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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

    Energy Technology Data Exchange (ETDEWEB)

    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. 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.

  3. 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

    reoxidation is observed in the wild type in the present of low concentrations of antimycin. 2. In contrast to the wild type, inhibition of electron transport in the mutant has a much higher antimycin titre than effects on cytochromes b (viz., aerobic steady-state reduction; reduction in the presence....... The difference between the effect of antimycin on electron transport and cytochromes b reduction is also found in intact cells of the mutant. 6. A model is suggested for the wild-type respiratory chain in which (i) the cytochromes b lie, in an uncoupled system, out of the main electron-transfer chain, (ii......) antimycin induces a conformation change in QH-2-cytochrome c reductase resulting in effects on cytochrome b and inhibition of electron transport, (iii) a second antimycin-binding site with low affinity to the antibiotic is present, capable of inhibiting electron transport....

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

    Science.gov (United States)

    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.

  5. Antimycin A treatment decreases respiratory internal rotenone-insensitive NADH oxidation capacity in potato leaves

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    Svensson Å Staffan

    2004-05-01

    Full Text Available Abstract Background The plant respiratory chain contains several energy-dissipating enzymes, these being type II NAD(PH dehydrogenases and the alternative oxidase, not present in mammals. The physiological functions of type II NAD(PH dehydrogenases are largely unclear and little is known about their responses to stress. In this investigation, potato plants (Solanum tuberosum L., cv. Desiree were sprayed with antimycin A, an inhibitor of the cytochrome pathway. Enzyme capacities of NAD(PH dehydrogenases (EC 1.6.5.3 and the alternative oxidase were then analysed in isolated leaf mitochondria. Results We report a specific decrease in internal rotenone-insensitive NADH dehydrogenase capacity in mitochondria from antimycin A-treated leaves. External NADPH dehydrogenase and alternative oxidase capacities remained unaffected by the treatment. Western blotting revealed no change in protein abundance for two characterised NAD(PH dehydrogenase homologues, NDA1 and NDB1, nor for two subunits of complex I. The alternative oxidase was at most only slightly increased. Transcript levels of nda1, as well as an expressed sequence tag derived from a previously uninvestigated closely related potato homologue, remained unchanged by the treatment. As compared to the daily rhythm-regulated nda1, the novel homologue displayed steady transcript levels over the time investigated. Conclusions The internal rotenone-insensitive NADH oxidation decreases after antimycin A treatment of potato leaves. However, the decrease is not due to changes in expression of known nda genes. One consequence of the lower NADH dehydrogenase capacity may be a stabilisation of the respiratory chain reduction level, should the overall capacity of the cytochrome and the alternative pathway be restricted.

  6. 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.

    Science.gov (United States)

    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

  7. 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.

  8. Identification of C3 beta chain as the human serum eosinophil cytotoxicity inhibitor

    OpenAIRE

    1991-01-01

    An eosinophil cytotoxicity inhibitor (ECI) was purified from serum of a human subject with severe allergic dermatitis. Molecular weight of the isolated polypeptide (75,000) and its NH2-terminal amino acid sequence identified it as the beta chain of the C3 complement component (apparently free, but perhaps attached to very small fragments of the alpha chain). Free beta chain, prepared from normal plasma by reduction of C3, inhibited both eosinophil cytotoxicity and neutrophil adherence functio...

  9. 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.

  10. Two Antimycin A Analogues from Marine-Derived Actinomycete Streptomyces lusitanus

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    Peiyuan Qian

    2012-03-01

    Full Text Available Two new antimycin A analogues, antimycin B1 and B2 (1–2, were isolated from a spent broth of a marine-derived bacterium, Streptomyces lusitanus. The structures of 1 and 2 were established on the basis of spectroscopic analyses and chemical methods. The isolated compounds were tested for their anti-bacterial potency. Compound 1 was found to be inactive against the bacteria Bacillus subtilis, Staphyloccocus aureus, and Loktanella hongkongensis. Compound 2 showed antibacterial activities against S. aureus and L. hongkongensis with MIC values of 32.0 and 8.0 μg/mL, respectively.

  11. 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.

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

    Data.gov (United States)

    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.

  13. 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.

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

    OpenAIRE

    Mohamad Hafizi Abu Bakar; Kian-Kai Cheng; Mohamad Roji Sarmidi; Harisun Yaakob; Hasniza Zaman Huri

    2015-01-01

    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 pathwa...

  15. Effect of isoniazid, a haem inhibitor, on globin chain synthesis in reticulocytes from non-thalassaemic and beta thalassaemic subjects.

    OpenAIRE

    Chalevelakis, G; Yalouris, A G; Lyberatos, C; Economopoulos, T; Anastasiou, C.; Hatziioannou, J; Raptis, S

    1989-01-01

    The effect of isonicotinic acid hydrazide (INH), a potent haem inhibitor, on globin chain synthesis was studied in reticulocytes from the following groups of patients: four non-thalassaemic patients (group i); five beta thalassaemia heterozygotes (group ii); three Hb S/beta thalassaemia heterozygotes (group iii); and two additional patients--one with homozygous beta thalassaemia and the other with thalassaemia intermedia (group iv). This was done to determine whether haem inhibitors depress a...

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

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    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. PMID:6091750

  17. Facilitators and Inhibitors of Supply Chain Innovation-prospects for Supply Chain Managment in the Irish Grocery Sector

    OpenAIRE

    Keegan, Joan; O'Callaghan, Edmund; Wilcox, Mary

    2001-01-01

    Supply chain management is one of the most significant strategic challenges currently facing the Irish grocery sector. The UK grocery market with its emphasis on composite deliveries via regional distribution centres is extremely sophisticated; the Irish grocery sector, however, is in the embryonic stage of implementing central distribution. The potential to develop innovative supply chain systems is mediated by both national logistic-related variables and company characteristics. In additio...

  18. Airway Smooth Muscle Cells Synthesize Hyaluronan Cable Structures Independent of Inter-α-inhibitor Heavy Chain Attachment*S⃞

    OpenAIRE

    Lauer, Mark E.; Fulop, Csaba; Mukhopadhyay, Durba; Comhair, Suzy; Erzurum, Serpil C.; Hascall, Vincent C.

    2009-01-01

    The covalent association of inter-α-inhibitor-derived heavy chains (HCs) with hyaluronan was first described in synovial fluid from arthritic patients and later described as a structural and functional component of hyaluronan “cable” structures produced by many different cells and stimuli. HC transfer has been shown to be mediated by the protein product of TSG-6 (tumor necrosis factor-stimulated gene 6). Considering the accumulation of hyaluronan in airways following a...

  19. 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.

  20. Effect of Hexavalent Chromium on Electron Leakage of Respiratory Chain in Mitochondria Isolated from Rat Liver

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    Ying Xie

    2013-03-01

    Full Text Available Background/Aims: In the present study, we explored reactive axygen species (ROS production in mitochondria, the mechanism of hexavalent chromium (Cr(VI hepatotoxicity, and the role of protection by GSH. Methods: Intact mitochondria were isolated from rat liver tissues and mitochondrial basal respiratory rates of NADH and FADH2 respiratory chains were determined. Mitochondria were treated with Cr(VI, GSH and several complex inhibitors. Mitochondria energized by glutamate/malate were separately or jointly treated with Rotenone (Rot, diphenyleneiodonium (DPI and antimycinA (Ant, while mitochondria energized by succinate were separately or jointly treated with Rot, DPI ‚ thenoyltrifluoroacetone (TTFA and Ant. Results: Cr(VI concentration-dependently induced ROS production in the NADH and FADH2 respiratory chain in liver mitochondria. Basal respiratory rate of the mitochondrial FADH2 respiratory chain was significantly higher than that of NADH respiratory chain. Hepatic mitochondrial electron leakage induced by Cr(VI from NADH respiratory chain were mainly from ubiquinone binding sites of complex I and complex III. Conclusion: Treatment with 50µM Cr(VI enhances forward movement of electrons through FADH2 respiratory chain and leaking through the ubiquinone binding site of complex III. Moreover, the protective effect of GSH on liver mitochondria electron leakage is through removing excess H2O2 and reducing total ROS.

  1. Inhibitors

    Science.gov (United States)

    ... wrong place in the body. Immune Tolerance Induction (ITI) Therapy: The goal of ITI therapy is to stop the inhibitor reaction from ... body to accept clotting factor concentrate treatments. With ITI therapy, people receive large amounts of clotting factor ...

  2. Modulation of the kinetics of cholesterol side-chain cleavage by an activator and by an inhibitor isolated from the cytosol of the cortex of bovine adrenals.

    OpenAIRE

    Warne, P A; Greenfield, N J; Lieberman, S.

    1983-01-01

    Two modulators of sterol side-chain cleavage activity have been detected in the cytosol from the cortex of bovine adrenals. One is an inhibitor of side-chain cleavage which increases the Km of a purified and reconstituted mitochondrial side-chain cleavage system for both cholesterol and cholesterol sulfate. It also lowers the Vmax of cleavage when cholesterol sulfate is the substrate. The other modulator is a low molecular weight protein which in the reconstituted system increases the Vmax of...

  3. 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. PMID:23417432

  4. 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.

  5. 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.

  6. 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.

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

    Science.gov (United States)

    Thomas, Simmy; Sharma, Natasha; Gonzalez, Reyna; Pao, Peng-Wen; Hofman, Florence M; Chen, Thomas C; Louie, Stan G; Pirrung, Michael C; Schönthal, Axel H

    2013-01-01

    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. PMID:23755268

  8. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  10. Discovery of a long-chain carbamoyl aminocarnitine derivative, a reversible carnitine palmitoyltransferase inhibitor with antiketotic and antidiabetic activity.

    Science.gov (United States)

    Giannessi, Fabio; Pessotto, Pompeo; Tassoni, Emanuela; Chiodi, Piero; Conti, Roberto; De Angelis, Francesco; Dell'Uomo, Natalina; Catini, Roberto; Deias, Roberto; Tinti, Maria Ornella; Carminati, Paolo; Arduini, Arduino

    2003-01-16

    The synthesis and pharmacological activity of reversible CPT I inhibitors as potential antiketotic and antidiabetic drugs are reported. Such inhibitors constitute a series of enantiomerically pure aminocarnitine derivatives having the general formula (CH3)3N+CH2CH(ZR)CH2COO- (with Z = ureido, carbamate, sulfonamide, and sulfamide moieties; R = C7-C14 linear alkyl chains). A primary pharmacological screening based on the evaluation of CPT I activity in intact rat liver (L-CPT I) mitochondria revealed the best activity for the (R) forms of ureidic derivative 17 (ZR = NHCONHR, R = C14), sulfonamidic derivative 7 (ZR = NHSO2R, R = C12), and sulfamidic derivative 9 (ZR = NHSO2NHR, R = C11). The IC50 values are 1.1, 0.7, and 0.8 microM, respectively. For the carbamic derivative 11 (ZR = NHCOOR, R = C8), an IC50 of 9.5 microM was observed. In addition, an extraordinarily high selectivity toward the liver isoform with respect to the heart isoform (muscle-CPT I identical with M-CPT I) was found for the ureidic compound 17 (IC50(M-CPT I) vs IC50(L-CPTI) = 39.4), as well as for other ureidic or carbamic compounds. Diabetic db/db mice treated orally with 17 and 7 for 45 days at a dose of 50 mg/kg twice a day showed a good reduction of serum glucose levels with respect to the untreated db/db mice (p < 0.01). In addition, 17 showed antiketotic activity in normal fasted rats. 17 has been selected for development as a potential antiketotic and antidiabetic drug. PMID:12519067

  11. 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

  12. 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.

  13. 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......-dependent respiration was significantly stronger than NADH-dependent respiration, indicating that this is a major respiratory electron donor in H. pylori. Fumarate and malonate exhibited a concentration-dependent inhibitory effect on the activity of succinate dehydrogenase. The activity of succinate-cytochrome c...... reductase was inhibited by antimycin, implying the presence of a classical pathway from complex II to complex III in this bacterium. The presence of NADH-fumarate reductase (FRD) was demonstrated in H. pylori and fumarate could reduce H2O2 production from NADH, indicating fumarate to be an endogenous...

  14. 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.

  15. 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.

  16. Pharmacological Modulation of the Mitochondrial Electron Transport Chain in Paclitaxel-Induced Painful Peripheral Neuropathy

    OpenAIRE

    Griffiths, Lisa A.; Flatters, Sarah J. L.

    2015-01-01

    Paclitaxel is an effective first-line chemotherapeutic with the major dose-limiting side effect of painful neuropathy. Mitochondrial dysfunction and oxidative stress have been implicated in paclitaxel-induced painful neuropathy. Here we show the effects of pharmacological modulation of mitochondrial sites that produce reactive oxygen species using systemic rotenone (complex I inhibitor) or antimycin A (complex III inhibitor) on the maintenance and development of paclitaxel-induced mechanical ...

  17. Repositioning of Verrucosidin, a Purported Inhibitor of Chaperone Protein GRP78, as an Inhibitor of Mitochondrial Electron Transport Chain Complex I

    OpenAIRE

    Simmy Thomas; Natasha Sharma; Reyna Gonzalez; Peng-Wen Pao; Hofman, Florence M; Thomas C. Chen; Louie, Stan G.; Pirrung, Michael C.; Schönthal, Axel H

    2013-01-01

    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 a...

  18. 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

  19. New C sub(21) Delta sup(20) pregnanes, inhibitors of mitochondrial respiratory chain,from Indopacific octocoral Carijoa sp.

    Digital Repository Service at National Institute of Oceanography (India)

    Ciavatta, M.L.; Gresa, M.P.L.; Manzo, E.; Gavagnin, M.; Wahidullah, S.; Cimino, G.

    showed a strong activity in the pre- liminary biological assay for the inhibition of the inte- grated electron transfer chain (NADH oxidase activity) in beef heart submitochondrial particles (SMP). 13 Inhibitory concentration 50% (IC 50 ) for com- pound 1...

  20. Purification and determination of C-reactive protein and inter-α-trypsin inhibitor heavy chain 4 in dogs after major surgery through generation of specific antibodies.

    Science.gov (United States)

    Soler, L; García, N; Unzueta, A; Piñeiro, M; Álava, M A; Lampreave, F

    2016-10-15

    Inter-α-trypsin inhibitor heavy chain 4 (ITIH4) and C-reactive protein (CRP) have been isolated from acute phase dog sera by affinity chromatography with insolubilized polyclonal antibodies anti pig Major Acute phase Protein (Pig-MAP) and with p-Aminophenyl Phosphoryl Choline, respectively. Isolated proteins were used to prepare specific polyclonal rabbit antisera that have allowed quantifying their concentration in serum samples by single radial immunodifussion. Both proteins were quantified in sera from female dogs that had undergone ovariohysterectomy (OVH, n=9) or mastectomy (n=10). The observed increases in CRP concentrations showed that surgical traumas induced an acute phase response of a great magnitude in the dogs. In both surgeries a four-fold increase of ITIH4 concentrations was detected. It can be concluded that ITIH4 is a new positive acute phase protein in dogs, as reported in other species. PMID:27590422

  1. Molecular regulation of MHC class I chain-related protein A expression after HDAC-inhibitor treatment of Jurkat T cells

    DEFF Research Database (Denmark)

    Andresen, Lars; Jensen, Helle; Pedersen, Marianne T;

    2007-01-01

    In this study, we characterize the molecular signal pathways that lead to MHC class I chain-related protein A (MICA) expression after histone deacetylase (HDAC)-inhibitor (HDAC-i) treatment of Jurkat T cells. Chelating calcium with BAPTA-AM or EGTA potently inhibited HDAC- and CMV-mediated MICA...... inhibit p65 expression by siRNA, it did not modify MICA/B expression. To identify important elements in MICA regulation, we made a promoter construct consisting of approximately 3 kb of the proximal MICA promoter in front of GFP. Deletion analysis showed that a germinal center-box containing a putative Sp......1 site from position -113 to -93 relative to the mRNA start site was important for HDAC and CMV-induced promoter activity. Sp1 was subsequently shown to be important, as targeted mutation of the Sp1 binding sequence or siRNA mediated down modulation of Sp1-inhibited MICA promoter activity...

  2. 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.

  3. 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.

  4. 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.

  5. 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

    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...... 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...

  6. Decomposition of ozone in water in the presence of organic solutes acting as promoters and inhibitors of radical chain reactions

    Energy Technology Data Exchange (ETDEWEB)

    Staehelin, J.; Hoigne, J.

    1985-12-01

    The decomposition of aqueous ozone is generally due to a chain reaction involving .OH radicals. Many organic solutes (impurities) can react with .OH to yield .O/sub 2//sup -/ upon addition of O/sub 2/. .O/sub 2//sup -/ transfers its electron to a further ozone molecule in a rather selective reaction. The ozonide anion (.O/sub 3//sup -/) formed immediately decomposes into a further .OH radical. Compounds that convert .OH radicals into ozone-selective .O/sub 2//sup -/, therefore, act as promoters of the chain reaction. The efficiencies of different .OH to .O/sub 2//sup -/ converters (e.g., formic acid, primary and secondary alcohols (including sugars), glyoxylic acid, and humic acids) are tested in the presence of other .OH radical scavengers that do not primarily produce .O/sub 2//sup -/ (carbonate, aliphatic alkyl compounds, and tert-butyl alcohol). The derived reaction kinetics allows one to qualitatively interpret the variation of the lifetime of O/sub 3/ found in model solutions and even in natural waters and during drinking water treatment.

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

    Science.gov (United States)

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

    2014-05-01

    Invasive pulmonary aspergillosis remains a matter of great concern in oncology/haematology, intensive care units and organ transplantation departments. Despite the availability of various diagnostic tools with attractive features, new markers of infection are required for better medical care. We therefore looked for potential pulmonary biomarkers of aspergillosis, by carrying out two-dimensional (2D) gel electrophoresis comparing the proteomes of bronchial-alveolar lavage fluids (BALF) from infected rats and from control rats presenting non-specific inflammation, both immunocompromised. A bioinformatic analysis of the 2D-maps revealed significant differences in the abundance of 20 protein spots (ANOVA P-value0.8). One of these proteins, identified by mass spectrometry, was considered of potential interest: inter-alpha-inhibitor H4 heavy-chain (ITIH4), characterised for the first time in this infectious context. Western blotting confirmed its overabundance in all infected BALF, particularly at early stages of murine aspergillosis. Further investigations were carried on rat serum, and confirmed that ITIH4 levels increased during experimental aspergillosis. Preliminary results in human samples strengthened this trend. To our knowledge, this is the first description of the involvement of ITIH4 in aspergillosis. PMID:24360996

  8. Effects of thyroid hormones on the bypasses of the antimycin A block in the bc1 complex of rat liver mitochondria.

    Science.gov (United States)

    Horrum, M A; Tobin, R B; Ecklund, R E

    1991-07-15

    The effect of thyroid hormones on the electron flow through the bc1 complex of rat liver mitochondria was studied using two dye bypasses of the Antimycin A block of the bc1 complex by the method of Alexandre and Lehninger (Biochim. Biophys. Acta 767:120; 1984). Bypass respiration rates with both DCIP (2,6-dichlorophenolindophenol) and TMPD (N,N,N',N'-tetramethyl-p-phenylenediamine dihydrochloride) were elevated in the hyperthyroid rats and depressed in the hypothyroid groups compared to the euthyroid controls. T3 treatment of hypothyroid rats returned the bypass rates to control levels in 24 hours with the TMPD dye but not for the DCIP. This further demonstrates that different portions of the bc1 complex respond individually to the thyroid state. PMID:1648915

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. Hypoxia sensing in the fetal chicken femoral artery is mediated by the mitochondrial electron transport chain

    DEFF Research Database (Denmark)

    Zoer, Bea; Cogolludo, Angel L; Perez-Vizcaino, Francisco;

    2010-01-01

    -induced relaxation was abolished or significantly reduced by the mETC inhibitors rotenone (complex I), myxothiazol and antimycin A (complex III), and NaN(3) (complex IV). The complex II inhibitor 3-nitroproprionic acid enhanced the hypoxic relaxation. In contrast, the relaxations mediated by acetylcholine, sodium...... nitroprusside, or forskolin were not affected by the mETC blockers. Hypoxia induced a slight increase in ROS production (as measured by 2,7-dichlorofluorescein-fluorescence), but hypoxia-induced relaxation was not affected by scavenging of superoxide (polyethylene glycol-superoxide dismutase) or H(2)O(2......) (polyethylene glycol-catalase) or by NADPH-oxidase inhibition (apocynin). Also, the K(+) channel inhibitors tetraethylammonium (nonselective), diphenyl phosphine oxide-1 (voltage-gated K(+) channel 1.5), glibenclamide (ATP-sensitive K(+) channel), iberiotoxin (large-conductance Ca(2+)-activated K(+) channel...

  15. Synthesis and in Vitro Screening of New Series of 2,6-Dipeptidyl-anthraquinones: Influence of Side Chain Length on HIV-1 Nucleocapsid Inhibitors.

    Science.gov (United States)

    Frecentese, Francesco; Sosic, Alice; Saccone, Irene; Gamba, Elia; Link, Kristina; Miola, Angelica; Cappellini, Marta; Cattelan, Massimiliano Gianni; Severino, Beatrice; Fiorino, Ferdinando; Magli, Elisa; Corvino, Angela; Perissutti, Elisa; Fabris, Dan; Gatto, Barbara; Caliendo, Giuseppe; Santagada, Vincenzo

    2016-03-10

    2,6-Dipeptidyl-anthraquinones are a promising class of nucleic acid-binding compounds that act as NC inhibitors in vitro. We designed, synthesized, and tested new series of 2,6-disubstituted-anthraquinones, which are able to bind viral nucleic acid substrates of NC. We demonstrate here that these novel derivatives interact preferentially with noncanonical structures of TAR and cTAR, stabilize their dynamics, and interfere with NC chaperone activity. PMID:26797100

  16. Semi-arid development: competitiveness factors in biodiesel productive chain

    OpenAIRE

    Breno Barros Telles do Carmo; Dmontier Pinheiro Aragão; Heráclito Lopes Jaguaribe Pontes; Bruno Magalhães Ribeiro; Marcos Ronaldo Albertin

    2009-01-01

    The new global market competitiveness considerer the competition between productive chains (PC) or supply chains, not just between enterprises. In this case, it can be observed collaboration and cooperation enterprises that dispute with others productives chain. The PC competitiveness can be impaired if is subject by inhibitors factors, that can impairer the performance. This paper analyses these competitiveness factors inhibitors in biodiesel productive chain (CPB) in semi-arid area: exporte...

  17. 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.

  18. 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.

  19. 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...

  20. Semi-arid development: competitiveness factors in biodiesel productive chain

    Directory of Open Access Journals (Sweden)

    Breno Barros Telles do Carmo

    2009-04-01

    Full Text Available The new global market competitiveness considerer the competition between productive chains (PC or supply chains, not just between enterprises. In this case, it can be observed collaboration and cooperation enterprises that dispute with others productives chain. The PC competitiveness can be impaired if is subject by inhibitors factors, that can impairer the performance. This paper analyses these competitiveness factors inhibitors in biodiesel productive chain (CPB in semi-arid area: exported product, market knowledge, competitiveness position, opportunities to aggregate value in chain, cooperation between enterprises, enterprises way of thinking and paternalism by government. It was done this analyses to compare CPB with the world.

  1. 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.

  2. Protease Inhibitors from Marine Venomous Animals and Their Counterparts in Terrestrial Venomous Animals

    OpenAIRE

    Mourão, Caroline B.F.; Elisabeth F Schwartz

    2013-01-01

    The Kunitz-type protease inhibitors are the best-characterized family of serine protease inhibitors, probably due to their abundance in several organisms. These inhibitors consist of a chain of ~60 amino acid residues stabilized by three disulfide bridges, and was first observed in the bovine pancreatic trypsin inhibitor (BPTI)-like protease inhibitors, which strongly inhibit trypsin and chymotrypsin. In this review we present the protease inhibitors (PIs) described to date from marine venomo...

  3. 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

  4. Chain Teleportation

    OpenAIRE

    Lee, Chien-er

    2004-01-01

    By means of the idea of measurements on the crossed space-time nonlocal observables, we extend the mechanism for the two-way quantum teleportation to the chain teleportation among N spatially separated spin-1/2 systems. Since in the process only the local interactions are used, the microcausality is automatically satisfied.

  5. Catch Chain

    OpenAIRE

    Talbert, Robert

    2010-01-01

    Catch Chain is a book of poems that traces the journey of a Corrections Officer who attempts to combat issues of isolation, inhumane treatment of inmates and societal rejection in jails by embarking upon a cross-country road trip. However, the same issues the officer initially wrestled with begin cropping up in different cities, on various highways and in a multitude of states. The excitement and adventure of the open road runs parallel to the recurring imprisonment of the guard's mind.

  6. 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).

  7. 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). PMID:7430148

  8. 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....... The deduced protein sequence of 338 residues was concordant with 173 residue positions of p36 determined at the protein level. The 5'- and 3'-ends of p36/6 contained 54 and 307 base pairs of untranslated sequence, respectively. Examination of poly(A)+ RNA prepared from the Madin-Darby cell line indicated a p...

  9. Chain reaction

    International Nuclear Information System (INIS)

    Chain Reaction is a work of recent American political history. It seeks to explain how and why America came to depend so heavily on its experts after World War II, how those experts translated that authority into political clout, and why that authority and political discretion declined in the 1970s. The author's research into the internal memoranda of the Atomic Energy Commission substantiates his argument in historical detail. It was not the ravages of American anti-intellectualism, as so many scholars have argued, that brought the experts back down to earth. Rather, their decline can be traced to the very roots of their success after World War II. The need to over-state anticipated results in order to garner public support, incessant professional and bureaucratic specialization, and the sheer proliferation of expertise pushed arcane and insulated debates between experts into public forums at the same time that a broad cross section of political participants found it easier to gain access to their own expertise. These tendencies ultimately undermined the political influence of all experts. (author)

  10. HDAC Inhibitors.

    Science.gov (United States)

    Olzscha, Heidi; Bekheet, Mina E; Sheikh, Semira; La Thangue, Nicholas B

    2016-01-01

    Lysine acetylation in proteins is one of the most abundant posttranslational modifications in eukaryotic cells. The dynamic homeostasis of lysine acetylation and deacetylation is dictated by the action of histone acetyltransferases (HAT) and histone deacetylases (HDAC). Important substrates for HATs and HDACs are histones, where lysine acetylation generally leads to an open and transcriptionally active chromatin conformation. Histone deacetylation forces the compaction of the chromatin with subsequent inhibition of transcription and reduced gene expression. Unbalanced HAT and HDAC activity, and therefore aberrant histone acetylation, has been shown to be involved in tumorigenesis and progression of malignancy in different types of cancer. Therefore, the development of HDAC inhibitors (HDIs) as therapeutic agents against cancer is of great interest. However, treatment with HDIs can also affect the acetylation status of many other non-histone proteins which play a role in different pathways including angiogenesis, cell cycle progression, autophagy and apoptosis. These effects have led HDIs to become anticancer agents, which can initiate apoptosis in tumor cells. Hematological malignancies in particular are responsive to HDIs, and four HDIs have already been approved as anticancer agents. There is a strong interest in finding adequate biomarkers to predict the response to HDI treatment. This chapter provides information on how to assess HDAC activity in vitro and determine the potency of HDIs on different HDACs. It also gives information on how to analyze cellular markers following HDI treatment and to analyze tissue biopsies from HDI-treated patients. Finally, a protocol is provided on how to detect HDI sensitivity determinants in human cells, based on a pRetroSuper shRNA screen upon HDI treatment. PMID:27246222

  11. Absolute Side-chain Structure at Position 13 Is Required for the Inhibitory Activity of Bromein*

    OpenAIRE

    Sawano, Yoriko; Hatano, Ken-ichi; Miyakawa, Takuya; Tanokura, Masaru

    2008-01-01

    Bromelain isoinhibitor (bromein), a cysteine proteinase inhibitor from pineapple stem, has a unique double-chain structure. The bromein precursor protein includes three homologous inhibitor domains, each containing an interchain peptide between the light and heavy chains. The interchain peptide in the single-chain precursor is immediately processed by bromelain, a target proteinase. In the present study, to clarify the essential inhibitory site of bromein, we construct...

  12. 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.

  13. [Characteristics of the respiratory chain and the oxidative phosphorylation system of mitochondria in the flavinogenic Eremothecium ashbyii strain].

    Science.gov (United States)

    Zviagil'skaia, R A; Korosteleva, N L; Mironov, V A

    1976-01-01

    Tightly coupled mitochondria were isolated from cells of the flavinogenic strain of Eremothecium ashbyii collected during the logarithmic and stationary growth phases. The composition of the respiratory chain and characteristics of the energy coupling system are described. The mitochondria show a wide spectrum of metabolic activity and oxidize Krebs cycle compenents and exogenous NADH. The terminal segment of the respiratory chain is represented by a typical cytochrome system. The mitochondria of the ascomycete collected during the logarithmic growth phase are characterized by a relatively high content of cytochromes b and c, a high rate of oxidation of NAD-dependent substrates, the presence of lower homologues of ubiquinone, UQ6 and UQ7, and extremely high sensitivity of respiration to the action of antimycin A, low content of a component sensitive to rotenone, contrasting with the operation of all three sites of phosphorylation. Transition to the stationary growth phase is accompanied with a decrease in the rate of oxidation of all substrates studied and a declined effectiveness of oxidative phosphorylation. The data obtained are discussed in relation to the ability of the cells for "overproduction" of flavins. PMID:187903

  14. 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 ...

  15. Silicone chain extender

    DEFF Research Database (Denmark)

    2015-01-01

    The present invention relates to a silicone chain extender, more particularly a chain extender for silicone polymers and copolymers, to a chain extended silicone polymer or copolymer and to a functionalized chain extended silicone polymer or copolymer, to a method for the preparation thereof and...

  16. 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. PMID:20407173

  17. Purification and inhibitory profile of phospholipase A2 inhibitors from Australian elapid sera.

    Science.gov (United States)

    Hains, P G; Broady, K W

    2000-02-15

    Although the resistance of snakes to their own venom is well known, until now no investigators have examined the serum of Australian snakes. Here we describe the identification and purification of a range of phospholipase A(2) (PLA(2)) inhibitors from the serum of Australian elapids. All PLA(2) inhibitors were composed of two protein chains, an alpha-chain and a beta-chain. The alpha-chains were approx. 22.5 kDa in size and variably glycosylated, whereas the beta-chains were approx. 19.8 kDa in size and not glycosylated. Identification of isoforms of the two subunit chains was significant because three of the six sera examined were from single snake specimens. In addition, the glycosylation patterns of the alpha-chains were thoroughly investigated in these unpooled sera. The functional and structural properties of the purified inhibitors were studied. Uniquely, a snake PLA(2) inhibitor was found to inhibit human type II PLA(2) enzyme, which has implications for the treatment of the many diseases in which PLA(2) enzymes have been implicated. Further, we demonstrate that the inhibitor forms a non-covalent association with a purified PLA(2) enzyme. Finally, the purified PLA(2) inhibitor was shown to protect in vivo against the lethal affects of a homologous PLA(2) enzyme, suggesting a role for PLA(2) inhibitors in the treatment of snake bite victims. PMID:10657250

  18. 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.

  19. Chain-Chain Based Routing Protocol

    Directory of Open Access Journals (Sweden)

    Samia A Ali

    2011-05-01

    Full Text Available Wireless sensor network (WSN is an emerging technology for monitoring physical world. WSNs consist of large numbers of sensor nodes operated by battery mostly in harsh environment. Thus energy conservation is a primary issue for organization of these sensor nodes. Another crucial issue is the data delivery time by sensor nodes to the sink node, especially in Military, medical fields, and security monitoring systems where minimum delay is desirable. Number of protocols has been proposed in the literature for routing. One of such protocols is the cluster based routing protocol LEACH (low energy adaptive clustering hierarchy. LEACH protocol organizes WSN into a set of clusters and a periodic voting for cluster head is performed in order to be evenly distributed among all the sensors of the WSN. This periodical cluster head voting in LEACH, however, consumes an amount of non-negligible energy and other resources. For energy conservation, PEGASIS (power efficient gathering in sensor information systems a near optimal chain-based protocol has been proposed, however, it is faced with the challenge of long delay for the transmitted data. Another routing protocol called CCM (Chain-Cluster based Mixed routing, which is mainly a hybrid of LEACH and PEGASIS is proposed, the consumed energy increases as network size increases. In this paper, we propose an efficient routing protocol called CCBRP (Chain-Chain based routing protocol, it achieves both minimum energy consumption and minimum delay. The CCBRP protocol mainly divides a WSN into a number of chains (Greedy algorithm is used to form each chain as in PEGSIS protocol and runs in two phases. In the first phase, sensor nodes in each chain transmit data to their chain leader nodes in parallel. In the second phase, all chain leader nodes form a chain (also, using Greedy algorithm and choose randomly a leader node then all chain leader nodes send their data to this chosen leader node. This chosen leader node

  20. Discrete Quantum Markov Chains

    CERN Document Server

    Faigle, Ulrich

    2010-01-01

    A framework for finite-dimensional quantum Markov chains on Hilbert spaces is introduced. Quantum Markov chains generalize both classical Markov chains with possibly hidden states and existing models of quantum walks on finite graphs. Quantum Markov chains are based on Markov operations that may be applied to quantum systems and include quantum measurements, for example. It is proved that quantum Markov chains are asymptotically stationary and hence possess ergodic and entropic properties. With a quantum Markov chain one may associate a quantum Markov process, which is a stochastic process in the classical sense. Generalized Markov chains allow a representation with respect to a generalized Markov source model with definite (but possibly hidden) states relative to which observables give rise to classical stochastic processes. It is demonstrated that this model allows for observables to violate Bell's inequality.

  1. 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...

  2. 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.

  3. 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...

  4. Economy, market and chain

    OpenAIRE

    Sukkel, W.; Hommes, M.

    2009-01-01

    In their pursuit of growth and professionalisation, the Dutch organic sector focuses primarily on market development. But how do you stimulate the market for organic foods? This is the subject of many research projects concerning market, consumer preferences and the supply chain. These projects focus specifically at consumer purchasing behaviour, product development, supply chain formation and minimising cost price. As a rule, this research takes place in close cooperation with chain actors

  5. Supply Chain Collaboration

    OpenAIRE

    Meca, Ana; Timmer, Judith

    2008-01-01

    In this chaper, we have reviewed and surveyed the literature on supply chain collaboration. As mentioned above, the game theory models that include cooperative behaviour among retailers seem to be a natural framework to model cooperation (collaboration) in supply chains that consist of a supplier and a finite number of retailers. Various researchers in this area have already adopted several cooperative models dealing with supply chain coordination, and it is expected to see many more in the n...

  6. Sustainable Supply Chain Management

    OpenAIRE

    Geentjens, Marlies

    2013-01-01

    This project investigates the phenomena Sustainable Supply Chain Management. The point of departure is Supply Chain Management, which we analyse in order to lock into an understanding of the development that occur when implementing sustainability. In the quest for higher understanding of the interlocking mechanisms of supply chain management, we combine a theoretical approach to the developmnent of sustainability with some relevant case-examples (mainly depicting IKEA). This focal point g...

  7. 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.

  8. Supply chain components

    OpenAIRE

    Vieraşu, T.; Bălăşescu, M.

    2011-01-01

    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.

  9. 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.

  10. 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 t...

  11. Integrated supply chain risk management

    OpenAIRE

    Riaan Bredell; Jackie Walters

    2007-01-01

    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 ...

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

    OpenAIRE

    Patalinghug, Epictetus E.

    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.

  13. Insulin resistance and the mitochondrial link. Lessons from cultured human myotubes

    DEFF Research Database (Denmark)

    Gaster, Michael

    2007-01-01

    lipid uptake. The metabolic phenotype during respiratory uncoupling resembled the above picture, except for an increase in glucose and palmitate oxidation. Antimycin A and oligomycin treatment induced insulin resistance at the level of glucose and palmitate uptake in all three study groups while......In order to better understand the impact of reduced mitochondrial function for the development of insulin resistance and cellular metabolism, human myotubes were established from lean, obese, and T2D subjects and exposed to mitochondrial inhibitors, either affecting the electron transport chain...... (Antimycin A), the ATP synthase (oligomycin) or respiratory uncoupling (2,4-dinitrophenol). Direct inhibition of the electron transport chain or the ATP synthase was followed by increased glucose uptake and lactate production, reduced glycogen synthesis, reduced lipid and glucose oxidation and unchanged...

  14. Understanding the supply chain

    Directory of Open Access Journals (Sweden)

    Aćimović Slobodan

    2006-01-01

    Full Text Available Supply chain management represents new business philosophy and includes strategically positioned and much wider scope of activity in comparison with its "older brother" - management of logistics. Philosophy of the concept of supply chain is directed to more coordination of key business functions of every link in distribution chain in the process of organization of the flow of both goods and information, while logistic managing instruments are focused on internal optimum of flows of goods and information within one company. Applying the concept of integrated supply chain among several companies makes the importance of operative logistics activity even greater on the level of one company, thus advancing processes of optimum and coordination within and between different companies and confirms the importance of logistics performances for the company’s profitability. Besides the fact that the borders between companies are being deleted, this concept of supply chain in one distribution channel influences increasing of importance of functional, i.e. traditional business managing approaches but instead it points out the importance of process managing approaches. Although the author is aware that "there is nothing harder, more dangerous and with uncertain success, but to find a way for introducing some novelties (Machiavelli, it would be even his additional stimulation for trying to bring closer the concept and goals of supply chain implementation that are identified in key, relevant, modern, theoretical and consulting approaches in order to achieve better understanding of the subject and faster implementation of the concept of supply chain management by domestic companies.

  15. 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....

  16. 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.

  17. 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.  

  18. Supply chain reliability modelling

    OpenAIRE

    Eugen Zaitsev

    2012-01-01

    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 ...

  19. Supply Chain Collaboration

    OpenAIRE

    Guy Rodrigue Ghomsi 1982

    2015-01-01

    Companies are now progressively looking beyond themselves to come up with ways to improve revenue and profit margins. This has resulted in a heightened focus on the efficiency of the supply chains. Inefficient supply chains are being perceived as cavities that can deprive the firm from its cash flows when inventory is not required and sales revenue when product is not available at the point of sales. This has stimulated development of business models that intend to leverage and enhance the su...

  20. Variance bounding Markov chains

    OpenAIRE

    Roberts, Gareth O.; Jeffrey S. Rosenthal

    2008-01-01

    We introduce a new property of Markov chains, called variance bounding. We prove that, for reversible chains at least, variance bounding is weaker than, but closely related to, geometric ergodicity. Furthermore, variance bounding is equivalent to the existence of usual central limit theorems for all L2 functionals. Also, variance bounding (unlike geometric ergodicity) is preserved under the Peskun order. We close with some applications to Metropolis–Hastings algorithms.

  1. Supply chain risk management

    OpenAIRE

    Christian Hollstein; Frank Himpel

    2013-01-01

    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-induct...

  2. Editorial: Supply Chain Management

    OpenAIRE

    Aidonis, D.; Folinas, D.; Triantafillou, D.

    2012-01-01

    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 m...

  3. 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.

  4. 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...

  5. 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.

  6. 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...

  7. Sunflower trypsin inhibitor-1.

    Science.gov (United States)

    Korsinczky, Michael L J; Schirra, Horst Joachim; Craik, David J

    2004-10-01

    SFTI-1 is a bicyclic 14 amino acid peptide that was originally isolated from the seeds of the sunflower Helianthus annuus. It is a potent inhibitor of trypsin, with a sub-nanomolar K(i) value and is homologous to the active site region of the well-known family of serine protease inhibitors known as the Bowman-Birk trypsin inhibitors. It has a cyclic backbone that is cross-braced by a single disulfide bridge and a network of hydrogen bonds that result in a well-defined structure. SFTI-1 is amenable to chemical synthesis, allowing for the creation of synthetic variants. Alterations to the structure such as linearising the backbone or removing the disulfide bridge do not reduce the potency of SFTI-1 significantly, and minimising the peptide to as few as nine residues results in only a small decrease in reactivity. The creation of linear variants of SFTI-1 also provides a tool for investigating putative linear precursor peptides. The mechanism of biosynthesis of SFTI-1 is not yet known but it seems likely that it is a gene-coded product that has arisen from a precursor protein that may be evolutionarily related to classic Bowman-Birk inhibitors. PMID:15544530

  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. A 2-chain can interlock with a k-chain

    OpenAIRE

    Glass, Julie; Langerman, Stefan; O'Rourke, Joseph; Snoeyink, Jack; Zhong, Jianyuan K.

    2004-01-01

    One of the open problems posed in [3] is: what is the minimal number k such that an open, flexible k-chain can interlock with a flexible 2-chain? In this paper, we establish the assumption behind this problem, that there is indeed some k that achieves interlocking. We prove that a flexible 2-chain can interlock with a flexible, open 16-chain.

  11. 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. PMID:26353069

  12. A 2-chain can interlock with an open 10-chain

    OpenAIRE

    Lu, Bin; O'Rourke, Joseph; Zhong, Jianyuan K.

    2013-01-01

    It is an open problem, posed in \\cite{SoCG}, to determine the minimal $k$ such that an open flexible $k$-chain can interlock with a flexible 2-chain. It was first established in \\cite{GLOSZ} that there is an open 16-chain in a trapezoid frame that achieves interlocking. This was subsequently improved in \\cite{GLOZ} to establish interlocking between a 2-chain and an open 11-chain. Here we improve that result once more, establishing interlocking between a 2-chain and a 10-chain. We present argu...

  13. Model for metabolic resistance against ALS inhibitors

    Directory of Open Access Journals (Sweden)

    Richter, Otto

    2014-02-01

    Full Text Available Due to herbicide selection pressure metabolic resistance has evolved in many weed species. In this paper we analyse the interaction between the branched chain amino acid (BBC pathway and detoxifying pathways for herbicide breakdown. The four phase detoxification pathway of herbicides comprising the action of P450, GST, glycosyltransferase and ABC transporter is modelled by a system of coupled enzyme kinetic reactions represented by nonlinear differential equations. The herbicide under consideration inhibits the enzyme ALS, which is the key enzyme for the biosynthesis of branched amino acids. For the kinetics of ALS a Monod approach is employed with a binding site for the inhibitor. Synthetic and detoxification pathways are coupled. The model is used to study the production of branched amino acids under the action of ALS inhibitors for different structures and modes of action of the detoxification pathway. The model is capable of generating typical dose response curves and their shift in dependence of the activity pattern of the enzymes of the detoxification pathway of the inhibitor.

  14. Supply chain quality management

    Directory of Open Access Journals (Sweden)

    Hannan Amoozad Mahdiraji

    2012-10-01

    Full Text Available 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 competitiveness power. Moreover, they have only one purpose that is customer satisfaction, and they are different only on their approaches to reach their objectives. In this research, we aim to study both approaches of quality management and supply chain, their positive increasing effects that may be generated after their integration. For this purpose, the concept and definitions of each approach is studied, independently, their similarities and differences are recognized, and finally, the advantages of their integration are introduced.

  15. Environmental Retail Supply Chains

    DEFF Research Database (Denmark)

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

    2011-01-01

    been undertaken through an investigative approach applying a web-scan framework which included the analysis of web sites and publicly published documents such as annual reports and corporate social responsibility reports. Findings – The authors identified 34 environmental sustainability initiatives......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...... which were grouped into eight categories; they refer to “fundamental environmental attitude”, “use of energy”, “use of input material”, “product”, “packaging”, “transport”, “consumption” and “waste”. The level of environmental supply chain management can be characterised as very operational and very...

  16. 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.

  17. 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.

  18. Building the resilient supply chain.

    OpenAIRE

    Christopher, Martin; Peck, Helen

    2004-01-01

    In today’s uncertain and turbulent markets, supply chain vulnerability has become an issue of significance for many companies. As supply chains become more complex as a result of global sourcing and the continued trend to ‘leaning-down’, supply chain risk increases. The challenge to business today is to manage and mitigate that risk through creating more resilient supply chains.

  19. 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...

  20. 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.

  1. Uptake of Branched-Chain Amino Acids by Streptococcus thermophilus

    OpenAIRE

    Akpemado, K. M.; Bracquart, P. A.

    1983-01-01

    The transport of branched-chain amino acids in Streptococcus thermophilus was energy dependent. The metabolic inhibitors of glycolysis and ATPase enzymes were active, but the proton-conducting uncouplers were not. Transport was optimal at temperatures of between 30 and 45°C and at pH 7.0 for the three amino acids leucine, valine, and isoleucine; a second peak existed at pH 5.0 with valine and isoleucine. By competition and kinetics studies, the branched-chain amino acids were found to share a...

  2. 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

  3. [JAK2 inhibitors].

    Science.gov (United States)

    Hernández Boluda, Juan Carlos; Gómez, Montse; Pérez, Ariadna

    2016-07-15

    Pharmacological inhibition of the kinase activity of JAK proteins can interfere with the signaling of immunomodulatory cytokines and block the constitutive activation of the JAK-STAT pathway that characterizes certain malignancies, including chronic myeloproliferative neoplasms. JAK inhibitors may, therefore, be useful to treat malignancies as well as inflammatory or immune disorders. Currently, the most significant advances have been made in the treatment of myelofibrosis, where these drugs may lead to a remarkable improvement in the control of hyperproliferative manifestations. However, available data suggest that this treatment is not curative of myelofibrosis. In general, JAK2 inhibition induces cytopaenias, with this being considered a class side-effect. By contrast, the extrahaematologic toxicity profile varies significantly among the different JAK inhibitors. At present, there are several clinical trials evaluating the combination of ruxolitinib with other drugs, in order to improve its therapeutic activity as well as reducing haematologic toxicity. PMID:27033437

  4. Alpha glucosidase inhibitors.

    Science.gov (United States)

    Kalra, Sanjay

    2014-04-01

    Alpha glucosidase inhibitors (AGIs) are a unique class of anti-diabetic drugs. Derived from bacteria, these oral drugs are enzyme inhibitors which do not have a pancreato -centred mechanism of action. Working to delay carbohydrate absorption in the gastrointestinal tract, they control postprandial hyperglycaemia and provide unquestioned cardiovascular benefit. Specially suited for a traditional Pakistani carbohydrate-rich diet, AGIs have been termed the 'untapped diamonds' of diabetology. The use of these oral antidiabetic drugs (OADs) that target pathophysiology in the early stages of type 2 diabetes, notably to reduce postprandial hyperglycaemia and hyperinsulinaemia will inevitably increase with time. This review describes the history of their development, mechanism of action, basic and clinical pharmacology, and suggests practical, evidence-based guidance for their optimal use. PMID:24864650

  5. 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

  6. Economy, market and chain

    NARCIS (Netherlands)

    Sukkel, W.; Hommes, M.

    2009-01-01

    In their pursuit of growth and professionalisation, the Dutch organic sector focuses primarily on market development. But how do you stimulate the market for organic foods? This is the subject of many research projects concerning market, consumer preferences and the supply chain. These projects focu

  7. 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...

  8. 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...

  9. Shared Value Chain Design

    DEFF Research Database (Denmark)

    Bals, Lydia; Tate, Wendy L.

    In Sustainable Supply Chain Management (SSCM) research still the classic economic perspective is the dominating perspective, although the triple bottom line (including economic, social and ecological) is well accepted. The theoretical foundation for the paper is Stakeholder Theory. Case studies o...

  10. Sustainable Supply Chain Design

    DEFF Research Database (Denmark)

    Bals, Lydia; Tate, Wendy

    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 to i...

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. Coagulation inhibitors in inflammation.

    Science.gov (United States)

    Esmon, C T

    2005-04-01

    Coagulation is triggered by inflammatory mediators in a number of ways. However, to prevent unwanted clot formation, several natural anticoagulant mechanisms exist, such as the antithrombin-heparin mechanism, the tissue factor pathway inhibitor mechanism and the protein C anticoagulant pathway. This review examines the ways in which these pathways are down-regulated by inflammation, thus limiting clot formation and decreasing the natural anti-inflammatory mechanisms that these pathways possess. PMID:15787615

  16. Osteocompatibility of Biofilm Inhibitors

    OpenAIRE

    Rawson, Monica; Haggard, Warren; Jennings, Jessica A.

    2014-01-01

    The demand for infection prevention therapies has led to the discovery of several biofilm inhibitors. These inhibiting signals are released by bacteria, fungi, or marine organisms to signal biofilm dispersal or disruption in Gram-positive, Gram-negative, and fungal microorganisms. The purpose of this study was to test the biocompatibility of five different naturally-produced biofilm chemical dispersal and inhibition signals with osteoblast-like cells: D-amino acids (D-AA), lysostaphin (LS), f...

  17. 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

  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. Benzoquinones as inhibitors of botulinum neurotoxin serotype A.

    Science.gov (United States)

    Bremer, Paul T; Hixon, Mark S; Janda, Kim D

    2014-08-01

    Although botulinum neurotoxin serotype A (BoNT/A) is known for its use in cosmetics, it causes a potentially fatal illness, botulism, and can be used as a bioterror weapon. Many compounds have been developed that inhibit the BoNTA zinc-metalloprotease light chain (LC), however, none of these inhibitors have advanced to clinical trials. In this study, a fragment-based approach was implemented to develop novel covalent inhibitors of BoNT/A LC. First, electrophilic fragments were screened against BoNT/A LC, and benzoquinone (BQ) derivatives were found to be active. In kinetic studies, BQ compounds acted as irreversible inhibitors that presumably covalently modify cysteine 165 of BoNT/A LC. Although most BQ derivatives were highly reactive toward glutathione in vitro, a few compounds such as natural product naphthazarin displayed low thiol reactivity and good BoNT/A inhibition. In order to increase the potency of the BQ fragment, computational docking studies were employed to elucidate a scaffold that could bind to sites adjacent to Cys165 while positioning a BQ fragment at Cys165 for covalent modification; 2-amino-N-arylacetamides met these criteria and when linked to BQ displayed at least a 20-fold increase in activity to low μM IC₅₀ values. Unlike BQ alone, the linked-BQ compounds demonstrated only weak irreversible inhibition and therefore acted mainly as non-covalent inhibitors. Further kinetic studies revealed a mutual exclusivity of BQ covalent inactivation and competitive inhibitor binding to sites adjacent to Cys165, refuting the viability of the current strategy for developing more potent irreversible BoNT/A inhibitors. The highlights of this study include the discovery of BQ compounds as irreversible BoNT/A inhibitors and the rational design of low μM IC50 competitive inhibitors that depend on the BQ moiety for activity. PMID:24984937

  20. 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....

  1. 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 ...

  2. 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...

  3. Heavy chain only antibodies

    DEFF Research Database (Denmark)

    Moghimi, Seyed Moein; Rahbarizadeh, Fatemeh; Ahmadvand, Davoud;

    2013-01-01

    Unlike conventional antibodies, heavy chain only antibodies derived from camel contain a single variable domain (VHH) and two constant domains (CH2 and CH3). Cloned and isolated VHHs possess unique properties that enable them to excel conventional therapeutic antibodies and their smaller antigen-...... for combating HER2+ breast cancer. © 2013 by Tabriz University of Medical Sciences.......Unlike conventional antibodies, heavy chain only antibodies derived from camel contain a single variable domain (VHH) and two constant domains (CH2 and CH3). Cloned and isolated VHHs possess unique properties that enable them to excel conventional therapeutic antibodies and their smaller antigen......-binding fragments in cancer targeting and therapy. VHHs express low immunogenicity, are highly robust and easy to manufacture and have the ability to recognize hidden or uncommon epitopes. We highlight the utility of VHH in design of new molecular, multifunctional particulate and immune cell-based systems...

  4. 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.

  5. 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|.

  6. Towards Intelligent Supply Chains

    DEFF Research Database (Denmark)

    Siurdyban, Artur; Møller, Charles

    2012-01-01

    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...... 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......, 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. Demand chain management-integrating marketing and supply chain management

    OpenAIRE

    Jüttner, Uta; Christopher, Martin; Baker, Susan

    2007-01-01

    This paper endorses demand chain management as a new business model aimed at creating value in today's marketplace, and combining the strengths of marketing and supply chain competencies. Demand chain design is based on a thorough market understanding and has to be managed in such a way as to effectively meet differing customer needs. Based on a literature review as well as the findings from a co-development workshop and focus group discussions with marketing and supply chain professionals, a...

  8. Supply Chain Initiatives Database

    Energy Technology Data Exchange (ETDEWEB)

    None

    2012-11-01

    The Supply Chain Initiatives Database (SCID) presents innovative approaches to engaging industrial suppliers in efforts to save energy, increase productivity and improve environmental performance. This comprehensive and freely-accessible database was developed by the Institute for Industrial Productivity (IIP). IIP acknowledges Ecofys for their valuable contributions. The database contains case studies searchable according to the types of activities buyers are undertaking to motivate suppliers, target sector, organization leading the initiative, and program or partnership linkages.

  9. Input chains and industrialization

    OpenAIRE

    Ciccone, Antonio

    2000-01-01

    A key aspect of industrialization is the adoption of increasing-returns-to-scale, industrial, technologies. Two other, well-documented aspects are that industrial technologies are adopted throughout intermediate-input chains and that they use intermediate inputs intensively relative to the technologies they replace. These features of industrial technologies combined imply that countries with access to similar technologies may have very different levels of industrial...

  10. Engineered Ionizable Side Chains.

    Science.gov (United States)

    Cymes, Gisela D; Grosman, Claudio

    2015-01-01

    One of the great challenges of mechanistic ion-channel biology is to obtain structural information from well-defined functional states. In the case of neurotransmitter-gated ion channels, the open-channel conformation is particularly elusive owing to its transient nature and brief mean lifetime. In this Chapter, we show how the analysis of single-channel currents recorded from mutants engineered to contain single ionizable side chains in the transmembrane region can provide specific information about the open-channel conformation without any interference from the closed or desensitized conformations. The method takes advantage of the fact that the alternate binding and unbinding of protons to and from an ionizable side chain causes the charge of the protein to fluctuate by 1 unit. We show that, in mutant muscle acetylcholine nicotinic receptors (AChRs), this fluctuating charge affects the rate of ion conduction in such a way that individual proton-transfer events can be identified in a most straightforward manner. From the extent to which the single-channel current amplitude is reduced every time a proton binds, we can learn about the proximity of the engineered side chain to the lumen of the pore. And from the kinetics of proton binding and unbinding, we can calculate the side-chain's affinity for protons (pK a), and hence, we can learn about the electrostatic properties of the microenvironment around the introduced ionizable group. The application of this method to systematically mutated AChRs allowed us to identify unambiguously the stripes of the M1, M2 and M3 transmembrane α-helices that face the pore's lumen in the open-channel conformation in the context of a native membrane. PMID:26381938

  11. Inclusive Global Value Chains

    OpenAIRE

    Cusolito, Ana Paula; Safadi, Raed; Taglioni, Daria

    2016-01-01

    This report's focus is making global value chains (GVCs) more inclusive. To achieve inclusiveness is by overcoming participation constraints for Small and Medium Enterprises (SMEs) and facilitation access for Low Income Developing Countries (LIDCs). The underlying assumption is that most firms in LIDCs are SMEs. Even larger firms in LIDCs are likely to face similar challenges to SMEs, including a less supportive domestic operating environment and weaker institutions that lead to higher fixed ...

  12. Polymerase chain reaction

    OpenAIRE

    Gaurav Solanki

    2015-01-01

    The polymerase chain reaction (PCR) is a technique in molecular biology to amplify a single or a few copies of a piece of DNA across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence. PCR is now a common and often indispensable technique used in medical and biological research labs for a variety of applications. There are three major steps involved in the PCR technique: denaturation, annealing and extension. PCR is useful in the investigation...

  13. 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.

  14. Tax efficient supply chain

    OpenAIRE

    Borralho, Joana Patrícia Costeira

    2014-01-01

    Master of Science in Business Administration. This case started with the following question: How supply chains and tax policy interact? This question was the starting point for this study and was developed under the areas of Logistics and International Tax Policy. In order to support this study, the adopted methodology was the selection of a Multinational company – LPR Portugal – which has the transportation and distribution in the European Union as a scope of service and...

  15. 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

  16. 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...

  17. 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....

  18. 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...

  19. 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. PMID:23611335

  20. 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.

  1. Risk Management in Logystics Chains

    OpenAIRE

    Butrin, Andrey; Vikulov, Vladimir

    2013-01-01

    Article is devoted to risk management of supply chain. The authors considered indicators of supply chain risks, including risks caused by supplier. Authors formed a method of optimizing the level of supply chain risk in the integration with suppliers and customers.

  2. 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

  3. Academic Education Chain Operation Model

    OpenAIRE

    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 can be used to develop an Academic Chain Operation Reference Model.

  4. 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.

  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. Molecular similarity of MDR inhibitors

    OpenAIRE

    Simon Gibbons; Mire Zloh

    2004-01-01

    Abstract: The molecular similarity of multidrug resistance (MDR) inhibitors was evaluated using the point centred atom charge approach in an attempt to find some common features of structurally unrelated inhibitors. A series of inhibitors of bacterial MDR were studied and there is a high similarity between these in terms of their shape, presence and orientation of aromatic ring moieties. A comparison of the lipophilic properties of these molecules has also been conducted suggesting that this ...

  7. 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.

  8. 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

  9. Synthesis and activity of 2-oxoamides containing long chain beta-amino acids.

    Science.gov (United States)

    Constantinou-Kokotou, Violetta; Peristeraki, Anna; Kokotos, Christoforos G; Six, David A; Dennis, Edward A

    2005-07-01

    2-Oxoamides based on long chain beta-amino acids were synthesized. 1-Benzyl substituted long chain amines, needed for such synthesis, were synthesized starting from Boc-phenylalaninol. The oxidative conversion of a phenyl group to a carboxyl group was used as the key transformation synthetic step. The compounds synthesized were studied for their activity against GIVA PLA(2), and were proven to be weak inhibitors. PMID:15635664

  10. 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.

  11. Musical Markov Chains

    Science.gov (United States)

    Volchenkov, Dima; Dawin, Jean René

    A system for using dice to compose music randomly is known as the musical dice game. The discrete time MIDI models of 804 pieces of classical music written by 29 composers have been encoded into the transition matrices and studied by Markov chains. Contrary to human languages, entropy dominates over redundancy, in the musical dice games based on the compositions of classical music. The maximum complexity is achieved on the blocks consisting of just a few notes (8 notes, for the musical dice games generated over Bach's compositions). First passage times to notes can be used to resolve tonality and feature a composer.

  12. Longwall AFC chain tension measurement

    Energy Technology Data Exchange (ETDEWEB)

    Lugg, P.; Guan, Z.; Pienaar, B.

    2009-10-01

    CRC Mining has developed a chain tension meter to measure the AFC chain tension during the operation. The device was certified Ex ia IP55 by SIMTARS for use in hazardous areas. In June 2007 this device was successfully trialled in an Australian longwall face. The trial was run monitoring AFC chain tensions over a few shifts. The dynamic behaviour and unequal sharing of load between the chains were recorded and found to be significant. During this trial the robustness of the tension meter electronics and protection housing was demonstrated, the measurement of AFC chain tensions on a working face can be achieved reliably. 2 refs., 14 figs.

  13. Purification, characterization and primary structure of a chymotrypsin inhibitor from Naja atra venom.

    Science.gov (United States)

    Zhou, Xing-Ding; Jin, Yang; Lu, Qiu-Min; Li, Dong-Sheng; Zhu, Shao-Wen; Wang, Wan-Yu; Xiong, Yu-Liang

    2004-02-01

    A chymotrypsin inhibitor, designated NA-CI, was isolated from the venom of the Chinese cobra Naja atra by three-step chromatography. It inhibited bovine alpha-chymotrypsin with a Ki of 25 nM. The molecular mass of NA-CI was determined to be 6403.8 Da by matrix-assisted laser-desorption ionization time-of-flight (MALDI-TOF) analysis. The complete amino acid sequence was determined after digestion of S-carboxymethylated inhibitor with Staphylococcus aureus V8 protease and porcine trypsin. NA-CI was a single polypeptide chain composed of 57 amino acid residues. The main contact site with the protease (P1) has a Phe, showing the specificity of the inhibitor. NA-CI shared great similarity with the chymotrypsin inhibitor from Naja naja venom (identities=89.5%) and other snake venom protease inhibitors. PMID:14990218

  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. 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

  16. 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.

  17. Selection criteria for corrosion inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Webb, L.; Boivin, J. [Cormetrics, Calgary, AB (Canada)

    2008-07-01

    The use of a corrosion inhibitor is the primary method to control internal corrosion of pipelines and to reduce costly failures. This presentation discussed the selection criteria for corrosion inhibitors. The selection process requires a detailed analysis of system chemistry; modeling flow regime; and laboratory testing protocols that challenge the inhibitor under conditions analogous to the field. The nature of corrosion inhibitors and inhibitor requirements were described. Physical factors were also presented. These included viscosity and pour point; stability; density; effect on elastomers and other materials; emulsion tendency; foaming tendency; gunking; polymerization/sludging; and reaction with gases and liquids. Other topics that were discussed included compatibility; solubility; partitioning; environmental effects; and selection requirements. Film tenacity was described in terms of corrosivity; water chemistry; and flow. The presentation concluded with a discussion of performance testing and wheel testing. figs.

  18. 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.

  19. Polymerase Chain Reaction

    Directory of Open Access Journals (Sweden)

    Gaurav Solanki

    2012-10-01

    Full Text Available The polymerase chain reaction (PCR is a technique in molecular biology to amplify a single or a few copies of a piece of DNA across several orders of magnitude, generating thousands to millions of copies of a particular DNA sequence. PCR is now a common and often indispensable technique used in medical and biological research labs for a variety of applications. There are three major steps involved in the PCR technique: denaturation, annealing and extension. PCR is useful in the investigation and diagnosis of a growing number of diseases. PCR is also used in forensics laboratories. PCR can identify genes that have been implicated in the development of cancer. The present paper is an attempt to review basics of PCR in relation to its methods, application and use.

  20. Supply chain reaction

    International Nuclear Information System (INIS)

    'Logic' (Leading Oil and Gas Industry Competitiveness) is a government-industry supply chain management initiative which aims to improve the competitiveness of the UK's North Sea business by 1 billion UK pounds by 2002 and its export performance by 50% inside 5 years. Much of the article is devoted to the background and views of Logic's chief executive Chris. Freeman. Freeman makes clear that 'unlike Crine, we are not a cost-reduction initiative: that may be one of the outcomes, but we are really focusing on the co-operation side of things'. Logic aims to change the culture of the UK offshore industry through example. Freeman believes that the creation of collaborative success will flag up industry and give credence to Logics objectives

  1. 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.

  2. 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......The purpose of this thesis is to increase the understanding of interplays between products and supply chains. In academia, there seem to be an acknowledgement that the nature of a given product has a major influence on the performance of the supply chain associated with it – for one.......e. by creating Focused Supply Chains. At the same time, customer satisfaction can be increased. As a second means to achieving a better fit between product and supply chain, the firm can deploy Design for Logistics, the discipline of considering the supply chain during product creation. The thesis sets out...

  3. Supply chain collaboration under uncertainty

    OpenAIRE

    Hasan, Saad; Eckert, Claudia; Earl, Chris

    2012-01-01

    In fluctuating economic conditions such as global recession, supply chains operate under changing conditions of uncertainty. The impact of this uncertainty and associated risk might be mitigated by collaboration. This paper proposes a model of supply chain collaboration based on information exchange and decision coordination at both the strategic and tactical levels. However, a collaborative supply chain can be exposed to associated risks such as the failure of individual actors. Governance r...

  4. 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...... that the metals which form chains exhibit pronounced many-atom interactions with strong bonding in low coordinated systems....

  5. 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.

  6. 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.

  7. Social Media and Supply Chain

    OpenAIRE

    Sonja Markova; Tatjana Petkovska-Mirčevska

    2013-01-01

    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 manageme...

  8. 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

  9. 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.

  10. 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

  11. Protease Inhibitors from Marine Venomous Animals and Their Counterparts in Terrestrial Venomous Animals

    Directory of Open Access Journals (Sweden)

    Caroline B. F. Mourão

    2013-06-01

    Full Text Available The Kunitz-type protease inhibitors are the best-characterized family of serine protease inhibitors, probably due to their abundance in several organisms. These inhibitors consist of a chain of ~60 amino acid residues stabilized by three disulfide bridges, and was first observed in the bovine pancreatic trypsin inhibitor (BPTI-like protease inhibitors, which strongly inhibit trypsin and chymotrypsin. In this review we present the protease inhibitors (PIs described to date from marine venomous animals, such as from sea anemone extracts and Conus venom, as well as their counterparts in terrestrial venomous animals, such as snakes, scorpions, spiders, Anurans, and Hymenopterans. More emphasis was given to the Kunitz-type inhibitors, once they are found in all these organisms. Their biological sources, specificity against different proteases, and other molecular blanks (being also K+ channel blockers are presented, followed by their molecular diversity. Whereas sea anemone, snakes and other venomous animals present mainly Kunitz-type inhibitors, PIs from Anurans present the major variety in structure length and number of Cys residues, with at least six distinguishable classes. A representative alignment of PIs from these venomous animals shows that, despite eventual differences in Cys assignment, the key-residues for the protease inhibitory activity in all of them occupy similar positions in primary sequence. The key-residues for the K+ channel blocking activity was also compared.

  12. 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.

  13. Synthesis of Lysine Methyltransferase Inhibitors

    Directory of Open Access Journals (Sweden)

    Tao eYe

    2015-07-01

    Full Text Available Lysine methyltransferase which catalyze methylation of histone and nonhistone proteins, play a crucial role in diverse biological processes and has emerged as a promising target for the development of various human diseases, including cancer, inflammation, and psychiatric disorders. However, inhibiting Lysine methyltransferases selectively has presented many challenges to medicinal chemists. During the past decade, lysine methyltransferase inhibitors covering many different structural classes have been designed and developed. In this review, we describe the development of selective, small-molecule inhibitors of lysine methyltransferases with an emphasis on their discovery and chemical synthesis. We highlight the current state of lysine methyltransferase inhibitors and discuss future directions and opportunities for lysine methyltransferase inhibitor discovery.

  14. Sodium phthalamates as corrosion inhibitors for carbon steel in aqueous hydrochloric acid solution

    International Nuclear Information System (INIS)

    Highlights: → N-Alkyl-sodium phthalamates as corrosion inhibitors for industry in acidic medium. → Compounds behaved as mixed type inhibitors and followed Langmuir adsorption isotherm. → Efficiencies were proportional to aliphatic chain length and inhibitor concentration. → Iron complexes and chelates with phthalamates contributed to carbon steel protection. - Abstract: Three compounds of N-alkyl-sodium phthalamates were synthesized and tested as corrosion inhibitors for carbon steel in 0.5 M aqueous hydrochloric acid. Tests showed that inhibitor efficiencies were related to aliphatic chain length and dependent on concentration. N-1-n-tetradecyl-sodium phthalamate displayed moderate efficiency against uniform corrosion, 42-86% at 25 deg. C and 25-60% at 40 oC. Tests indicated that compounds behave as mixed type inhibitors where molecular adsorption on steel followed Langmuir isotherm, whereas thermodynamic suggested that a physisorption process occurred. XPS analysis confirmed film formation on surface, where Fe+2 complexes and Fe+2 chelates with phthalamates prevented steel from further corrosion.

  15. 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

  16. 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...

  17. Realities of Supply Chain Collaboration

    NARCIS (Netherlands)

    Kampstra, R.P.; Ashayeri, J.; Gattorna, J.

    2006-01-01

    Successful supply chain collaboration (SCC) practices are rather exceptional, yet collaboration is believed to be the single most pressing need in supply chain management.In this paper we discuss the realities of SCC, present prerequisites for the collaboration process, indicate where the process st

  18. [Pharmacology of bone resorption inhibitor].

    Science.gov (United States)

    Menuki, Kunitaka; Sakai, Akinori

    2015-10-01

    Currently, bone resorption inhibitor is mainly used for osteoporosis. A number of these agents have been developed. These pharmacological action are various. Bisphosphonate inhibit functions of the osteoclasts by inducing apoptosis. On the one hand, RANK-ligand inhibitor and selective estrogen receptor modulator inhibit formation of osteoclasts. It is important to understand these pharmacological action for the selection of the appropriate medicine. PMID:26529923

  19. 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.

  20. Managing the Global Supply Chain

    DEFF Research Database (Denmark)

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

    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....

  1. 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. PMID:17766237

  2. 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...

  3. 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...... well as current examples of best practice of managing supply chains in a global context....... 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...

  4. Ximelagatran: direct thrombin inhibitor

    Directory of Open Access Journals (Sweden)

    Shir-Jing Ho

    2006-03-01

    -major orthopedic surgery. It has also been shown to be more effective than aspirin alone for prevention of recurrent major cardiovascular events in patients with recent myocardial infarction.Keywords: Ximelagatran, direct thrombin inhibitor, oral anticoagulants, thromboprophylaxis

  5. 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....

  6. 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.

  7. 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. PMID:27338660

  8. Conjugation to polymeric chains of influenza drugs targeting M2 ion channels partially restores inhibition of drug-resistant mutants

    OpenAIRE

    Larson, Alyssa M.; Chen, Jianzhu; Klibanov, Alexander M.

    2013-01-01

    By attaching multiple copies of the influenza M2 ion channel inhibitors amantadine (1) and rimantadine (2) to polymeric chains, we endeavored to recover their potency in inhibiting drug-resistant influenza viruses. Depending on loading densities, as well as the nature of the drug, the polymer, and the spacer arm, polymer-conjugated drugs were up to 30-fold more potent inhibitors of drug-resistant strains than their monomeric parents. In particular, a 20% loading density and a short linker gro...

  9. Evaluation of Inhibitor-Resistant Real-Time PCR Methods for Diagnostics in Clinical and Environmental Samples

    OpenAIRE

    Adrienne Trombley Hall; Ashley McKay Zovanyi; Deanna Rose Christensen; Jeffrey William Koehler; Timothy Devins Minogue

    2013-01-01

    Polymerase chain reaction (PCR) is commonly used for pathogen detection in clinical and environmental samples. These sample matrices often contain inhibitors of PCR, which is a primary reason for sample processing; however, the purification process is highly inefficient, becoming unacceptable at lower signature concentrations. One potential solution is direct PCR assessment without sample processing. Here, we evaluated nine inhibitor-resistant PCR reagents for direct detection of Francisella ...

  10. 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.

  11. 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.

  12. Improving supply chain collaborations and performance of inefficient supply chain

    Directory of Open Access Journals (Sweden)

    M. Sanei

    2010-03-01

    Full Text Available Modern manufacturing enterprises are required to collaborate by their business partners through their business process operations such as design, manufacture, distribution, and aftersales services. And furthermore performance evaluation is of great importance for effective supply chain man agement. Therefore, DEA can help companies to remove some of the in efficiencies in operational processes in order to become more effective. The current paper develops one approach for determining the DEA projections for inefficient supply chains. Meanwhile this approach aims at providing an easy, efficient and more practical approach based on the performance evaluation for the multi-member supply chain. And ultimately, this model is illustrated by an numerical example of Chinese commercial bank, and case study application to provide of machine-making supply chain.

  13. 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.

  14. 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

  15. Chains of Mean Field Models

    OpenAIRE

    Hassani, S. Hamed; Macris, Nicolas; Urbanke, Ruediger

    2011-01-01

    We consider a collection of Curie-Weiss (CW) spin systems, possibly with a random field, each of which is placed along the positions of a one-dimensional chain. The CW systems are coupled together by a Kac-type interaction in the longitudinal direction of the chain and by an infinite range interaction in the direction transverse to the chain. Our motivations for studying this model come from recent findings in the theory of error correcting codes based on spatially coupled graphs. We find tha...

  16. Microbial inhibitors of cysteine proteases.

    Science.gov (United States)

    Kędzior, Mateusz; Seredyński, Rafał; Gutowicz, Jan

    2016-08-01

    Cysteine proteases are one of the major classes of proteolytic enzymes involved in a number of physiological and pathological processes in plants, animals and microorganisms. When their synthesis, activity and localization in mammalian cells are altered, they may contribute to the development of many diseases, including rheumatoid arthritis, osteoporosis and cancer. Therefore, cysteine proteases have become promising drug targets for the medical treatment of these disorders. Inhibitors of cysteine proteases are also produced by almost every group of living organisms, being responsible for the control of intracellular proteolytic activity. Microorganisms synthesize cysteine protease inhibitors not only to regulate the activity of endogenous, often virulent enzymes, but also to hinder the host's proteolytic defense system and evade its immune responses against infections. Present work describes known to date microbial inhibitors of cysteine proteases in terms of their structure, enzyme binding mechanism, specificity and pathophysiological roles. The overview of both proteinaceous and small-molecule inhibitors produced by all groups of microorganisms (bacteria, archaea, fungi, protists) and viruses is provided. Subsequently, possible applications of microbial inhibitors in science, medicine and biotechnology are also highlighted. PMID:27048482

  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. 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...

  19. Ownership Structure in Agrifood Chains

    NARCIS (Netherlands)

    G.W.J. Hendrikse (George); W.J.J. Bijman (Jos)

    2000-01-01

    textabstractThis article analyses the impact of ownership structure on investments in a three-party supply chain from an incomplete contracting perspective. Circumstances are determined in which a marketing cooperative is the unique first-best ownership structure.

  20. 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 ...

  1. Supply Chain Management and Hypercompetition

    OpenAIRE

    Kotzab, H,; Grant, DB; Teller, C.; Halldorsson, A

    2008-01-01

    Firms nowadays face significant challenges in their operating environments, which have been characterised in two different ways. From a strategic management perspective these environments are in a state of hypercompetition while from a logistics or supply chain perspective these environments require market responsiveness predicated upon agile supply chains. However, firms must also rely on many interorganizational relationships to ensure efficient and effective movements within their supply c...

  2. Product Classification in Supply Chain

    OpenAIRE

    Xing, Lihong; Xu, Yaoxuan

    2010-01-01

    Oriflame is a famous international direct sale cosmetics company with complicated supply chain operation but it lacks of a product classification system. It is vital to design a product classification method in order to support Oriflame global supply planning and improve the supply chain performance. This article is aim to investigate and design the multi-criteria of product classification, propose the classification model, suggest application areas of product classification results and intro...

  3. 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.

  4. 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......, network theory, innovation theory, competence development and political science, which are proposed as focus in future capacity development as part of governmental strategies, which aim at supporting emergence and stabilisation of environmental concerns as part of product chain dynamics....

  5. Developing sustainable food supply chains

    OpenAIRE

    Smith, B. Gail

    2007-01-01

    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 so...

  6. 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.

  7. 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.

  8. A localized PCR inhibitor in a porcelain crab suggests a protective role

    Directory of Open Access Journals (Sweden)

    Mahmoud A. El-Maklizi

    2014-12-01

    Full Text Available A number of polymerase chain reaction (PCR inhibitors have been identified from biological and environmental samples. By and large, such substances are treated as random nuisances and contaminants with alternate functions; their inhibitory effects on DNA replication being a coincidental property of their molecular structure. Here, we demonstrate the presence of a localized PCR inhibitor in the foregut of the porcelain crab Petrolisthes rufescens (Anomura: Porcellanidae from the Red Sea. The inhibitor precluded amplification of 28s, 16s and 18s gene sequences effectively but lost activity at 10−2 dilutions from initial concentration. Heat treatment was ineffective in arresting inhibition and spectrophotometric techniques suggested that the inhibitor was not a melanin-type compound. The compound was not detected from midgut, hindgut, or gills of the crab. Activity of the inhibitor was precluded when samples were treated with suspensions from the midgut, suggesting that enzymatic degradation of the inhibitor likely happens at that part of the gut. As many microbial pathogens invade their hosts via ingestion, we suggest the presence of the localized inhibitor could carry a defensive or immunological role for P. rufescens. The identity of the inhibitory molecule remains unknown.

  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. 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....

  12. 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.

  13. 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...

  14. Risk Management in Biopharmaceutical Supply Chains

    OpenAIRE

    Ma, Yao

    2011-01-01

    Biopharmaceutical supply chains present considerable complexity issue for the formulation of optimal plans due to significant uncertainty in the supply chain. The primary goal of biopharmaceutical supply chain planning is to provide reliable supply to patients while coping with various supply chain risks. In chapter 1 first I discuss the key elements and basic characteristics of the biopharmaceutical supply chain . Then I present the major challenges in biopharmaceutical supply chain planning...

  15. 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.

  16. 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

  17. Linear chains and chain-like fractals from electrostatic heteroaggregation.

    Science.gov (United States)

    Kim, Anthony Y; Hauch, Kip D; Berg, John C; Martin, James E; Anderson, Robert A

    2003-04-01

    The internal structure of materials prepared by aggregation of oppositely charged polystyrene spheres (electrostatic heteroaggregation) is investigated by static light scattering, optical microscopy, and Brownian dynamics simulation. Light scattering indicates ultralow mass fractal dimensions, as low as 1.2. Such low fractal dimensions, approaching the theoretical limit of a linear object, imply a chaining mechanism. Optical micrographs reveal linear chains with the particle charge alternating down the chains. Brownian dynamics simulation gives additional support for a chaining mechanism. For the polystyrene system (120-nm primary particle diameters), the fractal dimension is found to increase from 1.2 to 1.7 as the background electrolyte is increased. In terms of electrostatic screening, the results match those reported recently for larger polystyrene spheres. The low fractal dimensions appear to represent a crossover from linear chains to a structure of diffusion-limited aggregates; however, experiments under density-neutral conditions imply that sedimentation plays an important role in the formation of ultralow fractal dimensions. The practical implication is that microcomposites with a locally uniform distribution of starting materials and almost any degree of branching can be prepared from oppositely charged particles. PMID:12742045

  18. Structural insight into the unique binding properties of pyridylethanol(phenylethyl)amine inhibitor in human CYP51.

    Science.gov (United States)

    Zelenko, Urška; Hodošček, Milan; Rozman, Damjana; Golič Grdadolnik, Simona

    2014-12-22

    Sterol 14α-demethylase (CYP51) is the main drug target for the treatment of fungal infections. The discovery of new efficient fungal CYP51 inhibitors requires an understanding of the structural requirements for selectivity for the fungal over the human ortholog. In this study, a binding mode of the pyridylethanol(phenylethyl)amine type CYP51 inhibitor to the human ortholog was determined at the atomic level. We isolated and purified a full-length human CYP51. The inhibitor-specific binding and its conformational and dynamic properties were evaluated using UV-visible and NMR spectroscopy. Considering the experimental data in docking calculations and molecular dynamics simulations, the location of the inhibitor moieties and their interactions with the enzyme active site were determined. The inhibitor binds to the enzyme in two diastereomeric forms, which have a common location of aromatic ring moieties, while the less bulky propyl chain can adapt to various hydrophobic regions of the enzyme active site. The halogenated phenyl ring binds in the substrate access channel making numerous contacts with the hydrophobic side chains, and its interactions with the unconserved residues are especially informative. The results reveal the unique binding properties of the investigated inhibitor in comparison to the azoles and provide novel directions for the design of selective fungal inhibitors. PMID:25419870

  19. Supply Chain Management Practices in Toy Supply Chains

    DEFF Research Database (Denmark)

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

    2005-01-01

    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...... (traditional mass-production or push-models). These low-responsive practices in the toy supply chain are not caused only by slow knowledge diffusion. SCM know-how is not yet capable of managing such levels of volatility and seasonality. Therefore, explanations of these theoretical gaps and what new theories...... are applicable and effective? This study seeks to explore SCM practices, and identify practical and theoretical gaps in toy supply chains. Design/methodology/approach - This article includes a longitudinal and in-depth case study during the past year in an international toy manufacturer, which includes...

  20. Cadmium absorption inhibitors for soil

    Energy Technology Data Exchange (ETDEWEB)

    Kitamura, S.

    1974-05-25

    Cadmium absorption by soil is one cause of soil pollution. Cadmium adsorption inhibitors were prepared by mixing alginic acid which contained brown algae (Ascophyllum nodosum) and an inorganic material, shell fossils. This mixture was highly effective in preventing cadmium absorption by the soil.

  1. 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

  2. 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

  3. 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.

  4. Competitive behaviour in supply chains

    Directory of Open Access Journals (Sweden)

    Sylwia Konecka

    2014-06-01

    Full Text Available Background: The article deals with the results of literature and empirical research into competitiveness and behaviour of entities in supply chains. Methods: A research hypothesis has been formulated that both partnership as well as dominance relations occur between enterprises functioning as suppliers-consignees. In order to verify the hypothesis a survey was completed in 2012. It encompassed 116 enterprises (manufacturers - 33, service providers - 32 and sellers - 24 as well as enterprises selling goods and providing services - 27 of which 54 were large, 26 medium and 36 were small enterprises. Competitive behaviour in supply chains has been identified and analysed. Furthermore, the authors intended to identify, reveal and examine possible interdependences between competitive behaviour and behaviour typical of supply chain strategies. Results and conclusions: The analysis of survey results revealed a tendency to preserve equilibrium between a chain leader and dependent enterprises. It may be easily justified in practice as on the one hand there is a need to keep the supply chain competitive and on the other hand to avoid the interruptions, which could occur as a result of elimination of dependent enterprises.

  5. Chains of Mean Field Models

    CERN Document Server

    Hassani, S Hamed; Urbanke, Ruediger

    2011-01-01

    We consider a collection of mean field spin systems, each of which is placed on the positions of a one-dimensional chain, coupled together by a Kac-type interaction along the chain. We analyze the simplest possible cases where the individual system is a Curie-Weiss model, possibly with a random field. We are interested in the regime where the size of each mean field model tends to infinity and, the length of the chain and range of the Kac interaction are large but finite. Below the critical temperature, there appears a series of equilibrium states representing kink-like interfaces between the two equilibrium states of the individual system. The van der Waals curve oscillates periodically around the Maxwell plateau. These oscillations have a period inversely proportional to the chain length and an amplitude exponentially small in the range of the interaction; in other words the spinodal points of the chain model lie exponentially close to the phase transition threshold. The amplitude of the oscillations is clo...

  6. Lipoxygenase inhibitor peptides and their use

    OpenAIRE

    Schurink, M.; Boeriu, C.G.; Berkel, van, A.M.; Wichers, H J

    2006-01-01

    The present invention is in the field of enzyme inhibition. In particular it relates to peptide inhibitors for lipoxygenases. The lipoxygenase peptide inhibitors of have the potential to be used as therapeutic drugs as well as food preservatives.

  7. Chain reconfiguration in active noise

    International Nuclear Information System (INIS)

    In a typical single molecule experiment, the dynamics of an unfolded protein is studied by determining the reconfiguration time using long-range Förster resonance energy transfer, where the reconfiguration time is the characteristic decay time of the position correlation between two residues of the protein. In this paper we theoretically calculate the reconfiguration time for a single flexible polymer in the presence of active noise. The study suggests that though the mean square displacement grows faster, the chain reconfiguration is always slower in the presence of long-lived active noise with exponential temporal correlation. Similar behavior is observed for a worm-like semi-flexible chain and a Zimm chain. However it is primarily the characteristic correlation time of the active noise and not the strength that controls the increase in the reconfiguration time. In brief, such active noise makes the polymer move faster but the correlation loss between the monomers becomes slow. (paper)

  8. Towards biotracing in food chains

    DEFF Research Database (Denmark)

    Hoorfar, Jeffrey; Wagner, Martin; Jordan, Kieran;

    2011-01-01

    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 int......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......, 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...

  9. Ligand chain length conveys thermochromism.

    Science.gov (United States)

    Ganguly, Mainak; Panigrahi, Sudipa; Chandrakumar, K R S; Sasmal, Anup Kumar; Pal, Anjali; Pal, Tarasankar

    2014-08-14

    Thermochromic properties of a series of non-ionic copper compounds have been reported. Herein, we demonstrate that Cu(II) ion with straight-chain primary amine (A) and alpha-linolenic (fatty acid, AL) co-jointly exhibit thermochromic properties. In the current case, we determined that thermochromism becomes ligand chain length-dependent and at least one of the ligands (A or AL) must be long chain. Thermochromism is attributed to a balanced competition between the fatty acids and amines for the copper(II) centre. The structure-property relationship of the non-ionic copper compounds Cu(AL)2(A)2 has been substantiated by various physical measurements along with detailed theoretical studies based on time-dependent density functional theory. It is presumed from our results that the compound would be a useful material for temperature-sensor applications. PMID:24943491

  10. Precise Nanoelectronics with Adatom Chains

    Science.gov (United States)

    Yamada, Toshishige

    1999-01-01

    Adatom chains on an atomically regulated substrate will be building components in future precise nanoelectronics. Adatoms need to be secured with chemical bonding, but then electronic isolation between the adatom and substrate systems is not guaranteed. A one-dimensional model shows that good isolation with existence of surface states is expected on an s-p crossing substrate such as Si, Ge, or GaAs, reflecting the bulk nature of the substrate. Isolation is better if adatoms are electronically similar to the substrate atoms, and can be manipulated by hydrogenation. Chain structures with group IV adatoms with two chemical bonds, or group III adatoms with one chemical bond, are semiconducting, reflecting the surface nature of the substrate. These structures are unintentionally doped due to the charge transfer across the chemical bonds. Physical properties of adatom chains have to be determined for the unified adatom-substrate system.

  11. 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.

  12. 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...

  13. 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

  14. 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....

  15. MANAGING RISK IN SUPPLY CHAIN

    OpenAIRE

    Karppinen, Sami

    2015-01-01

    In this master thesis the focus was to study risk management in supply chain management. During the work different types of risks were studied and how they affect purchasing in industry. The purpose of the work was also to enhance the writer’s ability to do his own daily work and to bring new views to his employer for managing a supply chain. In this work different techniques which have been introduced in the industry were reviewed. During the work, an interview survey was made among the ...

  16. T-cell receptor downregulation by ceramide-induced caspase activation and cleavage of the zeta chain

    DEFF Research Database (Denmark)

    Menné, C; Lauritsen, Jens Peter Holst; Dietrich, J;

    2001-01-01

    gamma L-based motif-dependent and the tyrosine kinase-dependent pathways. This pathway is dependent on ceramide-induced activation of caspases and correlate with caspase-mediated cleavage of the zeta chain. Thus, a 10--15% downregulation of the TCR was induced following the treatment of the T cells with...... ceramide for 4 h. A close correlation between TCR downregulation, caspase activation, and cleavage of the zeta chain was found. Furthermore, the caspase inhibitors abolished the cleavage of the zeta chain and TCR downregulation in parallel with the inhibition of the caspase activity....

  17. 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.

  18. 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...

  19. Sustainability Analysis for Gayo Coffee Supply Chain

    OpenAIRE

    Rachman Jaya; Machfud Machfud; Sapta Raharja; Marimin Marimin

    2013-01-01

    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 cons...

  20. Supply Chains and Social Network Analysis

    OpenAIRE

    Mueller, Rolf A.E.; Buergelt, Doreen; Seidel-Lass, Linda

    2008-01-01

    Judged by its currency, the supply chain is one of the more successful metaphors in economics. The metaphor borrows from mechanics the idea of the chain, that is something that consists of elements that are linked to each of their two immediate neighbors and which jointly provide a strong but flexible connection. The metaphor transplants the chain-idea into the sphere of economics where, before the introduction of supply chains, chains were, for most economists, things best left in the care o...

  1. 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...

  2. 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.

  3. OVERVIEW OF CHINESE CHAIN CATERING MARKET

    OpenAIRE

    Wang, Yiting

    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...

  4. 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.

  5. 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.

  6. Ontological Supply Chain Management: Concepts, Applications, Extensions

    OpenAIRE

    Ilter, H. Kemal

    2013-01-01

    SCOM: Multi-Layer Ontological Model for Supply Chain Systems© aims to create a model for tracking and tracing products, agents, flows and operations of a supply chain with an upper ontology.  It will hopefully let us to track or trace most properties in not-usual supply chains such as interstellar supply chains (eg. raw materials from the planet Mars), health-related supply chains (eg. blood products), food management (eg. genetic structures of agricultural products), envir...

  7. Combinatorial optimization of cystine-knot peptides towards high-affinity inhibitors of human matriptase-1.

    Directory of Open Access Journals (Sweden)

    Bernhard Glotzbach

    Full Text Available Cystine-knot miniproteins define a class of bioactive molecules with several thousand natural members. Their eponymous motif comprises a rigid structured core formed by six disulfide-connected cysteine residues, which accounts for its exceptional stability towards thermic or proteolytic degradation. Since they display a remarkable sequence tolerance within their disulfide-connected loops, these molecules are considered promising frameworks for peptide-based pharmaceuticals. Natural open-chain cystine-knot trypsin inhibitors of the MCoTI (Momordica cochinchinensis trypsin inhibitor and SOTI (Spinacia oleracea trypsin inhibitor families served as starting points for the generation of inhibitors of matriptase-1, a type II transmembrane serine protease with possible clinical relevance in cancer and arthritic therapy. Yeast surface-displayed libraries of miniproteins were used to select unique and potent matriptase-1 inhibitors. To this end, a knowledge-based library design was applied that makes use of detailed information on binding and folding behavior of cystine-knot peptides. Five inhibitor variants, four of the MCoTI family and one of the SOTI family, were identified, chemically synthesized and oxidatively folded towards the bioactive conformation. Enzyme assays revealed inhibition constants in the low nanomolar range for all candidates. One subnanomolar binder (Ki = 0.83 nM with an inverted selectivity towards trypsin and matriptase-1 was identified.

  8. 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.

  9. [Monitoring of Oral Thrombin Inhibitor].

    Science.gov (United States)

    Matsuno, Kazuhiko; Usami, Takayuki; Hatuse, Masanao; Shimizu, Chikara

    2014-10-01

    Dabigatran etexilate is a prodrug that is converted into its active metabolite, dabigatran, by hydrolysis. Dabigatran is a selective thrombin inhibitor that has been approved for the prevention of stroke in patients with non-valvular atrial fibrillation in Japan. Laboratory monitoring is not needed, but an assessment of its anticoagulant effect in certain clinical settings, such as emergency surgery, suspected overdose, or the occurrence of bleeding, is desirable. We overview the special coagulation assays, such as Hemoclot Thrombin Inhibitor (HTI), the thrombin generation assay (TGA), ecarin clotting time (ECT), ecarin chromogenic assay (ECA), prothrombinase-induced clotting time (PiCT), and activated clotting time (ACT). We also examined the relationship between dabigatran levels as determined by HTI, and the activated partial thromboplastin time (APTT) and prothrombin time (PT). APTT and PT demonstrated a positive correlation with the dabigatran levels. APTT, PT, and the combination of APTT and PT may estimate the dabigatran levels in plasma. PMID:27526541

  10. [Direct oral thrombin inhibitor, "dabigatran"].

    Science.gov (United States)

    Yasaka, Masahiro

    2013-01-01

    Dabigatran is an oral, direct, and competitive inhibitor of thrombin, which is administered to patients with non-valvular atrial fibrillation for prevention of stroke at a dose of 110 mg twice daily or 150 mg twice daily. Anticoagulation by dabigatran is "hybrid anticoagulation", consisting of action of both dabigatran and physiological coagulation inhibitors because warfarin inhibits production of protein C and protein S but dabigatran does not. Management of dabigatran is easier than that of warfarin because food restriction is unnecessary, drug interaction is small, and absorption time is short and serum concentration corresponds to the anticoagulatory effect in dabigatran treatment. The RE-LY trial confirmed effectiveness and safety of both doses of dabigatran for prevention of stroke and both doses of dabigatran had much lower risks of intracranial bleeding compared with warfarin. Compliance to guidance of dabigatran treatment is essential for avoidance of severe hemorrhagic complications. PMID:23631181

  11. The Service-Profit Chain

    DEFF Research Database (Denmark)

    Grønholdt, Lars; Martensen, Anne

    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...

  12. Smallest Nanoelectronics with Adatom Chains

    Science.gov (United States)

    Yamada, Toshishige; Saini, Subhash (Technical Monitor)

    1998-01-01

    This viewgraph presentation is focused on the general aspect of atomic chain electronics that I have been studying. Results have been published before, but are being rederived here using a new physical/mathematical picture/model, which deepens the physical understanding. Precise adatom structures can be used as a template on a regulated surface with no uncertainty.

  13. Synchronizing the Retail Supply Chain

    NARCIS (Netherlands)

    P. van der Vlist

    2007-01-01

    textabstractDit proefschrift ontwerpt een retail supply chain, die beter en goedkoper is dan de gangbare. Dit wordt bereikt door de distributie te synchroniseren op de productie¬momenten. Goederen zouden direct uit productie al stroomafwaarts moeten bewegen, van fabrikant naar retailer, tegen lage k

  14. 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

  15. Preisdifferenzierung im Supply Chain Management

    OpenAIRE

    Koppers, Laura

    2010-01-01

    In the field of marketing, pricing is a valuable and long-established steering tool. But in the logistics context of co-operative strategies like supply chain management, this field is mainly neglected. Therefore, the author describes the basic principles and effects of price differentiation and suggests some further research regarding pricing in SCM considerations as well as co-operative pricing concepts.

  16. Supply Chain Management: een overzicht

    NARCIS (Netherlands)

    Schuring, R.W.

    2012-01-01

    De laatste jaren wordt voor het managen van het netwerk van bedrijven die betrokken zijn bij het tot stand komen van producten of diensten het woord Supply Chain Management, ook wel SCM, gebruikt. SCM wordt als term vooral in grote industrieën gebruikt. Bijna ieder bedrijf heeft echter een toelevern

  17. Kinase Inhibitors from Marine Sponges

    Directory of Open Access Journals (Sweden)

    Ana Zivanovic

    2011-10-01

    Full Text Available Protein kinases play a critical role in cell regulation and their deregulation is a contributing factor in an increasing list of diseases including cancer. Marine sponges have yielded over 70 novel compounds to date that exhibit significant inhibitory activity towards a range of protein kinases. These compounds, which belong to diverse structural classes, are reviewed herein, and ordered based upon the kinase that they inhibit. Relevant synthetic studies on the marine natural product kinase inhibitors have also been included.

  18. ACE INHIBITORS: A COMPREHENSIVE REVIEW

    OpenAIRE

    Pradeep Kumar Arora* and Ashish Chauhan

    2013-01-01

    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...

  19. Natural Products as Aromatase Inhibitors

    OpenAIRE

    Balunas, Marcy J.; Su, Bin; Brueggemeier, Robert W.; Kinghorn, A. Douglas

    2008-01-01

    With the clinical success of several synthetic aromatase inhibitors (AIs) in the treatment of postmenopausal estrogen receptor-positive breast cancer, researchers have also been investigating also the potential of natural products as AIs. Natural products from terrestrial and marine organisms provide a chemically diverse array of compounds not always available through current synthetic chemistry techniques. Natural products that have been used traditionally for nutritional or medicinal purpos...

  20. Thrombin Inhibitors from Different Animals

    OpenAIRE

    Tanaka-Azevedo, A. M.; Morais-Zani, K.; Torquato, R. J. S.; A. S. Tanaka

    2010-01-01

    Venous and arterial thromboembolic diseases are still the most frequent causes of death and disability in high-income countries. Clinical anticoagulants are inhibitors of enzymes involved in the coagulation pathway, such as thrombin and factor Xa. Thrombin is a key enzyme of blood coagulation system, activating the platelets, converting the fibrinogen to the fibrin net, and amplifying its self-generation by the activation of factors V, VIII, and XI. Thrombin has long been a target for the dev...

  1. 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.

  2. 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....

  3. 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. PMID:24146385

  4. The burden of inhibitors in haemophilia patients.

    Science.gov (United States)

    Walsh, Christopher E; Jiménez-Yuste, Víctor; Auerswald, Guenter; Grancha, Salvador

    2016-08-31

    The burden of disease in haemophilia patients has wide ranging implications for the family and to society. There is evidence that having a current inhibitor increases the risk of morbidity and mortality. Morbidity is increased by the inability to treat adequately and its consequent disabilities, which then equates to a poor quality of life compared with non-inhibitor patients. The societal cost of care, or `burden of inhibitors', increases with the ongoing presence of an inhibitor. Therefore, it is clear that successful eradication of inhibitors by immune tolerance induction (ITI) is the single most important milestone one can achieve in an inhibitor patient. The type of factor VIII (FVIII) product used in ITI regimens varies worldwide. Despite ongoing debate, there is in vitro and retrospective clinical evidence to support the use of plasma-derived VWF-containing FVIII concentrates in ITI regimens in order to achieve early and high inhibitor eradication success rates. PMID:27528280

  5. Improving supply chain collaborations and performance of inefficient supply chain

    OpenAIRE

    M. Sanei; S. Mamizadeh-Chatghayeh

    2010-01-01

    Modern manufacturing enterprises are required to collaborate by their business partners through their business process operations such as design, manufacture, distribution, and aftersales services. And furthermore performance evaluation is of great importance for effective supply chain man agement. Therefore, DEA can help companies to remove some of the in efficiencies in operational processes in order to become more effective. The current paper develops one approach for determining the DEA p...

  6. 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...

  7. 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.

  8. 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.

  9. Benzoxazolone Carboxamides as Potent Acid Ceramidase Inhibitors: Synthesis and Structure-Activity Relationship (SAR) Studies.

    Science.gov (United States)

    Bach, Anders; Pizzirani, Daniela; Realini, Natalia; Vozella, Valentina; Russo, Debora; Penna, Ilaria; Melzig, Laurin; Scarpelli, Rita; Piomelli, Daniele

    2015-12-10

    Ceramides are lipid-derived intracellular messengers involved in the control of senescence, inflammation, and apoptosis. The cysteine amidase, acid ceramidase (AC), hydrolyzes these substances into sphingosine and fatty acid and, by doing so, regulates their signaling activity. AC inhibitors may 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 administration. The results expand our arsenal of AC inhibitors, thereby facilitating the use of these compounds as pharmacological tools and their potential development as drug leads. PMID:26560855

  10. 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.

  11. 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.

  12. Den teoretiske udvikling af Supply Chain Strategimodeller

    DEFF Research Database (Denmark)

    Arvad Johansen, Jens

    2011-01-01

    segmentering via postponement-princippet, har givet mærkbare forbedringer. Det beskrives endvidere, hvordan produkternes livscyklus påvirker valget af supply chain design. Begrebet Demand Chain Management( DCM), hvormed strategimodeller bruger klassiske marketingelementer sammen med Supply Chain Management......Denne artikel beskriver med udgangspunkt i artikler og virksomhedseksempler udviklingen inde for supply chain strategimodeller. Ved hjælp af tidligere udviklede koncepter besvares spørgsmålet: “Hvad er den rette supply chain for mine produkter?”. Virksomhedseksempler beskriver, hvordan supply chain...... (SCM), bliver behandlet og der udvikles en DCM-strategimodel....

  13. 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.

  14. CHARACTERISTICS OF THE VALUE CHAIN OF THE GLOBAL VALUE CHAIN AND THE SCOPE OF THE CHAIN ANALYSIS

    OpenAIRE

    Luu, Thai

    2013-01-01

    The value chain of vegetable industry is a line of production processing business of vegetable under the mode of globalization, of which, economic subjects of many countries involve in the different stages in the chain. The method of global approach under the value chain has been developed over time and is used as an analysis tool in market research of the global vegetable industry. Three key elements of the pattern of analysis scope of the global vegetable value chain analysis of the global ...

  15. Supply Chain Simulation: A Survey

    OpenAIRE

    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 by the model.Moreover, this paper summarizes novel sensitivity and robustness analyses.This sensitivity analysis yields a shortlist of the truly important factors in large simulation models with (sa...

  16. The Milk Supply Chain Project.

    OpenAIRE

    Smith, Howard; Thanassoulis, John

    2008-01-01

    This report presents the results of an Oxford University research project into the UK liquid milk supply chain. Financial sponsorship was kindly provided by the Milk Development Council (MDC) and by DEFRA. The research reported here is independent academic research which is not designed to further any group‟s particular agenda. We have striven to be as objective as possible. The project's aim is to investigate the competitive forces which influence the buyerseller relationsh...

  17. Organizing the Global Value Chain

    OpenAIRE

    Pol Antràs; Davin Chor

    2012-01-01

    We develop a property-rights model of the firm in which production entails a continuum of uniquely sequenced stages. In each stage, a final-good producer contracts with a distinct supplier for the procurement of a customized stage-specific component. Our model yields a sharp characterization for the optimal allocation of ownership rights along the value chain. We show that the incentive to integrate suppliers varies systematically with the relative position (upstream versus downstream) at whi...

  18. Demand and Supply Chain Management

    OpenAIRE

    Jack A.A. van der Veenl:; Robben, Henry S.J.

    1999-01-01

    In dit artikel wordt ingegaan op de recente ontwikkelingen met be-trekking tot de managementactiviteiten gericht op de keten die begint bij het winnen van grondstoffen en via toeleveranciers, fabrikanten en de (detail)handel loopt naar de eindgebruikers. De moderne denkbeelden op dit terrein worden samengevat met de term Demand & Supply Chain Management (DSCM); het management van de keten die onafhankelijke klanten en leveranciers verbindt als ware het een enkele en-titeit met het doel om waa...

  19. Markov Chain Ontology Analysis (MCOA

    Directory of Open Access Journals (Sweden)

    Frost H

    2012-02-01

    Full Text Available Abstract Background Biomedical ontologies have become an increasingly critical lens through which researchers analyze the genomic, clinical and bibliographic data that fuels scientific research. Of particular relevance are methods, such as enrichment analysis, that quantify the importance of ontology classes relative to a collection of domain data. Current analytical techniques, however, remain limited in their ability to handle many important types of structural complexity encountered in real biological systems including class overlaps, continuously valued data, inter-instance relationships, non-hierarchical relationships between classes, semantic distance and sparse data. Results In this paper, we describe a methodology called Markov Chain Ontology Analysis (MCOA and illustrate its use through a MCOA-based enrichment analysis application based on a generative model of gene activation. MCOA models the classes in an ontology, the instances from an associated dataset and all directional inter-class, class-to-instance and inter-instance relationships as a single finite ergodic Markov chain. The adjusted transition probability matrix for this Markov chain enables the calculation of eigenvector values that quantify the importance of each ontology class relative to other classes and the associated data set members. On both controlled Gene Ontology (GO data sets created with Escherichia coli, Drosophila melanogaster and Homo sapiens annotations and real gene expression data extracted from the Gene Expression Omnibus (GEO, the MCOA enrichment analysis approach provides the best performance of comparable state-of-the-art methods. Conclusion A methodology based on Markov chain models and network analytic metrics can help detect the relevant signal within large, highly interdependent and noisy data sets and, for applications such as enrichment analysis, has been shown to generate superior performance on both real and simulated data relative to existing

  20. 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.

  1. 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.

  2. 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.

  3. Inhibitors of Fatty Acid Synthesis Induce PPAR α -Regulated Fatty Acid β -Oxidative Genes: Synergistic Roles of L-FABP and Glucose

    OpenAIRE

    Huan Huang; McIntosh, Avery L.; Martin, Gregory G.; Petrescu, Anca D.; Landrock, Kerstin K.; Danilo Landrock; Kier, Ann B.; Friedhelm Schroeder

    2013-01-01

    While TOFA (acetyl CoA carboxylase inhibitor) and C75 (fatty acid synthase inhibitor) prevent lipid accumulation by inhibiting fatty acid synthesis, the mechanism of action is not simply accounted for by inhibition of the enzymes alone. Liver fatty acid binding protein (L-FABP), a mediator of long chain fatty acid signaling to peroxisome proliferator-activated receptor-α (PPARα) in the nucleus, was found to bind TOFA and its activated CoA th...

  4. 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. PMID:26664401

  5. Transition Probability Estimates for Reversible Markov Chains

    OpenAIRE

    Telcs, Andras

    2000-01-01

    This paper provides transition probability estimates of transient reversible Markov chains. The key condition of the result is the spatial symmetry and polynomial decay of the Green's function of the chain.

  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. Benchmarking carbon emissions performance in supply chains

    OpenAIRE

    Acquaye, Adolf; Genovese, Andrea; Barrett, John W.; Koh, Lenny

    2014-01-01

    Purpose – The paper aims to develop a benchmarking framework to address issues such as supply chain complexity and visibility, geographical differences and non-standardized data, ensuring that the entire supply chain environmental impact (in terms of carbon) and resource use for all tiers, including domestic and import flows, are evaluated. Benchmarking has become an important issue in supply chain management practice. However, challenges such as supply chain complexity and visibility, geogra...

  9. Supply chain management in product development.

    OpenAIRE

    Tzortzopoulos, Patricia; Kagioglou, Mike; Cooper, Rachel; Dyson, E

    2009-01-01

    Mounting emphasis on construction supply chain management (CSCM) is due to both global sourcing of materials and a shortage of labor. These factors force increasing amounts of value-added work to be conducted off-site deep in the supply chain. Construction Supply Chain Management Handbookcompiles in one comprehensive source an overview of the diverse research and examples of construction supply chain practice around the world.Reflecting the emergence of CSCM as an important area of multi-nati...

  10. Model Protocells from Single-Chain Lipids

    OpenAIRE

    Mansy, Sheref S.

    2009-01-01

    Significant progress has been made in the construction of laboratory models of protocells. Most frequently the developed vesicle systems utilize single-chain lipids rather than the double-chain lipids typically found in biological membranes. Although single-chain lipids yield less robust vesicles, their dynamic characteristics are highly exploitable for protocellular functions. Herein the advantages of using single-chain lipids in the construction of protocells are discussed.

  11. Model Protocells from Single-Chain Lipids

    Directory of Open Access Journals (Sweden)

    Sheref S. Mansy

    2009-03-01

    Full Text Available Significant progress has been made in the construction of laboratory models of protocells. Most frequently the developed vesicle systems utilize single-chain lipids rather than the double-chain lipids typically found in biological membranes. Although single-chain lipids yield less robust vesicles, their dynamic characteristics are highly exploitable for protocellular functions. Herein the advantages of using single-chain lipids in the construction of protocells are discussed.

  12. 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 ...

  13. Kooperationsanforderungen im Supply Chain Management (SCM)

    OpenAIRE

    Klumpp, Matthias; Koppers, Laura

    2007-01-01

    In this paper the general concept of Supply Chain Management (SCM) is described and the scientific cooperation models in the supply chain are discussed. Though there are several models to explain cooperations there is no clear perspective on the needed competencies in companies to shape a successful cooperation e.g. within a supply chain. Instead companies rely solely on experience and intuition in order to create and steer supply chain relationships with high business values. In order to mit...

  14. Model protocells from single-chain lipids.

    Science.gov (United States)

    Mansy, Sheref S

    2009-03-01

    Significant progress has been made in the construction of laboratory models of protocells. Most frequently the developed vesicle systems utilize single-chain lipids rather than the double-chain lipids typically found in biological membranes. Although single-chain lipids yield less robust vesicles, their dynamic characteristics are highly exploitable for protocellular functions. Herein the advantages of using single-chain lipids in the construction of protocells are discussed. PMID:19399223

  15. 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.

  16. 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...

  17. Linking corporate strategy and supply chain management

    OpenAIRE

    Hofmann, Erik

    2009-01-01

    Purpose of this paper: The paper researches the linkages between corporate and supply chain strategy. It represents a stage of an on-going research initiative aimed at providing a framework for understanding systematically the integration of corporate strategy making and supply chain management. Design/methodology/approach: The paper engaged itself in the theory/literature related to strategic and supply chain management. Four generic levels of strategy are linked to supply chain ma...

  18. Supply Chain Management in the Construction Industry

    OpenAIRE

    Olsson, Fredrik

    2000-01-01

    In this licentiate thesis the implications of a deliberate use of logistics knowledge have been investigated by describing and analyzing the use of a supply chain management approach in the construction industry.
    A five-step approach is used in the thesis. First, theoretical models are developed from the supply chain management literature. Two models are elaborated; One model identifying supply chain criteria and the other comparing traditional to supply chain-based.

  19. A concept for collaborative supply chain planning

    DEFF Research Database (Denmark)

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

    2012-01-01

    The main challenge for many manufacturers is the increased complexity of the supply chain, and as supply chains get more complicated enterprises require better tools for supply chain planning and execution. Many vendors offer systems to plan and control in-house operations, whereas mainly large v...... discusses current supply chain planning solutions and presents a more simple and adaptive concept to be used in both SMEs and larger enterprises....

  20. Large-scale asymmetric synthesis of a cathepsin S inhibitor.

    Science.gov (United States)

    Lorenz, Jon C; Busacca, Carl A; Feng, XuWu; Grinberg, Nelu; Haddad, Nizar; Johnson, Joe; Kapadia, Suresh; Lee, Heewon; Saha, Anjan; Sarvestani, Max; Spinelli, Earl M; Varsolona, Rich; Wei, Xudong; Zeng, Xingzhong; Senanayake, Chris H

    2010-02-19

    A potent reversible inhibitor of the cysteine protease cathepsin-S was prepared on large scale using a convergent synthetic route, free of chromatography and cryogenics. Late-stage peptide coupling of a chiral urea acid fragment with a functionalized aminonitrile was employed to prepare the target, using 2-hydroxypyridine as a robust, nonexplosive replacement for HOBT. The two key intermediates were prepared using a modified Strecker reaction for the aminonitrile and a phosphonation-olefination-rhodium-catalyzed asymmetric hydrogenation sequence for the urea. A palladium-catalyzed vinyl transfer coupled with a Claisen reaction was used to produce the aldehyde required for the side chain. Key scale up issues, safety calorimetry, and optimization of all steps for multikilogram production are discussed. PMID:20102230

  1. SjAPI, the first functionally characterized Ascaris-type protease inhibitor from animal venoms.

    Directory of Open Access Journals (Sweden)

    Zongyun Chen

    Full Text Available BACKGROUND: Serine protease inhibitors act as modulators of serine proteases, playing important roles in protecting animal toxin peptides from degradation. However, all known serine protease inhibitors discovered thus far from animal venom belong to the Kunitz-type subfamily, and whether there are other novel types of protease inhibitors in animal venom remains unclear. PRINCIPAL FINDINGS: Here, by screening scorpion venom gland cDNA libraries, we identified the first Ascaris-type animal toxin family, which contains four members: Scorpiops jendeki Ascaris-type protease inhibitor (SjAPI, Scorpiops jendeki Ascaris-type protease inhibitor 2 (SjAPI-2, Chaerilus tricostatus Ascaris-type protease inhibitor (CtAPI, and Buthus martensii Ascaris-type protease inhibitor (BmAPI. The detailed characterization of Ascaris-type peptide SjAPI from the venom gland of scorpion Scorpiops jendeki was carried out. The mature peptide of SjAPI contains 64 residues and possesses a classical Ascaris-type cysteine framework reticulated by five disulfide bridges, different from all known protease inhibitors from venomous animals. Enzyme and inhibitor reaction kinetics experiments showed that recombinant SjAPI was a dual function peptide with α-chymotrypsin- and elastase-inhibiting properties. Recombinant SjAPI inhibited α-chymotrypsin with a Ki of 97.1 nM and elastase with a Ki of 3.7 μM, respectively. Bioinformatics analyses and chimera experiments indicated that SjAPI contained the unique short side chain functional residues "AAV" and might be a useful template to produce new serine protease inhibitors. CONCLUSIONS/SIGNIFICANCE: To our knowledge, SjAPI is the first functionally characterized animal toxin peptide with an Ascaris-type fold. The structural and functional diversity of animal toxins with protease-inhibiting properties suggested that bioactive peptides from animal venom glands might be a new source of protease inhibitors, which will accelerate the

  2. 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...

  3. Inhibitors of Acetylcholinesterase and Butyrylcholinesterase Meet Immunity

    OpenAIRE

    Miroslav Pohanka

    2014-01-01

    Acetylcholinesterase (AChE) inhibitors are widely used for the symptomatic treatment of Alzheimer’s disease and other dementias. More recent use is for myasthenia gravis. Many of these inhibitors interact with the second known cholinesterase, butyrylcholinesterase (BChE). Further, evidence shows that acetylcholine plays a role in suppression of cytokine release through a “cholinergic anti-inflammatory pathway” which raises questions about the role of these inhibitors in the immune system. Thi...

  4. Magnetic Properties of Quantum Ferrimagnetic Spin Chains

    OpenAIRE

    Yamamoto, Shoji

    1998-01-01

    Magnetic susceptibilities of spin-$(S,s)$ ferrimagnetic Heisenberg chains are numerically investigated. It is argued how the ferromagnetic and antiferromagnetic features of quantum ferrimagnets are exhibited as functions of $(S,s)$. Spin-$(S,s)$ ferrimagnetic chains behave like combinations of spin-$(S-s)$ ferromagnetic and spin-$(2s)$ antiferromagnetic chains provided $S=2s$.

  5. 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

  6. 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…

  7. 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.

  8. 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…

  9. 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

  10. 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

  11. 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 const...

  12. Extending the "Knowledge Advantage": Creating Learning Chains

    Science.gov (United States)

    Maqsood, Tayyab; Walker, Derek; Finegan, Andrew

    2007-01-01

    Purpose: The purpose of this paper is to develop a synergy between the approaches of knowledge management in a learning organisation and supply chain management so that learning chains can be created in order to unleash innovation and creativity by managing knowledge in supply chains. Design/methodology/approach: Through extensive literature…

  13. Semiflexible Chains at Surfaces: Worm-Like Chains and beyond

    Directory of Open Access Journals (Sweden)

    Jörg Baschnagel

    2016-08-01

    Full Text Available We give an extended review of recent numerical and analytical studies on semiflexible chains near surfaces undertaken at Institut Charles Sadron (sometimes in collaboration with a focus on static properties. The statistical physics of thin confined layers, strict two-dimensional (2D layers and adsorption layers (both at equilibrium with the dilute bath and from irreversible chemisorption are discussed for the well-known worm-like-chain (WLC model. There is mounting evidence that biofilaments (except stable d-DNA are not fully described by the WLC model. A number of augmented models, like the (super helical WLC model, the polymorphic model of microtubules (MT and a model with (strongly nonlinear flexural elasticity are presented, and some aspects of their surface behavior are analyzed. In many cases, we use approaches different from those in our previous work, give additional results and try to adopt a more general point of view with the hope to shed some light on this complex field.

  14. 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.

  15. Imatinib resistance: a review of alternative inhibitors in chronic myeloid leukemia

    Directory of Open Access Journals (Sweden)

    Roberta Bitencourt

    2011-12-01

    Full Text Available The development of point mutations in the BCR-ABL kinase domain is the main reason for imatinib resistance in chronic myeloid leukemia. Different detection methods are used in chronic myeloid leukemia monitoring, such as direct sequencing, denaturing high performance liquid chromatography and allele specific polymerase chain reaction. Mutation analysis has become mandatory during patient workup of chronic myeloid leukemia in order for the physician to choose the most suitable tyrosine kinase inhibitor. This article, a review of possible therapies used to overcome imatinib resistance, investigates the current position by searching the PubMed electronic database using the following keywords: imatinib, dasatinib, nilotinib, aurora kinase, SRC kinase, mutation, treatment, drugs and resistance. New tyrosine kinase inhibitors include BCR-ABL kinase selective inhibitors, dual ABL/SRC kinase inhibitors and aurora kinase inhibitors. Awareness of the spectrum of new drugs against mutations, in particular the T315I mutation, makes it possible to properly select the best therapy for each patient.

  16. 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

  17. 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.

  18. Compressibility of Nickel Nanoparticle Chain

    Institute of Scientific and Technical Information of China (English)

    LI Xiao-Dong; TANG Ling-Yun; LI Yan-Chun; LIU Jing

    2007-01-01

    We perform the high-pressure energy dispersive x-ray diffraction experiments of nickel nanoparticle chain using a synchrotron source under quasi-hydrostatic compression up to 44.7GPa. There is no phase transition over the pressure range. The bulk modulus Kg, the first pressure derivative of bulk modulus K'0 and the volume Vo are calculated from the pressure-volume data using the Birch-Murnaghan equation of state. A decrease of compressibility is observed, in agreement with the Hall-Petch effect.

  19. 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....

  20. 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.)

  1. 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.

  2. 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.

  3. Maintaining Power Relations in Supply Chain

    OpenAIRE

    Ibishukcu, Ozlem; Datar, Aniket

    2016-01-01

    Managing supply chain relations has evolved over a decade and many companies have given importance to regulate their relations in supply chain relations to stay competitive in the market. In this context of adjusting relations among supply chain members, central point of discussion is the role of power. Power can be a component that persuades one member of supply chain to do certain things that he/she wouldn’t agree on doing it voluntarily. The implication of that power among supply chain mem...

  4. 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......; type I fimbriae expression significantly reduced cellular chain formation, presumably by steric hindrance. Cellular chain formation did not appear to be specific to E coli K-12. Although many urinary tract infection (UTI) isolates were found to form rather homogeneous, flat biofilms, three isolates...

  5. 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.

  6. 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...

  7. Molecular recognition at the active site of subtilisin BPN': crystallographic studies using genetically engineered proteinaceous inhibitor SSI (Streptomyces subtilisin inhibitor).

    Science.gov (United States)

    Takeuchi, Y; Noguchi, S; Satow, Y; Kojima, S; Kumagai, I; Miura, K; Nakamura, K T; Mitsui, Y

    1991-06-01

    Unlike trypsin-like serine proteases having only one conspicuous binding pocket in the active site, subtilisin BPN' has two such pockets, the S1 and S4 pockets, which accommodate the P1 and P4 residues of ligands (after Schechter and Berger notation) respectively. Using computer graphics, the geometrical nature of the two pockets was carefully examined and strategies for site-directed mutagenesis studies were set up against a protein SSI (Streptomyces subtilisin inhibitor), which is a strong proteinaceous inhibitor (or a substrate analogue) of subtilisin BPN'. It was decided to convert the P1 residue, methionine 73, into lysine (M73K) with or without additional conversion of the P4 residue, methionine 70, into glycine (M70G). The crystal structures of the two complexes of subtilisin BPN', one with the single mutant SSI (M73K) and the other with the double mutant SSI (M73K, M70G) were solved showing that (i) small 'electrostatic induced-fit movement' occurs in the S1 pocket upon introducing the terminal plus charge of the lysine side chain, and (ii) large 'mechanical induced-fit movement' occurs in the S4 pocket upon reducing the size of the P4 side chain from methionine to glycine. In both (i) and (ii), the induced-fit movement occurred in a concerted fashion involving both the enzyme and 'substrate' amino acid residues. The term 'substrate-assisted stabilization' was coined to stress the cooperative nature of the induced-fit movements. PMID:1891457

  8. 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.

  9. 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....

  10. Two Cases of Heavy Chain MGUS.

    Science.gov (United States)

    Van Keer, Jan; Meijers, Björn; Delforge, Michel; Verhoef, Gregor; Poesen, Koen

    2016-01-01

    Heavy chain diseases are rare variants of B-cell lymphomas that produce one of three classes of immunoglobulin heavy chains, without corresponding light chains. We describe two patients with asymptomatic heavy chain monoclonal gammopathy. The first patient is a 51-year-old woman with alpha paraprotein on serum immunofixation. The second case is a 46-year-old woman with gamma paraprotein on urine immunofixation. Neither patient had corresponding monoclonal light chains. Workup for multiple myeloma and lymphoma was negative in both patients. These two cases illustrate that heavy chain monoclonal gammopathy can exist in the absence of clinically apparent malignancy. Only a few reports of "heavy chain MGUS" have been described before. In the absence of specialized guidelines, we suggest a similar follow-up as for MGUS, while taking into account the higher probability of progression to lymphoma than to myeloma. PMID:27213064

  11. Two Cases of Heavy Chain MGUS

    Directory of Open Access Journals (Sweden)

    Jan Van Keer

    2016-01-01

    Full Text Available Heavy chain diseases are rare variants of B-cell lymphomas that produce one of three classes of immunoglobulin heavy chains, without corresponding light chains. We describe two patients with asymptomatic heavy chain monoclonal gammopathy. The first patient is a 51-year-old woman with alpha paraprotein on serum immunofixation. The second case is a 46-year-old woman with gamma paraprotein on urine immunofixation. Neither patient had corresponding monoclonal light chains. Workup for multiple myeloma and lymphoma was negative in both patients. These two cases illustrate that heavy chain monoclonal gammopathy can exist in the absence of clinically apparent malignancy. Only a few reports of “heavy chain MGUS” have been described before. In the absence of specialized guidelines, we suggest a similar follow-up as for MGUS, while taking into account the higher probability of progression to lymphoma than to myeloma.

  12. 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.

  13. 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.

  14. PV supply chain growing pains

    International Nuclear Information System (INIS)

    This article discussed issues involving the supply chain for photovoltaic (PV) equipment that is emerging in Ontario as a result of the Feed-in-Tariff (FIT) program that was launched in late 2009. The rapidly developing PV supply chain may not be taking a sustainable path. The domestic-content requirement is making manufacturers outlay capital to set up manufacturing in Ontario without reliable market data. Only a small number of dealer/installers have any meaningful experience designing and installing grid-tie PV. Until recently, wholesale distributors designed and supplied most grid-tie PV systems in Canada, and solar dealers/installers or electricians or electrical contractors did the installation. Instead of selling directly to dealer/installers, solar manufacturers should develop strong relationships with wholesalers, who have system design experience and product training. This would allow manufacturers to focus on their core strength, reach more customers, and keep lower inventory levels. Wholesale distributors in turn provide dealer/installers with expertise in product and system design, training from a range of manufacturers, marketing and logistics support, and immediate access to inventory. Manufacturers generally lack appropriate accounting, engineering, marketing, and logistics services to deal with a multitude of active accounts, and they are not structured to work with architects and engineers to do complete system design. Partnering with wholesale distributors allows manufacturers to take on the residential and small-scale commercial sectors by building brand awareness and increasing market share and sales across Canada. 2 figs.

  15. Artificial radioisotopes in food chains

    International Nuclear Information System (INIS)

    Use of uranium for nuclear fission involves the risk of environmental contamination by radiation during the processes of mining, concentration, peaceful and military application and storage, reprocessing and waste disposal. Three of the most dangerous radioisotopes have been followed here as they move through four different food chains. The main bottlenecks for fast and massive transfer are for 131I its rather short half life, for 137Cs the defective plant uptake from soil (and much less so also the pathway through the animal body), and for 90Sr its discrimination relative to calcium in several transport processes in the animal body, and its preference for the bone mass. Hence it is often of advantage for man to use animals as an additional food chain. Known exceptions are discussed: the reindeer and karibou living entirely on lichens during the winter and thereby acquiring for 137Cs nearly identical specific activity as plant food, and cow's milk for iodine during a short period after contamination. 15 refs.; 1 figure; 4 tabs

  16. Advances in Inhibitors of FXa.

    Science.gov (United States)

    Guo, Liwei; Ma, Shutao

    2015-01-01

    Thromboembolic diseases such as deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI) and ischemic strokes are mainly responsible for people's morbidity and mortality and have severely affected the people's quality of life all over the world. According to WHO statistics, an average of 17 million people are killed by the thromboembolic diseases each year globally. Therefore, the prevention and treatment of thromboembolic diseases have received widespread attention in recent years. Based on thrombotic mechanism, anti-thrombotic drugs are mainly divided into anticoagulants, antiplatelet agents and direct thrombolytic drugs. In particular, anticoagulants such as vitamin K antagonists (VKAs), unfractionated heparin (UFH), and low-molecular-weight heparins (LMWHs) have become the main therapies for pre-treatment of thromboembolic disorders. However, the limitations of traditional anticoagulants such as slow onset of action, dose-adjusted requirement, drug-drug and drug-food interactions have restricted their improvement in the clinical treatment. The mechanism of the thromboembolic disorders has indicated that coagulation factor Xa (fXa) plays a pivotal role in the blood coagulation cascade. Thus, selective inhibition of fXa by diminishing the amplified generation of thrombin without affecting the pre-existing thrombin levels can provide better antithrombotic effect, thereby causing less impairment of primary hemostasis. In this paper, we mainly introduce the recent advances of fXa inhibitors, with focus on their biological activity and structure-activity relationship (SAR) information. In particular, the inspirations from the structures of the fXa inhibitors and their future direction are highlighted. PMID:25981610

  17. High-Throughput Screening Uncovers Novel Botulinum Neurotoxin Inhibitor Chemotypes.

    Science.gov (United States)

    Bompiani, Kristin M; Caglič, Dejan; Krutein, Michelle C; Benoni, Galit; Hrones, Morgan; Lairson, Luke L; Bian, Haiyan; Smith, Garry R; Dickerson, Tobin J

    2016-08-01

    Botulism is caused by potent and specific bacterial neurotoxins that infect host neurons and block neurotransmitter release. Treatment for botulism is limited to administration of an antitoxin within a short time window, before the toxin enters neurons. Alternatively, current botulism drug development targets the toxin light chain, which is a zinc-dependent metalloprotease that is delivered into neurons and mediates long-term pathology. Several groups have identified inhibitory small molecules, peptides, or aptamers, although no molecule has advanced to the clinic due to a lack of efficacy in advanced models. Here we used a homogeneous high-throughput enzyme assay to screen three libraries of drug-like small molecules for new chemotypes that modulate recombinant botulinum neurotoxin light chain activity. High-throughput screening of 97088 compounds identified numerous small molecules that activate or inhibit metalloprotease activity. We describe four major classes of inhibitory compounds identified, detail their structure-activity relationships, and assess their relative inhibitory potency. A previously unreported chemotype in any context of enzyme inhibition is described with potent submicromolar inhibition (Ki = 200-300 nM). Additional detailed kinetic analyses and cellular cytotoxicity assays indicate the best compound from this series is a competitive inhibitor with cytotoxicity values around 4-5 μM. Given the potency and drug-like character of these lead compounds, further studies, including cellular activity assays and DMPK analysis, are justified. PMID:27314875

  18. DNA methyltransferase inhibitor CDA-II inhibits myogenic differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Zirong [State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060 (China); Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, Gainesville, FL 32610 (United States); Jin, Guorong [State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060 (China); Lin, Shuibin [Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, Gainesville, FL 32610 (United States); Lin, Xiumei [Department of Hematology, Guangzhou First Municipal People' s Hospital, Guangzhou 510180 (China); Gu, Yumei [Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, Gainesville, FL 32610 (United States); Zhu, Yujuan; Hu, Chengbin; Zhang, Qingjiong [State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060 (China); Wu, Lizi [Department of Molecular Genetics and Microbiology, Shands Cancer Center, University of Florida, Gainesville, FL 32610 (United States); Shen, Huangxuan, E-mail: shenhx@mail.sysu.edu.cn [State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou 510060 (China)

    2012-06-08

    Highlights: Black-Right-Pointing-Pointer CDA-II inhibits myogenic differentiation in a dose-dependent manner. Black-Right-Pointing-Pointer CDA-II repressed expression of muscle transcription factors and structural proteins. Black-Right-Pointing-Pointer CDA-II inhibited proliferation and migration of C2C12 myoblasts. -- Abstract: CDA-II (cell differentiation agent II), isolated from healthy human urine, is a DNA methyltransferase inhibitor. Previous studies indicated that CDA-II played important roles in the regulation of cell growth and certain differentiation processes. However, it has not been determined whether CDA-II affects skeletal myogenesis. In this study, we investigated effects of CDA-II treatment on skeletal muscle progenitor cell differentiation, migration and proliferation. We found that CDA-II blocked differentiation of murine myoblasts C2C12 in a dose-dependent manner. CDA-II repressed expression of muscle transcription factors, such as Myogenin and Mef2c, and structural proteins, such as myosin heavy chain (Myh3), light chain (Mylpf) and MCK. Moreover, CDA-II inhibited C1C12 cell migration and proliferation. Thus, our data provide the first evidence that CDA-II inhibits growth and differentiation of muscle progenitor cells, suggesting that the use of CDA-II might affect skeletal muscle functions.

  19. Angiotensin converting enzyme inhibitor induced hyperkalaemic paralysis

    OpenAIRE

    Dutta., D; Fischler, M; McClung, A

    2001-01-01

    Secondary hyperkalaemic paralysis is a rare condition often mimicking the Guillain-Barré syndrome. There have been a few case reports of hyperkalaemia caused by renal failure, trauma, and drugs where the presentation has been with muscle weakness. A case of hyperkalaemic paralysis caused by an angiotensin converting enzyme inhibitor is reported.


Keywords: hyperkalaemia; paralysis; ACE inhibitors

  20. [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

  1. Does plasminogen activator inhibitor-1 drive lymphangiogenesis?

    DEFF Research Database (Denmark)

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

    2010-01-01

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

  2. 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.

  3. Intellectual property issues of immune checkpoint inhibitors.

    Science.gov (United States)

    Storz, Ulrich

    2016-01-01

    Immune checkpoint inhibitors are drugs that interfere with tumor escape responses. Some members of this class are already approved, and expected to be blockbusters in the future. Many companies have developed patent activities in this field. This article focuses on the patent landscape, and discusses key players and cases related to immune checkpoint inhibitors. PMID:26466763

  4. Screening for potential inhibitors of influenza neuraminidase

    Institute of Scientific and Technical Information of China (English)

    Ai-linLIU; Guan-huaDU

    2004-01-01

    AIM: Applying the assay method of neuraminidase(NA) activity established for high throughput screening to find novel inhibitors of influenza virus NA. METHODS: Firstly, a virtual screening strategy was applied to our compound database to select drug-like compounds, and then a high throughput screening model of NA inhibitor was applied to test these compounds. RESULTS:

  5. Allosteric small-molecule kinase inhibitors

    DEFF Research Database (Denmark)

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

    2015-01-01

    -molecule allosteric inhibitor trametinib in 2013, the progress of more than 10 other allosteric inhibitors in clinical trials, and the emergence of a pipeline of highly selective and potent preclinical molecules, have been reported in the past decade. In this article, we present the current knowledge on allosteric...

  6. 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...

  7. 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

  8. Discovery of SCH 900229, a Potent Presenilin 1 Selective γ-Secretase Inhibitor for the Treatment of Alzheimer's Disease.

    Science.gov (United States)

    Wu, Wen-Lian; Domalski, Martin; Burnett, Duane A; Josien, Hubert; Bara, Thomas; Rajagopalan, Murali; Xu, Ruo; Clader, John; Greenlee, William J; Brunskill, Andrew; Hyde, Lynn A; Del Vecchio, Robert A; Cohen-Williams, Mary E; Song, Lixin; Lee, Julie; Terracina, Giuseppe; Zhang, Qi; Nomeir, Amin; Parker, Eric M; Zhang, Lili

    2012-11-01

    An exploration of the SAR of the side chain of a novel tricyclic series of γ-secretase inhibitors led to the identification of compound (-)-16 (SCH 900229), which is a potent and PS1 selective inhibitor of γ-secretase (Aβ40 IC50 = 1.3 nM). Compound (-)-16 demonstrated excellent lowering of Aβ after oral administration in preclinical animal models and was advanced to human clinical trials for further development as a therapeutic agent for the treatment of Alzheimer's disease. PMID:24900404

  9. Mutational analysis of target enzyme recognition of the beta-trefoil fold barley alpha-amylase/subtilisin inhibitor

    DEFF Research Database (Denmark)

    Bønsager, Birgit Christine; Nielsen, Per K.; Abou Hachem, Maher;

    2005-01-01

    The barley alpha-amylase/subtilisin inhibitor ( BASI) inhibits alpha-amylase 2 (AMY2) with subnanomolar affinity. The contribution of selected side chains of BASI to this high affinity is discerned in this study, and binding to other targets is investigated. Seven BASI residues along the AMY2-BASI...... interface and four residues in the putative protease-binding loop on the opposite side of the inhibitor were mutated. A total of 15 variants were compared with the wild type by monitoring the alpha-amylase and protease inhibitory activities using Blue Starch and azoalbumin, respectively, and the kinetics of...

  10. [Recent development of selective cyclooxygenase-2 inhibitors].

    Science.gov (United States)

    Kawai, Shinichi

    2002-12-01

    Nonsteroidal anti-inflammatory drugs(NSAIDs) are clinically effective against the inflammatory symptoms of rheumatoid arthritis. Recent attention has been focused on selective cyclooxygenase(COX)-2 inhibitors, a type of NSAID that inhibits a subtype of COX. Because of the different actions of COX-1 and COX-2, selective COX-2 inhibitors were expected to reduce adverse reactions such as gastrointestinal disorders. Various clinical studies have confirmed that the efficacy of COX-2 inhibitors for RA is similar to that of conventional NSAIDs, but they cause fewer severe gastrointestinal disorders. The incidence of complications related to renal dysfunction, such as edema and hypertension, is not different. Patients using selective COX-2 inhibitors have recently been reported to show an increase in thrombotic complications such as myocardial infarction. Therefore, more data on adverse events should be collected in the future from large-scale clinical studies to further clarify the actual value of selective COX-2 inhibitors. PMID:12510364

  11. Genes Involved in Formation and Attachment of a Two-Carbon Chain as a Component of Eurekanate, a Branched-Chain Sugar Moiety of Avilamycin A

    OpenAIRE

    Treede, Irina; Hauser, Gerd; Mühlenweg, Agnes; Hofmann, Carsten; Schmidt, Maraike; Weitnauer, Gabriele; Glaser, Steffen; Bechthold, Andreas

    2005-01-01

    Eurekanate belongs to the important class of branched-chain carbohydrates present in a wide variety of natural sources. It is a component of avilamycin A, a potent inhibitor of bacterial protein synthesis targeting the 50S ribosomal subunit. The present work provides experimental proof for the function of two genes of the avilamycin biosynthetic gene cluster, aviB1 and aviO2, that are both involved in avilamycin structure modification. The functions of both genes were identified by gene inact...

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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,...

  18. THE SPATIAL DISTRIBUTION AND MOMENTS OF CIRCULAR FREELY JOINTED CHAIN

    Institute of Scientific and Technical Information of China (English)

    HAO Minghong

    1991-01-01

    The spatial distribution function and second moments of circular freely jointed chain are derived based on an analytical method. The circular Gauss chain, which is simple for long chains, is compared with the circular freely jointed chain, which is exact for short chains. It is shown that the Gauss chain model predicts a more compact configurational distribution than the exact freely jointed chain. The two chain models, however, become closer to each other when the chain length increases.It is found that the difference of the mean square radius of gyration calculated with these two chain models is a constant, independent of the chain length.

  19. 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.)

  20. 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

  1. Toc Approach for Supply Chain Performance Enhancement

    Directory of Open Access Journals (Sweden)

    Brijesh Ainapur

    2011-12-01

    Full Text Available Field of Supply Chain Management witnessed rapid growth in recent past and proved to be a successful tool for organizations growth. Success of supply chain improvement initiative lies in selection of appropriate Key Performance Indicators (KPIs using best suitable supply chain framework. These KPI’s are to be measured, monitored and controlled with proper review mechanism. This study presents a methodology for identification of the constraint KPI from the supply chain metrics. Selection of the KPI’s is done using Supply Chain Operations Reference (SCOR framework. Analytical Hierarchy Process (AHP is used for decomposing the goal into micro level for analyzing and prioritizing KPIs. Subsequently, benchmarking study is carried by comparing foundry industry KPIs with global best practice industry average. Goal Programming function is formulated using AHP ratings and solved using WINQSB software. Finally Theory of Constraint (TOC management philosophy is applied for finding the constraints for supply chain performance enhancement.

  2. Position Paper on Intelligent Supply Chains

    DEFF Research Database (Denmark)

    Møller, Charles

    This paper is intended to present and to analyze the concept of the Intelligent Supply Chain (ISC). The purpose of the paper is to: 1) Clarify the concept of the intelligent supply chain; 2) Identify emerging research opportunities; and 3) Specify a research engagement model for further exploration...... 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...

  3. The story of a unique molecule in hemophilia A: recombinant single-chain factor VIII.

    Science.gov (United States)

    Pabinger-Fasching, Ingrid

    2016-05-01

    For patients with hemophilia A, replacement of deficient factor VIII (FVIII) using plasma-derived or recombinant FVIII (rFVIII) products to restore hemostatic control can reduce bleeding complications and preserve musculoskeletal function. Despite the clinical availability of several of these products, challenges remain in the treatment of hemophilia A, the most notable of which are the risk of inhibitor development and the limited half-life of existing FVIII concentrates, which can make prophylaxis burdensome for patients. The use of recombinant protein technology may lead to novel FVIII products with improved properties. This article describes the story of a unique recombinant FVIII protein, rVIII-SingleChain, which is currently in development. In contrast to native FVIII and other commercially available rFVIII preparations, rVIII-SingleChain uses a strong, covalent bond to connect the light and heavy chains, thereby creating a stable, single-chain rFVIII. It has enhanced intrinsic stability, better integrity after reconstitution, and a higher binding affinity to von Willebrand factor. The physicochemical profile of rVIII-SingleChain and preclinical data on its activity and phamacokinetics strengthened the rationale for its clinical investigation. Available data from the AFFINITY clinical trial program are promising; indicating that it has good hemostatic efficacy when used on demand, for prophylaxis, and in the surgical setting, and is also very well tolerated. A pediatric study and an extension study are ongoing as part of the AFFINITY program. PMID:27288063

  4. 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.

  5. The story of a unique molecule in hemophilia A: recombinant single-chain factor VIII.

    Science.gov (United States)

    Pabinger-Fasching, Ingrid

    2016-05-01

    For patients with hemophilia A, replacement of deficient factor VIII (FVIII) using plasma-derived or recombinant FVIII (rFVIII) products to restore hemostatic control can reduce bleeding complications and preserve musculoskeletal function. Despite the clinical availability of several of these products, challenges remain in the treatment of hemophilia A, the most notable of which are the risk of inhibitor development and the limited half-life of existing FVIII concentrates, which can make prophylaxis burdensome for patients. The use of recombinant protein technology may lead to novel FVIII products with improved properties. This article describes the story of a unique recombinant FVIII protein, rVIII-SingleChain, which is currently in development. In contrast to native FVIII and other commercially available rFVIII preparations, rVIII-SingleChain uses a strong, covalent bond to connect the light and heavy chains, thereby creating a stable, single-chain rFVIII. It has enhanced intrinsic stability, better integrity after reconstitution, and a higher binding affinity to von Willebrand factor. The physicochemical profile of rVIII-SingleChain and preclinical data on its activity and phamacokinetics strengthened the rationale for its clinical investigation. Available data from the AFFINITY clinical trial program are promising; indicating that it has good hemostatic efficacy when used on demand, for prophylaxis, and in the surgical setting, and is also very well tolerated. A pediatric study and an extension study are ongoing as part of the AFFINITY program.

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

    DEFF Research Database (Denmark)

    Møller, Charles

    2006-01-01

    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...... 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...

  7. The Evolutionary Dynamics of Biofuel Value Chains

    DEFF Research Database (Denmark)

    Ponte, Stefano

    2014-01-01

    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....

  8. Antecedents and Dimensions of Supply Chain Robustness

    OpenAIRE

    Durach, Christian F.; Wieland, Andreas; Machuca, Jose A.D.

    2015-01-01

    Purpose – The purpose of this paper is to provide groundwork for an emerging theory of supply chain robustness – which has been conceptualized as a dimension of supply chain resilience – through reviewing and synthesizing related yet disconnected studies. The paper develops a formal definition of supply chain robustness to build a framework that captures the dimensions, antecedents and moderators of the construct as discussed in the literature. Design/methodology/approach – The...

  9. Challenges of Responsible Supply Chain Management

    OpenAIRE

    Krisztina Szegedi; Károly Norbert Kerekes

    2012-01-01

    Many firms are increasing their focus on their Supply Chain as a strategic factor. This focus has primarily emphasized cost reducing and risk minimizing, although some proactive companies began to manage their supply chain in a responsible way several years ago. This paper provides a comprehensive review of the part of the Corporate Social Responsibility literature that introduces responsibility to the field of supply chain management; furthermore, it processes public documents and Internet s...

  10. Sustainability management in apparel & footwear supply chain

    OpenAIRE

    Cheng, Hau-chung; 鄭孝仲

    2014-01-01

    Self-regulatory Code of Conduct has widely been adopted by international brands to manage CSR issues in apparel and footwear supply chain for the last 2 decades. Increasingly, more apparel and footwear brands started to expand CSR scope to include environmental management in their supply chain. However, only very few international brands have disclosed their efforts on environmental management in their supply chain. This study aims to find out how apparel and footwear brands implement environ...

  11. Sustainability in Logistics and Supply Chain Management

    OpenAIRE

    2015-01-01

    The HICL-Conference celebrates its 10th anniversary, indicating major interest in the research fields of supply chain management and logistics. They are dedicated to make recommendations for new approaches and solutions that enable companies to cope with current and future challenges in supply chains and logistics. The second volume of the 2015 conference provides valuable insights into the highly relevant topic of sustainability in logistics and supply chains. Contributions concern ...

  12. Technical Aspects of Cyber Kill Chain

    OpenAIRE

    Yadav, Tarun; Mallari, Rao Arvind

    2016-01-01

    Recent trends in targeted cyber-attacks has increased the interest of research in the field of cyber security. Such attacks have massive disruptive effects on rganizations, enterprises and governments. Cyber kill chain is a model to describe cyber-attacks so as to develop incident response and analysis capabilities. Cyber kill chain in simple terms is an attack chain, the path that an intruder takes to penetrate information systems over time to execute an attack on the target. This paper broa...

  13. BEHAVIOURAL INSIGHTS INTO SUPPLY CHAIN RISK MANAGEMENT

    OpenAIRE

    Alexandra-Codruta Popescu (Bîzoi); Cristian-Gabriel Bîzoi

    2015-01-01

    Literature has focused largely on the field of supply chain risk management. Numerous risks occur within supply chain management. Until lately, behavioural risks (implying large amount of losses) have been neglected and considered not relevant. In this paper we provide an analysis of the importance of including behavioural research in logistics and supply chain risk management, what has been written so far and potential future research directions. Until now, literature on logistics and supply...

  14. Spectral methods for quantum Markov chains

    International Nuclear Information System (INIS)

    The aim of this project is to contribute to our understanding of quantum time evolutions, whereby we focus on quantum Markov chains. The latter constitute a natural generalization of the ubiquitous concept of a classical Markov chain to describe evolutions of quantum mechanical systems. We contribute to the theory of such processes by introducing novel methods that allow us to relate the eigenvalue spectrum of the transition map to convergence as well as stability properties of the Markov chain.

  15. Wear of conveyor chains with polymer rolls

    OpenAIRE

    Kerremans, Vincent; Rolly, Tom; DE BAETS, PATRICK; De Pauw, Jan; Sukumaran, Jacob; Perez Delgado, Yeczain

    2011-01-01

    Roller conveyor chains are common used to transport goods in production lines or assembly lines, such as pallets, cars or steel coils. They are sometimes used in severe environments, soiled with water, foreign particles, chemicals or other contaminants. Normal use will result in wear of the components of the chain which can lead to unexpected failure and costly production downtime. Today, few literature on the wear of conveyor chain is available and there are almost no reliable test-rigs to g...

  16. Ground states for nonuniform periodic Ising chains

    OpenAIRE

    Martínez-Garcilazo, J. P.; Ramírez, C.

    2014-01-01

    We give a generalization of Morita's works on ground states of Ising chains, for chains with a periodic structure with different spins, and distant neighbor interactions. The main assumption is translational invariance. The length of the irreducible blocks is a multiple of the period of the chain. In the case of parity invariance, it restricts the length in general only in the diatomic case. There are degenerated states and under certain circumstances there could be nonregular ground states. ...

  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. 1D ferrimagnetism in homometallic chains

    OpenAIRE

    Coronado Miralles, Eugenio; Gómez García, Carlos José; Borrás Almenar, Juan José

    1990-01-01

    The magnetic properties of the cobalt zigzag chain Co(bpy)(NCS)2 (bpy=2,2′‐bipyridine) are discussed on the basis of an Ising‐chain model that takes into account alternating Landé factors. It is emphasized, for the first time, that a homometallic chain containing only one type of site can give rise to a 1D ferrimagneticlike behavior. ,

  19. Achieving Supply Chain Integration within Construction Industry

    OpenAIRE

    Peter McDermotti; Malik Khalfan

    2012-01-01

    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 respo...

  20. Supply chain management tools and methods

    OpenAIRE

    IVANOVA, Ivelina

    2004-01-01

    In today's business environment, manufacturers need to manage their enterprises as an inseparable part of a supply chain. Key to achieving this is the creation of an extended and integrated information system. In an attempt to find out what needs to be done to improve current supply chain methods and tools, the current research project 1) reviewed the literature to establish current approaches to Supply Chain Management (SCM); 2) identified what tools and methods are availab...

  1. Supply chain management: An opportunity for metaheuristics

    OpenAIRE

    Ramalhinho-Louren??o, Helena

    2001-01-01

    In today?s highly competitive and global marketplace the pressure on organizations to find new ways to create and deliver value to customers grows ever stronger. In the last two decades, logistics and supply chain has moved to the center stage. There has been a growing recognition that it is through an effective management of the logistics function and the supply chain that the goal of cost reduction and service enhancement can be achieved. The key to success in Supply Chain...

  2. Sustaining Supply Chain Operations through Lean Manufacturing

    OpenAIRE

    Suphattra Ketsarapong; Kong Suwantaranrangsri; Kongkiti Phusavat; Binshan Lin

    2012-01-01

    Purpose – The study aims to report a case study in a Thai Electronics Manufacturing deploying a lean manufacturing approach, and to discuss the value gained in their supply chain operations. These experiences can be adapted by others for design, redesign, and problem shooting when analyzing the performance of supply chain operations. Approach – The paper is based on actual activities in a case study. This paper begins by reviewing the relevant literature on supply chain operations and supply ...

  3. 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...... and heterogeneous group of products to manage. The value of the paper lies in its pointing out detailed solutions to how in real-life supply chains data can be used efficiently to improve the performance of the supply chain....

  4. Stochastically Perturbed Chains of Variable Memory

    OpenAIRE

    Garcia, Nancy L.; Moreira, Lucas

    2013-01-01

    In this paper, we study inference for chains of variable order under two distinct contamination regimes. Consider we have a chain of variable memory on a finite alphabet containing zero. At each instant of time an independent coin is flipped and if it turns head a contamination occurs. In the first regime a zero is read independent of the value of the chain. In the second regime, the value of another chain of variable memory is observed instead of the original one. Our results state that the ...

  5. 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

  6. Toc Approach for Supply Chain Performance Enhancement

    Directory of Open Access Journals (Sweden)

    Brijesh Ainapur

    2011-12-01

    Full Text Available 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 organizations growth. Success of supply chain improvement initiative lies in selection ofappropriate Key Performance Indicators (KPIs using best suitable supply chain framework. Theseperformance indicators are to be measured, monitored and controlled with proper review mechanism.This study presents a methodology for identification of the KPI’s from the supply chain metrics suitablefor foundries. Selection of the KPI’s is done using Supply Chain Operations Reference (SCORframework. Analytical Hierarchy Process (AHP is used for decomposing the goal into micro level foranalyzing and prioritizing KPIs. In order to study the gap between as-is-state and as-to-be state,benchmarking is carried by comparing foundry industry KPIs with global best practice industry average.To optimize the supply chain performance, Goal Programming function is formulated using AHP ratingsand solved using WINQSB software. Theory of Constraint (TOC management philosophy is applied forfinding the constraints, on improving these constraints supply chain performance enhancement isachieved.

  7. 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.

  8. 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.

  9. Molecular Docking of Aromatase Inhibitors

    Directory of Open Access Journals (Sweden)

    Virapong Prachayasittikul

    2011-04-01

    Full Text Available Aromatase is an enzyme that plays a critical role in the development of estrogen receptor positive breast cancer. As aromatase catalyzes the aromatization of androstenedione to estrone, a naturally occurring estrogen, it is a promising drug target for therapeutic management. The undesirable effects found in aromatase inhibitors (AIs that are in clinical use necessitate the discovery of novel AIs with higher selectivity, less toxicity and improving potency. In this study, we elucidate the binding mode of all three generations of AI drugs to the crystal structure of aromatase by means of molecular docking. It was demonstrated that the docking protocol could reliably reproduce the interaction of aromatase with its substrate with an RMSD of 1.350 Å. The docking study revealed that polar (D309, T310, S478 and M374, aromatic (F134, F221 and W224 and non-polar (A306, A307, V370, L372 and L477 residues were important for interacting with the AIs. The insights gained from the study herein have great potential for the design of novel AIs.

  10. 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.

  11. VEGF Inhibitors for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Prakash S. Sukhramani

    2010-01-01

    Full Text Available Despite significant advances in systemic therapies, radiation oncology, and surgical techniques, many patients with cancer are still incurable. A novel therapeutic approach has been to target the vascular endothelial growth factors (VEGFs which are often mutated and/or over-expressed in many tumors. The ligands and receptors of VEGF family are well established as key regulators of angiogenesis and vasculogenesis processes. VEGF is a homodimeric, basic, 45 kDa glycoprotein specific for vascular endothelial cells. Specifically, VEGF participates in regulation of the female reproductive cycle, wound healing, inflammation, vascular permeability, vascular tone, hematopoiesis and also contributes to pathological angiogenesis disorders such as cancer, rheumatoid arthritis, diabetic retinopathy and the neovascular form of macular degeneration. Thus, the role of VEGF has been extensively studied in the pathogenesis and angiogenesis of human cancers. Clinical trials have anti-VEGF therapies are effective in reducing tumor size, metastasis and blood vessel formation. Clinically, this may result in increased progression free survival, overall patient survival rate and will expand the potential for combinatorial therapies. The aim of present review is on the cellular responses of VEGF inhibitors and their implications for cancer therapy.

  12. 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.  ……

  13. 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.

  14. Crystal structure of the E2 transactivation domain of human papillomavirus type 11 bound to a protein interaction inhibitor.

    Science.gov (United States)

    Wang, Yong; Coulombe, René; Cameron, Dale R; Thauvette, Louise; Massariol, Marie-Josée; Amon, Lynn M; Fink, Dominique; Titolo, Steve; Welchner, Ewald; Yoakim, Christiane; Archambault, Jacques; White, Peter W

    2004-02-20

    Interaction between the E2 protein and E1 helicase of human papillomaviruses (HPVs) is essential for the initiation of viral DNA replication. We recently described a series of small molecules that bind to the N-terminal transactivation domain (TAD) of HPV type 11 E2 and inhibits its interaction with E1 in vitro and in cellular assays. Here we report the crystal structures of both the HPV11 TAD and of a complex between this domain and an inhibitor, at 2.5- and 2.4-A resolution, respectively. The HPV11 TAD structure is very similar to that of the analogous domain of HPV16. Inhibitor binding caused no significant alteration of the protein backbone, but movements of several amino acid side chains at the binding site, in particular those of Tyr-19, His-32, Leu-94, and Glu-100, resulted in the formation of a deep hydrophobic pocket that accommodates the indandione moiety of the inhibitor. Mutational analysis provides functional evidence for specific interactions between Tyr-19 and E1 and between His-32 and the inhibitor. A second inhibitor molecule is also present at the binding pocket. Although evidence is presented that this second molecule makes only weak interactions with the protein and is likely an artifact of crystallization, its presence defines additional regions of the binding pocket that could be exploited to design more potent inhibitors. PMID:14634007

  15. 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.

  16. Purification and characterization of a trypsin inhibitor from the seeds of Artocarpus heterophyllus Lam.

    Science.gov (United States)

    Lyu, Junchen; Liu, Yuan; An, Tianchen; Liu, Yujun; Wang, Manchuriga; Song, Yanting; Zheng, Feifei; Wu, Dan; Zhang, Yingxia; Deng, Shiming

    2015-05-01

    A proteinaceous inhibitor against trypsin was isolated from the seeds of Artocarpus heterophyllus Lam. by successive ammonium sulfate precipitation, ion-exchange, and gel-filtration chromatography. The trypsin inhibitor, named as AHLTI (A. heterophyllus Lam. trypsin inhibitor), consisted of a single polypeptide chain with a molecular weight of 28.5 kDa, which was confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and gel-filtration chromatography. The N-terminal sequence of AHLTI was DEPPSELDAS, which showed no similarity to other known trypsin inhibitor sequence. AHLTI completely inhibited bovine trypsin at a molar ratio of 1:2 (AHLTI:trypsin) analyzed by native polyacrylamide gel electrophoresis, inhibition activity assay, and gel-filtration chromatography. Moreover, kinetic enzymatic studies were carried out to understand the inhibition mechanism of AHLTI against trypsin. Results showed that AHLTI was a competitive inhibitor with an equilibrium dissociation constant (Ki) of 3.7 × 10(-8) M. However, AHLTI showed weak inhibitory activity toward chymotrypsin and elastase. AHLTI was stable over a broad range of pH 4-8 and temperature 20-80°C. The reduction agent, dithiothreitol, had no obvious effect on AHLTI. The trypsin inhibition assays of AHLTI toward digestive enzymes from insect pest guts in vitro demonstrated that AHLTI was effective against enzymes from Locusta migratoria manilensis (Meyen). These results suggested that AHLTI might be a novel trypsin inhibitor from A. heterophyllus Lam. belonging to Kunitz family, and play an important role in protecting from insect pest. PMID:25851516

  17. 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.

  18. 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 ...

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

    DEFF Research Database (Denmark)

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

    1997-01-01

    proteases. We studied the influence of chemical anti-inhibitors (chloramine T, flufenamate, sodium lauryl sulfate, and methylamine) on fibrinolytic serine proteases and fibrinolytic enzyme inhibitors using the physiological substrate fibrin as plasmin substrate. Low concentrations of chloramine T (0.01 mmol....../l) prevent the inhibition of plasminogen activators. Higher concentrations (1 mmol/l) reduce the inhibition of plasmin, but simultaneously quench the plasminogen activator activity. Flufenamate eliminates most fibrinolytic enzyme inhibitors, but increases the activity of plasmin (apparent recovery 140......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...

  20. Optimizing Supply Chain Performance in China with Country-Specific Supply Chain Coordination

    OpenAIRE

    Herczeg, András; Vastag, Gyula

    2012-01-01

    The implementation of country-specific supply chain coordination techniques ensures an optimal global supply chain performance. This paper looks at success factors going with a supply chain coordination strategy within the global supply chain of a successful, medium-sized, privately-owned company, one having locations in North America (USA), Europe (Hungary) and Asia (China). Through the shown GSL’s Chinese plant, we will endeavor to argue that increased collaboration in the supply network wi...

  1. A new framework for supply chain risk management through supply chain management capability

    OpenAIRE

    Göçer, Aysu; Yumurtacı, Işık Özge; Yurt, Öznur; Baltacıoğlu, Tunçdan

    2015-01-01

    Supply chain risk management is considered as one of the most powerful competitive tools for the companies. Therefore, the concept has caught the attention of researchers especially in the recent years. However, supply chain risk management has not been examined in the literature by considering the maturity and capability levels of supply chain members. This study aims to address this gap and develops a new framework on supply chain risk management which focuses on different...

  2. Inhibitors of alanine racemase enzyme: a review.

    Science.gov (United States)

    Azam, Mohammed Afzal; Jayaram, Unni

    2016-08-01

    Alanine racemase is a fold type III PLP-dependent amino acid racemase enzyme catalysing the conversion of l-alanine to d-alanine utilised by bacterial cell wall for peptidoglycan synthesis. As there are no known homologs in humans, it is considered as an excellent antibacterial drug target. The standard inhibitors of this enzyme include O-carbamyl-d-serine, d-cycloserine, chlorovinyl glycine, alaphosphin, etc. d-Cycloserine is indicated for pulmonary and extra pulmonary tuberculosis but therapeutic use of drug is limited due to its severe toxic effects. Toxic effects due to off-target affinities of cycloserine and other substrate analogs have prompted new research efforts to identify alanine racemase inhibitors that are not substrate analogs. In this review, an updated status of known inhibitors of alanine racemase enzyme has been provided which will serve as a rich source of structural information and will be helpful in generating selective and potent inhibitor of alanine racemase. PMID:26024289

  3. Kinase inhibitors for advanced medullary thyroid carcinoma

    Directory of Open Access Journals (Sweden)

    Martin Schlumberger

    2012-01-01

    Full Text Available The recent availability of molecular targeted therapies leads to a reconsideration of the treatment strategy for patients with distant metastases from medullary thyroid carcinoma. In patients with progressive disease, treatment with kinase inhibitors should be offered.

  4. Pharmacophore Identification of Hydroxamate HDAC 1 Inhibitors

    Institute of Scientific and Technical Information of China (English)

    YU,Liqin; LIU,Fei; CHEN,Yadong; YOU,Qidong

    2009-01-01

    A three-dimensional pharmacophore model was established based on 24 hydroxamate histone deacetylase(HDAC)inhibitors by HypoGen algorithm embedded in Catalyst software.The best pharmacophore hypothesis(Hypol),consisting of four chemical features(one hydrogen-bond acceptor,one aromatic ring and two hydrophobicgroups).has a correlation coefficient of 0.946.The Hypol Was also validated by a test set consisting of 20 othercompounds.Compared with the prior studies towards HDAC inhibitors the detailed chemical features of the"CAP"region in the reported HDAC inhibitors were for the first time depicted,which would be helpful in the further de-signing of novel HDAC inhibitors.

  5. Inhibitors of Acetylcholinesterase and Butyrylcholinesterase Meet Immunity

    Directory of Open Access Journals (Sweden)

    Miroslav Pohanka

    2014-06-01

    Full Text Available Acetylcholinesterase (AChE inhibitors are widely used for the symptomatic treatment of Alzheimer’s disease and other dementias. More recent use is for myasthenia gravis. Many of these inhibitors interact with the second known cholinesterase, butyrylcholinesterase (BChE. Further, evidence shows that acetylcholine plays a role in suppression of cytokine release through a “cholinergic anti-inflammatory pathway” which raises questions about the role of these inhibitors in the immune system. This review covers research and discussion of the role of the inhibitors in modulating the immune response using as examples the commonly available drugs, donepezil, galantamine, huperzine, neostigmine and pyridostigmine. Major attention is given to the cholinergic anti-inflammatory pathway, a well-described link between the central nervous system and terminal effector cells in the immune system.

  6. Inhibitors of acetylcholinesterase and butyrylcholinesterase meet immunity.

    Science.gov (United States)

    Pohanka, Miroslav

    2014-01-01

    Acetylcholinesterase (AChE) inhibitors are widely used for the symptomatic treatment of Alzheimer's disease and other dementias. More recent use is for myasthenia gravis. Many of these inhibitors interact with the second known cholinesterase, butyrylcholinesterase (BChE). Further, evidence shows that acetylcholine plays a role in suppression of cytokine release through a "cholinergic anti-inflammatory pathway" which raises questions about the role of these inhibitors in the immune system. This review covers research and discussion of the role of the inhibitors in modulating the immune response using as examples the commonly available drugs, donepezil, galantamine, huperzine, neostigmine and pyridostigmine. Major attention is given to the cholinergic anti-inflammatory pathway, a well-described link between the central nervous system and terminal effector cells in the immune system. PMID:24893223

  7. Progress and prospects on DENV protease inhibitors.

    Science.gov (United States)

    Timiri, Ajay Kumar; Sinha, Barij Nayan; Jayaprakash, Venkatesan

    2016-07-19

    New treatments are desperately required to combat increasing rate of dengue fever cases reported in tropical and sub-tropical parts of the world. Among the ten proteins (structural and non-structural) encoded by dengue viral genome, NS2B-NS3 protease is an ideal target for drug discovery. It is responsible for the processing of poly protein that is required for genome replication of the virus. Moreover, inhibitors designed against proteases were found successful in Human Immuno-deficiency Virus (HIV) and Hepatitis C Virus (HCV). Complete molecular mechanism and a survey of inhibitors reported against dengue protease will be helpful in designing effective and potent inhibitors. This review provides an insight on molecular mechanism of dengue virus protease and covers up-to-date information on different inhibitors reported against dengue proteases with medicinal chemistry perspective. PMID:27092412

  8. 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.

  9. 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. PMID:26848511

  10. 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.

  11. 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.

  12. Relationships between structure and interaction kinetics for HIV-1 protease inhibitors.

    Science.gov (United States)

    Markgren, Per-Olof; Schaal, Wesley; Hämäläinen, Markku; Karlén, Anders; Hallberg, Anders; Samuelsson, Bertil; Danielson, U Helena

    2002-12-01

    The interaction between HIV-1 protease and 58 structurally diverse transition-state analogue inhibitors has been analyzed by a surface plasmon resonance based biosensor. Association and dissociation rate constants and affinities were determined and displayed as k(on)-k(off)-K(D) maps. It was shown that different classes of inhibitors fall into distinct clusters in these maps. Significant changes in association and dissociation rates were found as a result of modifying the P1/P1' or P2/P2' side chains of a linear lead compound. Similarly, cyclic urea and cyclic sulfamide inhibitors displayed different kinetic features and the affinities of both classes of cyclic compounds were limited by fast dissociation rates. These results confirm that association and dissociation rates are important features of drug-target interactions and indicate that optimization of inhibitor efficacy may be guided by aiming for high association and low dissociation rates rather than high affinity alone. The present approach thus provides a new tool for structure-interaction kinetic analysis and drug discovery. PMID:12459011

  13. 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.

  14. 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.

  15. 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.

  16. 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 the...

  17. 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.

  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. China Homeware Chain Sells Aussie Brands

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    @@ Australian products are to take prominence on the shelves of a new chain of home decor retail stores in China. China-based manufacturer Thomas Bryson International Ltd, which is listed on the Australian Securities Exchange, will for the first time open a chain of Thomas Bryson homeware stores throughout China.

  20. China Homeware Chain Sells Aussie Brands

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Australian products are to take prominence on the shelves of a new chain of home decor retail stores in China.China-based manufacturer Thomas Bryson International Ltd, which is listed on the Australian Securities Exchange, will for the first time open a chain of Thomas Bryson homeware stores throughout China.

  1. 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

  2. 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

  3. 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

  4. Vendor-Buyer Coordination in Supply Chains

    NARCIS (Netherlands)

    H.J.J. Verheijen (Bas)

    2010-01-01

    textabstractCollaboration between firms in order to coordinate supply chain operations can lead to both strategic and operational benefits. Many advanced forms of collaboration arrangements between firms exist with the aim to coordinate supply chain decisions and to reap these benefits. This dissert

  5. Stakeholder salience in humanitarian supply chain management

    OpenAIRE

    Schiffling, Sarah

    2013-01-01

    Mitchell et al.(1997) developed a framework for assessing the salience of stakeholder groups based on their power, urgency and the legitimacy of their claim. This has been applied to illustrate the complexities of stakeholder interactions in humanitarian supply chains and to provide insights for their management and further research. Keywords: Supply chain management, Humanitarian logistics, Stakeholder salience

  6. 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...

  7. Theory of chain association versus liquid condensation

    NARCIS (Netherlands)

    Roij, R. van

    1996-01-01

    We combine the original van der Waals description for liquid condensation with the association theory of ideal particles into a simple association theory of nonideal chains. The theory shows that vapor-liquid coexistence becomes metastable if the tendency to form weakly interacting chains is suffici

  8. 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

  9. 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

  10. 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

  11. Enterprise Architecture in the Supply Chain

    DEFF Research Database (Denmark)

    Tambo, Torben; Koch, Christian

    2010-01-01

    Information systems in supply chain management (SCM) is common, bringing architecture on the agenda . The paper uses three perspectives on enterprise architecture (EA) in the supply chain: The correlation view, the remote view and the institutional view. It is shown that the EA in the domain...

  12. 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

  13. 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.

  14. 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

  15. Driving Value in The Upstream Chain Management

    OpenAIRE

    Marc Helmold

    2011-01-01

    Lean principles and methods must be part of the total supplier management approach in any enterprise. Organisations can thus differentiate and create a competitive advantage. Surveys have shown that the lean integration of the supply chain and the elimination of waste within the upstream supply chain management lead to significant cost savings and benefits.

  16. Value Chain Responsibility in Emerging Technologies

    NARCIS (Netherlands)

    Bos, Colette; van Lente, Harro

    2014-01-01

    Corporate social responsibility (CSR) and value chain responsibility (VCR) have gained increasing importance for firms. The literature on these topics reports on CSR practices for established firms with existing technologies and stable value chains. This raises questions about the viability of CSR a

  17. 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.

  18. JAK2 inhibitors: are they the solution?

    OpenAIRE

    Santos, Fabio P S; Verstovsek, Srdan

    2011-01-01

    The discovery of the JAK2V617F mutation in patients with Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPNs) started the era of targeted therapy for these diseases. Until now, patients had few treatment options available, usually restricted to hydroxyurea, interferon preparations, and chemotherapy in more aggressive cases. JAK2 inhibitors have been developed over the past 5 years, and the results of the first clinical trials with JAK2 inhibitors for patients with myelofibros...

  19. Update on TNF Inhibitors in Dermatology.

    Science.gov (United States)

    Sobell, Jeffrey M

    2016-06-01

    Emerging data describe new potential indications for tumor necrosis factor (TNF) inhibitors in dermatology, including pediatric psoriasis and hidradenitis suppurativa. New biosimilar TNF agents are in late stages of development and may be available in the United States in the near future. Biosimilar agents are similar but not identical to available TNF inhibitors, and approval requires extensive analytic, toxicity, pharmacokinetic, pharmacodynamic, and clinical testing. Semin Cutan Med Surg 35(supp6):S104-S106. PMID:27537073

  20. Proton pump inhibitors decrease melanogenesis in melanocytes

    OpenAIRE

    Baek, Seung-Hwa; Lee, Sang-Han

    2015-01-01

    Proton pump inhibitors (PPIs) are widely used as inhibitors of gastric juice secretion for treatment of gastroesophageal reflux disease. However, there are no previous studies of the effects on melanogenesis resulting from PPI treatments. Therefore, the aim of the present study was to investigate the effects of PPIs on melanogenesis in melan-a cells derived from immortalized mouse melanocytes. Tyrosinase activity and copper-chelating activity were measured spectrophotometrically. In addition,...

  1. Endogenous angiogenesis inhibitors and their therapeutic implications.

    Science.gov (United States)

    Cao, Y

    2001-04-01

    A number of endogenous inhibitors targeting the tumor vasculature have recently been identified using in vitro and in vivo antiangiogenesis models. While many of these angiogenesis inhibitors display a broad spectrum of biological actions on several systems in the body, several inhibitors including angiostatin, endostatin, and serpin antithrombin seem to act specifically on the proliferating endothelial cell compartment of the newly formed blood vessels. The discovery of these specific endothelial inhibitors not only increases our understanding of the functions of these molecules in the regulation of physiological and pathological angiogenesis, but may also provide an important therapeutic strategy for the treatment of cancer and other angiogenesis dependent diseases, including diabetic retinopathy and chronic inflammations. Systemic administration of these angiogenesis inhibitors in animals significantly suppresses the growth of a variety of tumors and their metastases. However, their production as functional recombinant proteins has been proven to be difficult. In addition, high dosages of these inhibitors are required to suppress tumor growth in animal studies. Other disadvantages of the antiangiogenic protein therapy include repeated injections, prolonged treatment, transmission of toxins and infectious particles, and high cost for manufacturing large amounts of protein molecules. Thus, alternative strategies need to be developed in order to improve the clinical settings of antiangiogenic therapy. Developments of these strategies are ongoing and they include identification of more potent inhibitors, antiangiogenic gene therapy, improvement of protein/compound half-lives in the circulation, increase of their concentrations at the disease location, and combinatorial therapies with approaches including chemotherapy, radiotherapy, and immunotherapy. Despite the above-mentioned disadvantages, a few inhibitors have entered into the early stages of clinical trials and

  2. Novel hemagglutinin-based influenza virus inhibitors

    OpenAIRE

    Shen, Xintian; Zhang, Xuanxuan; Liu, Shuwen

    2013-01-01

    Influenza virus has caused seasonal epidemics and worldwide pandemics, which caused tremendous loss of human lives and socioeconomics. Nowadays, only two classes of anti-influenza drugs, M2 ion channel inhibitors and neuraminidase inhibitors respectively, are used for prophylaxis and treatment of influenza virus infection. Unfortunately, influenza virus strains resistant to one or all of those drugs emerge frequently. Hemagglutinin (HA), the glycoprotein in influenza virus envelope, plays a c...

  3. Therapeutic Potential of Monoacylglycerol Lipase Inhibitors

    OpenAIRE

    Mulvihill, Melinda M.; Nomura, Daniel K.

    2012-01-01

    Marijuana and aspirin have been used for millennia to treat a wide range of maladies including pain and inflammation. Both cannabinoids, like marijuana, that exert anti-inflammatory action through stimulating cannabinoid receptors, and cyclooxygenase (COX) inhibitors, like aspirin, that suppress pro-inflammatory eicosanoid production have shown benefitial outcomes in mouse models of neurodegenerative diseases and cancer. Both cannabinoids and COX inhibitors, however, have untoward effects tha...

  4. 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

  5. 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…

  6. 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

  7. Discovery and Optimization of Potent, Selective, and in Vivo Efficacious 2-Aryl Benzimidazole BCATm Inhibitors.

    Science.gov (United States)

    Deng, Hongfeng; Zhou, Jingye; Sundersingh, Flora; Messer, Jeffrey A; Somers, Donald O; Ajakane, Myriam; Arico-Muendel, Christopher C; Beljean, Arthur; Belyanskaya, Svetlana L; Bingham, Ryan; Blazensky, Emily; Boullay, Anne-Benedicte; Boursier, Eric; Chai, Jing; Carter, Paul; Chung, Chun-Wa; Daugan, Alain; Ding, Yun; Herry, Kenny; Hobbs, Clare; Humphries, Eric; Kollmann, Christopher; Nguyen, Van Loc; Nicodeme, Edwige; Smith, Sarah E; Dodic, Nerina; Ancellin, Nicolas

    2016-04-14

    To identify BCATm inhibitors suitable for in vivo study, Encoded Library Technology (ELT) was used to affinity screen a 117 million member benzimidazole based DNA encoded library, which identified an inhibitor series with both biochemical and cellular activities. Subsequent SAR studies led to the discovery of a highly potent and selective compound, 1-(3-(5-bromothiophene-2-carboxamido)cyclohexyl)-N-methyl-2-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamide (8b) with much improved PK properties. X-ray structure revealed that 8b binds to the active site of BACTm in a unique mode via multiple H-bond and van der Waals interactions. After oral administration, 8b raised mouse blood levels of all three branched chain amino acids as a consequence of BCATm inhibition. PMID:27096045

  8. Functional characterization of an invertase inhibitor gene involved in sucrose metabolism in tomato fruit.

    Science.gov (United States)

    Zhang, Ning; Jiang, Jing; Yang, Yan-li; Wang, Zhi-he

    2015-10-01

    In this study, we produced tomato plants overexpressing an invertase inhibitor gene (Sly-INH) from tomato, using a simple and efficient transient transformation system. Compared with control plants, the expression of Sly-INH was highly upregulated in Sly-INH overexpressing plants, as indicated by real-time polymerase chain reaction (PCR). Physiological analysis revealed that Sly-INH inhibited the activity of cell wall invertase (CWIN), which increased sugar accumulation in tomato fruit. Furthermore, Sly-INH mediated sucrose metabolism by regulating CWIN activity. Our results suggest that invertase activity is potentially regulated by the Sly-INH inhibitor at the post-translational level, and they demonstrate that the transient transformation system is an effective method for determining the functions of genes in tomato. PMID:26465132

  9. 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.

  10. Aromatase inhibitors in the treatment of endometriosis.

    Science.gov (United States)

    Słopień, Radosław; Męczekalski, Błażej

    2016-03-01

    Endometriosis is a chronic inflammatory condition in which foci of endometrial tissue grow outside of the uterine cavity. Endometriosis was estimated to affect 176 million women of childbearing potential all over the world in 2010. The presence of extrauterine endometrial tissue is associated with pain and infertility. Typical symptoms of endometriosis include dysmenorrhoea, dyspareunia, heavy menstrual periods (menorrhagia), pelvic pain that is not related to menstrual cycles, dysuria, and chronic fatigue. Medical treatments for endometriosis include combined oral contraceptive pills, danazol, gestrinone, medroxyprogesterone acetate, and gonadotropin-releasing hormone agonists (aGnRHs). A new class of medications called aromatase inhibitors has been identified in recent years as potential therapeutic agents for endometriosis. This article provides general information about aromatase inhibitors, their use in gynaecology, and their adverse effects. In particular, the paper discusses the use of aromatase inhibitors in the treatment of endometriosis in postmenopausal women. Unlike oral contraceptives, gestagens, aGnRHs, and danazol, which suppress ovarian oestrogen synthesis, aromatase inhibitors inhibit mainly extra-ovarian synthesis of oestrogens. Therefore, the use of aromatase inhibitors seems to be particularly relevant in older patients, as most of the body's oestrogen is produced outside the ovaries after menopause. The paper discusses also the use of aromatase inhibitors in the treatment of pain associated with endometriosis and infertility caused by endometriosis. PMID:27095958

  11. Aromatase inhibitors in the treatment of endometriosis

    Science.gov (United States)

    Męczekalski, Błażej

    2016-01-01

    Endometriosis is a chronic inflammatory condition in which foci of endometrial tissue grow outside of the uterine cavity. Endometriosis was estimated to affect 176 million women of childbearing potential all over the world in 2010. The presence of extrauterine endometrial tissue is associated with pain and infertility. Typical symptoms of endometriosis include dysmenorrhoea, dyspareunia, heavy menstrual periods (menorrhagia), pelvic pain that is not related to menstrual cycles, dysuria, and chronic fatigue. Medical treatments for endometriosis include combined oral contraceptive pills, danazol, gestrinone, medroxyprogesterone acetate, and gonadotropin-releasing hormone agonists (aGnRHs). A new class of medications called aromatase inhibitors has been identified in recent years as potential therapeutic agents for endometriosis. This article provides general information about aromatase inhibitors, their use in gynaecology, and their adverse effects. In particular, the paper discusses the use of aromatase inhibitors in the treatment of endometriosis in postmenopausal women. Unlike oral contraceptives, gestagens, aGnRHs, and danazol, which suppress ovarian oestrogen synthesis, aromatase inhibitors inhibit mainly extra-ovarian synthesis of oestrogens. Therefore, the use of aromatase inhibitors seems to be particularly relevant in older patients, as most of the body's oestrogen is produced outside the ovaries after menopause. The paper discusses also the use of aromatase inhibitors in the treatment of pain associated with endometriosis and infertility caused by endometriosis. PMID:27095958

  12. 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.

  13. 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.

  14. Sales Rebate Contracts in Fashion Supply Chains

    Directory of Open Access Journals (Sweden)

    Chun-Hung Chiu

    2012-01-01

    Full Text Available We explore in this paper the performance of sales rebate contracts in fashion supply chains. We conduct both analytical and numerical analyses via a mean-variance framework with reference to real empirical data. To be specific, we evaluate the expected profits and variance of profits (risk of the fashion supply chains, fashion retailers, and manufacturers under (1 the currently implemented sales rebate practices, (2 the case without sales rebate, and (3 the theoretical coordination situation (if target sales rebate is adopted. In addition, we analyze how sales effort affects the performances of the supply chain and its agents. Our analysis indicates that the rebate contracts may hurt the retailer and the manufacturer of a fashion supply chain when it is inappropriately set. Moreover, a properly designed sales rebate contract not only can coordinate the supply chain (with retail sales effort but can also improve expected profits and lower the levels of risk for both the manufacturer and the retailer.

  15. 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....

  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. 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.

  18. 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.

  19. 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, as...... 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 of......-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 for the...

  20. The Governance of Global Wealth Chains

    DEFF Research Database (Denmark)

    Seabrooke, Leonard; Wigan, Duncan

    This working paper creates a theoretical framework to explain how Global Wealth Chains are created, maintained, and governed. We draw upon different strands of literature, including scholarship in international political economy and economic geography on Global Value Chains, literature on finance...... 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...

  1. Automatically Discovering Hidden Transformation Chaining Constraints

    CERN Document Server

    Chenouard, Raphael; 10.1007/978-3-642-04425-0_8

    2010-01-01

    Model transformations operate on models conforming to precisely defined metamodels. Consequently, it often seems relatively easy to chain them: the output of a transformation may be given as input to a second one if metamodels match. However, this simple rule has some obvious limitations. For instance, a transformation may only use a subset of a metamodel. Therefore, chaining transformations appropriately requires more information. We present here an approach that automatically discovers more detailed information about actual chaining constraints by statically analyzing transformations. The objective is to provide developers who decide to chain transformations with more data on which to base their choices. This approach has been successfully applied to the case of a library of endogenous transformations. They all have the same source and target metamodel but have some hidden chaining constraints. In such a case, the simple metamodel matching rule given above does not provide any useful information.

  2. Integrating product design into the supply chain

    DEFF Research Database (Denmark)

    Khan, Omera; Stolte, Terje; Creazza, Alessandro;

    2016-01-01

    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...... 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...

  3. 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...

  4. 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.

  5. Ratchet behaviour of polarons in molecular chains

    Energy Technology Data Exchange (ETDEWEB)

    Brizhik, L S; Eremko, A A [Bogolyubov Institute for Theoretical Physics, 03680 Kyiv (Ukraine); Piette, B M A G; Zakrzewski, W J [Department of Mathematical Sciences, University of Durham, Durham DH1 3LE (United Kingdom)], E-mail: brizhik@bitp.kiev.ua, E-mail: eremko@bitp.kiev.ua, E-mail: B.M.A.G.Piette@durham.ac.uk, E-mail: W.J.Zakrzewski@durham.ac.uk

    2008-06-25

    We study the ratchet behaviour of polarons in diatomic molecular chains under the influence of an external electromagnetic field which is periodic in time. We show that in asymmetric chains a harmonic unbiased field causes a drift of polarons. This phenomenon has a threshold with respect to the intensity and the frequency of the field. In spatially symmetric chains a harmonic periodic electric field generates oscillations of polarons but does not result in their movement. The polaron drift current can be induced in symmetric chains by a time periodic asymmetric external field. This complex dynamics of polarons is generated by the interplay between the Peierls-Nabarro barrier and dissipative effects in the chains.

  6. Ratchet behaviour of polarons in molecular chains

    International Nuclear Information System (INIS)

    We study the ratchet behaviour of polarons in diatomic molecular chains under the influence of an external electromagnetic field which is periodic in time. We show that in asymmetric chains a harmonic unbiased field causes a drift of polarons. This phenomenon has a threshold with respect to the intensity and the frequency of the field. In spatially symmetric chains a harmonic periodic electric field generates oscillations of polarons but does not result in their movement. The polaron drift current can be induced in symmetric chains by a time periodic asymmetric external field. This complex dynamics of polarons is generated by the interplay between the Peierls-Nabarro barrier and dissipative effects in the chains

  7. 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. PMID:26990063

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

    OpenAIRE

    Kale, Shailendra; Palacios Fernández, Miguel; Tafur Segura, José Javier; Jarad, Rajendra; Chitale, C.M.

    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...

  9. 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...

  10. Plasminogen Activator Inhibitor-1 and Susceptibility to Lung Cancer: A Population Genetics Perspective

    OpenAIRE

    Bayramoglu, Aysegul; Gunes, Hasan Veysi; Metintas, Muzaffer; Degirmenci, Irfan; Guler, Halil Ibrahim; Ustuner, Cengiz; Musmul, Ahmet

    2014-01-01

    Aim: The aim of this study was to investigate the polymorphism frequency of plasminogen activator inhibitor-1 (PAI-1) (rs1799889) 4G/5G in patients with lung cancer. Methods: In this study, 286 genomic DNAs (154 lung cancer patients+132 subjects without lung cancer) were analyzed. Polymorphisms were determined by using the polymerase chain reaction (PCR) method, with 4G and 5G allele-specific primers. PCR products were assessed by a charge-coupled device camera and exposed to 2% agarose gel e...

  11. Benzoxazolone carboxamides as potent acid ceramidase inhibitors: Synthesis and structure-activity relationship (SAR) studies

    DEFF Research Database (Denmark)

    Bach, Anders

    2015-01-01

    Ceramides are lipid-derived intracellular messengers involved in the control of senescence, inflammation, and apoptosis. The cysteine amidase, acid ceramidase (AC), hydrolyzes these substances into sphingosine and fatty acid and, by doing so, regulates their signaling activity. AC inhibitors may...... 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...

  12. Inflammatory properties of inhibitor of DNA binding 1 secreted by synovial fibroblasts in rheumatoid arthritis

    OpenAIRE

    Edhayan, Gautam; Ohara, Ray A.; Stinson, W. Alex; Amin, M. Asif; Isozaki, Takeo; Ha, Christine M; Haines, G. Kenneth; Morgan, Rachel; Campbell, Phillip L.; Arbab, Ali S; Friday, Sean C.; Fox, David A; Ruth, Jeffrey H.

    2016-01-01

    Background Inhibitor of DNA binding 1 (Id1) is a nuclear protein containing a basic helix-loop-helix (bHLH) domain that regulates cell growth by selective binding and prevention of gene transcription. Sources of Id1 production in rheumatoid arthritis synovial tissue (RA ST) and its range of functional effects in RA remain to be clarified. Methods We analyzed Id1 produced from synovial fibroblasts and endothelial cells (ECs) with histology and real-time polymerase chain reaction (RT-PCR). Fibr...

  13. Issue on supply chain of renewable energy

    International Nuclear Information System (INIS)

    Highlights: • One of the most relevant debates, is related to energy and environmental issue. • The development of renewable energy usage is due to several factors. • Indeed challenges from a supply chain point of view are required. • Thorough survey on topics of supply chain and renewable energy has been conducted. • Findings are discussed against the backdrop of SCs as sustainable RE option. - Abstract: Actually, one of the most relevant debates, among both citizens that government, is related to energy and environmental issue. The development of renewable energy usage is due to several factors such as the political strategic decisions and geographical situation. Indeed the high development of renewable energies requires challenges from a supply chain point of view. In this paper, a thorough survey of the extant literature on the topic of supply chain (SC) and renewable energy (RE) has been conducted. English papers published on international peer-reviewed journals from 2003 to 2013 have been considered. Sustainable Supply Chain Management (SSCM) resolves the duality between environmental, economic and social aspects. Sustainable manufacturing practices play an essential role in promoting renewable energy development and commercialization; this will require significant changes to the industry’s traditional Supply Chain Management and business model. The aim of the paper is investigate literature insights useful to increase the performance and overcome barriers to the RE supply chain development. Like many typical supply chains, also supply chain related to RE includes elements such as: physical, information, and financial flows. The present research is useful to individualize characteristics of a RE supply chain. Moreover, the research is useful improve the performance of RE supply chain in some aspects like: • better control supply chain costs to make renewable energy more affordable; • manage supply chain to address weakened demand in the near

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-08-15

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

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. ACHIEVING SUPPLY CHAIN COMPETITIVENESS: SOME CRITICAL ISSUES

    Directory of Open Access Journals (Sweden)

    Ajay Verma,

    2010-11-01

    Full Text Available In today’s global marketplace, competitive priorities have forced organizations to change dramatically due to rising customer expectations, continually increasing competition on a world-wide scale, time and quality based competition and mass customization. The fierce competition in today’s market is led by advances in industrialtechnology, increased globalization, and tremendous improvement in information availability. With the development of information technology and economic globalization, modern competition has already become the competition among enterprises and their supply chains rather than the competition among enterprises only. In this era, the organizations are forced to rethink their operations, alliances, partnerships and strategies to cope with these and similar changes. Supply chain competitiveness has been emerged as one of the strongest tool for gaining competitive advantages. A company is competitive when it is able to create and deliver value for its customers. A supply chain is competitive if it is able to create and deliver value for its customers and its components. In the growing economy of India, supply chain competitiveness (SCC is a real solution to theproblems faced by organizations in this global environment. This paper identifies some of the supply chain competitiveness issues and presents roles of suppliers, manufacturers and distributors. Some future perspectives are then presented. The paper aims at identifying some critical issues related to supply chain competitiveness and presents roles of the major components of supply chain.

  20. Proteasome inhibitor treatment in alcoholic liver disease

    Institute of Scientific and Technical Information of China (English)

    Fawzia Bardag-Gorce

    2011-01-01

    Oxidative stress, generated by chronic ethanol consumption, is a major cause of hepatotoxicity and liver injury. Increased production of oxygen-derived free radicals due to ethanol metabolism by CYP2E1 is principally located in the cytoplasm and in the mitochondria, which does not only injure liver cells, but also other vital organs, such as the heart and the brain. Therefore, there is a need for better treatment to enhance the antioxidant response elements. To date, there is no established treatment to attenuate high levels of oxidative stress in the liver of alcoholic patients. To block this oxidative stress, proteasome inhibitor treatment has been found to significantly enhance the antioxidant response elements of hepatocytes exposed to ethanol. Recent studies have shown in an experimental model of alcoholic liver disease that proteasome inhibitor treatment at low dose has cytoprotective effects against ethanol-induced oxidative stress and liver steatosis. The beneficial effects of proteasome inhibitor treatment against oxidative stress occurred because antioxidant response elements (glutathione peroxidase 2, superoxide dismutase 2, glutathione synthetase, glutathione reductase, and GCLC) were upregulated when rats fed alcohol were treated with a low dose of PS-341 (Bortezomib, Velcade(r)). This is an important finding because proteasome inhibitor treatment up-regulated reactive oxygen species removal and glutathione recycling enzymes, while ethanol feeding alone down-regulated these antioxidant elements. For the first time, it was shown that proteasome inhibition by a highly specific and reversible inhibitor is different from the chronic ethanol feeding-induced proteasome inhibition. As previously shown by our group, chronic ethanol feeding causes a complex dysfunction in the ubiquitin proteasome pathway, which affects the proteasome system, as well as the ubiquitination system. The beneficial effects of proteasome inhibitor treatment in alcoholic liver disease