctate mechanical stimulation using a von Frey filament, capsaicin or distilled water (DW) applied topically to the vocal folds, and electrical stimulation of a superior laryngeal nerve (SLN) in anesthetized rats and were documented by recording electromyographic activation of the suprahyoid and thyrohyoid muscles and by visualizing laryngeal elevation. The effects of intraperitoneal or topical administration of each drug on swallowing function were studied. Systemic administration of diazepam and baclofen, but not memantine or dextromethorphan, inhibited swallowing evoked by mechanical, chemical, and electrical stimulation. Both benzodiazepines and GABA A receptor antagonists diminished the inhibitory effects of diazepam, whereas a GABA B receptor antagonist diminished the effects of baclofen. Topically applied diazepam or baclofen had no effect on swallowing. These data indicate that diazepam and baclofen act centrally to inhibit swallowing in anesthetized rats. NEW & NOTEWORTHY Systemic administration of diazepam and baclofen, but not memantine or dextromethorphan, inhibited swallowing evoked by mechanical, chemical, and electrical stimulation. Both benzodiazepines and GABA A receptor antagonists diminished the inhibitory effects of diazepam, whereas a GABA B receptor antagonist diminished the effects of baclofen. Topical applied diazepam or baclofen was without effect on swallowing. Diazepam and baclofen act centrally to inhibit swallowing in anesthetized rats. Copyright © 2017 the American Physiological Society.

  16. PROTEIN AGREGATION MODELS OF PARKINSONS DISEASE USING VIRAL VECTORS, PROTEASOME INHIBITION AND INOCULATION OF PREFORMED FIBRILS IN THE GOTTINGEN MINIPIG CNS

    DEFF Research Database (Denmark)

    Glud, Andreas Nørgaard; Lillethorup, Thea Pinholt; Landeck, Natalie

    SYN) fibrils, overexpressing aSYN using Lentivirus (LV) and Adeno Assosiated Virus (AAV) vectors or proteasome inhibition in the nigrostriatal system, we hope to create a new porcine models for PD. Methods: Using conventional human-intended stereotaxic neurosurgery methods, we apply aSYN or preformed fibrils...

  17. Intrusion detection: systems and models

    Science.gov (United States)

    Sherif, J. S.; Dearmond, T. G.

    2002-01-01

    This paper puts forward a review of state of the art and state of the applicability of intrusion detection systems, and models. The paper also presents a classfication of literature pertaining to intrusion detection.

  18. Plant and safety system model

    International Nuclear Information System (INIS)

    Beltracchi, Leo

    1999-01-01

    The design and development of a digital computer-based safety system for a nuclear power plant is a complex process. The process of design and product development must result in a final product free of critical errors; operational safety of nuclear power plants must not be compromised. This paper focuses on the development of a safety system model to assist designers, developers, and regulators in establishing and evaluating requirements for a digital computer-based safety system. The model addresses hardware, software, and human elements for use in the requirements definition process. The purpose of the safety system model is to assist and serve as a guide to humans in the cognitive reasoning process of establishing requirements. The goals in the use of the model are to: (1) enhance the completeness of the requirements and (2) reduce the number of errors associated with the requirements definition phase of a project

  19. Relationship between suicide ideation and Behavioral Inhibition/Activation Systems (BIS/BAS and perfectionism

    Directory of Open Access Journals (Sweden)

    Mansour Bairami

    2015-03-01

    Full Text Available Background: The present research investigated the relationship between suicide ideation and Behavioral Inhibition/Activation Systems (BIS/BAS and perfectionism in university Studants. Methods: This descriptive-correlational study was conducted on200 students at university of Tabriz that were selected by multistage cluster sampling. The subjects answered three questionnaires: Beck Scale for Suicide Ideation (BSSI, Multidimensional Perfectionism Scale (MPS and Gray-Wilson Personality Questionnaire (GWPQ. Data were analyzed by Pearson correlation and multiple regression. Results: Results showed that there is a significant relationship between suicide ideation and behavioral inhibition system (R=0/55, self-oriented perfectionism(R=0/40 and socially- prescribed perfectionism (0/47 (p=0.01. Also, the results of regression analysis showed that behavioral inhibition system, self-oriented and socially-prescribed perfectionism could significantly predict suicide ideation. Conclusion: Behavioral activation system (BIS and self-oriented /socially prescribed perfectionism were correlated to and could predict suicide ideation.

  20. Mathematical modeling of aeroelastic systems

    Science.gov (United States)

    Velmisov, Petr A.; Ankilov, Andrey V.; Semenova, Elizaveta P.

    2017-12-01

    In the paper, the stability of elastic elements of a class of designs that are in interaction with a gas or liquid flow is investigated. The definition of the stability of an elastic body corresponds to the concept of stability of dynamical systems by Lyapunov. As examples the mathematical models of flowing channels (models of vibration devices) at a subsonic flow and the mathematical models of protective surface at a supersonic flow are considered. Models are described by the related systems of the partial differential equations. An analytic investigation of stability is carried out on the basis of the construction of Lyapunov-type functionals, a numerical investigation is carried out on the basis of the Galerkin method. The various models of the gas-liquid environment (compressed, incompressible) and the various models of a deformable body (elastic linear and elastic nonlinear) are considered.

  1. ABSTRACT MODELS FOR SYSTEM VIRTUALIZATION

    Directory of Open Access Journals (Sweden)

    M. G. Koveshnikov

    2015-05-01

    Full Text Available The paper is dedicated to issues of system objects securing (system files and user system or application configuration files against unauthorized access including denial of service attacks. We have suggested the method and developed abstract system virtualization models, which are used toresearch attack scenarios for different virtualization modes. Estimation for system tools virtualization technology effectiveness is given. Suggested technology is based on redirection of access requests to system objects shared among access subjects. Whole and partial system virtualization modes have been modeled. The difference between them is the following: in the whole virtualization mode all copies of access system objects are created whereon subjects’ requests are redirected including corresponding application objects;in the partial virtualization mode corresponding copies are created only for part of a system, for example, only system objects for applications. Alternative solutions effectiveness is valued relating to different attack scenarios. We consider proprietary and approved technical solution which implements system virtualization method for Microsoft Windows OS family. Administrative simplicity and capabilities of correspondingly designed system objects security tools are illustrated on this example. Practical significance of the suggested security method has been confirmed.

  2. Aerodynamic and Mechanical System Modelling

    DEFF Research Database (Denmark)

    Jørgensen, Martin Felix

    This thesis deals with mechanical multibody-systems applied to the drivetrain of a 500 kW wind turbine. Particular focus has been on gearbox modelling of wind turbines. The main part of the present project involved programming multibody systems to investigate the connection between forces, moments...

  3. Study the effect of synthesized graft copolymer on the inhibitive water based drilling fluid system

    Directory of Open Access Journals (Sweden)

    Rajat Jain

    2017-12-01

    Full Text Available This research paper consists of the synthesis of carboxymethyl-graft-polyacrylamide copolymer by free radical polymerization technique and its characterization using Fourier transform infrared spectroscopy (FTIR, field-emission scanning electron microscopy (FESEM and thermogravimetric analysis. This graft copolymer was used as a drilling fluid additive and its effect on the Indian reactive shale sample was analyzed. The characterization of the shale sample used in this study was done by X-ray diffraction technique (XRD, FTIR, FESEM, and energy-dispersive X-ray spectroscopy (EDX to determine the presence of various clay minerals. Experimental investigations revealed that the synthesized graft copolymer has a significant effect on the rheological and filtration properties of the inhibitive drilling fluid system and has high shale recovery performance. Hence, inhibitive drilling fluid system using synthesized graft copolymer may be used for the drilling of water sensitive shale formations.

  4. Preface: the hydra model system.

    Science.gov (United States)

    Galliot, Brigitte

    2012-01-01

    The freshwater Hydra polyp emerged as a model system in 1741 when Abraham Trembley not only discovered its amazing regenerative potential, but also demonstrated that experimental manipulations pave the way to research in biology. Since then, Hydra flourished as a potent and fruitful model system to help answer questions linked to cell and developmental biology, as such as the setting up of an organizer to regenerate a complex missing structure, the establishment and maintainance of polarity in a multicellular organism, the development of mathematical models to explain the robust developmental rules observed in this animal, the maintainance of stemness and multipotency in a highly dynamic environment, the plasticity of differentiated cells, to name but a few. However the Hydra model system is not restricted to cell and developmental biology; during the past 270 years it has also been heavily used to investigate the relationships between Hydra and its environment, opening new horizons concerning neurophysiology, innate immunity, ecosystems, ecotoxicology, symbiosis...

  5. Modeling Multi-Level Systems

    CERN Document Server

    Iordache, Octavian

    2011-01-01

    This book is devoted to modeling of multi-level complex systems, a challenging domain for engineers, researchers and entrepreneurs, confronted with the transition from learning and adaptability to evolvability and autonomy for technologies, devices and problem solving methods. Chapter 1 introduces the multi-scale and multi-level systems and highlights their presence in different domains of science and technology. Methodologies as, random systems, non-Archimedean analysis, category theory and specific techniques as model categorification and integrative closure, are presented in chapter 2. Chapters 3 and 4 describe polystochastic models, PSM, and their developments. Categorical formulation of integrative closure offers the general PSM framework which serves as a flexible guideline for a large variety of multi-level modeling problems. Focusing on chemical engineering, pharmaceutical and environmental case studies, the chapters 5 to 8 analyze mixing, turbulent dispersion and entropy production for multi-scale sy...

  6. Escin inhibits type I allergic dermatitis in a novel porcine model.

    Science.gov (United States)

    Sipos, Wolfgang; Reutterer, Benjamin; Frank, Maria; Unger, Hermann; Grassauer, Andreas; Prieschl-Grassauer, Eva; Doerfler, Petra

    2013-01-01

    Current standard medications for the treatment of allergic inflammation consist primarily of glucocorticoids and anti-histamines, but adverse side effects or insufficient responsiveness by patient subpopulations illustrate the need for safe and novel alternatives. Thus, there is a demand to develop a porcine model that is able to mimic mast cell-mediated type I hypersensitivity. Previously, we found that escin, a pharmacologically active mix of triterpene saponins from horse chestnut extracts, exerts anti-allergic effects in murine models and merits further investigation as an anti-allergic therapeutic. We developed a new porcine model of allergic dermatitis based on a clinical prick test protocol. Histamine clearly provoked erythema and swelling at the prick site, whereas the mast cell-degranulating compound 48/80 even more pronounced caused wheal and flare reactions known from the human prick response. This model was used to test the anti-allergic efficacy of orally applied escin. Oral pretreatment of animals with escin strongly inhibited the allergic skin response induced by compound 48/80 in a dose-dependent manner. Additional in vitro data from murine mast cells indicate an engagement of the glucocorticoid receptor pathway upon treatment with escin. This model provides a valuable and easy-to-set-up tool for preclinical studies of mast cell-inhibiting compounds. The successful implementation of this model supports the development of oral escin applications as a novel anti-allergic therapy. Copyright © 2012 S. Karger AG, Basel.

  7. Ghrelin inhibits atherosclerotic plaque angiogenesis and promotes plaque stability in a rabbit atherosclerotic model.

    Science.gov (United States)

    Wang, Li; Chen, Qingwei; Ke, Dazhi; Li, Guiqiong

    2017-04-01

    Intraplaque angiogenesis associates with the instability of atherosclerotic plaques. In the present study, we investigated the effects of ghrelin on intraplaque angiogenesis and plaque instability in a rabbit model of atherosclerosis. The rabbits were randomly divided into three groups, namely, the control group, atherosclerotic model group, and ghrelin-treated group, with treatments lasting for 4 weeks. We found that the thickness ratio of the intima to media in rabbits of the ghrelin-treated group was significantly lower than that in rabbits of the atherosclerotic model group. The number of neovessels and the levels of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) decreased dramatically in rabbits of the ghrelin-treated group compared to those of the atherosclerotic model group. Ghrelin significantly decreased the plaque content of macrophages, matrix metalloproteinase (MMP)-2, and MMP-9, in a rabbit model of atherosclerosis. In addition, the level of the pro-inflammatory factor monocyte chemoattractant protein (MCP)-1 was significantly lower in rabbits of the ghrelin-treated group than in rabbits of the atherosclerotic model group. In summary, ghrelin can inhibit intraplaque angiogenesis and promote plaque stability by down-regulating VEGF and VEGFR2 expression, inhibiting the plaque content of macrophages, and reducing MCP-1 expression at an advanced stage of atherosclerosis in rabbits. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Vagus nerve stimulation inhibits trigeminal nociception in a rodent model of episodic migraine

    Science.gov (United States)

    Hawkins, Jordan L.; Cornelison, Lauren E.; Blankenship, Brian A.; Durham, Paul L.

    2017-01-01

    Abstract Introduction: Although neck muscle tension is considered a risk factor for migraine, pungent odors can act as a trigger to initiate an attack in sensitized individuals. Although noninvasive vagus nerve stimulation (nVNS) is now an approved treatment for chronic migraine, how it functions to inhibit trigeminal nociception in an episodic migraine model is not known. Objectives: The objectives of this study were to determine if nVNS could inhibit trigeminal nociception in a novel model of episodic migraine and investigate changes in the expression of proteins implicated in peripheral and central sensitization. Methods: Sprague-Dawley male rats were injected with an inflammatory agent in the trapezius muscle before exposure to pungent volatile compounds, which was used to initiate trigeminal nociceptor activation. The vagus nerve was stimulated transdermally by a 1-ms pulse of 5 kHz sine waves, repeated at 25 Hz for 2 minutes. Nocifensive head withdrawal response to von Frey filaments was determined and immunoreactive protein levels in the spinal cord and trigeminal ganglion (TG) were investigated. Results: Exposure to the pungent odor significantly increased the number of nocifensive withdrawals in response to mechanical stimulation of sensitized TG neurons mediated by neck muscle inflammation. Noninvasive vagus nerve stimulation inhibited nociception and repressed elevated levels of P-ERK in TG, Iba1 in microglia, and GFAP in astrocytes from sensitized animals exposed to the pungent odor. Conclusion: Our findings demonstrate that nVNS inhibits mechanical nociception and represses expression of proteins associated with peripheral and central sensitization of trigeminal neurons in a novel rodent model of episodic migraine. PMID:29392242

  9. Exploring BSEP Inhibition-Mediated Toxicity with a Mechanistic Model of Drug-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Jeffrey L Woodhead

    2014-11-01

    Full Text Available Inhibition of the bile salt export pump (BSEP has been linked to incidence of drug-induced liver injury (DILI, presumably by the accumulation of toxic bile acids in the liver. We have previously constructed and validated a model of bile acid disposition within DILIsym®, a mechanistic model of DILI. In this paper, we use DILIsym® to simulate the DILI response of the hepatotoxic BSEP inhibitors bosentan and CP-724,714 and the non-hepatotoxic BSEP inhibitor telmisartan in humans in order to explore whether we can predict that hepatotoxic BSEP inhibitors can cause bile acid accumulation to reach toxic levels. We also simulate bosentan in rats in order to illuminate potential reasons behind the lack of toxicity in rats compared to the toxicity observed in humans. DILIsym® predicts that bosentan, but not telmisartan, will cause mild hepatocellular ATP decline and serum ALT elevation in a simulated population of humans. The difference in hepatotoxic potential between bosentan and telmisartan is consistent with clinical observations. However, DILIsym® underpredicts the incidence of bosentan toxicity. DILIsym® also predicts that bosentan will not cause toxicity in a simulated population of rats, and that the difference between the response to bosentan in rats and in humans is primarily due to the less toxic bile acid pool in rats. Our simulations also suggest a potential synergistic role for bile acid accumulation and mitochondrial electron transport chain inhibition in producing the observed toxicity in CP-724,714, and suggest that CP-724,714 metabolites may also play a role in the observed toxicity. Our work also compares the impact of competitive and noncompetitive BSEP inhibition for CP-724,714 and demonstrates that noncompetitive inhibition leads to much greater bile acid accumulation and potential toxicity. Our research demonstrates the potential for mechanistic modeling to contribute to the understanding of how bile acid transport inhibitors

  10. Micelle System Based on Molecular Economy Principle for Overcoming Multidrug Resistance and Inhibiting Metastasis.

    Science.gov (United States)

    Qi, Yan; Qin, Xianya; Yang, Conglian; Wu, Tingting; Qiao, Qi; Song, Qingle; Zhang, Zhiping

    2018-03-05

    The high mortality of cancer is mainly attributed to multidrug resistance (MDR) and metastasis. A simple micelle system was constructed here to codeliver doxorubicin (DOX), adjudin (ADD), and nitric oxide (NO) for overcoming MDR and inhibiting metastasis. It was devised based on the "molecular economy" principle as the micelle system was easy to fabricate and exhibited high drug loading efficiency, and importantly, each component of the micelles would exert one or more active functions. DOX acted as the main cell killing agent supplemented with ADD, NO, and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). MDR was overcome by synergistic effects of mitochondria inhibition agents, TPGS and ADD. A TPGS-based NO donor can be used as a drug carrier, and it can release NO to enhance drug accumulation and penetration in tumor, resulting in a positive cycle of drug delivery. This DOX-ADD conjugate self-assembly system demonstrated controlled drug release, increased cellular uptake and cytotoxicity, enhanced accumulation at tumor site, and improved in vivo metastasis inhibition of breast cancer. The micelles can fully take advantage of the functions of each component, and they provide a potential strategy for nanomedicine design and clinical cancer treatment.

  11. Bistability, non-ergodicity, and inhibition in pairwise maximum-entropy models.

    Science.gov (United States)

    Rostami, Vahid; Porta Mana, PierGianLuca; Grün, Sonja; Helias, Moritz

    2017-10-01

    Pairwise maximum-entropy models have been used in neuroscience to predict the activity of neuronal populations, given only the time-averaged correlations of the neuron activities. This paper provides evidence that the pairwise model, applied to experimental recordings, would produce a bimodal distribution for the population-averaged activity, and for some population sizes the second mode would peak at high activities, that experimentally would be equivalent to 90% of the neuron population active within time-windows of few milliseconds. Several problems are connected with this bimodality: 1. The presence of the high-activity mode is unrealistic in view of observed neuronal activity and on neurobiological grounds. 2. Boltzmann learning becomes non-ergodic, hence the pairwise maximum-entropy distribution cannot be found: in fact, Boltzmann learning would produce an incorrect distribution; similarly, common variants of mean-field approximations also produce an incorrect distribution. 3. The Glauber dynamics associated with the model is unrealistically bistable and cannot be used to generate realistic surrogate data. This bimodality problem is first demonstrated for an experimental dataset from 159 neurons in the motor cortex of macaque monkey. Evidence is then provided that this problem affects typical neural recordings of population sizes of a couple of hundreds or more neurons. The cause of the bimodality problem is identified as the inability of standard maximum-entropy distributions with a uniform reference measure to model neuronal inhibition. To eliminate this problem a modified maximum-entropy model is presented, which reflects a basic effect of inhibition in the form of a simple but non-uniform reference measure. This model does not lead to unrealistic bimodalities, can be found with Boltzmann learning, and has an associated Glauber dynamics which incorporates a minimal asymmetric inhibition.

  12. Exposure to polystyrene nanoplastic leads to inhibition of anaerobic digestion system.

    Science.gov (United States)

    Fu, Shan-Fei; Ding, Jian-Nan; Zhang, Yun; Li, Yi-Fei; Zhu, Rong; Yuan, Xian-Zheng; Zou, Hua

    2018-06-01

    In this study, impacts of nanoplastic on the pure and mixed anaerobic digestion systems were investigated. Results showed the growth and metabolism of Acetobacteroides hydrogenigenes were partly inhibited by nanoplastic existed in the pure anaerobic digestion system. The anaerobic digestion of sewage sludge was also obviously inhibited by nanoplastic existed in the mixed anaerobic digestion system. Both the methane yield and methane production rate of the mixed anaerobic digestion system showed negative correlation with the nanoplastic concentration. Compared with anaerobic digestion system without nanoplastic, methane yield and maximum daily methane yield at the nanoplastic concentration of 0.2g/L decreased for 14.4% and 40.7%, respectively. In addition, the start-up of mixed anaerobic digestion system was prolonged by addition of nanoplastic. Microbial community structure analysis indicated the microbial community structures were also affected by nanoplastic existed in the system. At the nanoplastic concentration of 0.2g/L, the relative abundances of family Cloacamonaceae, Porphyromonadaceae, Anaerolinaceae and Gracilibacteraceae decreased partly. Conversely, the relative abundances of family Anaerolinaceae, Clostridiaceae, Geobacteraceae, Dethiosulfovibrionaceae and Desulfobulbaceae improved partly. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Dopamine receptor antagonist thioridazine inhibits tumor growth in a murine breast cancer model.

    Science.gov (United States)

    Yin, Tao; He, Sisi; Shen, Guobo; Ye, Tinghong; Guo, Fuchun; Wang, Yongsheng

    2015-09-01

    Neuropsychological factors have been shown to influence tumor progression and therapeutic response. The present study investigated the effect of the dopamine receptor antagonist thioridazine on murine breast cancer. The anti‑tumor efficacy of thioridazine was assessed using a murine breast cancer model. Cell apoptosis and proliferation were analyzed in vitro using flow cytometry (FCM) and the MTT assay, respectively. Western blot analysis was performed to assess Akt, phosphorylated (p)‑Akt, signal transducer and activator of transcription (STAT) 3, p‑STAT3 and p‑p65 in tumor cells following treatment with thioridazine. The Ki67 index and the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)‑positive apoptotic cells were assessed in the tumor sections. Thioridazine was found to reduce tumor growth, inhibit tumor cell proliferation and induce apoptosis in a dose‑ and time‑dependent manner in vitro. Thioridazine was also found to markedly inhibit tumor proliferation and induce tumor cell apoptosis in vivo as shown by the lower Ki67 index and increase in TUNEL‑positive cells. In addition, thioridazine was observed to inhibit the activation of the canonical nuclear factor κ‑light‑chain‑enhancer of activated B cells pathway and exert anti‑tumor effects by remodeling the tumor stroma, as well as inhibit angiogenesis in the tumor microenvironment. In conclusion, thioridazine was found to significantly inhibit breast tumor growth and the potential for thioridazine to be used in cancer therapy may be re‑evaluated and investigated in clinical settings.

  14. Inhibition of Hedgehog signaling antagonizes serous ovarian cancer growth in a primary xenograft model.

    Directory of Open Access Journals (Sweden)

    Christopher K McCann

    Full Text Available Recent evidence links aberrant activation of Hedgehog (Hh signaling with the pathogenesis of several cancers including medulloblastoma, basal cell, small cell lung, pancreatic, prostate and ovarian. This investigation was designed to determine if inhibition of this pathway could inhibit serous ovarian cancer growth.We utilized an in vivo pre-clinical model of serous ovarian cancer to characterize the anti-tumor activity of Hh pathway inhibitors cyclopamine and a clinically applicable derivative, IPI-926. Primary human serous ovarian tumor tissue was used to generate tumor xenografts in mice that were subsequently treated with cyclopamine or IPI-926.Both compounds demonstrated significant anti-tumor activity as single agents. When IPI-926 was used in combination with paclitaxel and carboplatinum (T/C, no synergistic effect was observed, though sustained treatment with IPI-926 after cessation of T/C continued to suppress tumor growth. Hh pathway activity was analyzed by RT-PCR to assess changes in Gli1 transcript levels. A single dose of IPI-926 inhibited mouse stromal Gli1 transcript levels at 24 hours with unchanged human intra-tumor Gli1 levels. Chronic IPI-926 therapy for 21 days, however, inhibited Hh signaling in both mouse stromal and human tumor cells. Expression data from the micro-dissected stroma in human serous ovarian tumors confirmed the presence of Gli1 transcript and a significant association between elevated Gli1 transcript levels and worsened survival.IPI-926 treatment inhibits serous tumor growth suggesting the Hh signaling pathway contributes to the pathogenesis of ovarian cancer and may hold promise as a novel therapeutic target, especially in the maintenance setting.

  15. System Convergence in Transport Modelling

    DEFF Research Database (Denmark)

    Rich, Jeppe; Nielsen, Otto Anker; Cantarella, Guilio E.

    2010-01-01

    A fundamental premise of most applied transport models is the existence and uniqueness of an equilibrium solution that balances demand x(t) and supply t(x). The demand consists of the people that travel in the transport system and on the defined network, whereas the supply consists of the resulting...... level-of-service attributes (e.g., travel time and cost) offered to travellers. An important source of complexity is the congestion, which causes increasing demand to affect travel time in a non-linear way. Transport models most often involve separate models for traffic assignment and demand modelling...

  16. Progression of renal cell carcinoma is inhibited by genistein and radiation in an orthotopic model

    International Nuclear Information System (INIS)

    Hillman, Gilda G; Wang, Yu; Che, Mingxin; Raffoul, Julian J; Yudelev, Mark; Kucuk, Omer; Sarkar, Fazlul H

    2007-01-01

    We have previously reported the potentiation of radiotherapy by the soy isoflavone genistein for prostate cancer using prostate tumor cells in vitro and orthotopic prostate tumor models in vivo. However, when genistein was used as single therapy in animal models, it promoted metastasis to regional para-aortic lymph nodes. To clarify whether these intriguing adverse effects of genistein are intrinsic to the orthotopic prostate tumor model, or these results could also be recapitulated in another model, we used the orthotopic metastatic KCI-18 renal cell carcinoma (RCC) model established in our laboratory. The KCI-18 RCC cell line was generated from a patient with papillary renal cell carcinoma. Following orthotopic renal implantation of KCI-18 RCC cells and serial in vivo kidney passages in nude mice, we have established a reliable and predictable metastatic RCC tumor model. Mice bearing established kidney tumors were treated with genistein combined with kidney tumor irradiation. The effect of the therapy was assessed on the primary tumor and metastases to various organs. In this experimental model, the karyotype and histological characteristics of the human primary tumor are preserved. Tumor cells metastasize from the primary renal tumor to the lungs, liver and mesentery mimicking the progression of RCC in humans. Treatment of established kidney tumors with genistein demonstrated a tendency to stimulate the growth of the primary kidney tumor and increase the incidence of metastasis to the mesentery lining the bowel. In contrast, when given in conjunction with kidney tumor irradiation, genistein significantly inhibited the growth and progression of established kidney tumors. These findings confirm the potentiation of radiotherapy by genistein in the orthotopic RCC model as previously shown in orthotopic models of prostate cancer. Our studies in both RCC and prostate tumor models demonstrate that the combination of genistein with primary tumor irradiation is a more

  17. Inhibition of the complement system by saliva of Anopheles (Nyssorhynchus) aquasalis.

    Science.gov (United States)

    Mendes-Sousa, Antonio Ferreira; Vale, Vladimir Fazito; Queiroz, Daniel Costa; Pereira-Filho, Adalberto Alves; da Silva, Naylene Carvalho Sales; Koerich, Leonardo Barbosa; Moreira, Luciano Andrade; Pereira, Marcos Horácio; Sant'Anna, Maurício Roberto; Araújo, Ricardo Nascimento; Andersen, John; Valenzuela, Jesus Gilberto; Gontijo, Nelder Figueiredo

    2018-01-01

    Anopheline mosquitoes are vectors of malaria parasites. Their saliva contains anti-hemostatic and immune-modulator molecules that favor blood feeding and parasite transmission. In this study, we describe the inhibition of the alternative pathway of the complement system (AP) by Anopheles aquasalis salivary gland extracts (SGE). According to our results, the inhibitor present in SGE acts on the initial step of the AP blocking deposition of C3b on the activation surfaces. Properdin, which is a positive regulatory molecule of the AP, binds to SGE. When SGE was treated with an excess of properdin, it was unable to inhibit the AP. Through SDS-PAGE analysis, A. aquasalis presented a salivary protein with the same molecular weight as recombinant complement inhibitors belonging to the SG7 family described in the saliva of other anopheline species. At least some SG7 proteins bind to properdin and are AP inhibitors. Searching for SG7 proteins in the A. aquasalis genome, we retrieved a salivary protein that shared an 85% identity with albicin, which is the salivary alternative pathway inhibitor from A. albimanus. This A. aquasalis sequence was also very similar (81% ID) to the SG7 protein from A. darlingi, which is also an AP inhibitor. Our results suggest that the salivary complement inhibitor from A. aquasalis is an SG7 protein that can inhibit the AP by binding to properdin and abrogating its stabilizing activity. Albicin, which is the SG7 from A. albimanus, can directly inhibit AP convertase. Given the high similarity of SG7 proteins, the SG7 from A. aquasalis may also directly inhibit AP convertase in the absence of properdin. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Leptin promotes systemic lupus erythematosus by increasing autoantibody production and inhibiting immune regulation.

    Science.gov (United States)

    Lourenço, Elaine V; Liu, Aijing; Matarese, Giuseppe; La Cava, Antonio

    2016-09-20

    Leptin is an adipocytokine that plays a key role in the modulation of immune responses and the development and maintenance of inflammation. Circulating levels of leptin are elevated in systemic lupus erythematosus (SLE) patients, but it is not clear whether this association can reflect a direct influence of leptin on the propathogenic events that lead to SLE. To investigate this possibility, we compared the extent of susceptibility to SLE and lupus manifestations between leptin-deficient (ob/ob) and H2-matched leptin-sufficient (wild-type, WT) mice that had been treated with the lupus-inducing agent pristane. Leptin deficiency protected ob/ob mice from the development of autoantibodies and renal disease and increased the frequency of immunoregulatory T cells (Tregs) compared with leptin-sufficient WT mice. The role of leptin in the development of SLE was confirmed in the New Zealand Black (NZB) × New Zealand White (NZW)F1 (NZB/W) mouse model of spontaneous SLE, where elevated leptin levels correlated with disease manifestations and the administration of leptin accelerated development of autoantibodies and renal disease. Conversely, leptin antagonism delayed disease progression and increased survival of severely nephritic NZB/W mice. At the cellular level, leptin promoted effector T-cell responses and facilitated the presentation of self-antigens to T cells, whereas it inhibited the activity of regulatory CD4 T cells. The understanding of the role of leptin in modulating autoimmune responses in SLE can open possibilities of leptin-targeted therapeutic intervention in the disease.

  19. Pharmacological Sirt6 inhibition improves glucose tolerance in a type 2 diabetes mouse model.

    Science.gov (United States)

    Sociali, Giovanna; Magnone, Mirko; Ravera, Silvia; Damonte, Patrizia; Vigliarolo, Tiziana; Von Holtey, Maria; Vellone, Valerio G; Millo, Enrico; Caffa, Irene; Cea, Michele; Parenti, Marco Daniele; Del Rio, Alberto; Murone, Maximilien; Mostoslavsky, Raul; Grozio, Alessia; Nencioni, Alessio; Bruzzone, Santina

    2017-07-01

    Sirtuin 6 (SIRT6) is a sirtuin family member involved in a wide range of physiologic and disease processes, including cancer and glucose homeostasis. Based on the roles played by SIRT6 in different organs, including its ability to repress the expression of glucose transporters and glycolytic enzymes, inhibiting SIRT6 has been proposed as an approach for treating type 2 diabetes mellitus (T2DM). However, so far, the lack of small-molecule Sirt6 inhibitors has hampered the conduct of in vivo studies to assess the viability of this strategy. We took advantage of a recently identified SIRT6 inhibitor, compound 1, to study the effect of pharmacological Sirt6 inhibition in a mouse model of T2DM ( i.e., in high-fat-diet-fed animals). The administration of the Sirt6 inhibitor for 10 d was well tolerated and improved oral glucose tolerance, it increased the expression of the glucose transporters GLUT1 and -4 in the muscle and enhanced the activity of the glycolytic pathway. Sirt6 inhibition also resulted in reduced insulin, triglycerides, and cholesterol levels in plasma. This study represents the first in vivo study of a SIRT6 inhibitor and provides the proof-of-concept that targeting SIRT6 may be a viable strategy for improving glycemic control in T2DM.-Sociali, G., Magnone, M., Ravera, S., Damonte, P., Vigliarolo, T., Von Holtey, M., Vellone, V. G., Millo, E., Caffa, I., Cea, M., Parenti, M. D., Del Rio, A., Murone, M., Mostoslavsky, R., Grozio, A., Nencioni, A., Bruzzone S. Pharmacological Sirt6 inhibition improves glucose tolerance in a type 2 diabetes mouse model. © FASEB.

  20. Forced notch signaling inhibits commissural axon outgrowth in the developing chick central nerve system.

    Directory of Open Access Journals (Sweden)

    Ming Shi

    Full Text Available BACKGROUND: A collection of in vitro evidence has demonstrated that Notch signaling plays a key role in the growth of neurites in differentiated neurons. However, the effects of Notch signaling on axon outgrowth in an in vivo condition remain largely unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study, the neural tubes of HH10-11 chick embryos were in ovo electroporated with various Notch transgenes of activating or inhibiting Notch signaling, and then their effects on commissural axon outgrowth across the floor plate midline in the chick developing central nerve system were investigated. Our results showed that forced expression of Notch intracellular domain, constitutively active form of RBPJ, or full-length Hes1 in the rostral hindbrain, diencephalon and spinal cord at stage HH10-11 significantly inhibited commissural axon outgrowth. On the other hand, inhibition of Notch signaling by ectopically expressing a dominant-negative form of RBPJ promoted commissural axonal growth along the circumferential axis. Further results revealed that these Notch signaling-mediated axon outgrowth defects may be not due to the alteration of axon guidance since commissural axon marker TAG1 was present in the axons in floor plate midline, and also not result from the changes in cell fate determination of commissural neurons since the expression of postmitotic neuron marker Tuj1 and specific commissural markers TAG1 and Pax7 was unchanged. CONCLUSIONS/SIGNIFICANCE: We first used an in vivo system to provide evidence that forced Notch signaling negatively regulates commissural axon outgrowth.

  1. Executive Information Systems' Multidimensional Models

    Directory of Open Access Journals (Sweden)

    2007-01-01

    Full Text Available Executive Information Systems are design to improve the quality of strategic level of management in organization through a new type of technology and several techniques for extracting, transforming, processing, integrating and presenting data in such a way that the organizational knowledge filters can easily associate with this data and turn it into information for the organization. These technologies are known as Business Intelligence Tools. But in order to build analytic reports for Executive Information Systems (EIS in an organization we need to design a multidimensional model based on the business model from the organization. This paper presents some multidimensional models that can be used in EIS development and propose a new model that is suitable for strategic business requests.

  2. Numerical Modeling of Microelectrochemical Systems

    DEFF Research Database (Denmark)

    Adesokan, Bolaji James

    for the reactants in the bulk electrolyte that are traveling waves. The first paper presents the mathematical model which describes an electrochemical system and simulates an electroanalytical technique called cyclic voltammetry. The model is governed by a system of advection–diffusion equations with a nonlinear...... reaction term at the boundary. We investigate the effect of flow rates, scan rates, and concentration on the cyclic voltammetry. We establish that high flow rates lead to the reduced hysteresis in the cyclic voltammetry curves and increasing scan rates lead to more pronounced current peaks. The final part...... of the paper shows that the response current in a cyclic voltammetry increases proportionally to the electrolyte concentration. In the second paper we present an experiment of an electrochemical system in a microfluidc system and compare the result to the numerical solutions. We investigate how the position...

  3. System Code Models and Capabilities

    International Nuclear Information System (INIS)

    Bestion, D.

    2008-01-01

    System thermalhydraulic codes such as RELAP, TRACE, CATHARE or ATHLET are now commonly used for reactor transient simulations. The whole methodology of code development is described including the derivation of the system of equations, the analysis of experimental data to obtain closure relation and the validation process. The characteristics of the models are briefly presented starting with the basic assumptions, the system of equations and the derivation of closure relationships. An extensive work was devoted during the last three decades to the improvement and validation of these models, which resulted in some homogenisation of the different codes although separately developed. The so called two-fluid model is the common basis of these codes and it is shown how it can describe both thermal and mechanical nonequilibrium. A review of some important physical models allows to illustrate the main capabilities and limitations of system codes. Attention is drawn on the role of flow regime maps, on the various methods for developing closure laws, on the role of interfacial area and turbulence on interfacial and wall transfers. More details are given for interfacial friction laws and their relation with drift flux models. Prediction of chocked flow and CFFL is also addressed. Based on some limitations of the present generation of codes, perspectives for future are drawn.

  4. Experimental Modeling of Dynamic Systems

    DEFF Research Database (Denmark)

    Knudsen, Morten Haack

    2006-01-01

    An engineering course, Simulation and Experimental Modeling, has been developed that is based on a method for direct estimation of physical parameters in dynamic systems. Compared with classical system identification, the method appears to be easier to understand, apply, and combine with physical...... insight. It is based on a sensitivity approach that is useful for choice of model structure, for experiment design, and for accuracy verification. The method is implemented in the Matlab toolkit Senstools. The method and the presentation have been developed with generally preferred learning styles in mind...

  5. Compositional Modeling of Biological Systems

    OpenAIRE

    Zámborszky, Judit

    2010-01-01

    Molecular interactions are wired in a fascinating way resulting in complex behavior of bio-logical systems. Theoretical modeling provides us a useful framework for understanding the dynamics and the function of such networks. The complexity of the biological systems calls for conceptual tools that manage the combinatorial explosion of the set of possible interac-tions. A suitable conceptual tool to attack complexity is compositionality, already success-fully used in the process algebra field ...

  6. The anti-tumor effect of HDAC inhibition in a human pancreas cancer model is significantly improved by the simultaneous inhibition of cyclooxygenase 2.

    Directory of Open Access Journals (Sweden)

    Olivier Peulen

    Full Text Available Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer death worldwide, with no satisfactory treatment to date. In this study, we tested whether the combined inhibition of cyclooxygenase-2 (COX-2 and class I histone deacetylase (HDAC may results in a better control of pancreatic ductal adenocarcinoma. The impact of the concomitant HDAC and COX-2 inhibition on cell growth, apoptosis and cell cycle was assessed first in vitro on human pancreas BxPC-3, PANC-1 or CFPAC-1 cells treated with chemical inhibitors (SAHA, MS-275 and celecoxib or HDAC1/2/3/7 siRNA. To test the potential antitumoral activity of this combination in vivo, we have developed and characterized, a refined chick chorioallantoic membrane tumor model that histologically and proteomically mimics human pancreatic ductal adenocarcinoma. The combination of HDAC1/3 and COX-2 inhibition significantly impaired proliferation of BxPC-3 cells in vitro and stalled entirely the BxPC-3 cells tumor growth onto the chorioallantoic membrane in vivo. The combination was more effective than either drug used alone. Consistently, we showed that both HDAC1 and HDAC3 inhibition induced the expression of COX-2 via the NF-kB pathway. Our data demonstrate, for the first time in a Pancreatic Ductal Adenocarcinoma (PDAC model, a significant action of HDAC and COX-2 inhibitors on cancer cell growth, which sets the basis for the development of potentially effective new combinatory therapies for pancreatic ductal adenocarcinoma patients.

  7. Baicalein Inhibits Staphylococcus aureus Biofilm Formation and the Quorum Sensing System In Vitro.

    Directory of Open Access Journals (Sweden)

    Yan Chen

    Full Text Available Biofilm formed by Staphylococcus aureus significantly enhances antibiotic resistance by inhibiting the penetration of antibiotics, resulting in an increasingly serious situation. This study aimed to assess whether baicalein can prevent Staphylococcus aureus biofilm formation and whether it may have synergistic bactericidal effects with antibiotics in vitro. To do this, we used a clinically isolated strain of Staphylococcus aureus 17546 (t037 for biofilm formation. Virulence factors were detected following treatment with baicalein, and the molecular mechanism of its antibiofilm activity was studied. Plate counting, crystal violet staining, and fluorescence microscopy revealed that 32 μg/mL and 64 μg/mL baicalein clearly inhibited 3- and 7-day biofilm formation in vitro. Moreover, colony forming unit count, confocal laser scanning microscopy, and scanning electron microscopy showed that vancomycin (VCM and baicalein generally enhanced destruction of biofilms, while VCM alone did not. Western blotting and real-time quantitative polymerase chain reaction analyses (RTQ-PCR confirmed that baicalein treatment reduced staphylococcal enterotoxin A (SEA and α-hemolysin (hla levels. Most strikingly, real-time qualitative polymerase chain reaction data demonstrated that 32 μg/mL and 64 μg/mL baicalein downregulated the quorum-sensing system regulators agrA, RNAIII, and sarA, and gene expression of ica, but 16 μg/mL baicalein had no effect. In summary, baicalein inhibited Staphylococcus aureus biofilm formation, destroyed biofilms, increased the permeability of vancomycin, reduced the production of staphylococcal enterotoxin A and α-hemolysin, and inhibited the quorum sensing system. These results support baicalein as a novel drug candidate and an effective treatment strategy for Staphylococcus aureus biofilm-associated infections.

  8. HSC-specific inhibition of Rho-kinase reduces portal pressure in cirrhotic rats without major systemic effects

    NARCIS (Netherlands)

    Klein, Sabine; Van Beuge, Marike Marjolijn; Granzow, Michaela; Beljaars, Leonie; Schierwagen, Robert; Kilic, Sibel; Heidari, Iren; Huss, Sebastian; Sauerbruch, Tilman; Poelstra, Klaas; Trebicka, Jonel

    2012-01-01

    Background & Aims: Rho-kinase activation mediates cell contraction and increases intrahepatic resistance and consequently portal pressure in liver cirrhosis. Systemic Rho-kinase inhibition decreases portal pressure in cirrhosis, but also arterial pressure. Thus, liver-specific Rho-kinase inhibition

  9. Quantifying second generation ethanol inhibition: Design of Experiments approach and kinetic model development.

    Science.gov (United States)

    Schneiderman, Steven J; Johnson, Roger W; Menkhaus, Todd J; Gilcrease, Patrick C

    2015-03-01

    While softwoods represent a potential feedstock for second generation ethanol production, compounds present in their hydrolysates can inhibit fermentation. In this study, a novel Design of Experiments (DoE) approach was used to identify significant inhibitory effects on Saccharomyces cerevisiae D5A for the purpose of guiding kinetic model development. Although acetic acid, furfural and 5-hydroxymethyl furfural (HMF) were present at potentially inhibitory levels, initial factorial experiments only identified ethanol as a significant rate inhibitor. It was hypothesized that high ethanol levels masked the effects of other inhibitors, and a subsequent factorial design without ethanol found significant effects for all other compounds. When these non-ethanol effects were accounted for in the kinetic model, R¯(2) was significantly improved over an ethanol-inhibition only model (R¯(2)=0.80 vs. 0.76). In conclusion, when ethanol masking effects are removed, DoE is a valuable tool to identify significant non-ethanol inhibitors and guide kinetic model development. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. A tentative model for the inhibition and the enhancement of the Ps formation in mixtures of two compounds

    International Nuclear Information System (INIS)

    In order to explain the so called inhibition of o-Ps formation by certain solutes, a model based on the hypothesis of hot reactions between the o-Ps atoms and the solute molecules has been proposed in previous papers. From this model an equation was derived which not only describes rather well the dependence of the o-Ps survival probability on the inhibitor concentration, but allowed some predictions which were experimentally verified. In the present paper it is reported that the equation mentioned above is a particular solution of a more comprehensive equation which can account, in principle at least, for the general problem of Ps formation in any system of two components. (author)

  11. Parametric Modeling for Fluid Systems

    Science.gov (United States)

    Pizarro, Yaritzmar Rosario; Martinez, Jonathan

    2013-01-01

    Fluid Systems involves different projects that require parametric modeling, which is a model that maintains consistent relationships between elements as is manipulated. One of these projects is the Neo Liquid Propellant Testbed, which is part of Rocket U. As part of Rocket U (Rocket University), engineers at NASA's Kennedy Space Center in Florida have the opportunity to develop critical flight skills as they design, build and launch high-powered rockets. To build the Neo testbed; hardware from the Space Shuttle Program was repurposed. Modeling for Neo, included: fittings, valves, frames and tubing, between others. These models help in the review process, to make sure regulations are being followed. Another fluid systems project that required modeling is Plant Habitat's TCUI test project. Plant Habitat is a plan to develop a large growth chamber to learn the effects of long-duration microgravity exposure to plants in space. Work for this project included the design and modeling of a duct vent for flow test. Parametric Modeling for these projects was done using Creo Parametric 2.0.

  12. Retinal Inhibition of CCR3 Induces Retinal Cell Death in a Murine Model of Choroidal Neovascularization.

    Directory of Open Access Journals (Sweden)

    Haibo Wang

    Full Text Available Inhibition of chemokine C-C motif receptor 3 (CCR3 signaling has been considered as treatment for neovascular age-related macular degeneration (AMD. However, CCR3 is expressed in neural retina from aged human donor eyes. Therefore, broad CCR3 inhibition may be harmful to the retina. We assessed the effects of CCR3 inhibition on retina and choroidal endothelial cells (CECs that develop into choroidal neovascularization (CNV. In adult murine eyes, CCR3 colocalized with glutamine-synthetase labeled Műller cells. In a murine laser-induced CNV model, CCR3 immunolocalized not only to lectin-stained cells in CNV lesions but also to the retina. Compared to non-lasered controls, CCR3 mRNA was significantly increased in laser-treated retina. An intravitreal injection of a CCR3 inhibitor (CCR3i significantly reduced CNV compared to DMSO or PBS controls. Both CCR3i and a neutralizing antibody to CCR3 increased TUNEL+ retinal cells overlying CNV, compared to controls. There was no difference in cleaved caspase-3 in laser-induced CNV lesions or in overlying retina between CCR3i- or control-treated eyes. Following CCR3i, apoptotic inducible factor (AIF was significantly increased and anti-apoptotic factor BCL2 decreased in the retina; there were no differences in retinal vascular endothelial growth factor (VEGF. In cultured human Műller cells exposed to eotaxin (CCL11 and VEGF, CCR3i significantly increased TUNEL+ cells and AIF but decreased BCL2 and brain derived neurotrophic factor, without affecting caspase-3 activity or VEGF. CCR3i significantly decreased AIF in RPE/choroids and immunostaining of phosphorylated VEGF receptor 2 (p-VEGFR2 in CNV with a trend toward reduced VEGF. In cultured CECs treated with CCL11 and/or VEGF, CCR3i decreased p-VEGFR2 and increased BCL2 without increasing TUNEL+ cells and AIF. These findings suggest that inhibition of retinal CCR3 causes retinal cell death and that targeted inhibition of CCR3 in CECs may be a safer if CCR3

  13. Curine inhibits eosinophil activation and airway hyper-responsiveness in a mouse model of allergic asthma

    Energy Technology Data Exchange (ETDEWEB)

    Ribeiro-Filho, Jaime [Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro (Brazil); Laboratório de Imunofarmacologia, Departamento de Fisiologia e Patologia, UFPB, João Pessoa, Paraíba (Brazil); Calheiros, Andrea Surrage; Vieira-de-Abreu, Adriana [Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro (Brazil); Moraes de Carvalho, Katharinne Ingrid [Laboratório de Inflamação, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro (Brazil); Silva Mendes, Diego da [Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro (Brazil); Melo, Christianne Bandeira [Laboratório de Inflamação, Instituto Biofisica Carlos Chagas Filho, UFRJ, Rio de Janeiro (Brazil); Martins, Marco Aurélio [Laboratório de Inflamação, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro (Brazil); Silva Dias, Celidarque da [Laboratório de Fitoquímica, Departamento de Ciências Farmacêuticas, UFPB, João Pessoa, Paraíba (Brazil); Piuvezam, Márcia Regina, E-mail: mrpiuvezam@ltf.ufpb.br [Laboratório de Imunofarmacologia, Departamento de Fisiologia e Patologia, UFPB, João Pessoa, Paraíba (Brazil); and others

    2013-11-15

    Allergic asthma is a chronic inflammatory airway disease with increasing prevalence around the world. Current asthma therapy includes drugs that usually cause significant side effects, justifying the search for new anti-asthmatic drugs. Curine is a bisbenzylisoquinoline alkaloid that modulates calcium influx in many cell types; however, its anti-allergic and putative toxic effects remain to be elucidated. Our aim was to investigate the effects of curine on eosinophil activation and airway hyper-responsiveness (AHR) and to characterize its potential toxic effects. We used a mouse model of allergic asthma induced by sensitization and challenge with ovalbumin (OVA) to evaluate the anti-allergic effects of oral treatment with curine. The oral administration of curine significantly inhibited eosinophilic inflammation, eosinophil lipid body formation and AHR in animals challenged with OVA compared with animals in the untreated group. The curine treatment also reduced eotaxin and IL-13 production triggered by OVA. Verapamil, a calcium channel antagonist, had similar anti-allergic properties, and curine pre-treatment inhibited the calcium-induced tracheal contractile response ex-vivo, suggesting that the mechanism by which curine exerts its effects is through the inhibition of a calcium-dependent response. A toxicological evaluation showed that orally administered curine did not significantly alter the biochemical, hematological, behavioral and physical parameters measured in the experimental animals compared with saline-treated animals. In conclusion, curine showed anti-allergic activity through mechanisms that involve inhibition of IL-13 and eotaxin and of Ca{sup ++} influx, without inducing evident toxicity and as such, has the potential for the development of anti-asthmatic drugs. - Highlights: • Curine is a bisbenzylisoquinoline alkaloid from Chondrodendron platyphyllum. • Curine inhibits eosinophil influx and activation and airway hyper-responsiveness. • Curine

  14. Novel Scabies Mite Serpins Inhibit the Three Pathways of the Human Complement System

    Science.gov (United States)

    Mika, Angela; Reynolds, Simone L.; Mohlin, Frida C.; Willis, Charlene; Swe, Pearl M.; Pickering, Darren A.; Halilovic, Vanja; Wijeyewickrema, Lakshmi C.; Pike, Robert N.; Blom, Anna M.; Kemp, David J.; Fischer, Katja

    2012-01-01

    Scabies is a parasitic infestation of the skin by the mite Sarcoptes scabiei that causes significant morbidity worldwide, in particular within socially disadvantaged populations. In order to identify mechanisms that enable the scabies mite to evade human immune defenses, we have studied molecules associated with proteolytic systems in the mite, including two novel scabies mite serine protease inhibitors (SMSs) of the serpin superfamily. Immunohistochemical studies revealed that within mite-infected human skin SMSB4 (54 kDa) and SMSB3 (47 kDa) were both localized in the mite gut and feces. Recombinant purified SMSB3 and SMSB4 did not inhibit mite serine and cysteine proteases, but did inhibit mammalian serine proteases, such as chymotrypsin, albeit inefficiently. Detailed functional analysis revealed that both serpins interfered with all three pathways of the human complement system at different stages of their activation. SMSB4 inhibited mostly the initial and progressing steps of the cascades, while SMSB3 showed the strongest effects at the C9 level in the terminal pathway. Additive effects of both serpins were shown at the C9 level in the lectin pathway. Both SMSs were able to interfere with complement factors without protease function. A range of binding assays showed direct binding between SMSB4 and seven complement proteins (C1, properdin, MBL, C4, C3, C6 and C8), while significant binding of SMSB3 occurred exclusively to complement factors without protease function (C4, C3, C8). Direct binding was observed between SMSB4 and the complement proteases C1s and C1r. However no complex formation was observed between either mite serpin and the complement serine proteases C1r, C1s, MASP-1, MASP-2 and MASP-3. No catalytic inhibition by either serpin was observed for any of these enzymes. In summary, the SMSs were acting at several levels mediating overall inhibition of the complement system and thus we propose that they may protect scabies mites from complement

  15. Mesoscopic segregation of excitation and inhibition in a brain network model.

    Directory of Open Access Journals (Sweden)

    Daniel Malagarriga

    2015-02-01

    Full Text Available Neurons in the brain are known to operate under a careful balance of excitation and inhibition, which maintains neural microcircuits within the proper operational range. How this balance is played out at the mesoscopic level of neuronal populations is, however, less clear. In order to address this issue, here we use a coupled neural mass model to study computationally the dynamics of a network of cortical macrocolumns operating in a partially synchronized, irregular regime. The topology of the network is heterogeneous, with a few of the nodes acting as connector hubs while the rest are relatively poorly connected. Our results show that in this type of mesoscopic network excitation and inhibition spontaneously segregate, with some columns acting mainly in an excitatory manner while some others have predominantly an inhibitory effect on their neighbors. We characterize the conditions under which this segregation arises, and relate the character of the different columns with their topological role within the network. In particular, we show that the connector hubs are preferentially inhibitory, the more so the larger the node's connectivity. These results suggest a potential mesoscale organization of the excitation-inhibition balance in brain networks.

  16. Mevalonate Pathway Antagonist Inhibits Proliferation of Serous Tubal Intraepithelial Carcinoma and Ovarian Carcinoma in Mouse Models

    Science.gov (United States)

    Kobayashi, Yusuke; Kashima, Hiroyasu; Wu, Ren-Chin; Jung, Jin- Gyoung; Kuan, Jen-Chun; Gu, Jinghua; Xuan, Jianhua; Sokoll, Lori; Visvanathan, Kala; Shih, Ie-Ming; Wang, Tian-Li

    2015-01-01

    Purpose Statins are among the most frequently prescribed drugs because of their efficacy and low toxicity in treating hypercholesterolemia. Recently, statins have been reported to inhibit the proliferative activity of cancer cells, especially those with TP53 mutations. Since TP53 mutations occur in almost all of the ovarian high-grade serous carcinoma, we determined if statins suppressed tumor growth in animal models of ovarian cancer. Experimental Design Two ovarian cancer mouse models were employed. The first one was a genetically engineered model, mogp-TAg, in which the promoter of oviduct glycoprotein-1 was used to drive the expression of SV40 T-antigen in gynecologic tissues. These mice spontaneously develop serous tubal intraepithelial carcinomas (STICs), which are known as ovarian cancer precursor lesions. The second model was a xenograft tumor model in which human ovarian cancer cells were inoculated into immunocompromised mice. Mice in both models were treated with lovastatin, and effects on tumor growth were monitored. The molecular mechanisms underlying the anti-tumor effects of lovastatin were also investigated. Results Lovastatin significantly reduced the development of STICs in mogp-TAg mice and inhibited ovarian tumor growth in the mouse xenograft model. Knockdown of prenylation enzymes in the mevalonate pathway recapitulated the lovastatin-induced anti-proliferative phenotype. Transcriptome analysis indicated that lovastatin affected the expression of genes associated with DNA replication, Rho/PLC signaling, glycolysis, and cholesterol biosynthesis pathways, suggesting that statins have pleiotropic effects on tumor cells. Conclusion The above results suggest that repurposing statin drugs for ovarian cancer may provide a promising strategy to prevent and manage this devastating disease. PMID:26109099

  17. MOSAIC: a multiscale model of osteogenesis and sprouting angiogenesis with lateral inhibition of endothelial cells.

    Directory of Open Access Journals (Sweden)

    Aurélie Carlier

    Full Text Available The healing of a fracture depends largely on the development of a new blood vessel network (angiogenesis in the callus. During angiogenesis tip cells lead the developing sprout in response to extracellular signals, amongst which vascular endothelial growth factor (VEGF is critical. In order to ensure a correct development of the vasculature, the balance between stalk and tip cell phenotypes must be tightly controlled, which is primarily achieved by the Dll4-Notch1 signaling pathway. This study presents a novel multiscale model of osteogenesis and sprouting angiogenesis, incorporating lateral inhibition of endothelial cells (further denoted MOSAIC model through Dll4-Notch1 signaling, and applies it to fracture healing. The MOSAIC model correctly predicted the bone regeneration process and recapitulated many experimentally observed aspects of tip cell selection: the salt and pepper pattern seen for cell fates, an increased tip cell density due to the loss of Dll4 and an excessive number of tip cells in high VEGF environments. When VEGF concentration was even further increased, the MOSAIC model predicted the absence of a vascular network and fracture healing, thereby leading to a non-union, which is a direct consequence of the mutual inhibition of neighboring cells through Dll4-Notch1 signaling. This result was not retrieved for a more phenomenological model that only considers extracellular signals for tip cell migration, which illustrates the importance of implementing the actual signaling pathway rather than phenomenological rules. Finally, the MOSAIC model demonstrated the importance of a proper criterion for tip cell selection and the need for experimental data to further explore this. In conclusion, this study demonstrates that the MOSAIC model creates enhanced capabilities for investigating the influence of molecular mechanisms on angiogenesis and its relation to bone formation in a more mechanistic way and across different time and spatial

  18. Model checking embedded system designs

    NARCIS (Netherlands)

    Brinksma, Hendrik; Mader, Angelika H.

    2002-01-01

    Model checking has established itself as a successful tool supported technique for the verification and debugging of various hardware and software systems [16]. Not only in academia, but also by industry this technique is increasingly being regarded as a promising and practical proposition,

  19. GENERIC model for multiphase systems

    NARCIS (Netherlands)

    Sagis, L.M.C.

    2010-01-01

    GENERIC is a nonequilibrium thermodynamic formalism in which the dynamic behavior of a system is described by a single compact equation involving two types of brackets: a Poisson bracket and a dissipative bracket. This formalism has proved to be a very powerful instrument to model the dynamic

  20. An extensible analysable system model

    DEFF Research Database (Denmark)

    Probst, Christian W.; Hansen, Rene Rydhof

    2008-01-01

    Analysing real-world systems for vulnerabilities with respect to security and safety threats is a difficult undertaking, not least due to a lack of availability of formalisations for those systems. While both formalisations and analyses can be found for artificial systems such as software......, this does not hold for real physical systems. Approaches such as threat modelling try to target the formalisation of the real-world domain, but still are far from the rigid techniques available in security research. Many currently available approaches to assurance of critical infrastructure security...... are based on (quite successful) ad-hoc techniques. We believe they can be significantly improved beyond the state-of-the-art by pairing them with static analyses techniques. In this paper we present an approach to both formalising those real-world systems, as well as providing an underlying semantics, which...

  1. BET inhibition silences expression of MYCN and BCL2 and induces cytotoxicity in neuroblastoma tumor models.

    Directory of Open Access Journals (Sweden)

    Anastasia Wyce

    Full Text Available BET family proteins are epigenetic regulators known to control expression of genes involved in cell growth and oncogenesis. Selective inhibitors of BET proteins exhibit potent anti-proliferative activity in a number of hematologic cancer models, in part through suppression of the MYC oncogene and downstream Myc-driven pathways. However, little is currently known about the activity of BET inhibitors in solid tumor models, and whether down-regulation of MYC family genes contributes to sensitivity. Here we provide evidence for potent BET inhibitor activity in neuroblastoma, a pediatric solid tumor associated with a high frequency of MYCN amplifications. We treated a panel of neuroblastoma cell lines with a novel small molecule inhibitor of BET proteins, GSK1324726A (I-BET726, and observed potent growth inhibition and cytotoxicity in most cell lines irrespective of MYCN copy number or expression level. Gene expression analyses in neuroblastoma cell lines suggest a role of BET inhibition in apoptosis, signaling, and N-Myc-driven pathways, including the direct suppression of BCL2 and MYCN. Reversal of MYCN or BCL2 suppression reduces the potency of I-BET726-induced cytotoxicity in a cell line-specific manner; however, neither factor fully accounts for I-BET726 sensitivity. Oral administration of I-BET726 to mouse xenograft models of human neuroblastoma results in tumor growth inhibition and down-regulation MYCN and BCL2 expression, suggesting a potential role for these genes in tumor growth. Taken together, our data highlight the potential of BET inhibitors as novel therapeutics for neuroblastoma, and suggest that sensitivity is driven by pleiotropic effects on cell growth and apoptotic pathways in a context-specific manner.

  2. Systems modeling for laser IFE

    Science.gov (United States)

    Meier, W. R.; Raffray, A. R.; Sviatoslavsky, I. N.

    2006-06-01

    A systems model of a laser-driven IFE power plant is being developed to assist in design trade-offs and optimization. The focus to date has been on modeling the fusion chamber, blanket and power conversion system. A self-consistent model has been developed to determine key chamber and thermal cycle parameters (e.g., chamber radius, structure and coolant temperatures, cycle efficiency, etc.) as a function of the target yield and pulse repetition rate. Temperature constraints on the tungsten armor, ferritic steel wall, and structure/coolant interface are included in evaluating the potential design space. Results are presented for a lithium cooled first wall coupled with a Brayton power cycle. LLNL work performed under the auspices of the US Department of Energy by the University of California LLNL under Contract W-7405-Eng-48.

  3. Cyclic AMP induces apoptosis in multiple myeloma cells and inhibits tumor development in a mouse myeloma model

    International Nuclear Information System (INIS)

    Follin-Arbelet, Virginie; Hofgaard, Peter O; Hauglin, Harald; Naderi, Soheil; Sundan, Anders; Blomhoff, Rune; Bogen, Bjarne; Blomhoff, Heidi K

    2011-01-01

    Multiple myeloma is an incurable disease requiring the development of effective therapies which can be used clinically. We have elucidated the potential for manipulating the cAMP signaling pathway as a target for inhibiting the growth of multiple myeloma cells. As a model system, we primarily used the murine multiple myeloma cell line MOPC315 which can be grown both in vivo and in vitro. Human multiple myeloma cell lines U266, INA-6 and the B-cell precursor acute lymphoblastic leukemia cell line Reh were used only for in vitro studies. Cell death was assessed by flow cytometry and western blot analysis after treatment with cAMP elevating agents (forskolin, prostaglandin E2 and rolipram) and cAMP analogs. We followed tumor growth in vivo after forskolin treatment by imaging DsRed-labelled MOPC315 cells transplanted subcutaneously in BALB/c nude mice. In contrast to the effect on Reh cells, 50 μM forskolin more than tripled the death of MOPC315 cells after 24 h in vitro. Forskolin induced cell death to a similar extent in the human myeloma cell lines U266 and INA-6. cAMP-mediated cell death had all the typical hallmarks of apoptosis, including changes in the mitochondrial membrane potential and cleavage of caspase 3, caspase 9 and PARP. Forskolin also inhibited the growth of multiple myeloma cells in a mouse model in vivo. Elevation of intracellular levels of cAMP kills multiple myeloma cells in vitro and inhibits development of multiple myeloma in vivo. This strongly suggests that compounds activating the cAMP signaling pathway may be useful in the field of multiple myeloma

  4. Strategies for the inhibition of gingipains for the potential treatment of periodontitis and associated systemic diseases

    Directory of Open Access Journals (Sweden)

    Ingar Olsen

    2014-08-01

    Full Text Available Gingipains are the major virulence factors of Porphyromonas gingivalis, the main periodontopathogen. It is expected that inhibition of gingipain activity in vivo could prevent or slow down the progression of adult periodontitis. To date, several classes of gingipain inhibitors have been recognized. These include gingipain N-terminal prodomains, synthetic compounds, inhibitors from natural sources, antibiotics, antiseptics, antibodies, and bacteria. Several synthetic compounds are potent gingipain inhibitors but inhibit a broad spectrum of host proteases and have undesirable side effects. Synthetic compounds with high specificity for gingipains have unknown toxicity effects, making natural inhibitors more promising as therapeutic gingipain blockers. Cranberry and rice extracts interfere with gingipain activity and prevent the growth and biofilm formation of periodontopathogens. Although the ideal gingipain inhibitor has yet to be discovered, gingipain inhibition represents a novel approach to treat and prevent periodontitis. Gingipain inhibitors may also help treat systemic disorders that are associated with periodontitis, including cardiovascular disease, rheumatoid arthritis, aspiration pneumonia, pre-term birth, and low birth weight.

  5. Persistent phenotypic shift in cardiac fibroblasts: impact of transient renin angiotensin system inhibition.

    Science.gov (United States)

    Hale, Taben M

    2016-04-01

    Fibrotic cardiac remodeling ultimately leads to heart failure - a debilitating and costly condition. Select antihypertensive agents have been effective in reducing or slowing the development of cardiac fibrosis. Moreover, some experimental studies have shown that the reduction in fibrosis induced by these agents persists long after stopping treatment. What has not been as well investigated is whether this transient treatment results in a protection against future fibrotic cardiac remodeling. In the present review, previously published studies are re-examined to assess whether the relative percent increase in collagen deposition over an off-treatment period is attenuated, relative to control, following transient antihypertensive treatment in young or adult rats. Present findings suggest that transient inhibition of the renin angiotensin system (RAS) not only produces a sustained reduction in cardiac fibrosis, but also results in a degree of protection against future collagen deposition. In addition, prior transient RAS inhibition appears to alter the cardiac fibroblast phenotype such that these cells show a muted response to myocardial injury - namely reduced proliferation, chemokine release, and collagen deposition. This review puts forth several potential mechanisms underlying this long-term cardiac protection that is afforded by transient RAS inhibition. Specifically, fibroblast phenotypic change, cardiac fibroblast apoptosis, sustained suppression of the RAS, persistent reduction in left ventricular hypertrophy, and persistent reduction in arterial pressure are each discussed. Identifying the mechanisms ultimately responsible for this change in cardiac fibroblast response to injury, hypertension, and aging may reveal novel targets for therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Insight into the novel inhibition mechanism of apigenin to Pneumolysin by molecular modeling

    Science.gov (United States)

    Niu, Xiaodi; Yang, Yanan; Song, Meng; Wang, Guizhen; Sun, Lin; Gao, Yawen; Wang, Hongsu

    2017-11-01

    In this study, the mechanism of apigenin inhibition was explored using molecular modelling, binding energy calculation, and mutagenesis assays. Energy decomposition analysis indicated that apigenin binds in the gap between domains 3 and 4 of PLY. Using principal component analysis, we found that binding of apigenin to PLY weakens the motion of domains 3 and 4. Consequently, these domains cannot complete the transition from monomer to oligomer, thereby blocking oligomerisation of PLY and counteracting its haemolytic activity. This inhibitory mechanism was confirmed by haemolysis assays, and these findings will promote the future development of an antimicrobial agent.

  7. Cotangent Models for Integrable Systems

    Science.gov (United States)

    Kiesenhofer, Anna; Miranda, Eva

    2017-03-01

    We associate cotangent models to a neighbourhood of a Liouville torus in symplectic and Poisson manifolds focusing on b-Poisson/ b-symplectic manifolds. The semilocal equivalence with such models uses the corresponding action-angle theorems in these settings: the theorem of Liouville-Mineur-Arnold for symplectic manifolds and an action-angle theorem for regular Liouville tori in Poisson manifolds (Laurent- Gengoux et al., IntMath Res Notices IMRN 8: 1839-1869, 2011). Our models comprise regular Liouville tori of Poisson manifolds but also consider the Liouville tori on the singular locus of a b-Poisson manifold. For this latter class of Poisson structures we define a twisted cotangent model. The equivalence with this twisted cotangent model is given by an action-angle theorem recently proved by the authors and Scott (Math. Pures Appl. (9) 105(1):66-85, 2016). This viewpoint of cotangent models provides a new machinery to construct examples of integrable systems, which are especially valuable in the b-symplectic case where not many sources of examples are known. At the end of the paper we introduce non-degenerate singularities as lifted cotangent models on b-symplectic manifolds and discuss some generalizations of these models to general Poisson manifolds.

  8. Inhibition, Updating Working Memory, and Shifting Predict Reading Disability Symptoms in a Hybrid Model: Project KIDS.

    Science.gov (United States)

    Daucourt, Mia C; Schatschneider, Christopher; Connor, Carol M; Al Otaiba, Stephanie; Hart, Sara A

    2018-01-01

    Recent achievement research suggests that executive function (EF), a set of regulatory processes that control both thought and action necessary for goal-directed behavior, is related to typical and atypical reading performance. This project examines the relation of EF, as measured by its components, Inhibition, Updating Working Memory, and Shifting, with a hybrid model of reading disability (RD). Our sample included 420 children who participated in a broader intervention project when they were in KG-third grade (age M = 6.63 years, SD = 1.04 years, range = 4.79-10.40 years). At the time their EF was assessed, using a parent-report Behavior Rating Inventory of Executive Function (BRIEF), they had a mean age of 13.21 years ( SD = 1.54 years; range = 10.47-16.63 years). The hybrid model of RD was operationalized as a composite consisting of four symptoms, and set so that any child could have any one, any two, any three, any four, or none of the symptoms included in the hybrid model. The four symptoms include low word reading achievement, unexpected low word reading achievement, poorer reading comprehension compared to listening comprehension, and dual-discrepancy response-to-intervention, requiring both low achievement and low growth in word reading. The results of our multilevel ordinal logistic regression analyses showed a significant relation between all three components of EF (Inhibition, Updating Working Memory, and Shifting) and the hybrid model of RD, and that the strength of EF's predictive power for RD classification was the highest when RD was modeled as having at least one or more symptoms. Importantly, the chances of being classified as having RD increased as EF performance worsened and decreased as EF performance improved. The question of whether any one EF component would emerge as a superior predictor was also examined and results showed that Inhibition, Updating Working Memory, and Shifting were equally valuable as predictors of the hybrid model of RD

  9. Inhibition, Updating Working Memory, and Shifting Predict Reading Disability Symptoms in a Hybrid Model: Project KIDS

    Directory of Open Access Journals (Sweden)

    Mia C. Daucourt

    2018-03-01

    Full Text Available Recent achievement research suggests that executive function (EF, a set of regulatory processes that control both thought and action necessary for goal-directed behavior, is related to typical and atypical reading performance. This project examines the relation of EF, as measured by its components, Inhibition, Updating Working Memory, and Shifting, with a hybrid model of reading disability (RD. Our sample included 420 children who participated in a broader intervention project when they were in KG-third grade (age M = 6.63 years, SD = 1.04 years, range = 4.79–10.40 years. At the time their EF was assessed, using a parent-report Behavior Rating Inventory of Executive Function (BRIEF, they had a mean age of 13.21 years (SD = 1.54 years; range = 10.47–16.63 years. The hybrid model of RD was operationalized as a composite consisting of four symptoms, and set so that any child could have any one, any two, any three, any four, or none of the symptoms included in the hybrid model. The four symptoms include low word reading achievement, unexpected low word reading achievement, poorer reading comprehension compared to listening comprehension, and dual-discrepancy response-to-intervention, requiring both low achievement and low growth in word reading. The results of our multilevel ordinal logistic regression analyses showed a significant relation between all three components of EF (Inhibition, Updating Working Memory, and Shifting and the hybrid model of RD, and that the strength of EF’s predictive power for RD classification was the highest when RD was modeled as having at least one or more symptoms. Importantly, the chances of being classified as having RD increased as EF performance worsened and decreased as EF performance improved. The question of whether any one EF component would emerge as a superior predictor was also examined and results showed that Inhibition, Updating Working Memory, and Shifting were equally valuable as predictors of the

  10. Graph modeling systems and methods

    Science.gov (United States)

    Neergaard, Mike

    2015-10-13

    An apparatus and a method for vulnerability and reliability modeling are provided. The method generally includes constructing a graph model of a physical network using a computer, the graph model including a plurality of terminating vertices to represent nodes in the physical network, a plurality of edges to represent transmission paths in the physical network, and a non-terminating vertex to represent a non-nodal vulnerability along a transmission path in the physical network. The method additionally includes evaluating the vulnerability and reliability of the physical network using the constructed graph model, wherein the vulnerability and reliability evaluation includes a determination of whether each terminating and non-terminating vertex represents a critical point of failure. The method can be utilized to evaluate wide variety of networks, including power grid infrastructures, communication network topologies, and fluid distribution systems.

  11. Probabilistic models for feedback systems.

    Energy Technology Data Exchange (ETDEWEB)

    Grace, Matthew D.; Boggs, Paul T.

    2011-02-01

    In previous work, we developed a Bayesian-based methodology to analyze the reliability of hierarchical systems. The output of the procedure is a statistical distribution of the reliability, thus allowing many questions to be answered. The principal advantage of the approach is that along with an estimate of the reliability, we also can provide statements of confidence in the results. The model is quite general in that it allows general representations of all of the distributions involved, it incorporates prior knowledge into the models, it allows errors in the 'engineered' nodes of a system to be determined by the data, and leads to the ability to determine optimal testing strategies. In this report, we provide the preliminary steps necessary to extend this approach to systems with feedback. Feedback is an essential component of 'complexity' and provides interesting challenges in modeling the time-dependent action of a feedback loop. We provide a mechanism for doing this and analyze a simple case. We then consider some extensions to more interesting examples with local control affecting the entire system. Finally, a discussion of the status of the research is also included.

  12. Stochastic Modelling of Hydrologic Systems

    DEFF Research Database (Denmark)

    Jonsdottir, Harpa

    2007-01-01

    In this PhD project several stochastic modelling methods are studied and applied on various subjects in hydrology. The research was prepared at Informatics and Mathematical Modelling at the Technical University of Denmark. The thesis is divided into two parts. The first part contains an introduct......In this PhD project several stochastic modelling methods are studied and applied on various subjects in hydrology. The research was prepared at Informatics and Mathematical Modelling at the Technical University of Denmark. The thesis is divided into two parts. The first part contains...... an introduction and an overview of the papers published. Then an introduction to basic concepts in hydrology along with a description of hydrological data is given. Finally an introduction to stochastic modelling is given. The second part contains the research papers. In the research papers the stochastic methods...... are described, as at the time of publication these methods represent new contribution to hydrology. The second part also contains additional description of software used and a brief introduction to stiff systems. The system in one of the papers is stiff....

  13. Validating the pivotal role of the immune system in low-dose radiation-induced tumor inhibition in Lewis lung cancer-bearing mice.

    Science.gov (United States)

    Zhou, Lei; Zhang, Xiaoying; Li, Hui; Niu, Chao; Yu, Dehai; Yang, Guozi; Liang, Xinyue; Wen, Xue; Li, Min; Cui, Jiuwei

    2018-04-01

    Although low-dose radiation (LDR) possesses the two distinct functions of inducing hormesis and adaptive responses, which result in immune enhancement and tumor inhibition, its clinical applications have not yet been elucidated. The major obstacle that hinders the application of LDR in the clinical setting is that the mechanisms underlying induction of tumor inhibition are unclear, and the risks associated with LDR are still unknown. Thus, to overcome this obstacle and elucidate the mechanisms mediating the antitumor effects of LDR, in this study, we established an in vivo lung cancer model to investigate the participation of the immune system in LDR-induced tumor inhibition and validated the pivotal role of the immune system by impairing immunity with high-dose radiation (HDR) of 1 Gy. Additionally, the LDR-induced adaptive response of the immune system was also observed by sequential HDR treatment in this mouse model. We found that LDR-activated T cells and natural killer cells and increased the cytotoxicity of splenocytes and the infiltration of T cells in the tumor tissues. In contrast, when immune function was impaired by HDR pretreatment, LDR could not induce tumor inhibition. However, when LDR was administered before HDR, the immunity could be protected from impairment, and tumor growth could be inhibited to some extent, indicating the induction of the immune adaptive response by LDR. Therefore, we demonstrated that immune enhancement played a key role in LDR-induced tumor inhibition. These findings emphasized the importance of the immune response in tumor radiotherapy and may help promote the application of LDR as a novel approach in clinical practice. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

  14. Discrete modelling of drapery systems

    Science.gov (United States)

    Thoeni, Klaus; Giacomini, Anna

    2016-04-01

    Drapery systems are an efficient and cost-effective measure in preventing and controlling rockfall hazards on rock slopes. The simplest form consists of a row of ground anchors along the top of the slope connected to a horizontal support cable from which a wire mesh is suspended down the face of the slope. Such systems are generally referred to as simple or unsecured draperies (Badger and Duffy 2012). Variations such as secured draperies, where a pattern of ground anchors is incorporated within the field of the mesh, and hybrid systems, where the upper part of an unsecured drapery is elevated to intercept rockfalls originating upslope of the installation, are becoming more and more popular. This work presents a discrete element framework for simulation of unsecured drapery systems and its variations. The numerical model is based on the classical discrete element method (DEM) and implemented into the open-source framework YADE (Šmilauer et al., 2010). The model takes all relevant interactions between block, drapery and slope into account (Thoeni et al., 2014) and was calibrated and validated based on full-scale experiments (Giacomini et al., 2012).The block is modelled as a rigid clump made of spherical particles which allows any shape to be approximated. The drapery is represented by a set of spherical particle with remote interactions. The behaviour of the remote interactions is governed by the constitutive behaviour of the wire and generally corresponds to a piecewise linear stress-strain relation (Thoeni et al., 2013). The same concept is used to model wire ropes. The rock slope is represented by rigid triangular elements where material properties (e.g., normal coefficient of restitution, friction angle) are assigned to each triangle. The capabilities of the developed model to simulate drapery systems and estimate the residual hazard involved with such systems is shown. References Badger, T.C., Duffy, J.D. (2012) Drapery systems. In: Turner, A.K., Schuster R

  15. Piriformospora indica root colonization triggers local and systemic root responses and inhibits secondary colonization of distal roots.

    Directory of Open Access Journals (Sweden)

    Lorenzo Pedrotti

    Full Text Available Piriformosporaindica is a basidiomycete fungus colonizing roots of a wide range of higher plants, including crop plants and the model plant Arabidopsis thaliana. Previous studies have shown that P. indica improves growth, and enhances systemic pathogen resistance in leaves of host plants. To investigate systemic effects within the root system, we established a hydroponic split-root cultivation system for Arabidopsis. Using quantitative real-time PCR, we show that initial P. indica colonization triggers a local, transient response of several defense-related transcripts, of which some were also induced in shoots and in distal, non-colonized roots of the same plant. Systemic effects on distal roots included the inhibition of secondary P. indica colonization. Faster and stronger induction of defense-related transcripts during secondary inoculation revealed that a P. indica pretreatment triggers root-wide priming of defense responses, which could cause the observed reduction of secondary colonization levels. Secondary P. indica colonization also induced defense responses in distant, already colonized parts of the root. Endophytic fungi therefore trigger a spatially specific response in directly colonized and in systemic root tissues of host plants.

  16. Piriformospora indica root colonization triggers local and systemic root responses and inhibits secondary colonization of distal roots.

    Science.gov (United States)

    Pedrotti, Lorenzo; Mueller, Martin J; Waller, Frank

    2013-01-01

    Piriformosporaindica is a basidiomycete fungus colonizing roots of a wide range of higher plants, including crop plants and the model plant Arabidopsis thaliana. Previous studies have shown that P. indica improves growth, and enhances systemic pathogen resistance in leaves of host plants. To investigate systemic effects within the root system, we established a hydroponic split-root cultivation system for Arabidopsis. Using quantitative real-time PCR, we show that initial P. indica colonization triggers a local, transient response of several defense-related transcripts, of which some were also induced in shoots and in distal, non-colonized roots of the same plant. Systemic effects on distal roots included the inhibition of secondary P. indica colonization. Faster and stronger induction of defense-related transcripts during secondary inoculation revealed that a P. indica pretreatment triggers root-wide priming of defense responses, which could cause the observed reduction of secondary colonization levels. Secondary P. indica colonization also induced defense responses in distant, already colonized parts of the root. Endophytic fungi therefore trigger a spatially specific response in directly colonized and in systemic root tissues of host plants.

  17. Effect of magnesium supplementation on blood rheology in NOS inhibition-induced hypertension model.

    Science.gov (United States)

    Cengiz, Melike; Ülker, Pinar; Üyüklü, Mehmet; Yaraş, Nazmi; Özen, Nur; Aslan, Mutay; Özyurt, Dilek; Basralı, Filiz

    2016-01-27

    This study investigated the effects of magnesium on blood rheological properties and blood pressure in nitric oxide synthase (NOS) inhibition-induced hypertension model. Hypertension was induced by oral administration of the nonselective NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME, 25 mg/kg/day) for 6 weeks and systolic blood pressure was measured by the tail-cuff method. The groups receiving magnesium supplementation were fed with rat chow containing 0.8% magnesium oxide during the experiment. At the end of experiment, blood samples were obtained from abdominal aorta, using ether anesthesia. Plasma and erythrocyte magnesium levels were determined by the atomic absorption spectrometer. RBC deformability and aggregation were determined by rotational ektacytometry. Plasma fibrinogen concentration was evaluated by ELISA. Whole blood and plasma viscosities were determined by viscometer and intracellular free Ca++ level was measured by using spectroflurometric method. Blood pressure was elevated in hypertensive groups and suppressed by magnesium therapy. Plasma viscosity and RBC aggregation were found to be higher in hypertensive rats than control animals and these parameters significantly decreased in magnesium supplemented hypertensive animals. Other measurements were not different between experimental groups. These results confirm that blood pressure, plasma viscosity and RBC aggregation increased in NOS inhibition-induced hypertension model and oral magnesium supplementation improved these parameters.

  18. Inhibiting sphingosine kinase 2 mitigates mutant Huntingtin-induced neurodegeneration in neuron models of Huntington disease.

    Science.gov (United States)

    Moruno-Manchon, Jose F; Uzor, Ndidi-Ese; Blasco-Conesa, Maria P; Mannuru, Sishira; Putluri, Nagireddy; Furr-Stimming, Erin E; Tsvetkov, Andrey S

    2017-04-01

    Huntington disease (HD) is the most common inherited neurodegenerative disorder. It has no cure. The protein huntingtin causes HD, and mutations to it confer toxic functions to the protein that lead to neurodegeneration. Thus, identifying modifiers of mutant huntingtin-mediated neurotoxicity might be a therapeutic strategy for HD. Sphingosine kinases 1 (SK1) and 2 (SK2) synthesize sphingosine-1-phosphate (S1P), a bioactive lipid messenger critically involved in many vital cellular processes, such as cell survival. In the nucleus, SK2 binds to and inhibits histone deacetylases 1 and 2 (HDAC1/2). Inhibiting both HDACs has been suggested as a potential therapy in HD. Here, we found that SK2 is nuclear in primary neurons and, unexpectedly, overexpressed SK2 is neurotoxic in a dose-dependent manner. SK2 promotes DNA double-strand breaks in cultured primary neurons. We also found that SK2 is hyperphosphorylated in the brain samples from a model of HD, the BACHD mice. These data suggest that the SK2 pathway may be a part of a pathogenic pathway in HD. ABC294640, an inhibitor of SK2, reduces DNA damage in neurons and increases survival in two neuron models of HD. Our results identify a novel regulator of mutant huntingtin-mediated neurotoxicity and provide a new target for developing therapies for HD. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  19. Molecular Modeling Analysis of the Inhibition of Mitochondrial Cytochrome BC1 Complex Activity by Tocol Derivatives

    Science.gov (United States)

    Singh, Awantika; Hauer-Jensen, Martin; Compadre, Cesar M.; Kumar, K. Sree

    2011-06-01

    The biological functions of vitamin E related compounds have been of interest in biomedical research for several decades. Among those compounds, α-, β-, δ-, and γ-tocopherols and their oxidation products, α-, β-, δ-, γ-tocopherylquinone and their analogs α-TQo, γ-TQo, TMC20 and TMC40 were recently shown to inhibit the mitochondrial cytochrome bc1 complex. In this investigation the effects of the structural variation on the inhibition of the mitochondrial cytochrome bc1 complex were analyzed using Comparative Molecular Field Analysis (CoMFA). CoMFA performed using steric and electrostatic molecular fields produced a very good correlation. The best CoMFA models were obtained using the manual alignment of 12 compounds with 5 components (q2 = 0.589, SPRESS = 0.515, r2 = 0.992, s = 0.068 and F value = 156.520). The resulting contour maps produced by the best CoMFA model were helpful in identifying the structural features required for the biological activity of compounds under study. These results would be helpful for predicting the activity of new compounds, and they could be used for guiding the design, synthesis and development of new and more effective agents.

  20. Halofuginone Inhibits Angiogenesis and Growth in Implanted Metastatic Rat Brain Tumor Model-an MRI Study

    Directory of Open Access Journals (Sweden)

    Rinat Abramovitch

    2004-09-01

    Full Text Available Tumor growth and metastasis depend on angiogenesis; therefore, efforts are made to develop specific angiogenic inhibitors. Halofuginone (HF is a potent inhibitor of collagen type α1(I. In solid tumor models, HF has a potent antitumor and antiangiogenic effect in vivo, but its effect on brain tumors has not yet been evaluated. By employing magnetic resonance imaging (MRI, we monitored the effect of HF on tumor progression and vascularization by utilizing an implanted malignant fibrous histiocytoma metastatic rat brain tumor model. Here we demonstrate that treatment with HF effectively and dose-dependently reduced tumor growth and angiogenesis. On day 13, HF-treated tumors were fivefold smaller than control (P < .001. Treatment with HF significantly prolonged survival of treated animals (142%; P = .001. In HF-treated rats, tumor vascularization was inhibited by 30% on day 13 and by 37% on day 19 (P < .05. Additionally, HF treatment inhibited vessel maturation (P = .03. Finally, in HF-treated rats, we noticed the appearance of a few clusters of satellite tumors, which were distinct from the primary tumor and usually contained vessel cores. This phenomenon was relatively moderate when compared to previous reports of other antiangiogenic agents used to treat brain tumors. We therefore conclude that HF is effective for treatment of metastatic brain tumors.

  1. Antitumor effect of combined NAMPT and CD73 inhibition in an ovarian cancer model.

    Science.gov (United States)

    Sociali, Giovanna; Raffaghello, Lizzia; Magnone, Mirko; Zamporlini, Federica; Emionite, Laura; Sturla, Laura; Bianchi, Giovanna; Vigliarolo, Tiziana; Nahimana, Aimable; Nencioni, Alessio; Raffaelli, Nadia; Bruzzone, Santina

    2016-01-19

    Nicotinamide phosphoribosyltransferase (NAMPT) is a crucial enzyme in the biosynthesis of intracellular NAD+. NAMPT inhibitors have potent anticancer activity in several preclinical models by depleting NAD+ and ATP levels. Recently, we demonstrated that CD73 enables the utilization of extracellular NAD+/nicotinamide mononucleotide (NMN) by converting them to Nicotinamide riboside (NR), which can cross the plasmamembrane and fuel intracellular NAD+ biosynthesis in human cells. These processes are herein confirmed to also occur in a human ovarian carcinoma cell line (OVCAR-3), by means of CD73 or NRK1 specific silencing. Next, we investigated the anti-tumor activity of the simultaneous inhibition of NAMPT (with FK866) and CD73 (with α, β-methylene adenosine 5'-diphosphate, APCP), in an in vivo human ovarian carcinoma model. Interestingly, the combined therapy was found to significantly decrease intratumor NAD+, NMN and ATP levels, compared with single treatments. In addition, the concentration of these nucleotides in ascitic exudates was more remarkably reduced in animals treated with both FK866 and APCP compared with single treatments. Importantly, tumors treated with FK866 in combination with APCP contained a statistically significant lower proportion of Ki67 positive proliferating cells and a higher percentage of necrotic area. Finally, a slight but significant increase in animal survival in response to the combined therapy, compared to the single agents, could be demonstrated. Our results indicate that the pharmacological inhibition of CD73 enzymatic activity could be considered as a means to potentiate the anti-cancer effects of NAMPT inhibitors.

  2. Modified ADM1 for modeling free ammonia inhibition in anaerobic acidogenic fermentation with high-solid sludge.

    Science.gov (United States)

    Bai, Jie; Liu, He; Yin, Bo; Ma, Huijun; Chen, Xinchun

    2017-02-01

    Anaerobic acidogenic fermentation with high-solid sludge is a promising method for volatile fatty acid (VFA) production to realize resource recovery. In this study, to model inhibition by free ammonia in high-solid sludge fermentation, the anaerobic digestion model No. 1 (ADM1) was modified to simulate the VFA generation in batch, semi-continuous and full scale sludge. The ADM1 was operated on the platform AQUASIM 2.0. Three kinds of inhibition forms, e.g., simple inhibition, Monod and non-inhibition forms, were integrated into the ADM1 and tested with the real experimental data for batch and semi-continuous fermentation, respectively. The improved particle swarm optimization technique was used for kinetic parameter estimation using the software MATLAB 7.0. In the modified ADM1, the K s of acetate is 0.025, the k m,ac is 12.51, and the K I_NH3 is 0.02, respectively. The results showed that the simple inhibition model could simulate the VFA generation accurately while the Monod model was the better inhibition kinetics form in semi-continuous fermentation at pH10.0. Finally, the modified ADM1 could successfully describe the VFA generation and ammonia accumulation in a 30m 3 full-scale sludge fermentation reactor, indicating that the developed model can be applicable in high-solid sludge anaerobic fermentation. Copyright © 2016. Published by Elsevier B.V.

  3. Efficient dynamic molecular simulation using QSAR model to know inhibition activity in breast cancer medicine

    Science.gov (United States)

    Zharifah, A.; Kusumowardani, E.; Saputro, A.; Sarwinda, D.

    2017-07-01

    According to data from GLOBOCAN (IARC) at 2012, breast cancer was the highest rated of new cancer case by 43.3 % (after controlled by age), with mortality rated as high as 12.9 %. Oncology is a major field which focusing on improving the development of drug and therapeutics cancer in pharmaceutical and biotechnology companies. Nowadays, many researchers lead to computational chemistry and bioinformatic for pharmacophore generation. A pharmacophore describes as a group of atoms in the molecule which is considered to be responsible for a pharmacological action. Prediction of biological function from chemical structure in silico modeling reduces the use of chemical reagents so the risk of environmental pollution decreased. In this research, we proposed QSAR model to analyze the composition of cancer drugs which assumed to be homogenous in character and treatment. Atomic interactions which analyzed are learned through parameters such as log p as descriptors hydrophobic, n_poinas descriptor contour strength and molecular structure, and also various concentrations inhibitor (micromolar and nanomolar) from NCBI drugs bank. The differences inhibitor activity was observed by the presence of IC 50 residues value from inhibitor substances at various concentration. Then, we got a general overview of the state of safety for drug stability seen from its IC 50 value. In our study, we also compared between micromolar and nanomolar inhibitor effect from QSAR model results. The QSAR model analysis shows that the drug concentration with nanomolar is better than micromolar, related with the content of inhibitor substances concentration. This QSAR model got the equation: Log 1/IC50 = (0.284) (±0.195) logP + (0.02) (±0.012) n_poin + (-0.005) (±0.083) Inhibition10.2nanoM + (0.1) (±0.079) Inhibition30.5nanoM + (-0.016) (±0.045) Inhibition91.5nanoM + (-2.572) (±1.570) (n = 13; r = 0.813; r2 = 0.660; s = 0.764; F = 2.720; q2 = 0.660).

  4. The Metabolic Inhibition Model Which Predicts the Intestinal Absorbability and Metabolizability of Drug: Theory and Experiment

    Directory of Open Access Journals (Sweden)

    Mizuma Takashi

    1998-01-01

    Full Text Available The intestinal absorption of analgesic peptides (leucine enkephalin and kyotorphin and modified peptides in rat were studied. Although these peptides were not absorbed, the absorbability (absorption clearance of these peptides were increased in the presence of peptidase inhibitors. In order to kinetically analyze these phenomena, we proposed the metabolic inhibition model, which incorporated the metabolic clearance (metabolizability with the absorption clearance. Metabolic activity was determined with intestinal homogenates. The higher the metabolic clearance was, the lower was the absorption clearance. The relationships between the absorption clearance and the metabolic clearance of the experimental data as well as of the theoretical values were hyperbolic. This model predicted the maximum absorption clearances of cellobiose-coupled leucine enkephalin (0.654 &mgr;l/min/cm and kyotorphin (0.247 &mgr;l/min/cm. Details of the experimental methods are described.

  5. Efficacy of chitosan in inhibiting the oxidation of (+)-catechin in white wine model solutions.

    Science.gov (United States)

    Chinnici, Fabio; Natali, Nadia; Riponi, Claudio

    2014-10-08

    The efficacy of chitosan and sulfites in inhibiting the oxidation of (+)-catechin in aerated model white wines has been compared by monitoring the browning development and the generation of oxidized phenolic compounds. In addition, the protecting effects of these two additives toward the oxidative decay of varietal thiols were investigated. Chitosan effectively contrasted the browning onset in model solutions all along the entire duration of the experimentation. Color development was limited and comparable in both the sulfite and chitosan added samples. Thanks to its polyelectrolyte behavior, chitosan adsorbed up to 80% of the more hydrophilic oxidized phenolic species and chelated 70 and 30% of Fe and Cu added to the solutions, respectively. Thiol oxidation was significantly lowered by chitosan, suggesting that this additive could contribute to maintain the varietal character of wines coming from aromatic grapes and vinified with reduced sulfite amounts.

  6. Computational models of complex systems

    CERN Document Server

    Dabbaghian, Vahid

    2014-01-01

    Computational and mathematical models provide us with the opportunities to investigate the complexities of real world problems. They allow us to apply our best analytical methods to define problems in a clearly mathematical manner and exhaustively test our solutions before committing expensive resources. This is made possible by assuming parameter(s) in a bounded environment, allowing for controllable experimentation, not always possible in live scenarios. For example, simulation of computational models allows the testing of theories in a manner that is both fundamentally deductive and experimental in nature. The main ingredients for such research ideas come from multiple disciplines and the importance of interdisciplinary research is well recognized by the scientific community. This book provides a window to the novel endeavours of the research communities to present their works by highlighting the value of computational modelling as a research tool when investigating complex systems. We hope that the reader...

  7. Model reduction of parametrized systems

    CERN Document Server

    Ohlberger, Mario; Patera, Anthony; Rozza, Gianluigi; Urban, Karsten

    2017-01-01

    The special volume offers a global guide to new concepts and approaches concerning the following topics: reduced basis methods, proper orthogonal decomposition, proper generalized decomposition, approximation theory related to model reduction, learning theory and compressed sensing, stochastic and high-dimensional problems, system-theoretic methods, nonlinear model reduction, reduction of coupled problems/multiphysics, optimization and optimal control, state estimation and control, reduced order models and domain decomposition methods, Krylov-subspace and interpolatory methods, and applications to real industrial and complex problems. The book represents the state of the art in the development of reduced order methods. It contains contributions from internationally respected experts, guaranteeing a wide range of expertise and topics. Further, it reflects an important effor t, carried out over the last 12 years, to build a growing research community in this field. Though not a textbook, some of the chapters ca...

  8. Computational Modeling of the Negative Priming Effect Based on Inhibition Patterns and Working Memory

    Directory of Open Access Journals (Sweden)

    Dongil eChung

    2013-11-01

    Full Text Available Negative priming (NP, slowing down of the response for target stimuli that have been previously exposed, but ignored, has been reported in multiple psychological paradigms including the Stroop task. Although NP likely results from the interplay of selective attention, episodic memory retrieval, working memory, and inhibition mechanisms, a comprehensive theoretical account of NP is currently unavailable. This lacuna may result from the complexity of stimuli combinations in NP. Thus, we aimed to investigate the presence of different degrees of the NP effect according to prime-probe combinations within a classic Stroop task. We recorded reaction times (RTs from 66 healthy participants during Stroop task performance and examined three different NP subtypes, defined according to the type of the Stroop probe in prime-probe pairs. Our findings show significant RT differences among NP subtypes that are putatively due to the presence of differential disinhibition, i.e., release from inhibition. Among the several potential origins for differential subtypes of NP, we investigated the involvement of selective attention and/or working memory using a parallel distributed processing (PDP model (employing selective attention only and a modified PDP model with working memory (PDP-WM, employing both selective attention and working memory. Our findings demonstrate that, unlike the conventional PDP model, the PDP-WM successfully simulates different levels of NP effects that closely follow the behavioral data. This outcome suggests that working memory engages in the re-accumulation of the evidence for target response and induces differential NP effects. Our computational model complements earlier efforts and may pave the road to further insights into an integrated theoretical account of complex NP effects.

  9. Roles of abscisic acid and auxin in shoot-supplied ammonium inhibition of root system development.

    Science.gov (United States)

    Li, Baohai; Li, Qing; Kronzucker, Herbert J; Shi, Weiming

    2011-10-01

    A plastic root system is a prerequisite for successful plant acclimation to variable environments. The normally functioning root system is the result of a complex interaction of root-borne signals and shoot-derived regulators. We recently demonstrated that AUX1, a well-studied component of auxin transport, mediates shoot-supplied ammonium (SSA) inhibition of lateral root (LR) formation in Arabidopsis. By contrast, the response did not involve ABA pathways, via which several other abiotic stresses affect LR formation. We proposed that SSA regulates LR emergence by interrupting AUX1-mediated auxin transport from shoot to root. Here, by analyzing both ABA- and auxin-related mutants, we show that AUX1 is also required for SSA-mediated suppression of primary root growth. Ammonium content in shoots was furthermore shown to increase linearly with shoot-, but not root-supplied, ammonium, suggesting it may represent the internal trigger for SSA inhibition of root development. Taken together, our data identify AUX1-mediated auxin transport as a key transmission step in the sensing of excessive ammonium exposure and its inhibitory effect on root development. 

  10. Modeling software systems by domains

    Science.gov (United States)

    Dippolito, Richard; Lee, Kenneth

    1992-01-01

    The Software Architectures Engineering (SAE) Project at the Software Engineering Institute (SEI) has developed engineering modeling techniques that both reduce the complexity of software for domain-specific computer systems and result in systems that are easier to build and maintain. These techniques allow maximum freedom for system developers to apply their domain expertise to software. We have applied these techniques to several types of applications, including training simulators operating in real time, engineering simulators operating in non-real time, and real-time embedded computer systems. Our modeling techniques result in software that mirrors both the complexity of the application and the domain knowledge requirements. We submit that the proper measure of software complexity reflects neither the number of software component units nor the code count, but the locus of and amount of domain knowledge. As a result of using these techniques, domain knowledge is isolated by fields of engineering expertise and removed from the concern of the software engineer. In this paper, we will describe kinds of domain expertise, describe engineering by domains, and provide relevant examples of software developed for simulator applications using the techniques.

  11. Picropodophyllin inhibits tumor growth of human nasopharyngeal carcinoma in a mouse model

    International Nuclear Information System (INIS)

    Yin, Shu-Cheng; Guo, Wei; Tao, Ze-Zhang

    2013-01-01

    Highlights: •We identified that PPP inhibits IGF-1R/Akt pathway in NPC cells. •PPP dose-dependently inhibits NPC cell proliferation in vitro. •PPP suppresses tumor growth of NPC in nude mice. •PPP have little effect on microtubule assembly. -- Abstract: Insulin-like growth factor-1 receptor (IGF-1R) is a cell membrane receptor with tyrosine kinase activity and plays important roles in cell transformation, tumor growth, tumor invasion, and metastasis. Picropodophyllin (PPP) is a selective IGF-1R inhibitor and shows promising antitumor effects for several human cancers. However, its antitumor effects in nasopharyngeal carcinoma (NPC) remain unclear. The purpose of this study is to investigate the antitumor activity of PPP in NPC using in vitro cell culture and in vivo animal model. We found that PPP dose-dependently decreased the IGF-induced phosphorylation and activity of IGF-1R and consequently reduced the phosphorylation of Akt, one downstream target of IGF-1R. In addition, PPP inhibited NPC cell proliferation in vitro. The half maximal inhibitory concentration (IC50) of PPP for NPC cell line CNE-2 was ⩽1 μM at 24 h after treatment and ⩽0.5 μM at 48 h after treatment, respectively. Moreover, administration of PPP by intraperitoneal injection significantly suppressed the tumor growth of xenografted NPC in nude mice. Taken together, these results suggest targeting IGF-1R by PPP may represent a new strategy for treatment of NPCs with positive IGF-1R expression

  12. Monitoring and Modeling Microbial Sulfate Reduction and Inhibition in a Mesoscale Tank Experiment

    Science.gov (United States)

    Hubbard, C. G.; Wu, Y.; Li, L.; Piceno, Y. M.; Cheng, Y.; Bill, M.; Coates, J. D.; Andersen, G. L.; Conrad, M. E.; Ajo Franklin, J. B.

    2014-12-01

    Subsurface biogeochemical cycling at the field-scale is controlled by a complex interplay between hydrological, geochemical and biological parameters. Mesoscale tank experiments can help to bridge the gap in complexity and understanding between well constrained batch and column experiments, and the interpretation of field data. In this contribution we present the results of a tank experiment investigating microbial sulfate reduction and inhibition in a porous media (20-30 mesh Ottawa sand). Microbial sulfate reduction is a process of wide biogeochemical significance, including in the context of oil reservoirs where the generation of sulfide can result in corrosion of steel infrastructure and additional downstream processing. Inhibition of sulfate reduction is therefore a high priority for this industry. Tracer experiments were conducted at the start and end of the experiment to constrain flow pathways and heterogeneities. The tank was inoculated with a San Francisco Bay mud/water enrichment utilizing acetate as the electron donor and continuous flow was initiated using bay-water with 10 mM acetate. Samples were taken from an array of 12 steel boreholes and showed spatiotemporal heterogeneities in the development of sulfidogenesis, reaching a peak of ~5 mM dissolved sulfide 71 days after inoculation. 10 mM perchlorate was then added to the influent to inhibit sulfidogenesis and dissolved sulfide decreased to ~0.03 mM by day 95. Stable isotope analysis of dissolved sulfate showed an increase in δ34S by ~10‰ compared with influent values but δ34S did not return to influent values by day 95, which may be indicative of the mixing between new and residual sulfate in the tank. Ongoing microbial community analyses are being used to help constrain microbial metabolisms. Finally, all the data is being integrated into a reactive transport model to better constrain the observed interplay between hydrology, geochemistry and biology.

  13. RANKL inhibition improves bone properties in a mouse model of osteogenesis imperfecta.

    Science.gov (United States)

    Bargman, Renee; Huang, Alice; Boskey, Adele L; Raggio, Cathleen; Pleshko, Nancy

    2010-04-01

    Recently, a new class of agents targeting the receptor activator of nuclear factor-kappaB ligand (RANKL) pathway has been developed for the treatment of osteoporosis and other bone diseases. In the current study, inhibition of the RANKL pathway was evaluated to assess effects on "bone quality" and fracture incidence in an animal model of osteogenesis imperfect (OI), the oim/oim mouse. Juvenile oim/oim ( approximately 6 weeks old) and wildtype (+/+) mice were treated with either a RANKL inhibitor (RANK-Fc) or saline. After treatment, bone density increased significantly in the femurs of both genotypes. Femoral length decreased with RANK-Fc in +/+ mice. Geometric measurements at mid-diaphysis in the oim/oim groups showed increases in the ML periosteal and endosteal diameters and AP cortical thickness in the treated groups. Within +/+ groups, ML cortical thickness and ML femoral periosteal diameter were significantly increased with RANK-Fc. Biomechanical testing revealed increased stiffness in oim/oim and +/+ mice. Total strain was increased with treatment in the +/+ mice. Histologically, RANKL inhibition resulted in retained growth plate cartilage in both genotypes. The average number of fractures sustained by RANK-Fc-treated oim/oim mice was not significantly decreased compared to saline treated oim/oim mice. This preclinical study demonstrated that RANKL inhibition at the current dose improved density and some geometric and biomechanical properties of oim/oim bone, but it did not decrease fracture incidence. Further studies that address commencement of therapy at earlier time points are needed to determine whether this mode of therapy will be clinically useful in OI.

  14. Blood Pressure Lowering and Safety Improvements With Liver Angiotensinogen Inhibition in Models of Hypertension and Kidney Injury.

    Science.gov (United States)

    Mullick, Adam E; Yeh, Steve T; Graham, Mark J; Engelhardt, Jeffery A; Prakash, Thazha P; Crooke, Rosanne M

    2017-09-01

    Uncontrolled hypertension is an important contributor to cardiovascular disease. Despite the armamentarium of antihypertensive treatments, there remains a need for novel agents effective in individuals who cannot reach acceptable blood pressure levels. Inhibitors targeting the renin-angiotensin-aldosterone system (RAAS) are widely used but may not optimally inhibit RAAS and demonstrate an acceptable safety profile. Experiments were conducted to characterize a series of AGT (angiotensinogen) antisense oligonucleotides (ASOs) and compare their efficacy and tolerability to traditional RAAS blockade. AGT ASOs which target multiple systemic sites of AGT versus an N-acetylgalactosamine-conjugated AGT ASO that targets the liver were compared with captopril and losartan. Spontaneously hypertensive rats fed an 8% NaCl diet, a model of malignant hypertension resistant to standard RAAS inhibitors, demonstrated robust and durable blood pressure reductions with AGT ASO treatments, which was not observed with standard RAAS blockade. Studies in rat models of acute kidney injury produced by salt deprivation revealed kidney injury with ASO treatment that reduced kidney-expressed AGT, but not in animals treated with the N-acetylgalactosamine AGT ASO despite comparable plasma AGT reductions. Administration of either captopril or losartan also produced acute kidney injury during salt deprivation. Thus, intrarenal RAAS derived from kidney AGT, and inhibited by the standard of care, contributes to the maintenance of renal function during severe RAAS challenge. Such improvements in efficacy and tolerability by a liver-selective AGT inhibitor could be desirable in individuals not at their blood pressure goal with existing RAAS blockade. © 2017 American Heart Association, Inc.

  15. Flight-induced inhibition of the cerebral median peptidergic neurosecretory system in Locusta migratoria

    International Nuclear Information System (INIS)

    Diederen, J.H.; van Etten, E.W.; Biegstraaten, A.I.; Terlou, M.; Vullings, H.G.; Jansen, W.F.

    1988-01-01

    This study discusses the effects of a 1-hr period of flight on the peptidergic pars intercerebralis (PI)-corpus cardiacum storage part (CCS) system in male Locusta migratoria, particularly the effect on material in this system stained by a histochemical method for peptidergic neurosecretory material (NSM) or labeled by in vivo incorporation of radioactive amino acid molecules. By use of an automatic image analysis system a number of parameters of the stained or radioactively labeled substances were measured to quantify the flight-induced effects and to get information on the manner in which the neurosecretory cell bodies in the PI and their axonal endings in the CCS accommodate changing amounts of NSM. The CCS of flown locusts contained distinctly more stained and radioactively labeled substances than the CCS of unflown locusts. A tendency to similar differences was observed in the cluster of neurosecretory cell bodies in the PI. The results indicate that 1 hr flight inhibited the release of NSM by the PI-CCS system. After the onset of reduced release activity by flight, some NSM continued to be synthesized and transported from the PI to the CCS, gradually filling up and expanding the entire PI-CCS system, the NSM at the same time becoming more and more densely packed. It is concluded that the peptidergic PI-CCS system is not actively involved in the control of flight metabolism or flight behavior

  16. Neuroprotective Functions Through Inhibition of ER Stress by Taurine or Taurine Combination Treatments in a Rat Stroke Model.

    Science.gov (United States)

    Prentice, Howard; Gharibani, Payam M; Ma, Zhiyuan; Alexandrescu, Anamaria; Genova, Rafaella; Chen, Po-Chih; Modi, Jigar; Menzie, Janet; Pan, Chunliu; Tao, Rui; Wu, Jang-Yen

    2017-01-01

    Taurine, as a free amino acid, is found at high levels in many tissues including brain, heart and skeletal muscle and is known to demonstrate neuroprotective effects in a range of disease conditions including stroke and neurodegenerative disease. Using in vitro culture systems we have demonstrated that taurine can elicit protection against endoplasmic reticulum stress (ER stress) from glutamate excitotoxicity or from excessive reactive oxygen species in PC12 cells or rat neuronal cultures. In our current investigation we hypothesized that taurine treatment after stroke in the rat middle cerebral artery occlusion (MCAO) model would render protection against ER stress processes as reflected in decreased levels of expression of ER stress pathway components. We demonstrated that taurine elicited high level protection and inhibited both ATF-6 and IRE-1 ER stress pathway components. As ischemic stroke has a complex pathology it is likely that certain combination treatment approaches targeting multiple disease mechanisms may have excellent potential for efficacy. We have previously employed the partial NMDA antagonist DETC-MeSO to render protection against in vivo ischemic stroke using a rat cerebral ischemia model. Here we tested administration of subcutaneous administration of 0.56 mg/kg DETC-MeSO or 40 mg/kg of taurine separately or as combined treatment after a 120 min cerebral ischemia in the rat MCAO model. Neither drug alone demonstrated protection at the low doses employed. Remarkably however the combination of low dose DETC-MeSO plus low dose taurine conferred a diminished infarct size and an enhanced Neuroscore (reflecting decreased neurological deficit). Analysis of ER stress markers pPERK, peIF-2-alpha and cleaved ATF-6 all showed decreased expression demonstrating that all 3 ER stress pathways were inhibited concurrent with a synergistic protective effect by the post-stroke administration of this DETC-MeSO-taurine combination treatment.

  17. Live imaging of osteoclast inhibition by bisphosphonates in a medaka osteoporosis model.

    Science.gov (United States)

    Yu, Tingsheng; Witten, Paul Eckhard; Huysseune, Ann; Buettner, Anita; To, Thuy Thanh; Winkler, Christoph

    2016-02-01

    Osteoclasts are bone-resorbing cells derived from the monocyte/macrophage lineage. Excess osteoclast activity leads to reduced bone mineral density, a hallmark of diseases such as osteoporosis. Processes that regulate osteoclast activity are therefore targeted in current osteoporosis therapies. To identify and characterize drugs for treatment of bone diseases, suitable in vivo models are needed to complement cell-culture assays. We have previously reported transgenic medaka lines expressing the osteoclast-inducing factor receptor activator of nuclear factor κB ligand (Rankl) under control of a heat shock-inducible promoter. Forced Rankl expression resulted in ectopic osteoclast formation, as visualized by live imaging in fluorescent reporter lines. This led to increased bone resorption and a dramatic reduction of mineralized matrix similar to the situation in humans with osteoporosis. In an attempt to establish the medaka as an in vivo model for osteoporosis drug screening, we treated Rankl-expressing larvae with etidronate and alendronate, two bisphosphonates commonly used in human osteoporosis therapy. Using live imaging, we observed an efficient, dose-dependent inhibition of osteoclast activity, which resulted in the maintenance of bone integrity despite an excess of osteoclast formation. Strikingly, we also found that bone recovery was efficiently promoted after inhibition of osteoclast activity and that osteoblast distribution was altered, suggesting effects on osteoblast-osteoclast coupling. Our data show that transgenic medaka lines are suitable in vivo models for the characterization of antiresorptive or bone-anabolic compounds by live imaging and for screening of novel osteoporosis drugs. © 2016. Published by The Company of Biologists Ltd.

  18. Live imaging of osteoclast inhibition by bisphosphonates in a medaka osteoporosis model

    Directory of Open Access Journals (Sweden)

    Tingsheng Yu

    2016-02-01

    Full Text Available Osteoclasts are bone-resorbing cells derived from the monocyte/macrophage lineage. Excess osteoclast activity leads to reduced bone mineral density, a hallmark of diseases such as osteoporosis. Processes that regulate osteoclast activity are therefore targeted in current osteoporosis therapies. To identify and characterize drugs for treatment of bone diseases, suitable in vivo models are needed to complement cell-culture assays. We have previously reported transgenic medaka lines expressing the osteoclast-inducing factor receptor activator of nuclear factor κB ligand (Rankl under control of a heat shock-inducible promoter. Forced Rankl expression resulted in ectopic osteoclast formation, as visualized by live imaging in fluorescent reporter lines. This led to increased bone resorption and a dramatic reduction of mineralized matrix similar to the situation in humans with osteoporosis. In an attempt to establish the medaka as an in vivo model for osteoporosis drug screening, we treated Rankl-expressing larvae with etidronate and alendronate, two bisphosphonates commonly used in human osteoporosis therapy. Using live imaging, we observed an efficient, dose-dependent inhibition of osteoclast activity, which resulted in the maintenance of bone integrity despite an excess of osteoclast formation. Strikingly, we also found that bone recovery was efficiently promoted after inhibition of osteoclast activity and that osteoblast distribution was altered, suggesting effects on osteoblast-osteoclast coupling. Our data show that transgenic medaka lines are suitable in vivo models for the characterization of antiresorptive or bone-anabolic compounds by live imaging and for screening of novel osteoporosis drugs.

  19. Oleanolic acid acetate inhibits atopic dermatitis and allergic contact dermatitis in a murine model.

    Science.gov (United States)

    Choi, Jin Kyeong; Oh, Hyun-Mee; Lee, Soyoung; Park, Jin-Woo; Khang, Dongwoo; Lee, Seung Woong; Lee, Woo Song; Rho, Mun-Chual; Kim, Sang-Hyun

    2013-05-15

    Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are common allergic and inflammatory skin diseases caused by a combination of eczema, scratching, pruritus, and cutaneous sensitization with allergens. This paper examines whether oleanolic acid acetate (OAA) modulates AD and ACD symptoms by using an existing AD model based on the repeated local exposure of mite extract (Dermatophagoides farinae extract, DFE) and 2,4-dinitrochlorobenzene to the ears of BALB/c mice. In addition, the paper uses a 2,4-dinitrofluorobenzene-sensitized local lymph node assay (LLNA) for the ACD model. The oral administration of OAA over a four-week period attenuated AD symptoms in terms of decreased skin lesions, epidermal thickness, the infiltration of immune cells (CD4⁺ cells, eosinophils, and mast cells), and serum IgE, IgG2a, and histamine levels. The gene expression of Th1, Th2, Th17, and Th22 cytokines was reduced by OAA in the lymph node and ear tissue, and the LLNA verified that OAA suppressed ACD. The oral administration of OAA over a three-day period attenuated ACD symptoms in terms of ear thickness, lymphocyte proliferation, and serum IgG2a levels. The gene expression of Th1, Th2, and Th17 cytokines was reduced by OAA in the thymus and ear tissue. Finally, to define the underlying mechanism, this paper uses a TNF-α/IFN-γ-activated human keratinocyte (HaCaT) model. OAA inhibited the expression of cytokines and chemokines through the downregulation of NF-κB and MAPKs in HaCaT cells. Taken together, the results indicate that OAA inhibited AD and ACD symptoms, suggesting that OAA may be effective in treating allergic skin disorders. Copyright © 2013 Elsevier Inc. All rights reserved.

  20. Tryptophan hydroxylase 1 Inhibition Impacts Pulmonary Vascular Remodeling in Two Rat Models of Pulmonary Hypertension.

    Science.gov (United States)

    Aiello, Robert J; Bourassa, Patricia-Ann; Zhang, Qing; Dubins, Jeffrey; Goldberg, Daniel R; De Lombaert, Stéphane; Humbert, Marc; Guignabert, Christophe; Cavasin, Maria A; McKinsey, Timothy A; Paralkar, Vishwas

    2017-02-01

    Pulmonary arterial hypertension (PAH) is a progressive disease defined by a chronic elevation in pulmonary arterial pressure with extensive pulmonary vascular remodeling and perivascular inflammation characterized by an accumulation of macrophages, lymphocytes, dendritic cells, and mast cells. Although the exact etiology of the disease is unknown, clinical as well as preclinical data strongly implicate a role for serotonin (5-HT) in the process. Here, we investigated the chronic effects of pharmacological inhibition of tryptophan hydroxylase 1 (TPH1), the rate-limiting enzyme in peripheral 5-HT biosynthesis, in two preclinical models of pulmonary hypertension (PH), the monocrotaline (MCT) rat and the semaxanib (SUGEN, Medinoah, Suzhou, China)-hypoxia rat. In both PH models, ethyl (S)-8-(2-amino-6-((R)-1-(5-chloro-[1,1'-biphenyl]-2-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate and ethyl (S)-8-(2-amino-6-((R)-1-(3',4'-dimethyl-3-(3-methyl-1 H-pyrazol-1-yl)-[1,1'-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate, novel orally active TPH1 inhibitors with nanomolar in vitro potency, decreased serum, gut, and lung 5-HT levels in a dose-dependent manner and significantly reduced pulmonary arterial pressure, and pulmonary vessel wall thickness and occlusion in male rats. In the MCT rat model, decreases in lung 5-HT significantly correlated with reductions in histamine levels and mast cell number (P pulmonary vascular remodeling and pressures. These data demonstrate that in addition to reducing vascular remodeling, TPH1 inhibition has the added benefit of reducing the perivascular mast cell accumulation associated with PH. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  1. Designed Coiled-Coil Peptides Inhibit the Type Three Secretion System of Enteropathogenic Escherichia coli

    Science.gov (United States)

    Larzábal, Mariano; Mercado, Elsa C.; Vilte, Daniel A.; Salazar-González, Hector; Cataldi, Angel; Navarro-Garcia, Fernando

    2010-01-01

    Background Enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli (EHEC) are two categories of E. coli strains associated with human disease. A major virulence factor of both pathotypes is the expression of a type three secretion system (TTSS), responsible for their ability to adhere to gut mucosa causing a characteristic attaching and effacing lesion (A/E). The TTSS translocates effector proteins directly into the host cell that subvert mammalian cell biochemistry. Methods/Principal Findings We examined synthetic peptides designed to inhibit the TTSS. CoilA and CoilB peptides, both representing coiled-coil regions of the translocator protein EspA, and CoilD peptide, corresponding to a coiled–coil region of the needle protein EscF, were effective in inhibiting the TTSS dependent hemolysis of red blood cells by the EPEC E2348/69 strain. CoilA and CoilB peptides also reduced the formation of actin pedestals by the same strain in HEp-2 cells and impaired the TTSS-mediated protein translocation into the epithelial cell. Interestingly, CoilA and CoilB were able to block EspA assembly, destabilizing the TTSS and thereby Tir translocation. This blockage of EspA polymerization by CoilA or CoilB peptides, also inhibited the correct delivery of EspB and EspD as detected by immunoblotting. Interestingly, electron microscopy of bacteria incubated with the CoilA peptide showed a reduction of the length of EspA filaments. Conclusions Our data indicate that coiled-coil peptides can prevent the assembly and thus the functionality of the TTSS apparatus and suggest that these peptides could provide an attractive tool to block EPEC and EHEC pathogenesis. PMID:20140230

  2. PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model.

    Science.gov (United States)

    Low, Pei Ching; Manzanero, Silvia; Mohannak, Nika; Narayana, Vinod K; Nguyen, Tam H; Kvaskoff, David; Brennan, Faith H; Ruitenberg, Marc J; Gelderblom, Mathias; Magnus, Tim; Kim, Hyun Ah; Broughton, Brad R S; Sobey, Christopher G; Vanhaesebroeck, Bart; Stow, Jennifer L; Arumugam, Thiruma V; Meunier, Frédéric A

    2014-03-14

    Stroke is a major cause of death worldwide and the leading cause of permanent disability. Although reperfusion is currently used as treatment, the restoration of blood flow following ischaemia elicits a profound inflammatory response mediated by proinflammatory cytokines such as tumour necrosis factor (TNF), exacerbating tissue damage and worsening the outcomes for stroke patients. Phosphoinositide 3-kinase delta (PI3Kδ) controls intracellular TNF trafficking in macrophages and therefore represents a prospective target to limit neuroinflammation. Here we show that PI3Kδ inhibition confers protection in ischaemia/reperfusion models of stroke. In vitro, restoration of glucose supply following an episode of glucose deprivation potentiates TNF secretion from primary microglia-an effect that is sensitive to PI3Kδ inhibition. In vivo, transient middle cerebral artery occlusion and reperfusion in kinase-dead PI3Kδ (p110δ(D910A/D910A)) or wild-type mice pre- or post-treated with the PI3Kδ inhibitor CAL-101, leads to reduced TNF levels, decreased leukocyte infiltration, reduced infarct size and improved functional outcome. These data identify PI3Kδ as a potential therapeutic target in ischaemic stroke.

  3. Iron Chelation Inhibits Osteoclastic Differentiation In Vitro and in Tg2576 Mouse Model of Alzheimer's Disease.

    Directory of Open Access Journals (Sweden)

    Jun-Peng Guo

    Full Text Available Patients of Alzheimer's disease (AD frequently have lower bone mineral density and higher rate of hip fracture. Tg2576, a well characterized AD animal model that ubiquitously express Swedish mutant amyloid precursor protein (APPswe, displays not only AD-relevant neuropathology, but also age-dependent bone deficits. However, the underlying mechanisms remain poorly understood. As APP is implicated as a regulator of iron export, and the metal chelation is considered as a potential therapeutic strategy for AD, we examined iron chelation's effect on the osteoporotic deficit in Tg2576 mice. Remarkably, in vivo treatment with iron chelator, clinoquinol (CQ, increased both trabecular and cortical bone-mass, selectively in Tg2576, but not wild type (WT mice. Further in vitro studies showed that low concentrations of CQ as well as deferoxamine (DFO, another iron chelator, selectively inhibited osteoclast (OC differentiation, without an obvious effect on osteoblast (OB differentiation. Intriguingly, both CQ and DFO's inhibitory effect on OC was more potent in bone marrow macrophages (BMMs from Tg2576 mice than that of wild type controls. The reduction of intracellular iron levels in BMMs by CQ was also more dramatic in APPswe-expressing BMMs. Taken together, these results demonstrate a potent inhibition on OC formation and activation in APPswe-expressing BMMs by iron chelation, and reveal a potential therapeutic value of CQ in treating AD-associated osteoporotic deficits.

  4. Curcumin Inhibits Tumor Growth and Angiogenesis in an Orthotopic Mouse Model of Human Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Sabrina Bimonte

    2013-01-01

    Full Text Available Pancreatic cancer is a malignant neoplasm originating from transformed cells arising in tissues forming the pancreas. The best chemotherapeutic agent used to treat pancreatic cancer is the gemcitabine. However, gemcitabine treatment is associated with many side effects. Thus novel strategies involving less toxic agents for treatment of pancreatic cancer are necessary. Curcumin is one such agent that inhibits the proliferation and angiogenesis of a wide variety of tumor cells, through the modulation of many cell signalling pathways. In this study, we investigated whether curcumin plays antitumor effects in MIA PaCa-2 cells. In vitro studies showed that curcumin inhibits the proliferation and enhances apoptosis of MIA PaCa-2 cells. To test whether the antitumor activity of curcumin is also observed in vivo, we generated an orthotopic mouse model of pancreatic cancer by injection of MIA PaCa-2 cells in nude mice. We placed mice on diet containing curcumin at 0.6% for 6 weeks. In these treated mice tumors were smaller with respect to controls and showed a downregulation of the transcription nuclear factor NF-κB and NF-κB-regulated gene products. Overall, our data indicate that curcumin has a great potential in treatment of human pancreatic cancer through the modulation of NF-κB pathway.

  5. Tanshinone inhibits neuronal cell apoptosis and inflammatory response in cerebral infarction rat model.

    Science.gov (United States)

    Zhou, Liang; Zhang, Jie; Wang, Chao; Sun, Qiangsan

    2017-06-01

    We aimed to investigate the effect and mechanisms of tanshinone (TSN) IIA in cerebral infarction. The cerebral infarction rat model was established by middle cerebral artery occlusion (MCAO). After pretreatment with TSN, cerebral infarct volume, cerebral edema, and neurological deficits score were evaluated, as well as cell apoptosis in hippocampus and cortex of the brain was examined with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and the levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and C-reactive protein (CRP) were determined by Enzyme-Linked Immunosorbent Assay (ELISA). In addition, rat primary neuronal cells were isolated and cultured in oxygen-glucose deprivation (OGD) conditions. After pretreatment with TSN, cell viability and apoptosis were observed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry analysis, respectively. The expressions of Bax and B-cell lymphoma 2 (Bcl-2) were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting. Compared with untreated cerebral infarction rat, TSN treatment significantly reduced cerebral infarct volume, cerebral edema, and neurological deficits score ( P TSN ( P TSN remarkably increased cell viability and inhibited cell apoptosis ratio ( P TSN significantly downregulated the expression of Bax and upregulated Bcl-2 ( P TSN IIA has a preventive effect on cerebral infarction by inhibiting neuronal cell apoptosis and inflammatory response in vitro and in vivo.

  6. Inhibition of Asthma in OVA Sensitized Mice Model by a Traditional Uygur Herb Nepeta bracteata Benth.

    Directory of Open Access Journals (Sweden)

    Jing Wang

    2016-01-01

    Full Text Available Asthma is a chronic lung inflammation which affects many people. As current therapies for asthma mainly rely on administration of glucocorticoids and have many side effects, new therapy is needed. In this study, we investigated Nepeta bracteata Benth., a traditional Uygur Herb, for its therapeutics effect in OVA induced asthmatic mice model. Treatment of OVA sensitized asthma mice with extract from Nepeta bracteata Benth. demonstrated improved lung pathology, as well as reduced infiltration of eosinophil and neutrophil. Nepeta bracteata Benth. extract also contributed to the rebalance of Th17/Treg cell via decreasing the Th17 cell and increasing the Treg, which was corresponding with the inhibited Th17 cytokine response and increased IL-10 level. Moreover, the reduced TGF-β level and Smad2/3 protein level also suggested that Nepeta bracteata Benth. extract could inhibit TGF-β mediated airway remodelling as well. Taken together, these data suggested that Nepeta bracteata Benth. may be a novel candidate for future antiasthma drug development.

  7. Peptide redesign for inhibition of the complement system: Targeting age-related macular degeneration

    Science.gov (United States)

    Mohan, Rohith R.; Cabrera, Andrea P.; Harrison, Reed E. S.; Gorham, Ronald D.; Johnson, Lincoln V.; Ghosh, Kaustabh

    2016-01-01

    Purpose To redesign a complement-inhibiting peptide with the potential to become a therapeutic for dry and wet age-related macular degeneration (AMD). Methods We present a new potent peptide (Peptide 2) of the compstatin family. The peptide is developed by rational design, based on a mechanistic binding hypothesis, and structural and physicochemical properties derived from molecular dynamics (MD) simulation. The inhibitory activity, efficacy, and solubility of Peptide 2 are evaluated using a hemolytic assay, a human RPE cell–based assay, and ultraviolet (UV) absorption properties, respectively, and compared to the respective properties of its parent peptide (Peptide 1). Results The sequence of Peptide 2 contains an arginine-serine N-terminal extension (a characteristic of parent Peptide 1) and a novel 8-polyethylene glycol (PEG) block C-terminal extension. Peptide 2 has significantly improved aqueous solubility compared to Peptide 1 and comparable complement inhibitory activity. In addition, Peptide 2 is more efficacious in inhibiting complement activation in a cell-based model that mimics the pathobiology of dry AMD. Conclusions We have designed a new peptide analog of compstatin that combines N-terminal polar amino acid extensions and C-terminal PEGylation extensions. This peptide demonstrates significantly improved aqueous solubility and complement inhibitory efficacy, compared to the parent peptide. The new peptide overcomes the aggregation limitation for clinical translation of previous compstatin analogs and is a candidate to become a therapeutic for the treatment of AMD. PMID:27829783

  8. Cognitive models embedded in system simulation models

    International Nuclear Information System (INIS)

    Siegel, A.I.; Wolf, J.J.

    1982-01-01

    If we are to discuss and consider cognitive models, we must first come to grips with two questions: (1) What is cognition; (2) What is a model. Presumably, the answers to these questions can provide a basis for defining a cognitive model. Accordingly, this paper first places these two questions into perspective. Then, cognitive models are set within the context of computer simulation models and a number of computer simulations of cognitive processes are described. Finally, pervasive issues are discussed vis-a-vis cognitive modeling in the computer simulation context

  9. Activation and inhibition of retinal ganglion cells in response to epiretinal electrical stimulation: a computational modelling study

    Science.gov (United States)

    Abramian, Miganoosh; Lovell, Nigel H.; Morley, John W.; Suaning, Gregg J.; Dokos, Socrates

    2015-02-01

    Objective. Retinal prosthetic devices aim to restore sight in visually impaired people by means of electrical stimulation of surviving retinal ganglion cells (RGCs). This modelling study aims to demonstrate that RGC inhibition caused by high-intensity cathodic pulses greatly influences their responses to epiretinal electrical stimulation and to investigate the impact of this inhibition on spatial activation profiles as well as their implications for retinal prosthetic device design. Another aim is to take advantage of this inhibition to reduce axonal activation in the nerve fibre layer. Approach. A three-dimensional finite-element model of epiretinal electrical stimulation was utilized to obtain RGC activation and inhibition threshold profiles for a range of parameters. Main results. RGC activation and inhibition thresholds were highly dependent on cell and stimulus parameters. Activation thresholds were 1.5, 3.4 and 11.3 μA for monopolar electrodes with 5, 20 and 50 μm radii, respectively. Inhibition to activation threshold ratios were mostly within the range 2-10. Inhibition significantly altered spatial patterns of RGC activation. With concentric electrodes and appropriately high levels of stimulus amplitudes, activation of passing axons was greatly reduced. Significance. RGC inhibition significantly impacts their spatial activation profiles, and therefore it most likely influences patterns of perceived phosphenes induced by retinal prosthetic devices. Thus this inhibition should be taken into account in future studies concerning retinal prosthesis development. It might be possible to utilize this inhibitory effect to bypass activation of passing axons and selectively stimulate RGCs near their somas and dendrites to achieve more localized phosphenes.

  10. Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics

    Science.gov (United States)

    Mangiafico, Sarah; Costello-Boerrigter, Lisa C.; Andersen, Ingrid A.; Cataliotti, Alessandro; Burnett, John C.

    2013-01-01

    Hypertension and heart failure (HF) are common diseases that, despite advances in medical therapy, continue to be associated with high morbidity and mortality. Therefore, innovative therapeutic strategies are needed. Inhibition of the neutral endopeptidase (NEPinh) had been investigated as a potential novel therapeutic approach because of its ability to increase the plasma concentrations of the natriuretic peptides (NPs). Indeed, the NPs have potent natriuretic and vasodilator properties, inhibit the activity of the renin–angiotensin–aldosterone system, lower sympathetic drive, and have antiproliferative and antihypertrophic effects. Such potentially beneficial effects can be theoretically achieved by the use of NEPinh. However, studies have shown that NEPinh alone does not result in clinically meaningful blood pressure-lowering actions. More recently, NEPinh has been used in combination with other cardiovascular agents, such as angiotensin-converting enzyme inhibitors, and antagonists of the angiotensin receptor. Another future possible combination would be the use of NEPinh with NPs or their newly developed chimeric peptides. This review summarizes the current knowledge of the use and effects of NEPinh alone or in combination with other therapeutic agents for the treatment of human cardiovascular disease such as HF and hypertension. PMID:22942338

  11. Stressing the ubiquitin-proteasome system without 20S proteolytic inhibition selectively kills cervical cancer cells.

    Directory of Open Access Journals (Sweden)

    Ravi K Anchoori

    Full Text Available Cervical cancer cells exhibit an increased requirement for ubiquitin-dependent protein degradation associated with an elevated metabolic turnover rate, and for specific signaling pathways, notably HPV E6-targeted degradation of p53 and PDZ proteins. Natural compounds with antioxidant properties including flavonoids and triterpenoids hold promise as anticancer agents by interfering with ubiquitin-dependent protein degradation. An increasing body of evidence indicates that their α-β unsaturated carbonyl system is the molecular determinant for inhibition of ubiquitin-mediated protein degradation up-stream of the catalytic sites of the 20S proteasome. Herein we report the identification and characterization of a new class of chalcone-based, potent and cell permeable chemical inhibitors of ubiquitin-dependent protein degradation, and a lead compound RAMB1. RAMB1 inhibits ubiquitin-dependent protein degradation without compromising the catalytic activities of the 20S proteasome, a mechanism distinct from that of Bortezomib. Treatment of cervical cancer cells with RAMB1 triggers unfolded protein responses, including aggresome formation and Hsp90 stabilization, and increases p53 steady state levels. RAMB1 treatment results in activation of lysosomal-dependent degradation pathways as a mechanism to compensate for increasing levels of poly-ubiquitin enriched toxic aggregates. Importantly, RAMB1 synergistically triggers cell death of cervical cancer cells when combined with the lysosome inhibitor Chloroquine.

  12. Combination inhibition of the renin-angiotensin system: is more better?

    Science.gov (United States)

    Krause, Michelle W; Fonseca, Vivian A; Shah, Sudhir V

    2011-08-01

    Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers are considered the standard of care for treatment of cardiovascular disease and chronic kidney disease. Combination therapy with both angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers effectively inhibits the renin-angiotensin system as well as potentiates the vasodilatory effects of bradykinin. It has been advocated that this dual blockade approach theoretically should result in improved clinical outcomes in both cardiovascular disease and chronic kidney disease. Clinical trial evidence for the use of combination therapy with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in cardiovascular disease has provided conflicting results in hypertension, congestive heart failure, and ischemic heart disease. Clinical trial evidence to support combination therapy with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in chronic kidney disease has largely been based on proteinuria reduction as a surrogate marker for clinically meaningful outcomes. Recent large-scale randomized clinical trials have not been able to validate protection in halting progression in chronic kidney disease with a dual blockade approach. This review serves as an appraisal on the clinical evidence of combination angiotensin-converting enzyme inhibition and angiotensin II receptor blockade in both cardiovascular disease and chronic kidney disease.

  13. Intravesical Dimethyl Sulfoxide Inhibits Acute and Chronic Bladder Inflammation in Transgenic Experimental Autoimmune Cystitis Models

    Directory of Open Access Journals (Sweden)

    Ronald Kim

    2011-01-01

    Full Text Available New animal models are greatly needed in interstitial cystitis/painful bladder syndrome (IC/PBS research. We recently developed a novel transgenic cystitis model (URO-OVA mice that mimics certain key aspects of IC/PBS pathophysiology. This paper aimed to determine whether URO-OVA cystitis model was responsive to intravesical dimethyl sulfoxide (DMSO and if so identify the mechanisms of DMSO action. URO-OVA mice developed acute cystitis upon adoptive transfer of OVA-specific OT-I splenocytes. Compared to PBS-treated bladders, the bladders treated with 50% DMSO exhibited markedly reduced bladder histopathology and expression of various inflammatory factor mRNAs. Intravesical DMSO treatment also effectively inhibited bladder inflammation in a spontaneous chronic cystitis model (URO-OVA/OT-I mice. Studies further revealed that DMSO could impair effector T cells in a dose-dependent manner in vitro. Taken together, our results suggest that intravesical DMSO improves the bladder histopathology of IC/PBS patients because of its ability to interfere with multiple inflammatory and bladder cell types.

  14. Studies of Catalytic Model Systems

    DEFF Research Database (Denmark)

    Holse, Christian

    of the Cu/ZnO nanoparticles is highly relevant to industrial methanol synthesis for which the direct interaction of Cu and ZnO nanocrystals synergistically boost the catalytic activity. The dynamical behavior of the nanoparticles under reducing and oxidizing environments were studied by means of ex situ X...... as the nanoparticles are reduced. The Cu/ZnO nanoparticles are tested on a  µ-reactor platform and prove to be active towards methanol synthesis, making it an excellent model system for further investigations into activity depended morphology changes....

  15. Visualization of the melanosome transfer-inhibition in a mouse epidermal cell co-culture model.

    Science.gov (United States)

    Kim, Hae Jong; Kazi, Julhash U; Lee, You-Ree; Nguyen, Dung H; Lee, Hyang-Bok; Shin, Jeong-Hyun; Soh, Jae-Won; Kim, Eun-Ki

    2010-02-01

    Transfer of melanin-containing melanosomes from melanocytes to neighboring keratinocytes results in skin pigmentation. To provide a more practical method of visualizing melanosomes in melanocytes as well as in keratinocytes, we attempted to use murine cell lines instead of human primary cells. We generated various fluorescent fusion proteins of tyrosinase, a melanin synthesis enzyme located in the melanosome, by using green fluorescent protein and red fluorescent protein. The intracellular localization of tyrosinase was then examined by fluorescence and confocal microscopy. Co-culture of murine melanocytes and keratinocytes was optimized and melanosome transfer was either stimulated with alphaMSH or partially inhibited by niacinamide. To the best of our knowledge, this is the first study showing that a murine co-culture model, in addition to human primary cell co-culture, can be a good tool for depigmenting agent screening by monitoring melanosome transfer.

  16. Sclerostin inhibition reverses skeletal fragility in an Lrp5-deficient mouse model of OPPG syndrome.

    Science.gov (United States)

    Kedlaya, Rajendra; Veera, Shreya; Horan, Daniel J; Moss, Rachel E; Ayturk, Ugur M; Jacobsen, Christina M; Bowen, Margot E; Paszty, Chris; Warman, Matthew L; Robling, Alexander G

    2013-11-13

    Osteoporosis pseudoglioma syndrome (OPPG) is a rare genetic disease that produces debilitating effects in the skeleton. OPPG is caused by mutations in LRP5, a WNT co-receptor that mediates osteoblast activity. WNT signaling through LRP5, and also through the closely related receptor LRP6, is inhibited by the protein sclerostin (SOST). It is unclear whether OPPG patients might benefit from the anabolic action of sclerostin neutralization therapy (an approach currently being pursued in clinical trials for postmenopausal osteoporosis) in light of their LRP5 deficiency and consequent osteoblast impairment. To assess whether loss of sclerostin is anabolic in OPPG, we measured bone properties in a mouse model of OPPG (Lrp5(-/-)), a mouse model of sclerosteosis (Sost(-/-)), and in mice with both genes knocked out (Lrp5(-/-);Sost(-/-)). Lrp5(-/-);Sost(-/-) mice have larger, denser, and stronger bones than do Lrp5(-/-) mice, indicating that SOST deficiency can improve bone properties via pathways that do not require LRP5. Next, we determined whether the anabolic effects of sclerostin depletion in Lrp5(-/-) mice are retained in adult mice by treating 17-week-old Lrp5(-/-) mice with a sclerostin antibody for 3 weeks. Lrp5(+/+) and Lrp5(-/-) mice each exhibited osteoanabolic responses to antibody therapy, as indicated by increased bone mineral density, content, and formation rates. Collectively, our data show that inhibiting sclerostin can improve bone mass whether LRP5 is present or not. In the absence of LRP5, the anabolic effects of SOST depletion can occur via other receptors (such as LRP4/6). Regardless of the mechanism, our results suggest that humans with OPPG might benefit from sclerostin neutralization therapies.

  17. Reservoir Model Information System: REMIS

    Science.gov (United States)

    Lee, Sang Yun; Lee, Kwang-Wu; Rhee, Taehyun; Neumann, Ulrich

    2009-01-01

    We describe a novel data visualization framework named Reservoir Model Information System (REMIS) for the display of complex and multi-dimensional data sets in oil reservoirs. It is aimed at facilitating visual exploration and analysis of data sets as well as user collaboration in an easier way. Our framework consists of two main modules: the data access point module and the data visualization module. For the data access point module, the Phrase-Driven Grammar System (PDGS) is adopted for helping users facilitate the visualization of data. It integrates data source applications and external visualization tools and allows users to formulate data query and visualization descriptions by selecting graphical icons in a menu or on a map with step-by-step visual guidance. For the data visualization module, we implemented our first prototype of an interactive volume viewer named REMVR to classify and to visualize geo-spatial specific data sets. By combining PDGS and REMVR, REMIS assists users better in describing visualizations and exploring data so that they can easily find desired data and explore interesting or meaningful relationships including trends and exceptions in oil reservoir model data.

  18. Modeling the detailed kinetics of mitochondrial cytochrome c oxidase: Catalytic mechanism and nitric oxide inhibition.

    Science.gov (United States)

    Pannala, Venkat R; Camara, Amadou K S; Dash, Ranjan K

    2016-11-01

    Cytochrome c oxidase (CcO) catalyzes the exothermic reduction of O 2 to H 2 O by using electrons from cytochrome c, and hence plays a crucial role in ATP production. Although details on the enzyme structure and redox centers involved in O 2 reduction have been known, there still remains a considerable ambiguity on its mechanism of action, e.g., the number of sequential electrons donated to O 2 in each catalytic step, the sites of protonation and proton pumping, and nitric oxide (NO) inhibition mechanism. In this work, we developed a thermodynamically constrained mechanistic mathematical model for the catalytic action of CcO based on available kinetic data. The model considers a minimal number of redox centers on CcO and couples electron transfer and proton pumping driven by proton motive force (PMF), and accounts for the inhibitory effects of NO on the reaction kinetics. The model is able to fit well all the available kinetic data under diverse experimental conditions with a physiologically realistic unique parameter set. The model predictions show that: 1) the apparent K m of O 2 varies considerably and increases from fully reduced to fully oxidized cytochrome c depending on pH and the energy state of mitochondria, and 2) the intermediate enzyme states depend on pH and cytochrome c redox fraction and play a central role in coupling mitochondrial respiration to PMF. The developed CcO model can easily be integrated into existing mitochondrial bioenergetics models to understand the role of the enzyme in controlling oxidative phosphorylation in normal and disease conditions. Copyright © 2016 the American Physiological Society.

  19. A biophysical model of endocannabinoid-mediated short term depression in hippocampal inhibition.

    Directory of Open Access Journals (Sweden)

    Margarita Zachariou

    Full Text Available Memories are believed to be represented in the synaptic pathways of vastly interconnected networks of neurons. The plasticity of synapses, that is, their strengthening and weakening depending on neuronal activity, is believed to be the basis of learning and establishing memories. An increasing number of studies indicate that endocannabinoids have a widespread action on brain function through modulation of synaptic transmission and plasticity. Recent experimental studies have characterised the role of endocannabinoids in mediating both short- and long-term synaptic plasticity in various brain regions including the hippocampus, a brain region strongly associated with cognitive functions, such as learning and memory. Here, we present a biophysically plausible model of cannabinoid retrograde signalling at the synaptic level and investigate how this signalling mediates depolarisation induced suppression of inhibition (DSI, a prominent form of short-term synaptic depression in inhibitory transmission in hippocampus. The model successfully captures many of the key characteristics of DSI in the hippocampus, as observed experimentally, with a minimal yet sufficient mathematical description of the major signalling molecules and cascades involved. More specifically, this model serves as a framework to test hypotheses on the factors determining the variability of DSI and investigate under which conditions it can be evoked. The model reveals the frequency and duration bands in which the post-synaptic cell can be sufficiently stimulated to elicit DSI. Moreover, the model provides key insights on how the state of the inhibitory cell modulates DSI according to its firing rate and relative timing to the post-synaptic activation. Thus, it provides concrete suggestions to further investigate experimentally how DSI modulates and is modulated by neuronal activity in the brain. Importantly, this model serves as a stepping stone for future deciphering of the role of

  20. Modeling learning technology systems as business systems

    NARCIS (Netherlands)

    Avgeriou, Paris; Retalis, Symeon; Papaspyrou, Nikolaos

    2003-01-01

    The design of Learning Technology Systems, and the Software Systems that support them, is largely conducted on an intuitive, ad hoc basis, thus resulting in inefficient systems that defectively support the learning process. There is now justifiable, increasing effort in formalizing the engineering

  1. Inhibition of GSK-3 ameliorates Abeta pathology in an adult-onset Drosophila model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Oyinkan Sofola

    2010-09-01

    Full Text Available Abeta peptide accumulation is thought to be the primary event in the pathogenesis of Alzheimer's disease (AD, with downstream neurotoxic effects including the hyperphosphorylation of tau protein. Glycogen synthase kinase-3 (GSK-3 is increasingly implicated as playing a pivotal role in this amyloid cascade. We have developed an adult-onset Drosophila model of AD, using an inducible gene expression system to express Arctic mutant Abeta42 specifically in adult neurons, to avoid developmental effects. Abeta42 accumulated with age in these flies and they displayed increased mortality together with progressive neuronal dysfunction, but in the apparent absence of neuronal loss. This fly model can thus be used to examine the role of events during adulthood and early AD aetiology. Expression of Abeta42 in adult neurons increased GSK-3 activity, and inhibition of GSK-3 (either genetically or pharmacologically by lithium treatment rescued Abeta42 toxicity. Abeta42 pathogenesis was also reduced by removal of endogenous fly tau; but, within the limits of detection of available methods, tau phosphorylation did not appear to be altered in flies expressing Abeta42. The GSK-3-mediated effects on Abeta42 toxicity appear to be at least in part mediated by tau-independent mechanisms, because the protective effect of lithium alone was greater than that of the removal of tau alone. Finally, Abeta42 levels were reduced upon GSK-3 inhibition, pointing to a direct role of GSK-3 in the regulation of Abeta42 peptide level, in the absence of APP processing. Our study points to the need both to identify the mechanisms by which GSK-3 modulates Abeta42 levels in the fly and to determine if similar mechanisms are present in mammals, and it supports the potential therapeutic use of GSK-3 inhibitors in AD.

  2. Bond graph modeling of centrifugal compression systems

    OpenAIRE

    Uddin, Nur; Gravdahl, Jan Tommy

    2015-01-01

    A novel approach to model unsteady fluid dynamics in a compressor network by using a bond graph is presented. The model is intended in particular for compressor control system development. First, we develop a bond graph model of a single compression system. Bond graph modeling offers a different perspective to previous work by modeling the compression system based on energy flow instead of fluid dynamics. Analyzing the bond graph model explains the energy flow during compressor surge. Two pri...

  3. Structuring Problem Analysis for Embedded Systems Modelling

    NARCIS (Netherlands)

    Marincic, J.; Mader, Angelika H.; Wieringa, Roelf J.; Lucas, Yan

    Our interest is embedded systems validation as part of the model-driven approach. To design a model, the modeller needs to obtain knowledge about the system and decide what is relevant to model and how. A part of the modelling activities is inherently informal - it cannot be formalised in such a way

  4. RITA plus 3-MA overcomes chemoresistance of head and neck cancer cells via dual inhibition of autophagy and antioxidant systems

    Directory of Open Access Journals (Sweden)

    Daiha Shin

    2017-10-01

    Condensed abstract: This study revealed a novel RITA resistant mechanism associated with the sustained induction of autophagy, p62 overexpression, and Keap1-Nrf2 antioxidant system activation. The combined treatment of RITA with the autophagy inhibitor 3-methyladenine overcomes RITA resistance via dual inhibition of autophagy and antioxidant systems in vitro and in vivo.

  5. Demands on response inhibition processes determine modulations of theta band activity in superior frontal areas and correlations with pupillometry - Implications for the norepinephrine system during inhibitory control.

    Science.gov (United States)

    Dippel, Gabriel; Mückschel, Moritz; Ziemssen, Tjalf; Beste, Christian

    2017-08-15

    Response inhibition processes are important for goal-directed behavior and particularly demanded when it is unlikely to inhibit automatically executed responses. It has been suggested that the norepinephrine (NE) system is important to consider for such likelihood effects. As an indirect measure of the NE system activity we used the pupil diameter and integrated this data with neurophysiological (EEG) data and beamforming analyses. The study shows that inhibitory control processes reflected by theta oscillations are strongly modulated by the likelihood to employ these processes and that these mechanisms were related to neural processes in the SMA and SFG. Probably, the modulations observed for theta band activity may reflect modulations in the encoding of a surprise, or conflict signal. Interestingly, correlation analyses of neuronal activity at the sensor and the source level with pupil diameter data revealed strong correlations that were only seen in the condition where inhibitory control processes were rarely demanded. On the basis of findings and theoretical models suggesting that the pupil diameter can be interpreted as a proximate of NE system activity the results may be interpreted that the NE system modulates inhibitory control processes via theta band activity in the SFB when the likelihood to inhibit a prepotent response tendency is low. From this it may be speculated that the NE system dynamically gains and loses relevance to modulate inhibitory control depending on boundary conditions that determine the mode of responding. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Polysaccharides from Arnebia euchroma Ameliorated Endotoxic Fever and Acute Lung Injury in Rats Through Inhibiting Complement System.

    Science.gov (United States)

    Ou, Ying-Ye; Jiang, Yun; Li, Hong; Zhang, Yun-Yi; Lu, Yan; Chen, Dao-Feng

    2017-02-01

    Arnebiaeuchroma (Royle) Johnst (Ruanzicao) is a traditional Chinese herbal medicine (TCM). It is extensively used in China and other countries for treatment of inflammatory diseases. It is known that hyper-activated complement system involves in the fever and acute lung injury (ALI) in rats. In our preliminary studies, anti-complementary activity of crude Arnebiaeuchroma polysaccharides (CAEP) had been demonstrated in vitro. This study aimed to investigate the role and mechanism of crude Arnebiaeuchroma polysaccharides (CAEP) using two animal models, which relate with inappropriate activation of complement system. In lipopolysaccharide (LPS)-induced fever model, the body temperature and leukocytes of peripheral blood in rats were significantly increased, while the complement levels of serum were remarkably decreased. CAEP administration alleviated the LPS-induced fever, reduced the number of leukocytes, and improved the levels of complement. Histological assay showed that there were severe damages and complement depositions in lung of the ALI rats. Further detection displayed that the oxidant stress was enhanced, and total hemolytic activity and C3/C4 levels in serum were decreased significantly in the ALI model group. Remarkably, CAEP not only attenuated the morphological injury, edema, and permeability in the lung but also significantly weakened the oxidant stress in bronchoalveolar lavage fluid (BALF) in the ALI rats. The levels of complement and complement depositions were improved by the CAEP treatment. In conclusion, the CAEP treatment ameliorated febrile response induced by LPS and acute lung injury induced by LPS plus ischemia-reperfusion. CAEP exerted beneficial effects on inflammatory disease potentially via inhibiting the inappropriate activation of complement system.

  7. CysLT(1)R antagonists inhibit tumor growth in a xenograft model of colon cancer.

    Science.gov (United States)

    Savari, Sayeh; Liu, Minghui; Zhang, Yuan; Sime, Wondossen; Sjölander, Anita

    2013-01-01

    The expression of the inflammatory G-protein coupled receptor CysLT1R has been shown to be upregulated in colon cancer patients and associated with poor prognosis. The present study investigated the correlation between CysLT1R and colon cancer development in vivo using CysLT1R antagonists (ZM198,615 or Montelukast) and the nude mouse xenograft model. Two drug administration regimens were established. The first regimen was established to investigate the importance of CysLT1R in tumor initiation. Nude mice were inoculated with 50 µM CysLT1R antagonist-pretreated HCT-116 colon cancer cells and received continued treatment (5 mg/kg/day, intraperitoneally). The second regimen aimed to address the role of CysLT1R in tumor progression. Nude mice were inoculated with non-pretreated HCT-116 cells and did not receive CysLT1R antagonist treatment until recordable tumor appearance. Both regimens resulted in significantly reduced tumor size, attributed to changes in proliferation and apoptosis as determined by reduced Ki-67 levels and increased levels of p21(WAF/Cip1) (Pcolon cancer cell line HCT-116 and CysLT1R antagonists. In addition to significant reductions in cell proliferation, adhesion and colony formation, we observed induction of cell cycle arrest and apoptosis in a dose-dependent manner. The ability of Montelukast to inhibit growth of human colon cancer xenograft was further validated by using two additional colon cancer cell lines, SW-480 and HT-29. Our results demonstrate that CysLT1R antagonists inhibit growth of colon cancer xenografts primarily by reducing proliferation and inducing apoptosis of the tumor cells.

  8. Pharmacological inhibition of leukotrienes in an animal model of bleomycin-induced acute lung injury

    Directory of Open Access Journals (Sweden)

    Crimi Nunzio

    2006-11-01

    Full Text Available Abstract Leukotrienes are increased locally in idiopathic pulmonary fibrosis. Furthermore, a role for these arachidonic acid metabolites has been thoroughly characterized in the animal bleomycin model of lung fibrosis by using different gene knock-out settings. We investigated the efficacy of pharmacological inhibition of leukotrienes activity in the development of bleomycin-induced lung injury by comparing the responses in wild-type mice with mice treated with zileuton, a 5-lipoxygenase inhibitor and MK-571, a cys-leukotrienes receptor antagonist. Mice were subjected to intra-tracheal administration of bleomycin or saline and were assigned to receive either MK-571 at 1 mg/Kg or zileuton at 50 mg/Kg daily. One week after bleomycin administration, BAL cell counts, lung histology with van Gieson for collagen staining and immunohistochemical analysis for myeloperoxidase, IL-1 and TNF-α were performed. Following bleomycin administration both MK-571 and zileuton treated mice exhibited a reduced degree of lung damage and inflammation when compared to WT mice as shown by the reduction of:(i loss of body weight, (ii mortality rate, (iii lung infiltration by neutrophils (myeloperoxidase activity, BAL total and differential cell counts, (iv lung edema, (v histological evidence of lung injury and collagen deposition, (vi lung myeloperoxidase, IL-1 and TNF-α staining. This is the first study showing that the pharmacological inhibition of leukotrienes activity attenuates bleomycin-induced lung injury in mice. Given our results as well as those coming from genetic studies, it might be considered meaningful to trial this drug class in the treatment of pulmonary fibrosis, a disease that still represents a major challenge to medical treatment.

  9. Novel A20-gene-eluting stent inhibits carotid artery restenosis in a porcine model

    Directory of Open Access Journals (Sweden)

    Zhou ZH

    2016-08-01

    Full Text Available Zhen-hua Zhou,1 Jing Peng,1 Zhao-you Meng,1 Lin Chen,1 Jia-Lu Huang,1 He-qing Huang,1 Li Li,2 Wen Zeng,2 Yong Wei,2 Chu-Hong Zhu,2 Kang-Ning Chen1 1Department of Neurology, Cerebrovascular Disease Research Institute, Southwest Hospital, 2Department of Anatomy, Key Laboratory for Biomechanics of Chongqing, Third Military Medical University, Chongqing, People’s Republic of China Background: Carotid artery stenosis is a major risk factor for ischemic stroke. Although carotid angioplasty and stenting using an embolic protection device has been introduced as a less invasive carotid revascularization approach, in-stent restenosis limits its long-term efficacy and safety. The objective of this study was to test the anti-restenosis effects of local stent-mediated delivery of the A20 gene in a porcine carotid artery model.Materials and methods: The pCDNA3.1EHA20 was firmly attached onto stents that had been collagen coated and treated with N-succinimidyl-3-(2-pyridyldithiolpropionate solution and anti-DNA immunoglobulin fixation. Anti-restenosis effects of modified vs control (the bare-metal stent and pCDNA3.1 void vector stents were assessed by Western blot and scanning electron microscopy, as well as by morphological and inflammatory reaction analyses.Results: Stent-delivered A20 gene was locally expressed in porcine carotids in association with significantly greater extent of re-endothelialization at day 14 and of neointimal hyperplasia inhibition at 3 months than stenting without A20 gene expression.Conclusion: The A20-gene-eluting stent inhibits neointimal hyperplasia while promoting re-endothelialization and therefore constitutes a novel potential alternative to prevent restenosis while minimizing complications. Keywords: restenosis, A20, gene therapy, stent, endothelialization

  10. Antithrombin nanoparticles inhibit stent thrombosis in ex vivo static and flow models.

    Science.gov (United States)

    Palekar, Rohun U; Vemuri, Chandu; Marsh, Jon N; Arif, Batool; Wickline, Samuel A

    2016-11-01

    Despite significant advances in intravascular stent technology, safe prevention of stent thrombosis over prolonged periods after initial deployment persists as a medical need to decrease device failure. The objective of this project was to assess the potential of perfluorocarbon nanoparticles (NP) conjugated with the direct thrombin inhibitor D-phenylalanyl-L-prolyl-L-arginyl chloromethylketone (PPACK-NP) to inhibit stent thrombosis. In a static model of stent thrombosis, 3 × 3-mm pieces of stainless steel coronary stents were cut and adsorbed with thrombin to create a procoagulant surface that would facilitate thrombus development. After treatment with PPACK-NP or control NP, stents were exposed to platelet-poor plasma (PPP) or platelet-rich plasma (PRP) for set time points up to 60 minutes. Measurements of final clot weight in grams were used for assessing the effect of NP treatment on limiting thrombosis. Additionally, groups of stents were exposed to flowing plasma containing various treatments (saline, free PPACK, control NP, and PPACK-NP) and generated thrombi were stained and imaged to investigate the treatment effects of PPACK-NP under flow conditions. The static model of stent thrombosis used in this study indicated a significant reduction in thrombus deposition with PPACK-NP treatment (0.00067 ± 0.00026 g; n = 3) compared with control NP (0.0098 ± 0.0015 g; n = 3; P = .026) in PPP. Exposure to PRP demonstrated similar effects with PPACK-NP treatment (0.00033 ± 0.00012 g; n = 3) vs control NP treatment (0.0045 ± 0.00012 g; n = 3; P = .000017). In additional studies, stents were exposed to both PRP pretreated with vorapaxar and PPACK-NP, which illustrated adjunctive benefit to oral platelet inhibitors for prevention of stent thrombosis. Additionally, an in vitro model of stent thrombosis under flow conditions established that PPACK-NP treatment inhibited thrombus deposition on stents significantly. This study demonstrates that

  11. Oleanolic acid acetate inhibits atopic dermatitis and allergic contact dermatitis in a murine model

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Jin Kyeong [CMRI, Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422 (Korea, Republic of); Oh, Hyun-Mee [Bio-Materials Research Institute, Korea Research Institute of Bioscience and Biotechnology, Jeongeup 580-185 (Korea, Republic of); Lee, Soyoung [CMRI, Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422 (Korea, Republic of); Park, Jin-Woo [Department of Periodontology, School of Dentistry, Kyungpook National University, Daegu 700-412 (Korea, Republic of); Khang, Dongwoo [School of Nano and Advanced Materials Science and Engineering, Gyeongsang National University, Jinju 660-701 (Korea, Republic of); Lee, Seung Woong; Lee, Woo Song [Bio-Materials Research Institute, Korea Research Institute of Bioscience and Biotechnology, Jeongeup 580-185 (Korea, Republic of); Rho, Mun-Chual, E-mail: rho-m@kribb.re.kr [Bio-Materials Research Institute, Korea Research Institute of Bioscience and Biotechnology, Jeongeup 580-185 (Korea, Republic of); Kim, Sang-Hyun, E-mail: shkim72@knu.ac.kr [CMRI, Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422 (Korea, Republic of)

    2013-05-15

    Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are common allergic and inflammatory skin diseases caused by a combination of eczema, scratching, pruritus, and cutaneous sensitization with allergens. This paper examines whether oleanolic acid acetate (OAA) modulates AD and ACD symptoms by using an existing AD model based on the repeated local exposure of mite extract (Dermatophagoides farinae extract, DFE) and 2,4-dinitrochlorobenzene to the ears of BALB/c mice. In addition, the paper uses a 2,4-dinitrofluorobenzene-sensitized local lymph node assay (LLNA) for the ACD model. The oral administration of OAA over a four-week period attenuated AD symptoms in terms of decreased skin lesions, epidermal thickness, the infiltration of immune cells (CD4{sup +} cells, eosinophils, and mast cells), and serum IgE, IgG2a, and histamine levels. The gene expression of Th1, Th2, Th17, and Th22 cytokines was reduced by OAA in the lymph node and ear tissue, and the LLNA verified that OAA suppressed ACD. The oral administration of OAA over a three-day period attenuated ACD symptoms in terms of ear thickness, lymphocyte proliferation, and serum IgG2a levels. The gene expression of Th1, Th2, and Th17 cytokines was reduced by OAA in the thymus and ear tissue. Finally, to define the underlying mechanism, this paper uses a TNF-α/IFN-γ-activated human keratinocyte (HaCaT) model. OAA inhibited the expression of cytokines and chemokines through the downregulation of NF-κB and MAPKs in HaCaT cells. Taken together, the results indicate that OAA inhibited AD and ACD symptoms, suggesting that OAA may be effective in treating allergic skin disorders. - Highlights: • OAA reduced both acute and chronic AD symptoms. • OAA had a controlling effect on the immune reaction for ACD. • The effect of OAA on allergic skin disorders was comparable to the cyclosporine A. • OAA might be a candidate for the treatment of allergic skin disorders.

  12. Inhibition of Clostridium botulinum in Model Reduced-Sodium Pasteurized Prepared Cheese Products.

    Science.gov (United States)

    Glass, Kathleen A; Mu, Ming; LeVine, Brian; Rossi, Frank

    2017-09-01

    The 1986 Food Research Institute-Tanaka et al. model predicts the safety of shelf-stable process cheese spread formulations using the parameters of moisture, pH, NaCl, and disodium phosphate (DSP) to inhibit toxin production by Clostridium botulinum. Although this model is very reliable for predicting safety for standard-of-identity spreads, the effects of additional factors have not been considered. The objective of this study was to create a predictive model to include the interactive effect of moisture, pH, fat, sorbic acid, and potassium-based replacements for NaCl and DSP to reflect modern reduced-sodium recipes. Eighty formulations were identified using a central composite design targeting seven factors: 50 to 60% moisture, pH 5.4 to 6.2, 0 to 0.2% sorbic acid, 10 to 30% fat, 1.7 to 2.4% NaCl, 0.8 to 1.6% DSP, and 0 to 50% potassium replacement for sodium salts. Samples were inoculated with proteolytic C. botulinum spores at 3 log spores per g, hot filled into sterile vials, and stored anaerobically at 27°C. Samples were assayed at 0, 1, 2, 3, 4, 8.5, 17.5, 26, and 40 weeks for the presence of botulinum toxin using the mouse bioassay. A parametric survival model was fit to the censored time-to-toxin data. All linear, quadratic, and pairwise effects were considered for model fit. As hypothesized, the effects of pH, sorbate, moisture, DSP, and NaCl were highly significant (P < 0.001). Fat concentration and potassium replacement effects were significant at P < 0.021 and P < 0.057, respectively. The model consistently predicted the safety failure of the toxic samples, but it also predicted failure for some samples that were not toxic. This model is an adjunct to existing models by adding the factors of potassium salts, fat, and sorbic acid to predict the botulinal safety of prepared process cheese products but is not intended to be a substitute for formulation evaluation by a competent process authority.

  13. Modeling Power Systems as Complex Adaptive Systems

    Energy Technology Data Exchange (ETDEWEB)

    Chassin, David P.; Malard, Joel M.; Posse, Christian; Gangopadhyaya, Asim; Lu, Ning; Katipamula, Srinivas; Mallow, J V.

    2004-12-30

    Physical analogs have shown considerable promise for understanding the behavior of complex adaptive systems, including macroeconomics, biological systems, social networks, and electric power markets. Many of today's most challenging technical and policy questions can be reduced to a distributed economic control problem. Indeed, economically based control of large-scale systems is founded on the conjecture that the price-based regulation (e.g., auctions, markets) results in an optimal allocation of resources and emergent optimal system control. This report explores the state-of-the-art physical analogs for understanding the behavior of some econophysical systems and deriving stable and robust control strategies for using them. We review and discuss applications of some analytic methods based on a thermodynamic metaphor, according to which the interplay between system entropy and conservation laws gives rise to intuitive and governing global properties of complex systems that cannot be otherwise understood. We apply these methods to the question of how power markets can be expected to behave under a variety of conditions.

  14. Visual computing model for immune system and medical system.

    Science.gov (United States)

    Gong, Tao; Cao, Xinxue; Xiong, Qin

    2015-01-01

    Natural immune system is an intelligent self-organizing and adaptive system, which has a variety of immune cells with different types of immune mechanisms. The mutual cooperation between the immune cells shows the intelligence of this immune system, and modeling this immune system has an important significance in medical science and engineering. In order to build a comprehensible model of this immune system for better understanding with the visualization method than the traditional mathematic model, a visual computing model of this immune system was proposed and also used to design a medical system with the immune system, in this paper. Some visual simulations of the immune system were made to test the visual effect. The experimental results of the simulations show that the visual modeling approach can provide a more effective way for analyzing this immune system than only the traditional mathematic equations.

  15. Ethanol inhibits LPS-induced signaling and modulates cytokine production in peritoneal macrophages in vivo in a model for binge drinking

    Directory of Open Access Journals (Sweden)

    Pruett Stephen B

    2009-09-01

    Full Text Available Abstract Background Previous reports indicate that ethanol, in a binge drinking model in mice, inhibits the production of pro-inflammatory cytokines in vivo. However, the inhibition of signaling through TLR4 has not been investigated in this experimental model in vivo. Considering evidence that signaling can be very different in vitro and in vivo, the present study was conducted to determine if effects of ethanol on TLR4 signaling reported for cells in culture or cells removed from ethanol treated mice and stimulated in culture also occur when ethanol treatment and TLR4 activation occur in vivo. Results Phosphorylated p38, ERK, and c-Jun (nuclear were quantified with kits or by western blot using samples taken 15, 30, and 60 min after stimulation of peritoneal macrophages with lipopolysaccharide in vivo. Effects of ethanol were assessed by administering ethanol by gavage at 6 g/kg 30 min before administration of lipopolysaccharide (LPS. Cytokine concentrations in the samples of peritoneal lavage fluid and in serum were determined at 1, 2, and 6 hr after lipopolysaccharide administration. All of these data were used to measure the area under the concentration vs time curve, which provided an indication of the overall effects of ethanol in this system. Ethanol suppressed production of most pro-inflammatory cytokines to a similar degree as it inhibited key TLR4 signaling events. However, NF-κB (p65 translocation to the nucleus was not inhibited by ethanol. To determine if NF-κB composed of other subunits was inhibited, transgenic mice with a luciferase reporter were used. This revealed a reproducible inhibition of NF-κB activity, which is consistent with the observed inhibition of cytokines whose expression is known to be NF-κB dependent. Conclusion Overall, the effects of ethanol on signalling in vivo were similar to those reported for in vitro exposure to ethanol and/or lipopolysaccharide. However, inhibition of the activation of NF-κB was

  16. In vitro toxicities of experimental jet fuel system ice-inhibiting agents.

    Science.gov (United States)

    Geiss, K T; Frazier, J M

    2001-07-02

    One research emphasis within the Department of Defense has been to seek the replacement of operational compounds with alternatives that pose less potential risk to human and ecological systems. Alternatives to glycol ethers, such as diethylene glycol monomethyl ether (M-DE), were investigated for use as jet fuel system ice-inhibiting agents (FSIIs). This group of chemicals includes three derivatives of 1,3-dioxolane-4-methanol (M-1, M-2, and M-3) and a 1,3-dioxane (M-27). In addition, M-DE was evaluated as a reference compound. Our approach was to implement an in vitro test battery based on primary rat hepatocyte cultures to perform initial toxicity evaluations. Hepatocytes were exposed to experimental chemicals (0, 0.001, 0.01, 0.1, 1, 10 mM dosages) for periods up to 24 h. Samples were assayed for lactate dehydrogenase (LDH) release, MTT dye reduction activity, glutathione level, and rate of protein synthesis as indicators of toxicity. Of the compounds tested, M-1, especially at the 10-mM dose, appeared to be more potent than the other chemicals, as measured by these toxicity assays. M-DE, the current FSII, elicited little response in the toxicity assays. Although some variations in toxicity were observed at the 10-mM dose, the in vitro toxicities of the chemicals tested (except for M-1) were not considerably greater than that of M-DE.

  17. Model Information Exchange System (MIXS).

    Science.gov (United States)

    2013-08-01

    Many travel demand forecast models operate at state, regional, and local levels. While they share the same physical network in overlapping geographic areas, they use different and uncoordinated modeling networks. This creates difficulties for models ...

  18. Tumor necrosis factor α inhibits expression of the iron regulating hormone hepcidin in murine models of innate colitis.

    Directory of Open Access Journals (Sweden)

    Nanda Kumar N Shanmugam

    Full Text Available Abnormal expression of the liver peptide hormone hepcidin, a key regulator of iron homeostasis, contributes to the pathogenesis of anemia in conditions such as inflammatory bowel disease (IBD. Since little is known about the mechanisms that control hepcidin expression during states of intestinal inflammation, we sought to shed light on this issue using mouse models.Hepcidin expression was evaluated in two types of intestinal inflammation caused by innate immune activation-dextran sulfate sodium (DSS-induced colitis in wild-type mice and the spontaneous colitis occurring in T-bet/Rag2-deficient (TRUC mice. The role of tumor necrosis factor (TNF α was investigated by in vivo neutralization, and by treatment of a hepatocyte cell line, as well as mice, with the recombinant cytokine. Expression and activation of Smad1, a positive regulator of hepcidin transcription, were assessed during colitis and following administration or neutralization of TNFα. Hepcidin expression progressively decreased with time during DSS colitis, correlating with changes in systemic iron distribution. TNFα inhibited hepcidin expression in cultured hepatocytes and non-colitic mice, while TNFα neutralization during DSS colitis increased it. Similar results were obtained in TRUC mice. These effects involved a TNFα-dependent decrease in Smad1 protein but not mRNA.TNFα inhibits hepcidin expression in two distinct types of innate colitis, with down-regulation of Smad1 protein playing an important role in this process. This inhibitory effect of TNFα may be superseded by other factors in the context of T cell-mediated colitis given that in the latter form of intestinal inflammation hepcidin is usually up-regulated.

  19. Two sustainable energy system analysis models

    DEFF Research Database (Denmark)

    Lund, Henrik; Goran Krajacic, Neven Duic; da Graca Carvalho, Maria

    2005-01-01

    This paper presents a comparative study of two energy system analysis models both designed with the purpose of analysing electricity systems with a substantial share of fluctuating renewable energy.......This paper presents a comparative study of two energy system analysis models both designed with the purpose of analysing electricity systems with a substantial share of fluctuating renewable energy....

  20. Models for multimegawatt space power systems

    Energy Technology Data Exchange (ETDEWEB)

    Edenburn, M.W.

    1990-06-01

    This report describes models for multimegawatt, space power systems which Sandia's Advanced Power Systems Division has constructed to help evaluate space power systems for SDI's Space Power Office. Five system models and models for associated components are presented for both open (power system waste products are exhausted into space) and closed (no waste products) systems: open, burst mode, hydrogen cooled nuclear reactor -- turboalternator system; open, hydrogen-oxygen combustion turboalternator system; closed, nuclear reactor powered Brayton cycle system; closed, liquid metal Rankine cycle system; and closed, in-core, reactor therminonic system. The models estimate performance and mass for the components in each of these systems. 17 refs., 8 figs., 15 tabs.

  1. Daily sesame oil supplementation attenuates local renin-angiotensin system via inhibiting MAPK activation and oxidative stress in cardiac hypertrophy.

    Science.gov (United States)

    Liu, Chuan-Teng; Liu, Ming-Yie

    2017-04-01

    The renin-angiotensin system (RAS) is involved in the development of left ventricular hypertrophy (LVH) by which increases cardiac morbidity and mortality. Activation of mitogen-activated protein kinases (MAPKs) and oxidative stress are important in RAS-mediated cardiac hypertrophy. Sesame oil, a potent antioxidant, attenuates hypertension-dependent LVH. We examined the protective role of sesame oil on RAS-mediated MAPK activation and oxidative stress in rats. We induced LVH using a hypertensive model by subcutaneously injecting deoxycorticosterone acetate (DOCA; 15 mg/ml/kg in mineral oil; twice weekly for 5 weeks) and supplementing with 1% sodium chloride drinking water (DOCA/salt) to uninephrectomized rats. Sesame oil was gavaged (0.5 or 1 ml/kg/day for 7 days) after 4 weeks of DOCA/salt treatment. Cardiac histopathology, RAS parameters, expression of MAPKs, reactive oxygen species and lipid peroxidation were assessed 24 h after the last dose of sesame oil. Sesame oil significantly decreased the size of cardiomyocytes and the levels of cardiac renin, angiotensin-converting enzyme and angiotensin II. In addition, sesame oil down-regulated the expression of angiotensin type 1 receptor, JNK and p38 MAPK and apoptosis signal regulating kinase 1, c-Fos and c-Jun in rats receiving DOCA/salt. Furthermore, the induction of nicotinamide adenine dinucleotide phosphate oxidase, superoxide anion and hydroxyl radical and lipid peroxidation by DOCA/salt were inhibited by sesame oil. Sesame oil modulates cardiac RAS to ameliorate LVH by inhibiting MAPK activation and lowering oxidative stress. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Inhibition of hemangioma development in a syngeneic mouse model correlates with bcl-2 suppression and the inhibition of Akt kinase activity.

    Science.gov (United States)

    Mabeta, Peace; Pepper, Michael S

    2012-03-01

    Hemangiomas are benign vascular tumors that are characterised by excessive angiogenesis. While there is no definitive treatment for these tumors, several angiogenesis inhibitors, including bleomycin, have been employed. To better understand the mechanism of bleomycin in accelerating haemangioma regression, we investigated the effects of the drug on hemangiomagenesis using a previously described mouse hemangioma model. The effects of bleomycin were tested in mice injected with endothelioma cells to induce hemangioma development. At termination, tissue samples from bleomycin-treated and control mice were stained with hematoxylin and eosin for histological examination. Bcl-2, flk-1 and vWF expression were studied by immunofluorescence microscopy. Hematological analysis was undertaken using a hemocounter. Akt activity was analyzed in tissue homogenates and endothelioma cells using ELISA. Also, caspase activity was analysed in endothelioma cells by ELISA. Bleomycin inhibited tumor growth in vivo in a dose-dependant manner. Our findings also revealed that bleomycin inhibited Akt activation and suppressed bcl-2. In vitro bleomycin increased caspase activation. Our observations reveal possible mechanisms for the inhibitory effects of bleomycin on hemangiomagenesis, and raise the possibility that bcl-2 might be an important therapeutic target in the treatment of hemangiomas.

  3. Systemic delivery of microRNA-101 potently inhibits hepatocellular carcinoma in vivo by repressing multiple targets.

    Directory of Open Access Journals (Sweden)

    Fang Zheng

    2015-02-01

    Full Text Available Targeted therapy based on adjustment of microRNA (miRNAs activity takes great promise due to the ability of these small RNAs to modulate cellular behavior. However, the efficacy of miR-101 replacement therapy to hepatocellular carcinoma (HCC remains unclear. In the current study, we first observed that plasma levels of miR-101 were significantly lower in distant metastatic HCC patients than in HCCs without distant metastasis, and down-regulation of plasma miR-101 predicted a worse disease-free survival (DFS, P<0.05. In an animal model of HCC, we demonstrated that systemic delivery of lentivirus-mediated miR-101 abrogated HCC growth in the liver, intrahepatic metastasis and distant metastasis to the lung and to the mediastinum, resulting in a dramatic suppression of HCC development and metastasis in mice without toxicity and extending life expectancy. Furthermore, enforced overexpression of miR-101 in HCC cells not only decreased EZH2, COX2 and STMN1, but also directly down-regulated a novel target ROCK2, inhibited Rho/Rac GTPase activation, and blocked HCC cells epithelial-mesenchymal transition (EMT and angiogenesis, inducing a strong abrogation of HCC tumorigenesis and aggressiveness both in vitro and in vivo. These results provide proof-of-concept support for systemic delivery of lentivirus-mediated miR-101 as a powerful anti-HCC therapeutic modality by repressing multiple molecular targets.

  4. Inhibition of group A streptococcal infection by Melaleuca alternifolia (tea tree) oil concentrate in the murine model.

    Science.gov (United States)

    Tsao, N; Kuo, C-F; Lei, H-Y; Lu, S-L; Huang, K-J

    2010-03-01

    To investigate the effect of a water-soluble Melaleuca alternifolia concentrate (MAC) on group A streptococcus (GAS; Streptococcus pyogenes)-induced necrotizing fasciitis. MAC pretreatment (1% and 2% v/v) was able to protect mice from GAS infection in an air pouch model. GAS-induced mouse death and skin injury were inhibited dose dependently by MAC. Administration of MAC at 6 h post-GAS infection partially delayed mouse death. Surveys of the exudates of the air pouch of MAC-treated mice revealed that the survival of infiltrating cells was prolonged, the bacteria were eliminated, and the production of inflammatory cytokines was inhibited. MAC could directly inhibit the growth of GAS in vitro, and the minimal inhibitory concentration (MIC) of MAC for GAS was determined as 0.05% v/v using the time-kill assay. Furthermore, a sub-MIC dose of MAC not only enhanced the bactericidal activity of RAW264.7 macrophage cells against GAS but also increased susceptibility of GAS for blood clearance. These results suggest that MAC may inhibit GAS-induced skin damage and mouse death by directly inhibiting GAS growth and enhancing the bactericidal activity of macrophages. Our results provide scientific data on the use of MAC for the treatment of GAS-induced necrotizing fasciitis in the murine model.

  5. Modeling traceability in system of systems

    NARCIS (Netherlands)

    Tekinerdogan, Bedir; Erata, Ferhat

    2017-01-01

    An important aspect in SoS is the realization of the concerns in different systems that work together. Identifying and locating these concerns is important to orchestrate the overall activities and hereby to achieve the overall goal of the SoS. Moreover, concerns in SoS are rarely stable and need

  6. Modeling of Nonlinear Systems using Genetic Algorithm

    Science.gov (United States)

    Hayashi, Kayoko; Yamamoto, Toru; Kawada, Kazuo

    In this paper, a newly modeling system by using Genetic Algorithm (GA) is proposed. The GA is an evolutionary computational method that simulates the mechanisms of heredity or evolution of living things, and it is utilized in optimization and in searching for optimized solutions. Most process systems have nonlinearities, so it is necessary to anticipate exactly such systems. However, it is difficult to make a suitable model for nonlinear systems, because most nonlinear systems have a complex structure. Therefore the newly proposed method of modeling for nonlinear systems uses GA. Then, according to the newly proposed scheme, the optimal structure and parameters of the nonlinear model are automatically generated.

  7. Decreased surface expression of the δ subunit of the GABAA receptor contributes to reduced tonic inhibition in dentate granule cells in a mouse model of fragile X syndrome.

    Science.gov (United States)

    Zhang, Nianhui; Peng, Zechun; Tong, Xiaoping; Lindemeyer, A Kerstin; Cetina, Yliana; Huang, Christine S; Olsen, Richard W; Otis, Thomas S; Houser, Carolyn R

    2017-11-01

    While numerous changes in the GABA system have been identified in models of Fragile X Syndrome (FXS), alterations in subunits of the GABA A receptors (GABA A Rs) that mediate tonic inhibition are particularly intriguing. Considering the key role of tonic inhibition in controlling neuronal excitability, reduced tonic inhibition could contribute to FXS-associated disorders such as hyperactivity, hypersensitivity, and increased seizure susceptibility. The current study has focused on the expression and function of the δ subunit of the GABA A R, a major subunit involved in tonic inhibition, in granule cells of the dentate gyrus in the Fmr1 knockout (KO) mouse model of FXS. Electrophysiological studies of dentate granule cells revealed a marked, nearly four-fold, decrease in tonic inhibition in the Fmr1 KO mice, as well as reduced effects of two δ subunit-preferring pharmacological agents, THIP and DS2, supporting the suggestion that δ subunit-containing GABA A Rs are compromised in the Fmr1 KO mice. Immunohistochemistry demonstrated a small but statistically significant decrease in δ subunit labeling in the molecular layer of the dentate gyrus in Fmr1 KO mice compared to wildtype (WT) littermates. The discrepancy between the large deficits in GABA-mediated tonic inhibition in granule cells in the Fmr1 KO mice and only modest reductions in immunolabeling of the δ subunit led to studies of surface expression of the δ subunit. Cross-linking experiments followed by Western blot analysis demonstrated a small, non-significant decrease in total δ subunit protein in the hippocampus of Fmr1 KO mice, but a four-fold decrease in surface expression of the δ subunit in these mice. No significant changes were observed in total or surface expression of the α4 subunit protein, a major partner of the δ subunit in the forebrain. Postembedding immunogold labeling for the δ subunit demonstrated a large, three-fold, decrease in the number of symmetric synapses with

  8. Measures of Behavioral Inhibition and Activation System Sensitivity as Predictors of Big Five Personality Traits

    Directory of Open Access Journals (Sweden)

    Valerija Križanić

    2015-07-01

    Full Text Available In the Reinforcement Sensitivity Theory, Gray (1987 described three hypothetical biological brain systems, assumed to represent underpinnings of the stable patterns of experience and behaviour. Most research has been devoted to studying behavioural inhibition system (BIS and behavioural activation system (BAS, which have shown relatively stable associations with neuroticism and extroversion, respectively. BIS/BAS scale (Carver & White, 1994 is one of the most frequently used instruments for measuring these constructs. The questionnaire contains one scale of BIS sensitivity that captures reactions to appearance or anticipation of punishment, and three subscales of BAS sensitivity which are aimed to assess distinct but related constructs: BAS – Drive, that relate to persistence in achieving desired goals; BAS - Fun seeking, that relates to desire for new rewarding experiences and indicates person's readiness to engage in potentially rewarding situation, and BAS – Reward sensitivity, that measures positive reactions to appearance or anticipation of reward.The aim of the current study was to explore to what extent individual differences in personality traits can be predicted based on measures of BIS and BAS sensitivity. In this paper we analysed the data of 284 female students, that completed translated and adapted Croatian version of BIS/BAS scales, as well as International Personality Item Pool (IPIP 50 which measures the Big-Five personality domains. Exploratory factor analysis indicated that the factor structure of Croatian version of BIS/BAS scale was comparable to the original instrument. Results of the regression analysis revealed that BIS scale was a significant predictor of emotional instability, while BAS subscales showed different patterns of relationships with measured personality traits. These results indicate the importance of measuring distinct aspects of BAS sensitivity.

  9. Chlorine gas exposure causes systemic endothelial dysfunction by inhibiting endothelial nitric oxide synthase-dependent signaling.

    Science.gov (United States)

    Honavar, Jaideep; Samal, Andrey A; Bradley, Kelley M; Brandon, Angela; Balanay, Joann; Squadrito, Giuseppe L; MohanKumar, Krishnan; Maheshwari, Akhil; Postlethwait, Edward M; Matalon, Sadis; Patel, Rakesh P

    2011-08-01

    Chlorine gas (Cl(2)) exposure during accidents or in the military setting results primarily in injury to the lungs. However, the potential for Cl(2) exposure to promote injury to the systemic vasculature leading to compromised vascular function has not been studied. We hypothesized that Cl(2) promotes extrapulmonary endothelial dysfunction characterized by a loss of endothelial nitric oxide synthase (eNOS)-derived signaling. Male Sprague Dawley rats were exposed to Cl(2) for 30 minutes, and eNOS-dependent vasodilation of aorta as a function of Cl(2) dose (0-400 ppm) and time after exposure (0-48 h) were determined. Exposure to Cl(2) (250-400 ppm) significantly inhibited eNOS-dependent vasodilation (stimulated by acetycholine) at 24 to 48 hours after exposure without affecting constriction responses to phenylephrine or vasodilation responses to an NO donor, suggesting decreased NO formation. Consistent with this hypothesis, eNOS protein expression was significantly decreased (∼ 60%) in aorta isolated from Cl(2)-exposed versus air-exposed rats. Moreover, inducible nitric oxide synthase (iNOS) mRNA was up-regulated in circulating leukocytes and aorta isolated 24 hours after Cl(2) exposure, suggesting stimulation of inflammation in the systemic vasculature. Despite decreased eNOS expression and activity, no changes in mean arterial blood pressure were observed. However, injection of 1400W, a selective inhibitor of iNOS, increased mean arterial blood pressure only in Cl(2)-exposed animals, suggesting that iNOS-derived NO compensates for decreased eNOS-derived NO. These results highlight the potential for Cl(2) exposure to promote postexposure systemic endothelial dysfunction via disruption of vascular NO homeostasis mechanisms.

  10. Chlorine Gas Exposure Causes Systemic Endothelial Dysfunction by Inhibiting Endothelial Nitric Oxide Synthase–Dependent Signaling

    Science.gov (United States)

    Honavar, Jaideep; Samal, Andrey A.; Bradley, Kelley M.; Brandon, Angela; Balanay, Joann; Squadrito, Giuseppe L.; MohanKumar, Krishnan; Maheshwari, Akhil; Postlethwait, Edward M.; Matalon, Sadis; Patel, Rakesh P.

    2011-01-01

    Chlorine gas (Cl2) exposure during accidents or in the military setting results primarily in injury to the lungs. However, the potential for Cl2 exposure to promote injury to the systemic vasculature leading to compromised vascular function has not been studied. We hypothesized that Cl2 promotes extrapulmonary endothelial dysfunction characterized by a loss of endothelial nitric oxide synthase (eNOS)-derived signaling. Male Sprague Dawley rats were exposed to Cl2 for 30 minutes, and eNOS-dependent vasodilation of aorta as a function of Cl2 dose (0–400 ppm) and time after exposure (0–48 h) were determined. Exposure to Cl2 (250–400 ppm) significantly inhibited eNOS-dependent vasodilation (stimulated by acetycholine) at 24 to 48 hours after exposure without affecting constriction responses to phenylephrine or vasodilation responses to an NO donor, suggesting decreased NO formation. Consistent with this hypothesis, eNOS protein expression was significantly decreased (∼ 60%) in aorta isolated from Cl2–exposed versus air-exposed rats. Moreover, inducible nitric oxide synthase (iNOS) mRNA was up-regulated in circulating leukocytes and aorta isolated 24 hours after Cl2 exposure, suggesting stimulation of inflammation in the systemic vasculature. Despite decreased eNOS expression and activity, no changes in mean arterial blood pressure were observed. However, injection of 1400W, a selective inhibitor of iNOS, increased mean arterial blood pressure only in Cl2–exposed animals, suggesting that iNOS-derived NO compensates for decreased eNOS-derived NO. These results highlight the potential for Cl2 exposure to promote postexposure systemic endothelial dysfunction via disruption of vascular NO homeostasis mechanisms. PMID:21131444

  11. Effect of delivery modalities on the physiologic inhibition system of coagulation of the neonate.

    Science.gov (United States)

    Franzoi, Malida; Simioni, Paolo; Luni, Sonia; Zerbinati, Patrizia; Girolami, Antonio; Zanardo, Vincenzo

    2002-01-01

    The perinatal period is associated with an increased incidence of thromboembolic complications, which may occur in both the maternal and fetal circulation in otherwise normal and healthy adults and fetuses, and this may be related to the activation of the coagulation system at the time of parturition. The risk of these complications is generally much higher in neonates, who have decreased activity of the physiologic inhibition system of coagulation (PISC), including protein C, protein S and antithrombin, in comparison with adults. Therefore, any additional obstetric iatrogenic factors could predispose the neonate to an increased risk of thromboembolic complications. The aim of this study was to evaluate the influence of modality of delivery (spontaneous vaginal delivery vs. elective caesarian section) on the neonatal PISC factor (protein C, protein S and antithrombin) levels and the fibrinolytic system (plasminogen and fibrinogen levels). We studied 41 consecutive healthy newborns, 18 delivered vaginally (mean gestational age 39.7 +/- 0.8) and 23 by elective caesarian section (mean gestational age 38.5 +/- 0.7). Plasma samples were collected from the umbilical cord at birth. AT activity, protein C antigen and activity, total and free protein S antigen, fibrinogen concentration and plasminogen activity were tested. Among PISC factors studied in cord blood of infants born after vaginal delivery, protein C antigen levels and antithrombin activity were statistically higher (41.3 +/- 9.4 vs. 33.9 +/- 7.2 and 58.5 +/- 10.0 vs. 48.4 +/- 12.7, respectively; Plabor stress of vaginal delivery may play a role in influencing the levels of some PISC factors in the cord blood of full-term neonates. In newborns with coagulation disorders, separate reference ranges in coagulation screening tests should be possibly needed depending on the delivery modality.

  12. Selective HDAC inhibition by ACY-241 enhances the activity of paclitaxel in solid tumor models.

    Science.gov (United States)

    Huang, Pengyu; Almeciga-Pinto, Ingrid; Jarpe, Matthew; van Duzer, John H; Mazitschek, Ralph; Yang, Min; Jones, Simon S; Quayle, Steven N

    2017-01-10

    ACY-241 is a novel, orally available and selective histone deacetylase (HDAC) 6 inhibitor in Phase 1b clinical development in multiple myeloma (NCT 02400242). Like the structurally related drug ACY-1215 (ricolinostat), ACY-241 has the potential for a substantially reduced side effect profile versus current nonselective HDAC inhibitor drug candidates due to reduced potency against Class I HDACs while retaining the potential for anticancer effectiveness. We now show that combination treatment of xenograft models with paclitaxel and either ricolinostat or ACY-241 significantly suppresses solid tumor growth. In cell lines from multiple solid tumor lineages, combination treatment with ACY-241 and paclitaxel enhanced inhibition of proliferation and increased cell death relative to either single agent alone. Combination treatment with ACY-241 and paclitaxel also resulted in more frequent occurrence of mitotic cells with abnormal multipolar spindles and aberrant mitoses, consistent with the observed increase of aneuploid cells. At the molecular level, multipolar mitotic spindle formation was observed to be NuMA-dependent and γ-tubulin independent, suggesting that treatment-induced multipolar spindle formation does not depend on centrosomal amplification. The significantly enhanced efficacy of ACY-241 plus paclitaxel observed here, in addition to the anticipated superior safety profile of a selective HDAC6 inhibitor versus pan-HDAC inhibitors, provides a strong rationale for clinical development of this combination in patients with advanced solid tumors.

  13. PARP-1 Inhibition Is Neuroprotective in the R6/2 Mouse Model of Huntington's Disease.

    Directory of Open Access Journals (Sweden)

    Antonella Cardinale

    Full Text Available Poly (ADP-ribose polymerase 1 (PARP-1 is a nuclear enzyme that is involved in physiological processes as DNA repair, genomic stability, and apoptosis. Moreover, published studies demonstrated that PARP-1 mediates necrotic cell death in response to excessive DNA damage under certain pathological conditions. In Huntington's disease brains, PARP immunoreactivity was described in neurons and in glial cells, thereby suggesting the involvement of apoptosis in HD. In this study, we sought to determine if the PARP-1 inhibitor exerts a neuroprotective effect in R6/2 mutant mice, which recapitulates, in many aspects, human HD. Transgenic mice were treated with the PARP-1 inhibitor INO-1001 mg/Kg daily starting from 4 weeks of age. After transcardial perfusion, histological and immunohistochemical studies were performed. We found that INO 1001-treated R6/2 mice survived longer and displayed less severe signs of neurological dysfunction than the vehicle treated ones. Primary outcome measures such as striatal atrophy, morphology of striatal neurons, neuronal intranuclear inclusions and microglial reaction confirmed a neuroprotective effect of the compound. INO-1001 was effective in significantly increasing activated CREB and BDNF in the striatal spiny neurons, which might account for the beneficial effects observed in this model. Our findings show that PARP-1 inhibition could be considered as a valid therapeutic approach for HD.

  14. Tocotrienol-adjuvanted dendritic cells inhibit tumor growth and metastasis: a murine model of breast cancer.

    Directory of Open Access Journals (Sweden)

    Sitti Rahma Abdul Hafid

    Full Text Available Tocotrienol-rich fraction (TRF from palm oil is reported to possess anti-cancer and immune-enhancing effects. In this study, TRF supplementation was used as an adjuvant to enhance the anti-cancer effects of dendritic cells (DC-based cancer vaccine in a syngeneic mouse model of breast cancer. Female BALB/c mice were inoculated with 4T1 cells in mammary pad to induce tumor. When the tumor was palpable, the mice in the experimental groups were injected subcutaneously with DC-pulsed with tumor lysate (TL from 4T1 cells (DC+TL once a week for three weeks and fed daily with 1 mg TRF or vehicle. Control mice received unpulsed DC and were fed with vehicle. The combined therapy of using DC+TL injections and TRF supplementation (DC+TL+TRF inhibited (p<0.05 tumor growth and metastasis. Splenocytes from the DC+TL+TRF group cultured with mitomycin-C (MMC-treated 4T1 cells produced higher (p<0.05 levels of IFN-γ and IL-12. The cytotoxic T-lymphocyte (CTL assay also showed enhanced tumor-specific killing (p<0.05 by CD8(+ T-lymphocytes isolated from mice in the DC+TL+TRF group. This study shows that TRF has the potential to be used as an adjuvant to enhance effectiveness of DC-based vaccines.

  15. Pharmacological Inhibition of Necroptosis Protects from Dopaminergic Neuronal Cell Death in Parkinson’s Disease Models

    Directory of Open Access Journals (Sweden)

    Angelo Iannielli

    2018-02-01

    Full Text Available Dysfunctions in mitochondrial dynamics and metabolism are common pathological processes associated with Parkinson’s disease (PD. It was recently shown that an inherited form of PD and dementia is caused by mutations in the OPA1 gene, which encodes for a key player in mitochondrial fusion and structure. iPSC-derived neural cells from these patients exhibited severe mitochondrial fragmentation, respiration impairment, ATP deficits, and heightened oxidative stress. Reconstitution of normal levels of OPA1 in PD-derived neural cells normalized mitochondria morphology and function. OPA1-mutated neuronal cultures showed reduced survival in vitro. Intriguingly, selective inhibition of necroptosis effectively rescued this survival deficit. Additionally, dampening necroptosis in MPTP-treated mice protected from DA neuronal cell loss. This human iPSC-based model captures both early pathological events in OPA1 mutant neural cells and the beneficial effects of blocking necroptosis, highlighting this cell death process as a potential therapeutic target for PD.

  16. Model Driven Development of Data Sensitive Systems

    DEFF Research Database (Denmark)

    Olsen, Petur

    2014-01-01

    to the values of variables. This theses strives to improve model-driven development of such data-sensitive systems. This is done by addressing three research questions. In the first we combine state-based modeling and abstract interpretation, in order to ease modeling of data-sensitive systems, while allowing...... efficient model-checking and model-based testing. In the second we develop automatic abstraction learning used together with model learning, in order to allow fully automatic learning of data-sensitive systems to allow learning of larger systems. In the third we develop an approach for modeling and model-based...... detection and pushing error detection to earlier stages of development. The complexity of modeling and the size of systems which can be analyzed is severely limited when introducing data variables. The state space grows exponentially in the number of variable and the domain size of the variables...

  17. Modeling of a Hydraulic Braking System

    OpenAIRE

    Lundin, Christopher

    2015-01-01

    The objective of this thesis is to derive an analytical model representing a reduced form of a mine hoist hydraulic braking system. Based primarily on fluid mechanical and mechanical physical modeling, along with a number of simplifying assumptions, the analytical model will be derived and expressed in the form of a system of differential equations including a set of static functions. The obtained model will be suitable for basic simulation and analysis of system dynamics, with the aim to cap...

  18. Graphical Model Debugger Framework for Embedded Systems

    DEFF Research Database (Denmark)

    Zeng, Kebin

    2010-01-01

    Model Driven Software Development has offered a faster way to design and implement embedded real-time software by moving the design to a model level, and by transforming models to code. However, the testing of embedded systems has remained at the code level. This paper presents a Graphical Model...... Debugger Framework, providing an auxiliary avenue of analysis of system models at runtime by executing generated code and updating models synchronously, which allows embedded developers to focus on the model level. With the model debugger, embedded developers can graphically test their design model...... and check the running status of the system, which offers a debugging capability on a higher level of abstraction. The framework intends to contribute a tool to the Eclipse society, especially suitable for model-driven development of embedded systems....

  19. Inhibition of sphingosine kinase-2 in a murine model of lupus nephritis.

    Directory of Open Access Journals (Sweden)

    Ashley J Snider

    Full Text Available Sphingosine-1-phosphate (S1P, a potent bioactive lipid, is emerging as a central mediator in inflammation and immune responses. We have previously implicated S1P and its synthetic enzyme sphingosine kinase (SK in inflammatory and autoimmune disorders, including inflammatory bowel disease and rheumatoid arthritis. Generation of S1P requires phosphorylation of sphingosine by SK, of which there are two isoforms. Numerous studies have implicated SK1 in immune cell trafficking, inflammation and autoimmune disorders. In this study, we set out to determine the role of SK and S1P in lupus nephritis (LN. To this end, we examined S1P and dihydro-S1P (dh-S1P levels in serum and kidney tissues from a mouse model of LN. Interestingly dh-S1P was significantly elevated in serum and kidney tissue from LN mice, which is more readily phosphorylated by SK2. Therefore, we employed the use of the specific SK2 inhibitor, ABC294640 in our murine model of LN. Treatment with ABC294640 did not improve vascular or interstitial pathology associated with LN. However, mice treated with the SK2 inhibitor did demonstrate decreases in glomerular pathology and accumulation of B and T cells in the spleen these were not statistically different from lpr mice treated with vehicle. LN mice treated with ABC294640 did not have improved urine thromboxane levels or urine proteinuria measurements. Both S1P and dh-S1P levels in circulation were significantly reduced with ABC294640 treatment; however, dh-S1P was actually elevated in kidneys from LN mice treated with ABC294640. Together these data demonstrate a role for SKs in LN; however, they suggest that inhibition of SK1 or perhaps both SK isoforms would better prevent elevations in S1P and dh-S1P and potentially better protect against LN.

  20. Faslodex inhibits estradiol-induced extracellular matrix dynamics and lung metastasis in a model of lymphangioleiomyomatosis.

    Science.gov (United States)

    Li, Chenggang; Zhou, Xiaobo; Sun, Yang; Zhang, Erik; Mancini, John D; Parkhitko, Andrey; Morrison, Tasha A; Silverman, Edwin K; Henske, Elizabeth P; Yu, Jane J

    2013-07-01

    Lymphangioleiomyomatosis (LAM) is a destructive lung disease primarily affecting women. Genetic studies indicate that LAM cells carry inactivating tuberous sclerosis complex (TSC)-2 mutations, and metastasize to the lung. We previously discovered that estradiol increases the metastasis of TSC2-deficient cells in mice carrying xenograft tumors. Here, we investigate the molecular basis underlying the estradiol-induced lung metastasis of TSC2-deficient cells, and test the efficacy of Faslodex (an estrogen receptor antagonist) in a preclinical model of LAM. We used a xenograft tumor model in which estradiol induces the lung metastasis of TSC2-deficient cells. We analyzed the impact of Faslodex on tumor size, the extracellular matrix organization, the expression of matrix metalloproteinase (MMP)-2, and lung metastasis. We also examined the effects of estradiol and Faslodex on MMP2 expression and activity in tuberin-deficient cells in vitro. Estradiol resulted in a marked reduction of Type IV collagen deposition in xenograft tumors, associated with 2-fold greater MMP2 concentrations compared with placebo-treated mice. Faslodex normalized the Type IV collagen changes in xenograft tumors, enhanced the survival of the mice, and completely blocked lung metastases. In vitro, estradiol enhanced MMP2 transcripts, protein accumulation, and activity. These estradiol-induced changes in MMP2 were blocked by Faslodex. In TSC2-deficient cells, estradiol increased MMP2 concentrations in vitro and in vivo, and induced extracellular matrix remodeling. Faslodex inhibits the estradiol-induced lung metastasis of TSC2-deficient cells. Targeting estrogen receptors with Faslodex may be of efficacy in the treatment of LAM.

  1. Inhibition of tumor growth in a glioma model treated with boron neutron capture therapy

    International Nuclear Information System (INIS)

    Goodman, J.H.; McGregor, J.M.; Clendenon, N.R.; Gahbauer, R.A.; Barth, R.F.; Soloway, A.H.; Fairchild, R.G.

    1990-01-01

    This investigation attempts to determine whether increased survival time seen when the F98 glioma model is treated with boron neutron capture therapy (BNCT) is a result of inhibition of tumor growth caused by radiation-induced alterations in endothelial cells and normal tissue components. This indirect effect of radiation has been called the tumor bed effect. A series of tumor-bearing rats was studied, using a standardized investigational BNCT protocol consisting of 50 mg/kg of Na2B12H11SH injected intravenously 14 to 17 hours before neutron irradiation at 4 x 10(12) n/cm2. Ten rats, serving as controls, received no treatment either before or after tumor implantation. A second group of 10 rats was treated with BNCT 4 days before tumor implantation; these animals received no further treatment. The remaining group of 10 rats received no pretreatment but was treated with BNCT 10 days after implantation. Histological and ultrastructural analyses were performed in 2 animals from each group 17 days after implantation. Survival times of the untreated control animals (mean, 25.8 days) did not differ statistically from the survival times of the rats in the pretreated group (mean, 25.5 days). The rats treated with BNCT after implantation survived significantly longer (P less than 0.02; mean, 33.2 days) than the controls and the preirradiated animals. Tumor size indices calculated from measurements taken at the time of death were similar in all groups. These results indicate that, with this tumor model, BNCT does not cause a tumor bed effect in cerebral tissue. The therapeutic gains observed with BNCT result from direct effects on tumor cells or on the peritumoral neovascularity

  2. The Relationship between Behavioral Activation/ Inhibition Systems (BAS/BIS and Bullying/ Victimization Behaviors among Male Adolescents

    Directory of Open Access Journals (Sweden)

    Sajjad Basharpoor

    2013-09-01

    Full Text Available Objective:This research was conducted to investigate the relationship between behavioral activation-inhibition systems and bullyingvictimization behaviors among adolescents.Method:This was a correlational and cross-sectional study. Two hundred and thirty school boys were selected randomly by multistage cluster sampling method, and participated in this research. This sample responded to a demographic questionnaire, the Revised Olweus Bully/ Victim questionnaire and the child version of behavioral inhibition/activation systems Scale in their classrooms and in the presence of the researcher. The collected data were analyzed by Pearson’s correlation and multiple regressions. Result:The results showed that bullying and victimization were correlated with both behavioral activation and behavioral inhibition systems (p<0.01. The results also showed that 18% of the variance in victimization and 31 % of the variance in bullying were explained by behavioral inhibition and behavioral activation systems respectively .Conclusion:The results of this study implied that BAS and BIS may play a role in the manifestation of bullying in adolescents.

  3. Sensitivity of Gray’s behavioral inhibition system in clinically anxious and non-anxious children and adolescents

    NARCIS (Netherlands)

    Vervoort, L.; Wolters, L.H.; Hogendoorn, S.M.; de Haan, E.; de Boer, F.; Prins, P.J.M.

    2010-01-01

    The child version of the Carver and White (1994) BIS/BAS-scales (Muris et al., 2005) was used to assess sensitivity of the Behavioral Inhibition and the Behavioral Activation System in clinically anxious and non-anxious youth (n = 175, ages 8-18 years, 70 boys). Results supported the hypothesis that

  4. Restriction-modification system with methyl-inhibited base excision and abasic-site cleavage activities.

    Science.gov (United States)

    Fukuyo, Masaki; Nakano, Toshiaki; Zhang, Yingbiao; Furuta, Yoshikazu; Ishikawa, Ken; Watanabe-Matsui, Miki; Yano, Hirokazu; Hamakawa, Takeshi; Ide, Hiroshi; Kobayashi, Ichizo

    2015-03-11

    The restriction-modification systems use epigenetic modification to distinguish between self and nonself DNA. A modification enzyme transfers a methyl group to a base in a specific DNA sequence while its cognate restriction enzyme introduces breaks in DNA lacking this methyl group. So far, all the restriction enzymes hydrolyze phosphodiester bonds linking the monomer units of DNA. We recently reported that a restriction enzyme (R.PabI) of the PabI superfamily with half-pipe fold has DNA glycosylase activity that excises an adenine base in the recognition sequence (5'-GTAC). We now found a second activity in this enzyme: at the resulting apurinic/apyrimidinic (AP) (abasic) site (5'-GT#C, # = AP), its AP lyase activity generates an atypical strand break. Although the lyase activity is weak and lacks sequence specificity, its covalent DNA-R.PabI reaction intermediates can be trapped by NaBH4 reduction. The base excision is not coupled with the strand breakage and yet causes restriction because the restriction enzyme action can impair transformation ability of unmethylated DNA even in the absence of strand breaks in vitro. The base excision of R.PabI is inhibited by methylation of the target adenine base. These findings expand our understanding of genetic and epigenetic processes linking those in prokaryotes and eukaryotes. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

  5. Hydrological modelling in forested systems

    Science.gov (United States)

    This chapter provides a brief overview of forest hydrology modelling approaches for answering important global research and management questions. Many hundreds of hydrological models have been applied globally across multiple decades to represent and predict forest hydrological p...

  6. Towards Modelling of Hybrid Systems

    DEFF Research Database (Denmark)

    Wisniewski, Rafal

    2006-01-01

    The article is an attempt to use methods of category theory and topology for analysis of hybrid systems. We use the notion of a directed topological space; it is a topological space together with a set of privileged paths. Dynamical systems are examples of directed topological spaces. A hybrid...... system consists of a number of dynamical systems that are glued together according to information encoded in the discrete part of the system. We develop a definition of a hybrid system as a functor from the category generated by a transition system to the category of directed topological spaces. Its...... directed homotopy colimit (geometric realization) is a single directed topological space. The behavior of hybrid systems can be then understood in terms of the behavior of dynamical systems through the directed homotopy colimit....

  7. Improved efficacy of allergen-specific immunotherapy by JAK inhibition in a murine model of allergic asthma

    DEFF Research Database (Denmark)

    Aguilar-Pimentel, Juan Antonio; Graessel, Anke; Alessandrini, Francesca

    2017-01-01

    )-induced allergic airway inflammation and allergen-specific immunotherapy was combined with the administration of Tofacitinib (TOFA, a FDA-approved JAK inhibitor) from 48 hours prior to 48 hours after therapeutic OVA-injection. The effect of TOFA on human FOXP3+CD4+ T cells was studied in vitro. RESULTS: AIT...... co-administration significantly reduced systemic IL-6, IL-1β and OVA-specific IgE levels and induced IgG1 to the same extent as AIT alone. Additionally, TOFA enhanced the induction of human FOXP3+CD4+ T cells. CONCLUSIONS: This proof of concept study shows that JAK inhibition did not inhibit...

  8. Inhibition of Tumor Growth of Human Hepatocellular Carcinoma HepG2 Cells in a Nude Mouse Xenograft Model by the Total Flavonoids from Arachniodes exilis

    Directory of Open Access Journals (Sweden)

    Huimin Li

    2017-01-01

    Full Text Available A tumor growth model of human hepatocellular carcinoma HepG2 cells in nude mice was employed to investigate the antitumor activity of the total flavonoids extracted from Arachniodes exilis (TFAE in vivo. Several biochemical assays including hematoxylin-eosin (HE staining, immunohistochemistry, and Western blot were performed to elucidate the mechanism of action of total flavonoids extracted from Arachniodes exilis (TFAE. The results showed that TFAE effectively inhibited the tumor growth of hepatocellular carcinoma in nude mice and had no significant effect on body weight, blood system, and functions of liver and kidney. Expression levels of proapoptotic proteins Bax and cleaved caspase-3 remarkably increased while the expressions of Bcl-2, HIF-1α, and VEGF were suppressed by TFAE. These results suggested that the antitumor potential of TFEA was implied by the apoptosis of tumor cells and the inhibition of angiogenesis in tumor tissue.

  9. Local delivery of cannabinoid-loaded microparticles inhibits tumor growth in a murine xenograft model of glioblastoma multiforme.

    Directory of Open Access Journals (Sweden)

    Dolores Hernán Pérez de la Ossa

    Full Text Available Cannabinoids, the active components of marijuana and their derivatives, are currently investigated due to their potential therapeutic application for the management of many different diseases, including cancer. Specifically, Δ(9-Tetrahydrocannabinol (THC and Cannabidiol (CBD - the two major ingredients of marijuana - have been shown to inhibit tumor growth in a number of animal models of cancer, including glioma. Although there are several pharmaceutical preparations that permit the oral administration of THC or its analogue nabilone or the oromucosal delivery of a THC- and CBD-enriched cannabis extract, the systemic administration of cannabinoids has several limitations in part derived from the high lipophilicity exhibited by these compounds. In this work we analyzed CBD- and THC-loaded poly-ε-caprolactone microparticles as an alternative delivery system for long-term cannabinoid administration in a murine xenograft model of glioma. In vitro characterization of THC- and CBD-loaded microparticles showed that this method of microencapsulation facilitates a sustained release of the two cannabinoids for several days. Local administration of THC-, CBD- or a mixture (1:1 w:w of THC- and CBD-loaded microparticles every 5 days to mice bearing glioma xenografts reduced tumour growth with the same efficacy than a daily local administration of the equivalent amount of those cannabinoids in solution. Moreover, treatment with cannabinoid-loaded microparticles enhanced apoptosis and decreased cell proliferation and angiogenesis in these tumours. Our findings support that THC- and CBD-loaded microparticles could be used as an alternative method of cannabinoid delivery in anticancer therapies.

  10. Service systems concepts, modeling, and programming

    CERN Document Server

    Cardoso, Jorge; Poels, Geert

    2014-01-01

    This SpringerBrief explores the internal workings of service systems. The authors propose a lightweight semantic model for an effective representation to capture the essence of service systems. Key topics include modeling frameworks, service descriptions and linked data, creating service instances, tool support, and applications in enterprises.Previous books on service system modeling and various streams of scientific developments used an external perspective to describe how systems can be integrated. This brief introduces the concept of white-box service system modeling as an approach to mo

  11. Personality Factors Predicting Smartphone Addiction Predisposition: Behavioral Inhibition and Activation Systems, Impulsivity, and Self-Control.

    Directory of Open Access Journals (Sweden)

    Yejin Kim

    Full Text Available The purpose of this study was to identify personality factor-associated predictors of smartphone addiction predisposition (SAP. Participants were 2,573 men and 2,281 women (n = 4,854 aged 20-49 years (Mean ± SD: 33.47 ± 7.52; participants completed the following questionnaires: the Korean Smartphone Addiction Proneness Scale (K-SAPS for adults, the Behavioral Inhibition System/Behavioral Activation System questionnaire (BIS/BAS, the Dickman Dysfunctional Impulsivity Instrument (DDII, and the Brief Self-Control Scale (BSCS. In addition, participants reported their demographic information and smartphone usage pattern (weekday or weekend average usage hours and main use. We analyzed the data in three steps: (1 identifying predictors with logistic regression, (2 deriving causal relationships between SAP and its predictors using a Bayesian belief network (BN, and (3 computing optimal cut-off points for the identified predictors using the Youden index. Identified predictors of SAP were as follows: gender (female, weekend average usage hours, and scores on BAS-Drive, BAS-Reward Responsiveness, DDII, and BSCS. Female gender and scores on BAS-Drive and BSCS directly increased SAP. BAS-Reward Responsiveness and DDII indirectly increased SAP. We found that SAP was defined with maximal sensitivity as follows: weekend average usage hours > 4.45, BAS-Drive > 10.0, BAS-Reward Responsiveness > 13.8, DDII > 4.5, and BSCS > 37.4. This study raises the possibility that personality factors contribute to SAP. And, we calculated cut-off points for key predictors. These findings may assist clinicians screening for SAP using cut-off points, and further the understanding of SA risk factors.

  12. Personality Factors Predicting Smartphone Addiction Predisposition: Behavioral Inhibition and Activation Systems, Impulsivity, and Self-Control.

    Science.gov (United States)

    Kim, Yejin; Jeong, Jo-Eun; Cho, Hyun; Jung, Dong-Jin; Kwak, Minjung; Rho, Mi Jung; Yu, Hwanjo; Kim, Dai-Jin; Choi, In Young

    2016-01-01

    The purpose of this study was to identify personality factor-associated predictors of smartphone addiction predisposition (SAP). Participants were 2,573 men and 2,281 women (n = 4,854) aged 20-49 years (Mean ± SD: 33.47 ± 7.52); participants completed the following questionnaires: the Korean Smartphone Addiction Proneness Scale (K-SAPS) for adults, the Behavioral Inhibition System/Behavioral Activation System questionnaire (BIS/BAS), the Dickman Dysfunctional Impulsivity Instrument (DDII), and the Brief Self-Control Scale (BSCS). In addition, participants reported their demographic information and smartphone usage pattern (weekday or weekend average usage hours and main use). We analyzed the data in three steps: (1) identifying predictors with logistic regression, (2) deriving causal relationships between SAP and its predictors using a Bayesian belief network (BN), and (3) computing optimal cut-off points for the identified predictors using the Youden index. Identified predictors of SAP were as follows: gender (female), weekend average usage hours, and scores on BAS-Drive, BAS-Reward Responsiveness, DDII, and BSCS. Female gender and scores on BAS-Drive and BSCS directly increased SAP. BAS-Reward Responsiveness and DDII indirectly increased SAP. We found that SAP was defined with maximal sensitivity as follows: weekend average usage hours > 4.45, BAS-Drive > 10.0, BAS-Reward Responsiveness > 13.8, DDII > 4.5, and BSCS > 37.4. This study raises the possibility that personality factors contribute to SAP. And, we calculated cut-off points for key predictors. These findings may assist clinicians screening for SAP using cut-off points, and further the understanding of SA risk factors.

  13. On Verification Modelling of Embedded Systems

    NARCIS (Netherlands)

    Brinksma, Hendrik; Mader, Angelika H.

    Computer-aided verification of embedded systems hinges on the availability of good verification models of the systems at hand. Such models must be much simpler than full design models or specifications to be of practical value, because of the unavoidable combinatorial complexities in the

  14. Balmorel open source energy system model

    DEFF Research Database (Denmark)

    Wiese, Frauke; Bramstoft, Rasmus; Koduvere, Hardi

    2018-01-01

    As the world progresses towards a cleaner energy future with more variable renewable energy sources, energy system models are required to deal with new challenges. This article describes design, development and applications of the open source energy system model Balmorel, which is a result of a l...... transport of local biomass as part of the optimisation and speeding up the model....

  15. Modeling, Control and Coordination of Helicopter Systems

    CERN Document Server

    Ren, Beibei; Chen, Chang; Fua, Cheng-Heng; Lee, Tong Heng

    2012-01-01

    Modeling, Control and Coordination of Helicopter Systems provides a comprehensive treatment of helicopter systems, ranging from related nonlinear flight dynamic modeling and stability analysis to advanced control design for single helicopter systems, and also covers issues related to the coordination and formation control of multiple helicopter systems to achieve high performance tasks. Ensuring stability in helicopter flight is a challenging problem for nonlinear control design and development. This book is a valuable reference on modeling, control and coordination of helicopter systems,providing readers with practical solutions for the problems that still plague helicopter system design and implementation. Readers will gain a complete picture of helicopters at the systems level, as well as a better understanding of the technical intricacies involved. This book also: Presents a complete picture of modeling, control and coordination for helicopter systems Provides a modeling platform for a general class of ro...

  16. Systems Biology—Biomedical Modeling

    OpenAIRE

    Sobie, Eric A.; Lee, Young-Seon; Jenkins, Sherry L.; Iyengar, Ravi

    2011-01-01

    Because of the complexity inherent in biological systems, many researchers frequently rely on a combination of global analysis and computational approaches to gain insight into both (i) how interacting components can produce complex system behaviors, and (ii) how changes in conditions may alter these behaviors. Because the biological details of a particular system are generally not taught along with the quantitative approaches that enable hypothesis generation and analysis of the system, we d...

  17. Modeling and simulation of systems using Matlab and Simulink

    CERN Document Server

    Chaturvedi, Devendra K

    2009-01-01

    Introduction to SystemsSystemClassification of SystemsLinear SystemsTime-Varying vs. Time-Invariant Systems Lumped vs. Distributed Parameter SystemsContinuous- and Discrete-Time Systems Deterministic vs. Stochastic Systems Hard and Soft Systems Analysis of Systems Synthesis of Systems Introduction to System Philosophy System Thinking Large and Complex Applied System Engineering: A Generic ModelingSystems ModelingIntroduction Need of System Modeling Modeling Methods for Complex Systems Classification of ModelsCharacteristics of Models ModelingMathematical Modeling of Physical SystemsFormulation of State Space Model of SystemsPhysical Systems Theory System Components and Interconnections Computation of Parameters of a Component Single Port and Multiport Systems Techniques of System Analysis Basics of Linear Graph Theoretic ApproachFormulation of System Model for Conceptual SystemFormulation System Model for Physical SystemsTopological RestrictionsDevelopment of State Model of Degenerative SystemSolution of Stat...

  18. Modelling and Verification of Relay Interlocking Systems

    DEFF Research Database (Denmark)

    Haxthausen, Anne Elisabeth; Bliguet, Marie Le; Kjær, Andreas

    2010-01-01

    This paper describes how relay interlocking systems as used by the Danish railways can be formally modelled and verified. Such systems are documented by circuit diagrams describing their static layout. It is explained how to derive a state transition system model for the dynamic behaviour of a re...

  19. Compositional Modelling of Stochastic Hybrid Systems

    NARCIS (Netherlands)

    Strubbe, S.N.

    2005-01-01

    In this thesis we present a modelling framework for compositional modelling of stochastic hybrid systems. Hybrid systems consist of a combination of continuous and discrete dynamics. The state space of a hybrid system is hybrid in the sense that it consists of a continuous component and a discrete

  20. Inhibition of soluble epoxide hydrolase attenuates high-fat-diet-induced hepatic steatosis by reduced systemic inflammatory status in mice.

    Directory of Open Access Journals (Sweden)

    Yan Liu

    Full Text Available Non-alcoholic fatty liver disease is associated with obesity and considered an inflammatory disease. Soluble epoxide hydrolase (sEH is a major enzyme hydrolyzing epoxyeicosatrienoic acids and attenuates their cardiovascular protective and anti-inflammatory effects. We examined whether sEH inhibition can protect against high-fat (HF-diet-induced fatty liver in mice and the underlying mechanism. Compared with wild-type littermates, sEH-null mice showed lower diet-induced lipid accumulation in liver, as seen by Oil-red O staining and triglycerides levels. We studied the effect of sEH inhibition on diet-induced fatty liver by feeding C57BL/6 mice an HF diet for 8 weeks (short-term or 16 weeks (long-term and administering t-AUCB, a selective sEH inhibitor. sEH inhibition had no effect on the HF-diet-increased body and adipose tissue weight or impaired glucose tolerance but alleviated the diet-induced hepatic steatosis. Adenovirus-mediated overexpression of sEH in liver increased the level of triglycerides in liver and the hepatic inflammatory response. Surprisingly, the induced expression of sEH in liver occurred only with the long-term but not short-term HF diet, which suggests a secondary effect of HF diet on regulating sEH expression. Furthermore, sEH inhibition attenuated the HF-diet-induced increase in plasma levels of proinflammatory cytokines and their mRNA upregulation in adipose tissue, which was accompanied by increased macrophage infiltration. Therefore, sEH inhibition could alleviate HF-diet-induced hepatic steatosis, which might involve its anti-inflammatory effect in adipose tissue and direct inhibition in liver. sEH may be a therapeutic target for HF-diet-induced hepatic steatosis in inhibiting systemic inflammation.

  1. Models of complex attitude systems

    DEFF Research Database (Denmark)

    Sørensen, Bjarne Taulo

    Existing research on public attitudes towards agricultural production systems is largely descriptive, abstracting from the processes through which members of the general public generate their evaluations of such systems. The present paper adopts a systems perspective on such evaluations, understa......Existing research on public attitudes towards agricultural production systems is largely descriptive, abstracting from the processes through which members of the general public generate their evaluations of such systems. The present paper adopts a systems perspective on such evaluations......, understanding them as embedded into a wider attitude system that consists of attitudes towards objects of different abstraction levels, ranging from personal value orientations over general socio-political attitudes to evaluations of specific characteristics of agricultural production systems. It is assumed...... that evaluative affect propagates through the system in such a way that the system becomes evaluatively consistent and operates as a schema for the generation of evaluative judgments. In the empirical part of the paper, the causal structure of an attitude system from which people derive their evaluations of pork...

  2. The Metalloporphyrin Antioxidant, MnTE-2-PyP, Inhibits Th2 Cell Immune Responses in an Asthma Model

    Directory of Open Access Journals (Sweden)

    Paiboon Jungsuwadee

    2012-08-01

    Full Text Available MnTE-2-PyP, a superoxide dismutase mimetic, inhibited OVA-induced airway inflammation in mice suggesting an effect on Th2 responsiveness. Thus, we hypothesized that MnTE-2-PyP may alter dendritic cell-Th2 interactions. Bone marrow derived dendritic cells (DC and OVA323-339-specific Th2 cells were cultured separately in the presence or absence of MnTE-2-PyP for 3 days prior to the co-culturing of the two cell types in the presence of an OVA323-339 peptide and in some cases stimulated with CD3/CD28. MnTE-2-PyP-pretreated DC inhibited IL-4, IL-5 and IFNγ production and inhibited Th2 cell proliferation in the DC-Th2 co-culturing system in the presence of the OVA323-339 peptide. Similar results were obtained using the CD3/CD28 cell-activation system; the addition of MnTE-2-PyP inhibited Th2 cell proliferation. MnTE-2-PyP suppressed CD25 expression on OVA-specific Th2 cells, which implied that MnTE-2-PyP can inhibit the activation of Th2 cells. MnTE-2-PyP also down-regulated co-stimulatory molecules: CD40, CD80 and CD86 on immature DC. Our studies suggest that the major mechanism by which MnTE-2-PyP inhibits airway inflammation is by acting on the DC and suppressing Th2 cell proliferation and activation.

  3. Inhibition of mirtazapine metabolism by Ecstasy (MDMA) in isolated perfused rat liver model.

    Science.gov (United States)

    Jamshidfar, Sanaz; Ardakani, Yalda H; Lavasani, Hoda; Rouini, Mohammadreza

    2017-06-28

    Nowadays MDMA (3,4-methylendioxymethamphetamine), known as ecstasy, is widely abused among the youth because of euphoria induction in acute exposure. However, abusers are predisposed to depression in chronic consumption of this illicit compound. Mirtazapine (MRZ), an antidepressant agent, may be prescribed in MDMA-induced depression. MRZ is extensively metabolized in liver by CYP450 isoenzymes. 8-hydroxymirtazapine (8-OH) is mainly produced by CYP2D6. N-desmethylmirtazapine (NDES) is generated by CYP3A4. MDMA is also metabolized by the mentioned isoenzymes and demonstrates mechanism-based inhibition (MBI) in association with CYP2D6. Several studies revealed that MDMA showed inhibitory effects on CYP3A4. In the present study, our aim was to evaluate the impact of MDMA on the metabolism of MRZ in liver. Therefore, isolated perfused rat liver model was applied as our model of choice in this assessment. The subjects of the study were categorized into two experimental groups. Rats in the control group received MRZ-containing Krebs-Henselit buffer (1 μg/ml). Rats in the treatment group received aqueous solution of 1 mg/ml MDMA (3 mg/kg) intraperitoneally 1 hour before receiving MRZ. Perfusate samples were analyzed by HPLC. Analyses of perfusate samples showed 80% increase in the parent drug concentrations and 50% decrease in the concentrations of both metabolites in our treatment group compared to the control group. In the treatment group compared to the control group, AUC (0-120) of the parent drug demonstrated 50% increase and AUC (0-120) of 8-OH and NDES showed 70% and 60% decrease, respectively. Observed decrease in metabolic ratios were 83% and 79% for 8-OH and NDES in treatment group compared to control group, respectively. Hepatic clearance (CL h ) and intrinsic clearance (Cl int ) showed 20% and 60% decrease in treatment group compared to control group. All findings prove the inhibitory effects of ecstasy on both CYP2D6 and CYP3A4 hepatic isoenzymes. In

  4. Pharmacological inhibition of GSK-3 in a guinea pig model of LPS-induced pulmonary inflammation: II. Effects on skeletal muscle atrophy.

    Science.gov (United States)

    Verhees, Koen J P; Pansters, Nicholas A M; Baarsma, Hoeke A; Remels, Alexander H V; Haegens, Astrid; de Theije, Chiel C; Schols, Annemie M W J; Gosens, Reinoud; Langen, Ramon C J

    2013-11-01

    Chronic obstructive pulmonary disease (COPD) is accompanied by pulmonary inflammation and associated with extra-pulmonary manifestations, including skeletal muscle atrophy. Glycogen synthase kinase-3 (GSK-3) has been implicated in the regulation of muscle protein- and myonuclear turnover; two crucial processes that determine muscle mass. In the present study we investigated the effect of the selective GSK-3 inhibitor SB216763 on muscle mass in a guinea pig model of lipopolysaccharide (LPS)-induced pulmonary inflammation-associated muscle atrophy. Guinea pigs were pretreated with either intranasally instilled SB216763 or corresponding vehicle prior to each LPS/saline challenge twice weekly. Pulmonary inflammation was confirmed and indices of muscle mass were determined after 12 weeks. Additionally, cultured skeletal muscle cells were incubated with tumor necrosis factor α (TNF-α) or glucocorticoids (GCs) to model the systemic effects of pulmonary inflammation on myogenesis, in the presence or absence of GSK-3 inhibitors. Repeated LPS instillation induced muscle atrophy based on muscle weight and muscle fiber cross sectional area. Intriguingly, GSK-3 inhibition using SB216763 prevented the LPS-induced muscle mass decreases and myofiber atrophy. Indices of protein turnover signaling were unaltered in guinea pig muscle. Interestingly, inhibition of myogenesis of cultured muscle cells by TNF-α or synthetic GCs was prevented by GSK-3 inhibitors. In a guinea pig model of LPS-induced pulmonary inflammation, GSK-3 inhibition prevents skeletal muscle atrophy without affecting pulmonary inflammation. Resistance to inflammation- or GC-induced impairment of myogenic differentiation, imposed by GSK-3 inhibition, suggests that sustained myogenesis may contribute to muscle mass maintenance despite persistent pulmonary inflammation. Collectively, these results warrant further exploration of GSK-3 as a potential novel drug target to prevent or reverse muscle wasting in COPD.

  5. Modeling Control Situations in Power System Operations

    DEFF Research Database (Denmark)

    Saleem, Arshad; Lind, Morten; Singh, Sri Niwas

    2010-01-01

    Increased interconnection and loading of the power system along with deregulation has brought new challenges for electric power system operation, control and automation. Traditional power system models used in intelligent operation and control are highly dependent on the task purpose. Thus, a model...... of explicit principles for model construction. This paper presents a work on using explicit means-ends model based reasoning about complex control situations which results in maintaining consistent perspectives and selecting appropriate control action for goal driven agents. An example of power system...... for intelligent operation and control must represent system features, so that information from measurements can be related to possible system states and to control actions. These general modeling requirements are well understood, but it is, in general, difficult to translate them into a model because of the lack...

  6. Reduced GABAergic inhibition explains cortical hyperexcitability in the wobbler mouse model of ALS

    DEFF Research Database (Denmark)

    Nieto-Gonzalez, Jose Luis; Moser, Jakob; Lauritzen, Martin

    2011-01-01

    underlie this dysfunction. Here, we studied the GABAergic system in cortex using patch-clamp recordings in the wobbler mouse, a model of ALS. In layer 5 pyramidal neurons of motor cortex, the frequency of GABA(A) receptor-mediated spontaneous inhibitory postsynaptic currents was reduced by 72% in wobbler......Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of the central nervous system. Symptomatic and presymptomatic ALS patients demonstrate cortical hyperexcitability, which raises the possibility that alterations in inhibitory gamma-aminobutyric acid (GABA)ergic system could...... interneurons and reduced vesicular GABA transporter immunoreactivity in the neuropil. Finally, we observed an increased input resistance and excitability of wobbler excitatory neurons, which could be explained by lack of GABA(A) receptor-mediated influences. In conclusion, we demonstrate decreases in GABAergic...

  7. Inhibition of soluble epoxide hydrolase reduces LPS-induced thermal hyperalgesia and mechanical allodynia in a rat model of inflammatory pain

    Science.gov (United States)

    Inceoglu, Bora; Jinks, Steven L.; Schmelzer, Kara R.; Waite, Troy; Kim, In Hae; Hammock, Bruce D.

    2007-01-01

    Soluble epoxide hydrolases catalyze the hydrolysis of epoxides in acyclic systems. In man this enzyme is the product of a single copy gene (EPXH-2) present on chromosome 8. The human sEH is of interest due to emerging roles of its endogenous substrates, epoxygenated fatty acids, in inflammation and hypertension. One of the consequences of inhibiting sEH in rodent inflammation models is a profound decrease in the production of pro-inflammatory and proalgesic lipid metabolites including prostaglandins. This prompted us to hypothesize that sEH inhibitors may have antinociceptive properties. Here we tested if sEH inhibitors can reduce inflammatory pain. Hyperalgesia was induced by intraplantar LPS injection and sEH inhibitors were delivered topically. We found that two structurally dissimilar but equally potent sEH inhibitors can be delivered through the transdermal route and that sEH inhibitors effectively attenuate thermal hyperalgesia and mechanical allodynia in rats treated with LPS. In addition we show that epoxydized arachidonic acid metabolites, EETs, are also effective in attenuating thermal hyperalgesia in this model. In parallel with the observed biological activity metabolic analysis of oxylipids showed that inhibition of sEH resulted with a decrease in PGD2 levels and sEH generated degradation products of linoleic and arachidonic acid metabolites with a concomitant increase in epoxides of linoleic acid. These data show that inhibition of sEH may become a viable therapeutic strategy to attain analgesia. PMID:16962614

  8. Zinc metalloproteinase ZmpC suppresses experimental pneumococcal meningitis by inhibiting bacterial invasion of central nervous systems.

    Science.gov (United States)

    Yamaguchi, Masaya; Nakata, Masanobu; Sumioka, Ryuichi; Hirose, Yujiro; Wada, Satoshi; Akeda, Yukihiro; Sumitomo, Tomoko; Kawabata, Shigetada

    2017-11-17

    Streptococcus pneumoniae is a leading cause of bacterial meningitis. Here, we investigated whether pneumococcal paralogous zinc metalloproteases contribute to meningitis onset. Findings of codon-based phylogenetic analyses indicated 3 major clusters in the Zmp family; ZmpA, ZmpC, and ZmpB, with ZmpD as a subgroup. In vitro invasion assays of human brain microvascular endothelial cells (hBMECs) showed that deletion of the zmpC gene in S. pneumoniae strain TIGR4 significantly increased bacterial invasion into hBMECs, whereas deletion of either zmpA or zmpB had no effect. In a mouse meningitis model, the zmpC deletion mutant exhibited increased invasion of the brain and was associated with increased matrix metalloproteinase-9 in plasma and mortality as compared with the wild type. We concluded that ZmpC suppresses pneumococcal virulence by inhibiting bacterial invasion of the central nervous system. Furthermore, ZmpC illustrates the evolutional theory stating that gene duplication leads to acquisition of novel function to suppress excessive mortality.

  9. Pharmacological Inhibition of PKCθ Counteracts Muscle Disease in a Mouse Model of Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    V. Marrocco

    2017-02-01

    Research in context: Duchenne muscular dystrophy (DMD is a severe muscle disease affecting 1:3500 male births. DMD is caused by a mutation in dystrophin gene, coding for a protein required for skeletal and cardiac muscle integrity. Lack of a functional dystrophin is primarily responsible for the muscle eccentric contraction-induced muscle damage, observed in dystrophic muscle. However, inflammation plays a considerable role in the progression of DMD. Glucocorticoids, which have anti-inflammatory properties, are being used to treat DMD with some success; however, long term treatment with these drugs induces muscle atrophy and wasting, outweighing their benefit. The identification of specific targets for anti-inflammatory therapies is one of the ongoing therapeutic options. Although blunting inflammation would not be a “cure” for the disease, the emerging clue is that multiple strategies, addressing different aspects of the pathology, which may eventually converge, may be successful. In this context, we previously showed that genetic ablation of Protein Kinase C θ (PKCθ, an enzyme known to be involved in immune response, in mdx, the mouse model of DMD, improves muscle healing and regeneration, preventing massive inflammation. To establish whether pharmacological targeting of PKCθ in DMD can be proposed as a therapeutic option, in this study we treated young mdx mice with the PKCθ inhibitor Compound 20 (C20. We show that C20 treatment led to a significant reduction in muscle damage associated with reduced immune cells infiltration, reduced inflammatory pathways activation, and maintained muscle regeneration. Importantly, C20 treatment is efficient in recovering muscle performance in mdx mice, by preserving muscle integrity. Together, these results provide proof of principle that pharmacological inhibition of PKCθ in DMD can be considered an attractive strategy to modulate immune response and prevent the progression of the disease.

  10. Brominated indoles from a marine mollusc inhibit inflammation in a murine model of acute lung injury.

    Directory of Open Access Journals (Sweden)

    Tarek B Ahmad

    Full Text Available New drug leads for the treatment of inflammation are urgently needed. Marine molluscs are widely used as traditional medicines for the treatment of inflammation. Here we report the positive effects of a hypobranchial gland (HBG extract and the dominant bioactive compound 6-bromoisatin from the Muricidae mollusc Dicathais orbita, for reducing lipopolysaccharide (LPS induced acute lung inflammation in a mouse model. Both 6-bromoisatin and the HBG extract suppressed the inflammatory response in mice that were pre-treated by oral gavage at 48, 24 and 1 h prior to LPS infusion. The inflammatory antagonists were tested at concentrations of 0.5 mg/g and 0.1 mg/g HBG extract and 0.1 mg/g and 0.05 mg/g 6-bromoisatin in carrier oil and all treatments reduced inflammation as indicated by a significant suppression of inflammatory markers present in bronchoalveolar lavage fluid (BALF, in comparison to LPS induced positive control mice administered the carrier oil alone (p < 0.0001. Tumour necrosis factor-alpha (TNFα and interleukin-1 beta (IL-1β levels, in addition to total protein concentration were all significantly reduced in BALF from mice treated with the extract or 6-bromoisatin. Furthermore, all treatment groups showed significant reductions in neutrophil sequestration and preservation of the lung tissue architecture compared to the positive control (p < 0.0001. The combined results from this study and our previous in vitro studies indicate that 6-bromoisatin in the HGB extracts inhibit the activation of inflammatory signalling pathway. The results from this study further confirm that the HBG extract from Muricidae molluscs and 6-bromoisatin are bioavailable and effective in vivo, thus have potential for development as natural therapeutic agents for inflammation.

  11. Tenomodulin Inhibits Retinal Neovascularization in a Mouse Model of Oxygen-Induced Retinopathy

    Directory of Open Access Journals (Sweden)

    Tatsuhiko Sato

    2012-11-01

    Full Text Available We aimed to determine the anti-angiogenic effect of tenomodulin (TeM on retinal neovascularization in an oxygen-induced retinopathy (OIR mouse model. OIR was induced in C57BL/6 mice by exposing seven-day-old mice to 75% oxygen for five days followed by room air for five days. Control mice were exposed to room air from birth until postnatal day 17. Mice received intravitreal injections of 1 μg of TeM in one eye and PBS in the contralateral eye at P7 before being exposed to 75% oxygen. Eyes were collected at postnatal day 17. Retinal blood vessel patterns were visualized by fluorescein angiography. We quantified the number of neovascular nuclei that were present beyond the inner limiting membrane (ILM using histological methods with a masked approach. Furthermore, double immunohistochemical staining of TeM was performed on retinas to identify nuclei protruding into the vitreous cavity. Western blot was used to detect exogenous TeM protein. The central nonperfusion area (NPA, mm2 of TeM-injected eyes was significantly different from that of OIR and PBS-injected eyes, and the number of nuclei in new blood vessels breaking through the ILM in each retinal cross-section significantly differed from that of OIR eyes and PBS-injected control eyes. Cellular nuclei of new blood vessels protruding into the vitreous cavity were also observed in TeM-injected retinas by immunohistochemistry. Western blotting revealed a 16-kDa immunoreactive protein, indicating incorporation of an exogenous TeM fragment into the retina. Our data shows that TeM can effectively inhibit pathological angiogenesis in mouse eyes; indicating its potential role in prevention and treatment of ocular neovascularization.

  12. Holonic Models for Traffic Control Systems

    Science.gov (United States)

    Ciufudean, Calin; Filote, Constantin

    This paper proposes a new time-placed net model for traffic control systems, respectively railway control traffic systems. This model can be interpreted as a holonic one, and contains three modules: Transport Planning Module, Transport Control Module and Priority Control Module. For railway traffic systems we introduce a strategy in a timed-place Petri net model to solve collision and traffic jam problems.

  13. Hydrological modeling in forested systems

    Science.gov (United States)

    H.E. Golden; G.R. Evenson; S. Tian; Devendra Amatya; Ge Sun

    2015-01-01

    Characterizing and quantifying interactions among components of the forest hydrological cycle is complex and usually requires a combination of field monitoring and modelling approaches (Weiler and McDonnell, 2004; National Research Council, 2008). Models are important tools for testing hypotheses, understanding hydrological processes and synthesizing experimental data...

  14. Evaluation and comparison of 3D-QSAR CoMSIA models for CDK1, CDK5, and GSK-3 inhibition by paullones

    DEFF Research Database (Denmark)

    Kunick, Conrad; Lauenroth, Kathrin; Wieking, Karen

    2004-01-01

    With a view to the rational design of selective GSK-3beta inhibitors, 3D-QSAR CoMSIA models were developed for the inhibition of the three serine/threonine kinases CDK1/cyclin B, CDK5/p25, and GSK-3beta by compounds from the paullone inhibitor family. The models are based on the kinase inhibition...

  15. Life-Cycle Models for Survivable Systems

    National Research Council Canada - National Science Library

    Linger, Richard

    2002-01-01

    .... Current software development life-cycle models are not focused on creating survivable systems, and exhibit shortcomings when the goal is to develop systems with a high degree of assurance of survivability...

  16. Model Updating Nonlinear System Identification Toolbox Project

    Data.gov (United States)

    National Aeronautics and Space Administration — ZONA Technology (ZONA) proposes to develop an enhanced model updating nonlinear system identification (MUNSID) methodology that utilizes flight data with...

  17. An expert system for dispersion model interpretation

    International Nuclear Information System (INIS)

    Skyllingstad, E.D.; Ramsdell, J.V.

    1988-10-01

    A prototype expert system designed to diagnose dispersion model uncertainty is described in this paper with application to a puff transport model. The system obtains qualitative information from the model user and through an expert-derived knowledge base, performs a rating of the current simulation. These results can then be used in combination with dispersion model output for deciding appropriate evacuation measures. Ultimately, the goal of this work is to develop an expert system that may be operated accurately by an individual uneducated in meteorology or dispersion modeling. 5 refs., 3 figs

  18. Semantic models for adaptive interactive systems

    CERN Document Server

    Hussein, Tim; Lukosch, Stephan; Ziegler, Jürgen; Calvary, Gaëlle

    2013-01-01

    Providing insights into methodologies for designing adaptive systems based on semantic data, and introducing semantic models that can be used for building interactive systems, this book showcases many of the applications made possible by the use of semantic models.Ontologies may enhance the functional coverage of an interactive system as well as its visualization and interaction capabilities in various ways. Semantic models can also contribute to bridging gaps; for example, between user models, context-aware interfaces, and model-driven UI generation. There is considerable potential for using

  19. Models of the venous system

    DEFF Research Database (Denmark)

    Mehlsen, J

    2000-01-01

    of the venous system require at least three elements: a resistor, a capacitor and an inductor, with the latter being of more importance in the venous than in the arterial system. Non-linearities must be considered in pressure/flow relations in the small venules, during venous collapse, or low flow conditions...

  20. Stochastic Models of Polymer Systems

    Science.gov (United States)

    2016-01-01

    published in non-peer-reviewed journals (N/A for none) The dynamics of stochastic gradient algorithms (submitted); Noisy Hegselmann- Krause Systems...algorithms for big data applications. (2) We studied stochastic dynamics of polymer systems in the mean field limit. (3) We studied noisy Hegselmann- Krause

  1. CaSO4 Scale Inhibition by a Trace Amount of Zinc Ion in Piping System

    Science.gov (United States)

    Mangestiyono, W.; Sutrisno

    2017-05-01

    Usually, a small steam generator is not complemented by equipment such as demineralization and chlorination process apparatus since the economic aspect was a precedence. Such phenomenon was uncovered in a case study of green tea industrial process in which the boiler capacity was not more than 1 ton/hour. The operation of the small boiler affected the scaling process in its piping system. In a year operation, there was already a large scale of calcium attached to the inner surface of the pipe. Such large scale formed a layer and decreased the overall heat transfer coefficient, prolonged the process time and decreased the production. The aim of the current research was to solve the problem through a laboratory research to inhibit the CaSO4 scale formation by the addition of trace amounts of zinc ion. This research was conducted through a built in-house experimental rig which consisted of a dosing pump for controlling the flow rate and a thermocouple to control the temperature. Synthesis solution was prepared with 3,500 ppm concentration of CaCl2 and Na2SO4. The concentration of zinc was set at 0.00; 5.00 and 10.00 ppm. The data found were characterized by scanning electron microscopy (SEM) to analyze crystal polymorph as the influence of zinc ion addition. The induction time was also investigated to analyze the nucleation time, and it was found on the 9th, 13th, and 19th minute of the zinc ion addition of 0.00, 5.00 and 10.00 ppm. After running for a four-hour duration, the scale grow-rate was found to be 5.799; 5.501 and 4.950 × 10-3 gr/min for 0.00; 5.00 and 10.00 ppm of zinc addition at 50 °C.

  2. Switching model photovoltaic pumping system

    Science.gov (United States)

    Anis, Wagdy R.; Abdul-Sadek Nour, M.

    Photovoltaic (PV) pumping systems are widely used due to their simplicity, high reliability and low cost. A directly-coupled PV pumping system is the most reliable and least-cost PV system. The d.c. motor-pump group is not, however, working at its optimum operating point. A battery buffered PV pumping system introduces a battery between the PV array and the d.c. motor-pump group to ensure that the motor-pump group is operating at its optimum point. The size of the battery storage depends on system economics. If the battery is fully charged while solar radiation is available, the battery will discharge through the load while the PV array is disconnected. Hence, a power loss takes place. To overcome the above mentioned difficulty, a switched mode PV pumping is proposed. When solar radiation is available and the battery is fully charged, the battery is disconnected and the d.c. motor-pump group is directly coupled to the PV array. To avoid excessive operating voltage for the motor, a part of the PV array is switched off to reduce the voltage. As a result, the energy loss is significantly eliminated. Detailed analysis of the proposed system shows that the discharged water increases by about 10% when compared with a conventional battery-buffered system. The system transient performance just after the switching moment shows that the system returns to a steady state in short period. The variations in the system parameters lie within 1% of the rated values.

  3. Multiple system modelling of waste management

    International Nuclear Information System (INIS)

    Eriksson, Ola; Bisaillon, Mattias

    2011-01-01

    Highlights: → Linking of models will provide a more complete, correct and credible picture of the systems. → The linking procedure is easy to perform and also leads to activation of project partners. → The simulation procedure is a bit more complicated and calls for the ability to run both models. - Abstract: Due to increased environmental awareness, planning and performance of waste management has become more and more complex. Therefore waste management has early been subject to different types of modelling. Another field with long experience of modelling and systems perspective is energy systems. The two modelling traditions have developed side by side, but so far there are very few attempts to combine them. Waste management systems can be linked together with energy systems through incineration plants. The models for waste management can be modelled on a quite detailed level whereas surrounding systems are modelled in a more simplistic way. This is a problem, as previous studies have shown that assumptions on the surrounding system often tend to be important for the conclusions. In this paper it is shown how two models, one for the district heating system (MARTES) and another one for the waste management system (ORWARE), can be linked together. The strengths and weaknesses with model linking are discussed when compared to simplistic assumptions on effects in the energy and waste management systems. It is concluded that the linking of models will provide a more complete, correct and credible picture of the consequences of different simultaneous changes in the systems. The linking procedure is easy to perform and also leads to activation of project partners. However, the simulation procedure is a bit more complicated and calls for the ability to run both models.

  4. Modeling of power electronic systems with EMTP

    Science.gov (United States)

    Tam, Kwa-Sur; Dravid, Narayan V.

    1989-01-01

    In view of the potential impact of power electronics on power systems, there is need for a computer modeling/analysis tool to perform simulation studies on power systems with power electronic components as well as to educate engineering students about such systems. The modeling of the major power electronic components of the NASA Space Station Freedom Electric Power System is described along with ElectroMagnetic Transients Program (EMTP) and it is demonstrated that EMTP can serve as a very useful tool for teaching, design, analysis, and research in the area of power systems with power electronic components. EMTP modeling of power electronic circuits is described and simulation results are presented.

  5. System Level Modelling and Performance Estimation of Embedded Systems

    DEFF Research Database (Denmark)

    Tranberg-Hansen, Anders Sejer

    The advances seen in the semiconductor industry within the last decade have brought the possibility of integrating evermore functionality onto a single chip forming functionally highly advanced embedded systems. These integration possibilities also imply that as the design complexity increases, so...... an efficient system level design methodology, a modelling framework for performance estimation and design space exploration at the system level is required. This thesis presents a novel component based modelling framework for system level modelling and performance estimation of embedded systems. The framework...... is performed by having the framework produce detailed quantitative information about the system model under investigation. The project is part of the national Danish research project, Danish Network of Embedded Systems (DaNES), which is funded by the Danish National Advanced Technology Foundation. The project...

  6. Network model of security system

    Directory of Open Access Journals (Sweden)

    Adamczyk Piotr

    2016-01-01

    Full Text Available The article presents the concept of building a network security model and its application in the process of risk analysis. It indicates the possibility of a new definition of the role of the network models in the safety analysis. Special attention was paid to the development of the use of an algorithm describing the process of identifying the assets, vulnerability and threats in a given context. The aim of the article is to present how this algorithm reduced the complexity of the problem by eliminating from the base model these components that have no links with others component and as a result and it was possible to build a real network model corresponding to reality.

  7. Significant inhibition of Tembusu virus envelope and NS5 gene using an adenovirus-mediated short hairpin RNA delivery system.

    Science.gov (United States)

    Wang, Hongzhi; Feng, Qiang; Wei, Lei; Zhuo, Liling; Chen, Hao; Diao, Youxiang; Tang, Yi

    2017-10-01

    Tembusu virus (TMUV) is a mosquito-borne flavivirus, which was first isolated in the tropics during the 1970s. Recently, a disease characterized by ovarian haemorrhage and neurological symptoms was observed in ducks in China, which threatens poultry production. However, there is no suitable vaccination strategy or effective antiviral drugs to combat TMUV infections. Consequently, there is an urgent need to develop a new anti-TMUV therapy. In this study, we report an efficient short hairpin RNA (shRNA) delivery strategy for the inhibition of TMUV production using an adenovirus vector system. Using specifically designed shRNAs based on the E and NS5 protein genes of TMUV, the vector-expressed viral genes, TMUV RNA replication and infectious virus production were downregulated at different levels in Vero cells, where the shRNA (NS52) was highly effective in inhibiting TMUV. Using the human adenovirus type 5 shRNA delivery system, the recombinant adenovirus (rAd-NS52) inhibited TMUV multiplication with high efficiency. Furthermore, the significant dose-dependent inhibition of viral RNA copies induced by rAd-NS52 was found in TMUV-infected cells, which could last for at least 96h post infection. Our results indicated that the adenovirus-mediated delivery of shRNAs could play an active role in future TMUV antiviral therapeutics. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Inhibition kinetics of lipid oxidation of model foods by using antioxidant extract of fermented soybeans.

    Science.gov (United States)

    Wardhani, Dyah H; Fuciños, Pablo; Vázquez, José A; Pandiella, Severino S

    2013-08-15

    Fermentation by using Aspergillus oryzae has been reported to increase antioxidant activity of soybeans significantly. The effectiveness of the extract from fermented soybeans was studied in 3 model foods with different complexities, i.e., linoleic acid emulsion, sunflower oil emulsions and bulk sunflower oil. For the emulsion systems, oxidation at two different pH values (4.5 and 7) was also compared. A reparameterised logistic equation was used to describe and to predict the experimental data. In general, a good agreement between experimental trends and simulated data from the model was found. A crude antioxidant extract (5 mg/g) showed a comparable antioxidant activity to 0.26 mg/g of butylated hydroxytoluene (BHT) in the linoleic acid emulsions. The extract exhibited a better capability to retard primary products in the linoleic acid systems than the secondary products. The opposite effect was observed in the bulk sunflower oil and its emulsion systems. Copyright © 2013 Elsevier Ltd. All rights reserved.

  9. Modeling Adaptive Behavior for Systems Design

    DEFF Research Database (Denmark)

    Rasmussen, Jens

    1994-01-01

    Field studies in modern work systems and analysis of recent major accidents have pointed to a need for better models of the adaptive behavior of individuals and organizations operating in a dynamic and highly competitive environment. The paper presents a discussion of some key characteristics...... of the predictive models required for the design of work supports systems, that is,information systems serving as the human-work interface. Three basic issues are in focus: 1.) Some fundamental problems in analysis and modeling modern dynamic work systems caused by the adaptive nature of human behavior; 2.......) The basic difference between the models of system functions used in engineering and design and those evolving from basic research within the various academic disciplines and finally 3.) The models and methods required for closed-loop, feedback system design....

  10. Model-based version management system framework

    International Nuclear Information System (INIS)

    Mehmood, W.

    2016-01-01

    In this paper we present a model-based version management system. Version Management System (VMS) a branch of software configuration management (SCM) aims to provide a controlling mechanism for evolution of software artifacts created during software development process. Controlling the evolution requires many activities to perform, such as, construction and creation of versions, identification of differences between versions, conflict detection and merging. Traditional VMS systems are file-based and consider software systems as a set of text files. File based VMS systems are not adequate for performing software configuration management activities such as, version control on software artifacts produced in earlier phases of the software life cycle. New challenges of model differencing, merge, and evolution control arise while using models as central artifact. The goal of this work is to present a generic framework model-based VMS which can be used to overcome the problem of tradition file-based VMS systems and provide model versioning services. (author)

  11. Very Large System Dynamics Models - Lessons Learned

    Energy Technology Data Exchange (ETDEWEB)

    Jacob J. Jacobson; Leonard Malczynski

    2008-10-01

    This paper provides lessons learned from developing several large system dynamics (SD) models. System dynamics modeling practice emphasize the need to keep models small so that they are manageable and understandable. This practice is generally reasonable and prudent; however, there are times that large SD models are necessary. This paper outlines two large SD projects that were done at two Department of Energy National Laboratories, the Idaho National Laboratory and Sandia National Laboratories. This paper summarizes the models and then discusses some of the valuable lessons learned during these two modeling efforts.

  12. Test-driven modeling of embedded systems

    DEFF Research Database (Denmark)

    Munck, Allan; Madsen, Jan

    2015-01-01

    To benefit maximally from model-based systems engineering (MBSE) trustworthy high quality models are required. From the software disciplines it is known that test-driven development (TDD) can significantly increase the quality of the products. Using a test-driven approach with MBSE may have...... a similar positive effect on the quality of the system models and the resulting products and may therefore be desirable. To define a test-driven model-based systems engineering (TD-MBSE) approach, we must define this approach for numerous sub disciplines such as modeling of requirements, use cases......, scenarios, behavior, architecture, etc. In this paper we present a method that utilizes the formalism of timed automatons with formal and statistical model checking techniques to apply TD-MBSE to the modeling of system architecture and behavior. The results obtained from applying it to an industrial case...

  13. Precipitation-runoff modeling system; user's manual

    Science.gov (United States)

    Leavesley, G.H.; Lichty, R.W.; Troutman, B.M.; Saindon, L.G.

    1983-01-01

    The concepts, structure, theoretical development, and data requirements of the precipitation-runoff modeling system (PRMS) are described. The precipitation-runoff modeling system is a modular-design, deterministic, distributed-parameter modeling system developed to evaluate the impacts of various combinations of precipitation, climate, and land use on streamflow, sediment yields, and general basin hydrology. Basin response to normal and extreme rainfall and snowmelt can be simulated to evaluate changes in water balance relationships, flow regimes, flood peaks and volumes, soil-water relationships, sediment yields, and groundwater recharge. Parameter-optimization and sensitivity analysis capabilites are provided to fit selected model parameters and evaluate their individual and joint effects on model output. The modular design provides a flexible framework for continued model system enhancement and hydrologic modeling research and development. (Author 's abstract)

  14. An Empirical Model for Energy Storage Systems

    Energy Technology Data Exchange (ETDEWEB)

    Rosewater, David Martin [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Scott, Paul [TransPower, Poway, CA (United States)

    2016-03-17

    Improved models of energy storage systems are needed to enable the electric grid’s adaptation to increasing penetration of renewables. This paper develops a generic empirical model of energy storage system performance agnostic of type, chemistry, design or scale. Parameters for this model are calculated using test procedures adapted from the US DOE Protocol for Uniformly Measuring and Expressing the Performance of Energy Storage. We then assess the accuracy of this model for predicting the performance of the TransPower GridSaver – a 1 MW rated lithium-ion battery system that underwent laboratory experimentation and analysis. The developed model predicts a range of energy storage system performance based on the uncertainty of estimated model parameters. Finally, this model can be used to better understand the integration and coordination of energy storage on the electric grid.

  15. Brief History of Agricultural Systems Modeling

    Science.gov (United States)

    Jones, James W.; Antle, John M.; Basso, Bruno O.; Boote, Kenneth J.; Conant, Richard T.; Foster, Ian; Godfray, H. Charles J.; Herrrero, Mario; Howitt, Richard E.; Janssen, Sandor; hide

    2016-01-01

    Agricultural systems science generates knowledge that allows researchers to consider complex problems or take informed agricultural decisions. The rich history of this science exemplifies the diversity of systems and scales over which they operate and have been studied. Modeling, an essential tool in agricultural systems science, has been accomplished by scientists from a wide range of disciplines, who have contributed concepts and tools over more than six decades. As agricultural scientists now consider the next generation models, data, and knowledge products needed to meet the increasingly complex systems problems faced by society, it is important to take stock of this history and its lessons to ensure that we avoid re-invention and strive to consider all dimensions of associated challenges. To this end, we summarize here the history of agricultural systems modeling and identify lessons learned that can help guide the design and development of next generation of agricultural system tools and methods. A number of past events combined with overall technological progress in other fields have strongly contributed to the evolution of agricultural system modeling, including development of process-based bio-physical models of crops and livestock, statistical models based on historical observations, and economic optimization and simulation models at household and regional to global scales. Characteristics of agricultural systems models have varied widely depending on the systems involved, their scales, and the wide range of purposes that motivated their development and use by researchers in different disciplines. Recent trends in broader collaboration across institutions, across disciplines, and between the public and private sectors suggest that the stage is set for the major advances in agricultural systems science that are needed for the next generation of models, databases, knowledge products and decision support systems. The lessons from history should be considered

  16. MicroRNA-184-mediated inhibition of tumour growth in an orthotopic murine model of neuroblastoma.

    Science.gov (United States)

    Tivnan, Amanda; Foley, Niamh H; Tracey, Lorraine; Davidoff, Andrew M; Stallings, Raymond L

    2010-11-01

    Neuroblastoma is a paediatric cancer which originates from precursor cells of the sympathetic nervous system. Previous studies have shown that miR-184 expression has anti-proliferative effects in neuroblastoma cells grown in culture. Therefore, it was of interest to evaluate this effect in vivo. Neuroblastoma cells overexpressing miR-184 were injected retroperitoneally into CB17-SCID mice and tumour burden was assessed by measuring bioluminescence. Overall survival was also evaluated. Ectopic overexpression of miR-184 in neuroblastoma cell lines is anti-proliferative. In addition, overexpression of miR-184 led to a significant reduction in tumour growth relative to negative control-treated cohorts in a xenograft model of neuroblastoma. This study demonstrated for the first time that miR-184 significantly reduces tumour growth and increases overall survival in an orthotopic murine model of neuroblastoma through assessment of tumour growth and moribundity relative to control miRNA-treated cohorts.

  17. Formal Modeling and Analysis of Timed Systems

    DEFF Research Database (Denmark)

    Larsen, Kim Guldstrand; Niebert, Peter

    This book constitutes the thoroughly refereed post-proceedings of the First International Workshop on Formal Modeling and Analysis of Timed Systems, FORMATS 2003, held in Marseille, France in September 2003. The 19 revised full papers presented together with an invited paper and the abstracts...... of two invited talks were carefully selected from 36 submissions during two rounds of reviewing and improvement. All current aspects of formal method for modeling and analyzing timed systems are addressed; among the timed systems dealt with are timed automata, timed Petri nets, max-plus algebras, real......-time systems, discrete time systems, timed languages, and real-time operating systems....

  18. Grey Box Modelling of Hydrological Systems

    DEFF Research Database (Denmark)

    Thordarson, Fannar Ørn

    The main topic of the thesis is grey box modelling of hydrologic systems, as well as formulation and assessment of their embedded uncertainties. Grey box model is a combination of a white box model, a physically-based model that is traditionally formulated using deterministic ordinary differential...... the lack of fit in state space formulation, and further support decisions for a model expansion. By using stochastic differential equations to formulate the dynamics of the hydrological system, either the complexity of the model can be increased by including the necessary hydrological processes...... in the model, or formulation of process noise can be considered so that it meets the physical limits of the hydrological system and give an adequate description of the embedded uncertainty in model structure. The thesis consists of two parts: a summary report and a part which contains six scientific papers...

  19. The Guided System Development Framework: Modeling and Verifying Communication Systems

    DEFF Research Database (Denmark)

    Carvalho Quaresma, Jose Nuno; Probst, Christian W.; Nielson, Flemming

    2014-01-01

    . The Guided System Development framework contributes to more secure communication systems by aiding the development of such systems. The framework features a simple modelling language, step-wise refinement from models to implementation, interfaces to security verification tools, and code generation from...... the verified specification. The refinement process carries thus security properties from the model to the implementation. Our approach also supports verification of systems previously developed and deployed. Internally, the reasoning in our framework is based on the Beliefs and Knowledge tool, a verification...

  20. System Advisor Model: Flat Plate Photovoltaic Performance Modeling Validation Report

    Energy Technology Data Exchange (ETDEWEB)

    Freeman, Janine [National Renewable Energy Lab. (NREL), Golden, CO (United States); Whitmore, Jonathan [National Renewable Energy Lab. (NREL), Golden, CO (United States); Kaffine, Leah [National Renewable Energy Lab. (NREL), Golden, CO (United States); Blair, Nate [National Renewable Energy Lab. (NREL), Golden, CO (United States); Dobos, Aron P. [National Renewable Energy Lab. (NREL), Golden, CO (United States)

    2013-12-01

    The System Advisor Model (SAM) is a free software tool that performs detailed analysis of both system performance and system financing for a variety of renewable energy technologies. This report provides detailed validation of the SAM flat plate photovoltaic performance model by comparing SAM-modeled PV system generation data to actual measured production data for nine PV systems ranging from 75 kW to greater than 25 MW in size. The results show strong agreement between SAM predictions and field data, with annualized prediction error below 3% for all fixed tilt cases and below 8% for all one axis tracked cases. The analysis concludes that snow cover and system outages are the primary sources of disagreement, and other deviations resulting from seasonal biases in the irradiation models and one axis tracking issues are discussed in detail.

  1. Analysis of factors that inhibiting implementation of Information Security Management System (ISMS) based on ISO 27001

    Science.gov (United States)

    Tatiara, R.; Fajar, A. N.; Siregar, B.; Gunawan, W.

    2018-03-01

    The purpose of this research is to determine multi factors that inhibiting the implementation of the ISMS based on ISO 2700. It is also to propose a follow-up recommendation on the factors that inhibit the implementation of the ISMS. Data collection is derived from questionnaires to 182 respondents from users in data center operation (DCO) at bca, Indonesian telecommunication international (telin), and data centre division at Indonesian Ministry of Health. We analysing data collection with multiple linear regression analysis and paired t-test. The results are multiple factors which inhibiting the implementation of the ISMS from the three organizations which has implement and operate the ISMS, ISMS documentation management, and continual improvement. From this research, we concluded that the processes of implementation in ISMS is the necessity of the role of all parties in succeeding the implementation of the ISMS continuously.

  2. Natural gas hydrate formation and inhibition in gas/crude oil/aqueous systems

    DEFF Research Database (Denmark)

    Daraboina, Nagu; Pachitsas, Stylianos; von Solms, Nicolas

    2015-01-01

    Gas hydrate formation in multi phase mixtures containing an aqueous phase (with dissolved salts), reservoir fluid (crude oil) and natural gas phase was investigated by using a standard rocking cell (RC-5) apparatus. The hydrate formation temperature was reduced in the presence of crude oils...... of the biodegradable commercial kinetic inhibitor (Luvicap-Bio) on natural gas hydrate formation with and without crude oil (30%) was investigated. The strength of kinetic inhibitor was not affected by salts, but decreased significantly in the presence of crude oil. Data for hydrate formation at practical conditions...... inhibition mechanisms and potentially a competition among inhibition-promotion mechanisms. Moreover, the hydrate formation time has been determined at different water cuts in each crude oil and it was found that the inhibition capability increases with an increase in the oil content. The effect...

  3. Sinapic acid prevents hypertension and cardiovascular remodeling in pharmacological model of nitric oxide inhibited rats.

    Science.gov (United States)

    Silambarasan, Thangarasu; Manivannan, Jeganathan; Krishna Priya, Mani; Suganya, Natarajan; Chatterjee, Suvro; Raja, Boobalan

    2014-01-01

    Hypertensive heart disease is a constellation of abnormalities that includes cardiac fibrosis in response to elevated blood pressure, systolic and diastolic dysfunction. The present study was undertaken to examine the effect of sinapic acid on high blood pressure and cardiovascular remodeling. An experimental hypertensive animal model was induced by L-NAME intake on rats. Sinapic acid (SA) was orally administered at a dose of 10, 20 and 40 mg/kg body weight (b.w.). Blood pressure was measured by tail cuff plethysmography system. Cardiac and vascular function was evaluated by Langendorff isolated heart system and organ bath studies, respectively. Fibrotic remodeling of heart and aorta was assessed by histopathologic analyses. Oxidative stress was measured by biochemical assays. mRNA and protein expressions were assessed by RT-qPCR and western blot, respectively. In order to confirm the protective role of SA on endothelial cells through its antioxidant property, we have utilized the in vitro model of H2O2-induced oxidative stress in EA.hy926 endothelial cells. Rats with hypertension showed elevated blood pressure, declined myocardial performance associated with myocardial hypertrophy and fibrosis, diminished vascular response, nitric oxide (NO) metabolites level, elevated markers of oxidative stress (TBARS, LOOH), ACE activity, depleted antioxidant system (SOD, CAT, GPx, reduced GSH), aberrant expression of TGF-β, β-MHC, eNOS mRNAs and eNOS protein. Remarkably, SA attenuated high blood pressure, myocardial, vascular dysfunction, cardiac fibrosis, oxidative stress and ACE activity. Level of NO metabolites, antioxidant system, and altered gene expression were also repaired by SA treatment. Results of in vitro study showed that, SA protects endothelial cells from oxidative stress and enhance the production of NO in a concentration dependent manner. Taken together, these results suggest that SA may have beneficial role in the treatment of hypertensive heart disease by

  4. Sinapic acid prevents hypertension and cardiovascular remodeling in pharmacological model of nitric oxide inhibited rats.

    Directory of Open Access Journals (Sweden)

    Thangarasu Silambarasan

    Full Text Available Hypertensive heart disease is a constellation of abnormalities that includes cardiac fibrosis in response to elevated blood pressure, systolic and diastolic dysfunction. The present study was undertaken to examine the effect of sinapic acid on high blood pressure and cardiovascular remodeling.An experimental hypertensive animal model was induced by L-NAME intake on rats. Sinapic acid (SA was orally administered at a dose of 10, 20 and 40 mg/kg body weight (b.w.. Blood pressure was measured by tail cuff plethysmography system. Cardiac and vascular function was evaluated by Langendorff isolated heart system and organ bath studies, respectively. Fibrotic remodeling of heart and aorta was assessed by histopathologic analyses. Oxidative stress was measured by biochemical assays. mRNA and protein expressions were assessed by RT-qPCR and western blot, respectively. In order to confirm the protective role of SA on endothelial cells through its antioxidant property, we have utilized the in vitro model of H2O2-induced oxidative stress in EA.hy926 endothelial cells.Rats with hypertension showed elevated blood pressure, declined myocardial performance associated with myocardial hypertrophy and fibrosis, diminished vascular response, nitric oxide (NO metabolites level, elevated markers of oxidative stress (TBARS, LOOH, ACE activity, depleted antioxidant system (SOD, CAT, GPx, reduced GSH, aberrant expression of TGF-β, β-MHC, eNOS mRNAs and eNOS protein. Remarkably, SA attenuated high blood pressure, myocardial, vascular dysfunction, cardiac fibrosis, oxidative stress and ACE activity. Level of NO metabolites, antioxidant system, and altered gene expression were also repaired by SA treatment. Results of in vitro study showed that, SA protects endothelial cells from oxidative stress and enhance the production of NO in a concentration dependent manner.Taken together, these results suggest that SA may have beneficial role in the treatment of hypertensive heart

  5. Coupling population dynamics with earth system models: the POPEM model.

    Science.gov (United States)

    Navarro, Andrés; Moreno, Raúl; Jiménez-Alcázar, Alfonso; Tapiador, Francisco J

    2017-09-16

    Precise modeling of CO 2 emissions is important for environmental research. This paper presents a new model of human population dynamics that can be embedded into ESMs (Earth System Models) to improve climate modeling. Through a system dynamics approach, we develop a cohort-component model that successfully simulates historical population dynamics with fine spatial resolution (about 1°×1°). The population projections are used to improve the estimates of CO 2 emissions, thus transcending the bulk approach of existing models and allowing more realistic non-linear effects to feature in the simulations. The module, dubbed POPEM (from Population Parameterization for Earth Models), is compared with current emission inventories and validated against UN aggregated data. Finally, it is shown that the module can be used to advance toward fully coupling the social and natural components of the Earth system, an emerging research path for environmental science and pollution research.

  6. Spinal Cord Injury Model System Information Network

    Science.gov (United States)

    ... the UAB-SCIMS Contact the UAB-SCIMS UAB Spinal Cord Injury Model System Newly Injured Health Daily Living Consumer ... Information Network The University of Alabama at Birmingham Spinal Cord Injury Model System (UAB-SCIMS) maintains this Information Network ...

  7. Statistical Model Checking for Stochastic Hybrid Systems

    DEFF Research Database (Denmark)

    David, Alexandre; Du, Dehui; Larsen, Kim Guldstrand

    2012-01-01

    This paper presents novel extensions and applications of the UPPAAL-SMC model checker. The extensions allow for statistical model checking of stochastic hybrid systems. We show how our race-based stochastic semantics extends to networks of hybrid systems, and indicate the integration technique ap...

  8. Systemic, Ecological Model for Rehabilitation Counseling.

    Science.gov (United States)

    Hershenson, David B.

    1998-01-01

    Presents a reformulation of Hershenson's theoretical model for rehabilitation counseling in systemic and ecological terms. This macrosystem is organized by precipitating event of disability and is composed of four systems: consumer, functional, provider, and contextual. Discusses the use of the model for selecting rehabilitation interventions…

  9. Modeling complex work systems - method meets reality

    NARCIS (Netherlands)

    van der Veer, Gerrit C.; Hoeve, Machteld; Lenting, Bert

    1996-01-01

    Modeling an existing task situation is often a first phase in the (re)design of information systems. For complex systems design, this model should consider both the people and the organization involved, the work, and situational aspects. Groupware Task Analysis (GTA) as part of a method for the

  10. System dynamics modelling of situation awareness

    CSIR Research Space (South Africa)

    Oosthuizen, R

    2015-11-01

    Full Text Available . The feedback loops and delays in the Command and Control system also contribute to the complex dynamic behavior. This paper will build on existing situation awareness models to develop a System Dynamics model to support a qualitative investigation through...

  11. Dynamic modeling of the INAPRO aquaponic system

    NARCIS (Netherlands)

    Karimanzira, Divas; Keesman, Karel J.; Kloas, Werner; Baganz, Daniela; Rauschenbach, Thomas

    2016-01-01

    The use of modeling techniques to analyze aquaponics systems is demonstrated with an example of dynamic modeling for the production of Nile tilapia (Oreochromis niloticus) and tomatoes (Solanum lycopersicon) using the innovative double recirculating aquaponic system ASTAF-PRO. For the management

  12. Formal heterogeneous system modeling with SystemC

    DEFF Research Database (Denmark)

    Niaki, Seyed Hosein Attarzadeh; Jakobsen, Mikkel Koefoed; Sulonen, Tero

    2012-01-01

    Electronic System Level (ESL) design of embedded systems proposes raising the abstraction level of the design entry to cope with the increasing complexity of such systems. To exploit the benefits of ESL, design languages should allow specification of models which are a) heterogeneous, to describe...... to focus on specifying the pure functional aspects. A key advantage is that the formalism is used to export the structure and behavior of the models via introspection as an abstract representation for further analysis and synthesis....

  13. Regression Models for Repairable Systems

    Czech Academy of Sciences Publication Activity Database

    Novák, Petr

    2015-01-01

    Roč. 17, č. 4 (2015), s. 963-972 ISSN 1387-5841 Institutional support: RVO:67985556 Keywords : Reliability analysis * Repair models * Regression Subject RIV: BB - Applied Statistics , Operational Research Impact factor: 0.782, year: 2015 http://library.utia.cas.cz/separaty/2015/SI/novak-0450902.pdf

  14. Pharmacological inhibition of Src kinase protects against acute kidney injury in a murine model of renal ischemia/reperfusion.

    Science.gov (United States)

    Xiong, Chongxiang; Zang, Xiujuan; Zhou, Xiaoxu; Liu, Lirong; Masucci, Monica V; Tang, Jinhua; Li, Xuezhu; Liu, Na; Bayliss, George; Zhao, Ting C; Zhuang, Shougang

    2017-05-09

    Activation of Src kinase has been implicated in the pathogenesis of acute brain, liver, and lung injury. However, the role of Src in acute kidney injury (AKI) remains unestablished. To address this, we evaluated the effects of Src inhibition on renal dysfunction and pathological changes in a murine model of AKI induced by ischemia/reperfusion (I/R). I/R injury to the kidney resulted in increased Src phosphorylation at tyrosine 416 (activation). Administration of PP1, a highly selective Src inhibitor, blocked Src phosphorylation, improved renal function and ameliorated renal pathological damage. PP1 treatment also suppressed renal expression of neutrophil gelatinase-associated lipocalin and reduced apoptosis in the injured kidney. Moreover, Src inhibition prevented downregulation of several adherens and tight junction proteins, including E-cadherin, ZO-1, and claudins-1/-4 in the kidney after I/R injury as well as in cultured renal proximal tubular cells following oxidative stress. Finally, PP1 inhibited I/R-induced renal expression of matrix metalloproteinase-2 and -9, phosphorylation of extracellular signal-regulated kinases1/2, signal transducer and activator of transcription-3, and nuclear factor-κB, and the infiltration of macrophages into the kidney. These data indicate that Src is a pivotal mediator of renal epithelial injury and that its inhibition may have a therapeutic potential to treat AKI.

  15. Inhibition of allergic dermal inflammation by the novel imidazopyridazine derivative TAK-427 in a guinea pig experimental model of eczema.

    Science.gov (United States)

    Fukuda, Shigeru; Midoro, Katsuo; Kamei, Takayuki; Gyoten, Michiyo; Kawano, Yasuhiko; Ashida, Yasuko; Nagaya, Hideaki

    2002-12-01

    Antigen challenge by patch ovalbumin emulsion induced an eczema-like skin lesion in epicutaneously sensitized guinea pigs. Diseased skin sites were macroscopically characterized by manifestations of dermatitis, such as erythema, edema, and papules, and microscopically characterized by acanthosis, spongiosis, and dermal infiltration by eosinophils. Using such lesions as a model of eczema, we evaluated the potential value of TAK-427 [2-[6-[[3-[4-(diphenylmethoxy)piperidino]propyl]amino] imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionic acid dihydrate] as a therapeutic agent for atopic dermatitis by comparing it with dexamethasone and antihistamines. TAK-427 (0.3-30 mg/kg, p.o.) and dexamethasone (3 and 10 mg/kg, p.o.) inhibited eosinophil infiltration into the skin and ameliorated the dermatitis manifestations and epidermal damage. By contrast, none of the antihistamines tested (azelastine, ketotifen, terfenadine, and cetirizine) suppressed the eosinophil infiltration or dermatitis manifestations. To elucidate the mechanism by which TAK-427 inhibited the development of eczema, we investigated cytokine expression in the affected skin. Both TAK-427 and dexamethasone suppressed the increased mRNA expression of interleukin (IL)-13, granulocyte-macrophage colony-stimulating factor, IL-1alpha, tumor necrosis factor-alpha, interferon-gamma, and IL-8, but not IL-10, suggesting that TAK-427 inhibits allergic inflammation of the skin leading to the development of eczema by inhibiting the expression of proinflammatory cytokines after antigen challenge.

  16. Inhibition of bacterial conjugation by phage M13 and its protein g3p: quantitative analysis and model.

    Science.gov (United States)

    Lin, Abraham; Jimenez, Jose; Derr, Julien; Vera, Pedro; Manapat, Michael L; Esvelt, Kevin M; Villanueva, Laura; Liu, David R; Chen, Irene A

    2011-01-01

    Conjugation is the main mode of horizontal gene transfer that spreads antibiotic resistance among bacteria. Strategies for inhibiting conjugation may be useful for preserving the effectiveness of antibiotics and preventing the emergence of bacterial strains with multiple resistances. Filamentous bacteriophages were first observed to inhibit conjugation several decades ago. Here we investigate the mechanism of inhibition and find that the primary effect on conjugation is occlusion of the conjugative pilus by phage particles. This interaction is mediated primarily by phage coat protein g3p, and exogenous addition of the soluble fragment of g3p inhibited conjugation at low nanomolar concentrations. Our data are quantitatively consistent with a simple model in which association between the pili and phage particles or g3p prevents transmission of an F plasmid encoding tetracycline resistance. We also observe a decrease in the donor ability of infected cells, which is quantitatively consistent with a reduction in pili elaboration. Since many antibiotic-resistance factors confer susceptibility to phage infection through expression of conjugative pili (the receptor for filamentous phage), these results suggest that phage may be a source of soluble proteins that slow the spread of antibiotic resistance genes.

  17. Inhibition of bacterial conjugation by phage M13 and its protein g3p: quantitative analysis and model.

    Directory of Open Access Journals (Sweden)

    Abraham Lin

    Full Text Available Conjugation is the main mode of horizontal gene transfer that spreads antibiotic resistance among bacteria. Strategies for inhibiting conjugation may be useful for preserving the effectiveness of antibiotics and preventing the emergence of bacterial strains with multiple resistances. Filamentous bacteriophages were first observed to inhibit conjugation several decades ago. Here we investigate the mechanism of inhibition and find that the primary effect on conjugation is occlusion of the conjugative pilus by phage particles. This interaction is mediated primarily by phage coat protein g3p, and exogenous addition of the soluble fragment of g3p inhibited conjugation at low nanomolar concentrations. Our data are quantitatively consistent with a simple model in which association between the pili and phage particles or g3p prevents transmission of an F plasmid encoding tetracycline resistance. We also observe a decrease in the donor ability of infected cells, which is quantitatively consistent with a reduction in pili elaboration. Since many antibiotic-resistance factors confer susceptibility to phage infection through expression of conjugative pili (the receptor for filamentous phage, these results suggest that phage may be a source of soluble proteins that slow the spread of antibiotic resistance genes.

  18. Mathematical Modeling Of Life-Support Systems

    Science.gov (United States)

    Seshan, Panchalam K.; Ganapathi, Balasubramanian; Jan, Darrell L.; Ferrall, Joseph F.; Rohatgi, Naresh K.

    1994-01-01

    Generic hierarchical model of life-support system developed to facilitate comparisons of options in design of system. Model represents combinations of interdependent subsystems supporting microbes, plants, fish, and land animals (including humans). Generic model enables rapid configuration of variety of specific life support component models for tradeoff studies culminating in single system design. Enables rapid evaluation of effects of substituting alternate technologies and even entire groups of technologies and subsystems. Used to synthesize and analyze life-support systems ranging from relatively simple, nonregenerative units like aquariums to complex closed-loop systems aboard submarines or spacecraft. Model, called Generic Modular Flow Schematic (GMFS), coded in such chemical-process-simulation languages as Aspen Plus and expressed as three-dimensional spreadsheet.

  19. Systematic modelling and simulation of refrigeration systems

    DEFF Research Database (Denmark)

    Rasmussen, Bjarne D.; Jakobsen, Arne

    1998-01-01

    The task of developing a simulation model of a refrigeration system can be very difficult and time consuming. In order for this process to be effective, a systematic method for developing the system model is required. This method should aim at guiding the developer to clarify the purpose of the s......The task of developing a simulation model of a refrigeration system can be very difficult and time consuming. In order for this process to be effective, a systematic method for developing the system model is required. This method should aim at guiding the developer to clarify the purpose...... of the simulation, to select appropriate component models and to set up the equations in a well-arranged way. In this paper the outline of such a method is proposed and examples showing the use of this method for simulation of refrigeration systems are given....

  20. Modeling and analysis of stochastic systems

    CERN Document Server

    Kulkarni, Vidyadhar G

    2011-01-01

    Based on the author's more than 25 years of teaching experience, Modeling and Analysis of Stochastic Systems, Second Edition covers the most important classes of stochastic processes used in the modeling of diverse systems, from supply chains and inventory systems to genetics and biological systems. For each class of stochastic process, the text includes its definition, characterization, applications, transient and limiting behavior, first passage times, and cost/reward models. Along with reorganizing the material, this edition revises and adds new exercises and examples. New to the second edi

  1. Formal heterogeneous system modeling with SystemC

    DEFF Research Database (Denmark)

    Niaki, Seyed Hosein Attarzadeh; Jakobsen, Mikkel Koefoed; Sulonen, Tero

    2012-01-01

    Electronic System Level (ESL) design of embedded systems proposes raising the abstraction level of the design entry to cope with the increasing complexity of such systems. To exploit the benefits of ESL, design languages should allow specification of models which are a) heterogeneous, to describe...

  2. Consumption of lycopene inhibits the growth and progression of colon cancer in a mouse xenograft model

    Science.gov (United States)

    A previous study indicated that lycopene could significantly inhibit the proliferation of human colon cancer cells in vitro. However, the in vivo anticancer effects of lycopene against colon cancer have not been demonstrated yet. Therefore, this study investigated whether consumption of lycopene cou...

  3. Systems Engineering Model for ART Energy Conversion

    Energy Technology Data Exchange (ETDEWEB)

    Mendez Cruz, Carmen Margarita [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Rochau, Gary E. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Wilson, Mollye C. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2017-02-01

    The near-term objective of the EC team is to establish an operating, commercially scalable Recompression Closed Brayton Cycle (RCBC) to be constructed for the NE - STEP demonstration system (demo) with the lowest risk possible. A systems engineering approach is recommended to ensure adequate requirements gathering, documentation, and mode ling that supports technology development relevant to advanced reactors while supporting crosscut interests in potential applications. A holistic systems engineering model was designed for the ART Energy Conversion program by leveraging Concurrent Engineering, Balance Model, Simplified V Model, and Project Management principles. The resulting model supports the identification and validation of lifecycle Brayton systems requirements, and allows designers to detail system-specific components relevant to the current stage in the lifecycle, while maintaining a holistic view of all system elements.

  4. Modeling aluminum-air battery systems

    Science.gov (United States)

    Savinell, R. F.; Willis, M. S.

    The performance of a complete aluminum-air battery system was studied with a flowsheet model built from unit models of each battery system component. A plug flow model for heat transfer was used to estimate the amount of heat transferred from the electrolyte to the air stream. The effect of shunt currents on battery performance was found to be insignificant. Using the flowsheet simulator to analyze a 100 cell battery system now under development demonstrated that load current, aluminate concentration, and electrolyte temperature are dominant variables controlling system performance. System efficiency was found to decrease as both load current and aluminate concentration increases. The flowsheet model illustrates the interdependence of separate units on overall system performance.

  5. Model-Based Design for Embedded Systems

    CERN Document Server

    Nicolescu, Gabriela

    2009-01-01

    Model-based design allows teams to start the design process from a high-level model that is gradually refined through abstraction levels to ultimately yield a prototype. This book describes the main facets of heterogeneous system design. It focuses on multi-core methodological issues, real-time analysis, and modeling and validation

  6. Critically Important Object Security System Element Model

    Directory of Open Access Journals (Sweden)

    I. V. Khomyackov

    2012-03-01

    Full Text Available A stochastic model of critically important object security system element has been developed. The model includes mathematical description of the security system element properties and external influences. The state evolution of the security system element is described by the semi-Markov process with finite states number, the semi-Markov matrix and the initial semi-Markov process states probabilities distribution. External influences are set with the intensity of the Poisson thread.

  7. A model for international border management systems.

    Energy Technology Data Exchange (ETDEWEB)

    Duggan, Ruth Ann

    2008-09-01

    To effectively manage the security or control of its borders, a country must understand its border management activities as a system. Using its systems engineering and security foundations as a Department of Energy National Security Laboratory, Sandia National Laboratories has developed such an approach to modeling and analyzing border management systems. This paper describes the basic model and its elements developed under Laboratory Directed Research and Development project 08-684.

  8. Intravenous S-Ketamine Does Not Inhibit Alveolar Fluid Clearance in a Septic Rat Model

    Science.gov (United States)

    Weber, Nina C.; van der Sluijs, Koen; Hackl, Florian; Hotz, Lorenz; Dahan, Albert; Hollmann, Markus W.; Berger, Marc M.

    2014-01-01

    We previously demonstrated that intratracheally administered S-ketamine inhibits alveolar fluid clearance (AFC), whereas an intravenous (IV) bolus injection had no effect. The aim of the present study was to characterize whether continuous IV infusion of S-ketamine, yielding clinically relevant plasma concentrations, inhibits AFC and whether its effect is enhanced in acute lung injury (ALI) which might favor the appearance of IV S-ketamine at the alveolar surface. AFC was measured in fluid-instilled rat lungs. S-ketamine was administered IV over 6 h (loading dose: 20 mg/kg, followed by 20 mg/kg/h), or intratracheally by addition to the instillate (75 µg/ml). ALI was induced by IV lipopolysaccharide (LPS; 7 mg/kg). Interleukin (IL)-6 and cytokine-induced neutrophil chemoattractant (CINC)-3 were measured by ELISA in plasma and bronchoalveolar lavage fluid. Isolated rat alveolar type-II cells were exposed to S-ketamine (75 µg/ml) and/or LPS (1 mg/ml) for 6 h, and transepithelial ion transport was measured as short circuit current (ISC). AFC was 27±5% (mean±SD) over 60 min in control rats and was unaffected by IV S-ketamine. Tracheal S-ketamine reduced AFC to 18±9%. In LPS-treated rats, AFC decreased to 16±6%. This effect was not enhanced by IV S-ketamine. LPS increased IL-6 and CINC-3 in plasma and bronchoalveolar lavage fluid. In alveolar type-II cells, S-ketamine reduced ISC by 37% via a decrease in amiloride-inhibitable sodium transport. Continuous administration of IV S-ketamine does not affect rat AFC even in endotoxin-induced ALI. Tracheal application with direct exposure of alveolar epithelial cells to S-ketamine decreases AFC by inhibition of amiloride-inhibitable sodium transport. PMID:25386677

  9. A strategic review of electricity systems models

    International Nuclear Information System (INIS)

    Foley, A.M.; O Gallachoir, B.P.; McKeogh, E.J.; Hur, J.; Baldick, R.

    2010-01-01

    Electricity systems models are software tools used to manage electricity demand and the electricity systems, to trade electricity and for generation expansion planning purposes. Various portfolios and scenarios are modelled in order to compare the effects of decision making in policy and on business development plans in electricity systems so as to best advise governments and industry on the least cost economic and environmental approach to electricity supply, while maintaining a secure supply of sufficient quality electricity. The modelling techniques developed to study vertically integrated state monopolies are now applied in liberalised markets where the issues and constraints are more complex. This paper reviews the changing role of electricity systems modelling in a strategic manner, focussing on the modelling response to key developments, the move away from monopoly towards liberalised market regimes and the increasing complexity brought about by policy targets for renewable energy and emissions. The paper provides an overview of electricity systems modelling techniques, discusses a number of key proprietary electricity systems models used in the USA and Europe and provides an information resource to the electricity analyst not currently readily available in the literature on the choice of model to investigate different aspects of the electricity system. (author)

  10. Systemic vascular resistance during brief withdrawal of angiotensin converting enzyme inhibition in heart failure

    DEFF Research Database (Denmark)

    Gabrielsen, A; Bie, P; Christensen, N J

    2002-01-01

    We tested the hypothesis that moderate increases in endogenous angiotensin II (Ang II) concentrations, induced by withdrawal of angiotensin converting enzyme inhibition (ACE-I) in patients with compensated heart failure (HF) on chronic medical therapy, do not increase or impair control of systemi...

  11. PI3K-δ and PI3K-γ inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models.

    Science.gov (United States)

    Winkler, David G; Faia, Kerrie L; DiNitto, Jonathan P; Ali, Janid A; White, Kerry F; Brophy, Erin E; Pink, Melissa M; Proctor, Jennifer L; Lussier, Jennifer; Martin, Christian M; Hoyt, Jennifer G; Tillotson, Bonnie; Murphy, Erin L; Lim, Alice R; Thomas, Brian D; Macdougall, John R; Ren, Pingda; Liu, Yi; Li, Lian-Sheng; Jessen, Katti A; Fritz, Christian C; Dunbar, Joi L; Porter, James R; Rommel, Christian; Palombella, Vito J; Changelian, Paul S; Kutok, Jeffery L

    2013-11-21

    Phosphoinositide-3 kinase (PI3K)-δ and PI3K-γ are preferentially expressed in immune cells, and inhibitors targeting these isoforms are hypothesized to have anti-inflammatory activity by affecting the adaptive and innate immune response. We report on a potent oral PI3K-δ and PI3K-γ inhibitor (IPI-145) and characterize this compound in biochemical, cellular, and in vivo assays. These studies demonstrate that IPI-145 exerts profound effects on adaptive and innate immunity by inhibiting B and T cell proliferation, blocking neutrophil migration, and inhibiting basophil activation. We explored the therapeutic value of combined PI3K-δ and PI3K-γ blockade, and IPI-145 showed potent activity in collagen-induced arthritis, ovalbumin-induced asthma, and systemic lupus erythematosus rodent models. These findings support the hypothesis that inhibition of immune function can be achieved through PI3K-δ and PI3K-γ blockade, potentially leading to significant therapeutic effects in multiple inflammatory, autoimmune, and hematologic diseases. Copyright © 2013 Elsevier Ltd. All rights reserved.

  12. Metabolic modelling of denitrification in Agrobacterium tumefaciens: a tool to study inhibiting and activating compounds for the denitrification pathway

    Directory of Open Access Journals (Sweden)

    Marlies J. Kampschreur

    2012-10-01

    Full Text Available A metabolic network model for facultative denitrification was developed based on experimental data obtained with Agrobacterium tumefaciens. The model includes kinetic regulation at the enzyme level and transcription regulation at the enzyme synthesis level. The objective of this work was to study the key factors regulating the metabolic response of the denitrification pathway to transition from oxic to anoxic respiration and to find parameter values for the biological processes that were modelled. The metabolic model was used to test hypotheses that were formulated based on the experimental results and offers a structured look on the processes that occur in the cell during transition in respiration. The main phenomena that were modelled are the inhibition of the cytochrome c oxidase by nitric oxide (NO, the (indirect inhibition of oxygen on the denitrification enzymes. The activation of transcription of nitrite reductase and NO reductase by their respective substrates were hypothesized. The general assumption that nitrite and NO reduction are controlled interdependently to prevent NO accumulation does not hold for A. tumefaciens. The metabolic network model was demonstrated to be a useful tool for unravelling the different factors involved in the complex response of A. tumefaciens to highly dynamic environmental conditions.

  13. Human performance modeling for system of systems analytics.

    Energy Technology Data Exchange (ETDEWEB)

    Dixon, Kevin R.; Lawton, Craig R.; Basilico, Justin Derrick; Longsine, Dennis E. (INTERA, Inc., Austin, TX); Forsythe, James Chris; Gauthier, John Henry; Le, Hai D.

    2008-10-01

    A Laboratory-Directed Research and Development project was initiated in 2005 to investigate Human Performance Modeling in a System of Systems analytic environment. SAND2006-6569 and SAND2006-7911 document interim results from this effort; this report documents the final results. The problem is difficult because of the number of humans involved in a System of Systems environment and the generally poorly defined nature of the tasks that each human must perform. A two-pronged strategy was followed: one prong was to develop human models using a probability-based method similar to that first developed for relatively well-understood probability based performance modeling; another prong was to investigate more state-of-art human cognition models. The probability-based modeling resulted in a comprehensive addition of human-modeling capability to the existing SoSAT computer program. The cognitive modeling resulted in an increased understanding of what is necessary to incorporate cognition-based models to a System of Systems analytic environment.

  14. Reliability models for Space Station power system

    Science.gov (United States)

    Singh, C.; Patton, A. D.; Kim, Y.; Wagner, H.

    1987-01-01

    This paper presents a methodology for the reliability evaluation of Space Station power system. The two options considered are the photovoltaic system and the solar dynamic system. Reliability models for both of these options are described along with the methodology for calculating the reliability indices.

  15. System identification application using Hammerstein model

    Indian Academy of Sciences (India)

    Saban Ozer

    because of its advanced theoretical background [3–5, 10]. However, many systems in real life have nonlinear beha- ... To describe a polynomial non-linear system with memory, the Volterra series expansion has been the ... suppression and adaptive noise suppression [19]. 2.3 Hammerstein model. Many systems can be ...

  16. Using Interaction Scenarios to Model Information Systems

    DEFF Research Database (Denmark)

    Bækgaard, Lars; Bøgh Andersen, Peter

    The purpose of this paper is to define and discuss a set of interaction primitives that can be used to model the dynamics of socio-technical activity systems, including information systems, in a way that emphasizes structural aspects of the interaction that occurs in such systems. The primitives...

  17. Diclofenac inhibits tumor growth in a murine model of pancreatic cancer by modulation of VEGF levels and arginase activity.

    Directory of Open Access Journals (Sweden)

    Nina Mayorek

    Full Text Available BACKGROUND: Diclofenac is one of the oldest anti-inflammatory drugs in use. In addition to its inhibition of cyclooxygenases (COX, diclofenac potently inhibits phospholipase A(2 (PLA(2, thus yielding a broad anti-inflammatory effect. Since inflammation is an important factor in the development of pancreatic tumors we explored the potential of diclofenac to inhibit tumor growth in mice inoculated with PANCO2 cells orthotopically. METHODOLOGY/PRINCIPAL FINDINGS: We found that diclofenac treatment (30 mg/kg/bw for 11 days of mice inoculated with PANC02 cells, reduced the tumor weight by 60%, correlating with increased apoptosis of tumor cells. Since this effect was not observed in vitro on cultured PANCO2 cells, we theorized that diclofenac beneficial treatment involved other mediators present in vivo. Indeed, diclofenac drastically decreased tumor vascularization by downregulating VEGF in the tumor and in abdominal cavity fluid. Furthermore, diclofenac directly inhibited vascular sprouting ex vivo. Surprisingly, in contrast to other COX-2 inhibitors, diclofenac increased arginase activity/arginase 1 protein content in tumor stroma cells, peritoneal macrophages and white blood cells by 2.4, 4.8 and 2 fold, respectively. We propose that the subsequent arginine depletion and decrease in NO levels, both in serum and peritoneal cavity, adds to tumor growth inhibition by malnourishment and poor vasculature development. CONCLUSION/SIGNIFICANCE: In conclusion, diclofenac shows pronounced antitumoral properties in pancreatic cancer model that can contribute to further treatment development. The ability of diclofenac to induce arginase activity in tumor stroma, peritoneal macrophages and white blood cells provides a tool to study a controversial issue of pro-and antitumoral effects of arginine depletion.

  18. Diclofenac inhibits tumor growth in a murine model of pancreatic cancer by modulation of VEGF levels and arginase activity.

    Science.gov (United States)

    Mayorek, Nina; Naftali-Shani, Nili; Grunewald, Myriam

    2010-09-15

    Diclofenac is one of the oldest anti-inflammatory drugs in use. In addition to its inhibition of cyclooxygenases (COX), diclofenac potently inhibits phospholipase A(2) (PLA(2)), thus yielding a broad anti-inflammatory effect. Since inflammation is an important factor in the development of pancreatic tumors we explored the potential of diclofenac to inhibit tumor growth in mice inoculated with PANCO2 cells orthotopically. We found that diclofenac treatment (30 mg/kg/bw for 11 days) of mice inoculated with PANC02 cells, reduced the tumor weight by 60%, correlating with increased apoptosis of tumor cells. Since this effect was not observed in vitro on cultured PANCO2 cells, we theorized that diclofenac beneficial treatment involved other mediators present in vivo. Indeed, diclofenac drastically decreased tumor vascularization by downregulating VEGF in the tumor and in abdominal cavity fluid. Furthermore, diclofenac directly inhibited vascular sprouting ex vivo. Surprisingly, in contrast to other COX-2 inhibitors, diclofenac increased arginase activity/arginase 1 protein content in tumor stroma cells, peritoneal macrophages and white blood cells by 2.4, 4.8 and 2 fold, respectively. We propose that the subsequent arginine depletion and decrease in NO levels, both in serum and peritoneal cavity, adds to tumor growth inhibition by malnourishment and poor vasculature development. In conclusion, diclofenac shows pronounced antitumoral properties in pancreatic cancer model that can contribute to further treatment development. The ability of diclofenac to induce arginase activity in tumor stroma, peritoneal macrophages and white blood cells provides a tool to study a controversial issue of pro-and antitumoral effects of arginine depletion.

  19. Pseudomonas aeruginosa Magnesium Transporter MgtE Inhibits Type III Secretion System Gene Expression by StimulatingrsmYZTranscription.

    Science.gov (United States)

    Chakravarty, Shubham; Melton, Cameron N; Bailin, Adam; Yahr, Timothy L; Anderson, Gregory G

    2017-12-01

    Pseudomonas aeruginosa causes numerous acute and chronic opportunistic infections in humans. One of its most formidable weapons is a type III secretion system (T3SS), which injects powerful toxins directly into host cells. The toxins lead to cell dysfunction and, ultimately, cell death. Identification of regulatory pathways that control T3SS gene expression may lead to the discovery of novel therapeutics to treat P. aeruginosa infections. In a previous study, we found that expression of the magnesium transporter gene mgtE inhibits T3SS gene transcription. MgtE-dependent inhibition appeared to interfere with the synthesis or function of the master T3SS transcriptional activator ExsA, although the exact mechanism was unclear. We now demonstrate that mgtE expression acts through the GacAS two-component system to activate rsmY and rsmZ transcription. This event ultimately leads to inhibition of exsA translation. This inhibitory effect is specific to exsA as translation of other genes in the exsCEBA operon is not inhibited by mgtE Moreover, our data reveal that MgtE acts solely through this pathway to regulate T3SS gene transcription. Our study reveals an important mechanism that may allow P. aeruginosa to fine-tune T3SS activity in response to certain environmental stimuli. IMPORTANCE The type III secretion system (T3SS) is a critical virulence factor utilized by numerous Gram-negative bacteria, including Pseudomonas aeruginosa , to intoxicate and kill host cells. Elucidating T3SS regulatory mechanisms may uncover targets for novel anti- P. aeruginosa therapeutics and provide deeper understanding of bacterial pathogenesis. We previously found that the magnesium transporter MgtE inhibits T3SS gene transcription in P. aeruginosa In this study, we describe the mechanism of MgtE-dependent inhibition of the T3SS. Our report also illustrates how MgtE might respond to environmental cues, such as magnesium levels, to fine-tune T3SS gene expression. Copyright © 2017 American

  20. Model Validation for Simulations of Vehicle Systems

    Science.gov (United States)

    2012-08-01

    jackknife”, Annals of Statistics, 7:1-26, 1979. [45] B. Efron and G. Gong, “A leisurely look at the bootstrap, the jackknife, and cross-validation”, The...battery model developed in the Automotive Research Center, a US Army Center of Excellence for modeling and simulation of ground vehicle systems...Sandia National Laboratories and a battery model developed in the Automotive Research Center, a US Army Center of Excellence for modeling and simulation

  1. Models of cuspy triaxial stellar systems. IV: Rotating systems

    OpenAIRE

    Carpintero, D. D.; Muzzio, J. C.

    2016-01-01

    We built two self-consistent models of triaxial, cuspy, rotating stellar systems adding rotation to non-rotating models presented in previous papers of this series. The final angular velocity of the material is not constant and varies with the distance to the center and with the height over the equator of the systems, but the figure rotation is very uniform in both cases. Even though the addition of rotation to the models modifies their original semiaxes ratios, the final rotating models are ...

  2. Spatial Models and Networks of Living Systems

    DEFF Research Database (Denmark)

    Juul, Jeppe Søgaard

    with interactions defined by network topology. In this thesis I first describe three different biological models of ageing and cancer, in which spatial structure is important for the system dynamics. I then turn to describe characteristics of ecosystems consisting of three cyclically interacting species......When studying the dynamics of living systems, insight can often be gained by developing a mathematical model that can predict future behaviour of the system or help classify system characteristics. However, in living cells, organisms, and especially groups of interacting individuals, a large number...... of different factors influence the time development of the system. This often makes it challenging to construct a mathematical model from which to draw conclusions. One traditional way of capturing the dynamics in a mathematical model is to formulate a set of coupled differential equations for the essential...

  3. Modelling and Optimization of Corrosion Inhibition of Mild Steel in Phosphoric Acid by Red Pomegranate Peels Aqueous Extract

    Directory of Open Access Journals (Sweden)

    Khalid Hamid Rashid

    2011-11-01

    Full Text Available Taguchi experimental design (TED is applied to find the optimum effectiveness of aqueous Red Pomegranate Peel (RPP extract as a green inhibitor for the corrosion of mild steel in 2M H3PO4 solution. The Taguchi methodology has been used to study the effects of changing, temperature, RPP concentration and contact period, at three levels. Weight-loss measurements were designed by construction a L9 orthogonal arrangement of experiments. Results of the efficiencies of inhibition were embraced for the signal to noise proportion & investigation of variance (ANOVA. The results were further processed with a MINITAB-17 software package to find the optimal conditions for inhibitor usage. Second order polynomial model was used for experimental data fitting. Optimum conditions for achieving the maximum corrosion inhibition efficiency are obtained from optimizing the above model and are found as follow: 39.66 °C temperature of acidic media, 38.29 ml/L inhibitor concentration and 2.95 h contact period. Results demonstrated that rate of corrosion was increased with temperature increasing & decreasing inhibitor concentration. It was concluded that the Taguchi design was adequately useful in the optimization of operating parameters and that RPP sufficiently inhibited the corrosion of steel at the range of variables studied.

  4. The Role of Inhibition in a Computational Model of an Auditory Cortical Neuron during the Encoding of Temporal Information

    Science.gov (United States)

    Bendor, Daniel

    2015-01-01

    In auditory cortex, temporal information within a sound is represented by two complementary neural codes: a temporal representation based on stimulus-locked firing and a rate representation, where discharge rate co-varies with the timing between acoustic events but lacks a stimulus-synchronized response. Using a computational neuronal model, we find that stimulus-locked responses are generated when sound-evoked excitation is combined with strong, delayed inhibition. In contrast to this, a non-synchronized rate representation is generated when the net excitation evoked by the sound is weak, which occurs when excitation is coincident and balanced with inhibition. Using single-unit recordings from awake marmosets (Callithrix jacchus), we validate several model predictions, including differences in the temporal fidelity, discharge rates and temporal dynamics of stimulus-evoked responses between neurons with rate and temporal representations. Together these data suggest that feedforward inhibition provides a parsimonious explanation of the neural coding dichotomy observed in auditory cortex. PMID:25879843

  5. From sounds to words: a neurocomputational model of adaptation, inhibition and memory processes in auditory change detection.

    Science.gov (United States)

    Garagnani, Max; Pulvermüller, Friedemann

    2011-01-01

    Most animals detect sudden changes in trains of repeated stimuli but only some can learn a wide range of sensory patterns and recognise them later, a skill crucial for the evolutionary success of higher mammals. Here we use a neural model mimicking the cortical anatomy of sensory and motor areas and their connections to explain brain activity indexing auditory change and memory access. Our simulations indicate that while neuronal adaptation and local inhibition of cortical activity can explain aspects of change detection as observed when a repeated unfamiliar sound changes in frequency, the brain dynamics elicited by auditory stimulation with well-known patterns (such as meaningful words) cannot be accounted for on the basis of adaptation and inhibition alone. Specifically, we show that the stronger brain responses observed to familiar stimuli in passive oddball tasks are best explained in terms of activation of memory circuits that emerged in the cortex during the learning of these stimuli. Such memory circuits, and the activation enhancement they entail, are absent for unfamiliar stimuli. The model illustrates how basic neurobiological mechanisms, including neuronal adaptation, lateral inhibition, and Hebbian learning, underlie neuronal assembly formation and dynamics, and differentially contribute to the brain's major change detection response, the mismatch negativity. Copyright © 2010 Elsevier Inc. All rights reserved.

  6. Towards quantitation of the effects of renal impairment and probenecid inhibition on kidney uptake and efflux transporters, using physiologically based pharmacokinetic modelling and simulations.

    Science.gov (United States)

    Hsu, Vicky; de L T Vieira, Manuela; Zhao, Ping; Zhang, Lei; Zheng, Jenny Huimin; Nordmark, Anna; Berglund, Eva Gil; Giacomini, Kathleen M; Huang, Shiew-Mei

    2014-03-01

    The kidney is a major drug-eliminating organ. Renal impairment or concomitant use of transporter inhibitors may decrease active secretion and increase exposure to a drug that is a substrate of kidney secretory transporters. However, prediction of the effects of patient factors on kidney transporters remains challenging because of the multiplicity of transporters and the lack of understanding of their abundance and specificity. The objective of this study was to use physiologically based pharmacokinetic (PBPK) modelling to evaluate the effects of patient factors on kidney transporters. Models for three renally cleared drugs (oseltamivir carboxylate, cidofovir and cefuroxime) were developed using a general PBPK platform, with the contributions of net basolateral uptake transport (T up,b) and apical efflux transport (T eff,a) being specifically defined. We demonstrated the practical use of PBPK models to: (1) define transporter-mediated renal secretion, using plasma and urine data; (2) inform a change in the system-dependent parameter (≥10-fold reduction in the functional 'proximal tubule cells per gram kidney') in severe renal impairment that is responsible for the decreased secretory transport activities of test drugs; (3) derive an in vivo, plasma unbound inhibition constant of T up,b by probenecid (≤1 μM), based on observed drug interaction data; and (4) suggest a plausible mechanism of probenecid preferentially inhibiting T up,b in order to alleviate cidofovir-induced nephrotoxicity.

  7. Mechatronic Systems Design Methods, Models, Concepts

    CERN Document Server

    Janschek, Klaus

    2012-01-01

    In this textbook, fundamental methods for model-based design of mechatronic systems are presented in a systematic, comprehensive form. The method framework presented here comprises domain-neutral methods for modeling and performance analysis: multi-domain modeling (energy/port/signal-based), simulation (ODE/DAE/hybrid systems), robust control methods, stochastic dynamic analysis, and quantitative evaluation of designs using system budgets. The model framework is composed of analytical dynamic models for important physical and technical domains of realization of mechatronic functions, such as multibody dynamics, digital information processing and electromechanical transducers. Building on the modeling concept of a technology-independent generic mechatronic transducer, concrete formulations for electrostatic, piezoelectric, electromagnetic, and electrodynamic transducers are presented. More than 50 fully worked out design examples clearly illustrate these methods and concepts and enable independent study of th...

  8. FSM Model of a Simple Photovoltaic System

    Directory of Open Access Journals (Sweden)

    Martina Latkova

    2015-01-01

    Full Text Available The paper describes a simulation model of a simple photovoltaic system intended as a tool for testing the use of finite state machines for simulations representing a long-term operation of renewable energy sources. The mathematical model of the photovoltaic system is described first. Then it is used to build a finite state machine model that calculates a power output of the photovoltaic system for changing values of a solar irradiance and a temperature. Data measured on a real photovoltaic installation are used to verify model’s accuracy through its comparison with a previously created and verified Matlab model. The finite state machine model presented in this paper was created using Ptolemy II software.

  9. Structural system identification: Structural dynamics model validation

    Energy Technology Data Exchange (ETDEWEB)

    Red-Horse, J.R.

    1997-04-01

    Structural system identification is concerned with the development of systematic procedures and tools for developing predictive analytical models based on a physical structure`s dynamic response characteristics. It is a multidisciplinary process that involves the ability (1) to define high fidelity physics-based analysis models, (2) to acquire accurate test-derived information for physical specimens using diagnostic experiments, (3) to validate the numerical simulation model by reconciling differences that inevitably exist between the analysis model and the experimental data, and (4) to quantify uncertainties in the final system models and subsequent numerical simulations. The goal of this project was to develop structural system identification techniques and software suitable for both research and production applications in code and model validation.

  10. Systemic Monocyte Chemotactic Protein-1 Inhibition Modifies Renal Macrophages and Restores Glomerular Endothelial Glycocalyx and Barrier Function in Diabetic Nephropathy.

    Science.gov (United States)

    Boels, Margien G S; Koudijs, Angela; Avramut, M Cristina; Sol, Wendy M P J; Wang, Gangqi; van Oeveren-Rietdijk, Annemarie M; van Zonneveld, Anton Jan; de Boer, Hetty C; van der Vlag, Johan; van Kooten, Cees; Eulberg, Dirk; van den Berg, Bernard M; IJpelaar, Daphne H T; Rabelink, Ton J

    2017-11-01

    Inhibition of monocyte chemotactic protein-1 (MCP-1) with the Spiegelmer emapticap pegol (NOX-E36) shows long-lasting albuminuria-reducing effects in diabetic nephropathy. MCP-1 regulates inflammatory cell recruitment and differentiation of macrophages. Because the endothelial glycocalyx is also reduced in diabetic nephropathy, we hypothesized that MCP-1 inhibition restores glomerular barrier function through influencing macrophage cathepsin L secretion, thus reducing activation of the glycocalyx-degrading enzyme heparanase. Four weeks of treatment of diabetic Apoe knockout mice with the mouse-specific NOX-E36 attenuated albuminuria without any change in systemic hemodynamics, despite persistent loss of podocyte function. MCP-1 inhibition, however, increased glomerular endothelial glycocalyx coverage, with preservation of heparan sulfate. Mechanistically, both glomerular cathepsin L and heparanase expression were reduced. MCP-1 inhibition resulted in reduced CCR2-expressing Ly6C hi monocytes in the peripheral blood, without affecting overall number of kidney macrophages at the tissue level. However, the CD206 + /Mac3 + cell ratio, as an index of presence of anti-inflammatory macrophages, increased in diabetic mice after treatment. Functional analysis of isolated renal macrophages showed increased release of IL-10, whereas tumor necrosis factor and cathepsin L release was reduced, further confirming polarization of tissue macrophages toward an anti-inflammatory phenotype during mouse-specific NOX-E36 treatment. We show that MCP-1 inhibition restores glomerular endothelial glycocalyx and barrier function and reduces tissue inflammation in the presence of ongoing diabetic injury, suggesting a therapeutic potential for NOX-E36 in diabetic nephropathy. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  11. Chloroquine, an Endocytosis Blocking Agent, Inhibits Zika Virus Infection in Different Cell Models

    Directory of Open Access Journals (Sweden)

    Rodrigo Delvecchio

    2016-11-01

    Full Text Available Zika virus (ZIKV infection in utero might lead to microcephaly and other congenital defects. Since no specific therapy is available thus far, there is an urgent need for the discovery of agents capable of inhibiting its viral replication and deleterious effects. Chloroquine is widely used as an antimalarial drug, anti-inflammatory agent, and it also shows antiviral activity against several viruses. Here we show that chloroquine exhibits antiviral activity against ZIKV in Vero cells, human brain microvascular endothelial cells, human neural stem cells, and mouse neurospheres. We demonstrate that chloroquine reduces the number of ZIKV-infected cells in vitro, and inhibits virus production and cell death promoted by ZIKV infection without cytotoxic effects. In addition, chloroquine treatment partially reveres morphological changes induced by ZIKV infection in mouse neurospheres.

  12. Chloroquine, an Endocytosis Blocking Agent, Inhibits Zika Virus Infection in Different Cell Models.

    Science.gov (United States)

    Delvecchio, Rodrigo; Higa, Luiza M; Pezzuto, Paula; Valadão, Ana Luiza; Garcez, Patrícia P; Monteiro, Fábio L; Loiola, Erick C; Dias, André A; Silva, Fábio J M; Aliota, Matthew T; Caine, Elizabeth A; Osorio, Jorge E; Bellio, Maria; O'Connor, David H; Rehen, Stevens; de Aguiar, Renato Santana; Savarino, Andrea; Campanati, Loraine; Tanuri, Amilcar

    2016-11-29

    Zika virus (ZIKV) infection in utero might lead to microcephaly and other congenital defects. Since no specific therapy is available thus far, there is an urgent need for the discovery of agents capable of inhibiting its viral replication and deleterious effects. Chloroquine is widely used as an antimalarial drug, anti-inflammatory agent, and it also shows antiviral activity against several viruses. Here we show that chloroquine exhibits antiviral activity against ZIKV in Vero cells, human brain microvascular endothelial cells, human neural stem cells, and mouse neurospheres. We demonstrate that chloroquine reduces the number of ZIKV-infected cells in vitro, and inhibits virus production and cell death promoted by ZIKV infection without cytotoxic effects. In addition, chloroquine treatment partially reveres morphological changes induced by ZIKV infection in mouse neurospheres.

  13. Asparagus polysaccharide and gum with hepatic artery embolization induces tumor growth and inhibits angiogenesis in an orthotopic hepatocellular carcinoma model.

    Science.gov (United States)

    Weng, Ling-Ling; Xiang, Jian-Feng; Lin, Jin-Bo; Yi, Shang-Hui; Yang, Li-Tao; Li, Yi-Sheng; Zeng, Hao-Tao; Lin, Sheng-Ming; Xin, Dong-Wei; Zhao, Hai-Liang; Qiu, Shu-Qi; Chen, Tao; Zhang, Min-Guang

    2014-01-01

    Liver cancer is one of leading digestive malignancies with high morbidity and mortality. There is an urgent need for the development of novel therapies for this deadly disease. It has been proven that asparagus polysaccharide, one of the most active derivates from the traditional medicine asparagus, possesses notable antitumor properties. However, little is known about the efficacy of asparagus polysaccharide as an adjuvant for liver cancer chemotherapy. Herein, we reported that asparagus polysaccharide and its embolic agent form, asparagus gum, significantly inhibited liver tumor growth with transcatheter arterial chemoembolization (TACE) therapy in an orthotopic hepatocellular carcinoma (HCC) tumor model, while significantly inhibiting angiogenesis and promoting tumor cell apoptosis. Moreover, asparagine gelatinous possessed immunomodulatory functions and showed little toxicity to the host. These results highlight the chemotherapeutic potential of asparagus polysaccharide and warrant a future focus on development as novel chemotherapeutic agent for liver cancer TACE therapy.

  14. Inhibition of TRF1 Telomere Protein Impairs Tumor Initiation and Progression in Glioblastoma Mouse Models and Patient-Derived Xenografts.

    Science.gov (United States)

    Bejarano, Leire; Schuhmacher, Alberto J; Méndez, Marinela; Megías, Diego; Blanco-Aparicio, Carmen; Martínez, Sonia; Pastor, Joaquín; Squatrito, Massimo; Blasco, Maria A

    2017-11-13

    Glioblastoma multiforme (GBM) is a deadly and common brain tumor. Poor prognosis is linked to high proliferation and cell heterogeneity, including glioma stem cells (GSCs). Telomere genes are frequently mutated. The telomere binding protein TRF1 is essential for telomere protection, and for adult and pluripotent stem cells. Here, we find TRF1 upregulation in mouse and human GBM. Brain-specific Trf1 genetic deletion in GBM mouse models inhibited GBM initiation and progression, increasing survival. Trf1 deletion increased telomeric DNA damage and reduced proliferation and stemness. TRF1 chemical inhibitors mimicked these effects in human GBM cells and also blocked tumor sphere formation and tumor growth in xenografts from patient-derived primary GSCs. Thus, targeting telomeres throughout TRF1 inhibition is an effective therapeutic strategy for GBM. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. A MICROCOMPUTER MODEL FOR IRRIGATION SYSTEM EVALUATION

    OpenAIRE

    Williams, Jeffery R.; Buller, Orlan H.; Dvorak, Gary J.; Manges, Harry L.

    1988-01-01

    ICEASE (Irrigation Cost Estimator and System Evaluator) is a microcomputer model designed and developed to meet the need for conducting economic evaluation of adjustments to irrigation systems and management techniques to improve the use of irrigated water. ICEASE can calculate the annual operating costs for irrigation systems and has five options that can be used to economically evaluate improvements in the pumping plant or the way the irrigation system is used for crop production.

  16. Misoprostol Inhibits Equine Neutrophil Adhesion, Migration, and Respiratory Burst in an In Vitro Model of Inflammation

    Directory of Open Access Journals (Sweden)

    Emily Medlin Martin

    2017-09-01

    Full Text Available In many equine inflammatory disease states, neutrophil activities, such as adhesion, migration, and reactive oxygen species (ROS production become dysregulated. Dysregulated neutrophil activation causes tissue damage in horses with asthma, colitis, laminitis, and gastric glandular disease. Non-steroidal anti-inflammatory drugs do not adequately inhibit neutrophil inflammatory functions and can lead to dangerous adverse effects. Therefore, novel therapies that target mechanisms of neutrophil-mediated tissue damage are needed. One potential neutrophil-targeting therapeutic is the PGE1 analog, misoprostol. Misoprostol is a gastroprotectant that induces intracellular formation of the secondary messenger molecule cyclic AMP (cAMP, which has been shown to have anti-inflammatory effects on neutrophils. Misoprostol is currently used in horses to treat NSAID-induced gastrointestinal injury; however, its effects on equine neutrophils have not been determined. We hypothesized that treatment of equine neutrophils with misoprostol would inhibit equine neutrophil adhesion, migration, and ROS production, in vitro. We tested this hypothesis using isolated equine peripheral blood neutrophils collected from 12 healthy adult teaching/research horses of mixed breed and gender. The effect of misoprostol treatment on adhesion, migration, and respiratory burst of equine neutrophils was evaluated via fluorescence-based adhesion and chemotaxis assays, and luminol-enhanced chemiluminescence, respectively. Neutrophils were pretreated with varying concentrations of misoprostol, vehicle, or appropriate functional inhibitory controls prior to stimulation with LTB4, CXCL8, PAF, lipopolysaccharide (LPS or immune complex (IC. This study revealed that misoprostol pretreatment significantly inhibited LTB4-induced adhesion, LTB4-, CXCL8-, and PAF-induced chemotaxis, and LPS-, IC-, and PMA-induced ROS production in a concentration-dependent manner. This data indicate that

  17. MODEL DRIVEN DEVELOPMENT OF ONLINE BANKING SYSTEMS

    Directory of Open Access Journals (Sweden)

    Bresfelean Vasile Paul

    2011-07-01

    Full Text Available In case of online applications the cycle of software development varies from the routine. The online environment, the variety of users, the treatability of the mass of information created by them, the reusability and the accessibility from different devices are all factors of these systems complexity. The use of model drive approach brings several advantages that ease up the development process. Working prototypes that simplify client relationship and serve as the base of model tests can be easily made from models describing the system. These systems make possible for the banks clients to make their desired actions from anywhere. The user has the possibility of accessing information or making transactions.

  18. Modelling and parameter estimation of dynamic systems

    CERN Document Server

    Raol, JR; Singh, J

    2004-01-01

    Parameter estimation is the process of using observations from a system to develop mathematical models that adequately represent the system dynamics. The assumed model consists of a finite set of parameters, the values of which are calculated using estimation techniques. Most of the techniques that exist are based on least-square minimization of error between the model response and actual system response. However, with the proliferation of high speed digital computers, elegant and innovative techniques like filter error method, H-infinity and Artificial Neural Networks are finding more and mor

  19. System Model of Daily Sediment Yield

    Science.gov (United States)

    Sharma, T. C.; Dickinson, W. T.

    1980-06-01

    Input-output systems concepts have been applied to the modeling of daily runoff-sediment yield of the Thames River in southern Ontario, Canada. Spectral and correlation techniques have been used to construct a parsimonious model of daily sediment yields. It is shown that a linear discrete dynamic model is possible in terms of the log-transformed daily runoff and sediment yield sequences. The fluvial system of the Thames River watershed exhibits a weak memory on a daily basis, and the noise component corrupting the watershed fluvial system resembles a white noise process.

  20. Impacts of selected dietary polyphenols on caramelization in model systems.

    Science.gov (United States)

    Zhang, Xinchen; Chen, Feng; Wang, Mingfu

    2013-12-15

    This study investigated the impacts of six dietary polyphenols (phloretin, naringenin, quercetin, epicatechin, chlorogenic acid and rosmarinic acid) on fructose caramelization in thermal model systems at either neutral or alkaline pH. These polyphenols were found to increase the browning intensity and antioxidant capacity of caramel. The chemical reactions in the system of sugar and polyphenol, which include formation of polyphenol-sugar adducts, were found to be partially responsible for the formation of brown pigments and heat-induced antioxidants based on instrumental analysis. In addition, rosmarinic acid was demonstrated to significantly inhibit the formation of 5-hydroxymethylfurfural (HMF). Thus this research added to the efforts of controlling caramelization by dietary polyphenols under thermal condition, and provided some evidence to propose dietary polyphenols as functional ingredients to modify the caramel colour and bioactivity as well as to lower the amount of heat-induced contaminants such as 5-hydroxymethylfurfural (HMF). Copyright © 2013 Elsevier Ltd. All rights reserved.

  1. Selective inhibition of TNFR1 reduces osteoclast numbers and is differentiated from anti-TNF in a LPS-driven model of inflammatory bone loss.

    Science.gov (United States)

    Espirito Santo, A I; Ersek, A; Freidin, A; Feldmann, M; Stoop, A A; Horwood, N J

    2015-09-04

    The treatment of autoimmune disorders has been revolutionised by the introduction of biologics such as anti-tumour necrosis factor (anti-TNF). Although in rheumatoid arthritis patients a bone sparing effect of anti-TNF has been shown, the mechanism is not fully understood. Anti-TNF molecules block tumour necrosis factor (TNF) and prevent signalling via both TNF receptor 1 (TNFR1; p55) and TNF receptor 2 (TNFR2; p75). However, signalling via TNFR2 is reported to have protective effects in a number of cell and organ systems. Hence we set out to investigate if pharmacological inhibition of TNFR1 had differential effects compared to pan-TNF inhibition in both an in vitro cell-based model of human osteoclast activity and an in vivo mouse model of lipopolysaccharide (LPS)-induced osteolysis. For the in vitro experiments the anti-human TNFR1 domain antibody (dAb) DMS5541 was used, whereas for the in vivo mouse experiments the anti-mouse TNFR1 dAb DMS5540 was used. We show that selective blocking of TNFR1 signalling reduced osteoclast formation in the presence of TNF. Subcutaneous LPS injection over the calvaria leads to the development of osteolytic lesions within days due to inflammation driven osteoclast formation. In this model, murine TNFR2 genetically fused with mouse IgG1 Fc domain (mTNFR2.Fc), an anti-TNF, did not protect from bone loss in contrast to anti-TNFR1, which significantly reduced lesion development, inflammatory infiltrate, and osteoclast number and size. These results support further exploring the use of TNFR1-selective inhibition in inflammatory bone loss disorders such as osteomyelitis and peri-prosthetic aseptic loosening. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Blocking p38 signalling inhibits chondrogenesis in vitro but not ankylosis in a model of ankylosing spondylitis in vivo.

    Science.gov (United States)

    Braem, Kirsten; Luyten, Frank P; Lories, Rik J U

    2012-05-01

    To investigate p38 mitogen activated protein kinase (MAPK) signalling in an in vitro model of bone morphogenetic protein (BMP) and transforming growth factor β (TGFβ)-induced chondrogenesis and in vivo, with specific attention to its potential role in ankylosing enthesitis. Human periosteum-derived cells (hPDCs) were cultured in pellets and stimulated with BMP2 or TGFβ1 in the presence or absence of a p38 inhibitor SB203580 or proinflammatory cytokines. Chondrogenic differentiation was evaluated using quantitative PCR. Male DBA/1 mice from different litters were caged together at the age of 8 weeks and treated with SB203580 in both a preventive and therapeutic strategy. The mice were evaluated for prospective signs of arthritis and the toe joints were analysed histologically to assess disease severity. p38 inhibition by SB203580 and proinflammatory cytokines downregulated chondrogenic markers in pellet cultures stimulated by BMP2 or TGFβ1. In contrast, the in vivo experiments resulted in an increased clinical incidence of arthritis and pathology severity score, reflecting progression towards ankylosis in mice given SB203580. Inhibition of p38 inhibited chondrogenic differentiation of progenitor cells, showing that not only the SMAD signalling pathways and also alternative activation of MAPKs including p38 contribute to chondrogenesis. Such an inhibitory effect is not found in an in vivo model of joint ankylosis and spondyloarthritis. Increased incidence and severity of disease in preventive experiments and shifts in disease stages in a therapeutic experimental set-up suggest that specific inhibition of p38 may have deleterious rather than beneficial effects.

  3. Noncompetitive Inhibition of 5-HT3 Receptors by Citral, Linalool, and Eucalyptol Revealed by Nonlinear Mixed-Effects Modeling

    Science.gov (United States)

    Jarvis, Gavin E.; Barbosa, Roseli

    2016-01-01

    Citral, eucalyptol, and linalool are widely used as flavorings, fragrances, and cosmetics. Here, we examined their effects on electrophysiological and binding properties of human 5-HT3 receptors expressed in Xenopus oocytes and human embryonic kidney 293 cells, respectively. Data were analyzed using nonlinear mixed-effects modeling to account for random variance in the peak current response between oocytes. The oils caused an insurmountable inhibition of 5‐HT–evoked currents (citral IC50 = 120 µM; eucalyptol = 258 µM; linalool = 141 µM) and did not compete with fluorescently labeled granisetron, suggesting a noncompetitive mechanism of action. Inhibition was not use‐dependent but required a 30-second preapplication. Compound washout caused a slow (∼180 seconds) but complete recovery. Coapplication of the oils with bilobalide or diltiazem indicated they did not bind at the same locations as these channel blockers. Homology modeling and ligand docking predicted binding to a transmembrane cavity at the interface of adjacent subunits. Liquid chromatography coupled to mass spectrometry showed that an essential oil extracted from Lippia alba contained 75.9% citral. This inhibited expressed 5‐HT3 receptors (IC50 = 45 µg ml−1) and smooth muscle contractions in rat trachea (IC50 = 200 µg ml−1) and guinea pig ileum (IC50 = 20 µg ml−1), providing a possible mechanistic explanation for why this oil has been used to treat gastrointestinal and respiratory ailments. These results demonstrate that citral, eucalyptol, and linalool inhibit 5-HT3 receptors, and their binding to a conserved cavity suggests a valuable target for novel allosteric modulators. PMID:26669427

  4. Preclinical Evidence of Anti-Tumor Activity Induced by EZH2 Inhibition in Human Models of Synovial Sarcoma.

    Directory of Open Access Journals (Sweden)

    Satoshi Kawano

    Full Text Available The catalytic activities of covalent and ATP-dependent chromatin remodeling are central to regulating the conformational state of chromatin and the resultant transcriptional output. The enzymes that catalyze these activities are often contained within multiprotein complexes in nature. Two such multiprotein complexes, the polycomb repressive complex 2 (PRC2 methyltransferase and the SWItch/Sucrose Non-Fermentable (SWI/SNF chromatin remodeler have been reported to act in opposition to each other during development and homeostasis. An imbalance in their activities induced by mutations/deletions in complex members (e.g. SMARCB1 has been suggested to be a pathogenic mechanism in certain human cancers. Here we show that preclinical models of synovial sarcoma-a cancer characterized by functional SMARCB1 loss via its displacement from the SWI/SNF complex through the pathognomonic SS18-SSX fusion protein-display sensitivity to pharmacologic inhibition of EZH2, the catalytic subunit of PRC2. Treatment with tazemetostat, a clinical-stage, selective and orally bioavailable small-molecule inhibitor of EZH2 enzymatic activity reverses a subset of synovial sarcoma gene expression and results in concentration-dependent cell growth inhibition and cell death specifically in SS18-SSX fusion-positive cells in vitro. Treatment of mice bearing either a cell line or two patient-derived xenograft models of synovial sarcoma leads to dose-dependent tumor growth inhibition with correlative inhibition of trimethylation levels of the EZH2-specific substrate, lysine 27 on histone H3. These data demonstrate a dependency of SS18-SSX-positive, SMARCB1-deficient synovial sarcomas on EZH2 enzymatic activity and suggests the potential utility of EZH2-targeted drugs in these genetically defined cancers.

  5. Externalizing Behaviour for Analysing System Models

    DEFF Research Database (Denmark)

    Ivanova, Marieta Georgieva; Probst, Christian W.; Hansen, René Rydhof

    2013-01-01

    System models have recently been introduced to model organisations and evaluate their vulnerability to threats and especially insider threats. Especially for the latter these models are very suitable, since insiders can be assumed to have more knowledge about the attacked organisation than outside......, if not impossible task to change behaviours. Especially when considering social engineering or the human factor in general, the ability to use different kinds of behaviours is essential. In this work we present an approach to make the behaviour a separate component in system models, and explore how to integrate...

  6. A Comparison of Behavioral Inhibition/ Activation System, Type D and Optimism in the Breast Cancer Patients and Healthy Controls

    Directory of Open Access Journals (Sweden)

    A Alipoor

    2015-04-01

    Full Text Available Background & aim: Nowadays, the role and importance of psychosocial factors on physical health, as well as the influence of personality characteristics in having psychosomatic diseases such as cancer are of interest to many researchers. In spite of increase in breast cancer in Iran, very few studies have been carried out on risk factors of breast cancer. The aim of this study was to evaluate the comparative Behavioral inhibition / Activation System, type D and optimism in the breast cancer patients and healthy individuals. Methods: In the present casual-comparative study, 190 people (95 Patients and 95 Normal Subjects were selected in Rasht, Iran. Moreover, the groups were matched for demographic characteristics (age, gender and education. All individuals diagnosed with Breast Cancer and Normal Subjects received a Gary-Wilson Personality Questionnaire, Life Orientation Test and Type D Personality Scale. Collected data were analyzed using multivariate analysis of variance and regression. Results: The findings revealed that there were significant differences between cancer and normal groups in behavioral inhibition/activation system, type D Personality and optimism. In this regard, the Breast Cancer group had higher scores subscales of negative affect, social inhibition, passive avoidance, extinction and fight-flight than normal group. In addition, subscales of approach, active avoidance and optimism in the normal group were more than the Breast Cancer group. Conclusion: The present study supported the role of psychological variables in breast cancer patients which is essential for improving patients’ health and quality of life.

  7. Inhibition of nitric oxide synthesis by systemic N(G)-monomethyl-L-arginine administration in humans

    DEFF Research Database (Denmark)

    Frandsen, U; Bangsbo, J; Langberg, Henning

    2000-01-01

    We examined whether the formation or the release of the vasodilators adenosine, prostacyclin (PGI(2)) and potassium (K(+)) increase in skeletal muscle interstitium in response to nitric oxide synthase (NOS) inhibition. Five subjects performed one-legged knee extensor exercise at 30 W without (con......-keto-prostaglandin F1alpha concentration in controls was 1.17+/-0.20 ng/ml at rest and increased (p0.05) in L-NAME. The interstitial K(+) concentration in controls increased (p...

  8. Estimation of fractions metabolized by hepatic CYP enzymes using a concept of inter-system extrapolation factors (ISEFs) - a comparison with the chemical inhibition method.

    Science.gov (United States)

    Umehara, Ken-Ichi; Huth, Felix; Gu, Helen; Schiller, Hilmar; Heimbach, Tycho; He, Handan

    2017-12-20

    For estimation of fractions metabolized (fm) by different hepatic recombinant human CYP enzymes (rhCYP), calculation of inter-system extrapolation factors (ISEFs) has been proposed. ISEF values for CYP1A2, CYP2C19 and CYP3A4/5 were measured. A CYP2C9 ISEF was taken from a previous report. Using a set of compounds, fractions metabolized by CYP enzymes (fm,CYP) values calculated with the ISEFs based on rhCYP data were compared with those from the chemical inhibition data. Oral pharmacokinetics (PK) profiles of midazolam were simulated using the physiologically based pharmacokinetics (PBPK) model with the CYP3A ISEF. For other CYPs, the in vitro fm,CYP values were compared with the reference fm,CYP data back-calculated with, e.g. modeling of test substrates by feeding clinical PK data. In vitro-in vitro fm,CYP3A4 relationship between the results from rhCYP incubation and chemical inhibition was drawn as an exponential correlation with R2=0.974. A midazolam PBPK model with the CYP3A4/5 ISEFs simulated the PK profiles within twofold error compared to the clinical observations. In a limited number of cases, the in vitro methods could not show good performance in predicting fm,CYP1A2, fm,CYP2C9 and fm,CYP2C19 values as reference data. The rhCYP data with the measured ISEFs provided reasonable calculation of fm,CYP3A4 values, showing slight over-estimation compared to chemical inhibition.

  9. Model transformation based information system modernization

    Directory of Open Access Journals (Sweden)

    Olegas Vasilecas

    2013-03-01

    Full Text Available Information systems begin to date increasingly faster because of rapidly changing business environment. Usually, small changes are not sufficient to adapt complex legacy information systems to changing business needs. A new functionality should be installed with the requirement of putting business data in the smallest possible risk. Information systems modernization problems are beeing analyzed in this paper and a method for information system modernization is proposed. It involves programming code transformation into abstract syntax tree metamodel (ASTM and model based transformation from ASTM into knowledge discovery model (KDM. The method is validated on example for SQL language.

  10. Photovoltaic System Modeling. Uncertainty and Sensitivity Analyses

    Energy Technology Data Exchange (ETDEWEB)

    Hansen, Clifford W. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States); Martin, Curtis E. [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

    2015-08-01

    We report an uncertainty and sensitivity analysis for modeling AC energy from ph otovoltaic systems . Output from a PV system is predicted by a sequence of models. We quantify u ncertainty i n the output of each model using empirical distribution s of each model's residuals. We propagate uncertainty through the sequence of models by sampli ng these distributions to obtain a n empirical distribution of a PV system's output. We consider models that: (1) translate measured global horizontal, direct and global diffuse irradiance to plane - of - array irradiance; (2) estimate effective irradiance; (3) predict cell temperature; (4) estimate DC voltage, current and power ; (5) reduce DC power for losses due to inefficient maximum power point tracking or mismatch among modules; and (6) convert DC to AC power . O ur analysis consider s a notional PV system com prising an array of FirstSolar FS - 387 modules and a 250 kW AC inverter ; we use measured irradiance and weather at Albuquerque, NM. We found the uncertainty in PV syste m output to be relatively small, on the order of 1% for daily energy. We found that unce rtainty in the models for POA irradiance and effective irradiance to be the dominant contributors to uncertainty in predicted daily energy. Our analysis indicates that efforts to reduce the uncertainty in PV system output predictions may yield the greatest improvements by focusing on the POA and effective irradiance models.

  11. Climate Model Diagnostic Analyzer Web Service System

    Science.gov (United States)

    Lee, S.; Pan, L.; Zhai, C.; Tang, B.; Kubar, T. L.; Li, J.; Zhang, J.; Wang, W.

    2015-12-01

    Both the National Research Council Decadal Survey and the latest Intergovernmental Panel on Climate Change Assessment Report stressed the need for the comprehensive and innovative evaluation of climate models with the synergistic use of global satellite observations in order to improve our weather and climate simulation and prediction capabilities. The abundance of satellite observations for fundamental climate parameters and the availability of coordinated model outputs from CMIP5 for the same parameters offer a great opportunity to understand and diagnose model biases in climate models. In addition, the Obs4MIPs efforts have created several key global observational datasets that are readily usable for model evaluations. However, a model diagnostic evaluation process requires physics-based multi-variable comparisons that typically involve large-volume and heterogeneous datasets, making them both computationally- and data-intensive. In response, we have developed a novel methodology to diagnose model biases in contemporary climate models and implementing the methodology as a web-service based, cloud-enabled, provenance-supported climate-model evaluation system. The evaluation system is named Climate Model Diagnostic Analyzer (CMDA), which is the product of the research and technology development investments of several current and past NASA ROSES programs. The current technologies and infrastructure of CMDA are designed and selected to address several technical challenges that the Earth science modeling and model analysis community faces in evaluating and diagnosing climate models. In particular, we have three key technology components: (1) diagnostic analysis methodology; (2) web-service based, cloud-enabled technology; (3) provenance-supported technology. The diagnostic analysis methodology includes random forest feature importance ranking, conditional probability distribution function, conditional sampling, and time-lagged correlation map. We have implemented the

  12. Transforming Graphical System Models to Graphical Attack Models

    DEFF Research Database (Denmark)

    Ivanova, Marieta Georgieva; Probst, Christian W.; Hansen, Rene Rydhof

    2016-01-01

    Manually identifying possible attacks on an organisation is a complex undertaking; many different factors must be considered, and the resulting attack scenarios can be complex and hard to maintain as the organisation changes. System models provide a systematic representation of organisations...... that helps in structuring attack identification and can integrate physical, virtual, and social components. These models form a solid basis for guiding the manual identification of attack scenarios. Their main benefit, however, is in the analytic generation of attacks. In this work we present a systematic...... approach to transforming graphical system models to graphical attack models in the form of attack trees. Based on an asset in the model, our transformations result in an attack tree that represents attacks by all possible actors in the model, after which the actor in question has obtained the asset....

  13. CTBT integrated verification system evaluation model supplement

    Energy Technology Data Exchange (ETDEWEB)

    EDENBURN,MICHAEL W.; BUNTING,MARCUS; PAYNE JR.,ARTHUR C.; TROST,LAWRENCE C.

    2000-03-02

    Sandia National Laboratories has developed a computer based model called IVSEM (Integrated Verification System Evaluation Model) to estimate the performance of a nuclear detonation monitoring system. The IVSEM project was initiated in June 1994, by Sandia's Monitoring Systems and Technology Center and has been funded by the U.S. Department of Energy's Office of Nonproliferation and National Security (DOE/NN). IVSEM is a simple, ''top-level,'' modeling tool which estimates the performance of a Comprehensive Nuclear Test Ban Treaty (CTBT) monitoring system and can help explore the impact of various sensor system concepts and technology advancements on CTBT monitoring. One of IVSEM's unique features is that it integrates results from the various CTBT sensor technologies (seismic, in sound, radionuclide, and hydroacoustic) and allows the user to investigate synergy among the technologies. Specifically, IVSEM estimates the detection effectiveness (probability of detection), location accuracy, and identification capability of the integrated system and of each technology subsystem individually. The model attempts to accurately estimate the monitoring system's performance at medium interfaces (air-land, air-water) and for some evasive testing methods such as seismic decoupling. The original IVSEM report, CTBT Integrated Verification System Evaluation Model, SAND97-25 18, described version 1.2 of IVSEM. This report describes the changes made to IVSEM version 1.2 and the addition of identification capability estimates that have been incorporated into IVSEM version 2.0.

  14. CTBT integrated verification system evaluation model supplement

    International Nuclear Information System (INIS)

    EDENBURN, MICHAEL W.; BUNTING, MARCUS; PAYNE, ARTHUR C. JR.; TROST, LAWRENCE C.

    2000-01-01

    Sandia National Laboratories has developed a computer based model called IVSEM (Integrated Verification System Evaluation Model) to estimate the performance of a nuclear detonation monitoring system. The IVSEM project was initiated in June 1994, by Sandia's Monitoring Systems and Technology Center and has been funded by the U.S. Department of Energy's Office of Nonproliferation and National Security (DOE/NN). IVSEM is a simple, ''top-level,'' modeling tool which estimates the performance of a Comprehensive Nuclear Test Ban Treaty (CTBT) monitoring system and can help explore the impact of various sensor system concepts and technology advancements on CTBT monitoring. One of IVSEM's unique features is that it integrates results from the various CTBT sensor technologies (seismic, in sound, radionuclide, and hydroacoustic) and allows the user to investigate synergy among the technologies. Specifically, IVSEM estimates the detection effectiveness (probability of detection), location accuracy, and identification capability of the integrated system and of each technology subsystem individually. The model attempts to accurately estimate the monitoring system's performance at medium interfaces (air-land, air-water) and for some evasive testing methods such as seismic decoupling. The original IVSEM report, CTBT Integrated Verification System Evaluation Model, SAND97-25 18, described version 1.2 of IVSEM. This report describes the changes made to IVSEM version 1.2 and the addition of identification capability estimates that have been incorporated into IVSEM version 2.0

  15. A distributed snow-evolution modeling system (SnowModel)

    Science.gov (United States)

    Glen E. Liston; Kelly. Elder

    2006-01-01

    SnowModel is a spatially distributed snow-evolution modeling system designed for application in landscapes, climates, and conditions where snow occurs. It is an aggregation of four submodels: MicroMet defines meteorological forcing conditions, EnBal calculates surface energy exchanges, SnowPack simulates snow depth and water-equivalent evolution, and SnowTran-3D...

  16. Deficits in Response Inhibition in Patients with Attention-Deficit/Hyperactivity Disorder: The Impaired Self-Protection System Hypothesis

    Directory of Open Access Journals (Sweden)

    Thales Vianna Coutinho

    2018-01-01

    Full Text Available Problems in inhibitory control are regarded in Psychology as a key problem associated with attention-deficit/hyperactivity disorder (ADHD. They, however, might not be primary deficits, but instead a consequence of inattention. At least two components have been identified and dissociated in studies in regards to inhibitory control: interference suppression, responsible for controlling interference by resisting irrelevant or misleading information, and response inhibition, referring to withholding a response or overriding an ongoing behavior. Poor error awareness and self-monitoring undermine an individual’s ability to inhibit inadequate responses and change course of action. In non-social contexts, an individual depends on his own cognition to regulate his mistakes. In social contexts, however, there are many social cues that should help that individual to perceive his mistakes and inhibit inadequate responses. The processes involved in perceiving and interpreting those social cues are arguably part of a self-protection system (SPS. Individuals with ADHD not only present impulsive behaviors in social contexts, but also have difficulty perceiving their inadequate responses and overriding ongoing actions toward more appropriate ones. In this paper, we discuss that those difficulties are arguably a consequence of an impaired SPS, due to visual attention deficits and subsequent failure in perceiving and recognizing accurately negative emotions in facial expressions, especially anger. We discuss evidence that children with ADHD exhibit problems in a series of components involved in the activation of that system and advocate that the inability to identify the anger expressed by others, and thus, not experiencing the fear response that should follow, is, ultimately, what prevents them from inhibiting the ongoing inappropriate behavior, since a potential threat is not registered. Getting involved in high-risk situations, such as reckless driving, could

  17. Deficits in Response Inhibition in Patients with Attention-Deficit/Hyperactivity Disorder: The Impaired Self-Protection System Hypothesis.

    Science.gov (United States)

    Coutinho, Thales Vianna; Reis, Samara Passos Santos; da Silva, Antonio Geraldo; Miranda, Debora Marques; Malloy-Diniz, Leandro Fernandes

    2017-01-01

    Problems in inhibitory control are regarded in Psychology as a key problem associated with attention-deficit/hyperactivity disorder (ADHD). They, however, might not be primary deficits, but instead a consequence of inattention. At least two components have been identified and dissociated in studies in regards to inhibitory control: interference suppression, responsible for controlling interference by resisting irrelevant or misleading information, and response inhibition, referring to withholding a response or overriding an ongoing behavior. Poor error awareness and self-monitoring undermine an individual's ability to inhibit inadequate responses and change course of action. In non-social contexts, an individual depends on his own cognition to regulate his mistakes. In social contexts, however, there are many social cues that should help that individual to perceive his mistakes and inhibit inadequate responses. The processes involved in perceiving and interpreting those social cues are arguably part of a self-protection system (SPS). Individuals with ADHD not only present impulsive behaviors in social contexts, but also have difficulty perceiving their inadequate responses and overriding ongoing actions toward more appropriate ones. In this paper, we discuss that those difficulties are arguably a consequence of an impaired SPS, due to visual attention deficits and subsequent failure in perceiving and recognizing accurately negative emotions in facial expressions, especially anger. We discuss evidence that children with ADHD exhibit problems in a series of components involved in the activation of that system and advocate that the inability to identify the anger expressed by others, and thus, not experiencing the fear response that should follow, is, ultimately, what prevents them from inhibiting the ongoing inappropriate behavior, since a potential threat is not registered. Getting involved in high-risk situations, such as reckless driving, could also be a

  18. Model Updating Nonlinear System Identification Toolbox Project

    Data.gov (United States)

    National Aeronautics and Space Administration — ZONA Technology proposes to develop an enhanced model updating nonlinear system identification (MUNSID) methodology by adopting the flight data with state-of-the-art...

  19. Power system coherency and model reduction

    CERN Document Server

    Chow, Joe H

    2014-01-01

    This book provides a comprehensive treatment for understanding interarea modes in large power systems and obtaining reduced-order models using the coherency concept and selective modal analysis method.

  20. Regional Ocean Modeling System (ROMS): Samoa

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Regional Ocean Modeling System (ROMS) 7-day, 3-hourly forecast for the region surrounding the islands of Samoa at approximately 3-km resolution. While considerable...

  1. Systemic Therapy: A New Brief Intervention Model.

    Science.gov (United States)

    Searight, H. Russell; Openlander, Patrick

    1984-01-01

    Describes a newly developing mode of problem-oriented brief therapy. The systemic therapy model emphasizes the interactional context of clients' problems and represents an efficient intervention paradigm. (Author/JAC)

  2. Regional Ocean Modeling System (ROMS): CNMI

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Regional Ocean Modeling System (ROMS) 7-day, 3-hourly forecast for the region surrounding the Commonwealth of the Northern Mariana Islands (CNMI) at approximately...

  3. Regional Ocean Modeling System (ROMS): Guam

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Regional Ocean Modeling System (ROMS) 6-day, 3-hourly forecast for the region surrounding Guam at approximately 2-km resolution. While considerable effort has been...

  4. A Telecommunications Industry Primer: A Systems Model.

    Science.gov (United States)

    Obermier, Timothy R.; Tuttle, Ronald H.

    2003-01-01

    Describes the Telecommunications Systems Model to help technical educators and students understand the increasingly complex telecommunications infrastructure. Specifically looks at ownership and regulatory status, service providers, transport medium, network protocols, and end-user services. (JOW)

  5. Modeling Approaches and Systems Related to Structured Modeling.

    Science.gov (United States)

    1987-02-01

    Lasdon 򒾂> and Maturana 򒾃> for surveys of several modern systems. A -6- N NN- %0 CAMPS (Lucas and Mitra 򒾁>) -- Computer Assisted Mathe- %l...583-589. MATURANA , S. 򒾃>. "Comparative Analysis of Mathematical Modeling Systems," informal note, Graduate School of Manage- ment, UCLA, February

  6. Adaptation and inhibition underlie responses to time-varying interaural phase cues in a model of inferior colliculus neurons.

    Science.gov (United States)

    Borisyuk, Alla; Semple, Malcolm N; Rinzel, John

    2002-10-01

    A mathematical model was developed for exploring the sensitivity of low-frequency inferior colliculus (IC) neurons to interaural phase disparity (IPD). The formulation involves a firing-rate-type model that does not include spikes per se. The model IC neuron receives IPD-tuned excitatory and inhibitory inputs (viewed as the output of a collection of cells in the medial superior olive). The model cell possesses cellular properties of firing rate adaptation and postinhibitory rebound (PIR). The descriptions of these mechanisms are biophysically reasonable, but only semi-quantitative. We seek to explain within a minimal model the experimentally observed mismatch between responses to IPD stimuli delivered dynamically and those delivered statically (McAlpine et al. 2000; Spitzer and Semple 1993). The model reproduces many features of the responses to static IPD presentations, binaural beat, and partial range sweep stimuli. These features include differences in responses to a stimulus presented in static or dynamic context: sharper tuning and phase shifts in response to binaural beats, and hysteresis and "rise-from-nowhere" in response to partial range sweeps. Our results suggest that dynamic response features are due to the structure of inputs and the presence of firing rate adaptation and PIR mechanism in IC cells, but do not depend on a specific biophysical mechanism. We demonstrate how the model's various components contribute to shaping the observed phenomena. For example, adaptation, PIR, and transmission delay shape phase advances and delays in responses to binaural beats, adaptation and PIR shape hysteresis in different ranges of IPD, and tuned inhibition underlies asymmetry in dynamic tuning properties. We also suggest experiments to test our modeling predictions: in vitro simulation of the binaural beat (phase advance at low beat frequencies, its dependence on firing rate), in vivo partial range sweep experiments (dependence of the hysteresis curve on

  7. Conceptual Modelling of Complex Production Systems

    Directory of Open Access Journals (Sweden)

    Nenad Perši

    2008-12-01

    Full Text Available Complex system dynamics, structure and behaviour performances call for a wide range of methods, algorithms and tools to reach a model capable of finding optimal performing parameters. In the modelling process, it is up to the analyst to select the appropriate combination of methods, algorithms and tools to express significant system performances. Such a methodology for designing complex systems should be based upon conceptual modelling to perform a sensitive analysis of different system levels and views, allowing system representations for developing computer models.Complex systems, such as business systems with a continuous-discrete production process, require a well organised supply chain highly reactive to production assortment changes. Aligning two different production components distinctive in their behaviour is especially delicate at the production parameters transition point. Such system performances require distinctive designing methods that can follow the double nature of the production process behaviour in accordance with their entities dynamics caused by assortment changes. Consequently, such systems need different conceptual presentations for their purpose to be realized from different views and aspects.

  8. Modeling of High Precision Positioning System

    Directory of Open Access Journals (Sweden)

    Giedrius Augustinavičius

    2014-02-01

    Full Text Available This paper presents the modeling of a flexure-based precisionpositioning system for micro-positioning uses. The positioningsystem is featured with monolithic architecture, flexure-basedjoints and ultra fine adjustment screws. Its workspace has beenevaluated via analytical approaches. Reduction mechanism isoptimally designed. The mathematical model of the positioningsystem has been derived, which is verified by resorting to finiteelement analysis (FEA. The established analytical and (FEAmodels are helpful for a reliable architecture optimization andperformance improvement of the positioning system.

  9. Ellipsoidal bag model for heavy quark system

    International Nuclear Information System (INIS)

    Bi Pinzhen; Fudan Univ., Shanghai

    1991-01-01

    The ellipsoidal bag model is used to describe heavy quark systems such as Qanti Q, Qanti Qg and Q 2 anti Q 2 . Instead of two step model, these states are described by an uniform picture. The potential derived from the ellipsoidal bag for Qanti Q is almost equivalent to the Cornell potential. For a Q 2 anti Q 2 system with large quark pair separation, an improvement of 70 MeV is obtained comparing with the spherical bag. (orig.)

  10. Hybrid Energy System Modeling in Modelica

    Energy Technology Data Exchange (ETDEWEB)

    William R. Binder; Christiaan J. J. Paredis; Humberto E. Garcia

    2014-03-01

    In this paper, a Hybrid Energy System (HES) configuration is modeled in Modelica. Hybrid Energy Systems (HES) have as their defining characteristic the use of one or more energy inputs, combined with the potential for multiple energy outputs. Compared to traditional energy systems, HES provide additional operational flexibility so that high variability in both energy production and consumption levels can be absorbed more effectively. This is particularly important when including renewable energy sources, whose output levels are inherently variable, determined by nature. The specific HES configuration modeled in this paper include two energy inputs: a nuclear plant, and a series of wind turbines. In addition, the system produces two energy outputs: electricity and synthetic fuel. The models are verified through simulations of the individual components, and the system as a whole. The simulations are performed for a range of component sizes, operating conditions, and control schemes.

  11. Model Reduction of Fuzzy Logic Systems

    Directory of Open Access Journals (Sweden)

    Zhandong Yu

    2014-01-01

    Full Text Available This paper deals with the problem of ℒ2-ℒ∞ model reduction for continuous-time nonlinear uncertain systems. The approach of the construction of a reduced-order model is presented for high-order nonlinear uncertain systems described by the T-S fuzzy systems, which not only approximates the original high-order system well with an ℒ2-ℒ∞ error performance level γ but also translates it into a linear lower-dimensional system. Then, the model approximation is converted into a convex optimization problem by using a linearization procedure. Finally, a numerical example is presented to show the effectiveness of the proposed method.

  12. System model development for nuclear thermal propulsion

    International Nuclear Information System (INIS)

    Walton, J.T.; Perkins, K.R.; Buksa, J.J.; Worley, B.A.; Dobranich, D.

    1992-01-01

    A critical enabling technology in the evolutionary development of nuclear thermal propulsion (NTP) is the ability to predict the system performance under a variety of operating conditions. Since October 1991, US (DOE), (DOD) and NASA have initiated critical technology development efforts for NTP systems to be used on Space Exploration Initiative (SEI) missions to the Moon and Mars. This paper presents the strategy and progress of an interagency NASA/DOE/DOD team for NTP system modeling. It is the intent of the interagency team to develop several levels of computer programs to simulate various NTP systems. An interagency team was formed for this task to use the best capabilities available and to assure appropriate peer review. The vision and strategy of the interagency team for developing NTP system models will be discussed in this paper. A review of the progress on the Level 1 interagency model is also presented

  13. Economic model of pipeline transportation systems

    Energy Technology Data Exchange (ETDEWEB)

    Banks, W. F.

    1977-07-29

    The objective of the work reported here was to develop a model which could be used to assess the economic effects of energy-conservative technological innovations upon the pipeline industry. The model is a dynamic simulator which accepts inputs of two classes: the physical description (design parameters, fluid properties, and financial structures) of the system to be studied, and the postulated market (throughput and price) projection. The model consists of time-independent submodels: the fluidics model which simulates the physical behavior of the system, and the financial model which operates upon the output of the fluidics model to calculate the economics outputs. Any of a number of existing fluidics models can be used in addition to that developed as a part of this study. The financial model, known as the Systems, Science and Software (S/sup 3/) Financial Projection Model, contains user options whereby pipeline-peculiar characteristics can be removed and/or modified, so that the model can be applied to virtually any kind of business enterprise. The several dozen outputs are of two classes: the energetics and the economics. The energetics outputs of primary interest are the energy intensity, also called unit energy consumption, and the total energy consumed. The primary economics outputs are the long-run average cost, profit, cash flow, and return on investment.

  14. System Identification, Environmental Modelling, and Control System Design

    CERN Document Server

    Garnier, Hugues

    2012-01-01

    System Identification, Environmetric Modelling, and Control Systems Design is dedicated to Professor Peter Young on the occasion of his seventieth birthday. Professor Young has been a pioneer in systems and control, and over the past 45 years he has influenced many developments in this field. This volume is comprised of a collection of contributions by leading experts in system identification, time-series analysis, environmetric modelling and control system design – modern research in topics that reflect important areas of interest in Professor Young’s research career. Recent theoretical developments in and relevant applications of these areas are explored treating the various subjects broadly and in depth. The authoritative and up-to-date research presented here will be of interest to academic researcher in control and disciplines related to environmental research, particularly those to with water systems. The tutorial style in which many of the contributions are composed also makes the book suitable as ...

  15. Automated statistical modeling of analytical measurement systems

    International Nuclear Information System (INIS)

    Jacobson, J.J.

    1992-01-01

    The statistical modeling of analytical measurement systems at the Idaho Chemical Processing Plant (ICPP) has been completely automated through computer software. The statistical modeling of analytical measurement systems is one part of a complete quality control program used by the Remote Analytical Laboratory (RAL) at the ICPP. The quality control program is an integration of automated data input, measurement system calibration, database management, and statistical process control. The quality control program and statistical modeling program meet the guidelines set forth by the American Society for Testing Materials and American National Standards Institute. A statistical model is a set of mathematical equations describing any systematic bias inherent in a measurement system and the precision of a measurement system. A statistical model is developed from data generated from the analysis of control standards. Control standards are samples which are made up at precise known levels by an independent laboratory and submitted to the RAL. The RAL analysts who process control standards do not know the values of those control standards. The object behind statistical modeling is to describe real process samples in terms of their bias and precision and, to verify that a measurement system is operating satisfactorily. The processing of control standards gives us this ability

  16. Modelling the Replication Management in Information Systems

    Directory of Open Access Journals (Sweden)

    Cezar TOADER

    2017-01-01

    Full Text Available In the modern economy, the benefits of Web services are significant because they facilitates the activities automation in the framework of Internet distributed businesses as well as the cooperation between organizations through interconnection process running in the computer systems. This paper presents the development stages of a model for a reliable information system. This paper describes the communication between the processes within the distributed system, based on the message exchange, and also presents the problem of distributed agreement among processes. A list of objectives for the fault-tolerant systems is defined and a framework model for distributed systems is proposed. This framework makes distinction between management operations and execution operations. The proposed model promotes the use of a central process especially designed for the coordination and control of other application processes. The execution phases and the protocols for the management and the execution components are presented. This model of a reliable system could be a foundation for an entire class of distributed systems models based on the management of replication process.

  17. Generic Sensor Failure Modeling for Cooperative Systems

    Directory of Open Access Journals (Sweden)

    Georg Jäger

    2018-03-01

    Full Text Available The advent of cooperative systems entails a dynamic composition of their components. As this contrasts current, statically composed systems, new approaches for maintaining their safety are required. In that endeavor, we propose an integration step that evaluates the failure model of shared information in relation to an application’s fault tolerance and thereby promises maintainability of such system’s safety. However, it also poses new requirements on failure models, which are not fulfilled by state-of-the-art approaches. Consequently, this work presents a mathematically defined generic failure model as well as a processing chain for automatically extracting such failure models from empirical data. By examining data of an Sharp GP2D12 distance sensor, we show that the generic failure model not only fulfills the predefined requirements, but also models failure characteristics appropriately when compared to traditional techniques.

  18. Generic Sensor Failure Modeling for Cooperative Systems

    Science.gov (United States)

    Jäger, Georg; Zug, Sebastian

    2018-01-01

    The advent of cooperative systems entails a dynamic composition of their components. As this contrasts current, statically composed systems, new approaches for maintaining their safety are required. In that endeavor, we propose an integration step that evaluates the failure model of shared information in relation to an application’s fault tolerance and thereby promises maintainability of such system’s safety. However, it also poses new requirements on failure models, which are not fulfilled by state-of-the-art approaches. Consequently, this work presents a mathematically defined generic failure model as well as a processing chain for automatically extracting such failure models from empirical data. By examining data of an Sharp GP2D12 distance sensor, we show that the generic failure model not only fulfills the predefined requirements, but also models failure characteristics appropriately when compared to traditional techniques. PMID:29558435

  19. Energy model in regional energy system

    International Nuclear Information System (INIS)

    Mura, P.G.; Baccoli, R.; Carlini, U.; Innamorati, R.; Mariotti, S.

    2005-01-01

    In this report is presented a computational model for analysis of energy, materials and mass flux in a complex energy system, at regional scale level. Specifically is described a calculation model of electric power generation for emission forecasting of CO 2 , SO x , NO x , particulate matter, ashes, limestone, chalks [it

  20. Immune System Model Calibration by Genetic Algorithm

    NARCIS (Netherlands)

    Presbitero, A.; Krzhizhanovskaya, V.; Mancini, E.; Brands, R.; Sloot, P.

    2016-01-01

    We aim to develop a mathematical model of the human immune system for advanced individualized healthcare where medication plan is fine-tuned to fit a patient's conditions through monitored biochemical processes. One of the challenges is calibrating model parameters to satisfy existing experimental

  1. Analytical system dynamics modeling and simulation

    CERN Document Server

    Fabien, Brian C

    2008-01-01

    This book offering a modeling technique based on Lagrange's energy method includes 125 worked examples. Using this technique enables one to model and simulate systems as diverse as a six-link, closed-loop mechanism or a transistor power amplifier.

  2. System level modelling with open source tools

    DEFF Research Database (Denmark)

    Jakobsen, Mikkel Koefoed; Madsen, Jan; Niaki, Seyed Hosein Attarzadeh

    , called ForSyDe. ForSyDe is available under the open Source approach, which allows small and medium enterprises (SME) to get easy access to advanced modeling capabilities and tools. We give an introduction to the design methodology through the system level modeling of a simple industrial use case, and we...

  3. Modafinil attenuates inflammation via inhibiting Akt/NF-κB pathway in apoE-deficient mouse model of atherosclerosis.

    Science.gov (United States)

    Han, Jinxia; Chen, Dongwei; Liu, Dayi; Zhu, Yanan

    2018-04-01

    Modafinil, an FDA approved wakefulness drug prescribed to narcolepsy patients, has recently been shown to have anti-inflammatory effects and provides protection against neuroinflammation. It is unknown if modafinil can also protect against atherosclerosis, pathogenesis of which implicates inflammation. Using an apoE-deficient mouse model, we tried to elucidate the effects of modafinil treatment on the development of atherosclerosis. We tested serum levels of cytokines. We isolated mouse bone marrow-derived macrophages (BMDMs), detected effect of modafinil on the viability and proliferation of BMDMs, and on oxidized low-density lipoprotein-induced IL-6 and TNF-α, and supernatant level of IFN-γ as well as NF-κB activity in BMDMs. Modafinil inhibited the development of atherosclerosis in apoE -/- mice. Modafinil suppressed the secretion of pro-inflammatory cytokines IL-6, TNF and IFN-γ, and promoted secretion of anti-inflammatory cytokines IL-4 and IL-10. Modafinil inhibited viability and proliferation of macrophages by negatively regulating levels of pro-inflammatory cytokines, p-Akt, p-IKBα and NF-κB activity in macrophages. Modafinil mitigates inflammation in apoE -/- atherosclerosis mice via inhibiting NF-κB activity in macrophages, and could potentially serve as a therapeutic agent for atherosclerosis.

  4. ACE Inhibition with Captopril Retards the Development of Signs of Neurodegeneration in an Animal Model of Alzheimer’s Disease

    Science.gov (United States)

    AbdAlla, Said; Langer, Andreas; Fu, Xuebin; Quitterer, Ursula

    2013-01-01

    Increased generation of reactive oxygen species (ROS) is a significant pathological feature in the brains of patients with Alzheimer’s disease (AD). Experimental evidence indicates that inhibition of brain ROS could be beneficial in slowing the neurodegenerative process triggered by amyloid-beta (Abeta) aggregates. The angiotensin II AT1 receptor is a significant source of brain ROS, and AD patients have an increased brain angiotensin-converting enzyme (ACE) level, which could account for an excessive angiotensin-dependent AT1-induced ROS generation. Therefore, we analyzed the impact of ACE inhibition on signs of neurodegeneration of aged Tg2576 mice as a transgenic animal model of AD. Whole genome microarray gene expression profiling and biochemical analyses demonstrated that the centrally active ACE inhibitor captopril normalized the excessive hippocampal ACE activity of AD mice. Concomitantly, the development of signs of neurodegeneration was retarded by six months of captopril treatment. The neuroprotective profile triggered by captopril was accompanied by reduced amyloidogenic processing of the amyloid precursor protein (APP), and decreased hippocampal ROS, which is known to enhance Abeta generation by increased activation of beta- and gamma-secretases. Taken together, our data present strong evidence that ACE inhibition with a widely used cardiovascular drug could interfere with Abeta-dependent neurodegeneration. PMID:23959119

  5. Inhibition of heme oxygenase activity using a microparticle formulation of zinc protoporphyrin in an acute hemolytic newborn mouse model.

    Science.gov (United States)

    Fujioka, Kazumichi; Kalish, Flora; Wong, Ronald J; Stevenson, David K

    2016-02-01

    Increased bilirubin production due to hemolysis can lead to neonatal hyperbilirubinemia. Inhibition of heme oxygenase (HO), the rate-limiting enzyme in heme catabolism, by metalloporphyrins (Mps) may be an ideal preventive strategy for neonatal hemolytic disease. Zinc protoporphyrin (ZnPP) is a naturally occurring Mp, potent, not phototoxic, with minimal HO-1 upregulation, but is not orally absorbed. Recently, we designed a lipid-based ZnPP formulation (ZnPP-Lipid), which is orally absorbed by newborn mice. Here, we evaluated the efficacy of ZnPP-Lipid in heme-loaded newborn mice, a model analogous to hemolytic infants. After 24 h of heme administration (30 µmol/kg s.c.), 4-d-old mice were given 30 µmol ZnPP-Lipid/kg via intragastric injections. After 3 h, liver and brain HO activity were measured. HO-1 upregulation was assessed by determinations of HO-1 protein, promoter activity, and mRNA by Western blot, in vivo bioluminescence imaging, and RT-PCR, respectively. After heme loading, liver HO activity significantly increased ~1.6-fold, which was inhibited in a dose-dependent manner by ZnPP-Lipid. A dose of 30 µmol/kg returned activity to control levels. Brain HO activity was not inhibited. No significant increases in liver and brain HO-1 protein, promoter activity, and mRNA were observed. ZnPP-Lipid is effective and thus has potential for treating neonatal hyperbilirubinemia due to hemolysis.

  6. Block of purinergic P2X7R inhibits tumor growth in a C6 glioma brain tumor animal model.

    Science.gov (United States)

    Ryu, Jae K; Jantaratnotai, Nattinee; Serrano-Perez, Maria C; McGeer, Patrick L; McLarnon, James G

    2011-01-01

    We examined the expression and pharmacological modulation of the purinergic receptor P2X7R in a C6 glioma model. Intrastriatal injection of C6 cells induced a time-dependent growth of tumor; at 2 weeks postinjection immunohistochemical analysis demonstrated higher levels of P2X7R in glioma-injected versus control vehicle-injected brains. P2X7R immunoreactivity colocalized with tumor cells and microglia, but not endogenous astrocytes. Intravenous administration of the P2X7R antagonist brilliant blue G (BBG) inhibited tumor growth in a spatially dependent manner from the C6 injection site. Treatment with BBG reduced tumor volume by 52% versus that in controls. Double immunostaining indicated that BBG treatment did not alter microgliosis, astrogliosis, or vasculature vessels in C6-injected animals. In vitro, BBG reduced the expression of P2X7R and glioma chemotaxis induced by the P2X7R ligand, 2',3'-O-(4-benzoyl-benzoyl)adenosine triphosphate (BzATP). Immunohistochemical staining of human glioblastoma tissue samples demonstrated greater expression of P2X7R compared to control nontumor samples. These results suggest that the efficacy of BBG in inhibiting tumor growth is primarily mediated by direct actions of the compound on P2X7R in glioma cells and that pharmacological inhibition of this purinergic receptor might serve as a strategy to slow the progression of brain tumors.

  7. Digestibility of Quinoa (Chenopodium quinoa Willd.) Protein Concentrate and Its Potential to Inhibit Lipid Peroxidation in the Zebrafish Larvae Model.

    Science.gov (United States)

    Vilcacundo, R; Barrio, D; Carpio, C; García-Ruiz, A; Rúales, J; Hernández-Ledesma, B; Carrillo, W

    2017-09-01

    Quinoa protein concentrate (QPC) was extracted and digested under in vitro gastrointestinal conditions. The protein content of QPC was in the range between 52.40 and 65.01% depending on the assay used. Quinoa proteins were almost completely hydrolyzed by pepsin at pH of 1.2, 2.0, and 3.2. At high pH, only partial hydrolysis was observed. During the duodenal phase, no intact proteins were visible, indicating their susceptibility to the in vitro simulated digestive conditions. Zebrafish larvae model was used to evaluate the in vivo ability of gastrointestinal digests to inhibit lipid peroxidation. Gastric digestion at pH 1.2 showed the highest lipid peroxidation inhibition percentage (75.15%). The lipid peroxidation activity increased after the duodenal phase. The digest obtained at the end of the digestive process showed an inhibition percentage of 82.10%, comparable to that showed when using BHT as positive control (87.13%).

  8. Decreased tonic inhibition in cerebellar granule cells causes motor dysfunction in a mouse model of Angelman syndrome.

    Science.gov (United States)

    Egawa, Kiyoshi; Kitagawa, Kyoko; Inoue, Koichi; Takayama, Masakazu; Takayama, Chitoshi; Saitoh, Shinji; Kishino, Tatsuya; Kitagawa, Masatoshi; Fukuda, Atsuo

    2012-12-05

    Angelman syndrome is a neurodevelopmental disorder caused by loss of function of the UBE3A gene encoding a ubiquitin E3 ligase. Motor dysfunction is a characteristic feature of Angelman syndrome, but neither the mechanisms of action nor effective therapeutic strategies have yet been elucidated. We report that tonic inhibition is specifically decreased in cerebellar granule cells of Ube3a-deficient mice, a model of Angelman syndrome. As a mechanism underlying this decrease in tonic inhibition, we show that Ube3a controls degradation of γ-aminobutyric acid (GABA) transporter 1 (GAT1) and that deficiency of Ube3a induces a surplus of GAT1 that results in a decrease in GABA concentrations in the extrasynaptic space. Administering low doses of 4,5,6,7-tetrahydroisothiazolo-[5,4-c]pyridin-3-ol (THIP), a selective extrasynaptic GABA(A) receptor agonist, improves the abnormal firing properties of a population of Purkinje cells in cerebellar brain slices and reduces cerebellar ataxia in Ube3a-deficient mice in vivo. These results suggest that pharmacologically increasing tonic inhibition may be a useful strategy for alleviating motor dysfunction in Angelman syndrome.

  9. Fibronectin connecting segment-1 peptide inhibits pathogenic leukocyte trafficking and inflammatory demyelination in experimental models of chronic inflammatory demyelinating polyradiculoneuropathy.

    Science.gov (United States)

    Dong, Chaoling; Greathouse, Kelsey M; Beacham, Rebecca L; Palladino, Steven P; Helton, E Scott; Ubogu, Eroboghene E

    2017-06-01

    The molecular determinants of pathogenic leukocyte migration across the blood-nerve barrier (BNB) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are unknown. Specific disease modifying therapies for CIDP are also lacking. Fibronectin connecting segment-1 (FNCS1), an alternatively spliced fibronectin variant expressed by microvascular endothelial cells at sites of inflammation in vitro and in situ, is a counterligand for leukocyte α 4 integrin (also known as CD49d) implicated in pathogenic leukocyte trafficking in multiple sclerosis and inflammatory bowel disease. We sought to determine the role of FNCS1 in CIDP patient leukocyte trafficking across the BNB in vitro and in severe chronic demyelinating neuritis in vivo using a representative spontaneous murine CIDP model. Peripheral blood mononuclear leukocytes from 7 untreated CIDP patients were independently infused into a cytokine-treated, flow-dependent in vitro BNB model system. Time-lapse digital video microscopy was performed to visualize and quantify leukocyte trafficking, comparing FNCS1 peptide blockade to relevant controls. Fifty 24-week old female B7-2 deficient non-obese diabetic mice with spontaneous autoimmune peripheral polyneuropathy (SAPP) were treated daily with 2mg/kg FNCS1 peptide for 5days via intraperitoneal injection with appropriate controls. Neurobehavioral measures of disease severity, motor nerve electrophysiology assessments and histopathological quantification of inflammation and morphometric assessment of demyelination were performed to determine in vivo efficacy. The biological relevance of FNCS1 and CD49d in CIDP was evaluated by immunohistochemical detection in affected patient sural nerve biopsies. 25μM FNCS1 peptide maximally inhibited CIDP leukocyte trafficking at the human BNB in vitro. FNCS1 peptide treatment resulted in significant improvements in disease severity, motor electrophysiological parameters of demyelination and histological measures of

  10. Modelling and control of dynamic systems using gaussian process models

    CERN Document Server

    Kocijan, Juš

    2016-01-01

    This monograph opens up new horizons for engineers and researchers in academia and in industry dealing with or interested in new developments in the field of system identification and control. It emphasizes guidelines for working solutions and practical advice for their implementation rather than the theoretical background of Gaussian process (GP) models. The book demonstrates the potential of this recent development in probabilistic machine-learning methods and gives the reader an intuitive understanding of the topic. The current state of the art is treated along with possible future directions for research. Systems control design relies on mathematical models and these may be developed from measurement data. This process of system identification, when based on GP models, can play an integral part of control design in data-based control and its description as such is an essential aspect of the text. The background of GP regression is introduced first with system identification and incorporation of prior know...

  11. Human performance modeling for system of systems analytics :soldier fatigue.

    Energy Technology Data Exchange (ETDEWEB)

    Lawton, Craig R.; Campbell, James E.; Miller, Dwight Peter

    2005-10-01

    The military has identified Human Performance Modeling (HPM) as a significant requirement and challenge of future systems modeling and analysis initiatives as can be seen in the Department of Defense's (DoD) Defense Modeling and Simulation Office's (DMSO) Master Plan (DoD 5000.59-P 1995). To this goal, the military is currently spending millions of dollars on programs devoted to HPM in various military contexts. Examples include the Human Performance Modeling Integration (HPMI) program within the Air Force Research Laboratory, which focuses on integrating HPMs with constructive models of systems (e.g. cockpit simulations) and the Navy's Human Performance Center (HPC) established in September 2003. Nearly all of these initiatives focus on the interface between humans and a single system. This is insufficient in the era of highly complex network centric SoS. This report presents research and development in the area of HPM in a system-of-systems (SoS). Specifically, this report addresses modeling soldier fatigue and the potential impacts soldier fatigue can have on SoS performance.

  12. Folate-targeted paclitaxel-conjugated polymeric micelles inhibits pulmonary metastatic hepatoma in experimental murine H22 metastasis models

    Directory of Open Access Journals (Sweden)

    Zhang Y

    2014-04-01

    Full Text Available Yan Zhang,1 Hui Zhang,2 Wenbin Wu,2 Fuhong Zhang,3,4 Shi Liu,3 Rui Wang,3 Yingchun Sun,1 Ti Tong,1 Xiabin Jing3 1Department of Thoracic Surgery, The Second Hospital of Jilin University, Changchun, Jilin, People's Republic of China; 2Department of Thoracic Surgery, Xuzhou Central Hospital, Xuzhou, Jiangsu, People's Republic of China; 3State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, People's Republic of China; 4Department of Otolaryngology, The First Hospital of Lanzhou University, Lanzhou, Gansu, People's Republic of China Abstract: Hepatocellular carcinoma shows low response to most conventional chemotherapies; additionally, extrahepatic metastasis from hepatoma is considered refractory to conventional systemic chemotherapy. Target therapy is a promising strategy for advanced hepatoma; however, targeted accumulation and controlled release of therapeutic agents into the metastatic site is still a great challenge. Folic acid (FA and paclitaxel (PTX containing composite micelles (FA-M[PTX] were prepared by coassembling the FA polymer conjugate and PTX polymer conjugate. The main purpose of this study is to investigate the inhibitory efficacy of FA-M(PTX on the pulmonary metastasis of intravenously injected murine hepatoma 22 (H22 on BALB/c mice models. The lung metastatic burden of H22 were measured and tissues were analyzed by immunohistochemistry and histology (hematoxylin and eosin stain, followed by survival analysis. The results indicated that FA-M(PTX prevented pulmonary metastasis of H22, and the efficacy was stronger than pure PTX and simple PTX-conjugated micelles. In particular, the formation of lung metastasis colonies in mice was evidently inhibited, which was paralleled with the downregulated expression of matrix metalloproteinase-2 and matrix metalloproteinase-9. Furthermore, the mice bearing pulmonary metastatic hepatoma in the FA

  13. Predictive Model of Systemic Toxicity (SOT)

    Science.gov (United States)

    In an effort to ensure chemical safety in light of regulatory advances away from reliance on animal testing, USEPA and L’Oréal have collaborated to develop a quantitative systemic toxicity prediction model. Prediction of human systemic toxicity has proved difficult and remains a ...

  14. CTBT Integrated Verification System Evaluation Model

    Energy Technology Data Exchange (ETDEWEB)

    Edenburn, M.W.; Bunting, M.L.; Payne, A.C. Jr.

    1997-10-01

    Sandia National Laboratories has developed a computer based model called IVSEM (Integrated Verification System Evaluation Model) to estimate the performance of a nuclear detonation monitoring system. The IVSEM project was initiated in June 1994, by Sandia`s Monitoring Systems and Technology Center and has been funded by the US Department of Energy`s Office of Nonproliferation and National Security (DOE/NN). IVSEM is a simple, top-level, modeling tool which estimates the performance of a Comprehensive Nuclear Test Ban Treaty (CTBT) monitoring system and can help explore the impact of various sensor system concepts and technology advancements on CTBT monitoring. One of IVSEM`s unique features is that it integrates results from the various CTBT sensor technologies (seismic, infrasound, radionuclide, and hydroacoustic) and allows the user to investigate synergy among the technologies. Specifically, IVSEM estimates the detection effectiveness (probability of detection) and location accuracy of the integrated system and of each technology subsystem individually. The model attempts to accurately estimate the monitoring system`s performance at medium interfaces (air-land, air-water) and for some evasive testing methods such as seismic decoupling. This report describes version 1.2 of IVSEM.

  15. Modeling a Longitudinal Relational Research Data Systems

    Science.gov (United States)

    Olsen, Michelle D. Hunt

    2010-01-01

    A study was conducted to propose a research-based model for a longitudinal data research system that addressed recommendations from a synthesis of literature related to: (1) needs reported by the U.S. Department of Education, (2) the twelve mandatory elements that define federally approved state longitudinal data systems (SLDS), (3) the…

  16. Economic Models and Algorithms for Distributed Systems

    CERN Document Server

    Neumann, Dirk; Altmann, Jorn; Rana, Omer F

    2009-01-01

    Distributed computing models for sharing resources such as Grids, Peer-to-Peer systems, or voluntary computing are becoming increasingly popular. This book intends to discover fresh avenues of research and amendments to existing technologies, aiming at the successful deployment of commercial distributed systems

  17. Installed water resource modelling systems for catchment ...

    African Journals Online (AJOL)

    Following international trends there are a growing number of modelling systems being installed for integrated water resource management, in Southern Africa. Such systems are likely to be installed for operational use in ongoing learning, research, strategic planning and consensus-building amongst stakeholders in the ...

  18. Knowledge Management System Model for Learning Organisations

    Science.gov (United States)

    Amin, Yousif; Monamad, Roshayu

    2017-01-01

    Based on the literature of knowledge management (KM), this paper reports on the progress of developing a new knowledge management system (KMS) model with components architecture that are distributed over the widely-recognised socio-technical system (STS) aspects to guide developers for selecting the most applicable components to support their KM…

  19. Eclectic Model in the Malaysian Education System

    Science.gov (United States)

    Othman, Nooraini; Mohamad, Khairul Azmi; Ilmuwan, Yayasan

    2011-01-01

    The present work aims at analysing the adoption of eclectic model in the Malaysian education system. The analysis is specifically looked from the angle of Islam and the Muslims. Malaysia has a long history of education system developments, from pre to post independence of the country. From what was initially traditional, modernity later came to…

  20. Modelling of functional systems of managerial accounting

    Directory of Open Access Journals (Sweden)

    O.V. Fomina

    2017-12-01

    Full Text Available The modern stage of managerial accounting development takes place under the powerful influence of managerial innovations. The article aimed at the development of integrational model of budgeting and the system of balanced indices in the system of managerial accounting that will contribute the increasing of relevance for making managerial decisions by managers of different levels management. As a result of the study the author proposed the highly pragmatical integration model of budgeting and system of the balanced indices in the system of managerial accounting, which is realized by the development of the system of gathering, consolidation, analysis, and interpretation of financial and nonfinancial information, contributes the increasing of relevance for making managerial decisions on the base of coordination and effective and purpose orientation both strategical and operative resources of an enterprise. The effective integrational process of the system components makes it possible to distribute limited resources rationally taking into account prospective purposes and strategic initiatives, to carry

  1. Degradation Modelling for Health Monitoring Systems

    International Nuclear Information System (INIS)

    Stetter, R; Witczak, M

    2014-01-01

    Condition-monitoring plays an increasingly important role for technical processes in order to improve reliability, availability, maintenance and lifetime of equipment. With increasing demands for efficiency and product quality, plus progress in the integration of automatic control systems in high-cost mechatronic and critical safety processes, the field of health monitoring is gaining interest. A similar research field is concerned with an estimation of the remaining useful life. A central question in these fields is the modelling of degradation; degradation is a process of a gradual and irreversible accumulation of damage which will finally result in a failure of the system. This paper is based on a current research project and explores various degradation modelling techniques. These results are explained on the basis of an industrial product – a system for the generation of health status information for pump systems. The result of this fuzzy-logic based system is a single number indicating the current health of a pump system

  2. World energy projection system: Model documentation

    International Nuclear Information System (INIS)

    1992-06-01

    The World Energy Project System (WEPS) is an accounting framework that incorporates projects from independently documented models and assumptions about the future energy intensity of economic activity (ratios of total energy consumption divided by gross domestic product) and about the rate of incremental energy requirements met by hydropower, geothermal, coal, and natural gas to produce projections of world energy consumption published annually by the Energy Information Administration (EIA) in the International Energy Outlook (IEO) (Figure 1). Two independently documented models presented in Figure 1, the Oil Market Simulation (OMS) model and the World Integrated Nuclear Evaluation System (WINES) provide projections of oil and nuclear power consumption published in the IEO. Output from a third independently documented model, and the International Coal Trade Model (ICTM), is not published in the IEO but is used in WEPS as a supply check on projections of world coal consumption produced by WEPS and published in the IEO. A WEPS model of natural gas production documented in this report provides the same type of implicit supply check on the WEPS projections of world natural gas consumption published in the IEO. Two additional models are included in Figure 1, the OPEC Capacity model and the Non-OPEC Oil Production model. These WEPS models provide inputs to the OMS model and are documented in this report

  3. OFFl Models: Novel Schema for Dynamical Modeling of Biological Systems.

    Directory of Open Access Journals (Sweden)

    C Brandon Ogbunugafor

    Full Text Available Flow diagrams are a common tool used to help build and interpret models of dynamical systems, often in biological contexts such as consumer-resource models and similar compartmental models. Typically, their usage is intuitive and informal. Here, we present a formalized version of flow diagrams as a kind of weighted directed graph which follow a strict grammar, which translate into a system of ordinary differential equations (ODEs by a single unambiguous rule, and which have an equivalent representation as a relational database. (We abbreviate this schema of "ODEs and formalized flow diagrams" as OFFL. Drawing a diagram within this strict grammar encourages a mental discipline on the part of the modeler in which all dynamical processes of a system are thought of as interactions between dynamical species that draw parcels from one or more source species and deposit them into target species according to a set of transformation rules. From these rules, the net rate of change for each species can be derived. The modeling schema can therefore be understood as both an epistemic and practical heuristic for modeling, serving both as an organizational framework for the model building process and as a mechanism for deriving ODEs. All steps of the schema beyond the initial scientific (intuitive, creative abstraction of natural observations into model variables are algorithmic and easily carried out by a computer, thus enabling the future development of a dedicated software implementation. Such tools would empower the modeler to consider significantly more complex models than practical limitations might have otherwise proscribed, since the modeling framework itself manages that complexity on the modeler's behalf. In this report, we describe the chief motivations for OFFL, carefully outline its implementation, and utilize a range of classic examples from ecology and epidemiology to showcase its features.

  4. Multi-targeted DATS Prevents Tumor Progression and Promotes Apoptosis in an Animal Model of Glioblastoma via HDAC-inhibition

    Science.gov (United States)

    Wallace, Gerald C; Haar, Catherine P; Vandergrift, W Alex; Giglio, Pierre; Ray, Swapan K; Patel, Sunil J; Banik, Naren L; Das, Arabinda

    2015-01-01

    Glioblastoma, the most malignant and lethal of brain tumors, remains incurable despite aggressive chemotherapy and surgical interventions. Few new chemotherapeutics for glioblastoma therapy have been explored in preclinical models, and some agents approved for have reached the clinical setting. However success rates are not significant. Previous investigations involving diallyl trisulfide (DATS), a garlic constituent, have indicated significant anti-cancer effects in vitro, including: glioblastoma growth inhibition, extrinsic and intrinsic apoptotic pathway activation, and cell death. DATS has also been shown to inhibit histone deacetylase activity and impede glioblastoma tumor progression. We hypothesized that DATS would block ectopic U87MG induced tumors by inhibiting multiple pro-apoptotic pathways via HDAC. To this end, ectopic tumors were developed in SCID mice and subsequently treated with daily intraperitoneal injections of DATS. Results indicate that a range of DATS doses (10μg/kg-10mg/kg) dose-dependently reduced tumor volume and number of mitotic cells within tumors after seven days. Our histological and biochemical assays demonstrate that DATS reduces mitosis in tumors, decreases HDAC activity, increases in acetylation of H3 and H4, inhibits cell cycle progression, promotes apoptotic cascade activation (m-calpian, Bax, caspase-3) and decreases pro-survival markers (Survivin, Bcl-2, p-Akt, c-Myc, mTOR, EGFR, VEGF). Our data also demonstrates an increase in p21/WAF1 expression, which correlates with increased p53 expression and MDM2 degradation following DATS treatment. Finally, histological assessment and enzyme assays suggest that even the highest dose of DATS administered in this study did not negatively impact hepatic function. These in vivo findings strongly support orthotopic investigation into the therapeutic potential of DATS and further review of the epigenetic mechanisms behind its anti-cancer activities. PMID:23754639

  5. Using Human Life Stage PBPK/PD Model Predictions of Perchlorate-Induced Iodide Inhibition to Inform Risk Assessment in Sensitive Populations

    National Research Council Canada - National Science Library

    Mattie, David R; Sterner, Teresa R; Merrill, Elaine A; Clewell, Rebecca A

    2006-01-01

    .... Recently, existing physiologically based pharmacokinetics/pharmacodynamic (PBPK/PD) models across life-stages in rat and in adult human were expanded to describe inhibition kinetics during-perinatal development in humans...

  6. Compiling models into real-time systems

    International Nuclear Information System (INIS)

    Dormoy, J.L.; Cherriaux, F.; Ancelin, J.

    1992-08-01

    This paper presents an architecture for building real-time systems from models, and model-compiling techniques. This has been applied for building a real-time model-based monitoring system for nuclear plants, called KSE, which is currently being used in two plants in France. We describe how we used various artificial intelligence techniques for building it: a model-based approach, a logical model of its operation, a declarative implementation of these models, and original knowledge-compiling techniques for automatically generating the real-time expert system from those models. Some of those techniques have just been borrowed from the literature, but we had to modify or invent other techniques which simply did not exist. We also discuss two important problems, which are often underestimated in the artificial intelligence literature: size, and errors. Our architecture, which could be used in other applications, combines the advantages of the model-based approach with the efficiency requirements of real-time applications, while in general model-based approaches present serious drawbacks on this point

  7. Compiling models into real-time systems

    International Nuclear Information System (INIS)

    Dormoy, J.L.; Cherriaux, F.; Ancelin, J.

    1992-08-01

    This paper presents an architecture for building real-time systems from models, and model-compiling techniques. This has been applied for building a real-time model-base monitoring system for nuclear plants, called KSE, which is currently being used in two plants in France. We describe how we used various artificial intelligence techniques for building it: a model-based approach, a logical model of its operation, a declarative implementation of these models, and original knowledge-compiling techniques for automatically generating the real-time expert system from those models. Some of those techniques have just been borrowed from the literature, but we had to modify or invent other techniques which simply did not exist. We also discuss two important problems, which are often underestimated in the artificial intelligence literature: size, and errors. Our architecture, which could be used in other applications, combines the advantages of the model-based approach with the efficiency requirements of real-time applications, while in general model-based approaches present serious drawbacks on this point

  8. Liposomal Nanoparticles Carrying anti-IL6R Antibody to the Tumour Microenvironment Inhibit Metastasis in Two Molecular Subtypes of Breast Cancer Mouse Models.

    Science.gov (United States)

    Guo, Chunlei; Chen, Yanan; Gao, Wenjuan; Chang, Antao; Ye, Yujie; Shen, Wenzhi; Luo, Yunping; Yang, Shengyong; Sun, Peiqing; Xiang, Rong; Li, Na

    2017-01-01

    Tumour microenvironment (TME) contributes significantly towards potentiating the stemness and metastasis properties of cancer cells. IL6-Stat3 is one of the important cell signaling pathways in mediating the communication between tumour and immune cells. Here, we have systematically developed a novel anti-CD44 antibody-mediated liposomal nanoparticle delivery system loaded with anti-IL6R antibody, which could specifically target the TME of CD44 + breast cancer cells in different mouse models for triple negative and luminal breast cancer. This nanoparticle had an enhanced and specific tumour targeting efficacy with dramatic anti-tumour metastasis effects in syngeneic BALB/c mice bearing 4T1 cells as was in the syngeneic MMTV-PyMT mice. It inhibited IL6R-Stat3 signaling and moderated the TME, characterized by the reduced expression of genes encoding Stat3, Sox2, VEGFA, MMP-9 and CD206 in the breast tissues. Furthermore, this nanoparticle reduced the subgroups of Sox2 + and CD206 + cells in the lung metastatic foci, demonstrating its inhibitory effect on the lung metastatic niche for breast cancer stem cells. Taken together, the CD44 targeted liposomal nanoparticles encapsulating anti-IL6R antibody achieved a significant effect to inhibit the metastasis of breast cancer in different molecular subtypes of breast cancer mouse models. Our results shed light on the application of nanoparticle mediated cancer immune-therapy through targeting TME.

  9. Inhibition of γ-secretase worsens memory deficits in a genetically congruous mouse model of Danish dementia

    Directory of Open Access Journals (Sweden)

    Tamayev Robert

    2012-04-01

    Full Text Available Abstract Background A mutation in the BRI2/ITM2b gene causes familial Danish dementia (FDD. BRI2 is an inhibitor of amyloid-β precursor protein (APP processing, which is genetically linked to Alzheimer’s disease (AD pathogenesis. The FDD mutation leads to a loss of BRI2 protein and to increased APP processing. APP haplodeficiency and inhibition of APP cleavage by β-secretase rescue synaptic/memory deficits of a genetically congruous mouse model of FDD (FDDKI. β-cleavage of APP yields the β-carboxyl-terminal (β-CTF and the amino-terminal-soluble APPβ (sAPPβ fragments. γ-secretase processing of β-CTF generates Aβ, which is considered the main cause of AD. However, inhibiting Aβ production did not rescue the deficits of FDDKI mice, suggesting that sAPPβ/β-CTF, and not Aβ, are the toxic species causing memory loss. Results Here, we have further analyzed the effect of γ-secretase inhibition. We show that treatment with a γ-secretase inhibitor (GSI results in a worsening of the memory deficits of FDDKI mice. This deleterious effect on memory correlates with increased levels of the β/α-CTFs APP fragments in synaptic fractions isolated from hippocampi of FDDKI mice, which is consistent with inhibition of γ-secretase activity. Conclusion This harmful effect of the GSI is in sharp contrast with a pathogenic role for Aβ, and suggests that the worsening of memory deficits may be due to accumulation of synaptic-toxic β/α-CTFs caused by GSI treatment. However, γ-secretase cleaves more than 40 proteins; thus, the noxious effect of GSI on memory may be dependent on inhibition of cleavage of one or more of these other γ-secretase substrates. These two possibilities do not need to be mutually exclusive. Our results are consistent with the outcome of a clinical trial with the GSI Semagacestat, which caused a worsening of cognition, and advise against targeting γ-secretase in the therapy of AD. Overall, the data also indicate that FDDKI

  10. Mechanistic Studies and Modeling Reveal the Origin of Differential Inhibition of Gag Polymorphic Viruses by HIV-1 Maturation Inhibitors.

    Science.gov (United States)

    Lin, Zeyu; Cantone, Joseph; Lu, Hao; Nowicka-Sans, Beata; Protack, Tricia; Yuan, Tian; Yang, Hong; Liu, Zheng; Drexler, Dieter; Regueiro-Ren, Alicia; Meanwell, Nicholas A; Cockett, Mark; Krystal, Mark; Lataillade, Max; Dicker, Ira B

    2016-11-01

    HIV-1 maturation inhibitors (MIs) disrupt the final step in the HIV-1 protease-mediated cleavage of the Gag polyprotein between capsid p24 capsid (CA) and spacer peptide 1 (SP1), leading to the production of infectious virus. BMS-955176 is a second generation MI with improved antiviral activity toward polymorphic Gag variants compared to a first generation MI bevirimat (BVM). The underlying mechanistic reasons for the differences in polymorphic coverage were studied using antiviral assays, an LC/MS assay that quantitatively characterizes CA/SP1 cleavage kinetics of virus like particles (VLPs) and a radiolabel binding assay to determine VLP/MI affinities and dissociation kinetics. Antiviral assay data indicates that BVM does not achieve 100% inhibition of certain polymorphs, even at saturating concentrations. This results in the breakthrough of infectious virus (partial antagonism) regardless of BVM concentration. Reduced maximal percent inhibition (MPI) values for BVM correlated with elevated EC50 values, while rates of HIV-1 protease cleavage at CA/SP1 correlated inversely with the ability of BVM to inhibit HIV-1 Gag polymorphic viruses: genotypes with more rapid CA/SP1 cleavage kinetics were less sensitive to BVM. In vitro inhibition of wild type VLP CA/SP1 cleavage by BVM was not maintained at longer cleavage times. BMS-955176 exhibited greatly improved MPI against polymorphic Gag viruses, binds to Gag polymorphs with higher affinity/longer dissociation half-lives and exhibits greater time-independent inhibition of CA/SP1 cleavage compared to BVM. Virological (MPI) and biochemical (CA/SP1 cleavage rates, MI-specific Gag affinities) data were used to create an integrated semi-quantitative model that quantifies CA/SP1 cleavage rates as a function of both MI and Gag polymorph. The model outputs are in accord with in vitro antiviral observations and correlate with observed in vivo MI efficacies. Overall, these findings may be useful to further understand antiviral

  11. Antroquinonol mitigates an accelerated and progressive IgA nephropathy model in mice by activating the Nrf2 pathway and inhibiting T cells and NLRP3 inflammasome.

    Science.gov (United States)

    Yang, Shun-Min; Ka, Shuk-Man; Hua, Kuo-Feng; Wu, Tzu-Hua; Chuang, Yi-Ping; Lin, Ya-Wen; Yang, Feng-Ling; Wu, Shih-Hsiung; Yang, Sung-Sen; Lin, Shih-Hua; Chang, Jia-Ming; Chen, Ann

    2013-08-01

    High levels of reactive oxygen species (ROS), systemic T cell activation, and macrophage infiltration in the kidney are implicated in the acceleration and progression of IgA nephropathy (IgAN), the most frequent type of primary glomerulonephritis. However, the pathogenic mechanism of IgAN is still little understood, and it remains a challenge to establish a specific therapeutic strategy for this type of glomerular disorder. Recently, we showed that antroquinonol (Antroq), a pure active compound from Antrodia camphorata mycelium, inhibits renal inflammation and reduces oxidative stress in a mouse model of renal fibrosis. But the anti-inflammatory and immune-regulatory effects of Antroq on the acceleration and progression of primary glomerular disorders have not been determined. In this study, we show that Antroq administration substantially impeded the development of severe renal lesions, such as intense glomerular proliferation, crescents, sclerosis, and periglomerular interstitial inflammation, in mice with induced accelerated and progressive IgAN (AcP-IgAN). Further mechanistic analysis in AcP-IgAN mice showed that, early in the developmental stage of the AcP-IgAN model, Antroq promoted the Nrf2 antioxidant pathway and inhibited the activation of T cells and NLRP3 inflammasome. Significantly improved proteinuria/renal function and histopathology in AcP-IgAN mice of an established stage supported potential therapeutic effects of Antroq on the disease. In addition, Antroq was shown to inhibit activation of NLRP3 inflammasome in vitro by an IgA immune complex (IC) partly involving a reduced ROS production in IgA-IC-primed macrophages, and this finding may be helpful in the understanding of the mode of action of Antroq in the treated AcP-IgAN mice. Copyright © 2013 Elsevier Inc. All rights reserved.

  12. 15-Deoxy-Delta-12,14-Prostaglandin J2 Inhibits Lung Inflammation and Remodeling in Distinct Murine Models of Asthma

    Directory of Open Access Journals (Sweden)

    Diego S. Coutinho

    2017-06-01

    Full Text Available 15-deoxy-Δ-12,14-prostaglandin J2 (15d-PGJ2 has been described as an anti-inflammatory lipid mediator in several in vitro and in vivo studies, but its effect on allergic pulmonary inflammation remains elusive. The aim of this study was to investigate the therapeutic potential of 15d-PGJ2 based on distinct murine models of allergic asthma triggered by either ovalbumin (OVA or house dust mite extract (HDM. Characteristics of lung inflammation, airway hyper-reactivity (AHR, mucus exacerbation, and lung remodeling in sensitized A/J mice treated or not with 15d-PGJ2 were assessed. 15d-PGJ2 treatments were carried out systemically or topically given via subcutaneous injection or intranasal instillation, respectively. Analyses were carried out 24 h after the last allergen provocation. Irrespective of the route of administration, 15d-PGJ2 significantly inhibited the peribronchial accumulation of eosinophils and neutrophils, subepithelial fibrosis and also mucus exacerbation caused by either OVA or HDM challenge. The protective effect of 15d-PGJ2 occurred in parallel with inhibition of allergen-induced AHR and lung tissue production of pro-inflammatory cytokines, such as interleukin (IL-5, IL-13, IL-17, and TNF-α. Finally, 15d-PGJ2 was found effective in inhibiting NF-κB phosphorylation upon HDM challenge as measured by Western blotting. In conclusion, our findings suggest that 15d-PGJ2 can reduce crucial features of asthma, including AHR, lung inflammation, and remodeling in distinct murine models of the disease. These effects are associated with a decrease in lung tissue generation of pro-inflammatory cytokines by a mechanism related to downregulation of NF-κB phosphorylation.

  13. Models for large superconducting toroidal magnet systems

    International Nuclear Information System (INIS)

    Arendt, F.; Brechna, H.; Erb, J.; Komarek, P.; Krauth, H.; Maurer, W.

    1976-01-01

    Prior to the design of large GJ toroidal magnet systems it is appropriate to procure small scale models, which can simulate their pertinent properties and allow to investigate their relevant phenomena. The important feature of the model is to show under which circumstances the system performance can be extrapolated to large magnets. Based on parameters such as the maximum magnetic field and the current density, the maximum tolerable magneto-mechanical stresses, a simple method of designing model magnets is presented. It is shown how pertinent design parameters are changed when the toroidal dimensions are altered. In addition some conductor cost estimations are given based on reactor power output and wall loading

  14. Deleterious Effects of VEGFR2 and RET Inhibition in a Preclinical Model of Parkinson's Disease.

    Science.gov (United States)

    Requejo, C; Ruiz-Ortega, J A; Bengoetxea, H; Bulnes, S; Ugedo, L; Lafuente, J V

    2018-01-01

    Neurotrophic factors (NTFs) are a promising therapeutic option for Parkinson's disease (PD). They exert their function through tyrosine kinase receptors. Our goal was to assess the effects of administering a selective tyrosine kinase inhibitor (vandetanib) that blocks VEGFR2 and RET receptors in a preclinical model of PD. Rats underwent intrastriatal injections of 6-hydroxydopamine (6-OHDA). Two weeks later, the rats received 30 mg/kg vandetanib or saline orally. The effects were assessed using the rotational behavioral test, tyrosine hydroxylase (TH) immunohistochemistry, and western blot. In 6-OHDA-lesioned rats, motor symptoms were almost undetectable, but morphological and biochemical changes were significant. Vandetanib treatment, combined with the presence of 6-OHDA lesions, significantly increased behavioral impairment and morphological and biochemical changes. Therefore, after vandetanib treatment, the TH-immunopositive striatal volume, the percentage of TH+ neurons, and the extent of the axodendritic network in the substantia nigra decreased. Glial fibrillary acidic protein-positivity significantly decreased in the striatum and substantia nigra in the vandetanib-treated group. In addition, p-Akt and p-ERK 1/2 levels were significantly lower and caspase-3 expression significantly increased after vandetanib administration. In conclusion, we demonstrate for the first time the deleterious effect of a tyrosine kinase inhibitor on the dopaminergic system, supporting the beneficial and synergistic effect of NTFs reported in previous papers.

  15. The systemic bone protective effects of Gushukang granules in ovariectomized mice by inhibiting osteoclastogenesis and stimulating osteoblastogenesis

    Directory of Open Access Journals (Sweden)

    Qiang Wang

    2018-03-01

    Full Text Available Primary osteoporosis (POP, which is caused by unbalanced bone remodeling, leads to significant economic and societal burdens globally. Gushukang (GSK granule serves as one commonly used prescription for POP in Traditional Chinese Medicine (TCM. The present study aimed to clarify the exact roles of GSK in bone remodeling with in vivo and in vitro assays. Here we showed that GSK prevented bone loss and the alternations of osteoporotic bone parameters as well as the decreased density of osteoclast in ovariectomized (OVX mice. GSK inhibited receptor activator for nuclear factor-κ B Ligand (RANKL-activated osteoclastogenesis in bone marrow macrophages (BMMs. At the molecular levels, GSK inhibited the expression of nuclear factor of activated T cells cytoplasm 1(NFATc1 and c-Fos, two master regulators of osteoclastogenesis. GSK also inhibited bone resorbed genetic expression of matrix metalloproteinase 9 (MMP9, cathepsin K (Ctsk, TRAP and carbonic anhydrase II (Car2. Meanwhile, GSK stimulated osteoblastogenesis from bone primary mesenchymal stem cells (MSCs and enhanced the expression of Osteirx, and Runx2. GSK also stimulated the expression of Col-1, Osteocalcein and alkaline phosphatase (ALP. Our investigation established the systemic bone protective effects of GSK by suppressing osteoclastogenesis and stimulating osteoblastogenesis and laid bases for new drugs discovery in treating POP. Keywords: Gushukang (GSK granule, Primary osteoporosis, Osteoclastogenesis, Osteoblastogenesis

  16. The systemic bone protective effects of Gushukang granules in ovariectomized mice by inhibiting osteoclastogenesis and stimulating osteoblastogenesis.

    Science.gov (United States)

    Wang, Qiang; Zhao, Yongjian; Sha, Nannan; Zhang, Yan; Li, Chenguang; Zhang, Hao; Tang, Dezhi; Lu, Sheng; Shi, Qi; Wang, Yongjun; Shu, Bing; Zhao, Dongfeng

    2018-03-01

    Primary osteoporosis (POP), which is caused by unbalanced bone remodeling, leads to significant economic and societal burdens globally. Gushukang (GSK) granule serves as one commonly used prescription for POP in Traditional Chinese Medicine (TCM). The present study aimed to clarify the exact roles of GSK in bone remodeling with in vivo and in vitro assays. Here we showed that GSK prevented bone loss and the alternations of osteoporotic bone parameters as well as the decreased density of osteoclast in ovariectomized (OVX) mice. GSK inhibited receptor activator for nuclear factor-κ B Ligand (RANKL)-activated osteoclastogenesis in bone marrow macrophages (BMMs). At the molecular levels, GSK inhibited the expression of nuclear factor of activated T cells cytoplasm 1(NFATc1) and c-Fos, two master regulators of osteoclastogenesis. GSK also inhibited bone resorbed genetic expression of matrix metalloproteinase 9 (MMP9), cathepsin K (Ctsk), TRAP and carbonic anhydrase II (Car2). Meanwhile, GSK stimulated osteoblastogenesis from bone primary mesenchymal stem cells (MSCs) and enhanced the expression of Osteirx, and Runx2. GSK also stimulated the expression of Col-1, Osteocalcein and alkaline phosphatase (ALP). Our investigation established the systemic bone protective effects of GSK by suppressing osteoclastogenesis and stimulating osteoblastogenesis and laid bases for new drugs discovery in treating POP. Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

  17. PARP Inhibition Attenuates Histopathological Lesion in Ischemia/Reperfusion Renal Mouse Model after Cold Prolonged Ischemia

    Directory of Open Access Journals (Sweden)

    Raimundo M. G. del Moral

    2013-01-01

    Full Text Available We test the hypothesis that PARP inhibition can decrease acute tubular necrosis (ATN and other renal lesions related to prolonged cold ischemia/reperfusion (IR in kidneys preserved at 4°C in University of Wisconsin (UW solution. Material and Methods. We used 30 male Parp1+/+ wild-type and 15 male Parp10/0 knockout C57BL/6 mice. Fifteen of these wild-type mice were pretreated with 3,4-dihydro-5-[4-(1-piperidinylbutoxyl]-1(2H-isoquinolinone (DPQ at a concentration of 15 mg/kg body weight, used as PARP inhibitor. Subgroups of mice were established (A: IR 45 min/6 h; B: IR + 48 h in UW solution; and C: IR + 48 h in UW solution plus DPQ. We processed samples for morphological, immunohistochemical, ultrastructural, and western-blotting studies. Results. Prolonged cold ischemia time in UW solution increased PARP-1 expression and kidney injury. Preconditioning with PARP inhibitor DPQ plus DPQ supplementation in UW solution decreased PARP-1 nuclear expression in renal tubules and renal damage. Parp10/0 knockout mice were more resistant to IR-induced renal lesion. In conclusion, PARP inhibition attenuates ATN and other IR-related renal lesions in mouse kidneys under prolonged cold storage in UW solution. If confirmed, these data suggest that pharmacological manipulation of PARP activity may have salutary effects in cold-stored organs at transplantation.

  18. ACE inhibition attenuates uremia-induced aortic valve thickening in a novel mouse model

    DEFF Research Database (Denmark)

    Simolin, Mikko A; Pedersen, Tanja X; Bro, Susanne

    2009-01-01

    BACKGROUND: We examined whether impaired renal function causes thickening of the aortic valve leaflets in hyperlipidemic apoE-knockout (apoE-/-) mice, and whether the putative effect on the aortic valves could be prevented by inhibiting the angiotensin-converting enzyme (ACE) with enalapril. METH...... for investigating the mechanisms of uremia-induced aortic valve disease, and also provides an opportunity to study its pharmacologic prevention.......BACKGROUND: We examined whether impaired renal function causes thickening of the aortic valve leaflets in hyperlipidemic apoE-knockout (apoE-/-) mice, and whether the putative effect on the aortic valves could be prevented by inhibiting the angiotensin-converting enzyme (ACE) with enalapril....... METHODS: Thickening of the aortic valve leaflets in apoE-/- mice was induced by producing mild or moderate chronic renal failure resulting from unilateral nephrectomy (1/2 NX, n = 18) or subtotal nephrectomy (5/6 NX, n = 22), respectively. Additionally, the 5/6 NX mice were randomized to no treatment (n...

  19. Repurposing of antiparasitic drugs: the hydroxy-naphthoquinone buparvaquone inhibits vertical transmission in the pregnant neosporosis mouse model.

    Science.gov (United States)

    Müller, Joachim; Aguado-Martínez, Adriana; Manser, Vera; Wong, Ho Ning; Haynes, Richard K; Hemphill, Andrew

    2016-02-17

    The three anti-malarial drugs artemiside, artemisone, and mefloquine, and the naphthoquinone buparvaquone known to be active against theileriosis in cattle and Leishmania infections in rodents, were assessed for activity against Neospora caninum infection. All four compounds inhibited the proliferation of N. caninum tachyzoites in vitro with IC50 in the sub-micromolar range, but artemisone and buparvaquone were most effective (IC50 = 3 and 4.9 nM, respectively). However, in a neosporosis mouse model for cerebral infection comprising Balb/c mice experimentally infected with the virulent isolate Nc-Spain7, the three anti-malarial compounds failed to exhibit any activity, since treatment did not reduce the parasite burden in brains and lungs compared to untreated controls. Thus, these compounds were not further evaluated in pregnant mice. On the other hand, buparvaquone, shown earlier to be effective in reducing the parasite load in the lungs in an acute neosporosis disease model, was further assessed in the pregnant mouse model. Buparvaquone efficiently inhibited vertical transmission in Balb/c mice experimentally infected at day 7 of pregnancy, reduced clinical signs in the pups, but had no effect on cerebral infection in the dams. This demonstrates proof-of-concept that drug repurposing may lead to the discovery of an effective compound against neosporosis that can protect offspring from vertical transmission and disease.

  20. Modeling and simulation of discrete event systems

    CERN Document Server

    Choi, Byoung Kyu

    2013-01-01

    Computer modeling and simulation (M&S) allows engineers to study and analyze complex systems. Discrete-event system (DES)-M&S is used in modern management, industrial engineering, computer science, and the military. As computer speeds and memory capacity increase, so DES-M&S tools become more powerful and more widely used in solving real-life problems. Based on over 20 years of evolution within a classroom environment, as well as on decades-long experience in developing simulation-based solutions for high-tech industries, Modeling and Simulation of Discrete-Event Systems is the only book on

  1. Modeling the heart and the circulatory system

    CERN Document Server

    2015-01-01

    The book comprises contributions by some of the most respected scientists in the field of mathematical modeling and numerical simulation of the human cardiocirculatory system. The contributions cover a wide range of topics, from the preprocessing of clinical data to the development of mathematical equations, their numerical solution, and both in-vivo and in-vitro validation. They discuss the flow in the systemic arterial tree and the complex electro-fluid-mechanical coupling in the human heart. Many examples of patient-specific simulations are presented. This book is addressed to all scientists interested in the mathematical modeling and numerical simulation of the human cardiocirculatory system.

  2. Quantitative Models and Analysis for Reactive Systems

    DEFF Research Database (Denmark)

    Thrane, Claus

    The majority of modern software and hardware systems are reactive systems, where input provided by the user (possibly another system) and the output of the system is exchanged continuously throughout the (possibly) indefinite execution of the system. Natural examples include control systems, mobi......, energy consumption, latency, mean-time to failure, and cost. For systems integrated in mass-market products, the ability to quantify trade-offs between performance and robustness, under given technical and economic constraints, is of strategic importance....... by the environment in which they are embedded. This thesis studies the semantics and properties of a model-based framework for re- active systems, in which models and specifications are assumed to contain quantifiable information, such as references to time or energy. Our goal is to develop a theory of approximation......, in terms of a new mathematical basis for systems modeling which can incompas behavioural properties as well as environmental constraints. They continue by pointing out that, continuous performance and robustness measures are paramount when dealing with physical resource levels such as clock frequency...

  3. Dopamine-signalled reward predictions generated by competitive excitation and inhibition in a spiking neural network model

    Directory of Open Access Journals (Sweden)

    Paul eChorley

    2011-05-01

    Full Text Available Dopaminergic neurons in the mammalian substantia nigra displaycharacteristic phasic responses to stimuli which reliably predict thereceipt of primary rewards. These responses have been suggested toencode reward prediction-errors similar to those used in reinforcementlearning. Here, we propose a model of dopaminergic activity in whichprediction error signals are generated by the joint action ofshort-latency excitation and long-latency inhibition, in a networkundergoing dopaminergic neuromodulation of both spike-timing dependentsynaptic plasticity and neuronal excitability. In contrast toprevious models, sensitivity to recent events is maintained by theselective modification of specific striatal synapses, efferent tocortical neurons exhibiting stimulus-specific, temporally extendedactivity patterns. Our model shows, in the presence of significantbackground activity, (i a shift in dopaminergic response from rewardto reward predicting stimuli, (ii preservation of a response tounexpected rewards, and (iii a precisely-timed below-baseline dip inactivity observed when expected rewards are omitted.

  4. An Integrated Ecological Modeling System for Assessing ...

    Science.gov (United States)

    We demonstrate a novel, spatially explicit assessment of the current condition of aquatic ecosystem services, with limited sensitivity analysis for the atmospheric contaminant mercury. The Integrated Ecological Modeling System (IEMS) forecasts water quality and quantity, habitat suitability for aquatic biota, fish biomasses, population densities, productivities, and contamination by methylmercury across headwater watersheds. We applied this IEMS to the Coal River Basin (CRB), West Virginia (USA), an 8-digit hydrologic unit watershed, by simulating a network of 97 stream segments using the SWAT watershed model, a watershed mercury loading model, the WASP water quality model, the PiSCES fish community estimation model, a fish habitat suitability model, the BASS fish community and bioaccumulation model, and an ecoservices post-processer. Model application was facilitated by automated data retrieval and model setup and updated model wrappers and interfaces for data transfers between these models from a prior study. This companion study evaluates baseline predictions of ecoservices provided for 1990 – 2010 for the population of streams in the CRB and serves as a foundation for future model development. Published in the journal, Ecological Modeling. Highlights: • Demonstrate a spatially-explicit IEMS for multiple scales. • Design a flexible IEMS for

  5. Modelling dependable systems using hybrid Bayesian networks

    International Nuclear Information System (INIS)

    Neil, Martin; Tailor, Manesh; Marquez, David; Fenton, Norman; Hearty, Peter

    2008-01-01

    A hybrid Bayesian network (BN) is one that incorporates both discrete and continuous nodes. In our extensive applications of BNs for system dependability assessment, the models are invariably hybrid and the need for efficient and accurate computation is paramount. We apply a new iterative algorithm that efficiently combines dynamic discretisation with robust propagation algorithms on junction tree structures to perform inference in hybrid BNs. We illustrate its use in the field of dependability with two example of reliability estimation. Firstly we estimate the reliability of a simple single system and next we implement a hierarchical Bayesian model. In the hierarchical model we compute the reliability of two unknown subsystems from data collected on historically similar subsystems and then input the result into a reliability block model to compute system level reliability. We conclude that dynamic discretisation can be used as an alternative to analytical or Monte Carlo methods with high precision and can be applied to a wide range of dependability problems

  6. Stochastic Modelling Of The Repairable System

    Directory of Open Access Journals (Sweden)

    Andrzejczak Karol

    2015-11-01

    Full Text Available All reliability models consisting of random time factors form stochastic processes. In this paper we recall the definitions of the most common point processes which are used for modelling of repairable systems. Particularly this paper presents stochastic processes as examples of reliability systems for the support of the maintenance related decisions. We consider the simplest one-unit system with a negligible repair or replacement time, i.e., the unit is operating and is repaired or replaced at failure, where the time required for repair and replacement is negligible. When the repair or replacement is completed, the unit becomes as good as new and resumes operation. The stochastic modelling of recoverable systems constitutes an excellent method of supporting maintenance related decision-making processes and enables their more rational use.

  7. A system model for water management.

    Science.gov (United States)

    Schenk, Colin; Roquier, Bastien; Soutter, Marc; Mermoud, André

    2009-03-01

    Although generally accepted as a necessary step to improve water management and planning, integrated water resources management (IWRM) methodology does not provide a clear definition of what should be integrated. The various water-related issues that IWRM might encompass are well documented in the literature, but they are generally addressed separately. Therefore, water management lacks a holistic, systems-based description, with a special emphasis on the interrelations between issues. This article presents such a system model for water management, including a graphical representation and textual descriptions of the various water issues, their components, and their interactions. This model is seen as an aide-memoire and a generic reference, providing background knowledge helping to elicit actual system definitions, in possible combination with other participatory systems approaches. The applicability of the model is demonstrated through its application to two test case studies.

  8. Intelligent Mechatronic Systems Modeling, Control and Diagnosis

    CERN Document Server

    Merzouki, Rochdi; Pathak, Pushparaj Mani; Ould Bouamama, Belkacem

    2013-01-01

    Acting as a support resource for practitioners and professionals looking to advance their understanding of complex mechatronic systems, Intelligent Mechatronic Systems explains their design and recent developments from first principles to practical applications. Detailed descriptions of the mathematical models of complex mechatronic systems, developed from fundamental physical relationships, are built on to develop innovative solutions with particular emphasis on physical model-based control strategies. Following a concurrent engineering approach, supported by industrial case studies, and drawing on the practical experience of the authors, Intelligent Mechatronic Systems covers range of topic and includes:  • An explanation of a common graphical tool for integrated design and its uses from modeling and simulation to the control synthesis • Introductions to key concepts such as different means of achieving fault tolerance, robust overwhelming control and force and impedance control • Dedicated chapters ...

  9. Renal targeting of captopril selectively enhances the intrarenal over the systemic effects of ACE inhibition in rats

    Science.gov (United States)

    Haverdings, R Folgert G; Haas, Marijke; Navis, Gerjan; van Loenen-Weemaes, Anne-miek; Meijer, Dirk K F; de Zeeuw, Dick; Moolenaar, Frits

    2002-01-01

    In previous studies on the renal targeting of the ACE inhibitor captopril, we demonstrated that a 6 fold increased concentration of this drug could be obtained in the kidney after conjugation to the low-molecular-weight protein lysozyme. In this study, we investigated in unrestrained rats whether systemic administration of captopril–lysozyme also results in an enhanced effect on renal parameters, relative to the systemic effects. Renal effects: intravenous infusion of captopril–lysozyme for 6 h resulted in a more pronounced increment of renal blood flow (31±2% vs 17±4% at 0.5 mg kg−1 6h−1, Pcaptopril as a free drug. In correspondence with these findings, renal ACE inhibition was potentiated approximately 5 fold (−50±4% vs −22±3% at 1 mg kg−1 6 h−1, Pcaptopril did not affect blood pressure in dosages up to 5 mg kg−1 6 h−1. This effect coincided with a less pronounced inhibition of the pressor response to intravenously administered angiotensin I (−12±3% vs −66±5% at 1 mg kg−1 6 h−1, Pcaptopril. An experiment of continued intravenous administration of captopril–lysozyme for 7 days in nephrotic syndrome demonstrated that the conjugate is also active in renal disease: the antiproteinuric response was substantially augmented (−67±5% vs −15±7% at 4 mg kg−1 24 h−1, Pcaptopril–lysozyme conjugate leads to more selective renal ACE inhibition and enhanced renal effects as well as less systemic effects compared to captopril itself. PMID:12163343

  10. Brand Equity Evolution: a System Dynamics Model

    Directory of Open Access Journals (Sweden)

    Edson Crescitelli

    2009-04-01

    Full Text Available One of the greatest challenges in brand management lies in monitoring brand equity over time. This paper aimsto present a simulation model able to represent this evolution. The model was drawn on brand equity concepts developed by Aaker and Joachimsthaler (2000, using the system dynamics methodology. The use ofcomputational dynamic models aims to create new sources of information able to sensitize academics and managers alike to the dynamic implications of their brand management. As a result, an easily implementable model was generated, capable of executing continuous scenario simulations by surveying casual relations among the variables that explain brand equity. Moreover, the existence of a number of system modeling tools will allow extensive application of the concepts used in this study in practical situations, both in professional and educational settings

  11. Identification models of the nervous system.

    Science.gov (United States)

    Zipser, D

    1992-01-01

    It has been widely observed that when artificial neural networks are trained by supervised learning to do computations that also occur in the nervous system, the behavior of the model neurons often closely resembles that of the real neurons involved in the task. It is not immediately clear why this should be the case or what use can be made of models generated by supervised learning. Here, recent developments are reviewed and analysed in an attempt to clarify these issues. This analysis is facilitated by treating supervised learning models of the brain as a special case of system identification, a general and well-studied modeling paradigm. The neural systems identification paradigm provides a systematic way to generate realistic models starting with a high-level description of a hypothesized computation and some architectural and physiological constraints about the area being modeled. There is no inherent limitation to the realism that can be incorporated into identification models. This approach eliminates the need to find neural implementation algorithms by ad hoc means and provides neuroscientists with a convenient way to build models that account for observed data.

  12. Prototype models for the MOIRA computerised system

    Energy Technology Data Exchange (ETDEWEB)

    Monte, Luigi [ENEA, Centro Ricerche Casaccia, Rome (Italy). Dipt. Ambiente; Hakanson, Lars [Uppsala, Univ. (Sweden). Institute of Earth Sciences; Brittain, John [Oslo, Univ. (Norway). Zoological Museum

    1997-06-01

    The main aim of the present report is to describe selected models and the principles of the Decision Analysis theory that will be applied to develop the model-based computerised system `MOIRA`. A dose model and a model for predicting radiocaesium migration in lakes and the effects of countermeasures to reduce the contamination levels in the components of lacustrine system are described in detail. The principles for developing prototype models for predicting the migration of {sup 90}Sr in lake abiotic and biotic components are discussed. The environmental models described in the report are based on the use of `collective parameters` which due to mutual compensation effects of different phenomena occurring in complex systems, show low variability when the environmental conditions change. Use of such `collective parameters` not only increases the predictive power of the models, but also increases the practical applicability of the model. Among the main results described in the report, the development of an objective hierarchy table for evaluating the effectiveness of a countermeasure when the economic, social and ecological impacts are accounted for, deserves special attention.

  13. Intrinsic Uncertainties in Modeling Complex Systems.

    Energy Technology Data Exchange (ETDEWEB)

    Cooper, Curtis S; Bramson, Aaron L.; Ames, Arlo L.

    2014-09-01

    Models are built to understand and predict the behaviors of both natural and artificial systems. Because it is always necessary to abstract away aspects of any non-trivial system being modeled, we know models can potentially leave out important, even critical elements. This reality of the modeling enterprise forces us to consider the prospective impacts of those effects completely left out of a model - either intentionally or unconsidered. Insensitivity to new structure is an indication of diminishing returns. In this work, we represent a hypothetical unknown effect on a validated model as a finite perturba- tion whose amplitude is constrained within a control region. We find robustly that without further constraints, no meaningful bounds can be placed on the amplitude of a perturbation outside of the control region. Thus, forecasting into unsampled regions is a very risky proposition. We also present inherent difficulties with proper time discretization of models and representing in- herently discrete quantities. We point out potentially worrisome uncertainties, arising from math- ematical formulation alone, which modelers can inadvertently introduce into models of complex systems. Acknowledgements This work has been funded under early-career LDRD project #170979, entitled "Quantify- ing Confidence in Complex Systems Models Having Structural Uncertainties", which ran from 04/2013 to 09/2014. We wish to express our gratitude to the many researchers at Sandia who con- tributed ideas to this work, as well as feedback on the manuscript. In particular, we would like to mention George Barr, Alexander Outkin, Walt Beyeler, Eric Vugrin, and Laura Swiler for provid- ing invaluable advice and guidance through the course of the project. We would also like to thank Steven Kleban, Amanda Gonzales, Trevor Manzanares, and Sarah Burwell for their assistance in managing project tasks and resources.

  14. Reliability modeling of an engineered barrier system

    International Nuclear Information System (INIS)

    Ananda, M.M.A.; Singh, A.K.; Flueck, J.A.

    1993-01-01

    The Weibull distribution is widely used in reliability literature as a distribution of time to failure, as it allows for both increasing failure rate (IFR) and decreasing failure rate (DFR) models. It has also been used to develop models for an engineered barrier system (EBS), which is known to be one of the key components in a deep geological repository for high level radioactive waste (HLW). The EBS failure time can more realistically be modelled by an IFR distribution, since the failure rate for the EBS is not expected to decrease with time. In this paper, we use an IFR distribution to develop a reliability model for the EBS

  15. Modelling and Analyses of Embedded Systems Design

    DEFF Research Database (Denmark)

    Brekling, Aske Wiid

    We present the MoVES languages: a language with which embedded systems can be specified at a stage in the development process where an application is identified and should be mapped to an execution platform (potentially multi- core). We give a formal model for MoVES that captures and gives......-based verification is a promising approach for assisting developers of embedded systems. We provide examples of system verifications that, in size and complexity, point in the direction of industrially-interesting systems....... semantics to the elements of specifications in the MoVES language. We show that even for seem- ingly simple systems, the complexity of verifying real-time constraints can be overwhelming - but we give an upper limit to the size of the search-space that needs examining. Furthermore, the formal model exposes...

  16. Multilevel Flow Modeling of Domestic Heating Systems

    DEFF Research Database (Denmark)

    Hu, Junjie; Lind, Morten; You, Shi

    2012-01-01

    of complementing this reasoning methodology. Domestic heating systems, as the main resource to meet the thermal requirements of end-users, have different implementations in Europe in order to achieve various degrees of controllability and heating efficiencies. As all the heating systems serve the same basic needs...... i.e. supplying and transferring thermal energy, it is off interest to use MFM to investigate similarities and differences between different implementations. In this paper, three typical domestic European heating systems, which differ from each other in the number of temperature sensors and auxiliary...... components e.g. storage tanks, are modeled using the MFM methodology. Both the goals and functions of material and energy processes and the control functions of the heating systems are represented in the MFM models. It is found that varying the physical system setup results in only little differences among...

  17. Modelling supervisory controller for hybrid power systems

    Energy Technology Data Exchange (ETDEWEB)

    Pereira, A.; Bindner, H.; Lundsager, P. [Risoe National Lab., Roskilde (Denmark); Jannerup, O. [Technical Univ. of Denmark, Dept. of Automation, Lyngby (Denmark)

    1999-03-01

    Supervisory controllers are important to achieve optimal operation of hybrid power systems. The performance and economics of such systems depend mainly on the control strategy for switching on/off components. The modular concept described in this paper is an attempt to design standard supervisory controllers that could be used in different applications, such as village power and telecommunication applications. This paper presents some basic aspects of modelling and design of modular supervisory controllers using the object-oriented modelling technique. The functional abstraction hierarchy technique is used to formulate the control requirements and identify the functions of the control system. The modular algorithm is generic and flexible enough to be used with any system configuration and several goals (different applications). The modularity includes accepting modification of system configuration and goals during operation with minor or no changes in the supervisory controller. (au)

  18. Mathematical Modeling of Hybrid Electrical Engineering Systems

    Directory of Open Access Journals (Sweden)

    A. A. Lobaty

    2016-01-01

    Full Text Available A large class of systems that have found application in various industries and households, electrified transportation facilities and energy sector has been classified as electrical engineering systems. Their characteristic feature is a combination of continuous and discontinuous modes of operation, which is reflected in the appearance of a relatively new term “hybrid systems”. A wide class of hybrid systems is pulsed DC converters operating in a pulse width modulation, which are non-linear systems with variable structure. Using various methods for linearization it is possible to obtain linear mathematical models that rather accurately simulate behavior of such systems. However, the presence in the mathematical models of exponential nonlinearities creates considerable difficulties in the implementation of digital hardware. The solution can be found while using an approximation of exponential functions by polynomials of the first order, that, however, violates the rigor accordance of the analytical model with characteristics of a real object. There are two practical approaches to synthesize algorithms for control of hybrid systems. The first approach is based on the representation of the whole system by a discrete model which is described by difference equations that makes it possible to synthesize discrete algorithms. The second approach is based on description of the system by differential equations. The equations describe synthesis of continuous algorithms and their further implementation in a digital computer included in the control loop system. The paper considers modeling of a hybrid electrical engineering system using differential equations. Neglecting the pulse duration, it has been proposed to describe behavior of vector components in phase coordinates of the hybrid system by stochastic differential equations containing generally non-linear differentiable random functions. A stochastic vector-matrix equation describing dynamics of the

  19. Imatinib mesylate exerts anti-proliferative effects on osteosarcoma cells and inhibits the tumour growth in immunocompetent murine models.

    Directory of Open Access Journals (Sweden)

    Bérengère Gobin

    Full Text Available Osteosarcoma is the most common primary malignant bone tumour characterized by osteoid production and/or osteolytic lesions of bone. A lack of response to chemotherapeutic treatments shows the importance of exploring new therapeutic methods. Imatinib mesylate (Gleevec, Novartis Pharma, a tyrosine kinase inhibitor, was originally developed for the treatment of chronic myeloid leukemia. Several studies revealed that imatinib mesylate inhibits osteoclast differentiation through the M-CSFR pathway and activates osteoblast differentiation through PDGFR pathway, two key cells involved in the vicious cycle controlling the tumour development. The present study investigated the in vitro effects of imatinib mesylate on the proliferation, apoptosis, cell cycle, and migration ability of five osteosarcoma cell lines (human: MG-63, HOS; rat: OSRGA; mice: MOS-J, POS-1. Imatinib mesylate was also assessed as a curative and preventive treatment in two syngenic osteosarcoma models: MOS-J (mixed osteoblastic/osteolytic osteosarcoma and POS-1 (undifferentiated osteosarcoma. Imatinib mesylate exhibited a dose-dependent anti-proliferative effect in all cell lines studied. The drug induced a G0/G1 cell cycle arrest in most cell lines, except for POS-1 and HOS cells that were blocked in the S phase. In addition, imatinib mesylate induced cell death and strongly inhibited osteosarcoma cell migration. In the MOS-J osteosarcoma model, oral administration of imatinib mesylate significantly inhibited the tumour development in both preventive and curative approaches. A phospho-receptor tyrosine kinase array kit revealed that PDGFRα, among 7 other receptors (PDFGFRβ, Axl, RYK, EGFR, EphA2 and 10, IGF1R, appears as one of the main molecular targets for imatinib mesylate. In the light of the present study and the literature, it would be particularly interesting to revisit therapeutic evaluation of imatinib mesylate in osteosarcoma according to the tyrosine-kinase receptor

  20. Imatinib mesylate exerts anti-proliferative effects on osteosarcoma cells and inhibits the tumour growth in immunocompetent murine models.

    Science.gov (United States)

    Gobin, Bérengère; Moriceau, Gatien; Ory, Benjamin; Charrier, Céline; Brion, Régis; Blanchard, Frederic; Redini, Françoise; Heymann, Dominique

    2014-01-01

    Osteosarcoma is the most common primary malignant bone tumour characterized by osteoid production and/or osteolytic lesions of bone. A lack of response to chemotherapeutic treatments shows the importance of exploring new therapeutic methods. Imatinib mesylate (Gleevec, Novartis Pharma), a tyrosine kinase inhibitor, was originally developed for the treatment of chronic myeloid leukemia. Several studies revealed that imatinib mesylate inhibits osteoclast differentiation through the M-CSFR pathway and activates osteoblast differentiation through PDGFR pathway, two key cells involved in the vicious cycle controlling the tumour development. The present study investigated the in vitro effects of imatinib mesylate on the proliferation, apoptosis, cell cycle, and migration ability of five osteosarcoma cell lines (human: MG-63, HOS; rat: OSRGA; mice: MOS-J, POS-1). Imatinib mesylate was also assessed as a curative and preventive treatment in two syngenic osteosarcoma models: MOS-J (mixed osteoblastic/osteolytic osteosarcoma) and POS-1 (undifferentiated osteosarcoma). Imatinib mesylate exhibited a dose-dependent anti-proliferative effect in all cell lines studied. The drug induced a G0/G1 cell cycle arrest in most cell lines, except for POS-1 and HOS cells that were blocked in the S phase. In addition, imatinib mesylate induced cell death and strongly inhibited osteosarcoma cell migration. In the MOS-J osteosarcoma model, oral administration of imatinib mesylate significantly inhibited the tumour development in both preventive and curative approaches. A phospho-receptor tyrosine kinase array kit revealed that PDGFRα, among 7 other receptors (PDFGFRβ, Axl, RYK, EGFR, EphA2 and 10, IGF1R), appears as one of the main molecular targets for imatinib mesylate. In the light of the present study and the literature, it would be particularly interesting to revisit therapeutic evaluation of imatinib mesylate in osteosarcoma according to the tyrosine-kinase receptor status of patients.

  1. Oxygen production System Models for Lunar ISRU

    Science.gov (United States)

    Santiago-Maldonado, Edgardo

    2007-01-01

    In-Situ Resource Utilization (ISRU) seeks to make human space exploration feasible; by using available resources from a planet or the moon to produce consumables, parts, and structures that otherwise would be brought from Earth. Producing these in situ reduces the mass of such that must be launched and doing so allows more payload mass' for each mission. The production of oxygen from lunar regolith, for life support and propellant, is one of the tasks being studied under ISRU. NASA is currently funding three processes that have shown technical merit for the production of oxygen from regolith: Molten Salt Electrolysis, Hydrogen Reduction of Ilmenite, and Carbothermal Reduction. The ISRU program is currently developing system models of, the , abovementioned processes to: (1) help NASA in the evaluation process to select the most cost-effective and efficient process for further prototype development, (2) identify key parameters, (3) optimize the oxygen production process, (4) provide estimates on energy and power requirements, mass and volume.of the system, oxygen production rate, mass of regolith required, mass of consumables, and other important parameters, and (5) integrate into the overall end-to-end ISRU system model, which could be integrated with mission architecture models. The oxygen production system model is divided into modules that represent unit operations (e.g., reactor, water electrolyzer, heat exchanger). Each module is modeled theoretically using Excel and Visual Basic for Applications (VBA), and will be validated using experimental data from on-going laboratory work. This modularity (plug-n-play) feature of each unit operation allows the use of the same model on different oxygen production systems simulations resulting in comparable results. In this presentation, preliminary results for mass, power, volume will be presented along with brief description of the oxygen production system model.

  2. Temporal profiling of the chromatin proteome reveals system-wide responses to replication inhibition

    DEFF Research Database (Denmark)

    Khoudoli, Guennadi A; Gillespie, Peter J; Stewart, Graeme

    2008-01-01

    Although the replication, expression, and maintenance of DNA are well-studied processes, the way that they are coordinated is poorly understood. Here, we report an analysis of the changing association of proteins with chromatin (the chromatin proteome) during progression through interphase...... of the cell cycle. Sperm nuclei were incubated in Xenopus egg extracts, and chromatin-associated proteins were analyzed by mass spectrometry at different times. Approximately 75% of the proteins varied in abundance on chromatin by more than 15%, suggesting that the chromatin proteome is highly dynamic....... Proteins were then assigned to one of 12 different clusters on the basis of their pattern of chromatin association. Each cluster contained functional groups of proteins involved in different nuclear processes related to progression through interphase. We also blocked DNA replication by inhibiting either...

  3. Inhibition of nitric oxide synthesis by systemic N(G)-monomethyl-L-arginine administration in humans

    DEFF Research Database (Denmark)

    Frandsen, U; Bangsbo, J; Langberg, Henning

    2000-01-01

    (controls) and with prior N(G)-nitro-L-arginine methyl ester (L-NAME) infusion (4 mg/kg, intravenously). Samples from the interstitial fluid were obtained at rest, during exercise and after exercise with the microdialysis technique. Interstitial adenosine in controls increased (p0.05) to controls. The 6......-keto-prostaglandin F1alpha concentration in controls was 1.17+/-0.20 ng/ml at rest and increased (p0.05) in L-NAME. The interstitial K(+) concentration in controls increased (p......We examined whether the formation or the release of the vasodilators adenosine, prostacyclin (PGI(2)) and potassium (K(+)) increase in skeletal muscle interstitium in response to nitric oxide synthase (NOS) inhibition. Five subjects performed one-legged knee extensor exercise at 30 W without...

  4. Qualitative models for space system engineering

    Science.gov (United States)

    Forbus, Kenneth D.

    1990-01-01

    The objectives of this project were: (1) to investigate the implications of qualitative modeling techniques for problems arising in the monitoring, diagnosis, and design of Space Station subsystems and procedures; (2) to identify the issues involved in using qualitative models to enhance and automate engineering functions. These issues include representing operational criteria, fault models, alternate ontologies, and modeling continuous signals at a functional level of description; and (3) to develop a prototype collection of qualitative models for fluid and thermal systems commonly found in Space Station subsystems. Potential applications of qualitative modeling to space-systems engineering, including the notion of intelligent computer-aided engineering are summarized. Emphasis is given to determining which systems of the proposed Space Station provide the most leverage for study, given the current state of the art. Progress on using qualitative models, including development of the molecular collection ontology for reasoning about fluids, the interaction of qualitative and quantitative knowledge in analyzing thermodynamic cycles, and an experiment on building a natural language interface to qualitative reasoning is reported. Finally, some recommendations are made for future research.

  5. LOKI: a practical modelling and support system for telepresence systems

    International Nuclear Information System (INIS)

    Griffin, M.; Bridgewater, C.E.

    1993-01-01

    The use of Virtual Reality headset systems, in combination with a tele-presence ''head'' is discussed. The system is attached to a Unimate Puma robot arm and manipulated by the operator, using information gathered by the camera and auditory system, displayed via the Virtual Reality helmet. Operator commands are cross checked by using a modelling system, held on the Virtual Reality system. This system was found to supply a good sense of spacial awareness of the robot's domain. Actions which might move the robot outside its suitable operating envelope, or create a collision with the environment, were successfully blocked. This approach is seen as useful within the area of tele-operation. (author)

  6. Inhibition of proliferation and invasion in 2D and 3D models by 2-methoxyestradiol in human melanoma cells.

    Science.gov (United States)

    Massaro, R R; Faião-Flores, F; Rebecca, V W; Sandri, S; Alves-Fernandes, D K; Pennacchi, P C; Smalley, K S M; Maria-Engler, S S

    2017-05-01

    Despite the recent advances in the clinical management of melanoma, there remains a need for new pharmacological approaches to treat this cancer. 2-methoxyestradiol (2ME) is a metabolite of estrogen that has shown anti-tumor effects in many cancer types. In this study we show that 2ME treatment leads to growth inhibition in melanoma cells, an effect associated with entry into senescence, decreased pRb and Cyclin B1 expression, increased p21/Cip1 expression and G2/M cell cycle arrest. 2ME treatment also inhibits melanoma cell growth in colony formation assay, including cell lines with acquired resistance to BRAF and BRAF+MEK inhibitors. We further show that 2ME is effective against melanoma with different BRAF and NRAS mutational status. Moreover, 2ME induced the retraction of cytoplasmic projections in a 3D spheroid model and significantly decreased cell proliferation in a 3D skin reconstruct model. Together our studies bring new insights into the mechanism of action of 2ME allowing melanoma targeted therapy to be further refined. Continued progress in this area is expected to lead to improved anti-cancer treatments and the development of new and more effective clinical analogues. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Inhibiting corticosterone synthesis during fear memory formation exacerbates cued fear extinction memory deficits within the single prolonged stress model.

    Science.gov (United States)

    Keller, Samantha M; Schreiber, William B; Stanfield, Briana R; Knox, Dayan

    2015-01-01

    Using the single prolonged stress (SPS) animal model of post-traumatic stress disorder (PTSD), previous studies suggest that enhanced glucocorticoid receptor (GR) expression leads to cued fear extinction retention deficits. However, it is unknown how the endogenous ligand of GRs, corticosterone (CORT), may contribute to extinction retention deficits in the SPS model. Given that CORT synthesis during fear learning is critical for fear memory consolidation and SPS enhances GR expression, CORT synthesis during fear memory formation could strengthen fear memory in SPS rats by enhancing GR activation during fear learning. In turn, this could lead to cued fear extinction retention deficits. We tested the hypothesis that CORT synthesis during fear learning leads to cued fear extinction retention deficits in SPS rats by administering the CORT synthesis inhibitor metyrapone to SPS and control rats prior to fear conditioning, and observed the effect this had on extinction memory. Inhibiting CORT synthesis during fear memory formation in control rats tended to decrease cued freezing, though this effect never reached statistical significance. Contrary to our hypothesis, inhibiting CORT synthesis during fear memory formation disrupted extinction retention in SPS rats. This finding suggests that even though SPS exposure leads to cued fear extinction memory deficits, CORT synthesis during fear memory formation enhances extinction retention in SPS rats. This suggests that stress-induced CORT synthesis in previously stressed rats can be beneficial. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Modeling and Control of Underwater Robotic Systems

    Energy Technology Data Exchange (ETDEWEB)

    Schjoelberg, I:

    1996-12-31

    This doctoral thesis describes modeling and control of underwater vehicle-manipulator systems. The thesis also presents a model and a control scheme for a system consisting of a surface vessel connected to an underwater robotic system by means of a slender marine structure. The equations of motion of the underwater vehicle and manipulator are described and the system kinematics and properties presented. Feedback linearization technique is applied to the system and evaluated through a simulation study. Passivity-based controllers for vehicle and manipulator control are presented. Stability of the closed loop system is proved and simulation results are given. The equation of motion for lateral motion of a cable/riser system connected to a surface vessel at the top end and to a thruster at the bottom end is described and stability analysis and simulations are presented. The equations of motion in 3 degrees of freedom of the cable/riser, surface vessel and robotic system are given. Stability analysis of the total system with PD-controllers is presented. 47 refs., 32 figs., 7 tabs.

  9. Modeling and simulation of blood collection systems.

    Science.gov (United States)

    Alfonso, Edgar; Xie, Xiaolan; Augusto, Vincent; Garraud, Olivier

    2012-03-01

    This paper addresses the modeling and simulation of blood collection systems in France for both fixed site and mobile blood collection with walk in whole blood donors and scheduled plasma and platelet donors. Petri net models are first proposed to precisely describe different blood collection processes, donor behaviors, their material/human resource requirements and relevant regulations. Petri net models are then enriched with quantitative modeling of donor arrivals, donor behaviors, activity times and resource capacity. Relevant performance indicators are defined. The resulting simulation models can be straightforwardly implemented with any simulation language. Numerical experiments are performed to show how the simulation models can be used to select, for different walk in donor arrival patterns, appropriate human resource planning and donor appointment strategies.

  10. PR-957 mediates neuroprotection by inhibiting Th17 differentiation and modulating cytokine production in a mouse model of ischaemic stroke.

    Science.gov (United States)

    Guo, Y; Chen, X; Li, D; Liu, H; Ding, Y; Han, R; Shi, Y; Ma, X

    2018-03-30

    Acute ischaemic stroke can induce secondary brain injury by activating an inflammatory response that contributes to clinical impairment. As a specific inhibitor of the immunoproteasome subunit low molecular weight polypeptide 7 (LMP7), PR-957 may participate in regulating pathophysiological and inflammatory responses in multiple diseases of the central nervous system (CNS). We investigated the neuroprotective properties of PR-957 in a mouse model of stroke, induced by middle cerebral artery occlusion (MCAO). After MCAO and injections of PR-957 or vehicle, we evaluated mice behaviourally using modified Neurological Severity Scores (mNSS) and sensorimotor tests, including the adhesive-removal test, a foot-fault test and an inclined plane test. Infarct volume was measured 24 and 72 h after MCAO. Infiltration by different lymphocyte subpopulations was evaluated by flow cytometry and immunofluorescent staining of brain tissue from the penumbral area. Quantitative real-time polymerase chain reaction analysis and enzyme-linked immunosorbent assay were used to measure the expression of proinflammatory cytokines: interkeukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL-17A, interferon (IFN)-γ, tumour necrosis factor (TNF)-α, granulocyte colony-stimulating factor (GCSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Expression of phosphorylated signal transducer and activator of transcription 3 (pSTAT-3) protein levels in brain was measured by immunoblot. MCAO mice treated with PR-957 showed a significant decrease in infarct volume and had mild neurological deficits compared to vehicle-treated mice. PR-957 administration also significantly decreased IL-1β, IL-6, IL-12, IL-17A and TNF-α. PR-957 provides neuroprotection via inhibiting T lymphocyte infiltration and decreasing T helper type 17 (Th17) cell differentiation in MCAO mice, which may result from the reduced expression of pSTAT-3. The neuroprotective effect of PR-957 indicates its

  11. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system and proinflammatory cytokines in hypertension

    International Nuclear Information System (INIS)

    Su, Qing; Qin, Da-Nian; Wang, Fu-Xin; Ren, Jun; Li, Hong-Bao; Zhang, Meng; Yang, Qing; Miao, Yu-Wang; Yu, Xiao-Jing; Qi, Jie; Zhu, Zhiming; Zhu, Guo-Qing; Kang, Yu-Ming

    2014-01-01

    Aims: To explore whether reactive oxygen species (ROS) scavenger (tempol) in the hypothalamic paraventricular nucleus (PVN) attenuates renin–angiotensin system (RAS) and proinflammatory cytokines (PICs), and decreases the blood pressure and sympathetic activity in angiotensin II (ANG II)-induced hypertension. Methods and results: Male Sprague–Dawley rats were infused intravenously with ANG II (10 ng/kg per min) or normal saline (NS) for 4 weeks. These rats were treated with bilateral PVN infusion of oxygen free radical scavenger tempol (TEMP, 20 μg/h) or vehicle (artificial cerebrospinal fluid, aCSF) for 4 weeks. ANG II infusion resulted in increased mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). These ANG II-infused rats also had higher levels of gp91 phox (a subunit of NAD(P)H oxidase), angiotensin-converting enzyme (ACE), and interleukin-1beta (IL-1β) in the PVN than the control animals. Treatment with PVN infusion of TEMP attenuated the overexpression of gp91 phox , ACE and IL-1β within the PVN, and decreased sympathetic activity and MAP in ANG II-infused rats. Conclusion: These findings suggest that ANG II infusion induces elevated PICs and oxidative stress in the PVN, which contribute to the sympathoexcitation in hypertension. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system, proinflammatory cytokines and oxidative stress in ANG II-induced hypertension. - Highlights: • The effect of chronic inhibiting PVN superoxide on hypertension was investigated. • ANG II infusion induced increased proinflammatory cytokines and superoxide in PVN. • ANG II infusion resulted in oxidative stress, sympathoexcitation and hypertension. • Chronic inhibiting PVN superoxide attenuates RAS and cytokines in hypertension

  12. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system and proinflammatory cytokines in hypertension

    Energy Technology Data Exchange (ETDEWEB)

    Su, Qing [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Qin, Da-Nian, E-mail: dnqin@stu.edu.cn [Department of Physiology, Shantou University Medical College, Shantou 515041 (China); Wang, Fu-Xin [Department of Neurology, The First Affiliated Hospital of Jiamusi University, Jiamusi 154002 (China); Ren, Jun [Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY 82071 (United States); Li, Hong-Bao; Zhang, Meng; Yang, Qing; Miao, Yu-Wang; Yu, Xiao-Jing; Qi, Jie [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China); Zhu, Zhiming [Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, The Third Military Medical University, Chongqing Institute of Hypertension, Chongqing 400042 (China); Zhu, Guo-Qing [Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029 (China); Kang, Yu-Ming, E-mail: ykang@mail.xjtu.edu.cn [Department of Physiology and Pathophysiology, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an Jiaotong University School of Medicine, Xi' an 710061 (China)

    2014-04-15

    Aims: To explore whether reactive oxygen species (ROS) scavenger (tempol) in the hypothalamic paraventricular nucleus (PVN) attenuates renin–angiotensin system (RAS) and proinflammatory cytokines (PICs), and decreases the blood pressure and sympathetic activity in angiotensin II (ANG II)-induced hypertension. Methods and results: Male Sprague–Dawley rats were infused intravenously with ANG II (10 ng/kg per min) or normal saline (NS) for 4 weeks. These rats were treated with bilateral PVN infusion of oxygen free radical scavenger tempol (TEMP, 20 μg/h) or vehicle (artificial cerebrospinal fluid, aCSF) for 4 weeks. ANG II infusion resulted in increased mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). These ANG II-infused rats also had higher levels of gp91{sup phox} (a subunit of NAD(P)H oxidase), angiotensin-converting enzyme (ACE), and interleukin-1beta (IL-1β) in the PVN than the control animals. Treatment with PVN infusion of TEMP attenuated the overexpression of gp91{sup phox}, ACE and IL-1β within the PVN, and decreased sympathetic activity and MAP in ANG II-infused rats. Conclusion: These findings suggest that ANG II infusion induces elevated PICs and oxidative stress in the PVN, which contribute to the sympathoexcitation in hypertension. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system, proinflammatory cytokines and oxidative stress in ANG II-induced hypertension. - Highlights: • The effect of chronic inhibiting PVN superoxide on hypertension was investigated. • ANG II infusion induced increased proinflammatory cytokines and superoxide in PVN. • ANG II infusion resulted in oxidative stress, sympathoexcitation and hypertension. • Chronic inhibiting PVN superoxide attenuates RAS and cytokines in hypertension.

  13. Modeling and Simulation Tools: From Systems Biology to Systems Medicine.

    Science.gov (United States)

    Olivier, Brett G; Swat, Maciej J; Moné, Martijn J

    2016-01-01

    Modeling is an integral component of modern biology. In this chapter we look into the role of the model, as it pertains to Systems Medicine, and the software that is required to instantiate and run it. We do this by comparing the development, implementation, and characteristics of tools that have been developed to work with two divergent methodologies: Systems Biology and Pharmacometrics. From the Systems Biology perspective we consider the concept of "Software as a Medical Device" and what this may imply for the migration of research-oriented, simulation software into the domain of human health.In our second perspective, we see how in practice hundreds of computational tools already accompany drug discovery and development at every stage of the process. Standardized exchange formats ar