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Sample records for chain inhibitor antimycin

  1. Binding of the Respiratory Chain Inhibitor Antimycin to theMitochondrial bc1 Complex: A New Crystal Structure Reveals an AlteredIntramolecular Hydrogen-Bonding Pattern

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    Huang, Li-shar; Cobessi, David; Tung, Eric Y.; Berry, Edward A.

    2005-05-10

    Antimycin A (antimycin), one of the first known and most potent inhibitors of the mitochondrial respiratory chain, binds to the quinone reduction site of the cytochrome bc1 complex.Structure-activity-relationship studies have shown that the N-formylamino-salicyl-amide group is responsible for most of the binding specificity, and suggested that a low pKa for the phenolic OH group and an intramolecular H-bond between that OH and the carbonyl O of the salicylamide linkage are important. Two previous X-ray structures of antimycin bound to vertebrate bc1 complex gave conflicting results. A new structure reported here of the bovine mitochondrial bc1 complex at 2.28Angstrom resolution with antimycin bound, allows us for the first time to reliably describe the binding of antimycin and shows that the intramolecular hydrogen bond described in solution and in the small-molecule structure is replaced by one involving the NH rather than carbonyl O of the amide linkage, with rotation of the amide group relative to the aromatic ring. The phenolic OH and formylamino N form H-bonds with conserved Asp228 of cyt b, and the formylamino O H-bonds via a water molecule to Lys227. A strong density the right size and shape for a diatomic molecule is found between the other side of the dilactone ring and the alpha-A helix.

  2. Comparative kinetics of Qi site inhibitors of cytochrome bc1 complex: picomolar antimycin and micromolar cyazofamid.

    Science.gov (United States)

    Li, Hui; Zhu, Xiao-Lei; Yang, Wen-Chao; Yang, Guang-Fu

    2014-01-01

    Antimycin and cyazofamid are specific inhibitors of the mitochondrial respiratory chain and bind to the Qi site of the cytochrome bc1 complex. With the aim to understand the detailed molecular inhibition mechanism of Qi inhibitors, we performed a comparative investigation of the inhibitory kinetics of them against the porcine bc1 complex. The results showed that antimycin is a slow tight-binding inhibitor of succinate-cytochrome c reductase (SCR) with Ki  = 0.033 ± 0.00027 nm and non-competitive inhibition with respect to cytochrome c. Cyazofamid is a classical inhibitor of SCR with Ki  = 12.90 ± 0.91 μm and a non-competitive inhibitor with respect to cytochrome c. Both of them show competitive inhibition with respect to substrate DBH2 . Further molecular docking and quantum mechanics calculations were performed. The results showed that antimycin underwent significant conformational change upon the binding. The energy barrier between the conformations in the crystal and in the binding pocket is ~13.63 kcal/mol. Antimycin formed an H-bond with Asp228 and two water-bridged H-bonds with Lys227 and His201, whereas cyazofamid formed only one H-bond with Asp228. The conformational change and the different hydrogen bonding network might account for why antimycin is a slow tight-binding inhibitor, whereas cyazofamid is a classic inhibitor.

  3. The regulation and biosynthesis of antimycins

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    Ryan F. Seipke

    2013-11-01

    Full Text Available Antimycins (>40 members were discovered nearly 65 years ago but the discovery of the gene cluster encoding antimycin biosynthesis in 2011 has facilitated rapid progress in understanding the unusual biosynthetic pathway. Antimycin A is widely used as a piscicide in the catfish farming industry and also has potent killing activity against insects, nematodes and fungi. The mode of action of antimycins is to inhibit cytochrome c reductase in the electron transport chain and halt respiration. However, more recently, antimycin A has attracted attention as a potent and selective inhibitor of the mitochondrial anti-apoptotic proteins Bcl-2 and Bcl-xL. Remarkably, this inhibition is independent of the main mode of action of antimycins such that an artificial derivative named 2-methoxyantimycin A inhibits Bcl-xL but does not inhibit respiration. The Bcl-2/Bcl-xL family of proteins are over-produced in cancer cells that are resistant to apoptosis-inducing chemotherapy agents, so antimycins have great potential as anticancer drugs used in combination with existing chemotherapeutics. Here we review what is known about antimycins, the regulation of the ant gene cluster and the unusual biosynthetic pathway.

  4. Extramitochondrial release of hydrogen peroxide from insect and mouse liver mitochondria using the respiratory inhibitors phosphine, myxothiazol, and antimycin and spectral analysis of inhibited cytochromes.

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    Bolter, C J; Chefurka, W

    1990-04-01

    The fumigant insecticide phosphine (PH3) is known to inhibit cytochrome c oxidase in vitro. Inhibition of the respiratory chain at this site has been shown to stimulate the generation of superoxide radicals (O2-), which dismutate to form hydrogen peroxide (H2O2). This study was performed in order to investigate the production of H2O2 by mitochondria isolated from granary weevil (Sitophilus granarius) and mouse liver on exposure to PH3. Other respiratory inhibitors, antimycin, myxothiazol, and rotenone were used with insect mitochondria. Hydrogen peroxide was measured spectrophotometrically using yeast cytochrome c peroxidase as an indicator. Insect and mouse liver mitochondria, utilizing endogenous substrate, both produced H2O2 after inhibition by PH3. Insect organelles released threefold more H2O2 than did mouse organelles, when exposed to PH3. Production of H2O2 by PH3-treated insect mitochondria was increased significantly on addition of the substrate alpha-glycerophosphate. Succinate did not enhance H2O2 production, however, indicating that the H2O2 did not result from the autoxidation of ubiquinone. NAD(+)-linked substrates, malate and pyruvate also had no effect on H2O2 production, suggesting that NADH-dehydrogenase was not the source of H2O2. Data obtained using antimycin and myxothiazol, both of which stimulated the release of H2O2 from insect mitochondria, lead to the conclusion that glycerophosphate dehydrogenase is a source of H2O2. The effect of combining PH3, antimycin, and myxothiazol on cytochrome spectra in insect mitochondria was also recorded. It was observed that PH3 reduces cytochrome c oxidase but none of the other cytochromes in the electron transport chain. There was no movement of electrons to cytochrome b when insect mitochondria are inhibited with PH3. The spectral data show that the inhibitors interact with the respiratory chain in a way that would allow the production of H2O2 from the sites proposed previously.

  5. All-atom molecular dynamics simulations reveal significant differences in interaction between antimycin and conserved amino acid residues in bovine and bacterial bc1 complexes.

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    Kokhan, Oleksandr; Shinkarev, Vladimir P

    2011-02-02

    Antimycin A is the most frequently used specific and powerful inhibitor of the mitochondrial respiratory chain. We used all-atom molecular dynamics (MD) simulations to study the dynamic aspects of the interaction of antimycin A with the Q(i) site of the bacterial and bovine bc(1) complexes embedded in a membrane. The MD simulations revealed considerable conformational flexibility of antimycin and significant mobility of antimycin, as a whole, inside the Q(i) pocket. We conclude that many of the differences in antimycin binding observed in high-resolution x-ray structures may have a dynamic origin and result from fluctuations of protein and antimycin between multiple conformational states of similar energy separated by low activation barriers, as well as from the mobility of antimycin within the Q(i) pocket. The MD simulations also revealed a significant difference in interaction between antimycin and conserved amino acid residues in bovine and bacterial bc(1) complexes. The strong hydrogen bond between antimycin and conserved Asp-228 (bovine numeration) was observed to be frequently broken in the bacterial bc(1) complex and only rarely in the bovine bc(1) complex. In addition, the distances between antimycin and conserved His-201 and Lys-227 were consistently larger in the bacterial bc(1) complex. The observed differences could be responsible for a weaker interaction of antimycin with the bacterial bc(1) complex.

  6. Electron transport chain inhibitors induce microglia activation through enhancing mitochondrial reactive oxygen species production.

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    Ye, Junli; Jiang, Zhongxin; Chen, Xuehong; Liu, Mengyang; Li, Jing; Liu, Na

    2016-01-15

    Reactive oxygen species (ROS) are believed to be mediators of excessive microglial activation, yet the resources and mechanism are not fully understood. Here we stimulated murine microglial BV-2 cells and primary microglial cells with different inhibitors of electron transport chain (ETC), rotenone, thenoyltrifluoroacetone (TTFA), antimycin A, and NaN3 to induce mitochondrial ROS production and we observed the role of mitochondrial ROS in microglial activation. Our results showed that ETC inhibitors resulted in significant changes in cell viability, microglial morphology, cell cycle arrest and mitochondrial ROS production in a dose-dependent manner in both primary cultural microglia and BV-2 cell lines. Moreover, ETC inhibitors, especially rotenone and antimycin A stimulated secretion of interleukin 1β (IL-1β), interleukin 6 (IL-6), interleukin 12 (IL-12) and tumor necrosis factor α (TNF-α) by microglia with marked activation of mitogen-activated proteinkinases (MAPKs) and nuclear factor κB (NF-κB), which could be blocked by specific inhibitors of MAPK and NF-κB and mitochondrial antioxidants, Mito-TEMPO. Taken together, our results demonstrated that inhibition of mitochondrial respiratory chain in microglia led to production of mitochondrial ROS and therefore may activate MAPK/NF-кB dependent inflammatory cytokines release in microglia, which indicated that mitochondrial-derived ROS were contributed to microglial activation.

  7. Mitochondrial morphology and dynamics in Triticum aestivum roots in response to rotenone and antimycin A.

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    Rakhmatullina, Daniya; Ponomareva, Anastasiya; Gazizova, Natalia; Minibayeva, Farida

    2016-09-01

    Mitochondria are dynamic organelles, capable of fusion and fission as a part of cellular responses to various signals, such as the shifts in the redox status of a cell. The mitochondrial electron transport chain (ETC.) is involved in the generation of reactive oxygen species (ROS), with complexes I and III contributing the most to this process. Disruptions of ETC. can lead to increased ROS generation. Here, we demonstrate the appearance of giant mitochondria in wheat roots in response to simultaneous application of the respiratory inhibitors rotenone (complex I of mitochondrial ETC.) and antimycin A (complex III of mitochondrial ETC.). The existence of such megamitochondria was temporary, and following longer treatment with inhibitors mitochondria resumed their conventional size and oval shape. Changes in mitochondrial morphology were accompanied with a decrease in mitochondrial potential and an unexpected increase in oxygen consumption. Changes in mitochondrial morphology and activity may result from the fusion and fission of mitochondria induced by the disruption of mitochondrial ETC. Results from experiments with the inhibitor of mitochondrial fission Mdivi-1 suggest that the retarded fission may facilitate plant mitochondria to appear in a fused shape. The processes of mitochondrial fusion and fission are involved in the regulation of the efficacy of the functions of the respiratory chain complexes and ROS metabolism during stresses. The changes in morphology of mitochondria, along with the changes in their functional activity, can be a part of the strategy of the plant adaptation to stresses.

  8. Inhibition of aldehyde dehydrogenase 2 activity enhances antimycin-induced rat cardiomyocytes apoptosis through activation of MAPK signaling pathway.

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    Zhang, Peng; Xu, Danling; Wang, Shijun; Fu, Han; Wang, Keqiang; Zou, Yunzeng; Sun, Aijun; Ge, Junbo

    2011-12-01

    Aldehyde dehydrogenase 2 (ALDH2), a mitochondrial-specific enzyme, has been proved to be involved in oxidative stress-induced cell apoptosis, while little is known in cardiomyocytes. This study was aimed at investigating the role of ALDH2 in antimycin A-induced cardiomyocytes apoptosis by suppressing ALDH2 activity with a specific ALDH2 inhibitor Daidzin. Antimycin A (40μg/ml) was used to induce neonatal cardiomyocytes apoptosis. Daidzin (60μM) effectively inhibited ALDH2 activity by 50% without own effect on cell apoptosis, and significantly enhanced antimycin A-induced cardiomyocytes apoptosis from 33.5±4.4 to 56.5±6.4% (Hochest method, pdaidzin treated cardiomyocytes compared to the cells treated with antimycin A alone. These findings indicated that modifying mitochondrial ALDH2 activity/expression might be a potential therapeutic option on reducing oxidative insults induced cardiomyocytes apoptosis.

  9. Mitochondrial Respiratory Chain Inhibitors Involved in ROS Production Induced by Acute High Concentrations of Iodide and the Effects of SOD as a Protective Factor

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    Lingyan Wang

    2015-01-01

    Full Text Available A major source of reactive oxygen species (ROS generation is the mitochondria. By using flow cytometry of the mitochondrial fluorescent probe, MitoSOX Red, western blot of mitochondrial ROS scavenger Peroxiredoxin (Prx 3 and fluorescence immunostaining, ELISA of cleaved caspases 3 and 9, and TUNEL staining, we demonstrated that exposure to 100 μM KI for 2 hours significantly increased mitochondrial superoxide production and Prx 3 protein expression with increased expressions of cleaved caspases 3 and 9. Besides, we indicated that superoxide dismutase (SOD at 1000 unit/mL attenuated the increase in mitochondrial superoxide production, Prx 3 protein expression, and lactate dehydrogenase (LDH release and improved the relative cell viability at 100 μM KI exposure. However, SOD inhibitor diethyldithiocarbamic acid (DETC (2 mM, Rotenone (0.5 μM, a mitochondrial complex I inhibitor, and Antimycin A (10 μM, a complex III inhibitor, caused an increase in mitochondrial superoxide production, Prx 3 protein expression, and LDH release and decreased the relative cell viability. We conclude that the inhibitors of mitochondrial respiratory chain complex I or III may be involved in oxidative stress caused by elevated concentrations of iodide, and SOD demonstrates its protective effect on the Fischer rat thyroid cell line (FRTL cells.

  10. Increased sensitivity of photosynthesis to antimycin A induced by inactivation of the chloroplast ndhB gene. Evidence for a participation of the NADH-dehydrogenase complex to cyclic electron flow around photosystem I.

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    Joët, T; Cournac, L; Horvath, E M; Medgyesy, P; Peltier, G

    2001-04-01

    Tobacco (Nicotiana tabacum var Petit Havana) ndhB-inactivated mutants (ndhB-) obtained by plastid transformation (E.M. Horvath, S.O. Peter, T. Joët, D. Rumeau, L. Cournac, G.V. Horvath, T.A. Kavanagh, C. Schäfer, G. Peltier, P. MedgyesyHorvath [2000] Plant Physiol 123: 1337-1350) were used to study the role of the NADH-dehydrogenase complex (NDH) during photosynthesis and particularly the involvement of this complex in cyclic electron flow around photosystem I (PSI). Photosynthetic activity was determined on leaf discs by measuring CO2 exchange and chlorophyll fluorescence quenchings during a dark-to-light transition. In the absence of treatment, both non-photochemical and photochemical fluorescence quenchings were similar in ndhB- and wild type (WT). When leaf discs were treated with 5 microM antimycin A, an inhibitor of cyclic electron flow around PSI, both quenchings were strongly affected. At steady state, maximum photosynthetic electron transport activity was inhibited by 20% in WT and by 50% in ndhB-. Under non-photorespiratory conditions (2% O2, 2,500 microL x L(-1) CO2), antimycin A had no effect on photosynthetic activity of WT, whereas a 30% inhibition was observed both on quantum yield of photosynthesis assayed by chlorophyll fluorescence and on CO2 assimilation in ndhB-. The effect of antimycin A on ndhB- could not be mimicked by myxothiazol, an inhibitor of the mitochondrial cytochrome bc1 complex, therefore showing that it is not related to an inhibition of the mitochondrial electron transport chain but rather to an inhibition of cyclic electron flow around PSI. We conclude to the existence of two different pathways of cyclic electron flow operating around PSI in higher plant chloroplasts. One of these pathways, sensitive to antimycin A, probably involves ferredoxin plastoquinone reductase, whereas the other involves the NDH complex. The absence of visible phenotype in ndhB- plants under normal conditions is explained by the complement of these two

  11. Cutting the chain of command: specific inhibitors of transcription.

    Science.gov (United States)

    Holt, J T

    1991-01-01

    Cell growth and differentiation are regulated (at least in part) by changes in gene transcription. The cloning and characterization of transcription factors has revealed that these factors coordinately regulate the transcription of specific genetic programs; for example, a number of phorbol ester-induced genes are activated by binding of the transcription factors Fos and Jun to specific DNA sequences. Clearly, inhibition of either the production or function of specific transcription factors would alter complete genetic programs, changing the expression of a great number of genes (analogous to cutting the chain of military command and affecting an entire brigade or division). Our laboratory and others have employed genetic methods to specifically inhibit transcription by two distinct methods: (1) antisense inhibition of the production of transcription factors; and (2) introduction of target DNA sequences to "soak up"or quench transcription factors. In this report, we present data showing that serum-stimulated induction of the c-fos gene may be reduced more than 90% by introduction of target DNA sequences containing the serum response element (SRE); identical amounts of mutant SRE sequences have no effect on gene induction. These studies demonstrate that specific inhibitors of transcription can have significant effects on cellular gene expression. The challenge is to modulate transcriptional programs without deleterious effects on normal cells.

  12. Synthesis and biological activities of the respiratory chain inhibitor aurachin D and new ring versus chain analogues

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    Xu-Wen Li

    2013-07-01

    Full Text Available Aurachins are myxobacterial 3-farnesyl-4(1H-quinolone derived compounds initially described as respiratory chain inhibitors, more specifically as inhibitors of various cytochrome complexes. They are also known as potent antibiotic compounds. We describe herein the first synthesis of aurachin D through a key Conrad–Limpach reaction. The same strategy was used to reach some ring as opposed to chain analogues, allowing for the description of structure–activity relationships. Biological screening of the analogues showed antiparasitic, cytotoxic, antibacterial and antifungal activities, and depletion of the mitochondrial membrane potential. The strongest activity was found on Plasmodium falciparum with a selectivity index of 345, compared to Vero cells, for the natural product and its geranyl analogue. The loss of mitochondrial membrane potential induced by aurachins in human U-2 OS osteosarcoma cells was studied, showing the best activity for aurachin D and a naphthalene analogue, yet without totally explaining the observed cytotoxic activity of the compounds. Finally, a synthetic entry is given to the complete carboheterocyclic core of aurachin H through the N-oxidation/epoxidation of aurachin D and a shorter chain analogue, followed by subsequent biomimetic cyclization.

  13. Mechanisms involved in the inhibition of glycolysis by cyanide and antimycin A in Candida albicans and its reversal by hydrogen peroxide. A common feature in Candida species.

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    Peña, Antonio; Sánchez, Norma Silvia; González-López, Omar; Calahorra, Martha

    2015-12-01

    In Candida albicans, cyanide and antimycin A inhibited K(+) transport, not only with ethanol-O2 as the substrate, but also with glucose. The reason for this was that they inhibited not only respiration, but also fermentation, decreasing ATP production. Measurements of oxygen levels in cell suspensions allowed identification of the electron pathways involved. NADH fluorescence levels increased in the presence of the inhibitors, indirectly indicating lower levels of NAD(+) and so pointing to glyceraldehyde-3-phosphate dehydrogenase as the limiting step responsible for the inhibition of glycolysis, which was confirmed by the levels of glycolytic intermediaries. The cyanide effect could be reversed by hydrogen peroxide, mainly due to an activity by which H2O2 can be reduced by electrons flowing from NADH through a pathway that can be inhibited by antimycin A, and appears to be a cytochrome c peroxidase. Therefore, the inhibition of glycolysis by the respiratory inhibitors seems to be due to the decreased availability of NAD(+), resulting in a decreased activity of glyceraldehyde-3-phosphate dehydrogenase. Compartmentalization of pyridine nucleotides in favor of the mitochondria can contribute to explaining the low fermentation capacity of C. albicans. Similar results were obtained with three C. albicans strains, Candida dubliniensis and, to a lower degree, Candida parapsilosis.

  14. Aminocarnitine and acylaminocarnitines: Carnitine acyltransferase inhibitors affecting long-chain fatty acid and glucose metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Clark, D.J.

    1989-01-01

    DL-Aminocarnitine (DL-3-amino-4-trimethylaminobutyrate) and the acylaminocarnitines acetyl-, decanoyl- and palmitoyl-DL-aminocarnitine have been synthesized and tested as inhibitors of carnitine palmitoyl-transferase and carnitine acetyltransferase in vitro and in vivo. Acetyl-DL-aaminocarnitine is the most potent reversible inhibitor of carnitine acetyltransferase reported to date, and is competitive with respect to acetyl-L-carnitine. Mice given acetyl-DL-aminocarnitine metabolize (U-{sup 14}C)acetyl-L-carnitine at about 60% of the rate of control mice. Palmitoyl-DL-aminocarnitine is the most potent reversible inhibitor of carnitine palmitoyltransferase reported to date. Decanoyl-DL-aminocarnitine and DL-aminocarnitine are also very potent inhibitors; all compounds inhibit the catabolism of ({sup 14}C)palmitate to {sup 14}CO{sub 2} in intact mice by at least 50%. Carnitine palmitoyltransferase controls the entry of long-chain fatty acids into the mitochondrial matrix for {beta}-oxidation. The inhibition of carnitine palmitoyltransferase by aminocarnitine or acylaminocarnitines in vivo prevents or reverses ketogenesis in fasted mice, and causes the reversible accumulation of triglycerides in liver, kidney and plasma. Administration of DL-aminocarnitine to streptozotocindiabetic mice lowers plasma glucose levels and improves the glucose tolerance test.

  15. U.S.D.A. Forest Service environmental analysis report on the use of antimycin to rehabilitate lakes and streams

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    US Fish and Wildlife Service, Department of the Interior — Report identifies characteristics of use of antimycin to destroy stickleback, chub, suckers and other competitors to salmon and dolly varden.

  16. Analysis of antimycin A by reversed-phase liquid chromatography/nuclear magnetic-resonance spectrometry

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    Ha, Steven T.K.; Wilkins, Charles L.; Abidi, Sharon L.

    1989-01-01

    A mixture of closely related streptomyces fermentation products, antimycin A, Is separated, and the components are identified by using reversed-phase high-performance liquid chromatography with directly linked 400-MHz proton nuclear magnetic resonance detection. Analyses of mixtures of three amino acids, alanine, glycine, and valine, are used to determine optimal measurement conditions. Sensitivity increases of as much as a factor of 3 are achieved, at the expense of some loss in chromatographic resolution, by use of an 80-μL NMR cell, Instead of a smaller 14-μL cell. Analysis of the antimycin A mixture, using the optimal analytical high performance liquid chromatography/nuclear magnetic resonance conditions, reveals it to consist of at least 10 closely related components.

  17. High-performance liquid chromatographic separation of subcomponents of antimycin A.

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    Abidi, S L

    1988-08-05

    Using a reversed-phase high-performance liquid chromatographic (HPLC) technique, a mixture of antimycins A was separated into eight hitherto unreported subcomponents, A1a, A1b, A2a, A2b, A3a, A3b, A4a, and A4b. Although a base-line resolution of the known four major antimycins A1, A2, A3, and A4 was readily achieved with mobile phases containing acetate buffers, the separation of the new antibiotic subcomponents was highly sensitive to variation in mobile phase conditions. The type and composition of organic modifers, the nature of buffer salts, and the concentration of added electrolytes had profound effects on capacity factors, separation factors, and peak resolution values. Of the numerous chromatographic systems examined, a mobile phase consisting of methanol-water (70:30) and 0.005 M tetrabutylammonium phosphate at pH 3.0 yielded the most satisfactory results for the separation of the subcomponents. Reversed-phase gradient HPLC separation of the dansylated or methylated antibiotic compounds produced superior chromatographic characteristics and the presence of added electrolytes was not a critical factor for achieving separation. Differences in the chromatographic outcome between homologous and structural isomers were interpreted based on a differential solvophobic interaction rationale. Preparative reversed-phase HPLC under optimal conditions enabled isolation of pure samples of the methylated antimycin subcomponents for use in structural studies.

  18. Reversed-phase thin-layer chromatography of homologs of Antimycin-A and related derivatives

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    Abidi, Sharon L.

    1989-01-01

    Using a reversed-phase high-performance liquid chromatographic (HPLC) technique, a mixture of antimycins A was separated into eight hitherto unreported subcomponents, Ala, Alb, A2a, A2b, A3a, A3b, A4a, and A4b. Although a base-line resolution of the known four major antimycins Al, A2, A3, and A4 was readily achieved with mobile phases containing acetate buffers, the separation of the new antibiotic subcomponents was highly sensitive to variation in mobile phase conditions. The type and composition of organic modifiers, the nature of buffer salts, and the concentration of added electrolytes had profound effects on capacity factors, separation factors, and peak resolution values. Of the numerous chromatographic systems examined, a mobile phase consisting of methanol-water (70:30) and 0.005 M tetrabutylammonium phosphate at pH 3.0 yielded the most satisfactory results for the separation of the subcomponents. Reversed-phase gradient HPLC separation of the dansylated or methylated antibiotic compounds produced superior chromatographic characteristics and the presence of added electrolytes was not a critical factor for achieving separation. Differences in the chromatographic outcome between homologous and structural isomers were interpretated based on a differential solvophobic interaction rationale. Preparative reversed-phase HPLC under optimal conditions enabled isolation of pure samples of the methylated antimycin subcomponents for use in structural studies.

  19. High-performance liquid-chromatographic separation of subcomponents of antimycin-A

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    Abidi, S.L.

    1988-01-01

    Using a reversed-phase high-performance liquid chromatographic (HPLC) technique, a mixture of antimycins A was separated into eight hitherto unreported subcomponents, Ala, Alb, A2a, A2b, A3a, A3b, A4a, and A4b. Although a base-line resolution of the known four major antimycins Al, A2, A3, and A4 was readily achieved with mobile phases containing acetate buffers, the separation of the new antibiotic subcomponents was highly sensitive to variation in mobile phase conditions. The type and composition of organic modifiers, the nature of buffer salts, and the concentration of added electrolytes had profound effects on capacity factors, separation factors, and peak resolution values. Of the numerous chromatographic systems examined, a mobile phase consisting of methanol-water (70:30) and 0.005 M tetrabutylammonium phosphate at pH 3.0 yielded the most satisfactory results for the separation of the subcomponents. Reversed-phase gradient HPLC separation of the dansylated or methylated antibiotic compounds produced superior chromatographic characteristics and the presence of added electrolytes was not a critical factor for achieving separation. Differences in the chromatographic outcome between homologous and structural isomers were interpretated based on a differential solvophobic interaction rationale. Preparative reversed-phase HPLC under optimal conditions enabled isolation of pure samples of the methylated antimycin subcomponents for use in structural studies.

  20. Characterization of the respiratory chain of Helicobacter pylori

    DEFF Research Database (Denmark)

    Chen, M; Andersen, L P; Zhai, L

    1999-01-01

    The respiratory chain of Helicobacter pylori has been investigated. The total insensitivity of activities of NADH dehydrogenase to rotenone and of NADH-cytochrome c reductase to antimycin is indicative of the absence of the classical complex I of the electron transfer chain in this bacterium. NADPH...

  1. Spermine binding to liver mitochondria deenergized by ruthenium red plus either FCCP or antimycin A.

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    Dalla Via, L; Di Noto, V; Toninello, A

    1998-01-23

    Thermodynamic analysis of spermine binding to mitochondria treated with ruthenium red and deenergized with either FCCP or antimycin A confirms the presence of two polyamine binding sites, S1 and S2, both with monocoordination, as previously observed in energized mitochondria [Dalla Via et al., Biochim. Biophys. Acta 1284 (1996) 247-252]. Both sites undergo a marked change in binding capacity and binding affinity upon mitochondrial deenergization. This change is most likely responsible for the incomplete or delayed spermine-mediated inhibition of the permeability transition induced in deenergized mitochondria.

  2. Probing BoNT/A protease exosites: implications for inhibitor design and light chain longevity.

    Science.gov (United States)

    Xue, Song; Javor, Sacha; Hixon, Mark S; Janda, Kim D

    2014-11-04

    Botulinum neurotoxin serotype A (BoNT/A) is one of the most lethal toxins known. Its extreme toxicity is due to its light chain (LC), a zinc protease that cleaves SNAP-25, a synaptosome-associated protein, leading to the inhibition of neuronal activity. Studies on BoNT/A LC have revealed that two regions, termed exosites, can play an important role in BoNT catalytic activity. A clear understanding of how these exosites influence neurotoxin catalytic activity would provide a critical framework for deciphering the mechanism of SNAP-25 cleavage and the design of inhibitors. Herein, based on the crystallographic structure of BoNT/A LC complexed with its substrate, we designed an α-exosite binding probe. Experiments with this unique probe demonstrated that α-exosite binding enhanced both catalytic activity and stability of the LC. These data help delineate why α-exosite binding is needed for SNAP-25 cleavage and also provide new insights into the extended lifetime observed for BoNT/A LC in vivo.

  3. Bypasses of the antimycin a block of mitochondrial electron transport in relation to ubisemiquinone function.

    Science.gov (United States)

    Alexandre, A; Lehninger, A L

    1984-10-26

    Two different bypasses around the antimycin block of electron transport from succinate to cytochrome c via the ubiquinol-cytochrome c oxidoreductase of intact rat liver mitochondria were analyzed, one promoted by N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) and the other by 2,6-dichlorophenolindophenol (DCIP). Both bypasses are inhibited by myxothiazol, which blocks electron flow from ubiquinol to the Rieske iron-sulfur center, and by 2-hydroxy-3-undecyl-1,4-naphthoquinone, which inhibits electron flow from the iron-sulfur center to cytochrome c1. In the bypass promoted by TMPD its oxidized form (Wurster's blue) acts as an electron acceptor from some reduced component prior to the antimycin block, which by exclusion of other possibilities is ubisemiquinone. In the DCIP bypass its reduced form acts as an electron donor, by reducing ubisemiquinone to ubiquinol; reduced DCIP is regenerated again at the expense of either succinate or ascorbate. The observations described are consistent with and support current models of the Q cycle. Bypasses promoted by artificial electron carriers provide an independent approach to analysis of electron flow through ubiquinol-cytochrome c oxidoreductase.

  4. Induction of the AOX1D Isoform of Alternative Oxidase in A. thaliana T-DNA Insertion Lines Lacking Isoform AOX1A Is Insufficient to Optimize Photosynthesis when Treated with Antimycin A

    Institute of Scientific and Technical Information of China (English)

    Inga Strodtkotter; Kollipara Padmasree; Challabathula Dinakar; Birgit Speth; Pamela S. Niazi; Joanna Wojtera; Ingo Voss; Phuc Thi Do; Adriano Nunes-Nesi; Alisdair R. Fernie; Vera Linke; Agepati S. Raghavendra; Renate Scheibe

    2009-01-01

    Plant respiration is characterized by two pathways for electron transfer to O2, namely the cytochrome path-way (CP) that is linked to ATP production, and the alternative pathway (AP), where electrons from ubiquinol are directly transferred to O2 via an alternative oxidase (AOX) without concomitant ATP production. This latter pathway is well suited to dispose of excess electrons in the light, leading to optimized photosynthetic performance. We have characterized T-DNA-insertion mutant lines of Arabidopsis thaliana that do not express the major isoform, AOXIA. In standard growth conditions, these plants did not show any phenotype, but restriction of electron flow through CP by antimycin A, which induces AOX1A expression in the wild-type, led to an increased expression of AOX1D in leaves of the aox1a-knockout mutant. Despite the increased presence of the AOX1D isoform in the mutant, antimycin A caused inhibition of photosyn-thesis, increased ROS, and ultimately resulted in amplified membrane leakage and necrosis when compared to the wild-type, which was only marginally affected by the inhibitor. It thus appears that AOX1D was unable to fully compensate for the loss of AOX1A when electron flow via the CP is restricted. A combination of inhibition studies, coupled to metabolite profiling and targeted expression analysis of the P-protein of glycine decarboxylase complex (GDC), suggests that the aox1a mutants attempt to increase their capacity for photorespiration. However, given their deficiency, it is intriguing that increase in expression neither of AOX1D nor of GDC could fully compensate for the lack of AOX1A to optimize pho-tosynthesis when treated with antimycin A. We suggest that the aox1a mutants can further be used to substantiate the current models concerning the influence of mitochondrial redox on photosynthetic performance and gene expression.

  5. Discovery of pyrazole carboxylic acids as potent inhibitors of rat long chain L-2-hydroxy acid oxidase.

    Science.gov (United States)

    Barawkar, Dinesh A; Bandyopadhyay, Anish; Deshpande, Anil; Koul, Summon; Kandalkar, Sachin; Patil, Pradeep; Khose, Goraksha; Vyas, Samir; Mone, Mahesh; Bhosale, Shubhangi; Singh, Umesh; De, Siddhartha; Meru, Ashwin; Gundu, Jayasagar; Chugh, Anita; Palle, Venkata P; Mookhtiar, Kasim A; Vacca, Joseph P; Chakravarty, Prasun K; Nargund, Ravi P; Wright, Samuel D; Roy, Sophie; Graziano, Michael P; Cully, Doris; Cai, Tian-Quan; Singh, Sheo B

    2012-07-01

    Long chain L-2-hydroxy acid oxidase 2 (Hao2) is a peroxisomal enzyme expressed in the kidney and the liver. Hao2 was identified as a candidate gene for blood pressure (BP) quantitative trait locus (QTL) but the identity of its physiological substrate and its role in vivo remains largely unknown. To define a pharmacological role of this gene product, we report the development of selective inhibitors of Hao2. We identified pyrazole carboxylic acid hits 1 and 2 from screening of a compound library. Lead optimization of these hits led to the discovery of 15-XV and 15-XXXII as potent and selective inhibitors of rat Hao2. This report details the structure activity relationship of the pyrazole carboxylic acids as specific inhibitors of Hao2.

  6. Structures of Clostridium Botulinum Neurotoxin Serotype A Light Chain Complexed with Small-Molecule Inhibitors Highlight Active-Site Flexibility

    Energy Technology Data Exchange (ETDEWEB)

    Silvaggi,N.; Boldt, G.; Hixon, M.; Kennedy, J.; Tzipori, S.; Janda, K.; Allen, K.

    2007-01-01

    The potential for the use of Clostridial neurotoxins as bioweapons makes the development of small-molecule inhibitors of these deadly toxins a top priority. Recently, screening of a random hydroxamate library identified a small-molecule inhibitor of C. botulinum Neurotoxin Serotype A Light Chain (BoNT/A-LC), 4-chlorocinnamic hydroxamate, a derivative of which has been shown to have in vivo efficacy in mice and no toxicity. We describe the X-ray crystal structures of BoNT/A-LC in complexes with two potent small-molecule inhibitors. The structures of the enzyme with 4-chlorocinnamic hydroxamate or 2,4-dichlorocinnamic hydroxamate bound are compared to the structure of the enzyme complexed with L-arginine hydroxamate, an inhibitor with modest affinity. Taken together, this suite of structures provides surprising insights into the BoNT/A-LC active site, including unexpected conformational flexibility at the S1' site that changes the electrostatic environment of the binding pocket. Information gained from these structures will inform the design and optimization of more effective small-molecule inhibitors of BoNT/A-LC.

  7. Putative Structural and Functional Coupling of the Mitochondrial BKCa Channel to the Respiratory Chain.

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    Piotr Bednarczyk

    Full Text Available Potassium channels have been found in the inner mitochondrial membranes of various cells. These channels regulate the mitochondrial membrane potential, the matrix volume and respiration. The activation of these channels is cytoprotective. In our study, the single-channel activity of a large-conductance Ca(2+-regulated potassium channel (mitoBKCa channel was measured by patch-clamping mitoplasts isolated from the human astrocytoma (glioblastoma U-87 MG cell line. A potassium-selective current was recorded with a mean conductance of 290 pS in symmetrical 150 mM KCl solution. The channel was activated by Ca(2+ at micromolar concentrations and by the potassium channel opener NS1619. The channel was inhibited by paxilline and iberiotoxin, known inhibitors of BKCa channels. Western blot analysis, immuno-gold electron microscopy, high-resolution immunofluorescence assays and polymerase chain reaction demonstrated the presence of the BKCa channel β4 subunit in the inner mitochondrial membrane of the human astrocytoma cells. We showed that substrates of the respiratory chain, such as NADH, succinate, and glutamate/malate, decrease the activity of the channel at positive voltages. This effect was abolished by rotenone, antimycin and cyanide, inhibitors of the respiratory chain. The putative interaction of the β4 subunit of mitoBKCa with cytochrome c oxidase was demonstrated using blue native electrophoresis. Our findings indicate possible structural and functional coupling of the mitoBKCa channel with the mitochondrial respiratory chain in human astrocytoma U-87 MG cells.

  8. Medium-chain fatty acids and glutathione derivatives as inhibitors of S-nitrosoglutathione reduction mediated by alcohol dehydrogenase 3.

    Science.gov (United States)

    Staab, Claudia A; Hellgren, Mikko; Grafström, Roland C; Höög, Jan-Olov

    2009-06-15

    Alcohol dehydrogenase 3 (ADH3) has emerged as an important regulator of protein S-nitrosation in its function as S-nitrosoglutathione (GSNO) reductase. GSNO depletion is associated with various disease conditions, emphasizing the potential value of a specific ADH3 inhibitor. The present study investigated inhibition of ADH3-mediated GSNO reduction by various substrate analogues, including medium-chain fatty acids and glutathione derivatives. The observed inhibition type was non-competitive. Similar to the Michaelis constants for the corresponding omega-hydroxy fatty acids, the inhibition constants for fatty acids were in the micromolar range and showed a clear dependency on chain length with optimal inhibitory capacity for eleven and twelve carbons. The most efficient inhibitors found were undecanoic acid, dodecanoic acid and dodecanedioic acid, with no significant difference in inhibition constant. All glutathione-derived inhibitors displayed inhibition constants in the millimolar range, at least three orders of magnitudes higher than the Michaelis constants of the high-affinity substrates GSNO and S-hydroxymethylglutathione. The experimental results as well as docking simulations with GSNO and S-methylglutathione suggest that for ADH3 ligands with a glutathione scaffold, in contrast to fatty acids, a zinc-binding moiety is imperative for correct orientation and stabilization of the hydrophilic glutathione scaffold within a predominantly hydrophobic active site.

  9. Urine of patients with early prostate cancer contains lower levels of light chain fragments of inter-alpha-trypsin inhibitor and saposin B but increased expression of an inter-alpha-trypsin inhibitor heavy chain 4 fragment.

    Science.gov (United States)

    Jayapalan, Jaime J; Ng, Keng L; Shuib, Adawiyah S; Razack, Azad H A; Hashim, Onn H

    2013-06-01

    The present study was aimed at the identification of proteins that are differentially expressed in the urine of patients with prostate cancer (PCa), those with benign prostatic hyperplasia (BPH) and age-matched healthy male control subjects. Using a combination of 2DE and MS/MS, significantly lower expression of urinary saposin B and two different fragments of inter-alpha-trypsin inhibitor light chain (ITIL) was demonstrated in the PCa patients compared to the controls. However, only one of the ITIL fragments was significantly different between the PCa and BPH patients. When image analysis was performed on urinary proteins that were transferred onto NC membranes and detected using a lectin that binds to O-glycans, a truncated fragment of inter-alpha-trypsin inhibitor heavy chain 4 was the sole protein found to be significantly enhanced in the PCa patients compared to the controls. Together, these urinary peptide fragments might be useful complementary biomarkers to indicate PCa as well as to distinguish it from BPH, although further epidemiological evidence on the specificity and sensitivity of the protein candidates is required.

  10. Cholesterol Analogs with Degradation-resistant Alkyl Side Chains Are Effective Mycobacterium tuberculosis Growth Inhibitors.

    Science.gov (United States)

    Frank, Daniel J; Zhao, Yan; Wong, Siew Hoon; Basudhar, Debashree; De Voss, James J; Ortiz de Montellano, Paul R

    2016-04-01

    Cholest-4-en-3-one, whether added exogenously or generated intracellularly from cholesterol, inhibits the growth ofMycobacterium tuberculosiswhen CYP125A1 and CYP142A1, the cytochrome P450 enzymes that initiate degradation of the sterol side chain, are disabled. Here we demonstrate that a 16-hydroxy derivative of cholesterol, which was previously reported to inhibit growth ofM. tuberculosis, acts by preventing the oxidation of the sterol side chain even in the presence of the relevant cytochrome P450 enzymes. The finding that (25R)-cholest-5-en-3β,16β,26-triol (1) (and its 3-keto metabolite) inhibit growth suggests that cholesterol analogs with non-degradable side chains represent a novel class of anti-mycobacterial agents. In accord with this, two cholesterol analogs with truncated, fluorinated side chains have been synthesized and shown to similarly block the growth in culture ofM. tuberculosis.

  11. Repositioning of Verrucosidin, a purported inhibitor of chaperone protein GRP78, as an inhibitor of mitochondrial electron transport chain complex I.

    Directory of Open Access Journals (Sweden)

    Simmy Thomas

    Full Text Available Verrucosidin (VCD belongs to a group of fungal metabolites that were identified in screening programs to detect molecules that preferentially kill cancer cells under glucose-deprived conditions. Its mode of action was proposed to involve inhibition of increased GRP78 (glucose regulated protein 78 expression during hypoglycemia. Because GRP78 plays an important role in tumorigenesis, inhibitors such as VCD might harbor cancer therapeutic potential. We therefore sought to characterize VCD's anticancer activity in vitro. Triple-negative breast cancer cell lines MDA-MB-231 and MDA-MB-468 were treated with VCD under different conditions known to trigger increased expression of GRP78, and a variety of cellular processes were analyzed. We show that VCD was highly cytotoxic only under hypoglycemic conditions, but not in the presence of normal glucose levels, and VCD blocked GRP78 expression only when glycolysis was impaired (due to hypoglycemia or the presence of the glycolysis inhibitor 2-deoxyglucose, but not when GRP78 was induced by other means (hypoxia, thapsigargin, tunicamycin. However, VCD's strictly hypoglycemia-specific toxicity was not due to the inhibition of GRP78. Rather, VCD blocked mitochondrial energy production via inhibition of complex I of the electron transport chain. As a result, cellular ATP levels were quickly depleted under hypoglycemic conditions, and common cellular functions, including general protein synthesis, deteriorated and resulted in cell death. Altogether, our study identifies mitochondria as the primary target of VCD. The possibility that other purported GRP78 inhibitors (arctigenin, biguanides, deoxyverrucosidin, efrapeptin, JBIR, piericidin, prunustatin, pyrvinium, rottlerin, valinomycin, versipelostatin might act in a similar GRP78-independent fashion will be discussed.

  12. A Preclinical Evaluation of Antimycin A as a Potential Antilung Cancer Stem Cell Agent

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    Chi-Tai Yeh

    2013-01-01

    Full Text Available Drug resistance and tumor recurrence are major obstacles in treating lung cancer patients. Accumulating evidence considers lung cancer stem cells (CSCs as the major contributor to these clinical challenges. Agents that can target lung CSCs could potentially provide a more effective treatment than traditional chemotherapy. Here, we utilized the side-population (SP method to isolate lung CSCs from A549 and PC-9 cell lines. Subsequently, a high throughput platform, connectivity maps (CMAPs, was used to identify potential anti-CSC agents. An antibiotic, antimycin A (AMA, was identified as a top candidate. SP A549 cells exhibited an elevated stemness profile, including Nanog, β-catenin, Sox2, and CD133, and increased self-renewal ability. AMA treatment was found to suppress β-catenin signaling components and tumor sphere formation. Furthermore, AMA treatment decreased the proliferation of gefitinib-resistant PC-9/GR cells and percentage of SP population. AMA demonstrated synergistic suppression of PC-9/GR cell viability when combined with gefitinib. Finally, AMA treatment suppressed tumorigenesis in mice inoculated with A549 SP cells. Collectively, we have identified AMA using CMAP as a novel antilung CSC agent, which acts to downregulate β-catenin signaling. The combination of AMA and targeted therapeutic agents could be considered for overcoming drug resistance and relapse in lung cancer patients.

  13. Celastrol Protects against Antimycin A-Induced Insulin Resistance in Human Skeletal Muscle Cells

    Directory of Open Access Journals (Sweden)

    Mohamad Hafizi Abu Bakar

    2015-05-01

    Full Text Available Mitochondrial dysfunction and inflammation are widely accepted as key hallmarks of obesity-induced skeletal muscle insulin resistance. The aim of the present study was to evaluate the functional roles of an anti-inflammatory compound, celastrol, in mitochondrial dysfunction and insulin resistance induced by antimycin A (AMA in human skeletal muscle cells. We found that celastrol treatment improved insulin-stimulated glucose uptake activity of AMA-treated cells, apparently via PI3K/Akt pathways, with significant enhancement of mitochondrial activities. Furthermore, celastrol prevented increased levels of cellular oxidative damage where the production of several pro-inflammatory cytokines in cultures cells was greatly reduced. Celastrol significantly increased protein phosphorylation of insulin signaling cascades with amplified expression of AMPK protein and attenuated NF-κB and PKC θ activation in human skeletal muscle treated with AMA. The improvement of insulin signaling pathways by celastrol was also accompanied by augmented GLUT4 protein expression. Taken together, these results suggest that celastrol may be advocated for use as a potential therapeutic molecule to protect against mitochondrial dysfunction-induced insulin resistance in human skeletal muscle cells.

  14. Synthesis, antidepressant evaluation and docking studies of long-chain alkylnitroquipazines as serotonin transporter inhibitors.

    Science.gov (United States)

    Gabrielsen, Mari; Wołosewicz, Karol; Zawadzka, Anna; Kossakowski, Jerzy; Nowak, Gabriel; Wolak, Małgorzata; Stachowicz, Katarzyna; Siwek, Agata; Ravna, Aina W; Kufareva, Irina; Kozerski, Lech; Bednarek, Elżbieta; Sitkowski, Jerzy; Bocian, Wojciech; Abagyan, Ruben; Bojarski, Andrzej J; Sylte, Ingebrigt; Chilmonczyk, Zdzisław

    2013-06-01

    Twelve alkyl analogues (1-12) of the high-affinity serotonin transporter (SERT) inhibitor 6-nitroquipazine (6-NQ) were synthesized and studied using in vitro radioligand competition binding assays to determine their binding affinity (Ki ). The putative antidepressant activity of five of the binders with the highest SERT binding affinities was studied by the forced swim and locomotor activity mouse tests. The three-dimensional (3D) structures of 8 and 9 were determined using NOE NMR technique. Flexible docking of the compounds was undertaken to illustrate the binding of the compounds in the SERT model. Our results showed that several of the 6-NQ analogues are high-affinity SERT inhibitors and indicated that the octyl (8), decyl (10) and dodecyl (12) 6-NQ analogues exhibit moderate antidepressant activity.

  15. Synergism of Antifungal Activity between Mitochondrial Respiration Inhibitors and Kojic Acid

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    Ronald P. Haff

    2013-01-01

    Full Text Available Co-application of certain types of compounds to conventional antimicrobial drugs can enhance the efficacy of the drugs through a process termed chemosensitization. We show that kojic acid (KA, a natural pyrone, is a potent chemosensitizing agent of complex III inhibitors disrupting the mitochondrial respiratory chain in fungi. Addition of KA greatly lowered the minimum inhibitory concentrations of complex III inhibitors tested against certain filamentous fungi. Efficacy of KA synergism in decreasing order was pyraclostrobin > kresoxim-methyl > antimycin A. KA was also found to be a chemosensitizer of cells to hydrogen peroxide (H2O2, tested as a mimic of reactive oxygen species involved in host defense during infection, against several human fungal pathogens and Penicillium strains infecting crops. In comparison, KA-mediated chemosensitization to complex III inhibitors/H2O2 was undetectable in other types of fungi, including Aspergillus flavus, A. parasiticus, and P. griseofulvum, among others. Of note, KA was found to function as an antioxidant, but not as an antifungal chemosensitizer in yeasts. In summary, KA could serve as an antifungal chemosensitizer to complex III inhibitors or H2O2 against selected human pathogens or Penicillium species. KA-mediated chemosensitization to H2O2 seemed specific for filamentous fungi. Thus, results indicate strain- and/or drug-specificity exist during KA chemosensitization.

  16. Rapid Optimization of Mcl-1 Inhibitors using Stapled Peptide Libraries Including Non-Natural Side Chains.

    Science.gov (United States)

    Rezaei Araghi, Raheleh; Ryan, Jeremy A; Letai, Anthony; Keating, Amy E

    2016-05-20

    Alpha helices form a critical part of the binding interface for many protein-protein interactions, and chemically stabilized synthetic helical peptides can be effective inhibitors of such helix-mediated complexes. In particular, hydrocarbon stapling of peptides to generate constrained helices can improve binding affinity and other peptide properties, but determining the best stapled peptide variant often requires laborious trial and error. Here, we describe the rapid discovery and optimization of a stapled-helix peptide that binds to Mcl-1, an antiapoptotic protein that is overexpressed in many chemoresistant cancers. To accelerate discovery, we developed a peptide library synthesis and screening scheme capable of identifying subtle affinity differences among Mcl-1-binding stapled peptides. We used our method to sample combinations of non-natural amino-acid substitutions that we introduced into Mcl-1 inhibitors in the context of a fixed helix-stabilizing hydrocarbon staple that increased peptide helical content and reduced proteolysis. Peptides discovered in our screen contained surprising substitutions at sites that are conserved in natural binding partners. Library-identified peptide M3d is the most potent molecule yet tested for selectively triggering mitochondrial permeabilization in Mcl-1 dependent cell lines. Our library approach for optimizing helical peptide inhibitors can be readily applied to the study of other biomedically important targets.

  17. Iron deficiency induces changes in riboflavin secretion and the mitochondrial electron transport chain in hairy roots of Hyoscyamus albus.

    Science.gov (United States)

    Higa, Ataru; Mori, Yuko; Kitamura, Yoshie

    2010-07-15

    Hyoscyamus albus hairy roots secrete riboflavin under Fe-deficient conditions. To determine whether this secretion was linked to an enhancement of respiration, both riboflavin secretion and the reduction of 2,3,5-triphenyltetrazolium chloride (TTC), as a measure of respiration activity, were determined in hairy roots cultured under Fe-deficient and Fe-replete conditions, with or without aeration. Appreciable TTC-reducing activity was detected at the root tips, at the bases of lateral roots and in internal tissues, notably the vascular system. TTC-reducing activity increased under Fe deficiency and this increase occurred in concert with riboflavin secretion and was more apparent under aeration. Riboflavin secretion was not apparent under Fe-replete conditions. In order to examine which elements of the mitochondrial electron transport chain might be involved, the effects of the respiratory inhibitors, barbiturate, dicoumarol, malonic acid, antimycin, KCN and salicylhydroxamic acid (SHAM) were investigated. Under Fe-deficient conditions, malonic acid affected neither root growth, TTC-reducing activity nor riboflavin secretion, whereas barbiturate and SHAM inhibited only root growth and TTC-reducing activity, respectively, and the other compounds variously inhibited growth and TTC-reducing activity. Riboflavin secretion was decreased, in concert with TTC-reducing activity, by dicoumarol, antimycin and KCN, but not by SHAM. In Fe-replete roots, all inhibitors which reduced riboflavin secretion in Fe-deficient roots showed somewhat different effects: notably, antimycin and KCN did not significantly inhibit TTC-reducing activity and the inhibition by dicoumarol was much weaker in Fe-replete roots. Combined treatment with KCN and SHAM also revealed that Fe-deficient and Fe-replete roots reduced TTC in different ways. A decrease in the Fe content of mitochondria in Fe-deficient roots was confirmed. Overall, the results suggest that, under conditions of Fe deficiency in H

  18. Platelet-Derived Short-Chain Polyphosphates Enhance the Inactivation of Tissue Factor Pathway Inhibitor by Activated Coagulation Factor XI

    Science.gov (United States)

    Puy, Cristina; Tucker, Erik I.; Ivanov, Ivan S.; Gailani, David; Smith, Stephanie A.; Morrissey, James H.; Gruber, András; McCarty, Owen J. T.

    2016-01-01

    Introduction Factor (F) XI supports both normal human hemostasis and pathological thrombosis. Activated FXI (FXIa) promotes thrombin generation by enzymatic activation of FXI, FIX, FX, and FV, and inactivation of alpha tissue factor pathway inhibitor (TFPIα), in vitro. Some of these reactions are now known to be enhanced by short-chain polyphosphates (SCP) derived from activated platelets. These SCPs act as a cofactor for the activation of FXI and FV by thrombin and FXIa, respectively. Since SCPs have been shown to inhibit the anticoagulant function of TFPIα, we herein investigated whether SCPs could serve as cofactors for the proteolytic inactivation of TFPIα by FXIa, further promoting the efficiency of the extrinsic pathway of coagulation to generate thrombin. Methods and Results Purified soluble SCP was prepared by size-fractionation of sodium polyphosphate. TFPIα proteolysis was analyzed by western blot. TFPIα activity was measured as inhibition of FX activation and activity in coagulation and chromogenic assays. SCPs significantly accelerated the rate of inactivation of TFPIα by FXIa in both purified systems and in recalcified plasma. Moreover, platelet-derived SCP accelerated the rate of inactivation of platelet-derived TFPIα by FXIa. TFPIα activity was not affected by SCP in recalcified FXI-depleted plasma. Conclusions Our data suggest that SCP is a cofactor for TFPIα inactivation by FXIa, thus, expanding the range of hemostatic FXIa substrates that may be affected by the cofactor functions of platelet-derived SCP. PMID:27764259

  19. Acyl chain preference and inhibitor identification of Moraxella catarrhalis LpxA: Insight through crystal structure and computational studies.

    Science.gov (United States)

    Pratap, Shivendra; Kesari, Pooja; Yadav, Ravi; Dev, Aditya; Narwal, Manju; Kumar, Pravindra

    2017-03-01

    Lipopolysaccharide (LPS) is an important surface component and a potential virulence factor in the pathogenesis of Gram-negative bacteria. UDP-N-acetylglucosamine acyltransferase (LpxA) enzyme catalyzes the first reaction of LPS biosynthesis, reversible transfer of R-3-hydroxy-acyl moiety from donor R-3-hydroxy-acyl-acyl carrier protein to the 3' hydroxyl position of UDP-N-acetyl-glucosamine. LpxA enzyme's essentiality in bacterial survival and absence of any homologous protein in humans makes it a promising target for anti-bacterial drug development. Herein, we present the crystal structure of Moraxella catarrhalis LpxA (McLpxA). We propose that L171 is responsible for limiting the acyl chain length in McLpxA to 10C or 12C. The study reveals the plausible interactions between the highly conserved clusters of basic residues at the C-terminal end of McLpxA and acidic residues of acyl carrier protein (ACP). Furthermore, the crystal structure of McLpxA was used to screen potential inhibitors from NCI open database using various computational approaches viz. pharmacophore mapping, virtual screening and molecular docking. Molecules Mol212032, Mol609399 and Mol152546 showed best binding affinity with McLpxA among all screened molecules. These molecules mimic the substrate-LpxA binding interactions.

  20. A shrimp pacifastin light chain-like inhibitor: molecular identification and role in the control of the prophenoloxidase system.

    Science.gov (United States)

    Sangsuriya, Pakkakul; Charoensapsri, Walaiporn; Chomwong, Sudarat; Senapin, Saengchan; Tassanakajon, Anchalee; Amparyup, Piti

    2016-01-01

    Pacifastin is a recently classified family of serine proteinase inhibitors that play essential roles in various biological processes, including in the regulation of the melanization cascade. Here, a novel pacifastin-related gene, termed PmPacifastin-like, was identified from a reverse suppression subtractive hybridization (SSH) cDNA library created from hemocytes of the prophenoloxidase PmproPO1/2 co-silenced black tiger shrimp Penaeus monodon. The full-length sequences of PmPacifastin-like and its homologue LvPacifastin-like from the Pacific white shrimp Litopenaeus vannamei were determined. Sequence analysis revealed that both sequences contained thirteen conserved pacifastin light chain domains (PLDs), followed by two putative kunitz domains. Expression analysis demonstrated that the PmPacifastin-like transcript was expressed in all tested shrimp tissues and larval developmental stages, and its expression responded to Vibrio harveyi challenge. To gain insight into the functional roles of PmPacifastin-like protein, the in vivo RNA interference experiment was employed; the results showed that PmPacifastin-like depletion strongly increased PO activity. Interestingly, suppression of PmPacifastin-like also down-regulated the expression of the proPO-activating enzyme PmPPAE2 transcript; the PmPacifastin-like transcript was down-regulated after the PmproPO1/2 transcripts were silenced. Taken together, these results suggest that PmPacifastin-like is important in the shrimp proPO system and may play an essential role in shrimp immune defense against bacterial infection. These results also expand the knowledge of how pacifastin-related protein participates in the negative regulation of the proPO system in shrimp.

  1. Determination of antimycin-A in water by liquid chromatographic/mass spectrometry: single-laboratory validation.

    Science.gov (United States)

    Bernardy, Jeffry A; Hubert, Terrance D; Ogorek, Jacob M; Schmidt, Larry J

    2013-01-01

    An LC/MS method was developed and validated for the quantitative determination and confirmation of antimycin-A (ANT-A) in water from lakes or streams. Three different water sample volumes (25, 50, and 250 mL) were evaluated. ANT-A was stabilized in the field by immediately extracting it from water into anhydrous acetone using SPE. The stabilized concentrated samples were then transported to a laboratory and analyzed by LC/MS using negative electrospray ionization. The method was determined to have adequate accuracy (78 to 113% recovery), precision (0.77 to 7.5% RSD with samples > or = 500 ng/L and 4.8 to 17% RSD with samples < or = 100 ng/L), linearity, and robustness over an LOQ range from 8 to 51 600 ng/L.

  2. Determination of Antimycin-A in water by liquid chromatographic/mass spectrometry: single-laboratory validation

    Science.gov (United States)

    Bernardy, Jeffry A.; Hubert, Terrance D.; Ogorek, Jacob M.; Schmidt, Larry J.

    2013-01-01

    An LC/MS method was developed and validated for the quantitative determination and confirmation of antimycin-A (ANT-A) in water from lakes or streams. Three different water sample volumes (25, 50, and 250 mL) were evaluated. ANT-A was stabilized in the field by immediately extracting it from water into anhydrous acetone using SPE. The stabilized concentrated samples were then transported to a laboratory and analyzed by LC/MS using negative electrospray ionization. The method was determined to have adequate accuracy (78 to 113% recovery), precision (0.77 to 7.5% RSD with samples ≥500 ng/L and 4.8 to 17% RSD with samples ≤100 ng/L), linearity, and robustness over an LOQ range from 8 to 51 600 ng/L.

  3. [Generation of superoxide radicals by the mitochondrial respiratory chain of isolated cardiomyocytes].

    Science.gov (United States)

    Kashkarov, K P; Vasil'eva, E V; Ruuge, E K

    1994-06-01

    Generation of superoxide radicals by the mitochondrial respiratory chain of cardiomyocites isolated from rat heart and treated with saponin was studied. The rate of O2- production was measured by electron paramagnetic resonance (EPR) spectroscopy using hydroxylamine TEMPONE-H as spin trap. A device has been constructed which provided permanent stirring of cardiomyocyte samples directly in the cavity and prevented cell aggregation. When substrates and antimycin A and/or rotenone are added, the radical production rate increased and reached its maximum in the presence of the both inhibitors. Superoxide dismutase as well as KCN suppressed the radical production, thus being suggestive of the generation of superoxide radicals in the bc1 complex, while the mechanism of O2- production is the same as was suggested for isolated mitochondria. The ratio between rates of O2- generation by isolated cardiomyocytes under various experimental conditions is in a good accord with corresponding parameter of isolated mitochondria. However, in the case of cardiomyocytes the absolute values of the O2- production rate are approximately twice as high as those in isolated mitochondria, presumably due to the partial damage of the mitochondrial respiratory chain during the isolation procedure.

  4. High resolution crystal structure of rat long chain hydroxy acid oxidase in complex with the inhibitor 4-carboxy-5-[(4-chlorophenyl)sulfanyl]-1, 2, 3-thiadiazole. Implications for inhibitor specificity and drug design

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Zhi-wei; Vignaud, Caroline; Jaafar, Adil; Lévy, Bernard; Guéritte, Françoise; Guénard, Daniel; Lederer, Florence; Mathews, F. Scott (CNRS-UMR); (WU-MED)

    2012-05-24

    Long chain hydroxy acid oxidase (LCHAO) is responsible for the formation of methylguanidine, a toxic compound with elevated serum levels in patients with chronic renal failure. Its isozyme glycolate oxidase (GOX), has a role in the formation of oxalate, which can lead to pathological deposits of calcium oxalate, in particular in the disease primary hyperoxaluria. Inhibitors of these two enzymes may have therapeutic value. These enzymes are the only human members of the family of FMN-dependent L-2-hydroxy acid-oxidizing enzymes, with yeast flavocytochrome b{sub 2} (Fcb2) among its well studied members. We screened a chemical library for inhibitors, using in parallel rat LCHAO, human GOX and the Fcb2 flavodehydrogenase domain (FDH). Among the hits was an inhibitor, CCPST, with an IC{sub 50} in the micromolar range for all three enzymes. We report here the crystal structure of a complex between this compound and LCHAO at 1.3 {angstrom} resolution. In comparison with a lower resolution structure of this enzyme, binding of the inhibitor induces a conformational change in part of the TIM barrel loop 4, as well as protonation of the active site histidine. The CCPST interactions are compared with those it forms with human GOX and those formed by two other inhibitors with human GOX and spinach GOX. These compounds differ from CCPST in having the sulfur replaced with a nitrogen in the five-membered ring as well as different hydrophobic substituents. The possible reason for the {approx}100-fold difference in affinity between these two series of inhibitors is discussed. The present results indicate that specificity is an issue in the quest for therapeutic inhibitors of either LCHAO or GOX, but they may give leads for this quest.

  5. Benzimidazole inhibitors of the protein kinase CHK2: Clarification of the binding mode by flexible side chain docking and protein–ligand crystallography

    Science.gov (United States)

    Matijssen, Cornelis; Silva-Santisteban, M. Cris; Westwood, Isaac M.; Siddique, Samerene; Choi, Vanessa; Sheldrake, Peter; van Montfort, Rob L.M.; Blagg, Julian

    2012-01-01

    Two closely related binding modes have previously been proposed for the ATP-competitive benzimidazole class of checkpoint kinase 2 (CHK2) inhibitors; however, neither binding mode is entirely consistent with the reported SAR. Unconstrained rigid docking of benzimidazole ligands into representative CHK2 protein crystal structures reveals an alternative binding mode involving a water-mediated interaction with the hinge region; docking which incorporates protein side chain flexibility for selected residues in the ATP binding site resulted in a refinement of the water-mediated hinge binding mode that is consistent with observed SAR. The flexible docking results are in good agreement with the crystal structures of four exemplar benzimidazole ligands bound to CHK2 which unambiguously confirmed the binding mode of these inhibitors, including the water-mediated interaction with the hinge region, and which is significantly different from binding modes previously postulated in the literature. PMID:23058106

  6. Positive Mode LC-MS/MS Analysis of Chondroitin Sulfate Modified Glycopeptides Derived from Light and Heavy Chains of The Human Inter-α-Trypsin Inhibitor Complex.

    Science.gov (United States)

    Gomez Toledo, Alejandro; Nilsson, Jonas; Noborn, Fredrik; Sihlbom, Carina; Larson, Göran

    2015-12-01

    The inter-α-trypsin inhibitor complex is a macromolecular arrangement of structurally related heavy chain proteins covalently cross-linked to the chondroitin sulfate (CS) chain of the proteoglycan bikunin. The inter-α-trypsin inhibitor complex is abundant in plasma and associated with inflammation, kidney diseases, cancer and diabetes. Bikunin is modified at Ser-10 by a single low-sulfated CS chain of 23-55 monosaccharides with 4-9 sulfate groups. The innermost four monosaccharides (GlcAβ3Galβ3Galβ4Xylβ-O-) compose the linkage region, believed to be uniform with a 4-O-sulfation to the outer Gal. The cross-linkage region of the bikunin CS chain is located in the nonsulfated nonreducing end, (GalNAcβ4GlcAβ3)(n), to which heavy chains (H1-H3) may be bound in GalNAc to Asp ester linkages. In this study we employed a glycoproteomics protocol to enrich and analyze light and heavy chain linkage and cross-linkage region CS glycopeptides derived from the IαI complex of human plasma, urine and cerebrospinal fluid samples. The samples were trypsinized, enriched by strong anion exchange chromatography, partially depolymerized with chondroitinase ABC and analyzed by LC-MS/MS using higher-energy collisional dissociation. The analyses demonstrated that the CS linkage region of bikunin is highly heterogeneous. In addition to sulfation of the Gal residue, Xyl phosphorylation was observed although exclusively in urinary samples. We also identified novel Neu5Ac and Fuc modifications of the linkage region as well as the presence of mono- and disialylated core 1 O-linked glycans on Thr-17. Heavy chains H1 and H2 were identified cross-linked to GalNAc residues one or two GlcA residues apart and H1 was found linked to either the terminal or subterminal GalNAc residues. The fragmentation behavior of CS glycopeptides under variable higher-energy collisional dissociation conditions displays an energy dependence that may be used to obtain complementary structural details. Finally

  7. Oxidative stress in duckweed (Lemna minor L.) induced by glyphosate: Is the mitochondrial electron transport chain a target of this herbicide?

    Science.gov (United States)

    Gomes, Marcelo Pedrosa; Juneau, Philippe

    2016-11-01

    We investigated the physiological responses of Lemna minor plants exposed to glyphosate. The deleterious effects of this herbicide on photosynthesis, respiration, and pigment concentrations were related to glyphosate-induced oxidative stress through hydrogen peroxide (H2O2) accumulation. By using photosynthetic and respiratory electron transport chain (ETC) inhibitors we located the primary site of reactive oxygen species (ROS) production in plants exposed to 500 mg glyphosate l(-1). Inhibition of mitochondrial ETC Complex I by rotenone reduced H2O2 concentrations in glyphosate-treated plants. Complex III activity was very sensitive to glyphosate which appears to act much like antimycin A (an inhibitor of mitochondrial ETC Complex III) by shunting electrons from semiquinone to oxygen, with resulting ROS formation. Confocal evaluations for ROS localization showed that ROS are initially produced outside of the chloroplasts upon initial glyphosate exposure. Our results indicate that in addition to interfering with the shikimate pathway, glyphosate can induce oxidative stress in plants through H2O2 formation by targeting the mitochondrial ETC, which would explain its observed effects on non-target organisms.

  8. ITIH4 (inter-alpha-trypsin inhibitor heavy chain 4) is a new acute-phase protein isolated from cattle during experimental infection

    DEFF Research Database (Denmark)

    Pineiro, M.; Andres, M.; Iturralde, M.;

    2004-01-01

    We have isolated from calf serum a protein with an apparent M, of 120,000. The protein was detected by using antibodies against major acute-phase protein in pigs with acute inflammation. The amino acid sequence of an internal fragment revealed that this protein is the bovine counterpart of ITIH4......, the heavy chain 4 of the inter-alpha-trypsin inhibitor family. The response of this protein in the sera was determined for animals during experimental bacterial and viral infections. In the bacterial model, animals were inoculated with a mixture of Actinomyces pyogenes, Fusobacterium necrophorum....... Because of the significant induction of the protein in the animals in the mastitis and BRSV infection models, we can conclude that ITIH4 is a new positive acute-phase protein in cattle....

  9. Discovery of 2-azetidinone and 1H-pyrrole-2,5-dione derivatives containing sulfonamide group at the side chain as potential cholesterol absorption inhibitors.

    Science.gov (United States)

    Yuan, Xinrui; Lu, Peng; Xue, Xiaojian; Qin, Hui; Fan, Chen; Wang, Yubin; Zhang, Qi

    2016-02-01

    Cholesterol absorption inhibitor (CAI) targeting Niemann-Pick C1-like1 protein was developed for the treatment of hyperlipidaemia and only ezetimibe was approved so far. For developing novel CAIs, we synthesized sixteen 2-azetidinone derivatives and thirteen 1H-pyrrole-2,5-dione derivatives containing sulfonamide group at the side chain, and their inhibitory activity of cholesterol absorption was evaluated in Caco-2 cell line in vitro. Furthermore, top six compounds were measured by cytotoxicity and partition coefficient, and 2-azetidinone analogue 9e was selected for in vivo study. Finally, 9e considerably reduced total cholesterol, LDL-C, FFA and triglyceride in the serum and increased the rate of HDL-C to total cholesterol, suggesting it could regulate the lipid metabolism and act as a potent CAI.

  10. Frequent expression loss of Inter-alpha-trypsin inhibitor heavy chain (ITIH genes in multiple human solid tumors: A systematic expression analysis

    Directory of Open Access Journals (Sweden)

    Werbowetski-Ogilvie Tamra

    2008-01-01

    Full Text Available Abstract Background The inter-alpha-trypsin inhibitors (ITI are a family of plasma protease inhibitors, assembled from a light chain – bikunin, encoded by AMBP – and five homologous heavy chains (encoded by ITIH1, ITIH2, ITIH3, ITIH4, and ITIH5, contributing to extracellular matrix stability by covalent linkage to hyaluronan. So far, ITIH molecules have been shown to play a particularly important role in inflammation and carcinogenesis. Methods We systematically investigated differential gene expression of the ITIH gene family, as well as AMBP and the interacting partner TNFAIP6 in 13 different human tumor entities (of breast, endometrium, ovary, cervix, stomach, small intestine, colon, rectum, lung, thyroid, prostate, kidney, and pancreas using cDNA dot blot analysis (Cancer Profiling Array, CPA, semiquantitative RT-PCR and immunohistochemistry. Results We found that ITIH genes are clearly downregulated in multiple human solid tumors, including breast, colon and lung cancer. Thus, ITIH genes may represent a family of putative tumor suppressor genes that should be analyzed in greater detail in the future. For an initial detailed analysis we chose ITIH2 expression in human breast cancer. Loss of ITIH2 expression in 70% of cases (n = 50, CPA could be confirmed by real-time PCR in an additional set of breast cancers (n = 36. Next we studied ITIH2 expression on the protein level by analyzing a comprehensive tissue micro array including 185 invasive breast cancer specimens. We found a strong correlation (p Conclusion Altogether, this is the first systematic analysis on the differential expression of ITIH genes in human cancer, showing frequent downregulation that may be associated with initiation and/or progression of these malignancies.

  11. Vasoactivity of rucaparib, a PARP-1 inhibitor, is a complex process that involves myosin light chain kinase, P2 receptors, and PARP itself.

    Directory of Open Access Journals (Sweden)

    Cian M McCrudden

    Full Text Available Therapeutic inhibition of poly(ADP-ribose polymerase (PARP, as monotherapy or to supplement the potencies of other agents, is a promising strategy in cancer treatment. We previously reported that the first PARP inhibitor to enter clinical trial, rucaparib (AG014699, induced vasodilation in vivo in xenografts, potentiating response to temozolomide. We now report that rucaparib inhibits the activity of the muscle contraction mediator myosin light chain kinase (MLCK 10-fold more potently than its commercially available inhibitor ML-9. Moreover, rucaparib produces additive relaxation above the maximal degree achievable with ML-9, suggesting that MLCK inhibition is not solely responsible for dilation. Inhibition of nitric oxide synthesis using L-NMMA also failed to impact rucaparib's activity. Rucaparib contains the nicotinamide pharmacophore, suggesting it may inhibit other NAD+-dependent processes. NAD+ exerts P2 purinergic receptor-dependent inhibition of smooth muscle contraction. Indiscriminate blockade of the P2 purinergic receptors with suramin abrogated rucaparib-induced vasodilation in rat arterial tissue without affecting ML-9-evoked dilation, although the specific receptor subtypes responsible have not been unequivocally identified. Furthermore, dorsal window chamber and real time tumor vessel perfusion analyses in PARP-1-/- mice indicate a potential role for PARP in dilation of tumor-recruited vessels. Finally, rucaparib provoked relaxation in 70% of patient-derived tumor-associated vessels. These data provide tantalising evidence of the complexity of the mechanism underlying rucaparib-mediated vasodilation.

  12. Cancer cells become susceptible to natural killer cell killing after exposure to histone deacetylase inhibitors due to glycogen synthase kinase-3-dependent expression of MHC class I-related chain A and B

    DEFF Research Database (Denmark)

    Skov, Søren; Pedersen, Marianne Terndrup; Andresen, Lars

    2005-01-01

    by small interfering RNA or by different inhibitors showed that GSK-3 activity is essential for the induced MICA/B expression. We thus present evidence that cancer cells which survive the direct induction of cell death by HDAC inhibitors become targets for NKG2D-expressing cells like NK cells, gammadelta T......We show that histone deacetylase (HDAC) inhibitors lead to functional expression of MHC class I-related chain A and B (MICA/B) on cancer cells, making them potent targets for natural killer (NK) cell-mediated killing through a NK group 2, member D (NKG2D) restricted mechanism. Blocking either...... apoptosis or oxidative stress caused by HDAC inhibitor treatment did not affect MICA/B expression, suggesting involvement of a separate signal pathway not directly coupled to induction of cell death. HDAC inhibitor treatment induced glycogen synthase kinase-3 (GSK-3) activity and down-regulation of GSK-3...

  13. Influence of growth regulators and respiration inhibitors on dark transformation of phytochrome in coleoptiles of oat seedlings

    Directory of Open Access Journals (Sweden)

    Jan Kopcewicz

    2014-02-01

    Full Text Available Irradiation with red light leads to the formation of an unstable, undergoing gradual destruction, physiologically active PFR form of phytochrome in the coleoptiles of oat seedlings. Growth substances: IAA, GA3, kinetin, ABA, ethrel as well acetylcholine do not influence the nature and rate of phytochrome dark transformation. Inhibitors of energy-producing processes such as KCN, 2,4-DNP, DCCD and antimycin A inhibit the process of dark destruction of the PFR form of phytochrome.

  14. Inhibition of the mitochondrial respiratory chain function abrogates quartz induced DNA damage in lung epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Li Hui [Institut fuer umweltmedizinische Forschung (IUF) at the Heinrich-Heine-University, Auf' m Hennekamp 50, D-40225 Duesseldorf (Germany); Haberzettl, Petra [Institut fuer umweltmedizinische Forschung (IUF) at the Heinrich-Heine-University, Auf' m Hennekamp 50, D-40225 Duesseldorf (Germany); Albrecht, Catrin [Institut fuer umweltmedizinische Forschung (IUF) at the Heinrich-Heine-University, Auf' m Hennekamp 50, D-40225 Duesseldorf (Germany); Hoehr, Doris [Institut fuer umweltmedizinische Forschung (IUF) at the Heinrich-Heine-University, Auf' m Hennekamp 50, D-40225 Duesseldorf (Germany); Knaapen, Ad M. [Department of Health Risk Analysis and Toxicology, Nutrition and Toxicology Research Institute Maastricht (NUTRIM), University of Maastricht (Netherlands); Borm, Paul J.A. [Institut fuer umweltmedizinische Forschung (IUF) at the Heinrich-Heine-University, Auf' m Hennekamp 50, D-40225 Duesseldorf (Germany); Hogeschool Zuyd Heerlen (Netherlands); Schins, Roel P.F. [Institut fuer umweltmedizinische Forschung (IUF) at the Heinrich-Heine-University, Auf' m Hennekamp 50, D-40225 Duesseldorf (Germany)]. E-mail: roel.schins@uni-duesseldorf.de

    2007-04-01

    Respirable quartz dust has been classified as a human carcinogen by the International Agency for Research on Cancer. The aim of our study was to investigate the mechanisms of DNA damage by DQ12 quartz in RLE-6TN rat lung epithelial type II cells (RLE). Transmission electron microscopy and flow-cytometry analysis showed a rapid particle uptake (30 min to 4 h) of quartz by the RLE cells, but particles were not found within the cell nuclei. This suggests that DNA strand breakage and induction of 8-hydroxydeoxyguanosine - as also observed in these cells during these treatment intervals - did not result from direct physical interactions between particles and DNA, or from short-lived particle surface-derived reactive oxygen species. DNA damage by quartz was significantly reduced in the presence of the mitochondrial inhibitors rotenone and antimycin-A. In the absence of quartz, these inhibitors did not affect DNA damage, but they reduced cellular oxygen consumption. No signs of apoptosis were observed by quartz. Flow-cytometry analysis indicated that the reduced DNA damage by rotenone was not due to a possible mitochondria-mediated reduction of particle uptake by the RLE cells. Further proof of concept for the role of mitochondria was shown by the failure of quartz to elicit DNA damage in mitochondria-depleted 143B (rho-0) osteosarcoma cells, at concentrations where it elicited DNA damage in the parental 143B cell line. In conclusion, our data show that respirable quartz particles can elicit oxidative DNA damage in vitro without entering the nuclei of type II cells, which are considered to be important target cells in quartz carcinogenesis. Furthermore, our observations indicate that such indirect DNA damage involves the mitochondrial electron transport chain function, by an as-yet-to-be elucidated mechanism.

  15. Ocular Inflammation and Corneal Permeability Alteration by Benzalkonium Chloride in Rats: A Protective Effect of a Myosin Light Chain Kinase Inhibitor

    Science.gov (United States)

    Droy-Lefaix, Marie Thérèse; Bueno, Lionel; Caron, Philippe; Belot, Eric; Roche, Olivier

    2013-01-01

    Purpose. The aim of this study was to evaluate the interest of an ophthalmic eyedrop preparation containing a myosin light chain kinase (MLCK) inhibitor, ML-7, in the treatment of ocular surface. The local protective effect on the inflammation and the increase of corneal permeability induced by benzalkonium (BAK) was evaluated. Methods. An ocular instillation of 10 μL BAK at a concentration of 0.1% in PBS was performed on rats. The eyes were rinsed with sterilized water, 10 minutes after BAK preceded by instillation at T −24, −12, and −0.5 hours of 10 μL of ML-7: 100 μg (10 μL) into a gel form vehicle. All animals were sacrificed 6 hours after BAK instillation. The eyes were isolated for study in a masked manner. The ocular surface inflammation was assessed by measuring the inflammatory cell infiltration by a histologic quantitative analysis and for total ocular myeloperoxidase (MPO) activity. The tight junction permeability was tested. Results. Instillation of 0.1% BAK increased the inflammation of the eye. The quantitative analysis showed an increase in the number of eosinophil and neutrophil polynuclears, and MPO activity. Pretreatment with ML-7 reduced inflammation (P < 0.05). The vehicle alone produced no notable effects. BAK instillation also thickened the fluorescent corneal front on frozen sections, indicating an increase of tight junction permeability. Pretreatment with ML-7 suppressed BAK-induced alterations of paracellular permeability while the vehicle had no visible effects. Conclusions. Our study indicates that the inhibition of corneal cytoskeleton contraction by an MLCK inhibitor prevents BAK-induced ocular inflammatory response, and that ML-7 may be a new and original preparation in the treatment of ocular surface pathologies. PMID:23518768

  16. Serum Inter-Alpha-Trypsin Inhibitor Heavy Chain 4 (ITIH4) in Children with Chronic Hepatitis C: Relation to Liver Fibrosis and Viremia.

    Science.gov (United States)

    Sira, Mostafa M; Behairy, Behairy E; Abd-Elaziz, Azza M; Abd Elnaby, Sameh A; Eltahan, Ehab E

    2014-01-01

    Liver fibrosis and viremia are determinant factors for the treatment policy and its outcome in chronic hepatitis C virus (HCV) infection. We aimed to investigate serum level of inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) and its relation to liver fibrosis and viremia in children with chronic HCV. ITIH4 was measured by ELISA in 33 treatment-naive children with proved chronic HCV and compared according to different clinical, laboratory and histopathological parameters. Liver histopathological changes were assessed using Ishak score and compared with aspartate transaminase-to-platelet ratio (APRI) and FIB-4 indices as simple noninvasive markers of fibrosis. ITIH4 was measured in a group of 30 age- and sex-matched healthy controls. ITIH4 was significantly higher in patients than in controls (54.2 ± 30.78 pg/mL versus 37.21 ± 5.39 pg/mL; P = 0.021). ITIH4, but not APRI or FIB-4, had a significant direct correlation with fibrosis stage (P = 0.015, 0.961, and 0.389, resp.), whereas, the negative correlation of ITIH4 with HCV viremia was of marginal significance (P = 0.071). In conclusion, ITIH4 significantly correlated with higher stages of fibrosis indicating a possible relation to liver fibrogenesis. The trend of higher ITIH4 with lower viremia points out a potential antiviral properties and further studies in this regard are worthwhile.

  17. Serum Inter-Alpha-Trypsin Inhibitor Heavy Chain 4 (ITIH4 in Children with Chronic Hepatitis C: Relation to Liver Fibrosis and Viremia

    Directory of Open Access Journals (Sweden)

    Mostafa M. Sira

    2014-01-01

    Full Text Available Liver fibrosis and viremia are determinant factors for the treatment policy and its outcome in chronic hepatitis C virus (HCV infection. We aimed to investigate serum level of inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4 and its relation to liver fibrosis and viremia in children with chronic HCV. ITIH4 was measured by ELISA in 33 treatment-naive children with proved chronic HCV and compared according to different clinical, laboratory and histopathological parameters. Liver histopathological changes were assessed using Ishak score and compared with aspartate transaminase-to-platelet ratio (APRI and FIB-4 indices as simple noninvasive markers of fibrosis. ITIH4 was measured in a group of 30 age- and sex-matched healthy controls. ITIH4 was significantly higher in patients than in controls (54.2±30.78 pg/mL versus 37.21±5.39 pg/mL; P=0.021. ITIH4, but not APRI or FIB-4, had a significant direct correlation with fibrosis stage (P=0.015, 0.961, and 0.389, resp., whereas, the negative correlation of ITIH4 with HCV viremia was of marginal significance (P=0.071. In conclusion, ITIH4 significantly correlated with higher stages of fibrosis indicating a possible relation to liver fibrogenesis. The trend of higher ITIH4 with lower viremia points out a potential antiviral properties and further studies in this regard are worthwhile.

  18. Myosin light chain kinase inhibitor ML7 improves vascular endothelial dysfunction via tight junction regulation in a rabbit model of atherosclerosis.

    Science.gov (United States)

    Cheng, Xiaowen; Wang, Xiaobian; Wan, Yufeng; Zhou, Qing; Zhu, Huaqing; Wang, Yuan

    2015-09-01

    Vascular endothelial dysfunction (VED) is an important factor in the initiation and development of atherosclerosis (AS). Previous studies have demonstrated that endothelial permeability is increased in diet‑induced AS. However, the precise underlying mechanisms remain poorly understood. The present study aimed to analyze whether the myosin light chain kinase (MLCK) inhibitor ML7 is able to improve VED and AS by regulating the expression of the tight junction (TJ) proteins zona occludens (ZO)‑1 and occludin via mechanisms involving MLCK and MLC phosphorylation in high‑fat diet‑fed rabbits. New Zealand white rabbits were randomly divided into three groups: Control group, AS group and ML7 group. The rabbits were fed a standard diet (control group), a high‑fat diet (AS group) or a high‑fat diet supplemented with 1 mg/kg/day ML7 (ML7 group). After 12 weeks, endothelium‑dependent relaxation and endothelium‑independent relaxation were measured using high-frequency ultrasound. Administration of a high‑fat diet significantly increased the levels of serum lipids and inflammatory markers in the rabbits in the AS group, as compared with those in the rabbits in the control group. Furthermore, a high‑fat diet contributed to the formation of a typical atherosclerotic plaque, as well as an increase in endothelial permeability and VED. These symptoms of AS were significantly improved following treatment with ML7, as demonstrated in the ML7 group. Hematoxylin & eosin and immunohistochemical staining indicated that ML7 was able to decrease the expression of MLCK and MLC phosphorylation in the arterial wall of rabbits fed a high‑fat diet. A similar change was observed for the TJ proteins ZO‑1 and occludin. In addition, western blot analysis demonstrated that ML7 increased the expression levels of occludin in the precipitate, but reduced its expression in the supernatant of lysed aortas. These results indicated that occludin, which is a dynamic protein at the TJ

  19. Inter-alpha-trypsin inhibitor heavy chain 4: a novel biomarker for environmental exposure to particulate air pollution in patients with chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Lee KY

    2015-04-01

    Full Text Available Kang-Yun Lee,1–3 Po-Hao Feng,1,2 Shu-Chuan Ho,4 Kai-Jen Chuang,5,6 Tzu-Tao Chen,2,3 Chien-Ling Su,2,4 Wen-Te Liu,2,4 Hsiao-Chi Chuang2,4 1Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, 2Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, 3Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 4School of Respiratory Therapy, College of Medicine, Taipei Medical University, 5Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, 6School of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan Abstract: Chronic obstructive pulmonary disease (COPD is a chronic inflammatory disease that is correlated with environmental stress. Particulate matter ≤10 µm (PM10 is considered to be a risk factor for COPD development; however, the effects of PM10 on the protein levels in COPD remain unclear. Fifty subjects with COPD and 15 healthy controls were recruited. Gene ontology analysis of differentially expressed proteins identified immune system process and binding as the most important biological process and molecular function, respectively, in the responses of PM10-exposed patients with COPD. Biomarkers for PM10 in COPD were identified and compared with the same in healthy controls and included proteoglycan 4 (PRG4, inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4, and apolipoprotein F (APOF. PRG4 and ITIH4 were associated with a past 3-year PM10 exposure level. The receiver operating characteristic curve analysis showed that ITIH4 is a sensitive and specific biomarker for PM10 exposure (area under the curve [AUC] =0.690, P=0.015 compared with PRG4 (AUC =0.636, P=0.083, APOF (AUC =0.523, P=0.766, 8-isoprostane (AUC =0.563, P=0.405, and C-reactive protein (CRP; AUC =0.634, P=0.086. ITIH4 levels were correlated with CRP (r=0

  20. Computational modeling analysis of mitochondrial superoxide production under varying substrate conditions and upon inhibition of different segments of the electron transport chain.

    Science.gov (United States)

    Markevich, Nikolai I; Hoek, Jan B

    2015-01-01

    A computational mechanistic model of superoxide (O2•-) formation in the mitochondrial electron transport chain (ETC) was developed to facilitate the quantitative analysis of factors controlling mitochondrial O2•- production and assist in the interpretation of experimental studies. The model takes into account all individual electron transfer reactions in Complexes I and III. The model accounts for multiple, often seemingly contradictory observations on the effects of ΔΨ and ΔpH, and for the effects of multiple substrate and inhibitor conditions, including differential effects of Complex III inhibitors antimycin A, myxothiazol and stigmatellin. Simulation results confirm that, in addition to O2•- formation in Complex III and at the flavin site of Complex I, the quinone binding site of Complex I is an additional superoxide generating site that accounts for experimental observations on O2•- production during reverse electron transfer. However, our simulation results predict that, when cytochrome c oxidase is inhibited during oxidation of succinate, ROS production at this site is eliminated and almost all superoxide in Complex I is generated by reduced FMN, even when the redox pressure for reverse electron transfer from succinate is strong. In addition, the model indicates that conflicting literature data on the kinetics of electron transfer in Complex III involving the iron-sulfur protein-cytochrome bL complex can be resolved in favor of a dissociation of the protein only after electron transfer to cytochrome bH. The model predictions can be helpful in understanding factors driving mitochondrial superoxide formation in intact cells and tissues.

  1. Physiological Concentration of Exogenous Lactate Reduces Antimycin A Triggered Oxidative Stress in Intestinal Epithelial Cell Line IPEC-1 and IPEC-J2 In Vitro

    Science.gov (United States)

    Kahlert, Stefan; Junnikkala, Sami; Renner, Lydia; Hynönen, Ulla; Hartig, Roland; Nossol, Constanze; Barta-Böszörményi, Anikó; Dänicke, Sven; Souffrant, Wolfgang-Bernhard; Palva, Airi; Rothkötter, Hermann-Josef; Kluess, Jeannette

    2016-01-01

    Weaning triggers an adaptation of the gut function including luminal lactate generation by lactobacilli, depending on gastrointestinal site. We hypothesized that both lactobacilli and lactate influence porcine intestinal epithelial cells. In vivo experiments showed that concentration of lactate was significantly higher in gastric, duodenal and jejunal chyme of suckling piglets compared to their weaned counterparts. In an in vitro study we investigated the impact of physiological lactate concentration as derived from the in vivo study on the porcine intestinal epithelial cells IPEC-1 and IPEC-J2. We detected direct adherence of lactobacilli on the apical epithelial surface and a modulated F-actin structure. Application of lactobacilli culture supernatant alone or lactate (25 mM) at low pH (pH 4) changed the F-actin structure in a similar manner. Treatment of IPEC cultures with lactate at near neutral pH resulted in a significantly reduced superoxide-generation in Antimycin A-challenged cells. This protective effect was nearly completely reversed by inhibition of cellular lactate uptake via monocarboxylate transporter. Lactate treatment enhanced NADH autofluorescence ratio (Fcytosol/Fnucleus) in non-challenged cells, indicating an increased availability of reduced nucleotides, but did not change the overall ATP content of the cells. Lactobacilli-derived physiological lactate concentration in intestine is relevant for alleviation of redox stress in intestinal epithelial cells. PMID:27054581

  2. Measurement of short-chain acyl-CoA dehydrogenase (SCAD) in cultured skin fibroblasts with hexanoyl-CoA as a competitive inhibitor to eliminate the contribution of medium-chain acyl-CoA dehydrogenase

    NARCIS (Netherlands)

    Niezen-Koning, K E; Wanders, R J; Nagel, G T; Sewell, A C; Heijmans, Hugo

    1994-01-01

    Short-chain acyl-CoA dehydrogenase (SCAD) deficiency has so far been reported in only very few patients. This is due, in part, to the problems involved in measuring the activity of SCAD unequivocally. The main reason for this difficulty is that butyryl-CoA, the substrate preferably used for SCAD act

  3. A computational perspective of molecular interactions through virtual screening, pharmacokinetic and dynamic prediction on ribosome toxin A chain and inhibitors of Ricinus communis

    Directory of Open Access Journals (Sweden)

    R Barani Kumar

    2012-01-01

    Full Text Available Background: Ricin is considered to be one of the most deadly toxins and gained its favor as a bioweapon that has a serious social and biological impact, due to its widespread nature and abundant availability. The hazardous effects of this toxin in human being are seen in almost all parts of the organ system. The severe consequences of the toxin necessitate the need for developing potential inhibitors that can effectively block its interaction with the host system. Materials and Methods: In order to identify potential inhibitors that can effectively block ricin, we employed various computational approaches. In this work, we computationally screened and analyzed 66 analogs and further tested their ADME/T profiles. From the kinetic and toxicity studies we selected six analogs that possessed appropriate pharmacokinetic and dynamic property. We have also performed a computational docking of these analogs with the target. Results: On the basis of the dock scores and hydrogen bond interactions we have identified analog 64 to be the best interacting molecule. Molecule 64 seems to have stable interaction with the residues Tyr80, Arg180, and Val81. The pharmacophore feature that describes the key functional features of a molecule was also studied and presented. Conclusion: The pharmacophore features of the drugs provided suggests the key functional groups that can aid in the design and synthesis of more potential inhibitors.

  4. The effect of the P1 side chain on the binding of optimized carboxylate and activated carbonyl inhibitors of the hepatitis C virus NS3 protease.

    Science.gov (United States)

    Kawai, Stephen H; LaPlante, Steven R; Llinàs-Brunet, Montse; Hucke, Oliver

    2010-07-01

    Peptidyl inhibitors of the hepatitis C virus NS3 protease hold much promise as direct-acting antiviral agents against hepatitis C infection. The optimization of N-terminal cleavage products, found to exhibit activity (product inhibition) against the enzyme, has led to potent tripeptide inhibitors that bear free C-terminal carboxylate groups. An analogous activated carbonyl compound (pentafluoroethyl ketone) bearing a P1 norvaline (Nva) was found to possess comparable activity against hepatitis C virus protease. However, an analogue bearing an aminocyclopropylcarboxylic acid (Acca) P1 residue exhibited very poor activity. (19)F-NMR studies indicate that the propensity of the Acca-derived activated carbonyl to form hemiketals is only slightly reduced compared with that of a P1 Nva equivalent. These results, as well as molecular modeling studies, argue against steric hindrance of the nucleophilic attack of Ser-139 accounting for the poor mechanism-based inhibition by the former. We hypothesize that the conformational properties of the respective C-termini in the context of an adaptable active site account for the divergent P1 structure-activity relationships.

  5. Structure-based design of selective inhibitors of dihydrofolate reductase: synthesis and antiparasitic activity of 2, 4-diaminopteridine analogues with a bridged diarylamine side chain.

    Science.gov (United States)

    Rosowsky, A; Cody, V; Galitsky, N; Fu, H; Papoulis, A T; Queener, S F

    1999-11-18

    As part of a larger search for potent as well as selective inhibitors of dihydrofolate reductase (DHFR) enzymes from opportunistic pathogens found in patients with AIDS and other immune disorders, N-[(2,4-diaminopteridin-6-yl)methyl]dibenz[b,f]azepine (4a) and the corresponding dihydrodibenz[b,f]azepine, dihydroacridine, phenoxazine, phenothiazine, carbazole, and diphenylamine analogues were synthesized from 2, 4-diamino-6-(bromomethyl)pteridine in 50-75% yield by reaction with the sodium salts of the amines in dry tetrahydrofuran at room temperature. The products were tested for the ability to inhibit DHFR from Pneumocystis carinii (pcDHFR), Toxoplasma gondii (tgDHFR), Mycobacterium avium (maDHFR), and rat liver (rlDHFR). The member of the series with the best combination of potency and species selectivity was 4a, with IC(50) values against the four enzymes of 0. 21, 0.043, 0.012, and 4.4 microM, respectively. The dihydroacridine, phenothiazine, and carbazole analogues were also potent, but nonselective. Of the compounds tested, 4a was the only one to successfully combine the potency of trimetrexate with the selectivity of trimethoprim. Molecular docking simulations using published 3D structural coordinates for the crystalline ternary complexes of pcDHFR and hDHFR suggested a possible structural interpretation for the binding selectivity of 4a and the lack of selectivity of the other compounds. According to this model, 4a is selective because of a unique propensity of the seven-membered ring in the dibenz[b,f]azepine moiety to adopt a puckered orientation that allows it to fit more comfortably into the active site of the P. carinii enzyme than into the active site of the human enzyme. Compound 4a was also evaluated for the ability to be taken up into, and retard the growth of, P. carinii and T. gondii in culture. The IC(50) of 4a against P. carinii trophozoites after 7 days of continuous drug treatment was 1.9 microM as compared with previously observed IC(50

  6. Falling chains

    Science.gov (United States)

    Wong, Chun Wa; Yasui, Kosuke

    2006-06-01

    The one-dimensional fall of a folded chain with one end suspended from a rigid support and a chain falling from a resting heap on a table is studied. Because their Lagrangians contain no explicit time dependence, the falling chains are conservative systems. Their equations of motion are shown to contain a term that enforces energy conservation when masses are transferred between subchains. We show that Cayley's 1857 energy nonconserving solution for a chain falling from a resting heap is incorrect because it neglects the energy gained when a link leaves a subchain. The maximum chain tension measured by Calkin and March for the falling folded chain is given a simple if rough interpretation. Other aspects of the falling folded chain are briefly discussed.

  7. Unwrapping Chains

    CERN Document Server

    Cambou, A D; Hamm, E; Hanna, J A; Menon, N; Santangelo, C D; Walsh, L

    2012-01-01

    A loop of chain can move along its own tangents, maintaining a steady shape. An open-ended chain undergoing a nontrivial motion must change its shape. One consequence is that chains pulled around objects will fail to follow the contours of the objects, unwrapping themselves instead. This short note accompanies a fluid dynamics video submission (83068) to the APS DFD Gallery of Fluid Motion 2012.

  8. Falling chains

    CERN Document Server

    Wong, C W; Wong, Chun Wa; Yasui, Kosuke

    2006-01-01

    The one-dimensional falling motion of a bungee chain suspended from a rigid support and of a chain falling from a resting heap on a table is studied. Their Lagrangians are found to contain no explicit time dependence. As a result, these falling chains are conservative systems. Each of their Lagrange's equations of motion is shown to contain a term that enforces energy conservation when masses are transferred between subchains. We show in particular that Cayley's 1857 energy nonconserving solution for a chain falling from a resting heap is incorrect because it neglects the energy gained when the transferred link is emitted by the emitting subchain. The maximum chain tension measured by Calkin and March for the falling bungee chain is given a simple if rough interpretation. In the simplified one-dimensional treatment, the kinetic energy of the center of mass of the falling bungee chain is found to be converted by the chain tension at the rigid support into the internal kinetic energy of the chain. However, as t...

  9. Chain Gang

    Science.gov (United States)

    2006-01-01

    6 August 2006 This Mars Global Surveyor (MGS) Mars Orbiter Camera (MOC) image shows a chain of clustered and battered craters. These were formed by secondary impact. That is, somewhere to the south (beyond the bottom of this image), a large impact crater formed. When this occurred, material ejected from the crater was thrown tens to hundreds of kilometers away. This material then impacted the martian surface, forming clusters and chains of smaller craters. Location near: 15.8oN, 35.6oW Image width: 3 km (1.9 mi) Illumination from: upper left Season: Northern Spring

  10. Evaluation of the electron transport chain inhibition and uncoupling of mitochondrial bioelectrocatalysis with antibiotics and nitro-based compounds

    Energy Technology Data Exchange (ETDEWEB)

    Arechederra, Marguerite N.; Fischer, Caitlin N.; Wetzel, David J. [Department of Chemistry, Saint Louis University, 3501 Laclede Ave., St. Louis, MO (United States); Minteer, Shelley D., E-mail: minteers@slu.ed [Department of Chemistry, Saint Louis University, 3501 Laclede Ave., St. Louis, MO (United States)

    2010-12-30

    Mitochondrial bioelectrocatalysis can be useful for sensing applications due to the unique metabolic pathways than can be selectively inhibited and uncoupled in mitochondria. This paper details the comparison of different inhibitors and nitro-containing explosive uncouplers in a mitochondria-catalyzed biofuel cell for self-powered explosive sensing. Previous research has reported inhibition of pyruvate oxidation at a mitochondria-modified electrode followed by nitroaromatic uncoupling of current and power. We have previously used oligomycin as the antibiotic and nitrobenzene as the uncoupler of the membrane in the mitochondria-catalyzed biofuel cell, but no comprehensive comparison of various mitochondria inhibitors or explosives has been performed. Results are discussed here for inhibitors targeting complex I, complex III, ATP synthases, adenine nucleotide transport and monocarboxylic acid transport. Reactivation with nitrobenzene was possible in the presence of these inhibitors: oligomycin, 3,3'-diindolylmethane, atractyloside, rotenone, {alpha}-cyano-4-hydroxy cinnamic acid and antimycin A. All eleven explosives studied, including: 2,4,6-trinitrotoluene (TNT) and 1,3,5-trinitroperhydro-1,3,5-triazine (RDX), caused uncoupling of the mitochondria function and could be detected by the biosensor.

  11. Primary structural analysis of sulfhydryl protease inhibitors from pineapple stem.

    Science.gov (United States)

    Reddy, M N; Keim, P S; Heinrikson, R L; Kezdy, F J

    1975-03-10

    Pineapple stem acetone powder provides a rich source of the sulfhydryl protease bromelain and of a family of compositionally similar but chromatographically distinct polypeptide inihibtors of this enzyme. The isoinhibitors have molecular weights of 5600, and they contain five disulfide bonds and about 50 amino acids each (Perlstein, S. H., AND Kezdy, F.J. (1973) J. Supramol. Struct. 1, 249-254). Primary structural analysis of one of the seven inhibitor fractions (VII) revealed extensive microheterogeneity. Each of the inhibitor molecules in Fraction VII was shown to be composed of two peptide chains joined by disulfide bonds. These chains, designated A and B on the basis of size, comprise 41 and 10-11 residues, respectively, and the amino acid sequence of one of each are given below: (see article for formular). On the basis of ionization properties and yields of the A and B chains, it would appear that one of the major inhibitor species in Fraction VII is the covalently linked complex of the two chains shown, namely [A-1, B-2]. The second major inhibitor component of Fraction VII is identical in structure with [A-1, B-2i1 except that residues 1 and 8 in the A chain are pyroglutamate and threonine, respectively, and in the B chain glutamine 11 is replaced by arginine. The third inhibitor in Fraction VII is a minor constituent identical with the second, except that residue 1 in the A chain is glutamate rather than pyroglutamate. This microheterogeneity in the inhibitors of Fraction VII is further increased by the fact that B chains may lack threonine 1, in which case they are decapeptides beginning with alanine. On the basis of the striking homology of the cysteine residues with those of other protease inhibitors, it is proposed that the bromelain inhibitors are generated enzymatically from single chain precursors by excision of a "bridge" paptide which links the NH-2 termal A chain to the COOH-terminal B chain.

  12. Primary structure of bovine calpactin I heavy chain (p36), a major cellular substrate for retroviral protein-tyrosine kinases: homology with the human phospholipase A2 inhibitor lipocortin

    DEFF Research Database (Denmark)

    Kristensen, Torsten; Sarin, C J; Hunter, T;

    1986-01-01

    An amplified Okayama-Berg plasmid cDNA library was constructed from total poly(A)+ RNA isolated from the Madin-Darby bovine kidney cell line MDBK. This library was screened with a partial murine calpactin I heavy chain (p36) cDNA clone, the identification of which was based on bovine p36 tryptic ...

  13. On the location of the H+-extruding steps in site 2 of the mitochondrial electron transport chain.

    Science.gov (United States)

    Alexandre, A; Galiazzo, F; Lehninger, A L

    1980-11-25

    The location of the H+-translocating reactions within energy-conserving Site 2 of the mitochondrial electron transport chain was evaluated from two sets of data. In the first, the H+/2e- ejection ratios and Ca2+/2e- uptake ratios were compared for electron flow from succinate dehydrogenase, whose active site is on the matrix side of the inner membrane and from glycerol phosphate dehydrogenase, whose active site is on the cytosolic side. In intact rat liver mitochondria both substrates yielded H+/2e- ejection ratios close to 4.0 and Ca2+/2e- uptake ratios close to 1.0 during antimycin-sensitive reduction of ferricyanide. With rat liver mitoplasts and ferricytochrome c as electron acceptor, both substrates again gave the same stoichiometric ratios. The second approach involved determination of the sidedness of H+ formation during electron flow from succinate to ferricyanide via bypass of the antimycin block of the cytochrome b.c1 complex provided by N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD), under conditions in which the TMPD-TMPD+ couple does not act as a membrane-penetrating protonophore. Electron flow in this system was inhibited by 2-then-oyltrifluoroacetone, indicating that TMPD probably accepts electrons from ubiquinol. The 2 H+ formed in this system were not delivered into the matrix but appeared directly in the medium in the absence of a protonophore. To accommodate the available evidence on Site 2 substrates, it is concluded that the substrate hydrogens are first transferred to ubiquinone, 2 H+ per 2e then appear in the medium by protolytic dehydrogenation of a species of ubiquinol or ubiquinol-protein having the appropriate sidedness (designated Site 2A), and the other 2 H+ are translocated from the matrix to the medium on passage of 2e- through the cytochrome b x c1 complex (designated Site 2B).

  14. Phenyltriazolinones as potent factor Xa inhibitors.

    Science.gov (United States)

    Quan, Mimi L; Pinto, Donald J P; Rossi, Karen A; Sheriff, Steven; Alexander, Richard S; Amparo, Eugene; Kish, Kevin; Knabb, Robert M; Luettgen, Joseph M; Morin, Paul; Smallwood, Angela; Woerner, Francis J; Wexler, Ruth R

    2010-02-15

    We have discovered that phenyltriazolinone is a novel and potent P1 moiety for coagulation factor Xa. X-ray structures of the inhibitors with a phenyltriazolinone in the P1 position revealed that the side chain of Asp189 has reoriented resulting in a novel S1 binding pocket which is larger in size to accommodate the phenyltriazolinone P1 substrate.

  15. Graphs: Associated Markov Chains

    OpenAIRE

    2012-01-01

    In this research paper, weighted / unweighted, directed / undirected graphs are associated with interesting Discrete Time Markov Chains (DTMCs) as well as Continuous Time Markov Chains (CTMCs). The equilibrium / transient behaviour of such Markov chains is studied. Also entropy dynamics (Shannon entropy) of certain structured Markov chains is investigated. Finally certain structured graphs and the associated Markov chains are studied.

  16. Antimycin-insensitive mutants of Candida utilis II. The effects of antimycin on Cytochrome b

    DEFF Research Database (Denmark)

    Grimmelikhuijzen, C J; Marres, C A; Slater, Conor

    1975-01-01

    1. Cytochrome b-562 is more reduced in submitochondrial particles of mutant 28 during the aerobic steady-state respiration with succinate than in particles of the wild type. When anaerobiosis is reached, the reduction of cytochrome b is preceded by a rapid reoxidation in the mutnat. A similar reo...

  17. Logistic chain modelling

    NARCIS (Netherlands)

    Slats, P.A.; Bhola, B.; Evers, J.J.M.; Dijkhuizen, G.

    1995-01-01

    Logistic chain modelling is very important in improving the overall performance of the total logistic chain. Logistic models provide support for a large range of applications, such as analysing bottlenecks, improving customer service, configuring new logistic chains and adapting existing chains to n

  18. Health supply chain management.

    Science.gov (United States)

    Zimmerman, Rolf; Gallagher, Pat

    2010-01-01

    This chapter gives an educational overview of: * The actual application of supply chain practice and disciplines required for service delivery improvement within the current health environment. * A rationale for the application of Supply Chain Management (SCM) approaches to the Health sector. * The tools and methods available for supply chain analysis and benchmarking. * Key supply chain success factors.

  19. Inhibitors of protein kinase C

    Institute of Scientific and Technical Information of China (English)

    LIU Shiying; JIANG Yuyang; CAO Jian; LIU Feng; MA Li; ZHAO Yufen

    2005-01-01

    Protein kinase catalyzes the transfer of the γ-phosphoryl group from ATP to the hydroxyl groups of protein side chains, which plays critical roles in signal transduction pathways by transmitting extracellular signals across the plasma membrane and nuclear membrane to the destination sites in the cytoplasm and the nucleus. Protein kinase C (PKC) is a superfamily of phospholipid-dependent Ser/Thr kinase. There are at least 12 isozymes in PKC family. They are distributed in different tissues and play different roles in physiological processes. On account of their concern with a variety of pathophysiologic states, such as cancer, inflammatory conditions, autoimmune disorder, and cardiac diseases, the inhibitors, which can inhibit the activity of PKC and the interaction of cytokine with receptor, and interfere signal transduction pathway, may be candidates of therapeutic drugs. Therefore, intense efforts have been made to develop specific protein kinase inhibitors as biological tools and therapeutic agents. This article reviews the recent development of some of PKC inhibitors based on their interaction with different conserved domains and different inhibition mechanisms.

  20. Biochemical characterization of Acacia schweinfurthii serine proteinase inhibitor.

    Science.gov (United States)

    Odei-Addo, Frank; Frost, Carminita; Smith, Nanette; Ogawa, Tomohisa; Muramoto, Koji; Oliva, Maria Luiza Vilela; Gráf, László; Naude, Ryno

    2014-10-01

    One of the many control mechanisms of serine proteinases is their specific inhibition by protein proteinase inhibitors. An extract of Acacia schweinfurthii was screened for potential serine proteinase inhibition. It was successfully purified to homogeneity by precipitating with 80% (v/v) acetone and sequential chromatographic steps, including ion-exchange, affinity purification and reversed-phase high performance liquid chromatography. Reducing sodium dodecyl sulphate polyacrylamide gel electrophoresis conditions revealed an inhibitor (ASTI) consisting of two polypeptide chains A and B of approximate molecular weights of 16 and 10 kDa, respectively, and under non-reducing conditions, 26 kDa was observed. The inhibitor was shown to inhibit bovine trypsin (Ki of 3.45 nM) at an approximate molar ratio of inhibitor:trypsin (1:1). The A- and B-chains revealed complete sequences of 140 and 40 amino acid residues, respectively. Sequence similarity (70%) was reported between ASTI A-chain and ACTI A-chain (Acacia confusa) using ClustalW. The B-chain produced a 76% sequence similarity between ASTI and Leucaena leucocephala trypsin inhibitor.

  1. Proton pump inhibitors

    Science.gov (United States)

    Proton pump inhibitors (PPIs) are medicines that work by reducing the amount of stomach acid made by ... Proton pump inhibitors are used to: Relieve symptoms of acid reflux, or gastroesophageal reflux disease (GERD). This ...

  2. Sustainable Supply Chain Design

    DEFF Research Database (Denmark)

    Bals, Lydia; Tate, Wendy

    to implement TBL goals across the supply chain. In supply chain design, the classic economic perspective still dominates, although the idea of the TBL is more widely disseminated. The purpose of this research is to add to the sustainable supply chain management literature (SSCM) research agenda......A significant conceptual and practical challenge is how to integrate triple bottom line (TBL; including economic, social and environmental) sustainability into global supply chains. Although this integration is necessary to slow down global resource depletion, understanding is limited of how...... by incorporating the physical chain, and the (information and financial) support chains into supply chain design. This manuscript tackles issues of what the chains are designed for and how they are designed structurally. Four sustainable businesses are used as illustrative case examples of innovative supply chain...

  3. The Global Value Chain

    DEFF Research Database (Denmark)

    Sørensen, Olav Jull

    The conference paper aims to develop the global value chain concept by including corporate internal value adding activities and competition to the basic framework in order to turn the global value chain into a strategic management tool......The conference paper aims to develop the global value chain concept by including corporate internal value adding activities and competition to the basic framework in order to turn the global value chain into a strategic management tool...

  4. Serum Free Light Chains

    Science.gov (United States)

    ... or of one of its component parts – a kappa or lambda light chain, or rarely, a heavy chain. Traditionally, plasma cell ... protein (M-protein) production and to calculate a kappa/lambda free light chain ratio. If the protein electrophoresis test is abnormal, ...

  5. Protective effects of rilmenidine and AGN 192403 on oxidative cytotoxicity and mitochondrial inhibitor-induced cytotoxicity in astrocytes.

    Science.gov (United States)

    Choi, Dong-Hee; Kim, Dong-Hoon; Park, Yun-Gyu; Chun, Boe-Gwun; Choi, Sang-Hyun

    2002-11-15

    Oxidative stress and mitochondrial dysfunction are important aspects of pathogenesis, particularly in the brain, which is highly dependent on oxygen, and the protection of astrocytes is essential for neuroprotection. In this context, imidazoline drugs have been reported to be neuroprotective. Our recent study showed that imidazoline drugs, including guanabenz, inhibit the naphthazarin-induced oxidative cytotoxicity associated with lysosomal destabilization. We now report on a study into the protective effects of rilmenidine and AGN 192403, which have affinity for imidazoline-1 receptors, on the cytotoxicity induced by naphthazarin and inhibitors of mitochondrial respiration in astrocytes. Cytotoxicity was measured grossly by LDH release and by measuring changes in lysosomal membrane stability and features of mitochondrial membrane permeabilization. Naphthazarin-induced cytotoxicity was evidenced by the ordered development of lysosomal acridine orange relocation, decrease in mitochondrial potential, cytochrome c release, and caspase-9 activation, and was inhibited by guanabenz, rilmenidine, and AGN 192403. Antimycin A and rotenone induced mitochondrial dysfunction primarily, and their cytotoxicities were inhibited only by AGN 192403. Rilmenidine and guanabenz may have a lysosomal stabilizing effect, which underlies their protective effects. AGN 192403 might affect the mitochondrial cell death cascades, and had a novel protective effect on the cytotoxicity associated with mitochondrial dysfunction.

  6. A Selective Cyclic Peptidic Human SIRT5 Inhibitor

    Directory of Open Access Journals (Sweden)

    Jiajia Liu

    2016-09-01

    Full Text Available In the current study, we discovered that a side chain-to-side chain cyclic pentapeptide harboring a central Nε-carboxyethyl-thiocarbamoyl-lysine residue behaved as a strong and selective (versus human SIRT1/2/3/6 inhibitor against human SIRT5-catalyzed deacylation reaction. This compound was also found to be proteolytically much more stable than its linear counterpart. This compound could be a valuable lead for developing stronger, selective, metabolically stable, and cell permeable human SIRT5 inhibitors.

  7. Gushing metal chain

    Science.gov (United States)

    Belyaev, Alexander; Sukhanov, Alexander; Tsvetkov, Alexander

    2016-03-01

    This article addresses the problem in which a chain falls from a glass from some height. This phenomenon demonstrates a paradoxical rise of the chain over the glass. To explain this effect, an initial hypothesis and an appropriate theory are proposed for calculating the steady fall parameters of the chain. For this purpose, the modified Cayley's problem of falling chain given its rise due to the centrifugal force of upward inertia is solved. Results show that the lift caused by an increase in linear density at the part of chain where it is being bent (the upper part) is due to the convergence of the chain balls to one another. The experiments confirm the obtained estimates of the lifting chain.

  8. Supply Chain Management og Supply Chain costing

    DEFF Research Database (Denmark)

    Nielsen, Steen; Mortensen, Ole

    2002-01-01

    Formålet med denne artikel er at belyse de muligheder som ligger i at integrere virksomhedens økonomiske styring med begrebet Supply Chain Management (SCM). Dette søges belyst ved først at beskrive den teoretiske ramme, hvori SCM indgår. Herefter analyseres begrebet Supply Chain Costing (SCC) som...... Århus. Et resultat er, at via begrebet Supply Chain Costing skabes der mulighed for at måle logistikkædens aktiviteter i kr./øre. Anvendelsen af denne information har også strategisk betydning for at kunne vælge kunde og leverandør. Ved hjælp af integrationen skabes der også helt nye mulighed...

  9. Understanding the Chain Fountain

    CERN Document Server

    Biggins, John Simeon

    2013-01-01

    If a chain is initially at rest in a beaker at a height h1 above the ground, and the end of the chain is pulled over the rim of the beaker and down towards the ground and then released, the chain will spontaneously "flow" out of the beaker under gravity. Furthermore, if h1 is sufficient, the beads do not simply drag over the edge of the beaker but form a fountain reaching a height h2 above it. We show that the formation of a fountain requires that the beads come into motion not only by being pulled upwards by the part of the chain immediately above the pile, but also by being pushed upwards by an anomalous reaction force from the pile of stationary chain. We propose possible origins for this force, argue that its magnitude will be proportional to the square of the chain velocity, and predict and verify experimentally that h2 is proportional to h1.

  10. Food supply chains

    OpenAIRE

    Zhou, Qian

    2011-01-01

    The dissertation analyses food waste in global supply chain. From the related managerial literature, the process of supply chain operation, from agriculture, manufacturing, warehouses, retailers to customers are explained clearly. Then the reasons and characteristics of food wastes in any point of food supply chain are analyzed. From some case studies and questionnaire investigation, some corresponding methods to reduce food waste are put forward in the following. Lastly, in terms of method s...

  11. Supply chain components

    Directory of Open Access Journals (Sweden)

    Vieraşu, T.

    2011-01-01

    Full Text Available In this article I will go through three main logistics components, which are represented by: transportation, inventory and facilities, and the three secondary logistical components: information, production location, price and how they determine performance of any supply chain. I will discuss then how these components are used in the design, planning and operation of a supply chain. I will also talk about some obstacles a supply chain manager may encounter.

  12. Supply chain planning classification

    Science.gov (United States)

    Hvolby, Hans-Henrik; Trienekens, Jacques; Bonde, Hans

    2001-10-01

    Industry experience a need to shift in focus from internal production planning towards planning in the supply network. In this respect customer oriented thinking becomes almost a common good amongst companies in the supply network. An increase in the use of information technology is needed to enable companies to better tune their production planning with customers and suppliers. Information technology opportunities and supply chain planning systems facilitate companies to monitor and control their supplier network. In spite if these developments, most links in today's supply chains make individual plans, because the real demand information is not available throughout the chain. The current systems and processes of the supply chains are not designed to meet the requirements now placed upon them. For long term relationships with suppliers and customers, an integrated decision-making process is needed in order to obtain a satisfactory result for all parties. Especially when customized production and short lead-time is in focus. An effective value chain makes inventory available and visible among the value chain members, minimizes response time and optimizes total inventory value held throughout the chain. In this paper a supply chain planning classification grid is presented based current manufacturing classifications and supply chain planning initiatives.

  13. Independent sets in chain cacti

    CERN Document Server

    Sedlar, Jelena

    2011-01-01

    In this paper chain cacti are considered. First, for two specific classes of chain cacti (orto-chains and meta-chains of cycles with h vertices) the recurrence relation for independence polynomial is derived. That recurrence relation is then used in deriving explicit expressions for independence number and number of maximum independent sets for such chains. Also, the recurrence relation for total number of independent sets for such graphs is derived. Finaly, the proof is provided that orto-chains and meta-chains are the only extremal chain cacti with respect to total number of independent sets (orto-chains minimal and meta-chains maximal).

  14. Decisive Markov Chains

    CERN Document Server

    Abdulla, Parosh Aziz; Mayr, Richard

    2007-01-01

    We consider qualitative and quantitative verification problems for infinite-state Markov chains. We call a Markov chain decisive w.r.t. a given set of target states F if it almost certainly eventually reaches either F or a state from which F can no longer be reached. While all finite Markov chains are trivially decisive (for every set F), this also holds for many classes of infinite Markov chains. Infinite Markov chains which contain a finite attractor are decisive w.r.t. every set F. In particular, this holds for probabilistic lossy channel systems (PLCS). Furthermore, all globally coarse Markov chains are decisive. This class includes probabilistic vector addition systems (PVASS) and probabilistic noisy Turing machines (PNTM). We consider both safety and liveness problems for decisive Markov chains, i.e., the probabilities that a given set of states F is eventually reached or reached infinitely often, respectively. 1. We express the qualitative problems in abstract terms for decisive Markov chains, and show...

  15. Fields From Markov Chains

    DEFF Research Database (Denmark)

    Justesen, Jørn

    2005-01-01

    A simple construction of two-dimensional (2-D) fields is presented. Rows and columns are outcomes of the same Markov chain. The entropy can be calculated explicitly.......A simple construction of two-dimensional (2-D) fields is presented. Rows and columns are outcomes of the same Markov chain. The entropy can be calculated explicitly....

  16. REVERSE SUPPLY CHAIN

    Directory of Open Access Journals (Sweden)

    Tomasz DOMAGAŁA

    2013-10-01

    Full Text Available The paper focuses on the presentation of the reverse supply chain, of which the role in the modern business grows along with the increasing number of environmental regulations and possibilities of reducing an operating cost. The paper also describes main problems in developing the profitable chain and possibilities to take an action in order to overcome them.

  17. Value Chain Engineering

    DEFF Research Database (Denmark)

    Wæhrens, Brian Vejrum; Slepniov, Dmitrij

    2015-01-01

    This workbook is recommended for the attention of students of and managers in Danish small and medium sized enterprises (SMEs). Danish SMEs are currently facing a number of key challenges related to their position in global value chains. This book provides an insight into value chain management...

  18. Supply Chain Management

    DEFF Research Database (Denmark)

    Wieland, Andreas; Handfield, Robert B.

    Supply chain management has made great strides in becoming a discipline with a standalone body of theories. As part of this evolution, researchers have sought to embed and integrate observed supply chain management phenomena into theoretical statements. In our review, we explore where we have been...

  19. Supply Chain Connectivity: Enhancing Participation in the Global Supply Chain

    OpenAIRE

    Epictetus E. Patalinghug

    2015-01-01

    Supply chain connectivity is vital for the efficient flow of trade among APEC economies. This paper reviews the literature and supply chain management, describes the barriers to enhancing participation in global supply chain, analyzes the various measures of supply chain performance, and suggests steps for the Philippines to fully reap the benefits of the global value chain.

  20. Structure-Based Design of Ricin Inhibitors

    Directory of Open Access Journals (Sweden)

    Jon D. Robertus

    2011-10-01

    Full Text Available Ricin is a potent cytotoxin easily purified in large quantities. It presents a significant public health concern due to its potential use as a bioterrorism agent. For this reason, extensive efforts have been underway to develop antidotes against this deadly poison. The catalytic A subunit of the heterodimeric toxin has been biochemically and structurally well characterized, and is an attractive target for structure-based drug design. Aided by computer docking simulations, several ricin toxin A chain (RTA inhibitors have been identified; the most promising leads belonging to the pterin family. Development of these lead compounds into potent drug candidates is a challenging prospect for numerous reasons, including poor solubility of pterins, the large and highly polar secondary binding pocket of RTA, as well as the enzyme’s near perfect catalytic efficiency and tight binding affinity for its natural substrate, the eukaryotic ribosome. To date, the most potent RTA inhibitors developed using this approach are only modest inhibitors with apparent IC50 values in the 10−4 M range, leaving significant room for improvement. This review highlights the variety of techniques routinely employed in structure-based drug design projects, as well as the challenges faced in the design of RTA inhibitors.

  1. Side Chain Cyclized Aromatic Amino Acids

    DEFF Research Database (Denmark)

    Van der Poorten, Olivier; Knuhtsen, Astrid; Sejer Pedersen, Daniel

    2016-01-01

    Constraining the conformation of flexible peptides is a proven strategy to increase potency, selectivity, and metabolic stability. The focus has mostly been on constraining the backbone dihedral angles; however, the correct orientation of the amino acid side chains (χ-space) that constitute...... the peptide pharmacophore is equally important. Control of χ-space utilizes conformationally constrained amino acids that favor, disfavor, or exclude the gauche (-), the gauche (+), or the trans conformation. In this review we focus on cyclic aromatic amino acids in which the side chain is connected...... to the peptide backbone to provide control of χ(1)- and χ(2)-space. The manifold applications for cyclized analogues of the aromatic amino acids Phe, Tyr, Trp, and His within peptide medicinal chemistry are showcased herein with examples of enzyme inhibitors and ligands for G protein-coupled receptors....

  2. Project Decision Chain

    DEFF Research Database (Denmark)

    Rolstadås, Asbjørn; Pinto, Jeffrey K.; Falster, Peter

    2015-01-01

    To add value to project performance and help obtain project success, a new framework for decision making in projects is defined. It introduces the project decision chain inspired by the supply chain thinking in the manufacturing sector and uses three types of decisions: authorization, selection......, and plan decision. A primitive decision element is defined where all the three decision types can be accommodated. Each task in the primitive element can in itself contain subtasks that in turn will comprise new primitive elements. The primitive elements are nested together in a project decision chain....

  3. Plastic value chains

    DEFF Research Database (Denmark)

    Baxter, John; Wahlstrom, Margareta; Zu Castell-Rüdenhausen, Malin

    2014-01-01

    Optimizing plastic value chains is regarded as an important measure in order to increase recycling of plastics in an efficient way. This can also lead to improved awareness of the hazardous substances contained in plastic waste, and how to avoid that these substances are recycled. As an example......, plastics from WEEE is chosen as a Nordic case study. The project aims to propose a number of improvements for this value chain together with representatives from Nordic stakeholders. Based on the experiences made, a guide for other plastic value chains shall be developed....

  4. Supply chain risk management

    Directory of Open Access Journals (Sweden)

    Christian Hollstein

    2013-03-01

    Full Text Available Background: Supply chain risk management increasingly gains prominence in many international industries. In order to strengthen supply chain structures, processes, and networks, adequate potentials for risk management need to be built (focus on effective logistics and to be utilized (focus on efficient logistics. Natural-based disasters, such as the case of Fukushima, illustrate how crucial risk management is. Method: By aligning a theoretical-conceptual framework with empirical-inductive findings, it may be hypothesized that logistical systems do have a positive effect on supply chain risk management activities.  Result/conclusion:  Flexibility and capacity, as well as redundancy and standardization, are often viewed as being conflictionary. It shows, however, that in the light of supply chain risk management, those factors may yield a common benefit if proper logistics systems are applied.  

  5. Editorial: Supply Chain Management

    Directory of Open Access Journals (Sweden)

    Aidonis, D.

    2012-01-01

    Full Text Available This special issue has followed up the 2nd Olympus International Conference on Supply Chains held on October 5-6, 2012, in Katerini, Greece. The Conference was organized by the Department of Logistics of Alexander Technological Educational Institution (ATEI of Thessaloniki, in collaboration with the Laboratory of Quantitative Analysis, Logistics and Supply Chain Management of the Department of Mechanical Engineering, Aristotle University of Thessaloniki (AUTH. During the 2-Days Conference more than 50 research papers were presented covering the following thematic areas: (i Business Logistics, (ii Transportation, Telematics and Distribution Networks, (iii Green Logistics, (iv Information and Communication Technologies in Supply Chain Management, and (v Services and Quality. Three keynote invited speakers addressed interesting issues for the Humanitarian Logistics, Green Supply Chains of the Agrifood Sector and the Opportunities and Prospects of Greek Ports chaired Round Tables with other Greek and Foreign Scientists and Specialists.

  6. Moldova - Value Chain Training

    Data.gov (United States)

    Millennium Challenge Corporation — The evaluation of the GHS value chain training subactivity wwas designed to measure the extent, if any, to which the training activities improved the productivity...

  7. Light chain nephropathy

    Directory of Open Access Journals (Sweden)

    Sihem Darouich

    2015-01-01

    Full Text Available Light chain deposition disease (LCDD is characterized by the tissue deposition of monotypic immunoglobulin light chains of either kappa or lambda isotype. It is the archetypal systemic disease that is most frequently diagnosed on a kidney biopsy, although the deposits may involve several other organs. This brief review focuses on the clinicopathological features of LCDD-associated nephropathy with an emphasis on the diagnostic and therapeutic difficulties related to this elusive condition.

  8. Supply Chain Interoperability Measurement

    Science.gov (United States)

    2015-06-19

    Base, Ohio DISTRIBUTION STATEMENT A. APPROVED FOR PUBLIC RELEASE; DISTRIBUTION UNLIMITED. The views expressed in this thesis ...chain connections are often hindered by inconsistent vocabularies , terms, ontologies, and semantics utilized by various supply chain members (Ye et...eg.COOPERATION PROCESS)-Don’t address synergies between SC X X X X X X X X Don’t track effectiveness over time-lack of learning by experience Loss of SC

  9. Supply chain quality management

    OpenAIRE

    Hannan Amoozad Mahdiraji; Meysam Arabzadeh; Reza Ghaffari

    2012-01-01

    In recent years, there are several methods introduced for the improvement of operational performances. Total quality management and supply chain management are two methods recommended for this purpose. These two approaches have been studied in most researches separately, while they have objectives in common, and this makes them a strategic means, which can be used, simultaneously. Total quality management and supply chain management play significant roles to increase the organizational compet...

  10. Innovation Across the Supply Chain

    DEFF Research Database (Denmark)

    Druehl, Cheryl; Carrillo, Janice; Hsuan, Juliana

    Innovation is an integral part of every firm’s ongoing operations. Beyond product innovation, supply chain innovations offer a unique source of competitive advantage. We synthesize recent research on innovation in the supply chain, specifically, innovative supply chain processes...

  11. MASTERING SUPPLY CHAIN RISKS

    Directory of Open Access Journals (Sweden)

    Borut Jereb

    2012-11-01

    Full Text Available Risks in supply chains represent one of the major business issues today. Since every organizationstrives for success and uninterrupted operations, efficient supply chain risk management is crucial.During supply chain risk research at the Faculty of Logistics in Maribor (Slovenia some keyissues in the field were identified, the major being the lack of instruments which can make riskmanagement in an organization easier and more efficient. Consequently, a model which captures anddescribes risks in an organization and its supply chain was developed. It is in accordance with thegeneral risk management and supply chain security standards, the ISO 31000 and ISO 28000families. It also incorporates recent finding from the risk management field, especially from theviewpoint of segmenting of the public.The model described in this paper focuses on the risks itself by defining them by different keydimensions, so that risk management is simplified and can be undertaken in every supply chain andorganizations within them. Based on our mode and consequent practical research in actualorganizations, a freely accessible risk catalog has been assembled and published online from the risksthat have been identified so far. This catalog can serve as a checklist and a starting point in supplychain risk management in organizations. It also incorporates experts from the field into a community,in order to assemble an ever growing list of possible risks and to provide insight into the model andits value in practice.

  12. Issues on Supply Chain Management

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Although supply chain is regarded as an integrated pr ocess, actually, researchers and practitioners have primarily investigated the v arious processes of the supply chain individually. The competitive field in most markets requires well-designed integrated supply chain instead of individual o perations. In this paper, some traditional thinking of supply chain is given fir st, then SCM (Supply Chain Management) is introduced, which views the entire sup ply chain as a whole rather than individual process a...

  13. Cholinesterase inhibitors from botanicals

    Directory of Open Access Journals (Sweden)

    Faiyaz Ahmed

    2013-01-01

    Full Text Available Alzheimer′s disease (AD is a progressive neurodegenerative disease, wherein a progressive loss of cholinergic synapses occurs in hippocampus and neocortex. Decreased concentration of the neurotransmitter, acetylcholine (ACh, appears to be critical element in the development of dementia, and the most appropriate therapeutic approach to treat AD and other form of dementia is to restore acetylcholine levels by inhibiting both major form of cholinesterase: Acetylcholinesterase (AChE and butyrylcholinesterase (BChE. Consequently, researches have focused their attention towards finding cholinesterase inhibitors from natural products. A large number of such inhibitors have been isolated from medicinal plants. This review presents a comprehensive account of the advances in field of cholinesterase inhibitor phytoconstituents. The structures of some important phytoconstituents (collected through www.Chemspider.com are also presented and the scope for future research is discussed.

  14. Phasic Triplet Markov Chains.

    Science.gov (United States)

    El Yazid Boudaren, Mohamed; Monfrini, Emmanuel; Pieczynski, Wojciech; Aïssani, Amar

    2014-11-01

    Hidden Markov chains have been shown to be inadequate for data modeling under some complex conditions. In this work, we address the problem of statistical modeling of phenomena involving two heterogeneous system states. Such phenomena may arise in biology or communications, among other fields. Namely, we consider that a sequence of meaningful words is to be searched within a whole observation that also contains arbitrary one-by-one symbols. Moreover, a word may be interrupted at some site to be carried on later. Applying plain hidden Markov chains to such data, while ignoring their specificity, yields unsatisfactory results. The Phasic triplet Markov chain, proposed in this paper, overcomes this difficulty by means of an auxiliary underlying process in accordance with the triplet Markov chains theory. Related Bayesian restoration techniques and parameters estimation procedures according to the new model are then described. Finally, to assess the performance of the proposed model against the conventional hidden Markov chain model, experiments are conducted on synthetic and real data.

  15. Spatial Data Supply Chains

    Science.gov (United States)

    Varadharajulu, P.; Azeem Saqiq, M.; Yu, F.; McMeekin, D. A.; West, G.; Arnold, L.; Moncrieff, S.

    2015-06-01

    This paper describes current research into the supply of spatial data to the end user in as close to real time as possible via the World Wide Web. The Spatial Data Infrastructure paradigm has been discussed since the early 1990s. The concept has evolved significantly since then but has almost always examined data from the perspective of the supplier. It has been a supplier driven focus rather than a user driven focus. The current research being conducted is making a paradigm shift and looking at the supply of spatial data as a supply chain, similar to a manufacturing supply chain in which users play a significant part. A comprehensive consultation process took place within Australia and New Zealand incorporating a large number of stakeholders. Three research projects that have arisen from this consultation process are examining Spatial Data Supply Chains within Australia and New Zealand and are discussed within this paper.

  16. Environmental Retail Supply Chains

    DEFF Research Database (Denmark)

    Kotzab, Herbert; Munch, Hilde; de Faultrier, Birgitte;

    2011-01-01

    Purpose – The purpose of this paper is to develop a scale that evaluates the environmental elements in retail supply chains and to examine the environmental supply chain management initiatives of the world's largest 100 retailing companies. Design/methodology/approach – The empirical evaluation has...... short-term oriented (green operations). Long-term oriented green design initiatives were hardly observed. Furthermore, the specific environmental activities of three retailers from Denmark, France and the UK were compared. Research limitations/implications – The empirical study investigates supply chain...... operations of retailers and excludes other areas of retail management. The results are based on material that is published by the respective companies and thus do not include internal reports. Originality/value – The main contribution of this paper is to test the proposition that global retailers follow...

  17. Fuzzy Markov chains: uncertain probabilities

    OpenAIRE

    2002-01-01

    We consider finite Markov chains where there are uncertainties in some of the transition probabilities. These uncertainties are modeled by fuzzy numbers. Using a restricted fuzzy matrix multiplication we investigate the properties of regular, and absorbing, fuzzy Markov chains and show that the basic properties of these classical Markov chains generalize to fuzzy Markov chains.

  18. Essentials of supply chain management

    CERN Document Server

    Hugos, Michael H

    2011-01-01

    The latest thinking, strategies, developments, and technologies to stay current in supply chain management Presenting the core concepts and techniques of supply chain management in a clear, concise and easily readable style, the Third Edition of Essentials of Supply Chain Management outlines the most crucial tenets and concepts of supply chain management.

  19. Supply-Chain Optimization Template

    Science.gov (United States)

    Quiett, William F.; Sealing, Scott L.

    2009-01-01

    The Supply-Chain Optimization Template (SCOT) is an instructional guide for identifying, evaluating, and optimizing (including re-engineering) aerospace- oriented supply chains. The SCOT was derived from the Supply Chain Council s Supply-Chain Operations Reference (SCC SCOR) Model, which is more generic and more oriented toward achieving a competitive advantage in business.

  20. Electron Transfer Chain Catalysis

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    @@ Electron-transfer chain (ETC) catalysis belongs to the family of chain reactions where the electron is the catalyst. The ETC mechanism could be initiated by chemical activation, electrochemistry, or photolysis. If this pathway is applied to the preparation of organometallic complexes, it utilizes the greatly enhanced reactivity of organometallic 17e and 19e radicals. The chemical propagation is followed by the cross electron-transfer while the electron-transfer step is also followed by the chemical propagation, creating a loop in which reactants are facilely transformed into products. Interestingly the overall reaction is without any net redox change.

  1. Electron Transfer Chain Catalysis

    Institute of Scientific and Technical Information of China (English)

    LIU; LingKang

    2001-01-01

    Electron-transfer chain (ETC) catalysis belongs to the family of chain reactions where the electron is the catalyst. The ETC mechanism could be initiated by chemical activation, electrochemistry, or photolysis. If this pathway is applied to the preparation of organometallic complexes, it utilizes the greatly enhanced reactivity of organometallic 17e and 19e radicals. The chemical propagation is followed by the cross electron-transfer while the electron-transfer step is also followed by the chemical propagation, creating a loop in which reactants are facilely transformed into products. Interestingly the overall reaction is without any net redox change.  ……

  2. METRODOS: Meteorological preprocessor chain

    DEFF Research Database (Denmark)

    Astrup, P.; Mikkelsen, T.; Deme, S.

    2001-01-01

    The METRODOS meteorological preprocessor chain combines measured tower data and coarse grid numerical weather prediction (NWP) data with local scale flow models and similarity scaling to give high resolution approximations of the meteorological situation. Based on available wind velocity...... - heat flux related measurement, e.g. a temperature gradient, are used to give local values of friction velocity and Monin-Obukhov length plus an estimate of the mixing height. The METRODOS meteorological preprocessor chain is an integral part of the RODOS - Real Time On Line Decision Support - program...

  3. Modelling the coal chain

    Energy Technology Data Exchange (ETDEWEB)

    Gertenbach, J.-D.; Varendorff, R. von [Knowledge Based Engineering, Sandton (South Africa)

    1999-03-01

    Managing the supply chain in an integrated coal operation involves many operation and control options often too complex for the human mind to comprehend and react to. By integrating all the knowledge of a supply chain into an expert system, both off-line and on-line real time decisions are possible. Knowledge Based Engineering based in South Africa, has gained valuable experience in modelling such mining operations. The article discusses the methodologies that the company has implemented. KBE uses Gensym`s G2 Real Time Expert System as the foundation of the system and the knowledge base is developed modularly.

  4. Integrated supply chain risk management

    Directory of Open Access Journals (Sweden)

    Riaan Bredell

    2007-11-01

    Full Text Available Integrated supply chain risk management (ISCRM has become indispensable to the theory and practice of supply chain management. The economic and political realities of the modern world require not only a different approach to supply chain management, but also bold steps to secure supply chain performance and sustainable wealth creation. Integrated supply chain risk management provides supply chain organisations with a level of insight into their supply chains yet to be achieved. If correctly applied, this process may optimise management decision-making and assist in the protection and enhancement of shareholder value.

  5. Thrombin inhibitor design.

    Science.gov (United States)

    Sanderson, P E; Naylor-Olsen, A M

    1998-08-01

    Recently, iv formulated direct thrombin inhibitors have been shown to be safe and efficacious alternatives to heparin. These results have fueled the hopes for an orally active compound. Such a compound could be a significant advance over warfarin if it had predictable pharmacokinetics and a duration of action sufficient for once or twice a day dosing. In order to develop an orally active compound which meets these criteria, the deficiencies of the prototype inhibitor efegatran have had to be addressed. First, using a combination of structure based design and empirical structure optimization, more selective compounds have been identified by modifying the P1 group or by incorporating different peptidomimetic P2/P3 scaffolds. Secondly, this optimization has resulted in the development of potent and selective non-covalent inhibitors, thus bypassing the liabilities of the serine trap. Thirdly, oral bioavailability has been achieved while maintaining selectivity and efficacy through the incorporation of progressively less basic P1 groups. The duration of action of these compounds remains to be optimized. Other advances in thrombin inhibitor design have included the development of uncharged P1 groups and the discovery of two non-peptide templates.

  6. ACE inhibitors and proteinuria

    NARCIS (Netherlands)

    Gansevoort, RT; deZeeuw, D; deJong, PE

    1996-01-01

    This review discusses the clinical consequences of urinary protein loss and the effects of inhibitors of the angiotensin converting enzyme (ACE) on this clinical finding. Proteinuria appears to be an important risk factor for renal function deterioration and for cardiovascular mortality. ACE inhibit

  7. Transglutaminase inhibitor from milk

    NARCIS (Netherlands)

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

    2003-01-01

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

  8. Inhibitors of histone demethylases

    DEFF Research Database (Denmark)

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

    2011-01-01

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

  9. Inhibitors of histone deacetylase

    DEFF Research Database (Denmark)

    2015-01-01

    The present invention relates to compounds of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein X1, X2, X3, X4, X5, W1, W2, W3, and W4 are as described. The present invention relates generally to inhibitors of histone deacetylase and to methods...

  10. Independent sets in chain cacti

    OpenAIRE

    Sedlar, Jelena

    2011-01-01

    In this paper chain cacti are considered. First, for two specific classes of chain cacti (orto-chains and meta-chains of cycles with h vertices) the recurrence relation for independence polynomial is derived. That recurrence relation is then used in deriving explicit expressions for independence number and number of maximum independent sets for such chains. Also, the recurrence relation for total number of independent sets for such graphs is derived. Finaly, the proof is provided that orto-ch...

  11. Standard handbook of chains chains for power transmission and material handling

    CERN Document Server

    Chain Association, American

    2005-01-01

    A BRIEF HISTORY OF THE DEVELOPMENT OF CHAINEarly DevelopmentsCog ChainCast Detachable ChainCast Pintle ChainPrecision Roller ChainEngineering Steel ChainSilent ChainFlat-Top ChainTerminologyA CHAIN OVERVIEW: USES AND ADVANTAGESGeneralTypes of ChainScope of Chains CoveredStyles and Forms of ChainsStraight and Offset Link ChainsChains With and Without RollersUses of ChainStandard Chains and Their UsesThe Advantages of Chains in ApplicationsAdvantages of Roller Chains in DrivesAdvantages of Silent Chain Drives

  12. Development Value Chains meet Business Supply Chains : The concept of Global Value Chains unraveled

    NARCIS (Netherlands)

    S. Drost (Sarah); J.C.A.C. van Wijk (Jeroen); S. Vellema (Sietze)

    2011-01-01

    textabstractValue chain promotion is considered a key element of private sector development strategies and pro-poor growth. However, (value) chain concepts are rather complex and unclear. This paper unravels the concept of global value chains and studies the diversity of key value chain-related (sup

  13. Nodal-chain metals

    Science.gov (United States)

    Bzdušek, Tomáš; Wu, Quansheng; Rüegg, Andreas; Sigrist, Manfred; Soluyanov, Alexey A.

    2016-10-01

    The band theory of solids is arguably the most successful theory of condensed-matter physics, providing a description of the electronic energy levels in various materials. Electronic wavefunctions obtained from the band theory enable a topological characterization of metals for which the electronic spectrum may host robust, topologically protected, fermionic quasiparticles. Many of these quasiparticles are analogues of the elementary particles of the Standard Model, but others do not have a counterpart in relativistic high-energy theories. A complete list of possible quasiparticles in solids is lacking, even in the non-interacting case. Here we describe the possible existence of a hitherto unrecognized type of fermionic excitation in metals. This excitation forms a nodal chain—a chain of connected loops in momentum space—along which conduction and valence bands touch. We prove that the nodal chain is topologically distinct from previously reported excitations. We discuss the symmetry requirements for the appearance of this excitation and predict that it is realized in an existing material, iridium tetrafluoride (IrF4), as well as in other compounds of this class of materials. Using IrF4 as an example, we provide a discussion of the topological surface states associated with the nodal chain. We argue that the presence of the nodal-chain fermions will result in anomalous magnetotransport properties, distinct from those of materials exhibiting previously known excitations.

  14. CHAINE DES ROTISSEUR @ HILTON

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    The annual gala dinner of Chaine des Rotisseurs was hosted by Hilton Beijing. The “Ballet Dinner” - a great creation for both art and fine dining lovers was taken place in varies places within the hotel, including hotel lobby, 3rd floor and lobby lounge.

  15. Exploration Supply Chain Simulation

    Science.gov (United States)

    2008-01-01

    The Exploration Supply Chain Simulation project was chartered by the NASA Exploration Systems Mission Directorate to develop a software tool, with proper data, to quantitatively analyze supply chains for future program planning. This tool is a discrete-event simulation that uses the basic supply chain concepts of planning, sourcing, making, delivering, and returning. This supply chain perspective is combined with other discrete or continuous simulation factors. Discrete resource events (such as launch or delivery reviews) are represented as organizational functional units. Continuous resources (such as civil service or contractor program functions) are defined as enabling functional units. Concepts of fixed and variable costs are included in the model to allow the discrete events to interact with cost calculations. The definition file is intrinsic to the model, but a blank start can be initiated at any time. The current definition file is an Orion Ares I crew launch vehicle. Parameters stretch from Kennedy Space Center across and into other program entities (Michaud Assembly Facility, Aliant Techsystems, Stennis Space Center, Johnson Space Center, etc.) though these will only gain detail as the file continues to evolve. The Orion Ares I file definition in the tool continues to evolve, and analysis from this tool is expected in 2008. This is the first application of such business-driven modeling to a NASA/government-- aerospace contractor endeavor.

  16. Innovation in Supply Chains

    DEFF Research Database (Denmark)

    Maier, Maximilian; Korbel, Jakob; Brem, Alexander

    2015-01-01

    . Moreover, along with the fourth industrial revolution – industry 4.0 – new technologies such as cyber physical systems are fast gaining popularity. Hence, based on the analysis of relevant literature, we further develop the supply chain committee model, developed by Kaluza et al. (2003) to demonstrate how...

  17. Supply chain reliability modelling

    Directory of Open Access Journals (Sweden)

    Eugen Zaitsev

    2012-03-01

    Full Text Available Background: Today it is virtually impossible to operate alone on the international level in the logistics business. This promotes the establishment and development of new integrated business entities - logistic operators. However, such cooperation within a supply chain creates also many problems related to the supply chain reliability as well as the optimization of the supplies planning. The aim of this paper was to develop and formulate the mathematical model and algorithms to find the optimum plan of supplies by using economic criterion and the model for the probability evaluating of non-failure operation of supply chain. Methods: The mathematical model and algorithms to find the optimum plan of supplies were developed and formulated by using economic criterion and the model for the probability evaluating of non-failure operation of supply chain. Results and conclusions: The problem of ensuring failure-free performance of goods supply channel analyzed in the paper is characteristic of distributed network systems that make active use of business process outsourcing technologies. The complex planning problem occurring in such systems that requires taking into account the consumer's requirements for failure-free performance in terms of supply volumes and correctness can be reduced to a relatively simple linear programming problem through logical analysis of the structures. The sequence of the operations, which should be taken into account during the process of the supply planning with the supplier's functional reliability, was presented.

  18. Decreased Pasteur effect in platelets of aged individuals.

    Science.gov (United States)

    D'Aurelio, M; Merlo Pich, M; Catani, L; Sgarbi, G L; Bovina, C; Formiggini, G; Parenti Castelli, G; Baum, H; Tura, S; Lenaz, G

    2001-06-01

    We have investigated the mitochondrial energy state in human platelets of young (19-30 years old) and aged individuals (65-87 years old) exploiting the Pasteur effect, i.e. stimulation of lactate production by incubation of the purified platelets with the mitochondrial respiratory chain inhibitor, antimycin A. This assay allows the determination of mitochondrial function with respect to glycolysis, and the ratio of mitochondrial adenosine triphosphate (ATP) to glycolytic ATP. A significant increase of basal, non-stimulated lactate production and decrease of the stimulation by antimycin A were observed in the older individuals, suggesting that the impairment of oxidative phosphorylation detectable in post-mitotic tissues of aged individuals can be observed also in easily collectable blood cells.

  19. A Bacterial Cell Shape-Determining Inhibitor.

    Science.gov (United States)

    Liu, Yanjie; Frirdich, Emilisa; Taylor, Jennifer A; Chan, Anson C K; Blair, Kris M; Vermeulen, Jenny; Ha, Reuben; Murphy, Michael E P; Salama, Nina R; Gaynor, Erin C; Tanner, Martin E

    2016-04-15

    Helicobacter pylori and Campylobacter jejuni are human pathogens and causative agents of gastric ulcers/cancer and gastroenteritis, respectively. Recent studies have uncovered a series of proteases that are responsible for maintaining the helical shape of these organisms. The H. pylori metalloprotease Csd4 and its C. jejuni homologue Pgp1 cleave the amide bond between meso-diaminopimelate and iso-d-glutamic acid in truncated peptidoglycan side chains. Deletion of either csd4 or pgp1 results in bacteria with a straight rod phenotype, a reduced ability to move in viscous media, and reduced pathogenicity. In this work, a phosphinic acid-based pseudodipeptide inhibitor was designed to act as a tetrahedral intermediate analog against the Csd4 enzyme. The phosphinic acid was shown to inhibit the cleavage of the alternate substrate, Ac-l-Ala-iso-d-Glu-meso-Dap, with a Ki value of 1.5 μM. Structural analysis of the Csd4-inhibitor complex shows that the phosphinic acid displaces the zinc-bound water and chelates the metal in a bidentate fashion. The phosphinate oxygens also interact with the key acid/base residue, Glu222, and the oxyanion-stabilizing residue, Arg86. The results are consistent with the "promoted-water pathway" mechanism for carboxypeptidase A catalysis. Studies on cultured bacteria showed that the inhibitor causes significant cell straightening when incubated with H. pylori at millimolar concentrations. A diminished, yet observable, effect on the morphology of C. jejuni was also apparent. Cell straightening was more pronounced with an acapsular C. jejuni mutant strain compared to the wild type, suggesting that the capsule impaired inhibitor accessibility. These studies demonstrate that a highly polar compound is capable of crossing the outer membrane and altering cell shape, presumably by inhibiting cell shape determinant proteases. Peptidoglycan proteases acting as cell shape determinants represent novel targets for the development of antimicrobials

  20. The binding mechanism of a peptidic cyclic serine protease inhibitor

    DEFF Research Database (Denmark)

    Jiang, Longguang; Svane, Anna S P; Sørensen, Hans Peter

    2011-01-01

    Serine proteases are classical objects for studies of catalytic and inhibitory mechanisms as well as interesting as therapeutic targets. Since small-molecule serine protease inhibitors generally suffer from specificity problems, peptidic inhibitors, isolated from phage-displayed peptide libraries...... inhibitory mechanism and an unusually high specificity. Using a number of modified variants of upain-1, we characterised the upain-1-urokinase-type plasminogen activator complex using X-ray crystal structure analysis, determined a model of the peptide in solution by NMR spectroscopy, and analysed binding...... kinetics and thermodynamics by surface plasmon resonance and isothermal titration calorimetry. We found that upain-1 changes both main-chain conformation and side-chain orientations as it binds to the protease, in particular its Trp3 residue and the surrounding backbone. The properties of upain-1...

  1. Benzoylurea Chitin Synthesis Inhibitors.

    Science.gov (United States)

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

    2015-08-12

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

  2. The design of supply chains

    DEFF Research Database (Denmark)

    Bøge Sørensen, Lars

    2004-01-01

    Keywords Supply Chain Management, Supply Chain Design, Literature studyAbstract Argues stability is a design objective for supply chain design alongside cost, leadtime and responsiveness. Performs an extensive literature study on supply chain design,identifies methods, theories and objectives...... in the existing literature. Describes the conceptexternal specificity and how it's used to design supply chains. Using the concept upstream,archetypes of risk minimal and maximal design are identified. Downstream the conceptdescribes two viable scenarios, one minimizing the impact, the other minimizing...... theprobability of (intended) departure of a supply chain partner. Finally, principles for supplychain design are described and managerial outlined....

  3. Decision-Making for Supply Chain Integration Supply Chain Integration

    CERN Document Server

    Lettice, Fiona; Durowoju, Olatunde

    2012-01-01

    Effective supply chain integration, and the tight co-ordination it creates, is an essential pre-requisite for successful supply chain management.  Decision-Making for Supply Chain Integration is a practical reference on recent research in the area of supply chain integration focusing on distributed decision-making problems. Recent applications of various decision-making tools for integrating supply chains are covered including chapters focusing on: •Supplier selection, pricing strategy and inventory decisions in multi-level supply chains, •RFID-enabled distributed decision-making, •Operational risk issues and time-critical decision-making for sensitive logistics nodes, Modelling end to end processes to improve supply chain integration, and •Integrated systems to improve service delivery and optimize resource use. Decision-Making for Supply Chain Integration provides an insight into the tools and methodologies of this field with support from real-life case studies demonstrating successful application ...

  4. Sequencing of aromatase inhibitors

    OpenAIRE

    2005-01-01

    Since the development of the third-generation aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, these agents have been the subject of intensive research to determine their optimal use in advanced breast cancer. Not only have they replaced progestins in second-line therapy and challenged the role of tamoxifen in first-line, but there is also evidence for a lack of cross-resistance between the steroidal and nonsteroidal AIs, meaning that they may be used in sequence to obtain p...

  5. Update on Aromatase Inhibitors

    Directory of Open Access Journals (Sweden)

    Seifert-Klauss V

    2015-01-01

    Full Text Available Aromatase inhibitors (AI block the last phase of estrogen production in many types of tissues which express the enzym aromatase, among them muscle, liver, adrenal, brain and fat. The enzyme catalyzes the last step of the biosynthesis of the estrogens, i. e. the aromatisation of testosterone to estradiol and of androstendion to estrone. Aromatase is localized in the membrane of the endoplasmatic reticulum and is also produced in the placenta and the gonads. Mutations in the gene CYP19A1, which codes for aromatase, can lead either to lack or excess of aromatase. Gene polymorphisms also influence the amount of bioavailable estrogen and bone density.br Indications: AI are approved for the treatment of postmenopausal women with hormone receptor positive breast cancer, both in the adjuvant setting as well as after recurrence and in progressive disease. In premenopausal and in perimenopausal women AI cause an increased sensitivity of the ovaries to follicle stimulating hormone (FSH and can thereby lead to a boosted estrogen answer – this effect is particularly pronounced in early perimenopausal women – so that these situations demand a combination with GnRH-analogue if AI treatment is to be initiated. Alternatively, tamoxifene may be used in premenopausal patients, with or without GnRH analogues. Treatment of premenopausal patients with hormone receptor positive breast cancer with aromatase inhibiting therapy alone constitutes an absolute contraindication. Aromatase inhibitors do not lead to estrogen receptor downregulation or block the receptor such as tamoxifene. An exceptional application is the application in reproductive medicine in women who do not have hormone receptor positive breast cancer: because of the higher sensitivity induced by AI-co-therapy, FSH-doses and -costs for assisted reproduction are reduced, and ovarian hyperstimulation syndrome (OHSS may be avoided. For premenopausal diseases which are said to be positively affected by

  6. Towards Intelligent Supply Chains

    DEFF Research Database (Denmark)

    Siurdyban, Artur; Møller, Charles

    2012-01-01

    applied to the context of organizational processes can increase the success rate of business operations. The framework is created using a set of theoretical based constructs grounded in a discussion across several streams of research including psychology, pedagogy, artificial intelligence, learning...... of deploying inapt operations leading to deterioration of profits. To address this problem, we propose a unified business process design framework based on the paradigm of intelligence. Intelligence allows humans and human-designed systems cope with environmental volatility, and we argue that its principles......, business process management and supply chain management. It outlines a number of system tasks combined in four integrated management perspectives: build, execute, grow and innovate, put forward as business process design propositions for Intelligent Supply Chains....

  7. Perioperative supply chain management.

    Science.gov (United States)

    Feistritzer, N R; Keck, B R

    2000-09-01

    Faced with declining revenues and increasing operating expenses, hospitals are evaluating numerous mechanisms designed to reduce costs while simultaneously maintaining quality care. Many facilities have targeted initial cost reduction efforts in the reduction of labor expenses. Once labor expenses have been "right sized," facilities have continued to focus on service delivery improvements by the optimization of the "supply chain" process. This report presents a case study of the efforts of Vanderbilt University Medical Center in the redesign of its supply chain management process in the department of Perioperative Services. Utilizing a multidisciplinary project management structure, 3 work teams were established to complete the redesign process. To date, the project has reduced costs by $2.3 million and enhanced quality patient care by enhancing the delivery of appropriate clinical supplies during the perioperative experience.

  8. Volumes of chain links

    CERN Document Server

    Kaiser, James; Rollins, Clint

    2011-01-01

    Agol has conjectured that minimally twisted n-chain links are the smallest volume hyperbolic manifolds with n cusps, for n at most 10. In his thesis, Venzke mentions that these cannot be smallest volume for n at least 11, but does not provide a proof. In this paper, we give a proof of Venzke's statement. The proof for n at least 60 is completely rigorous. The proof for n between 11 and 59 uses a computer calculation, and can be made rigorous for manifolds of small enough complexity, using methods of Moser and Milley. Finally, we prove that the n-chain link with 2m or 2m+1 half-twists cannot be the minimal volume hyperbolic manifold with n cusps, provided n is at least 60 or |m| is at least 8, and we give computational data indicating this remains true for smaller n and |m|.

  9. Extended linear chain compounds

    CERN Document Server

    Linear chain substances span a large cross section of contemporary chemistry ranging from covalent polymers, to organic charge transfer com­ plexes to nonstoichiometric transition metal coordination complexes. Their commonality, which coalesced intense interest in the theoretical and exper­ imental solid state physics/chemistry communities, was based on the obser­ vation that these inorganic and organic polymeric substrates exhibit striking metal-like electrical and optical properties. Exploitation and extension of these systems has led to the systematic study of both the chemistry and physics of highly and poorly conducting linear chain substances. To gain a salient understanding of these complex materials rich in anomalous aniso­ tropic electrical, optical, magnetic, and mechanical properties, the conver­ gence of diverse skills and talents was required. The constructive blending of traditionally segregated disciplines such as synthetic and physical organic, inorganic, and polymer chemistry, crystallog...

  10. The innovation value chain.

    Science.gov (United States)

    Hansen, Morten T; Birkinshaw, Julian

    2007-06-01

    The challenges of coming up with fresh ideas and realizing profits from them are different for every company. One firm may excel at finding good ideas but may have weak systems for bringing them to market. Another organization may have a terrific process for funding and rolling out new products and services but a shortage of concepts to develop. In this article, Hansen and Birkinshaw caution executives against using the latest and greatest innovation approaches and tools without understanding the unique deficiencies in their companies' innovation systems. They offer a framework for evaluating innovation performance: the innovation value chain. It comprises the three main phases of innovation (idea generation, conversion, and diffusion) as well as the critical activities performed during those phases (looking for ideas inside your unit; looking for them in other units; looking for them externally; selecting ideas; funding them; and promoting and spreading ideas companywide). Using this framework, managers get an end-to-end view of their innovation efforts. They can pinpoint their weakest links and tailor innovation best practices appropriately to strengthen those links. Companies typically succumb to one of three broad "weakest-link" scenarios. They are idea poor, conversion poor, or diffusion poor. The article looks at the ways smart companies - including Intuit, P&G, Sara Lee, Shell, and Siemens- modify the best innovation practices and apply them to address those organizations' individual needs and flaws. The authors warn that adopting the chain-based view of innovation requires new measures of what can be delivered by each link in the chain. The approach also entails new roles for employees "external scouts" and "internal evangelists," for example. Indeed, in their search for new hires, companies should seek out those candidates who can help address particular weaknesses in the innovation value chain.

  11. Monitoring Global Supply Chains

    OpenAIRE

    2014-01-01

    Firms reliant on supply chains to manufacture their goods risk reputational harm if the working conditions in those factories are revealed to be dangerous, illegal, or otherwise problematic. While firms are increasingly relying on private-sector "social auditors" to assess factory conditions, little had been known about the accuracy of those assessments. We analyzed nearly 17,000 code-of-conduct audits conducted at nearly 6,000 suppliers around the world. We found that audits yield fewer viol...

  12. Port supply chain integration : analyzing biofuel supply chains

    NARCIS (Netherlands)

    Stevens, Leonie C. E.; Vis, Iris F. A.

    2016-01-01

    This paper focuses on port supply chain integration to strengthen operational and business performance. We provide a structured and comprehensive method to enable port supply chain integration and demonstrate its applicability to the biofuel supply chain. We define the value proposition, role, activ

  13. Spin-labelled vacuolar-ATPase inhibitors in lipid membranes.

    Science.gov (United States)

    Dixon, Neil; Páli, Tibor; Kee, Terence P; Marsh, Derek

    2004-10-11

    Two spin-labelled derivatives of the 5-(2-indolyl)-2,4-pentadienoyl class of inhibitors of the vacuolar ATPase have been synthesised and their EPR properties characterised in phospholipid membranes. One spin-labelled inhibitor is the amide derivative of pentadienic acid and 4-amino-TEMPO (INDOL6), and the other is the 3-hydroxymethyl-PROXYL ester (INDOL5). The response of the EPR spectra to the chain-melting transition of dimyristoyl phosphatidylcholine (DMPC) bilayers demonstrates that both derivatives incorporate in phospholipid membranes. The axially anisotropic EPR spectra of INDOL6 in fluid DMPC membranes indicate that the indolyl-pentadienoyl inhibitors intercalate between the lipid chains, in the membrane. INDOL5, designed to possess additional internal segmental mobility, exhibits more nearly isotropic motion of the spin-label moiety in fluid membranes than does INDOL6. The EPR characteristics of INDOL5 are therefore well suited to detecting specific ligand-protein interactions. Progressive saturation EPR experiments with polar and hydrophobic relaxation agents (aqueous Ni2+ and oxygen) show that the nitroxide group is buried in the membrane, with the indole moiety providing the anchor at the membrane polar-apolar interface. Rates of spin-label reduction by externally added ascorbate confirm this assignment. These two spin-labelled derivatives provide complementary EPR probes of the lipid environment (INDOL6), and of ligand-protein interactions (INDOL5), for this class of V-ATPase inhibitor.

  14. Adjustable chain trees for proteins

    DEFF Research Database (Denmark)

    Winter, Pawel; Fonseca, Rasmus

    2012-01-01

    A chain tree is a data structure for changing protein conformations. It enables very fast detection of clashes and free energy potential calculations. A modified version of chain trees that adjust themselves to the changing conformations of folding proteins is introduced. This results in much...... tighter bounding volume hierarchies and therefore fewer intersection checks. Computational results indicate that the efficiency of the adjustable chain trees is significantly improved compared to the traditional chain trees....

  15. Supply chain dynamics in Asia

    OpenAIRE

    Banomyong, Ruth

    2010-01-01

    Supply chain management in Asia is a relatively novel topic but a key challenge for all Asian based manufacturers and traders when trying to integrate into the "global market". The purpose of the paper is to describe key supply chain issues faced in Asia. These issues are related to supply chain security that forces Asian firms to comply with numerous requirements as well as the importance of a properly managed supply chain in enhancing firms' competitiveness. The critical role played by Asia...

  16. Requirements of supply chain management in differentiating European pork chains.

    Science.gov (United States)

    Trienekens, Jacques; Wognum, Nel

    2013-11-01

    This paper summarizes results obtained by research into pork chain management in the EU Integrated Project Q-Porkchains. Changing demands for intrinsic and extrinsic quality attributes of pork products impact the way supply chain management should be organized from the farmer down to the consumer. The paper shows the importance of Quality Management Systems for integrating supply chains and enhancing consumer confidence. The paper also presents innovations in information system integration for aligning information exchange in the supply chain and logistics concepts based on innovative measurement technologies at the slaughterhouse stage. In the final section research challenges towards sustainable pork supply chains satisfying current consumer demands are presented.

  17. On chains of centered valuations

    Directory of Open Access Journals (Sweden)

    Rachid Chibloun

    2003-01-01

    Full Text Available We study chains of centered valuations of a domain A and chains of centered valuations of A [X1,…,Xn] corresponding to valuations of A. Finally, we make some applications to chains of valuations centered on the same ideal of A [X1,…,Xn] and extending the same valuation of A.

  18. Designing structural supply chain flexibility

    NARCIS (Netherlands)

    Mulinski, Ksawery Jan

    2012-01-01

    In a continuously changing business environment the role of supply chain flexibility is constantly increasing. A flexible supply chain can ensure survival in quickly changing market conditions as well as enable sustainable growth. This thesis explores the topic of supply chain flexibility with focus

  19. Profits in reverse? An examination of the decisive factors for reverse supply chain profitability

    DEFF Research Database (Denmark)

    Larsen, Samuel; Jacobsen, Peter

    2015-01-01

    Although the concept of the reverse supply chain (RSC) is not unknown in industry, an inhibitor for its successful use is low (or no) profitability. A research challenge is investigating ways to establish the RSC as a profit-creating center in the organization. This paper contributes to this chal......Although the concept of the reverse supply chain (RSC) is not unknown in industry, an inhibitor for its successful use is low (or no) profitability. A research challenge is investigating ways to establish the RSC as a profit-creating center in the organization. This paper contributes...

  20. Variable context Markov chains for HIV protease cleavage site prediction.

    Science.gov (United States)

    Oğul, Hasan

    2009-06-01

    Deciphering the knowledge of HIV protease specificity and developing computational tools for detecting its cleavage sites in protein polypeptide chain are very desirable for designing efficient and specific chemical inhibitors to prevent acquired immunodeficiency syndrome. In this study, we developed a generative model based on a generalization of variable order Markov chains (VOMC) for peptide sequences and adapted the model for prediction of their cleavability by certain proteases. The new method, called variable context Markov chains (VCMC), attempts to identify the context equivalence based on the evolutionary similarities between individual amino acids. It was applied for HIV-1 protease cleavage site prediction problem and shown to outperform existing methods in terms of prediction accuracy on a common dataset. In general, the method is a promising tool for prediction of cleavage sites of all proteases and encouraged to be used for any kind of peptide classification problem as well.

  1. An efficient protocol for isolation of inhibitor-free nucleic acids even from recalcitrant plants

    OpenAIRE

    2016-01-01

    For fast and easy isolation of inhibitor-free genomic DNA even from the toughest plant leaf samples, including those high in polyphenols and polysaccharides, a protocol has been developed. To prevent the solubility of polysaccharides in the DNA extract, high salt concentration (1.4 M) was used in the extraction buffer. Polyvinylpyrrolidone (PVP) was used for the removal of polyphenols as polymerase chain reaction (PCR) inhibitors. Proteins like various enzymes were degraded by proteinase K an...

  2. Radiology's value chain.

    Science.gov (United States)

    Enzmann, Dieter R

    2012-04-01

    A diagnostic radiology value chain is constructed to define its main components, all of which are vulnerable to change, because digitization has caused disaggregation of the chain. Some components afford opportunities to improve productivity, some add value, while some face outsourcing to lower labor cost and to information technology substitutes, raising commoditization risks. Digital image information, because it can be competitive at smaller economies of scale, allows faster, differential rates of technological innovation of components, initiating a centralization-to-decentralization technology trend. Digitization, having triggered disaggregation of radiology's professional service model, may soon usher in an information business model. This means moving from a mind-set of "reading images" to an orientation of creating and organizing information for greater accuracy, faster speed, and lower cost in medical decision making. Information businesses view value chain investments differently than do small professional services. In the former model, producing a better business product will extend image interpretation beyond a radiologist's personal fund of knowledge to encompass expanding external imaging databases. A follow-on expansion with integration of image and molecular information into a report will offer new value in medical decision making. Improved interpretation plus new integration will enrich and diversify radiology's key service products, the report and consultation. A more robust, information-rich report derived from a "systems" and "computational" radiology approach will be facilitated by a transition from a professional service to an information business. Under health care reform, radiology will transition its emphasis from volume to greater value. Radiology's future brightens with the adoption of a philosophy of offering information rather than "reads" for decision making. Staunchly defending the status quo via turf wars is unlikely to constitute a

  3. Supply Chain Costing

    DEFF Research Database (Denmark)

    Asmussen, Jesper Normann; Kristensen, Jesper; Wæhrens, Brian Vejrum

    2016-01-01

    Based Costing (ABC) på et forsyningskædeniveau – heri benævnt Supply Chain Costing (SCC). Udoverdefordelederfindesved ABCtilføjerSCCogså et økonomisk grundlag til det strategiske rationale, der ofte ligger bag opbygningen af virksomhedens forsyningskæde, og kan dermed medvirke til konkret....... Virksomhedens evne til at udarbejde relevantinformation fremstår derfor som en vigtig parameter, såfremt virksomheden skal forblive konkurrencedygtig i en stadig mere kompleks verden, hvor udviklingen foregår stadig hurtigere. Denne arbejdsboggiverindsigtidemuligheder,der eksisterer ved at anvende Activity...

  4. [Trophic chains in soil].

    Science.gov (United States)

    Goncharov, A A; Tiunov, A V

    2013-01-01

    Trophic links of soil animals are extensively diverse but also flexible. Moreover, feeding activity of large soil saprotrophs often cascades into a range of ecosystem-level consequences via the ecological engineering. Better knowledge on the main sources of energy utilized by soil animals is needed for understanding functional structure of soil animal communities and their participation in the global carbon cycling. Using published and original data, we consider the relative importance of dead organic matter and saprotrophic microorganisms as a basal energy source in the detritus-based food chains, the feeding of endogeic macrofauna on the stabilized soil organic matter, and the role of recent photosynthate in the energy budget of soil communities. Soil food webs are spatially and functionally compartmentalized, though the separation of food chains into bacteria- and fungi-based channels seems to be an over-simplification. The regulation of the litter decomposition rates via top-down trophic interactions across more than one trophic level is only partly supported by experimental data, but mobile litter-dwelling predators play a crucial role in integrating local food webs within and across neighboring ecosystems.

  5. Inhibitors of lysosomal cysteine proteases

    Directory of Open Access Journals (Sweden)

    Lyanna O. L.

    2011-04-01

    Full Text Available The review is devoted to the inhibitors of cysteine proteinases which are believed to be very important in many biochemical processes of living organisms. They participate in the development and progression of numerous diseases that involve abnormal protein turnover. One of the main regulators of these proteinases is their specific inhibitors: cystatins. The aim of this review was to present current knowledge about endogenous inhibitors of lysosomal cysteine proteases and their synthetic analogs.

  6. ACE INHIBITORS: A COMPREHENSIVE REVIEW

    Directory of Open Access Journals (Sweden)

    Pradeep Kumar Arora* and Ashish Chauhan

    2013-02-01

    Full Text Available Hypertension is a chronic increase in blood pressure, characterized as primary and secondary hypertension. The disorder is associated with various risk factors like obesity, diabetes, age, lack of exercise etc. Hypertension is being treated since ancient times by Ayurvedic, Chinese and Unani medicine. Now various allopathic drugs are available which include diuretics, calcium channel blockers, α-blockers, β-blockers, vasodilators, central sympatholytics and ACE-inhibitors. Non-pharmacological treatments include weight reduction, dietary sodium reduction, increased potassium intake and reduction in alcohol consumption. ACE-inhibitors are widely used in the treatment of hypertension by inhibiting the angiotensin converting enzyme responsible for the conversion of angiotensin I to angiotensin II (responsible for vasoconstriction. Various structure activity relationship studies led to the synthesis of ACE-inhibitors, some are under clinical development. This comprehensive review gives various guidelines on classification of hypertension, hypertension therapy including ancient, pharmacological, non-pharmacological therapies, pharmacoeconomics, historical perspectives of ACE, renin, renin angiotensin system (circulating vs local RAS, mechanism of ACE inhibitors, and development of ACE inhibitors. Review also emphasizes on the recent advancements on ACE inhibitors including drugs in clinical trials, computational studies on ACE-inhibitors, peptidomimetics, dual, natural, multi-functional ACE inhibitors, and conformational requirements for ACE-inhibitors.

  7. Polyphenol Compound as a Transcription Factor Inhibitor

    Directory of Open Access Journals (Sweden)

    Seyeon Park

    2015-10-01

    Full Text Available A target-based approach has been used to develop novel drugs in many therapeutic fields. In the final stage of intracellular signaling, transcription factor–DNA interactions are central to most biological processes and therefore represent a large and important class of targets for human therapeutics. Thus, we focused on the idea that the disruption of protein dimers and cognate DNA complexes could impair the transcriptional activation and cell transformation regulated by these proteins. Historically, natural products have been regarded as providing the primary leading compounds capable of modulating protein–protein or protein-DNA interactions. Although their mechanism of action is not fully defined, polyphenols including flavonoids were found to act mostly as site-directed small molecule inhibitors on signaling. There are many reports in the literature of screening initiatives suggesting improved drugs that can modulate the transcription factor interactions responsible for disease. In this review, we focus on polyphenol compound inhibitors against dimeric forms of transcription factor components of intracellular signaling pathways (for instance, c-jun/c-fos (Activator Protein-1; AP-1, c-myc/max, Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB and β-catenin/T cell factor (Tcf.

  8. Polyketide chain length control by chain length factor.

    Science.gov (United States)

    Tang, Yi; Tsai, Shiou-Chuan; Khosla, Chaitan

    2003-10-22

    Bacterial aromatic polyketides are pharmacologically important natural products. A critical parameter that dictates product structure is the carbon chain length of the polyketide backbone. Systematic manipulation of polyketide chain length represents a major unmet challenge in natural product biosynthesis. Polyketide chain elongation is catalyzed by a heterodimeric ketosynthase. In contrast to homodimeric ketosynthases found in fatty acid synthases, the active site cysteine is absent from the one subunit of this heterodimer. The precise role of this catalytically silent subunit has been debated over the past decade. We demonstrate here that this subunit is the primary determinant of polyketide chain length, thereby validating its designation as chain length factor. Using structure-based mutagenesis, we identified key residues in the chain length factor that could be manipulated to convert an octaketide synthase into a decaketide synthase and vice versa. These results should lead to novel strategies for the engineered biosynthesis of hitherto unidentified polyketide scaffolds.

  9. Information in the supply chain: measuring supply chain performance

    OpenAIRE

    Bytheway, Andrew

    1995-01-01

    Information is one of many factors in the development of supply chain operations. It is a key factor in a number of new initiatives, such as: business process management. partnership development, efficient customer response, tighter integration of supply chain operations and outsourcing of ancillary operations. Improvement of the supply chain takes place at different levels: simple efficiency (the Improvement of existing processes), improved quality of service (the redesign of ...

  10. Doping of Semiconducting Atomic Chains

    Science.gov (United States)

    Toshishige, Yamada; Kutler, Paul (Technical Monitor)

    1997-01-01

    Due to the rapid progress in atom manipulation technology, atomic chain electronics would not be a dream, where foreign atoms are placed on a substrate to form a chain, and its electronic properties are designed by controlling the lattice constant d. It has been shown theoretically that a Si atomic chain is metallic regardless of d and that a Mg atomic chain is semiconducting or insulating with a band gap modified with d. For electronic applications, it is essential to establish a method to dope a semiconducting chain, which is to control the Fermi energy position without altering the original band structure. If we replace some of the chain atoms with dopant atoms randomly, the electrons will see random potential along the chain and will be localized strongly in space (Anderson localization). However, if we replace periodically, although the electrons can spread over the chain, there will generally appear new bands and band gaps reflecting the new periodicity of dopant atoms. This will change the original band structure significantly. In order to overcome this dilemma, we may place a dopant atom beside the chain at every N lattice periods (N > 1). Because of the periodic arrangement of dopant atoms, we can avoid the unwanted Anderson localization. Moreover, since the dopant atoms do not constitute the chain, the overlap interaction between them is minimized, and the band structure modification can be made smallest. Some tight-binding results will be discussed to demonstrate the present idea.

  11. Dynamics of Polymer Chains.

    Science.gov (United States)

    Hong, Tzay-Ming

    A major objective of this research is to establish at a more fundamental level some of the qualitative or semi-quantitative treatments in use at the present time, such as the Doi-Edwards tube picture, the switch from non -ideal to ideal behavior, and dynamical aspects of the reptation model. The main topics are: (I) An attempt was made to determine the order of magnitude of the elastic time interval of a viscoelastic polymer melt, defining it as the reciprocal of the average rate at which the total entanglement (clockwise plus anticlockwise) passes through zero due to thermal agitation. We calculated the case of a free chain winding about a straight rod both in friction-independent regime and in high friction regime. (II) By successively coarse -graining and rescaling the monomer-monomer interaction (using a modified Wilson recursion formula) we found that the interaction is driven to a very strong but short-ranged one. This verifies the observation that polymers in dilute solutions tend to curl up and behave like hard spheres. (III) We studied the case of chemical equilibrium of i-mers with their nucleating monomers and on the basis of a Flory-Huggins -type mean field theory find that in the dilute limit the swelling of the i-mers takes on the traditional N ^{3over5} law only for sufficiently small monomer chemical potential. When that potential is large enough, then, assuming a Flory law of chain propagation, the law seems to become N^{1over3 }. This is distinct from the problem of changeover from dilute to semidilute polymer system, which we also studied by imposing total polymer density as a constraint equation. (IV) Another item examined concerns the form of the space curve that a very long polymer must assume in order to minimize its free energy (we found that a family of helices with a definite functional relation between pitch and radius renders the free energy stationary). Because a chain is a one-dimensional object, this does not mean that helical shapes

  12. Energetic, Structural, and Antimicrobial Analyses of [beta]-Lactam Side Chain Recognition by [beta]-Lactamases

    Energy Technology Data Exchange (ETDEWEB)

    Caselli, E.; Powers, R.A.; Blaszczak, L.C.; Wu, C.Y.E.; Prati, F.; Shoichet, B.K. (NWU)

    2010-03-05

    Penicillins and cephalosporins are among the most widely used and successful antibiotics. The emergence of resistance to these {beta}-lactams, most often through bacterial expression of {beta}-lactamases, threatens public health. To understand how {beta}-lactamases recognize their substrates, it would be helpful to know their binding energies. Unfortunately, these have been difficult to measure because {beta}-lactams form covalent adducts with {beta}-lactamases. This has complicated functional analyses and inhibitor design. To investigate the contribution to interaction energy of the key amide (R1) side chain of {beta}-lactam antibiotics, eight acylglycineboronic acids that bear the side chains of characteristic penicillins and cephalosporins, as well as four other analogs, were synthesized. These transition-state analogs form reversible adducts with serine {beta}-lactamases. Therefore, binding energies can be calculated directly from K{sub i} values. The K{sub i} values measured span four orders of magnitude against the Group I {beta}-lactamase AmpC and three orders of magnitude against the Group II {beta}-lactamase TEM-1. The acylglycineboronic acids have K{sub i} values as low as 20 nM against AmpC and as low as 390 nM against TEM-1. The inhibitors showed little activity against serine proteases, such as chymotrypsin. R1 side chains characteristic of {beta}-lactam inhibitors did not have better affinity for AmpC than did side chains characteristic of {beta}-lactam substrates. Two of the inhibitors reversed the resistance of pathogenic bacteria to {beta}-lactams in cell culture. Structures of two inhibitors in their complexes with AmpC were determined by X-ray crystallography to 1.90 {angstrom} and 1.75 {angstrom} resolution; these structures suggest interactions that are important to the affinity of the inhibitors. Acylglycineboronic acids allow us to begin to dissect interaction energies between {beta}-lactam side chains and {beta}-lactamases. Surprisingly

  13. Role of myosin light chain and myosin light chain kinase in advanced glycation end product-induced endothelial hyperpermeability in vitro and in vivo.

    Science.gov (United States)

    Wu, Fan; Guo, Xiaohua; Xu, Jing; Wang, Weiju; Li, Bingling; Huang, Qiaobing; Su, Lei; Xu, Qiulin

    2016-03-01

    We have previously reported that advanced glycation end products activated Rho-associated protein kinase and p38 mitogen-activated protein kinase, causing endothelial hyperpermeability. However, the mechanisms involved were not fully clarified. Here, we explored the role of myosin light chain kinase in advanced glycation end product-induced endothelial hyperpermeability. Myosin light chain phosphorylation significantly increased by advanced glycation end products in endothelial cells in a time- and dose-dependent manner, indicating that myosin light chain phosphorylation is involved in the advanced glycation end product pathway. Advanced glycation end products also induced myosin phosphatase-targeting subunit 1 phosphorylation, and small interfering RNA knockdown of the receptor for advanced glycation end products, or blocking myosin light chain kinase with its inhibitor, ML-7, or small interfering RNA abated advanced glycation end product-induced myosin light chain phosphorylation. Advanced glycation end product-induced F-actin rearrangement and endothelial hyperpermeability were also diminished by inhibition of receptor for advanced glycation end product or myosin light chain kinase signalling. Moreover, inhibiting myosin light chain kinase with ML-7 or blocking receptor for advanced glycation end product with its neutralizing antibody attenuated advanced glycation end product-induced microvascular hyperpermeability. Our findings suggest a novel role for myosin light chain and myosin light chain kinase in advanced glycation end product-induced endothelial hyperpermeability.

  14. Resistance mechanism of human immunodeficiency virus type-1 protease to inhibitors: A molecular dynamic approach

    Directory of Open Access Journals (Sweden)

    Mohammad Reza Dayer

    2014-12-01

    Full Text Available Human immunodeficiency virus type 1 (HIV-1 protease inhibitors comprise an important class of drugs used in HIV treatments. However, mutations of protease genes accelerated by low fidelity of reverse transcriptase yield drug resistant mutants of reduced affinities for the inhibitors. This problem is considered to be a serious barrier against HIV treatment for the foreseeable future. In this study, molecular dynamic simulation method was used to examine the combinational and additive effects of all known mutations involved in drug resistance against FDA approved inhibitors. Results showed that drug resistant mutations are not randomly distributed along the protease sequence; instead, they are localized on flexible or hot points of the protein chain. Substitution of more hydrophobic residues in flexible points of protease chains tends to increase the folding, lower the flexibility and decrease the active site area of the protease. The reduced affinities of HIV-1 protease for inhibitors seemed to be due to substantial decrease in the size of the active site and flap mobility. A correlation was found between the binding energy of inhibitors and their affinities for each mutant suggesting the distortion of the active site geometry in drug resistance by preventing effective fitting of inhibitors into the enzymes' active site. To overcome the problem of drug resistance of HIV-1 protease, designing inhibitors of variable functional groups and configurations is proposed.

  15. Quivers via anomaly chains

    Energy Technology Data Exchange (ETDEWEB)

    Casero, Roberto [Dipartimento di Fisica, Universita di Milano-Bicocca, Piazza della Scienza, 3, 20126 Milan (Italy)]. E-mail: roberto.casero@mib.infn.it; Trincherini, Enrico [Dipartimento di Fisica, Universita di Milano-Bicocca, Piazza della Scienza, 3, 20126 Milan (Italy)

    2003-09-01

    We study quivers in the context of matrix models. We introduce chains of generalized Konishi anomalies to write the quadratic and cubic equations that constrain the resolvents of general affine A-circumflex{sub n-1} and non-affine A{sub n} quiver gauge theories, and give a procedure to calculate all higher-order relations. For these theories we also evaluate, as functions of the resolvents, VEV's of chiral operators with two and four bi-fundamental insertions. As an example of the general procedure we explicitly consider the two simplest quivers A{sub 2} and A-circumflex{sub 1}, obtaining in the first case a cubic algebraic curve, and for the affine theory the same equation as that of U(N) theories with adjoint matter, successfully reproducing the RG cascade result. (author)

  16. Quivers via anomaly chains

    CERN Document Server

    Casero, R; Casero, Roberto; Trincherini, Enrico

    2003-01-01

    We study quivers in the context of matrix models. We introduce chains of generalized Konishi anomalies to write the quadratic and cubic equations that constrain the resolvents of general affine and non-affine quiver gauge theories, and give a procedure to calculate all higher-order relations. For these theories we also evaluate, as functions of the resolvents, VEV's of chiral operators with two and four bifundamental insertions. As an example of the general procedure we explicitly consider the two simplest quivers A2 and A1(affine), obtaining in the first case a cubic algebraic curve, and for the affine theory the same equation as that of U(N) theories with adjoint matter, successfully reproducing the RG cascade result.

  17. NNSA TRITIUM SUPPLY CHAIN

    Energy Technology Data Exchange (ETDEWEB)

    Wyrick, Steven [Savannah River National Laboratory, Aiken, SC, USA; Cordaro, Joseph [Savannah River National Laboratory, Aiken, SC, USA; Founds, Nanette [National Nuclear Security Administration, Albuquerque, NM, USA; Chambellan, Curtis [National Nuclear Security Administration, Albuquerque, NM, USA

    2013-08-21

    Savannah River Site plays a critical role in the Tritium Production Supply Chain for the National Nuclear Security Administration (NNSA). The entire process includes: • Production of Tritium Producing Burnable Absorber Rods (TPBARs) at the Westinghouse WesDyne Nuclear Fuels Plant in Columbia, South Carolina • Production of unobligated Low Enriched Uranium (LEU) at the United States Enrichment Corporation (USEC) in Portsmouth, Ohio • Irradiation of TPBARs with the LEU at the Tennessee Valley Authority (TVA) Watts Bar Reactor • Extraction of tritium from the irradiated TPBARs at the Tritium Extraction Facility (TEF) at Savannah River Site • Processing the tritium at the Savannah River Site, which includes removal of nonhydrogen species and separation of the hydrogen isotopes of protium, deuterium and tritium.

  18. PHONONS IN POLYACENIC CHAINS

    Institute of Scientific and Technical Information of China (English)

    O. Rafil; M. Tamine; B. Bourahla; R. Tigrine; S. Amoudache; A. Khater

    2006-01-01

    We have theoretically resolved phonon excitations in quasi-two-dimensional organic crystals of polyacenic semiconductor material which may be obtained by the pyrolytic treatment of phenol-formaldehyde resin. A model for studying the dynamical properties using three polyacene chains is proposed with the aim to present the vibrational properties of this structure. It employs the formalism of solid states in two dimensions which admit phonons. A simulation process of the two-dimensional lattice structure shows that elastic waves may explain the existence of vibrational modes in the frequency range 100-400 cm-1. The presence of acoustic and optical like phonons is discussed in terms of the elastic force constants. A hyperfine resonance structure is obtained. It allows the analysis of the dynamical evolution in thin films of polyacene. It is found that the behavior of the phonon density of states exhibits resonance between modes in the structure.

  19. Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

    OpenAIRE

    Čolović, Mirjana B.; Krstić, Danijela Z; Lazarević-Pašti, Tamara D; Bondžić, Aleksandra M; Vasić, Vesna M

    2013-01-01

    Acetylcholinesterase is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways in the central and peripheral nervous systems. The enzyme inactivation, induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotinic and muscarinic receptors, and disrupted neurotransmission. Hence, acetylcholinesterase inhibitors, interacting with the enzyme as their primary target, are appl...

  20. Chains, bombs, potrzebies and slugs

    Science.gov (United States)

    Jewess, Mike; McDowell, Alex; Maxfield, Stephen; Hunt, A. G.; Hicks, Bruce

    2010-03-01

    I read with pleasure Robert Crease's article on unusual units (February pp17-19). However, the article stated that an acre is 10×10 chains, when it is in fact 10×1 chains. Incidentally, a distance of 10 chains (220 yards) is known as a furlong, a word that suggests the length of a ploughed furrow and that is still used in horse-racing.

  1. DOS cones along atomic chains

    Science.gov (United States)

    Kwapiński, Tomasz

    2017-03-01

    The electron transport properties of a linear atomic chain are studied theoretically within the tight-binding Hamiltonian and the Green’s function method. Variations of the local density of states (DOS) along the chain are investigated. They are crucial in scanning tunnelling experiments and give important insight into the electron transport mechanism and charge distribution inside chains. It is found that depending on the chain parity the local DOS at the Fermi level can form cone-like structures (DOS cones) along the chain. The general condition for the local DOS oscillations is obtained and the linear behaviour of the local density function is confirmed analytically. DOS cones are characterized by a linear decay towards the chain which is in contrast to the propagation properties of charge density waves, end states and Friedel oscillations in one-dimensional systems. We find that DOS cones can appear due to non-resonant electron transport, the spin–orbit scattering or for chains fabricated on a substrate with localized electrons. It is also shown that for imperfect chains (e.g. with a reduced coupling strength between two neighboring sites) a diamond-like structure of the local DOS along the chain appears.

  2. Risikobasiertes Supply-Chain-Management

    DEFF Research Database (Denmark)

    Wieland, Andreas; Schinz, Philipp

    2015-01-01

    Das Management erlebt seit einigen Jahren dahingehend einen Paradigmenwechsel, dass nicht mehr Unternehmen als einzelne autonome Einheiten im Wettbewerb zueinander stehen, sondern die Supply Chains, in denen diese Unternehmen eingebunden sind. Ursachen hierfür sind beispielsweise die Auslagerung...... von Nicht-Kernprozessen auf vorgelagerte Stufen der Supply Chain oder auf Supply-Chain-Dienstleister sowie die Internationalisierung der Beschaffung. Dieser Paradigmenwechsel hat traditionelles Denken in den Schranken des Systems „Unternehmen“ abgelöst und zum Supply- Chain-Denken geführt, das vor......- und nachgelagerte Stufen des Systems „End-to-End-Supply-Chain“ einbezieht, etwa auch die Lieferanten von Lieferanten....

  3. Social Media and Supply Chain

    Directory of Open Access Journals (Sweden)

    Sonja Markova

    2013-02-01

    Full Text Available Web 2.0, also referred to as social media, is the use of the World Wide Web to increase creativity, information sharing, and collaboration among users. Social media is driving the rethinking of many of the principles of economics. The use of social media within supply chains is lagging behind their usage for other operational functions, however supply chain management is evolving into supply chain management 2.0.The purpose of this article is to provide researches of the supply chain management a reference with the main concepts of social media: social profiles, social applications, brand outposts and communities, and the social ecosystem.

  4. Integrating the healthcare supply chain.

    Science.gov (United States)

    Brennan, C D

    1998-01-01

    Today's integrated delivery systems (IDSs) require efficient supply chain processes to speed products to users at the lowest possible cost. Most excess costs within the supply chain are a result of inefficient and redundant processes involved in the transport and delivery of supplies from suppliers to healthcare providers. By integrating and assuming control of these supply chain processes, improving supply chain management practices, and organizing and implementing a disciplined redesign plan, IDSs can achieve substantial savings and better focus their organizations on their core patient care mission.

  5. Proteinaceous alpha-araylase inhibitors

    DEFF Research Database (Denmark)

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

    2004-01-01

    Proteins that inhibit alpha-amylases have been isolated from plants and microorganisms. These inhibitors can have natural roles in the control of endogenous a-amylase activity or in defence against pathogens and pests; certain inhibitors are reported to be antinutritional factors. The alpha-amylase...... inhibitors belong to seven different protein structural families, most of which also contain evolutionary related proteins without inhibitory activity. Two families include bifunctional inhibitors acting both on alpha-amylases and proteases. High-resolution structures are available of target alpha-amylases...... in complex with inhibitors from five families. These structures indicate major diversity but also some similarity in the structural basis of alpha-amylase inhibition. Mutational analysis of the mechanism of inhibition was performed in a few cases and various protein engineering and biotechnological...

  6. Proteinase inhibitors in Brazilian leguminosae

    Directory of Open Access Journals (Sweden)

    C. A. M. Sampaio

    1991-01-01

    Full Text Available Serine proteinase inhitors, in the seeds of several Leguminosae from the Pantanal region (West Brazil, were studied using bovine trypsin, a digestive enzyme, Factor XIIa and human plasma Kallikrein, two blood clotting factors. The inhibitors were purified from Enterolobium contortisiliquum (Mr=23,000, Torresea cearensis (Mr = 13,000, Bauhinia pentandra (Mr = 20,000 and Bauhinia bauhinioides (Mr = 20,000. E. contortisiliquum inhibitor inactivates all three enzymes, whereas the T. cearensis inhibitor inactivates trypsin and Factor XSSa, but does nor affect plasma kallikrein; both Bauhinia inhibitors, on the other hand, inactivate trypsin and plasma kallikrein but only the Bpentandra inhibitor affects Factor XIIa. Ki values were calculated between 10 [raised to the power of] -7 and 10 [raised to the power of] -8 M.

  7. Requirements of supply chain management in differentiating European pork chains

    NARCIS (Netherlands)

    Trienekens, J.H.; Wognum, P.M.

    2013-01-01

    This paper summarizes results obtained by research into pork chain management in the EU Integrated Project Q-Porkchains. Changing demands for intrinsic and extrinsic quality attributes of pork products impact the way supply chain management should be organized from the farmer down to the consumer. T

  8. SUPPLY CHAIN STRATEGIES IN THE CONTEXT OF AN E-COMMERCE CHAIN (E-CHAIN

    Directory of Open Access Journals (Sweden)

    João Gilberto Mendes do Reis

    2014-05-01

    Full Text Available This paper purpose to explore the relationships between supply chain strategies and product performance in retail e-commerce. In this case, we concern that in current, in order to bear up under competition, organizations have to manage their supply chains so that they meet the needs of their final customers. With this concept in mind, the research presented in this study focuses on establishing the right strategy for supply chains according to their product segment. Thus, after a Literature Review, the paper explain a methodology based in different authors studies. Finally the article focuses on a pratical case in e-commerce retail that describes its application in this field. The research shows that it is possible to use a methodology for classifying supply chains using chain strategies and product features. The use of the right strategy for supply chains will improve the competitive advantage of businesses. One limitation is that the methodology study focuses on only two e-commerce segment; future studies may go further in refining the proposed framework for other segments. The aim of this research is to offer businesses a model for evaluating supply chains, allowing them to improve the performance of their products and services by using the right strategy for supply chains. The classification proposal of this paper presents an original model for classification of supply chains based on different studies on the theme.

  9. Therapeutic dosing of an orally active, selective cathepsin S inhibitor suppresses disease in models of autoimmunity

    NARCIS (Netherlands)

    Baugh, Mark; Black, Darcey; Westwood, Paul; Kinghorn, Emma; McGregor, Kieran; Bruin, John; Hamilton, William; Dempster, Maureen; Claxton, Christopher; Cai, Jiaqiang; Bennett, Jonathan; Long, Clive; Mckinnon, Heather; Vink, Paul; den Hoed, Leontien; Gorecka, Monika; Vora, Kalpit; Grant, Ethan; Percival, M. David; Boots, A. Mieke H.; van Lierop, Marie-Jose; Boots, Annemieke

    2011-01-01

    The purpose of the study was to examine the potential of inhibition of cathepsin S as a treatment for autoimmune diseases. A highly selective cathepsin S inhibitor, CSI-75, was shown to upregulate levels of the cathepsin S substrate, invariant chain Lip10, in vitro as well as in vivo in C57Bl/6 mice

  10. Academic Education Chain Operation Model

    NARCIS (Netherlands)

    Ruskov, Petko; Ruskov, Andrey

    2007-01-01

    This paper presents an approach for modelling the educational processes as a value added chain. It is an attempt to use a business approach to interpret and compile existing business and educational processes towards reference models and suggest an Academic Education Chain Operation Model. The model

  11. Spectral Analysis of Markov Chains

    OpenAIRE

    2007-01-01

    The paper deals with the problem of a statistical analysis of Markov chains connected with the spectral density. We present the expressions for the function of spectral density. These expressions may be used to estimate the parameter of the Markov chain.

  12. LEAN SUPPLY CHAIN DESIGN PRINCIPLES

    OpenAIRE

    Kozlov, Aleksandr

    2015-01-01

    The article presents a set of principles, which can guide the design of lean supply chains. The author divides design principles into 3 main categories. The first two sets describe internal production processes while the 3-rd set relates to the entire supply chain.

  13. Negotiations in Supply Chain Management

    DEFF Research Database (Denmark)

    Zachariassen, Frederik

    2008-01-01

    negotiation literature. Subsequently, an empirical case study is presented, which explicitly aims at exploring the role of negotiations between members of a supply chain. Based on the findings, the paper concludes on specific, normative guidelines for negotiations for improved supply chain competitiveness...

  14. Chain formation of metal atoms

    DEFF Research Database (Denmark)

    Bahn, Sune Rastad; Jacobsen, Karsten Wedel

    2001-01-01

    The possibility of formation of single-atomic chains by manipulation of nanocontacts is studied for a selection of metals (Ni, Pd, Pt, Cu, Ag, Au). Molecular dynamics simulations show that the tendency for chain formation is strongest for Au and Pt. Density functional theory calculations indicate...

  15. Verifying the Hanging Chain Model

    Science.gov (United States)

    Karls, Michael A.

    2013-01-01

    The wave equation with variable tension is a classic partial differential equation that can be used to describe the horizontal displacements of a vertical hanging chain with one end fixed and the other end free to move. Using a web camera and TRACKER software to record displacement data from a vibrating hanging chain, we verify a modified version…

  16. Inhibitors of polyhydroxyalkanoate (PHA) synthases: synthesis, molecular docking, and implications.

    Science.gov (United States)

    Zhang, Wei; Chen, Chao; Cao, Ruikai; Maurmann, Leila; Li, Ping

    2015-01-01

    Polyhydroxyalkanoate (PHA) synthases (PhaCs) catalyze the formation of biodegradable PHAs that are considered to be ideal alternatives to non-biodegradable synthetic plastics. However, study of PhaCs has been challenging because the rate of PHA chain elongation is much faster than that of initiation. This difficulty, along with lack of a crystal structure, has become the main hurdle to understanding and engineering PhaCs for economical PHA production. Here we report the synthesis of two carbadethia CoA analogues--sT-CH2-CoA (26 a) and sTet-CH2-CoA (26 b)--as well as sT-aldehyde (saturated trimer aldehyde, 29), as new PhaC inhibitors. Study of these analogues with PhaECAv revealed that 26 a/b and 29 are competitive and mixed inhibitors, respectively. Both the CoA moiety and extension of PHA chain will increase binding affinity; this is consistent with our docking study. Estimation of the Kic values of 26 a and 26 b predicts that a CoA analogue incorporating an octameric hydroxybutanoate (HB) chain might facilitate the formation of a kinetically well-behaved synthase.

  17. Correlations between papillary thyroid cancer and peripheral blood levels of matrix metalloproteinase-2, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, and tissue inhibitor of metalloproteinase-2

    Institute of Scientific and Technical Information of China (English)

    ZHOU Shao-fei; HU San-yuan; MA Lei; MIAO Lei; MAO Wei-zheng

    2013-01-01

    Background The relationship between the presence of metalloproteinases and thyroid cancer remains unknown,and many controversies still exist in this field.The objective of this study was to investigate the correlations between papillary thyroid cancer and peripheral blood levels of matrix metalloproteinase-2,matrix metalloproteinase-9,tissue inhibitor of metalloproteinase-1,and tissue inhibitor of metalloproteinase-2.Methods The correlations were studied by detecting the levels of matrix metalloproteinase-2,matrix metalloproteinase-9,tissue inhibitor of metalloproteinase-1,and tissue inhibitor of metalloproteinase-2 by enzyme-linked immunosorbant assay and reverse-transcription polymerase chain reaction in the peripheral blood of 30 patients with papillary thyroid carcinoma,27 patients with benign thyroid disease,and 25 healthy volunteers.Results The levels of matrix metalloproteinase-2,matrix metalloproteinase-9,tissue inhibitor of metalloproteinase-1,and tissue inhibitor of metalloproteinase-2 in the peripheral blood of patients with papillary thyroid carcinoma were significantly higher than those in the peripheral blood of patients with benign thyroid disease and healthy volunteers (P <0.05).However,there were no significant differences between patients with benign thyroid disease and healthy volunteers (P >0.05).The accuracy of detection by both enzyme-linked immunosorbant assay and reverse-transcription polymerase chain reaction in the papillary thyroid cancer group was 83.33%.Conclusions The levels of matrix metalloproteinase-2,matrix metalloproteinase-9,tissue inhibitor of metalloproteinase-1,and tissue inhibitor of metalloproteinase-2 in the peripheral blood are helpful in identifying thyroid carcinoma and aid in preoperative assessment.

  18. Developing sustainable food supply chains.

    Science.gov (United States)

    Smith, B Gail

    2008-02-27

    This paper reviews the opportunities available for food businesses to encourage consumers to eat healthier and more nutritious diets, to invest in more sustainable manufacturing and distribution systems and to develop procurement systems based on more sustainable forms of agriculture. The important factors in developing more sustainable supply chains are identified as the type of supply chain involved and the individual business attitude to extending responsibility for product quality into social and environmental performance within their own supply chains. Interpersonal trust and working to standards are both important to build more sustainable local and many conserved food supply chains, but inadequate to transform mainstream agriculture and raw material supplies to the manufactured and commodity food markets. Cooperation among food manufacturers, retailers, NGOs, governmental and farmers' organizations is vital in order to raise standards for some supply chains and to enable farmers to adopt more sustainable agricultural practices.

  19. Managing the Global Supply Chain

    DEFF Research Database (Denmark)

    Hsuan, Juliana; Skjøtt-Larsen, Tage; Kinra, Aseem

    edition has been fully updated with recent changes in concepts, technology and practice. Integration and collaboration are keywords in future competition. Firms must be agile and lean at the same time. The book gives an insightful overview of the conceptual foundations of the global supply chain, as......The world today faces global competition. The supply chain is vital part of the globalization process. Presenting a global view of the scope and complexity of supply chain management, this book reflects the rapid change that has taken place within the supply chain and its environment. This new...... well as current examples of best practice of managing supply chains in a global context....

  20. Environmental Management in Product Chains

    DEFF Research Database (Denmark)

    Jørgensen, Michael Søgaard; Forman, Marianne

    2009-01-01

    ). An overview of examples from our own research and from literature of the type and the role of environmental issues and initiatives in product chains (fourth section). A typology for characterizing corporate strategies as part of environmental management in product chains and characterizing those competencies......The chapter aims at giving background to companies, consultants, governmental regulators, NGOs etc. for the analysis and planning of environmental management in specific product chains through: A framework for understanding environmental management in product chains as shaped by the interaction...... between existing resources, norms and values and external pressures for environmental management (second section). A model for the types of corporate network relations that need to be mapped and understood in order to analyze and/or develop environmental management in a product chain (third section...

  1. The Service-Profit Chain

    DEFF Research Database (Denmark)

    Grønholdt, Lars; Martensen, Anne

    2016-01-01

    evidence of the employee-customer-profit chain. As it is possible to estimate the links, we have demonstrated their effect on company profitability. The research findings provide a better understanding of the service-profit chain and may help practitioners in improving company financial performance.......This paper examines the links between employee attitudes, customer loyalty and company profitability. From a conceptual point of view, this employee-customer-profit chain, also known as the service-profit chain, is well founded and generally accepted. But for many companies, it seems difficult...... to demonstrate such links, and several issues must be addressed to uncover the links. To investigate these links empirically, a hotel chain provided data matching employee and customer measures with measures of profitability. We have successfully employed a modeling approach, and the paper reports empirical...

  2. Managing the Global Supply Chain

    DEFF Research Database (Denmark)

    Skjøtt-Larsen, Tage; Schary, Philip B.; Mikkola, Juliana Hsuan

    The world today faces global competition. The supply chain is vital part of the globalization process. Presenting a global view of the scope and complexity of supply chain management, this book reflects the rapid change that has taken place within the supply chain and its environment. This new...... edition has been fully updated with recent changes in concepts, technology and practice. Integration and collaboration are keywords in future competition. Firms must be agile and lean at the same time. The book gives an insightful overview of the conceptual foundations of the global supply chain, as...... well as current examples of best practice of managing supply chains in a global context....

  3. Uncovering Molecular Bases Underlying Bone Morphogenetic Protein Receptor Inhibitor Selectivity.

    Directory of Open Access Journals (Sweden)

    Abdelaziz Alsamarah

    Full Text Available Abnormal alteration of bone morphogenetic protein (BMP signaling is implicated in many types of diseases including cancer and heterotopic ossifications. Hence, small molecules targeting BMP type I receptors (BMPRI to interrupt BMP signaling are believed to be an effective approach to treat these diseases. However, lack of understanding of the molecular determinants responsible for the binding selectivity of current BMP inhibitors has been a big hindrance to the development of BMP inhibitors for clinical use. To address this issue, we carried out in silico experiments to test whether computational methods can reproduce and explain the high selectivity of a small molecule BMP inhibitor DMH1 on BMPRI kinase ALK2 vs. the closely related TGF-β type I receptor kinase ALK5 and vascular endothelial growth factor receptor type 2 (VEGFR2 tyrosine kinase. We found that, while the rigid docking method used here gave nearly identical binding affinity scores among the three kinases; free energy perturbation coupled with Hamiltonian replica-exchange molecular dynamics (FEP/H-REMD simulations reproduced the absolute binding free energies in excellent agreement with experimental data. Furthermore, the binding poses identified by FEP/H-REMD led to a quantitative analysis of physical/chemical determinants governing DMH1 selectivity. The current work illustrates that small changes in the binding site residue type (e.g. pre-hinge region in ALK2 vs. ALK5 or side chain orientation (e.g. Tyr219 in caALK2 vs. wtALK2, as well as a subtle structural modification on the ligand (e.g. DMH1 vs. LDN193189 will cause distinct binding profiles and selectivity among BMP inhibitors. Therefore, the current computational approach represents a new way of investigating BMP inhibitors. Our results provide critical information for designing exclusively selective BMP inhibitors for the development of effective pharmacotherapy for diseases caused by aberrant BMP signaling.

  4. Cholinesterase inhibitors and memory.

    Science.gov (United States)

    Pepeu, Giancarlo; Giovannini, Maria Grazia

    2010-09-06

    A consensus exists that cholinesterase inhibitors (ChEIs) are efficacious for mild to moderate Alzheimer's Disease (AD). Unfortunately, the number of non-responders is large and the therapeutic effect is usually short-lasting. In experimental animals, ChEIs exert three main actions: inhibit cholinesterase (ChE), increase extracellular levels of brain acetylcholine (ACh), improve cognitive processes, particularly when disrupted in models of AD. In this overview we shall deal with the cognitive processes that are improved by ChEI treatment because they depend on the integrity of brain cholinergic pathways and their activation. The role of cholinergic system in cognition can be investigated using different approaches. Microdialysis experiments demonstrate the involvement of the cholinergic system in attention, working, spatial and explicit memory, information encoding, sensory-motor gating, skill learning. No involvement in long-term memory has yet been demonstrated. Conversely, memory consolidation is facilitated by low cholinergic activity. Experiments on healthy human subjects, notwithstanding caveats concerning age, dose, and different memory tests, confirm the findings of animal experiments and demonstrate that stimulation of the cholinergic system facilitates attention, stimulus detection, perceptual processing and information encoding. It is not clear whether information retrieval may be improved but memory consolidation is reduced by cholinergic activation. ChEI effects in AD patients have been extensively investigated using rating scales that assess cognitive and behavioural responses. Few attempts have been made to identify which scale items respond better to ChEIs and therefore, presumably, depend on the activity of the cholinergic system. Improvement in attention and executive functions, communication, expressive language and mood stability have been reported. Memory consolidation and retrieval may be impaired by high ACh levels. Therefore, considering

  5. Exploring the inhibitor binding pocket of respiratory complex I.

    Science.gov (United States)

    Fendel, Uta; Tocilescu, Maja A; Kerscher, Stefan; Brandt, Ulrich

    2008-01-01

    Numerous hydrophobic and amphipathic compounds including several detergents are known to inhibit the ubiquinone reductase reaction of respiratory chain complex I (proton pumping NADH:ubiquinone oxidoreductase). Guided by the X-ray structure of the peripheral arm of complex I from Thermus thermophilus we have generated a large collection of site-directed mutants in the yeast Yarrowia lipolytica targeting the proposed ubiquinone and inhibitor binding pocket of this huge multiprotein complex at the interface of the 49-kDa and PSST subunits. We could identify a number of residues where mutations changed I(50) values for representatives from all three groups of hydrophobic inhibitors. Many mutations around the domain of the 49-kDa subunit that is homologous to the [NiFe] centre binding region of hydrogenase conferred resistance to DQA (class I/type A) and rotenone (class II/type B) indicating a wider overlap of the binding sites for these two types of inhibitors. In contrast, a region near iron-sulfur cluster N2, where the binding of the n-alkyl-polyoxyethylene-ether detergent C(12)E(8) (type C) was exclusively affected, appeared comparably well separated. Taken together, our data provide structure-based support for the presence of distinct but overlapping binding sites for hydrophobic inhibitors possibly extending into the ubiquinone reduction site of mitochondrial complex I.

  6. [ACE inhibitors and the kidney].

    Science.gov (United States)

    Hörl, W H

    1996-01-01

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

  7. Elastic Behavior of Polymer Chains

    Institute of Scientific and Technical Information of China (English)

    Teng Lu; Tao Chen; Hao-jun Liang

    2008-01-01

    The elastic behavior of the polymer chain was investigated in a three-dimensional off-lattice model. We sample more than 109 conformations of each kind of polymer chain by using a Monte Carlo algorithm, then analyze them with the non-Gaussian theory of rubberlike elasticity, and end with a statistical study. Through observing the effect of the chain flexibility and the stretching ratio on the mean-square end-to-end distance,the average energy, the average Helmholtz free energy, the elastic force, the contribution of energy to the elastic force, and the entropy contribution to elastic force of the polymer chain, we find that a rigid polymer chain is much easier to stretch than a flexible polymer chain. Also, a rigid polymer chain will become difficult to stretch only at a quite high stretching ratio because of the effect of the entropy contribution.These results of our simulation calculation may explain some of the macroscopic phenomena of polymer and biomacromolecular elasticity.

  8. HIV-1 Reverse Transcriptase Still Remains a New Drug Target: Structure, Function, Classical Inhibitors, and New Inhibitors with Innovative Mechanisms of Actions

    Directory of Open Access Journals (Sweden)

    Francesca Esposito

    2012-01-01

    Full Text Available During the retrotranscription process, characteristic of all retroviruses, the viral ssRNA genome is converted into integration-competent dsDNA. This process is accomplished by the virus-coded reverse transcriptase (RT protein, which is a primary target in the current treatments for HIV-1 infection. In particular, in the approved therapeutic regimens two classes of drugs target RT, namely, nucleoside RT inhibitors (NRTIs and nonnucleoside RT inhibitors (NNRTIs. Both classes inhibit the RT-associated polymerase activity: the NRTIs compete with the natural dNTP substrate and act as chain terminators, while the NNRTIs bind to an allosteric pocket and inhibit polymerization noncompetitively. In addition to these two classes, other RT inhibitors (RTIs that target RT by distinct mechanisms have been identified and are currently under development. These include translocation-defective RTIs, delayed chain terminators RTIs, lethal mutagenesis RTIs, dinucleotide tetraphosphates, nucleotide-competing RTIs, pyrophosphate analogs, RT-associated RNase H function inhibitors, and dual activities inhibitors. This paper describes the HIV-1 RT function and molecular structure, illustrates the currently approved RTIs, and focuses on the mechanisms of action of the newer classes of RTIs.

  9. Traceability in food supply chain:: Towards the synchronised supply chain

    OpenAIRE

    Lindh, Helena; Skjöldebrand, Christina; Olsson, Annika

    2008-01-01

    Today, food products are distributed all over the world. This has led to advantages in terms of availability but disadvantages in terms of more complex food supply chains. Global food competition is intense and therefore actors have started to adapt their mindsets toward a more holistic view and a supply chain perspective. In addition, food scares during recent years have turned focus towards food safety and traceability in a “farm-to-fork” perspective. The aim of this study is to explore...

  10. Markov chains theory and applications

    CERN Document Server

    Sericola, Bruno

    2013-01-01

    Markov chains are a fundamental class of stochastic processes. They are widely used to solve problems in a large number of domains such as operational research, computer science, communication networks and manufacturing systems. The success of Markov chains is mainly due to their simplicity of use, the large number of available theoretical results and the quality of algorithms developed for the numerical evaluation of many metrics of interest.The author presents the theory of both discrete-time and continuous-time homogeneous Markov chains. He carefully examines the explosion phenomenon, the

  11. Markov Chains and Markov Processes

    OpenAIRE

    2016-01-01

    Markov chain, which was named after Andrew Markov is a mathematical system that transfers a state to another state. Many real world systems contain uncertainty. This study helps us to understand the basic idea of a Markov chain and how is been useful in our daily lives. For some times there had been suspense on distinct predictions and future existences. Also in different games there had been different expectations or results involved. That is the reason why we need Markov chains to predict o...

  12. New sensors and processing chain

    CERN Document Server

    Yaakoubi, Nourdin

    2014-01-01

    A vital tool for researchers, engineers, and students, New Sensors and Processing Chain focuses on the processing chain to set up in order to extract relevant information on various systems. Highlighting the design of new microsensors and various applications, the authors present recent progress in instrumentation and microsystem design, providing insight to the modification of the sensor itself as well as its environment. Various applications illustrate the presentations, which show how a processing chain is organized from the data acquired by a specific sensor.

  13. Kinetics studies on triacontanyl palmitate: a urease inhibitor.

    Science.gov (United States)

    Lodhi, Muhammad Arif; Abbasi, Muhammad Athar; Choudhary, Muhammad Iqbal; Ahmad, Viqar Uddin

    2007-07-10

    The mechanism of inhibition of jack bean and Bacillus pasteurii ureases was investigated by triacontanyl palmitate (1) which is a long-chain fatty ester and has been isolated from Symplocos racemosa Roxb. Lineweaver-Burk, Dixon plots, and their secondary replots showed that 1 is a non-competitive inhibitor of these enzymes. K(i) values were found to be 60.03 +/- 1.72 and 88.23 +/- 0.31 microM against jack bean and B. pasteurii ureases, respectively.

  14. CANSTATIN, A ENDOGENOUS INHIBITOR OF ANGIOGENESIS AND TUMOR GROWTH

    Institute of Scientific and Technical Information of China (English)

    苏影; 朱建思

    2004-01-01

    Canstatin is a novel inhibitor of angiogenesis and tumor growth, derived from the C-terminal globular non-collageneous (NCl) domain of the (2 chain of type IV collagen. It inhibits endothelial cell proliferation and migration in a dose-dependent manner, and induces endothelial cell apoptosis. In vivo experiments show that canstatin significantly inhibits solid tumor growth. The canstatin mediated inhibition of tumor is related to apoptosis. Canstatin- induced apoptosis is associated with phosphatidylinositol 3-kinase/Akt inhibition and is dependend upon signaling events transduced trough membrane death receptor.

  15. Selective mGAT2 (BGT-1) GABA Uptake Inhibitor

    DEFF Research Database (Denmark)

    Vogensen, Stine Byskov; Jørgensen, Lars; Madsen, Karsten Kirkegaard;

    2013-01-01

    β-Amino acids sharing a lipophilic diaromatic side chain were synthesized and characterized pharmacologically on mouse GABA transporter subtypes mGAT1−4. The parent amino acids were also characterized. Compounds 13a, 13b, and 17b displayed more than 6-fold selectivity for mGAT2 over mGAT1. Compound...... 17b displayed anticonvulsive properties inferring a role of mGAT2 in epileptic disorders. These results provide new neuropharmacological tools and a strategy for designing subtype selective GABA transport inhibitors....

  16. A new motif for inhibitors of geranylgeranyl diphosphate synthase.

    Science.gov (United States)

    Foust, Benjamin J; Allen, Cheryl; Holstein, Sarah A; Wiemer, David F

    2016-08-15

    The enzyme geranylgeranyl diphosphate synthase (GGDPS) is believed to receive the substrate farnesyl diphosphate through one lipophilic channel and release the product geranylgeranyl diphosphate through another. Bisphosphonates with two isoprenoid chains positioned on the α-carbon have proven to be effective inhibitors of this enzyme. Now a new motif has been prepared with one isoprenoid chain on the α-carbon, a second included as a phosphonate ester, and the potential for a third at the α-carbon. The pivaloyloxymethyl prodrugs of several compounds based on this motif have been prepared and the resulting compounds have been tested for their ability to disrupt protein geranylgeranylation and induce cytotoxicity in myeloma cells. The initial biological studies reveal activity consistent with GGDPS inhibition, and demonstrate a structure-function relationship which is dependent on the nature of the alkyl group at the α-carbon.

  17. Supply Chain Shipment Pricing Data

    Data.gov (United States)

    US Agency for International Development — This data set provides supply chain health commodity shipment and pricing data. Specifically, the data set identifies Antiretroviral (ARV) and HIV lab shipments to...

  18. Environmental management in product chains

    DEFF Research Database (Denmark)

    Jørgensen, Michael Søgaard; Forman, Marianne; Hansen, Anne Grethe

    of environmental initiatives, a number of recommendations for governmental regulation, which can support the further diffusion of environmental management in product chains, are developed. Furthermore, the report describes a number of theoretical perspectives from sociology of technology, organisation theory...

  19. Bibliometric Application of Markov Chains.

    Science.gov (United States)

    Pao, Miranda Lee; McCreery, Laurie

    1986-01-01

    A rudimentary description of Markov Chains is presented in order to introduce its use to describe and to predict authors' movements among subareas of the discipline of ethnomusicology. Other possible applications are suggested. (Author)

  20. Gravity Waves from Chain Inflation

    CERN Document Server

    Ashoorioon, Amjad

    2008-01-01

    Chain inflation proceeds through a series of first order phase transitions, which can release considerable gravitational waves (GW). We demonstrate that bubble collisions can leave an observable signature for future high-frequency probes of GWs, such as advanced LIGO, LISA and BBO. A "smoking gun" for chain inflation would be wiggles in the spectrum (and consequently in the tensor spectral index) due to the multiple phase transitions. The spectrum could also be distinguished from a single first order phase transition by a small difference in the amplitude at low frequency. A second origin of GWs in chain inflation are tensor modes from quantum fluctuations; these GW can dominate and be observed on large scales. The consistency relation between scalar and tensor modes is different for chain inflation than for standard rolling models and is testable by Cosmic Microwave Background experiments. If inflation happened through a series of rapid tunnelings in the string landscape, future high frequency probes of GW c...

  1. Markov Chains and Chemical Processes

    Science.gov (United States)

    Miller, P. J.

    1972-01-01

    Views as important the relating of abstract ideas of modern mathematics now being taught in the schools to situations encountered in the sciences. Describes use of matrices and Markov chains to study first-order processes. (Author/DF)

  2. The chain re-action

    CERN Multimedia

    2009-01-01

    On 18 March, beam commissioning started in the first ‘link’ of the accelerator chain – LINAC 2. This marks the start of what will be the longest period of beam operations in CERN’s history, with the accelerator complex remaining operational throughout the winter to supply the LHC. The Bulletin finds out what is being done to make sure the whole chain is ready for this historic run.

  3. Using steric hindrance to design new inhibitors of class C beta-lactamases

    Energy Technology Data Exchange (ETDEWEB)

    Trehan, Indi; Morandi, F.; Blaszczak, L.C.; Shoichet, Brian K. (NWU)

    2010-03-08

    {beta}-lactamases confer resistance to {beta}-lactam antibiotics such as penicillins and cephalosporins. However, {beta}-lactams that form an acyl-intermediate with the enzyme but subsequently are hindered from forming a catalytically competent conformation seem to be inhibitors of {beta}-lactamases. This inhibition may be imparted by specific groups on the ubiquitous R1 side chain of {beta}-lactams, such as the 2-amino-4-thiazolyl methoxyimino (ATMO) group common among third-generation cephalosporins. Using steric hindrance of deacylation as a design guide, penicillin and carbacephem substrates were converted into effective {beta}-lactamase inhibitors and antiresistance antibiotics. To investigate the structural bases of inhibition, the crystal structures of the acyl-adducts of the penicillin substrate amoxicillin and the new analogous inhibitor ATMO-penicillin were determined. ATMO-penicillin binds in a catalytically incompetent conformation resembling that adopted by third-generation cephalosporins, demonstrating the transferability of such sterically hindered groups in inhibitor design.

  4. "Bullwhip Effect" in Supply Chains

    Directory of Open Access Journals (Sweden)

    Anđelko Ščukanec

    2007-09-01

    Full Text Available The system which connects all the elements between theproducer and the consumer is called the supply chain. This definitionof the supply chain shows its complexity, dynamics anduncertainty. Successful operation of supply chains requires thebest possible coordination of its elements, which obviously indicatesthe utmost importance of the information flow alongthem. The operation of supply chains on the whole has to bemore successful than the operation of their individual elements.It should be noted that such a complex process may give rise toa series of problems, unwanted events, as well as substantial reductionin profits and the level of service. One of such unwantedphenomena which may occur in the supply chain is the"bullwhip effect". This is a possible increase in the diversity oforders which occurs when we move along the elements of thesupply chain (from the customers' orders to the producers' orders.The work analyses the processes within the supply chainsand the occurrence of the bullwhip effect. The main causes ofthe bullwhip effect that we encounter daily in the supply chainshave been clearly defined. The paper also presents the mainnegative consequences of such a disturbance within the supplychains, and provides possible solutions for avoiding the bullwhipeffect.

  5. Reinforcement learning in supply chains.

    Science.gov (United States)

    Valluri, Annapurna; North, Michael J; Macal, Charles M

    2009-10-01

    Effective management of supply chains creates value and can strategically position companies. In practice, human beings have been found to be both surprisingly successful and disappointingly inept at managing supply chains. The related fields of cognitive psychology and artificial intelligence have postulated a variety of potential mechanisms to explain this behavior. One of the leading candidates is reinforcement learning. This paper applies agent-based modeling to investigate the comparative behavioral consequences of three simple reinforcement learning algorithms in a multi-stage supply chain. For the first time, our findings show that the specific algorithm that is employed can have dramatic effects on the results obtained. Reinforcement learning is found to be valuable in multi-stage supply chains with several learning agents, as independent agents can learn to coordinate their behavior. However, learning in multi-stage supply chains using these postulated approaches from cognitive psychology and artificial intelligence take extremely long time periods to achieve stability which raises questions about their ability to explain behavior in real supply chains. The fact that it takes thousands of periods for agents to learn in this simple multi-agent setting provides new evidence that real world decision makers are unlikely to be using strict reinforcement learning in practice.

  6. Sports Nutrition Food Industry Chain Development Research

    OpenAIRE

    Jie Yin

    2015-01-01

    Through the study of Henan sports nutrition food industry chain optimization, the study analyses development advantage and competitive advantage of Henan in sports nutrition food industry chain and existing problems and challenges in Henan sports nutrition food industry chain and at the same time introduces the theory of supply chain management to the development of sports nutrition food industry chain, clearly optimizes countermeasures of sports nutrition food industry chain. Pointing out sp...

  7. Demand chain management - The evolution

    Directory of Open Access Journals (Sweden)

    D Ericsson

    2011-06-01

    Full Text Available The concepts of Supply Chain Management (SCM and Demand Chain Management (DCM are among the new and debated topics concerning logistics in the literature. The question considered in this paper is: “Are these concepts needed or will they just add to the confusion?” Lasting business concepts have always evolved in close interaction between business and academia. Different approaches start out in business and they are then, more or less si- multaneously, aligned, integrated, systemised and structured in academia. In this way a terminology (or language is provided that helps in further diffusion of the concepts. There is a lack of consensus on the definition of the concept of SCM. This may be one of the major reasons for the difficulty in advancing the science and measuring the results of implementation in business. Relationships in SCM span from rather loose coalitions to highly structured virtual network integrations. DCM is a highly organised chain in which the key is mutual interdependence and partnership. The purpose is to create a distinctive competence for the chain as a whole that helps to identify and satisfy customer needs and wishes. The classical research concerning vertical marketing systems is very helpful in systemising the rather unstructured discussions in current SCM research. The trend lies in increasing competition between channels rather than between companies, which in turn leads to the creation of channels with a high degree of partnership and mutual interdependence between members. These types of channels are known as organised vertical marketing systems in the classic marketing channel research. The behaviour in these types of channels, as well as the formal and informal structures, roles in the network, power and dependence relations, etc. are well covered topics in the literature. The concept of vertical marketing systems lies behind the definition of demand chains and demand chain management proposed in this paper. A

  8. Bortezomib partially improves laminin α2 chain-deficient muscular dystrophy.

    Science.gov (United States)

    Körner, Zandra; Fontes-Oliveira, Cibely C; Holmberg, Johan; Carmignac, Virginie; Durbeej, Madeleine

    2014-05-01

    Congenital muscular dystrophy, caused by mutations in LAMA2 (the gene encoding laminin α2 chain), is a severe and incapacitating disease for which no therapy is yet available. We have recently demonstrated that proteasome activity is increased in laminin α2 chain-deficient muscle and that treatment with the nonpharmaceutical proteasome inhibitor MG-132 reduces muscle pathology in laminin α2 chain-deficient dy(3K)/dy(3K) mice. Here, we explore the use of the selective and therapeutic proteasome inhibitor bortezomib (currently used for treatment of relapsed multiple myeloma and mantle cell lymphoma) in dy(3K)/dy(3K) mice and in congenital muscular dystrophy type 1A muscle cells. Outcome measures included quantitative muscle morphology, gene and miRNA expression analyses, proteasome activity, motor activity, and survival. Bortezomib improved several histological hallmarks of disease, partially normalized miRNA expression (miR-1 and miR-133a), and enhanced body weight, locomotion, and survival of dy(3K)/dy(3K) mice. In addition, bortezomib reduced proteasome activity in congenital muscular dystrophy type 1A myoblasts and myotubes. These findings provide evidence that the proteasome inhibitor bortezomib partially reduces laminin α2 chain-deficient muscular dystrophy. Investigation of the clinical efficacy of bortezomib administration in congenital muscular dystrophy type 1A clinical trials may be warranted.

  9. Diverse inhibitors of aflatoxin biosynthesis.

    Science.gov (United States)

    Holmes, Robert A; Boston, Rebecca S; Payne, Gary A

    2008-03-01

    Pre-harvest and post-harvest contamination of maize, peanuts, cotton, and tree nuts by members of the genus Aspergillus and subsequent contamination with the mycotoxin aflatoxin pose a widespread food safety problem for which effective and inexpensive control strategies are lacking. Since the discovery of aflatoxin as a potently carcinogenic food contaminant, extensive research has been focused on identifying compounds that inhibit its biosynthesis. Numerous diverse compounds and extracts containing activity inhibitory to aflatoxin biosynthesis have been reported. Only recently, however, have tools been available to investigate the molecular mechanisms by which these inhibitors affect aflatoxin biosynthesis. Many inhibitors are plant-derived and a few may be amenable to pathway engineering for tissue-specific expression in susceptible host plants as a defense against aflatoxin contamination. Other compounds show promise as protectants during crop storage. Finally, inhibitors with different modes of action could be used in comparative transcriptional and metabolomic profiling experiments to identify regulatory networks controlling aflatoxin biosynthesis.

  10. Corrosion inhibitors from expired drugs.

    Science.gov (United States)

    Vaszilcsin, Nicolae; Ordodi, Valentin; Borza, Alexandra

    2012-07-15

    This paper presents a method of expired or unused drugs valorization as corrosion inhibitors for metals in various media. Cyclic voltammograms were drawn on platinum in order to assess the stability of pharmaceutically active substances from drugs at the metal-corrosive environment interface. Tafel slope method was used to determine corrosion rates of steel in the absence and presence of inhibitors. Expired Carbamazepine and Paracetamol tablets were used to obtain corrosion inhibitors. For the former, the corrosion inhibition of carbon steel in 0.1 mol L(-1) sulfuric acid solution was about 90%, whereas for the latter, the corrosion inhibition efficiency of the same material in the 0.25 mol L(-1) acetic acid-0.25 mol L(-1) sodium acetate buffer solution was about 85%.

  11. Crystal structure of a human cyclin-dependent kinase 6 complexwith a flavonol inhibitor, Fisetin

    Energy Technology Data Exchange (ETDEWEB)

    Lu, Heshu; Chang, Debbie J.; Baratte, Blandine; Meijer, Laurent; Schulze-Gahmen, Ursula

    2005-01-10

    Cyclin-dependent kinases (CDKs) play a central role in cell cycle control, apoptosis, transcription and neuronal functions. They are important targets for the design of drugs with anti-mitotic and/or anti-neurodegenerative effects. CDK4 and CDK6 form a subfamily among the CDKs in mammalian cells, as defined by sequence similarities. Compared to CDK2 and CDK5, structural information on CDK4 and CDK6 is sparse. We describe here the crystal structure of human CDK6 in complex with a viral cyclin and a flavonol inhibitor, fisetin. Fisetin binds to the active form of CDK6, forming hydrogen bonds with the side chains of residues in the binding pocket that undergo large conformational changes during CDK activation by cyclin binding. The 4-keto group and the 3-hydroxyl group of fisetin are hydrogen bonded with the backbone in the hinge region between the N-terminal and C-terminal kinase domain, as has been observed for many CDK inhibitors. However, CDK2 and HCK kinase in complex with other flavone inhibitors such as quercetin and flavopiridol showed a different binding mode with the inhibitor rotated by about 180. The structural information of the CDK6-fisetin complex is correlated with the binding affinities of different flavone inhibitors for CDK6. This complex structure is the first description of an inhibitor complex with a kinase from the CDK4/6 subfamily and can provide a basis for selecting and designing inhibitor compounds with higher affinity and specificity.

  12. Structural Basis for Accelerated Cleavage of Bovine Pancreatic Trypsin Inhibitor (BPTI) by Human Mesotrypsin

    Energy Technology Data Exchange (ETDEWEB)

    Salameh,M.; Soares, A.; Hockla, A.; Radisky, E.

    2008-01-01

    Human mesotrypsin is an isoform of trypsin that displays unusual resistance to polypeptide trypsin inhibitors and has been observed to cleave several such inhibitors as substrates. Whereas substitution of arginine for the highly conserved glycine 193 in the trypsin active site has been implicated as a critical factor in the inhibitor resistance of mesotrypsin, how this substitution leads to accelerated inhibitor cleavage is not clear. Bovine pancreatic trypsin inhibitor (BPTI) forms an extremely stable and cleavage-resistant complex with trypsin, and thus provides a rigorous challenge of mesotrypsin catalytic activity toward polypeptide inhibitors. Here, we report kinetic constants for mesotrypsin and the highly homologous (but inhibitor sensitive) human cationic trypsin, describing inhibition by, and cleavage of BPTI, as well as crystal structures of the mesotrypsin-BPTI and human cationic trypsin-BPTI complexes. We find that mesotrypsin cleaves BPTI with a rate constant accelerated 350-fold over that of human cationic trypsin and 150,000-fold over that of bovine trypsin. From the crystal structures, we see that small conformational adjustments limited to several side chains enable mesotrypsin-BPTI complex formation, surmounting the predicted steric clash introduced by Arg-193. Our results show that the mesotrypsin-BPTI interface favors catalysis through (a) electrostatic repulsion between the closely spaced mesotrypsin Arg-193 and BPTI Arg-17, and (b) elimination of two hydrogen bonds between the enzyme and the amine leaving group portion of BPTI. Our model predicts that these deleterious interactions accelerate leaving group dissociation and deacylation.

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

    DEFF Research Database (Denmark)

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

    1997-01-01

    Fibrinolytic enzyme inhibitors hamper the determination of the specific fibrinolytic serine protease activity. Reportedly, chemical anti-inhibitors eliminate the influence of fibrinolytic inhibitors, but it remains unclear to what extent they change the specific activity of fibrinolytic serine pr...

  14. Structure-based design and synthesis of pyrazinones containing novel P1 'side pocket' moieties as inhibitors of TF/VIIa.

    Science.gov (United States)

    Schweitzer, Barbara A; Neumann, William L; Rahman, Hayat K; Kusturin, Carrie L; Sample, Kirby R; Poda, Gennadiy I; Kurumbail, Ravi G; Stevens, Anna M; Stegeman, Roderick A; Stallings, William C; South, Michael S

    2005-06-15

    We describe the structure-based design, synthesis, and enzymatic activity of a series of substituted pyrazinones as inhibitors of the TF/VIIa complex. These inhibitors contain substituents meta to the P(1) amidine designed to explore additional interactions with the VIIa residues in the so-called 'S(1) side pocket'. A crystal structure of the designed inhibitors demonstrates the ability of the P(1) side pocket moiety to engage Lys192 and main chain of Gly216 via hydrogen bond interactions, thus, providing additional possibility for chemical modification to improve selectivity and/or physical properties of inhibitors.

  15. Application of thiopropyl sepharose 6B for removal of PCR inhibitors from DNA extracts of a thigh bone recovered from the sea

    DEFF Research Database (Denmark)

    Sørensen, Erik; Hansen, Steen Holger; Eriksen, Birthe;

    2003-01-01

    PCR amplification of DNA from forensic samples often proves difficult due to the presence of inhibitors of the polymerase chain reaction. One possible way to remove PCR inhibitors from a DNA extract is the use of the affinity resin thiopropyl sepharose 6B (TS), which has been used previously...... for the removal of PCR inhibitors in DNA extracts originating from stains on clothing. Here we show that TS is efficient also for the removal of inhibitors from PCR extracts from a highly decomposed human thigh bone. TS treatment, however, leads to a substantial loss of DNA making the technique best suited when...... substantial amounts of DNA are present....

  16. Tunneling magnetoresistance of silicon chains

    Science.gov (United States)

    Matsuura, Yukihito

    2016-05-01

    The tunneling magnetoresistance (TMR) of a silicon chain sandwiched between nickel electrodes was examined by using first-principles density functional theory. The relative orientation of the magnetization in a parallel-alignment (PA) configuration of two nickel electrodes enhanced the current with a bias less than 0.4 V compared with that in an antiparallel-alignment configuration. Consequently, the silicon chain-nickel electrodes yielded good TMR characteristics. In addition, there was polarized spin current in the PA configuration. The spin polarization of sulfur atoms functioning as a linking bridge between the chain and nickel electrode played an important role in the magnetic effects of the electric current. Moreover, the hybridization of the sulfur 3p orbital and σ-conjugated silicon 3p orbital contributed to increasing the total current.

  17. MODELING SUPPLY CHAIN PERFORMANCE VARIABLES

    Directory of Open Access Journals (Sweden)

    Ashish Agarwal

    2005-01-01

    Full Text Available In order to understand the dynamic behavior of the variables that can play a major role in the performance improvement in a supply chain, a System Dynamics-based model is proposed. The model provides an effective framework for analyzing different variables affecting supply chain performance. Among different variables, a causal relationship among different variables has been identified. Variables emanating from performance measures such as gaps in customer satisfaction, cost minimization, lead-time reduction, service level improvement and quality improvement have been identified as goal-seeking loops. The proposed System Dynamics-based model analyzes the affect of dynamic behavior of variables for a period of 10 years on performance of case supply chain in auto business.

  18. Who Manages Our Supply Chains?

    DEFF Research Database (Denmark)

    Flöthmann, Christoph

    to manage the manifold tasks they face on a daily basis. Unfortunately, as globalization has simultaneously increased the complexity of supply chains and the demand for highly qualified personnel, companies are facing a significant undersupply of talent (Cottrill, 2010). Moreover, organizations appear......While managers in traditional management functions focus on developing strong expertise to become “specialists” in their own discipline, supply chain managers are a different species: They have to combine a cross-functional understanding of various business fields and multi-faceted competencies...... to lack understanding of supply chain personnel and how to support their recruitment, succession planning, and training and development (John, 2015). Surprisingly, at the same time, scientific research on that topic is relatively scarce. In response, the overarching purpose of this paper...

  19. Designing the Reverse Supply Chain

    DEFF Research Database (Denmark)

    Gobbi, Chiara

    2011-01-01

    for the reverse supply chain. Design/methodology/approach – In order to identify the relevance of the Fisher model, the model needs to be recast in terms of PRV, which, in this context, is considered the independent variable in the reverse logistics arena. Products defined as innovative in Fisher's taxonomy......Purpose – The purpose of this paper is to explore the impact of the product residual value (PRV) and the loss of value over time of returned products in the reverse supply chain configuration. It also examines whether or not the distinction of Fisher's functional and innovative products holds...... correspond to disposed products with high residual value, whereas functional products correspond to disposed products with low residual value. Furthermore, the PRV and the speed at which returned products lose their value are considered in order to determine the configuration of the reverse supply chain...

  20. Markov chains and mixing times

    CERN Document Server

    Levin, David A; Wilmer, Elizabeth L

    2009-01-01

    This book is an introduction to the modern approach to the theory of Markov chains. The main goal of this approach is to determine the rate of convergence of a Markov chain to the stationary distribution as a function of the size and geometry of the state space. The authors develop the key tools for estimating convergence times, including coupling, strong stationary times, and spectral methods. Whenever possible, probabilistic methods are emphasized. The book includes many examples and provides brief introductions to some central models of statistical mechanics. Also provided are accounts of r

  1. Quantum crystals and spin chains

    Energy Technology Data Exchange (ETDEWEB)

    Dijkgraaf, Robbert [KdV Institute for Mathematics, University of Amsterdam, Plantage Muidergracht 24, 1018 TV Amsterdam (Netherlands); Institute for Theoretical Physics, University of Amsterdam, Valckenierstraat 65, 1018 XE Amsterdam (Netherlands); Orlando, Domenico [Institut de Physique, Universite de Neuchatel, Rue Breguet 1, CH-2000 Neuchatel (Switzerland); Reffert, Susanne [Institute for Theoretical Physics, University of Amsterdam, Valckenierstraat 65, 1018 XE Amsterdam (Netherlands)], E-mail: sreffert@gmail.com

    2009-04-21

    In this article, we discuss the quantum version of the melting crystal corner in one, two, and three dimensions, generalizing the treatment for the quantum dimer model. Using a mapping to spin chains we find that the two-dimensional case (growth of random partitions) is integrable and leads directly to the Hamiltonian of the Heisenberg XXZ ferromagnet. The three-dimensional case of the melting crystal corner is described in terms of a system of coupled XXZ spin chains. We give a conjecture for its mass gap and analyze the system numerically.

  2. Quantum crystals and spin chains

    Science.gov (United States)

    Dijkgraaf, Robbert; Orlando, Domenico; Reffert, Susanne

    2009-04-01

    In this article, we discuss the quantum version of the melting crystal corner in one, two, and three dimensions, generalizing the treatment for the quantum dimer model. Using a mapping to spin chains we find that the two-dimensional case (growth of random partitions) is integrable and leads directly to the Hamiltonian of the Heisenberg XXZ ferromagnet. The three-dimensional case of the melting crystal corner is described in terms of a system of coupled XXZ spin chains. We give a conjecture for its mass gap and analyze the system numerically.

  3. Thermodynamics of Dipolar Chain Systems

    DEFF Research Database (Denmark)

    R. Armstrong, J.; Zinner, Nikolaj Thomas; V. Fedorov, D.

    2012-01-01

    The thermodynamics of a quantum system of layers containing perpendicularly oriented dipolar molecules is studied within an oscillator approximation for both bosonic and fermionic species. The system is assumed to be built from chains with one molecule in each layer. We consider the effects...... numerically. Our findings indicate that thermodynamic observables, such as the heat capacity, can be used to probe the signatures of the intralayer interaction between chains. This should be relevant for near future experiments on polar molecules with strong dipole moments....

  4. Reseach of Supply Chain Modeling Technology

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    The supply chain modeling technology is research. Firstly, the concept of supply chain and supply chain management is introduced. Secondly, enterprise-modeling methods, such as CIM-OSA, GIM-GRAI, PERA and ARIS, are analyzed and compared. The supply chain modeling technology is studied. Then the ARIS-based supply chain modeling method is proposed and the supply chain operation reference model is set up. Finally, the applications of ARIS-based supply chain modeling method in Shanghai Turbine Generator Co. Ltd. (STGC) is described in detail.

  5. Proton pump inhibitors and gastroenteritis

    NARCIS (Netherlands)

    R.J. Hassing (Robert); A. Verbon (Annelies); H. de Visser (Herman); A. Hofman (Albert); B.H.Ch. Stricker (Bruno)

    2016-01-01

    textabstractAn association between proton pump inhibitor (PPI) therapy and bacterial gastroenteritis has been suggested as well as contradicted. The aim of this study was to examine the association between the use of PPIs and occurrence of bacterial gastroenteritis in the prospective Rotterdam Study

  6. Corrosion Inhibitors for Reinforced Concrete

    OpenAIRE

    ECT Team, Purdue

    2007-01-01

    Steel corrosion in reinforced concrete structures has been a major problem across the U.S. Steel-reinforced concrete structures are continually subject to attack by corrosion brought on by naturally occurring environmental conditions. FerroGard, a corrosion inhibitor, developed by Sika Corporation, penetrates hardened concrete to dramatically reduce corrosion by 65% and extend the structure's service life.

  7. Biocatalysts with enhanced inhibitor tolerance

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Shihui; Linger, Jeffrey; Franden, Mary Ann; Pienkos, Philip T.; Zhang, Min

    2015-12-08

    Disclosed herein are biocatalysts for the production of biofuels, including microorganisms that contain genetic modifications conferring tolerance to growth and fermentation inhibitors found in many cellulosic feedstocks. Methods of converting cellulose-containing materials to fuels and chemicals, as well as methods of fermenting sugars to fuels and chemicals, using these biocatalysts are also disclosed.

  8. Renal targeting of kinase inhibitors

    NARCIS (Netherlands)

    Dolman, M. E. M.; Fretz, M. M.; Segers, Gj. W.; Lacombe, M.; Prakash, J.; Storm, G.; Hennink, W. E.; Kok, R. J.

    2008-01-01

    Activation of proximal tubular cells by fibrotic and inflammatory mediators is an important hallmark of chronic kidney disease. We have developed a novel strategy to intervene in renal fibrosis, by means of locally delivered kinase inhibitors. Such compounds will display enhanced activity within tub

  9. Cellular Activity of New Small Molecule Protein Arginine Deiminase 3 (PAD3) Inhibitors.

    Science.gov (United States)

    Jamali, Haya; Khan, Hasan A; Tjin, Caroline C; Ellman, Jonathan A

    2016-09-08

    The protein arginine deiminases (PADs) catalyze the post-translational deimination of arginine side chains. Multiple PAD isozymes have been characterized, and abnormal PAD activity has been associated with several human disease states. PAD3 has been characterized as a modulator of cell growth via apoptosis inducing factor and has been implicated in the neurodegenerative response to spinal cord injury. Here, we describe the design, synthesis, and evaluation of conformationally constrained versions of the potent and selective PAD3 inhibitor 2. The cell activity of representative inhibitors in this series was also demonstrated for the first time by rescue of thapsigargin-induced cell death in PAD3-expressing HEK293T cells.

  10. Inactivation of Protein Tyrosine Phosphatases by Peracids Correlates with the Hydrocarbon Chain Length

    Directory of Open Access Journals (Sweden)

    Alicja Kuban-Jankowska

    2015-06-01

    Full Text Available Background/Aims: Protein tyrosine phosphatases are crucial enzymes controlling numerous physiological and pathophysiological events and can be regulated by oxidation of the catalytic domain cysteine residue. Peracids are highly oxidizing compounds, and thus may induce inactivation of PTPs. The aim of the present study was to evaluate the inhibitory effect of peracids with different length of hydrocarbon chain on the activity of selected PTPs. Methods: The enzymatic activity of human CD45, PTP1B, LAR, bacterial YopH was assayed under the cell-free conditions, and activity of cellular CD45 in human Jurkat cell lysates. The molecular docking and molecular dynamics were performed to evaluate the peracids binding to the CD45 active site. Results: Here we demonstrate that peracids reduce enzymatic activity of recombinant CD45, PTP1B, LAR, YopH and cellular CD45. Our studies indicate that peracids are more potent inhibitors of CD45 than hydrogen peroxide (with an IC50 value equal to 25 nM for peroctanoic acid and 8 µM for hydrogen peroxide. The experimental data show that the inactivation caused by peracids is dependent on hydrocarbon chain length of peracids with maximum inhibitory effect of medium-chain peracids (C8-C12 acyl chain, which correlates with calculated binding affinities to the CD45 active site. Conclusion: Peracids are potent inhibitors of PTPs with the strongest inhibitory effect observed for medium-chain peracids.

  11. Supply chain management and optimization in manufacturing

    CERN Document Server

    Pirim, Harun; Yilbas, Bekir Sami

    2014-01-01

    This book introduces general supply chain terminology particularly for novice readers, state of the art supply chain management and optimization issues and problems in manufacturing. The book provides insights for making supply chain decisions, planning and scheduling through supply chain network. It introduces optimization problems, i.e. transportation of raw materials, products and location, inventory of plants, warehouses and retailers, faced throughout the supply chain network.

  12. Precise low cost chain gears for heliostats

    Science.gov (United States)

    Liedke, Phillip; Lewandowski, Arkadiusz; Pfahl, Andreas; Hölle, Erwin

    2016-05-01

    This work investigates the potential of chain gears as precise and low cost driving systems for rim drive heliostats. After explaining chain gear basics the polygon effect and chain lengthening are investigated. The polygon effect could be measured by a heliostat with chain rim gear and the chain lengthening with an accordant test set up. Two gear stages are scope of this work: a rim gear and an intermediate gear. Dimensioning, pretensioning and designing for both stages are explained.

  13. Social Value Propagation for Supply Chain Formation

    OpenAIRE

    2013-01-01

    Supply Chain Formation is the process of determining the participants in a supply chain, who will exchange what with whom, and the terms of the exchanges. Decentralized supply chain formation appears as a highly intricate task because agents only possess local information, have limited knowledge about the capabilities of other agents, and prefer to preserve privacy. State-of-the-art decentralized supply chain formation approaches can either: (i) #12;find supply chains of high value at the ...

  14. Information system for the supply chain management

    OpenAIRE

    Delia Adriana Marincas

    2008-01-01

    Supply chain management SCM is the integration and management of supply chain organizations and activities through collaboration, effective business processes and high levels of information sharing. The supply chain concept has become a concern due to global competition and increasing customer demand for value. Thus, the information must be available in real time across the supply chain and this can not be achieved without an integrated software system for supply chain management. Supply chai...

  15. OVERVIEW OF CHINESE CHAIN CATERING MARKET

    OpenAIRE

    2012-01-01

    This thesis is a market overview for chain catering business situation in China. Chinese chain catering market is developing rapidly in recent years, it is a business where everybody can become a customer, but the business is highly competitive. The subject of this thesis is to give an overview of the market situation and strategies for market expansion of Chinese chain catering industry. It contains knowledge of chain management and introduction of Chinese chain catering ma...

  16. SUPPLY CHAIN MANAGEMENT – KEY FACTORS

    OpenAIRE

    Magdalena Daniela DINU

    2014-01-01

    This paper exposes Supply Chain Management by its key factors. Briefly, where the Supply Chain Management is treated as strategic part of a company then maintaining both control and influence throughout the entire supply chain are key factors and critical to success. On the other hand, finding the right partner to manage the non-strategic Supply Chains would be another key factor too. To define the most important key factors within Supply Chain Management means a deeply understanding of bot...

  17. Research on Integrated Green Supply Chain Management

    Institute of Scientific and Technical Information of China (English)

    DENG Lei; WANG Xu

    2006-01-01

    On the basis of the analyzing product life cycle and value chain management in green supply chain, integrated green supply chain is put forward and constructed which involve lean production, agile manufacturing and green supply chain. This integrated structure provides an effective method for resolving some questions such as cost, market, environment, etc. in enterprise. A case study is presented at the end of paper to demonstrate how integrated supply chain implemented successfully in enterprise.

  18. Inhibition of synthesis of heparan sulfate by selenate: Possible dependence on sulfation for chain polymerization

    Energy Technology Data Exchange (ETDEWEB)

    Dietrich, C.P.; Nader, H.B. (Paulist School of Medicine, Sao Paulo (Brazil)); Buonassisi, V.; Colburn, P. (W. Alton Jones Cell Science Center, Lake Placid, NY (USA))

    1988-01-01

    Selenate, a sulfation inhibitor, blocks the synthesis of heparan sulfate and chondroitin sulfate by cultured endothelial cells. In contrast, selenate does not affect the production of hyaluronic acid, a nonsulfated glycosaminoglycan. No differences in molecular weight, ({sup 3}H)glucosamine/({sup 35}S)sulfuric acid ratios, or disaccharide composition were observed when the heparan sulfate synthesized by selenate-treated cells was compared with that of control cells. The absence of undersulfated chains in preparations from cultures exposed to selenate supports the concept that, in the intact cell, the polymerization of heparan sulfate might be dependent on the sulfation of the saccharide units added to the growing glycosaminoglycan chain.

  19. Quadratic Variation by Markov Chains

    DEFF Research Database (Denmark)

    Hansen, Peter Reinhard; Horel, Guillaume

    We introduce a novel estimator of the quadratic variation that is based on the the- ory of Markov chains. The estimator is motivated by some general results concerning filtering contaminated semimartingales. Specifically, we show that filtering can in prin- ciple remove the effects of market...

  20. Spin Chains and Gustafson's Integrals

    CERN Document Server

    Derkachov, S E

    2016-01-01

    The Gustafson's integrals are the multidimensional generalization of the classical Mellin--Barnes integrals. We show that some of these integrals arise from relations between matrix elements in the Sklyanin's representation of Separated Variables in the spin chain models. We also present several new integrals.

  1. Concurrent Product & Supply Chain Creation

    DEFF Research Database (Denmark)

    Gubi, Ebbe

    it is a structural premise. We also know that logistics costs generally are estimated 15-20% of total product costs. Accordingly, it stands to reason that a company can reduce costs, and thereby gain an edge on its competitors, by tailoring the supply chain in question to an individual product or product family; i...

  2. Replicator dynamics in value chains

    DEFF Research Database (Denmark)

    Cantner, Uwe; Savin, Ivan; Vannuccini, Simone

    2016-01-01

    dynamics may revert its effect. In these regressive developments of market selection, firms with low fitness expand because of being integrated with highly fit partners, and the other way around; ii) allowing partner's switching within a value chain illustrates that periods of instability in the early...

  3. Maximal right smooth extension chains

    CERN Document Server

    Huang, Yun Bao

    2010-01-01

    If $w=u\\alpha$ for $\\alpha\\in \\Sigma=\\{1,2\\}$ and $u\\in \\Sigma^*$, then $w$ is said to be a \\textit{simple right extension}of $u$ and denoted by $u\\prec w$. Let $k$ be a positive integer and $P^k(\\epsilon)$ denote the set of all $C^\\infty$-words of height $k$. Set $u_{1},\\,u_{2},..., u_{m}\\in P^{k}(\\epsilon)$, if $u_{1}\\prec u_{2}\\prec ...\\prec u_{m}$ and there is no element $v$ of $P^{k}(\\epsilon)$ such that $v\\prec u_{1}\\text{or} u_{m}\\prec v$, then $u_{1}\\prec u_{2}\\prec...\\prec u_{m}$ is said to be a \\textit{maximal right smooth extension (MRSE) chains}of height $k$. In this paper, we show that \\textit{MRSE} chains of height $k$ constitutes a partition of smooth words of height $k$ and give the formula of the number of \\textit{MRSE} chains of height $k$ for each positive integer $k$. Moreover, since there exist the minimal height $h_1$ and maximal height $h_2$ of smooth words of length $n$ for each positive integer $n$, we find that \\textit{MRSE} chains of heights $h_1-1$ and $h_2+1$ are good candidates t...

  4. Towards biotracing in food chains

    DEFF Research Database (Denmark)

    Hoorfar, Jeffrey; Wagner, Martin; Jordan, Kieran

    2011-01-01

    , and 21 cross-disciplinary work packages that cover tracing and tracking of contamination in feed, meat and dairy chains, in addition to accidental and deliberate contamination of bottled water. The BIOTRACER Consortium consists of 46 partners, including Europe's largest food/feed industries, several SMEs...

  5. Supply Chain Simulation : A Survey

    NARCIS (Netherlands)

    Kleijnen, J.P.C.

    2003-01-01

    This paper provides a survey of simulation in supply chain management.It reviews four types of simulation, namely spreadsheet simulation, system dynamics, discreteevent simulation, and business games.Which simulation type should be applied, depends on the type of managerial question to be answered b

  6. Labour in Global Value Chains

    DEFF Research Database (Denmark)

    Lund-Thomsen, Peter; Nadvi, Khalid; Chan, Anita

    2012-01-01

    A critical challenge facing developing country producers is to meet international labour standards and codes of conduct in order to engage in global value chains. Evidence of gains for workers from compliance with such standards and codes remains limited and patchy. This article focuses on the gl......A critical challenge facing developing country producers is to meet international labour standards and codes of conduct in order to engage in global value chains. Evidence of gains for workers from compliance with such standards and codes remains limited and patchy. This article focuses...... on the global football industry, a sector dominated by leading global brands that manage dispersed global value chains. It assesses the working conditions for football stitchers engaged in different forms of work organization, factories, stitching centres and home-based settings in Pakistan, India and China...... production contexts that influence work conditions. In doing so, it argues that current debates on the role of labour in global value chains have to go beyond a narrow focus on labour standards and corporate social responsibility compliance and engage with economic, technological and social upgrading...

  7. Supply chain challenges. building relationships.

    Science.gov (United States)

    Beth, Scott; Burt, David N; Copacino, William; Gopal, Chris; Lee, Hau L; Lynch, Robert Porter; Morris, Sandra

    2003-07-01

    Supply chain management is all about software and systems, right? Put in the best technology, sit back, and watch as your processes run smoothly and the savings roll in? Apparently not. When HBR convened a panel of leading thinkers in the field of supply chain management, technology was not top of mind. People and relationships were the dominant issues of the day. The opportunities and problems created by globalization, for example, are requiring companies to establish relationships with new types of suppliers. The ever-present pressure for speed and cost containment is making it even more important to break down stubbornly high internal barriers and establish more effective cross-functional relationships. The costs of failure have never been higher. The leading supply chain performers are applying new technology, new innovations, and process thinking to far greater advantage than the laggards, reaping tremendous gains in all the variables that affect shareholder value: cost, customer service, asset productivity, and revenue generation. And the gap between the leaders and the losers is growing in almost every industry. This roundtable gathered many of the leading thinkers and doers in the field of supply chain management, including practitioners Scott Beth of Intuit, Sandra Morris of Intel, and Chris Gopal of Unisys. David Burt of the University of San Diego and Stanford's Hau Lee bring the latest research from academia. Accenture's William Copacino and the Warren Company's Robert Porter Lynch offer the consultant's perspectives. Together, they take a wide-ranging view of such topics as developing talent, the role of the chief executive, and the latest technologies, exploring both the tactical and the strategic in the current state of supply chain management.

  8. Nicotinamide phosphoribosyltransferase inhibitors, design, preparation and SAR

    DEFF Research Database (Denmark)

    Christensen, Mette Knak; Erichsen, Kamille Dumong; Olesen, Uffe Hogh;

    2013-01-01

    Existing pharmacological inhibitors for nicotinamide phosphoribosyltransferase (NAMPT) are promising therapeutics for treating cancer. Using medicinal and computational chemistry methods, the structure-activity relationship for novel classes of NAMPT inhibitors is described and compounds optimized....... Compounds are designed inspired by the NAMPT inhibitor APO866 and cyanoguanidine inhibitor scaffolds. In comparison with recently published derivatives the new analogues exhibit an equally potent anti-proliferative activity in vitro and comparable activity in vivo. The best performing compounds from...

  9. Efficacy of new inhibitors of ethylene perception in improvement of display quality of miniature potted roses (Rosa hybrida L.)

    DEFF Research Database (Denmark)

    Buanong, Mantana; Mibus, Heiko; Sisler, Edward C.

    2005-01-01

    1-Octylcyclopropene (1-OCP)and 1-Decylcyclopropene (1-DCP),ethylene receptor inhibitors,analogues to 1-MCP,substituted with longer carbon chain in the 1-position were investigated in miniature potted roses cultivar ‘Lavender ’.All levels of both chemicals protected as compared to untreated plants...

  10. Allosteric small-molecule kinase inhibitors

    DEFF Research Database (Denmark)

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

    2015-01-01

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

  11. Supply Chain Management Practices in Toy Supply Chains

    DEFF Research Database (Denmark)

    Wong, Chee Yew; Arlbjørn, Jan Stentoft; Johansen, John

    2005-01-01

    qualitative semi-structured interviews and questionnaire with 11 main European toy retailers. Findings - The study concludes that there are three main SCM practices for toy retailers in terms of ordering behaviours (one-off, JIT, and mixed model), and one dominated SCM practice for toy manufacturers...... are required for such extreme volatility and seasonality are proposed. Originality/value - It reveals actual SCM practices in a volatile and seasonal supply chain, such that theoretical and practical gaps are identified. Also, it proposes a model to match manufacturing SCM-practices with retailer SCM-practices.......Purpose - Innovative products usually experience highly unpredictable and variable demand. This is especially valid for the volatile and seasonal toy industry, which produces high obsolete inventory, lost sales and markdown. In such a volatile industry, what supply chain management (SCM) practices...

  12. Supply Chain Management Performance in Tourism. Continental Hotels Chain Case

    OpenAIRE

    Gabriela Ţigu; Bogdan Călăreţu

    2013-01-01

    With its origins in logistics, Supply Chain Management (SCM) concept is covering all managerial aspects of the flow of materials and information from source to customer, across the entire range of materials handling and movement functions, and throughout an organization and its supply channels. In tourism, these issues relate to the whole process of providing tourism services from sourcing of raw materials, products or different services) to supply and distribution, and SCM performance can ul...

  13. chains

    Directory of Open Access Journals (Sweden)

    Gabriel Pérez-Salas

    2015-01-01

    Full Text Available Las barreras y aranceles al comercio exterior han disminuido significativamente gracias a los acuerdos multilaterales y los mecanismos de integración entre las naciones. Los costos logísticos representan una proporción significativa del precio final de los artículos, especialmente de los commodities. Por esta razón, minimizar los costos logísticos es un desafío importante para las naciones para fomentar la competitividad del comercio exterior y en particular para aprovechar la renta de los recursos naturales. En este artículo, proponemos un marco de referencia integral para la medición de costos logísticos, enfocado en determinar los extra-costos que resultan por procedimientos ineficientes y la falta de políticas públicas y regulaciones de las entidades públicas. Estos elementos no han sido considerados en la literatura, y este artículo aborda esta brecha. Como caso de estudio, presentamos la aplicación del marco de referencia para estimar los extra-costos en algunas cadenas logísticas de recursos naturales en Bolivia. Se presenta una discusión de los resultados encontrados, así como recomendaciones para trabajo futuro.

  14. Conversion of calcineurin inhibitors with mammalian target of rapamycin inhibitors after kidney transplant.

    Science.gov (United States)

    Nikoueinejad, Hassan; Soleimani, Alireza; Mirshafiey, Abbas; Amirzargar, Aliakbar; Sarrafnejad, Abdolfattah; Kamkar, Ideh; Einollahi, Behzad

    2013-02-01

    One way to overcome chronic allograft nephropathy induced by calcineurin inhibitors in immunosuppression protocols for organ transplants is to replace such inhibitors with mammalian target of rapamycin inhibitors, which are not clinically nephrotoxic because they have better renal function. If patients tolerate replacement, there could be a clear preference for mammalian target of rapamycin inhibitors as a maintenance immunosuppressant after renal transplant. This replacement could be sufficient if it were used for a certain time after calcineurin inhibitors. This review considers the conversion effects of calcineurin inhibitors with mammalian target of rapamycin inhibitors from the view point of kidney function during different periods after a kidney transplant.

  15. PCR inhibitor removal using the NucleoSpin® DNA Clean-Up XS kit.

    Science.gov (United States)

    Faber, Korie L; Person, Eric C; Hudlow, William R

    2013-01-01

    Forensic evidence samples are collected from an unlimited variety of substrates, which may contain compounds known to inhibit the polymerase chain reaction (PCR). These PCR inhibitors are co-extracted with the DNA sample and can negatively affect the DNA typing results, which can range from partial to complete inhibition of the short tandem repeat (STR) PCR. One potential solution is to remove the PCR inhibitors from the extracts prior to the STR PCR with the NucleoSpin(®) DNA Clean-Up XS kit. The kit contains a NucleoSpin(®) XS silica column that has a special funnel design of thrust rings along with a very small silica membrane, which allows for sample elution in a small volume that is appropriate for use with current STR typing kits. The NucleoSpin(®) DNA Clean-Up XS kit was optimized for the best possible DNA recovery and then evaluated for its ability to remove eight commonly encountered PCR inhibitors including: bile salt, collagen, hematin, humic acid, indigo, melanin, tannic acid and urea. Each of these PCR inhibitors was effectively removed by the NucleoSpin(®) DNA Clean-Up XS kit as demonstrated by generating more complete STR profiles from the cleaned up inhibitor samples than from the raw inhibitor samples.

  16. Covalent docking of selected boron-based serine beta-lactamase inhibitors

    Science.gov (United States)

    Sgrignani, Jacopo; Novati, Beatrice; Colombo, Giorgio; Grazioso, Giovanni

    2015-05-01

    AmpC β-lactamase is a hydrolytic enzyme conferring resistance to β-lactam antibiotics in multiple Gram-negative bacteria. Therefore, identification of non-β-lactam compounds able to inhibit the enzyme is crucial for the development of novel antibacterial therapies. In general, AmpC inhibitors have to engage the highly solvent-exposed catalytic site of the enzyme. Therefore, understanding the implications of ligand-protein induced-fit and water-mediated interactions behind the inhibitor-enzyme recognition process is fundamental for undertaking structure-based drug design process. Here, we focus on boronic acids, a promising class of beta-lactamase covalent inhibitors. First, we optimized a docking protocol able to reproduce the experimentally determined binding mode of AmpC inhibitors bearing a boronic group. This goal was pursued (1) performing rigid and flexible docking calculations aiming to establish the role of the side chain conformations; and (2) investigating the role of specific water molecules in shaping the enzyme active site and mediating ligand protein interactions. Our calculations showed that some water molecules, conserved in the majority of the considered X-ray structures, are needed to correctly predict the binding pose of known covalent AmpC inhibitors. On this basis, we formalized our findings in a docking and scoring protocol that could be useful for the structure-based design of new boronic acid AmpC inhibitors.

  17. Notch Inhibitors for Cancer Treatment

    OpenAIRE

    Espinoza, Ingrid; Miele, Lucio

    2013-01-01

    Notch signaling is an evolutionarily conserved cell signaling pathway involved in cell fate during development, stem cell renewal and differentiation in postnatal tissues. Roles for Notch in carcinogenesis, in the biology of cancer stem cells and tumor angiogenesis have been reported. These features identify Notch as a potential therapeutic target in oncology. Based on the molecular structure of Notch receptor, Notch ligands and Notch activators, a set of Notch pathway inhibitors have been de...

  18. Nelfinavir: fourth protease inhibitor approved.

    Science.gov (United States)

    1997-01-01

    The Food and Drug Administration (FDA) has granted accelerated approval to nelfinavir in both adult and pediatric formulations. Agouron, the manufacturer, used innovative computerized drug design techniques to discover, design, and refine the nelfinavir molecule. Nelfinavir is marketed under the trade name Viracept, and costs $5,000 per year. Early clinical trials find it to be as powerful as the other protease inhibitors, but with a different resistance profile. The drug has relatively few drug indications; however, several compounds have been contraindicated.

  19. The fishing industry - toward supply chain modelling

    DEFF Research Database (Denmark)

    Jensen, Toke Koldborg; Nielsen, Jette; Larsen, Erling P.

    Mathematical models for simulating and optimizing supply chain aspects such as distribution planning and optimal use of raw materials are widely used. However, modelling based on a holistic chain view is less studied, and food-related aspects such as quality and shelf life issues enforce additional...... requirements onto the chains. In this paper, we consider the supply chain structure of the Danish fishing industry and illustrate the potential of using mathematical models to identify quality and value-adding activities. This is a first step toward innovative supply chain modelling aimed to identify benefits...... for actors along chains in the fishing industry....

  20. The chain relation in sofic subshifts

    CERN Document Server

    Kazda, Alexandr

    2009-01-01

    The paper gives a characterisation of the chain relation of a sofic subshift. Every sofic subshift $\\Sigma$ can be described by a labelled graph $G$. Factorising $G$ in a suitable way we obtain the graph $G/_\\approx$ that offers insight into some properties of the original subshift. Using $G/_\\approx$ we describe first the chain relation in $\\Sigma$, then characterise chain-transitive sofic subshifts, chain-mixing sofic subshifts and finally the attractors of the subshift dynamic system. At the end we present (straightforward) algorithms deciding chain-transitivity and chain-mixing properties of a sofic subshift and listing all the attractors of the subshift system.

  1. Carbonic anhydrase inhibitors drug design.

    Science.gov (United States)

    McKenna, Robert; Supuran, Claudiu T

    2014-01-01

    Inhibition of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) has pharmacologic applications in the field of antiglaucoma, anticonvulsant, antiobesity, and anticancer agents but is also emerging for designing anti-infectives (antifungal and antibacterial agents) with a novel mechanism of action. As a consequence, the drug design of CA inhibitors (CAIs) is a very dynamic field. Sulfonamides and their isosteres (sulfamates/sulfamides) constitute the main class of CAIs which bind to the metal ion in the enzyme active site. Recently the dithiocarbamates, possessing a similar mechanism of action, were reported as a new class of inhibitors. Other families of CAIs possess a distinct mechanism of action: phenols, polyamines, some carboxylates, and sulfocoumarins anchor to the zinc-coordinated water molecule. Coumarins and five/six-membered lactones are prodrug inhibitors, binding in hydrolyzed form at the entrance of the active site cavity. Novel drug design strategies have been reported principally based on the tail approach for obtaining all these types of CAIs, which exploit more external binding regions within the enzyme active site (in addition to coordination to the metal ion), leading thus to isoform-selective compounds. Sugar-based tails as well as click chemistry were the most fruitful developments of the tail approach. Promising compounds that inhibit CAs from bacterial and fungal pathogens, of the dithiocarbamate, phenol and carboxylate types have also been reported.

  2. Substituted androstanes as aromatase inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Levina, Inna S [N.D.Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow (Russian Federation)

    1998-11-30

    The synthesis and structure-activity relationships of inhibitors of steroid aromatase which catalyses the last stage of a multistep biotransformation of cholesterol into estrogens, viz., aromatisation of C{sub 19}-steroids into C{sub 18}-phenolic steroids, are discussed. Compounds of the androstane series which are structurally related to the natural substrate, viz., androst-4-ene-3,17-dione, are the subjects of consideration. The review encompasses problems of synthesis of various substituted androstanes and their aromatase-inhibiting activities and structural requirements for selective specific aromatase inhibitors based on in vitro and in vivo structure-activity studies of compounds synthesised, their biological properties and the results of clinical trials. Special attention is paid to practical applications of aromatase inhibitors in the treatment of hormone-dependent mammary and ovarian tumours as well as benign prostatic tumours. In writing this report, the author has used all the information currently available in the chemical, biochemical, endocrinological and medicinal literature as well as in patents. The bibliography includes 173 references.

  3. Substituted androstanes as aromatase inhibitors

    Science.gov (United States)

    Levina, Inna S.

    1998-11-01

    The synthesis and structure-activity relationships of inhibitors of steroid aromatase which catalyses the last stage of a multistep biotransformation of cholesterol into estrogens, viz., aromatisation of C19-steroids into C18-phenolic steroids, are discussed. Compounds of the androstane series which are structurally related to the natural substrate, viz., androst-4-ene-3,17-dione, are the subjects of consideration. The review encompasses problems of synthesis of various substituted androstanes and their aromatase-inhibiting activities and structural requirements for selective specific aromatase inhibitors based on in vitro and in vivo structure-activity studies of compounds synthesised, their biological properties and the results of clinical trials. Special attention is paid to practical applications of aromatase inhibitors in the treatment of hormone-dependent mammary and ovarian tumours as well as benign prostatic tumours. In writing this report, the author has used all the information currently available in the chemical, biochemical, endocrinological and medicinal literature as well as in patents. The bibliography includes 173 references.

  4. A cyclic peptidic serine protease inhibitor

    DEFF Research Database (Denmark)

    Zhao, Baoyu; Xu, Peng; Jiang, Longguang;

    2014-01-01

    Peptides are attracting increasing interest as protease inhibitors. Here, we demonstrate a new inhibitory mechanism and a new type of exosite interactions for a phage-displayed peptide library-derived competitive inhibitor, mupain-1 (CPAYSRYLDC), of the serine protease murine urokinase...... pocket, its carbonyl group aligning improperly relative to Ser195 and the oxyanion hole, explaining why the peptide is an inhibitor rather than a substrate. Substitution of the P1 Arg with novel unnatural Arg analogues with aliphatic or aromatic ring structures led to an increased affinity, depending...... of this peptidic inhibitor, a concept different from conventional attempts at improving inhibitor affinity by reducing the entropic burden....

  5. Conformation-specific inhibitors of Raf kinases.

    Science.gov (United States)

    Wang, Xiaolun; Schleicher, Kristin

    2013-01-01

    Since the discovery linking B-Raf mutations to human tumors in 2002, significant advances in the development of Raf inhibitors have been made, leading to the recent approval of two Raf inhibitor drugs. This chapter includes a brief introduction to B-Raf as a validated target and focuses on the three different binding modes observed with Raf small-molecule inhibitors. These various binding modes lock the Raf kinase in different conformations that impact the toxicity profiles of the inhibitors. Possible solutions to mitigate the side effects caused by inhibitor-induced dimerization are also discussed.

  6. Single-Chain Antibody Fragment VEGF Inhibitor RTH258 for Neovascular Age-Related Macular Degeneration

    DEFF Research Database (Denmark)

    Holz, Frank G; Dugel, Pravin U; Weissgerber, Georges

    2016-01-01

    PURPOSE: To assess the safety and efficacy of different doses of RTH258 applied as single intravitreal administration compared with ranibizumab 0.5 mg in patients with neovascular age-related macular degeneration (AMD). DESIGN: Six-month, phase 1/2, prospective, multicenter, double-masked, random...

  7. Synthesis of lipophilic 1-deoxygalactonojirimycin derivatives as D-galactosidase inhibitors

    Directory of Open Access Journals (Sweden)

    Georg Schitter

    2010-03-01

    Full Text Available N-Alkylation at the ring nitrogen of the D-galactosidase inhibitor 1-deoxygalactonojirimycin with a functionalised C6 alkyl chain followed by modification with different aromatic substituents provided lipophilic 1-deoxygalactonojirimycin derivatives which exhibit inhibitory properties against β-glycosidases from E. coli and Agrobacterium sp. as well as green coffee bean α-galactosidase. In preliminary studies, these compounds also showed potential as chemical chaperones for GM1-gangliosidosis related β-galactosidase mutants.

  8. VALUE CHAINS IN EMERGING MARKETS

    Directory of Open Access Journals (Sweden)

    Abdyramanova, Z.

    2016-11-01

    Full Text Available The textiles sector is one of the main industry sectors in Kyrgyzstan in terms of output, employment and increasingly exports. Textile clusters are developing and patterns in cluster formations are emerging that reflect the differing economic conditions of the regions, demonstrating particular influences on the value chain. These differences are both depicted in the two regions of Kyrgyzstan-south and north. In the north of the Republic the infrastructure is more developed, there is greater facility to access international markets (exports. In the south the infrastructure is less developed, and garment producers in the region serve mainly local niche and near-neighbour markets. The research objective is to assess the key drivers of the value chain and profitability in the textiles sector in Kyrgyzstan, by comparing the garment sewing sector in the two contrasting regions of south and north Kyrgyzstan.

  9. Formation of helical ion chains

    CERN Document Server

    Nigmatullin, Ramil; De Chiara, Gabriele; Morigi, Giovanna; Plenio, Martin B; Retzker, Alex

    2011-01-01

    We study the nonequilibrium dynamics of the linear to zigzag structural phase transition exhibited by an ion chain confined in a trap with periodic boundary conditions. The transition is driven by reducing the transverse confinement at a finite quench rate, which can be accurately controlled. This results in the formation of zigzag domains oriented along different transverse planes. The twists between different domains can be stabilized by the topology of the trap and under laser cooling the system relaxes to a helical chain with possibly nonzero winding number. Molecular dynamics simulations are used to obtain a large sample of possible trajectories for different quench rates. The scaling of the average winding number with different quench rates is compared to the prediction of the Kibble-Zurek theory, and a good quantitative agreement is found.

  10. Supply Chain Reorganization and Coordination

    Institute of Scientific and Technical Information of China (English)

    WANG Feng-bin

    2001-01-01

    Three generic forms of governance--hierarchy, hybrid and market are proposed in the newinstitutional economics, giving an abstract description of alternative coordination and control mechanisms forgeneral use. While this theory is known as far away from being operational and specified, a few researchersin the management and organization area are trying to extend Galbraith and/or Mintzberg's organizationaldesign theories into the application of logistical coordination for obtaining a smooth flow of products along thesupply chain within and without the focal organization. In this paper, we present an explorative case study onthe design of various organizational architectures of logistics activities and their relevant coordinationmechanisms, especially internal and external contracts as one new kind of hybrid mechanisms forcoordinating effective supply chains.

  11. Mobilizing Sustainable Bioenergy Supply Chains

    OpenAIRE

    Baxter, David; Cowie, Annette; BERNDES Goran; Junginger, Martin; MCMILLAN James D; Saddler, J N; VAN REE Rene

    2015-01-01

    Analysis of the five globally significant supply chains conducted by IEA Bioenergy inter-Task teams – boreal and temperate forests, agricultural crop residues, biogas, lignocellulosic crops, and cultivated grasslands and pastures in Brazil – has confirmed that feedstocks produced using logistically efficient production systems can be mobilized to make significant contributions to achieving global targets for bioenergy. However, the very significant challenges identified in this report indi...

  12. China's Role in Purchasing Chain

    Institute of Scientific and Technical Information of China (English)

    Eva; Alice

    2007-01-01

    @@ In current world market,"Made-in-China"often means good price and competitive quality.In terms of China's trade pattern,more than half of Chinese exporting products belong to processing trade industry according to the demands and requirements of international orders.On the purchasing chain,China is learning from its international partners.Safety and quality always tops all issues.

  13. The dynamic chain event graph

    OpenAIRE

    2015-01-01

    In this paper we develop a formal dynamic version of Chain Event Graphs (CEGs), a particularly expressive family of discrete graphical models. We demonstrate how this class links to semi-Markov models and provides a convenient generalization of the Dynamic Bayesian Network (DBN). In particular we develop a repeating time-slice Dynamic CEG providing a useful and simpler model in this family. We demonstrate how the Dynamic CEG’s graphical formulation exhibits asymmetric conditional independence...

  14. On Markov Chains and Filtrations

    OpenAIRE

    1997-01-01

    In this paper we rederive some well known results for continuous time Markov processes that live on a finite state space.Martingale techniques are used throughout the paper. Special attention is paid to the construction of a continuous timeMarkov process, when we start from a discrete time Markov chain. The Markov property here holds with respect tofiltrations that need not be minimal.

  15. Modeling Continuous IED Supply Chains

    Science.gov (United States)

    2014-03-27

    criminals, pirates, drug traffickers and terrorists. Moreover, JIEDDO has pointed out the spread of IED use to places such as Thailand and Norway. U.S... human networks that place IEDs. Dekker categorizes two main human aspects of IED placement. The first is motivation which 8 affects the number of...methods provided in this thesis and apply them to combat other threats. For example, drug trafficking supply chains. IED and drug trafficking supply

  16. Supply-Chain Risk Analysis

    Science.gov (United States)

    2016-06-07

    Classic Buffer Overflow 1. http://cwe.mitre.org/top25/ SANS (SysAdmin, Audit, Network , Security ) Institute 23 Veracode: State of Software Security ...Approved for public release; distribution unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT 15. SUBJECT TERMS 16. SECURITY CLASSIFICATION OF: 17...supply-chain risks. He participated in the design and development of the DHS Build- Security -In Web site and continues to contribute articles to it

  17. Synchronization Algorithms on Oriented Chains

    Directory of Open Access Journals (Sweden)

    D. Bein

    2008-01-01

    Full Text Available We present a space- and time-optimal self-stabilizing algorithm, SSDS, for a given synchronization problem on asynchronous oriented chains. SSDS is uniform and works under the unfair distributed daemon. From SSDS we derive solutions for the local mutual exclusion and distributed sorting. Algorithm SSDS can also be used to obtain optimal space solutions for other problems such as broadcasting, leader election, and mutual exclusion.

  18. Supply Chain Performance Evaluation: Trends and Challenges

    Directory of Open Access Journals (Sweden)

    Ezutah U. Olugu

    2009-01-01

    Full Text Available Problem statement: In today’s manufacturing world, globalization policies and rejuvenation have created a more intensive competition amongst manufacturers. On the other hand, manufacturers have turned to the option of adopting innovative technologies, process re-engineering and strategies such as efficient supply chain management to achieve a sustainable competitive advantage. Effective supply chain performance measurement has been identified as a key issue towards efficient supply chain management. To explore the extent of research in supply chain performance measurement and establish the gap in knowledge in supply chain performance measurement using fuzzy logic operation. Approach: Literatures in the area of supply chain performance measurement had been extensively reviewed. Both traditional and fuzzy logic approaches to supply chain performance measurement were scrutinized. Further scrutiny was carried out to establish potential research areas in the application of fuzzy logic operations in supply chain performance measurement. Results: The supply chain performance measurement using fuzzy logic operation was identified as a new direction in measuring the uncertainty and ambiguity surrounding supply chain performance measurement. Direction for further studies in the application of fuzzy logic operation in supply chain management and its performance measurement were also identified. Conclusion: Result of this study implied that there is still a gap in knowledge in the area of supply chain performance measurement. This new direction of studies involved extending the existing supply chains to incorporate product recovery after the useful life.

  19. Dynamics of the substrate binding pocket in the presence of an inhibitor covalently attached to a fungal lipase.

    Science.gov (United States)

    Peters, G H; Jensen, M O; Bywater, R P

    2001-08-01

    To gain insight into the mobility of the occupied ligand-binding pocket of the Rhizomucor miehei lipase we have conducted a rigorous molecular dynamics analysis. The covalently attached inhibitor, ethylhexylphosphonate, was employed as a mimic of the putative tetrahedral intermediate in the esterolytic reaction. Our results show that in this lipase, ligand recognition is influenced by the flexibility of the binding pocket, a feature that is common to many other enzymes. Several regions around the active site were found to move significantly to adapt to the inhibitor. These motions are correlated to the flexibility of the inhibitor. In particular, the hexyl chain of the inhibitor shows considerable mobility, and adjacent residues in the binding cleft accommodate to this flexibility. Pronounced fluctuations in the binding pocket induced by the flexibility of the inhibitor are observed in the hinge region F79-S82, the active site loop region W88-V95 and the protein regions P209-F215/H257-Y260. The flexibility in the regions F79-S82 and H257-Y260, where the shorter ethyl chain is located, indicates that additional space in this binding cleft region is available for accommodating a larger moiety. Fluctuations in the region W88-V95 and P209-F215 are due to the relatively short flexible hexyl carbon chain. This part of the binding pocket could be stiffened by the presence of a longer carbon chain. Though the inhibitor is covalently attached through the phosphonate moiety, interaction of the remainder of the molecule and the enzyme are determined by hydrophobic interactions, where the Van der Waals energies are approximately 25% lower than the electrostatic contributions.

  20. ARCHITECTURAL CONCEPTS FOR VALUE CHAINS

    Directory of Open Access Journals (Sweden)

    A.C. Janse van Rensburg

    2012-01-01

    Full Text Available

    ENGLISH ABSTRACT:The Porter Value Chain has been widely adopted by the business community as a mechanism to understand and comprehend complexity in business environments, with the ultimate goal of structuring the business to maximize its competitive advantage. Implementing the Value Chain is not easy: a number of organizations can testify to their failure to derive any benefits at all from this concept. To overcome this problem, an approach is presented to assist the organization in creating a Value Chain reference model within the broader context of the organization’s enterprise architecture.

    AFRIKAANSE OPSOMMING: Die “Porter Waardeketting” is ’n algemene aanvaarde praktyk wat deur maatskappye gebruik word om die kompleksiteit van besigheidsomgewings mee te verstaan. Die uiteindelike doel hiervan is om die besigheid se mededings voordele te optimiseer. Om die Waardekettingkonsep te implementeer, is nie ’n maklike taak nie – verskeie organisasies kan getuig van mislukte implementeringspogings. Hierdie artikel beskryf ’n benadering beskryf wat gebruik kan word om die organisasie te help om ’n Waardekettingmodel te skep in die bree konteks van die organisasie se besigheidsargitektuur.

  1. Towards biotracing in food chains.

    Science.gov (United States)

    Hoorfar, Jeffrey; Wagner, Martin; Jordan, Kieran; Bouquin, Solveig Lind; Skiby, Jeffrey

    2011-03-01

    Biotracing is tracing (backward)/tracking (forward) biological contamination in the food/feed chain. Advances in detection technologies, improvements in molecular marker identification, clearer understanding of pathogenicity markers, improved modelling methodologies and, more importantly, the integration of these disciplines will lead to better capability in full-chain tracing and tracking biological contaminations (biotracing). The advantages of improved biotraceability are faster intervention, limited recalls and more targeted remedial action. The project is not dealing with risk assessments but developing tools that can be used in "second-generation" risk assessments involving quantitative microbiology. This concept is the core activity of BIOTRACER, which is an Integrated Project (2007-2011) funded by the EU 6th Framework Programme. The research in biotracing is organised into five Research Areas, and 21 cross-disciplinary work packages that cover tracing and tracking of contamination in feed, meat and dairy chains, in addition to accidental and deliberate contamination of bottled water. The BIOTRACER Consortium consists of 46 partners, including Europe's largest food/feed industries, several SMEs, and relevant International Cooperation (INCO) countries. The Consortium includes experts in predictive microbiology, database developers, software companies, risk assessors, risk managers, system biologists, food and molecular microbiologists, legislative officers, standardization and validation members and food retailers. The outcomes will ensure a more reliable and rapid response to a microbial contamination event.

  2. Agrobacterium-mediated transformation of chickpea with -amylase inhibitor gene for insect resistance

    Indian Academy of Sciences (India)

    S Ignacimuthu; S Prakash

    2006-09-01

    Chickpea is the world’s third most important pulse crop and India produces 75% of the world’s supply. Chickpea seeds are attacked by Callosobruchus maculatus and C. chinensis which cause extensive damage. The -amylase inhibitor gene isolated from Phaseolus vulgaris seeds was introduced into chickpea cultivar K850 through Agrobacterium-mediated transformation. A total of 288 kanamycin resistant plants were regenerated. Only 0.3% of these were true transformants. Polymerase chain reaction (PCR) analysis and Southern hybridization confirmed the presence of 4.9 kb -amylase inhibitor gene in the transformed plants. Western blot confirmed the presence of -amylase inhibitor protein. The results of bioassay study revealed a significant reduction in the survival rate of bruchid weevil C. maculatus reared on transgenic chickpea seeds. All the transgenic plants exhibited a segregation ratio of 3:1.

  3. Phenylalanine and Phenylglycine Analogues as Arginine Mimetics in Dengue Protease Inhibitors.

    Science.gov (United States)

    Weigel, Lena F; Nitsche, Christoph; Graf, Dominik; Bartenschlager, Ralf; Klein, Christian D

    2015-10-01

    Dengue virus is an increasingly global pathogen. One of the promising targets for antiviral drug discovery against dengue and related flaviviruses such as West Nile virus is the viral serine protease NS2B-NS3. We here report the synthesis and in vitro characterization of potent peptidic inhibitors of dengue virus protease that incorporate phenylalanine and phenylglycine derivatives as arginine-mimicking groups with modulated basicity. The most promising compounds were (4-amidino)-L-phenylalanine-containing inhibitors, which reached nanomolar affinities against dengue virus protease. The type and position of the substituents on the phenylglycine and phenylalanine side chains has a significant effect on the inhibitory activity against dengue virus protease and selectivity against other proteases. In addition, the non-natural, basic amino acids described here may have relevance for the development of other peptidic and peptidomimetic drugs such as inhibitors of the blood clotting cascade.

  4. Enhancing the Pharmacokinetic Properties of Botulinum Neurotoxin Serotype A Protease Inhibitors Through Rational Design.

    Science.gov (United States)

    Capek, Petr; Zhang, Yan; Barlow, Deborah J; Houseknecht, Karen L; Smith, Garry R; Dickerson, Tobin J

    2011-06-15

    Botulinum neurotoxin (BoNT), the etiological agent that causes the neuroparalytic disease botulism, has become a highly studied drug target in light of the potential abuse of this toxin as a weapon of bioterrorism. In particular, small molecule inhibitors of the light chain metalloprotease of BoNT serotype A have received significant attention and a number of small molecule and biologic inhibitors have been reported. However, all small molecules reported have been identified from either primary screens or medicinal chemistry follow-up studies, and the pharmacokinetic profiles of these compounds have not been addressed. In this study, we have removed the pharmacologic liabilities of one of the best compounds reported to date, 2,4-dichlorocinnamate hydroxamic acid, and in the process, uncovered a related class of benzothiophene hydroxamic acids that are significantly more potent inhibitors of the BoNT/A light chain, while also possessing greatly improved ADME properties, with the best compound showing the most potent inhibition of BoNT/A light chain reported (K(i) = 77 nM). Using a strategy of incorporating traditional drug development filters early into the discovery process, potential liabilities in BoNT/A lead compounds have been illuminated and removed, clearing the path for advancement into further pharmacologic optimization and in vivo efficacy testing.

  5. Polymerization as a Model Chain Reaction

    Science.gov (United States)

    Morton, Maurice

    1973-01-01

    Describes the features of the free radical, anionic, and cationic mechanisms of chain addition polymerization. Indicates that the nature of chain reactions can be best taught through the study of macromolecules. (CC)

  6. Supply chain strategies, issues and models

    CERN Document Server

    Ramanathan, Ramakrishnan

    2014-01-01

    In the 21st century, supply chain operations and relationships among supply chain partners have become highly challenging, necessitating new approaches, e.g., the development of new models. Supply Chain Strategies, Issues and Models discusses supply chain issues and models with examples from actual industrial cases. Expert authors with a wide spectrum of knowledge working in various areas of supply chain management from various geographical locations offer refreshing, novel and insightful ideas and address possible solutions using established theories and models. Supply Chain Strategies, Issues and Models features studies that have used mathematical modeling, statistical analyses and also descriptive qualitative studies. The chapters cover many relevant themes related to supply chains and logistics including supply chain complexity, information sharing, quality (six sigma), electronic Kanbans, inventory models, scheduling, purchasing and contracts. To facilitate easy reading, the chapters that deal with suppl...

  7. SUPPLY CHAIN MANAGEMENT – KEY FACTORS

    Directory of Open Access Journals (Sweden)

    Magdalena Daniela DINU

    2014-06-01

    Full Text Available This paper exposes Supply Chain Management by its key factors. Briefly, where the Supply Chain Management is treated as strategic part of a company then maintaining both control and influence throughout the entire supply chain are key factors and critical to success. On the other hand, finding the right partner to manage the non-strategic Supply Chains would be another key factor too. To define the most important key factors within Supply Chain Management means a deeply understanding of both Supply Chain’ s components, procedures, workflow, processes and the importance of Supply Chain Management into maximizing company's value. SCORE model able to provide solid information about measuring performance and identifying priorities within Supply Chain Management will help us to understand the key factors by analyzing its elements: Plan, Source, Make, Deliver,Return, Enable. These elements covers all the challenging areas from first to third tier of Supply Chain Management.

  8. Information flow in the pharmaceutical supply chain.

    Science.gov (United States)

    Yousefi, Nazila; Alibabaei, Ahmad

    2015-01-01

    Managing the supply chain plays an important role in creating competitive advantages for companies. Adequate information flow in supply chain is one of the most important issues in SCM. Therefore, using certain Information Systems can have a significant role in managing and integrating data and information within the supply chain. Pharmaceutical supply chain is more complex than many other supply chains, in the sense that it can affect social and political perspectives. On the other hand, managing the pharmaceutical supply chain is difficult because of its complexity and also government regulations in this field. Although, Iran has progressed a lot in pharmaceutical manufacturing, still there are many unsolved issues in managing the information flow in the pharmaceutical supply chain. In this study, we reviewed the benefits of using different levels of an integrated information system in the supply chain and the possible challenges ahead.

  9. BUSINESS TENDENCIES IN SERVICES WITHIN SUPPLY CHAIN

    OpenAIRE

    Beata Skowron-Grabowska

    2008-01-01

    Supply chain management has been a major component of competitive strategy to enhance organizational productivity and profitability. Client satisfaction and improvement in profitability are two basic goals while organizing supply chain. In the paper author tried to prove that there is a correlation between organization of supply chain and subjective evaluation of economic situation by enterprises. Logistics integration helps enterprises to find their place in the supply chain.

  10. Supply Chain Integration: Challenges and Solutions

    OpenAIRE

    Sweeney, Edward

    2011-01-01

    Rapid changes in technological development are forcing businesses to continuously innovate to improve their competitiveness, which is particularly evident in logistics and supply chain management (SCM), where innovation impacts both the strategic and operational levels. Supply Chain Innovation for Competing in Highly Dynamic Markets: Challenges and Solutions investigates the role of innovation in the management of supply chains of today. This book focuses on supply chain integration from both...

  11. Australian Lamb Supply Chain: A Conceptual Framework

    OpenAIRE

    Jie, Ferry

    2011-01-01

    In the last decade, supply chain management has played an important role to lead agribusiness today to succeed in their business goals, to gain competitive advantages, and to improve business performance. As the result of that, there has been extensive studying in a popular topic of strategic supply chain management in order to improve business performance as well as along supply chain performance under the real situation. This is because in current business world, supply chain practices are ...

  12. Visualisation for System Learning in Supply Chains

    Science.gov (United States)

    Lindskog, Magnus; Abrahamsson, Mats; Aronsson, Hakan

    2007-01-01

    Contemporary supply chains are vastly complex, and decisions made by actors have system-wide consequences that these might not be able to foresee. There are gaps between "best practice"-founded theory and actual practice in supply chains. To remedy this, we argue, the supply chain actors need to enhance systems knowledge. There is a need to…

  13. Learning to Integrate: Supply Chains Reconceptualised

    Science.gov (United States)

    Sense, Andrew J.; Clements, Michael D. J.

    2007-01-01

    This paper introduces and explains a conception of supply chains from a situated learning perspective. This non-conventional supply chain perspective invites the reader to consider supply chain scenarios as "situated learning opportunities involving multiple communities of practice" interacting and participating together. It is argued that by…

  14. Cellular chain formation in Escherichia coli biofilms

    DEFF Research Database (Denmark)

    Vejborg, Rebecca Munk; Klemm, Per

    2009-01-01

    In this study we report on a novel structural phenotype in Escherichia coli biofilms: cellular chain formation. Biofilm chaining in E. coli K-12 was found to occur primarily by clonal expansion, but was not due to filamentous growth. Rather, chain formation was the result of intercellular...

  15. A concept for collaborative supply chain planning

    DEFF Research Database (Denmark)

    Alfnes, E.; Dreyer, H.C.; Hvolby, Hans-Henrik

    2012-01-01

    vendors such as Oracle, SAP and I2 offer supply chain planning systems. This limits the ability for SMEs to exploit the supply chain planning options. This paper is part of a research project carried out to develop a new supply chain add-on for Microsoft AX, a very common system for SMEs. The paper...

  16. The Advancement Value Chain: An Exploratory Model

    Science.gov (United States)

    Leonard, Edward F., III

    2005-01-01

    Since the introduction of the value chain concept in 1985, several varying, yet virtually similar, value chains have been developed for the business enterprise. Shifting to higher education, can a value chain be found that links together the various activities of advancement so that an institution's leaders can actually look at the philanthropic…

  17. Secure Supply Chains: Design Restrictions & Organizational Boundaries

    NARCIS (Netherlands)

    Ludema, M.W.

    2009-01-01

    An important issue in the design of secure supply chains is the understanding of the relation between supply chains and the organizational responsibility of specific parts of these supply chains. Organizational boundaries change over time by means of vertical and/or horizontal (des)-integration and

  18. On a Result for Finite Markov Chains

    Science.gov (United States)

    Kulathinal, Sangita; Ghosh, Lagnojita

    2006-01-01

    In an undergraduate course on stochastic processes, Markov chains are discussed in great detail. Textbooks on stochastic processes provide interesting properties of finite Markov chains. This note discusses one such property regarding the number of steps in which a state is reachable or accessible from another state in a finite Markov chain with M…

  19. Compressing redundant information in Markov chains

    OpenAIRE

    2006-01-01

    Given a strongly stationary Markov chain and a finite set of stopping rules, we prove the existence of a polynomial algorithm which projects the Markov chain onto a minimal Markov chain without redundant information. Markov complexity is hence defined and tested on some classical problems.

  20. STATISTICS OF A CLASS OF MARKOV CHAINS

    Institute of Scientific and Technical Information of China (English)

    DENG Yingchun; CAO Xianbing

    2004-01-01

    In this paper we prove that the distributions of their sojourn time and hitting time at one special state for random walks which are allowed to be finite or infinite and Markov chains on star-graphs with discrete time can uniquely determine the probability distribution of the whole chains. This result also suggests a new statistical method for Markov chains.

  1. Consistency and Refinement for Interval Markov Chains

    DEFF Research Database (Denmark)

    Delahaye, Benoit; Larsen, Kim Guldstrand; Legay, Axel;

    2012-01-01

    Interval Markov Chains (IMC), or Markov Chains with probability intervals in the transition matrix, are the base of a classic specification theory for probabilistic systems [18]. The standard semantics of IMCs assigns to a specification the set of all Markov Chains that satisfy its interval...

  2. Chains versus Independents: Newspaper and Market Characteristics.

    Science.gov (United States)

    Hale, F. Dennis

    A study examined the marketing differences between large chain newspapers and small chain and independent newspapers by analyzing differences in characteristics of the newspapers, patterns of circulation, economic and social conditions of the market, and competition from other print media. The 200 newspapers studied--113 large chain and 87 small…

  3. Principles in Halal Supply Chain Management

    NARCIS (Netherlands)

    Tieman, H.; Vorst, van der J.G.A.J.; Maznah Che Ghazali,

    2012-01-01

    Purpose – The purpose of this paper is to introduce a new framework to optimise the design of halal food supply chains, called the “Halal Supply Chain Model”. In this research the main logistics business processes are defined, which are the determinants for the halal supply chain performance. Design

  4. Systematic Methodology of Integrated Supply Chain Management

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Supply chain management (SCM) is a strategy for global competition. Th e characteristics of SCM are integration, systematic and coordination. Using sys tematic, coordination thoughts and integration theory, a new model of enterprise integration based on supply chain management is put forward and an implementing paradigm for systematic methodology of supply chain management is developed.

  5. Experiences with the Mango Chain Game

    NARCIS (Netherlands)

    Meijer, S.A.; Zuñiga-Arias, G.; Sterrenburg, S.

    2005-01-01

    The mango chain game is a simulation game used for research purposes. It facilitated studying the bargaining power of Costa Rican mango producers in international supply chains of mango. The game simulates a simplified mango export chain in which real world local producers can play the role of produ

  6. Review of Published Chain Information System Research

    NARCIS (Netherlands)

    Storer, C.E.; Trienekens, J.H.; Beulens, A.J.M.; Quaddus, M.A.

    2006-01-01

    This paper provides a review of the literature on chains and networks that examine interorganisational information systems used to manage chains of organisations. Difficulty was found in finding out how organisations exchanged information to manage relationships with customers and suppliers in chain

  7. Tissue factor pathway inhibitor endocytosis.

    Science.gov (United States)

    Schwartz, A L; Broze, G J

    1997-10-01

    Tissue factor pathway inhibitor (TFPI), a 42 kD protein, provides the physiological inhibition of tissue factor initiated coagulation by inhibition of both factor Xa and factor VIIa/tissue factor. In plasma, most TFPI is lipoprotein bound with an additional "releasable" pool bound to the endothelial cell surface. TFPI clearance is via receptor mediated endocytosis into liver. Heparin sulfate proteoglycans and LRP (low density lipoprotein receptor-related protein), an extremely large (∼600 kD) cell surface protein, primarily mediate this clearance, although additional TFPI binding sites and endocytosis pathways exist. (Trends Cardiovasc Med 1997; 7:234-239). © 1997, Elsevier Science Inc.

  8. Supply Chain Management Performance in Tourism. Continental Hotels Chain Case

    Directory of Open Access Journals (Sweden)

    Gabriela Ţigu

    2013-02-01

    Full Text Available With its origins in logistics, Supply Chain Management (SCM concept is covering all managerial aspects of the flow of materials and information from source to customer, across the entire range of materials handling and movement functions, and throughout an organization and its supply channels. In tourism, these issues relate to the whole process of providing tourism services from sourcing of raw materials, products or different services to supply and distribution, and SCM performance can ultimately be measured by customer satisfaction. Thus, an important component of tourism SCM is the demand management. Therefore, this study aims to highlight the features of the concept of SCM and demand management in tourism, with an emphasis on a hotel chain in Romania, based on research and analysis of tourist traffic indicators as well as assessment of customers satisfaction. The sources of information are the internal company statistics, as well as various hotels booking websites that offer customers’ feedback. The results of the study provide a snapshot of how the hotel demand management can influence SCM performance in tourism.

  9. Stereocontrolled Synthesis of a Potential Transition-State Inhibitor of the Salicylate Synthase MbtI from Mycobacterium tuberculosis.

    Science.gov (United States)

    Liu, Zheng; Liu, Feng; Aldrich, Courtney C

    2015-07-02

    Mycobactins are small-molecule iron chelators (siderophores) produced by Mycobacterium tuberculosis (Mtb) for iron mobilization. The bifunctional salicylate synthase MbtI catalyzes the first step of mycobactin biosynthesis through the conversion of the primary metabolite chorismate into salicylic acid via isochorismate. We report the design, synthesis, and biochemical evaluation of an inhibitor based on the putative transition state (TS) for the isochorismatase partial reaction of MbtI. The inhibitor mimics the hypothesized charge buildup at C-4 of chorismate in the TS as well as C-O bond formation at C-6. Another important design element of the inhibitor is replacement of the labile pyruvate side chain in chorismate with a stable C-linked propionate isostere. We developed a stereocontrolled synthesis of the highly functionalized cyclohexene inhibitor that features an asymmetric aldol reaction using a titanium enolate, diastereoselective Grignard addition to a tert-butanesulfinyl aldimine, and ring closing olefin metathesis as key steps.

  10. The influence of power in supply chain innovation; a case study of the Dutch wheat chain

    NARCIS (Netherlands)

    Pol, Hanneke; Visscher, Klaasjan

    2010-01-01

    The purpose of this article is to clarify the relation between the power structure of a supply chain and the possibilities to realize supply chain innovations. In an in-depth case study of the faltering start of an innovation trajectory in the Dutch wheat supply chain, we show that supply chain inno

  11. Supply chain management - safety aspects

    Directory of Open Access Journals (Sweden)

    2010-12-01

    Full Text Available Developing economy, growing customer requirements and competition make the service level higher. Delivery safety - as the highest priority - has to be maintained at the same time. Customers more and more often require transport to be very flexible, fast, and complex in terms of carrying every quantity of goods of different sizes, from and to different countries, through customs clearance, storing and distribution of shipments. Meeting these requirements depends on complex information on transport processes and their safety. The article presents safety foundations and institution Authorized Economic Operator - AEO in supply chains.

  12. TBA for the Toda chain

    Energy Technology Data Exchange (ETDEWEB)

    Kozlowski, K.K.; Teschner, J.

    2010-06-15

    We give a direct derivation of a proposal of Nekrasov-Shatashvili concerning the quantization conditions of the Toda chain. The quantization conditions are formulated in terms of solutions to a nonlinear integral equation similar to the ones coming from the thermodynamic Bethe ansatz. This is equivalent to extremizing a certain function called Yang's potential. It is shown that the Nekrasov-Shatashvili formulation of the quantization conditions follows from the solution theory of the Baxter equation, suggesting that this way of formulating the quantization conditions should indeed be applicable to large classes of quantized algebraically integrable models. (orig.)

  13. MODELING SUPPLY CHAIN WITH SIMULATION

    OpenAIRE

    János Benkõ

    2010-01-01

    Supply Chain Management faces a lot of challenging issues involving difficult decisions which can be company-oriented and customer-oriented issues. In this study we deal with customeroriented issues. For example, a customer’s demand may not be fully satisfied from stock on hand and the shortage may be backordered or the sale may be lost. Either way, it is desirable to balance the holding cost which depends on the magnitude of inventory against the cost of not fully satisfying customer demand....

  14. Heat transport in coupled inhomogeneous chains

    Institute of Scientific and Technical Information of China (English)

    Hu Tao; Bai Meng; Hu Ke; Tang Yi

    2011-01-01

    We first investigate the heat transport in a network model consisting of two coupled dimerized chains. Results indicate that the thermal resistance of each chain increases with the decrease of the mass ratio γ of the two types of atoms. Then, we find, when a light impurity or a heavy one is added in the two coupled homogeneous chains and coupled with a particle of another chain, the interface thermal resistances Rlint andRγint present different dependences on the mass ratio γ'. Finally, a persistent circulation of energy current is observed in coupled inhomogeneous chains with two pairs of interchain coupling.

  15. Integration of Forestry Industrial Chain in China

    Institute of Scientific and Technical Information of China (English)

    Zhanzhan; LAN; Liqun; WANG

    2013-01-01

    Based on the Smile Curve and Michael E. Porter’ value chain model,this paper points out that China’s forestry industry stays at the low end of the value chain for a long time. Raw materials are imported from foreign countries and also sold in foreign countries. Then,the authors analyze characteristics and existing problems of China’s forestry industrial chain. They put forward the development direction of China’s forestry industrial chain with reference to International Paper Company. Finally,they present their recommendations for integration of China’s forestry industrial chain.

  16. Uncertainty quantification for Markov chain models.

    Science.gov (United States)

    Meidani, Hadi; Ghanem, Roger

    2012-12-01

    Transition probabilities serve to parameterize Markov chains and control their evolution and associated decisions and controls. Uncertainties in these parameters can be associated with inherent fluctuations in the medium through which a chain evolves, or with insufficient data such that the inferential value of the chain is jeopardized. The behavior of Markov chains associated with such uncertainties is described using a probabilistic model for the transition matrices. The principle of maximum entropy is used to characterize the probability measure of the transition rates. The formalism is demonstrated on a Markov chain describing the spread of disease, and a number of quantities of interest, pertaining to different aspects of decision-making, are investigated.

  17. Physalis alkekengi carotenoidic extract inhibitor of soybean lipoxygenase-1 activity.

    Science.gov (United States)

    Chedea, Veronica Sanda; Pintea, Adela; Bunea, Andrea; Braicu, Cornelia; Stanila, Andreea; Socaciu, Carmen

    2014-01-01

    The aim of this study was to evaluate the effect of the carotenoidic saponified extract of Physalis alkekengi sepals (PA) towards the lipoxygenase (LOX) oxidation of linoleic acid. Lipoxygenase activity in the presence of carotenoids, standard and from extract, was followed by its kinetic behaviour determining the changes in absorption at 234 nm. The standard carotenoids used were β-carotene (β-car), lutein (Lut), and zeaxanthin (Zea). The calculated enzymatic specific activity (ESA) after 600 s of reaction proves that PA carotenoidic extract has inhibitory effect on LOX oxidation of linoleic acid. A longer polyenic chain of carotenoid structure gives a higher ESA during the first reaction seconds. This situation is not available after 600 s of reaction and may be due to a destruction of this structure by cooxidation of carotenoids, besides the classical LOX reaction. The PA carotenoidic extract inhibiting the LOX-1 reaction can be considered a source of lipoxygenase inhibitors.

  18. Affinity purification and enzymatic cleavage of inter-alpha inhibitor proteins using antibody and elastase immobilized on CIM monolithic disks.

    Science.gov (United States)

    Lim, Yow-Pin; Josic, Djuro; Callanan, Helen; Brown, Jeanne; Hixson, Douglas C

    2005-02-11

    Epoxy-activated monolithic CIM disks seem to be excellent supports for immobilization of protein ligands. The potential use of enzymes, immobilized on monolithic disks for rapid preparative cleavage proteins in solution was investigated. Digestion of complex plasma proteins was demonstrated by using inter-alpha inhibitors with elastase, immobilized on epoxy-activated CIM disks. Recently, a monoclonal antibody against human inter-alpha inhibitor proteins (MAb 69.31) was developed. MAb 69.31 blocks the inhibitory activity of inter-alpha inhibitor proteins to serine proteases. These results suggest that the epitope defined by this antibody is located within or proximal to the active site of the inhibitor molecule. This antibody, immobilized on monolithic disk, was used for very rapid isolation of inter-alpha proteins. The isolated complex protein was used for enzymatic digestion and isolation of cleavage products, especially from inter-alpha inhibitor light chain to elucidate precisely the target sequence for MAb 69.31 by N-terminal amino acid sequencing. Bovine pancreatic elastase immobilized on monolithic disk cleaves inter-alpha inhibitor protein complex into small fragments which are still reactive with MAb 69.31. One of these proteolytic fragments was isolated and partially sequenced. It could be shown that this sequence is located at the beginning of two proteinase inhibitor domains of the inter-alpha inhibitor light chain (bikunin). Elastase immobilized on monolithic disk offers a simple and rapid method for preparative isolation of protease cleavage fragments. The immobilized enzyme is stable and still active after repeated runs. A partial or complete digestion can be achieved by varying the flow rate.

  19. Aromatase inhibitors and bone loss.

    Science.gov (United States)

    Perez, Edith A; Weilbaecher, Katherine

    2006-08-01

    The aromatase inhibitors (AIs) anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are significantly more effective than the selective estrogen-receptor modulator (SERM) tamoxifen in preventing recurrence in estrogen receptor-positive early breast cancer. Aromatase inhibitors are likely to replace SERMs as first-line adjuvant therapy for many patients. However, AIs are associated with significantly more osteoporotic fractures and greater bone mineral loss. As antiresorptive agents, oral and intravenous bisphosphonates such as alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), pamidronate (Aredia), and zoledronic acid (Zometa) have efficacy in preventing postmenopausal osteoporosis, cancer treatment-related bone loss, or skeletal complications of metastatic disease. Clinical practice guidelines recommend baseline and annual follow-up bone density monitoring for all patients initiating AI therapy. Bisphosphonate therapy should be prescribed for patients with osteoporosis (T score vitamin D intake, weight-bearing exercise, and smoking cessation should be addressed. Adverse events associated with bisphosphonates include gastrointestinal toxicity, renal toxicity, and osteonecrosis of the jaw. These safety concerns should be balanced with the potential of bisphosphonates to minimize or prevent the debilitating effects of AI-associated bone loss in patients with early, hormone receptor-positive breast cancer.

  20. Myeloperoxidase Inhibitors as Potential Drugs.

    Science.gov (United States)

    Lazarević-Pasti, Tamara; Leskovac, Andreja; Vasić, Vesna

    2015-01-01

    Myeloperoxidase (MPO) is an important member of the haem peroxidase - cyclooxygenase superfamily. This enzyme is physiologically expressed in circulating neutrophils, monocytes and some tissue macrophages including microglia. MPO plays an essential role in the antimicrobial and antiviral system of humans. The microbicidal activity of MPO exists due to its capability to oxidize halide and pseudohalide ions (CI(-), Br(-), I(-) and SCN(-)) by H2O2, thereby producing respective hypohalous acids (HOX). During the phagocytosis of pathogens, azurophilic granules release their content together with MPO into phagolysosomes. On the other hand, MPO can be discharged outside the phagocytes. Due to this, tissue damage during inflammation is greatly promoted by MPO-derived oxidants. Regarding its activity, MPO is a key factor in a great number of conditions within the group of cardiovascular diseases, inflammatory diseases, neurodegenerative diseases, kidney diseases and immune-mediated diseases. Therefore, MPO and its downstream inflammatory pathways might be attractive targets for both prognostic and therapeutic intervention in the prophylaxis of all mentioned illnesses. Nowadays, structure and reaction mechanism of MPO are known, which enable rational strategy in the development of specific MPO inhibitors that still preserve MPO activity during host defense from bacteria, but hinder pathophysiologically persistent activation of MPO. Various methods for MPO activity inhibition and unfavorable effects of MPO-derived oxidants remodeling will be discussed. Emphasis will be put on various known inhibitors, as well as on newly investigated natural products, which can also inhibit MPO activity.

  1. Proton pump inhibitors and osteoporosis

    DEFF Research Database (Denmark)

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

    2016-01-01

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

  2. The fish industry - toward supply chain modelling

    DEFF Research Database (Denmark)

    Jensen, Toke Koldborg; Nielsen, Jette; Larsen, Erling

    2010-01-01

    Mathematical models for simulating and optimizing aspects of supply chains such as distribution, planning, and optimal handling of raw materials are widely used. However, modeling based on a holistic chain view including several or all supply chain agents is less studied, and food-related aspects...... such as quality and shelf-life issues enforce additional requirements onto the chains. In this article, we consider the supply chain structure of the fish industry. We discuss and illustrate the potential of using mathematical models to identify quality and value-adding activities. The article provides a first...... step toward innovative supply chain modeling aimed to identify benefits for all agents along chains in the fish industry....

  3. Sustainability Analysis for Gayo Coffee Supply Chain

    Directory of Open Access Journals (Sweden)

    Rachman Jaya

    2013-01-01

    Full Text Available Sustainable supply chain is a development of the conventional supply chains that discuses trade-off among economic, social and environmental dimensions in order to achieve better responsiveness in terms of quality, quantity and time-delivery in the supply chain structure. The objective of this research was to determine the Gayo coffee supply chain sustainability. The research was conducted at Bener Meriah and Aceh Tengah Districts, Aceh Province, Indonesia. Key actors in the supply chain considered were farmers, collectors, agro-industry and exporter. Sustainability dimensions considered in this research were the economic, social, environmental and material resources. The performance of each aspect was analyzed by using Multi-dimensional scaling and leverage analysis. The result of the research showed that the composite of Gayo coffee supply chain sustainability index was 33.53 which mean less sustainable level. Therefore it is recommended to reengineering the Gayo coffee supply chain by considering all of the four sustainability dimensions above.

  4. Determining an optimal supply chain strategy

    Directory of Open Access Journals (Sweden)

    Intaher M. Ambe

    2012-11-01

    Full Text Available In today’s business environment, many companies want to become efficient and flexible, but have struggled, in part, because they have not been able to formulate optimal supply chain strategies. Often this is as a result of insufficient knowledge about the costs involved in maintaining supply chains and the impact of the supply chain on their operations. Hence, these companies find it difficult to manufacture at a competitive cost and respond quickly and reliably to market demand. Mismatched strategies are the root cause of the problems that plague supply chains, and supply-chain strategies based on a one-size-fits-all strategy often fail. The purpose of this article is to suggest instruments to determine an optimal supply chain strategy. This article, which is conceptual in nature, provides a review of current supply chain strategies and suggests a framework for determining an optimal strategy.

  5. Configurational statistics of confined polymer chains

    Energy Technology Data Exchange (ETDEWEB)

    Lohse, David John

    1978-01-01

    The work on confined chain statistics is reviewed. The work on the general statistics is discussed first, and then some of the theories for the applications of statistics are considered. Two methods for determining the general statistics of a confined chain are discussed. The first is the method of images. The second method involves the use of differential equations. In a specific case the statistics of the unconfined chain are chosen to be defined by the Gaussian real chain distribution. The confinement is provided by two parallel walls. The distribution for the four possible types of chains, bridges (tie chains), loops, cilia (dangling chain ends), and floating (unattached) chains, are derived. These statistics are then applied to two polymer systems in which the confinement is due to internal surfaces, semicrystalline polymers and block copolymers. Both systems are modelled by chains between two walls for a number of morphologies. Mechanical properties are calculated for both systems and for block copolymers swelling is also considered. The main result of this work is that there are two effects which determine the behavior of the chains in these systems. The first is the effect of the confinement which operates on all the chains, since the mode of attachment is not important. The confinement reduces the number of configurations available to the chains. This effect is larger the closer the walls are, relative to the length and stiffness of the chains. The second effect operates only on bridges, since it requires that the ends of the chain be attached to different walls. This is the inherent elastic nature of the bridge, which means that the number of configurations is reduced when it is stretched beyond its equilibrium length. All the behavior calculated here can be explained by these two effects.

  6. MODELING A VALUE CHAIN IN PUBLIC SECTOR

    Directory of Open Access Journals (Sweden)

    Daiva Rapcevičienė

    2014-08-01

    Full Text Available Purpose – Over the past three decades comprehensive insights were made in order to design and manage the value chain. A lot of scholars discuss differences between private sector value chain – creation profit for the business and public sector value chain, the approach that public sector creates value through the services that it provides. However, there is a lack of a common understanding of what public sector value chain is in general. This paper reviews the literature on how the private value chain was transformed into public value chain and reviews a determination and architecture of a value chain in public sector which gives a structural approach to greater picture of how all structure works. It reviews an approach that the value chain for the public sector shows how the public sector organizes itself to ensure it is of value to the citizens. Design/methodology/approach – descriptive method, analysis of scientific literature. Findings – The public sector value chain is an adaptation of the private sector value chain. The difference between the two is that the customer is the focus of the public sector context, versus the profit focus in the private sector context. There are significant similarities between the two chain models. Each of the chain models are founded on a series of core components. For the public sector context, the core components are people, service and trust. Research limitations/implications – this paper based on presenting value chain for both private and public sectors and giving deeper knowledge for public sector value chain model. Practical implications – comprehension of general value chain model concept and public sector value chain model helps to see multiple connections throughout the entire process: from the beginning to the end. The paper presents the theoretical framework for further study of the value chain model for waste management creation. Originality/Value – The paper reveals the systematic

  7. Clinical utility of the oral JAK inhibitor tofacitinib in the treatment of rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    Cutolo M

    2013-11-01

    Full Text Available Maurizio Cutolo, Marianna Meroni Research Laboratories and Academic Division of Clinical Rheumatology, Department of Internal Medicine, University of Genova, Genova, Italy Abstract: Immune/inflammatory cells act in rheumatoid arthritis (RA-affected patients by synthesizing several inflammatory mediators, including cytokines that initiate intracellular signaling. Recently, small molecule inhibitors of transduction and transcription signals that influence the intracellular pathways (such as the Janus kinase [JAK] family of tyrosine kinases have been tested for RA treatment. Four members of the JAK family are known: JAK1, JAK2, JAK3, and TyK2. JAK1/JAK3 constitutively binds to the cytoplasmic portion of the cytokine receptor – the common gamma chain – that represents a common subunit of several cytokines involved in T-cell and natural killer cell development, as well as in B-cell activation. Tofacitinib is an oral JAK inhibitor that is now available and effective in RA treatment, as shown in multiple Phase II and Phase III clinical trials. However, long-term safety data and comparisons with other disease-modifying antirheumatic drugs and small molecule inhibitors are necessary to better determine the role of tofacitinib in RA. Keywords: Janus kinase inhibitors, tofacitinib, rheumatoid arthritis, kinases, small molecules inhibitors, intracellular signaling

  8. In silico identification and crystal structure validation of caspase-3 inhibitors without a P1 aspartic acid moiety

    Science.gov (United States)

    Ganesan, Rajkumar; Jelakovic, Stjepan; Mittl, Peer R. E.; Caflisch, Amedeo; Grütter, Markus G.

    2011-01-01

    Using a fragment-based docking procedure, several small-molecule inhibitors of caspase-3 were identified and tested and the crystal structures of three inhibitor complexes were determined. The crystal structures revealed that one inhibitor (NSC 18508) occupies only the S1 subsite, while two other inhibitors (NSC 89167 and NSC 251810) bind only to the prime part of the substrate-binding site. One of the major conformational changes observed in all three caspase-3–inhibitor complexes is a rotation of the Tyr204 side chain, which blocks the S2 subsite. In addition, the structural variability of the residues shaping the S1–S4 as well as the S1′ subsites supports an induced-fit mechanism for the binding of the inhibitors in the active site. The high-resolution crystal structures reported here provide novel insights into the architecture of the substrate-binding site, which might be useful for the design of more potent caspase inhibitors. PMID:21821879

  9. Growth morphologies of wax in the presence of kinetic inhibitors

    Science.gov (United States)

    Tetervak, Alexander A.

    Driven by the need to prevent crystallization of normal alkanes from diesel fuels in cold climates, the petroleum industry has developed additives to slow the growth of these crystals and alter their morphologies. Although the utility of these kinetic inhibitors has been well demonstrated in the field, few studies have directly monitored their effect at microscopic morphology, and the mechanisms by which they act remain poorly understood. Here we present a study of the effects of such additives on the crystallization of long-chain n-alkanes from solution. The additives change the growth morphology from plate-like crystals to a microcrystalline mesh. When we impose a front velocity by moving the sample through a temperature gradient, the mesh growth may form a macroscopic banded pattern and also exhibit a burst-crystallization behavior. In this study, we characterize these crystallization phenomena and also two growth models: a continuum model that demonstrates the essential behavior of the banded crystallization, and a simple qualitative cellular automata model that captures basics of the burst-crystallization process. Keywords: solidification; mesh crystallization; kinetic inhibitor; burst growth.

  10. Identification and structural analysis of ricin inhibitors. Final report

    Energy Technology Data Exchange (ETDEWEB)

    Robertus, J.D.

    1996-12-01

    Ricin is a potent cytotoxin which has been used by governments and terrorists as a poison. The three-dimensional structure of this toxic molecule was solved by X-ray crystallography, including an atomic description of its active site. The goal of this project was to use computer searches and other molecular modeling techniques to identify an inhibitor or ricin A chain (RTA). The program CHEM-X was used to predict that pteroic acid (PTA) would bind to RTA. This was shown to be the case by kinetic assays, where PTA protected ribosomes against the action of RTA, and by X-ray crystallography. The affinity of PTA is weak, with a Ki estimated at 600 Micrometers. The pterin group of PTA was observed to make many polar interactions with RTA within the specificity site of the enzyme, and to bind more strongly than the natural substrate adenine. Further work will be required to increase the binding affinity of this class of inhibitors, and to improve their solubility if efficacious antidotes are to be designed from this lead.

  11. Low-dose methotrexate enhances cycling of highly anaplastic cancer cells

    Science.gov (United States)

    Marzi, Ilaria; Olivotto, Massimo

    2017-01-01

    ABSTRACT We previously showed that cellular RedOx state governs the G1-S transition of AH130 hepatoma, a tumor spontaneously reprogrammed to the embryonic stem cell stage. This transition is impaired when the mithocondrial electron transport system is blocked by specific inhibitors (antimycin A) or the respiratory chain is saturated by adding to the cells high concentrations of pyruvate. The antimycin A or pyruvate block is removed by the addition of adequate concentrations of folate (F). This suggests that the G1-S transition of AH130 cells depends on a respiration-linked step of DNA synthesis related to folate metabolism. In the study reported here, we characterized the effects of methotrexate (MTX), an inhibitor of dihydofolate-reductase, on the G1-S transition of hepatoma cells, in the absence or the presence of exogenously added F, dihydrofolate (FH2) or tetrahydrofolate (FH4). MTX, at 1 μM or higher concentrations, inhibited G1-S transition. This inhibition was completely removed by exogenous folates. Surprisingly, 10 nM MTX stimulated G1-S transition. The addition of F, but not FH2 or FH4, significantly increased this effect. Furthermore, 10 nM MTX removed the block of the G1-S transition operated by antimycin A or pyruvate, an effect which was enhanced in the presence of F. Finally, the stimulatory effect of 10 nM MTX was inhibited in the presence of serine. Our findings indicated that, under certain conditions, MTX may stimulate, rather than inhibiting, the cycling of cancer cells exhibiting a stem cell-like phenotype, such as AH130 cells. This may impact the therapeutic use of MTX and of folates as supportive care. PMID:27841718

  12. Light chain immunofluorescence in various nephropathies

    Directory of Open Access Journals (Sweden)

    Megha S Uppin

    2011-01-01

    Full Text Available Context: Light chain immunofluoresence (IF in renal biopsy is routinely used in the diagnosis of light chain deposition disease (LCDD, amyloidosis and cast nephropathy. Light chain predominance has also been reported in certain glomerulopathies like IgA nephropathy. However, pathogenesis of this pattern of deposition in various glomerulopathies is uncertain. Aim: To discuss the pathogenesis and utility of light chain IF in nephropathies. Setting and Design: Retrospective study. Materials and Methods: The pattern of light chain IF and light microscopic diagnosis in 306 cases of various nephropathies was reviewed. Direct IF was done in all these cases with commercial fluorescence (Fluoresciene Isothiocynate conjugated polyclonal rabbit anti-human antisera against IgM, IgG, IgA, C3, C1q, kappa and lambda light chains. Results: Light chain deposits were seen in 240 (78.43% cases. In IgA nephropathy, lupus nephritis and post-infectious glomerulonephritis (PIGN, lambda positivity was more as compared to kappa. Light chain deposits in LCDD and membranous nephropathy were more kappa type. The IF pattern in amyloidosis was not consistent. Conclusion: The pathogenesis of light chain predominance in glomerulopathies is not clear and it depends on isoelectric point and size of the immune complex. Light chain IF should be performed routinely in all the renal biopsies.

  13. Structure of polymer chains under confinement

    Indian Academy of Sciences (India)

    Jyotsana Lal

    2008-11-01

    We observe by SANS the structure of neutral polystyrene and charged polystyrene sulphonate chains in semi-dilute solutions confined in a model nanoporous glass, Vycor. The size of the free chains in solution is always larger than the pore diameter, 70. The use of a suitable mixture of hydrogenated and deuterated solvents and polymers enables us to measure directly the form factor of one single chain among the others. Single chain form factor was observed both for bulk and confined chains using the condition of zero average contrast. Our measurements on neutral polymer chains are in agreement with the theoretical predictions established by Daoud and de Gennes for chains confined in a cylindrical pore when the chains are entangled and laterally squeezed but remain ideal at large scale along the cylinder axis because of the screening of the excluded volume interactions (so-called regime of ``semi-dilute cigars"). For confined charged polymers, a peak is observed whose intensity increases with molecular weight and the asymptotic 1/ scattering region is extended compared to the bulk. We infer that the chains are sufficiently extended, under the influence of confinement, to highlight the large scale disordered structure of Vycor even under contrast matched conditions. The asymptotic behaviour of the observed interchain structure factor is ≈ 1/2 and ≈ 1/ for free and confined chains respectively.

  14. Phase behaviour of polyethylene knotted ring chains

    Institute of Scientific and Technical Information of China (English)

    Wen Xiao-Hui; Zhang Lin-Xi; Xia A-Gen; Chen Hong-Ping

    2011-01-01

    The phase behaviour of polyethylene knotted ring chains is investigated by using molecular dynamics simulations.In this paper, we focus on the collapse of the polyethylene knotted ring chain, and also present the results of linear and ring chains for comparison. At high temperatures, a fully extensive knot structure is observed. The mean-square radius of gyration per bond〈S2〉/(Nb2)and the shape factor(δ*)depend on not only the chain length but also the knot type.With temperature decreasing, chain collapse is observed, and the collapse temperature decreases with the chain length increasing. The actual collapse transition can be determined by the specific heat capacity Cv, and the knotted ring chain undergoes gas-liquid-solid-like transition directly. The phase transition of a knotted ring chain is only one-stage collapse, which is different from the polyethylene linear and ring chains. This investigation can provide some insights into the statistical properties of knotted polymer chains.

  15. Glycine Transporters and Their Inhibitors

    Science.gov (United States)

    Gilfillan, Robert; Kerr, Jennifer; Walker, Glenn; Wishart, Grant

    Glycine plays a ubiquitous role in many biological processes. In the central nervous system it serves as an important neurotransmitter acting as an agonist at strychnine-sensitive glycine receptors and as an essential co-agonist with glutamate at the NMDA receptor complex. Control of glycine concentrations in the vicinity of these receptors is mediated by the specific glycine transporters, GlyT1 and GlyT2. Inhibition of these transporters has been postulated to be of potential benefit in several therapeutic indications including schizophrenia and pain. In this review we discuss our current knowledge of glycine transporters and focus on recent advances in the medicinal chemistry of GlyT1 and GlyT2 inhibitors.

  16. TYROSINE KINASE INHIBITORS AND PREGNANCY

    Directory of Open Access Journals (Sweden)

    Elisabetta Abruzzese

    2014-04-01

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

  17. Evolutionary conservation of heavy chain protein transfer between glycosaminoglycans.

    Science.gov (United States)

    Sanggaard, Kristian W; Hansen, Lone; Scavenius, Carsten; Wisniewski, Hans-Georg; Kristensen, Torsten; Thøgersen, Ida B; Enghild, Jan J

    2010-04-01

    The bikunin proteins are composed of heavy chains (HCs) covalently linked to a chondroitin sulfate chain originating from Ser-10 of bikunin. Tumor necrosis factor stimulated gene-6 protein (TSG-6)/heavy chain 2 (HC2) cleaves this unique cross-link and transfers the HCs to hyaluronan and other glycosaminoglycans via a covalent HC*TSG-6 intermediate. In the present study, we have investigated if this reaction is evolutionary conserved based on the hypothesis that it is of fundamental importance. The results revealed that plasma/serum samples from mammal, bird, and reptile were able to form TSG-6 complexes suggesting the presence of proteins with the same function as the human bikunin proteins. To substantiate this, the complex forming protein from Gallus gallus (Gg) plasma was purified and identified as a Gg homolog of human HC2*bikunin. In addition, Gg pre-alpha-inhibitor and smaller amount of high molecular weight forms composed of bikunin and two HCs were purified. Like the human bikunin proteins, the purified Gg proteins were all stabilized by a protein-glycosaminoglycan-protein cross-link, i.e. the HCs were covalently attached to a chondroitin sulfate originating from bikunin. Furthermore, the complex formed between Gg HC2*bikunin and human TSG-6 appeared to be identical to that of the human proteins. Akin to human, Gg HC2 was further transferred to hyaluronan when present, and when incubated in vitro, Gg pre-alpha-inhibitor and TSG-6, failed to form the intermediate covalent complex, essential for HC transfer. Significantly, Gg HC2, analogous to human HC2, promoted complex formation between human HC3 and human TSG-6, substantiating the evolutionary conservation of these interactions. The present study demonstrates that the unique interactions between bikunin proteins, glycosaminoglycans, and TSG-6 are evolutionary conserved, emphasizing the physiological importance of the TSG-6/HC2-mediated HC-transfer reaction. In addition, the data show that the evolution of

  18. Aromatase inhibitors in gynecologic cancers.

    Science.gov (United States)

    Krasner, Carolyn

    2007-01-01

    The female genital tract is hormonally responsive, and consequently some tumors, which arise within in it, may be treated at least in part, with hormonal manipulation. The range of responses in clinical trials and case reports will be reviewed. Many of these diseases are too rare for clinical trial testing, and in some cases evidence is anecdotal at best. Recurrences of ovarian cancer have been treated with tamoxifen and megesterol acetate with variable response rates from 0 to 56%. The favorable toxicity profile of aromatase inhibitors led to trials of these agents for the treatment of relapsed epithelial ovarian cancer. These agents have proved tolerable with minor response rates but a significant disease stabilization rate, which may be prolonged in a minority of cases. It is unclear if these responses may be predicted by estrogen receptor expression or aromatase expression. Anastrazole has also been tried in combination with an EGFR receptor-inhibitor, again showing minor responses but possibly an increase in TTT in some patients. Granulosa cell tumors of the ovary are rare, hormonally sensitive tumors, with reported responses to a variety of hormonal manipulations, including aromatase inhibition. In addition, combined endocrine blockade, including aromatase inhibition, has been tried with reports of success. Endometrial cancers, particularly type I lesions, are often treated with hormonal manipulation, most commonly with progestins, but also with antiestrogens such as tamoxifen. A trial of aromatase inhibition in the treatment of recurrent endometrial cancer showed minimal responses. Endometrial stromal sarcoma, an uncommon uterine malignancy, has shown response to hormonal treatments, with multiple case reports of efficacy of aromatase inhibition. Despite the rarity of some of these tumor types, rare tumor study groups, such as within the Gynecologic Oncology Group, should make an effort to prospectively define the utility of these treatments.

  19. A possible chain of motivation

    Directory of Open Access Journals (Sweden)

    Rodica Ianole

    2007-12-01

    Full Text Available On a world-wide basis there is a growing concern about organization' s capability to retain their top talents. In the specific case of a student's organization . Team Work - we confront with the same problems: how to inspire our members to act in the spirit of the values we share: professionalism, team work and voluntariate, and how to determine them to remain part of the system. This is where motivation appears like one of those terms that can mean very different things depending on exactly where you sit. The aim of the present paper is to draw a schematic picture of how it can work a chain of motivation in Team Work and other similar organizations.

  20. The stylohyoid chain: CT imaging

    Energy Technology Data Exchange (ETDEWEB)

    Uysal Ramadan, Selma, E-mail: uysalselma@yahoo.co [Department of Radiology, Ankara Training and Research Hospital, Ankara 06590 (Turkey); Goekharman, Dilek, E-mail: gokharman@ttnet.net.t [Department of Radiology, Ankara Training and Research Hospital, Ankara 06590 (Turkey); Kosar, Pinar, E-mail: pkosar@hotmail.co [Department of Radiology, Ankara Training and Research Hospital, Ankara 06590 (Turkey); Kacar, Mahmut, E-mail: mkacar1961@gamil.co [Department of Radiology, Ankara Training and Research Hospital, Ankara 06590 (Turkey); Kosar, Ugur, E-mail: ugurkosar@hotmail.co [Department of Radiology, Ankara Training and Research Hospital, Ankara 06590 (Turkey)

    2010-09-15

    We aimed in this report to discuss the embryology, anatomy, theories of ossification and symptoms, clinical presentation, and diagnosis of the stylohyoid chain (SHC) variations, together with the role of radiographs, computed tomography (CT) and three-dimensional (3D)-CT in showing these variations. Because CT/3D-CT additionally facilitates visualization of the entire SHC with different axes, it is the most valuable method for establishing the relationship between the SHC and the surrounding tissue. SHC variation can be discovered during CT performed for indications other than ossified SHC. It is important to diagnose whether or not the SHC is ossified, since one of the treatment procedures in ossified SHC is total excision. If the clinician and radiologist are aware of these variations observed in the SHC, patients with vague symptoms may be spared unnecessary investigations and may be properly diagnosed earlier.

  1. Worldline as a Spin Chain

    CERN Document Server

    Fatollahi, Amir H

    2016-01-01

    The general theoretical ground for the models based on the compact angle coordinates is presented. It is observed that the proper dependence on compact coordinates has to be through the group elements and is achieved most naturally in a discrete-time formulation of the theory. By the construction, the discrete worldline inlaid by compact coordinates resembles the spin chains of magnetic systems. As examples, the models based on the groups U(1), $\\mathbb{Z}_N$ and SU(2) are explicitly constructed and their exact energy spectra are obtained. As the consequence of minima in the spectra, the models exhibit a phase transition of first-order. The dynamics by U(1) group is attempted to be fitted to the proposed role for monopoles in the dual Meissner effect of confinement mechanism.

  2. Revisiting Causality in Markov Chains

    CERN Document Server

    Shojaee, Abbas

    2016-01-01

    Identifying causal relationships is a key premise of scientific research. The growth of observational data in different disciplines along with the availability of machine learning methods offers the possibility of using an empirical approach to identifying potential causal relationships, to deepen our understandings of causal behavior and to build theories accordingly. Conventional methods of causality inference from observational data require a considerable length of time series data to capture cause-effect relationship. We find that potential causal relationships can be inferred from the composition of one step transition rates to and from an event. Also known as Markov chain, one step transition rates are a commonly available resource in different scientific disciplines. Here we introduce a simple, effective and computationally efficient method that we termed 'Causality Inference using Composition of Transitions CICT' to reveal causal structure with high accuracy. We characterize the differences in causes,...

  3. Spin chains and string theory.

    Science.gov (United States)

    Kruczenski, Martin

    2004-10-15

    Recently, an important test of the anti de Sitter/conformal field theory correspondence has been done using rotating strings with two angular momenta. We show that such a test can be described more generally as the agreement between two actions: one a low energy description of a spin chain appearing in the field theory side, and the other a limit of the string action in AdS5xS5. This gives a map between the mean value of the spin in the boundary theory and the position of the string in the bulk, and shows how a string action can emerge from a gauge theory in the large-N limit.

  4. Mathematical description of the position of mining chain links on a driving chain wheel

    Energy Technology Data Exchange (ETDEWEB)

    Dolipski, M.

    1982-01-01

    The paper analyzes effects of geometry on interaction between the chain and chain wheels of face conveyors in underground coal mines. Interaction between chain links and wheel toothing is investigated using mathematical models. Three mesh types are comparatively evaluated, so-called normal mesh, nominal mesh and special mesh. Chain position on the chain wheel is shown in 3 schemes. Mathematical formulae used for characterizing mesh types are derived. Effects of the following factors on interaction between a chain link and a chain wheel are analyzed: link quality and differences in quality and dimensions among chain links, friction wear of links and toothing, elastic and plastic chain elongation, friction between links and toothing. A geometric model of the interaction between the chain wheel and haulage chain (in the form of a double polygon) is used. The mathematical model permits the following problems to be analyzed: load distribution among chain links on a chain wheel, load distribution on toothing, load fluctuations, effects of friction wear of chain and toothing. Examples of practical use of the formulae are discussed. (14 refs.)

  5. The Evolutionary Dynamics of Biofuel Value Chains

    DEFF Research Database (Denmark)

    Ponte, Stefano

    2014-01-01

    In this paper I propose to push the frontier of global value chain (GVC) governance analysis through the concept of ‘polarity’. Much of the existing GVC literature has focused on ‘unipolar’ value chains, where one group of ‘lead firms’ inhabiting a specific function in a chain plays a dominant role...... and multipolarity. Empirically, I do so by examining the evolutionary dynamics of governance in biofuel value chains, with specific focus on the key regulatory and institutional features that facilitated their emergence and expansion. First, I examine the formation, evolution, and governance of three national....../regional value chains (in Brazil, the US, and the EU); then, I provide evidence to support a trend towards the increasing but still partial formation of a global biofuel value chain and examine its governance traits....

  6. Kinetic Chain Rehabilitation: A Theoretical Framework

    Directory of Open Access Journals (Sweden)

    Aaron Sciascia

    2012-01-01

    Full Text Available Sequenced physiologic muscle activations in the upper and lower extremity result in an integrated biomechanical task. This sequencing is known as the kinetic chain, and, in upper extremity dominant tasks, the energy development and output follows a proximal to distal sequencing. Impairment of one or more kinetic chain links can create dysfunctional biomechanical output leading to pain and/or injury. When deficits exist in the preceding links, they can negatively affect the shoulder. Rehabilitation of shoulder injuries should involve evaluation for and restoration of all kinetic chain deficits that may hinder kinetic chain function. Rehabilitation programs focused on eliminating kinetic chain deficits, and soreness should follow a proximal to distal rationale where lower extremity impairments are addressed in addition to the upper extremity impairments. A logical progression focusing on flexibility, strength, proprioception, and endurance with kinetic chain influence is recommended.

  7. Kinetic chain rehabilitation: a theoretical framework.

    Science.gov (United States)

    Sciascia, Aaron; Cromwell, Robin

    2012-01-01

    Sequenced physiologic muscle activations in the upper and lower extremity result in an integrated biomechanical task. This sequencing is known as the kinetic chain, and, in upper extremity dominant tasks, the energy development and output follows a proximal to distal sequencing. Impairment of one or more kinetic chain links can create dysfunctional biomechanical output leading to pain and/or injury. When deficits exist in the preceding links, they can negatively affect the shoulder. Rehabilitation of shoulder injuries should involve evaluation for and restoration of all kinetic chain deficits that may hinder kinetic chain function. Rehabilitation programs focused on eliminating kinetic chain deficits, and soreness should follow a proximal to distal rationale where lower extremity impairments are addressed in addition to the upper extremity impairments. A logical progression focusing on flexibility, strength, proprioception, and endurance with kinetic chain influence is recommended.

  8. Position Paper on Intelligent Supply Chains

    DEFF Research Database (Denmark)

    Møller, Charles

    the concept of Intelligent Supply Chain and to establish an overall perspective based on information management. The claim made here is that the notion of the intelligent enterprise contributes with a new perspective on supply chain management that addresses the current challenges in an industrial supply...... chain. The argument is further that the existing information systems embodied in the standard enterprise information systems (EIS) have an important role in driving the development of modern supply chains though business processes. This is warranted by an analysis of the role of EIS on the development...... of intelligent supply chains. It is concluded that information management is critical to intelligent supply chains and a research agenda is outlined....

  9. Advances of Inhibitors in Drilling Fluid

    Institute of Scientific and Technical Information of China (English)

    杨仕伟; 周丹

    2012-01-01

    The development history of the inhibitors of drilling fluid reviewed in this paper. The advances of inhibitors commonly used at home and abroad were included. That the inhibitive ability was good enough whose inhibiting mechanisms and effects were introduced in the past 10 years.

  10. [Interaction between clopidogrel and proton pump inhibitors

    NARCIS (Netherlands)

    Harmsze, A.M.; Boer, A. de; Boot, H.; Deneer, V.H.; Heringa, M.; Mol, P.G.; Schalekamp, T.; Verduijn, M.M.; Verheugt, F.W.A.; Comte, M. le

    2011-01-01

    The drug interaction between proton pump inhibitors and clopidogrel has been the subject of much study in recent years. Contradictory results regarding the effect of proton pump inhibitors on platelet reactivity and on clinical outcome in clopidogrel-treated patients have been reported in literature

  11. A cyclic peptidic serine protease inhibitor

    DEFF Research Database (Denmark)

    Zhao, Baoyu; Xu, Peng; Jiang, Longguang;

    2014-01-01

    Peptides are attracting increasing interest as protease inhibitors. Here, we demonstrate a new inhibitory mechanism and a new type of exosite interactions for a phage-displayed peptide library-derived competitive inhibitor, mupain-1 (CPAYSRYLDC), of the serine protease murine urokinase...

  12. The effect of chain flexibility and chain mobility on radiation crosslinking of polymers

    Energy Technology Data Exchange (ETDEWEB)

    Jia Zhen, Sun

    2001-07-01

    Radiation crosslinking of polymers mainly depends on the structure of polymer chain. The flexibility and mobility of chain directly influence the possibility of the reactive radicals recombination. Flexible chain is easier to crosslink than rigid-chain polymer. The latter must be crosslinked at high temperature, as most polymers can only crosslink above their melting point. Structural effect also influences the mechanism of radiation crosslinking of polymers. We find from the results in literature and in our laboratory that, the flexibility chain polymer mainly crosslinked with H type, but the rigid chain polymer mainly crosslinked with Y type. (author)

  13. The effect of chain flexibility and chain mobility on radiation crosslinking of polymers

    Science.gov (United States)

    Jia Zhen, Sun

    2001-01-01

    Radiation crosslinking of polymers mainly depends on the structure of polymer chain. The flexibility and mobility of chain directly influence the possibility of the reactive radicals recombination. Flexible chain is easier to crosslink than rigid-chain polymer. The latter must be crosslinked at high temperature, as most polymers can only crosslink above their melting point. Structural effect also influences the mechanism of radiation crosslinking of polymers. We find from the results in literature and in our laboratory that, the flexibility chain polymer mainly crosslinked with H type, but the rigid chain polymer mainly crosslinked with Y type.

  14. The role of enterprise systems in supply chain networks: a taxonomy of supply chain strategies

    DEFF Research Database (Denmark)

    Møller, Charles

    2006-01-01

    in the supply chain and to choose the right supply chain strategy. The work is based on a comprehensive study of the Supply Chain Management (SCM) and Enterprise Resource Planning (ERP) literature and the study suggests that there is an emerging new research potential for Enterprise Systems (ES) in the supply......This paper proposes a taxonomy for supply chain integration strategies. The taxonomy is based on the contingencies of supply chain network coupling and the Extended Enterprise Systems (EES) architecture in the supply chain. The purpose of this model is to map the portfolio of relations...

  15. Strategy to Enhance International Supply Chain Security

    Science.gov (United States)

    2007-07-01

    a strategic plan to enhance the security of the international supply chain , including protocols for the expeditious resumption of the flow of trade...following a transportation disruption or transportation security incident. The Strategy to Enhance International Supply Chain Security exists within a...extensive risk analysis specific to the risk area they cover in the supply chain . Assessments are used to identify the highest risk areas and resources

  16. Evaluating Reverse Supply Chain Efficiency: Manufacturer's Perspective

    DEFF Research Database (Denmark)

    Kumar, M.; Tiwari, M. K.; Wong, K. Y.

    2014-01-01

    The paper aims to illustrate the use of fuzzy data envelopment analysis (DEA) in analyzing reverse supply chain (RSC) performance from the manufacturer's perspective. By using an alternative alpha-cut approach, the fuzzy DEA model was converted into a crisp linear programming problem, thereby...... usually ensures an environmentally friendly supply chain network, companies which have implemented RSC techniques since a longer duration do not necessarily have a more efficient supply chain in general....

  17. Supply Chain Performance Evaluation: Trends and Challenges

    OpenAIRE

    Ezutah U. Olugu; Kuan Y. Wong

    2009-01-01

    Problem statement: In todays manufacturing world, globalization policies and rejuvenation have created a more intensive competition amongst manufacturers. On the other hand, manufacturers have turned to the option of adopting innovative technologies, process re-engineering and strategies such as efficient supply chain management to achieve a sustainable competitive advantage. Effective supply chain performance measurement has been identified as a key issue towards efficient supply chain manag...

  18. PRINCIPLES OF THE SUPPLY CHAIN PERFORMANCE MEASUREMENT

    OpenAIRE

    BEATA ŒLUSARCZYK; SEBASTIAN KOT

    2012-01-01

    Measurement of performance in every business management is a crucial activity allowing for effectiveness increase. The lack of suitable performance measurement is especially noticed in complex systems as supply chains. Responsible persons cannot manage effectively without suitable set of measures those are base for comparison to previous data or effects of other supply chain functioning. The analysis shows that it is very hard to find balanced set of supply chain performance measures those sh...

  19. Finding gold in the supply chain.

    Science.gov (United States)

    Caudle, Allen

    2009-12-01

    To optimize supply chain performance and achieve savings that enhance the bottom line, hospitals should: Generate purchase orders for every item purchased. Ensure the organization is protected from undue vendor influence. Keep track of where supply chain dollars are going. Review contracts regularly to ensure competitiveness. Have a contract for each product category. Buy only what the organization is sure to use. Get rid of excess inventory. Develop a strategic plan for continued supply chain savings.

  20. Toc Approach for Supply Chain Performance Enhancement

    OpenAIRE

    Brijesh Ainapur; Ritesh Singh; P.R.Vittal

    2011-01-01

    Many foundries are operating at lower levels than the installed capacities. Study of 56 foundries acrossIndia has shown that only 68% of installed capacities are being utilized. This is mainly because of lack ofco-ordination among the supply chain partners. This study is an effort in identifying these gaps using TOCapproach which will help in supply chain performance enhancement.Field of Supply Chain Management witnessed rapid growth in recent past and proved to be a successfultool for organi...

  1. Supply chain integration:challenges and solutions

    OpenAIRE

    Sweeney, Edward

    2011-01-01

    Since its introduction by management consultants in the early 1980s, supply chain management (SCM) has been primarily concerned with the integration of processes and activities both within and between organisations. The concept of supply chain integration (SCI) is based on documented evidence that suggests that much of the waste throughout businesses is a consequence of fragmented supply chain configurations. However, there is also evidence to suggest that the achievement of higher levels of ...

  2. Parallel Computing Properties of Tail Copolymer Chain

    Directory of Open Access Journals (Sweden)

    Hong Li

    2013-08-01

    Full Text Available The properties of a AB diblock copolymer chain are calculated by Monte Carlo methods. Monomer A contacting to the surface has an adsorption energy E=-1 and monomer B E= 0. The polymer chain is simulated by self-avoiding walk in simple cubic lattice. The adsorption properties and the conformation properties of the polymer chain are computed by using message passing interface (MPI. The speedup is close to linear speedup by parallel computing independent samples.    

  3. Collaborative Planning in Modern Supply Chain

    OpenAIRE

    Nýdlová, Olga

    2009-01-01

    This master thesis describes and proves how companies can improve their operational performance and supplier relationships by using modern collaborative and planning practices, specifically the Collaborative Planning Forecasting and Replenishment (CPFR) concept. The theoretical part depicts main developments in supply chain planning over time, shows common challenges in the world of supply chain and offers possible solutions in terms of collaborative supply chain planning practices. The pract...

  4. Histone deacetylase inhibitors (HDACIs: multitargeted anticancer agents

    Directory of Open Access Journals (Sweden)

    Ververis K

    2013-02-01

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

  5. Responsive supply chain: modeling and simulation

    Directory of Open Access Journals (Sweden)

    Amit Kumar Sinha

    2015-06-01

    Full Text Available Unexpected occurrence like natural calamity, abruptly change in customer demands, upgradation of technologies, necessity of compatible suppliers etc. is the most challenging issues even for efficient global supply chain management. Therefore, modeling of responsive supply chain is an emerging technology for sustaining any firm/industry in future competitive environment. In this paper, an attempt has been made to not only analyze the performance of efficient supply chain management but also how to improve the performance of existing supply chain with the objective of developing a modeling of responsive supply chain management. The complexity of the model is also highlighted with the help of numerical example. This paper also explores the possibility to mathematical modeling of the responsive supply chain which will be an emerging topic for researchers and practitioners. The modeling of responsive supply chain can be employed as a competitive strategy for e-commerce, green supply chain, and compatible supplier selection problem. The another salient feature of this paper is that a distinct comparative literature review of the lean, agile, efficient, and responsive supply chain management has been presented.

  6. Towards traceability in cocoa - chocolate supply chain

    OpenAIRE

    Syahruddin, Normansyah

    2011-01-01

    The multi – events of food alerts and food risks which occurred in a lengthy period and various locations, grows concern of consumers to question the safety of the food that they consumed. For food producers, occurrences of food alert forced them to review their supply chain to identify what went wrong in their supply chain. To do this, they need a good traceability system that capable in revealing the problems occurred along the chains. In general, a typical food supply chain is consists of ...

  7. Metastability of exponentially perturbed Markov chains

    Institute of Scientific and Technical Information of China (English)

    陈大岳; 冯建峰; 钱敏平

    1996-01-01

    A family of irreducible Markov chains on a finite state space is considered as an exponential perturbation of a reducible Markov chain. This is a generalization of the Freidlin-Wentzell theory, motivated by studies of stochastic Ising models, neural network and simulated annealing. It is shown that the metastability is a universal feature for this wide class of Markov chains. The metastable states are simply those recurrent states of the reducible Markov chain. Higher level attractors, related attractive basins and their pyramidal structure are analysed. The logarithmic asymptotics of the hitting time of various sets are estimated. The hitting time over its mean converges in law to the unit exponential distribution.

  8. Electronic properties of aperiodic quantum dot chains

    Science.gov (United States)

    Korotaev, P. Yu.; Vekilov, Yu. Kh.; Kaputkina, N. E.

    2012-04-01

    The electronic spectral and transport properties of aperiodic quantum dot chains are investigated. The systems with singular continuous energy spectrum are considered: Thue-Morse chain, double-periodic chain, Rudin-Shapiro chain. The influence of electronic energy in quantum dot on the spectral properties, band structure, density of states and spectral resistivity, is discussed. Low resistivity regions correspond to delocalized states and these states could be current states. Also we discuss the magnetic field application as the way to tune electronic energy in quantum dot and to obtain metallic or insulating conducting states of the systems.

  9. Tests for intact and collapsed magnetofossil chains

    Science.gov (United States)

    Egli, R.

    2012-04-01

    In recent years, new techniques for the detection of magnetofossils have been proposed, based on their unique first-order reversal curves (FORC) and ferromagnetic resonance (FMR) signatures. These signatures are related to the non-interacting (FORC) and strongly uniaxial anisotropy (FMR) of isolated chains of magnetic particles. However, little is known about the fate of these signatures in sediments where magnetosome chains collapsed during early diagenetic processes. Due to the impossibility of observing the particle arrangement in-situ, the structure of collapsed chains can only be inferred from TEM images of magnetic extracts and from first-principles consideration on the mechanical stability of magnetosome chains once the biological material around them is dissolved. The magnetic properties of double chains, produced by some strains of cocci, are also not known. According to these considerations, four main magnetofossil structures were taken into consideration: (1) isolated, linear chains, (2) double, half-staggered chains, where the gaps of one chain face the magnetosomes in the other chain, (3) double chains with side-to-side magnetosomes, which might result from a "jackknife" type of collapse of a single, long chain, and (4) zig-zag collapsed chains of elongated crystals, where the magnetosome long axes are perpendicular to the chain axis. The collapsed structures might be relevant in sediments where magnetofossils carry a significant part of the remanent magnetization, because chain collapse tends to cancel the original natural remanent magnetization. Detailed models for the hysteretic and anhysteretic properties of structures (1-4) have been calculated by taking realistic distributions of magnetosome size, elongation, and spacing into account, as inferred from a number of published TEM observations. Model calculations took a total of >2 years continuous running time on two computers in an effort to obtain realistic results, which are shown here for the

  10. Lymphoplasmacytic lymphoma causing light chain cast nephropathy.

    Science.gov (United States)

    Pérez, Nuria S; Garcia-Herrera, Adriana; Rosiñol, Laura; Palos, Lily; Santiago, Evelyn; Espinosa, Gerard; Solé, Manel; Campistol, Josep M; Quintana, Luis F

    2012-01-01

    Plasma cell dyscrasias are frequently associated with kidney disease through the production of monoclonal immunoglobulin but with a diverse set of pathologic renal patterns. While almost all patients with a renal biopsy showing a cast nephropathy have myeloma, kidney involvement associated with pathological immunoglobulin light chains and lymphoma is rare. To our knowledge, this is the first report of a cast nephropathy associated with lymphoplasmacytic lymphoma. We emphasize the relation between light chain deposition and renal dysfunction in this disease with production of light chains. A therapeutic approach that decreases light chain production appears to be warranted in these patients.

  11. Molecular Wring Resonances in Chain Molecules

    DEFF Research Database (Denmark)

    Bohr, Henrik; Brunak, Søren; Bohr, Jakob

    1997-01-01

    It is shown that the eigenfrequency of collective twist excitations in chain molecules can be in the megahertz and gigahertz range. Accordingly, resonance states can be obtained at specific frequencies, and phenomena that involve structural properties can take place. Chain molecules can alter...... their conformation and their ability to function, and a breaking of the chain can result. It is suggested that this phenomenon forms the basis for effects caused by the interaction of microwaves and biomolecules, e.g. microwave assisted hydrolysis of chain molecules....

  12. Business alignment in the procurement domain: a study of antecedents and determinants of supply chain performance

    Directory of Open Access Journals (Sweden)

    Patrick Mikalef

    2014-01-01

    Full Text Available With organizations now placing an increasing amount on attention on the management of their supply chain activities, the role of Information Technology (IT in supporting these operations has been put in the spotlight. In spite of extensive research examining how IT can be employed in various activities of supply chain management, the majority of studies are limited in identifying enablers and inhibitors of adoption. Empirical studies examining post-adoption conditions that facilitate performance improvement still remain scarce. In this study we focus on procurement as part of the supply chain management activities. We apply the business-IT alignment perspective to the domain of procurement, and examine how certain organizational factors impact the attainment of this state. Additionally, we research the effect that procurement alignment has on supply chain management performance. In order to do so, we apply Partial Least Squares (PLS analysis on a sample of 172 European companies. We find that firms that opt for a centralized governance structure, as well as larger firms, are more likely to attain a state of procurement alignment. Furthermore, our results empirically support the statement that procurement alignment is positively correlated with operational efficiency and competitive performance of the supply chain.

  13. Designing Inhibitors of Anthrax Toxin

    Science.gov (United States)

    Nestorovich, Ekaterina M.; Bezrukov, Sergey M.

    2014-01-01

    Introduction Present-day rational drug design approaches are based on exploiting unique features of the target biomolecules, small- or macromolecule drug candidates, and physical forces that govern their interactions. The 2013 Nobel Prize in chemistry awarded “for the development of multiscale models for complex chemical systems” once again demonstrated the importance of the tailored drug discovery that reduces the role of the trial and error approach to a minimum. The “rational drug design” term is rather comprehensive as it includes all contemporary methods of drug discovery where serendipity and screening are substituted by the information-guided search for new and existing compounds. Successful implementation of these innovative drug discovery approaches is inevitably preceded by learning the physics, chemistry, and physiology of functioning of biological structures under normal and pathological conditions. Areas covered This article provides an overview of the recent rational drug design approaches to discover inhibitors of anthrax toxin. Some of the examples include small-molecule and peptide-based post-exposure therapeutic agents as well as several polyvalent compounds. The review also directs the reader to the vast literature on the recognized advances and future possibilities in the field. Expert opinion Existing options to combat anthrax toxin lethality are limited. With the only anthrax toxin inhibiting therapy (PA-targeting with a monoclonal antibody, raxibacumab) approved to treat inhalational anthrax, in our view, the situation is still insecure. The FDA’s animal rule for drug approval, which clears compounds without validated efficacy studies on humans, creates a high level of uncertainty, especially when a well-characterized animal model does not exist. Besides, unlike PA, which is known to be unstable, LF remains active in cells and in animal tissues for days. Therefore, the effectiveness of the post-exposure treatment of the individuals

  14. Effects of enterprise technology on supply chain collaboration: analysis of China-linked supply chain

    Science.gov (United States)

    Li, Ling

    2012-02-01

    Supply chain collaboration has received increasing attention from scholars and practitioners in recent years. However, our understanding of how enterprise information technology facilitates supply chain collaboration is still very limited, especially with regard to Chinese enterprise ownerships such as state-owned firms, joint-venture firms and local village-owned firms. This paper extends the theory established in enterprise information technology (IT) and supply chain collaboration literature and relates it with coordination in China-linked supply chain. Drawing upon an empirical study from 177 Chinese companies, we provide three major findings: (i) uncovered the importance of leveraging enterprise IT through supply chain collaboration; (ii) identified the relationship between enterprise ownership and enterprise technology use and supply chain collaboration in China-linked supply chain and (iii) illustrated effects of supply chain collaborative activities on operational and market performance.

  15. An online algorithm for generating fractal hash chains applied to digital chains of custody

    CERN Document Server

    Bradford, Phillip G

    2007-01-01

    This paper gives an online algorithm for generating Jakobsson's fractal hash chains. Our new algorithm compliments Jakobsson's fractal hash chain algorithm for preimage traversal since his algorithm assumes the entire hash chain is precomputed and a particular list of Ceiling(log n) hash elements or pebbles are saved. Our online algorithm for hash chain traversal incrementally generates a hash chain of n hash elements without knowledge of n before it starts. For any n, our algorithm stores only the Ceiling(log n) pebbles which are precisely the inputs for Jakobsson's amortized hash chain preimage traversal algorithm. This compact representation is useful to generate, traverse, and store a number of large digital hash chains on a small and constrained device. We also give an application using both Jakobsson's and our new algorithm applied to digital chains of custody for validating dynamically changing forensics data.

  16. Supply Chain Systems Architecture and Engineering Design: Green-field Supply Chain Integration

    OpenAIRE

    Radanliev, Petar

    2015-01-01

    This paper developed a new theory for supply chain architecture, and engineering design that enables integration of the business and supply chain strategies. The architecture starts with individual supply chain participants and derives insights into the complex and abstract concept of green-field integration design. The paper presented a conceptual system for depicting the interactions between business and supply chain strategy engineering. The system examines the decisions made when engineer...

  17. Geometry behind chordal Loewner chains

    CERN Document Server

    Contreras, Manuel D; Gumenyuk, Pavel

    2010-01-01

    Loewner Theory is a deep technique in Complex Analysis affording a basis for many further important developments such as the proof of famous Bieberbach's conjecture and well-celebrated Schramm's Stochastic Loewner Evolution (SLE). It provides analytic description of expanding domains dynamics in the plane. Two cases have been developed in the classical theory, namely the {\\it radial} and the {\\it chordal} Loewner evolutions, referring to the associated families of holomorphic self-mappings being normalized at an internal or boundary point of the reference domain, respectively. Recently there has been introduced a new approach [arXiv:0807.1594v1, arXiv:0807.1715v1, arXiv:0902.3116v1] bringing together, and containing as quite special cases, radial and chordal variants of Loewner Theory. In the framework of this approach we address the question what kind of systems of simply connected domains can be described by means of Loewner chains of chordal type. As an answer to this question we establish a necessary and ...

  18. Leflunomide, a Reversible Monoamine Oxidase Inhibitor.

    Science.gov (United States)

    Petzer, Jacobus P; Petzer, Anél

    2016-01-01

    A screening study aimed at identifying inhibitors of the enzyme, monoamine oxidase (MAO), among clinically used drugs have indicated that the antirheumatic drug, leflunomide, is an inhibitor of both MAO isoforms. Leflunomide inhibits human MAO-A and MAO-B and exhibits IC50 values of 19.1 μM and 13.7 μM, respectively. The corresponding Ki values are 17.7 μM (MAO-A) and 10.1 μM (MAO-B). Dialyses of mixtures of the MAO enzymes and leflunomide show that inhibition of the MAOs by leflunomide is reversible. The principal metabolite of leflunomide, teriflunomide (A77 1726), in contrast is not an MAO inhibitor. This study concludes that, although leflunomide is only moderately potent as an MAO inhibitor, isoxazole derivatives may represent a general class of MAO inhibitors and this heterocycle may find application in MAO inhibitor design. In this respect, MAO inhibitors are used in the clinic for the treatment of depressive illness and Parkinson's disease, and are under investigation as therapy for certain types of cancer, Alzheimer's disease and age-related impairment of cardiac function.

  19. Vascular calcification: Inducers and inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Donghyun, E-mail: dhlee@cau.ac.kr [Department of Biomedical Engineering, Division of Integrative Engineering, Chung-Ang University, 221 Heukseok-Dong, Dongjak-Gu, Seoul 156-756 (Korea, Republic of)

    2011-09-15

    Highlights: {center_dot} Types of vascular calcification processes. {center_dot} Inducers of vascular calcification. {center_dot} Inhibitors of vascular calcifications. {center_dot} Clinical utility for vascular calcification therapy. {center_dot} Implications for the development of new tissue engineering strategies. - Abstract: Unlike the traditional beliefs, there are mounting evidences suggesting that ectopic mineral depositions, including vascular calcification are mostly active processes, many times resembling that of the bone mineralization. Numbers of agents are involved in the differentiation of certain subpopulation of smooth muscle cells (SMCs) into the osteoblast-like entity, and the activation and initiation of extracellular matrix ossification process. On the other hand, there are factors as well, that prevent such differentiation and ectopic calcium phosphate formation. In normal physiological environments, activities of such procalcific and anticalcific regulatory factors are in harmony, prohibiting abnormal calcification from occurring. However, in certain pathophysiological conditions, such as atherosclerosis, chronic kidney disease (CKD), and diabetes, such balances are altered, resulting in abnormal ectopic mineral deposition. Understanding the factors that regulate the formation and inhibition of ectopic mineral formation would be beneficial in the development of tissue engineering strategies for prevention and/or treatment of such soft-tissue calcification. Current review focuses on the factors that seem to be clinically relevant and/or could be useful in developing future tissue regeneration strategies. Clinical utilities and implications of such factors are also discussed.

  20. ALK inhibitors, a pharmaceutical perspective

    Directory of Open Access Journals (Sweden)

    Arturo eGalvani

    2012-02-01

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

  1. Jetfighter: An Experiential Value Chain Exercise

    Science.gov (United States)

    Sheehan, Norman T.; Gamble, Edward N.

    2010-01-01

    Value chain analysis is widely taught in business schools and applied by practitioners to improve business performance. Despite its ubiquity, many students struggle to understand and apply value chain concepts in practice. JetFighter uses a complex manufacturing process (making intricate paper planes) to provide students an opportunity to enhance…

  2. The Future of Resilient Supply Chains

    DEFF Research Database (Denmark)

    Donadoni, Mattia; Roden, Sinéad; Scholten, Kirstin

    This research aims to advance theoretical understanding around the management of supply chain disruptions through a multi-stage Delphi study on supply chain resilience. Stage one focused on polling academic experts followed by a second stage with practitioners from automotive, electronics and food...

  3. Achieving Supply Chain Integration within Construction Industry

    Directory of Open Access Journals (Sweden)

    Peter McDermotti

    2012-11-01

    Full Text Available The main driver behind the adoption of supply chain management (SCM philosophy into the construction industry was the successes within other industry sectors. SCM can be defined as network of different organisations, linked upstream and downstream in a chain, aiming to produce quality and value in the services and products for the end consumers through integrated processes and activities. In order to achieve the optimised level of integration of the whole supply chain, the industry has responded in various forms. This paper will discuss different initiatives by the researchers,construction industry,and the UK government in order to achieve optimal level of supply chain integration. This paper will discuss the concept of aggregation,and also look at other supply chain integration related concepts including client-led supply chain, knowledge about the whole supply chain, effects of procurement on integration of supply chain, etc. The paper will give a brief overview and initial findings of a project undertaken by the authors, and also include examples from the UK construction industry on bundling of the supply and demand.

  4. Design Principles for Closed Loop Supply Chains

    NARCIS (Netherlands)

    H.R. Krikke (Harold); C.P. Pappis (Costas); G.T. Tsoulfas; J.M. Bloemhof-Ruwaard (Jacqueline)

    2001-01-01

    textabstractIn this paper we study design principles for closed loop supply chains. Closed loop supply chains aim at closing material flows thereby limiting emission and residual waste, but also providing customer service at low cost. We study 'traditional' and 'new' design principles known in the l

  5. A modeling framework for supply chain simulation

    NARCIS (Netherlands)

    van der Zee, D.J.; van der Vorst, J.G.A.J.

    2002-01-01

    In many industries logistic optimization on a company scale is no longer sufficient to meet the competition. Nowadays, competition takes place between supply chains. Intrinsic to the concept and success of a supply chain is the tuning of the activities of the companies involved. Given the complexity

  6. Using Games to Teach Markov Chains

    Science.gov (United States)

    Johnson, Roger W.

    2003-01-01

    Games are promoted as examples for classroom discussion of stationary Markov chains. In a game context Markov chain terminology and results are made concrete, interesting, and entertaining. Game length for several-player games such as "Hi Ho! Cherry-O" and "Chutes and Ladders" is investigated and new, simple formulas are given. Slight…

  7. Towards effective food chains : models and applications

    NARCIS (Netherlands)

    Trienekens, J.H.; Top, J.L.; Vorst, van der J.G.A.J.; Beulens, A.J.M.

    2010-01-01

    Food chain management research can help in the analysis and redesign of value creation and the product flow throughout the chain from primary producer down to the consumer. The aim is to meet consumer and societal requirements effectively at minimal cost. In the Wageningen UR strategic research prog

  8. Operational excellence in logistics and supply chains

    OpenAIRE

    2015-01-01

    This volume contains research contributions by an international group of authors focusing on innovative models to optimize logistics and supply chains at an operational level. They address process efficiency and data-related aspects. Supply chain security insights are also given.

  9. Current Control Strategy of Chain Circuit STATCOM

    Institute of Scientific and Technical Information of China (English)

    WANG Xuan; FU Jian; TENG Letian; SUN Lijing; ZHAO Ruibin; WU Shouyuan; DENG Zhanfeng

    2012-01-01

    In order to study the current control strategy based on the chain circuit static synchronous compensator (STATCOM) dynamic model and the design control system with good stability and tracking accuracy, this paper applies the chain circuit STATCOM small signal AC model, and proposes the following assumptions:

  10. On robustness in food supply chain networks

    NARCIS (Netherlands)

    Vlajic, J.V.; Vorst, van der J.G.A.J.; Hendrix, E.M.T.

    2010-01-01

    Purpose: Today's business environment is characterized by challenges of strong global competition where companies tend to achieve leanness and maximum responsiveness to customer demand. Lean supply chain networks are vulnerable to all kind of disruptions. For food supply chain networks (FSCNs), due

  11. Using management information in broiler supply chains

    NARCIS (Netherlands)

    Yassin, H.

    2012-01-01

    The Dutch broiler supply chain involves several interdependent firms such as breeding and feed companies, rearing farms, breeder farms, broiler hatcheries and broiler farms. To stay competitive and sustain continuity, evaluation of production at each level of the chain is crucial. Good quality data

  12. Localized Lymph Node Light Chain Amyloidosis

    Directory of Open Access Journals (Sweden)

    Binod Dhakal

    2015-01-01

    Full Text Available Immunoglobulin-derived light chain amyloidosis can occasionally be associated with localized disease. We present a patient with localized lymph node light chain amyloidosis without an underlying monoclonal protein or lymphoproliferative disorder and review the literature of lymph node amyloidosis discussing work-up and risk factors for systemic progression.

  13. Waste Reduction in Fresh Food Supply Chains

    DEFF Research Database (Denmark)

    Kaipia, Riikka; Loikkanen, Lauri; Dukovska-Popovska, Iskra

    2011-01-01

    The paper studies a well-known phenomenon, information sharing in supply chains, in a new context, fresh foods, with a specific goal, supporting sustainable performance in the supply chain. Fresh foods are important for retail stores, representing around half of retail sales, but form a challenging...

  14. Molecular dynamics studies of entangled polymer chains

    NARCIS (Netherlands)

    Bulacu, Monica Iulia

    2008-01-01

    The thesis presents three molecular dynamics studies of polymeric ensembles in which the chain entanglement plays the major role in the internal dynamics of the system. A coarse-grained model is used for representing the polymer chains as strings of beads connected by finite-extensible springs. In a

  15. Bethe vectors for XXX-spin chain

    Science.gov (United States)

    Burdík, Čestmír; Fuksa, Jan; Isaev, Alexei

    2014-11-01

    The paper deals with algebraic Bethe ansatz for XXX-spin chain. Generators of Yang-Baxter algebra are expressed in basis of free fermions and used to calculate explicit form of Bethe vectors. Their relation to N-component models is used to prove conjecture about their form in general. Some remarks on inhomogeneous XXX-spin chain are included.

  16. Qualitative methodology for efficient food chain design

    NARCIS (Netherlands)

    Apaiah, R.K.; Hendrix, E.M.T.; Meerdink, G.; Linnemann, A.R.

    2005-01-01

    This paper presents a methodology to efficiently design food supply chains. The goals of quality, cost and environmental load are looked at independently of each other. Food chains are made up of links and are designed to deliver a particular product with consumer-specified attributes. These attribu

  17. Synchronize Your Supply Chain with RFID

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    1 Executive Summary Driving efficiencies throughout your supply chain and increasing the velocity of items through the supply chain from creation to consumer is more than a business mandate today; it’s a matter of business survival. If your company doesn’t do it, your competition will. Radio Frequency Identification (RFID) is a true next-generation

  18. Cooperation and profit allocation in distribution chains

    NARCIS (Netherlands)

    Guardiola, L.A.; Meca, A.; Timmer, J.B.

    2005-01-01

    We study the coordination of actions and the allocation of profit in distribution chains under decentralized control. We consider distribution chains in which a single supplier supplies goods for replenishment of stocks of several retailers who, in turn, sell these goods to their own separate market

  19. Extremal hexagonal chains concerning largest eigenvalue

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    In this paper, we define a roll-attaching operation of a hexagonal chain, and prove Gutman's conjecture affirmatively by using the operation. The idea of the proof is also applicable to the results concerning extremal hexagonal chains for the Hosoya index and Merrifield-Simmons index.

  20. Effective food supply chains; generating, modelling and evaluating supply chain scenarios

    NARCIS (Netherlands)

    Vorst, van der J.G.A.J.

    2000-01-01

    Logistical co-ordination in FMCG supply chains

    The overall objectives of the research described in this thesis were to obtain insight into the applicability of the concept Supply Chain Management (SCM) in food supply chains (SCs) from a logistical point of view, and to find an efficient and

  1. A conceptual framework for supply chain governance: An application to agri-food chains in China

    NARCIS (Netherlands)

    Zhang, X.Y.; Aramyan, L.H.

    2009-01-01

    Purpose - Chinese agri-food chains consist of the millions of small scale farmers, who are not well structured and organized in the supply chain. Owing to market liberalization and globalization, one of the most challenging issues along agri-food chains in China is becoming the issue of how to link

  2. Teaching Lean Six Sigma within a Supply Chain Context: The Airplane Supply Chain Simulation

    Science.gov (United States)

    Ellis, Scott C.; Goldsby, Thomas J.; Bailey, Ana M.; Oh, Jae-Young

    2014-01-01

    Lean six sigma is a management methodology that firms can employ to achieve substantial improvement in supply chain performance. However, few pedagogical exercises facilitate students' use of a comprehensive set of lean six sigma principles within a supply chain context. We describe the Airplane Supply Chain Simulation that helps students…

  3. Design and Synthesis of Caspase Inhibitors

    Institute of Scientific and Technical Information of China (English)

    BAI Xu

    2001-01-01

    @@ Apoptosis (programmed cell death) is an evolutionarily conserved process of cell suicide. It requires specialized machinery which involving a family of proteases named caspases. Manipulation of apoptosis through inhibiting or activating caspases has been of great therapeutic interests in the pharmaceutical industry. Using substrate based approach, a systematic investigation of conformationally constrained peptidomimetic inhibitors has led to the discovery of highly selective ones against selected members of the caspase family. It also resulted novel dipeptide inhibitors as useful tools and possible therapeutic agents against diseases caused by excessive apoptotic cell death. This presentation will focus on the design, synthesis and application of novel caspase inhibitors.

  4. Migrating corrosion inhibitor protection of concrete

    Energy Technology Data Exchange (ETDEWEB)

    Bjegovic, D.; Miksic, B.

    1999-11-01

    Migrating corrosion inhibitors (MCI) were developed to protect steel rebar from corrosion in concrete. They were designed to be incorporated as an admixture during concrete batching or used for surface impregnation of existing concrete structures. Two investigations are summarized. One studied the effectiveness of MCIs as a corrosion inhibitor for steel rebar when used as an admixture in fresh concrete mix. The other is a long-term study of MCI concrete impregnation that chronicles corrosion rates of rebar in concrete specimens. Based on data from each study, it was concluded that migrating corrosion inhibitors are compatible with concrete and effectively delay the onset of corrosion.

  5. Design and Synthesis of Caspase Inhibitors

    Institute of Scientific and Technical Information of China (English)

    BAI; Xu

    2001-01-01

    Apoptosis (programmed cell death) is an evolutionarily conserved process of cell suicide. It requires specialized machinery which involving a family of proteases named caspases. Manipulation of apoptosis through inhibiting or activating caspases has been of great therapeutic interests in the pharmaceutical industry.  Using substrate based approach, a systematic investigation of conformationally constrained peptidomimetic inhibitors has led to the discovery of highly selective ones against selected members of the caspase family. It also resulted novel dipeptide inhibitors as useful tools and possible therapeutic agents against diseases caused by excessive apoptotic cell death. This presentation will focus on the design, synthesis and application of novel caspase inhibitors.  ……

  6. An Updated Review of Tyrosinase Inhibitors

    Directory of Open Access Journals (Sweden)

    Te-Sheng Chang

    2009-05-01

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

  7. Integrating product design into the supply chain

    DEFF Research Database (Denmark)

    Khan, Omera; Stolte, Terje; Creazza, Alessandro

    2016-01-01

    of opportunities and challenges when integrating product design and the supply chain and subsequently a step-by-step guide is developed to address these. Practical Implications: The research provides key recommendations to companies on how to create competitive capabilities by integrating product design...... into the supply chain. Originality/Value: This paper provides novel insights to both practitioners and researchers. For practitioners detailed recommendations are given on how they can maximise benefits through integrating product design into the supply chain. The RBV has been harnessed to highlight how......Purpose: The aim of the research is to illustrate how companies can create competitive capabilities through integration of product design into the supply chain. In doing so the paper reveals the challenges and the opportunities that companies face when integrating product design and supply chain...

  8. Direct current hopping conductance along DNA chain

    Institute of Scientific and Technical Information of China (English)

    Ma Song-Shan; Xu Hui; Liu Xiao-Liang; Li Ming-Jun

    2007-01-01

    This paper proposes a model of direct current(DC) electron hopping transport in DNA,in which DNA is considered as a binary one-dimensional disordered system.To quantitatively study the DC conductivity in DNA,it numerically calculates the DC conductivity of DNA chains with difierent parameter values.The result shows that the DC conductivity of DNA chain increases with the increase of temperature.And the conductivity of DNA chain is depended on the probability P.which represents the degree of compositional disorder in a DNA sequence to some extent.For P<0.5,the conductivity of DNA chain decreases with the increase of P,while for P≥0.5,the conductivity increases with the increase of p.The DC conductivity in DNA chain also varies with the change of the electric field,it presents non-Ohm's law conductivity characteristics.

  9. Chain graph models and their causal interpretations

    DEFF Research Database (Denmark)

    Lauritzen, Steffen Lilholt; Richardson, Thomas S.

    2002-01-01

    the equilibrium distributions of dynamic models with feed-back. These dynamic interpretations lead to a simple theory of intervention, extending the theory developed for directed acyclic graphs. Finally, we contrast chain graph models under this interpretation with simultaneous equation models which have......Chain graphs are a natural generalization of directed acyclic graphs and undirected graphs. However, the apparent simplicity of chain graphs belies the subtlety of the conditional independence hypotheses that they represent. There are many simple and apparently plausible, but ultimately fallacious......, interpretations of chain graphs that are often invoked, implicitly or explicitly. These interpretations also lead to flawed methods for applying background knowledge to model selection. We present a valid interpretation by showing how the distribution corresponding to a chain graph may be generated from...

  10. Structural repertoire of immunoglobulin λ light chains

    KAUST Repository

    Chailyan, Anna

    2011-03-01

    The immunoglobulin λ isotype is present in nearly all vertebrates and plays an important role in the human immune system. Despite its importance, few systematic studies have been performed to analyze the structural conformation of its variable regions, contrary to what is the case for κ and heavy chains. We show here that an analysis of the structures of λ chains allows the definition of a discrete set of recurring conformations (canonical structures) of their hypervariable loops and, most importantly, the identification of sequence constraints that can be used to predict their structure. We also show that the structural repertoire of λ chains is different and more varied than that of the κ chains, consistently with the current view of the involvement of the two major light-chain families in complementary strategies of the immune system to ensure a fine tuning between diversity and stability in antigen recognition. © 2011 Wiley-Liss, Inc.

  11. Quantum Markov Chain Mixing and Dissipative Engineering

    DEFF Research Database (Denmark)

    Kastoryano, Michael James

    2012-01-01

    This thesis is the fruit of investigations on the extension of ideas of Markov chain mixing to the quantum setting, and its application to problems of dissipative engineering. A Markov chain describes a statistical process where the probability of future events depends only on the state...... of the system at the present point in time, but not on the history of events. Very many important processes in nature are of this type, therefore a good understanding of their behaviour has turned out to be very fruitful for science. Markov chains always have a non-empty set of limiting distributions...... (stationary states). The aim of Markov chain mixing is to obtain (upper and/or lower) bounds on the number of steps it takes for the Markov chain to reach a stationary state. The natural quantum extensions of these notions are density matrices and quantum channels. We set out to develop a general mathematical...

  12. IMPLEMENTING SUSTAINABILITY INTO SUPPLY CHAIN OPERATIONS

    DEFF Research Database (Denmark)

    Jørsfeldt, Lilyana Makarowa

    2016-01-01

    Sustainability is acknowledged as a top strategic agenda by many global companies. As increasing globalization and outsourcing trends shift competition from single company affairs to competition among supply chains, the implementation of sustainability within companies’ supply chain operations...... of sustainable supply chain management SSCM in practice. This study aims to explore in detail the implementation of sustainability in ongoing supply chain operations. Specifically, it investigates how a company approaches the implementation of sustainability in different areas of its supply chain operations...... functions and across the organizations involved in the supply chain—to achieve sustainability deployment. The outcomes of the study are as follows: (1) Conceptual frameworks are developed based on empirical data from the case study. These frameworks cover three different levels of the business system...

  13. The Tax-Efficient Supply Chain

    DEFF Research Database (Denmark)

    Webber, Stuart

    2011-01-01

    Many multinational enterprises are restructuring supply chains to reduce their cost structures. As trade barriers fall and communications technologies improve, it has become easier and more cost-effective to manage business operations across international borders. This has motivated businesses...... their supply chains, and they should endeavor to maximize net income when doing so. This recommendation differs from the great majority of supply chain literature, which has generally recommended that businesses seek to minimize pretax costs. One of the most important activities for both supply chain and tax...... -- specifically a variety of legal organizations within the MNE -- to determine the best opportunities for integrated supply chain and income tax planning. This article also identifies a number of tax issues firms need to consider when making these important decisions....

  14. Research Methodologies in Supply Chain Management

    DEFF Research Database (Denmark)

    Kotzab, Herbert

    While supply chain management has risen to great prominence in recent year, there are hardly related developments in research methodologies. Yet, as supply chains cover more than one company, one central issue is how to collect and analyse data along the whole or relevant part of the supply chain....... Within the 36 chapters 70 authors bring together a rich selection of theoretical and practical examples of how research methodologies are applied in supply chain management. The book contains papers on theoretical implications as well as papers on a range of key methods, such as modelling, surveys, case...... studies or action research. It will be of great interest to researchers in the area of supply chain management and logistics, but also to neighbouring fields, such as network management or global operations....

  15. Environmental management the supply chain perspective

    CERN Document Server

    Wong, Christina W Y; Lun, Y H Venus; Cheng, T C E

    2015-01-01

    In view of the increasing quest for environmental management in businesses, this book provides a good reference to firms to understand how they may manage their supply chains to improve business and environmental performance. The book consists of six chapters covering such topics as environmental management, environmental management practices with supply chain efforts, collaborative environmental management, organizational capabilities in environmental management, environmental disclosure, and closed-loop supply chains. The book presents theory-driven discussions on the link between environmental management and business performance in the context of supply chain management. The book will be useful for firms to learn from the research findings and real-life cases to develop plans to implement environmental management practices jointly with supply chain partners.

  16. Supply Chain Management in Industrial Symbiosis Networks

    DEFF Research Database (Denmark)

    Herczeg, Gabor

    2016-01-01

    Sustainable supply chain management deals with the design and operation of profitable supply chains that also respect limitations on natural resources, do no harm to the environment, and consider the social systems they operate in. In academic research on sustainable supply chain management...... sustainable develop- ment efforts, and emphasize synergistic relations, community, and collabora- tion. This thesis takes an operations and supply chain management perspec- tive on industrial symbiosis networks. More specifically, the thesis elaborates on the collaborative and competitive characteristics......-product allocation strategies, which turn out to have different requirements and consequences for the organization and facilitation of the collaborative efforts. Overall, this thesis aims to ground industrial symbiosis in operations and supply chain management theory. The thesis thereby provides a basis...

  17. Packing of charged chains on toroidal geometries

    Science.gov (United States)

    Yao, Zhenwei; de la Cruz, Monica Olvera

    2013-01-01

    We study a strongly adsorbed flexible polyelectrolyte chain on tori. In this generalized Thomson problem, the patterns of the adsorbed chain are analyzed in the space of the toroidal coordinates and in terms of the orientation of each chain segment. Various patterns are found, including double spirals, disclination-like structures, Janus tori, and uniform wrappings, arising from the long-range electrostatic interaction and the toroidal geometry. Their broken mirror symmetry is quantitatively characterized by introducing an order parameter, an integral of the torsion. The uniform packing, which breaks the mirror symmetry the least, has the lowest value of the order parameter. In addition, it is found that the electrostatic energy of confined chains on tori conforms to a power law regardless of the screening effect in some typical cases studied. Furthermore, we study random walks on tori that generate chain configurations in the large screening limit or at large thermal fluctuation; some features associated with the toroidal geometry are discussed.

  18. Designing value-creating supply chain networks

    CERN Document Server

    Martel, Alain

    2016-01-01

    Focusing on the design of robust value-creating supply chain networks (SCN) and key strategic issues related to the number; location, capacity and mission of supply chain facilities (plants, distribution centers) – as well as the network structure required to provide flexibility and resilience in an uncertain world – this book presents an innovative methodology for SCN reengineering that can be used to significantly improve the bottom line of supply chain dependent businesses. Providing readers with the tools needed to analyze and model value creation activities, Designing Value-Creating Supply Chain Networks examines the risks faced by modern supply chains, and shows how to develop plausible future scenarios to evaluate potential SCN designs. The design methods proposed are based on a visual representation formalism that facilitates the analysis and modeling of SCN design problems, book chapters incorporate several example problems and exercises which can be solved with Excel tools (Analysis tools and So...

  19. Synergistic inhibition of colon carcinoma cell growth by Hedgehog-Gli1 inhibitor arsenic trioxide and phosphoinositide 3-kinase inhibitor LY294002.

    Science.gov (United States)

    Cai, Xinyi; Yu, Kun; Zhang, Lijuan; Li, Yunfeng; Li, Qiang; Yang, Zhibin; Shen, Tao; Duan, Lincan; Xiong, Wei; Wang, Weiya

    2015-01-01

    The Hedgehog (Hh) signaling pathway not only plays important roles in embryogenesis and adult tissue homeostasis, but also in tumorigenesis. Aberrant Hh pathway activation has been reported in a variety of malignant tumors including colon carcinoma. Here, we sought to investigate the regulation of the Hh pathway transcription factor Gli1 by arsenic trioxide and phosphoinositide 3-kinase (PI3K) inhibitor LY294002 in colon carcinoma cells. We transfected cells with siGli1 and observed a significant reduction of Gli1 expression in HCT116 and HT29 cells, which was confirmed by quantitative real-time polymerase chain reaction and Western blots. Knocking down endogenous Gli1 reduced colon carcinoma cell viability through inducing cell apoptosis. Similarly, knocking down Gli2 using short interfering RNA impaired colon carcinoma cell growth in vitro. To elucidate the regulation of Gli1 expression, we found that both Gli inhibitor arsenic trioxide and PI3K inhibitor LY294002 significantly reduced Gli1 protein expression and colon carcinoma cell proliferation. Arsenic trioxide treatment also reduced Gli1 downstream target gene expression, such as Bcl2 and CCND1. More importantly, the inhibition of Hedgehog-Gli1 by arsenic trioxide showed synergistic anticancer effect with the PI3K inhibitor LY294002 in colon carcinoma cells. Our findings suggest that the Hh pathway transcription factor Gli1 is involved in the regulation of colon carcinoma cell viability. Inhibition of Hedgehog-Gli1 expression by arsenic trioxide and PI3K inhibitor synergistically reduces colon cancer cell proliferation, indicating that they could be used as an effective anti-colon cancer combination therapy.

  20. Structural and thermodynamic study on aldose reductase: nitro-substituted inhibitors with strong enthalpic binding contribution.

    Science.gov (United States)

    Steuber, Holger; Heine, Andreas; Klebe, Gerhard

    2007-05-04

    To prevent diabetic complications derived from enhanced glucose flux via the polyol pathway the development of aldose reductase inhibitors (ARIs) has been established as a promising therapeutic concept. In order to identify novel lead compounds, a virtual screening (VS) was performed successfully suggesting carboxylate-type inhibitors of sub-micromolar to micromolar affinity. Here, we combine a structural characterization of the binding modes observed by X-ray crystallography with isothermal titration calorimetry (ITC) measurements providing insights into the driving forces of inhibitor binding, particularly of the first leads from VS. Characteristic features of this novel inhibitor type include a carboxylate head group connected via an alkyl spacer to a heteroaromatic moiety, which is linked to a further nitro-substituted aromatic portion. The crystal structures of two enzyme-inhibitor complexes have been determined at resolutions of 1.43 A and 1.55 A. Surprisingly, the carboxylic group of the most potent VS lead occupies the catalytic pocket differently compared to the interaction geometry observed in almost all other crystal structures with structurally related ligands and obtained under similar conditions, as an interstitial water molecule is picked up upon ligand binding. The nitro-aromatic moiety of both leads occupies the specificity pocket of the enzyme, however, adopting a different geometry compared to the docking prediction: unexpectedly, the nitro group binds to the bottom of the specificity pocket and provokes remarkable induced-fit adaptations. A peptide group located at the active site orients in such a way that H-bond formation to one nitro group oxygen atom is enabled, whereas a neighbouring tyrosine side-chain performs a slight rotation off from the binding cavity to accommodate the nitro group. Identically constituted ligands, lacking this nitro group, exhibit an affinity drop of one order of magnitude. In addition, thermodynamic data suggest a

  1. Auto component supply chain: a path to global India

    OpenAIRE

    2011-01-01

    Supply chain management works to bring the supplier, the distributor, and the customer into one cohesive process. The Supply Chain Council defined supply chain as ‘Supply Chain: The flow and transformation of raw materials into products from suppliers through production and distribution facilities to the ultimate consumer., and then Sunil Chopra and Meindl, (2001) have define Supply chain management as ‘Supply Chain Management involves the flows between and among stages in a supply chain to m...

  2. Single chain Fab (scFab fragment

    Directory of Open Access Journals (Sweden)

    Brenneis Mariam

    2007-03-01

    Full Text Available Abstract Background The connection of the variable part of the heavy chain (VH and and the variable part of the light chain (VL by a peptide linker to form a consecutive polypeptide chain (single chain antibody, scFv was a breakthrough for the functional production of antibody fragments in Escherichia coli. Being double the size of fragment variable (Fv fragments and requiring assembly of two independent polypeptide chains, functional Fab fragments are usually produced with significantly lower yields in E. coli. An antibody design combining stability and assay compatibility of the fragment antigen binding (Fab with high level bacterial expression of single chain Fv fragments would be desirable. The desired antibody fragment should be both suitable for expression as soluble antibody in E. coli and antibody phage display. Results Here, we demonstrate that the introduction of a polypeptide linker between the fragment difficult (Fd and the light chain (LC, resulting in the formation of a single chain Fab fragment (scFab, can lead to improved production of functional molecules. We tested the impact of various linker designs and modifications of the constant regions on both phage display efficiency and the yield of soluble antibody fragments. A scFab variant without cysteins (scFabΔC connecting the constant part 1 of the heavy chain (CH1 and the constant part of the light chain (CL were best suited for phage display and production of soluble antibody fragments. Beside the expression system E. coli, the new antibody format was also expressed in Pichia pastoris. Monovalent and divalent fragments (DiFabodies as well as multimers were characterised. Conclusion A new antibody design offers the generation of bivalent Fab derivates for antibody phage display and production of soluble antibody fragments. This antibody format is of particular value for high throughput proteome binder generation projects, due to the avidity effect and the possible use of

  3. Structural Origins of Martian Pit Chains

    Science.gov (United States)

    Wyrick, D.; Ferrill, D. A.; Morris, A. P.; Colton, S. L.; Sims, D. W.

    2003-12-01

    Pit craters are circular to elliptical depressions found in alignments (chains), which in many cases coalesce into linear troughs, and are common on the surface of Mars. Pit craters lack an elevated rim, ejecta deposits, or lava flows that are associated with impact craters or calderas. It is generally agreed that these features are formed by collapse into a subsurface cavity. Hypotheses regarding the formation of pit crater chains require development of a substantial subsurface void to accommodate collapse of the overlying sediments. Suggested mechanisms of formation include: collapsed lava tubes, dike swarms, collapsed magma chamber, karst dissolution, fissuring beneath loose material, and dilational faulting. The research described here is intended to constrain current interpretations of pit crater chain formation by analyzing their distribution and morphology. The western hemisphere of Mars was systematically mapped using Mars Orbiter Camera (MOC) images to generate ArcView Geographic Information System (GIS) coverages. All visible pit crater chains were mapped, including their orientations and associations with other structures. We found that pit chains commonly occur in areas that show regional extension or local fissuring. There is a strong correlation between pit chains and fault-bounded grabens. Frequently, there are transitions along strike from (i) visible faulting to (ii) faults and pits to (iii) pits alone. We performed a detailed quantitative analysis of pit crater morphology using MOC narrow angle images, Thermal Emission Imaging System (THEMIS) visual images and Mars Orbiter Laser Altimeter (MOLA) data. This allowed us to interpret a pattern of pit chain evolution and calculate pit depth, slope, and volume. The information collected in the study was then compared with non-Martian examples of pit chains and physical analog models. We evaluated the various mechanisms for pit chain development based on the data collected and conclude that dilational

  4. Virtualization of work in global supply chains

    Directory of Open Access Journals (Sweden)

    Sabina Wyrwich-Płotka

    2016-12-01

    Full Text Available Background: The paper is devoted to the notion and benefits of implementing virtual work in global supply chains. Virtual work must be understood as an intentional activity of a human being, aimed at rendering services (tangible and intangible, by means of ITC tools, performed in a distance from the traditional place of work, in a mobile manner. The empirical research were conducted on the basis of 4 case studies of global leaders of supply chains, which in accordance with M. Fisher's classification, represent two types. The case studies confirmed the positive influence of virtual work both in effective and flexible supply chains. Favourable market and technological conditions and increasing awareness of benefits of virtual work will make it more and more widespread in companies comprising global supply chains. The aim of the study is to demonstrate the cause and effect relationships between virtual work and competitiveness of efficient and flexible supply chain. Methods: The paper is based on the available recent scientific-theoretical research and publication.  The authors analyzed 4 enterprises in Poland. The enterprises representing a flexible or an effective supply chain, either using or not a virtual work. The study carried out the authors had the form of individual interviews. The authors used case studies to show that virtual work brings notable benefits in an effective and flexible supply chain.  Results: Based on these case studies, the authors demonstrated reasons to implement virtual work in selected enterprises. The reasons to implement virtual work are determinants of possible achieve economies in effective and flexible supply chain Conclusions: The examined case studies show that virtual work brings different benefits. In the effective supply chain, virtual workers enable to increase effectiveness and financial results for example. In the flexible supply chain the virtual work can be a way to maintain and build long

  5. HIV-1 Protease with 20 Mutations Exhibits Extreme Resistance to Clinical Inhibitors through Coordinated Structural Rearrangements

    Energy Technology Data Exchange (ETDEWEB)

    Agniswamy, Johnson; Shen, Chen-Hsiang; Aniana, Annie; Sayer, Jane M.; Louis, John M.; Weber, Irene T. (GSU); (NIH)

    2012-06-28

    The escape mutant of HIV-1 protease (PR) containing 20 mutations (PR20) undergoes efficient polyprotein processing even in the presence of clinical protease inhibitors (PIs). PR20 shows >3 orders of magnitude decreased affinity for PIs darunavir (DRV) and saquinavir (SQV) relative to PR. Crystal structures of PR20 crystallized with yttrium, substrate analogue p2-NC, DRV, and SQV reveal three distinct conformations of the flexible flaps and diminished interactions with inhibitors through the combination of multiple mutations. PR20 with yttrium at the active site exhibits widely separated flaps lacking the usual intersubunit contacts seen in other inhibitor-free dimers. Mutations of residues 35-37 in the hinge loop eliminate interactions and perturb the flap conformation. Crystals of PR20/p2-NC contain one uninhibited dimer with one very open flap and one closed flap and a second inhibitor-bound dimer in the closed form showing six fewer hydrogen bonds with the substrate analogue relative to wild-type PR. PR20 complexes with PIs exhibit expanded S2/S2' pockets and fewer PI interactions arising from coordinated effects of mutations throughout the structure, in agreement with the strikingly reduced affinity. In particular, insertion of the large aromatic side chains of L10F and L33F alters intersubunit interactions and widens the PI binding site through a network of hydrophobic contacts. The two very open conformations of PR20 as well as the expanded binding site of the inhibitor-bound closed form suggest possible approaches for modifying inhibitors to target extreme drug-resistant HIV.

  6. Glucose, Lactate and Glutamine but not Glutamate Support Depolarization-Induced Increased Respiration in Isolated Nerve Terminals

    DEFF Research Database (Denmark)

    Hohnholt, Michaela C; Andersen, Vibe H; Bak, Lasse K;

    2016-01-01

    and glycolytic rate in presence of different substrates. Mitochondrial function was tested by sequentially exposure of the synaptosomes to the ATP synthase inhibitor, oligomycin, the uncoupler FCCP (carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone) and the electron transport chain inhibitors rotenone...... and antimycin A. The synaptosomes exhibited intense respiratory activity using glucose as substrate. The FCCP-dependent respiration was significantly higher with 10 mM glucose compared to 1 mM glucose. Synaptosomes also readily used pyruvate as substrate, which elevated basal respiration, activity....... Synaptosomal respiration using glutamate and glutamine as substrates was significantly higher compared to basal respiration, whereas oligomycin-dependent and FCCP-induced respiration was lower compared to the responses obtained in the presence of glucose as substrate. We provide evidence that synaptosomes...

  7. Fresh fish distribution chains: An analysis of three Danish and three Australian chains

    DEFF Research Database (Denmark)

    Frederiksen, Marco Thorup; Bremner, Allan

    2001-01-01

    . Traceability is a most important issue in the high value product chains in Australia. No information technology methods, were in evidence. In the Danish chains, nearly all traceability was lost after the collector/auction stage and the only evaluation of quality parameters was by inspection.......Information on traceability was gathered for three domestic Danish fish chains typical of the current trading practices in fresh seafood and for three chains exporting products from Australia to Japan. The same standard questionnaires, coupled with personal interviews, were used in all six chains...

  8. Measuring performance at the supply chain level: the role of the chain director

    Directory of Open Access Journals (Sweden)

    Job A.C. De Haan

    2016-05-01

    The findings show when an attempt to implement a PMS at the supply chain level might be appropriate and effective (if a chain exists and has a director, and how the system’s content should be focused on what is needed to improve chain performance (with end customers’ demands as a starting point. The paper highlights the benefits obtained by the other partners if they comply with the best informed supply chain member in the development of the chain’s PMS, as well as how a PMS cannot be developed when none of the partners can be labelled as chain director.

  9. The New-generation of Green Surfactant(Alkylpolyglucoside)as an Inhibitor to the Corrosion of 907 Steel in Seawater

    Institute of Scientific and Technical Information of China (English)

    Min DU; Rong Jie GAO; Ping GONG; Qing Zhang WANG

    2004-01-01

    Weight-loss trials and potentiodynamic polarization curves have been used to study the inhibitive properties of alkylpolyglucoside (APG) towards the 907 steel in seawater.The inhibition was different, if the length of alkyl chain APG was different.As the result, calcium gluconate, zinc sulfate and APG can protect 907 steel from being corrupted in static seawater.The compound corrosion inhibitor was found to control both the anodic process and the cathodic process.

  10. Short-Chain Fatty Acid Acetate Stimulates Adipogenesis and Mitochondrial Biogenesis via GPR43 in Brown Adipocytes.

    Science.gov (United States)

    Hu, Jiamiao; Kyrou, Ioannis; Tan, Bee K; Dimitriadis, Georgios K; Ramanjaneya, Manjunath; Tripathi, Gyanendra; Patel, Vanlata; James, Sean; Kawan, Mohamed; Chen, Jing; Randeva, Harpal S

    2016-05-01

    Short-chain fatty acids play crucial roles in a range of physiological functions. However, the effects of short-chain fatty acids on brown adipose tissue have not been fully investigated. We examined the role of acetate, a short-chain fatty acid formed by fermentation in the gut, in the regulation of brown adipocyte metabolism. Our results show that acetate up-regulates adipocyte protein 2, peroxisomal proliferator-activated receptor-γ coactivator-1α, and uncoupling protein-1 expression and affects the morphological changes of brown adipocytes during adipogenesis. Moreover, an increase in mitochondrial biogenesis was observed after acetate treatment. Acetate also elicited the activation of ERK and cAMP response element-binding protein, and these responses were sensitive to G(i/o)-type G protein inactivator, Gβγ-subunit inhibitor, phospholipase C inhibitor, and MAPK kinase inhibitor, indicating a role for the G(i/o)βγ/phospholipase C/protein kinase C/MAPK kinase signaling pathway in these responses. These effects of acetate were mimicked by treatment with 4-chloro-α-(1-methylethyl)-N-2-thiazolylbenzeneacetamide, a synthetic G protein-coupled receptor 43 (GPR43) agonist and were impaired in GPR43 knockdown cells. Taken together, our results indicate that acetate may have important physiological roles in brown adipocytes through the activation of GPR43.

  11. Relationship between plasminogen activator inhibitor type-1 (PAI-1 gene polymorphisms and osteoporosis in Turkish women

    Directory of Open Access Journals (Sweden)

    Merih Ozgen

    2012-11-01

    Full Text Available OBJECTIVE: The development of osteoporosis is associated with several risk factors, such as genetic structures that affect bone turnover and bone mass. The impact of genetic structures on osteoporosis is not known. Plasminogen activator inhibitor type-1 regulates the bone matrix and bone balance. This study assessed the correlation between plasminogen activator inhibitor type-1 gene 4G/5G polymorphisms and osteoporosis in a population of Turkish women. METHODS: A total of 195 postmenopausal female patients who were diagnosed with osteoporosis (Group I based on bone mineral density measurements via dual-energy x-ray absorptiometry and 90 females with no osteoporosis (Group II were included in this study. Correlations between PAI-1 gene 4G/5G polymorphisms and osteoporosis were investigated through the identification of PAI-1 gene 4G/5G polymorphism genotypes using the polymerase chain reaction. RESULTS: No significant differences in the genotype and allele frequency of 4G/5G plasminogen activator inhibitor type-1 polymorphisms were observed between the two groups, and both groups exhibited the most frequently observed 4G5G genotype. CONCLUSION: No correlation between the development of osteoporosis in the female Turkish population and 4G/5G plasminogen activator inhibitor type-1 gene polymorphisms was observed.

  12. Rational design and validation of a Tip60 histone acetyltransferase inhibitor

    Science.gov (United States)

    Gao, Chunxia; Bourke, Emer; Scobie, Martin; Famme, Melina Arcos; Koolmeister, Tobias; Helleday, Thomas; Eriksson, Leif A.; Lowndes, Noel F.; Brown, James A. L.

    2014-06-01

    Histone acetylation is required for many aspects of gene regulation, genome maintenance and metabolism and dysfunctional acetylation is implicated in numerous diseases, including cancer. Acetylation is regulated by histone acetyltransferases (HATs) and histone deacetylases and currently, few general HAT inhibitors have been described. We identified the HAT Tip60 as an excellent candidate for targeted drug development, as Tip60 is a key mediator of the DNA damage response and transcriptional co-activator. Our modeling of Tip60 indicated that the active binding pocket possesses opposite charges at each end, with the positive charges attributed to two specific side chains. We used structure based drug design to develop a novel Tip60 inhibitor, TH1834, to fit this specific pocket. We demonstrate that TH1834 significantly inhibits Tip60 activity in vitro and treating cells with TH1834 results in apoptosis and increased unrepaired DNA damage (following ionizing radiation treatment) in breast cancer but not control cell lines. Furthermore, TH1834 did not affect the activity of related HAT MOF, as indicated by H4K16Ac, demonstrating specificity. The modeling and validation of the small molecule inhibitor TH1834 represents a first step towards developing additional specific, targeted inhibitors of Tip60 that may lead to further improvements in the treatment of breast cancer.

  13. Structure activity relationships of benzylproline-derived inhibitors of the glutamine transporter ASCT2

    Science.gov (United States)

    Singh, Kurnvir; Tanui, Rose; Gameiro, Armanda; Eisenberg, Gilad; Colas, Claire; Schlessinger, Avner; Grewer, Christof

    2017-01-01

    The glutamine transporter ASCT2 has been identified as a promising target to inhibit rapid growth of cancer cells. However, ASCT2 pharmacology is not well established. In this report, we performed a systematic structure activity analysis of a series of substituted benzylproline derivatives. Substitutions on the phenyl ring resulted in compounds with characteristics of ASCT2 inhibitors. Apparent binding affinity increased with increasing hydrophobicity of the side chain. In contrast, interaction of the ASCT2 binding site with specific positions on the phenyl ring was not observed. The most potent compound inhibits the ASCT2 anion conductance with a Ki of 3 μM, which is in the same range as that of more bulky and higher molecular weight inhibitors recently reported by others. The experimental results are consistent with computational analysis based on docking of the inhibitors against an ASCT2 homology model. The benzylproline scaffold provides a valuable tool for further improving binding potency of future ASCT2 inhibitors. PMID:28057420

  14. Structures of HIV Protease Guide Inhibitor Design to Overcome Drug Resistance

    Energy Technology Data Exchange (ETDEWEB)

    Weber, Irene T.; Kovalevsky, Andrey Y.; Harrison, Robert W. (GSU)

    2008-06-03

    The HIV/AIDS infection continues to be a major epidemic worldwide despite the initial promise of antiviral drugs. Current therapy includes a combination of drugs that inhibit two of the virally-encoded enzymes, the reverse transcriptase and the protease. The first generation of HIV protease inhibitors that have been in clinical use for treatment of AIDS since 1995 was developed with the aid of structural analysis of protease-inhibitor complexes. These drugs were successful in improving the life span of HIV-infected people. Subsequently, the rapid emergence of drug resistance has necessitated the design of new inhibitors that target mutant proteases. This second generation of antiviral protease inhibitors has been developed with the aid of data from medicinal chemistry, kinetics, and X-ray crystallographic analysis. Traditional computational methods such as molecular mechanics and dynamics can be supplemented with intelligent data mining approaches. One approach, based on similarities to the protease interactions with substrates, is to incorporate additional interactions with main chain atoms that cannot easily be eliminated by mutations. Our structural and inhibition data for darunavir have helped to understand its antiviral activity and effectiveness on drug resistant HIV and demonstrate the success of this approach.

  15. Discovery of Novel Nonactive Site Inhibitors of the Prothrombinase Enzyme Complex.

    Science.gov (United States)

    Kapoor, Karan; McGill, Nicole; Peterson, Cynthia B; Meyers, Harold V; Blackburn, Michael N; Baudry, Jerome

    2016-03-28

    The risk of serious bleeding is a major liability of anticoagulant drugs that are active-site competitive inhibitors targeting the Factor Xa (FXa) prothrombin (PT) binding site. The present work identifies several new classes of small molecule anticoagulants that can act as nonactive site inhibitors of the prothrombinase (PTase) complex composed of FXa and Factor Va (FVa). These new classes of anticoagulants were identified, using a novel agnostic computational approach to identify previously unrecognized binding pockets at the FXa-FVa interface. From about three million docking calculations of 281,128 compounds in a conformational ensemble of FXa heavy chains identified by molecular dynamics (MD) simulations, 97 compounds and their structural analogues were selected for experimental validation, through a series of inhibition assays. The compound selection was based on their predicted binding affinities to FXa and their ability to successfully bind to multiple protein conformations while showing selectivity for particular binding sites at the FXa/FVa interface. From these, thirty-one (31) compounds were experimentally identified as nonactive site inhibitors. Concentration-based assays further identified 10 compounds represented by four small-molecule families of inhibitors that achieve dose-independent partial inhibition of PTase activity in a nonactive site-dependent and self-limiting mechanism. Several compounds were identified for their ability to bind to protein conformations only seen during MD, highlighting the importance of accounting for protein flexibility in structure-based drug discovery approaches.

  16. Musical hallucinations treated with acetylcholinesterase inhibitors

    Directory of Open Access Journals (Sweden)

    Jan Dirk eBlom

    2015-04-01

    Full Text Available Musical hallucinations are relatively rare auditory percepts which, due to their intrusive nature and the accompanying fear of impending mental decline, tend to cause significant distress and impairment. Although their etiology and pathophysiology appear to be heterogeneous and no evidence-based treatment methods are available, case reports indicate that acetylcholinesterase inhibitors may yield positive results in patients with comorbid hearing loss. We present two female patients (aged 76 and 78 years both of whom suffered from hearing impairment and practically incessant musical hallucinations. Both patients were successfully treated with the acetylcholinesterase inhibitor rivastigmine. Based on these two case descriptions and an overview of studies describing the use of acetylcholinesterase inhibitors in similar patients, we discuss possible mechanisms and propose further research on the use of acetylcholinesterase inhibitors for musical hallucinations experienced in concordance with hearing loss.

  17. Drug design from the cryptic inhibitor envelope.

    Science.gov (United States)

    Lee, Chul-Jin; Liang, Xiaofei; Wu, Qinglin; Najeeb, Javaria; Zhao, Jinshi; Gopalaswamy, Ramesh; Titecat, Marie; Sebbane, Florent; Lemaitre, Nadine; Toone, Eric J; Zhou, Pei

    2016-02-25

    Conformational dynamics plays an important role in enzyme catalysis, allosteric regulation of protein functions and assembly of macromolecular complexes. Despite these well-established roles, such information has yet to be exploited for drug design. Here we show by nuclear magnetic resonance spectroscopy that inhibitors of LpxC--an essential enzyme of the lipid A biosynthetic pathway in Gram-negative bacteria and a validated novel antibiotic target--access alternative, minor population states in solution in addition to the ligand conformation observed in crystal structures. These conformations collectively delineate an inhibitor envelope that is invisible to crystallography, but is dynamically accessible by small molecules in solution. Drug design exploiting such a hidden inhibitor envelope has led to the development of potent antibiotics with inhibition constants in the single-digit picomolar range. The principle of the cryptic inhibitor envelope approach may be broadly applicable to other lead optimization campaigns to yield improved therapeutics.

  18. Strategies for discontinuation of proton pump inhibitors

    DEFF Research Database (Denmark)

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

    2014-01-01

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

  19. Musical hallucinations treated with acetylcholinesterase inhibitors.

    Science.gov (United States)

    Blom, Jan Dirk; Coebergh, Jan Adriaan F; Lauw, René; Sommer, Iris E C

    2015-01-01

    Musical hallucinations are relatively rare auditory percepts which, due to their intrusive nature and the accompanying fear of impending mental decline, tend to cause significant distress and impairment. Although their etiology and pathophysiology appear to be heterogeneous and no evidence-based treatment methods are available, case reports indicate that acetylcholinesterase inhibitors may yield positive results in patients with comorbid hearing loss. We present two female patients (aged 76 and 78 years) both of whom suffered from hearing impairment and practically incessant musical hallucinations. Both patients were successfully treated with the acetylcholinesterase inhibitor rivastigmine. Based on these two case descriptions and an overview of studies describing the use of acetylcholinesterase inhibitors in similar patients, we discuss possible mechanisms and propose further research on the use of acetylcholinesterase inhibitors for musical hallucinations experienced in concordance with hearing loss.

  20. The composite supply chain efficiency model: A case study of the Sishen-Saldanha supply chain

    Directory of Open Access Journals (Sweden)

    Leila L. Goedhals-Gerber

    2016-01-01

    Full Text Available As South Africa strives to be a major force in global markets, it is essential that South African supply chains achieve and maintain a competitive advantage. One approach to achieving this is to ensure that South African supply chains maximise their levels of efficiency. Consequently, the efficiency levels of South Africa’s supply chains must be evaluated. The objective of this article is to propose a model that can assist South African industries in becoming internationally competitive by providing them with a tool for evaluating their levels of efficiency both as individual firms and as a component in an overall supply chain. The Composite Supply Chain Efficiency Model (CSCEM was developed to measure supply chain efficiency across supply chains using variables identified as problem areas experienced by South African supply chains. The CSCEM is tested in this article using the Sishen-Saldanda iron ore supply chain as a case study. The results indicate that all three links or nodes along the Sishen-Saldanha iron ore supply chain performed well. The average efficiency of the rail leg was 97.34%, while the average efficiency of the mine and the port were 97% and 95.44%, respectively. The results also show that the CSCEM can be used by South African firms to measure their levels of supply chain efficiency. This article concludes with the benefits of the CSCEM.

  1. The role of butyrate, a histone deacetylase inhibitor in diabetes mellitus: experimental evidence for therapeutic intervention.

    Science.gov (United States)

    Khan, Sabbir; Jena, Gopabandhu

    2015-01-01

    The contribution of epigenetic mechanisms in diabetes mellitus (DM), β-cell reprogramming and its complications is an emerging concept. Recent evidence suggests that there is a link between DM and histone deacetylases (HDACs), because HDAC inhibitors promote β-cell differentiation, proliferation, function and improve insulin resistance. Moreover, gut microbes and diet-derived products can alter the host epigenome. Furthermore, butyrate and butyrate-producing microbes are decreased in DM. Butyrate is a short-chain fatty acid produced from the fermentation of dietary fibers by microbiota and has been proven as an HDAC inhibitor. The present review provides a pragmatic interpretation of chromatin-dependent and independent complex signaling/mechanisms of butyrate for the treatment of Type 1 and Type 2 DM, with an emphasis on the promising strategies for its drugability and therapeutic implication.

  2. Role of electron transport chain of chloroplasts in oxidative burst of interaction between Erwinia amylovora and host cells.

    Science.gov (United States)

    Abdollahi, Hamid; Ghahremani, Zahra; Erfaninia, Kobra; Mehrabi, Rahim

    2015-05-01

    Erwinia amylovora is a necrogenic bacterium, causing the fire blight disease on many rosaceous plants. Triggering oxidative burst by E. amylovora is a key response by which host plants try to restrain pathogen spread. Electron transport chain (ETC) of chloroplasts is known as an inducible source of reactive oxygen species generation in various stresses. This research was performed to assess the role of this ETC in E. amylovora-host interaction using several inhibitors of this chain in susceptible and resistant apple and pear genotypes. All ETC inhibitors delayed appearance of disease necrosis, but the effects of methyl viologen, glutaraldehyde, and DCMU were more significant. In the absence of inhibitors, resistant genotypes showed an earlier and severe H2O2 generation and early suppression of redox dependent, psbA gene. The effects of inhibitors were corresponding to the redox potential of ETC inhibitory sites. In addition, delayed necrosis appearance was associated with the decreased disease severity and delayed H2O2 generation. These results provide evidences for the involvement of this ETC in host oxidative burst and suggest that chloroplast ETC has significant role in E. amylovora-host interaction.

  3. Morphology and Mechanism of Benign Inhibitors

    Science.gov (United States)

    2012-07-01

    the water response of vanadate inhibitor films can be determined. Because the absorbed water usually resides in molecular-level free space inside...Schaefer, Water absorption and transport in bis- silane films. Physical Chemistry Chemical Physics, 2009. 11(1), p. 161 - 166. 23. Y. Wang, E. Watkins, J...Ooij, Effects of addition of corrosion inhibitors to silane films on the performance of AA2024-T3 in a 0.5M NaCl solution. Progress in Organic

  4. Enzyme-inhibitor mediated red cell labelling

    Energy Technology Data Exchange (ETDEWEB)

    Ackery, D.M.; Singh, J.; Wyeth, P. (Southampton Univ. (UK). Dept. of Chemistry)

    Red blood cells contain 90% of the body's enzyme carbonic anhydrase to which aromatic sulphonamide inhibitors bind tightly. P-iodo-benzene sulphonamide (PIBS) is a lipophilic inhibitor which would afford rapid cell labelling. Radioiodinated PIBS was prepared, in high yield, by radio ion exchange in the presence of ammonium sulphate. After intravenous injection of /sup 131/I-PIBS the radiolabel was found in the blood pool.

  5. Polypeptide Inhibitors of Mineral Scaling and Corrosion

    Science.gov (United States)

    1989-06-01

    peptides are based on natural protein inhibitors of mineral formation and generally are enriched in aspartic acid and phosphoserine. Specifically, the...the protein inhibitors of mineral formation , we evaluated several methods of preparation of phosphopeptides. These included direct polymerization of 2...number of assays have been developed to measure the ability of the peptides to inhibit mineral formation . These include methods for assessing effects on

  6. Inhibitor development in nonsevere hemophilia A

    OpenAIRE

    2014-01-01

    Hemophilia A is an X-linked inherited bleeding disorder that affects approximately 1 in 5000 male live births. It is caused by a deficient plasma level of clotting factor VIII and can be treated by the intravenous administration of factor VIII concentrates. A severe complication of the treatment with factor VIII concentrates is the development of inhibiting antibodies against factor VIII, also called inhibitors. Inhibitors challenge the treatment of hemophilia A as they inactivate factor VIII...

  7. Characterization of cereulide synthetase, a toxin-producing macromolecular machine.

    Directory of Open Access Journals (Sweden)

    Diego A Alonzo

    Full Text Available Cereulide synthetase is a two-protein nonribosomal peptide synthetase system that produces a potent emetic toxin in virulent strains of Bacillus cereus. The toxin cereulide is a depsipeptide, as it consists of alternating aminoacyl and hydroxyacyl residues. The hydroxyacyl residues are derived from keto acid substrates, which cereulide synthetase selects and stereospecifically reduces with imbedded ketoreductase domains before incorporating them into the growing depsipeptide chain. We present an in vitro biochemical characterization of cereulide synthetase. We investigate the kinetics and side chain specificity of α-keto acid selection, evaluate the requirement of an MbtH-like protein for adenylation domain activity, assay the effectiveness of vinylsulfonamide inhibitors on ester-adding modules, perform NADPH turnover experiments and evaluate in vitro depsipeptide biosynthesis. This work also provides biochemical insight into depsipeptide-synthesizing nonribosomal peptide synthetases responsible for other bioactive molecules such as valinomycin, antimycin and kutzneride.

  8. Polyclonal light chains in cerebrovascular disease

    Directory of Open Access Journals (Sweden)

    Patrizia Fiori

    2010-08-01

    Full Text Available Patrizia Fiori1, Maria Giannetti Luigi2, Linda Iurato1, Carminantonio Tammaro3, Gigliola Esposito3, Antonio Monaco11Central Operative Unit of Neurology (Dir. A Monaco, 2Infantile Neuropsychiatry and Social Service (Dir. LM Giannetti, 3Laboratory (Dir. CA Tammaro, ASL AV, Civil Hospital of Ariano Irpino, University of Naples, ItalyAbstract: Altered membrane permeability is a hallmark of inflammation and ischemia with systemic spreading. Renal dysfunction is a risk factor for cardiovascular, cerebrovascular, and metabolic diseases. The aim of the present study was to assess proteinuria and urinary polyclonal light chains in acute stroke and chronic cerebrovascular disease compared with other neurologic diseases. Our results showed significantly increased levels of urinary polyclonal light chains in cerebrovascular disease compared with other neurologic diseases. The highest values of urinary polyclonal κ chains were found in acute stroke compared with chronic cerebrovascular disease and other neurologic diseases, while the level of λ chains was mainly increased in chronic cerebrovascular diseases. The shift to chronic renal failure seems to be signaled by a decreased polyclonal light chain/creatinemia ratio. The absence of a significant correlation with blood pressure and other seric parameters suggests that polyclonal light chains are an early marker of reversible vascular impairment with renal dysfunction before progression to irreversible renal failure and need for dialysis and/or intensive care.Keywords: polyclonal light chains, cerebrovascular disease, renal failure

  9. Observing of chain-schedule stimuli.

    Science.gov (United States)

    Slezak, Jonathan M; Anderson, Karen G

    2014-06-01

    A classical-conditioning account of the processes maintaining behavior under chained schedules entails a backward transmission of conditioned-reinforcement effects. Assessing this process in traditional chain schedules is limited because the response maintained by stimulus onset accompanied by each link in a chain schedule may also be maintained by the primary reinforcer. In the present experiment, an observing response was used to measure the conditioned-reinforcing effects of stimuli associated with a three-link chain variable-time (VT) food schedule, and resistance-to-change tests (extinction and prefeeding) were implemented to examine if a backward transmission of reinforcement effects occur. Four pigeons served as subjects. Observing was maintained by the production of stimuli correlated with links of a three-link chain VT schedule with the middle-link stimulus maintaining the highest rate of observing, followed by the initial-link stimulus and the terminal-link stimulus maintaining the lowest observing rate. Results from resistance-to-change tests of extinction and prefeeding were not supportive of a backward transmission of reinforcement effects and in general, the pattern of resistance-to-change was forward. Based on past and current research, it appears that a backward pattern of relative rate decreases in responses maintained by stimuli correlated with a chain schedule due to disruption (i.e., extinction and prefeeding) is not a ubiquitous process that is evident within different chain-schedule arrangements.

  10. Screening and Quantification of Aliphatic Primary Alkyl Corrosion Inhibitor Amines in Water Samples by Paper Spray Mass Spectrometry.

    Science.gov (United States)

    Jjunju, Fred P M; Maher, Simon; Damon, Deidre E; Barrett, Richard M; Syed, S U; Heeren, Ron M A; Taylor, Stephen; Badu-Tawiah, Abraham K

    2016-01-19

    Direct analysis and identification of long chain aliphatic primary diamine Duomeen O (n-oleyl-1,3-diaminopropane), corrosion inhibitor in raw water samples taken from a large medium pressure water tube boiler plant water samples at low LODs (corrosion inhibitors in an industrial water boiler plant and other related samples in the water treatment industry. This approach was applied for the analysis of three complex water samples including feedwater, condensate water, and boiler water, all collected from large medium pressure (MP) water tube boiler plants, known to be dosed with varying amounts of polyamine and amine corrosion inhibitor components. Polyamine chemistry is widely used for example in large high pressure (HP) boilers operating in municipal waste and recycling facilities to prevent corrosion of metals. The samples used in this study are from such a facility in Coventry waste treatment facility, U.K., which has 3 × 40 tonne/hour boilers operating at 17.5 bar.

  11. Synthesis and evaluation of M. tuberculosis salicylate synthase (MbtI) inhibitors designed to probe plasticity in the active site.

    Science.gov (United States)

    Manos-Turvey, Alexandra; Cergol, Katie M; Salam, Noeris K; Bulloch, Esther M M; Chi, Gamma; Pang, Angel; Britton, Warwick J; West, Nicholas P; Baker, Edward N; Lott, J Shaun; Payne, Richard J

    2012-12-14

    Mycobacterium tuberculosis salicylate synthase (MbtI) catalyses the first committed step in the biosynthesis of mycobactin T, an iron-chelating siderophore essential for the virulence and survival of M. tuberculosis. Co-crystal structures of MbtI with members of a first generation inhibitor library revealed large inhibitor-induced rearrangements within the active site of the enzyme. This plasticity of the MbtI active site was probed via the preparation of a library of inhibitors based on a 2,3-dihydroxybenzoate scaffold with a range of substituted phenylacrylate side chains appended to the C3 position. Most compounds exhibited moderate inhibitory activity against the enzyme, with inhibition constants in the micromolar range, while several dimethyl ester variants possessed promising anti-tubercular activity in vitro.

  12. Antisense downregulation of the barley limit dextrinase inhibitor modulates starch granule size distribution, starch composition and amylopectin structure.

    Science.gov (United States)

    Stahl, Yvonne; Coates, Steve; Bryce, James H; Morris, Peter C

    2004-08-01

    The barley protein limit dextrinase inhibitor (LDI), structurally related to the alpha-amylase/trypsin inhibitor family, is an inhibitor of the starch debranching enzyme limit dextrinase (LD). In order to investigate the function of LDI, and the consequences for starch metabolism of reduced LDI activity, transgenic barley plants designed to downregulate LDI by antisense were generated. Homozygous antisense lines with reduced LDI protein level and activity were analysed and found to have enhanced free LD activity in both developing and germinating grains. In addition the antisense lines showed unpredicted pleiotropic effects on numerous enzyme activities, for example, alpha- and beta-amylases and starch synthases. Analysis of the starch showed much reduced numbers of the small B-type starch granules, as well as reduced amylose relative to amylopectin levels and reduced total starch. The chain length distribution of the amylopectin was modified with less of the longer chains (>25 units) and enhanced number of medium chains (10-15 units). These results suggest an important role for LDI and LD during starch synthesis as well as during starch breakdown.

  13. Development of Radiosensitizer using farnesyltransferase inhibitors

    Energy Technology Data Exchange (ETDEWEB)

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

    1999-03-01

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

  14. PARP1 Inhibitors: antitumor drug design.

    Science.gov (United States)

    Malyuchenko, N V; Kotova, E Yu; Kulaeva, O I; Kirpichnikov, M P; Studitskiy, V M

    2015-01-01

    The poly (ADP-ribose) polymerase 1 (PARP1) enzyme is one of the promising molecular targets for the discovery of antitumor drugs. PARP1 is a common nuclear protein (1-2 million molecules per cell) serving as a "sensor" for DNA strand breaks. Increased PARP1 expression is sometimes observed in melanomas, breast cancer, lung cancer, and other neoplastic diseases. The PARP1 expression level is a prognostic indicator and is associated with a poor survival prognosis. There is evidence that high PARP1 expression and treatment-resistance of tumors are correlated. PARP1 inhibitors are promising antitumor agents, since they act as chemo- and radiosensitizers in the conventional therapy of malignant tumors. Furthermore, PARP1 inhibitors can be used as independent, effective drugs against tumors with broken DNA repair mechanisms. Currently, third-generation PARP1 inhibitors are being developed, many of which are undergoing Phase II clinical trials. In this review, we focus on the properties and features of the PARP1 inhibitors identified in preclinical and clinical trials. We also describe some problems associated with the application of PARP1 inhibitors. The possibility of developing new PARP1 inhibitors aimed at DNA binding and transcriptional activity rather than the catalytic domain of the protein is discussed.

  15. Growth inhibition of Erwinia amylovora and related Erwinia species by neutralized short‑chain fatty acids.

    Science.gov (United States)

    Konecki, Katrin; Gernold, Marina; Wensing, Annette; Geider, Klaus

    2013-11-01

    Short-chain fatty acids (SCFAs) are used to preserve food and could be a tool for control of fire blight caused by Erwinia amylovora on apple, pear and related rosaceous plants. Neutralized acids were added to buffered growth media at 0.5–75 mM and tested at pHs ranging from 6.8 to 5.5. Particularly at low pH, SCFAs with a chain length exceeding that of acetic acid such as propionic acid were effective growth inhibitors of E. amylovora possibly due to uptake of free acid and its intracellular accumulation. We also observed high inhibition with monochloroacetic acid. An E. billingiae strain was as sensitive to the acids as E. amylovora or E. tasmaniensis. Fire blight symptoms on pear slices were reduced when the slices were pretreated with neutralized propionic acid. Propionic acid is well water soluble and could be applied in orchards as a control agent for fire blight.

  16. The Use of Inhibitors of Mechanosensitive Ion Channels as Local Inhibitors of Peripheral Pain

    Science.gov (United States)

    2015-01-01

    type currents are more closely associated with  nociception .  Although the current associated with the two main types of  pain  are not restricted to a...Award Number: W81XWH-11-2-0125 TITLE: The Use of Inhibitors of Mechanosensitive Ion Channels as Local Inhibitors of Peripheral Pain PRINCIPAL...2011 - 24 Oct 2014 4. TITLE AND SUBTITLE The Use of Inhibitors of Mechanosensitive Ion Channels as Local Inhibitors of Peripheral Pain 5a. CONTRACT

  17. A scaling analysis of a cat and mouse Markov chain

    NARCIS (Netherlands)

    Litvak, Nelly; Robert, Philippe

    2012-01-01

    If ($C_n$) a Markov chain on a discrete state space $S$, a Markov chain ($C_n, M_n$) on the product space $S \\times S$, the cat and mouse Markov chain, is constructed. The first coordinate of this Markov chain behaves like the original Markov chain and the second component changes only when both coo

  18. Study on Green Supply Chain Management Based on Circular Economy

    Science.gov (United States)

    Ying, Jiang; Li-jun, Zhou

    The article starts with circular economy and the connotation of green supply chain, then analyzes the difference between green supply chain and traditional supply chain and elaborates the content of green supply chain management. On that basis, the approach to implement green supply chain management in china shall be put forward.

  19. Selectivity of commonly used inhibitors of clathrin-mediated and caveolae-dependent endocytosis of G protein-coupled receptors.

    Science.gov (United States)

    Guo, Shuohan; Zhang, Xiaohan; Zheng, Mei; Zhang, Xiaowei; Min, Chengchun; Wang, Zengtao; Cheon, Seung Hoon; Oak, Min-Ho; Nah, Seung-Yeol; Kim, Kyeong-Man

    2015-10-01

    Among the multiple G protein-coupled receptor (GPCR) endocytic pathways, clathrin-mediated endocytosis (CME) and caveolar endocytosis are more extensively characterized than other endocytic pathways. A number of endocytic inhibitors have been used to block CME; however, systemic studies to determine the selectivity of these inhibitors are needed. Clathrin heavy chain or caveolin1-knockdown cells have been employed to determine the specificity of various chemical and molecular biological tools for CME and caveolar endocytosis. Sucrose, concanavalin A, and dominant negative mutants of dynamin blocked other endocytic pathways, in addition to CME. In particular, concanavalin A nonspecifically interfered with the signaling of several GPCRs tested in the study. Decreased pH, monodansylcadaverine, and dominant negative mutants of epsin were more specific for CME than other treatments were. A recently introduced CME inhibitor, Pitstop2™, showed only marginal selectivity for CME and interfered with receptor expression on the cell surface. Blockade of receptor endocytosis by epsin mutants and knockdown of the clathrin heavy chain enhanced the β2AR-mediated ERK activation. Overall, our studies show that previous experimental results should be interpreted with discretion if they included the use of endocytic inhibitors that were previously thought to be CME-selective. In addition, our study shows that endocytosis of β2 adrenoceptor through clathrin-mediated pathway has negative effects on ERK activation.

  20. Discovering anti-platelet drug combinations with an integrated model of activator-inhibitor relationships, activator-activator synergies and inhibitor-inhibitor synergies.

    Directory of Open Access Journals (Sweden)

    Federica Lombardi

    2015-04-01

    Full Text Available Identifying effective therapeutic drug combinations that modulate complex signaling pathways in platelets is central to the advancement of effective anti-thrombotic therapies. However, there is no systems model of the platelet that predicts responses to different inhibitor combinations. We developed an approach which goes beyond current inhibitor-inhibitor combination screening to efficiently consider other signaling aspects that may give insights into the behaviour of the platelet as a system. We investigated combinations of platelet inhibitors and activators. We evaluated three distinct strands of information, namely: activator-inhibitor combination screens (testing a panel of inhibitors against a panel of activators; inhibitor-inhibitor synergy screens; and activator-activator synergy screens. We demonstrated how these analyses may be efficiently performed, both experimentally and computationally, to identify particular combinations of most interest. Robust tests of activator-activator synergy and of inhibitor-inhibitor synergy required combinations to show significant excesses over the double doses of each component. Modeling identified multiple effects of an inhibitor of the P2Y12 ADP receptor, and complementarity between inhibitor-inhibitor synergy effects and activator-inhibitor combination effects. This approach accelerates the mapping of combination effects of compounds to develop combinations that may be therapeutically beneficial. We integrated the three information sources into a unified model that predicted the benefits of a triple drug combination targeting ADP, thromboxane and thrombin signaling.

  1. Ideal-Chain Collapse in Biopolymers

    CERN Document Server

    Neumann, R M

    2000-01-01

    A conceptual difficulty in the Hooke's-law description of ideal Gaussian polymer-chain elasticity is sometimes apparent in analyses of experimental data or in physical models designed to simulate the behavior of biopolymers. The problem, the tendency of a chain to collapse in the absence of external forces, is examined in the following examples: DNA-stretching experiments, gel electrophoresis, and protein folding. We demonstrate that the application of a statistical-mechanically derived repulsive force, acting between the chain ends, whose magnitude is proportional to the absolute temperature and inversely proportional to the scalar end separation removes this difficulty.

  2. The weight of a falling chain, revisited

    CERN Document Server

    Hamm, Eugenio

    2010-01-01

    A vertically hanging chain is released from rest and falls due to gravity on a scale pan. We discuss the various experimental and theoretical aspects of this classic problem. Careful time-resolved force measurements allow us to determine the differences between the idealized and its implementation in the laboratory problem. We observe that, in spite of the upward force exerted by the pan on the chain, the free end at the top falls faster than a freely falling body. Because a real chain exhibits a finite minimum radius of curvature, the contact at the bottom results in a tensional force which pulls the falling part downward.

  3. Environmental Management Initiatives in Product Chains

    DEFF Research Database (Denmark)

    Forman, Marianne; Hansen, Anne Grethe; Jørgensen, Michael Søgaard

    The Environmental Council for Cleaner Products in 2000-2001 initiated a collection of experience from the environmental co-operation in 25 product chains. This collection of experience was to elucidate the concrete co-operation between suppliers, enterprises and purchasers, to go through tools...... and to report on opportunities and barriers for environmental efforts in the entire product chain. This paper aims at giving a comprehensive analysis of the experiences, on the basis of the reporting of the 25 companies and their supply chains (reported by Ettrup and Bauer in 2002. The 25 case studies have been...

  4. Superadiabatic quantum state transfer in spin chains

    Science.gov (United States)

    Agundez, R. R.; Hill, C. D.; Hollenberg, L. C. L.; Rogge, S.; Blaauboer, M.

    2017-01-01

    In this paper we propose a superadiabatic protocol where quantum state transfer can be achieved with arbitrarily high accuracy and minimal control across long spin chains with an odd number of spins. The quantum state transfer protocol only requires the control of the couplings between the qubits on the edge and the spin chain. We predict fidelities above 0.99 for an evolution of nanoseconds using typical spin-exchange coupling values of μ eV . Furthermore, by building a superadiabatic formalism on top of this protocol, we propose an effective superadiabatic protocol that retains the minimal control over the spin chain and further improves the fidelity.

  5. Spectroscopy of element 115 decay chains

    Energy Technology Data Exchange (ETDEWEB)

    Rudolph, Dirk [Lund University, Sweden; Forsberg, U. [Lund University, Sweden; Golubev, P. [Lund University, Sweden; Sarmiento, L. G. [Lund University, Sweden; Yakushev, A. [Gesellschaft fur Schwerionenforschung (GSI), Germany; Andersson, L.-L. [Johannes Gutenberg-Universitaet Mainz, Mainz, Germany; Di Nitto, A. [Johannes Gutenberg-Universitaet Mainz, Mainz, Germany; Duehllmann, Ch. E. [Gesellschaft fur Schwerionenforschung (GSI), Germany; Gates, J. M. [Lawrence Berkeley National Laboratory (LBNL); Gregorich, K. E. [Lawrence Berkeley National Laboratory (LBNL); Gross, Carl J [ORNL; Hessberger, F. P. [Gesellschaft fur Schwerionenforschung (GSI), Germany; Herzberg, R.-D [University of Liverpool; Khuyagbaatar, J. [Johannes Gutenberg-Universitaet Mainz, Mainz, Germany; Kratz, J. V. [Johannes Gutenberg-Universitaet Mainz, Mainz, Germany; Rykaczewski, Krzysztof Piotr [ORNL; Schaedel, M. [Gesellschaft fur Schwerionenforschung (GSI), Germany; Aberg, S. [Lund University, Sweden; Ackermann, D. [GSI-Hemholtzzentrum fur Schwerionenforschung, Darmstadt, Germany; Block, M. [Gesellschaft fur Schwerionenforschung (GSI), Germany; Brand, H. [Gesellschaft fur Schwerionenforschung (GSI), Germany; Carlsson, B. G. [Lund University, Sweden; Cox, D. [University of Liverpool; Derkx, X. [Johannes Gutenberg-Universitaet Mainz, Mainz, Germany; Eberhardt, K. [Johannes Gutenberg-Universitaet Mainz, Mainz, Germany; Even, J. [Johannes Gutenberg-Universitaet Mainz, Mainz, Germany; Fahlander, C. [Lund University, Sweden; Gerl, J. [Gesellschaft fur Schwerionenforschung (GSI), Germany; Jaeger, E. [Gesellschaft fur Schwerionenforschung (GSI), Germany; Kindler, B. [Gesellschaft fur Schwerionenforschung (GSI), Germany; Krier, J. [Gesellschaft fur Schwerionenforschung (GSI), Germany; Kojouharov, I. [Gesellschaft fur Schwerionenforschung (GSI), Germany; Kurz, N. [Gesellschaft fur Schwerionenforschung (GSI), Germany; Lommel, B. [Gesellschaft fur Schwerionenforschung (GSI), Germany; Mistry, A. [University of Liverpool; Mokry, C. [Johannes Gutenberg-Universitaet Mainz, Mainz, Germany; Nitsche, H. [Lawrence Berkeley National Laboratory (LBNL); Omtvedt, J. P. [Paul Scherrer Institut, Villigen, Switzerland; Papadakis, P. [University of Liverpool; Ragnarsson, I. [Lund University, Sweden; Runke, J. [Gesellschaft fur Schwerionenforschung (GSI), Germany; Schaffner, H. [Gesellschaft fur Schwerionenforschung (GSI), Germany; Schausten, B. [Gesellschaft fur Schwerionenforschung (GSI), Germany; Thoerle-Pospiech, P. [Johannes Gutenberg-Universitaet Mainz, Mainz, Germany; Torres, T. [Gesellschaft fur Schwerionenforschung (GSI), Germany; Traut, T. [Johannes Gutenberg-Universitaet Mainz, Mainz, Germany; Trautmann, N. [Johannes Gutenberg-Universitaet Mainz, Mainz, Germany; Tuerler, A. [Paul Scherrer Institut, Villigen, Switzerland; Ward, A. [University of Liverpool; Ward, D. E. [Lund University, Sweden; Wiehl, N. [Johannes Gutenberg-Universitaet Mainz, Mainz, Germany

    2013-01-01

    A high-resolution a, X-ray and -ray coincidence spectroscopy experiment was conducted at the GSI Helmholtzzentrum fu r Schwerionenforschung. Thirty correlated a-decay chains were detected following the fusion-evaporation reaction 48Ca + 243Am. The observations are consistent with previous assignments of similar decay chains to originate from element Z = 115. The data includes first candidates of fingerprinting the decay step Mt --> Bh with characteristic X rays. For the first time, precise spectroscopy allows the derivation of excitation schemes of isotopes along the decay chains starting with elements Z > 112. Comprehensive Monte-Carlo simulations accompany the data analysis. Nuclear structure models provide a first level interpretation.

  6. Kinematics and Dynamics of Roller Chain Drives

    DEFF Research Database (Denmark)

    Fuglede, Niels

    with a clear derivation of the seating and release configurations, as well as the driven sprocket angular position, velocity and discontinuous acceleration. The approximate analysis allows for simple expressions describing the seating and release configurations and shows the influence of main design parameters...... is presented, which also allows for exact sprocket center positions for a chain with a given number of links. Results show that the total chain wrapping length varies periodically with the tooth frequency. These results are of practical importance to both the design, installation and operation of roller chain...

  7. Switching of antiferromagnetic chains with magnetic pulses

    Science.gov (United States)

    Tao, Kun; Polyakov, Oleg P.; Stepanyuk, Valeri S.

    2016-04-01

    Recent experimental studies have demonstrated the possibility of information storage in short antiferromagnetic chains on an insulator substrate [S. Loth et al., Science 335, 196 (2012), 10.1126/science.1214131]. Here, using the density functional theory and atomistic spin dynamics simulations, we show that a local magnetic control of such chains with a magnetic tip and magnetic pulses can be used for fast switching of their magnetization. Furthermore, by changing the position of the tip one can engineer the magnetization dynamics of the chains.

  8. Entanglement in spin-one Heisenberg chains

    CERN Document Server

    Wang, X G; Sun, Z; Li, Y Q; Wang, XiaoGuang; Li, HaiBin; Sun, Zhe; Li, You-Quan

    2005-01-01

    By using the concept of negativity, we study entanglement in spin-one Heisenberg chains. Both the bilinear chain and the bilinear-biquadratic chain are considered. Due to the SU(2) symmetry, the negativity can be determined by two correlators, which greatly facilitate the study of entanglement properties. Analytical results of negativity are obtained in the bilinear model up to four spins and the two-spin bilinear-biquadratic model, and numerical results of negativity are presented. We determine the threshold temperature before which the thermal state is doomed to be entangled.

  9. The Governance of Global Wealth Chains

    DEFF Research Database (Denmark)

    Seabrooke, Leonard; Wigan, Duncan

    and law in institutional economics, and work from economic sociology on network dynamics within markets. This scholarship assists us in highlighting three variables in how Global Wealth Chains are articulated and change according to: (1) the complexity of transactions, (2) regulatory liability and (3...... to highly complex and flexible innovative financial products produced by large financial institutions and corporations. This paper highlights how Global Wealth Chains intersect with value chains and real economies, and provides three brief case studies on offshore shell companies, family property trusts...

  10. Improving construction performance through supply chain management

    Institute of Scientific and Technical Information of China (English)

    王要武; 薛小龙

    2004-01-01

    A typical model of construction supply chain (CSC) is presented firstly. Then the characteristics and problems of CSC are identified. The authors also describe the progress towards adoption of supply chain management (SCM) in the construction industry. Traditional construction management approaches (CMAs) are compared with new SCM-based CMAs. The authors suggest that integrated SCM based on cooperating competition is crucial to improve construction performance. Based on relevant results from related research, a framework for integrated construction supply chain management (CSCM) is developed to guide the effective implementation of SCM in construction.

  11. Optical response of metal nanoparticle chains

    CERN Document Server

    Fung, K H; Fung, Kin Hung

    2006-01-01

    We study the optical responses of metal nanoparticle chains. Multiple scattering calculations are used to study the extinction cross sections of silver nanosphere chains of finite length embedded in a glass matrix. The transmission and reflection coefficients of periodic 2D arrays of silver nanospheres are also calculated to understand the interaction between nanoparticle chains. The results are in agreement with recent experiments. The splitting of plasmon-resonance modes for different polarizations of the incident light are explored. Results on the effect of disorder are also presented.

  12. Supreme: Supply Chain Integration by Reconfigurable Modules

    Science.gov (United States)

    Nishioka, Y.; Kasai, F.; Kamio, Y.

    This paper deals with dynamic supply chain configuration problems for one-of-a-kind production (OKP) environment. We propose an architecture named SUPREME, which supports collaborative planning and scheduling for web-based virtual enterprises. In this architecture, each system is located on the site of the network members as well as on the site of the supply chain coordinator, who performs as an agent configuring and managing the supply chain dynamically. A prototype system of SUPREME is developed and illustrated in order to evaluate effectiveness of the proposed architecture.

  13. Markov chains models, algorithms and applications

    CERN Document Server

    Ching, Wai-Ki; Ng, Michael K; Siu, Tak-Kuen

    2013-01-01

    This new edition of Markov Chains: Models, Algorithms and Applications has been completely reformatted as a text, complete with end-of-chapter exercises, a new focus on management science, new applications of the models, and new examples with applications in financial risk management and modeling of financial data.This book consists of eight chapters.  Chapter 1 gives a brief introduction to the classical theory on both discrete and continuous time Markov chains. The relationship between Markov chains of finite states and matrix theory will also be highlighted. Some classical iterative methods

  14. CONFORMATIONAL PROPERTIES OF STRETCHED POLYETHYLENE CHAIN

    Institute of Scientific and Technical Information of China (English)

    Lin-xi Zhang; De-lu Zhao

    2000-01-01

    When polyethylene chains are stretched, the chains are regarded as being confined in an infinite cylinder with decreasing diameter. The conformational properties of polyethylene chains confined in an infinite cylinder are investigated by using rotational isomeric state model. Using the average conformational energy and entropy and the average length, we can determine the elastic force f, or the fraction of the energy term to the total force fe/f, where fe=(б)/(б)/(б). Comparisons with experimental data are also made. The results of these microscopic calculations are discussed in terms of the macroscopic phenomena of rubber elasticity.

  15. Analyzing effective elements in agile supply chain

    Directory of Open Access Journals (Sweden)

    Babak Jamshidi Navid

    2012-01-01

    Full Text Available Agile supply chain plays an important role on having efficient production planning. There are different factors affecting the efficiency of a supply chain and the attempt of this paper is to find the most important elements in agile supply chain. The proposed model of this paper gathers decision makers' opinions and based on DEMATEL technique determines the most important items. The preliminary results of this survey indicate that we could divide the factors into four groups and two elements including automation and utilization of technical tools of relations and information play the most important roles among other factors.

  16. Spectroscopy of element 115 decay chains.

    Science.gov (United States)

    Rudolph, D; Forsberg, U; Golubev, P; Sarmiento, L G; Yakushev, A; Andersson, L-L; Di Nitto, A; Düllmann, Ch E; Gates, J M; Gregorich, K E; Gross, C J; Heßberger, F P; Herzberg, R-D; Khuyagbaatar, J; Kratz, J V; Rykaczewski, K; Schädel, M; Åberg, S; Ackermann, D; Block, M; Brand, H; Carlsson, B G; Cox, D; Derkx, X; Eberhardt, K; Even, J; Fahlander, C; Gerl, J; Jäger, E; Kindler, B; Krier, J; Kojouharov, I; Kurz, N; Lommel, B; Mistry, A; Mokry, C; Nitsche, H; Omtvedt, J P; Papadakis, P; Ragnarsson, I; Runke, J; Schaffner, H; Schausten, B; Thörle-Pospiech, P; Torres, T; Traut, T; Trautmann, N; Türler, A; Ward, A; Ward, D E; Wiehl, N

    2013-09-13

    A high-resolution α, x-ray, and γ-ray coincidence spectroscopy experiment was conducted at the GSI Helmholtzzentrum für Schwerionenforschung. Thirty correlated α-decay chains were detected following the fusion-evaporation reaction 48Ca + 243Am. The observations are consistent with previous assignments of similar decay chains to originate from element Z=115. For the first time, precise spectroscopy allows the derivation of excitation schemes of isotopes along the decay chains starting with elements Z>112. Comprehensive Monte Carlo simulations accompany the data analysis. Nuclear structure models provide a first level interpretation.

  17. Stochastic Simulation of a Full-Chain Reptation Model with Constraint Release, Chain-Length Fluctuations and Chain Stretching

    DEFF Research Database (Denmark)

    Neergaard, Jesper; Schieber, Jay D.

    1999-01-01

    A self-consistent reptation model that includes chain stretching, chain-length fluctuations, segment connectivity and constraint release is used to predict transient and steady flows. Quantitative comparisons are made with entangledsolution data. The model is able to capture quantitatively all fe...... for differentmolecular weight, the transient and steady-state behavior of the extinction angle, and the stress relaxation in cessation of steady shear flow....

  18. Benzoxazolone carboxamides as potent acid ceramidase inhibitors: Synthesis and structure-activity relationship (SAR) studies

    DEFF Research Database (Denmark)

    Bach, Anders

    2015-01-01

    be useful in the treatment of pathological conditions, such as cancer, in which ceramide levels are abnormally reduced. Here, we present a systematic SAR investigation of the benzoxazolone carboxamides, a recently described class of AC inhibitors that display high potency and systemic activity in mice. We...... examined a diverse series of substitutions on both benzoxazolone ring and carboxamide side chain. Several modifications enhanced potency and stability, and one key compound with a balanced activity-stability profile (14) was found to inhibit AC activity in mouse lungs and cerebral cortex after systemic...

  19. Selective serotonin reuptake inhibitor exposure.

    Science.gov (United States)

    Fitzgerald, Kevin T; Bronstein, Alvin C

    2013-02-01

    Many antidepressants inhibit serotonin or norepinephrine reuptake or both to achieve their clinical effect. The selective serotonin reuptake inhibitor class of antidepressants (SSRIs) includes citalopram, escitalopram (active enantiomer of citalopram), fluoxetine, fluvoxamine, paroxetine, and sertraline. The SSRIs are as effective as tricyclic antidepressants in treatment of major depression with less significant side effects. As a result, they have become the largest class of medications prescribed to humans for depression. They are also used to treat obsessive-compulsive disorder, panic disorders, alcoholism, obesity, migraines, and chronic pain. An SSRI (fluoxetine) has been approved for veterinary use in treatment of canine separation anxiety. SSRIs act specifically on synaptic serotonin concentrations by blocking its reuptake in the presynapse and increasing levels in the presynaptic membrane. Clinical signs of SSRI overdose result from excessive amounts of serotonin in the central nervous system. These signs include nausea, vomiting, mydriasis, hypersalivation, and hyperthermia. Clinical signs are dose dependent and higher dosages may result in the serotonin syndrome that manifests itself as ataxia, tremors, muscle rigidity, hyperthermia, diarrhea, and seizures. Current studies reveal no increase in appearance of any specific clinical signs of serotonin toxicity with regard to any SSRI medication. In people, citalopram has been reported to have an increased risk of electrocardiographic abnormalities. Diagnosis of SSRI poisoning is based on history, clinical signs, and response to therapy. No single clinical test is currently available to confirm SSRI toxicosis. The goals of treatment in this intoxication are to support the animal, prevent further absorption of the drug, support the central nervous system, control hyperthermia, and halt any seizure activity. The relative safety of the SSRIs in overdose despite the occurrence of serotonin syndrome makes them

  20. Branched-chain amino acid aminotransferase and methionine formation in Mycobacterium tuberculosis

    Directory of Open Access Journals (Sweden)

    Radford Cynthia L

    2004-10-01

    Full Text Available Abstract Background Tuberculosis remains a major world-wide health threat which demands the discovery and characterisation of new drug targets in order to develop future antimycobacterials. The regeneration of methionine consumed during polyamine biosynthesis is an important pathway present in many microorganisms. The final step of this pathway, the conversion of ketomethiobutyrate to methionine, can be performed by aspartate, tyrosine, or branched-chain amino acid aminotransferases depending on the particular species examined. Results The gene encoding for branched-chain amino acid aminotransferase in Mycobacterium tuberculosis H37Rv has been cloned, expressed, and characterised. The enzyme was found to be a member of the aminotransferase IIIa subfamily, and closely related to the corresponding aminotransferase in Bacillus subtilis, but not to that found in B. anthracis or B. cereus. The amino donor preference for the formation of methionine from ketomethiobutyrate was for isoleucine, leucine, valine, glutamate, and phenylalanine. The enzyme catalysed branched-chain amino acid and ketomethiobutyrate transamination with a Km of 1.77 – 7.44 mM and a Vmax of 2.17 – 5.70 μmol/min/mg protein, and transamination of ketoglutarate with a Km of 5.79 – 6.95 mM and a Vmax of 11.82 – 14.35 μmol/min/mg protein. Aminooxy compounds were examined as potential enzyme inhibitors, with O-benzylhydroxylamine, O-t-butylhydroxylamine, carboxymethoxylamine, and O-allylhydroxylamine yielding mixed-type inhibition with Ki values of 8.20 – 21.61 μM. These same compounds were examined as antimycobacterial agents against M. tuberculosis and a lower biohazard M. marinum model system, and were found to completely prevent cell growth. O-Allylhydroxylamine was the most effective growth inhibitor with an MIC of 78 μM against M. marinum and one of 156 ��M against M. tuberculosis. Conclusion Methionine formation from ketomethiobutyrate is catalysed by a