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Sample records for transport inhibiting benzothiepines

  1. The Kinetics of Carrier Transport Inhibition

    DEFF Research Database (Denmark)

    Rosenberg, T.; Wilbrandt, Robert Walter

    1962-01-01

    The kinetical treatment of enzymatic carrier transports as given in previous communications has been extended to conditions of inhibition. Various possible types of inhibitors have been considered differing in the site of attack (enzyme or carrier), in the mode of action (competing with the subst......The kinetical treatment of enzymatic carrier transports as given in previous communications has been extended to conditions of inhibition. Various possible types of inhibitors have been considered differing in the site of attack (enzyme or carrier), in the mode of action (competing...... with the substrate for the enzyme or the carrier or for both, competing with the carrier for the enzyme, or non-competitive) and in the ability of penetrating the membrane. Experiments are reported on the inhibition of glucose and fructose transport across the human red cell membrane by phlorizine, phloretine...... and polyphloretinephosphate. The results of the analysis for these inhibitors indicate a substrate competitive mode of action. The effect of reversing the transport direction by interchanging the substrate concentration has been treated for the case of a non-penetrating substrate competitive inhibitor in the external medium...

  2. Intermittency inhibited by transport: An exactly solvable model

    Science.gov (United States)

    Zanette, Damián H.

    1994-04-01

    Transport is incorporated in a discrete-time stochastic model of a system undergoing autocatalytic reactions of the type A-->2A and A-->0, whose population field is known to exhibit spatiotemporal intermittency. The temporal evolution is exactly solved, and it is shown that if the transport process is strong enough, intermittency is inhibited. This inhibition is nonuniform, in the sense that, as transport is strengthened, low-order population moments are affected before the high-order ones. Numerical simulations are presented to support the analytical results.

  3. Influence of norepinephrine transporter inhibition on hemodynamic response to hypergravitation

    OpenAIRE

    Strempel, Sebastian

    2011-01-01

    Background: Sympathetically-mediated tachycardia and vasoconstriction maintain blood pressure during hypergravitational stress, thereby preventing gravitation-induced loss of consciousness (g-LOC). Norepinephrine transporter (NET) inhibition prevents neurally-mediated (pre)syncope during gravitational stress imposed by head-up tilt testing. Thus, it seems reasonable that NET inhibition could increase tolerance to hypergravitational stress. Methods. We performed a double-blind, randomized...

  4. Norepinephrine transporter inhibition alters the hemodynamic response to hypergravitation.

    Science.gov (United States)

    Strempel, Sebastian; Schroeder, Christoph; Hemmersbach, Ruth; Boese, Andrea; Tank, Jens; Diedrich, André; Heer, Martina; Luft, Friedrich C; Jordan, Jens

    2008-03-01

    Sympathetically mediated tachycardia and vasoconstriction maintain blood pressure during hypergravitational stress, thereby preventing gravitation-induced loss of consciousness. Norepinephrine transporter (NET) inhibition prevents neurally mediated (pre)syncope during gravitational stress imposed by head-up tilt testing. Thus it seems reasonable that NET inhibition could increase tolerance to hypergravitational stress. We performed a double-blind, randomized, placebo-controlled crossover study in 11 healthy men (26 +/- 1 yr, body mass index 24 +/- 1 kg/m2), who ingested the selective NET inhibitor reboxetine (4 mg) or matching placebo 25, 13, and 1 h before testing on separate days. We monitored heart rate, blood pressure, and thoracic impedance in three different body positions (supine, seated, standing) and during a graded centrifuge run (incremental steps of 0.5 g for 3 min each, up to a maximal vertical acceleration load of 3 g). NET inhibition increased supine blood pressure and heart rate. With placebo, blood pressure increased in the seated position and was well maintained during standing. However, with NET inhibition, blood pressure decreased in the seated and standing position. During hypergravitation, blood pressure increased in a graded fashion with placebo. With NET inhibition, the increase in blood pressure during hypergravitation was profoundly diminished. Conversely, the tachycardic responses to sitting, standing, and hypergravitation all were greatly increased with NET inhibition. In contrast to our expectation, short-term NET inhibition did not improve tolerance to hypergravitation. Redistribution of sympathetic activity to the heart or changes in baroreflex responses could explain the excessive tachycardia that we observed.

  5. Salmonella infection inhibits intestinal biotin transport: cellular and molecular mechanisms.

    Science.gov (United States)

    Ghosal, Abhisek; Jellbauer, Stefan; Kapadia, Rubina; Raffatellu, Manuela; Said, Hamid M

    2015-07-15

    Infection with the nontyphoidal Salmonella is a common cause of food-borne disease that leads to acute gastroenteritis/diarrhea. Severe/prolonged cases of Salmonella infection could also impact host nutritional status, but little is known about its effect on intestinal absorption of vitamins, including biotin. We examined the effect of Salmonella enterica serovar Typhimurium (S. typhimurium) infection on intestinal biotin uptake using in vivo (streptomycin-pretreated mice) and in vitro [mouse (YAMC) and human (NCM460) colonic epithelial cells, and human intestinal epithelial Caco-2 cells] models. The results showed that infecting mice with wild-type S. typhimurium, but not with its nonpathogenic isogenic invA spiB mutant, leads to a significant inhibition in jejunal/colonic biotin uptake and in level of expression of the biotin transporter, sodium-dependent multivitamin transporter. In contrast, infecting YAMC, NCM460, and Caco-2 cells with S. typhimurium did not affect biotin uptake. These findings suggest that the effect of S. typhimurium infection is indirect and is likely mediated by proinflammatory cytokines, the levels of which were markedly induced in the intestine of S. typhimurium-infected mice. Consistent with this hypothesis, exposure of NCM460 cells to the proinflammatory cytokines TNF-α and IFN-γ led to a significant inhibition of biotin uptake, sodium-dependent multivitamin transporter expression, and activity of the SLC5A6 promoter. The latter effects appear to be mediated, at least in part, via the NF-κB signaling pathway. These results demonstrate that S. typhimurium infection inhibits intestinal biotin uptake, and that the inhibition is mediated via the action of proinflammatory cytokines.

  6. Hypoxia inhibits colonic ion transport via activation of AMP kinase.

    LENUS (Irish Health Repository)

    Collins, Danielle

    2012-02-01

    BACKGROUND AND AIMS: Mucosal hypoxia is a common endpoint for many pathological processes including ischemic colitis, colonic obstruction and anastomotic failure. Previous studies suggest that hypoxia modulates colonic mucosal function through inhibition of chloride secretion. However, the molecular mechanisms underlying this observation are poorly understood. AMP-activated protein kinase (AMPK) is a metabolic energy regulator found in a wide variety of cells and has been linked to cystic fibrosis transmembrane conductance regulator (CFTR) mediated chloride secretion in several different tissues. We hypothesized that AMPK mediates many of the acute effects of hypoxia on human and rat colonic electrolyte transport. METHODS: The fluorescent chloride indicator dye N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide was used to measure changes in intracellular chloride concentrations in isolated single rat colonic crypts. Ussing chamber experiments in human colonic mucosa were conducted to evaluate net epithelial ion transport. RESULTS: This study demonstrates that acute hypoxia inhibits electrogenic chloride secretion via AMPK mediated inhibition of CFTR. Pre-treatment of tissues with the AMPK inhibitor 6-[4-(2-piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyyrazolo [1,5-a] pyrimidine (compound C) in part reversed the effects of acute hypoxia on chloride secretion. CONCLUSION: We therefore suggest that AMPK is a key component of the adaptive cellular response to mucosal hypoxia in the colon. Furthermore, AMPK may represent a potential therapeutic target in diseased states or in prevention of ischemic intestinal injury.

  7. Artemisinin inhibits chloroplast electron transport activity: mode of action.

    Directory of Open Access Journals (Sweden)

    Adyasha Bharati

    Full Text Available Artemisinin, a secondary metabolite produced in Artemisia plant species, besides having antimalarial properties is also phytotoxic. Although, the phytotoxic activity of the compound has been long recognized, no information is available on the mechanism of action of the compound on photosynthetic activity of the plant. In this report, we have evaluated the effect of artemisinin on photoelectron transport activity of chloroplast thylakoid membrane. The inhibitory effect of the compound, under in vitro condition, was pronounced in loosely and fully coupled thylakoids; being strong in the former. The extent of inhibition was drastically reduced in the presence of uncouplers like ammonium chloride or gramicidin; a characteristic feature described for energy transfer inhibitors. The compound, on the other hand, when applied to plants (in vivo, behaved as a potent inhibitor of photosynthetic electron transport. The major site of its action was identified to be the Q(B; the secondary quinone moiety of photosystemII complex. Analysis of photoreduction kinetics of para-benzoquinone and duroquinone suggest that the inhibition leads to formation of low pool of plastoquinol, which becomes limiting for electron flow through photosystemI. Further it was ascertained that the in vivo inhibitory effect appeared as a consequence of the formation of an unidentified artemisinin-metabolite rather than by the interaction of the compound per se. The putative metabolite of artemisinin is highly reactive in instituting the inhibition of photosynthetic electron flow eventually reducing the plant growth.

  8. Sodium glucose transporter 2 (SGLT2 inhibition and ketogenesis

    Directory of Open Access Journals (Sweden)

    Sanjay Kalra

    2015-01-01

    Full Text Available Sodium glucose transporter 2 (SGLT2 inhibitors are a recently developed class of drug that have been approved for use in type 2 diabetes. Their unique extra-pancreatic glucuretic mode of action has encouraged their usage in type 1 diabetes as well. At the same time, reports of pseudo ketoacidosis and ketoacidosis related to their use have been published. No clear mechanism for this phenomenon has been demonstrated so far. This communication delves into the biochemical effects of SGLT2 inhibition, discusses the utility of these drugs and proposes steps to maximize safe usage of the molecules.

  9. The Mechanistic Basis for Noncompetitive Ibogaine Inhibition of Serotonin and Dopamine Transporters*

    Science.gov (United States)

    Bulling, Simon; Schicker, Klaus; Zhang, Yuan-Wei; Steinkellner, Thomas; Stockner, Thomas; Gruber, Christian W.; Boehm, Stefan; Freissmuth, Michael; Rudnick, Gary; Sitte, Harald H.; Sandtner, Walter

    2012-01-01

    Ibogaine, a hallucinogenic alkaloid proposed as a treatment for opiate withdrawal, has been shown to inhibit serotonin transporter (SERT) noncompetitively, in contrast to all other known inhibitors, which are competitive with substrate. Ibogaine binding to SERT increases accessibility in the permeation pathway connecting the substrate-binding site with the cytoplasm. Because of the structural similarity between ibogaine and serotonin, it had been suggested that ibogaine binds to the substrate site of SERT. The results presented here show that ibogaine binds to a distinct site, accessible from the cell exterior, to inhibit both serotonin transport and serotonin-induced ionic currents. Ibogaine noncompetitively inhibited transport by both SERT and the homologous dopamine transporter (DAT). Ibogaine blocked substrate-induced currents also in DAT and increased accessibility of the DAT cytoplasmic permeation pathway. When present on the cell exterior, ibogaine inhibited SERT substrate-induced currents, but not when it was introduced into the cytoplasm through the patch electrode. Similar to noncompetitive transport inhibition, the current block was not reversed by increasing substrate concentration. The kinetics of inhibitor binding and dissociation, as determined by their effect on SERT currents, indicated that ibogaine does not inhibit by forming a long-lived complex with SERT, but rather binds directly to the transporter in an inward-open conformation. A kinetic model for transport describing the noncompetitive action of ibogaine and the competitive action of cocaine accounts well for the results of the present study. PMID:22451652

  10. The mechanistic basis for noncompetitive ibogaine inhibition of serotonin and dopamine transporters.

    Science.gov (United States)

    Bulling, Simon; Schicker, Klaus; Zhang, Yuan-Wei; Steinkellner, Thomas; Stockner, Thomas; Gruber, Christian W; Boehm, Stefan; Freissmuth, Michael; Rudnick, Gary; Sitte, Harald H; Sandtner, Walter

    2012-05-25

    Ibogaine, a hallucinogenic alkaloid proposed as a treatment for opiate withdrawal, has been shown to inhibit serotonin transporter (SERT) noncompetitively, in contrast to all other known inhibitors, which are competitive with substrate. Ibogaine binding to SERT increases accessibility in the permeation pathway connecting the substrate-binding site with the cytoplasm. Because of the structural similarity between ibogaine and serotonin, it had been suggested that ibogaine binds to the substrate site of SERT. The results presented here show that ibogaine binds to a distinct site, accessible from the cell exterior, to inhibit both serotonin transport and serotonin-induced ionic currents. Ibogaine noncompetitively inhibited transport by both SERT and the homologous dopamine transporter (DAT). Ibogaine blocked substrate-induced currents also in DAT and increased accessibility of the DAT cytoplasmic permeation pathway. When present on the cell exterior, ibogaine inhibited SERT substrate-induced currents, but not when it was introduced into the cytoplasm through the patch electrode. Similar to noncompetitive transport inhibition, the current block was not reversed by increasing substrate concentration. The kinetics of inhibitor binding and dissociation, as determined by their effect on SERT currents, indicated that ibogaine does not inhibit by forming a long-lived complex with SERT, but rather binds directly to the transporter in an inward-open conformation. A kinetic model for transport describing the noncompetitive action of ibogaine and the competitive action of cocaine accounts well for the results of the present study.

  11. Feedback inhibition of ammonium (methylammonium) ion transport in Escherichia coli by glutamine and glutamine analogs

    International Nuclear Information System (INIS)

    Jayakumar, A.; Hong, J.S.; Barnes, E.M. Jr.

    1987-01-01

    When cultured with glutamate or glutamine as the nitrogen source, Escherichia coli expresses a specific ammonium (methylammonium) transport system. Over 95% of the methylammonium transport activity in washed cells was blocked by incubation with 100 μM L-glutamine in the presence of chloramphenicol (100 μg/ml). The inhibition of transport by L-glutamine was noncompetitive with respect to the [ 14 C]methylammonium substrate. D-Glutamine had no significant effect. The glutamine analogs γ-L-glutamyl hydroxamate and γ-L-glutamyl hydrazide were also noncompetitive inhibitors of methylammonium transport, suggesting that glutamine metabolism is not required. The role of the intracellular glutamine pool in the regulation of ammonium transport was investigated by using mutants carrying defects in the operon of glnP, the gene for the glutamine transporter. The glnP mutants had normal rates of methylammonium transport but were refractory to glutamine inhibition. Glycylglycine, a noncompetitive inhibitor of methylammonium uptake in wild-type cells, was equipotent in blocking transport in glnP mutants. Although ammonium transport is also subject to repression by growth of E. coli in the presence of ammonia, this phenomenon is unrelated to glutamine inhibition

  12. Inhibition of the norepinephrine transporter by χ-conotoxin dendrimers.

    Science.gov (United States)

    Wan, Jingjing; Brust, Andreas; Bhola, Rebecca F; Jha, Prerna; Mobli, Mehdi; Lewis, Richard J; Christie, Macdonald J; Alewood, Paul F

    2016-05-01

    Peptide dendrimers are a novel class of macromolecules of emerging interest with the potential of delayed renal clearance due to their molecular size and enhanced activity due to the multivalency effect. In this work, an active analogue of the disulfide-rich χ-conotoxin χ-MrIA (χ-MrIA), a norepinephrine reuptake (norepinephrine transporter) inhibitor, was grafted onto a polylysine dendron. Dendron decoration was achieved by employing copper-catalyzed alkyne-azide cycloaddition with azido-PEG chain-modified χ-MrIA analogues, leading to homogenous 4-mer and 8-mer χ-MrIA dendrimers with molecular weights ranging from 8 to 22 kDa. These dendrimers were investigated for their impact on peptide secondary structure, in vitro functional activity, and potential anti-allodynia in vivo. NMR studies showed that the χ-MrIA tertiary structure was maintained in the χ-MrIA dendrimers. In a functional norepinephrine transporter reuptake assay, χ-MrIA dendrimers showed slightly increased potency relative to the azido-PEGylated χ-MrIA analogues with similar potency to the parent peptide. In contrast to χ-MrIA, no anti-allodynic action was observed when the χ-MrIA dendrimers were administered intrathecally in a rat model of neuropathic pain, suggesting that the larger dendrimer structures are unable to diffuse through the spinal column tissue and reach the norepinephrine transporter. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

  13. Wortmannin inhibits both insulin- and contraction-stimulated glucose uptake and transport in rat skeletal muscle

    DEFF Research Database (Denmark)

    Wojtaszewski, Jørgen; Hansen, B F; Ursø, Birgitte

    1996-01-01

    The role of phosphatidylinositol (PI) 3-kinase for insulin- and contraction-stimulated muscle glucose transport was investigated in rat skeletal muscle perfused with a cell-free perfusate. The insulin receptor substrate-1-associated PI 3-kinase activity was increased sixfold upon insulin...... stimulation but was unaffected by contractions. In addition, the insulin-stimulated PI 3-kinase activity and muscle glucose uptake and transport in individual muscles were dose-dependently inhibited by wortmannin with one-half maximal inhibition values of approximately 10 nM and total inhibition at 1 micro......M. This concentration of wortmannin also decreased the contraction-stimulated glucose transport and uptake by approximately 30-70% without confounding effects on contractility or on muscle ATP and phosphocreatine concentrations. At higher concentrations (3 and 10 microM), wortmannin completely blocked the contraction...

  14. Inhibition by nucleosides of glucose-transport activity in human erythrocytes.

    OpenAIRE

    Jarvis, S M

    1988-01-01

    The interaction of nucleosides with the glucose carrier of human erythrocytes was examined by studying the effect of nucleosides on reversible cytochalasin B-binding activity and glucose transport. Adenosine, inosine and thymidine were more potent inhibitors of cytochalasin B binding to human erythrocyte membranes than was D-glucose [IC50 (concentration causing 50% inhibition) values of 10, 24, 28 and 38 mM respectively]. Moreover, low concentrations of thymidine and adenosine inhibited D-glu...

  15. Thienoquinolins exert diuresis by strongly inhibiting UT-A urea transporters

    Science.gov (United States)

    Ren, Huiwen; Wang, Yanhua; Xing, Yongning; Ran, Jianhua; Liu, Ming; Lei, Tianluo; Zhou, Hong; Li, Runtao; Sands, Jeff M.

    2014-01-01

    Urea transporters (UT) play an important role in the urine concentration mechanism by mediating intrarenal urea recycling, suggesting that UT inhibitors could have therapeutic use as a novel class of diuretic. Recently, we found a thienoquinolin UT inhibitor, PU-14, that exhibited diuretic activity. The purpose of this study was to identify more potent UT inhibitors that strongly inhibit UT-A isoforms in the inner medullary collecting duct (IMCD). Efficient thienoquinolin UT inhibitors were identified by structure-activity relationship analysis. Urea transport inhibition activity was assayed in perfused rat terminal IMCDs. Diuretic activity of the compound was determined in rats and mice using metabolic cages. The results show that the compound PU-48 exhibited potent UT-A inhibition activity. The inhibition was 69.5% with an IC50 of 0.32 μM. PU-48 significantly inhibited urea transport in perfused rat terminal IMCDs. PU-48 caused significant diuresis in UT-B null mice, which indicates that UT-A is the target of PU-48. The diuresis caused by PU-48 did not change blood Na+, K+, or Cl− levels or nonurea solute excretion in rats and mice. No toxicity was detected in cells or animals treated with PU-48. The results indicate that thienoquinolin UT inhibitors induce a diuresis by inhibiting UT-A in the IMCD. This suggests that they may have the potential to be developed as a novel class of diuretics with fewer side effects than classical diuretics. PMID:25298523

  16. Sites of inhibition of mitochondrial electron transport in macrophage-injured neoplastic cells.

    Science.gov (United States)

    Granger, D L; Lehninger, A L

    1982-11-01

    Previous work has shown that injury of neoplastic cells by cytotoxic macrophages (CM) in cell culture is accompanied by inhibition of mitochondrial respiration. We have investigated the nature of this inhibition by studying mitochondrial respiration in CM-injured leukemia L1210 cells permeabilized with digitonin. CM-induced injury affects the mitochondrial respiratory chain proper. Complex I (NADH-coenzyme Q reductase) and complex II (succinate-coenzyme Q reductase) are markedly inhibited. In addition a minor inhibition of cytochrome oxidase was found. Electron transport from alpha-glycerophosphate through the respiratory chain to oxygen is unaffected and permeabilized CM-injured L1210 cells oxidizing this substrate exhibit acceptor control. However, glycerophosphate shuttle activity was found not to occur within CM-injured or uninjured L1210 cells in culture hence, alpha-glycerophosphate is apparently unavailable for mitochondrial oxidation in the intact cell. It is concluded that the failure of respiration of intact neoplastic cells injured by CM is caused by the nearly complete inhibition of complexes I and II of the mitochondrial electron transport chain. The time courses of CM-induced electron transport inhibition and arrest of L1210 cell division are examined and the possible relationship between these phenomena is discussed.

  17. Interplay between inhibited transport and reaction in nanoporous materials

    Energy Technology Data Exchange (ETDEWEB)

    Ackerman, David Michael [Iowa State Univ., Ames, IA (United States)

    2013-01-01

    This work presents a detailed formulation of reaction and diffusion dynamics of molecules in confined pores such as mesoporous silica and zeolites. A general reaction-diffusion model and discrete Monte Carlo simulations are presented. Both transient and steady state behavior is covered. Failure of previous mean-field models for these systems is explained and discussed. A coarse-grained, generalized hydrodynamic model is developed that accurately captures the interplay between reaction and restricted transport in these systems. This method incorporates the non-uniform chemical diffusion behavior present in finite pores with multi-component diffusion. Two methods of calculating these diffusion values are developed: a random walk based approach and a driven diffusion model based on an extension of Fick's law. The effects of reaction, diffusion, pore length, and catalytic site distribution are investigated. In addition to strictly single file motion, quasi-single file diffusion is incorporated into the model to match a range of experimental systems. The connection between these experimental systems and model parameters is made through Langevin dynamics modeling of particles in confined pores.

  18. Trypanocidal Effect of Isotretinoin through the Inhibition of Polyamine and Amino Acid Transporters in Trypanosoma cruzi.

    Directory of Open Access Journals (Sweden)

    Chantal Reigada

    2017-03-01

    Full Text Available Polyamines are essential compounds to all living organisms and in the specific case of Trypanosoma cruzi, the causative agent of Chagas disease, they are exclusively obtained through transport processes since this parasite is auxotrophic for polyamines. Previous works reported that retinol acetate inhibits Leishmania growth and decreases its intracellular polyamine concentration. The present work describes a combined strategy of drug repositioning by virtual screening followed by in vitro assays to find drugs able to inhibit TcPAT12, the only polyamine transporter described in T. cruzi. After a screening of 3000 FDA-approved drugs, 7 retinoids with medical use were retrieved and used for molecular docking assays with TcPAT12. From the docked molecules, isotretinoin, a well-known drug used for acne treatment, showed the best interaction score with TcPAT12 and was selected for further in vitro studies. Isotretinoin inhibited the polyamine transport, as well as other amino acid transporters from the same protein family (TcAAAP, with calculated IC50 values in the range of 4.6-10.3 μM. It also showed a strong inhibition of trypomastigote burst from infected cells, with calculated IC50 of 130 nM (SI = 920 being significantly less effective on the epimastigote stage (IC50 = 30.6 μM. The effect of isotretinoin on the parasites plasma membrane permeability and on mammalian cell viability was tested, and no change was observed. Autophagosomes and apoptotic bodies were detected as part of the mechanisms of isotretinoin-induced death indicating that the inhibition of transporters by isotretinoin causes nutrient starvation that triggers autophagic and apoptotic processes. In conclusion, isotretinoin is a promising trypanocidal drug since it is a multi-target inhibitor of essential metabolites transporters, in addition to being an FDA-approved drug largely used in humans, which could reduce significantly the requirements for its possible application in the

  19. Glucocorticoids inhibit glucose transport and glutamate uptake in hippocampal astrocytes: implications for glucocorticoid neurotoxicity.

    Science.gov (United States)

    Virgin, C E; Ha, T P; Packan, D R; Tombaugh, G C; Yang, S H; Horner, H C; Sapolsky, R M

    1991-10-01

    Glucocorticoids (GCs), the adrenal steroid hormones secreted during stress, can damage the hippocampus and impair its capacity to survive coincident neurological insults. This GC endangerment of the hippocampus is energetic in nature, as it can be prevented when neurons are supplemented with additional energy substrates. This energetic endangerment might arise from the ability of GCs to inhibit glucose transport into both hippocampal neurons and astrocytes. The present study explores the GC inhibition in astrocytes. (1) GCs inhibited glucose transport approximately 15-30% in both primary and secondary hippocampal astrocyte cultures. (2) The parameters of inhibition agreed with the mechanisms of GC inhibition of glucose transport in peripheral tissues: A minimum of 4 h of GC exposure were required, and the effect was steroid specific (i.e., it was not triggered by estrogen, progesterone, or testosterone) and tissue specific (i.e., it was not triggered by GCs in cerebellar or cortical cultures). (3) Similar GC treatment caused a decrease in astrocyte survival during hypoglycemia and a decrease in the affinity of glutamate uptake. This latter observation suggests that GCs might impair the ability of astrocytes to aid neurons during times of neurologic crisis (i.e., by impairing their ability to remove damaging glutamate from the synapse).

  20. Biguanides sensitize leukemia cells to ABT-737-induced apoptosis by inhibiting mitochondrial electron transport

    Science.gov (United States)

    Velez, Juliana; Pan, Rongqing; Lee, Jason T.C.; Enciso, Leonardo; Suarez, Marta; Duque, Jorge Eduardo; Jaramillo, Daniel; Lopez, Catalina; Morales, Ludis; Bornmann, William; Konopleva, Marina; Krystal, Gerald; Andreeff, Michael; Samudio, Ismael

    2016-01-01

    Metformin displays antileukemic effects partly due to activation of AMPK and subsequent inhibition of mTOR signaling. Nevertheless, Metformin also inhibits mitochondrial electron transport at complex I in an AMPK-independent manner, Here we report that Metformin and rotenone inhibit mitochondrial electron transport and increase triglyceride levels in leukemia cell lines, suggesting impairment of fatty acid oxidation (FAO). We also report that, like other FAO inhibitors, both agents and the related biguanide, Phenformin, increase sensitivity to apoptosis induction by the bcl-2 inhibitor ABT-737 supporting the notion that electron transport antagonizes activation of the intrinsic apoptosis pathway in leukemia cells. Both biguanides and rotenone induce superoxide generation in leukemia cells, indicating that oxidative damage may sensitize toABT-737 induced apoptosis. In addition, we demonstrate that Metformin sensitizes leukemia cells to the oligomerization of Bak, suggesting that the observed synergy with ABT-737 is mediated, at least in part, by enhanced outer mitochondrial membrane permeabilization. Notably, Phenformin was at least 10-fold more potent than Metformin in abrogating electron transport and increasing sensitivity to ABT-737, suggesting that this agent may be better suited for targeting hematological malignancies. Taken together, our results suggest that inhibition of mitochondrial metabolism by Metformin or Phenformin is associated with increased leukemia cell susceptibility to induction of intrinsic apoptosis, and provide a rationale for clinical studies exploring the efficacy of combining biguanides with the orally bioavailable derivative of ABT-737, Venetoclax. PMID:27283492

  1. Rapid redistribution and inhibition of renal sodium transporters during acute pressure natriuresis

    DEFF Research Database (Denmark)

    Zhang, Y; Mircheff, A K; Hensley, C B

    1996-01-01

    and basolateral Na+ pumps to internal membranes. Arterial pressure was increased 50 mmHg by constricting various arteries. We also tested whether transporter internalization occurred when PT Na+ reabsorption was inhibited with the carbonic anhydrase inhibitor benzolamide. Five minutes after initiating either...

  2. Development of norepinephrine transporter reuptake inhibition assays using SK-N-BE(2C cells

    Directory of Open Access Journals (Sweden)

    Ann M. Decker

    2018-05-01

    Full Text Available This report describes efforts to develop and validate novel norepinephrine transporter reuptake inhibition assays using human neuroblastoma SK-N-BE(2C cells in 24-well format. Before conducting the assays, the SK-N-BE(2C cells were first evaluated for their ability to uptake [3H]norepinephrine and were shown to have a saturable uptake with a KM value of 416 nM. Using this determined KM value, reuptake inhibition assays were then conducted with a variety of ligands including antidepressants, as well as piperazine and phenyltropane derivatives. The results obtained with the SK-N-BE(2C cells indicate that this model system can detect a range of ligand potencies, which compare well with other established transporter assays. Our data suggest that SK-N-BE(2C cells have potential utility to serve as another model system to detect norepinephrine reuptake inhibition activity.

  3. Glycolysis inhibition inactivates ABC transporters to restore drug sensitivity in malignant cells.

    Directory of Open Access Journals (Sweden)

    Ayako Nakano

    Full Text Available Cancer cells eventually acquire drug resistance largely via the aberrant expression of ATP-binding cassette (ABC transporters, ATP-dependent efflux pumps. Because cancer cells produce ATP mostly through glycolysis, in the present study we explored the effects of inhibiting glycolysis on the ABC transporter function and drug sensitivity of malignant cells. Inhibition of glycolysis by 3-bromopyruvate (3BrPA suppressed ATP production in malignant cells, and restored the retention of daunorubicin or mitoxantrone in ABC transporter-expressing, RPMI8226 (ABCG2, KG-1 (ABCB1 and HepG2 cells (ABCB1 and ABCG2. Interestingly, although side population (SP cells isolated from RPMI8226 cells exhibited higher levels of glycolysis with an increased expression of genes involved in the glycolytic pathway, 3BrPA abolished Hoechst 33342 exclusion in SP cells. 3BrPA also disrupted clonogenic capacity in malignant cell lines including RPMI8226, KG-1, and HepG2. Furthermore, 3BrPA restored cytotoxic effects of daunorubicin and doxorubicin on KG-1 and RPMI8226 cells, and markedly suppressed subcutaneous tumor growth in combination with doxorubicin in RPMI8226-implanted mice. These results collectively suggest that the inhibition of glycolysis is able to overcome drug resistance in ABC transporter-expressing malignant cells through the inactivation of ABC transporters and impairment of SP cells with enhanced glycolysis as well as clonogenic cells.

  4. Tubule urate and PAH transport: sensitivity and specificity of serum protein inhibition

    International Nuclear Information System (INIS)

    Grantham, J.J.; Kennedy, J.; Cowley, B.

    1987-01-01

    Macromolecules in rabbit serum inhibit the cellular uptake and transepithelial secretion of [ 14 C]urate and p-[ 3 H]aminohippurate ([ 3 H]PAH) in rabbit S 2 proximal tubule segments. To understand better the potential role these inhibitors may have in the regulation of renal organic anion excretion, the authors examined the specificity and relative inhibitory effects on tubule urate and PAH transport of albumin and γ-globulin, the major inhibitory proteins in rabbit serum. Native rabbit serum markedly inhibited the cellular accumulation or urate and PAH by isolated nonperfused segments. Urate and PAH transport was also inhibited by bovine serum, human serum, Cohn-fractionated rabbit albumin, and rabbit γ-globulin, but not by Cohn-fractionated bovine serum albumin. α-Lactalbumin and β-lactoglobulin, derived from milk, also inhibited urate and PAH transport, but to a lesser extent than albumin and γ-globulin. The transport inhibitory effects of proteins were independent of their binding to urate and PAH. Unidirectional influx and the steady-state intracellular accumulation of urate and PAH in suspensions of proximal tubules were decreased by rabbit serum proteins, suggesting that these inhibitors act on the external face of the cells to diminish the uptake of the organic anions. These studies indicate that the principal plasma proteins (albumin and γ-globulin) significantly inhibit urate and PAH transporters in the basolateral membranes of S 2 proximal tubules. They suggest that circulating plasma proteins that can penetrate the basement membrane of proximal tubules may directly modulate the renal excretion of urate and PAH

  5. Inhibiting Cadmium Transport Process in Root Cells of Plants: A Review

    Directory of Open Access Journals (Sweden)

    ZHAO Yan-ling

    2016-05-01

    Full Text Available Cadmium(Cd is the most common element found in the heavy-metal contaminated soils in China. Roots of rice and vegetables can concentrate Cd from acid soils, and then transport Cd to above-ground parts. Cd in edible part of plants directly influences the food safety. Cellwall, plasma membrane and organells of root cells in plant can discriminate Cd from other elements. A lot of Cd can be fixed in root cells by precipitation, complexation, compartmentation, and so on, to inhibit its transport from roots to shoot and guarantee the physiological activities in above-ground parts carrying out normally. This paper summarized recent advance on inhibiting Cd transport process in subcellular fractions of root cells of plants, which is in advantage of exploring excellent germplasms and gene resources in the future.

  6. Intracellular ascorbic acid inhibits transport of glucose by neurons, but not by astrocytes.

    Science.gov (United States)

    Castro, Maite A; Pozo, Miguel; Cortés, Christian; García, María de Los Angeles; Concha, Ilona I; Nualart, Francisco

    2007-08-01

    It has been demonstrated that glutamatergic activity induces ascorbic acid (AA) depletion in astrocytes. Additionally, different data indicate that AA may inhibit glucose accumulation in primary cultures of rat hippocampal neurons. Thus, our hypothesis postulates that AA released from the astrocytes during glutamatergic synaptic activity may inhibit glucose uptake by neurons. We observed that cultured neurons express the sodium-vitamin C cotransporter 2 and the facilitative glucose transporters (GLUT) 1 and 3, however, in hippocampal brain slices GLUT3 was the main transporter detected. Functional activity of GLUTs was confirmed by means of kinetic analysis using 2-deoxy-d-glucose. Therefore, we showed that AA, once accumulated inside the cell, inhibits glucose transport in both cortical and hippocampal neurons in culture. Additionally, we showed that astrocytes are not affected by AA. Using hippocampal slices, we observed that upon blockade of monocarboxylate utilization by alpha-cyano-4-hydroxycinnamate and after glucose deprivation, glucose could rescue neuronal response to electrical stimulation only if AA uptake is prevented. Finally, using a transwell system of separated neuronal and astrocytic cultures, we observed that glutamate can reduce glucose transport in neurons only in presence of AA-loaded astrocytes, suggesting the essential role of astrocyte-released AA in this effect.

  7. VU-B radiation inhibits the photosynthetic electron transport chain in chlamydomonas reinhardtii

    International Nuclear Information System (INIS)

    Cai, W.; Li, X.; Chen, L.

    2016-01-01

    UV radiation of sunlight is one of harmful factors for earth organisms, especially for photoautotrophs because they require light for energy and biomass production. A number of works have already been done regarding the effects of UV-B radiation at biochemical and molecular level, which showed that UV-B radiation could inhibit photosynthesis activity and reduce photosynthetic electron transport. However quite limited information can accurately make out inhibition site of UV-B radiation on photosynthetic electron transport. In this study, this issue was investigated through measuring oxygen evolution activity, chlorophyll a fluorescence and gene expression in a model unicellular green alga Chlamydomonas reinhardtii. Our results indicated that UV-B radiation could evidently decrease photosynthesis activity and inhibit electron transport by blocking electron transfer process from the first plastoquinone electron acceptors QA to second plastoquinone electron acceptors QB, but not impair electron transfer from the water oxidizing complex to QA. The psbA gene expression was also altered by UV-B radiation, where up-regulation occurred at 2, 4 and 6h after exposure and down-regulation happened at 12 and 24 h after exposure. These results suggested that UV-B could affects D1 protein normal turnover, so there was not enough D1 for binding with QB, which may affect photosynthetic electron transport and photosynthesis activity. (author)

  8. Strigolactone Inhibition of Branching Independent of Polar Auxin Transport1[OPEN

    Science.gov (United States)

    Mason, Michael G.; Beveridge, Christine A.

    2015-01-01

    The outgrowth of axillary buds into branches is regulated systemically via plant hormones and the demand of growing shoot tips for sugars. The plant hormone auxin is thought to act via two mechanisms. One mechanism involves auxin regulation of systemic signals, cytokinins and strigolactones, which can move into axillary buds. The other involves suppression of auxin transport/canalization from axillary buds into the main stem and is enhanced by a low sink for auxin in the stem. In this theory, the relative ability of the buds and stem to transport auxin controls bud outgrowth. Here, we evaluate whether auxin transport is required or regulated during bud outgrowth in pea (Pisum sativum). The profound, systemic, and long-term effects of the auxin transport inhibitor N-1-naphthylphthalamic acid had very little inhibitory effect on bud outgrowth in strigolactone-deficient mutants. Strigolactones can also inhibit bud outgrowth in N-1-naphthylphthalamic acid-treated shoots that have greatly diminished auxin transport. Moreover, strigolactones can inhibit bud outgrowth despite a much diminished auxin supply in in vitro or decapitated plants. These findings demonstrate that auxin sink strength in the stem is not important for bud outgrowth in pea. Consistent with alternative mechanisms of auxin regulation of systemic signals, enhanced auxin biosynthesis in Arabidopsis (Arabidopsis thaliana) can suppress branching in yucca1D plants compared with wild-type plants, but has no effect on bud outgrowth in a strigolactone-deficient mutant background. PMID:26111543

  9. Inhibition of epithelial Na+ transport by atriopeptin, protein kinase c, and pertussis toxin

    International Nuclear Information System (INIS)

    Mohrmann, M.; Cantiello, H.F.; Ausiello, D.A.

    1987-01-01

    The authors have recently shown the selective inhibition of an amiloride-sensitive, conductive pathway for Na + by atrial natriuretic peptide and 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP) in the renal epithelial cell line, LLC-PK i . Using 22 Na + fluxes, they further investigated the modulation of Na + transport by atrial natriuretic peptide and by agents that increase cGMP production, activate protein kinase c, or modulate guanine nucleotide regulatory protein function. Sodium nitroprusside increases intracellular cGMP concentrations without affecting cAMP concentrations and completely inhibits amiloride-sensitive Na + uptake in a time- and concentration-dependent manner. Oleoyl 2-acetylglycerol and phorbol 12-myristate 13-acetate, activators of protein kinase c, inhibit Na + uptake by 93 ± 13 and 51 ± 10%, respectively. Prolonged incubation with phorbol ester results in the downregulation of protein kinase c activity and reduces the inhibitory effect of atrial natriuretic peptide, suggesting that the action of this peptide involves stimulation of protein kinase c. Pertussis toxin, which induces the ADP-ribosylation of a 41-kDa guanine nucleotide regulatory protein in LLC-PK i cells, inhibits 22 Na + influx to the same extent as amiloride. Thus, increasing cGMP, activating protein kinase c, and ADP-ribosylating a guanine nucleotide regulatory protein all inhibit Na + uptake. These events may be sequentially involved in the action of atrial natriuretic peptide

  10. Predicted consequences of diabetes and SGLT inhibition on transport and oxygen consumption along a rat nephron

    Science.gov (United States)

    Vallon, Volker; Edwards, Aurélie

    2016-01-01

    Diabetes increases the reabsorption of Na+ (TNa) and glucose via the sodium-glucose cotransporter SGLT2 in the early proximal tubule (S1-S2 segments) of the renal cortex. SGLT2 inhibitors enhance glucose excretion and lower hyperglycemia in diabetes. We aimed to investigate how diabetes and SGLT2 inhibition affect TNa and sodium transport-dependent oxygen consumption QO2active along the whole nephron. To do so, we developed a mathematical model of water and solute transport from the Bowman space to the papillary tip of a superficial nephron of the rat kidney. Model simulations indicate that, in the nondiabetic kidney, acute and chronic SGLT2 inhibition enhances active TNa in all nephron segments, thereby raising QO2active by 5–12% in the cortex and medulla. Diabetes increases overall TNa and QO2active by ∼50 and 100%, mainly because it enhances glomerular filtration rate (GFR) and transport load. In diabetes, acute and chronic SGLT2 inhibition lowers QO2active in the cortex by ∼30%, due to GFR reduction that lowers proximal tubule active TNa, but raises QO2active in the medulla by ∼7%. In the medulla specifically, chronic SGLT2 inhibition is predicted to increase QO2active by 26% in late proximal tubules (S3 segments), by 2% in medullary thick ascending limbs (mTAL), and by 9 and 21% in outer and inner medullary collecting ducts (OMCD and IMCD), respectively. Additional blockade of SGLT1 in S3 segments enhances glucose excretion, reduces QO2active by 33% in S3 segments, and raises QO2active by SGLT2 blockade in diabetes lowers cortical QO2active and raises medullary QO2active, particularly in S3 segments. PMID:26764207

  11. Allyl Isothiocyanate Inhibits Actin-Dependent Intracellular Transport in Arabidopsis thaliana

    Directory of Open Access Journals (Sweden)

    Bjørnar Sporsheim

    2015-12-01

    Full Text Available Volatile allyl isothiocyanate (AITC derives from the biodegradation of the glucosinolate sinigrin and has been associated with growth inhibition in several plants, including the model plant Arabidopsis thaliana. However, the underlying cellular mechanisms of this feature remain scarcely investigated in plants. In this study, we present evidence of an AITC-induced inhibition of actin-dependent intracellular transport in A. thaliana. A transgenic line of A. thaliana expressing yellow fluorescent protein (YFP-tagged actin filaments was used to show attenuation of actin filament movement by AITC. This appeared gradually in a time- and dose-dependent manner and resulted in actin filaments appearing close to static. Further, we employed four transgenic lines with YFP-fusion proteins labeling the Golgi apparatus, endoplasmic reticulum (ER, vacuoles and peroxisomes to demonstrate an AITC-induced inhibition of actin-dependent intracellular transport of or, in these structures, consistent with the decline in actin filament movement. Furthermore, the morphologies of actin filaments, ER and vacuoles appeared aberrant following AITC-exposure. However, AITC-treated seedlings of all transgenic lines tested displayed morphologies and intracellular movements similar to that of the corresponding untreated and control-treated plants, following overnight incubation in an AITC-absent environment, indicating that AITC-induced decline in actin-related movements is a reversible process. These findings provide novel insights into the cellular events in plant cells following exposure to AITC, which may further expose clues to the physiological significance of the glucosinolate-myrosinase system.

  12. Piracetam and TRH analogues antagonise inhibition by barbiturates, diazepam, melatonin and galanin of human erythrocyte D-glucose transport

    Science.gov (United States)

    Naftalin, Richard J; Cunningham, Philip; Afzal-Ahmed, Iram

    2004-01-01

    Nootropic drugs increase glucose uptake into anaesthetised brain and into Alzheimer's diseased brain. Thyrotropin-releasing hormone, TRH, which has a chemical structure similar to nootropics increases cerebellar uptake of glucose in murine rolling ataxia. This paper shows that nootropic drugs like piracetam (2-oxo 1 pyrrolidine acetamide) and levetiracetam and neuropeptides like TRH antagonise the inhibition of glucose transport by barbiturates, diazepam, melatonin and endogenous neuropeptide galanin in human erythrocytes in vitro. The potencies of nootropic drugs in opposing scopolamine-induced memory loss correlate with their potencies in antagonising pentobarbital inhibition of erythrocyte glucose transport in vitro (Pnootropics, D-levetiracetam and D-pyroglutamate, have higher antagonist Ki's against pentobarbital inhibition of glucose transport than more potent L-stereoisomers (Pnootropics, like aniracetam and levetiracetam, while antagonising pentobarbital action, also inhibit glucose transport. Analeptics like bemigride and methamphetamine are more potent inhibitors of glucose transport than antagonists of hypnotic action on glucose transport. There are similarities between amino-acid sequences in human glucose transport protein isoform 1 (GLUT1) and the benzodiazepine-binding domains of GABAA (gamma amino butyric acid) receptor subunits. Mapped on a 3D template of GLUT1, these homologies suggest that the site of diazepam and piracetam interaction is a pocket outside the central hydrophilic pore region. Nootropic pyrrolidone antagonism of hypnotic drug inhibition of glucose transport in vitro may be an analogue of TRH antagonism of galanin-induced narcosis. PMID:15148255

  13. Cation-Inhibited Transport of Graphene Oxide Nanomaterials in Saturated Porous Media: The Hofmeister Effects.

    Science.gov (United States)

    Xia, Tianjiao; Qi, Yu; Liu, Jing; Qi, Zhichong; Chen, Wei; Wiesner, Mark R

    2017-01-17

    Transport of negatively charged nanoparticles in porous media is largely affected by cations. To date, little is known about how cations of the same valence may affect nanoparticle transport differently. We observed that the effects of cations on the transport of graphene oxide (GO) and sulfide-reduced GO (RGO) in saturated quartz sand obeyed the Hofmeister series; that is, transport-inhibition effects of alkali metal ions followed the order of Na + cations having large ionic radii (and thus being weakly hydrated) interacted with quartz sand and GO and RGO more strongly than did cations of small ionic radii. In particular, the monovalent Cs + and divalent Ca 2+ and Ba 2+ , which can form inner-sphere complexes, resulted in very significant deposition of GO and RGO via cation bridging between quartz sand and GO and RGO, and possibly via enhanced straining, due to the enhanced aggregation of GO and RGO from cation bridging. The existence of the Hofmeister effects was further corroborated with the interesting observation that cation bridging was more significant for RGO, which contained greater amounts of carboxyl and phenolic groups (i.e., metal-complexing moieties) than did GO. The findings further demonstrate that transport of nanoparticles is controlled by the complex interplay between nanoparticle surface functionalities and solution chemistry constituents.

  14. Borreliacidal activity of Borrelia metal transporter A (BmtA binding small molecules by manganese transport inhibition

    Directory of Open Access Journals (Sweden)

    Wagh D

    2015-02-01

    Full Text Available Dhananjay Wagh,* Venkata Raveendra Pothineni,* Mohammed Inayathullah, Song Liu, Kwang-Min Kim, Jayakumar Rajadas Biomaterials and Advanced Drug Delivery Laboratory, Stanford Cardiovascular Pharmacology Division, Cardiovascular Institute, Stanford University School of Medicine, Palo Alto, CA, USA *These authors contributed equally to this work  Abstract: Borrelia burgdorferi, the causative agent of Lyme disease, utilizes manganese (Mn for its various metabolic needs. We hypothesized that blocking Mn transporter could be a possible approach to inhibit metabolic activity of this pathogen and eliminate the infection. We used a combination of in silico protein structure prediction together with molecular docking to target the Borrelia metal transporter A (BmtA, a single known Mn transporter in Borrelia and screened libraries of FDA approved compounds that could potentially bind to the predicted BmtA structure with high affinity. Tricyclic antihistamines such as loratadine, desloratadine, and 3-hydroxydesloratadine as well as yohimbine and tadalafil demonstrated a tight binding to the in silico folded BmtA transporter. We, then, tested borreliacidal activity and dose response of the shortlisted compounds from this screen using a series of in vitro assays. Amongst the probed compounds, desloratadine exhibited potent borreliacidal activity in vitro at and above 78 µg/mL (250 µM. Borrelia treated with lethal doses of desloratadine exhibited a significant loss of intracellular Mn specifically and a severe structural damage to the bacterial cell wall. Our results support the possibility of developing a novel, targeted therapy to treat Lyme disease by targeting specific metabolic needs of Borrelia.  Keywords: Lyme disease, BmtA, Borrelia burgdorferi, desloratadine, Bac Titer-Glo assay

  15. Antimycobacterial and Photosynthetic Electron Transport Inhibiting Activity of Ring-Substituted 4-Arylamino-7-Chloroquinolinium Chlorides

    Directory of Open Access Journals (Sweden)

    Alois Cizek

    2013-09-01

    Full Text Available In this study, a series of twenty-five ring-substituted 4-arylamino-7-chloroquinolinium chlorides were prepared and characterized. The compounds were tested for their activity related to inhibition of photosynthetic electron transport (PET in spinach (Spinacia oleracea L. chloroplasts and also primary in vitro screening of the synthesized compounds was performed against mycobacterial species. 4-[(2-Bromophenylamino]-7-chloroquinolinium chloride showed high biological activity against M. marinum, M. kansasii, M. smegmatis and 7-chloro-4-[(2-methylphenylamino]quinolinium chloride demonstrated noteworthy biological activity against M. smegmatis and M. avium subsp. paratuberculosis. The most effective compounds demonstrated quite low toxicity (LD50 > 20 μmol/L against the human monocytic leukemia THP-1 cell line within preliminary in vitro cytotoxicity screening. The tested compounds were found to inhibit PET in photosystem II. The PET-inhibiting activity expressed by IC50 value of the most active compound 7-chloro-4-[(3-trifluoromethylphenylamino]quinolinium chloride was 27 μmol/L and PET-inhibiting activity of ortho-substituted compounds was significantly lower than this of meta- and para-substituted ones. The structure-activity relationships are discussed for all compounds.

  16. Impairment of GABA transporter GAT-1 terminates cortical recurrent network activity via enhanced phasic inhibition

    Directory of Open Access Journals (Sweden)

    Daniel Simon Razik

    2013-09-01

    Full Text Available In the central nervous system, GABA transporters (GATs very efficiently clear synaptically released GABA from the extracellular space, and thus exert a tight control on GABAergic inhibition. In neocortex, GABAergic inhibition is heavily recruited during recurrent phases of spontaneous action potential activity which alternate with neuronally quiet periods. Therefore, such activity should be quite sensitive to minute alterations of GAT function. Here, we explored the effects of a gradual impairment of GAT-1 and GAT-2/3 on spontaneous recurrent network activity – termed network bursts and silent periods – in organotypic slice cultures of rat neocortex. The GAT-1 specific antagonist NO-711 depressed activity already at nanomolar concentrations (IC50 for depression of spontaneous multiunit firing rate of 42 nM, reaching a level of 80% at 500-1000 nM. By contrast, the GAT-2/3 preferring antagonist SNAP-5114 had weaker and less consistent effects. Several lines of evidence pointed towards an enhancement of phasic GABAergic inhibition as the dominant activity-depressing mechanism: network bursts were drastically shortened, phasic GABAergic currents decayed slower, and neuronal excitability during ongoing activity was diminished. In silent periods, NO-711 had little effect on neuronal excitability or membrane resistance, quite in contrast to the effects of muscimol, a GABA mimetic which activates GABAA receptors tonically. Our results suggest that an enhancement of phasic GABAergic inhibition efficiently curtails cortical recurrent activity and may mediate antiepileptic effects of therapeutically relevant concentrations of GAT-1 antagonists.

  17. The multidrug transporter ABCG2 (BCRP) is inhibited by plant-derived cannabinoids.

    Science.gov (United States)

    Holland, M L; Lau, D T T; Allen, J D; Arnold, J C

    2007-11-01

    Cannabinoids are used therapeutically for the palliation of the adverse side effects associated with cancer chemotherapy. However, cannabinoids also inhibit both the activity and expression of the multidrug transporter, P-glycoprotein in vitro. Here we address the interaction of cannabinol (CBN), cannabidiol (CBD) and delta 9-tetrahydrocannabinol (THC) with the related multidrug transporter, ABCG2. Cannabinoid inhibition of Abcg2/ABCG2 was assessed using flow cytometric analysis of substrate accumulation and ATPase activity assays. The cytotoxicity and chemosensitization by cannabinoids was determined with cell viability assays. Expression of cannabinoid and vanilloid receptors was assessed using reverse transcriptase polymerase chain reaction, and cannabinoid modulation of ABCG2 expression was examined using immunoblotting. CBN, CBD and THC increased the intracellular accumulation of the Abcg2/ABCG2 substrate, mitoxantrone, in an over-expressing cell line. The THC metabolite, (-)-11-nor-9-carboxy-delta 9-THC was much less potent. The plant cannabinoids inhibited both basal and substrate stimulated ATPase activity of human ABCG2. Cannabinoid cytotoxicity occurred in the absence of known cannabinoid cell surface receptors, and only at concentrations higher than those required for Abcg2/ABCG2 inhibition. Sub-toxic concentrations of the cannabinoids resensitized the overexpressing cell line to the cytotoxic effect of Abcg2/ABCG2 substrates, mitoxantrone and topotecan. This occurred in the absence of any effect on ABCG2 expression. Cannabinoids are novel Abcg2/ABCG2 inhibitors, reversing the Abcg2-mediated multidrug-resistant phenotype in vitro. This finding may have implications for the co-administration of cannabinoids with pharmaceuticals that are ABCG2 substrates.

  18. Okadaic acid inhibits cell growth and photosynthetic electron transport in the alga Dunaliella tertiolecta

    Energy Technology Data Exchange (ETDEWEB)

    Perreault, Francois; Matias, Marcelo Seleme; Oukarroum, Abdallah [Department of Chemistry, Universite du Quebec a Montreal, 2101, Rue Jeanne Mance, Montreal, QC, Canada H2X 2J6 (Canada); Matias, William Gerson [Department of Chemistry, Universite du Quebec a Montreal, 2101, Rue Jeanne Mance, Montreal, QC, Canada H2X 2J6 (Canada); Laboratorio de Toxicologia Ambiental, LABTOX, Depto. de Engenharia Sanitaria e Ambiental, Universidade Federal de Santa Catarina, Campus Universitario, CEP: 88040-970, Florianopolis, SC (Brazil); Popovic, Radovan, E-mail: popovic.radovan@uqam.ca [Department of Chemistry, Universite du Quebec a Montreal, 2101, Rue Jeanne Mance, Montreal, QC, Canada H2X 2J6 (Canada)

    2012-01-01

    Okadaic acid (OA), which is produced by several dinoflagellate species, is a phycotoxin known to induce a decrease of biomass production in phytoplankton. However, the mechanisms of OA cytotoxicity are still unknown in microalgae. In this study, we exposed the green microalga Dunaliella tertiolecta to OA concentrations of 0.05 to 0.5 {mu}M in order to evaluate its effects on cell division, reactive oxygen species production and photosynthetic electron transport. After 72 h of treatment under continuous illumination, OA concentrations higher than 0.10 {mu}M decreased culture cell density, induced oxidative stress and inhibited photosystem II electron transport capacity. OA effect in D. tertiolecta was strongly light dependent since no oxidative stress was observed when D. tertiolecta was exposed to OA in the dark. In the absence of light, the effect of OA on culture cell density and photosystem II activity was also significantly reduced. Therefore, light appears to have a significant role in the toxicity of OA in microalgae. Our results indicate that the site of OA interaction on photosynthetic electron transport is likely to be at the level of the plastoquinone pool, which can lead to photo-oxidative stress when light absorbed by the light-harvesting complex of photosystem II cannot be dissipated via photochemical pathways. These findings allowed for a better understanding of the mechanisms of OA toxicity in microalgae. - Highlights: Black-Right-Pointing-Pointer Exposition of Dunaliella tertiolecta to okadaic acid in light conditions results in reactive oxygen species formation. Black-Right-Pointing-Pointer Inhibition of photosystem II is dependent on oxidative stress and effects of okadaic acid on the plastoquinone pool. Black-Right-Pointing-Pointer Oxidative stress and inhibition of photosynthesis increase okadaic acid effect on cell density in light conditions. Black-Right-Pointing-Pointer Okadaic acid induces toxicity in algae via both light-dependent and light

  19. Activation of glycolysis and inhibition of glucose transport into leaves by fluoride

    Energy Technology Data Exchange (ETDEWEB)

    Lustinec, J; Pokorna, V; Ruzicka, J

    1962-01-01

    During stimulation of wheat leaf respiration by fluoride at 100 to 200 ppM fluorine in dry tissue the ratio of radioactivities of /sup 14/CO/sub 2/ released from glucose-6-/sup 14/C and that released from glucose-1-/sup 14/C (C/sub 6//C/sub 1/) increases due especially to an increased output of 6-/sup 14/CO/sub 2/ which suggests an activation of glycolysis. The absolute values of radioactivity of /sup 14/CO/sub 2/, however, are decreased by the action of fluoride due to its inhibition of the transport of glucose into leaves. 15 references, 2 figures, 2 tables.

  20. K+ channel openers restore verapamil-inhibited lung fluid resolution and transepithelial ion transport

    Directory of Open Access Journals (Sweden)

    Su Xue-Feng

    2010-05-01

    Full Text Available Abstract Background Lung epithelial Na+ channels (ENaC are regulated by cell Ca2+ signal, which may contribute to calcium antagonist-induced noncardiogenic lung edema. Although K+ channel modulators regulate ENaC activity in normal lungs, the therapeutical relevance and the underlying mechanisms have not been completely explored. We hypothesized that K+ channel openers may restore calcium channel blocker-inhibited alveolar fluid clearance (AFC by up-regulating both apical and basolateral ion transport. Methods Verapamil-induced depression of heterologously expressed human αβγ ENaC in Xenopus oocytes, apical and basolateral ion transport in monolayers of human lung epithelial cells (H441, and in vivo alveolar fluid clearance were measured, respectively, using the two-electrode voltage clamp, Ussing chamber, and BSA protein assays. Ca2+ signal in H441 cells was analyzed using Fluo 4AM. Results The rate of in vivo AFC was reduced significantly (40.6 ± 6.3% of control, P Ca3.1 (1-EBIO and KATP (minoxidil channel openers significantly recovered AFC. In addition to short-circuit current (Isc in intact H441 monolayers, both apical and basolateral Isc levels were reduced by verapamil in permeabilized monolayers. Moreover, verapamil significantly altered Ca2+ signal evoked by ionomycin in H441 cells. Depletion of cytosolic Ca2+ in αβγ ENaC-expressing oocytes completely abolished verapamil-induced inhibition. Intriguingly, KV (pyrithione-Na, K Ca3.1 (1-EBIO, and KATP (minoxidil channel openers almost completely restored the verapamil-induced decrease in Isc levels by diversely up-regulating apical and basolateral Na+ and K+ transport pathways. Conclusions Our observations demonstrate that K+ channel openers are capable of rescuing reduced vectorial Na+ transport across lung epithelial cells with impaired Ca2+ signal.

  1. Disruption of mitochondrial electron transport chain function potentiates the pro-apoptotic effects of MAPK inhibition.

    Science.gov (United States)

    Trotta, Andrew P; Gelles, Jesse D; Serasinghe, Madhavika N; Loi, Patrick; Arbiser, Jack L; Chipuk, Jerry E

    2017-07-14

    The mitochondrial network is a major site of ATP production through the coupled integration of the electron transport chain (ETC) with oxidative phosphorylation. In melanoma arising from the V600E mutation in the kinase v-RAF murine sarcoma viral oncogene homolog B (BRAF V600E ), oncogenic signaling enhances glucose-dependent metabolism while reducing mitochondrial ATP production. Likewise, when BRAF V600E is pharmacologically inhibited by targeted therapies ( e.g. PLX-4032/vemurafenib), glucose metabolism is reduced, and cells increase mitochondrial ATP production to sustain survival. Therefore, collateral inhibition of oncogenic signaling and mitochondrial respiration may help enhance the therapeutic benefit of targeted therapies. Honokiol (HKL) is a well tolerated small molecule that disrupts mitochondrial function; however, its underlying mechanisms and potential utility with targeted anticancer therapies remain unknown. Using wild-type BRAF and BRAF V600E melanoma model systems, we demonstrate here that HKL administration rapidly reduces mitochondrial respiration by broadly inhibiting ETC complexes I, II, and V, resulting in decreased ATP levels. The subsequent energetic crisis induced two cellular responses involving cyclin-dependent kinases (CDKs). First, loss of CDK1-mediated phosphorylation of the mitochondrial division GTPase dynamin-related protein 1 promoted mitochondrial fusion, thus coupling mitochondrial energetic status and morphology. Second, HKL decreased CDK2 activity, leading to G 1 cell cycle arrest. Importantly, although pharmacological inhibition of oncogenic MAPK signaling increased ETC activity, co-treatment with HKL ablated this response and vastly enhanced the rate of apoptosis. Collectively, these findings integrate HKL action with mitochondrial respiration and shape and substantiate a pro-survival role of mitochondrial function in melanoma cells after oncogenic MAPK inhibition.

  2. Acropetal Auxin Transport Inhibition Is Involved in Indeterminate But Not Determinate Nodule Formation

    Directory of Open Access Journals (Sweden)

    Jason L. P. Ng

    2018-02-01

    Full Text Available Legumes enter into a symbiotic relationship with nitrogen-fixing rhizobia, leading to nodule development. Two main types of nodules have been widely studied, indeterminate and determinate, which differ in the location of the first cell division in the root cortex, and persistency of the nodule meristem. Here, we compared the control of auxin transport, content, and response during the early stages of indeterminate and determinate nodule development in the model legumes Medicago truncatula and Lotus japonicus, respectively, to investigate whether differences in auxin transport control could explain the differences in the location of cortical cell divisions. While auxin responses were activated in dividing cortical cells during nodulation of both nodule types, auxin (indole-3-acetic acid content at the nodule initiation site was transiently increased in M. truncatula, but transiently reduced in L. japonicus. Root acropetal auxin transport was reduced in M. truncatula at the very start of nodule initiation, in contrast to a prolonged increase in acropetal auxin transport in L. japonicus. The auxin transport inhibitors 2,3,5-triiodobenzoic acid and 1-N-naphthylphthalamic acid (NPA only induced pseudonodules in legume species forming indeterminate nodules, but failed to elicit such structures in a range of species forming determinate nodules. The development of these pseudonodules in M. truncatula exhibited increased auxin responses in a small primordium formed from the pericycle, endodermis, and inner cortex, similar to rhizobia-induced nodule primordia. In contrast, a diffuse cortical auxin response and no associated cortical cell divisions were found in L. japonicus. Collectively, we hypothesize that a step of acropetal auxin transport inhibition is unique to the process of indeterminate nodule development, leading to auxin responses in pericycle, endodermis, and inner cortex cells, while increased auxin responses in outer cortex cells likely

  3. Inhibition of serotonin transport by (+)McN5652 is noncompetitive

    Energy Technology Data Exchange (ETDEWEB)

    Hummerich, Rene [Biochemical Laboratory, Central Institute of Mental Health, 68159 Mannheim (Germany); Schulze, Oliver [Department of Nuclear Medicine, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg (Germany); Raedler, Thomas [Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg (Germany); Mikecz, Pal [Department of Nuclear Medicine, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg (Germany); Reimold, Matthias [Department of Nuclear Medicine, University Hospital Tuebingen, D-72076 Tuebingen (Germany); Brenner, Winfried [Department of Nuclear Medicine, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg (Germany); Clausen, Malte [Department of Nuclear Medicine, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg (Germany); Schloss, Patrick [Biochemical Laboratory, Central Institute of Mental Health, 68159 Mannheim (Germany); Buchert, Ralph [Department of Nuclear Medicine, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg (Germany)]. E-mail: buchert@uke.uni-hamburg.de

    2006-04-15

    Introduction: Imaging of the serotonergic innervation of the brain using positron emission tomography (PET) with the serotonin transporter (SERT) ligand [{sup 11C}] (+)McN5652 might be affected by serotonin in the synaptic cleft if there is relevant interaction between [{sup 11}C] (+)McN5652 and serotonin at the SERT. The aim of the present study therefore was to pharmacologically characterize the interaction of [{sup 11}C] (+)McN5652 and serotonin at the SERT. Methods: In vitro saturation analyses of [{sup 3}H]serotonin uptake into HEK293 cells stably expressing the human SERT were performed in the absence and presence of unlabelled (+)McN5652. Data were evaluated assuming Michaelis-Menten kinetics. Results: Unlabelled (+)McN5652 significantly reduced the maximal rate of serotonin transport V {sub max} of SERT without affecting the Michaelis-Menten constant K {sub M}. Conclusions: This finding indicates that (+)McN5652 inhibits serotonin transport through the SERT in a noncompetitive manner. This might suggest that [{sup 11}C] (+)McN5652 PET is not significantly affected by endogenous serotonin.

  4. Inhibition of serotonin transport by (+)McN5652 is noncompetitive

    International Nuclear Information System (INIS)

    Hummerich, Rene; Schulze, Oliver; Raedler, Thomas; Mikecz, Pal; Reimold, Matthias; Brenner, Winfried; Clausen, Malte; Schloss, Patrick; Buchert, Ralph

    2006-01-01

    Introduction: Imaging of the serotonergic innervation of the brain using positron emission tomography (PET) with the serotonin transporter (SERT) ligand [ 11C ] (+)McN5652 might be affected by serotonin in the synaptic cleft if there is relevant interaction between [ 11 C] (+)McN5652 and serotonin at the SERT. The aim of the present study therefore was to pharmacologically characterize the interaction of [ 11 C] (+)McN5652 and serotonin at the SERT. Methods: In vitro saturation analyses of [ 3 H]serotonin uptake into HEK293 cells stably expressing the human SERT were performed in the absence and presence of unlabelled (+)McN5652. Data were evaluated assuming Michaelis-Menten kinetics. Results: Unlabelled (+)McN5652 significantly reduced the maximal rate of serotonin transport V max of SERT without affecting the Michaelis-Menten constant K M . Conclusions: This finding indicates that (+)McN5652 inhibits serotonin transport through the SERT in a noncompetitive manner. This might suggest that [ 11 C] (+)McN5652 PET is not significantly affected by endogenous serotonin

  5. Lapatinib potentiates cytotoxicity of YM155 in neuroblastoma via inhibition of the ABCB1 efflux transporter

    DEFF Research Database (Denmark)

    Radic-Sarikas, Branka; Halasz, Melinda; Huber, Kilian V. M.

    2017-01-01

    and simultaneously help to overcome drug resistance. Neuroblastoma is the most common cancer in infancy and extremely heterogeneous in clinical presentation and features. Applying a systematic pairwise drug combination screen we observed a highly potent synergy in neuroblastoma cells between the EGFR kinase...... inhibitor lapatinib and the anticancer compound YM155 that is preserved across several neuroblastoma variants. Mechanistically, the synergy was based on a lapatinib induced inhibition of the multidrug-resistance efflux transporter ABCB1, which is frequently expressed in resistant neuroblastoma cells, which...... allowed prolonged and elevated cytotoxicity of YM155. In addition, the drug combination (i.e. lapatinib plus YM155) decreased neuroblastoma tumor size in an in vivo model....

  6. Phenyl Ring-Substituted Lobelane Analogs: Inhibition of [3H]Dopamine Uptake at the Vesicular Monoamine Transporter-2

    OpenAIRE

    Nickell, Justin R.; Zheng, Guangrong; Deaciuc, Agripina G.; Crooks, Peter A.; Dwoskin, Linda P.

    2011-01-01

    Lobeline attenuates the behavioral effects of methamphetamine via inhibition of the vesicular monoamine transporter (VMAT2). To increase selectivity for VMAT2, chemically defunctionalized lobeline analogs, including lobelane, were designed to eliminate nicotinic acetylcholine receptor affinity. The current study evaluated the ability of lobelane analogs to inhibit [3H]dihydrotetrabenazine (DTBZ) binding to VMAT2 and [3H]dopamine (DA) uptake into isolated synaptic vesicles and determined the m...

  7. Heterocyclic cyclohexanone monocarbonyl analogs of curcumin can inhibit the activity of ATP-binding cassette transporters in cancer multidrug resistance.

    Science.gov (United States)

    Revalde, Jezrael L; Li, Yan; Hawkins, Bill C; Rosengren, Rhonda J; Paxton, James W

    2015-02-01

    Curcumin (CUR) is a phytochemical that inhibits the xenobiotic ABC efflux transporters implicated in cancer multidrug resistance (MDR), such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins 1 and 5 (MRP1 and MRP5). The use of CUR in the clinic however, is complicated by its instability and poor pharmacokinetic profile. Monocarbonyl analogs of CUR (MACs) are compounds without CUR's unstable β-diketone moiety and were reported to have improved stability and in vivo disposition. Whether the MACs can be used as MDR reversal agents is less clear, as the absence of a β-diketone may negatively impact transporter inhibition. In this study, we investigated 23 heterocyclic cyclohexanone MACs for inhibitory effects against P-gp, BCRP, MRP1 and MRP5. Using flow cytometry and resistance reversal assays, we found that many of these compounds inhibited the transport activity of the ABC transporters investigated, often with much greater potency than CUR. Overall the analogs were most effective at inhibiting BCRP and we identified three compounds, A12 (2,6-bis((E)-2,5-dimethoxy-benzylidene)cyclohexanone), A13 (2,6-bis((E)-4-hydroxyl-3-methoxybenzylidene)-cyclohexanone) and B11 (3,5-bis((E)-2-fluoro-4,5-dimethoxybenzylidene)-1-methylpiperidin-4-one), as the most promising BCRP inhibitors. These compounds inhibited BCRP activity in a non-cell line, non-substrate-specific manner. Their inhibition occurred by direct transporter interaction rather than modulating protein or cell surface expression. From these results, we concluded that MACs, such as the heterocyclic cyclohexanone analogs in this study, also have potential as MDR reversal agents and may be superior alternatives to the unstable parent compound, CUR. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Drug-protein hydrogen bonds govern the inhibition of the ATP hydrolysis of the multidrug transporter P-glycoprotein.

    Science.gov (United States)

    Chufan, Eduardo E; Kapoor, Khyati; Ambudkar, Suresh V

    2016-02-01

    P-glycoprotein (P-gp) is a member of the ATP-binding cassette transporter superfamily. This multidrug transporter utilizes energy from ATP hydrolysis for the efflux of a variety of hydrophobic and amphipathic compounds including anticancer drugs. Most of the substrates and modulators of P-gp stimulate its basal ATPase activity, although some inhibit it. The molecular mechanisms that are in play in either case are unknown. In this report, mutagenesis and molecular modeling studies of P-gp led to the identification of a pair of phenylalanine-tyrosine structural motifs in the transmembrane region that mediate the inhibition of ATP hydrolysis by certain drugs (zosuquidar, elacridar and tariquidar), with high affinity (IC50's ranging from 10 to 30nM). Upon mutation of any of these residues, drugs that inhibit the ATPase activity of P-gp switch to stimulation of the activity. Molecular modeling revealed that the phenylalanine residues F978 and F728 interact with tyrosine residues Y953 and Y310, respectively, in an edge-to-face conformation, which orients the tyrosines in such a way that they establish hydrogen-bond contacts with the inhibitor. Biochemical investigations along with transport studies in intact cells showed that the inhibitors bind at a high affinity site to produce inhibition of ATP hydrolysis and transport function. Upon mutation, they bind at lower affinity sites, stimulating ATP hydrolysis and only poorly inhibiting transport. These results also reveal that screening chemical compounds for their ability to inhibit the basal ATP hydrolysis can be a reliable tool to identify modulators with high affinity for P-gp. Published by Elsevier Inc.

  9. Urotensin II inhibits skeletal muscle glucose transport signaling pathways via the NADPH oxidase pathway.

    Directory of Open Access Journals (Sweden)

    Hong-Xia Wang

    Full Text Available Our previous studies have demonstrated that the urotensin (UII and its receptor are up-regulated in the skeletal muscle of mice with type II diabetes mellitus (T2DM, but the significance of UII in skeletal muscle insulin resistance remains unknown. The purpose of this study was to investigate the effect of UII on NADPH oxidase and glucose transport signaling pathways in the skeletal muscle of mice with T2DM and in C2C12 mouse myotube cells. KK/upj-AY/J mice (KK mice were divided into the following groups: KK group, with saline treatment for 2 weeks; KK+ urantide group, with daily 30 µg/kg body weight injections over the same time period of urantide, a potent urotensin II antagonist peptide; Non-diabetic C57BL/6J mice were used as normal controls. After urantide treatment, mice were subjected to an intraperitoneal glucose tolerance test, in addition to measurements of the levels of ROS, NADPH oxidase and the phosphorylated AKT, PKC and ERK. C2C12 cells were incubated with serum-free DMEM for 24 hours before conducting the experiments, and then administrated with 100 nM UII for 2 hours or 24 hours. Urantide treatment improved glucose tolerance, decreased the translocation of the NADPH subunits p40-phox and p47-phox, and increased levels of the phosphorylated PKC, AKT and ERK. In contrast, UII treatment increased ROS production and p47-phox and p67-phox translocation, and decreased the phosphorylated AKT, ERK1/2 and p38MAPK; Apocynin abrogated this effect. In conclusion, UII increased ROS production by NADPH oxidase, leading to the inhibition of signaling pathways involving glucose transport, such as AKT/PKC/ERK. Our data imply a role for UII at the molecular level in glucose homeostasis, and possibly in skeletal muscle insulin resistance in T2DM.

  10. Dopamine-induced apoptosis in human neuronal cells: inhibition by nucleic acides antisense to the dopamine transporter

    International Nuclear Information System (INIS)

    Porat, S.; Gabbay, M.; Tauber, M.; Ratovitski, T.; Blinder, E.; Simantov, R.

    1996-01-01

    Human neuroblastoma NMB cells take up [ 3 H]dopamine in a selective manner indicating that dopamine transporters are responsible for this uptake. These cells were therefore used as a model to study dopamine neurotoxicity, and to elucidate the role of dopamine transporters in controlling cell death. Treatment with 0.05-0.4 mM dopamine changed cells' morphology within 4 h, accompanied by retraction of processes, shrinkage, apoptosis-like atrophy, accumulation of apoptotic particles, DNA fragmentation and cell death. Cycloheximide inhibited dopamine's effect, suggesting that induction of apoptosis by dopamine was dependent upon protein synthesis. Dopamine cytotoxicity, monitored morphologically by flow cytometric analysis, and by lactate dehydrogenase released, was blocked by cocaine but not by the noradrenaline and serotonin uptake blockers desimipramine and imipramine, respectively. Attempting to inhibit dopamine transport and toxicity in a drug-free and highly selective way, three 18-mer dopamine transporter antisense phosphorothioate oligonucleotides (numbers 1, 2 and 3) and a new plasmid vector expressing the entire rat dopamine transporter complementary DNA in the antisense orientation were prepared and tested. Antisense phosphorothioate oligonucleotide 3 inhibited [ 3 H]dopamine uptake in a time- and dose-dependent manner. Likewise, transient transfection of NMB cells with the plasmid expressing dopamine transporter complementary DNA in the antisense orientation partially blocked [ 3 H]dopamine uptake. Antisense phosphorothioate oligonucleotide 3 also decreased, dose-dependently, the toxic effect of dopamine and 6-hydroxydopamine. Western blot analysis with newly prepared anti-human dopamine transporter antibodies showed that antisense phosphorothioate oligonucleotide 3 decreased the transporter protein level. These studies contribute to better understand the mechanism of dopamine-induced apoptosis and neurotoxicity. (Copyright (c) 1996 Elsevier Science B

  11. CD147 silencing inhibits tumor growth by suppressing glucose transport in melanoma.

    Science.gov (United States)

    Su, Juan; Gao, Tianyuan; Jiang, Minghao; Wu, Lisha; Zeng, Weiqi; Zhao, Shuang; Peng, Cong; Chen, Xiang

    2016-10-04

    Melanoma is a very malignant disease and there are still no effective treatments. CD147 participates in the carcinogenesis of multiple human cancers and GLUT-1, as a glucose transporter, is associated with tumor growth. However, the function of CD147 and GLUT-1 in melanoma have not been completely understood. Thus, in this study we investigated the expression of CD147 and GLUT-1 in melanoma tissue, which were overexpressed compared with that in nevus tissue. In addition, CD147 and GLUT-1 were co-localized in the cytoplasm of human melanoma A375 cells. Immunoprecipitation proved that CD147 interacted with GLUT-1 at D105-199. Silencing CD147 by specific siRNA could downregulate GLUT-1 level via inhibiting PI3K/Akt signaling and decrease glucose uptake in A375 cells. In vivo experiments also supported that CD147 knockdown suppressed the tumor growth in melanoma subcutaneous mice model, observed by micro PET/CT. Our results could help validate CD147 as a new therapeutic target for treating melanoma.

  12. Erythrocytes L-arginine y+ transporter inhibition by N-ethylmaleimide in ice-bath.

    Science.gov (United States)

    Pinheiro da Costa, Bartira Ercília; de Almeida, Priscilla Barcellos; Conceição, Ioná Rosine; Antonello, Ivan Carlos Ferreira; d'Avila, Domingos O; Poli-de-Figueiredo, Carlos Eduardo

    2010-11-01

    Erythrocytes L: -arginine uptake is conveyed by y+ and y+L membrane transport systems. Pre-incubation with N-ethylmaleimide for 10 min at 37°C inhibits the y+ system. The aim of this study was to determine the ideal pre-incubation temperature in evaluating y+ and y+L systems. Cells were pre-incubated with or without N-ethylmaleimide for 10 min at 4°C and 37°C. L: -Arginine uptake was quantified by radioisotope and standard erythrocytes membrane flux methodology. Results demonstrate that erythrocytes L: -arginine content is depleted by pre-incubation at 37°C for 10 min, thus changing the V (max) measurement. The inhibitory effect of N-ethylmaleimide pre-incubation was temperature independent and already complete after 1 min of incubation. No significant difference in kinetic parameters was detected between cells pre-incubated at 37°C or 4°C, under zero-trans conditions. In conclusion, we suggest that measurement of erythrocytes L: -arginine uptake by y+ and y+L systems could be carried out without N-ethylmaleimide pre-incubation at 37°C.

  13. Intestinal Serotonin Transporter Inhibition by Toll-Like Receptor 2 Activation. A Feedback Modulation.

    Directory of Open Access Journals (Sweden)

    Eva Latorre

    Full Text Available TLR2 is a microbiota recognition receptor that has been described to contribute to intestinal homeostasis and to ameliorate inflammatory intestinal injury. In this context, serotonin (5-HT has shown to be an essential intestinal physiological neuromodulator that is also involved in intestinal inflammatory diseases. Since the interaction between TLR2 activation and the intestinal serotoninergic system remains non-investigated, our main aim was to analyze the effect of TLR2 on intestinal serotonin transporter (SERT activity and expression and the intracellular pathways involved. Caco-2/TC7 cells were used to analyze SERT and TLR2 molecular expression and SERT activity by measuring 5-HT uptake. The results showed that apical TLR2 activation inhibits SERT activity in Caco-2/TC7 cells mainly by reducing SERT protein level either in the plasma membrane, after short-term TLR2 activation or in both the plasma membrane and cell lysate, after long-term activation. cAMP/PKA pathway appears to mediate short-term inhibitory effect of TLR2 on SERT; however, p38 MAPK pathway has been shown to be involved in both short- and long-term TLR2 effect. Reciprocally, 5-HT long-term treatment yielded TLR2 down regulation in Caco-2/TC7 cells. Finally, results from in vivo showed an augmented intestinal SERT expression in mice Tlr2-/-, thus confirming our inhibitory effect of TLR2 on intestinal SERT in vitro. The present work infers that TLR2 may act in intestinal pathophysiology, not only by its inherent innate immune role, but also by regulating the intestinal serotoninergic system.

  14. Piracetam and TRH analogues antagonise inhibition by barbiturates, diazepam, melatonin and galanin of human erythrocyte D-glucose transport

    OpenAIRE

    Naftalin, Richard J; Cunningham, Philip; Afzal-Ahmed, Iram

    2004-01-01

    Nootropic drugs increase glucose uptake into anaesthetised brain and into Alzheimer's diseased brain. Thyrotropin-releasing hormone, TRH, which has a chemical structure similar to nootropics increases cerebellar uptake of glucose in murine rolling ataxia. This paper shows that nootropic drugs like piracetam (2-oxo 1 pyrrolidine acetamide) and levetiracetam and neuropeptides like TRH antagonise the inhibition of glucose transport by barbiturates, diazepam, melatonin and endogenous neuropeptide...

  15. Ergopeptines bromocriptine and ergovaline and the dopamine type-2 receptor inhibitor domperidone inhibit bovine equilibrative nucleoside transporter 1-like activity.

    Science.gov (United States)

    Miles, Edwena D; Xue, Yan; Strickland, James R; Boling, James A; Matthews, James C

    2011-09-14

    Neotyphodium coenophialum-infected tall fescue contains ergopeptines. Except for interactions with biogenic amine receptors (e.g., dopamine type-2 receptor, D2R), little is known about how ergopeptines affect animal metabolism. The effect of ergopeptines on bovine nucleoside transporters (NT) was evaluated using Madin-Darby bovine kidney (MDBK) cells. Equilibrative NT1 (ENT1)-like activity accounted for 94% of total NT activity. Inhibitory competition (IC(50)) experiments found that this activity was inhibited by both bromocriptine (a synthetic model ergopeptine and D2R agonist) and ergovaline (a predominant ergopeptine of tall fescue). Kinetic inhibition analysis indicated that bromocriptine inhibited ENT1-like activity through a competitive and noncompetitive mechanism. Domperidone (a D2R antagonist) inhibited ENT1 activity more in the presence than in the absence of bromocriptine and displayed an IC(50) value lower than that of bromocriptine or ergovaline, suggesting that inhibition was not through D2R-mediated events. These novel mechanistic findings imply that cattle consuming endophyte-infected tall fescue have reduced ENT1 activity and, thus, impaired nucleoside metabolism.

  16. Intestinal drug transport via the proton-coupled amino acid transporter PAT1 (SLC36A1) is inhibited by Gly-X(aa) dipeptides

    DEFF Research Database (Denmark)

    Frølund, Sidsel; Langthaler, Louise; Kall, Morten A

    2012-01-01

    -Sar as substrates of the amino acid transporter PAT1. The aim of the present study is to investigate if other Gly-containing dipeptides interact with PAT1, and whether they can inhibit PAT1 mediated drug absorption, in vitro and in vivo. The in vitro methods included two-electrode voltage clamp measurements on h...... of different dipeptides. The in vivo part consisted of a pharmacokinetic study in rats following oral administration of gaboxadol and preadministration of 200 mg/kg dipeptide. The results showed that in hPAT1 expressing oocytes Gly-Tyr, Gly-Pro, and Gly-Phe inhibited currents induced by drug substances......, the present study identifies selected dipeptides as inhibitors of PAT1 mediated drug absorption in various in vitro models....

  17. Interleukin-1β inhibits insulin signaling and prevents insulin-stimulated system A amino acid transport in primary human trophoblasts.

    Science.gov (United States)

    Aye, Irving L M H; Jansson, Thomas; Powell, Theresa L

    2013-12-05

    Interleukin-1β (IL-1β) promotes insulin resistance in tissues such as liver and skeletal muscle; however the influence of IL-1β on placental insulin signaling is unknown. We recently reported increased IL-1β protein expression in placentas of obese mothers, which could contribute to insulin resistance. In this study, we tested the hypothesis that IL-1β inhibits insulin signaling and prevents insulin-stimulated amino acid transport in cultured primary human trophoblast (PHT) cells. Cultured trophoblasts isolated from term placentas were treated with physiological concentrations of IL-1β (10pg/ml) for 24h. IL-1β increased the phosphorylation of insulin receptor substrate-1 (IRS-1) at Ser307 (inhibitory) and decreased total IRS-1 protein abundance but did not affect insulin receptor β expression. Furthermore, IL-1β inhibited insulin-stimulated phosphorylation of IRS-1 (Tyr612, activation site) and Akt (Thr308) and prevented insulin-stimulated increase in PI3K/p85 and Grb2 protein expression. IL-1β alone stimulated cRaf (Ser338), MEK (Ser221) and Erk1/2 (Thr202/Tyr204) phosphorylation. The inflammatory pathways nuclear factor kappa B and c-Jun N-terminal kinase, which are involved in insulin resistance, were also activated by IL-1β treatment. Moreover, IL-1β inhibited insulin-stimulated System A, but not System L amino acid uptake, indicating functional impairment of insulin signaling. In conclusion, IL-1β inhibited the insulin signaling pathway by inhibiting IRS-1 signaling and prevented insulin-stimulated System A transport, thereby promoting insulin resistance in cultured PHT cells. These findings indicate that conditions which lead to increased systemic maternal or placental IL-1β levels may attenuate the effects of maternal insulin on placental function and consequently fetal growth. Published by Elsevier Ireland Ltd.

  18. Basolateral P2X receptors mediate inhibition of NaCl transport in mouse medullary thick ascending limb (mTAL)

    DEFF Research Database (Denmark)

    Marques, Rita D; de Bruijn, Pauline I.A.; Sørensen, Mads Vaarby

    2012-01-01

    Extracellular nucleotides regulate epithelial transport via luminal and basolateral P2 receptors. Renal epithelia express multiple P2 receptors, which mediate significant inhibition of solute absorption. Recently, we identified several P2 receptors in the medullary thick ascending limb (m...

  19. Electroacupuncture Confers Antinociceptive Effects via Inhibition of Glutamate Transporter Downregulation in Complete Freund's Adjuvant-Injected Rats

    Directory of Open Access Journals (Sweden)

    Ha-Neui Kim

    2012-01-01

    Full Text Available When we evaluated changes of glial fibrillary acidic protein (GFAP and two glutamate transporter (GTs by immunohistochemistry, expression of GFAP showed a significant increase in complete Freund's adjuvant (CFA-injected rats; however, this expression was strongly inhibited by electroacupuncture (EA stimulation. Robust downregulation of glutamate-aspartate transporter (GLAST and glutamate transporter-1 (GLT-1 was observed in CFA-injected rats; however, EA stimulation resulted in recovery of this expression. Double-labeling staining showed co-localization of a large proportion of GLAST or GLT-1 with GFAP. Using Western blot, we confirmed protein expression of two GTs, but no differences in the mRNA content of these GTs were observed. Because EA treatment resulted in strong inhibition of CFA-induced proteasome activities, we examined the question of whether thermal sensitivities and GTs expression could be regulated by proteasome inhibitor MG132. CFA-injected rats co-treated with EA and MG132 showed a significantly longer thermal sensitivity, compared with CFA-injected rats with or without MG132. Both EA and MG132 blocked CFA-induced GLAST and GLT-1 downregulation within the spinal cord. These results provide evidence for involvement of GLAST and GLT-1 in response to activation of spinal astrocytes in an EA antinociceptive effect. Antinociceptive effect of EA may be induced via proteasome-mediated regulation of spinal GTs.

  20. Inhibition of beta-amino acid transport by diamide does not involve the brush border membrane surface

    International Nuclear Information System (INIS)

    Chesney, R.W.; Gusowski, N.; Albright, P.

    1985-01-01

    Diamide (dicarboxylic acid bis-(N,N-dimethylamide) has been shown in previous studies to block the uptake of the beta-amino acid taurine at its high affinity transport site in rat renal cortex slices. Diamide may act by increasing the efflux of taurine from the slice. Studies performed in rat slices again indicate enhanced efflux over 8-12 minutes. The time course of reduced glutathione (GSH) depletion from renal cortex is similar, indicating a potential interaction between GSH depletion and inhibition of taurine accumulation. The effect of 9 mM diamide on the Na+ -dependent accumulation of taurine (10 and 250 microM) by brush border membrane vesicles was examined, and the taurine uptake value both initially and at equilibrium was the same in the presence and absence of diamide. Isolation of the brush border surface and subsequent transport studies of taurine are not influenced by diamide. Thus, diamide inhibition of taurine uptake does not involve physiochemical alteration of the membrane surface where active amino acid transport occurs, despite the thiol-oxidizing properties of this agent. Further, these studies suggest that diamide either acts at the basolateral surface, rather than the brush border surface of rat renal cortex or requires the presence of an intact tubule, capable of metabolism, prior to its inhibitory action

  1. Caffeine inhibition of GLUT1 is dependent on the activation state of the transporter.

    Science.gov (United States)

    Gunnink, Leesha K; Busscher, Brianna M; Wodarek, Jeremy A; Rosette, Kylee A; Strohbehn, Lauren E; Looyenga, Brendan D; Louters, Larry L

    2017-06-01

    Caffeine has been shown to be a robust uncompetitive inhibitor of glucose uptake in erythrocytes. It preferentially binds to the nucleotide-binding site on GLUT1 in its tetrameric form and mimics the inhibitory action of ATP. Here we demonstrate that caffeine is also a dose-dependent, uncompetitive inhibitor of 2-deoxyglucose (2DG) uptake in L929 fibroblasts. The inhibitory effect on 2DG uptake in these cells was reversible with a rapid onset and was additive to the competitive inhibitory effects of glucose itself, confirming that caffeine does not interfere with glucose binding. We also report for the first time that caffeine inhibition was additive to inhibition by curcumin, suggesting distinct binding sites for curcumin and caffeine. In contrast, caffeine inhibition was not additive to that of cytochalasin B, consistent with previous data that reported that these two inhibitors have overlapping binding sites. More importantly, we show that the magnitude of maximal caffeine inhibition in L929 cells is much lower than in erythrocytes (35% compared to 90%). Two epithelial cell lines, HCLE and HK2, have both higher concentrations of GLUT1 and increased basal 2DG uptake (3-4 fold) compared to L929 cells, and subsequently display greater maximal inhibition by caffeine (66-70%). Interestingly, activation of 2DG uptake (3-fold) in L929 cells by glucose deprivation shifted the responsiveness of these cells to caffeine inhibition (35%-70%) without a change in total GLUT1 concentration. These data indicate that the inhibition of caffeine is dependent on the activity state of GLUT1, not merely on the concentration. Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  2. Inhibition of bile salt transport by drugs associated with liver injury in primary hepatocytes from human, monkey, dog, rat, and mouse.

    Science.gov (United States)

    Zhang, Jie; He, Kan; Cai, Lining; Chen, Yu-Chuan; Yang, Yifan; Shi, Qin; Woolf, Thomas F; Ge, Weigong; Guo, Lei; Borlak, Jürgen; Tong, Weida

    2016-08-05

    Interference of bile salt transport is one of the underlying mechanisms for drug-induced liver injury (DILI). We developed a novel bile salt transport activity assay involving in situ biosynthesis of bile salts from their precursors in primary human, monkey, dog, rat, and mouse hepatocytes in suspension as well as LC-MS/MS determination of extracellular bile salts transported out of hepatocytes. Glycine- and taurine-conjugated bile acids were rapidly formed in hepatocytes and effectively transported into the extracellular medium. The bile salt formation and transport activities were time‒ and bile-acid-concentration‒dependent in primary human hepatocytes. The transport activity was inhibited by the bile salt export pump (BSEP) inhibitors ketoconazole, saquinavir, cyclosporine, and troglitazone. The assay was used to test 86 drugs for their potential to inhibit bile salt transport activity in human hepatocytes, which included 35 drugs associated with severe DILI (sDILI) and 51 with non-severe DILI (non-sDILI). Approximately 60% of the sDILI drugs showed potent inhibition (with IC50 values monkey, dog, rat and mouse hepatocytes. Species differences in potency were observed with mouse being less sensitive than other species to inhibition of bile salt transport. In summary, a novel assay has been developed using hepatocytes in suspension from human and animal species that can be used to assess the potential for drugs and/or drug-derived metabolites to inhibit bile salt transport and/or formation activity. Drugs causing sDILI, except those by immune-mediated mechanism, are highly associated with potent inhibition of bile salt transport. Published by Elsevier Ireland Ltd.

  3. Tissue transglutaminase inhibits the TRPV5-dependent calcium transport in an N-glycosylation-dependent manner

    DEFF Research Database (Denmark)

    Boros, Sandor; Xi, Qi; Dimke, Henrik Anthony

    2011-01-01

    Tissue transglutaminase (tTG) is a multifunctional Ca(2+)-dependent enzyme, catalyzing protein crosslinking. The transient receptor potential vanilloid (TRPV) family of cation channels was recently shown to contribute to the regulation of TG activities in keratinocytes and hence skin barrier form......, these observations imply that tTG is a novel extracellular enzyme inhibiting the activity of TRPV5. The inhibition of TRPV5 occurs in an N-glycosylation-dependent manner, signifying a common final pathway by which distinct extracellular factors regulate channel activity....

  4. Testosterone increases urinary calcium excretion and inhibits expression of renal calcium transport proteins.

    NARCIS (Netherlands)

    Hsu, Y.J.; Dimke, H.; Schoeber, J.P.H.; Hsu, S.C.; Lin, S.H.; Chu, P.; Hoenderop, J.G.J.; Bindels, R.J.M.

    2010-01-01

    Although gender differences in the renal handling of calcium have been reported, the overall contribution of androgens to these differences remains uncertain. We determined here whether testosterone affects active renal calcium reabsorption by regulating calcium transport proteins. Male mice had

  5. Inhibition or knockdown of ABC transporters enhances susceptibility of adult and juvenile schistosomes to Praziquantel.

    Directory of Open Access Journals (Sweden)

    Ravi S Kasinathan

    2014-10-01

    Full Text Available Parasitic flatworms of the genus Schistosoma cause schistosomiasis, a neglected tropical disease that affects hundreds of millions. Treatment of schistosomiasis depends almost entirely on the drug praziquantel (PZQ. Though essential to treating and controlling schistosomiasis, a major limitation of PZQ is that it is not active against immature mammalian-stage schistosomes. Furthermore, there are reports of field isolates with heritable reductions in PZQ susceptibility, and researchers have selected for PZQ-resistant schistosomes in the laboratory. P-glycoprotein (Pgp; ABCB1 and other ATP binding cassette (ABC transporters remove a wide variety of toxins and xenobiotics from cells, and have been implicated in multidrug resistance (MDR. Changes in ABC transporter structure or expression levels are also associated with reduced drug susceptibility in parasitic helminths, including schistosomes. Here, we show that the activity of PZQ against schistosome adults and juveniles ex vivo is potentiated by co-administration of either the highly potent Pgp inhibitor tariquidar or combinations of inhibitors targeting multiple ABC multidrug transporters. Adult worms exposed to sublethal PZQ concentrations remain active, but co-administration of ABC transporter inhibitors results in complete loss of motility and disruption of the tegument. Notably, juvenile schistosomes (3-4 weeks post infection, normally refractory to 2 µM PZQ, become paralyzed when transporter inhibitors are added in combination with the PZQ. Experiments using the fluorescent PZQ derivative (R-PZQ-BODIPY are consistent with the transporter inhibitors increasing effective intraworm concentrations of PZQ. Adult worms in which expression of ABC transporters has been suppressed by RNA interference show increased responsiveness to PZQ and increased retention of (R-PZQ-BODIPY consistent with an important role for these proteins in setting levels of PZQ susceptibility. These results indicate that

  6. Inhibition of serotonin transporters disrupts the enhancement of fear memory extinction by 3,4-methylenedioxymethamphetamine (MDMA).

    Science.gov (United States)

    Young, Matthew B; Norrholm, Seth D; Khoury, Lara M; Jovanovic, Tanja; Rauch, Sheila A M; Reiff, Collin M; Dunlop, Boadie W; Rothbaum, Barbara O; Howell, Leonard L

    2017-10-01

    3,4-Methylenedioxymethamphetamine (MDMA) persistently improves symptoms of post-traumatic stress disorder (PTSD) when combined with psychotherapy. Studies in rodents suggest that these effects can be attributed to enhancement of fear memory extinction. Therefore, MDMA may improve the effects of exposure-based therapy for PTSD, particularly in treatment-resistant patients. However, given MDMA's broad pharmacological profile, further investigation is warranted before moving to a complex clinical population. We aimed to inform clinical research by providing a translational model of MDMA's effect, and elucidating monoaminergic mechanisms through which MDMA enhances fear extinction. We explored the importance of monoamine transporters targeted by MDMA to fear memory extinction, as measured by reductions in conditioned freezing and fear-potentiated startle (FPS) in mice. Mice were treated with selective inhibitors of individual monoamine transporters prior to combined MDMA treatment and fear extinction training. MDMA enhanced the lasting extinction of FPS. Acute and chronic treatment with a 5-HT transporter (5-HTT) inhibitor blocked MDMA's effect on fear memory extinction. Acute inhibition of dopamine (DA) and norepinephrine (NE) transporters had no effect. 5-HT release alone did not enhance extinction. Blockade of MDMA's effect by 5-HTT inhibition also downregulated 5-HT 2A -mediated behavior, and 5-HT 2A antagonism disrupted MDMA's effect on extinction. We validate enhancement of fear memory extinction by MDMA in a translational behavioral model, and reveal the importance of 5-HTT and 5-HT 2A receptors to this effect. These observations support future clinical research of MDMA as an adjunct to exposure therapy, and provide important pharmacological considerations for clinical use in a population frequently treated with 5-HTT inhibitors.

  7. Inverse agonism at the P2Y12 receptor and ENT1 transporter blockade contribute to platelet inhibition by ticagrelor.

    Science.gov (United States)

    Aungraheeta, Riyaad; Conibear, Alexandra; Butler, Mark; Kelly, Eamonn; Nylander, Sven; Mumford, Andrew; Mundell, Stuart J

    2016-12-08

    Ticagrelor is a potent antagonist of the P2Y 12 receptor (P2Y 12 R) and consequently an inhibitor of platelet activity effective in the treatment of atherothrombosis. Here, we sought to further characterize its molecular mechanism of action. Initial studies showed that ticagrelor promoted a greater inhibition of adenosine 5'-diphosphate (ADP)-induced Ca 2+ release in washed platelets vs other P2Y 12 R antagonists. This additional effect of ticagrelor beyond P2Y 12 R antagonism was in part as a consequence of ticagrelor inhibiting the equilibrative nucleoside transporter 1 (ENT1) on platelets, leading to accumulation of extracellular adenosine and activation of G s -coupled adenosine A 2A receptors. This contributed to an increase in basal cyclic adenosine monophosphate (cAMP) and vasodilator-stimulated phosphoprotein phosphorylation (VASP-P). In addition, ticagrelor increased platelet cAMP and VASP-P in the absence of ADP in an adenosine receptor-independent manner. We hypothesized that this increase originated from a direct effect on basal agonist-independent P2Y 12 R signaling, and this was validated in 1321N1 cells stably transfected with human P2Y 12 R. In these cells, ticagrelor blocked the constitutive agonist-independent activity of the P2Y 12 R, limiting basal G i -coupled signaling and thereby increasing cAMP levels. These data suggest that ticagrelor has the pharmacological profile of an inverse agonist. Based on our results showing insurmountable inhibition of ADP-induced Ca 2+ release and forskolin-induced cAMP, the mode of antagonism of ticagrelor also appears noncompetitive, at least functionally. In summary, our studies describe 2 novel modes of action of ticagrelor, inhibition of platelet ENT1 and inverse agonism at the P2Y 12 R that contribute to its effective inhibition of platelet activation. © 2016 by The American Society of Hematology.

  8. Serotonin Transporter Genotype Moderates the Link between Children's Reports of Overprotective Parenting and Their Behavioral Inhibition

    Science.gov (United States)

    Burkhouse, Katie L.; Gibb, Brandon E.; Coles, Meredith E.; Knopik, Valerie S.; McGeary, John E.

    2011-01-01

    The goal of the current study was to examine environmental and genetic correlates of children's levels of behavioral inhibition (BI). Participants were 100 mother child pairs drawn from the community who were part of a larger study of the intergenerational transmission of depression. Results indicated that higher levels of maternal overprotection,…

  9. Decreased bio-inhibition of building materials due to transport of biocides

    NARCIS (Netherlands)

    Erich, S.J.F.; Mendoza, S.M.; Floor, W.; Hermanns, S.P.M.; Homan, W.J.; Adan, O.C.G.

    2011-01-01

    Bio-inhibition of buildings and structures is an important issue. In many cases building materials have biocides added to prevent growth of micro-organisms. Growth of microorganisms on building materials has several negative effects; (1) Aesthetic damage, e.g. fungi, algae grow on the material,

  10. The anti-epileptic drug substance vigabatrin inhibits taurine transport in intestinal and renal cell culture models

    DEFF Research Database (Denmark)

    Plum, Jakob Munk; Nøhr, Martha Kampp; Hansen, Steen H

    2014-01-01

    , such evidence does not preclude the involvement of other transporters. The aim of the present study was, therefore, to investigate if vigabatrin interacts with taurine transport. The uptake of taurine was measured in intestinal human Caco-2 and canine MDCK cell monolayers in the absence or presence of amino...... acids such as GABA and vigabatrin. Vigabatrin inhibits the uptake of taurine in Caco-2 and MDCK cells to 34±3 and 53±2%, respectively, at a concentration of 30mM. In Caco-2 cells the uptake of vigabatrin under neutral pH conditions is concentration-dependent and saturable with a Km-value of 27mM (log......Km is 1.43±0.09). In conclusion, the present study shows that vigabatrin was able to inhibit the uptake of taurine in intestinal and renal cell culture models. Furthermore, uptake of vigabatrin in Caco-2 cells under neutral pH conditions was concentration-dependent and saturable and suggesting...

  11. A Macrocyclic Peptide that Serves as a Cocrystallization Ligand and Inhibits the Function of a MATE Family Transporter

    Directory of Open Access Journals (Sweden)

    Hiroaki Suga

    2013-08-01

    Full Text Available The random non-standard peptide integrated discovery (RaPID system has proven to be a powerful approach to discover de novo natural product-like macrocyclic peptides that inhibit protein functions. We have recently reported three macrocyclic peptides that bind to Pyrococcus furiosus multidrug and toxic compound extrusion (PfMATE transporter and inhibit the transport function. Moreover, these macrocyclic peptides were successfully employed as cocrystallization ligands of selenomethionine-labeled PfMATE. In this report, we disclose the details of the RaPID selection strategy that led to the identification of these three macrocyclic peptides as well as a fourth macrocyclic peptide, MaD8, which is exclusively discussed in this article. MaD8 was found to bind within the cleft of PfMATE’s extracellular side and blocked the path of organic small molecules being extruded. The results of an ethidium bromide efflux assay confirmed the efflux inhibitory activity of MaD8, whose behavior was similar to that of previously reported MaD5.

  12. Inhibition of macrophage oxidative stress prevents the reduction of ABCA-1 transporter induced by advanced glycated albumin.

    Science.gov (United States)

    de Souza Pinto, Raphael; Castilho, Gabriela; Paim, Bruno Alves; Machado-Lima, Adriana; Inada, Natalia M; Nakandakare, Edna Regina; Vercesi, Aníbal Eugênio; Passarelli, Marisa

    2012-05-01

    We investigated the role of aminoguanidine and benfotiamine on the inhibition of reactive oxygen species (ROS) generation in macrophages induced by advanced glycated albumin (AGE-albumin) and its relationship with cell cholesterol homeostasis, emphasizing the expression of the ATP binding cassette transporter A-1 (ABCA-1). AGE-albumin was made by incubating fatty acid-free albumin with 10 mM glycolaldehyde. ROS production and ABCA-1 protein level were determined by flow cytometry in J774 macrophages treated along time with control (C) or AGE-albumin alone or in the presence of aminoguanidine or benfotiamine. Mitochondrial function was evaluated by oxygraphy. Compared to C-albumin, AGE-albumin increased ROS production in macrophages, which was ascribed to the activities of NADPH oxidase and of the mitochondrial system. Mitochondrial respiratory chain activity was reduced in cells incubated with AGE-albumin. ROS generation along time was associated with the reduction in macrophage ABCA-1 protein level. Aminoguanidine prevented ROS elevation and restored the ABCA-1 content in macrophages; on the other hand, benfotiamine that promoted a lesser reduction in ROS generation was not able to restore ABCA-1 levels. Inhibition of oxidative stress induced by AGE-albumin prevents disturbances in reverse cholesterol transport by curbing the reduction of ABCA-1 elicited by advanced glycation in macrophages and therefore may contribute to the prevention of atherosclerosis in diabetes mellitus.

  13. Enhanced Absorption and Growth Inhibition with Amino Acid Monoester Prodrugs of Floxuridine by Targeting hPEPT1 Transporters

    Directory of Open Access Journals (Sweden)

    Gordon L. Amidon

    2008-06-01

    Full Text Available A series of amino acid monoester prodrugs of floxuridine was synthesized and evaluated for the improvement of oral bioavailability and the feasibility of target drug delivery via oligopeptide transporters. All floxuridine 5′-amino acid monoester prodrugs exhibited PEPT1 affinity, with inhibition coefficients of Gly-Sar uptake (IC50 ranging from 0.7 – 2.3 mM in Caco-2 and 2.0 – 4.8 mM in AsPC-1 cells, while that of floxuridine was 7.3 mM and 6.3 mM, respectively. Caco-2 membrane permeabilities of floxuridine prodrugs (1.01 – 5.31 x 10-6 cm/sec and floxuridine (0.48 x 10-6 cm/sec were much higher than that of 5-FU (0.038 x 10-6 cm/sec. MDCK cells stably transfected with the human oligopeptide transporter PEPT1 (MDCK/hPEPT1 exhibited enhanced cell growth inhibition in the presence of the prodrugs. This prodrug strategy offers great potential, not only for increased drug absorption but also for improved tumor selectivity and drug efficacy.

  14. Enhanced absorption and growth inhibition with amino acid monoester prodrugs of floxuridine by targeting hPEPT1 transporters.

    Science.gov (United States)

    Tsume, Yasuhiro; Vig, Balvinder S; Sun, Jing; Landowski, Christopher P; Hilfinger, John M; Ramachandran, Chandrasekharan; Amidon, Gordon L

    2008-06-28

    A series of amino acid monoester prodrugs of floxuridine was synthesized and evaluated for the improvement of oral bioavailability and the feasibility of target drug delivery via oligopeptide transporters. All floxuridine 5'-amino acid monoester prodrugs exhibited PEPT1 affinity, with inhibition coefficients of Gly-Sar uptake (IC50) ranging from 0.7 - 2.3 mM in Caco-2 and 2.0 - 4.8 mM in AsPC-1 cells, while that of floxuridine was 7.3 mM and 6.3 mM, respectively. Caco-2 membrane permeabilities of floxuridine prodrugs (1.01 - 5.31 x 10(-6 )cm/sec) and floxuridine (0.48 x 10(-6 )cm/sec) were much higher than that of 5-FU (0.038 x 10(-6) cm/sec). MDCK cells stably transfected with the human oligopeptide transporter PEPT1 (MDCK/hPEPT1) exhibited enhanced cell growth inhibition in the presence of the prodrugs. This prodrug strategy offers great potential, not only for increased drug absorption but also for improved tumor selectivity and drug efficacy.

  15. Direct detection of SERCA calcium transport and small-molecule inhibition in giant unilamellar vesicles

    International Nuclear Information System (INIS)

    Bian, Tengfei; Autry, Joseph M.; Casemore, Denise; Li, Ji; Thomas, David D.; He, Gaohong; Xing, Chengguo

    2016-01-01

    We have developed a charge-mediated fusion method to reconstitute the sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) in giant unilamellar vesicles (GUV). Intracellular Ca 2+ transport by SERCA controls key processes in human cells such as proliferation, signaling, and contraction. Small-molecule effectors of SERCA are urgently needed as therapeutics for Ca 2+ dysregulation in human diseases including cancer, diabetes, and heart failure. Here we report the development of a method for efficiently reconstituting SERCA in GUV, and we describe a streamlined protocol based on optimized parameters (e.g., lipid components, SERCA preparation, and activity assay requirements). ATP-dependent Ca 2+ transport by SERCA in single GUV was detected directly using confocal fluorescence microscopy with the Ca 2+ indicator Fluo-5F. The GUV reconstitution system was validated for functional screening of Ca 2+ transport using thapsigargin (TG), a small-molecule inhibitor of SERCA currently in clinical trials as a prostate cancer prodrug. The GUV system overcomes the problem of inhibitory Ca 2+ accumulation for SERCA in native and reconstituted small unilamellar vesicles (SUV). We propose that charge-mediated fusion provides a widely-applicable method for GUV reconstitution of clinically-important membrane transport proteins. We conclude that GUV reconstitution is a technological advancement for evaluating small-molecule effectors of SERCA.

  16. Root cortical aerenchyma inhibits radial nutrient transport in maize (Zea mays).

    Science.gov (United States)

    Hu, Bo; Henry, Amelia; Brown, Kathleen M; Lynch, Jonathan P

    2014-01-01

    Formation of root cortical aerenchyma (RCA) can be induced by nutrient deficiency. In species adapted to aerobic soil conditions, this response is adaptive by reducing root maintenance requirements, thereby permitting greater soil exploration. One trade-off of RCA formation may be reduced radial transport of nutrients due to reduction in living cortical tissue. To test this hypothesis, radial nutrient transport in intact roots of maize (Zea mays) was investigated in two radiolabelling experiments employing genotypes with contrasting RCA. In the first experiment, time-course dynamics of phosphate loading into the xylem were measured from excised nodal roots that varied in RCA formation. In the second experiment, uptake of phosphate, calcium and sulphate was measured in seminal roots of intact young plants in which variation in RCA was induced by treatments altering ethylene action or genetic differences. In each of three paired genotype comparisons, the rate of phosphate exudation of high-RCA genotypes was significantly less than that of low-RCA genotypes. In the second experiment, radial nutrient transport of phosphate and calcium was negatively correlated with the extent of RCA for some genotypes. The results support the hypothesis that RCA can reduce radial transport of some nutrients in some genotypes, which could be an important trade-off of this trait.

  17. Benomyl inhibits phosphorus transport but not fungal alkaline phosphatase activity in a Glomus-cucumber symbiosis

    DEFF Research Database (Denmark)

    Larsen, J.; Thingstrup, I.; Jakobsen, I.

    1996-01-01

    when benomyl was applied to the HC at 10 µg g-1 soil, whereas the uptake of 32P from RHC I roots + hyphae) was reduced only at the highest dose of application to the RHC (100 µ g g-1 soil). In contrast to the marked reduction of benomyl on fungal P transport, the activity of fungal alkaline phosphatase...

  18. Serotonin Transporter Knockout Rats Show Improved Strategy Set-Shifting and Reduced Latent Inhibition

    Science.gov (United States)

    Nonkes, Lourens J. P.; van de Vondervoort, Ilse I. G. M.; de Leeuw, Mark J. C.; Wijlaars, Linda P.; Maes, Joseph H. R.; Homberg, Judith R.

    2012-01-01

    Behavioral flexibility is a cognitive process depending on prefrontal areas allowing adaptive responses to environmental changes. Serotonin transporter knockout (5-HTT[superscript -/-]) rodents show improved reversal learning in addition to orbitofrontal cortex changes. Another form of behavioral flexibility, extradimensional strategy set-shifting…

  19. Lansoprazole Exacerbates Pemetrexed-Mediated Hematologic Toxicity by Competitive Inhibition of Renal Basolateral Human Organic Anion Transporter 3.

    Science.gov (United States)

    Ikemura, Kenji; Hamada, Yugo; Kaya, Chinatsu; Enokiya, Tomoyuki; Muraki, Yuichi; Nakahara, Hiroki; Fujimoto, Hajime; Kobayashi, Tetsu; Iwamoto, Takuya; Okuda, Masahiro

    2016-10-01

    Pemetrexed, a multitargeted antifolate, is eliminated by tubular secretion via human organic anion transporter 3 (hOAT3). Although proton pump inhibitors (PPIs) are frequently used in cancer patients, the drug interaction between PPIs and pemetrexed remains to be clarified. In this study, we examined the drug interaction between pemetrexed and PPIs in hOAT3-expressing cultured cells, and retrospectively analyzed the impact of PPIs on the development of hematologic toxicity in 108 patients who received pemetrexed and carboplatin treatment of nonsquamous non-small cell lung cancer for the first time between January 2011 and June 2015. We established that pemetrexed was transported via hOAT3 (Km = 68.3 ± 11.1 µM). Lansoprazole, rabeprazole, pantoprazole, esomeprazole, omeprazole, and vonoprazan inhibited hOAT3-mediated uptake of pemetrexed in a concentration-dependent manner. The inhibitory effect of lansoprazole was much greater than those of other PPIs and the apparent IC50 value of lansoprazole against pemetrexed transport via hOAT3 was 0.57 ± 0.17 µM. The inhibitory type of lansoprazole was competitive. In a retrospective study, multivariate analysis revealed that coadministration of lansoprazole, but not other PPIs, with pemetrexed and carboplatin was an independent risk factor significantly contributing to the development of hematologic toxicity (odds ratio: 10.004, P = 0.005). These findings demonstrated that coadministration of lansoprazole could exacerbate the hematologic toxicity associated with pemetrexed, at least in part, by competitive inhibition of hOAT3. Our results would aid clinicians to make decisions of coadministration drugs to avoid drug interaction-induced side effects for achievement of safe and appropriate chemotherapy with pemetrexed. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  20. INHIBITION OF MYCOLIC ACID TRANSPORT ACROSS THE MYCOBACTERIUM TUBERCULOSIS PLASMA MEMBRANE

    Science.gov (United States)

    Grzegorzewicz, Anna E.; Pham, Ha; Gundi, Vijay A. K. B.; Scherman, Michael S.; North, Elton J.; Hess, Tamara; Jones, Victoria; Gruppo, Veronica; Born, Sarah E. M.; Korduláková, Jana; Chavadi, Sivagami Sundaram; Morisseau, Christophe; Lenaerts, Anne J.; Lee, Richard E.; McNeil, Michael R.; Jackson, Mary

    2011-01-01

    New chemotherapeutics active against multidrug-resistant Mycobacterium tuberculosis (M. tb) are urgently needed. We report on the identification of an adamantyl urea compound displaying potent bactericidal activity against M. tb and a unique mode of action, namely the abolition of the translocation of mycolic acids from the cytoplasm where they are synthesized to the periplasmic side of the plasma membrane where they are transferred onto cell wall arabinogalactan or used in the formation of virulence-associated outer membrane trehalose-containing glycolipids. Whole genome sequencing of spontaneous resistant mutants of M. tb selected in vitro followed by genetic validation experiments revealed that our prototype inhibitor targets the inner membrane transporter, MmpL3. Conditional gene expression of mmpL3 in mycobacteria and analysis of inhibitor-treated cells validate MmpL3 as essential for mycobacterial growth and support the involvement of this transporter in the translocation of trehalose monomycolate across the plasma membrane. PMID:22344175

  1. Inhibition of GABA transporters fails to afford significant protection following focal cerebral ischemia

    DEFF Research Database (Denmark)

    Lie, Maria Ek; Gowing, Emma K; Clausen, Rasmus P

    2017-01-01

    Brain ischemia triggers excitotoxicity and cell death, yet no neuroprotective drugs have made it to the clinic. While enhancing GABAergic signaling to counterbalance excitotoxicity has shown promise in animal models, clinical studies have failed. Blockade of GABA transporters (GATs) offers...... show that tiagabine can promote protection, our findings indicate that caution should be had when using GAT1 and GAT3 inhibitors for conditions of brain ischemia....

  2. Inhibition of the NorA multi-drug transporter by oxygenated monoterpenes.

    Science.gov (United States)

    Coêlho, Mayara Ladeira; Ferreira, Josie Haydée Lima; de Siqueira Júnior, José Pinto; Kaatz, Glenn W; Barreto, Humberto Medeiros; de Carvalho Melo Cavalcante, Ana Amélia

    2016-10-01

    The aim of this study was to investigate intrinsic antimicrobial activity of three monoterpenes nerol, dimethyl octanol and estragole, against bacteria and yeast strains, as well as, investigate if these compounds are able to inhibit the NorA efflux pump related to fluoroquinolone resistance in Staphylococcus aureus. Minimal inhibitory concentrations (MICs) of the monoterpenes against Staphylococcus aureus, Escherichia coli and Candida albicans strains were determined by micro-dilution assay. MICs of the norfloxacin against a S. aureus strain overexpressing the NorA protein were determined in the absence or in the presence of the monoterpenes at subinhibitory concentrations, aiming to verify the ability of this compounds act as efflux pump inhibitors. The monoterpenes were inactive against S. aureus however the nerol was active against E. coli and C. albicans. The addition of the compounds to growth media at sub-inhibitory concentrations enhanced the activity of norfloxacin against S. aureus SA1199-B. This result shows that bioactives tested, especially the nerol, are able to inhibit NorA efflux pump indicating a potential use as adjuvants of norfloxacin for therapy of infections caused by multi-drug resistant S. aureus strains. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Killing them with kindness? In-hive medications may inhibit xenobiotic efflux transporters and endanger honey bees.

    Directory of Open Access Journals (Sweden)

    David J Hawthorne

    Full Text Available BACKGROUND: Honey bees (Apis mellifera have recently experienced higher than normal overwintering colony losses. Many factors have been evoked to explain the losses, among which are the presence of residues of pesticides and veterinary products in hives. Multiple residues are present at the same time, though most often in low concentrations so that no single product has yet been associated with losses. Involvement of a combination of residues to losses may however not be excluded. To understand the impact of an exposure to combined residues on honey bees, we propose a mechanism-based strategy, focusing here on Multi-Drug Resistance (MDR transporters as mediators of those interactions. METHODOLOGY/PRINCIPAL FINDINGS: Using whole-animal bioassays, we demonstrate through inhibition by verapamil that the widely used organophosphate and pyrethroid acaricides coumaphos and τ-fluvalinate, and three neonicotinoid insecticides: imidacloprid, acetamiprid and thiacloprid are substrates of one or more MDR transporters. Among the candidate inhibitors of honey bee MDR transporters is the in-hive antibiotic oxytetracycline. Bees prefed oxytetracycline were significantly sensitized to the acaricides coumaphos and τ-fluvalinate, suggesting that the antibiotic may interfere with the normal excretion or metabolism of these pesticides. CONCLUSIONS/SIGNIFICANCE: Many bee hives receive regular treatments of oxytetracycline and acaricides for prevention and treatment of disease and parasites. Our results suggest that seasonal co-application of these medicines to bee hives could increase the adverse effects of these and perhaps other pesticides. Our results also demonstrate the utility of a mechanism-based strategy. By identifying pesticides and apicultural medicines that are substrates and inhibitors of xenobiotic transporters we prioritize the testing of those chemical combinations most likely to result in adverse interactions.

  4. Antioxidant defense in quiescent cells determines selectivity of electron transport chain inhibition-induced cell death

    Czech Academy of Sciences Publication Activity Database

    Blecha, Jan; Novais, Silvia Magalhaes; Rohlenová, Kateřina; Novotná, Eliška; Lettlová, Sandra; Schmitt, S.; Zischka, H.; Neužil, Jiří; Rohlena, Jakub

    2017-01-01

    Roč. 112, NOV 2017 (2017), s. 253-266 ISSN 0891-5849 R&D Projects: GA ČR GA16-22823S; GA ČR GA17-20904S; GA ČR GA16-12719S; GA MZd(CZ) NV16-31604A; GA MŠk(CZ) LM2015062; GA MŠk(CZ) LQ1604; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:86652036 Keywords : Electron transport chain * Supercomplexes * Antioxidant defense * SOD2 Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Biochemistry and molecular biology Impact factor: 5.606, year: 2016

  5. Lapatinib potentiates cytotoxicity of  YM155 in neuroblastoma via inhibition of the ABCB1 efflux transporter.

    Science.gov (United States)

    Radic-Sarikas, Branka; Halasz, Melinda; Huber, Kilian V M; Winter, Georg E; Tsafou, Kalliopi P; Papamarkou, Theodore; Brunak, Søren; Kolch, Walter; Superti-Furga, Giulio

    2017-06-08

    Adverse side effects of cancer agents are of great concern in the context of childhood tumors where they can reduce the quality of life in young patients and cause life-long adverse effects. Synergistic drug combinations can lessen potential toxic side effects through lower dosing and simultaneously help to overcome drug resistance. Neuroblastoma is the most common cancer in infancy and extremely heterogeneous in clinical presentation and features. Applying a systematic pairwise drug combination screen we observed a highly potent synergy in neuroblastoma cells between the EGFR kinase inhibitor lapatinib and the anticancer compound YM155 that is preserved across several neuroblastoma variants. Mechanistically, the synergy was based on a lapatinib induced inhibition of the multidrug-resistance efflux transporter ABCB1, which is frequently expressed in resistant neuroblastoma cells, which allowed prolonged and elevated cytotoxicity of YM155. In addition, the drug combination (i.e. lapatinib plus YM155) decreased neuroblastoma tumor size in an in vivo model.

  6. Active glucose transport and proton pumping in tonoplast membrane of Zea mays L. coleoptiles are inhibited by anti-H+-ATPase antibodies

    International Nuclear Information System (INIS)

    Rausch, T.; Butcher, D.N.; Taiz, L.

    1987-01-01

    A tonoplast enriched fraction was obtained from Zea mays L. coleoptiles by isopycnic centrifugation of microsomal membranes in a sucrose step gradient. At the 18/26% interface chloride-stimulated and nitrate-inhibited proton pumping activity coincided with a Mg 2+ -ATP dependent accumulation of 3-O-methyl-D-glucose (OMG) as determined by a membrane filtration technique using 14 C-labeled substrate. OMG transport showed an apparently saturable component with a K/sub m/ of 110 micromolar, and was completely inhibited by 10 micromolar carbonyl cyanide m-chlorophenylhydrazone. Polyclonal antibodies against solubilized native tonoplast H + -ATPase and its 62 and 72 kilodalton subunits were assayed for their ability to inhibit proton pumping and OMG accumulation. Antibodies against both the native enzyme and the putative catalytic subunit strongly inhibited proton pumping and OMG transport whereas antibodies against the 62 kilodalton subunit had only a slight effect on both processes

  7. A series of structurally simple chloroquine chemosensitizing dibemethin derivatives that inhibit chloroquine transport by PfCRT.

    Science.gov (United States)

    Zishiri, Vincent K; Hunter, Roger; Smith, Peter J; Taylor, Dale; Summers, Robert; Kirk, Kiaran; Martin, Rowena E; Egan, Timothy J

    2011-05-01

    A series of 12 new dibemethin (N-benzyl-N-methyl-1-phenylmethanamine) derivatives bearing an N-aminomethyl group attached to the one phenyl ring and an H, Cl, OCH3 or N(CH3)2 group on the other have been synthesized. These compounds all showed strong chloroquine chemosensitizing activity, comparable to verapamil, when present at 1 μM in an in vitro culture of the chloroquine-resistant W2 strain of the human malaria parasite, Plasmodium falciparum. Their N-formylated derivatives also exhibited resistance-reversing activity, but only at substantially higher IC10 concentrations. A number of the dibemethin derivatives were shown to inhibit chloroquine transport via the parasite's 'chloroquine resistance transporter' (PfCRT) in a Xenopus laevis oocyte expression system. The reduced resistance-reversing activity of the formylated compounds relative to their free amine counterparts can probably be ascribed to two factors: decreased accumulation of the formylated dibemethins within the parasite's internal digestive vacuole (believed to be the site of action of chloroquine), and a reduced ability to inhibit PfCRT. The resistance-reversing activity of the compounds described here demonstrates that the amino group need not be attached to the two aromatic rings via a three or four carbon chain as has been suggested by previous QSAR studies. These compounds may be useful as potential side chains for attaching to a 4,7-dichloroquinoline group in order to generate new resistance-reversing chloroquine analogues with inherent antimalarial activity. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

  8. Tofacitinib restores the inhibition of reverse cholesterol transport induced by inflammation: understanding the lipid paradox associated with rheumatoid arthritis.

    Science.gov (United States)

    Pérez-Baos, S; Barrasa, J I; Gratal, P; Larrañaga-Vera, A; Prieto-Potin, I; Herrero-Beaumont, G; Largo, R

    2017-09-01

    Patients with active rheumatoid arthritis (RA) have increased cardiovascular mortality, paradoxically associated with reduced circulating lipid levels. The JAK inhibitor tofacitinib ameliorates systemic and joint inflammation in RA with a concomitant increase in serum lipids. We analysed the effect of tofacitinib on the lipid profile of hyperlipidaemic rabbits with chronic arthritis (CA) and on the changes in reverse cholesterol transport (RCT) during chronic inflammation. CA was induced in previously immunized rabbits, fed a high-fat diet, by administering four intra-articular injections of ovalbumin. A group of rabbits received tofacitinib (10 mg·kg -1 ·day -1 ) for 2 weeks. Systemic and synovial inflammation and lipid content were evaluated. For in vitro studies, THP-1-derived macrophages were exposed to high lipid concentrations and then stimulated with IFNγ in the presence or absence of tofacitinib in order to study mediators of RCT. Tofacitinib decreased systemic and synovial inflammation and increased circulating lipid levels. Although it did not modify synovial macrophage density, it reduced the lipid content within synovial macrophages. In foam macrophages in culture, IFNγ further stimulated intracellular lipid accumulation, while the JAK/STAT inhibition provoked by tofacitinib induced lipid release by increasing the levels of cellular liver X receptor α and ATP-binding cassette transporter (ABCA1) synthesis. Active inflammation could be associated with lipid accumulation within macrophages of CA rabbits. JAK inhibition induced lipid release through RCT activation, providing a plausible explanation for the effect of tofacitinib on the lipid profile of RA patients. © 2017 The British Pharmacological Society.

  9. The fungal phytotoxin alternariol 9-methyl ether and some of its synthetic analogues inhibit the photosynthetic electron transport chain.

    Science.gov (United States)

    Demuner, Antonio Jacinto; Barbosa, Luiz Cláudio Almeida; Miranda, Ana Cristina Mendes; Geraldo, Guilherme Carvalho; da Silva, Cleiton Moreira; Giberti, Samuele; Bertazzini, Michele; Forlani, Giuseppe

    2013-12-27

    Alternariol and monomethylalternariol are natural phytotoxins produced by some fungal strains, such as Nimbya and Alternaria. These substances confer virulence to phytopathogens, yet no information is available concerning their mode of action. Here we show that in the micromolar range alternariol 9-methyl ether is able to inhibit the electron transport chain (IC50 = 29.1 ± 6.5 μM) in isolated spinach chloroplasts. Since its effectiveness is limited by poor solubility in water, several alternariol analogues were synthesized using different aromatic aldehydes. The synthesized 6H-benzo[c]cromen-6-ones, 5H-chromene[4,3-b]pyridin-5-one, and 5H-chromene[4,3-c]pyridin-5-one also showed inhibitory properties, and three 6H-benzo[c]cromen-6-ones were more effective (IC50 = 12.8-22.8 μM) than the lead compound. Their addition to the culture medium of a cyanobacterial model strain was found to inhibit algal growth, with a relative effectiveness that was consistent with their activity in vitro. In contrast, the growth of a nonphotosynthetic plant cell culture was poorly affected. These compounds may represent a novel lead for the development of new active principles targeting photosynthesis.

  10. MDM2 Antagonist Nutlin-3a Reverses Mitoxantrone Resistance by Inhibiting Breast Cancer Resistance Protein Mediated Drug Transport

    Science.gov (United States)

    Zhang, Fan; Throm, Stacy L.; Murley, Laura L.; Miller, Laura A.; Zatechka, D. Steven; Guy, R. Kiplin; Kennedy, Rachel; Stewart, Clinton F.

    2011-01-01

    Breast cancer resistance protein (BCRP; ABCG2), a clinical marker for identifying the side population (SP) cancer stem cell subgroup, affects intestinal absorption, brain penetration, hepatobiliary excretion, and multidrug resistance of many anti-cancer drugs. Nutlin-3a is currently under pre-clinical investigation in a variety of solid tumor and leukemia models as a p53 reactivation agent, and has been recently demonstrated to also have p53 independent actions in cancer cells. In the present study, we first report that nutlin-3a can inhibit the efflux function of BCRP. We observed that although the nutlin-3a IC50 did not differ between BCRP over-expressing and vector control cells, nutlin-3a treatment significantly potentiated the cells to treatment with the BCRP substrate mitoxantrone. Combination index calculations suggested synergism between nutlin-3a and mitoxantrone in cell lines over-expressing BCRP. Upon further investigation, it was confirmed that nutlin-3a increased the intracellular accumulation of BCRP substrates such as mitoxantrone and Hoechst 33342 in cells expressing functional BCRP without altering the expression level or localization of BCRP. Interestingly, nutlin-3b, considered virtually “inactive” in disrupting the MDM2/p53 interaction, reversed Hoechst 33342 efflux with the same potency as nutlin-3a. Intracellular accumulation and bi-directional transport studies using MDCKII cells suggested that nutlin-3a is not a substrate of BCRP. Additionally, an ATPase assay using Sf9 insect cell membranes over-expressing wild-type BCRP indicated that nutlin-3a inhibits BCRP ATPase activity in a dose-dependent fashion. In conclusion, our studies demonstrate that nutlin-3a inhibits BCRP efflux function, which consequently reverses BCRP-related drug resistance. PMID:21459080

  11. Inhibition of polar calcium movement and gravitropism in roots treated with auxin-transport inhibitors

    Science.gov (United States)

    Lee, J. S.; Mulkey, T. J.; Evans, M. L.

    1984-01-01

    Primary roots of maize (Zea mays L.) and pea (Pisum sativum L.) exhibit strong positive gravitropism. In both species, gravistimulation induces polar movement of calcium across the root tip from the upper side to the lower side. Roots of onion (Allium cepa L.) are not responsive to gravity and gravistimulation induces little or no polar movement of calcium across the root tip. Treatment of maize or pea roots with inhibitors of auxin transport (morphactin, naphthylphthalamic acid, 2,3,5-triiodobenzoic acid) prevents both gravitropism and gravity-induced polar movement of calcium across the root tip. The results indicate that calcium movement and auxin movement are closely linked in roots and that gravity-induced redistribution of calcium across the root cap may play an important role in the development of gravitropic curvature.

  12. Substrate-Dependent Inhibition of P-glycoprotein Mediated Efflux Transport of Digoxin

    DEFF Research Database (Denmark)

    Saaby, Lasse; Ozgür, Burak; Brodin, Birger

    , distribution and excretion of a wide range of structurally diverse drug compounds and P-gp therefore constitutes a potential site for drug-drug interactions. The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) recommend that all new investigational drugs be screened...... for interactions with P-gp among other transporters in vitro. This includes an evaluation of new drug compounds as inhibitors of P-gp, preferably in competition with a clinically relevant probe substrate such as digoxin. However, increasing evidence indicates that the binding pocket of P-gp contains several...... overlapping binding sites for substrates. This suggests that drug-drug interactions may be pairwise specific and observations of interaction from a single drug-drug combination may therefore not apply to a second drug combination. At present, it is not known which drug combinations should be considered...

  13. Transport inhibition of digoxin using several common P-gp expressing cell lines is not necessarily reporting only on inhibitor binding to P-gp.

    Directory of Open Access Journals (Sweden)

    Annie Albin Lumen

    Full Text Available We have reported that the P-gp substrate digoxin required basolateral and apical uptake transport in excess of that allowed by digoxin passive permeability (as measured in the presence of GF120918 to achieve the observed efflux kinetics across MDCK-MDR1-NKI (The Netherlands Cancer Institute confluent cell monolayers. That is, GF120918 inhibitable uptake transport was kinetically required. Therefore, IC50 measurements using digoxin as a probe substrate in this cell line could be due to inhibition of P-gp, of digoxin uptake transport, or both. This kinetic analysis is now extended to include three additional cell lines: MDCK-MDR1-NIH (National Institute of Health, Caco-2 and CPT-B2 (Caco-2 cells with BCRP knockdown. These cells similarly exhibit GF120918 inhibitable uptake transport of digoxin. We demonstrate that inhibition of digoxin transport across these cell lines by GF120918, cyclosporine, ketoconazole and verapamil is greater than can be explained by inhibition of P-gp alone. We examined three hypotheses for this non-P-gp inhibition. The inhibitors can: (1 bind to a basolateral digoxin uptake transporter, thereby inhibiting digoxin's cellular uptake; (2 partition into the basolateral membrane and directly reduce membrane permeability; (3 aggregate with digoxin in the donor chamber, thereby reducing the free concentration of digoxin, with concomitant reduction in digoxin uptake. Data and simulations show that hypothesis 1 was found to be uniformly acceptable. Hypothesis 2 was found to be uniformly unlikely. Hypothesis 3 was unlikely for GF120918 and cyclosporine, but further studies are needed to completely adjudicate whether hetero-dimerization contributes to the non-P-gp inhibition for ketoconazole and verapamil. We also find that P-gp substrates with relatively low passive permeability such as digoxin, loperamide and vinblastine kinetically require basolateral uptake transport over that allowed by +GF120918 passive permeability, while

  14. Lipophilic triphenylphosphonium cations inhibit mitochondrial electron transport chain and induce mitochondrial proton leak.

    Directory of Open Access Journals (Sweden)

    Jan Trnka

    Full Text Available The lipophilic positively charged moiety of triphenylphosphonium (TPP+ has been used to target a range of biologically active compounds including antioxidants, spin-traps and other probes into mitochondria. The moiety itself, while often considered biologically inert, appears to influence mitochondrial metabolism.We used the Seahorse XF flux analyzer to measure the effect of a range of alkylTPP+ on cellular respiration and further analyzed their effect on mitochondrial membrane potential and the activity of respiratory complexes. We found that the ability of alkylTPP+ to inhibit the respiratory chain and decrease the mitochondrial membrane potential increases with the length of the alkyl chain suggesting that hydrophobicity is an important determinant of toxicity.More hydrophobic TPP+ derivatives can be expected to have a negative impact on mitochondrial membrane potential and respiratory chain activity in addition to the effect of the biologically active moiety attached to them. Using shorter linker chains or adding hydrophilic functional groups may provide a means to decrease this negative effect.

  15. Bafetinib (INNO-406) reverses multidrug resistance by inhibiting the efflux function of ABCB1 and ABCG2 transporters

    Science.gov (United States)

    Zhang, Yun-Kai; Zhang, Guan-Nan; Wang, Yi-Jun; Patel, Bhargav A.; Talele, Tanaji T.; Yang, Dong-Hua; Chen, Zhe-Sheng

    2016-05-01

    ATP-Binding Cassette transporters are involved in the efflux of xenobiotic compounds and are responsible for decreasing drug accumulation in multidrug resistant (MDR) cells. Discovered by structure-based virtual screening algorithms, bafetinib, a Bcr-Abl/Lyn tyrosine kinase inhibitor, was found to have inhibitory effects on both ABCB1- and ABCG2-mediated MDR in this in-vitro investigation. Bafetinib significantly sensitized ABCB1 and ABCG2 overexpressing MDR cells to their anticancer substrates and increased the intracellular accumulation of anticancer drugs, particularly doxorubicin and [3H]-paclitaxel in ABCB1 overexpressing cells; mitoxantrone and [3H]-mitoxantrone in ABCG2 overexpressing cells, respectively. Bafetinib stimulated ABCB1 ATPase activities while inhibited ABCG2 ATPase activities. There were no significant changes in the expression level or the subcellular distribution of ABCB1 and ABCG2 in the cells exposed to 3 μM of bafetinib. Overall, our study indicated that bafetinib reversed ABCB1- and ABCG2-mediated MDR by blocking the drug efflux function of these transporters. These findings might be useful in developing combination therapy for MDR cancer treatment.

  16. Mucociliary transport in porcine trachea: differential effects of inhibiting chloride and bicarbonate secretion.

    Science.gov (United States)

    Cooper, Jeffrey L; Quinton, Paul M; Ballard, Stephen T

    2013-02-01

    This study was designed to assess the relative importance of Cl(-) and HCO(3)(-) secretion to mucociliary transport rate (MCT) in ex vivo porcine tracheas. MCT was measured in one group of tissues that was exposed to adventitial HCO(3)(-)-free solution while a parallel group was exposed to adventitial HCO(3)(-)-replete solution. After measurement of baseline MCT rates, acetylcholine (ACh) was added to stimulate submucosal gland mucous liquid secretion, and MCT rates were again measured. Before ACh addition, the mean MCT was higher in the HCO(3)(-)-free group (4.2 ± 0.9 mm/min) than in the HCO(3)(-)-replete group (2.3 ± 0.3 mm/min), but this difference was not statistically significant. ACh addition significantly increased MCT in both groups, but ACh-stimulated MCT was significantly lower in the HCO(3)(-)-free group (11.0 ± 1.5 mm/min) than in the HCO(3)(-)-replete group (17.0 ± 2.0 mm/min). A second series of experiments examined the effect on MCT of blocking Cl(-) secretion with 100 μM bumetanide. Before adding ACh, MCT in the bumetanide-treated group (1.0 ± 0.2 mm/min) was significantly lower than in the control group (3.8 ± 1.1 mm/min). ACh addition significantly increased MCT in both groups, but there was no significant difference between the bumetanide-treated group (21.4 ± 1.7 mm/min) and control group (19.5 ± 3.4 mm/min). These results indicate that ACh-stimulated MCT has greater dependence on HCO(3)(-) secretion, whereas the basal MCT rate has greater dependence on Cl(-) secretion.

  17. Gibberellins inhibit adventitious rooting in hybrid aspen and Arabidopsis by affecting auxin transport.

    Science.gov (United States)

    Mauriat, Mélanie; Petterle, Anna; Bellini, Catherine; Moritz, Thomas

    2014-05-01

    Knowledge of processes involved in adventitious rooting is important to improve both fundamental understanding of plant physiology and the propagation of numerous plants. Hybrid aspen (Populus tremula × tremuloïdes) plants overexpressing a key gibberellin (GA) biosynthesis gene (AtGA20ox1) grow rapidly but have poor rooting efficiency, which restricts their clonal propagation. Therefore, we investigated the molecular basis of adventitious rooting in Populus and the model plant Arabidopsis. The production of adventitious roots (ARs) in tree cuttings is initiated from the basal stem region, and involves the interplay of several endogenous and exogenous factors. The roles of several hormones in this process have been characterized, but the effects of GAs have not been fully investigated. Here, we show that a GA treatment negatively affects the numbers of ARs produced by wild-type hybrid aspen cuttings. Furthermore, both hybrid aspen plants and intact Arabidopsis seedlings overexpressing AtGA20ox1, PttGID1.1 or PttGID1.3 genes (with a 35S promoter) produce few ARs, although ARs develop from the basal stem region of hybrid aspen and the hypocotyl of Arabidopsis. In Arabidopsis, auxin and strigolactones are known to affect AR formation. Our data show that the inhibitory effect of GA treatment on adventitious rooting is not mediated by perturbation of the auxin signalling pathway, or of the strigolactone biosynthetic and signalling pathways. Instead, GAs appear to act by perturbing polar auxin transport, in particular auxin efflux in hybrid aspen, and both efflux and influx in Arabidopsis. © 2014 The Authors The Plant Journal © 2014 John Wiley & Sons Ltd.

  18. Protective effect of S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721) on irradiation-induced inhibition of intestinal transport function

    International Nuclear Information System (INIS)

    Chen, T.S.; Ando, M.

    1983-01-01

    The purpose of this study was to investigate the protective effect of S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721) on whole-body irradiation-induced inhibition of intestinal transport function. The jejunal transport of fluid and sugars was studied in male Swiss-Webster mice before and 3 days after whole-body irradiation (1000 rads). The rates of glucose and water transport were decreased by 86 and 70%, respectively, in irradiated animals. However, the rate of transport of 3-O-methyl-D-glucose (3MG) was not affected. In mice receiving WR-2721 (500 mg/kg, ip) 15 to 30 min prior to whole-body irradiation, net water flux was unaffected and the rate of D-glucose transport was decreased only 8%. WR-2721 administered alone (500 mg/kg, ip) had no effect on either D-glucose transport or net water flux across the jejunal mucosa. The results suggest that WR-2721 protects against irradiation-induced inhibition of some intestinal transport functions

  19. Membrane polypeptide in rabbit erythrocytes associated with the inhibition of L-lactate transport by a synthetic anhydride of lactic acid

    International Nuclear Information System (INIS)

    Donovan, J.A.; Jennings, M.L.

    1985-01-01

    The synthetic lactyl anhydride isobutylcarbonyl lactyl anhydride (iBCLA), a selective and potent inhibitor of L-(+)-lactate transport in rabbit erythrocytes, reduces the chemical labeling of a 40-50-kdalton polypeptide by tritiated 4,4'-diisothiocyanato-2,2'-dihydrostilbenedisulfonate ([ 3 H]H 2 DIDS). iBCLA does so in a dose-dependent manner at concentrations that strongly inhibit lactate-lactate exchange but not chloride-phosphate exchange. These labeling experiments and inhibition reversal studies using iBCLA, p-(chloro-mercuri)benzenesulfonic acid (pCMBS), and dithiothreitol (DDT) suggest that iBCLA does not act at sulfhydryl groups but at or near an amino group that is near a disulfide linkage in the polypeptide which catalyzes lactate transport. These experiments support the association between specific monocarboxylate transport and a 40-50-kdalton membrane-bound polypeptide of the rabbit erythrocyte

  20. Epidermal growth factor inhibits glycyl sarcosine transport and hPepT1 expression in a human intestinal cell line

    DEFF Research Database (Denmark)

    Nielsen, Carsten Uhd; Amstrup, Jan; Steffansen, Bente

    2001-01-01

    Intestinal oligopeptide transporter, growth factor, immunocytochemistry, laser scanning confocal microscopy......Intestinal oligopeptide transporter, growth factor, immunocytochemistry, laser scanning confocal microscopy...

  1. Fentanyl Enhances Hepatotoxicity of Paclitaxel via Inhibition of CYP3A4 and ABCB1 Transport Activity in Mice

    Science.gov (United States)

    Pan, Jia-Hao; Bi, Bing-Tian; Feng, Kun-Yao; Huang, Wan; Zeng, Wei-An

    2015-01-01

    Fentanyl, a potent opioid analgesic that is used to treat cancer pain, is commonly administered with paclitaxel in advanced tumors. However, the effect of fentanyl on the hepatotoxicity of paclitaxel and its potential mechanism of action is not well studied. The purpose of this study was to investigate the effect of fentanyl on the hepatotoxicity of paclitaxel and its potential mechanisms of action. Pharmacokinetic parameters of paclitaxel were tested using reversed phase high-performance liquid chromatography (RP-HPLC). Aspartate transaminase (AST), alanine aminotransferase (ALT), and mouse liver histopathology were examined. Moreover, the cytotoxicity of anti-carcinogens was examined using 1-(4, 5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), and the intracellular accumulation of doxorubicin and rhodamine 123 was detected by flow cytometry. Furthermore, the expression of ABCB1 and the activity of ABCB1 ATPase and CYP3A4 were also examined. In this study, the co-administration of fentanyl and paclitaxel prolonged the half-life (t1/2) of paclitaxel from 1.455 hours to 2.344 hours and decreased the clearance (CL) from 10.997 ml/h to 7.014 ml/h in mice. Fentanyl significantly increased the levels of ALT in mice to 88.2 U/L, which is more than 2-fold higher than the level detected in the control group, and it increased the histological damage in mouse livers. Furthermore, fentanyl enhanced the cytotoxicity of anti-carcinogens that are ABCB1 substrates and increased the accumulation of doxorubicin and rhodamine 123. Additionally, fentanyl stimulated ABCB1 ATPase activity and inhibited CYP3A4 activity in the liver microsomes of mice. Our study indicates that the obvious hepatotoxicity during this co-administration was due to the inhibition of CYP3A4 activity and ABCB1 transport activity. These findings suggested that the accumulation-induced hepatotoxicity of paclitaxel when it is combined with fentanyl should be avoided. PMID:26633878

  2. The Complexities of Interpreting Reversible Elevated Serum Creatinine Levels in Drug Development: Does a Correlation with Inhibition of Renal Transporters Exist?

    Science.gov (United States)

    Chu, Xiaoyan; Bleasby, Kelly; Chan, Grace Hoyee; Nunes, Irene; Evers, Raymond

    2016-09-01

    In humans, creatinine is formed by a multistep process in liver and muscle and eliminated via the kidney by a combination of glomerular filtration and active transport. Based on current evidence, creatinine can be taken up into renal proximal tubule cells by the basolaterally localized organic cation transporter 2 (OCT2) and the organic anion transporter 2, and effluxed into the urine by the apically localized multidrug and toxin extrusion protein 1 (MATE1) and MATE2K. Drug-induced elevation of serum creatinine (SCr) and/or reduced creatinine renal clearance is routinely used as a marker for acute kidney injury. Interpretation of elevated SCr can be complex, because such increases can be reversible and explained by inhibition of renal transporters involved in active secretion of creatinine or other secondary factors, such as diet and disease state. Distinction between these possibilities is important from a drug development perspective, as increases in SCr can result in the termination of otherwise efficacious drug candidates. In this review, we discuss the challenges associated with using creatinine as a marker for kidney damage. Furthermore, to evaluate whether reversible changes in SCr can be predicted prospectively based on in vitro transporter inhibition data, an in-depth in vitro-in vivo correlation (IVIVC) analysis was conducted for 16 drugs with in-house and literature in vitro transporter inhibition data for OCT2, MATE1, and MATE2K, as well as total and unbound maximum plasma concentration (Cmax and Cmax,u) data measured in the clinic. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

  3. Transportation

    National Research Council Canada - National Science Library

    Adams, James; Carr, Ron; Chebl, Maroun; Coleman, Robert; Costantini, William; Cox, Robert; Dial, William; Jenkins, Robert; McGovern, James; Mueller, Peter

    2006-01-01

    ...., trains, ships, etc.) and maximizing intermodal efficiency. A healthy balance must be achieved between the flow of international commerce and security requirements regardless of transportation mode...

  4. Analysis of the repaglinide concentration increase produced by gemfibrozil and itraconazole based on the inhibition of the hepatic uptake transporter and metabolic enzymes.

    Science.gov (United States)

    Kudo, Toshiyuki; Hisaka, Akihiro; Sugiyama, Yuichi; Ito, Kiyomi

    2013-02-01

    The plasma concentration of repaglinide is reported to increase greatly when given after repeated oral administration of itraconazole and gemfibrozil. The present study analyzed this interaction based on a physiologically based pharmacokinetic (PBPK) model incorporating inhibition of the hepatic uptake transporter and metabolic enzymes involved in repaglinide disposition. Firstly, the plasma concentration profiles of inhibitors (itraconazole, gemfibrozil, and gemfibrozil glucuronide) were reproduced by a PBPK model to obtain their pharmacokinetic parameters. The plasma concentration profiles of repaglinide were then analyzed by a PBPK model, together with those of the inhibitors, assuming a competitive inhibition of CYP3A4 by itraconazole, mechanism-based inhibition of CYP2C8 by gemfibrozil glucuronide, and inhibition of organic anion transporting polypeptide (OATP) 1B1 by gemfibrozil and its glucuronide. The plasma concentration profiles of repaglinide were well reproduced by the PBPK model based on the above assumptions, and the optimized values for the inhibition constants (0.0676 nM for itraconazole against CYP3A4; 14.2 μM for gemfibrozil against OATP1B1; and 5.48 μM for gemfibrozil glucuronide against OATP1B1) and the fraction of repaglinide metabolized by CYP2C8 (0.801) were consistent with the reported values. The validity of the obtained parameters was further confirmed by sensitivity analyses and by reproducing the repaglinide concentration increase produced by concomitant gemfibrozil administration at various timings/doses. The present findings suggested that the reported concentration increase of repaglinide, suggestive of synergistic effects of the coadministered inhibitors, can be quantitatively explained by the simultaneous inhibition of the multiple clearance pathways of repaglinide.

  5. Transport by SLC5A8 with subsequent inhibition of histone deacetylase 1 (HDAC1) and HDAC3 underlies the antitumor activity of 3-bromopyruvate.

    Science.gov (United States)

    Thangaraju, Muthusamy; Karunakaran, Senthil K; Itagaki, Shiro; Gopal, Elangovan; Elangovan, Selvakumar; Prasad, Puttur D; Ganapathy, Vadivel

    2009-10-15

    3-bromopyruvate is an alkylating agent with antitumor activity. It is currently believed that blockade of adenosine triphosphate production from glycolysis and mitochondria is the primary mechanism responsible for this antitumor effect. The current studies uncovered a new and novel mechanism for the antitumor activity of 3-bromopyruvate. The transport of 3-bromopyruvate by sodium-coupled monocarboxylate transporter SMCT1 (SLC5A8), a tumor suppressor and a sodium (Na+)-coupled, electrogenic transporter for short-chain monocarboxylates, was studied using a mammalian cell expression and the Xenopus laevis oocyte expression systems. The effect of 3-bromopyruvate on histone deacetylases (HDACs) was monitored using the lysate of the human breast cancer cell line MCF7 and human recombinant HDAC isoforms as the enzyme sources. Cell viability was monitored by fluorescence-activated cell-sorting analysis and colony-formation assay. The acetylation status of histone H4 was evaluated by Western blot analysis. 3-Bromopyruvate is a transportable substrate for SLC5A8, and that transport process is Na+-coupled and electrogenic. MCF7 cells did not express SLC5A8 and were not affected by 3-bromopyruvate. However, when transfected with SLC5A8 or treated with inhibitors of DNA methylation, these cells underwent apoptosis in the presence of 3-bromopyruvate. This cell death was associated with the inhibition of HDAC1/HDAC3. Studies with different isoforms of human recombinant HDACs identified HDAC1 and HDAC3 as the targets for 3-bromopyruvate. 3-Bromopyruvate was transported into cells actively through the tumor suppressor SLC5A8, and the process was energized by an electrochemical Na+ gradient. Ectopic expression of the transporter in MCF7 cells led to apoptosis, and the mechanism involved the inhibition of HDAC1/HDAC3. Copyright (c) 2009 American Cancer Society.

  6. Transportation

    International Nuclear Information System (INIS)

    Anon.

    1998-01-01

    Here is the decree of the thirtieth of July 1998 relative to road transportation, to trade and brokerage of wastes. It requires to firms which carry out a road transportation as well as to traders and to brokers of wastes to declare their operations to the prefect. The declaration has to be renewed every five years. (O.M.)

  7. Celecoxib sensitizes imatinib-resistant K562 cells to imatinib by inhibiting MRP1-5, ABCA2 and ABCG2 transporters via Wnt and Ras signaling pathways.

    Science.gov (United States)

    Dharmapuri, Gangappa; Doneti, Ravinder; Philip, Gundala Harold; Kalle, Arunasree M

    2015-07-01

    Imatinib mesylate, a tyrosine kinase inhibitor, is very effective in the treatment of chronic myeloid leukemia (CML). However, development of resistance to imatinib therapy is also a very common mechanism observed with long-term administration of the drug. Our previous studies have highlighted the role of cyclooxygenase-2 (COX-2) in regulating the expression of multidrug resistant protein-1 (MDR1), P-gp, in imatinib-resistant K562 cells (IR-K562) via PGE2-cAMP-PKC-NF-κB pathway and inhibition of COX-2 by celecoxib, a COX-2 specific inhibitor, inhibits this pathway and reverses the drug resistance. Studies have identified that not only MDR1 but other ATP-binding cassette transport proteins (ABC transporters) are involved in the development of imatinib resistance. Here, we tried to study the role of COX-2 in the regulation of other ABC transporters such as MRP1, MRP2, MRP3, ABCA2 and ABCG2 that have been already implicated in imatinib resistance development. The results of the study clearly indicated that overexpression of COX-2 lead to upregulation of MRP family proteins in IR-K562 cells and celecoxib down-regulated the ABC transporters through Wnt and MEK signaling pathways. The study signifies that celecoxib in combination with the imatinib can be a good alternate treatment strategy for the reversal of imatinib resistance. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Quantitative analysis of elevation of serum creatinine via renal transporter inhibition by trimethoprim in healthy subjects using physiologically-based pharmacokinetic model.

    Science.gov (United States)

    Nakada, Tomohisa; Kudo, Toshiyuki; Kume, Toshiyuki; Kusuhara, Hiroyuki; Ito, Kiyomi

    2018-02-01

    Serum creatinine (SCr) levels rise during trimethoprim therapy for infectious diseases. This study aimed to investigate whether the elevation of SCr can be quantitatively explained using a physiologically-based pharmacokinetic (PBPK) model incorporating inhibition by trimethoprim on tubular secretion of creatinine via renal transporters such as organic cation transporter 2 (OCT2), OCT3, multidrug and toxin extrusion protein 1 (MATE1), and MATE2-K. Firstly, pharmacokinetic parameters in the PBPK model of trimethoprim were determined to reproduce the blood concentration profile after a single intravenous and oral administration of trimethoprim in healthy subjects. The model was verified with datasets of both cumulative urinary excretions after a single administration and the blood concentration profile after repeated oral administration. The pharmacokinetic model of creatinine consisted of the creatinine synthesis rate, distribution volume, and creatinine clearance (CL cre ), including tubular secretion via each transporter. When combining the models for trimethoprim and creatinine, the predicted increments in SCr from baseline were 29.0%, 39.5%, and 25.8% at trimethoprim dosages of 5 mg/kg (b.i.d.), 5 mg/kg (q.i.d.), and 200 mg (b.i.d.), respectively, which were comparable with the observed values. The present model analysis enabled us to quantitatively explain increments in SCr during trimethoprim treatment by its inhibition of renal transporters. Copyright © 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

  9. Transport via SLC5A8 with Subsequent Inhibition of Histone Deacetylases HDAC1 and HDAC3 Underlies the Antitumor Activity of 3-Bromopyruvate

    Science.gov (United States)

    Thangaraju, Muthusamy; Karunakaran, Senthil K.; Itagaki, Shiro; Gopal, Elangovan; Elangovan, Selvakumar; Prasad, Puttur D.; Ganapathy, Vadivel

    2009-01-01

    Background 3-Bromopyruvate is an alkylating agent with antitumor activity. It is currently believed that blockade of ATP production from glycolysis and mitochondria is the primary mechanism responsible for this antitumor effect. The present studies have uncovered a new and novel mechanism for the antitumor activity of 3-bromopyruvate. Methods Transport of 3-bromopyruvate via SLC5A8, a tumor suppressor and a Na+-coupled electrogenic transporter for short-chain monocarboxylates, was studied using a mammalian cell expression and the Xenopus laevis oocyte expression systems. The effect of 3-bromopyruvate on histone deacetylases (HDACs) was monitored using the lysate of the human breast cancer cell line MCF7 and human recombinant HDAC isoforms as the enzyme sources. Cell viability was monitored by FACS analysis and colony formation assay. Acetylation status of histone H4 was evaluated by Western blot. Results 3-Bromopyruvate is a transportable substrate for SLC5A8, with the transport process being Na+-coupled and electrogenic. MCF7 cells do not express SLC5A8 and are not affected by 3-bromopyruvate. However, when transfected with SLC5A8 or treated with inhibitors of DNA methylation, these cells undergo apoptosis in the presence of 3-bromopyruvate. This cell death is associated with inhibition of HDAC1/HDAC3. Studies with different isoforms of human recombinant HDACs identify HDAC1 and HDAC3 as the targets for 3-bromopyruvate. Conclusions 3-Bromopyruvate is transported into cells actively via the tumor suppressor SLC5A8 and the process is energized by an electrochemical Na+ gradient. Ectopic expression of the transporter in MCF7 cells leads to apoptosis, and the mechanism involves inhibition of HDAC1/HDAC3. PMID:19637353

  10. Active Hydrophilic Components of the Medicinal Herb Salvia miltiorrhiza (Danshen Potently Inhibit Organic Anion Transporters 1 (Slc22a6 and 3 (Slc22a8

    Directory of Open Access Journals (Sweden)

    Li Wang

    2012-01-01

    Full Text Available Many active components of herbal products are small organic anions, and organic anion transporters were previously demonstrated to be a potential site of drug-drug interactions. In this study, we assessed the inhibitory effects of six hydrophilic components of the herbal medicine Danshen, lithospermic acid, protocatechuic acid, rosmarinic acid, salvianolic acid A, salvianolic acid B, and tanshinol, on the function of the murine organic anion transporters, mOat1 and mOat3. All of Danshen components significantly inhibited mOat1- and mOat3-mediated substrate uptake (<0.001 with lithospermic acid (LSA, protocatechuic acid, rosmarinic acid (RMA, and salvianolic acid A (SAA producing virtually complete inhibition under test conditions. Kinetic analysis demonstrated that LSA, RMA, and SAA were competitive inhibitors. As such, values were estimated as 14.9±4.9 μM for LSA, 5.5±2.2 μM for RMA, and 4.9±2.2 μM for SAA on mOat1-mediated transport, and as 31.1±7.0 μM for LSA, 4.3±0.2 μM for RMA, and 21.3±7.7 μM for SAA on mOat3-mediated transport. These data suggest that herb-drug interactions may occur in vivo on the human orthologs of these transporters in situations of polypharmacy involving Danshen and clinical therapeutics known to be organic anion transporter substrates.

  11. Transportation

    National Research Council Canada - National Science Library

    Allshouse, Michael; Armstrong, Frederick Henry; Burns, Stephen; Courts, Michael; Denn, Douglas; Fortunato, Paul; Gettings, Daniel; Hansen, David; Hoffman, D. W; Jones, Robert

    2007-01-01

    .... The ability of the global transportation industry to rapidly move passengers and products from one corner of the globe to another continues to amaze even those wise to the dynamics of such operations...

  12. Celecoxib Induced Tumor Cell Radiosensitization by Inhibiting Radiation Induced Nuclear EGFR Transport and DNA-Repair: A COX-2 Independent Mechanism

    International Nuclear Information System (INIS)

    Dittmann, Klaus H.; Mayer, Claus; Ohneseit, Petra A.; Raju, Uma; Andratschke, Nickolaus H.; Milas, Luka; Rodemann, H. Peter

    2008-01-01

    Purpose: The purpose of the study was to elucidate the molecular mechanisms mediating radiosensitization of human tumor cells by the selective cyclooxygenase (COX)-2 inhibitor celecoxib. Methods and Materials: Experiments were performed using bronchial carcinoma cells A549, transformed fibroblasts HH4dd, the FaDu head-and-neck tumor cells, the colon carcinoma cells HCT116, and normal fibroblasts HSF7. Effects of celecoxib treatment were assessed by clonogenic cell survival, Western analysis, and quantification of residual DNA damage by γH 2 AX foci assay. Results: Celecoxib treatment resulted in a pronounced radiosensitization of A549, HCT116, and HSF7 cells, whereas FaDu and HH4dd cells were not radiosensitized. The observed radiosensitization could neither be correlated with basal COX-2 expression pattern nor with basal production of prostaglandin E2, but was depended on the ability of celecoxib to inhibit basal and radiation-induced nuclear transport of epidermal growth factor receptor (EGFR). The nuclear EGFR transport was strongly inhibited in A549-, HSF7-, and COX-2-deficient HCT116 cells, which were radiosensitized, but not in FaDu and HH4dd cells, which resisted celecoxib-induced radiosensitization. Celecoxib inhibited radiation-induced DNA-PK activation in A549, HSF7, and HCT116 cells, but not in FaDu and HH4dd cells. Consequentially, celecoxib increased residual γH2AX foci after irradiation, demonstrating that inhibition of DNA repair has occurred in responsive A549, HCT116, and HSF7 cells only. Conclusions: Celecoxib enhanced radiosensitivity by inhibition of EGFR-mediated mechanisms of radioresistance, a signaling that was independent of COX-2 activity. This novel observation may have therapeutic implications such that COX-2 inhibitors may improve therapeutic efficacy of radiation even in patients whose tumor radioresistance is not dependent on COX-2

  13. Lipopolysaccharide inhibits colonic biotin uptake via interference with membrane expression of its transporter: a role for a casein kinase 2-mediated pathway.

    Science.gov (United States)

    Lakhan, Ram; Said, Hamid M

    2017-04-01

    Biotin (vitamin B7), an essential micronutrient for normal cellular functions, is obtained from both dietary sources as well as gut microbiota. Absorption of biotin in both the small and large intestine is via a carrier-mediated process that involves the sodium-dependent multivitamin transporter (SMVT). Although different physiological and molecular aspects of intestinal biotin uptake have been delineated, nothing is known about the effect of LPS on the process. We addressed this issue using in vitro (human colonic epithelial NCM460 cells) and in vivo (mice) models of LPS exposure. Treating NCM460 cells with LPS was found to lead to a significant inhibition in carrier-mediated biotin uptake. Similarly, administration of LPS to mice led to a significant inhibition in biotin uptake by native colonic tissue. Although no changes in total cellular SMVT protein and mRNA levels were observed, LPS caused a decrease in the fraction of SMVT expressed at the cell surface. A role for casein kinase 2 (CK2) (whose activity was also inhibited by LPS) in mediating the endotoxin effects on biotin uptake and on membrane expression of SMVT was suggested by findings that specific inhibitors of CK2, as well as mutating the putative CK2 phosphorylation site (Thr 78 Ala) in the SMVT protein, led to inhibition in biotin uptake and membrane expression of SMVT. This study shows for the first time that LPS inhibits colonic biotin uptake via decreasing membrane expression of its transporter and that these effects likely involve a CK2-mediated pathway.

  14. Inhibition of the MRP1-mediated transport of the menadione-glutathione conjugate (thiodione) in HeLa cells as studied by SECM.

    Science.gov (United States)

    Koley, Dipankar; Bard, Allen J

    2012-07-17

    Oxidative stress induced in live HeLa cells by menadione (2-methyl-1,4-napthaquinone) was studied in real time by scanning electrochemical microscopy (SECM). The hydrophobic molecule menadione diffuses through a living cell membrane where it is toxic to the cell. However, in the cell it is conjugated with glutathione to form thiodione. Thiodione is then recognized and transported across the cell membrane via the ATP-driven MRP1 pump. In the extracellular environment, thiodione was detected by the SECM tip at levels of 140, 70, and 35 µM upon exposure of the cells to menadione concentrations of 500, 250, and 125 µM, respectively. With the aid of finite element modeling, the kinetics of thiodione transport was determined to be 1.6 10(-7) m/s, about 10 times faster than menadione uptake. Selective inhibition of these MRP1 pumps inside live HeLa cells by MK571 produced a lower thiodione concentration of 50 µM in presence of 500 µM menadione and 50 µM MK571. A similar reduced (50% drop) thiodione efflux was observed in the presence of monoclonal antibody QCRL-4, a selective blocking agent of the MRP1 pumps. The reduced thiodione flux confirmed that thiodione was transported by MRP1, and that glutathione is an essential substrate for MRP1-mediated transport. This finding demonstrates the usefulness of SECM in quantitative studies of MRP1 inhibitors and suggests that monoclonal antibodies can be a useful tool in inhibiting the transport of these MDR pumps, and thereby aiding in overcoming multidrug resistance.

  15. Higher concentrations of nanoscale zero-valent iron (nZVI) in soil induced rice chlorosis due to inhibited active iron transportation

    International Nuclear Information System (INIS)

    Wang, Jie; Fang, Zhanqiang; Cheng, Wen; Yan, Xiaomin; Tsang, Pokeung Eric; Zhao, Dongye

    2016-01-01

    In this study, the effects of concentrations 0, 100, 250, 500, 750 and 1000 mg kg"−"1 of nanoscale zero-valent iron (nZVI) on germination, seedlings growth, physiology and toxicity mechanisms were investigated. The results showed that nZVI had no effect on germination, but inhibited the rice seedlings growth in higher concentrations (>500 mg kg"−"1 nZVI). The highest suppression rate of the length of roots and shoots reached 46.9% and 57.5%, respectively. The 1000mg kg"−"1 nZVI caused the highest suppression rates for chlorophyll and carotenoids, at 91.6% and 85.2%, respectively. In addition, the activity of antioxidant enzymes was altered by the translocation of nanoparticles and changes in active iron content. Visible symptoms of iron deficiency were observed at higher concentrations, at which the active iron content decreased 61.02% in the shoots, but the active iron content not decreased in roots. Interestingly, the total and available amounts of iron in the soil were not less than those in the control. Therefore, the plants iron deficiency was not caused by (i) deficiency of available iron in the soil and (ii) restraint of the absorption that plant takes in the available iron, while induced by (ⅲ) the transport of active iron from the root to the shoot was blocked. The cortex tissues were seriously damaged by nZVI which was transported from soil to the root, these were proved by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and energy dispersive spectroscopy (EDS). This current study shows that the mechanism of iron deficiency in rice seedling was due to transport of active iron from the root to the shoot blocked, which was caused by the uptake of nZVI. - Highlights: • Higher concentrations of nZVI induced iron deficiency in rice seedlings visibly. • nZVI was taken in rice seedlings and transported form root to shoot. • The pathway of active iron transport from root to shoot was inhibited. • The cortex tissues

  16. In vitro characterization of luseogliflozin, a potent and competitive sodium glucose co-transporter 2 inhibitor: Inhibition kinetics and binding studies

    Directory of Open Access Journals (Sweden)

    Saeko Uchida

    2015-05-01

    Full Text Available In this study, we evaluated an inhibition model of luseogliflozin on sodium glucose co-transporter 2 (SGLT2. We also analyzed the binding kinetics of the drug to SGLT2 protein using [3H]-luseogliflozin. Luseogliflozin competitively inhibited human SGLT2 (hSGLT2-mediated glucose uptake with a Ki value of 1.10 nM. In the absence of glucose, [3H]-luseogliflozin exhibited a high affinity for hSGLT2 with a Kd value of 1.3 nM. The dissociation half-time was 7 h, suggesting that luseogliflozin dissociates rather slowly from hSGLT2. These profiles of luseogliflozin might contribute to the long duration of action of this drug.

  17. Assessment of vandetanib as an inhibitor of various human renal transporters: inhibition of multidrug and toxin extrusion as a possible mechanism leading to decreased cisplatin and creatinine clearance.

    Science.gov (United States)

    Shen, Hong; Yang, Zheng; Zhao, Weiping; Zhang, Yueping; Rodrigues, A David

    2013-12-01

    Vandetanib was evaluated as an inhibitor of human organic anion transporter 1 (OAT1), OAT3, organic cation transporter 2 (OCT2), and multidrug and toxin extrusion (MATE1 and MATE2K) transfected (individually) into human embryonic kidney 293 cells (HEK293). Although no inhibition of OAT1 and OAT3 was observed, inhibition of OCT2-mediated uptake of 1-methyl-4-phenylpyridinium (MPP(+)) and metformin was evident (IC(50) of 73.4 ± 14.8 and 8.8 ± 1.9 µM, respectively). However, vandetanib was an even more potent inhibitor of MATE1- and MATE2K-mediated uptake of MPP(+) (IC(50) of 1.23 ± 0.05 and 1.26 ± 0.06 µM, respectively) and metformin (IC(50) of 0.16 ± 0.05 and 0.30 ± 0.09 µM, respectively). Subsequent cytotoxicity studies demonstrated that transport inhibition by vandetanib (2.5 µM) significantly decreased the sensitivity [right shift in concentration of cisplatin giving rise to 50% cell death; IC(50(CN))] of MATE1-HEK and MATE2K-HEK cells to cisplatin [IC(50(CN)) of 1.12 ± 0.13 versus 2.39 ± 0.44 µM; 0.85 ± 0.09 versus 1.99 ± 0.16 µM; P cisplatin nephrotoxicity (reduced cisplatin clearance), in some subjects receiving vandetanib therapy.

  18. Transportation

    Science.gov (United States)

    2007-01-01

    Faculty ii INDUSTRY TRAVEL Domestic Assistant Deputy Under Secretary of Defense (Transportation Policy), Washington, DC Department of...developed between the railroad and trucking industries. Railroads: Today’s seven Class I freight railroad systems move 42% of the nation’s intercity ...has been successfully employed in London to reduce congestion and observed by this industry study during its travels . It is currently being

  19. Creatine Monohydrate Enhances Energy Status and Reduces Glycolysis via Inhibition of AMPK Pathway in Pectoralis Major Muscle of Transport-Stressed Broilers.

    Science.gov (United States)

    Zhang, Lin; Wang, Xiaofei; Li, Jiaolong; Zhu, Xudong; Gao, Feng; Zhou, Guanghong

    2017-08-16

    Creatine monohydrate (CMH) contributes to reduce transport-induced muscle rapid glycolysis and improve meat quality of broilers, but the underlying mechanism is still unknown. Therefore, this study aimed to investigate the molecular mechanisms underlying the ameliorative effects of CMH on muscle glycolysis metabolism of transported broilers during summer. The results showed that 3 h transport during summer elevated chicken live weight loss and plasma corticosterone concentration; decreased muscle concentrations of ATP, creatine, and energy charge value; increased muscle AMP concentration and AMP/ATP ratio; and upregulated muscle mRNA expression of LKB1 and AMPKα2, as well as protein expression of p-LKB1 Thr189 and p-AMPKα Thr172 , which subsequently resulted in rapid glycolysis in the pectoralis major muscle and consequent reduction of meat quality. Dietary addition of CMH at 1200 mg/kg ameliorated transport-induced rapid muscle glycolysis and reduction of meat quality via enhancement of the energy-buffering capacity of intramuscular phosphocreatine/creatine system and inhibition of AMPK pathway.

  20. Excessive fructose intake causes 1,25-(OH)2D3-dependent inhibition of intestinal and renal calcium transport in growing rats

    Science.gov (United States)

    Douard, Veronique; Sabbagh, Yves; Lee, Jacklyn; Patel, Chirag; Kemp, Francis W.; Bogden, John D.; Lin, Sheldon

    2013-01-01

    We recently discovered that chronic high fructose intake by lactating rats prevented adaptive increases in rates of active intestinal Ca2+ transport and in levels of 1,25-(OH)2D3, the active form of vitamin D. Since sufficient Ca2+ absorption is essential for skeletal growth, our discovery may explain findings that excessive consumption of sweeteners compromises bone integrity in children. We tested the hypothesis that 1,25-(OH)2D3 mediates the inhibitory effect of excessive fructose intake on active Ca2+ transport. First, compared with those fed glucose or starch, growing rats fed fructose for 4 wk had a marked reduction in intestinal Ca2+ transport rate as well as in expression of intestinal and renal Ca2+ transporters that was tightly associated with decreases in circulating levels of 1,25-(OH)2D3, bone length, and total bone ash weight but not with serum parathyroid hormone (PTH). Dietary fructose increased the expression of 24-hydroxylase (CYP24A1) and decreased that of 1α-hydroxylase (CYP27B1), suggesting that fructose might enhance the renal catabolism and impair the synthesis, respectively, of 1,25-(OH)2D3. Serum FGF23, which is secreted by osteocytes and inhibits CYP27B1 expression, was upregulated, suggesting a potential role of bone in mediating the fructose effects on 1,25-(OH)2D3 synthesis. Second, 1,25-(OH)2D3 treatment rescued the fructose effect and normalized intestinal and renal Ca2+ transporter expression. The mechanism underlying the deleterious effect of excessive fructose intake on intestinal and renal Ca2+ transporters is a reduction in serum levels of 1,25-(OH)2D3. This finding is significant because of the large amounts of fructose now consumed by Americans increasingly vulnerable to Ca2+ and vitamin D deficiency. PMID:23571713

  1. Exclusion of mRNPs and ribosomal particles from a thin zone beneath the nuclear envelope revealed upon inhibition of transport

    International Nuclear Information System (INIS)

    Kylberg, Karin; Bjoerk, Petra; Fomproix, Nathalie; Ivarsson, Birgitta; Wieslander, Lars; Daneholt, Bertil

    2010-01-01

    We have studied the nucleocytoplasmic transport of a specific messenger RNP (mRNP) particle, named Balbiani ring (BR) granule, and ribosomal RNP (rRNP) particles in the salivary glands of the dipteran Chironomus tentans. The passage of the RNPs through the nuclear pore complex (NPC) was inhibited with the nucleoporin-binding wheat germ agglutinin, and the effects were examined by electron microscopy. BR mRNPs bound to the nuclear basket increased in number, while BR mRNPs translocating through the central channel decreased, suggesting that the initiation of translocation proper had been inhibited. The rRNPs accumulated heavily in nucleoplasm, while no or very few rRNPs were recorded within nuclear baskets. Thus, the transport of rRNPs had been blocked prior to the entry into the baskets. Remarkably, the rRNPs had been excluded both from baskets and the space in between the baskets. We propose that normally basket fibrils move freely and repel RNPs from the exclusion zone unless the particles have affinity for and bind to nucleoporins within the baskets.

  2. Epidermal growth factor inhibits glycylsarcosine transport and hPepT1 expression in a human intestinal cell line

    DEFF Research Database (Denmark)

    Nielsen, C U; Amstrup, J; Steffansen, B

    2001-01-01

    (max) decreased from 2.61 +/- 0.4 to 1.06 +/- 0.1 nmol x cm(-2) x min(-1) (n = 3, P PepT1 mRNA (using glucose-6-phosphate dehydrogenase mRNA as control......) in cells treated with EGF. Western blotting indicated a decrease in hPepT1 protein in cell lysates. We conclude that EGF treatment decreases Gly-Sar transport in Caco-2 cells by decreasing the number of peptide transporter molecules in the apical membrane....

  3. Galectin-3 silencing inhibits epirubicin-induced ATP binding cassette transporters and activates the mitochondrial apoptosis pathway via β-catenin/GSK-3β modulation in colorectal carcinoma.

    Directory of Open Access Journals (Sweden)

    Yung-Kuo Lee

    Full Text Available Multidrug resistance (MDR, an unfavorable factor compromising the treatment efficacy of anticancer drugs, involves the upregulation of ATP binding cassette (ABC transporters and induction of galectin-3 signaling. Galectin-3 plays an anti-apoptotic role in many cancer cells and regulates various pathways to activate MDR. Thus, the inhibition of galectin-3 has the potential to enhance the efficacy of the anticancer drug epirubicin. In this study, we examined the effects and mechanisms of silencing galectin-3 via RNA interference (RNAi on the β-catenin/GSK-3β pathway in human colon adenocarcinoma Caco-2 cells. Galectin-3 knockdown increased the intracellular accumulation of epirubicin in Caco-2 cells; suppressed the mRNA expression of galectin-3, β-catenin, cyclin D1, c-myc, P-glycoprotein (P-gp, MDR-associated protein (MRP 1, and MRP2; and downregulated the protein expression of P-gp, cyclin D1, galectin-3, β-catenin, c-Myc, and Bcl-2. Moreover, galectin-3 RNAi treatment significantly increased the mRNA level of GSK-3β, Bax, caspase-3, and caspase-9; remarkably increased the Bax-to-Bcl-2 ratio; and upregulated the GSK-3β and Bax protein expressions. Apoptosis was induced by galectin-3 RNAi and/or epirubicin as demonstrated by chromatin condensation, a higher sub-G1 phase proportion, and increased caspase-3 and caspase-9 activity, indicating an intrinsic/mitochondrial apoptosis pathway. Epirubicin-mediated resistance was effectively inhibited via galectin-3 RNAi treatment. However, these phenomena could be rescued after galectin-3 overexpression. We show for the first time that the silencing of galectin-3 sensitizes MDR cells to epirubicin by inhibiting ABC transporters and activating the mitochondrial pathway of apoptosis through modulation of the β-catenin/GSK-3β pathway in human colon cancer cells.

  4. Different transport mechanisms for cadmium and mercury in Caco-2 cells: inhibition of Cd uptake by Hg without evidence for reciprocal effects

    International Nuclear Information System (INIS)

    Aduayom, Ismaeel; Campbell, Peter G.C.; Denizeau, Francine; Jumarie, Catherine

    2003-01-01

    Cadmium/Hg interactions have been studied in the TC7 clone of the enterocytic-like Caco-2 cells to test the hypothesis that these metals may compete for intestinal transport. Comparison of the kinetic parameter values for 203 Hg(II) and 109 Cd(II) uptake in a serum-free medium revealed that Hg is accumulated much more rapidly and to higher concentrations. The very rapid uptake/binding step and the initial uptake rate of 109 Cd were both significantly inhibited by an excess of unlabeled Cd or Hg (apparent K i for Hg of 9.3 ± 1.2 μM) without reciprocal effects. 109 Cadmium uptake was highly sensitive to temperature and a significant fraction of accumulation (12%) was EDTA extractable. 203 Hg uptake remained insensitive to temperature or the EDTA washing procedure. However, the uptake of both tracers was half-decreased when an excess of the respective unlabeled metal was added in the stop solution, suggesting an exchange mechanism for adsorption. Cell pretreatment with N-ethylmaleimide (NEM) led to a 30% decrease or a 73% increase in the 3-min specific transport of 109 Cd when NEM was still present in or removed from the uptake medium, respectively. NEM had no effect on 203 Hg uptake. Overall our results suggest the involvement of a saturable specific mechanism for Cd, which is highly sensitive to inhibition by Hg and NEM under some conditions, and a nonspecific passive diffusion for Hg. The Hg- or NEM-induced inhibition of Cd uptake likely involves a thiol-mediated reaction, but our results suggest that NEM pretreatment may activate other cellular mechanisms leading to a stimulatory effect

  5. Effects of cyclooxygenase and lipoxygenase inhibition on basal- and serotonin-induced ion transport in rat colon

    DEFF Research Database (Denmark)

    Engelmann, Bodil Elisabeth; Bindslev, Niels; Poulsen, Steen Seier

    2002-01-01

    basal conditions. Furthermore, data suggest neither the COX-1 nor the COX-2 enzyme to be of major importance for 5-HT-induced ion transport in rat colon in vitro. In conclusion, this study supports 5-HT as a mediator of chloride secretion by activating several receptor subtypes and the LOX enzyme...

  6. Phloem flow and sugar transport in Ricinus communis L. is inhibited under anoxic conditions of shoot or roots

    NARCIS (Netherlands)

    Peuke, A.D.; Gessler, A.; Trumbore, S.; Windt, C.W.; Homan, N.; Gerkema, E.; As, van H.

    2015-01-01

    Anoxic conditions should hamper the transport of sugar in the phloem, as this is an active process. The canopy is a carbohydrate source and the roots are carbohydrate sinks.By fumigating the shoot with N2 or flooding the rhizosphere, anoxic conditions in the source or sink, respectively, were

  7. Inhibition of insulin-stimulated hydrogen peroxide production prevents stimulation of sodium transport in A6 cell monolayers.

    NARCIS (Netherlands)

    Markadieu, N.Y.G.; Crutzen, R.; Boom, A.; Erneux, C.; Beauwens, R.

    2009-01-01

    Insulin-stimulated sodium transport across A6 cell (derived from amphibian distal nephron) monolayers involves the activation of a phosphatidylinositol (PI) 3-kinase. We previously demonstrated that exogenous addition of H2O2 to the incubation medium of A6 cell monolayers provokes an increase in PI

  8. Zinc transporter 7 deficiency affects lipid synthesis in adipocytes by inhibiting insulin-dependent Akt activity and glucose uptake

    Science.gov (United States)

    Mice deficient for zinc transporter 7 (Znt7) are mildly zinc deficient, accompanied with low body weight gain and body fat accumulation. To investigate the underlying mechanism of Znt7 deficiency in body adiposity, we investigated fatty acid composition and insulin sensitivity in visceral (epididyma...

  9. Virus-induced plasma membrane aquaporin PsPIP2;1 silencing inhibits plant water transport of Pisum sativum.

    Science.gov (United States)

    Song, Juanjuan; Ye, Guoliang; Qian, Zhengjiang; Ye, Qing

    2016-12-01

    Aquaporins (AQPs) are known to facilitate water transport across cell membranes, but the role of a single AQP in regulating plant water transport, particularly in plants other than Arabidopsis remains largely unexplored. In the present study, a virus-induced gene silencing (VIGS) technique was employed to suppress the expression of a specific plasma membrane aquaporin PsPIP2;1 of Pea plants (Pisum sativum), and subsequent effects of the gene suppression on root hydraulic conductivity (Lp r ), leaf hydraulic conductivity (K leaf ), root cell hydraulic conductivity (Lp rc ), and leaf cell hydraulic conductivity (Lp lc ) were investigated, using hydroponically grown Pea plants. Compared with control plants, VIGS-PsPIP2;1 plants displayed a significant suppression of PsPIP2;1 in both roots and leaves, while the expression of other four PIP isoforms (PsPIP1;1, PsPIP1;2, PsPIP2;2, and PsPIP2;3) that were simultaneously monitored were not altered. As a consequence, significant declines in water transport of VIGS-PsPIP2;1 plants were observed at both organ and cell levels, i.e., as compared to control plants, Lp r and K leaf were reduced by 29 %, and Lp rc and Lp lc were reduced by 20 and 29 %, respectively. Our results demonstrate that PsPIP2;1 alone contributes substantially to root and leaf water transport in Pea plants, and highlight VIGS a useful tool for investigating the role of a single AQP in regulating plant water transport.

  10. Upregulating reverse cholesterol transport with cholesteryl ester transfer protein inhibition requires combination with the LDL-lowering drug berberine in dyslipidemic hamsters.

    Science.gov (United States)

    Briand, François; Thieblemont, Quentin; Muzotte, Elodie; Sulpice, Thierry

    2013-01-01

    This study aimed to investigate whether cholesteryl ester transfer protein inhibition promotes in vivo reverse cholesterol transport in dyslipidemic hamsters. In vivo reverse cholesterol transport was measured after an intravenous injection of (3)H-cholesteryl-oleate-labeled/oxidized low density lipoprotein particles ((3)H-oxLDL), which are rapidly cleared from plasma by liver-resident macrophages for further (3)H-tracer egress in plasma, high density lipoprotein (HDL), liver, and feces. A first set of hamsters made dyslipidemic with a high-fat and high-fructose diet was treated with vehicle or torcetrapib 30 mg/kg (TOR) over 2 weeks. Compared with vehicle, TOR increased apolipoprotein E-rich HDL levels and significantly increased (3)H-tracer appearance in HDL by 30% over 72 hours after (3)H-oxLDL injection. However, TOR did not change (3)H-tracer recovery in liver and feces, suggesting that uptake and excretion of cholesterol deriving from apolipoprotein E-rich HDL is not stimulated. As apoE is a potent ligand for the LDL receptor, we next evaluated the effects of TOR in combination with the LDL-lowering drug berberine, which upregulates LDL receptor expression in dyslipidemic hamsters. Compared with TOR alone, treatment with TOR+berberine 150 mg/kg resulted in lower apolipoprotein E-rich HDL levels. After (3)H-oxLDL injection, TOR+berberine significantly increased (3)H-tracer appearance in fecal cholesterol by 109%. Our data suggest that cholesteryl ester transfer protein inhibition alone does not stimulate reverse cholesterol transport in dyslipidemic hamsters and that additional effects mediated by the LDL-lowering drug berberine are required to upregulate this process.

  11. Neuroprotective effects of the novel glutamate transporter inhibitor (-)-3-hydroxy-4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]-isoxazole-4-carboxylic acid, which preferentially inhibits reverse transport (glutamate release) compared with glutamate reuptake

    DEFF Research Database (Denmark)

    Colleoni, Simona; Jensen, Anders Asbjørn; Landucci, Elisa

    2008-01-01

    on the three hEAAT subtypes. (-)-HIP-A maintained the remarkable property, previously reported with the racemates, of inhibiting synaptosomal glutamate-induced [3H]D-aspartate release (reverse transport) at concentrations significantly lower than those inhibiting [3H]L-glutamate uptake. New data suggest...

  12. The monoaminergic pathways and inhibition of monoamine transporters interfere with the antidepressive-like behavior of ketamine

    Directory of Open Access Journals (Sweden)

    Glauce Socorro de Barros Viana

    2018-06-01

    Full Text Available Ketamine (KET, a NMDA receptor antagonist, has been studied for its rapid and efficacious antidepressant effect, even for the treatment-resistant depression. Although depression is a major cause of disability worldwide, the treatment can be feasible, affordable and cost-effective, decreasing the population health burden. We evaluated the antidepressive-like effects of KET and its actions on monoamine contents (DA and its metabolites, as well as 5-HT and on tyrosine hydroxylase (TH. In addition DAT and SERT (DA and 5-HT transporters, respectively were also assessed. Male Swiss mice were divided into Control and KET-treated groups. The animals were acutely treated with KET (2, 5 or 10 mg/kg, i.p. and subjected to the forced swimming test, for evaluation of the antidepressive-like behavior. Imipramine and fluoxetine were used as references. The results showed that KET decreased dose-dependently the immobility time and shortly after the test, the animals were euthanized for striatal dissections and monoamine determinations. In addition, the brain (striata, hippocampi and prefrontal cortices was immunohistochemically processed for TH, DAT and SERT. KET at its higher dose increased DA and its metabolites (DOPAC and HVA and mainly 5-HT contents, in mice striata, effects associated with increases in TH and decreases in DAT immunoreactivities. Furthermore, reductions in SERT immunoreactivities were observed in the striatum and hippocampus. The results indicate that KET antidepressive-like effect probably involves, among other factors, monoaminergic pathways, as suggested by the increased striatal TH immunoreactivity and reduced brain DA (DAT and 5-HT (SERT transporters. Keywords: Ketamine, Antidepressive effect, Dopaminergic neurotransmission, Serotonergic neurotransmission, Monoamine transporters

  13. Natural and azido fatty acids inhibit phosphate transport and activate fatty acid anion uniport mediated by the mitochondrial phosphate carrier

    Czech Academy of Sciences Publication Activity Database

    Engstová, Hana; Žáčková, Markéta; Růžička, Michal; Meinhardt, A.; Hanuš, Jan; Krämer, R.; Ježek, Petr

    2001-01-01

    Roč. 276, č. 7 (2001), s. 4683-4691 ISSN 0021-9258 R&D Projects: GA ČR GA301/95/0620; GA ČR GA301/98/0568; GA MŠk ME 085; GA MŠk ME 389 Grant - others:US(US) Czechoslovak Science and Technology Program 94043 Institutional research plan: CEZ:AV0Z5011922 Keywords : phosphate transport * fatty acids Subject RIV: CE - Biochemistry Impact factor: 7.258, year: 2001

  14. Mitochondrial electron transport is inhibited by disappearance of metallothionein in human bronchial epithelial cells following exposure to silver nitrate.

    Science.gov (United States)

    Miyayama, Takamitsu; Arai, Yuta; Suzuki, Noriyuki; Hirano, Seishiro

    2013-03-08

    Silver (Ag) possesses antibacterial activity and has been used in wound dressings and deodorant powders worldwide. However, the metabolic behavior and biological roles of Ag in mammals have not been well characterized. In the present study, we exposed human bronchial epithelial cells (BEAS-2B) to AgNO3 and investigated uptake and intracellular distribution of Ag, expression of metallothionein (MT), generation of reactive oxygen species (ROS), and changes in mitochondrial respiration. The culture medium concentration of Ag decreased with time and stabilized at 12h. The concentration of both Ag and MT in the soluble cellular fraction increased up to 3h and then decreased, indicating that cytosolic Ag relocated to the insoluble fraction of the cells. The levels of mRNAs for the major human MT isoforms MT-I and MT-II paralleled with the protein levels of Ag-MT. The intensity of fluorescence derived from ROS was elevated in the mitochondrial region at 24h. Ag decreased mitochondrial oxygen consumption in a dose-dependent manner and the activity of mitochondrial complex I-IV enzymes was significantly inhibited following exposure to Ag. In a separate experiment, we found that hydrogen peroxide (H2O2) at concentrations as low as 0.001% (equivalent to the concentration of H2O2 in Ag-exposed cells) removed Ag from MT. These results suggest MT was decomposed by cytosolic H2O2, and then Ag released from MT relocated to insoluble cellular fractions and inhibited electron chain transfer of mitochondrial complexes, which eventually led to cell damage. Crown Copyright © 2013. Published by Elsevier Ireland Ltd. All rights reserved.

  15. Electrophysiological evidence of increased glycine receptor-mediated phasic and tonic inhibition by blockade of glycine transporters in spinal superficial dorsal horn neurons of adult mice

    Directory of Open Access Journals (Sweden)

    Misa Oyama

    2017-03-01

    Full Text Available To understand the synaptic and/or extrasynaptic mechanisms underlying pain relief by blockade of glycine transporter subtypes GlyT1 and GlyT2, whole-cell recordings were made from dorsal horn neurons in spinal slices from adult mice, and the effects of NFPS and ALX-1393, selective GlyT1 and GlyT2 inhibitors, respectively, on phasic evoked or miniature glycinergic inhibitory postsynaptic currents (eIPSCs or mIPSCs were examined. NFPS and ALX-1393 prolonged the decay phase of eIPSCs without affecting their amplitude. In the presence of tetrodotoxin to record mIPSCs, NFPS and ALX-1393 induced a tonic inward current that was reversed by strychnine. Although NFPS had no statistically significant influences on mIPSCs, ALX-1393 significantly increased their frequency. We then further explored the role of GlyTs in the maintenance of glycinergic IPSCs. To facilitate vesicular release of glycine, repetitive high-frequency stimulation (HFS was applied at 10 Hz for 3 min during continuous recordings of eIPSCs at 0.1 Hz. Prominent suppression of eIPSCs was evident after HFS in the presence of ALX-1393, but not NFPS. Thus, it appears that phasic and tonic inhibition may contribute to the analgesic effects of GlyT inhibitors. However, reduced glycinergic inhibition due to impaired vesicular refilling could hamper the analgesic efficacy of GlyT2 inhibitors.

  16. Inhibition of serotonin but not norepinephrine transport during development produces delayed, persistent perturbations of emotional behaviors in mice.

    Science.gov (United States)

    Ansorge, Mark S; Morelli, Emanuela; Gingrich, Jay A

    2008-01-02

    Serotonin (5-HT) acts as a neurotransmitter, but also modulates brain maturation during early development. The demonstrated influence of genetic variants on brain function, personality traits, and susceptibility to neuropsychiatric disorders suggests a critical importance of developmental mechanisms. However, little is known about how and when developmentally perturbed 5-HT signaling affects circuitry and resulting behavior. The 5-HT transporter (5-HTT) is a key regulator of extracellular 5-HT levels and we used pharmacologic strategies to manipulate 5-HTT function during development and determine behavioral consequences. Transient exposure to the 5-HTT inhibitors fluoxetine, clomipramine, and citalopram from postnatal day 4 (P4) to P21 produced abnormal emotional behaviors in adult mice. Similar treatment with the norepinephrine transporter (NET) inhibitor, desipramine, did not adversely affect adult behavior, suggesting that 5-HT and norepinephrine (NE) do not share the same effects on brain development. Shifting our period of treatment/testing to P90/P185 failed to mimic the effect of earlier exposure, demonstrating that 5-HT effects on adult behavior are developmentally specific. We have hypothesized that early-life perturbations of 5-HT signaling affect corticolimbic circuits that do not reach maturity until the peri-adolescent period. In support of this idea, we found that abnormal behaviors resulting from postnatal fluoxetine exposure have a post-pubescent onset and persist long after reaching adult age. A better understanding of the underlying 5-HT sensitive circuits and how they are perturbed should lead to new insights into how various genetic polymorphisms confer their risk to carriers. Furthermore, these studies should help determine whether in utero exposure to 5-HTT blocking drugs poses a risk for behavioral abnormalities in later life.

  17. Structure-activity relationships of bumetanide derivatives: correlation between diuretic activity in dogs and inhibition of the human NKCC2A transporter.

    Science.gov (United States)

    Lykke, Kasper; Töllner, Kathrin; Römermann, Kerstin; Feit, Peter W; Erker, Thomas; MacAulay, Nanna; Löscher, Wolfgang

    2015-06-23

    The N-K-Cl cotransporters (NKCCs) mediate the coupled, electroneutral movement of Na + , K + and Cl - ions across cell membranes. There are two isoforms of this cation co-transporter, NKCC1 and NKCC2. NKCC2 is expressed primarily in the kidney and is the target of diuretics such as bumetanide. Bumetanide was discovered by screening ∼5000 3-amino-5-sulfamoylbenzoic acid derivatives, long before NKCC2 was identified in the kidney. Therefore, structure-activity studies on effects of bumetanide derivatives on NKCC2 are not available. In this study, the effect of a series of diuretically active bumetanide derivatives was investigated on human NKCC2 variant A (hNKCC2A) expressed in Xenopus laevis oocytes. Bumetanide blocked hNKCC2A transport with an IC 50 of 4 μM. There was good correlation between the diuretic potency of bumetanide and its derivatives in dogs and their inhibition of hNKCC2A (r 2 = 0.817; P human NKCC2 splice variants, and may lead to the discovery of novel high-ceiling diuretics. © 2015 The British Pharmacological Society.

  18. Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia

    Science.gov (United States)

    Rieg, Timo; Masuda, Takahiro; Gerasimova, Maria; Mayoux, Eric; Platt, Kenneth; Powell, David R.; Thomson, Scott C.; Koepsell, Hermann

    2013-01-01

    In the kidney, the sodium-glucose cotransporters SGLT2 and SGLT1 are thought to account for >90 and ∼3% of fractional glucose reabsorption (FGR), respectively. However, euglycemic humans treated with an SGLT2 inhibitor maintain an FGR of 40–50%, mimicking values in Sglt2 knockout mice. Here, we show that oral gavage with a selective SGLT2 inhibitor (SGLT2-I) dose dependently increased urinary glucose excretion (UGE) in wild-type (WT) mice. The dose-response curve was shifted leftward and the maximum response doubled in Sglt1 knockout (Sglt1−/−) mice. Treatment in diet with the SGLT2-I for 3 wk maintained 1.5- to 2-fold higher urine glucose/creatinine ratios in Sglt1−/− vs. WT mice, associated with a temporarily greater reduction in blood glucose in Sglt1−/− vs. WT after 24 h (−33 vs. −11%). Subsequent inulin clearance studies under anesthesia revealed free plasma concentrations of the SGLT2-I (corresponding to early proximal concentration) close to the reported IC50 for SGLT2 in mice, which were associated with FGR of 64 ± 2% in WT and 17 ± 2% in Sglt1−/−. Additional intraperitoneal application of the SGLT2-I (maximum effective dose in metabolic cages) increased free plasma concentrations ∼10-fold and reduced FGR to 44 ± 3% in WT and to −1 ± 3% in Sglt1−/−. The absence of renal glucose reabsorption was confirmed in male and female Sglt1/Sglt2 double knockout mice. In conclusion, SGLT2 and SGLT1 account for renal glucose reabsorption in euglycemia, with 97 and 3% being reabsorbed by SGLT2 and SGLT1, respectively. When SGLT2 is fully inhibited by SGLT2-I, the increase in SGLT1-mediated glucose reabsorption explains why only 50–60% of filtered glucose is excreted. PMID:24226519

  19. Short-term and long-term ethanol administration inhibits the placental uptake and transport of valine in rats

    International Nuclear Information System (INIS)

    Patwardhan, R.V.; Schenker, S.; Henderson, G.I.; Abou-Mourad, N.N.; Hoyumpa, A.M. Jr.

    1981-01-01

    Ethanol ingestion during pregnancy causes a pattern of fetal/neonatal dysfunction called the FAS. The effects of short- and long-term ethanol ingestion on the placental uptake and maternal-fetal transfer of valine were studied in rats. The in vivo placental uptake and fetal uptake were estimated after injection of 0.04 micromol of /sub 14/C-valine intravenously on day 20 of gestation in Sprague-Dawley rats. Short-term ethanol ingestion (4 gm/kg) caused a significant reduction in the placental uptake of /sub 14/C-valine by 33%, 60%, and 30%, and 31% at 2.5, 5, 10, and 15 min after valine administration, respectively (p less than 0.01), and a similar significant reduction occurred in the fetal uptake of /sub 14/C-valine (p less than 0.01). Long-term ethanol ingestion prior to and throughout gestation resulted in a 47% reduction in placental valine uptake (p less than 0.01) and a 46% reduction in fetal valine uptake (p less than 0.01). Long-term ethanol feeding from day 4 to day 20 of gestation caused a 32% reduction in placental valine uptake (p less than 0.01) and a 26% reduction in fetal valine uptake (p less than 0.01). We conclude that both short- and long-term ingestion of ethanol inhibit the placental uptake and maternal-fetal transfer of an essential amino acid--valine. An alteration of placental function may contribute to the pathogenesis of the FAS

  20. Role of calcium in phosphoinositide metabolism and inhibition of norepinephrine transport into synaptic vesicles by amphetamine analogs

    International Nuclear Information System (INIS)

    Knepper, S.M.

    1985-01-01

    Norepinephrine-(NE) and calcium ionophore A23187-stimulated phosphoinositide (PIn) metabolism in rat brain slices was studied under varying calcium conditions. Tissue was labelled with 3 H-myo-inositol and 3 H-inositol phosphates (IPn), products of PIn metabolism were measured. In the absence of media calcium the response to NE was decreased while that to A23187 was little affected A23187 can release calcium from intracellular stores. Basal and stimulated accumulation of 3 H-IPn was reversibly antagonized with EGTA by addition of calcium. Using calcium buffers, approximately 10 -7 M free calcium was required to support hydrolysis. Free intracellular calcium is maintained at approximately this level. Thus calcium is required for PIn hydrolysis but appears to play a permissive role, basal levels being sufficient to support metabolism. Conformationally-defined (rigid) and -restricted (semi-rigid) analogs of the most stable conformations of amphetamine, antiperiplanar (exo) and gauche (endo), were utilized to probe the conformational requirements of vesicular NE transport. Analogs tested were 2-aminotetralin (2AT), 3-methyltetrahydroisoquinoline, anti- and syn-9-aminobenzobicyclo[2.2.1]heptene, and endo and exo conformers of 2-aminobenzobicyclo[2.2.1]heptene and 2-aminobenzobicyclo[2.2.2]octene

  1. Possibility of Predicting Serotonin Transporter Occupancy From the In Vitro Inhibition Constant for Serotonin Transporter, the Clinically Relevant Plasma Concentration of Unbound Drugs, and Their Profiles for Substrates of Transporters.

    Science.gov (United States)

    Yahata, Masahiro; Chiba, Koji; Watanabe, Takao; Sugiyama, Yuichi

    2017-09-01

    Accurate prediction of target occupancy facilitates central nervous system drug development. In this review, we discuss the predictability of serotonin transporter (SERT) occupancy in human brain estimated from in vitro K i values for human SERT and plasma concentrations of unbound drug (C u,plasma ), as well as the impact of drug transporters in the blood-brain barrier. First, the geometric means of in vitro K i values were compared with the means of in vivo K i values (K i,u,plasma ) which were calculated as C u,plasma values at 50% occupancy of SERT obtained from previous clinical positron emission tomography/single photon emission computed tomography imaging studies for 6 selective serotonin transporter reuptake inhibitors and 3 serotonin norepinephrine reuptake inhibitors. The in vitro K i values for 7 drugs were comparable to their in vivo K i,u,plasma values within 3-fold difference. SERT occupancy was overestimated for 5 drugs (P-glycoprotein substrates) and underestimated for 2 drugs (presumably uptake transporter substrates, although no evidence exists as yet). In conclusion, prediction of human SERT occupancy from in vitro K i values and C u,plasma was successful for drugs that are not transporter substrates and will become possible in future even for transporter substrates, once the transporter activities will be accurately estimated from in vitro experiments. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  2. A pharmacokinetic/pharmacodynamic investigation: assessment of edivoxetine and atomoxetine on systemic and central 3,4-dihydroxyphenylglycol, a biochemical marker for norepinephrine transporter inhibition.

    Science.gov (United States)

    Kielbasa, William; Pan, Alan; Pereira, Alvaro

    2015-03-01

    Inhibition of norepinephrine (NE) reuptake into noradrenergic nerves is a common therapeutic target in the central nervous system (CNS). In noradrenergic nerves, NE is oxidized by monoamine oxidase to 3,4-dihydroxyphenylglycol (DHPG). In this study, 40 healthy male subjects received the NE transporter (NET) inhibitor edivoxetine (EDX) or atomoxetine (ATX), or placebo. The pharmacokinetic and pharmacodynamic profile of these drugs in plasma and cerebrospinal fluid (CSF) was assessed. In Part A, subjects received EDX once daily (QD) for 14 or 15 days at targeted doses of 6mg or 9mg. In Part B, subjects received 80mg ATX QD for 14 or 15 days. Each subject received a lumbar puncture before receiving drug and after 14 or 15 days of dosing. Plasma and urine were collected at baseline and after 14 days of dosing. Edivoxetine plasma and CSF concentrations increased dose dependently. The time to maximum plasma concentration of EDX was 2h, and the half-life was 9h. At the highest EDX dose of 9mg, DHPG concentrations were reduced from baseline by 51% at 8h postdose in CSF, and steady-state plasma and urine DHPG concentrations decreased by 38% and 26%, respectively. For 80mg ATX, the decrease of plasma, CSF, or urine DHPG was similar to EDX. Herein we provide clinical evidence that EDX and ATX decrease DHPG concentrations in the periphery and CNS, presumably via NET inhibition. EDX and ATX concentrations measured in the CSF confirmed the availability of those drugs in the CNS. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  3. Quilamine HQ1-44, an iron chelator vectorized toward tumor cells by the polyamine transport system, inhibits HCT116 tumor growth without adverse effect.

    Science.gov (United States)

    Renaud, Stéphanie; Corcé, Vincent; Cannie, Isabelle; Ropert, Martine; Lepage, Sylvie; Loréal, Olivier; Deniaud, David; Gaboriau, François

    2015-08-01

    Tumor cell growth requires large iron quantities and the deprivation of this metal induced by synthetic metal chelators is therefore an attractive method for limiting the cancer cell proliferation. The antiproliferative effect of the Quilamine HQ1-44, a new iron chelator vectorized toward tumor cells by a polyamine chain, is related to its high selectivity for the Polyamine Transport System (PTS), allowing its preferential uptake by tumoral cells. The difference in PTS activation between healthy cells and tumor cells enables tumor cells to be targeted, whereas the strong dependence of these cells on iron ensures a secondary targeting. Here, we demonstrated in vitro that HQ1-44 inhibits DNA synthesis and cell proliferation of HCT116 cells by modulating the intracellular metabolism of both iron and polyamines. Moreover, in vivo, in xenografted athymic nude mice, we found that HQ1-44 was as effective as cis-platin in reducing HCT116 tumor growth, without its side effects. Furthermore, as suggested by in vitro data, the depletion in exogenous or endogenous polyamines, known to activate the PTS, dramatically enhanced the antitumor efficiency of HQ1-44. These data support the need for further studies to assess the value of HQ1-44 as an adjuvant treatment in cancer. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Glaucarubinone sensitizes KB cells to paclitaxel by inhibiting ABC transporters via ROS-dependent and p53-mediated activation of apoptotic signaling pathways.

    Science.gov (United States)

    Karthikeyan, Subburayan; Hoti, Sugeerappa Laxmanappa; Nazeer, Yasin; Hegde, Harsha Vasudev

    2016-07-05

    Multidrug resistance (MDR) is considered to be the major contributor to failure of chemotherapy in oral squamous cell carcinoma (SCC). This study was aimed to explore the effects and mechanisms of glaucarubinone (GLU), one of the major quassinoids from Simarouba glauca DC, in potentiating cytotoxicity of paclitaxel (PTX), an anticancer drug in KB cells. Our data showed that the administration of GLU pre-treatment significantly enhanced PTX anti-proliferative effect in ABCB1 over-expressing KB cells. The Rh 123 drug efflux studies revealed that there was a significant transport function inhibition by GLU-PTX treatment. Interestingly, it was also found that this enhanced anticancer efficacy of GLU was associated with PTX-induced cell arrest in the G2/M phase of cell cycle. Further, the combined treatment of GLU-PTX had significant decrease in the expression levels of P-gp, MRPs, and BCRP in resistant KB cells at both mRNA and protein levels. Furthermore, the combination treatments showed significant reactive oxygen species (ROS) production, chromatin condensation and reduced mitochondrial membrane potential in resistant KB cells. The results from DNA fragmentation analysis also demonstrated the GLU induced apoptosis in KB cells and its synergy with PTX. Importantly, GLU and/or PTX triggered apoptosis through the activation of pro-apoptotic proteins such as p53, Bax, and caspase-9. Our findings demonstrated for the first time that GLU causes cell death in human oral cancer cells via the ROS-dependent suppression of MDR transporters and p53-mediated activation of the intrinsic mitochondrial pathway of apoptosis. Additionally, the present study also focussed on investigation of the protective effect of GLU and combination drugs in human normal blood lymphocytes. Normal blood lymphocytes assay indicated that GLU is able to induce selective toxicity in cancer cells and in silico molecular docking studies support the choice of GLU as ABC inhibitor to enhance PTX efficacy

  5. Inhibition of K+ transport through Na+, K+-ATPase by capsazepine: role of membrane span 10 of the α-subunit in the modulation of ion gating.

    Science.gov (United States)

    Mahmmoud, Yasser A; Shattock, Michael; Cornelius, Flemming; Pavlovic, Davor

    2014-01-01

    Capsazepine (CPZ) inhibits Na+,K+-ATPase-mediated K+-dependent ATP hydrolysis with no effect on Na+-ATPase activity. In this study we have investigated the functional effects of CPZ on Na+,K+-ATPase in intact cells. We have also used well established biochemical and biophysical techniques to understand how CPZ modifies the catalytic subunit of Na+,K+-ATPase. In isolated rat cardiomyocytes, CPZ abolished Na+,K+-ATPase current in the presence of extracellular K+. In contrast, CPZ stimulated pump current in the absence of extracellular K+. Similar conclusions were attained using HEK293 cells loaded with the Na+ sensitive dye Asante NaTRIUM green. Proteolytic cleavage of pig kidney Na+,K+-ATPase indicated that CPZ stabilizes ion interaction with the K+ sites. The distal part of membrane span 10 (M10) of the α-subunit was exposed to trypsin cleavage in the presence of guanidinum ions, which function as Na+ congener at the Na+ specific site. This effect of guanidinium was amplified by treatment with CPZ. Fluorescence of the membrane potential sensitive dye, oxonol VI, was measured following addition of substrates to reconstituted inside-out Na+,K+-ATPase. CPZ increased oxonol VI fluorescence in the absence of K+, reflecting increased Na+ efflux through the pump. Surprisingly, CPZ induced an ATP-independent increase in fluorescence in the presence of high extravesicular K+, likely indicating opening of an intracellular pathway selective for K+. As revealed by the recent crystal structure of the E1.AlF4-.ADP.3Na+ form of the pig kidney Na+,K+-ATPase, movements of M5 of the α-subunit, which regulate ion selectivity, are controlled by the C-terminal tail that extends from M10. We propose that movements of M10 and its cytoplasmic extension is affected by CPZ, thereby regulating ion selectivity and transport through the K+ sites in Na+,K+-ATPase.

  6. Inhibition of K+ transport through Na+, K+-ATPase by capsazepine: role of membrane span 10 of the α-subunit in the modulation of ion gating.

    Directory of Open Access Journals (Sweden)

    Yasser A Mahmmoud

    Full Text Available Capsazepine (CPZ inhibits Na+,K+-ATPase-mediated K+-dependent ATP hydrolysis with no effect on Na+-ATPase activity. In this study we have investigated the functional effects of CPZ on Na+,K+-ATPase in intact cells. We have also used well established biochemical and biophysical techniques to understand how CPZ modifies the catalytic subunit of Na+,K+-ATPase. In isolated rat cardiomyocytes, CPZ abolished Na+,K+-ATPase current in the presence of extracellular K+. In contrast, CPZ stimulated pump current in the absence of extracellular K+. Similar conclusions were attained using HEK293 cells loaded with the Na+ sensitive dye Asante NaTRIUM green. Proteolytic cleavage of pig kidney Na+,K+-ATPase indicated that CPZ stabilizes ion interaction with the K+ sites. The distal part of membrane span 10 (M10 of the α-subunit was exposed to trypsin cleavage in the presence of guanidinum ions, which function as Na+ congener at the Na+ specific site. This effect of guanidinium was amplified by treatment with CPZ. Fluorescence of the membrane potential sensitive dye, oxonol VI, was measured following addition of substrates to reconstituted inside-out Na+,K+-ATPase. CPZ increased oxonol VI fluorescence in the absence of K+, reflecting increased Na+ efflux through the pump. Surprisingly, CPZ induced an ATP-independent increase in fluorescence in the presence of high extravesicular K+, likely indicating opening of an intracellular pathway selective for K+. As revealed by the recent crystal structure of the E1.AlF4-.ADP.3Na+ form of the pig kidney Na+,K+-ATPase, movements of M5 of the α-subunit, which regulate ion selectivity, are controlled by the C-terminal tail that extends from M10. We propose that movements of M10 and its cytoplasmic extension is affected by CPZ, thereby regulating ion selectivity and transport through the K+ sites in Na+,K+-ATPase.

  7. Inhibition of intestinal bile acid transporter Slc10a2 improves triglyceride metabolism and normalizes elevated plasma glucose levels in mice.

    Directory of Open Access Journals (Sweden)

    Thomas Lundåsen

    Full Text Available Interruption of the enterohepatic circulation of bile acids increases cholesterol catabolism, thereby stimulating hepatic cholesterol synthesis from acetate. We hypothesized that such treatment should lower the hepatic acetate pool which may alter triglyceride and glucose metabolism. We explored this using mice deficient of the ileal sodium-dependent BA transporter (Slc10a2 and ob/ob mice treated with a specific inhibitor of Slc10a2. Plasma TG levels were reduced in Slc10a2-deficient mice, and when challenged with a sucrose-rich diet, they displayed a reduced response in hepatic TG production as observed from the mRNA levels of several key enzymes in fatty acid synthesis. This effect was paralleled by a diminished induction of mature sterol regulatory element-binding protein 1c (Srebp1c. Unexpectedly, the SR-diet induced intestinal fibroblast growth factor (FGF 15 mRNA and normalized bile acid synthesis in Slc10a2-/- mice. Pharmacologic inhibition of Slc10a2 in diabetic ob/ob mice reduced serum glucose, insulin and TGs, as well as hepatic mRNA levels of Srebp1c and its target genes. These responses are contrary to those reported following treatment of mice with a bile acid binding resin. Moreover, when key metabolic signal transduction pathways in the liver were investigated, those of Mek1/2-Erk1/2 and Akt were blunted after treatment of ob/ob mice with the Slc10a2 inhibitor. It is concluded that abrogation of Slc10a2 reduces hepatic Srebp1c activity and serum TGs, and in the diabetic ob/ob model it also reduces glucose and insulin levels. Hence, targeting of Slc10a2 may be a promising strategy to treat hypertriglyceridemia and diabetes.

  8. Quantitative Analysis of Complex Drug-Drug Interactions Between Repaglinide and Cyclosporin A/Gemfibrozil Using Physiologically Based Pharmacokinetic Models With In Vitro Transporter/Enzyme Inhibition Data.

    Science.gov (United States)

    Kim, Soo-Jin; Toshimoto, Kota; Yao, Yoshiaki; Yoshikado, Takashi; Sugiyama, Yuichi

    2017-09-01

    Quantitative analysis of transporter- and enzyme-mediated complex drug-drug interactions (DDIs) is challenging. Repaglinide (RPG) is transported into the liver by OATP1B1 and then is metabolized by CYP2C8 and CYP3A4. The purpose of this study was to describe the complex DDIs of RPG quantitatively based on unified physiologically based pharmacokinetic (PBPK) models using in vitro K i values for OATP1B1, CYP3A4, and CYP2C8. Cyclosporin A (CsA) or gemfibrozil (GEM) increased the blood concentrations of RPG. The time profiles of RPG and the inhibitors were analyzed by PBPK models, considering the inhibition of OATP1B1 and CYP3A4 by CsA or OATP1B1 inhibition by GEM and its glucuronide and the mechanism-based inhibition of CYP2C8 by GEM glucuronide. RPG-CsA interaction was closely predicted using a reported in vitro K i,OATP1B1 value in the presence of CsA preincubation. RPG-GEM interaction was underestimated compared with observed data, but the simulation was improved with the increase of f m,CYP2C8 . These results based on in vitro K i values for transport and metabolism suggest the possibility of a bottom-up approach with in vitro inhibition data for the prediction of complex DDIs using unified PBPK models and in vitro f m value of a substrate for multiple enzymes should be considered carefully for the prediction. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  9. Inhibition of Glucose Transport by Tomatoside A, a Tomato Seed Steroidal Saponin, through the Suppression of GLUT2 Expression in Caco-2 Cells.

    Science.gov (United States)

    Li, Baorui; Terazono, Yusuke; Hirasaki, Naoto; Tatemichi, Yuki; Kinoshita, Emiko; Obata, Akio; Matsui, Toshiro

    2018-02-14

    We investigated whether tomatoside A (5α-furostane-3β,22,26-triol-3-[O-β-d-glucopyranosyl (1→2)-β-d-glucopyranosyl (1→4)-β-d-galactopyranoside] 26-O-β-d-glucopyranoside), a tomato seed saponin, may play a role in the regulation of intestinal glucose transport in human intestinal Caco-2 cells. Tomatoside A could not penetrate through Caco-2 cell monolayers, as observed in the transport experiments using liquid chromatography-mass spectrometry. The treatment of cells with 10 μM tomatoside A for 3 h resulted in a 46.0% reduction in glucose transport as compared to untreated cells. Western blotting analyses revealed that tomatoside A significantly (p transporter 2 (GLUT2) in Caco-2 cells, while no change in the expression of sodium-dependent glucose transporter 1 was observed. In glucose transport experiments, the reduced glucose transport by tomatoside A was ameliorated by a protein kinase C (PKC) inhibitor and a multidrug resistance-associated protein 2 (MRP2) inhibitor. The tomatoside A-induced reduction in glucose transport was restored in cells treated with apical sodium-dependent bile acid transporter (ASBT) siRNA or an ASBT antagonist. These findings demonstrated for the first time that the nontransportable tomato seed steroidal saponin, tomatoside A, suppressed GLUT2 expression via PKC signaling pathway during the ASBT-influx/MRP2-efflux process in Caco-2 cells.

  10. Structure/activity relationship of thapsigargin inhibition on the purified Golgi/secretory pathway Ca2+/Mn2+-transport ATPase (SPCA1a)

    DEFF Research Database (Denmark)

    Chen, Jialin; De Raeymaecker, Joren; Hovgaard, Jannik Brondsted

    2017-01-01

    SPCA1a displays a higher apparent Ca2+ affinity and lower maximal turnover rate than the purified sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA1a). The lipids cholesteryl hemisuccinate, linole-/oleamide and phosphatidyl ethanolamine inhibit, whereas phosphatidic acid and sphingomyelin enhance SPCA1a...... activity. Moreover, SPCA1a is blocked by μM concentrations of commonly used SERCA1a inhibitors thapsigargin (Tg), cyclopiazonic acid (CPA) and 2,5-di-tert-butyl hydroquinone (BHQ). Since tissue-specific targeting of SERCA2b by Tg analogues is considered for prostate cancer therapy, the inhibition of SPCA1a...

  11. The influence of ascorbic acid on the oxygen consumption and the heat production by the cells of wheat seedling roots with their mitochondrial electron transport chain inhibited at complexes I and III

    International Nuclear Information System (INIS)

    Gordon, L.K.; Rakhmatullina, D.F.; Ogorodnikova, T.I.; Alyabyev, A.J.; Minibayeva, F.V.; Loseva, N.L.; Mityashina, S.Y.

    2007-01-01

    The influence of exogenous ascorbic acid (AsA) on oxidative phosphorylation was studied using wheat seedling roots. Treatment of them with AsA stimulated the rates of oxygen consumption and the heat production and caused a decrease of the respiratory coefficient. The increase in respiration was prevented by inhibitors of ascorbate oxidase, diethyldithiocarbamate (DEDTC), and of cytochrome oxidase, cyanide (KCN). Exogenous AsA sharply stimulated the rate of oxygen consumption of roots when complexes I and III of the mitochondrial electron transport chain were inhibited by rotenone and antimycin A, respectively, while the rates of heat production did not change significantly. It is concluded that AsA is a potent energy substrate, which can be used in conditions of failing I and III complexes in the mitochondrial electron transport chain

  12. Resveratrol Inhibits Porcine Intestinal Glucose and Alanine Transport: Potential Roles of Na+/K+-ATPase Activity, Protein Kinase A, AMP-Activated Protein Kinase and the Association of Selected Nutrient Transport Proteins with Detergent Resistant Membranes

    Directory of Open Access Journals (Sweden)

    Stefanie Klinger

    2018-03-01

    Full Text Available Background: Beneficial effects of Resveratrol (RSV have been demonstrated, including effects on transporters and channels. However, little is known about how RSV influences intestinal transport. The aim of this study was to further characterize the effects of RSV on intestinal transport and the respective mechanisms. Methods: Porcine jejunum and ileum were incubated with RSV (300 µM, 30 min in Ussing chambers (functional studies and tissue bathes (detection of protein expression, phosphorylation, association with detergent resistant membranes (DRMs. Results: RSV reduced alanine and glucose-induced short circuit currents (ΔIsc and influenced forskolin-induced ΔIsc. The phosphorylation of sodium–glucose-linked transporter 1 (SGLT1, AMP-activated protein kinase (AMPK, protein kinase A substrates (PKA-S and liver kinase B1 (LKB1 increased but a causative relation to the inhibitory effects could not directly be established. The DRM association of SGLT1, peptide transporter 1 (PEPT1 and (phosphorylated Na+/H+-exchanger 3 (NHE3 did not change. Conclusion: RSV influences the intestinal transport of glucose, alanine and chloride and is likely to affect other transport processes. As the effects of protein kinase activation vary between the intestinal localizations, it would appear that increasing cyclic adenosine monophosphate (cAMP levels are part of the mechanism. Nonetheless, the physiological responses depend on cell type-specific structures.

  13. Inhibition of protein kinase CbetaII increases glucose uptake in 3T3-L1 adipocytes through elevated expression of glucose transporter 1 at the plasma membrane

    NARCIS (Netherlands)

    Bosch, Remko R.; Bazuine, Merlijn; Wake, Michelle M.; Span, Paul N.; Olthaar, André J.; Schürmann, Annette; Maassen, J. Antonie; Hermus, Ad R. M. M.; Willems, Peter H. G. M.; Sweep, C. G. J.

    2003-01-01

    The mechanism via which diacylglycerol-sensitive protein kinase Cs (PKCs) stimulate glucose transport in insulin-sensitive tissues is poorly defined. Phorbol esters, such as phorbol-12-myristate-13-acetate (PMA), are potent activators of conventional and novel PKCs. Addition of PMA increases the

  14. Effects of sodium-glucose co-transporter 2 (SGLT2 inhibition on renal function and albuminuria in patients with type 2 diabetes: a systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Lubin Xu

    2017-06-01

    Full Text Available Aim To evaluate the effects of sodium-glucose co-transporter 2 (SGLT2 inhibition on renal function and albuminuria in patients with type 2 diabetes. Methods We conducted systematic searches of PubMed, Embase and Cochrane Central Register of Controlled Trials up to June 2016 and included randomized controlled trials of SGLT2 inhibitors in adult type 2 diabetic patients reporting estimated glomerular filtration rate (eGFR and/or urine albumin/creatinine ratio (ACR changes. Data were synthesized using the random-effects model. Results Forty-seven studies with 22,843 participants were included. SGLT2 inhibition was not associated with a significant change in eGFR in general (weighted mean difference (WMD, −0.33 ml/min per 1.73 m2, 95% CI [−0.90 to 0.23] or in patients with chronic kidney disease (CKD (WMD −0.78 ml/min per 1.73 m2, 95% CI [−2.52 to 0.97]. SGLT2 inhibition was associated with eGFR reduction in short-term trials (WMD −0.98 ml/min per 1.73 m2, 95% CI [−1.42 to −0.54], and with eGFR preservation in long-term trials (WMD 2.01 ml/min per 1.73 m2, 95% CI [0.86 to 3.16]. Urine ACR reduction after SGLT2 inhibition was not statistically significant in type 2 diabetic patients in general (WMD −7.24 mg/g, 95% CI [−15.54 to 1.06], but was significant in patients with CKD (WMD −107.35 mg/g, 95% CI [−192.53 to −22.18]. Conclusions SGLT2 inhibition was not associated with significant changes in eGFR in patients with type 2 diabetes, likely resulting from a mixture of an initial reduction of eGFR and long-term renal function preservation. SGLT2 inhibition was associated with statistically significant albuminuria reduction in type 2 diabetic patients with CKD.

  15. Lipid nanocapsules containing the non-ionic surfactant Solutol HS15 inhibit the transport of calcium through hyperforin-activated channels in neuronal cells.

    Science.gov (United States)

    Chauvet, Sylvain; Barras, Alexandre; Boukherroub, Rabah; Bouron, Alexandre

    2015-12-01

    Hyperforin is described as a natural antidepressant inhibiting the reuptake of neurotransmitters and also activating cation channels. However the blood-brain barrier limits the access to the brain of this biomolecule. To circumvent this problem it was envisaged to encapsulate hyperforin into biomimetic lipid nano-carriers like lipid nanocapsules (LNCs). When testing the safety of 25 nm LNCs it appeared that they strongly blocked hyperforin-activated Ca2+ channels of cultured cortical neurons. This inhibition was due to one of their main component: solutol HS15 (polyoxyethylene-660-12-hydroxy stearate), a non-ionic soluble surfactant. Solutol HS15 rapidly depresses in a concentration-dependent manner the entry of Ca2+ through hyperforin-activated channels without influencing store-operated channels. This effect is mimicked by Brij58 but not by PEG600, indicating that the lipid chain of Solutol HS15 is important in determining its effects on the channels. The inhibition of the Ca2+ fluxes depends on the cellular cholesterol content; it is stronger after depleting cholesterol with methyl-β-cyclodextrin and is nearly absent on cells cultured in a cholesterol-rich medium. When chronically applied for 24 h, Solutol HS15 slightly up-regulates the entry of Ca2+ through hyperforin-activated channels. Similar observations were made when testing 25 nm lipid nanocapsules containing the surfactant Solutol HS15. Altogether, this study shows that Solutol HS15 perturbs in a cholesterol-dependent manner the activity of some neuronal channels. This is the first demonstration that LNCs containing this surfactant can influence cellular calcium signaling in the brain, a finding that can have important clinical implications. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Inhibition of K+ Transport through Na+, K+-ATPase by Capsazepine: Role of Membrane Span 10 of the α-Subunit in the Modulation of Ion Gating

    OpenAIRE

    Mahmmoud, Yasser A.; Shattock, Michael; Cornelius, Flemming; Pavlovic, Davor

    2014-01-01

    Capsazepine (CPZ) inhibits Na+,K+-ATPase-mediated K+-dependent ATP hydrolysis with no effect on Na+-ATPase activity. In this study we have investigated the functional effects of CPZ on Na+,K+-ATPase in intact cells. We have also used well established biochemical and biophysical techniques to understand how CPZ modifies the catalytic subunit of Na+,K+-ATPase. In isolated rat cardiomyocytes, CPZ abolished Na+,K+-ATPase current in the presence of extracellular K+. In contrast, CPZ stimulated pum...

  17. Chronic treatment with amyloid beta(1-42) inhibits non-cholinergic high-affinity choline transport in NG108-15 cells through protein kinase C signaling

    Czech Academy of Sciences Publication Activity Database

    Nováková, Jana; Mikasová, Lenka; Machová, Eva; Lisá, Věra; Doležal, Vladimír

    2005-01-01

    Roč. 1062, č. 1-2 (2005), s. 101-110 ISSN 0006-8993 R&D Projects: GA AV ČR(CZ) IAA5011206; GA MŠk(CZ) LC554 Grant - others:Lipidiet(XE) QLK1-CT-2002-00172 Institutional research plan: CEZ:AV0Z50110509 Keywords : choline transporter * beta-amyloid * protein kinase C Subject RIV: ED - Physiology Impact factor: 2.296, year: 2005

  18. Inhibition of time-dependent enhancement of amino acid transport by leukemic leukocytes: a possible index of the sensitivity of cells to drugs

    Energy Technology Data Exchange (ETDEWEB)

    Frengley, P A; Peck, W A; Lichtman, M A

    1975-01-01

    Leukemic leukocytes increase their rates of alpha aminoisobutyric acid (AIB) accumulation when incubated for prolonged periods in amino acid deficient media. The time-dependent increase was prevented by concurrent exposure of cells to cycloheximide or actinomycin D in vitro. In addition, the increase in AIB uptake was not present in leukemic blasts studied in vitro when the cells were obtained from subjects with acute myeloblastic leukemia who had received antileukemic therapy. Cortisol added to cell suspensions in vitro inhibited the development of time-dependent increases in AIB uptake in lymphoid cells, but accentuated the process slightly in myeloblasts. Cortisol administered to a subject with CLL by infusion reduced the time-dependent increase in AIB uptake by CLL cells subsequently studied in vitro. These data indicate that the time-dependent increase in AIB uptake may be a means of testing the sensitivity of leukemic cells to drugs.

  19. Heat shock protein 70 inhibits shrinkage-induced programmed cell death via mechanisms independent of effects on cell volume-regulatory membrane transport proteins

    DEFF Research Database (Denmark)

    Nylandsted, J; Jäättelä, M; Hoffmann, E K

    2004-01-01

    Cell shrinkage is a ubiquitous feature of programmed cell death (PCD), but whether it is an obligatory signalling event in PCD is unclear. Heat shock protein 70 (Hsp70) potently counteracts PCD in many cells, by mechanisms that are incompletely understood. In the present investigation, we found...... that severe hypertonic stress greatly diminished the viability of murine fibrosarcoma cells (WEHI-902) and immortalized murine embryonic fibroblasts (iMEFs). This effect was attenuated markedly by Hsp70 over-expression. To determine whether the protective effect of Hsp70 was mediated via an effect on volume...... regulatory ion transport, we compared regulatory volume decrease (RVD) and increase (RVI) in control WEHI-902 cells and after increasing Hsp70 levels by heat shock or over-expression (WEHI-912). Hsp70 levels affected neither RVD, RVI nor the relative contributions of the Na(+)/H(+)-exchanger (NHE1) and Na...

  20. The antimalarial activities of methylene blue and the 1,4-naphthoquinone 3-[4-(trifluoromethyl)benzyl]-menadione are not due to inhibition of the mitochondrial electron transport chain.

    Science.gov (United States)

    Ehrhardt, Katharina; Davioud-Charvet, Elisabeth; Ke, Hangjun; Vaidya, Akhil B; Lanzer, Michael; Deponte, Marcel

    2013-05-01

    Methylene blue and a series of recently developed 1,4-naphthoquinones, including 3-[4-(substituted)benzyl]-menadiones, are potent antimalarial agents in vitro and in vivo. The activity of these structurally diverse compounds against the human malaria parasite Plasmodium falciparum might involve their peculiar redox properties. According to the current theory, redox-active methylene blue and 3-[4-(trifluoromethyl)benzyl]-menadione are "subversive substrates." These agents are thought to shuttle electrons from reduced flavoproteins to acceptors such as hemoglobin-associated or free Fe(III)-protoporphyrin IX. The reduction of Fe(III)-protoporphyrin IX could subsequently prevent essential hemoglobin digestion and heme detoxification in the parasite. Alternatively, owing to their structures and redox properties, methylene blue and 1,4-naphthoquinones might also affect the mitochondrial electron transport chain. Here, we tested the latter hypothesis using an established system of transgenic P. falciparum cell lines and the antimalarial agents atovaquone and chloroquine as controls. In contrast to atovaquone, methylene blue and 3-[4-(trifluoromethyl)benzyl]-menadione do not inhibit the mitochondrial electron transport chain. A systematic comparison of the morphologies of drug-treated parasites furthermore suggests that the three drugs do not share a mechanism of action. Our findings support the idea that methylene blue and 3-[4-(trifluoromethyl)benzyl]-menadione exert their antimalarial activity as redox-active subversive substrates.

  1. Transport Statistics - Transport - UNECE

    Science.gov (United States)

    Sustainable Energy Statistics Trade Transport Themes UNECE and the SDGs Climate Change Gender Ideas 4 Change UNECE Weekly Videos UNECE Transport Areas of Work Transport Statistics Transport Transport Statistics About us Terms of Reference Meetings and Events Meetings Working Party on Transport Statistics (WP.6

  2. Statin-induced inhibition of breast cancer proliferation and invasion involves attenuation of iron transport: intermediacy of nitric oxide and antioxidant defence mechanisms.

    Science.gov (United States)

    Kanugula, Anantha Koteswararao; Gollavilli, Paradesi Naidu; Vasamsetti, Sathish Babu; Karnewar, Santosh; Gopoju, Raja; Ummanni, Ramesh; Kotamraju, Srigiridhar

    2014-08-01

    Accumulating evidence from in vitro, in vivo, clinical and epidemiological studies shows promising results for the use of statins against many cancers including breast carcinoma. However, the molecular mechanisms responsible for the anti-proliferative and anti-invasive properties of statins still remain elusive. In this study, we investigated the involvement of nitric oxide, iron homeostasis and antioxidant defence mechanisms in mediating the anti-proliferative and anti-invasive properties of hydrophobic statins in MDA-MB-231, MDA-MB-453 and BT-549 metastatic triple negative breast cancer cells. Fluvastatin and simvastatin significantly increased cytotoxicity which was reversed with mevalonate. Interestingly, fluvastatin downregulated transferrin receptor (TfR1), with a concomitant depletion of intracellular iron levels in these cells. Statin-induced effects were mimicked by geranylgeranyl transferase inhibitor (GGTI-298) but not farnesyl transferase inhibitor (FTI-277). Further, it was observed that TfR1 downregulation is mediated by increased nitric oxide levels via inducible nitric oxide synthase (iNOS) expression. NOS inhibitors (asymmetric dimethylarginine and 1400W) counteracted and sepiapterin, a precursor of tetrahydrobiopterin, exacerbated statin-induced depletion of intracellular iron levels. Notably, fluvastatin increased manganese superoxide dismutase (by repressing the transcription factor DNA damage-binding protein 2), catalase and glutathione which, in turn, diminished H2 O2 levels. Fluvastatin-induced downregulation of TfR1, matrix metalloproteinase-2, -9 and inhibition of invasion were reversed in the presence of aminotriazole, a specific inhibitor of catalase. Finally, we conclude that fluvastatin, by altering iron homeostasis, nitric oxide generation and antioxidant defence mechanisms, induces triple negative breast cancer cell death. © 2014 FEBS.

  3. Effects of γ-Aminobutyric acid transporter 1 inhibition by tiagabine on brain glutamate and γ-Aminobutyric acid metabolism in the anesthetized rat In vivo.

    Science.gov (United States)

    Patel, Anant B; de Graaf, Robin A; Rothman, Douglas L; Behar, Kevin L

    2015-07-01

    γ-Aminobutyric acid (GABA) clearance from the extracellular space after release from neurons involves reuptake into terminals and astrocytes through GABA transporters (GATs). The relative flows through these two pathways for GABA released from neurons remains unclear. This study determines the effect of tiagabine, a selective inhibitor of neuronal GAT-1, on the rates of glutamate (Glu) and GABA metabolism and GABA resynthesis via the GABA-glutamine (Gln) cycle. Halothane-anesthetized rats were administered tiagabine (30 mg/kg, i.p.) and 45 min later received an intravenous infusion of either [1,6-(13)C2]glucose (in vivo) or [2-(13)C]acetate (ex vivo). Nontreated rats served as controls. Metabolites and (13)C enrichments were measured with (1)H-[(13)C]-nuclear magnetic resonance spectroscopy and referenced to their corresponding endpoint values measured in extracts from in situ frozen brain. Metabolic flux estimates of GABAergic and glutamatergic neurons were determined by fitting a metabolic model to the (13)C turnover data measured in vivo during [1,6-(13)C2]glucose infusion. Tiagabine-treated rats were indistinguishable (P > 0.05) from controls in tissue amino acid levels and in (13)C enrichments from [2-(13)C]acetate. Tiagabine reduced average rates of glucose oxidation and neurotransmitter cycling in both glutamatergic neurons (↓18%, CMR(glc(ox)Glu): control, 0.27 ± 0.05 vs. tiagabine, 0.22 ± 0.04 µmol/g/min; ↓11%, V(cyc(Glu-Gln)): control 0.23 ± 0.05 vs. tiagabine 0.21 ± 0.04 µmol/g/min and GABAergic neurons (↓18-25%, CMR(glc(ox)GABA): control 0.09 ± 0.02 vs. tiagabine 0.07 ± 0.03 µmol/g/min; V(cyc(GABA-Gln)): control 0.08 ± 0.02 vs. tiagabine 0.07 ± 0.03 µmol/g/min), but the changes in glutamatergic and GABAergic fluxes were not significant (P > 0.10). The results suggest that any reduction in GABA metabolism by tiagabine might be an indirect response to reduced glutamatergic drive rather than direct compensatory effects. © 2015 Wiley

  4. Corrosion inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Fisher, A O

    1965-12-29

    An acid corrosion-inhibiting composition consists essentially of a sugar, and an alkali metal salt selected from the group consisting of iodides and bromides. The weight ratio of the sugar to the alkali metal salt is between 2:1 and about 20,000:1. Also, a corrosion- inhibited phosphoric acid composition comprising at least about 20 wt% of phosphoric acid and between about 0.1 wt% and about 10 wt% of molasses, and between about 0.0005 wt% and about 1 wt% of potassium iodide. The weight ratio of molasses to iodide is greater than about 2:1. (11 claims)

  5. Evaluation of pharmacokinetic and pharmacodynamic interaction between repaglinide and atazanavir in healthy, diabetic and hepatic impaired rats: possible inhibition of CYP3A, OATP, and P-glycoprotein transporters

    Directory of Open Access Journals (Sweden)

    Thirumal Eswara Goud

    2016-10-01

    Full Text Available The metabolic syndrome in HIV infected patients is particularly associated with the use protease inhibitors. Atazanavir is an inhibitor of the cytochrome P 450 (CYP system, in particular CYP3A4 and CYP2C9 which can affect the metabolism of several drugs. To treat metabolic syndrome in HIV patients repaglinide is used and it is a short acting insulin secretagogues undergoing metabolism with CYP 3A4 and CYP 2C8 enzyme system. The purpose of this study was to assess the possible pharmacokinetic and pharmacodynamic drug interaction of repaglinide and atazanavir in healthy, diabetic and impaired hepatic function rats. Human oral therapeutic doses of atazanavir and repaglinide were extrapolated to rats based on the body surface area. The pharmacokinetic parameters and blood glucose concentrations of repaglinide were determined after oral administration of repaglinide alone (0.5 mg/kg and in the presence of atazanavir (36 mg/kg in normal, diabetic and hepatic impaired rats. The pharmacokinetics (PK and blood glucose concentrations of repaglinide were significantly altered in the presence of atazanavir. The peak plasma concentration (Cmax, area under the plasma concentration time profile (AUC and elimination half-life of repaglinide were significantly (P<0.0001 increased. The repaglinide clearance (CL was significantly (P<0.0001 decreased in the presence of atazanavir treatment. In the presence of atazanavir, repaglinide hypoglycaemic activity was increased significantly (P<0.0001 when compared with the repaglinide control group. The present study demonstrated the significant difference in the PK/PD changes due to the enhanced bioavailability and decreased total body clearance of repaglinide may be due to the inhibition of the CYP P450 metabolic system, OATP and P-gp transporters by atazanavir.

  6. Analysis of Proton Transport Experiments.

    Science.gov (United States)

    1980-09-05

    which can inhibit transport, may grow . The abrupt loss of transport at higher currents in the small channel suggests this possibility. Future experiments... Unicorn Park Drive Woburn, MA 01801 Attn: H. Linnerud 1 copy Lawrence Livermore Laboratory P. 0. Box 808 Livermore, CA 94550 Attn: R. J. Briggs 1 copy R

  7. Mechanistic kinetic modeling generates system-independent P-glycoprotein mediated transport elementary rate constants for inhibition and, in combination with 3D SIM microscopy, elucidates the importance of microvilli morphology on P-glycoprotein mediated efflux activity.

    Science.gov (United States)

    Ellens, Harma; Meng, Zhou; Le Marchand, Sylvain J; Bentz, Joe

    2018-06-01

    In vitro transporter kinetics are typically analyzed by steady-state Michaelis-Menten approximations. However, no clear evidence exists that these approximations, applied to multiple transporters in biological membranes, yield system-independent mechanistic parameters needed for reliable in vivo hypothesis generation and testing. Areas covered: The classical mass action model has been developed for P-glycoprotein (P-gp) mediated transport across confluent polarized cell monolayers. Numerical integration of the mass action equations for transport using a stable global optimization program yields fitted elementary rate constants that are system-independent. The efflux active P-gp was defined by the rate at which P-gp delivers drugs to the apical chamber, since as much as 90% of drugs effluxed by P-gp partition back into nearby microvilli prior to reaching the apical chamber. The efflux active P-gp concentration was 10-fold smaller than the total expressed P-gp for Caco-2 cells, due to their microvilli membrane morphology. The mechanistic insights from this analysis are readily extrapolated to P-gp mediated transport in vivo. Expert opinion: In vitro system-independent elementary rate constants for transporters are essential for the generation and validation of robust mechanistic PBPK models. Our modeling approach and programs have broad application potential. They can be used for any drug transporter with minor adaptations.

  8. The serotonin transporter: Examination of the changes in transporter affinity induced by ligand binding

    International Nuclear Information System (INIS)

    Humphreys, C.J.

    1989-01-01

    The plasmalemmal serotonin transporter uses transmembrane gradients of Na + , Cl - and K + to accumulate serotonin within blood platelets. Transport is competitively inhibited by the antidepressant imipramine. Like serotonin transport, imipramine binding requires Na + . Unlike serotonin, however, imipramine does not appear to be transported. To gain insight into the mechanism of serotonin transport the author have analyzed the influences of Na + and Cl - , the two ions cotransported with serotonin, on both serotonin transport and the interaction of imipramine and other antidepressant drugs with the plasmalemmal serotonin transporter of human platelets. Additionally, the author have synthesized, purified and characterized the binding of 2-iodoimipramine to the serotonin transporter. Finally, the author have conducted a preliminary study of the inhibition of serotonin transport and imipramine binding produced by dicyclohexylcarbodiimide. My results reveal many instances of positive heterotropic cooperativity in ligand binding to the serotonin transporter. Na + binding enhances the transporters affinity for imipramine and several other antidepressant drugs, and also increases the affinity for Cl - . Cl - enhances the transporters affinity for imipramine, as well as for Na + . At concentrations in the range of its K M for transport serotonin is a competitive inhibitor of imipramine binding. At much higher concentrations, however, serotonin also inhibits imipramines dissociation rate constant. This latter effect which is Na + -independent and species specific, is apparently produced by serotonin binding at a second, low affinity site on, or near, the transporter complex. Iodoimipramine competitively inhibit both [ 3 H]imipramine binding and [ 3 H]serotonin transport

  9. Radiation Transport

    Energy Technology Data Exchange (ETDEWEB)

    Urbatsch, Todd James [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2015-06-15

    We present an overview of radiation transport, covering terminology, blackbody raditation, opacities, Boltzmann transport theory, approximations to the transport equation. Next we introduce several transport methods. We present a section on Caseology, observing transport boundary layers. We briefly broach topics of software development, including verification and validation, and we close with a section on high energy-density experiments that highlight and support radiation transport.

  10. Chamber transport

    International Nuclear Information System (INIS)

    Olson, Craig L.

    2001-01-01

    Heavy ion beam transport through the containment chamber plays a crucial role in all heavy ion fusion (HIF) scenarios. Here, several parameters are used to characterize the operating space for HIF beams; transport modes are assessed in relation to evolving target/accelerator requirements; results of recent relevant experiments and simulations of HIF transport are summarized; and relevant instabilities are reviewed. All transport options still exist, including (1) vacuum ballistic transport, (2) neutralized ballistic transport, and (3) channel-like transport. Presently, the European HIF program favors vacuum ballistic transport, while the US HIF program favors neutralized ballistic transport with channel-like transport as an alternate approach. Further transport research is needed to clearly guide selection of the most attractive, integrated HIF system

  11. INHIBITION IN SPEAKING PERFORMANCE

    OpenAIRE

    Humaera, Isna

    2015-01-01

    The most common problem encountered by the learner in the languageacquisition process is learner inhibition. Inhibition refers to a temperamentaltendency to display wariness, fearfulness, or restrain in response tounfamiliar people, objects, and situations. There are some factors that causeinhibition, such as lack of motivation, shyness, self-confidence, self-esteem,and language ego. There are also levels of inhibition, it refers to kinds ofinhibition and caused of inhibition itself. Teacher ...

  12. Effects of flavonoid mixtures on the transport of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) through Caco-2 monolayers: An in vitro and kinetic modeling approach to predict the combined effects on transporter inhibition

    NARCIS (Netherlands)

    Schutte, M.E.; Boersma, M.G.; Verhallen, D.A.M.; Groten, J.P.; Rietjens, I.M.C.M.

    2008-01-01

    This study describes and kinetically models the effect of flavonoid mixtures on PhIP transport through Caco-2 monolayers. Previously it was shown that quercetin, luteolin, naringenin and myricetin increase the apical to basolateral PhIP transport in Caco-2 monolayers. In this study, apigenin was

  13. Inhibition of poliovirus RNA synthesis by brefeldin A.

    OpenAIRE

    Maynell, L A; Kirkegaard, K; Klymkowsky, M W

    1992-01-01

    Brefeldin A (BFA), a fungal metabolite that blocks transport of newly synthesized proteins from the endoplasmic reticulum, was found to inhibit poliovirus replication 10(5)- to 10(6)-fold. BFA does not inhibit entry of poliovirus into the cell or translation of viral RNA. Poliovirus RNA synthesis, however, is completely inhibited by BFA. A specific class of membranous vesicles, with which the poliovirus replication complex is physically associated, is known to proliferate in poliovirus-infect...

  14. Transport phenomena

    International Nuclear Information System (INIS)

    Kirczenow, G.; Marro, J.

    1974-01-01

    Some simple remarks on the basis of transport theory. - Entropy, dynamics and scattering theory. - Response, relaxation and fluctuation. - Fluctuating hydrodynamics and renormalization of susceptibilities and transport coefficients. - Irreversibility of the transport equations. - Ergodic theory and statistical mechanics. - Correlation functions in Heisenberg magnets. - On the Enskog hard-sphere kinetic eqquation and the transport phenomena of dense simple gases. - What can one learn from Lorentz models. - Conductivity in a magnetic field. - Transport properties in gases in presence of external fields. - Transport properties of dilute gases with internal structure. (orig.) [de

  15. Nitrate dosage system in a reclaimed wastewater pipeline for the inhibition of sulfide build-up; Sistema de dosificacion de nitrato en una conduccion de transporte de agua depurada para evitar la generacion de sulfuro

    Energy Technology Data Exchange (ETDEWEB)

    Monteagudo Perez-Machado, T.; Rodriguez Gomez, L. E.; Alvarez Diaz, M.

    2007-07-01

    During reclaimed wastewater transportation under anaerobic conditions sulfide generation may take place, which should be avoided due to the numerous problems related to it. This is the case of the reclaimed wastewater reuse scheme of Tenerife, one of whose elements is a completely filled 61 km long gravity pipeline, 0,60 m in diameter. In order to avoid the appearance of anaerobic conditions a controlled nitrate dosage system has been designed to be installed at the pipeline inlet, with nitrate dosage to be controlled by the organic matter content of the reclaimed wastewater, using turbidity as an indicator of it. (Author) 26 refs.

  16. Neurotransmitter transporters

    DEFF Research Database (Denmark)

    Gether, Ulrik; Andersen, Peter H; Larsson, Orla M

    2006-01-01

    The concentration of neurotransmitters in the extracellular space is tightly controlled by distinct classes of membrane transport proteins. This review focuses on the molecular function of two major classes of neurotransmitter transporter that are present in the cell membrane of neurons and....... Recent research has provided substantial insight into the structure and function of these transporters. In particular, the recent crystallizations of bacterial homologs are of the utmost importance, enabling the first reliable structural models of the mammalian neurotransmitter transporters...

  17. Does SGLT2 inhibition with dapagliflozin overcome individual therapy resistance to RAAS inhibition?

    NARCIS (Netherlands)

    Petrykiv, Sergei; Laverman, Gozewijn D.; de Zeeuw, Dick; Heerspink, Hiddo J. L.

    Individual patients show a large variation in their response to renin-angiotensin-aldosteron system (RAAS) inhibition (RAASi), both in surrogates such as albuminuria and in hard renal outcomes. Sodium-glucose co-transporter 2 inhibitors (SGLT2) have been shown to lower albuminuria and to confer

  18. Sustainable Transportation

    DEFF Research Database (Denmark)

    Hall, Ralph P.; Gudmundsson, Henrik; Marsden, Greg

    2014-01-01

    The transportation system is the backbone of economic and social progress and the means by which humans access goods and services and connect with one another. Yet, as the scale of transportation activities has grown worldwide, so too have the negative environmental, social, and economic impacts...... that relate to the construction and maintenance of transportation infrastructure and the operation or use of the different transportation modes. The concept of sustainable transportation emerged in response to these concerns as part of the broader notion of sustainable development. Given the transportation...... sector’s significant contribution to global challenges such as climate change, it is often said that sustainable development cannot be achieved without sustainable transportation....

  19. Ectopic expression of eIF4E-transporter triggers the movement of eIF4E into P-bodies, inhibiting steady-state translation but not the pioneer round of translation

    International Nuclear Information System (INIS)

    Lee, Hyung Chul; Cho, Hana; Kim, Yoon Ki

    2008-01-01

    Nonsense-mediated mRNA decay (NMD) is the best-characterized mRNA surveillance mechanism; this process removes faulty mRNAs harboring premature termination codons (PTCs). NMD targets newly synthesized mRNAs bound by nuclear cap-binding proteins 80/20 (CBP80/20) and exon junction complex (EJC), the former of which is thought to recruit the ribosome to initiate the pioneer round of translation. After completion of the pioneer round of translation, CBP80/20 is replaced by the cytoplasmic cap-binding protein eIF4E, which mediates steady-state translation in the cytoplasm. Here, we show that overexpression of eIF4E-T preferentially inhibits cap-dependent steady-state translation, but not the pioneer round of translation. We also demonstrate that overexpression of eIF4E-T or Dcp1a triggers the movement of eIF4E into the processing bodies. These results suggest that the pioneer round of translation differs from steady-state translation in terms of ribosome recruitment

  20. Inhibition of electron transfer and uncoupling effects by emodin and emodinanthrone in Escherichia coli.

    OpenAIRE

    Ubbink-Kok, T; Anderson, J A; Konings, W N

    1986-01-01

    The anthraquinones emodin (1,3,delta-trihydroxy-6-methylanthraquinone) and emodinanthrone (1,3,8-trihydroxy-6-methylanthrone) inhibited respiration-driven solute transport at micromolar concentrations in membrane vesicles of Escherichia coli. This inhibition was enhanced by Ca ions. The inhibitory action on solute transport is caused by inhibition of electron flow in the respiratory chain, most likely at the level between ubiquinone and cytochrome b, and by dissipation of the proton motive fo...

  1. Nuclear transport

    International Nuclear Information System (INIS)

    Anon.

    2003-01-01

    During january and february 2003, a unique event concerning nuclear transport was reported and rated 1 on the INES scale. This event concerns the absence of a maintenance operation on a shipping cask. This shipping cask was used for several years for nuclear transport inside La-hague site before being re-assigned to transport on public thoroughfare. The re-assignment of the cask should have been preceded and conditioned by a maintenance operation whose purpose is to check the efficiency of its radiation shield. During this period 2 on-site inspections concerning the transport of nuclear materials were performed. (A.C.)

  2. Ocean transportation

    National Research Council Canada - National Science Library

    Frankel, Ernst G; Marcus, Henry S

    1973-01-01

    .... This analysis starts with a review of ocean transportation demand and supply including projections of ship capacity demand and world shipbuilding capacity under various economic and political assumptions...

  3. An allosteric binding site at the human serotonin transporter mediates the inhibition of escitalopram by R-citalopram: kinetic binding studies with the ALI/VFL-SI/TT mutant.

    Science.gov (United States)

    Zhong, Huailing; Hansen, Kasper B; Boyle, Noel J; Han, Kiho; Muske, Galina; Huang, Xinyan; Egebjerg, Jan; Sánchez, Connie

    2009-10-25

    The human serotonin transporter (hSERT) has primary and allosteric binding sites for escitalopram and R-citalopram. Previous studies have established that the interaction of these two compounds at a low affinity allosteric binding site of hSERT can affect the dissociation of [(3)H]escitalopram from hSERT. The allosteric binding site involves a series of residues in the 10th, 11th, and 12th trans-membrane domains of hSERT. The low affinity allosteric activities of escitalopram and R-citalopram are essentially eliminated in a mutant hSERT with changes in some of these residues, namely A505V, L506F, I507L, S574T, I575T, as measured in dissociation binding studies. We confirm that in association binding experiments, R-citalopram at clinically relevant concentrations reduces the association rate of [(3)H]escitalopram as a ligand to wild type hSERT. We demonstrate that the ability of R-citalopram to reduce the association rate of escitalopram is also abolished in the mutant hSERT (A505V, L506F, I507L, S574T, I575T), along with the expected disruption the low affinity allosteric function on dissociation binding. This suggests that the allosteric binding site mediates both the low affinity and higher affinity interactions between R-citalopram, escitalopram, and hSERT. Our data add an additional structural basis for the different efficacies of escitalopram compared to racemic citalopram reported in animal studies and clinical trials, and substantiate the hypothesis that hSERT has complex allosteric mechanisms underlying the unexplained in vivo activities of its inhibitors.

  4. Neutron transport

    International Nuclear Information System (INIS)

    Berthoud, Georges; Ducros, Gerard; Feron, Damien; Guerin, Yannick; Latge, Christian; Limoge, Yves; Santarini, Gerard; Seiler, Jean-Marie; Vernaz, Etienne; Coste-Delclaux, Mireille; M'Backe Diop, Cheikh; Nicolas, Anne; Andrieux, Catherine; Archier, Pascal; Baudron, Anne-Marie; Bernard, David; Biaise, Patrick; Blanc-Tranchant, Patrick; Bonin, Bernard; Bouland, Olivier; Bourganel, Stephane; Calvin, Christophe; Chiron, Maurice; Damian, Frederic; Dumonteil, Eric; Fausser, Clement; Fougeras, Philippe; Gabriel, Franck; Gagnier, Emmanuel; Gallo, Daniele; Hudelot, Jean-Pascal; Hugot, Francois-Xavier; Dat Huynh, Tan; Jouanne, Cedric; Lautard, Jean-Jacques; Laye, Frederic; Lee, Yi-Kang; Lenain, Richard; Leray, Sylvie; Litaize, Olivier; Magnaud, Christine; Malvagi, Fausto; Mijuin, Dominique; Mounier, Claude; Naury, Sylvie; Nicolas, Anne; Noguere, Gilles; Palau, Jean-Marc; Le Pallec, Jean-Charles; Peneliau, Yannick; Petit, Odile; Poinot-Salanon, Christine; Raepsaet, Xavier; Reuss, Paul; Richebois, Edwige; Roque, Benedicte; Royer, Eric; Saint-Jean, Cyrille de; Santamarina, Alain; Serot, Olivier; Soldevila, Michel; Tommasi, Jean; Trama, Jean-Christophe; Tsilanizara, Aime; Behar, Christophe; Provitina, Olivier; Lecomte, Michael; Forestier, Alain; Bender, Alexandra; Parisot, Jean-Francois; Finot, Pierre

    2013-10-01

    This bibliographical note presents a reference book which addresses the study of neutron transport in matter, the study of conditions for a chain reaction and the study of modifications of matter composition due to nuclear reactions. This book presents the main nuclear data, their measurement, assessment and processing, and the spallation. It proposes an overview of methods applied for the study of neutron transport: basic equations and their derived forms, deterministic methods and Monte Carlo method of resolution of the Boltzmann equation, methods of resolution of generalized Bateman equations, methods of time resolution of space kinetics coupled equations. It presents the main calculation codes, discusses the qualification and experimental aspects, and gives an overview of neutron transport applications: neutron transport calculation of reactors, neutron transport coupled with other disciplines, physics of fuel cycle, criticality

  5. Inhibition of lactation.

    Science.gov (United States)

    Llewellyn-Jones, D

    1975-01-01

    The mechanism and hormonal regulation of lactation is explained and illustrated with a schematic representation. Circulating estrogen above a critical amount seems to be the inhibitory factor controlling lactation during pregnancy. Once delivery occurs, the level of estrogen falls, that of prolactin rises, and lactation begins. Nonsuckling can be used to inhibit lactation. Estrogens can also be used to inhibit lactation more quickly and with less pain. The reported association between estrogens and puerperal thromboembolism cannot be considered conclusive due to defects in the reporting studies. There is no reason not to use estrogens in lactation inhibition except for women over 35 who experienced a surgical delivery. Alternative therapy is available for these women. The recently-developed drug, brom-ergocryptine, may replace other methods of lactation inhibition.

  6. Screening for Inhibitors of Essential Leishmania Glucose Transporters

    Science.gov (United States)

    2013-07-01

    Leishmania Glucose Transporters PRINCIPAL INVESTIGATOR: Scott M. Landfear, Ph.D. CONTRACTING ORGANIZATION: Oregon Health & Science...COVERED 1 July 2009- 30 June 2013 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Screening for Inhibitors of Essential Leishmania Glucose Transporters 5b...The objective of this project was to identify compounds that selectively inhibit the essential Leishmania glucose transporters and could hence serve

  7. Animal Transports

    Directory of Open Access Journals (Sweden)

    Diana Ludrovcová

    2016-08-01

    Full Text Available Purpose and Originality: The research is aimed to the animal transports issue, from two points of view – first is the animal cruelty and second is the policy and economic consideration. The goal is to acquaint the readers with the transports risks and its cruelty and evaluation of the economic, political aspects for he involved countries. The study is oriented on more points of view, what is rare in works with a similar theme. Method: This paper examines many issues and examinations from different authors and subsequently summarized the findings with authors own knowledge to one expanded unit. Results: Results proves, that livestock transports have negative impact on animal´s health, environment. Number of transported animals is rising every year. Society: Research familiarize the society with the animal transports, cruelty against animals during them, and influence of transports on some countries, their economy, policy. People get better informed and can form their own opinion on this topic. They may start acting, undertaking some steps to improve the present situation, what could help a lot to animals and environment. Limitations / further research: Future research could show progress and improvement of transports, quality of food supply and economics.

  8. Ocean transportation

    National Research Council Canada - National Science Library

    Frankel, Ernst G; Marcus, Henry S

    1973-01-01

    .... The discussion of technology considers the ocean transportation system as a whole, and the composite subsystems such as hull, outfit, propulsion, cargo handling, automation, and control and interface technology...

  9. Ocean transportation

    National Research Council Canada - National Science Library

    Frankel, Ernst G; Marcus, Henry S

    1973-01-01

    .... In ocean transportation economics we present investment and operating costs as well as the results of a study of financing of shipping. Similarly, a discussion of government aid to shipping is presented.

  10. Nicaragua - Transportation

    Data.gov (United States)

    Millennium Challenge Corporation — The evaluation examines impacts of the Transportation Project in three ways. First, we calculate economic rates of return associated with reduced user costs for each...

  11. Sediment Transport

    DEFF Research Database (Denmark)

    Liu, Zhou

    Flow and sediment transport are important in relation to several engineering topics, e.g. erosion around structures, backfilling of dredged channels and nearshore morphological change. The purpose of the present book is to describe both the basic hydrodynamics and the basic sediment transport...... mechanics. Chapter 1 deals with fundamentals in fluid mechanics with emphasis on bed shear stress by currents, while chapter 3 discusses wave boundary layer theory. They are both written with a view to sediment transport. Sediment transport in rivers, cross-shore and longshore are dealt with in chapters 2......, 4 and 5, respectively. It is not the intention of the book to give a broad review of the literature on this very wide topic. The book tries to pick up information which is of engineering importance. An obstacle to the study of sedimentation is the scale effect in model tests. Whenever small...

  12. RF transport

    International Nuclear Information System (INIS)

    Choroba, Stefan

    2013-01-01

    This paper deals with the techniques of transport of high-power radiofrequency (RF) power from a RF power source to the cavities of an accelerator. Since the theory of electromagnetic waves in waveguides and of waveguide components is very well explained in a number of excellent text books it will limit itself on special waveguide distributions and on a number of, although not complete list of, special problems which sometimes occur in RF power transportation systems. (author)

  13. Public transport

    OpenAIRE

    Lethbridge, Jane

    2008-01-01

    Public transport plays an essential role in enabling people from low income and other disadvantaged groups to access employment and services. It also contributes to the development of social networks and social capital, by helping people to visit friends and relatives and take part in community and other social activities. Public policy makers have begun to recognise that adequate public transport provision can play an important role in reducing social exclusion. [Taken from introductory para...

  14. The solute carrier 6 family of transporters

    DEFF Research Database (Denmark)

    Bröer, Stefan; Gether, Ulrik

    2012-01-01

    of these transporters is associated with a variety of diseases. Pharmacological inhibition of the neurotransmitter transporters in this family is an important strategy in the management of neurological and psychiatric disorders. This review provides an overview of the biochemical and pharmacological properties......The solute carrier 6 (SLC6) family of the human genome comprises transporters for neurotransmitters, amino acids, osmolytes and energy metabolites. Members of this family play critical roles in neurotransmission, cellular and whole body homeostasis. Malfunction or altered expression...... of the SLC6 family transporters....

  15. Orbital transport

    International Nuclear Information System (INIS)

    Oertel, H. Jr.; Koerner, H.

    1993-01-01

    The Third Aerospace Symposium in Braunschweig presented, for the first time, the possibility of bringing together the classical disciplines of aerospace engineering and the natural science disciplines of meteorology and air chemistry in a european setting. In this way, aspects of environmental impact on the atmosphere could be examined quantitatively. An essential finding of the european conference, is the unrestricted agreement of the experts that the given launch frequencies of the present orbital transport result in a negligible amount of pollutants being released in the atmosphere. The symposium does, however, call attention to the increasing need to consider the effect of orbital and atmospheric environmental impact of a future increase in launch frequencies of orbital transport in connection with future space stations. The Third Aerospace Symposium, 'Orbital Transport, Technical, Meteorological and Chemical Aspects', constituted a first forum of discussion for engineers and scientists. Questions of new orbital transport technologies and their environmental impact were to be discussed towards a first consensus. Through the 34 reports and articles, the general problems of space transportation and environmental protection were addressed, as well as particular aspects of high temperatures during reentry in the atmosphere of the earth, precision navigation of flight vehicles or flow behavior and air chemistry in the stratosphere. (orig./CT). 342 figs

  16. Enzyme inhibition by iminosugars

    DEFF Research Database (Denmark)

    López, Óscar; Qing, Feng-Ling; Pedersen, Christian Marcus

    2013-01-01

    Imino- and azasugar glycosidase inhibitors display pH dependant inhibition reflecting that both the inhibitor and the enzyme active site have groups that change protonation state with pH. With the enzyme having two acidic groups and the inhibitor one basic group, enzyme-inhibitor complexes...

  17. Quorum sensing inhibition

    DEFF Research Database (Denmark)

    Persson, T.; Givskov, Michael Christian; Nielsen, J.

    2005-01-01

    /receptor transcriptional regulator in some clinically relevant Gram-negative bacteria. The present review contains all reported compound types that are currently known to inhibit the QS transcriptional regulator in Gram-negative bacteria. These compounds are sub-divided into two main groups, one comprising structural...

  18. Cooperation for Better Inhibiting.

    Science.gov (United States)

    Novoa, Eva Maria; Ribas de Pouplana, Lluís

    2015-06-18

    Cladosporin is an antimalarial drug that acts as an ATP-mimetic to selectively inhibit Plasmodium lysyl-tRNA synthetase. Using multiple crystal structures, Fang et al. (2015) reveal in this issue of Chemistry & Biology the fascinating mechanism responsible for cladosporin selectivity. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Travel and transport

    DEFF Research Database (Denmark)

    Bill, Jan; Roesdahl, Else

    2007-01-01

    On the interrelationship between travel, transport and society; on land transport, sea and river transport, and on winter transport;  on the related technologies and their developments......On the interrelationship between travel, transport and society; on land transport, sea and river transport, and on winter transport;  on the related technologies and their developments...

  20. Transport system

    NARCIS (Netherlands)

    Drenth, K.F.

    1999-01-01

    The transport system comprises at least one road surface (2) and at least one vehicle (4) on wheels (6). The road surface (2) has a substantially bowl-shaped cross section and the vehicle (4) is designed so that the wheels (6) run directly on the road surface (2) while the road surface (2) acts as a

  1. Optimal transport

    CERN Document Server

    Eckmann, B

    2008-01-01

    At the close of the 1980s, the independent contributions of Yann Brenier, Mike Cullen and John Mather launched a revolution in the venerable field of optimal transport founded by G Monge in the 18th century, which has made breathtaking forays into various other domains of mathematics ever since. The author presents a broad overview of this area.

  2. Nuclear transport

    International Nuclear Information System (INIS)

    Anon.

    2001-01-01

    Here is given the decree (2001/1199) of the 10. of december 2001 relative to the passing of safety rules concerning the maritime transport of spent fuels, plutonium and high-level radioactive wastes contained in packages. (O.M.)

  3. Transport fuel

    DEFF Research Database (Denmark)

    Ronsse, Frederik; Jørgensen, Henning; Schüßler, Ingmar

    2014-01-01

    Worldwide, the use of transport fuel derived from biomass increased four-fold between 2003 and 2012. Mainly based on food resources, these conventional biofuels did not achieve the expected emission savings and contributed to higher prices for food commod - ities, especially maize and oilseeds...

  4. Passive water and ion transport by cotransporters

    DEFF Research Database (Denmark)

    Loo, D D; Hirayama, B A; Meinild, A K

    1999-01-01

    the Lp of control oocytes. Passive Na+ transport (Na+ leak) was obtained from the blocker-sensitive Na+ currents in the absence of substrates (glucose and GABA). 2. Passive Na+ and water transport through SGLT1 were blocked by phlorizin with the same sensitivity (inhibitory constant (Ki), 3-5 micro......1. The rabbit Na+-glucose (SGLT1) and the human Na+-Cl--GABA (GAT1) cotransporters were expressed in Xenopus laevis oocytes, and passive Na+ and water transport were studied using electrical and optical techniques. Passive water permeabilities (Lp) of the cotransporters were determined from......M). When Na+ was replaced with Li+, phlorizin also inhibited Li+ and water transport, but with a lower affinity (Ki, 100 microM). When Na+ was replaced by choline, which is not transported, the SGLT1 Lp was indistinguishable from that in Na+ or Li+, but in this case water transport was less sensitive...

  5. Plastics for corrosion inhibition

    CERN Document Server

    Goldade, Victor A; Makarevich, Anna V; Kestelman, Vladimir N

    2005-01-01

    The development of polymer composites containing inhibitors of metal corrosion is an important endeavour in modern materials science and technology. Corrosion inhibitors can be located in a polymer matrix in the solid, liquid or gaseous phase. This book details the thermodynamic principles for selecting these components, their compatibility and their effectiveness. The various mechanisms of metal protection – barrier, inhibiting and electromechanical – are considered, as are the conflicting requirements placed on the structure of the combined material. Two main classes of inhibited materials (structural and films/coatings) are described in detail. Examples are given of structural plastics used in friction units subjected to mechano-chemical wear and of polymer films/coatings for protecting metal objects against corrosion.

  6. Inhibiting the inevitable

    DEFF Research Database (Denmark)

    Shashoua, Yvonne

    2006-01-01

    conservation is to ‘buy time’ for the object. Inhibitive conservation of plastics involves the removal or reduction of factors causing or accelerating degradation including light, oxygen, acids, relative humidity and acidic breakdown products. Specific approaches to conservation have been developed......Once plastics objects are registered in museum collections, the institution becomes responsible for their long term preservation, until the end of their useful lifetime. Plastics appear to deteriorate faster than other materials in museum collections and have a useful lifetime between 5 and 25...... years. Preventive or inhibitive conservation involves controlling the environments in which objects are placed during storage and display, with the aim of slowing the major deterioration reactions. Once in progress, degradation of plastics cannot be stopped or reversed, so the aim of preventive...

  7. Nuclear transport

    International Nuclear Information System (INIS)

    Anon.

    2002-01-01

    During September and October 2001, 1 event has been reported and classified at the first level of the INES scale. This incident concerns the violation of the European regulation that imposes to any driver of radioactive matter of being the holder of a certificate asserting that he attended a special training. During this period, 13 in-site inspections have been made in places related to nuclear transport. (A.C.)

  8. Comparison of "type I" and "type II" organic cation transport by organic cation transporters and organic anion-transporting polypeptides

    NARCIS (Netherlands)

    Van Montfoort, JE; Muller, M; Groothuis, GMM; Meijer, DKF; Koepsell, H; Meier, PJ

    Previous inhibition studies with taurocholate and cardiac glycosides suggested the presence of separate uptake systems for small "type I" (system1) and for bulky "type II" (system2) organic cations in rat hepatocytes. To identify the transport systems involved in type I and type II organic cation

  9. Adiponectin inhibits insulin function in primary trophoblasts by PPARα-mediated ceramide synthesis.

    Science.gov (United States)

    Aye, Irving L M H; Gao, Xiaoli; Weintraub, Susan T; Jansson, Thomas; Powell, Theresa L

    2014-04-01

    Maternal adiponectin (ADN) levels are inversely correlated with birth weight, and ADN infusion in pregnant mice down-regulates placental nutrient transporters and decreases fetal growth. In contrast to the insulin-sensitizing effects in adipose tissue and muscle, ADN inhibits insulin signaling in the placenta. However, the molecular mechanisms involved are unknown. We hypothesized that ADN inhibits insulin signaling and insulin-stimulated amino acid transport in primary human trophoblasts by peroxisome proliferator-activated receptor-α (PPARα)-mediated ceramide synthesis. Primary human term trophoblast cells were treated with ADN and/or insulin. ADN increased the phosphorylation of p38 MAPK and PPARα. ADN inhibited insulin signaling and insulin-stimulated amino acid transport. This effect was dependent on PPARα, because activation of PPARα with an agonist (GW7647) inhibited insulin signaling and function, whereas PPARα-small interfering RNA reversed the effects of ADN on the insulin response. ADN increased ceramide synthase expression and stimulated ceramide production. C2-ceramide inhibited insulin signaling and function, whereas inhibition of ceramide synthase (with Fumonisin B1) reversed the effects of ADN on insulin signaling and amino acid transport. These findings are consistent with the model that maternal ADN limits fetal growth mediated by activation of placental PPARα and ceramide synthesis, which inhibits placental insulin signaling and amino acid transport, resulting in reduced fetal nutrient availability.

  10. Michigan transportation facts & figures : public transportation

    Science.gov (United States)

    2002-08-16

    This on-line document is part of a series, Transportation Facts & Figures, by the Michigan Department of Transportation (MDOT). The Public Transit section of Transportation Facts & Figures cover such topics as intercity bus service, intercity rail se...

  11. Analysis of transport administrators and sustainable transport ...

    African Journals Online (AJOL)

    Analysis of transport administrators and sustainable transport development in Lagos, Ogun and Oyo States, Nigeria. ... A good transportation system planning and management is considered vital for ... EMAIL FULL TEXT EMAIL FULL TEXT

  12. Transporter Classification Database (TCDB)

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Transporter Classification Database details a comprehensive classification system for membrane transport proteins known as the Transporter Classification (TC)...

  13. Astrocytic GABA transporter activity modulates excitatory neurotransmission

    DEFF Research Database (Denmark)

    Boddum, Kim; Jensen, Thomas P.; Magloire, Vincent

    2016-01-01

    unrecognized role for the astrocytic GABA transporter, GAT-3. GAT-3 activity results in a rise in astrocytic Na(+) concentrations and a consequent increase in astrocytic Ca(2+) through Na(+)/Ca(2+) exchange. This leads to the release of ATP/adenosine by astrocytes, which then diffusely inhibits neuronal...

  14. Functional inhibition of UQCRB suppresses angiogenesis in zebrafish

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Yoon Sun; Jung, Hye Jin [Chemical Genomics National Research Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Seok, Seung Hyeok [Department of Microbiology and Immunology, Institute for Experimental Animals, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Payumo, Alexander Y.; Chen, James K. [Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305 (United States); Kwon, Ho Jeong, E-mail: kwonhj@yonsei.ac.kr [Chemical Genomics National Research Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of)

    2013-04-19

    Highlights: ► This is the first functional characterization of UQCRB in vivo model. ► Angiogenesis is inhibited with UQCRB loss of function in zebrafish. ► UQCRB is introduced as a prognostic marker for mitochondria- and angiogenesis-related diseases. -- Abstract: As a subunit of mitochondrial complex III, UQCRB plays an important role in complex III stability, electron transport, and cellular oxygen sensing. Herein, we report UQCRB function regarding angiogenesis in vivo with the zebrafish (Danio rerio). UQCRB knockdown inhibited angiogenesis in zebrafish leading to the suppression of VEGF expression. Moreover, the UQCRB-targeting small molecule terpestacin also inhibited angiogenesis and VEGF levels in zebrafish, supporting the role of UQCRB in angiogenesis. Collectively, UQCRB loss of function by either genetic and pharmacological means inhibited angiogenesis, indicating that UQCRB plays a key role in this process and can be a prognostic marker of angiogenesis- and mitochondria-related diseases.

  15. Functional inhibition of UQCRB suppresses angiogenesis in zebrafish

    International Nuclear Information System (INIS)

    Cho, Yoon Sun; Jung, Hye Jin; Seok, Seung Hyeok; Payumo, Alexander Y.; Chen, James K.; Kwon, Ho Jeong

    2013-01-01

    Highlights: ► This is the first functional characterization of UQCRB in vivo model. ► Angiogenesis is inhibited with UQCRB loss of function in zebrafish. ► UQCRB is introduced as a prognostic marker for mitochondria- and angiogenesis-related diseases. -- Abstract: As a subunit of mitochondrial complex III, UQCRB plays an important role in complex III stability, electron transport, and cellular oxygen sensing. Herein, we report UQCRB function regarding angiogenesis in vivo with the zebrafish (Danio rerio). UQCRB knockdown inhibited angiogenesis in zebrafish leading to the suppression of VEGF expression. Moreover, the UQCRB-targeting small molecule terpestacin also inhibited angiogenesis and VEGF levels in zebrafish, supporting the role of UQCRB in angiogenesis. Collectively, UQCRB loss of function by either genetic and pharmacological means inhibited angiogenesis, indicating that UQCRB plays a key role in this process and can be a prognostic marker of angiogenesis- and mitochondria-related diseases

  16. Tubular transport and metabolism of cimetidine in chicken kidneys

    International Nuclear Information System (INIS)

    Rennick, B.; Ziemniak, J.; Smith, I.; Taylor, M.; Acara, M.

    1984-01-01

    Renal tubular transport and renal metabolism of [ 14 C]cimetidine (CIM) were investigated by unilateral infusion into the renal portal circulation in chickens (Sperber technique). [ 14 C]CIM was actively transported at a rate 88% that of simultaneously infused p-aminohippuric acid, and its transport was saturable. The following organic cations competitively inhibited the tubular transport of [ 14 C]CIM with decreasing potency: CIM, ranitidine, thiamine, procainamide, guanidine and choline. CIM inhibited the transport of [ 14 C]thiamine, [ 14 C]amiloride and [ 14 C]tetraethylammonium. During CIM infusion, two renal metabolites, CIM sulfoxide and hydroxymethylcimetidine, were found in urine. When CIM sulfoxide was infused, its transport efficiency was 32% and not saturable. CIM sulfoxide did ot inhibit the simultaneous renal tubular transport of p-aminohippuric acid or tetraethylammonium. CIM is transported by the organic cation transport system and the kidney metabolizes CIM. Transport of CIM and other cationic drugs could produce a drug interaction to alter drug excretion

  17. Energy transport

    International Nuclear Information System (INIS)

    Anon.

    1982-01-01

    The measurement of primary interaction cross sections and the incorporation of these data into Monte Carlo calculations provide detailed information about the initial spatial distribution of absorbed dose. Our theoretical energy transport studies have focused on the use of this information to predict the evolution of chemical species formed as a result of the energy deposition. This effort has led to a stochastic approach to diffusion kinetics that can account for the influence of track structure on the yield of free radicals in the radiolysis of water. Fluorescence studies with pulsed alpha particle and proton beams provided the first experimental test of our stochastic model of tract structure effects. Our experimental studies use time-resolved emission spectroscopy to investigate the mechanism of energy transport in nonpolar liquids. Studies of the concentration dependence of time-resolved emission from solutions of benzene in cyclohexane also show the importance of using low benzene concentrations to minimize the influence of benzene dimers on the emission kinetics

  18. National transportation statistics 2011

    Science.gov (United States)

    2011-04-01

    Compiled and published by the U.S. Department of Transportation's Bureau of Transportation Statistics : (BTS), National Transportation Statistics presents information on the U.S. transportation system, including : its physical components, safety reco...

  19. National Transportation Statistics 2008

    Science.gov (United States)

    2009-01-08

    Compiled and published by the U.S. Department of Transportations Bureau of Transportation Statistics (BTS), National Transportation Statistics presents information on the U.S. transportation system, including its physical components, safety record...

  20. State Transportation Statistics 2012

    Science.gov (United States)

    2013-08-15

    The Bureau of Transportation Statistics (BTS), a part of the U.S. Department of Transportation's (USDOT) Research and Innovative Technology Administration (RITA), presents State Transportation Statistics 2012, a statistical profile of transportation ...

  1. National Transportation Statistics 2009

    Science.gov (United States)

    2010-01-21

    Compiled and published by the U.S. Department of Transportation's Bureau of Transportation Statistics (BTS), National Transportation Statistics presents information on the U.S. transportation system, including its physical components, safety record, ...

  2. State Transportation Statistics 2014

    Science.gov (United States)

    2014-12-15

    The Bureau of Transportation Statistics (BTS) presents State Transportation Statistics 2014, a statistical profile of transportation in the 50 states and the District of Columbia. This is the 12th annual edition of State Transportation Statistics, a ...

  3. Inhibition of electron transfer and uncoupling effects by emodin and emodinanthrone in Escherichia coli.

    Science.gov (United States)

    Ubbink-Kok, T; Anderson, J A; Konings, W N

    1986-07-01

    The anthraquinones emodin (1,3,delta-trihydroxy-6-methylanthraquinone) and emodinanthrone (1,3,8-trihydroxy-6-methylanthrone) inhibited respiration-driven solute transport at micromolar concentrations in membrane vesicles of Escherichia coli. This inhibition was enhanced by Ca ions. The inhibitory action on solute transport is caused by inhibition of electron flow in the respiratory chain, most likely at the level between ubiquinone and cytochrome b, and by dissipation of the proton motive force. The uncoupling action was confirmed by studies on the proton motive force in beef heart cytochrome oxidase proteoliposomes. These two effects on energy transduction in cytoplasmic membranes explain the antibiotic properties of emodin and emodinanthrone.

  4. Transport of radioactive substances

    International Nuclear Information System (INIS)

    2014-12-01

    The report on the transport of radioactive substances covers the following topics: facts on radioactive materials transport, safety of the transport of radioactive substances, legal regulations and guidelines: a multiform but consistent system, transport of nuclear fuels, safety during the transport of nuclear fuel, future transport of spent fuel elements and high-level radioactive wastes in Germany.

  5. Anxiety and retrieval inhibition: support for an enhanced inhibition account.

    Science.gov (United States)

    Nuñez, Mia; Gregory, Josh; Zinbarg, Richard E

    2017-02-01

    Retrieval inhibition of negative associations is important for exposure therapy for anxiety, but the relationship between memory inhibition and anxiety is not well understood-anxiety could either be associated with enhanced or deficient inhibition. The present study tested these two competing hypotheses by measuring retrieval inhibition of negative stimuli by related neutral stimuli. Non-clinically anxious undergraduates completed measures of trait and state anxiety and completed a retrieval induced forgetting task. Adaptive forgetting varied with state anxiety. Low levels of state anxiety were associated with no evidence for retrieval inhibition for either threatening or non-threatening categories. Participants in the middle tertile of state anxiety scores exhibited retrieval inhibition for non-threatening categories but not for threatening categories. Participants in the highest tertile of state anxiety, however, exhibited retrieval inhibition for both threatening and non-threatening categories with the magnitude of retrieval inhibition being greater for threatening than non-threatening categories. The data are in line with the avoidance aspect of the vigilance-avoidance theory of anxiety and inhibition. Implications for cognitive behavioural therapy practices are discussed.

  6. Inhibition of polyphenoloxidase by sulfite

    International Nuclear Information System (INIS)

    Sayavedra-Soto, L.A.; Montgomery, M.W.

    1986-01-01

    When polyphenoloxidase (PPO) was exposed to sulfite prior to substrate addition, inhibition was irreversible. Trials to regenerate PPO activity, using extensive dialysis, column chromatography, and addition of copper salts were not successful. Increased concentrations of sulfite and pH levels less than 5 enhanced the inhibition of PPO by sulfite. At pH 4, concentrations greater than 0.04 mg/mL completely inhibited 1000 units of PPO activity almost instantaneously. This suggested that the HSO 3 - molecule was the main component in the sulfite system inhibiting PPO. Column chromatography, extensive dialysis, and gel electrophoresis did not demonstrate 35 SO 2 bound to purified pear PPO protein. Formation of extra protein bands of sulfite inhibited purified pear PPO fractions on gel electrophoresis was demonstrated. This and other evidence suggested that the major mode of direct irreversible inhibition of PPO was modification of the protein structure, with retention of its molecular unity

  7. Selected Phytochemicals and Culinary Plant Extracts Inhibit Fructose Uptake in Caco-2 Cells.

    Science.gov (United States)

    Lee, Yurim; Lim, Yeni; Kwon, Oran

    2015-09-18

    This study compared the ability of nine culinary plant extracts containing a wide array of phytochemicals to inhibit fructose uptake and then explored the involvement of intestinal fructose transporters and phytochemicals for selected samples. The chemical signature was characterized by high performance liquid chromatography with mass spectrometry. Inhibition of [(14)C]-fructose uptake was tested by using human intestinal Caco-2 cells. Then, the relative contribution of the two apical-facing intestinal fructose transporters, GLUT2 and GLUT5, and the signature components for fructose uptake inhibition was confirmed in naive, phloretin-treated and forskolin-treated Caco-2 cells. HPLC/MS analysis of the chemical signature revealed that guava leaf contained quercetin and catechin, and turmeric contained curcumin, bisdemethoxycurcumin and dimethoxycurcumin. Similar inhibition of fructose uptake (by ~50%) was observed with guava leaf and turmeric in Caco-2 cells, but with a higher contribution of GLUT2 for turmeric and that of GLUT5 for guava leaf. The data suggested that, in turmeric, demethoxycurcumin specifically contributed to GLUT2-mediated fructose uptake inhibition, and curcumin did the same to GLUT5-mediated fructose uptake inhibition, but GLUT2 inhibition was more potent. By contrast, in guava leaf, catechin specifically contributed to GLUT5-mediated fructose uptake inhibition, and quercetin affected both GLUT5- and GLUT2-mediated fructose uptake inhibition, resulting in the higher contribution of GLUT5. These results suggest that demethoxycurcumin is an important contributor to GLUT2-mediated fructose uptake inhibition for turmeric extract, and catechin is the same to GLUT5-mediated fructose uptake inhibition for guava leaf extract. Quercetin, curcumin and bisdemethoxycurcumin contributed to both GLUT5- and GLUT2-mediated fructose uptake inhibition, but the contribution to GLUT5 inhibition was higher than the contribution to GLUT2 inhibition.

  8. Chemical transport reactions

    CERN Document Server

    Schäfer, Harald

    2013-01-01

    Chemical Transport Reactions focuses on the processes and reactions involved in the transport of solid or liquid substances to form vapor phase reaction products. The publication first offers information on experimental and theoretical principles and the transport of solid substances and its special applications. Discussions focus on calculation of the transport effect of heterogeneous equilibria for a gas motion between equilibrium spaces; transport effect and the thermodynamic quantities of the transport reaction; separation and purification of substances by means of material transport; and

  9. Beam transport

    International Nuclear Information System (INIS)

    1988-01-01

    Considerable experience has now been gained with the various beam transport lines, and a number of minor changes have been made to improve the ease of operation. These include: replacement of certain little-used slits by profile monitors (harps or scanners); relocation of steering magnets, closer to diagnostic harps or profile scanners; installation of a scanner inside the isocentric neutron therapy system; and conversion of a 2-doublet quadrupole telescope (on the neutron therapy beamline) to a 2-triplet telescope. The beam-swinger project has been delayed by very late delivery of the magnet iron to the manufacturer, but is now progressing smoothly. The K=600 spectrometer magnets have now been delivered and are being assembled for field mapping. The x,y-table with its associated mapping equipment is complete, together with the driver software. One of the experimental areas has been dedicated to the production of collimated neutron beams and has been equipped with a bending magnet and beam dump, together with steel collimators fixed at 4 degrees intervals from 0 degrees to 16 degrees. Changes to the target cooling and shielding system for isotope production have led to a request for much smaller beam spot sizes on target, and preparations have been made for rearrangement of the isotope beamline to permit installation of quadrupole triplets on the three beamlines after the switching magnet. A practical system of quadrupoles for matching beam properties to the spectrometer has been designed. 6 figs

  10. Modeling intentional inhibition of actions

    NARCIS (Netherlands)

    Thilakarathne, D.J.; Treur, J.

    2015-01-01

    Inspired by cognitive and neurological literature on action ownership and action awareness, in this paper a computational cognitive model for intentional inhibition (i.e.; the capacity to voluntarily suspend or inhibit an action) is introduced. The interplay between (positive) potential selection of

  11. Can Arousal Modulate Response Inhibition?

    Science.gov (United States)

    Weinbach, Noam; Kalanthroff, Eyal; Avnit, Amir; Henik, Avishai

    2015-01-01

    The goal of the present study was to examine if and how arousal can modulate response inhibition. Two competing hypotheses can be drawn from previous literature. One holds that alerting cues that elevate arousal should result in an impulsive response and therefore impair response inhibition. The other suggests that alerting enhances processing of…

  12. Contribution of the organic anion transporter OAT2 to the renal active tubular secretion of creatinine and mechanism for serum creatinine elevations caused by cobicistat.

    Science.gov (United States)

    Lepist, Eve-Irene; Zhang, Xuexiang; Hao, Jia; Huang, Jane; Kosaka, Alan; Birkus, Gabriel; Murray, Bernard P; Bannister, Roy; Cihlar, Tomas; Huang, Yong; Ray, Adrian S

    2014-08-01

    Many xenobiotics including the pharmacoenhancer cobicistat increase serum creatinine by inhibiting its renal active tubular secretion without affecting the glomerular filtration rate. This study aimed to define the transporters involved in creatinine secretion, applying that knowledge to establish the mechanism for xenobiotic-induced effects. The basolateral uptake transporters organic anion transporter OAT2 and organic cation transporters OCT2 and OCT3 were found to transport creatinine. At physiologic creatinine concentrations, the specific activity of OAT2 transport was over twofold higher than OCT2 or OCT3, establishing OAT2 as a likely relevant creatinine transporter and further challenging the traditional view that creatinine is solely transported by a cationic pathway. The apical multidrug and toxin extrusion transporters MATE1 and MATE2-K demonstrated low-affinity and high-capacity transport. All drugs known to affect creatinine inhibited OCT2 and MATE1. Similar to cimetidine and ritonavir, cobicistat had the greatest effect on MATE1 with a 50% inhibition constant of 0.99 μM for creatinine transport. Trimethoprim potently inhibited MATE2-K, whereas dolutegravir preferentially inhibited OCT2. Cimetidine was unique, inhibiting all transporters that interact with creatinine. Thus, the clinical observation of elevated serum creatinine in patients taking cobicistat is likely a result of OCT2 transport, facilitating intracellular accumulation, and MATE1 inhibition.

  13. Contribution of the organic anion transporter OAT2 to the renal active tubular secretion of creatinine and mechanism for serum creatinine elevations caused by cobicistat

    Science.gov (United States)

    Lepist, Eve-Irene; Zhang, Xuexiang; Hao, Jia; Huang, Jane; Kosaka, Alan; Birkus, Gabriel; Murray, Bernard P; Bannister, Roy; Cihlar, Tomas; Huang, Yong; Ray, Adrian S

    2014-01-01

    Many xenobiotics including the pharmacoenhancer cobicistat increase serum creatinine by inhibiting its renal active tubular secretion without affecting the glomerular filtration rate. This study aimed to define the transporters involved in creatinine secretion, applying that knowledge to establish the mechanism for xenobiotic-induced effects. The basolateral uptake transporters organic anion transporter OAT2 and organic cation transporters OCT2 and OCT3 were found to transport creatinine. At physiologic creatinine concentrations, the specific activity of OAT2 transport was over twofold higher than OCT2 or OCT3, establishing OAT2 as a likely relevant creatinine transporter and further challenging the traditional view that creatinine is solely transported by a cationic pathway. The apical multidrug and toxin extrusion transporters MATE1 and MATE2-K demonstrated low-affinity and high-capacity transport. All drugs known to affect creatinine inhibited OCT2 and MATE1. Similar to cimetidine and ritonavir, cobicistat had the greatest effect on MATE1 with a 50% inhibition constant of 0.99 μM for creatinine transport. Trimethoprim potently inhibited MATE2-K, whereas dolutegravir preferentially inhibited OCT2. Cimetidine was unique, inhibiting all transporters that interact with creatinine. Thus, the clinical observation of elevated serum creatinine in patients taking cobicistat is likely a result of OCT2 transport, facilitating intracellular accumulation, and MATE1 inhibition. PMID:24646860

  14. Plant Transporter Identification

    DEFF Research Database (Denmark)

    Larsen, Bo

    Membrane transport proteins (transporters) play a critical role for numerous biological processes, by controlling the movements of ions and molecules in and out of cells. In plants, transporters thus function as gatekeepers between the plant and its surrounding environment and between organs......, tissues, cells and intracellular compartments. Since plants are highly compartmentalized organisms with complex transportation infrastructures, they consequently have many transporters. However, the vast majority of predicted transporters have not yet been experimentally verified to have transport...... activity. This project contains a review of the implemented methods, which have led to plant transporter identification, and present our progress on creating a high-throughput functional genomics transporter identification platform....

  15. Transport of Radioactive Materials

    International Nuclear Information System (INIS)

    2001-01-01

    This address overviews the following aspects: concepts on transport of radioactive materials, quantities used to limit the transport, packages, types of packages, labeling, index transport calculation, tags, labeling, vehicle's requirements and documents required to authorize transportation. These requirements are considered in the regulation of transport of radioactive material that is in drafting step

  16. Transportation and the environment.

    NARCIS (Netherlands)

    Banister, D.; Anderton, K.; Bonilla, D.; Givoni, M.; Schwanen, T.

    2011-01-01

    The growth of CO2-intensive transport, mobility and the impact of transport on the environment are reviewed. The recent global exponential growth in transport is unsustainable and must end unless the transport sector can decarbonize. The paper examines solutions for low-carbon transport systems; the

  17. Effect of erythropoietin on the glucose transport of rat erythrocytes and bone marrow cells

    International Nuclear Information System (INIS)

    Ghosal, J.; Chakraborty, M.; Biswas, T.; Ganguly, C.K.; Datta, A.G.

    1987-01-01

    The effect of Ep on radioactive glucose and methyl-alpha-D-glucoside transport by rat erythrocytes and bone marrow cells were studied. There is initial linearity followed by saturation kinetics of [ 14 C]glucose transport by the erythrocytes of starved and starved plus Ep-treated rats at different concentrations of glucose. Starvation caused slight inhibition of glucose transport which increased markedly on Ep administration to starved rats. Normal animals failed to show any significant change in glucose transport after Ep treatment. Methyl-alpha-D-glucoside inhibited the Ep-stimulated glucose transport significantly. Ep also stimulated the transport of radioactive methyl-alpha-D-glucoside which was competitively inhibited in presence of D-glucose. Glucose transport in erythrocytes was found to be sensitive to metabolic inhibitors like azide and DNP. A sulfhydryl reagent and ouabain also inhibited the transport process. Ep stimulated glucose and methyl-alpha-D-glucoside transport in the bone marrow cells of starved rats. The sugar analog competitively inhibited the glucose transport in bone marrow cells and vice versa

  18. Selenium inhibits the phytotoxicity of mercury in garlic (Allium sativum)

    International Nuclear Information System (INIS)

    Zhao, Jiating; Gao, Yuxi; Li, Yu-Feng; Hu, Yi; Peng, Xiaomin; Dong, Yuanxing; Li, Bai; Chen, Chunying; Chai, Zhifang

    2013-01-01

    To investigate the influence of selenium on mercury phytotoxicity, the levels of selenium and mercury were analyzed with inductively coupled plasma-mass spectrometry (ICP-MS) in garlic tissues upon exposure to different dosages of inorganic mercury (Hg 2+ ) and selenite (SeO 3 2− ) or selenate (SeO 4 2− ). The distributions of selenium and mercury were examined with micro-synchrotron radiation X-ray fluorescence (μ-SRXRF), and the mercury speciation was investigated with micro-X-ray absorption near edge structure (μ-XANES). The results show that Se at higher exposure levels (>1 mg/L of SeO 3 2− or SeO 4 2− ) would significantly inhibit the absorption and transportation of Hg when Hg 2+ levels are higher than 1 mg/L in culture media. SeO 3 2− and SeO 4 2− were found to be equally effective in reducing Hg accumulation in garlic. The inhibition of Hg uptake by Se correlates well with the influence of Se on Hg phytotoxicity as indicated by the growth inhibition factor. Elemental imaging using μ-SRXRF also shows that Se could inhibit the accumulation and translocation of Hg in garlic. μ-XANES analysis shows that Hg is mainly present in the forms of Hg–S bonding as Hg(GSH) 2 and Hg(Met) 2 . Se exposure elicited decrease of Hg–S bonding in the form of Hg(GSH) 2 , together with Se-mediated alteration of Hg absorption, transportation and accumulation, may account for attenuated Hg phytotoxicity by Se in garlic. -- Highlights: ► Hg phytotoxicity can be mitigated by Se supplement in garlic growth. ► Se can inhibit the accumulation and transportation of Hg in garlic tissues. ► Localization and speciation of Hg in garlic can be modified by Se

  19. Interplay between toxin transport and flotillin localization

    DEFF Research Database (Denmark)

    Pust, Sascha; Dyve, Anne Berit; Torgersen, Maria L

    2010-01-01

    The flotillin proteins are localized in lipid domains at the plasma membrane as well as in intracellular compartments. In the present study, we examined the importance of flotillin-1 and flotillin-2 for the uptake and transport of the bacterial Shiga toxin (Stx) and the plant toxin ricin and we...... for flotillin-1 or -2. However, the Golgi-dependent sulfation of both toxins was significantly reduced in flotillin knockdown cells. Interestingly, when the transport of ricin to the ER was investigated, we obtained an increased mannosylation of ricin in flotillin-1 and flotillin-2 knockdown cells. The toxicity...... of both toxins was twofold increased in flotillin-depleted cells. Since BFA (Brefeldin A) inhibits the toxicity even in flotillin knockdown cells, the retrograde toxin transport is apparently still Golgi-dependent. Thus, flotillin proteins regulate and facilitate the retrograde transport of Stx and ricin....

  20. Diuretics and salt transport along the nephron.

    Science.gov (United States)

    Bernstein, Paul L; Ellison, David H

    2011-11-01

    The clinical use of diuretics almost uniformly predated the localization of their site of action. The consequence of diuretic specificity predicts clinical application and side effect, and the proximity of the sodium transporters, one to the next, often dictates potency or diuretic efficiency. All diuretics function by inhibiting the normal transport of sodium from the filtrate into the renal tubular cells. This movement of sodium into the renal epithelial cells on the apical side is facilitated by a series of transporters whose function is, in turn, dependent on the adenosine triphosphate (ATP)-dependent Na-K cotransporter on the basolateral side of the cell. Our growing understanding of the physiology of sodium transport has spawned new possibilities for diuretic development. Copyright © 2011 Elsevier Inc. All rights reserved.

  1. Transportation librarian's toolkit

    Science.gov (United States)

    2007-12-01

    The Transportation Librarians Toolkit is a product of the Transportation Library Connectivity pooled fund study, TPF- 5(105), a collaborative, grass-roots effort by transportation libraries to enhance information accessibility and professional expert...

  2. Advanced Transportation Institute 2008.

    Science.gov (United States)

    2009-02-01

    The seventh version of the Advanced Transportation Institute (ATI-08) was conducted in 2008 to encourage high school students to pursue careers in the field of transportation engineering. The University Transportation Center for Alabama partnered wit...

  3. Advanced Transportation Institute 2009.

    Science.gov (United States)

    2009-09-01

    The eighth version of the Advanced Transportation Institute (ATI-09) was conducted in 2009 to encourage high school students to pursue careers in the field of transportation engineering. The University Transportation Center for Alabama partnered with...

  4. Innovative Technologies in Transportation

    Science.gov (United States)

    2004-12-01

    An historical overview of the transportation infrastructure of the United States and Texas is provided. Data for trends in transportation is analyzed and projections for the future are postulated. A survey of current technologies in transportation is...

  5. State Transportation Statistics 2010

    Science.gov (United States)

    2011-09-14

    The Bureau of Transportation Statistics (BTS), a part of DOTs Research and Innovative Technology Administration (RITA), presents State Transportation Statistics 2010, a statistical profile of transportation in the 50 states and the District of Col...

  6. State transportation statistics 2009

    Science.gov (United States)

    2009-01-01

    The Bureau of Transportation Statistics (BTS), a part of DOTs Research and : Innovative Technology Administration (RITA), presents State Transportation : Statistics 2009, a statistical profile of transportation in the 50 states and the : District ...

  7. State Transportation Statistics 2011

    Science.gov (United States)

    2012-08-08

    The Bureau of Transportation Statistics (BTS), a part of DOTs Research and Innovative Technology Administration (RITA), presents State Transportation Statistics 2011, a statistical profile of transportation in the 50 states and the District of Col...

  8. State Transportation Statistics 2013

    Science.gov (United States)

    2014-09-19

    The Bureau of Transportation Statistics (BTS), a part of the U.S. Department of Transportations (USDOT) Research and Innovative Technology Administration (RITA), presents State Transportation Statistics 2013, a statistical profile of transportatio...

  9. How LeuT shapes our understanding of the mechanisms of sodium-coupled neurotransmitter transporters.

    Science.gov (United States)

    Penmatsa, Aravind; Gouaux, Eric

    2014-03-01

    Neurotransmitter transporters are ion-coupled symporters that drive the uptake of neurotransmitters from neural synapses. In the past decade, the structure of a bacterial amino acid transporter, leucine transporter (LeuT), has given valuable insights into the understanding of architecture and mechanism of mammalian neurotransmitter transporters. Different conformations of LeuT, including a substrate-free state, inward-open state, and competitive and non-competitive inhibitor-bound states, have revealed a mechanistic framework for the transport and transport inhibition of neurotransmitters. The current review integrates our understanding of the mechanistic and pharmacological properties of eukaryotic neurotransmitter transporters obtained through structural snapshots of LeuT.

  10. Inhibition of glycolysis by misonidazole in hypoxic cells

    International Nuclear Information System (INIS)

    Ling, L.; Sutherland, R.

    1984-01-01

    Inhibition of glycolysis has been postulated to be a mechanism of misonidazole (MISO) toxicity in hypoxic cells. To investigate the effect of MISO on glycolysis, glucose transport and its consumption and lactate formation were measured. Exponential EMT6 cells (10/sup 6/ cells/ml) were made hypoxix by continuous gassing in 3% CO/sub 2/ in N/sub 2/. They were then treated with 5mM MISO for various times, then washed and analysed for their rates of anaerobic glycolysis. Glucose and lactate content were determined enzymatically. The rates of both glucose consumption and lactate formation decreased after 30 min hypoxic incubation with MISO. After 90 min, the rates were not measurable even though the cells still excluded Trypan Blue. There was, however, a parallel decrease in plating efficiency. These data suggest that the inhibition of glycolysis is an important mechanism of hypoxic toxicity of MISO. To locate the site of inhibition, studies were initiated to look at glucose transport by following the uptake of /sup 14/-C-3-0-methyl-glucose, a nonmetabolised glucose analog. Results obtained so far indicate that up to 90 min of hypoxic incubation with MISO, there was no change in the kinetics of the uptake of his analog. Therefore, the results showed that in hypoxic cells treated with MISO, the glucose transport system was unaffected. However, there was a rapid decrease in anaerobic glycolysis

  11. Transport of 3-bromopyruvate across the human erythrocyte membrane.

    Science.gov (United States)

    Sadowska-Bartosz, Izabela; Soszyński, Mirosław; Ułaszewski, Stanisław; Ko, Young; Bartosz, Grzegorz

    2014-06-01

    3-Bromopyruvic acid (3-BP) is a promising anticancer compound because it is a strong inhibitor of glycolytic enzymes, especially glyceraldehyde 3-phosphate dehydrogenase. The Warburg effect means that malignant cells are much more dependent on glycolysis than normal cells. Potential complications of anticancer therapy with 3-BP are side effects due to its interaction with normal cells, especially erythrocytes. Transport into cells is critical for 3-BP to have intracellular effects. The aim of our study was the kinetic characterization of 3-BP transport into human erythrocytes. 3-BP uptake by erythrocytes was linear within the first 3 min and pH-dependent. The transport rate decreased with increasing pH in the range of 6.0-8.0. The Km and Vm values for 3-BP transport were 0.89 mM and 0.94 mmol/(l cells x min), respectively. The transport was inhibited competitively by pyruvate and significantly inhibited by DIDS, SITS, and 1-cyano-4-hydroxycinnamic acid. Flavonoids also inhibited 3-BP transport: the most potent inhibition was found for luteolin and quercetin.

  12. Smart Growth and Transportation

    Science.gov (United States)

    Describes the relationship between smart growth and transportation, focusing smart and sustainable street design, transit-oriented development, parking management, sustainable transportation planning, and related resources.

  13. Neoclassical transport in NCSX

    International Nuclear Information System (INIS)

    Mikkelsen, D.R.; Zarnstorff, M.C.; Beidler, C.D.; Maassberg, H.; Houlberg, W.A.; Spong, D.A.; Tribaldos, V.

    2003-01-01

    Methods for calculating neoclassical transport in the National Compact Stellarator Experiment (NCSX) are discussed, with particular attention to developing computationally inexpensive predictions of neoclassical transport. (orig.)

  14. Journal of transportation engineering

    National Research Council Canada - National Science Library

    1983-01-01

    The Journal of Transportation Engineering contains technical and professional articles on the planning, design, construction, maintenance, and operation of air, highway, rail, and urban transportation...

  15. Transportation Industry 2004

    National Research Council Canada - National Science Library

    Miller, Evan; Kathir, Nathan; Brogan, Dennis M

    2004-01-01

    .... Because the defense sector relies on commercial transportation for both peacetime activities and for power projection, senior military leaders must understand the global transportation industry...

  16. Saxton Transportation Operations Laboratory

    Data.gov (United States)

    Federal Laboratory Consortium — The Saxton Transportation Operations Laboratory (Saxton Laboratory) is a state-of-the-art facility for conducting transportation operations research. The laboratory...

  17. Selective inhibition of distracting input.

    Science.gov (United States)

    Noonan, MaryAnn P; Crittenden, Ben M; Jensen, Ole; Stokes, Mark G

    2017-10-16

    We review a series of studies exploring distractor suppression. It is often assumed that preparatory distractor suppression is controlled via top-down mechanisms of attention akin to those that prepare brain areas for target enhancement. Here, we consider two alternative mechanisms: secondary inhibition and expectation suppression within a predictive coding framework. We draw on behavioural studies, evidence from neuroimaging and some animal studies. We conclude that there is very limited evidence for selective top-down control of preparatory inhibition. By contrast, we argue that distractor suppression often relies secondary inhibition of non-target items (relatively non-selective inhibition) and on statistical regularities of the environment, learned through direct experience. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

  18. Transport of cefodizime, a novel third generation cephalosporin antibiotic, in isolated rat choroid plexus

    International Nuclear Information System (INIS)

    Nohjoh, T.; Suzuki, H.; Sawada, Y.; Sugiyama, Y.; Iga, T.; Hanano, M.

    1989-01-01

    To characterize the transport system by which cephalosporin antibiotics are accumulated by the choroid plexus, kinetic analysis of cefodizime transport was performed. Accumulation of cefodizime was against an electrochemical potential gradient via a saturable process (Km = 470 microM, Vmax = 174 nmol/ml of tissue per min) that was inhibited by metabolic inhibitors (KCN and 2,4-dinitrophenol), hypothermia, a sulfhydryl reagent (p-hydroxymer-curibenzoic acid) and anion transport inhibitors (probenecid and 4,4'-diisothiocyanostilbene -2,2'-disulfonic acid). Accumulation of cefodizime was inhibited competitively by benzylpenicillin with an inhibition constant of aproximately 100 microM. Cefodizime inhibited competitively the accumulation of benzylpenicillin with an inhibition constant of approximately 500 microM. Kinetic analysis using 16 kinds of beta-lactam antibiotics also supported the view (1) that the transport system of cefodizime is shared by benzylpenicillin and (2) that these beta-lactam antibiotics are transported via a common transport system. These findings indicate that the major transport system of cephalosporin antibiotics in the rat choroid plexus is via a carrier-mediated active anion transport process. The affinity of beta-lactam antibiotics for this transport system in the choroid plexus may be a major factor in determining their pharmacokinetics in the cerebrospinal fluid

  19. An evolved xylose transporter from Zymomonas mobilis enhances sugar transport in Escherichia coli

    Directory of Open Access Journals (Sweden)

    Zhang Jingqing

    2009-12-01

    Full Text Available Abstract Background Xylose is a second most abundant sugar component of lignocellulose besides glucose. Efficient fermentation of xylose is important for the economics of biomass-based biorefineries. However, sugar mixtures are sequentially consumed in xylose co-fermentation with glucose due to carbon catabolite repression (CCR in microorganisms. As xylose transmembrance transport is one of the steps repressed by CCR, it is therefore of interest to develop a transporter that is less sensitive to the glucose inhibition or CCR. Results The glucose facilitator protein Glf transporter from Zymomonas mobilis, also an efficient transporter for xylose, was chosen as the target transporter for engineering to eliminate glucose inhibition on xylose uptake. The evolution of Glf transporter was carried out with a mixture of glucose and xylose in E. coli. Error-prone PCR and random deletion were employed respectively in two rounds of evolution. Aided by a high-throughput screening assay using xylose analog p-nitrophenyl-β-D-xylopyranoside (pNPX in 96-well plates, a best mutant 2-RD5 was obtained that contains several mutations, and a deletion of 134 residues (about 28% of total residues, or three fewer transmembrane sections (TMSs. It showed a 10.8-fold improvement in terms of pNPX transport activity in the presence of glucose. The fermentation performance results showed that this mutant improved xylose consumption by 42% with M9 minimal medium containing 20 g L-1 xylose only, while with the mixture sugar of xylose and glucose, 28% more glucose was consumed, but no obvious co-utilization of xylose was observed. Further glucose fed-batch experiments suggested that the intracellular metabolism of xylose was repressed by glucose. Conclusions Through random mutagenesis and partial deletion coupled with high-throughput screening, a mutant of the Glf transporter (2-RD5 was obtained that relieved the inhibition of xylose transport by glucose. The fermentation

  20. [Concepts of inhibition in psychiatry].

    Science.gov (United States)

    Auroux, Y; Bourrat, M M; Brun, J P

    1978-01-01

    Following a historical approach, the authors first describe the original development of the concept of inhibition in neurophysiology and then analyze the subsequent adaptations made in psychiatry around such concept including those of: -- Pavlov, Hull, Watson and the behaviorists, -- Freud and the Freudian School, -- clinicians and psychopharmacologists. The concept of inhibition has thus various meanings in psychiatry. Although some unity is achieved on the semiological level, this aspect cannot explain the extent of the process.

  1. Inhibition of MMPs by alcohols

    Science.gov (United States)

    Tezvergil-Mutluay, Arzu; Agee, Kelli A.; Hoshika, Tomohiro; Uchiyama, Toshikazu; Tjäderhane, Leo; Breschi, Lorenzo; Mazzoni, Annalisa; Thompson, Jeremy M.; McCracken, Courtney E.; Looney, Stephen W.; Tay, Franklin R.; Pashley, David H.

    2011-01-01

    Objectives While screening the activity of potential inhibitors of matrix metalloproteinases (MMPs), due to the limited water solubility of some of the compounds, they had to be solubilized in ethanol. When ethanol solvent controls were run, they were found to partially inhibit MMPs. Thus, the purpose of this study was to compare the MMP-inhibitory activity of a series of alcohols. Methods The possible inhibitory activity of a series of alcohols was measured against soluble rhMMP-9 and insoluble matrix-bound endogenous MMPs of dentin in completely demineralized dentin. Increasing concentrations (0.17, 0.86, 1.71 and 4.28 moles/L) of a homologous series of alcohols (i.e. methanol, ethanol, propanols, butanols, pentanols, hexanols, the ethanol ester of methacrylic acid, heptanols and octanol) were compared to ethanediol, and propanediol by regression analysis to calculate the molar concentration required to inhibit MMPs by 50% (i.e. the IC50). Results Using two different MMP models, alcohols were shown to inhibit rhMMP-9 and the endogenous proteases of dentin matrix in a dose-dependent manner. The degree of MMP inhibition by alcohols increased with chain length up to 4 methylene groups. Based on the molar concentration required to inhibit rhMMP-9 fifty percent, 2-hydroxyethylmethacrylate (HEMA), 3-hexanol, 3-heptanol and 1-octanol gave the strongest inhibition. Significance The results indicate that alcohols with 4 methylene groups inhibit MMPs more effectively than methanol or ethanol. MMP inhibition was inversely related to the Hoy's solubility parameter for hydrogen bonding forces of the alcohols (i.e. to their hydrophilicity). PMID:21676453

  2. Benzoate transport in Pseudomonas putida CSV86.

    Science.gov (United States)

    Choudhary, Alpa; Purohit, Hemant; Phale, Prashant S

    2017-07-03

    Pseudomonas putida strain CSV86 metabolizes variety of aromatic compounds as the sole carbon source. Genome analysis revealed the presence of genes encoding putative transporters for benzoate, p-hydroxybenzoate, phenylacetate, p-hydroxyphenylacetate and vanillate. Bioinformatic analysis revealed that benzoate transport and metabolism genes are clustered at the ben locus as benK-catA-benE-benF. Protein topology prediction suggests that BenK (aromatic acid-H+ symporter of major facilitator superfamily) has 12 transmembrane α-helices with the conserved motif LADRXGRKX in loop 2, while BenE (benzoate-H+ symporter protein) has 11 predicted transmembrane α-helices. benF and catA encode benzoate specific porin, OprD and catechol 1,2-dioxygenase, respectively. Biochemical studies suggest that benzoate was transported by an inducible and active process. Inhibition (90%-100%) in the presence of dinitrophenol suggests that the energy for the transport process is derived from the proton motive force. The maximum rate of benzoate transport was 484 pmole min-1 mg-1 cells with an affinity constant, Kmof 4.5 μM. Transcriptional analysis of the benzoate and glucose-grown cells showed inducible expression of benF, benK and benE, suggesting that besides outer membrane porin, both inner membrane transporters probably contribute for the benzoate transport in P. putida strain CSV86. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  3. Modelling freight transport

    NARCIS (Netherlands)

    Tavasszy, L.A.; Jong, G. de

    2014-01-01

    Freight Transport Modelling is a unique new reference book that provides insight into the state-of-the-art of freight modelling. Focusing on models used to support public transport policy analysis, Freight Transport Modelling systematically introduces the latest freight transport modelling

  4. Transport of radioactive materials

    International Nuclear Information System (INIS)

    2013-01-01

    This ninth chapter presents de CNEN-NE--5.01 norm 'Transport of radioactive material'; the specifications of the radioactive materials for transport; the tests of the packages; the requests for controlling the transport and the responsibilities during the transport of radioactive material

  5. Methanol Extract of Myelophycus caespitosus Inhibits the ...

    African Journals Online (AJOL)

    Methanol Extract of Myelophycus caespitosus Inhibits the Inflammatory Response in Lipopolysaccharidestimulated BV2 Microglial Cells by Downregulating NF-kB via Inhibition of the Akt Signaling Pathway.

  6. Water-transporting proteins

    DEFF Research Database (Denmark)

    Zeuthen, Thomas

    2010-01-01

    . In the K(+)/Cl(-) and the Na(+)/K(+)/2Cl(-) cotransporters, water is entirely cotransported, while water transport in glucose uniporters and Na(+)-coupled transporters of nutrients and neurotransmitters takes place by both osmosis and cotransport. The molecular mechanism behind cotransport of water...... transport. Epithelial water transport is energized by the movements of ions, but how the coupling takes place is uncertain. All epithelia can transport water uphill against an osmotic gradient, which is hard to explain by simple osmosis. Furthermore, genetic removal of aquaporins has not given support...... to osmosis as the exclusive mode of transport. Water cotransport can explain the coupling between ion and water transport, a major fraction of transepithelial water transport and uphill water transport. Aquaporins enhance water transport by utilizing osmotic gradients and cause the osmolarity...

  7. Labor Inhibits Placental Mechanistic Target of Rapamycin Complex 1 Signaling

    Science.gov (United States)

    LAGER, Susanne; AYE, Irving L.M.H.; GACCIOLI, Francesca; RAMIREZ, Vanessa I.; JANSSON, Thomas; POWELL, Theresa L.

    2014-01-01

    Introduction Labor induces a myriad of changes in placental gene expression. These changes may represent a physiological adaptation inhibiting placental cellular processes associated with a high demand for oxygen and energy (e.g., protein synthesis and active transport) thereby promoting oxygen and glucose transfer to the fetus. We hypothesized that mechanistic target of rapamycin complex 1 (mTORC1) signaling, a positive regulator of trophoblast protein synthesis and amino acid transport, is inhibited by labor. Methods Placental tissue was collected from healthy, term pregnancies (n=15 no-labor; n=12 labor). Activation of Caspase-1, IRS1/Akt, STAT, mTOR, and inflammatory signaling pathways was determined by Western blot. NFκB p65 and PPARγ DNA binding activity was measured in isolated nuclei. Results Labor increased Caspase-1 activation and mTOR complex 2 signaling, as measured by phosphorylation of Akt (S473). However, mTORC1 signaling was inhibited in response to labor as evidenced by decreased phosphorylation of mTOR (S2448) and 4EBP1 (T37/46 and T70). Labor also decreased NFκB and PPARγ DNA binding activity, while having no effect on IRS1 or STAT signaling pathway. Discussion and conclusion Several placental signaling pathways are affected by labor, which has implications for experimental design in studies of placental signaling. Inhibition of placental mTORC1 signaling in response to labor may serve to down-regulate protein synthesis and amino acid transport, processes that account for a large share of placental oxygen and glucose consumption. We speculate that this response preserves glucose and oxygen for transfer to the fetus during the stressful events of labor. PMID:25454472

  8. Functional characterization of a recombinant sodium-dependent nucleoside transporter with selectivity for pyrimidine nucleosides (cNT1rat) by transient expression in cultured mammalian cells.

    OpenAIRE

    Fang, X; Parkinson, F E; Mowles, D A; Young, J D; Cass, C E

    1996-01-01

    We have demonstrated that monkey kidney (COS-1) cells have a single type of nucleoside transport process, which, because it was equilibrative, sodium-independent and could be inhibited by nitrobenzylthioinosine (NBMPR), was identified as the 'equilibrative sensitive' or 'es' transporter. Using NBMPR or dilazep to inhibit the endogenous nucleoside transport activity, we have transiently expressed a cDNA that encodes an inhibitor-insensitive, concentrative nucleoside transporter protein (cNT1ra...

  9. Blood Sample Transportation by Pneumatic Transportation Systems

    DEFF Research Database (Denmark)

    Nybo, Mads; Lund, Merete E; Titlestad, Kjell

    2018-01-01

    BACKGROUND: Pneumatic transportation systems (PTSs) are increasingly used for transportation of blood samples to the core laboratory. Many studies have investigated the impact of these systems on different types of analyses, but to elucidate whether PTSs in general are safe for transportation...... analysis, and the hemolysis index). CONCLUSIONS: Owing to their high degree of heterogeneity, the retrieved studies were unable to supply evidence for the safety of using PTSs for blood sample transportation. In consequence, laboratories need to measure and document the actual acceleration forces...

  10. Magnetic type transportation system

    International Nuclear Information System (INIS)

    Kobama, Masao.

    1981-01-01

    Purpose: To enable automatic transportation of nuclear substances with optional setting for the transportation distance, even for a long distance, facilitating the automation of the transportation and decreasing the space for the installation of a direction converging section of the transporting path. Constitution: A transporting vehicle having a pair of permanent magnets or ferromagnetic bodies mounted with a predetermined gap to each other along the transporting direction is provided in the transporting path including a bent direction change section for transporting specimens such as nuclear materials, and a plurality of driving vehicles having permanent magnets or ferromagnetic bodies for magnetically attracting the transporting vehicle from outside of the transporting path are arranged to the outside of the transporting path. At least one of the driving vehicles is made to run along the transporting direction of the transporting path by a driving mechanism incorporating running section such as an endless chain to drive the transportation vehicle, and the transporting vehicle is successively driven by each of the driving mechanisms. (Kawakami, Y.)

  11. Xylitol-mediated transient inhibition of ribitol utilization by Lactobacillus casei.

    OpenAIRE

    London, J; Hausman, S

    1982-01-01

    The growth of Lactobacillus casei strain Cl-16 at the expense or ribitol was inhibited if the non-metabolizable substrate xylitol was included in the medium at concentrations of 6 mM or greater. At these concentrations, xylitol, did not competitively inhibit ribitol transport. The cessation of growth was caused by the intracellular accumulation of xylitol-5-phosphate, which occurred because growth on ribitol had gratuitously induced a functional xylitol-specific phosphotransferase system but ...

  12. Neuronal and non-neuronal GABA transporters as targets for antiepileptic drugs

    DEFF Research Database (Denmark)

    Madsen, Karsten K; White, H Steve; Schousboe, Arne

    2010-01-01

    of transmembrane transport and enzymatic degradation. The development of tiagabine selectively inhibiting the GABA transporter GAT1 constitutes a proof of concept that the GABA transporters are interesting drug targets in the context of antiepileptic drugs. The review provides a detailed analysis of the role......,5,6,7-tetrahydrobenzo[d]isoxazol-3-ol) has been shown to possess a novel anticonvulsant profile in animal models of epilepsy, involving the ability to inhibit GABA transport mediated by GAT1 and BGT1 at the same time....

  13. Two independent anion transport systems in rabbit mandibular salivary glands

    DEFF Research Database (Denmark)

    Novak, I; Young, J A

    1986-01-01

    Cholinergically stimulated Cl and HCO3 transport in perfused rabbit mandibular glands has been studied with extracellular anion substitution and administration of transport inhibitors. In glands perfused with HCO3-free solutions, replacement of Cl with other anions supported secretion in the foll......Cholinergically stimulated Cl and HCO3 transport in perfused rabbit mandibular glands has been studied with extracellular anion substitution and administration of transport inhibitors. In glands perfused with HCO3-free solutions, replacement of Cl with other anions supported secretion...... stimulated secretion by about 30%, but when infused in addition to furosemide (0.1 mmol/l), it inhibited by about 20%. Amiloride (1.0 mmol/l) caused no inhibition. The results suggest that there are at least three distinct carriers in the rabbit mandibular gland. One is a furosemide-sensitive Na-coupled Cl...

  14. Early metabolic effects and mechanism of ammonium transport in yeast

    International Nuclear Information System (INIS)

    Pena, A.; Pardo, J.P.; Ramirez, J.

    1987-01-01

    Studies were performed to define the effects and mechanism of NH+4 transport in yeast. The following results were obtained. Glucose was a better facilitator than ethanol-H 2 O 2 for ammonium transport; low concentrations of uncouplers or respiratory inhibitors could inhibit the transport with ethanol as the substrate. With glucose, respiratory inhibitors showed only small inhibitory effects, and only high concentrations of azide or trifluoromethoxy carbonylcyanide phenylhydrazone could inhibit ammonium transport. Ammonium in the free state could be concentrated approximately 200-fold by the cells. Also, the addition of ammonium produced stimulation of both respiration and fermentation; an increased rate of H+ extrusion and an alkalinization of the interior of the cell; a decrease of the membrane potential, as monitored by fluorescent cyanine; an immediate decrease of the levels of ATP and an increase of ADP, which may account for the stimulation of both fermentation and respiration; and an increase of the levels of inorganic phosphate. Ammonium was found to inhibit 86Rb+ transport much less than K+. Also, while K+ produced a competitive type of inhibition, that produced by NH4+ was of the noncompetitive type. From the distribution ratio of ammonium and the pH gradient, an electrochemical potential gradient of around -180 mV was calculated. The results indicate that ammonium is transported in yeast by a mechanism similar to that of monovalent alkaline cations, driven by a membrane potential. The immediate metabolic effects of this cation seem to be due to an increased [H+]ATPase, to which its transport is coupled. However, the carriers seem to be different. The transport system studied in this work was that of low affinity

  15. Transportation Technology: Rail Transport and Logistics

    Science.gov (United States)

    Lang, Aaron B.

    2011-01-01

    Transportation can simply be defined as the movement of goods, services, and people from one location to another. Without an efficient means to transport goods from place to place, the economy would be nothing like it is today. Throughout the history of the United States, American railroads have paved the way toward creating a nation of great…

  16. An In-Vitro Model of Ciprofloxacin and Minocycline Transport by Oral Epithelial Cells

    Science.gov (United States)

    Brayton, James J.; Yang, Qing; Nakkula, Robin J.; Walters, John D.

    2008-01-01

    Background Fluoroquinolones and tetracyclines can penetrate epithelial cells, but the mechanism by which they cross the plasma membrane is unclear. In this study, a cell line derived from oral epithelium was used as a model to demonstrate a role for active transport. Methods Transport of ciprofloxacin and minocycline by confluent cell monolayers was assayed by measuring the increase in cell-associated fluorescence. Results Uptake of both agents was saturable and was inhibited at low temperatures. At 37° C, the cells transported ciprofloxacin and minocycline with Km values of 351 and 133 μg/ml, respectively, and maximum velocities of 5.11 and 13.4 ng/min/μg cell protein, respectively. When ciprofloxacin and minocycline were removed from the extracellular medium, the intracellular levels of both agents decreased. Ciprofloxacin efflux from loaded cells occurred more rapidly than with minocycline. Cells accumulated intracellular drug levels that were at least 8-fold higher than extracellular levels for ciprofloxacin and at least 40-fold higher for minocycline. Transport of ciprofloxacin and minocycline was significantly influenced by pH and was most favorable at pH 7.7 and 7.2, respectively. While ciprofloxacin transport was Na+-independent, minocycline transport was strongly inhibited when sodium in the medium was replaced with choline. Transport of both agents was inhibited by a variety of organic cations, but the pattern of inhibition was different. Papaverine, phenylephrine and doxycycline competitively inhibited minocycline transport, but inhibited ciprofloxacin transport by a noncompetitive mechanism. Conclusions Epithelial cells take up ciprofloxacin and minocycline via different active transport systems. These transporters may play an important role in enhancing the effectiveness of these agents against invasive pathogens. PMID:12479629

  17. Coupled transport in field-reversed configurations

    Science.gov (United States)

    Steinhauer, L. C.; Berk, H. L.; TAE Team

    2018-02-01

    Coupled transport is the close interconnection between the cross-field and parallel fluxes in different regions due to topological changes in the magnetic field. This occurs because perpendicular transport is necessary for particles or energy to leave closed field-line regions, while parallel transport strongly affects evolution of open field-line regions. In most toroidal confinement systems, the periphery, namely, the portion with open magnetic surfaces, is small in thickness and volume compared to the core plasma, the portion with closed surfaces. In field-reversed configurations (FRCs), the periphery plays an outsized role in overall confinement. This effect is addressed by an FRC-relevant model of coupled particle transport that is well suited for immediate interpretation of experiments. The focus here is particle confinement rather than energy confinement since the two track together in FRCs. The interpretive tool yields both the particle transport rate χn and the end-loss time τǁ. The results indicate that particle confinement depends on both χn across magnetic surfaces throughout the plasma and τǁ along open surfaces and that they provide roughly equal transport barriers, inhibiting particle loss. The interpretation of traditional FRCs shows Bohm-like χn and inertial (free-streaming) τǁ. However, in recent advanced beam-driven FRC experiments, χn approaches the classical rate and τǁ is comparable to classic empty-loss-cone mirrors.

  18. Information disclosure on transport

    International Nuclear Information System (INIS)

    Kubo, M.

    1998-01-01

    In Japan, the transport of nuclear fuel materials strictly meets the above international convention and domestic regulations as well. Information on the transport of nuclear fuel materials within the country and between the country and foreign countries is treated carefully. Nuclear fuel materials are categorized for transport and are physically protected accordingly. Certain transportation information is treated with special precautions, including prior arrangements among sender, recipient and carrier, and prior agreement between entities subject to the jurisdiction and regulation of supplier and recipient countries. In the case of international transport, this information includes specifying time, place and procedures for transferring transport and responsibility. (O.M.)

  19. Secure Transportation Management

    International Nuclear Information System (INIS)

    Gibbs, P. W.

    2014-01-01

    Secure Transport Management Course (STMC) course provides managers with information related to procedures and equipment used to successfully transport special nuclear material. This workshop outlines these procedures and reinforces the information presented with the aid of numerous practical examples. The course focuses on understanding the regulatory framework for secure transportation of special nuclear materials, identifying the insider and outsider threat(s) to secure transportation, organization of a secure transportation unit, management and supervision of secure transportation units, equipment and facilities required, training and qualification needed.

  20. Monte Carlo Transport for Electron Thermal Transport

    Science.gov (United States)

    Chenhall, Jeffrey; Cao, Duc; Moses, Gregory

    2015-11-01

    The iSNB (implicit Schurtz Nicolai Busquet multigroup electron thermal transport method of Cao et al. is adapted into a Monte Carlo transport method in order to better model the effects of non-local behavior. The end goal is a hybrid transport-diffusion method that combines Monte Carlo Transport with a discrete diffusion Monte Carlo (DDMC). The hybrid method will combine the efficiency of a diffusion method in short mean free path regions with the accuracy of a transport method in long mean free path regions. The Monte Carlo nature of the approach allows the algorithm to be massively parallelized. Work to date on the method will be presented. This work was supported by Sandia National Laboratory - Albuquerque and the University of Rochester Laboratory for Laser Energetics.

  1. Homo economicus belief inhibits trust.

    Directory of Open Access Journals (Sweden)

    Ziqiang Xin

    Full Text Available As a foundational concept in economics, the homo economicus assumption regards humans as rational and self-interested actors. In contrast, trust requires individuals to believe partners' benevolence and unselfishness. Thus, the homo economicus belief may inhibit trust. The present three experiments demonstrated that the direct exposure to homo economicus belief can weaken trust. And economic situations like profit calculation can also activate individuals' homo economicus belief and inhibit their trust. It seems that people's increasing homo economicus belief may serve as one cause of the worldwide decline of trust.

  2. Homo Economicus Belief Inhibits Trust

    Science.gov (United States)

    Xin, Ziqiang; Liu, Guofang

    2013-01-01

    As a foundational concept in economics, the homo economicus assumption regards humans as rational and self-interested actors. In contrast, trust requires individuals to believe partners’ benevolence and unselfishness. Thus, the homo economicus belief may inhibit trust. The present three experiments demonstrated that the direct exposure to homo economicus belief can weaken trust. And economic situations like profit calculation can also activate individuals’ homo economicus belief and inhibit their trust. It seems that people’s increasing homo economicus belief may serve as one cause of the worldwide decline of trust. PMID:24146907

  3. Inhibition of Retinoblastoma Protein Inactivation

    Science.gov (United States)

    2017-11-01

    CONTRACT NUMBER Inhibition of Retinoblastoma Protein Inactivation 5b. GRANT NUMBER W81XWH-14-1-0329 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Seth M...confirmed 108 compounds as giving a dose-response curve with at least 30% inhibition at 10 µM. The flowchart of hit progression is shown on the...Cancer Research Program under Award No. W81XWH-14-1-0329 to S.M.R. Opinions, interpretations, conclusions, and recommendations are those of the author

  4. Mutations affecting substrate specificity of the Bacillus subtilis multidrug transporter Bmr.

    OpenAIRE

    Klyachko, K A; Schuldiner, S; Neyfakh, A A

    1997-01-01

    The Bacillus subtilis multidrug transporter Bmr, a member of the major facilitator superfamily of transporters, causes the efflux of a number of structurally unrelated toxic compounds from cells. We have shown previously that the activity of Bmr can be inhibited by the plant alkaloid reserpine. Here we demonstrate that various substitutions of residues Phe143 and Phe306 of Bmr not only reduce its sensitivity to reserpine inhibition but also significantly change its substrate specificity. Cros...

  5. Inhibition of calmodulin - regulated calcium pump activity in rat brain by toxaphene

    International Nuclear Information System (INIS)

    Trottman, C.H.; Moorthy, K.S.

    1986-01-01

    In vivo effects of toxaphene on calcium pump activity in rat brain synaptosomes was studied. Male Sprague-Dawley rats were dosed with toxaphene at 0,25,50, and 100 mg/kg/day for 3 days and sacrificed 24 h after last dose. Ca 2+ -ATPase activity and 45 Ca uptake were determined in brain P 2 fraction. Toxaphene inhibited both Ca 2+ -ATPase activity and 45 Ca 2+ uptake and the inhibition was dose dependent. Both substrate and Ca 2+ activation kinetics of Ca 2+ -ATPase indicated non-competitive type of inhibition as evidenced by decreased catalytic velocity but not enzyme-substrate affinity. The inhibited Ca 2+ -ATPase activity and Ca 2+ uptake were restored to normal level by exogenously added calmodulin which increased both velocity and affinity. The inhibition of Ca 2+ -ATPase activity and Ca 2+ uptake and restoration by calmodulin suggests that toxaphene may impair active calcium transport mechanisms by decreasing regulator protein calmodulin levels

  6. Specific lysosomal transport of small neutral amino acids

    International Nuclear Information System (INIS)

    Pisoni, R.L.; Flickinger, K.S.; Thoene, J.G.; Christensen, H.N.

    1986-01-01

    Studies of amino acid exodus from lysosomes have allowed us previously to describe transport systems specific for cystine and another for cationic amino acids in fibroblast lysosomes. They are now able to study amino acid uptake into highly purified fibroblast lysosomes obtained by separating crude granular fraction on gradients formed by centrifugation in 35% isoosmotic Percoll solutions. Analog inhibition and saturation studies indicate that L-[ 14 C]proline (50 μM) uptake by fibroblast lysosomes at 37 0 C in 50 mM citrate/tris pH 7.0 buffer containing 0.25 M sucrose is mediated by two transport systems, one largely specific for L-proline and the other for which transport is shared with small neutral amino acids such as alanine, serine and threonine. At 7 mM, L-proline inhibits L-[ 14 C]proline uptake almost completely, whereas ala, ser, val, thr, gly, N-methylalanine and sarcosine inhibit proline uptake by 50-65%. The system shared by alanine, serine and threonine is further characterized by these amino acids strongly inhibiting the uptakes of each other. Lysosomal proline transport is selective for the L-isomer of the amino acid, and is scarcely inhibited by 7 mM arg, glu, asp, leu, phe, his, met, (methylamino) isobutyrate, betaine or N,N-dimethylglycine. Cis or trans-4-hydroxy-L-proline inhibit proline uptake only slightly. In sharp contrast to the fibroblast plasma membrane in which Na + is required for most proline and alanine transport, lysosomal uptake of these amino acids occurs independently of Na +

  7. Neurofilament subunit (NFL) head domain phosphorylation regulates axonal transport of neurofilaments.

    LENUS (Irish Health Repository)

    Yates, Darran M

    2009-04-01

    Neurofilaments are the intermediate filaments of neurons and are synthesised in neuronal cell bodies and then transported through axons. Neurofilament light chain (NFL) is a principal component of neurofilaments, and phosphorylation of NFL head domain is believed to regulate the assembly of neurofilaments. However, the role that NFL phosphorylation has on transport of neurofilaments is poorly understood. To address this issue, we monitored axonal transport of phosphorylation mutants of NFL. We mutated four known phosphorylation sites in NFL head domain to either preclude phosphorylation, or mimic permanent phosphorylation. Mutation to preclude phosphorylation had no effect on transport but mutation of three sites to mimic permanent phosphorylation inhibited transport. Mutation of all four sites together to mimic permanent phosphorylation proved especially potent at inhibiting transport and also disrupted neurofilament assembly. Our results suggest that NFL head domain phosphorylation is a regulator of neurofilament axonal transport.

  8. Functional characterization of water transport and cellular localization of three aquaporin paralogs in the salmonid intestine

    DEFF Research Database (Denmark)

    Madsen, Steffen S; Olesen, Jesper H; Bedal, Konstanze

    2011-01-01

    Intestinal water absorption is greatly enhanced in salmonids upon acclimation from freshwater (FW) to seawater (SW); however, the molecular mechanism for water transport is unknown. We conducted a pharmacological characterization of water absorption in the rainbow trout intestine along......%), 0.1 ouabain (72%), and 0.1 bumetanide (82%) suggesting that active transport, Na(+), K(+)-ATPase and Na(+), K(+), 2Cl(-)-co-transport are involved in establishing the driving gradient for water transport. J(v) was also inhibited by 1 mmol L(-1) HgCl(2), serosally (23% in M and 44% in P), mucosally...... (27% in M), or both (61% in M and 58% in P), suggesting involvement of both apical and basolateral aquaporins in water transport. The inhibition was antagonized by 5 mmol L(-1) mercaptoethanol. By comparison, 10 mmol L(-1) mucosal tetraethylammonium, an inhibitor of certain aquaporins, inhibited J...

  9. Sustainable Transportation and Health

    Directory of Open Access Journals (Sweden)

    Norbert Mundorf

    2018-03-01

    Full Text Available We are experiencing a shift in thinking about Transportation and Mobility, which makes this Special Issue on Sustainable Transportation and Health in the International Journal of Environmental Research and Public Health especially timely.[...

  10. Arizona transportation history.

    Science.gov (United States)

    2011-12-01

    The Arizona transportation history project was conceived in anticipation of Arizonas centennial, which will be : celebrated in 2012. Following approval of the Arizona Centennial Plan in 2007, the Arizona Department of : Transportation (ADOT) recog...

  11. Department of Transportation

    Science.gov (United States)

    ... of Drone Integration Pilot Program MEET THE SECRETARY TRANSPORTATION TUESDAY FEATURED NEWS The Briefing Room Connect With ... Carriers - Get a DOT Number Find Your State Transportation Department 5 Star Automobile Crash Test Ratings Office ...

  12. Transportation Management Workshop: Proceedings

    Energy Technology Data Exchange (ETDEWEB)

    1993-10-01

    This report is a compilation of discussions presented at the Transportation Management Workshop held in Gaithersburg, Maryland. Topics include waste packaging, personnel training, robotics, transportation routing, certification, containers, and waste classification.

  13. TRANSPORTATION ECONOMIC TRENDS 2017

    Science.gov (United States)

    2018-01-05

    The report has eight chapters: - Chapter 1 introduces the Transportation Services Index, a monthly summary of freight and passenger movement. - Chapter 2 explains what transportation contributes to the American economy. - Chapter 3 examines the costs...

  14. Oxygen transport membrane

    DEFF Research Database (Denmark)

    2015-01-01

    The present invention relates to a novel composite oxygen transport membrane as well as its preparation and uses thereof.......The present invention relates to a novel composite oxygen transport membrane as well as its preparation and uses thereof....

  15. Transport not as others

    International Nuclear Information System (INIS)

    Gruhier, Fabien.

    1979-01-01

    Transport of radioactive materials will increase with the development of nuclear power station. Problems arising are examined. Some examples of past accidents are given. Thermal and impact tests of containers and categories of transport are recalled [fr

  16. Transportation Management Workshop: Proceedings

    International Nuclear Information System (INIS)

    1993-01-01

    This report is a compilation of discussions presented at the Transportation Management Workshop held in Gaithersburg, Maryland. Topics include waste packaging, personnel training, robotics, transportation routing, certification, containers, and waste classification

  17. National transportation statistics 2010

    Science.gov (United States)

    2010-01-01

    National Transportation Statistics presents statistics on the U.S. transportation system, including its physical components, safety record, economic performance, the human and natural environment, and national security. This is a large online documen...

  18. Transportation Services Index

    Data.gov (United States)

    Department of Transportation — The TSI is a monthly measure of the volume of services performed by the for-hire transportation sector. The index covers the activities of for-hire freight carriers,...

  19. 1979 CECAM workshop on transport of fast electrons in laser fusion plasmas. Progress report

    International Nuclear Information System (INIS)

    Mason, R.J.

    1979-01-01

    Attention is given to three problem areas in laser-driven electron transport: (1) ion-acoustic turbulence as a source of inhibition, (2) the effects of anti E times anti j heating of the thermals, and (3) the possibility of thermal inhibition by thermal electron runaway or trapping

  20. Is forgetting caused by inhibition?

    NARCIS (Netherlands)

    Raaijmakers, J.G.W.; Jakab, E.

    2013-01-01

    A well-known finding in memory research is the forgetting effect that occurs because of practicing some Item A on the recall of a related Item B. The traditional explanation for such interference effects is based on the notion of competition. According to the inhibition theory of forgetting,

  1. Testing of Biologically Inhibiting Surface

    DEFF Research Database (Denmark)

    Bill Madsen, Thomas; Larsen, Erup

    2003-01-01

    The main purpose of this course is to examine a newly developed biologically inhibiting material with regards to galvanic corrosion and electrochemical properties. More in detail, the concern was how the material would react when exposed to cleaning agents, here under CIP cleaning (Cleaning...

  2. Propranolol transport across the inner blood-retinal barrier: potential involvement of a novel organic cation transporter.

    Science.gov (United States)

    Kubo, Yoshiyuki; Shimizu, Yoshimi; Kusagawa, Yusuke; Akanuma, Shin-Ichi; Hosoya, Ken-Ichi

    2013-09-01

    The influx transport of propranolol across the inner blood-retinal barrier (BRB) was investigated. In the in vivo analysis of carotid artery single-injection method, [(3) H]propranolol uptake by the retina was greater than that of an internal reference compound, and was reduced by several organic cations. In the in vitro uptake study, TR-iBRB2 cells, an in vitro model of the inner BRB, showed a time-, concentration-, pH- and temperature-dependent [(3) H]propranolol uptake, suggesting the involvement of a carrier-mediated transport process in the influx of propranolol across the inner BRB. In the inhibition study, various organic cations, including drugs and candidates for the treatment of the retinal diseases, inhibited the [(3) H]propranolol uptake by TR-iBRB2 cells with no significant effects by the substrates and inhibitors of well-characterized organic cation transporters, suggesting that the influx transport of propranolol is performed by a novel transporter at the inner BRB. An analysis of the relationship between the inhibitory effect and the lipophilicity of inhibitors suggests a lipophilicity-dependent inhibitory effect of amines on the [(3) H]propranolol uptake by TR-iBRB2 cells. These results showed that influx transport of propranolol across the inner BRB is performed by a carrier-mediated transport process, suggesting the involvement of a novel organic cation transporter. Copyright © 2013 Wiley Periodicals, Inc.

  3. Transport of MOX fuel

    International Nuclear Information System (INIS)

    Porter, I.R.; Carr, M.

    1997-01-01

    The regulatory framework which governs the transport of MOX fuel is set out, including packages, transport modes and security requirements. Technical requirements for the packages are reviewed and BNFL's experience in plutonium and MOX fuel transport is described. The safety of such operations and the public perception of safety are described and the question of gaining public acceptance for MOX fuel transport is addressed. The paper concludes by emphasising the need for proactive programmes to improve the public acceptance of these operations. (Author)

  4. Radioactive materials transport

    International Nuclear Information System (INIS)

    Talbi, B.

    1996-01-01

    The development of peaceful applications of nuclear energy results in the increase of transport operations of radioactive materials. Therefore strong regulations on transport of radioactive materials turns out to be a necessity in Tunisia. This report presents the different axes of regulations which include the means of transport involved, the radiation protection of the carriers, the technical criteria of security in transport, the emergency measures in case of accidents and penalties in case of infringement. (TEC). 12 refs., 1 fig

  5. TRANSPORTATION INFORMATION CLEARINGHOUSE

    OpenAIRE

    Allen, Karin; Dijohn, Joseph; Misek, Shamus

    2005-01-01

    The Transportation Information Clearinghouse (TIC) Project was the result of collaboration among the Regional Transportation Authority, the Workforce Boards of Metropolitan Chicago and the Urban Transportation Center (UTC) at the University of Illinois at Chicago (UIC). The primary objective of the project was to identify privatelyprovided, employer-based, non-traditional transportation services in operation as well as specific information about these services in order for employers, Workforc...

  6. Transport statistics 1995

    CSIR Research Space (South Africa)

    De Haan, ML

    1996-04-01

    Full Text Available This publication contains information on all major modes of transport in South Africa. The transport sector is placed in perspective relative to the macro economy and a number of important transport indicators are given. The document also contains...

  7. Transports of radioactive materials

    International Nuclear Information System (INIS)

    Sousselier, Yves

    1982-01-01

    Transport safety depends on the packaging, and the degree of safety must be adapted to the potential hazards of the substance carried. The various kinds of packagings and their strength are examined and the transport of irradiated fuels from the safety angle is taken as example and a comparison is made with the transport of conventional dangerous substances [fr

  8. Transport of radioactive materials

    International Nuclear Information System (INIS)

    Lenail, B.

    1984-01-01

    Transport of radioactive materials is dependent of transport regulations. In practice integrated doses for personnel during transport are very low but are more important during loading or unloading a facility (reactor, plant, laboratory, ...). Risks occur also if packagings are used outside specifications. Recommendations to avoid these risks are given [fr

  9. Transportation in African Development.

    Science.gov (United States)

    Altschul, Robert D.

    1980-01-01

    Examines the structure, role, and needs of Africa's national and intracontinental transportation system. Characteristics of rail, water, road, and air transportation are examined. The conclusion is that high investment in transportation systems is essential to the development process. (Author/KC)

  10. Competing Transport Networks

    NARCIS (Netherlands)

    M.J. van der Leij (Marco)

    2003-01-01

    textabstractIn a circular city model, I consider network design and pricing decisions for a single fast transport connection that faces competition from a slower but better accessible transport mode. To access the fast transport network individuals have to make complementary trips by slow mode. This

  11. NATURAL GAS TRANSPORTATION

    OpenAIRE

    Stanis³aw Brzeziñski

    2007-01-01

    In the paper, Author presents chosen aspects of natural gas transportation within global market. Natural gas transportation is a technicaly complicated and economicly expensive process; in infrastructure construction and activities costs. The paper also considers last and proposed initiatives in natural gas transportation.

  12. Assessing Sensitiveness to Transport

    DEFF Research Database (Denmark)

    Lieb, Christoph; Suter, Stefan; Sánchez, Alfredo

    Summary The EU-project ASSET (ASessing SEnsitiveness to Transport) aims at developing and implementing a concise concept to assess transport sensitive areas (TSA) in a European context, i.e. areas in which transport leads to more serious impacts than in other areas. The aim of work package 2 (WP2...

  13. The VPAC2 agonist peptide histidine isoleucine (PHI) up-regulates glutamate transport in the corpus callosum of a rat model of amyotrophic lateral sclerosis (hSOD1G93A) by inhibiting caspase-3 mediated inactivation of GLT-1a.

    Science.gov (United States)

    Goursaud, Stéphanie; Focant, Marylène C; Berger, Julie V; Nizet, Yannick; Maloteaux, Jean-Marie; Hermans, Emmanuel

    2011-10-01

    Degeneration of corpus callosum appears in patients with amyotrophic lateral sclerosis (ALS) before clinical signs of upper motor neuron death. Considering the ALS-associated impairment of astrocytic glutamate uptake, we have characterized the expression and activity of the glutamate transporter isoforms GLT-1a and GLT-1b in the corpus callosum of transgenic rats expressing a mutated form of the human superoxide dismutase 1 (hSOD1(G93A)). We have also studied the effect of peptide histidine isoleucine (PHI), a vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating polypeptide (PACAP) receptor 2 (VPAC(2)) agonist on glutamate transporters both in vivo and in callosal astrocytes. Before the onset of motor symptoms, the expression of both transporter isoforms was correlated with a constitutive activity of caspase-3. This enzyme participates in the down-regulation of GLT-1 in ALS, and here we demonstrated its involvement in the selective degradation of GLT-1a in the white matter. A single stereotactic injection of PHI into the corpus callosum of symptomatic rats decreased caspase-3 activity and promoted GLT-1a expression and uptake activity. Together, with evidence for a reduced expression of prepro-VIP/PHI mRNA in the corpus callosum of transgenic animals, these data shed light on the modulatory role of the VIP/PHI system on the glutamatergic transmission in ALS.

  14. Inhibiting cancer cell hallmark features through nuclear export inhibition.

    Science.gov (United States)

    Sun, Qingxiang; Chen, Xueqin; Zhou, Qiao; Burstein, Ezra; Yang, Shengyong; Jia, Da

    2016-01-01

    Treating cancer through inhibition of nuclear export is one of the best examples of basic research translation into clinical application. Nuclear export factor chromosomal region maintenance 1 (CRM1; Xpo1 and exportin-1) controls cellular localization and function of numerous proteins that are critical for the development of many cancer hallmarks. The diverse actions of CRM1 are likely to explain the broad ranging anti-cancer potency of CRM1 inhibitors observed in pre-clinical studies and/or clinical trials (phase I-III) on both advanced-stage solid and hematological tumors. In this review, we compare and contrast the mechanisms of action of different CRM1 inhibitors, and discuss the potential benefit of unexplored non-covalent CRM1 inhibitors. This emerging field has uncovered that nuclear export inhibition is well poised as an attractive target towards low-toxicity broad-spectrum potent anti-cancer therapy.

  15. Road Transport Entrepreneurs and Road Transportation Revolution ...

    African Journals Online (AJOL)

    Toshiba

    upon a massive road-building programme throughout the colony. The rapid expansion ..... transportation problems of his textile customers and palm produce producers and ... unflinching loyalty and solidarity with their illustrious son, General.

  16. 18 CFR 284.7 - Firm transportation service.

    Science.gov (United States)

    2010-04-01

    ... include in its tariff any provision that inhibits the development of market centers. (c) Reasonable... as part of its transportation tariff. (d) Segmentation. An interstate pipeline that offers... purpose of releasing that capacity to replacement shippers to the extent such segmentation is...

  17. Transporters affecting biochemical test results: Creatinine-drug interactions.

    Science.gov (United States)

    Chu, X; Bleasby, K; Chan, G H; Nunes, I; Evers, R

    2016-11-01

    Creatinine is eliminated by the kidneys through a combination of glomerular filtration and active transport. Drug-induced increases in serum creatinine (SCr) and/or reduced creatinine renal clearance are used as a marker for acute kidney injury. However, inhibition of active transport of creatinine can result in reversible and, therefore, benign increases in SCr levels. Herein, the transporters involved in creatinine clearance are discussed, in addition to limitations of using creatinine as a biomarker for kidney damage. © 2016 American Society for Clinical Pharmacology and Therapeutics.

  18. Transportation and public health.

    Science.gov (United States)

    Litman, Todd

    2013-01-01

    This article investigates various ways that transportation policy and planning decisions affect public health and better ways to incorporate public health objectives into transport planning. Conventional planning tends to consider some public health impacts, such as crash risk and pollution emissions measured per vehicle-kilometer, but generally ignores health problems resulting from less active transport (reduced walking and cycling activity) and the additional crashes and pollution caused by increased vehicle mileage. As a result, transport agencies tend to undervalue strategies that increase transport system diversity and reduce vehicle travel. This article identifies various win-win strategies that can help improve public health and other planning objectives.

  19. Convective transport in tokamaks

    International Nuclear Information System (INIS)

    D'Ippolito, D.A.; Myra, J.R.; Russell, D.A.; Krasheninnikov, S.I.; Pigarov, A.Yu.; Yu, G.Q.; Xu, X.Q.; Nevins, W.M.

    2005-01-01

    Scrape-off-layer (SOL) convection in fusion experiments appears to be a universal phenomenon that can 'short-circuit' the divertor in some cases. The theory of 'blob' transport provides a simple and robust physical paradigm for studying convective transport. This paper summarizes recent advances in the theory of blob transport and its comparison with 2D and 3D computer simulations. We also discuss the common physical basis relating radial transport of blobs, pellets, and ELMs and a new blob regime that may lead to a connection between blob transport and the density limit. (author)

  20. Theory of contributon transport

    International Nuclear Information System (INIS)

    Painter, J.W.; Gerstl, S.A.W.; Pomraning, G.C.

    1980-10-01

    A general discussion of the physics of contributon transport is presented. To facilitate this discussion, a Boltzmann-like transport equation for contributons is obtained, and special contributon cross sections are defined. However, the main goal of this study is to identify contributon transport equations and investigate possible deterministic solution techniques. Four approaches to the deterministic solution of the contributon transport problem are investigated. These approaches are an attempt to exploit certain attractive properties of the contributon flux, psi = phi phi + , where phi and phi + are the solutions to the forward and adjoint Boltzmann transport equations

  1. Transportation Business Plan

    International Nuclear Information System (INIS)

    1986-01-01

    The Transportation Business Plan is a step in the process of procuring the transportation system. It sets the context for business strategy decisions by providing pertinent background information, describing the legislation and policies governing transportation under the NWPA, and describing requirements of the transportation system. Included in the document are strategies for procuring shipping casks and transportation support services. In the spirit of the NWPA directive to utilize the private sector to the maximum extent possible, opportunities for business ventures are obvious throughout the system development cycle

  2. Transportation safety training

    International Nuclear Information System (INIS)

    Jones, E.

    1990-01-01

    Over the past 25 years extensive federal legislation involving the handling and transport of hazardous materials/waste has been passed that has resulted in numerous overlapping regulations administered and enforced by different federal agencies. The handling and transport of hazardous materials/waste involves a significant number of workers who are subject to a varying degree of risk should an accident occur during handling or transport. Effective transportation training can help workers address these risks and mitigate them, and at the same time enable ORNL to comply with the federal regulations concerning the transport of hazardous materials/waste. This presentation will outline how the Environmental and Health Protection Division's Technical Resources and Training Section at the Oak Ridge National Laboratory, working with transportation and waste disposal personnel, have developed and implemented a comprehensive transportation safety training program to meet the needs of our workers while satisfying appropriate federal regulations. 8 refs., 3 tabs

  3. Transportation System Requirements Document

    International Nuclear Information System (INIS)

    1993-09-01

    This Transportation System Requirements Document (Trans-SRD) describes the functions to be performed by and the technical requirements for the Transportation System to transport spent nuclear fuel (SNF) and high-level radioactive waste (HLW) from Purchaser and Producer sites to a Civilian Radioactive Waste Management System (CRWMS) site, and between CRWMS sites. The purpose of this document is to define the system-level requirements for Transportation consistent with the CRWMS Requirement Document (CRD). These requirements include design and operations requirements to the extent they impact on the development of the physical segments of Transportation. The document also presents an overall description of Transportation, its functions, its segments, and the requirements allocated to the segments and the system-level interfaces with Transportation. The interface identification and description are published in the CRWMS Interface Specification

  4. TRANSPORT/HANDLING REQUESTS

    CERN Multimedia

    Groupe ST/HM

    2002-01-01

    A new EDH document entitled 'Transport/Handling Request' will be in operation as of Monday, 11th February 2002, when the corresponding icon will be accessible from the EDH desktop, together with the application instructions. This EDH form will replace the paper-format transport/handling request form for all activities involving the transport of equipment and materials. However, the paper form will still be used for all vehicle-hire requests. The introduction of the EDH transport/handling request form is accompanied by the establishment of the following time limits for the various services concerned: 24 hours for the removal of office items, 48 hours for the transport of heavy items (of up to 6 metric tons and of standard road width), 5 working days for a crane operation, extra-heavy transport operation or complete removal, 5 working days for all transport operations relating to LHC installation. ST/HM Group, Logistics Section Tel: 72672 - 72202

  5. Selenium inhibits the phytotoxicity of mercury in garlic (Allium sativum)

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Jiating [CAS Key Laboratory of Nuclear Analytical Techniques, Key Lab for Biomedical Effects of Nanomaterial and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049 (China); Gao, Yuxi, E-mail: gaoyx@ihep.ac.cn [CAS Key Laboratory of Nuclear Analytical Techniques, Key Lab for Biomedical Effects of Nanomaterial and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049 (China); Li, Yu-Feng; Hu, Yi; Peng, Xiaomin [CAS Key Laboratory of Nuclear Analytical Techniques, Key Lab for Biomedical Effects of Nanomaterial and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049 (China); Dong, Yuanxing [Department of Physics, Xinzhou Teachers University, Xinzhou 034000 (China); Li, Bai; Chen, Chunying [CAS Key Laboratory of Nuclear Analytical Techniques, Key Lab for Biomedical Effects of Nanomaterial and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049 (China); Chai, Zhifang, E-mail: chaizf@ihep.ac.cn [CAS Key Laboratory of Nuclear Analytical Techniques, Key Lab for Biomedical Effects of Nanomaterial and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049 (China)

    2013-08-15

    To investigate the influence of selenium on mercury phytotoxicity, the levels of selenium and mercury were analyzed with inductively coupled plasma-mass spectrometry (ICP-MS) in garlic tissues upon exposure to different dosages of inorganic mercury (Hg{sup 2+}) and selenite (SeO{sub 3}{sup 2−}) or selenate (SeO{sub 4}{sup 2−}). The distributions of selenium and mercury were examined with micro-synchrotron radiation X-ray fluorescence (μ-SRXRF), and the mercury speciation was investigated with micro-X-ray absorption near edge structure (μ-XANES). The results show that Se at higher exposure levels (>1 mg/L of SeO{sub 3}{sup 2−} or SeO{sub 4}{sup 2−}) would significantly inhibit the absorption and transportation of Hg when Hg{sup 2+} levels are higher than 1 mg/L in culture media. SeO{sub 3}{sup 2−} and SeO{sub 4}{sup 2−} were found to be equally effective in reducing Hg accumulation in garlic. The inhibition of Hg uptake by Se correlates well with the influence of Se on Hg phytotoxicity as indicated by the growth inhibition factor. Elemental imaging using μ-SRXRF also shows that Se could inhibit the accumulation and translocation of Hg in garlic. μ-XANES analysis shows that Hg is mainly present in the forms of Hg–S bonding as Hg(GSH){sub 2} and Hg(Met){sub 2}. Se exposure elicited decrease of Hg–S bonding in the form of Hg(GSH){sub 2}, together with Se-mediated alteration of Hg absorption, transportation and accumulation, may account for attenuated Hg phytotoxicity by Se in garlic. -- Highlights: ► Hg phytotoxicity can be mitigated by Se supplement in garlic growth. ► Se can inhibit the accumulation and transportation of Hg in garlic tissues. ► Localization and speciation of Hg in garlic can be modified by Se.

  6. Transport of lipoprotein lipase across endothelial cells

    International Nuclear Information System (INIS)

    Saxena, U.; Klein, M.G.; Goldberg, I.J.

    1991-01-01

    Lipoprotein lipase (LPL), synthesized in muscle and fat, hydrolyzes plasma triglycerides primarily while bound to luminal endothelial cell surfaces. To obtain information about the movement of LPL from the basal to the luminal endothelial cell surface, the authors studied the transport of purified bovine milk LPL across bovine aortic endothelial cell monolayers. 125 I-labeled LPL ( 125 I-LPL) added to the basal surface of the monolayers was detected on the apical side of the cells in two compartments: (1) in the medium of the upper chamber, and (2) bound to the apical cell surface. The amount of 125 I-LPL on the cell surface, but not in the medium, reached saturation with time and LPL dose. Catalytically active LPL was transported to the apical surface but very little LPL activity appeared in the medium. Heparinase treatment of the basal cell surface and addition of dextran sulfate to the lower chamber decreased the amount of 125 I-LPL appearing on the apical surface. Similarly, the presence of increasing molar ratios of oleic acid/bovine serum albumin at the basal surface decreased the transport of active LPL across the monolayer. Thus, a saturable transport system, which requires haparan sulfate proteoglycans and is inhibited by high concentrations of free fatty acids on the basal side of the cells, appears to exist for passage of enzymatically active LPL across endothelial cells. They postulate that regulation of LPL transport to the endothelial luminal surface modulates the physiologically active pool of LPL in vivo

  7. On inhibition of dental erosion.

    Science.gov (United States)

    Rölla, Gunnar; Jonski, Grazyna; Saxegaard, Erik

    2013-11-01

    To examine the erosion-inhibiting effect of different concentrations of hydrofluoric acid. Thirty-six human molars were individually treated with 10 ml of 0.1 M citric acid for 30 min (Etch 1), acid was collected and stored until analysis. The teeth were randomly divided into six groups and then individually treated with 10 ml of one of six dilutions (from 0.1-1%) of hydrofluoric acid. The teeth were then again treated with citric acid (Etch 2). The individual acid samples from Etch 1 and 2 were analyzed for calcium by flame atomic absorption spectroscopy and difference in calcium loss was calculated. The highest erosion inhibiting effect was obtained in groups with the highest concentrations of hydrofluoric acid, where the pH was lowest, below pKa of 3.17, thus the hydrofluoric acids being mainly in an undissociated state. Diluted hydrofluoric acid is present in aqueous solution of SnF2 and TiF4 (which are known to inhibit dental erosion): SnF2 + 3H2O = Sn(OH)2 + 2HF + H2O and TiF4 + 5H2O = Ti(OH)4 + 4HF + H2O. It is also known that pure, diluted hydrofluoric acid can inhibit dental erosion. Teeth treated with hydrofluoric acid are covered by a layer of CaF2-like mineral. This mineral is acid resistant at pH acid resistant mineral, initiated by tooth enamel treatment with hydrofluoric acid. Hydrofluoric acid is different in having fluoride as a conjugated base, which provides this acid with unique properties.

  8. Entanglement and inhibited quantum evolution

    International Nuclear Information System (INIS)

    Toschek, P E; Balzer, Chr; Hannemann, Th; Wunderlich, Ch; Neuhauser, W

    2003-01-01

    The evolution of a quantum system is impeded by the system's state being observed. A test on an ensemble neither proves the causal nexus nor discloses the nature of the inhibition. Two recent experiments that make use of sequential optical or microwave-optical double resonance on an individual trapped ion disprove a dynamical effect of back action by meter or environment. They rather indicate the ionic states involved in the evolution being entangled with the potentially recorded bivalued scattered-light signal

  9. Transport of radioactive substances; Der Transport radioaktiver Stoffe

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2014-12-15

    The report on the transport of radioactive substances covers the following topics: facts on radioactive materials transport, safety of the transport of radioactive substances, legal regulations and guidelines: a multiform but consistent system, transport of nuclear fuels, safety during the transport of nuclear fuel, future transport of spent fuel elements and high-level radioactive wastes in Germany.

  10. Stochastic models of intracellular transport

    KAUST Repository

    Bressloff, Paul C.; Newby, Jay M.

    2013-01-01

    mechanisms for intracellular transport: passive diffusion and motor-driven active transport. Diffusive transport can be formulated in terms of the motion of an overdamped Brownian particle. On the other hand, active transport requires chemical energy, usually

  11. Antidepressant Binding Site in a Bacterial Homologue of Neurotransmitter Transporters

    Energy Technology Data Exchange (ETDEWEB)

    Singh,S.; Yamashita, A.; Gouaux, E.

    2007-01-01

    Sodium-coupled transporters are ubiquitous pumps that harness pre-existing sodium gradients to catalyse the thermodynamically unfavourable uptake of essential nutrients, neurotransmitters and inorganic ions across the lipid bilayer. Dysfunction of these integral membrane proteins has been implicated in glucose/galactose malabsorption, congenital hypothyroidism, Bartter's syndrome, epilepsy, depression, autism and obsessive-compulsive disorder. Sodium-coupled transporters are blocked by a number of therapeutically important compounds, including diuretics, anticonvulsants and antidepressants, many of which have also become indispensable tools in biochemical experiments designed to probe antagonist binding sites and to elucidate transport mechanisms. Steady-state kinetic data have revealed that both competitive and noncompetitive modes of inhibition exist. Antagonist dissociation experiments on the serotonin transporter (SERT) have also unveiled the existence of a low-affinity allosteric site that slows the dissociation of inhibitors from a separate high-affinity site. Despite these strides, atomic-level insights into inhibitor action have remained elusive. Here we screen a panel of molecules for their ability to inhibit LeuT, a prokaryotic homologue of mammalian neurotransmitter sodium symporters, and show that the tricyclic antidepressant (TCA) clomipramine noncompetitively inhibits substrate uptake. Cocrystal structures show that clomipramine, along with two other TCAs, binds in an extracellular-facing vestibule about 11 {angstrom} above the substrate and two sodium ions, apparently stabilizing the extracellular gate in a closed conformation. Off-rate assays establish that clomipramine reduces the rate at which leucine dissociates from LeuT and reinforce our contention that this TCA inhibits LeuT by slowing substrate release. Our results represent a molecular view into noncompetitive inhibition of a sodium-coupled transporter and define principles for the

  12. Antidepressant Binding Site in a Bacterial Homologue of Neurotransmitter Transporters

    International Nuclear Information System (INIS)

    Singh, S.; Yamashita, A.; Gouaux, E.

    2007-01-01

    Sodium-coupled transporters are ubiquitous pumps that harness pre-existing sodium gradients to catalyse the thermodynamically unfavourable uptake of essential nutrients, neurotransmitters and inorganic ions across the lipid bilayer. Dysfunction of these integral membrane proteins has been implicated in glucose/galactose malabsorption, congenital hypothyroidism, Bartter's syndrome, epilepsy, depression, autism and obsessive-compulsive disorder. Sodium-coupled transporters are blocked by a number of therapeutically important compounds, including diuretics, anticonvulsants and antidepressants, many of which have also become indispensable tools in biochemical experiments designed to probe antagonist binding sites and to elucidate transport mechanisms. Steady-state kinetic data have revealed that both competitive and noncompetitive modes of inhibition exist. Antagonist dissociation experiments on the serotonin transporter (SERT) have also unveiled the existence of a low-affinity allosteric site that slows the dissociation of inhibitors from a separate high-affinity site. Despite these strides, atomic-level insights into inhibitor action have remained elusive. Here we screen a panel of molecules for their ability to inhibit LeuT, a prokaryotic homologue of mammalian neurotransmitter sodium symporters, and show that the tricyclic antidepressant (TCA) clomipramine noncompetitively inhibits substrate uptake. Cocrystal structures show that clomipramine, along with two other TCAs, binds in an extracellular-facing vestibule about 11 (angstrom) above the substrate and two sodium ions, apparently stabilizing the extracellular gate in a closed conformation. Off-rate assays establish that clomipramine reduces the rate at which leucine dissociates from LeuT and reinforce our contention that this TCA inhibits LeuT by slowing substrate release. Our results represent a molecular view into noncompetitive inhibition of a sodium-coupled transporter and define principles for the rational

  13. Modelling of transport phenomena

    International Nuclear Information System (INIS)

    Itoh, Kimitaka; Itoh, Sanae; Fukuyama, Atsushi.

    1993-09-01

    In this review article, we discuss key features of the transport phenomena and theoretical modelling to understand them. Experimental observations have revealed the nature of anomalous transport, i.e., the enhancement of the transport coefficients by the gradients of the plasma profiles, the pinch phenomena, the radial profile of the anomalous transport coefficients, the variation of the transport among the Bohm diffusion, Pseudo-classical confinement, L-mode and variety of improved confinement modes, and the sudden jumps such as L-H transition. Starting from the formalism of the transport matrix, the modelling based on the low frequency instabilities are reviewed. Theoretical results in the range of drift wave frequency are examined. Problems in theories based on the quasilinear and mixing-length estimates lead to the renewal of the turbulence theory, and the physics picture of the self-sustained turbulence is discussed. The theory of transport using the fluid equation of plasma is developed, showing that the new approach is very promising in explaining abovementioned characteristics of anomalous transport in both L-mode and improved confinement plasmas. The interference of the fluxes is the key to construct the physics basis of the bifurcation theory for the L-H transition. The present status of theories on the mechanisms of improved confinement is discussed. Modelling on the nonlocal nature of transport is briefly discussed. Finally, the impact of the anomalous transport on disruptive phenomena is also described. (author) 95 refs

  14. Transport, energy and environment

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1996-12-01

    Transportation demands a large and increasing share of total energy consumption in Europe. At the same time many European countries are facing difficult decisions in achieving their long term environmental goals. Therefore energy policy, environmental policy and transport policy should be seen and discussed in a common perspective. In particular the relative contribution from the transport sector and the energy sector involves a number of important and difficult issues. The aim of the conference was to bring together economists, scientists, manufactures, energy planners, transport planners, and decision makers in order to discuss the importance of the transport sector in relation to energy demand and long term environmental goals. General conference sessions covered. Trends in Transport Energy Demand and Environmental constraints, Technological Development and New Transport Systems, Lifestyle Changes and the Transport Sector, Megacities: Solutions to the Transport and Air Pollution Problems, Effectiveness of Public Policies, Transport and Energy sector, and Methods, Models and Data. The conference took place at Hotel Marienlyst, Elsinore, Denmark and attracted wide interest. The participants represented 14 different countries covering international organisations, ministries, universities, research centres, consulting firms, industry etc. (EG)

  15. Organic anion transporter 3- and organic anion transporting polypeptides 1B1- and 1B3-mediated transport of catalposide

    Directory of Open Access Journals (Sweden)

    Jeong HU

    2015-01-01

    Full Text Available Hyeon-Uk Jeong,1 Mihwa Kwon,2 Yongnam Lee,3 Ji Seok Yoo,3 Dae Hee Shin,3 Im-Sook Song,2 Hye Suk Lee1 1College of Pharmacy, The Catholic University of Korea, Bucheon 420-743, Korea; 2College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, Korea; 3Central R&D Institute, Yungjin Pharm Co., Ltd., Suwon 443-270, Korea Abstract: We investigated the in vitro transport characteristics of catalposide in HEK293 cells overexpressing organic anion transporter 1 (OAT1, OAT3, organic anion transporting polypeptide 1B1 (OATP1B1, OATP1B3, organic cation transporter 1 (OCT1, OCT2, P-glycoprotein (P-gp, and breast cancer resistance protein (BCRP. The transport mechanism of catalposide was investigated in HEK293 and LLC-PK1 cells overexpressing the relevant transporters. The uptake of catalposide was 319-, 13.6-, and 9.3-fold greater in HEK293 cells overexpressing OAT3, OATP1B1, and OATP1B3 transporters, respectively, than in HEK293 control cells. The increased uptake of catalposide via the OAT3, OATP1B1, and OATP1B3 transporters was decreased to basal levels in the presence of representative inhibitors such as probenecid, furosemide, and cimetidine (for OAT3 and cyclosporin A, gemfibrozil, and rifampin (for OATP1B1 and OATP1B3. The concentration-dependent OAT3-mediated uptake of catalposide revealed the following kinetic parameters: Michaelis constant (Km =41.5 µM, maximum uptake rate (Vmax =46.2 pmol/minute, and intrinsic clearance (CLint =1.11 µL/minute. OATP1B1- and OATP1B3-mediated catalposide uptake also showed concentration dependency, with low CLint values of 0.035 and 0.034 µL/minute, respectively. However, the OCT1, OCT2, OAT1, P-gp, and BCRP transporters were apparently not involved in the uptake of catalposide into cells. In addition, catalposide inhibited the transport activities of OAT3, OATP1B1, and OATP1B3 with half-maximal inhibitory concentration values of 83, 200, and 235 µ

  16. Energy policy in transport and transport policy

    International Nuclear Information System (INIS)

    Van Dender, Kurt

    2009-01-01

    Explanations for, and indirect evidence of, imperfections in the market for private passenger vehicle fuel economy suggest there is a reasonable case for combining fuel economy standards and fuel or carbon taxes to contribute to an energy policy that aims to reduce greenhouse gas emissions and improve energy security. Estimates of key elasticities, including the rebound effect, indicate that the positive and negative side-effects of fuel economy measures on transport activities and external costs are limited. However, an energy policy for transport does not replace a transport policy that aims to manage the main transport externalities including congestion and local pollution. Conventional marginal cost estimates and standard cost-benefit reasoning suggest that policies that address congestion and local pollution likely bring benefits at least as large as those from fuel economy measures. But the large uncertainty on the possible effects of greenhouse gas emissions constitutes a strong challenge for standard cost-benefit reasoning. Emerging results from methods to cope with this uncertainty suggest that policies to stimulate the widespread adoption of low-carbon technologies in transport are justified.

  17. Energy policy in transport and transport policy

    Energy Technology Data Exchange (ETDEWEB)

    Van Dender, Kurt [Joint Transport Research Centre of the International Transport Forum and the OECD, 2 rue Andre Pascale, F-75775 Paris Cedex 16 (France)

    2009-10-15

    Explanations for, and indirect evidence of, imperfections in the market for private passenger vehicle fuel economy suggest there is a reasonable case for combining fuel economy standards and fuel or carbon taxes to contribute to an energy policy that aims to reduce greenhouse gas emissions and improve energy security. Estimates of key elasticities, including the rebound effect, indicate that the positive and negative side-effects of fuel economy measures on transport activities and external costs are limited. However, an energy policy for transport does not replace a transport policy that aims to manage the main transport externalities including congestion and local pollution. Conventional marginal cost estimates and standard cost-benefit reasoning suggest that policies that address congestion and local pollution likely bring benefits at least as large as those from fuel economy measures. But the large uncertainty on the possible effects of greenhouse gas emissions constitutes a strong challenge for standard cost-benefit reasoning. Emerging results from methods to cope with this uncertainty suggest that policies to stimulate the widespread adoption of low-carbon technologies in transport are justified. (author)

  18. Inhibition of mitochondrial respiration by the anticancer agent 2-methoxyestradiol

    International Nuclear Information System (INIS)

    Hagen, Thilo; D'Amico, Gabriela; Quintero, Marisol; Palacios-Callender, Miriam; Hollis, Veronica; Lam, Francis; Moncada, Salvador

    2004-01-01

    2-Methoxyestradiol (2ME2), a naturally occurring metabolite of estradiol, is known to have antiproliferative, antiangiogenic, and proapoptotic activity. Mechanistically, 2ME2 has been shown to downregulate hypoxia-inducible factor 1α (HIF1α) and to induce apoptosis in tumour cells by generating reactive oxygen species (ROS). In this study we report that 2ME2 inhibits mitochondrial respiration in both intact cells and submitochondrial particles, and that this effect is due to inhibition of complex I of the mitochondrial electron transport chain (ETC). The prevention by 2ME2 of hypoxia-induced stabilisation of HIF1α in HEK293 cells was found not to be due to an effect on HIF1α synthesis but rather to an effect on protein degradation. This is in agreement with our recent observation using other inhibitors of mitochondrial respiration which bring about rapid degradation of HIF1α in hypoxia due to increased availability of oxygen and reactivation of prolyl hydroxylases. The concentrations of 2ME2 that inhibited complex I also induced the generation of ROS. 2ME2 did not, however, cause generation of ROS in 143B rho - cells, which lack a functional mitochondrial ETC. We conclude that inhibition of mitochondrial respiration explains, at least in part, the effect of 2ME2 on hypoxia-dependent HIF1α stabilisation and cellular ROS production. Since these actions of 2ME2 occur at higher concentrations than those known to inhibit cell proliferation, it remains to be established whether they contribute to its therapeutic effect

  19. Intestinal transport and metabolism of acrylamide

    International Nuclear Information System (INIS)

    Zoedl, Bettina; Schmid, Diethart; Wassler, Georg; Gundacker, Claudia; Leibetseder, Valentin; Thalhammer, Theresia; Ekmekcioglu, Cem

    2007-01-01

    There has been an intensive debate whether dietary exposure to acrylamide could increase the risk of human cancer since the first description of the presence of acrylamide in food in 2002. As the intestinal mechanisms of acrylamide absorption are poorly investigated we studied the transport of acrylamide in differentiated Caco-2 cells and its effects on biotransformation enzymes (CYP2E1 and glutathione S-transferase) and glutathione levels. We found that the apparent permeability of [1- 14 C] acrylamide from the basal to the apical compartment was approximately 20% higher compared to that in the opposite direction. No differences were detected for apical-basal transport against a basal gradient. Transport rates from the apical to the basal chamber at 4 deg. C were about 50% lower than at 37 deg. C. Concentration dependent transport from apical to basal was linear. Predominantly, basal to apical transport was decreased when energy metabolism of the cells was inhibited by application of sodium azide and 2-deoxy-D-glucose. Finally, more acrylamide was transported at luminal pH 6 compared to pH 7.4 from basal to the apical direction. Increasing levels of acrylamide showed no effects on the activity of glutathione S-transferase but resulted in a depletion of total glutathione concentrations. In conclusion transport of acrylamide in the intestine is mediated primarily by passive processes possibly combined with a modest energy- and pH-dependent active secretory component. Depletion of cellular glutathione levels may be one potential mechanism for acrylamide (geno)toxicity

  20. Inhibition Performance in Children with Math Disabilities

    OpenAIRE

    Winegar, Kathryn Lileth

    2013-01-01

    This study examined the inhibition deficit hypothesis in children with math disabilities (MD). Children with and without MD were compared on two inhibition tasks that included the random generation of numbers and letters. The results addressed three hypotheses. Weak support was found for the first hypothesis which stated difficulties related to inhibition are significantly related to math performance. I found partial support for this hypothesis in that inhibition was related to math problem s...

  1. EBS Radionuclide Transport Abstraction

    International Nuclear Information System (INIS)

    J. Prouty

    2006-01-01

    The purpose of this report is to develop and analyze the engineered barrier system (EBS) radionuclide transport abstraction model, consistent with Level I and Level II model validation, as identified in Technical Work Plan for: Near-Field Environment and Transport: Engineered Barrier System: Radionuclide Transport Abstraction Model Report Integration (BSC 2005 [DIRS 173617]). The EBS radionuclide transport abstraction (or EBS RT Abstraction) is the conceptual model used in the total system performance assessment (TSPA) to determine the rate of radionuclide releases from the EBS to the unsaturated zone (UZ). The EBS RT Abstraction conceptual model consists of two main components: a flow model and a transport model. Both models are developed mathematically from first principles in order to show explicitly what assumptions, simplifications, and approximations are incorporated into the models used in the TSPA. The flow model defines the pathways for water flow in the EBS and specifies how the flow rate is computed in each pathway. Input to this model includes the seepage flux into a drift. The seepage flux is potentially split by the drip shield, with some (or all) of the flux being diverted by the drip shield and some passing through breaches in the drip shield that might result from corrosion or seismic damage. The flux through drip shield breaches is potentially split by the waste package, with some (or all) of the flux being diverted by the waste package and some passing through waste package breaches that might result from corrosion or seismic damage. Neither the drip shield nor the waste package survives an igneous intrusion, so the flux splitting submodel is not used in the igneous scenario class. The flow model is validated in an independent model validation technical review. The drip shield and waste package flux splitting algorithms are developed and validated using experimental data. The transport model considers advective transport and diffusive transport

  2. EBS Radionuclide Transport Abstraction

    Energy Technology Data Exchange (ETDEWEB)

    J. Prouty

    2006-07-14

    The purpose of this report is to develop and analyze the engineered barrier system (EBS) radionuclide transport abstraction model, consistent with Level I and Level II model validation, as identified in Technical Work Plan for: Near-Field Environment and Transport: Engineered Barrier System: Radionuclide Transport Abstraction Model Report Integration (BSC 2005 [DIRS 173617]). The EBS radionuclide transport abstraction (or EBS RT Abstraction) is the conceptual model used in the total system performance assessment (TSPA) to determine the rate of radionuclide releases from the EBS to the unsaturated zone (UZ). The EBS RT Abstraction conceptual model consists of two main components: a flow model and a transport model. Both models are developed mathematically from first principles in order to show explicitly what assumptions, simplifications, and approximations are incorporated into the models used in the TSPA. The flow model defines the pathways for water flow in the EBS and specifies how the flow rate is computed in each pathway. Input to this model includes the seepage flux into a drift. The seepage flux is potentially split by the drip shield, with some (or all) of the flux being diverted by the drip shield and some passing through breaches in the drip shield that might result from corrosion or seismic damage. The flux through drip shield breaches is potentially split by the waste package, with some (or all) of the flux being diverted by the waste package and some passing through waste package breaches that might result from corrosion or seismic damage. Neither the drip shield nor the waste package survives an igneous intrusion, so the flux splitting submodel is not used in the igneous scenario class. The flow model is validated in an independent model validation technical review. The drip shield and waste package flux splitting algorithms are developed and validated using experimental data. The transport model considers advective transport and diffusive transport

  3. Transportation: Grade 8. Cluster IV.

    Science.gov (United States)

    Calhoun, Olivia H.

    A curriculum guide for grade 8, the document is devoted to the occupational cluster "Transportation." It is divided into five units: surface transportation, interstate transportation, air transportation, water transportation, and subterranean transportation (the Metro). Each unit is introduced by a statement of the topic, the unit's…

  4. Diabetic Hyperglycemia: Link to Impaired Glucose Transport in Pancreatic β Cells

    Science.gov (United States)

    Unger, Roger H.

    1991-03-01

    Glucose uptake into pancreatic β cells by means of the glucose transporter GLUT-2, which has a high Michaelis constant, is essential for the normal insulin secretory response to hyperglycemia. In both autoimmune and nonautoimmune diabetes, this glucose transport is reduced as a consequence of down-regulation of the normal β-cell transporter. In autoimmune diabetes, circulating immunoglobulins can further impair this glucose transport by inhibiting functionally intact transporters. Insights into mechanisms of the unresponsiveness of β cells to hyperglycemia may improve the management and prevention of diabetes.

  5. Transport Energy Efficiency

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    2010-07-01

    Transport is the sector with the highest final energy consumption and, without any significant policy changes, is forecast to remain so. In 2008, the IEA published 25 energy efficiency recommendations, among which four are for the transport sector. The recommendations focus on road transport and include policies on improving tyre energy efficiency, fuel economy standards for both light-duty vehicles and heavy-duty vehicles, and eco-driving. Implementation of the recommendations has been weaker in the transport sector than others. This paper updates the progress that has been made in implementing the transport energy efficiency recommendations in IEA countries since March 2009. Many countries have in the last year moved from 'planning to implement' to 'implementation underway', but none have fully implemented all transport energy efficiency recommendations. The IEA calls therefore for full and immediate implementation of the recommendations.

  6. Transportation Emissions: some basics

    DEFF Research Database (Denmark)

    Kontovas, Christos A.; Psaraftis, Harilaos N.

    2016-01-01

    transportation and especially carbon dioxide emissions are at the center stage of discussion by the world community through various international treaties, such as the Kyoto Protocol. The transportation sector also emits non-CO2 pollutants that have important effects on air quality, climate, and public health......Transportation is the backbone of international trade and a key engine driving globalization. However, there is growing concern that the Earth’s atmospheric composition is being altered by human activities, including transportation, which can lead to climate change. Air pollution from....... The main purpose of this chapter is to introduce some basic concepts that are relevant in the quest of green transportation logistics. First, we present the basics of estimating emissions from transportation activities, the current statistics and future trends, as well as the total impact of air emissions...

  7. Astrocytic GABA Transporters

    DEFF Research Database (Denmark)

    Schousboe, Arne; Wellendorph, Petrine; Frølund, Bente

    2017-01-01

    , and several of these compounds have been shown to exhibit pronounced anticonvulsant activity in a variety of animal seizure models. As proof of concept of the validity of this drug development approach, one GABA-transport inhibitor, tiagabine, has been developed as a clinically active antiepileptic drug......Inactivation of GABA-mediated neurotransmission is achieved by high-affinity transporters located at both GABAergic neurons and the surrounding astrocytes. Early studies of the pharmacological properties of neuronal and glial GABA transporters suggested that different types of transporters might...... be expressed in the two cell types, and such a scenario was confirmed by the cloning of four distinctly different GABA transporters from a number of different species. These GABA-transport entities have been extensively characterized using a large number of GABA analogues of restricted conformation...

  8. Direct observation of electrogenic NH4(+) transport in ammonium transport (Amt) proteins.

    Science.gov (United States)

    Wacker, Tobias; Garcia-Celma, Juan J; Lewe, Philipp; Andrade, Susana L A

    2014-07-08

    Ammonium transport (Amt) proteins form a ubiquitous family of integral membrane proteins that specifically shuttle ammonium across membranes. In prokaryotes, archaea, and plants, Amts are used as environmental NH4(+) scavengers for uptake and assimilation of nitrogen. In the eukaryotic homologs, the Rhesus proteins, NH4(+)/NH3 transport is used instead in acid-base and pH homeostasis in kidney or NH4(+)/NH3 (and eventually CO2) detoxification in erythrocytes. Crystal structures and variant proteins are available, but the inherent challenges associated with the unambiguous identification of substrate and monitoring of transport events severely inhibit further progress in the field. Here we report a reliable in vitro assay that allows us to quantify the electrogenic capacity of Amt proteins. Using solid-supported membrane (SSM)-based electrophysiology, we have investigated the three Amt orthologs from the euryarchaeon Archaeoglobus fulgidus. Af-Amt1 and Af-Amt3 are electrogenic and transport the ammonium and methylammonium cation with high specificity. Transport is pH-dependent, with a steep decline at pH values of ∼5.0. Despite significant sequence homologies, functional differences between the three proteins became apparent. SSM electrophysiology provides a long-sought-after functional assay for the ubiquitous ammonium transporters.

  9. The binding sites for cocaine and dopamine in the dopamine transporter overlap

    DEFF Research Database (Denmark)

    Beuming, Thijs; Kniazeff, Julie; Bergmann, Marianne L

    2008-01-01

    Cocaine is a widely abused substance with psychostimulant effects that are attributed to inhibition of the dopamine transporter (DAT). We present molecular models for DAT binding of cocaine and cocaine analogs constructed from the high-resolution structure of the bacterial transporter homolog Leu......T. Our models suggest that the binding site for cocaine and cocaine analogs is deeply buried between transmembrane segments 1, 3, 6 and 8, and overlaps with the binding sites for the substrates dopamine and amphetamine, as well as for benztropine-like DAT inhibitors. We validated our models by detailed...... inhibition of dopamine transport by cocaine....

  10. Transport of radioactive wastes

    International Nuclear Information System (INIS)

    Stuller, C.

    2003-01-01

    In this article author describes the system of transport and processing of radioactive wastes from nuclear power of Slovenske elektrarne, plc. It is realized the assurance of transport of liquid and solid radioactive wastes to processing links from places of their formation, or of preliminary storage and consistent transports of treated radioactive wastes fixed in cement matrix of fibre-concrete container into Rebublic storage of radioactive wastes in Mochovce

  11. Transport of radioactive materials

    International Nuclear Information System (INIS)

    1991-07-01

    The purpose of this Norm is to establish, relating to the TRANSPORT OF RADIOACTIVE MATERIALS, safety and radiological protection requirements to ensure an adequate control level of the eventual exposure of persons, properties and environment to the ionizing radiation comprising: specifications on radioactive materials for transport; package type selection; specification of the package design and acceptance test requirements; arrangements relating to the transport itself; administrative requirements and responsibilities. (author)

  12. Radioactive material air transportation

    International Nuclear Information System (INIS)

    Pader y Terry, Claudio Cosme

    2002-01-01

    As function of the high aggregated value, safety regulations and the useful life time, the air transportation has been used more regularly because is fast, reliable, and by giving great security to the cargo. Based on the International Atomic Energy Agency (IAEA), the IATA (International Air Transportation Association) has reproduced in his dangerous goods manual (Dangerous Goods Regulations - DGR IATA), the regulation for the radioactive material air transportation. Those documents support this presentation

  13. Handling and Transport Problems

    Energy Technology Data Exchange (ETDEWEB)

    Pomarola, J. [Head of Technical Section, Atomic Energy Commission, Saclay (France); Savouyaud, J. [Head of Electro-Mechanical Sub-Division, Atomic Energy Commission, Saclay (France)

    1960-07-01

    Arrangements for special or dangerous transport operations by road arising out of the activities of the Atomic Energy Commission are made by the Works and Installations Division which acts in concert with the Monitoring and Protection Division (MPD) whenever radioactive substances or appliances are involved. In view of the risk of irradiation and contamination entailed in handling and transporting radioactive substances, including waste, a specialized transport and storage team has been formed as a complement to the emergency and decontamination teams.

  14. Transport Nuclear Liability Insurance

    International Nuclear Information System (INIS)

    Folens, M.

    2006-01-01

    Although transport of nuclear substances represents only a very small part of the global transport of dangerous goods, it takes place every day all over the world and it is part of our daily life. Transport of nuclear material takes also place at every stage of the nuclear fuel cycle; radioactive materials are carried out all over the world by all major modes of transport: sea, air, road and rail. Despite the large number of nuclear transports, they are not considered as posing a serious risk. A major nuclear incident is almost always associated with the operating of fixed installations such as nuclear power plants; just think about Three Mile Island and Chernobyl. This perception is strengthened by the absence so far of serious accidents in the nuclear transport sector and this finding is in fact proof of the very safe conditions of nuclear transport. But accidents can never be excluded entirely and in some cases damages could be as large as those caused by fixed installations. This means that protection of the interests of possible victims should also be covered in a correct way. That is why the special nuclear liability regime has also been developed to cover damage caused by a nuclear transport accident. As stated by Patrick Reyners, the prime motivation for originally adopting a special nuclear regime was the harmonisation of national legislation and that nowhere more than in the field of international transport operations is such harmonisation felt desirable . The international legal regime has been developed along two tracks, one based on the mode of transport and the other based on the notion of dangerous goods. The linkage between those two tracks is of permanent concern and the mode of transport is the key element to determine which international instrument should be applicable. The purpose of this paper is to briefly introduce the financial security provided by the insurance industry to cover the international nuclear liability regime for nuclear

  15. Freight transport and intermodality

    OpenAIRE

    Barbero Mañanes, Eduardo

    2010-01-01

    During recent decades, there has been very substantial growth in the freight transport sector. Freight transport is increasing faster than the economy or passenger transport. Demand is increasing more rapidly than supply and is resulting in environmental and social problems. Increasing congestion, too, is affecting efficient and reliable freight distribution, and consequently having a deleterious effect on local economies. Intermodality is therefore needed to make better use of alternative mo...

  16. Climate Change and Transportation

    OpenAIRE

    Yevdokimov, Yuri

    2010-01-01

    As stated at the beginning of this chapter, the relationship between transportation and climate is two-directional. Based on our statistical analysis performed for Canada, we can make some general conclusions about this relationship. On the one hand, transportation is one of the largest contributors to GHG emissions which, in turn, cause various changes in climate. On the other hand, these climate changes negatively affect transportation in terms of its infrastructure and operations. Therefor...

  17. Molecular mechanism of α-tocopheryl-phosphate transport across the cell membrane

    International Nuclear Information System (INIS)

    Negis, Yesim; Meydani, Mohsen; Zingg, Jean-Marc; Azzi, Angelo

    2007-01-01

    α-Tocopheryl-phosphate (α-TP) is synthesized and hydrolyzed in animal cells and tissues where it modulates several functions. α-TP is more potent than α-T in inhibiting cell proliferation, down-regulating CD36 transcription, inhibiting atherosclerotic plaque formation. Administration of α-TP to cells or animals requires its transfer through membranes, via a transporter. We show here that α-TP is passing the plasma membrane via a system that is inhibited by glibenclamide and probenecid, inhibitors of a number of transporters. Glibenclamide and probenecid prevent dose-dependently α-TP inhibition of cell proliferation. The two inhibitors act on ATP binding cassette (ABC) and organic anion transporters (OAT). Since ABC transporters function to export solutes and α-TP is transported into cells, it may be concluded that α-TP transport may occur via an OAT family member. Due to the protection by glibenclamide and probenecid on the α-TP induced cell growth inhibition it appears that α-TP acts after its uptake inside cells

  18. A Single Pair of Serotonergic Neurons Counteracts Serotonergic Inhibition of Ethanol Attraction in Drosophila.

    Science.gov (United States)

    Xu, Li; He, Jianzheng; Kaiser, Andrea; Gräber, Nikolas; Schläger, Laura; Ritze, Yvonne; Scholz, Henrike

    2016-01-01

    Attraction to ethanol is common in both flies and humans, but the neuromodulatory mechanisms underlying this innate attraction are not well understood. Here, we dissect the function of the key regulator of serotonin signaling-the serotonin transporter-in innate olfactory attraction to ethanol in Drosophila melanogaster. We generated a mutated version of the serotonin transporter that prolongs serotonin signaling in the synaptic cleft and is targeted via the Gal4 system to different sets of serotonergic neurons. We identified four serotonergic neurons that inhibit the olfactory attraction to ethanol and two additional neurons that counteract this inhibition by strengthening olfactory information. Our results reveal that compensation can occur on the circuit level and that serotonin has a bidirectional function in modulating the innate attraction to ethanol. Given the evolutionarily conserved nature of the serotonin transporter and serotonin, the bidirectional serotonergic mechanisms delineate a basic principle for how random behavior is switched into targeted approach behavior.

  19. Transport barriers in plasmas

    International Nuclear Information System (INIS)

    Caldas, I L; Szezech, J D Jr; Kroetz, T; Marcus, F A; Roberto, M; Viana, R L; Lopes, S R

    2012-01-01

    We discuss the creation of transport barriers in magnetically confined plasmas with non monotonic equilibrium radial profiles. These barriers reduce the transport in the shearless region (i.e., where the twist condition does not hold). For the chaotic motion of particles in an equilibrium electric field with a nonmonotonic radial profile, perturbed by electrostatic waves, we show that a nontwist transport barrier can be created in the plasma by modifying the electric field radial profile. We also show non twist barriers in chaotic magnetic field line transport in the plasma near to the tokamak wall with resonant modes due to electric currents in external coils.

  20. Urban transportation projects conceptualised:

    DEFF Research Database (Denmark)

    Pineda, Andres Felipe Valderrama

    is straightforward: transportation projects transform cities. The paradoxical reality thus is that a problem that has been traditionally conceptualized in technical terms (transportation engineering, transportation economics, planning theory, traffic engineering, urban planning, etc.), has tremendous consequences...... operation when discussing transportation projects in big cities. The tradition of Science and Technology Studies might have provided some clues. In the following paper we discuss the most prominent aspects of some theories in STS in order to understand and conceptualize the cases of Bogotá and Copenhagen...

  1. WASTE PACKAGE TRANSPORTER DESIGN

    International Nuclear Information System (INIS)

    Weddle, D.C.; Novotny, R.; Cron, J.

    1998-01-01

    The purpose of this Design Analysis is to develop preliminary design of the waste package transporter used for waste package (WP) transport and related functions in the subsurface repository. This analysis refines the conceptual design that was started in Phase I of the Viability Assessment. This analysis supports the development of a reliable emplacement concept and a retrieval concept for license application design. The scope of this analysis includes the following activities: (1) Assess features of the transporter design and evaluate alternative design solutions for mechanical components. (2) Develop mechanical equipment details for the transporter. (3) Prepare a preliminary structural evaluation for the transporter. (4) Identify and recommend the equipment design for waste package transport and related functions. (5) Investigate transport equipment interface tolerances. This analysis supports the development of the waste package transporter for the transport, emplacement, and retrieval of packaged radioactive waste forms in the subsurface repository. Once the waste containers are closed and accepted, the packaged radioactive waste forms are termed waste packages (WP). This terminology was finalized as this analysis neared completion; therefore, the term disposal container is used in several references (i.e., the System Description Document (SDD)) (Ref. 5.6). In this analysis and the applicable reference documents, the term ''disposal container'' is synonymous with ''waste package''

  2. WASTE PACKAGE TRANSPORTER DESIGN

    Energy Technology Data Exchange (ETDEWEB)

    D.C. Weddle; R. Novotny; J. Cron

    1998-09-23

    The purpose of this Design Analysis is to develop preliminary design of the waste package transporter used for waste package (WP) transport and related functions in the subsurface repository. This analysis refines the conceptual design that was started in Phase I of the Viability Assessment. This analysis supports the development of a reliable emplacement concept and a retrieval concept for license application design. The scope of this analysis includes the following activities: (1) Assess features of the transporter design and evaluate alternative design solutions for mechanical components. (2) Develop mechanical equipment details for the transporter. (3) Prepare a preliminary structural evaluation for the transporter. (4) Identify and recommend the equipment design for waste package transport and related functions. (5) Investigate transport equipment interface tolerances. This analysis supports the development of the waste package transporter for the transport, emplacement, and retrieval of packaged radioactive waste forms in the subsurface repository. Once the waste containers are closed and accepted, the packaged radioactive waste forms are termed waste packages (WP). This terminology was finalized as this analysis neared completion; therefore, the term disposal container is used in several references (i.e., the System Description Document (SDD)) (Ref. 5.6). In this analysis and the applicable reference documents, the term ''disposal container'' is synonymous with ''waste package''.

  3. EUROPEAN MARITIME TRANSPORT POLICY

    Directory of Open Access Journals (Sweden)

    Jerzy Kujawa

    2014-03-01

    Full Text Available The article describes the common EU policy on maritime transport, which comprises almost 80% of the volume of external trade of the Union and about 40% of internal transport needs. The first part of the paper presents the origins of the common maritime transport policy and the difficulties encountered during its initial formation. Subsequently, the evolution of the concepts of the policy and its current shape is discussed. The final, substantial part of the article describes the main aims and directions of the EU maritime transport policy and includes an evaluation of the effects of the policy.

  4. Intelligent Freigth Transport Systems

    DEFF Research Database (Denmark)

    Overø, Helene Martine; Larsen, Allan; Røpke, Stefan

    2009-01-01

    is to enhance the efficiency and lower the environmental impact in freight transport. In this paper, a pilot project involving real-time waste collection at a Danish waste collection company is described, and a solution approach is proposed. The problem corresponds to the dynamic version of the waste collection......The Danish innovation project entitled “Intelligent Freight Transport Systems” aims at developing prototype systems integrating public intelligent transport systems (ITS) with the technology in vehicles and equipment as well as the IT-systems at various transport companies. The objective...

  5. Moisture Transport in Wood

    DEFF Research Database (Denmark)

    Astrup, Thomas; Hansen, Kurt Kielsgaard; Hoffmeyer, Preben

    2005-01-01

    Modelling of moisture transport in wood is of great importance as most mechanical and physical properties of wood depend on moisture content. Moisture transport in porous materials is often described by Ficks second law, but several observations indicate that this does not apply very well to wood....... Recently at the Technical University of Denmark, Department of Civil Engineering, a new model for moisture transport in wood has been developed. The model divides the transport into two phases, namely water vapour in the cell lumens and bound water in the cell walls....

  6. UZ Colloid Transport Model

    International Nuclear Information System (INIS)

    McGraw, M.

    2000-01-01

    The UZ Colloid Transport model development plan states that the objective of this Analysis/Model Report (AMR) is to document the development of a model for simulating unsaturated colloid transport. This objective includes the following: (1) use of a process level model to evaluate the potential mechanisms for colloid transport at Yucca Mountain; (2) Provide ranges of parameters for significant colloid transport processes to Performance Assessment (PA) for the unsaturated zone (UZ); (3) Provide a basis for development of an abstracted model for use in PA calculations

  7. Heavy transport problems

    International Nuclear Information System (INIS)

    Haas, K.F.

    1975-01-01

    Assuming that very often a long transport route from the factory of the manufacturer to the provided site has to be reckoned with, in general only transport with a ship is possible. As each site is only called by a certain steamship line, at a very early stage of planning the nuclear power plant the possibilities and capacities of the lines and means of transportation under discussion should be investigated. In planning the unloading equipment at the site, due consideration should be given to the fact that at a later time this equipment should also be suitable for the transport of heavy components and spent fuel assemblies. (orig.) [de

  8. Heme transport and erythropoiesis

    Science.gov (United States)

    Yuan, Xiaojing; Fleming, Mark D.; Hamza, Iqbal

    2013-01-01

    In humans, systemic heme homeostasis is achieved via coordinated regulation of heme synthesis, transport and degradation. Although the heme biosynthesis and degradation pathways have been well characterized, the pathways for heme trafficking and incorporation into hemoproteins remains poorly understood. In the past few years, researchers have exploited genetic, cellular and biochemical tools, to identify heme transporters and, in the process, reveal unexpected functions for this elusive group of proteins. However, given the complexity of heme trafficking pathways, current knowledge of heme transporters is fragmented and sometimes contradictory. This review seeks to focus on recent studies on heme transporters with specific emphasis on their functions during erythropoiesis. PMID:23415705

  9. Hopping transport in solids

    CERN Document Server

    Pollak, M

    1991-01-01

    The hopping process, which differs substantially from conventional transport processes in crystals, is the central process in the transport phenomena discussed in this book. Throughout the book the term ``hopping'' is defined as the inelastic tunneling transfer of an electron between two localized electronic states centered at different locations. Such processes do not occur in conventional electronic transport in solids, since localized states are not compatible with the translational symmetry of crystals.The rapid growth of interest in hopping transport has followed in the footsteps of the

  10. Mitochondrial thiol modification by a targeted electrophile inhibits metabolism in breast adenocarcinoma cells by inhibiting enzyme activity and protein levels

    Directory of Open Access Journals (Sweden)

    M. Ryan Smith

    2016-08-01

    Full Text Available Many cancer cells follow an aberrant metabolic program to maintain energy for rapid cell proliferation. Metabolic reprogramming often involves the upregulation of glutaminolysis to generate reducing equivalents for the electron transport chain and amino acids for protein synthesis. Critical enzymes involved in metabolism possess a reactive thiolate group, which can be modified by certain oxidants. In the current study, we show that modification of mitochondrial protein thiols by a model compound, iodobutyl triphenylphosphonium (IBTP, decreased mitochondrial metabolism and ATP in MDA-MB 231 (MB231 breast adenocarcinoma cells up to 6 days after an initial 24 h treatment. Mitochondrial thiol modification also depressed oxygen consumption rates (OCR in a dose-dependent manner to a greater extent than a non-thiol modifying analog, suggesting that thiol reactivity is an important factor in the inhibition of cancer cell metabolism. In non-tumorigenic MCF-10A cells, IBTP also decreased OCR; however the extracellular acidification rate was significantly increased at all but the highest concentration (10 µM of IBTP indicating that thiol modification can have significantly different effects on bioenergetics in tumorigenic versus non-tumorigenic cells. ATP and other adenonucleotide levels were also decreased by thiol modification up to 6 days post-treatment, indicating a decreased overall energetic state in MB231 cells. Cellular proliferation of MB231 cells was also inhibited up to 6 days post-treatment with little change to cell viability. Targeted metabolomic analyses revealed that thiol modification caused depletion of both Krebs cycle and glutaminolysis intermediates. Further experiments revealed that the activity of the Krebs cycle enzyme, aconitase, was attenuated in response to thiol modification. Additionally, the inhibition of glutaminolysis corresponded to decreased glutaminase C (GAC protein levels, although other protein levels were

  11. Transepithelial transport of flavanone in intestinal Caco-2 cell monolayers

    International Nuclear Information System (INIS)

    Kobayashi, Shoko; Konishi, Yutaka

    2008-01-01

    Our recent study [S. Kobayashi, S. Tanabe, M. Sugiyama, Y. Konishi, Transepithelial transport of hesperetin and hesperidin in intestinal Caco-2 cell monolayers, Biochim. Biophys. Acta, 1778 (2008) 33-41] shows that the mechanism of absorption of hesperetin involves both proton-coupled active transport and transcellular passive diffusion. Here, as well as analyzing the cell permeability of hesperetin, we also study the transport of other flavanones, naringenin and eriodictyol, using Caco-2 cell monolayers. Similar to hesperetin mentioned, naringenin and eriodictyol showed proton-coupled polarized transport in apical-to-basolateral direction in non-saturable manner, constant permeation in the apical-to-basolateral direction (J ap→bl ) irrespective of the transepithelial electrical resistance (TER), and preferable distribution into the basolateral side after apical loading in the presence of a proton gradient. Furthermore, the proton-coupled J ap→bl of hesperetin, naringenin and eriodictyol, were inhibited by substrates of the monocarboxylic acid transporter (MCT), such as benzoic acid, but not by ferulic acid. In contrast, both benzoic and ferulic acids have no stimulatory effect on J ap→bl of each flavanone by trans-stimulation analysis. These results indicates that proton-driven active transport is commonly participated in the absorption of flavanone in general, and that its transport is presumed to be unique other than MCT-mediated transport for absorption of phenolic acids (PAs), sodium-dependent MCT (SMCT) nor anion exchanger-mediated transport

  12. Entanglement and inhibited quantum evolution

    Energy Technology Data Exchange (ETDEWEB)

    Toschek, P E; Balzer, Chr; Hannemann, Th; Wunderlich, Ch; Neuhauser, W [Universitaet Hamburg, Institut fuer Laser-Physik, Jungiusstrasse 9, D-20355 Hamburg (Germany)

    2003-03-14

    The evolution of a quantum system is impeded by the system's state being observed. A test on an ensemble neither proves the causal nexus nor discloses the nature of the inhibition. Two recent experiments that make use of sequential optical or microwave-optical double resonance on an individual trapped ion disprove a dynamical effect of back action by meter or environment. They rather indicate the ionic states involved in the evolution being entangled with the potentially recorded bivalued scattered-light signal.

  13. Molecular modeling of auxin transport inhibitors

    International Nuclear Information System (INIS)

    Gardner, G.; Black-Schaefer, C.; Bures, M.G.

    1990-01-01

    Molecular modeling techniques have been used to study the chemical and steric properties of auxin transport inhibitors. These bind to a specific site on the plant plasma membrane characterized by its affinity for N-1-naphthylphthalamic acid (NPA). A three-dimensional model was derived from critical features of ligands for the NPA receptor, and a suggested binding conformation is proposed. This model, along with three-dimensional structural searching techniques, was then used to search the Abbott corporate database of chemical structures. Of the 467 compounds that satisfied the search criteria, 77 representative molecules were evaluated for their ability to compete for [ 3 H]NPA binding to corn microsomal membranes. Nineteen showed activity that ranged from 16 to 85% of the maximum NPA binding. Four of the most active of these, from chemical classes not included in the original compound set, also inhibited polar auxin transport through corn coleoptile sections

  14. Acute inhibition of iron bioavailability by zinc: studies in humans.

    Science.gov (United States)

    Olivares, Manuel; Pizarro, Fernando; Ruz, Manuel; de Romaña, Daniel López

    2012-08-01

    Iron (Fe) and zinc (Zn) deficiencies constitute two of the most important nutritional and public health problems affecting developing countries. Combined supplementation or fortification with Zn and Fe are strategies that can be used to improve the Zn and Fe status of a population. However, there is concern about potential negative interactions between these two micronutrients due to a competitive binding to DMT1 and Zip14 transporter. Studies performed in humans have shown an inhibitory effect of Zn on Fe absorption when both minerals are given together as a solution in fasting conditions. We found that at low doses of iron (0.5 mg) the threshold for the inhibition of iron bioavailability was at a Zn:Fe wt/wt ratio ≥5.9:1, whereas at higher doses of Fe (10 mg) this inhibition occurred at 1:1 Zn:Fe wt/wt ratio. This differential response could be explained by the variation in the abundance of both cations as they compete for a limited number of shared transporters at the enterocyte. Conflicting results have been obtained when this interaction was studied in different food matrices. A negative interaction was not observed when Fe and Zn were provided in a composite hamburger meal, premature formula, human milk, or cow milk. A decrease on Fe absorption was observed in only 1 of 3 studies when Fe and Zn were supplied in wheat flour. The possibility of a negative interaction should be considered for supplementation or fortification programs with both microminerals.

  15. Histone Deacetylase Inhibition Restores Retinal Pigment Epithelium Function in Hyperglycemia.

    Directory of Open Access Journals (Sweden)

    Danielle Desjardins

    Full Text Available In diabetic individuals, macular edema is a major cause of vision loss. This condition is refractory to insulin therapy and has been attributed to metabolic memory. The retinal pigment epithelium (RPE is central to maintaining fluid balance in the retina, and this function is compromised by the activation of advanced glycation end-product receptors (RAGE. Here we provide evidence that acute administration of the RAGE agonist, glycated-albumin (gAlb or vascular endothelial growth factor (VEGF, increased histone deacetylase (HDAC activity in RPE cells. The administration of the class I/II HDAC inhibitor, trichostatin-A (TSA, suppressed gAlb-induced reductions in RPE transepithelial resistance (in vitro and fluid transport (in vivo. Systemic TSA also restored normal RPE fluid transport in rats with subchronic hyperglycemia. Both gAlb and VEGF increased HDAC activity and reduced acetyl-α-tubulin levels. Tubastatin-A, a relatively specific antagonist of HDAC6, inhibited gAlb-induced changes in RPE cell resistance. These data are consistent with the idea that RPE dysfunction following exposure to gAlb, VEGF, or hyperglycemia is associated with increased HDAC6 activity and decreased acetyl-α-tubulin. Therefore, we propose inhibiting HDAC6 in the RPE as a potential therapy for preserving normal fluid homeostasis in the hyperglycemic retina.

  16. Chloride sensing by WNK1 kinase involves inhibition of autophosphorylation

    Science.gov (United States)

    Piala, Alexander T.; Moon, Thomas M.; Akella, Radha; He, Haixia; Cobb, Melanie H.; Goldsmith, Elizabeth J.

    2014-01-01

    WNK1 [with no lysine (K)] is a serine-threonine kinase associated with a form of familial hypertension. WNK1 is at the top of a kinase cascade leading to phosphorylation of several cotransporters, in particular those transporting sodium, potassium, and chloride (NKCC), sodium and chloride (NCC), and potassium and chloride (KCC). The responsiveness of NKCC, NCC, and KCC to changes in extracellular chloride parallels their phosphorylation state, provoking the proposal that these transporters are controlled by a chloride-sensitive protein kinase. Here, we found that chloride stabilizes the inactive conformation of WNK1, preventing kinase autophosphorylation and activation. Crystallographic studies of inactive WNK1 in the presence of chloride revealed that chloride binds directly to the catalytic site, providing a basis for the unique position of the catalytic lysine. Mutagenesis of the chloride binding site rendered the kinase less sensitive to inhibition of autophosphorylation by chloride, validating the binding site. Thus, these data suggest that WNK1 functions as a chloride sensor through direct binding of a regulatory chloride ion to the active site, which inhibits autophosphorylation. PMID:24803536

  17. Canadian pipeline transportation system : transportation assessment

    International Nuclear Information System (INIS)

    2009-07-01

    In addition to regulating the construction and operation of 70,000 km of oil and natural gas pipelines in Canada, the National Energy Board (NEB) regulates the trade of natural gas, oil and natural gas liquids. This report provided an assessment of the Canadian hydrocarbon transportation system in relation to its ability to provide a robust energy infrastructure. Data was collected from NEB-regulated pipeline companies and a range of publicly available sources to determine if adequate pipeline capacity is in place to transport products to consumers. The NEB also used throughput and capacity information received from pipeline operators as well as members of the investment community. The study examined price differentials compared with firm service tolls for transportation paths, as well as capacity utilization on pipelines and the degree of apportionment on major oil pipelines. This review indicated that in general, the Canadian pipeline transportation system continues to work effectively, with adequate pipeline capacity in place to move products to consumers who need them. 9 tabs., 30 figs., 3 appendices.

  18. Behavioral inhibition and obsessive-compulsive disorder.

    Science.gov (United States)

    Coles, Meredith E; Schofield, Casey A; Pietrefesa, Ashley S

    2006-01-01

    Behavioral inhibition is frequently cited as a vulnerability factor for development of anxiety. However, few studies have examined the unique relationship between behavioral inhibition and obsessive-compulsive disorder (OCD). Therefore, the current study addressed the relationship between behavioral inhibition and OCD in a number of ways. In a large unselected student sample, frequency of current OC symptoms was significantly correlated with retrospective self-reports of total levels of childhood behavioral inhibition. In addition, frequency of current OC symptoms was also significantly correlated with both social and nonsocial components of behavioral inhibition. Further, there was evidence for a unique relationship between behavioral inhibition and OC symptoms beyond the relationship of behavioral inhibition and social anxiety. In addition, results showed that reports of childhood levels of behavioral inhibition significantly predicted levels of OCD symptoms in adulthood. Finally, preliminary evidence suggested that behavioral inhibition may be more strongly associated with some types of OC symptoms than others, and that overprotective parenting may moderate the impact of behavioral inhibition on OC symptoms. The current findings suggest the utility of additional research examining the role of behavioral inhibition in the etiology of OCD.

  19. Self-regulation, ego depletion, and inhibition.

    Science.gov (United States)

    Baumeister, Roy F

    2014-12-01

    Inhibition is a major form of self-regulation. As such, it depends on self-awareness and comparing oneself to standards and is also susceptible to fluctuations in willpower resources. Ego depletion is the state of reduced willpower caused by prior exertion of self-control. Ego depletion undermines inhibition both because restraints are weaker and because urges are felt more intensely than usual. Conscious inhibition of desires is a pervasive feature of everyday life and may be a requirement of life in civilized, cultural society, and in that sense it goes to the evolved core of human nature. Intentional inhibition not only restrains antisocial impulses but can also facilitate optimal performance, such as during test taking. Self-regulation and ego depletion- may also affect less intentional forms of inhibition, even chronic tendencies to inhibit. Broadly stated, inhibition is necessary for human social life and nearly all societies encourage and enforce it. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. The inhibition of the Human Immunodeficiency Virus type 1 activity by crude and purified human pregnancy plug mucus and mucins in an inhibition assay

    Directory of Open Access Journals (Sweden)

    Schoeman Leann

    2008-05-01

    Full Text Available Abstract Background The female reproductive tract is amongst the main routes for Human Immunodeficiency Virus (HIV transmission. Cervical mucus however is known to protect the female reproductive tract from bacterial invasion and fluid loss and regulates and facilitates sperm transport to the upper reproductive tract. The purpose of this study was to purify and characterize pregnancy plug mucins and determine their anti-HIV-1 activity in an HIV inhibition assay. Methods Pregnancy plug mucins were purified by caesium chloride density-gradient ultra-centrifugation and characterized by Western blotting analysis. The anti-HIV-1 activities of the crude pregnancy plug mucus and purified pregnancy plug mucins was determined by incubating them with HIV-1 prior to infection of the human T lymphoblastoid cell line (CEM SS cells. Results The pregnancy plug mucus had MUC1, MUC2, MUC5AC and MUC5B. The HIV inhibition assay revealed that while the purified pregnancy plug mucins inhibit HIV-1 activity by approximately 97.5%, the crude pregnancy plug mucus failed to inhibit HIV-1 activity. Conclusion Although it is not clear why the crude sample did not inhibit HIV-1 activity, it may be that the amount of mucins in the crude pregnancy plug mucus (which contains water, mucins, lipids, nucleic acids, lactoferrin, lysozyme, immunoglobulins and ions, is insufficient to cause viral inhibition or aggregation.

  1. Passenger transport research

    CSIR Research Space (South Africa)

    Mokonyama, Mathetha T

    2008-03-01

    Full Text Available In South Africa, airport and airline services epitomise what many would like to see in everyday public transport. The CSIR investigates what it will take to provide a commercial public transport service in South Africa which resembles commercial air...

  2. Bronchial mucus transport

    NARCIS (Netherlands)

    van der Schans, Cees P.

    Effective clearance of inhaled particles requires mucus production and continuous mucus transport from the lower airways to the oropharynx. Mucus production takes place mainly in the peripheral airways. Mucus transport is achieved by the action of the ciliated cells that cover the inner surface of

  3. Biofuels for sustainable transportation

    Energy Technology Data Exchange (ETDEWEB)

    Neufeld, S.

    2000-05-23

    Biomass is an attractive energy source, and transportation fuels made from biomass offer a number of benefits. Developing the technology to produce and use biofuels will create transportation fuel options that can positively impact the national energy security, the economy, and the environment. Biofuels include ethanol, methanol, biodiesel, biocrude, and methane.

  4. Emissions of road transport

    International Nuclear Information System (INIS)

    Maekelae, K.; Tuominen, A.

    2001-01-01

    Information on the emissions and energy consumption of different vehicles per transported amount of goods has up to last years been minimal. The unit emissions mean the amount of harmful compounds in the flue gases of a vehicle per service, time or energy unit. National three-year MOBILE 2-research program, started in 1999, determines the unit emissions of all the traffic sectors in Finland. VTT Building and Transport mainly carry out the research, but the Institute of Transportation Engineering of the Tampere University of Technology (TTKK) is responsible for a part of the research. The objective of the project is to create common rules for the determination of unit emissions values, and to determine the best possible values for Finnish conditions. Unit emission data is mainly needed for evaluation of the environmental impacts of production plants and other activities containing transportation of commodities. At the web sites of VTT Building and Transport there are about 60 pages of text and tables (about 4000 values) on unit emissions. The URL of the pages is http://www.vtt.fi/rte/projects/lipastoe/index.htm. These web pages present data on all the transportation sectors (road, railroad, water and air transportation), most of the materials concerning road transportation. Following compounds and values are included: CO, HC, NO x , particulates, SO 2 , CO 2 and energy consumption. Methane and nitrous oxide emissions values have also been presented

  5. Trajectory structures and transport

    International Nuclear Information System (INIS)

    Vlad, Madalina; Spineanu, Florin

    2004-01-01

    The special problem of transport in two-dimensional divergence-free stochastic velocity fields is studied by developing a statistical approach, the nested subensemble method. The nonlinear process of trapping determined by such fields generates trajectory structures whose statistical characteristics are determined. These structures strongly influence the transport

  6. Porters and neurotransmitter transporters

    NARCIS (Netherlands)

    Nelson, Nathan; Lill, H

    1994-01-01

    Uptake of neurotransmitters involves multiple transporters acting in different brain locations under different physiological conditions. The vesicular transporters are driven by a proton-motive force generated by a V-ATPase and their substrates are taken up via proton/substrate exchange. The plasma

  7. Nuclear materials transportation

    International Nuclear Information System (INIS)

    Ushakov, B.A.

    1986-01-01

    Various methods of nuclear materials transportation at different stages of the fuel cycle (U 3 O 8 , UF 6 production enrichment, fuel element manufacturing, storage) are considered. The advantages and drawbacks of railway, automobile, maritime and air transport are analyzed. Some types of containers are characterized

  8. Human peptide transporters

    DEFF Research Database (Denmark)

    Nielsen, Carsten Uhd; Brodin, Birger; Jørgensen, Flemming Steen

    2002-01-01

    Peptide transporters are epithelial solute carriers. Their functional role has been characterised in the small intestine and proximal tubules, where they are involved in absorption of dietary peptides and peptide reabsorption, respectively. Currently, two peptide transporters, PepT1 and PepT2, wh...

  9. Transport of plutonium nitrate

    International Nuclear Information System (INIS)

    1982-02-01

    This leaflet discusses the subject under the headings: why do we need plutonium; why must we transport it; what action is carried out; how is it moved; what are the risks. The transport of the material in specially designed containers, from Dounreay in Caithness by road and sea to Sellafield in Cumbria, is described. (U.K.)

  10. Electronic transport properties

    International Nuclear Information System (INIS)

    Young, W.H.

    1985-01-01

    The theory of the electron transport properties of liquid alkali metals is described. Conductivity coefficients, Boltzmann theory, Ziman theory, alkali form factors, Ziman theory and alkalis, Faber-Ziman alloy theory, Faber-Ziman theory and alkali-alkali methods, status of Ziman theory, and other transport properties, are all discussed. (UK)

  11. Transport and Sustainability

    DEFF Research Database (Denmark)

    Jørgensen, Kaj

    1997-01-01

    Ph.D. study of the scope for sustainable transport in Denmark, and particularly of the role of the motor vehicle in this context. The distribution of groceries is used as case study of the introduction of the motor vehicle in Denmark, concluding that this has resulted in increases of the transport...

  12. Macropores and macropore transport

    DEFF Research Database (Denmark)

    Iversen, Bo Vangsø; Lamandé, Mathieu; Torp, Søren Bent

    2012-01-01

    Preferential transport of water through soil macropores is a governing process in the facilitated transport of strongly sorbing compounds. The aim of this study was to investigate the relationships between macropore density and the hydraulic conductivity of the soil and to test the sampling...

  13. Graphene: corrosion-inhibiting coating.

    Science.gov (United States)

    Prasai, Dhiraj; Tuberquia, Juan Carlos; Harl, Robert R; Jennings, G Kane; Rogers, Bridget R; Bolotin, Kirill I

    2012-02-28

    We report the use of atomically thin layers of graphene as a protective coating that inhibits corrosion of underlying metals. Here, we employ electrochemical methods to study the corrosion inhibition of copper and nickel by either growing graphene on these metals, or by mechanically transferring multilayer graphene onto them. Cyclic voltammetry measurements reveal that the graphene coating effectively suppresses metal oxidation and oxygen reduction. Electrochemical impedance spectroscopy measurements suggest that while graphene itself is not damaged, the metal under it is corroded at cracks in the graphene film. Finally, we use Tafel analysis to quantify the corrosion rates of samples with and without graphene coatings. These results indicate that copper films coated with graphene grown via chemical vapor deposition are corroded 7 times slower in an aerated Na(2)SO(4) solution as compared to the corrosion rate of bare copper. Tafel analysis reveals that nickel with a multilayer graphene film grown on it corrodes 20 times slower while nickel surfaces coated with four layers of mechanically transferred graphene corrode 4 times slower than bare nickel. These findings establish graphene as the thinnest known corrosion-protecting coating.

  14. Action inhibition in Tourette syndrome.

    Science.gov (United States)

    Ganos, Christos; Kühn, Simone; Kahl, Ursula; Schunke, Odette; Feldheim, Jan; Gerloff, Christian; Roessner, Veit; Bäumer, Tobias; Thomalla, Götz; Haggard, Patrick; Münchau, Alexander

    2014-10-01

    Tourette syndrome is a neuropsychiatric disorder characterized by tics. Tic generation is often linked to dysfunction of inhibitory brain networks. Some previous behavioral studies found deficiencies in inhibitory motor control in Tourette syndrome, but others suggested normal or even better-than-normal performance. Furthermore, neural correlates of action inhibition in these patients are poorly understood. We performed event-related functional magnetic resonance imaging during a stop-signal reaction-time task in 14 uncomplicated adult Tourette patients and 15 healthy controls. In patients, we correlated activations in stop-signal reaction-time task with their individual motor tic frequency. Task performance was similar in both groups. Activation of dorsal premotor cortex was stronger in the StopSuccess than in the Go condition in healthy controls. This pattern was reversed in Tourette patients. A significant positive correlation was present between motor tic frequency and activations in the supplementary motor area during StopSuccess versus Go in patients. Inhibitory brain networks differ between healthy controls and Tourette patients. In the latter the supplementary motor area is probably a key relay of inhibitory processes mediating both suppression of tics and inhibition of voluntary action. © 2014 International Parkinson and Movement Disorder Society.

  15. Transport in the Nordic countries

    International Nuclear Information System (INIS)

    Gustafsson, B.; Pettersson, S.; Vilkamo, S.

    1989-01-01

    Transport of radioactive material from different fields of operation is well advanced in the Nordic countries: waste from the medical sector, industry, research, and now in increasing amounts from reactor operation, including spent fuel. In the future, waste from decommissioning will also be transported. This report gives the amount of radioactive waste material to be transported in the Nordic countries. Transport routes, transport containers, and transport systems are described. Legislations and transport regulatins are discussed. (author)

  16. Cationic Polymers Inhibit the Conductance of Lysenin Channels

    Directory of Open Access Journals (Sweden)

    Daniel Fologea

    2013-01-01

    Full Text Available The pore-forming toxin lysenin self-assembles large and stable conductance channels in natural and artificial lipid membranes. The lysenin channels exhibit unique regulation capabilities, which open unexplored possibilities to control the transport of ions and molecules through artificial and natural lipid membranes. Our investigations demonstrate that the positively charged polymers polyethyleneimine and chitosan inhibit the conducting properties of lysenin channels inserted into planar lipid membranes. The preservation of the inhibitory effect following addition of charged polymers on either side of the supporting membrane suggests the presence of multiple binding sites within the channel's structure and a multistep inhibition mechanism that involves binding and trapping. Complete blockage of the binding sites with divalent cations prevents further inhibition in conductance induced by the addition of cationic polymers and supports the hypothesis that the binding sites are identical for both multivalent metal cations and charged polymers. The investigation at the single-channel level has shown distinct complete blockages of each of the inserted channels. These findings reveal key structural characteristics which may provide insight into lysenin’s functionality while opening innovative approaches for the development of applications such as transient cell permeabilization and advanced drug delivery systems.

  17. Neuroglobin Overexpression Inhibits AMPK Signaling and Promotes Cell Anabolism.

    Science.gov (United States)

    Cai, Bin; Li, Wenjun; Mao, XiaoOu; Winters, Ali; Ryou, Myoung-Gwi; Liu, Ran; Greenberg, David A; Wang, Ning; Jin, Kunlin; Yang, Shao-Hua

    2016-03-01

    Neuroglobin (Ngb) is a recently discovered globin with preferential localization to neurons. Growing evidence indicates that Ngb has distinct physiological functions separate from the oxygen storage and transport roles of other globins, such as hemoglobin and myoglobin. We found increased ATP production and decreased glycolysis in Ngb-overexpressing immortalized murine hippocampal cell line (HT-22), in parallel with inhibition of AMP-activated protein kinase (AMPK) signaling and activation of acetyl-CoA carboxylase (ACC). In addition, lipid and glycogen content was increased in Ngb-overexpressing HT-22 cells. AMPK signaling was also inhibited in the brain and heart from Ngb-overexpressing transgenic mice. Although Ngb overexpression did not change glycogen content in whole brain, glycogen synthase was activated in cortical neurons of Ngb-overexpressing mouse brain and Ngb overexpression primary neurons. Moreover, lipid and glycogen content was increased in hearts derived from Ngb-overexpressing mice. These findings suggest that Ngb functions as a metabolic regulator and enhances cellular anabolism through the inhibition of AMPK signaling.

  18. Identification of a disulfide bridge important for transport function of SNAT4 neutral amino acid transporter.

    Directory of Open Access Journals (Sweden)

    Rugmani Padmanabhan Iyer

    Full Text Available SNAT4 is a member of system N/A amino acid transport family that primarily expresses in liver and muscles and mediates the transport of L-alanine. However, little is known about the structure and function of the SNAT family of transporters. In this study, we showed a dose-dependent inhibition in transporter activity of SNAT4 with the treatment of reducing agents, dithiothreitol (DTT and Tris(2-carboxyethylphosphine (TCEP, indicating the possible involvement of disulfide bridge(s. Mutation of residue Cys-232, and the two highly conserved residues Cys-249 and Cys-321, compromised the transport function of SNAT4. However, this reduction was not caused by the decrease of SNAT4 on the cell surface since the cysteine-null mutant generated by replacing all five cysteines with alanine was equally capable of being expressed on the cell surface as wild-type SNAT4. Interestingly, by retaining two cysteine residues, 249 and 321, a significant level of L-alanine uptake was restored, indicating the possible formation of disulfide bond between these two conserved residues. Biotinylation crosslinking of free thiol groups with MTSEA-biotin provided direct evidence for the existence of a disulfide bridge between Cys-249 and Cys-321. Moreover, in the presence of DTT or TCEP, transport activity of the mutant retaining Cys-249 and Cys-321 was reduced in a dose-dependent manner and this reduction is gradually recovered with increased concentration of H2O2. Disruption of the disulfide bridge also decreased the transport of L-arginine, but to a lesser degree than that of L-alanine. Together, these results suggest that cysteine residues 249 and 321 form a disulfide bridge, which plays an important role in substrate transport but has no effect on trafficking of SNAT4 to the cell surface.

  19. Planning Public Transport

    DEFF Research Database (Denmark)

    Andersen, Jonas Lohmann Elkjær; Landex, Alex

    2009-01-01

    This good practice guide is composed for the master course 13120 Public Transport Planning held at the Department of Transport, Technical University of Denmark. It is intended to use as guide in the different planning aspects and assignments of the course. Since the course is about the planning...... of new public transport infrastructure this guide also focuses on the planning of new infrastructure. Furthermore, the new infrastructure in the course is expected to be a light rail and even though this guide aims at being general for public transport some of the issues evidently become more relevant...... will enable a capability for planning both bus and rail. The guide is build as a full sketch investigation of a new public transport project ranging chronological from project clarification to physical and timetable planning to traffic modeling and project appraisal. The same steps that are expected...

  20. Porters and neurotransmitter transporters.

    Science.gov (United States)

    Nelson, N; Lill, H

    1994-11-01

    Uptake of neurotransmitters involves multiple transporters acting in different brain locations under different physiological conditions. The vesicular transporters are driven by a proton-motive force generated by a V-ATPase and their substrates are taken up via proton/substrate exchange. The plasma membrane transporters are driven by an electrochemical gradient of sodium generated by a Na+/K(+)-ATPase. Two distinct families of transporters were identified in this group. One cotransports sodium with glutamate and other amino acids and requires additionally an outwardly directed potassium gradient. The second cotransports sodium, chloride and a variety of neurotransmitters, including gamma-aminobutyric acid (GABA), glycine and monoamines. Genes and cDNA encoding several members of the latter family have been cloned and studied in detail. The structure and function as well as the evolutionary relationships among these neurotransmitter transporters are discussed.

  1. Fuel transporting device

    International Nuclear Information System (INIS)

    Shiratori, Hirozo.

    1979-01-01

    Purpose: In a liquid-metal cooled reactor, to reduce the waiting time of fuel handling apparatuses and shorten the fuel exchange time. Constitution: A fuel transporting machine is arranged between a reactor vessel and an out-pile storage tank, thereby dividing the transportation line of the pot for contracting fuel and transporting the same. By assuming such a construction, the flow of fuel transportation which has heretofore been carried out through fuel transportation pipes is not limited to one direction but the take-out of fuels from the reactor and the take-in thereof from the storage tank can be carried out constantly, and much time is not required for fuel exchange. (Kamimura, M.)

  2. Fuelling tomorrow's transport

    International Nuclear Information System (INIS)

    Cadwallader, S.; Donovan, N.

    1995-11-01

    Fuelling Tomorrow's Transport provides a thorough analysis of key industry trends; developments in technology, fuel use and efficiency; environmental and legislative constraints; and company and governmental policy. It discusses in detail the changes facing the transport industry and analyses how the various technological, political and economic developments will affect the industry into the next century. Key issues addressed include: current and future fuel use in road, marine and aviation transport; growth in the transport sector and the impact on the oil market; likely scenarios for future transport fuelling; the latest developments in alternative fuels and engines, including electricity, natural gas, nuclear power and liquid hydrogen, and the commercial feasibility of these technologies; government policy and current and proposed legislative and fiscal incentives for the development and take-up of alternative fuels and engines; the driving force of the environmental debate; the current research and development programmes of individual companies; and the commercial openings offered by these developments. (author)

  3. Transport, environment and sustainability

    DEFF Research Database (Denmark)

    Joumard, Robert; Gudmundsson, Henrik; Kehagia, Fotini

    2010-01-01

    This report is the final report of the action COST 356 'EST - Towards the definition of a measurable environmentally sustainable transport'. It tries to answer the following questions: How can environmental impacts of transport be measured? How can measurements be transformed into operational...... indicators? How can several indicators be jointly considered? And how can indicators be used in planning and decision making? Firstly we provide definition of 'indicator of environmental sustainability in transport'. The functions, strengths and weaknesses of indicators as measurement tools, and as decision...... support tools are discussed. We define what "environmental sustainability in transport" may mean through the transport system, the concepts of sustainable development and of environment. The concept of 'chain of causality' between a source and a final target is developed, as a common reference...

  4. Endothelial Thermotolerance Impairs Nanoparticle Transport in Tumors.

    Science.gov (United States)

    Bagley, Alexander F; Scherz-Shouval, Ruth; Galie, Peter A; Zhang, Angela Q; Wyckoff, Jeffrey; Whitesell, Luke; Chen, Christopher S; Lindquist, Susan; Bhatia, Sangeeta N

    2015-08-15

    The delivery of diagnostic and therapeutic agents to solid tumors is limited by physical transport barriers within tumors, and such restrictions directly contribute to decreased therapeutic efficacy and the emergence of drug resistance. Nanomaterials designed to perturb the local tumor environment with precise spatiotemporal control have demonstrated potential to enhance drug delivery in preclinical models. Here, we investigated the ability of one class of heat-generating nanomaterials called plasmonic nanoantennae to enhance tumor transport in a xenograft model of ovarian cancer. We observed a temperature-dependent increase in the transport of diagnostic nanoparticles into tumors. However, a transient, reversible reduction in this enhanced transport was seen upon reexposure to heating, consistent with the development of vascular thermotolerance. Harnessing these observations, we designed an improved treatment protocol combining plasmonic nanoantennae with diffusion-limited chemotherapies. Using a microfluidic endothelial model and genetic tools to inhibit the heat-shock response, we found that the ability of thermal preconditioning to limit heat-induced cytoskeletal disruption is an important component of vascular thermotolerance. This work, therefore, highlights the clinical relevance of cellular adaptations to nanomaterials and identifies molecular pathways whose modulation could improve the exposure of tumors to therapeutic agents. ©2015 American Association for Cancer Research.

  5. Cadmium interacts with the transport of essential micronutrients in the mammary gland-A study in rural Bangladeshi women

    International Nuclear Information System (INIS)

    Kippler, Maria; Loennerdal, Bo; Goessler, Walter; Ekstroem, Eva-Charlotte; El Arifeen, Shams; Vahter, Marie

    2009-01-01

    Although the concentrations of the toxic metal cadmium in breast milk are generally low ( s = 0.56; p s = 0.55; p s = -0.17; p = 0.05), indicating that cadmium inhibits the transport of calcium to breast milk. In conclusion, the present study may indicate that cadmium shares common transporters with iron and manganese for transfer to breast milk, but inhibits secretion of calcium to breast milk

  6. SEP-225289 serotonin and dopamine transporter occupancy: a PET study.

    Science.gov (United States)

    DeLorenzo, Christine; Lichenstein, Sarah; Schaefer, Karen; Dunn, Judith; Marshall, Randall; Organisak, Lisa; Kharidia, Jahnavi; Robertson, Brigitte; Mann, J John; Parsey, Ramin V

    2011-07-01

    SEP-225289 is a novel compound that, based on in vitro potencies for transporter function, potentially inhibits reuptake at dopamine, norepinephrine, and serotonin transporters. An open-label PET study was conducted during the development of SEP-225289 to investigate its dopamine and serotonin transporter occupancy. Different single doses of SEP-225289 were administered to healthy volunteers in 3 cohorts: 8 mg (n = 7), 12 mg (n = 5), and 16 mg (n = 7). PET was performed before and approximately 24 h after oral administration of SEP-225289, to assess occupancy at trough levels. Dopamine and serotonin transporter occupancies were estimated from PET using (11)C-N-(3-iodoprop-2E-enyl)-2β-carbomethoxy-3β-(4-methylphenyl)nortropane ((11)C-PE2I) and (11)C-N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine ((11)C-DASB), respectively. Plasma concentration of SEP-225289 was assessed before ligand injection, and subjects were monitored for adverse events. Average dopamine and serotonin transporter occupancies increased with increasing doses of SEP-225289. Mean dopamine and serotonin transporter occupancies were 33% ± 11% and 2% ± 13%, respectively, for 8 mg; 44% ± 4% and 9% ± 10%, respectively, for 12 mg; and 49% ± 7% and 14% ± 15%, respectively, for 16 mg. On the basis of the relationship between occupancy and plasma concentration, dopamine transporter IC(50) (the plasma concentration of drug at 50% occupancy) was determined (4.5 ng/mL) and maximum dopamine transporter occupancy was extrapolated (85%); however, low serotonin transporter occupancy prevented similar serotonin transporter calculations. No serious adverse events were reported. At the doses evaluated, occupancy of the dopamine transporter was significantly higher than that of the serotonin transporter, despite similar in vitro potencies, confirming that, in addition to in vitro assays, PET occupancy studies can be instrumental to the drug development process by informing early decisions about

  7. Flavonoids as modulators of metabolic enzymes and drug transporters.

    Science.gov (United States)

    Miron, Anca; Aprotosoaie, Ana Clara; Trifan, Adriana; Xiao, Jianbo

    2017-06-01

    Flavonoids, natural compounds found in plants and in plant-derived foods and beverages, have been extensively studied with regard to their capacity to modulate metabolic enzymes and drug transporters. In vitro, flavonoids predominantly inhibit the major phase I drug-metabolizing enzyme CYP450 3A4 and the enzymes responsible for the bioactivation of procarcinogens (CYP1 enzymes) and upregulate the enzymes involved in carcinogen detoxification (UDP-glucuronosyltransferases, glutathione S-transferases (GSTs)). Flavonoids have been reported to inhibit ATP-binding cassette (ABC) transporters (multidrug resistance (MDR)-associated proteins, breast cancer-resistance protein) that contribute to the development of MDR. P-glycoprotein, an ABC transporter that limits drug bioavailability and also induces MDR, was differently modulated by flavonoids. Flavonoids and their phase II metabolites (sulfates, glucuronides) inhibit organic anion transporters involved in the tubular uptake of nephrotoxic compounds. In vivo studies have partially confirmed in vitro findings, suggesting that the mechanisms underlying the modulatory effects of flavonoids are complex and difficult to predict in vivo. Data summarized in this review strongly support the view that flavonoids are promising candidates for the enhancement of oral drug bioavailability, chemoprevention, and reversal of MDR. © 2017 New York Academy of Sciences.

  8. Logistic innovations in transport

    Directory of Open Access Journals (Sweden)

    Mirosław Antonowicz

    2014-03-01

    Full Text Available Introduction: The article discusses the issue of logistic innovations in transport. The essentials of logistic innovations in transport together with some examples of specific innovations are presented. The role of the client's needs in transport innovations is indicated. The most vital postulates affecting the innovativeness of shipping companies and derived from the author's experience as well as scholarly publications, are time, safety, reliability as well as comprehensiveness of service offer. Following the analysis of the issue, and on the grounds of Kaizen's and Lean's method, the concept of continuous innovations is suggested as very useful for the development of transport. The potential of clusters as the source of logistic innovations in transport is emphasised. Methods: The discussion of the issue was preceded by the author's analysis of written sources on innovativeness, the evaluation of ratings of innovativeness as well as the analysis of rewarded innovative solutions in transport subsequent to the businesses participation in the programme of innovative solutions in transport. The role of innovation practical business operations is argued following the analysis of some strategic documents such as: 2011 White Paper and the Strategy for the Development of Transport by 2020 adopted by the Polish government in 2013. Aim: The aim of the article is to present the role and significance of the issue of logistic innovations in transport and to cite instances of practical solutions implemented by shipping companies, the solutions which resulted in measurable effects. Following the author's observation of the instances of innovative solutions as well as his analysis of the ratings of innovativeness, the article aims to present the conclusions as for the specific kinds of activities which are indispensable to foster innovativeness in transport. Conclusions: The conclusions derived from the author's analyses and observations show that logistic

  9. Shoot-supplied ammonium targets the root auxin influx carrier AUX1 and inhibits lateral root emergence in Arabidopsis

    KAUST Repository

    Li, Baohai

    2011-03-24

    Deposition of ammonium (NH4 +) from the atmosphere is a substantial environmental problem. While toxicity resulting from root exposure to NH4 + is well studied, little is known about how shoot-supplied ammonium (SSA) affects root growth. In this study, we show that SSA significantly affects lateral root (LR) development. We show that SSA inhibits lateral root primordium (LRP) emergence, but not LRP initiation, resulting in significantly impaired LR number. We show that the inhibition is independent of abscisic acid (ABA) signalling and sucrose uptake in shoots but relates to the auxin response in roots. Expression analyses of an auxin-responsive reporter, DR5:GUS, and direct assays of auxin transport demonstrated that SSA inhibits root acropetal (rootward) auxin transport while not affecting basipetal (shootward) transport or auxin sensitivity of root cells. Mutant analyses indicated that the auxin influx carrier AUX1, but not the auxin efflux carriers PIN-FORMED (PIN)1 or PIN2, is required for this inhibition of LRP emergence and the observed auxin response. We found that AUX1 expression was modulated by SSA in vascular tissues rather than LR cap cells in roots. Taken together, our results suggest that SSA inhibits LRP emergence in Arabidopsis by interfering with AUX1-dependent auxin transport from shoot to root. © 2011 Blackwell Publishing Ltd.

  10. Transportation Consumer Education Curriculum Guide.

    Science.gov (United States)

    Finn, Peter; And Others

    Materials in this curriculum guide represent a selection of the major transportation consumer topics and ideas and are designed to set the stage for more intensive transportation consumer education curriculum development and teacher efforts. (Eleven manuals covering the four transportation topics of public transportation, transportation and the…

  11. Children and transportation

    Energy Technology Data Exchange (ETDEWEB)

    Anon

    2003-12-09

    This issue of the 'Sustainable Transportation Monitor', published by the Centre for Sustainable Transportation located in Mississauga, Ontario, reports on key findings from a project involving children and transportation in the Halton and Peel regions of Ontario, recently completed by the Centre. Excerpts from the report summarized in this issue include data on children's travel in Halton and Peel, and a discussion on possible contribution of transport practices to the growing incidence of obesity among Canadian children. Results of the study indicate that until about age 18, travel by children on schooldays is dominated by the journey to and from school. School bus is the choice of 28 per cent, and passenger car by 23 per cent among 11-to-14- year-olds; the share of travel by car is larger for older young people and also likely larger among 6-to-10-year-olds. Physical inactivity has been highlighted as the contributing factor to excess body weight and obesity in this, and other studies. Data collected for this study corroborates the findings of other studies by showing a positive correlation between obesity and transport energy use in 18 affluent countries, suggesting that a high level of use of motorized transport contributes to inactivity and body weight gain. Several alternate means of transportation, with the potential to combat obesity, are proposed. 46 refs.

  12. Canadian hydrocarbon transportation system : transportation assessment

    International Nuclear Information System (INIS)

    2006-06-01

    This document provided an assessment of the Canadian hydrocarbon transportation system. In addition to regulating the construction and operation of Canada's 45,000 km of pipeline that cross international and provincial borders, Canada's National Energy Board (NEB) regulates the trade of natural gas, oil and natural gas liquids. The ability of pipelines to delivery this energy is critical to the country's economic prosperity. The pipeline system includes large-diameter, cross-country, high-pressure natural gas pipelines, low-pressure crude oil and oil products pipelines and small-diameter pipelines. In order to assess the hydrocarbon transportation system, staff at the NEB collected data from pipeline companies and a range of publicly available sources. The Board also held discussions with members of the investment community regarding capital markets and emerging issues. The assessment focused largely on evaluating whether Canadians benefit from an efficient energy infrastructure and markets. The safety and environmental integrity of the pipeline system was also evaluated. The current adequacy of pipeline capacity was assessed based on price differentials compared with firm service tolls for major transportation paths; capacity utilization on pipelines; and, the degree of apportionment on major oil pipelines. The NEB concluded that the Canadian hydrocarbon transportation system is working effectively, with an adequate capacity in place on existing natural gas pipelines, but with a tight capacity on oil pipelines. It was noted that shippers continue to indicate that they are reasonably satisfied with the services provided by pipeline companies and that the NEB-regulated pipeline companies are financially stable. 14 refs, 11 tabs., 28 figs., 4 appendices

  13. Transports and environment; Transports et environnements

    Energy Technology Data Exchange (ETDEWEB)

    Anon,

    2004-07-01

    In the framework of the greenhouse gases reduction, this study proposes many advices to control the fuel consumption of the vehicles and to change habits in the transportation sector. It presents also the alternatives to the pollutant today vehicles in the domain of the vehicles and buses fuels but also the new motors. Many Internet addresses are provided to complete the presentation. (A.L.B.)

  14. Source to sink transport and regulation by environmental factors

    Directory of Open Access Journals (Sweden)

    Remi eLemoine

    2013-07-01

    Full Text Available Source-to-sink transport of sugar is one of the major determinants of plant growth and relies on the efficient and controlled distribution of sucrose (and some other sugars such as raffinose and polyols across plant organs through the phloem. However, sugar transport through the phloem can be affected by many environmental factors that alter source/sink relationships. In this paper, we summarize current knowledge about the phloem transport mechanisms and review the effects of several abiotic (water and salt stress, mineral deficiency, CO2, light, temperature, air and soil pollutants and biotic (mutualistic and pathogenic microbes, viruses, aphids and parasitic plants factors. Concerning abiotic constraints, alteration of the distribution of sugar among sinks is often reported, with some sinks as roots favoured in case of mineral deficiency. Many of these constraints impair the transport function of the phloem but the exact mechanisms are far from being completely known. Phloem integrity can be disrupted (e.g. by callose deposition and under certain conditions, phloem transport is affected, earlier than photosynthesis. Photosynthesis inhibition could result from the increase in sugar concentration due to phloem transport decrease. Biotic interactions (aphids, fungi, viruses… also affect crop plant productivity. Recent breakthroughs have identified some of the sugar transporters involved in these interactions on the host and pathogen sides. The different data are discussed in relation to the phloem transport pathways. When possible, the link with current knowledge on the pathways at the molecular level will be highlighted.

  15. Membrane Transporters: Structure, Function and Targets for Drug Design

    Science.gov (United States)

    Ravna, Aina W.; Sager, Georg; Dahl, Svein G.; Sylte, Ingebrigt

    Current therapeutic drugs act on four main types of molecular targets: enzymes, receptors, ion channels and transporters, among which a major part (60-70%) are membrane proteins. This review discusses the molecular structures and potential impact of membrane transporter proteins on new drug discovery. The three-dimensional (3D) molecular structure of a protein contains information about the active site and possible ligand binding, and about evolutionary relationships within the protein family. Transporters have a recognition site for a particular substrate, which may be used as a target for drugs inhibiting the transporter or acting as a false substrate. Three groups of transporters have particular interest as drug targets: the major facilitator superfamily, which includes almost 4000 different proteins transporting sugars, polyols, drugs, neurotransmitters, metabolites, amino acids, peptides, organic and inorganic anions and many other substrates; the ATP-binding cassette superfamily, which plays an important role in multidrug resistance in cancer chemotherapy; and the neurotransmitter:sodium symporter family, which includes the molecular targets for some of the most widely used psychotropic drugs. Recent technical advances have increased the number of known 3D structures of membrane transporters, and demonstrated that they form a divergent group of proteins with large conformational flexibility which facilitates transport of the substrate.

  16. Transport of hazardous goods

    International Nuclear Information System (INIS)

    1989-01-01

    The course 'Transport of hazardous goods' was held in Berlin in November 1988 in cooperation with the Bundesanstalt fuer Materialforschung und -pruefung. From all lecturs, two are recorded separately: 'Safety of tank trucks - requirements on the tank, development possibiities of active and passive safety' and 'Requirements on the transport of radioactive materials - possible derivations for other hazardous goods'. The other lectures deal with hazardous goods law, requirements on packinging, risk assessment, railroad transport, hazardous goods road network, insurance matters, EC regulations, and waste tourism. (HSCH) [de

  17. TRANSPORTATION SYSTEM REQUIREMENTS DOCUMENT

    International Nuclear Information System (INIS)

    2004-01-01

    This document establishes the Transportation system requirements for the U.S. Department of Energy's (DOE's) Civilian Radioactive Waste Management System (CRWMS). These requirements are derived from the Civilian Radioactive Waste Management System Requirements Document (CRD). The Transportation System Requirements Document (TSRD) was developed in accordance with LP-3.1Q-OCRWM, Preparation, Review, and Approval of Office of National Transportation Level-2 Baseline Requirements. As illustrated in Figure 1, the TSRD forms a part of the DOE Office of Civilian Radioactive Waste Management (OCRWM) Technical Baseline

  18. Transport in stellarators

    International Nuclear Information System (INIS)

    Maassberg, H.; Brakel, R.; Burhenn, R.; Gasparino, U.; Grigull, P.; Kick, M.; Kuehner, G.; Ringler, H.; Sardei, F.; Stroth, U.; Weller, A.

    1993-01-01

    The local electron and ion heat transport as well as the particle and impurity transport properties in stellarators are reviewed. In this context, neoclassical theory is used as a guideline for the comparison of the experimental results of the quite different confinement concepts. At sufficiently high temperatures depending on the specific magnetic configuration, neoclassical predictions are confirmed by experimental findings. The confinement properties in the LMFP collisionality regime are discussed with respect to the next stellarator generation, for which at higher temperatures the neoclassical transport is expected to become more important. (orig.)

  19. CNG transport opportunities

    International Nuclear Information System (INIS)

    Anon

    2000-01-01

    The recent announcement by the Australian Government of funding for a dramatic increase in supply infrastructure for Compressed Natural Gas (CNG) powered vehicles has shored up predictions that natural gas will achieve a thirty-fold increase in its share of the Australian transport energy market by 2015. This projection, would put sales of natural gas for transport fuel in the year 2014/15 at about 10% of current retail sales across the nation. In the general transport sector, the lower particulate and noise pollution, compared with diesel-powered vehicles, is a significant advantage

  20. Means of Transport

    DEFF Research Database (Denmark)

    Balle, Søren Hattesen

    The car is probably one of the most central signifiers of modern scientific and technological progress. Not only did its introduction in early 20th century America quite literally move scientific progress into the street, it also provided its increasing number of users with new and technologically....... According to film theorist Julian Smith, the automobile has been just as much “embraced … as a form of emotional transport, the state or condition of being transported by ecstasy” as “perceived as a mode of transportation in the primary and ordinary sense of the word.” This paper analyses the ways in which...

  1. Transport Coefficients of Fluids

    CERN Document Server

    Eu, Byung Chan

    2006-01-01

    Until recently the formal statistical mechanical approach offered no practicable method for computing the transport coefficients of liquids, and so most practitioners had to resort to empirical fitting formulas. This has now changed, as demonstrated in this innovative monograph. The author presents and applies new methods based on statistical mechanics for calculating the transport coefficients of simple and complex liquids over wide ranges of density and temperature. These molecular theories enable the transport coefficients to be calculated in terms of equilibrium thermodynamic properties, and the results are shown to account satisfactorily for experimental observations, including even the non-Newtonian behavior of fluids far from equilibrium.

  2. Ornithine transport and exchange in Streptococcus lactis

    International Nuclear Information System (INIS)

    Thompson, J.

    1987-01-01

    Resting cells of Streptococcus lactis 133 appeared to accumulate [ 14 C]ornithine to a high concentration in the absence of an exogenous energy source. However, analysis of intracellular amino acid pool constituents and results of transport experiments revealed that the accumulation of ornithine represented a homoexchange between extracellular [ 14 C]ornithine and unlabeled ornithine in the cell. The energy-independent exchange of ornithine was not inhibited by proton-conducting uncouplers or by metabolic inhibitors. Intracellular [ 14 C]ornithine was retained by resting cells after suspension in a buffered medium. However, addition of unlabeled ornithine to the suspension elicited rapid exit of labeled amino acid. The initial rate of exist of [ 14 C]ornithine was dependent on the concentration of unlabeled ornithine in the medium, but this accelerative exchange diffusion process caused no net loss of amino acid. By contrast, the presence of a fermentable energy source caused a rapid expulsion of and new decrease in the concentration of intracellular ornithine. Kinetic analyses of amino acid transport demonstrated competitive inhibition between lysine and ornithine, and data obtained by two-dimensional thin-layer chromatography established the heteroexchange of these basic amino acids. The effects of amino acids and of ornithine analogs on both entry and exit of [ 14 C]ornithine have been examined. The data suggest that common carrier mediates the entry and exchange of lysine, arginine, and ornithine in cells of S. lactis

  3. EBS Radionuclide Transport Abstraction

    Energy Technology Data Exchange (ETDEWEB)

    J.D. Schreiber

    2005-08-25

    The purpose of this report is to develop and analyze the engineered barrier system (EBS) radionuclide transport abstraction model, consistent with Level I and Level II model validation, as identified in ''Technical Work Plan for: Near-Field Environment and Transport: Engineered Barrier System: Radionuclide Transport Abstraction Model Report Integration'' (BSC 2005 [DIRS 173617]). The EBS radionuclide transport abstraction (or EBS RT Abstraction) is the conceptual model used in the total system performance assessment for the license application (TSPA-LA) to determine the rate of radionuclide releases from the EBS to the unsaturated zone (UZ). The EBS RT Abstraction conceptual model consists of two main components: a flow model and a transport model. Both models are developed mathematically from first principles in order to show explicitly what assumptions, simplifications, and approximations are incorporated into the models used in the TSPA-LA. The flow model defines the pathways for water flow in the EBS and specifies how the flow rate is computed in each pathway. Input to this model includes the seepage flux into a drift. The seepage flux is potentially split by the drip shield, with some (or all) of the flux being diverted by the drip shield and some passing through breaches in the drip shield that might result from corrosion or seismic damage. The flux through drip shield breaches is potentially split by the waste package, with some (or all) of the flux being diverted by the waste package and some passing through waste package breaches that might result from corrosion or seismic damage. Neither the drip shield nor the waste package survives an igneous intrusion, so the flux splitting submodel is not used in the igneous scenario class. The flow model is validated in an independent model validation technical review. The drip shield and waste package flux splitting algorithms are developed and validated using experimental data. The transport

  4. EBS Radionuclide Transport Abstraction

    International Nuclear Information System (INIS)

    J.D. Schreiber

    2005-01-01

    The purpose of this report is to develop and analyze the engineered barrier system (EBS) radionuclide transport abstraction model, consistent with Level I and Level II model validation, as identified in ''Technical Work Plan for: Near-Field Environment and Transport: Engineered Barrier System: Radionuclide Transport Abstraction Model Report Integration'' (BSC 2005 [DIRS 173617]). The EBS radionuclide transport abstraction (or EBS RT Abstraction) is the conceptual model used in the total system performance assessment for the license application (TSPA-LA) to determine the rate of radionuclide releases from the EBS to the unsaturated zone (UZ). The EBS RT Abstraction conceptual model consists of two main components: a flow model and a transport model. Both models are developed mathematically from first principles in order to show explicitly what assumptions, simplifications, and approximations are incorporated into the models used in the TSPA-LA. The flow model defines the pathways for water flow in the EBS and specifies how the flow rate is computed in each pathway. Input to this model includes the seepage flux into a drift. The seepage flux is potentially split by the drip shield, with some (or all) of the flux being diverted by the drip shield and some passing through breaches in the drip shield that might result from corrosion or seismic damage. The flux through drip shield breaches is potentially split by the waste package, with some (or all) of the flux being diverted by the waste package and some passing through waste package breaches that might result from corrosion or seismic damage. Neither the drip shield nor the waste package survives an igneous intrusion, so the flux splitting submodel is not used in the igneous scenario class. The flow model is validated in an independent model validation technical review. The drip shield and waste package flux splitting algorithms are developed and validated using experimental data. The transport model considers

  5. Fluorescein transport properties across artificial lipid membranes, Caco-2 cell monolayers and rat jejunum.

    Science.gov (United States)

    Berginc, Katja; Zakelj, Simon; Levstik, Lea; Ursic, Darko; Kristl, Albin

    2007-05-01

    Membrane transport characteristics of a paracellular permeability marker fluorescein were evaluated using artificial membrane, Caco-2 cell monolayers and rat jejunum, all mounted in side-by-side diffusion cells. Modified Ringer buffers with varied pH values were applied as incubation salines on both sides of artificial membrane, cell culture monolayers or rat jejunum. Passive transport according to pH partition theory was determined using all three permeability models. In addition to that, active transport of fluorescein in the M-S (mucosal-to-serosal) direction through rat jejunum was observed. The highest M-S P(app) values regarding the active transport through the rat jejunum were observed in incubation saline with pH 6.5. Fluorescein transport through the rat jejunum was inhibited by DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid) and alpha-CHC (alpha-cyano-4-hydroxycinnamic acid). Thus, we assume that two pH-dependent influx transporters could be involved in the fluorescein membrane transport through the intestinal (jejunal) epithelium. One is very likely an MCT (monocarboxylic acid cotransporter) isoform, inhibited by specific MCT inhibitor alpha-CHC, while the involvement of the second one with overlapping substrate/inhibitor specificities (most probably a member of the organic anion-transporting polypeptide family, inhibited at least partially by DIDS) could not be excluded.

  6. STIR: Assessing and Training Response Inhibition Abilities

    Science.gov (United States)

    2014-07-30

    Learning to stop responding to alcohol cues reduces alcohol intake via reduced affective associations rather than increased response inhibition. Addiction ...requires an abstract application of the core learning principle1,2, and viable examples are often hard to find and/or assess. If exposure to non...inhibition training that expands upon previous successful “near transfer” response inhibition training efforts—such as treating alcohol addictions by

  7. Inhibition of cortiocosteroidogenesis by delta-9-tetrahydrocannabinol.

    Science.gov (United States)

    Warner, W; Harris, L S; Carchman, R A

    1977-12-01

    ACTH, cholera toxin, cyclic AMP but not pregnenolone-induced steroidogenesis in Y-1 functional mouse adrenal tumor cells was significantly inhibited by delta-9-tetrahydrocannabinol, cannabidiol, and cannabinol. The inhibition of steroidogenesis could not be correlated with a general depression in cell function or viability. The data suggest that cannabinoids inhibit corticosteroidogenesis at a site between the synthesis of cAMP and of pregnenolone.

  8. BiP Negatively Affects Ricin Transport

    Directory of Open Access Journals (Sweden)

    Kirsten Sandvig

    2013-05-01

    Full Text Available The AB plant toxin ricin binds both glycoproteins and glycolipids at the cell surface via its B subunit. After binding, ricin is endocytosed and then transported retrogradely through the Golgi to the endoplasmic reticulum (ER. In the ER, the A subunit is retrotranslocated to the cytosol in a chaperone-dependent process, which is not fully explored. Recently two separate siRNA screens have demonstrated that ER chaperones have implications for ricin toxicity. ER associated degradation (ERAD involves translocation of misfolded proteins from ER to cytosol and it is conceivable that protein toxins exploit this pathway. The ER chaperone BiP is an important ER regulator and has been implicated in toxicity mediated by cholera and Shiga toxin. In this study, we have investigated the role of BiP in ricin translocation to the cytosol. We first show that overexpression of BiP inhibited ricin translocation and protected cells against the toxin. Furthermore, shRNA-mediated depletion of BiP enhanced toxin translocation resulting in increased cytotoxicity. BiP-dependent inhibition of ricin toxicity was independent of ER stress. Our findings suggest that in contrast to what was shown with the Shiga toxin, the presence of BiP does not facilitate, but rather inhibits the entry of ricin into the cytosol.

  9. NJ transportation fact book, 2007

    Science.gov (United States)

    2010-01-01

    The New Jersey Transportation Fact Book 2006-07 presents information about the New Jersey Department of Transportation : and other agencies that provide transportation services in New Jersey. We hope it will prove helpful.

  10. National Transportation Atlas Databases : 2013.

    Science.gov (United States)

    2013-01-01

    The National Transportation Atlas Databases 2013 (NTAD2013) is a set of nationwide geographic datasets of transportation facilities, transportation networks, associated infrastructure, and other political and administrative entities. These datasets i...

  11. National Transportation Atlas Databases : 2015.

    Science.gov (United States)

    2015-01-01

    The National Transportation Atlas Databases 2015 (NTAD2015) is a set of nationwide geographic datasets of transportation facilities, transportation networks, associated infrastructure, and other political and administrative entities. These datasets i...

  12. National Transportation Atlas Databases : 2012.

    Science.gov (United States)

    2012-01-01

    The National Transportation Atlas Databases 2012 (NTAD2012) is a set of nationwide geographic databases of transportation facilities, transportation networks, and associated infrastructure. These datasets include spatial information for transportatio...

  13. National Transportation Atlas Databases : 2011.

    Science.gov (United States)

    2011-01-01

    The National Transportation Atlas Databases 2011 (NTAD2011) is a set of nationwide geographic databases of transportation facilities, transportation networks, and associated infrastructure. These datasets include spatial information for transportatio...

  14. National Transportation Atlas Databases : 2009.

    Science.gov (United States)

    2009-01-01

    The National Transportation Atlas Databases 2009 (NTAD2009) is a set of nationwide geographic databases of transportation facilities, transportation networks, and associated infrastructure. These datasets include spatial information for transportatio...

  15. National Transportation Atlas Databases : 2014.

    Science.gov (United States)

    2014-01-01

    The National Transportation Atlas Databases 2014 (NTAD2014) is a set of nationwide geographic datasets of transportation facilities, transportation networks, associated infrastructure, and other political and administrative entities. These datasets i...

  16. National Transportation Atlas Databases : 2010.

    Science.gov (United States)

    2010-01-01

    The National Transportation Atlas Databases 2010 (NTAD2010) is a set of nationwide geographic databases of transportation facilities, transportation networks, and associated infrastructure. These datasets include spatial information for transportatio...

  17. Development of Indian passenger transport

    Energy Technology Data Exchange (ETDEWEB)

    Ramanathan, R. [Indira Ghandi Institute of Development Research, Mumbai (India)

    1998-05-01

    The Indian transport sector has been studied using logistic substitution. The share of rail transport is declining, while road and air transport are increasing. These developments are not desirable from an energy-efficiency perspective. (author)

  18. Transportation statistics annual report 2010

    Science.gov (United States)

    2011-01-01

    The Transportation Statistics Annual Report (TSAR) presents data and information compiled by the Bureau of Transportation Statistics (BTS), a component of the U.S. Department of Transportations (USDOTs) Research and Innovative Technology Admini...

  19. Transportation statistics annual report 2009

    Science.gov (United States)

    2009-01-01

    The Transportation Statistics Annual Report (TSAR) presents data and information selected by the Bureau of Transportation Statistics (BTS), a component of the U.S. Department of Transportation's (USDOT's) Research and Innovative Technology Administra...

  20. Pocket Guide to Transportation 2012

    Science.gov (United States)

    2012-01-01

    The Bureau of Transportation Statistics (BTS) of the Research and Innovative Technology Administration produces the Pocket Guide to Transportation as a compact resource that provides snapshots of the U.S. transportation system and highlights major tr...

  1. Pocket Guide to Transportation 2018

    Science.gov (United States)

    2018-01-01

    The 2018 BTS Pocket Guide to Transportation is a quick reference guide that provides transportation statistics at your fingertips. It provides key information and highlights major trends on the U.S. transportation system. This year features a new and...

  2. Effects of a series of acidic drugs on L-lactic acid transport by the monocarboxylate transporters MCT1 and MCT4.

    Science.gov (United States)

    Leung, Yat Hei; Belanger, Francois; Lu, Jennifer; Turgeon, Jacques; Michaud, Veronique

    2018-03-07

    Drug-induced myopathy is a serious side effect that often requires removal of a medication from a drug regimen. For most drugs, the underlying mechanism of drug-induced myopathy remains unclear. Monocarboxylate transporters (MCTs) mediate L-lactic acid transport, and inhibition of MCTs may potentially lead to perturbation of L-lactic acid accumulation and muscular disorders. Therefore, we hypothesized that L-lactic acid transport may be involved in the development of drug-induced myopathy. The aim of this study was to assess the inhibitory potential of 24 acidic drugs on L-lactic acid transport using breast cancer cell lines Hs578T and MDA-MB-231, which selectively express MCT1 and MCT4, respectively. The influx transport of L-lactic acid was minimally inhibited by all drugs tested. The efflux transport was next examined: loratadine (IC50: 10 and 61 µM) and atorvastatin (IC50: 78 and 41 µM) demonstrated the greatest potency for inhibition of L-lactic acid efflux by MCT1 and MCT4, respectively. Acidic drugs including fluvastatin, cerivastatin, simvastatin acid, lovastatin acid, irbesartan and losartan exhibited weak inhibitory potency on L-lactic acid efflux. Our results suggest that some acidic drugs, such as loratadine and atorvastatin, can inhibit the efflux transport of L-lactic acid. This inhibition may cause an accumulation of intracellular L-lactic acid leading to acidification and muscular disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  3. Accident resistant transport container

    Science.gov (United States)

    Anderson, J.A.; Cole, K.K.

    The invention relates to a container for the safe air transport of plutonium having several intermediate wood layers and a load spreader intermediate an inner container and an outer shell for mitigation of shock during a hypothetical accident.

  4. Molecular electronic junction transport

    DEFF Research Database (Denmark)

    Solomon, Gemma C.; Herrmann, Carmen; Ratner, Mark

    2012-01-01

    Whenasinglemolecule,oracollectionofmolecules,isplacedbetween two electrodes and voltage is applied, one has a molecular transport junction. We discuss such junctions, their properties, their description, and some of their applications. The discussion is qualitative rather than quantitative, and f...

  5. Transportation energy data book

    Science.gov (United States)

    2009-01-01

    The Transportation Energy Data Book: Edition 28 is a statistical compendium prepared and : published by Oak Ridge National Laboratory (ORNL) under contract with the U.S. Department of : Energy, Office of Energy Efficiency and Renewable Energy, Vehicl...

  6. Interfacial transport phenomena

    CERN Document Server

    Slattery, John C; Oh, Eun-Suok

    2007-01-01

    Revised and updated extensively from the previous editionDiscusses transport phenomena at common lines or three-phase lines of contactProvides a comprehensive summary about the extensions of continuum mechanics to the nanoscale.

  7. Transport of radioactive materials

    International Nuclear Information System (INIS)

    1988-07-01

    The norm which establishes the requirements of radiation protection and safety related to the transport of radioactive materials, aiming to keep a suitable control level of eventual exposure of personnels, materials and environment of ionizing radiation, including: specifications on radioactive materials for transport, selection of package type; specification of requirements of the design and assays of acceptance of packages; disposal related to the transport; and liability and administrative requirements, are presented. This norm is applied to: truckage, water carriage and air service; design, fabrication, assays and mantenaince of packages; preparation, despatching, handling, loading storage in transition and reception in the ultimate storage of packages; and transport of void packages which have been contained radioactive materials. (M.C.K.) [pt

  8. Transport and the environment

    Energy Technology Data Exchange (ETDEWEB)

    Sharp, C; Jennings, T

    1976-01-01

    This book examines the impact of transport operations on the environment. Noise, air pollution, vibration, accidents, delays caused by slow-moving vehicles, road wear, visual intrusion, the severance of communities--all these social costs of transport are studied, together with policies that might reduce them. The difficulties in measuring costs and benefits and the value judgments that may guide transport policy are reviewed. Specific problems examined include the journey to work, traffic-free shopping streets, urban motor-ways, and inter-change depots for goods vehicles. The role of central and local government is considered, particular attention being given to methods of allowing for environmental benefits when planning new transport investment; the implications of EEC policy are also noted.

  9. Transportation Network Topologies

    Science.gov (United States)

    Alexandrov, Natalia (Editor)

    2004-01-01

    The existing U.S. hub-and-spoke air transportation system is reaching saturation. Major aspects of the current system, such as capacity, safety, mobility, customer satisfaction, security, communications, and ecological effects, require improvements. The changing dynamics - increased presence of general aviation, unmanned autonomous vehicles, military aircraft in civil airspace as part of homeland defense - contributes to growing complexity of airspace. The system has proven remarkably resistant to change. NASA Langley Research Center and the National Institute of Aerospace conducted a workshop on Transportation Network Topologies on 9-10 December 2003 in Williamsburg, Virginia. The workshop aimed to examine the feasibility of traditional methods for complex system analysis and design as well as potential novel alternatives in application to transportation systems, identify state-of-the-art models and methods, conduct gap analysis, and thus to lay a foundation for establishing a focused research program in complex systems applied to air transportation.

  10. Modelling Ballast Water Transport

    Digital Repository Service at National Institute of Oceanography (India)

    Jayakumar, S.; Babu, M.T.; Vethamony, P.

    Ballast water discharges in the coastal environs have caused a great concern over the recent periods as they account for transporting marine organisms from one part of the world to the other. The movement of discharged ballast water as well...

  11. Transportation Industry 2004

    National Research Council Canada - National Science Library

    Miller, Evan; Kathir, Nathan; Brogan, Dennis M

    2004-01-01

    ... and the environment in which the private sector operates. They must also assess the role of government in determining transportation policy, as federal, state, and local agencies regulate every mode of this industry. While the U.S...

  12. Transportation Security Administration

    Science.gov (United States)

    ... content Official website of the Department of Homeland Security Transportation Security Administration A - Z Index Blog What Can I ... Search form Search the Site Main menu Travel Security Screening Special Procedures TSA Pre✓® Passenger Support Travel ...

  13. Remote controlled transport device

    International Nuclear Information System (INIS)

    Nakahira, Masataka; Oka, Kiyoshi; Ito, Akira; Tada, Eisuke; Sato, Masaki

    1998-01-01

    The present invention provides a device for transporting equipments for maintenance and parts between a maintenance port and a facility for maintenance by remote control in a radioactive material handling facility such as a nuclear power plant. Namely, a power supply bus bar is disposed along a transferring path in order to supply power to a transporting means, and is divided into every region having a predetermined length. Each of the power supply bus bar regions is controlled for the power supply by a control device. Accordingly, the transporting means can be moved and driven successively being independent on every power supply bus bar region. Accordingly, a plurality of transporting means can be operated independently in a transferring path without laying around power cables and control signal cables. (I.S.)

  14. Active transport and heat.

    Science.gov (United States)

    Tait, Peter W

    2011-07-01

    Increasing heat may impede peoples' ability to be active outdoors thus limiting active transport options. Co-benefits from mitigation of and adaptation to global warming should not be assumed but need to be actively designed into strategies.

  15. Transportation and Tourism

    Science.gov (United States)

    2012-08-01

    This project explored the link between transportation and tourism in Texas. A session on transit and tourism was organized and conducted as part of the 2012 Texas Transit Conference. Speakers at the session described public transit services oriented ...

  16. Risicobeheersing transport diervoeders

    NARCIS (Netherlands)

    Meijer, G.A.L.; Houwers, H.W.J.; Ipema, A.H.; Boekhoff, M.

    2007-01-01

    Welke knelpunten en oplossingsrichtingen bestaan in de praktijk van het transport diervoeders met betrekking tot de implementatie van de diervoederhygiëneverordening, toegespitst op informatievoorziening over wettelijke en bovenwettelijke eisen, naleving, controle en handhaving?

  17. Offsite transportation hazards assessment

    International Nuclear Information System (INIS)

    Burnside, M.E.

    1997-01-01

    This report documents the emergency preparedness Hazards Assessment for the offsite transportation of hazardous material from the Hanford Site. The assessment is required by the US Department of Energy (DOE) Order 151.1. Offsite transportation accidents are categorized using the DOE system to assist communication within the DOE and assure that appropriate assistance is provided to the people in charge at the scene. The assistance will initially include information about the load and the potential hazards. Local authorities will use the information to protect the public following a transportation accident. This Hazards Assessment will focus on the material being transported from the Hanford Site. Shipments coming to Hanford are the responsibility of the shipper and the carrier and, therefore, are not included in this Hazards Assessment, unless the DOE elects to be the shipper of record

  18. Manpower and Transportation Planning

    NARCIS (Netherlands)

    Lai, S.W.

    2014-01-01

    This thesis studies three routing and scheduling problems arising in manpower and transportation planning. These problems are rooted in real applications, and carry interesting characteristics. By exploiting the structures of the problems, this thesis provides effective mathematical models and

  19. Energy and transportation(*

    Directory of Open Access Journals (Sweden)

    Hermans J.

    2015-01-01

    Full Text Available Transportation takes a considerable and increasing fraction of the energy use worldwide, and more than half the oil consumption. By far the largest part is used by cars powered by internal combustion engines. The advantage of using internal combustion engines is that the energy density of liquid fuels is extremely high. The disadvantage is that gasoline and diesel engines have a poor performance: 20 to 25% only. How does this compare with electric cars? What are the alternative transportation systems and their efficiencies anyway? In this lecture we analyse the efficiency of various transport systems, using elementary physics principles. We will look at cars, buses, trains and TGVs, ships and aircraft. In addition, the efficiency of human powered vehicles will be considered. New and promising developments in the field of Intelligent Transportation Systems, like Cooperative Adaptive Cruise Control, are also discussed.

  20. MANAGEMENT OF TOURISM TRANSPORT

    Directory of Open Access Journals (Sweden)

    Gabriela Cecilia STĂNCIULESCU

    2016-06-01

    Full Text Available Undoubtedly, the relevance of transport activities in relation to tourism activities is essential, because it is extremely important and necessary to offer feasible information about tourism services to help consumer to choose the mode of travel to destinations ideal holiday. The methods used in the development of this hypothesis were explanation, exemplification (brief presentation of each mode of transport comparison etc. Analyzing the current situation of national, European and World Wide tourism transportation, the paper proposes practical applications able to explain that the conduct of economic activities as an integral part of the sector of trade and services within a national economy, would not be possible without the involvement of transport, whether by road, rail and air and naval. The results of the analysis are perfectly applicable offering guests the opportunity to reach the most remote corners of the world in a short time, high degree of comfort and affordable price.

  1. Crew Transportation Operations Standards

    Science.gov (United States)

    Mango, Edward J.; Pearson, Don J. (Compiler)

    2013-01-01

    The Crew Transportation Operations Standards contains descriptions of ground and flight operations processes and specifications and the criteria which will be used to evaluate the acceptability of Commercial Providers' proposed processes and specifications.

  2. Accident resistant transport container

    International Nuclear Information System (INIS)

    Andersen, J.A.; Cole, J.K.

    1980-01-01

    The invention relates to a container for the safe air transport of plutonium having several intermediate wood layers and a load spreader intermediate an inner container and an outer shell for mitigation of shock during a hypothetical accident

  3. Cooperative Transport Planning

    NARCIS (Netherlands)

    Zutt, J.; De Weerdt, M.M.

    2000-01-01

    To test and compare different forms of cooperative planning algorithms developed in the CABS project we use a generic simulator called MARS. Examples in the transportation sector are implemented in this simulator.

  4. Energy and transportation(*)

    Science.gov (United States)

    Hermans, J.

    2015-08-01

    Transportation takes a considerable and increasing fraction of the energy use worldwide, and more than half the oil consumption. By far the largest part is used by cars powered by internal combustion engines. The advantage of using internal combustion engines is that the energy density of liquid fuels is extremely high. The disadvantage is that gasoline and diesel engines have a poor performance: 20 to 25% only. How does this compare with electric cars? What are the alternative transportation systems and their efficiencies anyway? In this lecture we analyse the efficiency of various transport systems, using elementary physics principles. We will look at cars, buses, trains and TGVs, ships and aircraft. In addition, the efficiency of human powered vehicles will be considered. New and promising developments in the field of Intelligent Transportation Systems, like Cooperative Adaptive Cruise Control, are also discussed.

  5. Transport statistics 1996

    CSIR Research Space (South Africa)

    Shepperson, L

    1997-12-01

    Full Text Available This publication contains transport and related statistics on roads, vehicles, infrastructure, passengers, freight, rail, air, maritime and road traffic, and international comparisons. The information compiled in this publication has been gathered...

  6. CHARTB multigroup transport package

    International Nuclear Information System (INIS)

    Baker, L.

    1979-03-01

    The physics and numerical implementation of the radiation transport routine used in the CHARTB MHD code are discussed. It is a one-dimensional (Cartesian, cylindrical, and spherical symmetry), multigroup,, diffusion approximation. Tests and applications will be discussed as well

  7. Animal transportation networks

    Science.gov (United States)

    Perna, Andrea; Latty, Tanya

    2014-01-01

    Many group-living animals construct transportation networks of trails, galleries and burrows by modifying the environment to facilitate faster, safer or more efficient movement. Animal transportation networks can have direct influences on the fitness of individuals, whereas the shape and structure of transportation networks can influence community dynamics by facilitating contacts between different individuals and species. In this review, we discuss three key areas in the study of animal transportation networks: the topological properties of networks, network morphogenesis and growth, and the behaviour of network users. We present a brief primer on elements of network theory, and then discuss the different ways in which animal groups deal with the fundamental trade-off between the competing network properties of travel efficiency, robustness and infrastructure cost. We consider how the behaviour of network users can impact network efficiency, and call for studies that integrate both network topology and user behaviour. We finish with a prospectus for future research. PMID:25165598

  8. On linear transport problems

    International Nuclear Information System (INIS)

    Ignatovich, V.K.

    1989-01-01

    The equations. governing the transport of radiation in plane media of finite thickness are formulated and solved in terms reflection and extintion of radiation inthe case of semi infinite media. 13 refs

  9. Improved electron transport layer

    DEFF Research Database (Denmark)

    2012-01-01

    The present invention provides: a method of preparing a coating ink for forming a zinc oxide electron transport layer, comprising mixing zinc acetate and a wetting agent in water or methanol; a coating ink comprising zinc acetate and a wetting agent in aqueous solution or methanolic solution......; a method of preparing a zinc oxide electron transporting layer, which method comprises: i) coating a substrate with the coating ink of the present invention to form a film; ii) drying the film; and iii) heating the dry film to convert the zinc acetate substantially to ZnO; a method of preparing an organic...... photovoltaic device or an organic LED having a zinc oxide electron transport layer, the method comprising, in this order: a) providing a substrate bearing a first electrode layer; b) forming an electron transport layer according to the following method: i) coating a coating ink comprising an ink according...

  10. Inhibition of apparent photosynthesis by nitrogen oxides

    Energy Technology Data Exchange (ETDEWEB)

    Hill, A C; Bennett, J H

    1970-01-01

    The nitrogen oxides (NO/sub 2/ and NO) inhibited apparent photosynthesis of oats and alfalfa at concentrations below those required to cause visible injury. There appeared to be a threshold concentration of about 0.6 ppm for each pollutant. An additive effect in depressing apparent photosynthesis occurred when the plants were exposed to a mixture of NO and NO/sub 2/. Although NO produced a more rapid effect on the plants, lower concentrations of NO/sub 2/ were required to cause a given inhibition after 2 hour of exposure. Inhibition by nitric oxide was more closely related to its partial pressure than was inhibition by NO/sub 2/.

  11. Transportation Network Topologies

    Science.gov (United States)

    Holmes, Bruce J.; Scott, John

    2004-01-01

    A discomforting reality has materialized on the transportation scene: our existing air and ground infrastructures will not scale to meet our nation's 21st century demands and expectations for mobility, commerce, safety, and security. The consequence of inaction is diminished quality of life and economic opportunity in the 21st century. Clearly, new thinking is required for transportation that can scale to meet to the realities of a networked, knowledge-based economy in which the value of time is a new coin of the realm. This paper proposes a framework, or topology, for thinking about the problem of scalability of the system of networks that comprise the aviation system. This framework highlights the role of integrated communication-navigation-surveillance systems in enabling scalability of future air transportation networks. Scalability, in this vein, is a goal of the recently formed Joint Planning and Development Office for the Next Generation Air Transportation System. New foundations for 21st thinking about air transportation are underpinned by several technological developments in the traditional aircraft disciplines as well as in communication, navigation, surveillance and information systems. Complexity science and modern network theory give rise to one of the technological developments of importance. Scale-free (i.e., scalable) networks represent a promising concept space for modeling airspace system architectures, and for assessing network performance in terms of scalability, efficiency, robustness, resilience, and other metrics. The paper offers an air transportation system topology as framework for transportation system innovation. Successful outcomes of innovation in air transportation could lay the foundations for new paradigms for aircraft and their operating capabilities, air transportation system architectures, and airspace architectures and procedural concepts. The topology proposed considers air transportation as a system of networks, within which

  12. Heat transport and storage

    International Nuclear Information System (INIS)

    Despois, J.

    1977-01-01

    Recalling the close connections existing between heat transport and storage, some general considerations on the problem of heat distribution and transport are presented 'in order to set out the problem' of storage in concrete form. This problem is considered in its overall plane, then studied under the angle of the different technical choices it involves. The two alternatives currently in consideration are described i.e.: storage in a mined cavity and underground storage as captive sheet [fr

  13. Transportation and its Infrastructure

    OpenAIRE

    Ribeiro, Suzana K; Kobayashi, Shigeki; Beuthe, Michel; Gasca, Jorge; Greene, David; Lee, David S.; Muromachi, Yasunori; Newton, Peter J.; Plotkin, Steven; Sperling, Daniel; Wit, Ron; Zhou, Peter J

    2007-01-01

    Transport activity, a key component of economic development and human welfare, is increasing around the world as economies grow. For most policymakers, the most pressing problems associated with this increasing transport activity are traffic fatalities and injuries, congestion, air pollution and petroleum dependence. These problems are especially acute in the most rapidly growing economies of the developing world. Mitigating greenhouse gas (GHG) emissions can take its place among these other ...

  14. Transportation of radioactive elements

    International Nuclear Information System (INIS)

    Thubert, Francis; Rentien, Guy; Jacquet, Michel

    1981-01-01

    The production and marketing of artificial radioactive elements engaged in by the 'Office des Rayonnements Ionisants' requires the use of specially designed packagings and assorted means of transport. The authors begin by describing the different kinds of products involved and the forms of packagings needed, and go on to discuss the various means of transport used, underlining the fact that, in terms of number and gravity, the incidents that have occurred to date have indeed been few and far between [fr

  15. Tape transport mechanism

    International Nuclear Information System (INIS)

    Groh, E.F.; McDowell, W.; Modjeski, N.S.; Keefe, D.J.; Groer, P.

    1979-01-01

    A device is provided for transporting, in a stepwise manner, tape between a feed reel and takeup reel. An indexer moves across the normal path of the tape displacing it while the tape on the takeup reel side of the indexer is braked. After displacement, the takeup reel takes up the displaced tape while the tape on the feed reel side of the indexer is braked, providing stepwise tape transport in precise intervals determined by the amount of displacement caused by the indexer

  16. Monitoring of transport contamination

    International Nuclear Information System (INIS)

    Turkin, N.F.

    1980-01-01

    Organization of monitoring of transport contamination is considered. A particularly thorough monitoring is recommended to be carried out in loading-unloading operations. The monitoring is performed when leaving loading-unloading site and zone under control and prior to preventive examination, technical service or repair. The method of monitoring of auto transport contamination with high-energy β-emitters by means of a special stand permitting the automation of the monitoring process is described [ru

  17. Digital intelligence sources transporter

    International Nuclear Information System (INIS)

    Zhang Zhen; Wang Renbo

    2011-01-01

    It presents from the collection of particle-ray counting, infrared data communication, real-time monitoring and alarming, GPRS and other issues start to realize the digital management of radioactive sources, complete the real-time monitoring of all aspects, include the storing of radioactive sources, transporting and using, framing intelligent radioactive sources transporter, as a result, achieving reliable security supervision of radioactive sources. (authors)

  18. Spin transport in nanowires

    OpenAIRE

    Pramanik, S.; bandyopadhyay, S.; Cahay, M.

    2003-01-01

    We study high-field spin transport of electrons in a quasi one-dimensional channel of a $GaAs$ gate controlled spin interferometer (SPINFET) using a semiclassical formalism (spin density matrix evolution coupled with Boltzmann transport equation). Spin dephasing (or depolarization) is predominantly caused by D'yakonov-Perel' relaxation associated with momentum dependent spin orbit coupling effects that arise due to bulk inversion asymmetry (Dresselhaus spin orbit coupling) and structural inve...

  19. Thermoelectric transport in superlattices

    Energy Technology Data Exchange (ETDEWEB)

    Reinecke, T L; Broido, D A

    1997-07-01

    The thermoelectric transport properties of superlattices have been studied using an exact solution of the Boltzmann equation. The role of heat transport along the barrier layers, of carrier tunneling through the barriers, of valley degeneracy and of the well width and energy dependences of the carrier-phonon scattering rates on the thermoelectric figure of merit are given. Calculations are given for Bi{sub 2}Te{sub 3} and for PbTe, and the results of recent experiments are discussed.

  20. Transport of reservoir fines

    DEFF Research Database (Denmark)

    Yuan, Hao; Shapiro, Alexander; Stenby, Erling Halfdan

    Modeling transport of reservoir fines is of great importance for evaluating the damage of production wells and infectivity decline. The conventional methodology accounts for neither the formation heterogeneity around the wells nor the reservoir fines’ heterogeneity. We have developed an integral...... dispersion equation in modeling the transport and the deposition of reservoir fines. It successfully predicts the unsymmetrical concentration profiles and the hyperexponential deposition in experiments....

  1. Effect of insulin and glucocorticoids on glucose transporters in rat adipocytes

    International Nuclear Information System (INIS)

    Carter-Su, C.; Okamoto, K.

    1987-01-01

    The ability of glucocorticoids to modify the effect of insulin on glucose (L-1- 3 H(N)]glucose and D-[ 14 C-U]glucose) transport was investigated in both intact isolated rat adipocytes and in membranes isolated from hormone-treated adipocytes. In intact adipocytes, dexamethasone, a potent synthetic glucocorticoid, inhibited insulin-stimulated 3-O-methylglucose transport at all concentrations of insulin tested. Insulin sensitivity, as well as the maximal response to insulin, was decreased by dexamethasone in the absence of a change in 125 I insulin binding. The inhibition was observed regardless of which hormone acted first, was blocked by actinomycin D, and resulted from a decrease in V/sub max/ rather than an increase in K/sub t/ of transport. In plasma membranes isolated from insulin-treated adipocytes, glucose transport activity and the amount of glucose transporter covalently labeled with [ 3 H]cytochalasin B were increased in parallel in a dose-dependent fashion. The amount of labeled transporter in a low-density microsomal fraction (LDMF) was decreased in a reciprocal fashion. In contrast, addition of dexamethasone to insulin-stimulated cells caused decreases in both transport activity and amount of labeled transporter in the plasma membranes. This was accompanied by a small increase in the amount of [ 3 H]cytochalasin B incorporated into the glucose transporter in the LDMF. These results are consistent with both insulin and glucocorticoids altering the distribution of glucose transporters between the plasma membrane and LDMF, in opposite directions

  2. Polymorphism in ABC transporter genes of Dirofilaria immitis

    Directory of Open Access Journals (Sweden)

    Thangadurai Mani

    2017-08-01

    Full Text Available Dirofilaria immitis, a filarial nematode, causes dirofilariasis in dogs, cats and occasionally in humans. Prevention of the disease has been mainly by monthly use of the macrocyclic lactone (ML endectocides during the mosquito transmission season. Recently, ML resistance has been confirmed in D. immitis and therefore, there is a need to find new classes of anthelmintics. One of the mechanisms associated with ML resistance in nematodes has been the possible role of ATP binding cassette (ABC transporters in reducing drug concentrations at receptor sites. ABC transporters, mainly from sub-families B, C and G, may contribute to multidrug resistance (MDR by active efflux of drugs out of the cell. Gene products of ABC transporters may thus serve as the targets for agents that may modulate susceptibility to drugs, by inhibiting drug transport. ABC transporters are believed to be involved in a variety of physiological functions critical to the parasite, such as sterol transport, and therefore may also serve as the target for drugs that can act as anthelmintics on their own. Knowledge of polymorphism in these ABC transporter genes in nematode parasites could provide useful information for the process of drug design. We have identified 15 ABC transporter genes from sub-families A, B, C and G, in D. immitis, by comparative genomic approaches and analyzed them for polymorphism. Whole genome sequencing data from four ML susceptible (SUS and four loss of efficacy (LOE pooled populations were used for single nucleotide polymorphism (SNP genotyping. Out of 231 SNPs identified in those 15 ABC transporter genes, 89 and 75 of them were specific to the SUS or LOE populations, respectively. A few of the SNPs identified may affect gene expression, protein function, substrate specificity or resistance development and may be useful for transporter inhibitor/anthelmintic drug design, or in order to anticipate resistance development. Keywords: Dirofilaria immitis

  3. Climate change : transportation table

    International Nuclear Information System (INIS)

    Ogilvie, K.

    1999-01-01

    The Kyoto Protocol sets greenhouse gas (GHG) reduction targets for the post-2000 period. If ratified, Canada will be committed to reduce emissions of GHGs by 6 per cent below 1990 levels during the period 2008-2012. A recommended national strategy is to establish 'issue tables' that will advise the Ministers of Energy and Environment on preferred options to reach the Kyoto target and to identify early actions that can be taken. The 'Transportation Table' which is the focus of this paper, is one of the 15 sectoral tables. The Transportation Table will identify by July 1999, specific measures to mitigate GHG emissions from Canada's transportation sector. Currently, GHG emissions from the transportation sector are predicted to be 27 per cent above 1990 levels by 2010. Fuel taxes, emissions trading, and research into improved vehicle technologies and automotive fuels are some of the recommended options which can help reduce emissions trading from the transportation sector. Studies are underway to deal with emissions from transport in two sub-groups, freight and passenger. 1 fig

  4. Experimental constraints on transport

    International Nuclear Information System (INIS)

    Luce, T.C.; Petty, K.H.; Burrell, K.H.; Forest, C.B.; Gohil, P.; Groebner, R.J.; De Haas, J.C.M.; James, R.A.; Makowski, M.A.

    1994-12-01

    Characterization of the cross-field energy transport in magnetic confinement experiments in a manner applicable to the accurate assessment of future machine performance continues to be a challenging goal. Experimental results from the DIII-D tokamak in the areas of dimensionless scaling and non-diffusive transport represent progress toward this goal. Dimensionless scaling shows how beneficial the increase in machine size and magnetic field is for future devices. The experiments on DIII-D are the first to determine separately the electron and ion scaling with normalized gyroradius ρ * ; the electrons scale as expected from gyro-Bohm class theories, while the ions scale consistent with the Goldston empirical scaling. This result predicts an increase in transport relative to Bohm diffusion as ρ * decreases in future devices. The existence of distinct ρ * scalings for ions and electrons cautions against a physical interpretation of one-fluid or global analysis. The second class of experiments reported here are the first to demonstrate the existence of non-diffusive energy transport. Electron cyclotron heating was applied at the half radius; the electron temperature profile remains substantially peaked. Power balance analysis indicates that heat must flow in the direction of increasing temperature, which is inconsistent with purely diffusive transport. The dynamics of electron temperature perturbations indicate the presence in the heat flux of a term dependent on temperature rather than its gradient. These two observations strongly constrain the types of models which can be applied to cross-field heat transport

  5. Transportation of nuclear materials

    International Nuclear Information System (INIS)

    Brobst, W.A.

    1977-01-01

    Twenty years of almost accident-free transport of nuclear materials is pointed to as evidence of a fundamentally correct approach to the problems involved. The increased volume and new technical problems in the future will require extension of these good practices in both regulations and packaging. The general principles of safety in the transport of radioactive materials are discussed first, followed by the transport of spent fuel and of radioactive waste. The security and physical protection of nuclear shipments is then treated. In discussing future problems, the question of public understanding and acceptance is taken first, thereafter transport safeguards and the technical bases for the safety regulations. There is also said to be a need for a new technology for spent fuel casks, while a re-examination of the IAEA transport standards for radiation doses is recommended. The IAEA regulations regarding quality assurance are said to be incomplete, and more information is required on correlations between engineering analysis, scale model testing and full scale crash testing. Transport stresses on contents need to be considered while administrative controls have been neglected. (JIW)

  6. Transport processes in plasmas

    International Nuclear Information System (INIS)

    Balescu, R.

    1988-01-01

    This part is devoted to the classical transport theory in plasmas. Ch. 1 is a chapter of 'pure' hamiltonian mechanics and starts with the study of the motion of an individual charged particle in the presence of an electromagnetic field. Ch. 2 introduces the tools of statistical mechanics for the study of large collections of charged particles. A kinetic theory is derived as a basic tool for transport theory. In ch. 3 the hydro-dynamic - or plasmadynamic - balance equations are derived. The macroscopic dynamical equations have the structure of an infinite hierarchy. This introduces the necessity of construction of a transport theory, by which te infinite set of equations can be reduced to a finite, closed set. This can only be done by a detailed analysis of the kinetic equation under well defined conditions. The tools for such nan analysis are developed in ch. 4. In ch. 5 the transport equations, relating the unknown fluxes of matter, momentum, energy and electricity to the hydrodynamic variables, are derived and discussed. In ch. 6 the results are incorporated into the wider framework of non-equilibrium thermodynamics by connecting the transport processes to the central concept of entropy production. In ch. 7 the results of transport theory are put back into the equations of plasmadynamics

  7. Transport of radioisotopes

    International Nuclear Information System (INIS)

    Aoki, Shigefumi

    1978-01-01

    Presently the amount of radioisotopes increased very much and the application spread to wide fields in Japan. Since facilities using radioisotopes are distributed to every place in the country, every transport means such as airplanes, automobiles, railways, ships and mail are employed. The problems in the transport of radioisotopes include too much difference in the recognition of criticality among the persons concerning the transportation and treatment, knowledges of shielding and energy difference in the types of radiation and handling of sealed and unsealed sources and the casks for transport. IAEA established the latest regulation on the package of radioisotopes in 1973, and in Japan, the related regulations will be revised according to the IAEA's regulation in near future. The present status in the inspection at the time of shipment, supervision, and the measures to the accidents are described for the transport means of airplanes, ships and automobiles. Finally, concerning the insurance for cargo, the objects of the insurance for radioisotopes include either the radioisotopes contained in casks for transportation or radioisotopes only. Generally, radioisotopes are accepted in all-risk condition including casks and limited to the useful radioisotopes for peaceful use. (Wakatsuki, Y

  8. Conditions With High Intracellular Glucose Inhibit Sensing Through Glucose Sensor Snf3 in Saccharomyces cerevisiae

    DEFF Research Database (Denmark)

    Karhumaa, Kaisa; Wu, B.Q.; Kielland-Brandt, Morten

    2010-01-01

    as for amino acids. An alternating-access model of the function of transporter-like sensors has been previously suggested based on amino acid sensing, where intracellular ligand inhibits binding of extracellular ligand. Here we studied the effect of intracellular glucose on sensing of extracellular glucose...... through the transporter-like sensor Snf3 in yeast. Sensing through Snf3 was determined by measuring degradation of Mth1 protein. High intracellular glucose concentrations were achieved by using yeast strains lacking monohexose transporters which were grown on maltose. The apparent affinity...... of extracellular glucose to Snf3 was measured for cells grown in non-fermentative medium or on maltose. The apparent affinity for glucose was lowest when the intracellular glucose concentration was high. The results conform to an alternating-access model for transporter-like sensors. J. Cell. Biochem. 110: 920...

  9. Magnetic-flutter-induced pedestal plasma transport

    International Nuclear Information System (INIS)

    Callen, J.D.; Hegna, C.C.; Cole, A.J.

    2013-01-01

    Plasma toroidal rotation can limit reconnection of externally applied resonant magnetic perturbation (RMP) fields δB on rational magnetic flux surfaces. Hence it causes the induced radial perturbations δB ρ to be small there, thereby inhibiting magnetic island formation and stochasticity at the top of pedestals in high (H-mode) confinement tokamak plasmas. However, the δB ρ s induced by RMPs increase away from rational surfaces and are shown to induce significant sinusoidal radial motion (flutter) of magnetic field lines with a radial extent that varies linearly with δB ρ and inversely with distance from the rational surface because of the magnetic shear. This produces a radial electron thermal diffusivity that is (1/2)(δB ρ /B 0 ) 2 times a kinetically derived, electron-collision-induced, magnetic-shear-reduced, effective parallel electron thermal diffusivity in the absence of magnetic stochasticity. These low collisionality flutter-induced transport processes and thin magnetic island effects are shown to be highly peaked in the vicinity of rational surfaces at the top of low collisionality pedestals. However, the smaller but finite level of magnetic-flutter-induced electron heat transport midway between rational surfaces is the primary factor that determines the electron temperature difference between rational surfaces at the pedestal top. The magnetic-flutter-induced non-ambipolar electron density transport can be large enough to push the plasma toward an electron density transport root. Requiring ambipolar density transport is shown to determine the radial electric field, the plasma toroidal rotation (via radial force balance), a reduced electron thermal diffusivity and increased ambipolar density transport in the pedestal. At high collisionality the various flutter effects are less strongly peaked at rational surfaces and generally less significant. They are thus less likely to exhibit flutter-induced resonant behaviour and transition toward an

  10. Magnetic-flutter-induced pedestal plasma transport

    Science.gov (United States)

    Callen, J. D.; Hegna, C. C.; Cole, A. J.

    2013-11-01

    Plasma toroidal rotation can limit reconnection of externally applied resonant magnetic perturbation (RMP) fields δB on rational magnetic flux surfaces. Hence it causes the induced radial perturbations δBρ to be small there, thereby inhibiting magnetic island formation and stochasticity at the top of pedestals in high (H-mode) confinement tokamak plasmas. However, the δBρs induced by RMPs increase away from rational surfaces and are shown to induce significant sinusoidal radial motion (flutter) of magnetic field lines with a radial extent that varies linearly with δBρ and inversely with distance from the rational surface because of the magnetic shear. This produces a radial electron thermal diffusivity that is (1/2)(δBρ/B0)2 times a kinetically derived, electron-collision-induced, magnetic-shear-reduced, effective parallel electron thermal diffusivity in the absence of magnetic stochasticity. These low collisionality flutter-induced transport processes and thin magnetic island effects are shown to be highly peaked in the vicinity of rational surfaces at the top of low collisionality pedestals. However, the smaller but finite level of magnetic-flutter-induced electron heat transport midway between rational surfaces is the primary factor that determines the electron temperature difference between rational surfaces at the pedestal top. The magnetic-flutter-induced non-ambipolar electron density transport can be large enough to push the plasma toward an electron density transport root. Requiring ambipolar density transport is shown to determine the radial electric field, the plasma toroidal rotation (via radial force balance), a reduced electron thermal diffusivity and increased ambipolar density transport in the pedestal. At high collisionality the various flutter effects are less strongly peaked at rational surfaces and generally less significant. They are thus less likely to exhibit flutter-induced resonant behaviour and transition toward an electron

  11. Choline transport via choline transporter-like protein 1 in conditionally immortalized rat syncytiotrophoblast cell lines TR-TBT.

    Science.gov (United States)

    Lee, N-Y; Choi, H-M; Kang, Y-S

    2009-04-01

    Choline is an essential nutrient for phospholipids and acetylcholine biosynthesis in normal development of fetus. In the present study, we investigated the functional characteristics of choline transport system and inhibitory effect of cationic drugs on choline transport in rat conditionally immortalized syncytiotrophoblast cell line (TR-TBT). Choline transport was weakly Na(+) dependent and significantly influenced by extracellular pH and by membrane depolarization. The transport process of choline is saturable with Michaelis-Menten constants (K(m)) of 68microM and 130microM in TR-TBT 18d-1 and TR-TBT 18d-2 respectively. Choline uptake in the cells was inhibited by unlabeled choline and hemicholinium-3 as well as various organic cations including guanidine, amiloride and acetylcholine. However, the prototypical organic cation tetraethylammonium and cimetidine showed very little inhibitory effect of choline uptake in TR-TBT cells. RT-PCR revealed that choline transporter-like protein 1 (CTL1) and organic cation transporter 2 (OCT2) are expressed in TR-TBT cells. The transport properties of choline in TR-TBT cells were similar or identical to that of CTL1 but not OCT2. CTL1 was also detected in human placenta. In addition, several cationic drugs such as diphenhydramine and verapamil competitively inhibited choline uptake in TR-TBT 18d-1 with K(i) of 115microM and 55microM, respectively. Our results suggest that choline transport system, which has intermediate affinity and weakly Na(+) dependent, in TR-TBT seems to occur through a CTL1 and this system may have relevance with the uptake of pharmacologically important organic cation drugs.

  12. Biosensor discovery of thyroxine transport disrupting chemicals

    International Nuclear Information System (INIS)

    Marchesini, Gerardo R.; Meimaridou, Anastasia; Haasnoot, Willem; Meulenberg, Eline; Albertus, Faywell; Mizuguchi, Mineyuki; Takeuchi, Makoto; Irth, Hubertus; Murk, Albertinka J.

    2008-01-01

    Ubiquitous chemicals may interfere with the thyroid system that is essential in the development and physiology of vertebrates. We applied a surface plasmon resonance (SPR) biosensor-based screening method for the fast screening of chemicals with thyroxine (T4) transport disrupting activity. Two inhibition assays using the main thyroid hormone transport proteins, T4 binding globulin (TBG) and transthyretin (TTR), in combination with a T4-coated biosensor chip were optimized and automated for screening chemical libraries. The transport protein-based biosensor assays were rapid, high throughput and bioeffect-related. A library of 62 chemicals including the natural hormones, polychlorinated biphenyls (PCBs), polybrominated diphenylethers (PBDEs) and metabolites, halogenated bisphenol A (BPA), halogenated phenols, pharmaceuticals, pesticides and other potential environmentally relevant chemicals was tested with the two assays. We discovered ten new active compounds with moderate to high affinity for TBG with the TBG assay. Strikingly, the most potent binding was observed with hydroxylated metabolites of the brominated diphenyl ethers (BDEs) BDE 47, BDE 49 and BDE 99, that are commonly found in human plasma. The TTR assay confirmed the activity of previously identified hydroxylated metabolites of PCBs and PBDEs, halogenated BPA and genistein. These results show that the hydroxylated metabolites of the ubiquitous PBDEs not only target the T4 transport at the TTR level, but also, and to a great extent, at the TBG level where most of the T4 in humans is circulating. The optimized SPR biosensor-based transport protein assay is a suitable method for high throughput screening of large libraries for potential thyroid hormone disrupting compounds

  13. Biosensor discovery of thyroxine transport disrupting chemicals.

    Science.gov (United States)

    Marchesini, Gerardo R; Meimaridou, Anastasia; Haasnoot, Willem; Meulenberg, Eline; Albertus, Faywell; Mizuguchi, Mineyuki; Takeuchi, Makoto; Irth, Hubertus; Murk, Albertinka J

    2008-10-01

    Ubiquitous chemicals may interfere with the thyroid system that is essential in the development and physiology of vertebrates. We applied a surface plasmon resonance (SPR) biosensor-based screening method for the fast screening of chemicals with thyroxine (T4) transport disrupting activity. Two inhibition assays using the main thyroid hormone transport proteins, T4 binding globulin (TBG) and transthyretin (TTR), in combination with a T4-coated biosensor chip were optimized and automated for screening chemical libraries. The transport protein-based biosensor assays were rapid, high throughput and bioeffect-related. A library of 62 chemicals including the natural hormones, polychlorinated biphenyls (PCBs), polybrominated diphenylethers (PBDEs) and metabolites, halogenated bisphenol A (BPA), halogenated phenols, pharmaceuticals, pesticides and other potential environmentally relevant chemicals was tested with the two assays. We discovered ten new active compounds with moderate to high affinity for TBG with the TBG assay. Strikingly, the most potent binding was observed with hydroxylated metabolites of the brominated diphenyl ethers (BDEs) BDE 47, BDE 49 and BDE 99, that are commonly found in human plasma. The TTR assay confirmed the activity of previously identified hydroxylated metabolites of PCBs and PBDEs, halogenated BPA and genistein. These results show that the hydroxylated metabolites of the ubiquitous PBDEs not only target the T4 transport at the TTR level, but also, and to a great extent, at the TBG level where most of the T4 in humans is circulating. The optimized SPR biosensor-based transport protein assay is a suitable method for high throughput screening of large libraries for potential thyroid hormone disrupting compounds.

  14. Cell Membrane Transport Mechanisms: Ion Channels and Electrical Properties of Cell Membranes.

    Science.gov (United States)

    Kulbacka, Julita; Choromańska, Anna; Rossowska, Joanna; Weżgowiec, Joanna; Saczko, Jolanta; Rols, Marie-Pierre

    2017-01-01

    Cellular life strongly depends on the membrane ability to precisely control exchange of solutes between the internal and external (environmental) compartments. This barrier regulates which types of solutes can enter and leave the cell. Transmembrane transport involves complex mechanisms responsible for passive and active carriage of ions and small- and medium-size molecules. Transport mechanisms existing in the biological membranes highly determine proper cellular functions and contribute to drug transport. The present chapter deals with features and electrical properties of the cell membrane and addresses the questions how the cell membrane accomplishes transport functions and how transmembrane transport can be affected. Since dysfunctions of plasma membrane transporters very often are the cause of human diseases, we also report how specific transport mechanisms can be modulated or inhibited in order to enhance the therapeutic effect.

  15. Inhibition of photosynthesis by carbon monoxide and suspension of the carbon monoxide inhibition by light

    Energy Technology Data Exchange (ETDEWEB)

    Gewitz, H S; Voelker, W

    1963-08-01

    The experimental subject was the autotroph Chlorella pyrenoidosa. It was found that growth conditions determine whether the alga is inhibited by carbon monoxide or not. Respiration and photosynthesis are inhibited by carbon monoxide if the cells have grown rapidly under high light intensities. The inhibition of respiration and photosynthesis found in such cells is completely reversible. The inhibition depends not only on carbon monoxide pressure, but also on the oxygen pressure prevailing at the same time. 5 references, 1 figure, 3 tables.

  16. Paleoclassical transport explains electron transport barriers in RTP and TEXTOR

    NARCIS (Netherlands)

    Hogeweij, G. M. D.; Callen, J.D.

    2008-01-01

    The recently developed paleoclassical transport model sets the minimum level of electron thermal transport in a tokamak. This transport level has proven to be in good agreement with experimental observations in many cases when fluctuation-induced anomalous transport is small, i.e. in (near-) ohmic

  17. ANALYISIS OF TRANSPORTATION SYSTEMS AND TRANSPORTATION POLICIES IN TURKEY

    Directory of Open Access Journals (Sweden)

    Ali Payıdar AKGÜNGÖR

    2004-03-01

    Full Text Available Transportation systems have to be considered and analysed as a whole while transportation demand, becoming as a natural outcome of socioeconomic and socio-cultural structure, is being evaluated. It is desired that transportation system, which will be selected for both passenger and freight transport, should be rapid, economic, safe, causing least harm to environment and appropriate for the conditions of a country. However, it is difficult for a transportation system to have all these properties. Every transportation system has advantages and disadvantages over each other. Therefore, comprehensive plans for future periods have to be prepared and how the sources of the country should be reasonably distributed among transportation systems must be investigated. Also, transportation plans have to be prepared to get coordinated operations among transportation systems while great investments are instituted in the entire country. There is no doubt that it is possible with combined transportation instead of concentration on one transportation system. Transportation policies in Turkey should be questioned since the level of highway transportation usage reaches to 95 % and level of sea transportation usage drops to less than 1 % in spite of being surrounded with sea in three sides of our land. In this paper, transportation systems and transportation policies in Turkey are evaluated in general and problems are analysed. Proposals are presented for the solutions of these problems.

  18. Spent fuel transportation problems

    International Nuclear Information System (INIS)

    Kondrat'ev, A.N.; Kosarev, Yu.A.; Yulikov, E.A.

    1977-01-01

    In this paper, problems of transportation of nuclear spent fuel to reprocessing plants are discussed. The solutions proposed are directed toward the achievement of the transportation as economic and safe as possible. The increase of the nuclear power plants number in the USSR and the great distances between these plants and the reprocessing plants involve an intensification of the spent fuel transportation. Higher burnup and holdup time reduction cause the necessity of more bulky casks. In this connection, the economic problems become still more important. One of the ways of the problem solution is the development of rational and cheap cask designs. Also, the enforcement in the world of the environmental and personnel health protection requires to increase the transportation reliability and safety. The paper summarizes safe transportation rules with clarifying the following questions: the increase of the transport unit quantity of the spent fuel; rational shipment organization that minimizes vehicle turnover cycle duration; development of the reliable calculation methods to determine strength, thermal conditions and nuclear safety of transport packaging as applied to the vehicles of high capacity; maximum unification of vehicles, calculation methods and documents; and cask testing on models and in pilot scale on specific test rigs to assure that they meet the international safe fuel shipment rules. Besides, some considerations on the choice and use of structural materials for casks are given, and problems of manufacturing such casks from uranium and lead are considered, as well as problems of the development of fireproof shells, control instrumentation, vehicles decontamination, etc. All the problems are considered from the point of view of normal and accidental shipment conditions. Conclusions are presented [ru

  19. Salicylhydroxamic acid (SHAM) inhibition of the DIC-pump in unicellular algae

    International Nuclear Information System (INIS)

    Goyal, A.; Tolbert, N.E.

    1989-01-01

    SHAM at 1 or 2 mM inhibits dissolved inorganic carbon (DIC) concentrating mechanisms in unicellular green algae as measured by photosynthetic oxygen evolution or by 14 C-inorganic carbon uptake (using silicone oil centrifugation techniques). This inhibition was reversed by high levels of DIC whereby the cells do not require the concentrating mechanism. SHAM inhibited the DIC-pump, which uses external CO 2 , in three species of algae, Dunaliella tertiolecta, Chlamydomonas reinhardtii, and Scenedesmus obliquus when adapted to low CO 2 and assayed around neutral pH. Scenedesmus adapted to air at pH 9.0 to use external HCO 3 - were not affected by SHAM. It is important to establish low optimum concentrations of SHAM, which varied with the algal species. The mechanism of SHAM inhibition of the CO 2 concentrating process is unknown. SHAM inhibits alternative respiration in these algae, but SHAM may also inhibit other reactions involving H + gradients or transporters associated with the DIC-pump

  20. 7-Piperazinethylchrysin inhibits melanoma cell proliferation by ...

    African Journals Online (AJOL)

    In B16F10 and A375 cells, treatment with PEC caused the inhibition ... Conclusion: PEC inhibited melanoma cell proliferation, apparently by blocking the cell cycle at G0/G1 .... all statistical analyses. .... Financial support from the Department of.