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Sample records for transport chain inhibited

  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. 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)

  3. 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.

  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. 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.

  6. 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

  7. Optimizing sales areas of combined transport chains

    Directory of Open Access Journals (Sweden)

    Philip Michalk

    2013-12-01

    Full Text Available Background: Combined transport chains (such as intermodal transport, have certain advantages. The main advantage from customer points of view is the possibility to bundle freight and thereby decrease transport costs. On the other hand, a combined transport chain can cause longer transport times, due to the necessary transshipment processes. Methods: The area around a terminal, in which a combined service has favourable properties to a customer in comparison to a direct transport, can be understood as a sales-area, in which a combined transport product is marketable. The aim of this paper was to find a method to determine the best shape and size of this area. Results and conclusions: The paper at hand lined out a method in order to calculate such a sales area and determine which geographical points around a terminal have an advantage in comparison to a direct transport service.

  8. Electron transport chains of lactic acid bacteria

    NARCIS (Netherlands)

    Brooijmans, R.J.W.

    2008-01-01

    Lactic acid bacteria are generally considered facultative anaerobic obligate fermentative bacteria. They are unable to synthesize heme. Some lactic acid bacteria are unable to form menaquinone as well. Both these components are cofactors of respiratory (electron transport) chains of prokaryotic

  9. Melatonin and the electron transport chain.

    Science.gov (United States)

    Hardeland, Rüdiger

    2017-11-01

    Melatonin protects the electron transport chain (ETC) in multiple ways. It reduces levels of ·NO by downregulating inducible and inhibiting neuronal nitric oxide synthases (iNOS, nNOS), thereby preventing excessive levels of peroxynitrite. Both ·NO and peroxynitrite-derived free radicals, such as ·NO 2 , hydroxyl (·OH) and carbonate radicals (CO 3 · - ) cause blockades or bottlenecks in the ETC, by ·NO binding to irons, protein nitrosation, nitration and oxidation, changes that lead to electron overflow or even backflow and, thus, increased formation of superoxide anions (O 2 · - ). Melatonin improves the intramitochondrial antioxidative defense by enhancing reduced glutathione levels and inducing glutathione peroxidase and Mn-superoxide dismutase (Mn-SOD) in the matrix and Cu,Zn-SOD in the intermembrane space. An additional action concerns the inhibition of cardiolipin peroxidation. This oxidative change in the membrane does not only initiate apoptosis or mitophagy, as usually considered, but also seems to occur at low rate, e.g., in aging, and impairs the structural integrity of Complexes III and IV. Moreover, elevated levels of melatonin inhibit the opening of the mitochondrial permeability transition pore and shorten its duration. Additionally, high-affinity binding sites in mitochondria have been described. The assumption of direct binding to the amphipathic ramp of Complex I would require further substantiation. The mitochondrial presence of the melatonin receptor MT 1 offers the possibility that melatonin acts via an inhibitory G protein, soluble adenylyl cyclase, decreased cAMP and lowered protein kinase A activity, a signaling pathway shown to reduce Complex I activity in the case of a mitochondrial cannabinoid receptor.

  10. 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.

  11. Spike propagation in driven chain networks with dominant global inhibition

    International Nuclear Information System (INIS)

    Chang Wonil; Jin, Dezhe Z.

    2009-01-01

    Spike propagation in chain networks is usually studied in the synfire regime, in which successive groups of neurons are synaptically activated sequentially through the unidirectional excitatory connections. Here we study the dynamics of chain networks with dominant global feedback inhibition that prevents the synfire activity. Neural activity is driven by suprathreshold external inputs. We analytically and numerically demonstrate that spike propagation along the chain is a unique dynamical attractor in a wide parameter regime. The strong inhibition permits a robust winner-take-all propagation in the case of multiple chains competing via the inhibition.

  12. Logistics Chains in Freight Transport Modelling

    NARCIS (Netherlands)

    Davydenko, I.Y.

    2015-01-01

    The flow of trade is not equal to transport flows, mainly due to the fact that warehouses and distribution facilities are used as intermediary stops on the way from production locations to the points of consumption or further rework of goods. This thesis proposes a logistics chain model, which

  13. The Electron Transport Chain: An Interactive Simulation

    Science.gov (United States)

    Romero, Chris; Choun, James

    2014-01-01

    This activity provides students an interactive demonstration of the electron transport chain and chemiosmosis during aerobic respiration. Students use simple, everyday objects as hydrogen ions and electrons and play the roles of the various proteins embedded in the inner mitochondrial membrane to show how this specific process in cellular…

  14. Energy Chain Analysis of Passenger Car Transport

    Directory of Open Access Journals (Sweden)

    Hans Jakob Walnum

    2011-02-01

    Full Text Available Transport makes up 20 percent of the World’s energy use; in OECD countries this has exceeded 30 percent. The International Energy Agency (IEA estimates that the global energy consumption will increase by 2.1 percent annually, a growth rate that is higher than for any other sector. The high energy consumption means that transportation accounts for nearly 30 percent of CO2 emission in OECD countries and is also one of the main sources of regional and local air pollution. In this article, we analyze energy consumption and greenhouse gas emissions from passenger car transport using an energy chain analysis. The energy chain analysis consists of three parts: the net direct energy use, the energy required for vehicle propulsion; the gross direct chain, which includes the net direct energy consumption plus the energy required to produce it; and, finally, the indirect energy chain, which includes the energy consumption for production, maintenance and operation of infrastructure plus manufacturing of the vehicle itself. In addition to energy consumption, we also analyze emissions of greenhouse gases measured by CO2-equivalents. We look at the trade-offs between energy use and greenhouse gas emissions to see whether some drivetrains and fuels perform favourable on both indicators. Except for the case of electric cars, where hydropower is the only energy source in the Norwegian context, no single car scores favourably on both energy consumption and greenhouse gas emissions.

  15. Linear ubiquitin chain induces apoptosis and inhibits tumor growth.

    Science.gov (United States)

    Qin, Zhoushuai; Jiang, Wandong; Wang, Guifen; Sun, Ying; Xiao, Wei

    2018-01-01

    Ubiquitination of proliferating cell nuclear antigen (PCNA) plays an important role in DNA damage response. Ectopic expression of PCNA fused at either terminus with ubiquitin (Ub) lacking two C-terminal glycine residues induces translesion DNA synthesis which resembles synthesis mediated by PCNA monoubiquitination. PCNA fused with Ub containing the C-terminal Gly residues at the C-terminus can be further polyubiquitinated in a Gly-dependent manner, which inhibits cell proliferation and induces ATR-dependent replication checkpoint. In this study, we surprisingly found that PCNA fused to a head-to-tail linear Ub chain induces apoptosis in a Ub chain length-dependent manner. Further investigation revealed that the apoptotic effect is actually induced by the linear Ub chain independently from PCNA, as the Ub chain fused to GFP or an epitope tag still efficiently induces apoptosis. It is revealed that the artificial linear Ub chain differs from endogenously encoded linear Ub chains in that its Ubs contain a Ub-G76S substitution, making the Ub chain resistant to cleavage by deubiquitination enzymes. We demonstrated in this study that ectopic expression of the artificial Ub chain alone in cultured human cancer cells is sufficient to inhibit tumor growth in a xenograft mouse model, making the linear Ub chain a putative anti-cancer agent.

  16. Simple model of inhibition of chain-branching combustion processes

    Science.gov (United States)

    Babushok, Valeri I.; Gubernov, Vladimir V.; Minaev, Sergei S.; Miroshnichenko, Taisia P.

    2017-11-01

    A simple kinetic model has been suggested to describe the inhibition and extinction of flame propagation in reaction systems with chain-branching reactions typical for hydrocarbon systems. The model is based on the generalised model of the combustion process with chain-branching reaction combined with the one-stage reaction describing the thermal mode of flame propagation with the addition of inhibition reaction steps. Inhibitor addition suppresses the radical overshoot in flame and leads to the change of reaction mode from the chain-branching reaction to a thermal mode of flame propagation. With the increase of inhibitor the transition of chain-branching mode of reaction to the reaction with straight-chains (non-branching chain reaction) is observed. The inhibition part of the model includes a block of three reactions to describe the influence of the inhibitor. The heat losses are incorporated into the model via Newton cooling. The flame extinction is the result of the decreased heat release of inhibited reaction processes and the suppression of radical overshoot with the further decrease of the reaction rate due to the temperature decrease and mixture dilution. A comparison of the results of modelling laminar premixed methane/air flames inhibited by potassium bicarbonate (gas phase model, detailed kinetic model) with the results obtained using the suggested simple model is presented. The calculations with the detailed kinetic model demonstrate the following modes of combustion process: (1) flame propagation with chain-branching reaction (with radical overshoot, inhibitor addition decreases the radical overshoot down to the equilibrium level); (2) saturation of chemical influence of inhibitor, and (3) transition to thermal mode of flame propagation (non-branching chain mode of reaction). The suggested simple kinetic model qualitatively reproduces the modes of flame propagation with the addition of the inhibitor observed using detailed kinetic models.

  17. Transport in nanoparticle chains influenced by reordering

    International Nuclear Information System (INIS)

    Luedtke, T.; Mirovsky, P.; Huether, R.; Govor, L.; Bauer, G.H.; Parisi, J.; Haug, R.J.

    2011-01-01

    Nanoparticles are deposited onto a mica substrate in a dewetting process of hexane solution containing the nanoparticles. The array of nanoparticles was measured inside an electron beam microscope containing a self-developed probing-tip setup. Transport measurements performed under vacuum conditions at room temperature show a power law behavior as expected for low-dimensional cluster systems. During the measurement a variation of the threshold voltage in the nonlinear current-voltage (I-V) characteristic was observed which we attribute to a reordering of the system by an applied electric field. - Highlights: → Fabrication of chains of ordered Au-nanoparticles. → Contact these nanoparticles without further chemical treatment with probing tips inside an electron microscope. → Observation of low-dimensional transport and Coulomb blockade. → Reordering of nanoparticles due to the applied electric field between the tips.

  18. Transport properties of a ladder with two random dimer chains

    International Nuclear Information System (INIS)

    Hu Dong-Sheng; Zhu Chen-Ping; Zhang Yong-Mei

    2011-01-01

    We investigate the transport properties of a ladder with two random dimer (RD) chains. It is found that there are two extended states in the ladder with identical RD chains and a critical state regarded as an extended state in the ladder with pairing RD chains. Such a critical state is caused by the chiral symmetry. The ladder with identical RD chains can be decoupled into two isolated RD chains and the ladder with pairing RD chains can not. The analytic expressions of the extended states are presented for the ladder with identical RD chains. (condensed matter: electronic structure, electrical, magnetic, and optical properties)

  19. UNCERTAINTY SUPPLY CHAIN MODEL AND TRANSPORT IN ITS DEPLOYMENTS

    Directory of Open Access Journals (Sweden)

    Fabiana Lucena Oliveira

    2014-05-01

    Full Text Available This article discusses the Model Uncertainty of Supply Chain, and proposes a matrix with their transportation modes best suited to their chains. From the detailed analysis of the matrix of uncertainty, it is suggested transportation modes best suited to the management of these chains, so that transport is the most appropriate optimization of the gains previously proposed by the original model, particularly when supply chains are distant from suppliers of raw materials and / or supplies.Here we analyze in detail Agile Supply Chains, which is a result of Uncertainty Supply Chain Model, with special attention to Manaus Industrial Center. This research was done at Manaus Industrial Pole, which is a model of industrial agglomerations, based in Manaus, State of Amazonas (Brazil, which contemplates different supply chains and strategies sharing same infrastructure of transport, handling and storage and clearance process and uses inbound for suppliers of raw material.  The state of art contemplates supply chain management, uncertainty supply chain model, agile supply chains, Manaus Industrial Center (MIC and Brazilian legislation, as a business case, and presents concepts and features, of each one. The main goal is to present and discuss how transport is able to support Uncertainty Supply Chain Model, in order to complete management model. The results obtained confirms the hypothesis of integrated logistics processes are able to guarantee attractivity for industrial agglomerations, and open discussions when the suppliers are far from the manufacturer center, in a logistics management.

  20. 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...

  1. Electron transport chain in a thermotolerant yeast.

    Science.gov (United States)

    Mejía-Barajas, Jorge A; Martínez-Mora, José A; Salgado-Garciglia, Rafael; Noriega-Cisneros, Ruth; Ortiz-Avila, Omar; Cortés-Rojo, Christian; Saavedra-Molina, Alfredo

    2017-04-01

    Yeasts capable of growing and surviving at high temperatures are regarded as thermotolerant. For appropriate functioning of cellular processes and cell survival, the maintenance of an optimal redox state is critical of reducing and oxidizing species. We studied mitochondrial functions of the thermotolerant Kluyveromyces marxianus SLP1 and the mesophilic OFF1 yeasts, through the evaluation of its mitochondrial membrane potential (ΔΨ m ), ATPase activity, electron transport chain (ETC) activities, alternative oxidase activity, lipid peroxidation. Mitochondrial membrane potential and the cytoplasmic free Ca 2+ ions (Ca 2+ cyt) increased in the SLP1 yeast when exposed to high temperature, compared with the mesophilic yeast OFF1. ATPase activity in the mesophilic yeast diminished 80% when exposed to 40° while the thermotolerant SLP1 showed no change, despite an increase in the mitochondrial lipid peroxidation. The SLP1 thermotolerant yeast exposed to high temperature showed a diminution of 33% of the oxygen consumption in state 4. The uncoupled state 3 of oxygen consumption did not change in the mesophilic yeast when it had an increase of temperature, whereas in the thermotolerant SLP1 yeast resulted in an increase of 2.5 times when yeast were grown at 30 o , while a decrease of 51% was observed when it was exposed to high temperature. The activities of the ETC complexes were diminished in the SLP1 when exposed to high temperature, but also it was distinguished an alternative oxidase activity. Our results suggest that the mitochondria state, particularly ETC state, is an important characteristic of the thermotolerance of the SLP1 yeast strain.

  2. Managing supply chains : transport optimization and chain synchronization

    NARCIS (Netherlands)

    van Woensel, T.; Dabia, S.; de Kok, A.G.; van Nunen, J.A.E.E.; Huijbregts, P.; Rietveld, P.

    2011-01-01

    Transport optimization is part of the broad area of physical distribution and logistics management. Physical distribution involves the handling, movement, and storage of goods from the point of origin to their point of consumption or use, via various channels of distribution. Logistics management

  3. Research on the Logistics Supply Chain in Port Logistics Transportation

    OpenAIRE

    Wang Yan-liang

    2013-01-01

    The aim of this study is to improve and increase the logistics system effectiveness and to solve the problem of optimal movement of different flows. Logistics transport carrying the world on material resources transfer exchange important mission and economic development and our lives are closely linked, logistics chain logistics transport occupies an important position and in the e logistics chain in port logistics has play a decisive role. For many coastal countries port logistics is the eco...

  4. The economic performance of supply chain(s) served by the mega freight transport vehicles

    NARCIS (Netherlands)

    Janic, M.

    2014-01-01

    This paper deals with the economic performances of supply chain(s) served by different including the mega freight transport vehicles. These performances are considered as a dimension of the supply chain’s sustainability together with the infrastructural, technical/technological, operational,

  5. Value Creation in the Maritime Chain of Transportation

    DEFF Research Database (Denmark)

    Roslyng Olesen, Thomas

    This report has examined the concept of value creation in the maritime chain of transportation. A maritime transport chain can best be conceptualized as a network through which carriers (e.g. shipping companies and haulage providers) and third parties (e.g. terminal operators, freight forwarders......, brokers and agents) provide services for the movement of cargo provided by shippers. The main actors in the maritime chain of transportation are the carriers who add value to the shipper by moving goods from areas with excess supply to areas with excess demand. In this process a number of (independent...... of the production chain and provide services which manufacturers don’t consider their core business (service). This includes assembly, quality control, customizing and packing of goods, pest control and after sales services. Third party ship management companies may reduce costs through economies of scale (cost...

  6. Hinterland transportation in container supply chains

    NARCIS (Netherlands)

    Bouchery, Y.; Fazi, S.; Fransoo, J.C.; Lee, C.Y.; Meng, Q.

    2015-01-01

    The increase in traded container volumes worldwide puts pressure on the hinterland road network, leading congestion and emission problems. This leads to a requirement to develop intermodal transportation systems. In this chapter, we analyze the most important features of such container

  7. Heptachlor induced mitochondria-mediated cell death via impairing electron transport chain complex III

    International Nuclear Information System (INIS)

    Hong, Seokheon; Kim, Joo Yeon; Hwang, Joohyun; Shin, Ki Soon; Kang, Shin Jung

    2013-01-01

    Highlights: •Heptachlor inhibited mitochondrial electron transport chain complex III activity. •Heptachlor promoted generation of reactive oxygen species. •Heptachlor induced Bax activation. •Heptachlor induced mitochondria-mediated and caspase-dependent apoptosis. -- Abstract: Environmental toxins like pesticides have been implicated in the pathogenesis of Parkinson’s disease (PD). Epidemiological studies suggested that exposures to organochlorine pesticides have an association with an increased PD risk. In the present study, we examined the mechanism of toxicity induced by an organochlorine pesticide heptachlor. In a human dopaminergic neuroblastoma SH-SY5Y cells, heptachlor induced both morphological and functional damages in mitochondria. Interestingly, the compound inhibited mitochondrial electron transport chain complex III activity. Rapid generation of reactive oxygen species and the activation of Bax were then detected. Subsequently, mitochondria-mediated, caspase-dependent apoptosis followed. Our results raise a possibility that an organochlorine pesticide heptachlor can act as a neurotoxicant associated with PD

  8. Heptachlor induced mitochondria-mediated cell death via impairing electron transport chain complex III

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Seokheon; Kim, Joo Yeon; Hwang, Joohyun [Department of Molecular Biology, Sejong University, Seoul 143-747 (Korea, Republic of); Shin, Ki Soon [Department of Biology, Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul 130-701 (Korea, Republic of); Kang, Shin Jung, E-mail: sjkang@sejong.ac.kr [Department of Molecular Biology, Sejong University, Seoul 143-747 (Korea, Republic of)

    2013-08-09

    Highlights: •Heptachlor inhibited mitochondrial electron transport chain complex III activity. •Heptachlor promoted generation of reactive oxygen species. •Heptachlor induced Bax activation. •Heptachlor induced mitochondria-mediated and caspase-dependent apoptosis. -- Abstract: Environmental toxins like pesticides have been implicated in the pathogenesis of Parkinson’s disease (PD). Epidemiological studies suggested that exposures to organochlorine pesticides have an association with an increased PD risk. In the present study, we examined the mechanism of toxicity induced by an organochlorine pesticide heptachlor. In a human dopaminergic neuroblastoma SH-SY5Y cells, heptachlor induced both morphological and functional damages in mitochondria. Interestingly, the compound inhibited mitochondrial electron transport chain complex III activity. Rapid generation of reactive oxygen species and the activation of Bax were then detected. Subsequently, mitochondria-mediated, caspase-dependent apoptosis followed. Our results raise a possibility that an organochlorine pesticide heptachlor can act as a neurotoxicant associated with PD.

  9. 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.

  10. The impact of transport processes standardization on supply chain efficiency

    Directory of Open Access Journals (Sweden)

    Maciej Stajniak

    2016-03-01

    Full Text Available Background: During continuous market competition, focusing on the customer service level, lead times and supply flexibility is very important to analyze the efficiency of logistics processes. Analysis of supply chain efficiency is one of the fundamental elements of controlling analysis. Transport processes are a key process that provides physical material flow through the supply chain. Therefore, in this article Authors focus attention on the transport processes efficiency. Methods: The research carried out in the second half of 2014 year, in 210 enterprises of the Wielkopolska Region. Observations and business practice studies conducted by the authors, demonstrate a significant impact of standardization processes on supply chain efficiency. Based on the research results, have been developed standard processes that have been assessed as being necessary to standardize in business practice. Results: Based on these research results and observations, authors have developed standards for transport processes by BPMN notation. BPMN allows authors to conduct multivariate simulation of these processes in further stages of research. Conclusions: Developed standards are the initial stage of research conducted by Authors in the assessment of transport processes efficiency. Further research direction is to analyze the use efficiency of transport processes standards in business practice and their impact on the effectiveness of the entire supply chain.

  11. Anticancer Drugs Targeting the Mitochondrial Electron Transport Chain

    Czech Academy of Sciences Publication Activity Database

    Rohlena, Jakub; Dong, L.-F.; Ralph, S.J.; Neužil, Jiří

    2011-01-01

    Roč. 15, č. 12 (2011), s. 2951-2974 ISSN 1523-0864 R&D Projects: GA AV ČR(CZ) KAN200520703 Institutional research plan: CEZ:AV0Z50520701 Keywords : Targets for anticancer drugs * mitochondrial electron transport chain * mitocans Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 8.456, year: 2011

  12. Land transportation model for supply chain manufacturing industries

    Science.gov (United States)

    Kurniawan, Fajar

    2017-12-01

    Supply chain is a system that integrates production, inventory, distribution and information processes for increasing productivity and minimize costs. Transportation is an important part of the supply chain system, especially for supporting the material distribution process, work in process products and final products. In fact, Jakarta as the distribution center of manufacturing industries for the industrial area. Transportation system has a large influences on the implementation of supply chain process efficiency. The main problem faced in Jakarta is traffic jam that will affect on the time of distribution. Based on the system dynamic model, there are several scenarios that can provide solutions to minimize timing of distribution that will effect on the cost such as the construction of ports approaching industrial areas other than Tanjung Priok, widening road facilities, development of railways system, and the development of distribution center.

  13. Bias-dependent oscillatory electron transport of monatomic sulfur chains

    KAUST Repository

    Yu, Jing-Xin; Cheng, Yan; Sanvito, Stefano; Chen, Xiang-Rong

    2012-01-01

    The bias-dependent oscillatory electron transport of monatomic sulfur chains sandwiched between gold electrodes is investigated with density functional theory and non-equilibrium Green's function method. At zero bias, in contrast to the typical odd-even oscillations observed in most metallic chains, we find that the conductance oscillates with a period of four atoms. However, as the bias voltage is increased the current displays a two-atom periodicity. This emerges gradually, first for the longer chains and then, at voltages larger than 0.7 V, for lengths. The oscillatory behaviors are analyzed by the density of states and the energy-dependent and bias-dependent transmission coefficients. © 2012 American Institute of Physics.

  14. Bias-dependent oscillatory electron transport of monatomic sulfur chains

    KAUST Repository

    Yu, Jing-Xin

    2012-01-01

    The bias-dependent oscillatory electron transport of monatomic sulfur chains sandwiched between gold electrodes is investigated with density functional theory and non-equilibrium Green\\'s function method. At zero bias, in contrast to the typical odd-even oscillations observed in most metallic chains, we find that the conductance oscillates with a period of four atoms. However, as the bias voltage is increased the current displays a two-atom periodicity. This emerges gradually, first for the longer chains and then, at voltages larger than 0.7 V, for lengths. The oscillatory behaviors are analyzed by the density of states and the energy-dependent and bias-dependent transmission coefficients. © 2012 American Institute of Physics.

  15. Transportation and concentration inequalities for bifurcating Markov chains

    DEFF Research Database (Denmark)

    Penda, S. Valère Bitseki; Escobar-Bach, Mikael; Guillin, Arnaud

    2017-01-01

    We investigate the transportation inequality for bifurcating Markov chains which are a class of processes indexed by a regular binary tree. Fitting well models like cell growth when each individual gives birth to exactly two offsprings, we use transportation inequalities to provide useful...... concentration inequalities.We also study deviation inequalities for the empirical means under relaxed assumptions on the Wasserstein contraction for the Markov kernels. Applications to bifurcating nonlinear autoregressive processes are considered for point-wise estimates of the non-linear autoregressive...

  16. Gathering Information from Transport Systems for Processing in Supply Chains

    Science.gov (United States)

    Kodym, Oldřich; Unucka, Jakub

    2016-12-01

    Paper deals with complex system for processing information from means of transport acting as parts of train (rail or road). It focuses on automated information gathering using AutoID technology, information transmission via Internet of Things networks and information usage in information systems of logistic firms for support of selected processes on MES and ERP levels. Different kinds of gathered information from whole transport chain are discussed. Compliance with existing standards is mentioned. Security of information in full life cycle is integral part of presented system. Design of fully equipped system based on synthesized functional nodes is presented.

  17. Ocean container transport : an underestimated and critical link in global supply chain performance

    NARCIS (Netherlands)

    Fransoo, J.C.; Lee, C.Y.

    2010-01-01

    With supply chains distributed across global markets, ocean container transport now is a critical element of any such supply chain. We identify key characteristics of ocean container transport from a supply chain perspective. We find that unlike continental (road) transport, service offerings tend

  18. The critical role of ocean container transport in global supply chain performance

    NARCIS (Netherlands)

    Fransoo, J.C.; Lee, C.Y.

    2013-01-01

    With supply chains distributed across global markets, ocean container transport now is a critical element of any such supply chain. We identify key characteristics of ocean container transport from a supply chain perspective. We find that unlike continental (road) transport, service offerings tend

  19. 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.

  20. Inhibition of gastrin-stimulated gastric acid secretion by medium-chain triglycerides and long-chain triglycerides in healthy young men.

    NARCIS (Netherlands)

    Maas, M.I.M.; Hopman, W.P.M.; Katan, M.B.; Jansen, J.B.M.J.

    1996-01-01

    Long-chain triglycerides inhibit gastric acid secretion, but the effect of medium-chain triglycerides in humans is unknown. We compared the effects of intraduodenally perfused saline, medium-chain and long-chain triglycerides on gastrin-stimulated gastric acid secretion and cholecystokinin release.

  1. Electromagnetic energy transport in nanoparticle chains via dark plasmon modes.

    Science.gov (United States)

    Solis, David; Willingham, Britain; Nauert, Scott L; Slaughter, Liane S; Olson, Jana; Swanglap, Pattanawit; Paul, Aniruddha; Chang, Wei-Shun; Link, Stephan

    2012-03-14

    Using light to exchange information offers large bandwidths and high speeds, but the miniaturization of optical components is limited by diffraction. Converting light into electron waves in metals allows one to overcome this problem. However, metals are lossy at optical frequencies and large-area fabrication of nanometer-sized structures by conventional top-down methods can be cost-prohibitive. We show electromagnetic energy transport with gold nanoparticles that were assembled into close-packed linear chains. The small interparticle distances enabled strong electromagnetic coupling causing the formation of low-loss subradiant plasmons, which facilitated energy propagation over many micrometers. Electrodynamic calculations confirmed the dark nature of the propagating mode and showed that disorder in the nanoparticle arrangement enhances energy transport, demonstrating the viability of using bottom-up nanoparticle assemblies for ultracompact opto-electronic devices. © 2012 American Chemical Society

  2. Histone Deacetylase Inhibition and Dietary Short-Chain Fatty Acids

    OpenAIRE

    Licciardi, Paul V.; Ververis, Katherine; Karagiannis, Tom C.

    2011-01-01

    Changes in diet can also have dramatic effects on the composition of gut microbiota. Commensal bacteria of the gastrointestinal tract are critical regulators of health and disease by protecting against pathogen encounter whilst also maintaining immune tolerance to certain allergens. Moreover, consumption of fibre and vegetables typical of a non-Western diet generates substantial quantities of short-chain fatty acids (SCFAs) which have potent anti-inflammatory properties. Dietary interventions...

  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. Field dependent spin transport of anisotropic Heisenberg chain

    Energy Technology Data Exchange (ETDEWEB)

    Rezania, H., E-mail: rezania.hamed@gmail.com

    2016-04-01

    We have addressed the static spin conductivity and spin Drude weight of one-dimensional spin-1/2 anisotropic antiferromagnetic Heisenberg chain in the finite magnetic field. We have investigated the behavior of transport properties by means of excitation spectrum in terms of a hard core bosonic representation. The effect of in-plane anisotropy on the spin transport properties has also been studied via the bosonic model by Green's function approach. This anisotropy is considered for exchange constants that couple spin components perpendicular to magnetic field direction. We have found the temperature dependence of the spin conductivity and spin Drude weight in the gapped field induced spin-polarized phase for various magnetic field and anisotropy parameters. Furthermore we have studied the magnetic field dependence of static spin conductivity and Drude weight for various anisotropy parameters. Our results show the regular part of spin conductivity vanishes in isotropic case however Drude weight has a finite non-zero value and the system exhibits ballistic transport properties. We also find the peak in the static spin conductivity factor moves to higher temperature upon increasing the magnetic field at fixed anisotropy. The static spin conductivity is found to be monotonically decreasing with magnetic field due to increase of energy gap in the excitation spectrum. Furthermore we have studied the temperature dependence of spin Drude weight for different magnetic field and various anisotropy parameters. - Highlights: • Theoretical calculation of spin conductivity of spin chain Heisenberg model. • The investigation of the effects of anisotropy and magnetic field on the temperature dependence of spin conductivity. • The study of the effect of temperature on the spin Drude weight.

  5. Inhibition of Long Chain Fatty Acyl-CoA Synthetase (ACSL) and Ischemia Reperfusion Injury

    Science.gov (United States)

    Prior, Allan M.; Zhang, Man; Blakeman, Nina; Datta, Palika; Pham, Hung; Young, Lindon H.; Weis, Margaret T.; Hua, Duy H.

    2014-01-01

    Various triacsin C analogs, containing different alkenyl chains and carboxylic acid bioisoteres including 4-aminobenzoic acid, isothiazolidine dioxide, hydroxylamine, hydroxytriazene, and oxadiazolidine dione, were synthesized and their inhibitions of long chain fatty acyl-CoA synthetase (ACSL) were examined. Two methods, a cell-based assay of ACSL activity and an in situ [14C]-palmitate incorporation into extractable lipids were used to study the inhibition. Using an in vivo leukocyte recruitment inhibition protocol, the translocation of one or more cell adhesion molecules from the cytoplasm to the plasma membrane on either the endothelium or leukocyte or both was inhibited by inhibitors 1, 9, and triacsin C. The results suggest that inhibition of ACSL may attenuate the vascular inflammatory component associated with ischemia reperfusion injury and lead to a decrease of infarct expansion. PMID:24480468

  6. Proton Transport Chains in Glucose Metabolism: Mind the Proton

    Directory of Open Access Journals (Sweden)

    Dirk Roosterman

    2018-06-01

    Full Text Available The Embden–Meyerhof–Parnas (EMP pathway comprises eleven cytosolic enzymes interacting to metabolize glucose to lactic acid [CH3CH(OHCOOH]. Glycolysis is largely considered as the conversion of glucose to pyruvate (CH3COCOO-. We consider glycolysis to be a cellular process and as such, transporters mediating glucose uptake and lactic acid release and enable the flow of metabolites through the cell, must be considered as part of the EMP pathway. In this review, we consider the flow of metabolites to be coupled to a flow of energy that is irreversible and sufficient to form ordered structures. This latter principle is highlighted by discussing that lactate dehydrogenase (LDH complexes irreversibly reduce pyruvate/H+ to lactate [CH3CH(OHCOO-], or irreversibly catalyze the opposite reaction, oxidation of lactate to pyruvate/H+. However, both LDH complexes are considered to be driven by postulated proton transport chains. Metabolism of glucose to two lactic acids is introduced as a unidirectional, continuously flowing pathway. In an organism, cell membrane-located proton-linked monocarboxylate transporters catalyze the final step of glycolysis, the release of lactic acid. Consequently, both pyruvate and lactate are discussed as intermediate products of glycolysis and substrates of regulated crosscuts of the glycolytic flow.

  7. Liver mitochondrial dysfunction and electron transport chain defect induced by high dietary copper in broilers.

    Science.gov (United States)

    Yang, Fan; Cao, Huabin; Su, Rongsheng; Guo, Jianying; Li, Chengmei; Pan, Jiaqiang; Tang, Zhaoxin

    2017-09-01

    Copper is an important trace mineral in the diet of poultry due to its biological activity. However, limited information is available concerning the effects of high copper on mitochondrial dysfunction. In this study, 72 broilers were used to investigate the effects of high dietary copper on liver mitochondrial dysfunction and electron transport chain defect. Birds were fed with different concentrations [11, 110, 220, and 330 mg of copper/kg dry matter (DM)] of copper from tribasic copper chloride (TBCC). The experiment lasted for 60 d. Liver tissues on d 60 were subjected to histopathological observation. Additionally, liver mitochondrial function was recorded on d 12, 36, and 60. Moreover, a site-specific defect in the electron transport chain in liver mitochondria was also identified by using various chemical inhibitors of mitochondrial respiration. The results showed different degrees of degeneration, mitochondrial swelling, and high-density electrons in hepatocytes. In addition, the respiratory control ratio (RCR) and oxidative phosphorylation rate (OPR) in liver mitochondria increased at first and then decreased in high-dose groups. Moreover, hydrogen peroxide (H2O2) generation velocity in treated groups was higher than that in control group, which were magnified by inhibiting electron transport at Complex IV. The results indicated that high dietary copper could decline liver mitochondrial function in broilers. The presence of a site-specific defect at Complex IV in liver mitochondria may be responsible for liver mitochondrial dysfunction caused by high dietary copper. © 2017 Poultry Science Association Inc.

  8. Changes in mitochondrial electron transport chain activity during insect metamorphosis.

    Science.gov (United States)

    Chamberlin, M E

    2007-02-01

    The midgut of the tobacco hornworm (Manduca sexta) is a highly aerobic tissue that is destroyed by programmed cell death during larval-pupal metamorphosis. The death of the epithelium begins after commitment to pupation, and the oxygen consumption of isolated midgut mitochondria decreases soon after commitment. To assess the role of the electron transport chain in this decline in mitochondrial function, the maximal activities of complexes I-IV of the respiratory chain were measured in isolated midgut mitochondria. Whereas there were no developmental changes in the activity of complex I or III, activities of complexes II and IV [cytochrome c oxidase (COX)] were higher in mitochondria from precommitment than postcommitment larvae. This finding is consistent with a higher rate of succinate oxidation in mitochondria isolated from precommitment larvae and reveals that the metamorphic decline in mitochondrial respiration is due to the targeted destruction or inactivation of specific sites within the mitochondria, rather than the indiscriminate destruction of the organelles. The COX turnover number (e- x s(-1) x cytochrome aa3(-1)) was greater for the enzyme from precommitment than postcommitment larvae, indicating a change in the enzyme structure and/or its lipid environment during the early stages of metamorphosis. The turnover number of COX in the intact mitochondria (in organello COX) was also lower in postcommitment larvae. In addition to changes in the protein or membrane phospholipids, the metamorphic decline in this rate constant may be a result of the observed loss of endogenous cytochrome c.

  9. Inhibition of DNA chain elongation in Chinese hamster cells by damage localized behind the replication fork

    Energy Technology Data Exchange (ETDEWEB)

    Ben-Hur, E [Israel Atomic Energy Commission, Beersheba. Nuclear Research Center-Negev; Hagan, M P [Armed Forces Radiobiology Research Inst., Bethesda, MD (USA)

    1984-05-01

    Chinese hamster fibroblasts were pulse labelled with 5-bromodeoxyuridine and exposed at time intervals (Tsub(i)) to near-ultraviolet (U.V.A.) light in the presence of a bisbenzimidazole derivative (Hoechst 33342). The sensitivity of the cells in terms of colony forming ability fluctuated depending on Tsub(i). Inhibition of DNA synthesis also depended on Tsub(i) and was maximal when Tsub(i)=O. Using the alkaline elution technique it was shown that the effect of a large dose of light was to inhibit both initiation and elongation of DNA chains. These effects were most pronounced for Tsub(i)=O. It is concluded that DNA damage in an active replicon can inhibit initiation of new replicons and that damage localized behind the replication fork can retard elongation of nascent DNA chains. This effect on chain elongation decreases with increased distance of the damage from the replication fork.

  10. The Impacts of Phosphorus Deficiency on the Photosynthetic Electron Transport Chain1[OPEN

    Science.gov (United States)

    2018-01-01

    Phosphorus (P) is an essential macronutrient, and P deficiency limits plant productivity. Recent work showed that P deficiency affects electron transport to photosystem I (PSI), but the underlying mechanisms are unknown. Here, we present a comprehensive biological model describing how P deficiency disrupts the photosynthetic machinery and the electron transport chain through a series of sequential events in barley (Hordeum vulgare). P deficiency reduces the orthophosphate concentration in the chloroplast stroma to levels that inhibit ATP synthase activity. Consequently, protons accumulate in the thylakoids and cause lumen acidification, which inhibits linear electron flow. Limited plastoquinol oxidation retards electron transport to the cytochrome b6f complex, yet the electron transfer rate of PSI is increased under steady-state growth light and is limited under high-light conditions. Under P deficiency, the enhanced electron flow through PSI increases the levels of NADPH, whereas ATP production remains restricted and, hence, reduces CO2 fixation. In parallel, lumen acidification activates the energy-dependent quenching component of the nonphotochemical quenching mechanism and prevents the overexcitation of photosystem II and damage to the leaf tissue. Consequently, plants can be severely affected by P deficiency for weeks without displaying any visual leaf symptoms. All of the processes in the photosynthetic machinery influenced by P deficiency appear to be fully reversible and can be restored in less than 60 min after resupply of orthophosphate to the leaf tissue. PMID:29540590

  11. The Impacts of Phosphorus Deficiency on the Photosynthetic Electron Transport Chain.

    Science.gov (United States)

    Carstensen, Andreas; Herdean, Andrei; Schmidt, Sidsel Birkelund; Sharma, Anurag; Spetea, Cornelia; Pribil, Mathias; Husted, Søren

    2018-05-01

    Phosphorus (P) is an essential macronutrient, and P deficiency limits plant productivity. Recent work showed that P deficiency affects electron transport to photosystem I (PSI), but the underlying mechanisms are unknown. Here, we present a comprehensive biological model describing how P deficiency disrupts the photosynthetic machinery and the electron transport chain through a series of sequential events in barley ( Hordeum vulgare ). P deficiency reduces the orthophosphate concentration in the chloroplast stroma to levels that inhibit ATP synthase activity. Consequently, protons accumulate in the thylakoids and cause lumen acidification, which inhibits linear electron flow. Limited plastoquinol oxidation retards electron transport to the cytochrome b 6 f complex, yet the electron transfer rate of PSI is increased under steady-state growth light and is limited under high-light conditions. Under P deficiency, the enhanced electron flow through PSI increases the levels of NADPH, whereas ATP production remains restricted and, hence, reduces CO 2 fixation. In parallel, lumen acidification activates the energy-dependent quenching component of the nonphotochemical quenching mechanism and prevents the overexcitation of photosystem II and damage to the leaf tissue. Consequently, plants can be severely affected by P deficiency for weeks without displaying any visual leaf symptoms. All of the processes in the photosynthetic machinery influenced by P deficiency appear to be fully reversible and can be restored in less than 60 min after resupply of orthophosphate to the leaf tissue. © 2018 American Society of Plant Biologists. All Rights Reserved.

  12. K-252a, a novel microbial product, inhibits smooth muscle myosin light chain kinase

    International Nuclear Information System (INIS)

    Nakanishi, S.; Yamada, K.; Kase, H.; Nakamura, S.; Nonomura, Y.

    1988-01-01

    Effects of K-252a, purified from the culture broth of Nocardiopsis sp., on the activity of myosin (light chain kinase were investigated. 1) K-252a affected three characteristic properties of chicken gizzard myosin-B, natural actomyosin, to a similar degree: the Ca 2+ -dependent activity of ATPase, superprecipitation, and the phosphorylation of the myosin light chain. 2) K-252a inhibited the activities of the purified myosin light chain kinase and a Ca 2+ -independent form of the enzyme which was constructed by cross-linking of myosin light chain kinase and calmodulin using glutaraldehyde. The degrees of inhibition by 3 x 10 -6 M K-252a were 69 and 48% of the control activities with the purified enzyme and the cross-linked complex, respectively. Chlorpromazine (3 x 10 -4 M), a calmodulin antagonist, inhibited the native enzyme, but not the cross-linked one. These results suggested that K-252a inhibited myosin light chain kinase by direct interaction with the enzyme, whereas chlorpromazine suppressed the enzyme activation by interacting with calmodulin. 3) The inhibition by K-252a of the cross-linked kinase was affected by the concentration of ATP, a phosphate donor. The concentration causing 50% inhibition was two orders magnitude lowere in the presence of 100 μM ATP than in the presence of 2 mM ATP. 4) Kinetic analyses using [γ- 32 P]ATP indicated that the inhibitory mode of K-252a was competitive with respect to ATP. These results suggest that K-252a interacts at the ATP-binding domain of myosin light chain kinase

  13. Copper accumulation and transport in a marine food chain composed of Platymonas subcordiformis, brachionus plicatilis and Penaeus monodon

    Science.gov (United States)

    Cai, A.-Gen; Chen, Wei-Qi; Li, Wen-Quan

    1997-09-01

    Accumulation, transport and toxicity of Cu in the food chain consisting of Platymonas subcordiformis, Brachionus plicatilis and Penaeus monodon were studied. Effects of Cu on the growth of organisms in the food chain were investigated and the inhibiting effect concentration (EC50) of Cu was then determined according to the dynamics of the relative number of cells or total individuals of organisms, expressed in percentages with reference to the controlled system, under different culture conditions. On the basis of the variations in accumulation and percentages of accumulation of Cu in the biological phase, the relationship between the accumulation of Cu in organisms and its toxicity was analyzed and the main approach for determining the transport of Cu in the food chain was then discussed.

  14. Inhibition of telomerase by linear-chain fatty acids: a structural analysis.

    Science.gov (United States)

    Oda, Masako; Ueno, Takamasa; Kasai, Nobuyuki; Takahashi, Hirotada; Yoshida, Hiromi; Sugawara, Fumio; Sakaguchi, Kengo; Hayashi, Hideya; Mizushina, Yoshiyuki

    2002-01-01

    In the present study, we have found that mono-unsaturated linear-chain fatty acids in the cis configuration with C(18) hydrocarbon chains (i.e. oleic acid) strongly inhibited the activity of human telomerase in a cell-free enzymic assay, with an IC(50) value of 8.6 microM. Interestingly, fatty acids with hydrocarbon chain lengths below 16 or above 20 carbons substantially decreased the potency of inhibition of telomerase. Moreover, the cis-mono-unsaturated C(18) linear-chain fatty acid oleic acid was the strongest inhibitor of all the fatty acids tested. A kinetic study revealed that oleic acid competitively inhibited the activity of telomerase ( K (i)=3.06 microM) with respect to the telomerase substrate primer. The energy-minimized three-dimensional structure of the linear-chain fatty acid was calculated and modelled. A molecule width of 11.53-14.26 A (where 1 A=0.1 nm) in the C(16) to C(20) fatty acid structure was suggested to be important for telomerase inhibition. The three-dimensional structure of the telomerase active site (i.e. the substrate primer-binding site) appears to have a pocket that could bind oleic acid, with the pocket being 8.50 A long and 12.80 A wide. PMID:12121150

  15. Histone deacetylase inhibition and dietary short-chain Fatty acids.

    Science.gov (United States)

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

    2011-01-01

    Changes in diet can also have dramatic effects on the composition of gut microbiota. Commensal bacteria of the gastrointestinal tract are critical regulators of health and disease by protecting against pathogen encounter whilst also maintaining immune tolerance to certain allergens. Moreover, consumption of fibre and vegetables typical of a non-Western diet generates substantial quantities of short-chain fatty acids (SCFAs) which have potent anti-inflammatory properties. Dietary interventions such as probiotic supplementation have been investigated for their pleiotropic effects on microbiota composition and immune function. Probiotics may restore intestinal dysbiosis and improve clinical disease through elevated SCFA levels in the intestine. Although the precise mechanisms by which such dietary factors mediate these effects, SCFA metabolites such as butyrate also function as histone deacetylase inhibitors (HDACi), that can act on the epigenome through chromatin remodeling changes. The aim of this review is to provide an overview of HDAC enzymes and to discuss the biological effects of HDACi. Further, we discuss the important relationship between diet and the balance between health and disease and how novel dietary interventions such as probiotics could be alternative approach for the prevention and/or treatment of chronic inflammatory disease through modulation of the intestinal microbiome.

  16. Adapting transport modes to supply chains classified by the uncertainty supply chain model: A case study at Manaus Industrial Pole

    Directory of Open Access Journals (Sweden)

    Fabiana Lucena Oliveira

    2017-01-01

    Full Text Available This paper discusses transport modes supporting Uncertainty Supply Chain Model (USCM in the case of Manaus Industrial Pole (PIM, an industrial cluster in the Brazilian Amazon that hosts six hundred factories with diverse logistics and supply chain managerial strategies. USCM (Lee, 2002; Fisher, 1997develops a dot matrix classification of the supply chains considering several attributes (e.g., agility, cost, security, responsiveness and argues that emergent economies industrial clusters, in the effort to keep attractiveness for technological frontier firms, need to adapt supply chain strategies according to USCM attributes. The paper takes a further step, discussing which transport modes are suitable to each supply chain classified at the USCM in PIM´s case. The research´s methods covered the use of PIM´s statistical official database (secondary data, interviews with the main logistical services providers of PIM and phone survey with a sample of firms (primary data. Findings confirm the theoretical argument that different supply chains will demand different transport modes running at the same time in the same industrial cluster (Oliveira, 2009. In the case of PIM, this implies investments on port and airport infrastructure and a strategic focus on air transport mode, due to (1 short life cycle of products, (2 distance from suppliers, (3 quick response to demand and (4 the fact that even PIM´s standard products use, in average, forty per cent of air transport at inbound logistics.

  17. Evaluation of functioning of mitochondrial electron transport chain with NADH and FAD autofluorescence

    Science.gov (United States)

    Danylovych, H V

    2016-01-01

    We prove the feasibility of evaluation of mitochondrial electron transport chain function in isolated mitochondria of smooth muscle cells of rats from uterus using fluorescence of NADH and FAD coenzymes. We found the inversely directed changes in FAD and NADH fluorescence intensity under normal functioning of mitochondrial electron transport chain. The targeted effect of inhibitors of complex I, III and IV changed fluorescence of adenine nucleotides. Rotenone (5 μM) induced rapid increase in NADH fluorescence due to inhibition of complex I, without changing in dynamics of FAD fluorescence increase. Antimycin A, a complex III inhibitor, in concentration of 1 μg/ml caused sharp increase in NADH fluorescence and moderate increase in FAD fluorescence in comparison to control. NaN3 (5 mM), a complex IV inhibitor, and CCCP (10 μM), a protonophore, caused decrease in NADH and FAD fluorescence. Moreover, all the inhibitors caused mitochondria swelling. NO donors, e.g. 0.1 mM sodium nitroprusside and sodium nitrite similarly to the effects of sodium azide. Energy-dependent Ca2+ accumulation in mitochondrial matrix (in presence of oxidation substrates and Mg-ATP2- complex) is associated with pronounced drop in NADH and FAD fluorescence followed by increased fluorescence of adenine nucleotides, which may be primarily due to Ca2+- dependent activation of dehydrogenases of citric acid cycle. Therefore, the fluorescent signal of FAD and NADH indicates changes in oxidation state of these nucleotides in isolated mitochondria, which may be used to assay the potential of effectors of electron transport chain.

  18. Cannabinoid-Induced Changes in the Activity of Electron Transport Chain Complexes of Brain Mitochondria.

    Science.gov (United States)

    Singh, Namrata; Hroudová, Jana; Fišar, Zdeněk

    2015-08-01

    The aim of this study was to investigate changes in the activity of individual mitochondrial respiratory chain complexes (I, II/III, IV) and citrate synthase induced by pharmacologically different cannabinoids. In vitro effects of selected cannabinoids on mitochondrial enzymes were measured in crude mitochondrial fraction isolated from pig brain. Both cannabinoid receptor agonists, Δ(9)-tetrahydrocannabinol, anandamide, and R-(+)-WIN55,212-2, and antagonist/inverse agonists of cannabinoid receptors, AM251, and cannabidiol were examined in pig brain mitochondria. Different effects of these cannabinoids on mitochondrial respiratory chain complexes and citrate synthase were found. Citrate synthase activity was decreased only by Δ(9)-tetrahydrocannabinol and AM251. Significant increase in the complex I activity was induced by anandamide. At micromolar concentration, all the tested cannabinoids inhibited the activity of electron transport chain complexes II/III and IV. Stimulatory effect of anandamide on activity of complex I may participate on distinct physiological effects of endocannabinoids compared to phytocannabinoids or synthetic cannabinoids. Common inhibitory effect of cannabinoids on activity of complex II/III and IV confirmed a non-receptor-mediated mechanism of cannabinoid action on individual components of system of oxidative phosphorylation.

  19. Influence of polymer chain architecture of poly(vinyl alcohol) on the inhibition of ice recrystallization

    NARCIS (Netherlands)

    Olijve, L.L.C.; Hendrix, M.M.R.M.; Voets, I.K.

    2016-01-01

    Poly(vinyl alcohol) (PVA) is a water-soluble synthetic polymer well-known to effectively block the recrystallization of ice. The effect of polymer chain architecture on the ice recrystallization inhibition (IRI) by PVA remains unexplored. In this work, the synthesis of PVA molecular bottlebrushes is

  20. On Production and Green Transportation Coordination in a Sustainable Global Supply Chain

    Directory of Open Access Journals (Sweden)

    Feng Guo

    2017-11-01

    Full Text Available This paper addresses a coordination problem of production and green transportation and the effects of production and transportation coordination on supply chain sustainability in a global supply chain environment with the consideration of important realistic characteristics, including parallel machines, different order processing complexities, fixed delivery departure times, green transportation and multiple transportation modes. We formulate the measurements for carbon emissions of different transportation modes, including air, sea and land transportation. A hybrid genetic algorithm-based optimization approach is developed to handle this problem, in which a hybrid genetic algorithm and heuristic procedures are combined. The effectiveness of the proposed approach is validated by means of various problem instances. We observe that the coordination of production and green transportation has a large effect on the overall supply chain sustainability, which can reduce the total supply chain cost by 9.60% to 21.90%.

  1. Currents and fluctuations of quantum heat transport in harmonic chains

    International Nuclear Information System (INIS)

    Motz, T; Ankerhold, J; Stockburger, J T

    2017-01-01

    Heat transport in open quantum systems is particularly susceptible to the modeling of system–reservoir interactions. It thus requires us to consistently treat the coupling between a quantum system and its environment. While perturbative approaches are successfully used in fields like quantum optics and quantum information, they reveal deficiencies—typically in the context of thermodynamics, when it is essential to respect additional criteria such as fluctuation-dissipation theorems. We use a non-perturbative approach for quantum dissipative dynamics based on a stochastic Liouville–von Neumann equation to provide a very general and extremely efficient formalism for heat currents and their correlations in open harmonic chains. Specific results are derived not only for first- but also for second-order moments, which requires us to account for both real and imaginary parts of bath–bath correlation functions. Spatiotemporal patterns are compared with weak coupling calculations. The regime of stronger system–reservoir couplings gives rise to an intimate interplay between reservoir fluctuations and heat transfer far from equilibrium. (paper)

  2. Heat Transport in Gapped Spin-Chain Systems

    International Nuclear Information System (INIS)

    Shimshoni, E.

    2006-01-01

    Full Text: We study the contribution of magnetic excitations to the heat transport in gapped spin-chain systems. These systems are characterized by a substantially enhanced heat conductivity, which can be traced back to the existence of weakly violated conservation laws. We focus particularly on the behavior of clean two-leg spin ladder compounds, where one-dimensional exotic spin excitations are coupled to three-dimensional phonons. We show that the contributions of the two types of heat carriers can not be easily disentangled. Depending on the ratios of spin gaps and the Debye energy, the heat conductivity can be either exponentially increasing or exponentially decreasing as a function of temperature (T). In addition, the magnetic contribution to the total heat conductivity may be either positive or negative. We discuss its T-dependence in various possible regimes, and note that in most regimes it is dominated by spin-phonon drag: the two types of heat carriers have almost the

  3. Short chain molecular junctions: Charge transport versus dipole moment

    International Nuclear Information System (INIS)

    Ikram, I. Mohamed; Rabinal, M.K.

    2015-01-01

    Graphical abstract: - Highlights: • The role of dipole moment of organic molecules on molecular junctions has been studied. • Molecular junctions constituted using propargyl molecules of different dipole moments. • The electronic properties of the molecules were calculated using Gaussian software. • Junctions show varying rectification due to their varying dipole moment and orientation. - Abstract: The investigation of the influence of dipole moment of short chain organic molecules having three carbon atoms varying in end group on silicon surface was carried on. Here, we use three different molecules of propargyl series varying in dipole moment and its orientation to constitute molecular junctions. The charge transport mechanism in metal–molecules–semiconductor (MMS) junction obtained from current–voltage (I–V) characteristics shows the rectification behavior for two junctions whereas the other junction shows a weak rectification. The electronic properties of the molecules were calculated using Gaussian software package. The observed rectification behavior of these junctions is examined and found to be accounted to the orientation of dipole moment and electron cloud density distribution inside the molecules

  4. Using Adobe Flash Animations of Electron Transport Chain to Teach and Learn Biochemistry

    Science.gov (United States)

    Teplá, Milada; Klímová, Helena

    2015-01-01

    Teaching the subject of the electron transport chain is one of the most challenging aspects of the chemistry curriculum at the high school level. This article presents an educational program called "Electron Transport Chain" which consists of 14 visual animations including a biochemistry quiz. The program was created in the Adobe Flash…

  5. Signal peptide-dependent inhibition of MHC class I heavy chain translation by rhesus cytomegalovirus.

    Directory of Open Access Journals (Sweden)

    Colin J Powers

    2008-10-01

    Full Text Available The US2-11 region of human and rhesus cytomegalovirus encodes a conserved family of glycoproteins that inhibit MHC-I assembly with viral peptides, thus preventing cytotoxic T cell recognition. Since HCMV lacking US2-11 is no longer able to block assembly and transport of MHC-I, we examined whether this is also observed for RhCMV lacking the corresponding region. Unexpectedly, recombinant RhCMV lacking US2-11 was still able to inhibit MHC-I expression in infected fibroblasts, suggesting the presence of an additional MHC-I evasion mechanism. Progressive deletion analysis of RhCMV-specific genomic regions revealed that MHC-I expression is fully restored upon additional deletion of rh178. The protein encoded by this RhCMV-specific open reading frame is anchored in the endoplasmic reticulum membrane. In the presence of rh178, RhCMV prevented MHC-I heavy chain (HC expression, but did not inhibit mRNA transcription or association of HC mRNA with translating ribosomes. Proteasome inhibitors stabilized a HC degradation intermediate in the absence of rh178, but not in its presence, suggesting that rh178 prevents completion of HC translation. This interference was signal sequence-dependent since replacing the signal peptide with that of CD4 or murine HC rendered human HCs resistant to rh178. We have identified an inhibitor of antigen presentation encoded by rhesus cytomegalovirus unique in both its lack of homology to any other known protein and in its mechanism of action. By preventing signal sequence-dependent HC translocation, rh178 acts prior to US2, US3 and US11 which attack MHC-I proteins after protein synthesis is completed. Rh178 is the first viral protein known to interfere at this step of the MHC-I pathway, thus taking advantage of the conserved nature of HC leader peptides, and represents a new mechanism of translational interference.

  6. Insights into the post-transcriptional regulation of the mitochondrial electron transport chain.

    Science.gov (United States)

    Sirey, Tamara M; Ponting, Chris P

    2016-10-15

    The regulation of the mitochondrial electron transport chain is central to the control of cellular homeostasis. There are significant gaps in our understanding of how the expression of the mitochondrial and nuclear genome-encoded components of the electron transport chain are co-ordinated, and how the assembly of the protein complexes that constitute the electron transport chain are regulated. Furthermore, the role post-transcriptional gene regulation may play in modulating these processes needs to be clarified. This review summarizes the current knowledge regarding the post-transcriptional gene regulation of the electron transport chain and highlights how noncoding RNAs may contribute significantly both to complex electron transport chain regulatory networks and to mitochondrial dysfunction. © 2016 The Author(s).

  7. Relationship between mitochondrial electron transport chain dysfunction, development, and life extension in Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    Shane L Rea

    2007-10-01

    Full Text Available Prior studies have shown that disruption of mitochondrial electron transport chain (ETC function in the nematode Caenorhabditis elegans can result in life extension. Counter to these findings, many mutations that disrupt ETC function in humans are known to be pathologically life-shortening. In this study, we have undertaken the first formal investigation of the role of partial mitochondrial ETC inhibition and its contribution to the life-extension phenotype of C. elegans. We have developed a novel RNA interference (RNAi dilution strategy to incrementally reduce the expression level of five genes encoding mitochondrial proteins in C. elegans: atp-3, nuo-2, isp-1, cco-1, and frataxin (frh-1. We observed that each RNAi treatment led to marked alterations in multiple ETC components. Using this dilution technique, we observed a consistent, three-phase lifespan response to increasingly greater inhibition by RNAi: at low levels of inhibition, there was no response, then as inhibition increased, lifespan responded by monotonically lengthening. Finally, at the highest levels of RNAi inhibition, lifespan began to shorten. Indirect measurements of whole-animal oxidative stress showed no correlation with life extension. Instead, larval development, fertility, and adult size all became coordinately affected at the same point at which lifespan began to increase. We show that a specific signal, initiated during the L3/L4 larval stage of development, is sufficient for initiating mitochondrial dysfunction-dependent life extension in C. elegans. This stage of development is characterized by the last somatic cell divisions normally undertaken by C. elegans and also by massive mitochondrial DNA expansion. The coordinate effects of mitochondrial dysfunction on several cell cycle-dependent phenotypes, coupled with recent findings directly linking cell cycle progression with mitochondrial activity in C. elegans, lead us to propose that cell cycle checkpoint control

  8. Razjašnjenje definisanja transportnog lanca / Clarification of a term transport chain

    Directory of Open Access Journals (Sweden)

    Aleksandar B. Cakić

    2010-01-01

    Full Text Available U radu je pregledno prikazano na koji način se u savremenoj naučnoj praksi definiše pojam transportnog lanca i njegova optimizacija. Radi pojašnjenja dato je poređenje sa logističkim i snabdevačkim lancem, i definisane su razlike i sličnosti u ovim pojmovima radi razgraničenja različitog definisanja pojmova. Takođe, upoređeni su pojmovi optimizacije transportnih i optimizacije logističkih lanaca i danas vrlo prisutnog pojma upravljanja snabdevačkim lancima - supply chain management (SCM. / INTRODUCTION This paper describes a few different approaches to define the terms 'transport chain' and 'supply chain' aiming at their clarification. TERM TRANSPORT CHAIN The author gives a survey of 'transport' definitions from international, civilian and military, and national literature. Then he gives his definition of a transport chain as a sequence of overall operations, necessary for exchange of goods in time and space within the framework of goods flow during transit from the source to the consumption point. The transport chain is connected neither with the limits of production organizations, particular industrial branches nor other structures of national economy. Transport chains also exist in the Army of Serbia (AS. Optimization of transport chains during peace time has a goal to enable easy and fast selection of an optimal transportation chain. DIFFERENCES AND SIMILARITIES IN DEFINING THE TERMS OF LOGISTIC, SUPPLY AND TRANSPORT CHAIN Modern authors define differently the terms which generally represent similar processes and activities while having almost an identical function. These terms are logistic chain, supply chain and transport chain. For better clarification, these terms are compared herein. Term supply chain The terms supply and supply chain dominate in world literature, as well as supply chain management (SCM, as a specific scientific field. This field is subject to special attention due to its importance in decision

  9. Allocation of Transportation Cost & CO2 Emission in Pooled Supply Chains Using Cooperative Game Theory

    OpenAIRE

    Xiaozhou Xu; Shenle Pan; Eric Ballot

    2012-01-01

    International audience; The sustainability of supply chain,both economical and ecological, has attracted intensive attentions of academic and industry. It is proven in former works that supply chain pooling given by horizontal cooperation among several independent supply chains create a new common supply chain network that could reduce the costs and the transport CO2 emissions. In this regard, this paper introduces a scheme to share in a fairly manner the savings. After a summary of the conce...

  10. Supply chain cost analysis of long-distance transportation of energy wood in Finland

    International Nuclear Information System (INIS)

    Tahvanainen, Timo; Anttila, Perttu

    2011-01-01

    The increasing use of bioenergy has resulted in a growing demand for long-distance transportation of energy wood. For both biofuels and traditional forest products, the importance of energy efficiency and rail use is growing. A GIS-based model for energy wood supply chains was created and used to simulate the costs for several supply chains in a study area in eastern Finland. Cost curves of ten supply chains for logging residues and full trees based on roadside, terminal and end-facility chipping were analyzed. The average procurement costs from forest to roadside storage were included. Railway transportation was compared to the most commonly used truck transportation options in long-distance transport. The potential for the development of supply chains was analyzed using a sensitivity analysis of 11 modified supply chain scenarios. For distances shorter than 60 km, truck transportation of loose residues and end-facility comminution was the most cost-competitive chain. Over longer distances, roadside chipping with chip truck transportation was the most cost-efficient option. When the transportation distance went from 135 to 165 km, depending on the fuel source, train-based transportation offered the lowest costs. The most cost-competitive alternative for long-distance transport included a combination of roadside chipping, truck transportation to the terminal and train transportation to the plant. Due to the low payload, the energy wood bundle chain with train transportation was not cost-competitive. Reduction of maximum truck weight increased the relative competitiveness of loose residue chains and train-based transportation, while reduction of fuel moisture increased competitiveness, especially of chip trucks.

  11. 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.

  12. 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.

  13. Newton's Cradle and Entanglement Transport in a Flexible Rydberg Chain

    International Nuclear Information System (INIS)

    Wuester, S.; Ates, C.; Eisfeld, A.; Rost, J. M.

    2010-01-01

    In a regular, flexible chain of Rydberg atoms, a single electronic excitation localizes on two atoms that are in closer mutual proximity than all others. We show how the interplay between excitonic and atomic motion causes electronic excitation and diatomic proximity to propagate through the Rydberg chain as a combined pulse. In this manner entanglement is transferred adiabatically along the chain, reminiscent of momentum transfer in Newton's cradle.

  14. 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.

  15. 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.

  16. Atomic carbon chains as spin-transmitters: An ab initio transport study

    DEFF Research Database (Denmark)

    Fürst, Joachim Alexander; Brandbyge, Mads; Jauho, Antti-Pekka

    2010-01-01

    An atomic carbon chain joining two graphene flakes was recently realized in a ground-breaking experiment by Jin et al. (Phys. Rev. Lett., 102 (2009) 205501). We present ab initio results for the electron transport properties of such chains and demonstrate complete spin-polarization of the transmi......An atomic carbon chain joining two graphene flakes was recently realized in a ground-breaking experiment by Jin et al. (Phys. Rev. Lett., 102 (2009) 205501). We present ab initio results for the electron transport properties of such chains and demonstrate complete spin...

  17. Comparative studies on mitochondrial electron transport chain complexes of Sitophilus zeamais treated with allyl isothiocyanate and calcium phosphide.

    Science.gov (United States)

    Zhang, Chao; Wu, Hua; Zhao, Yuan; Ma, Zhiqing; Zhang, Xing

    2016-01-01

    With Sitophilus zeamais as the target organism, the present study for the first time attempted to elucidate the comparative effects between allyl isothiocyanate (AITC) and calcium phosphide (Ca3P2), exposure on mitochondrial electron transport chain (ETC.) complex I & IV and their downstream effects on enzymes relevant to reactive oxygen species (ROS). In vivo, both AITC and Ca3P2 inhibited complex I and IV with similar downstream effects. In contrast with Ca3P2, the inhibition of complex I caused by AITC was dependent on time and dose. In vitro, AITC inhibited complex IV more significantly than complex I. These results indicate that mitochondrial complex IV is the primary target of AITC, and that complex I is another potential target. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. 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.

  19. Local excitation-inhibition ratio for synfire chain propagation in feed-forward neuronal networks

    Science.gov (United States)

    Guo, Xinmeng; Yu, Haitao; Wang, Jiang; Liu, Jing; Cao, Yibin; Deng, Bin

    2017-09-01

    A leading hypothesis holds that spiking activity propagates along neuronal sub-populations which are connected in a feed-forward manner, and the propagation efficiency would be affected by the dynamics of sub-populations. In this paper, how the interaction between local excitation and inhibition effects on synfire chain propagation in feed-forward network (FFN) is investigated. The simulation results show that there is an appropriate excitation-inhibition (EI) ratio maximizing the performance of synfire chain propagation. The optimal EI ratio can significantly enhance the selectivity of FFN to synchronous signals, which thereby increases the stability to background noise. Moreover, the effect of network topology on synfire chain propagation is also investigated. It is found that synfire chain propagation can be maximized by an optimal interlayer linking probability. We also find that external noise is detrimental to synchrony propagation by inducing spiking jitter. The results presented in this paper may provide insights into the effects of network dynamics on neuronal computations.

  20. Inactivation of brain mitochondrial Lon protease by peroxynitrite precedes electron transport chain dysfunction.

    Science.gov (United States)

    Stanyer, Lee; Jorgensen, Wenche; Hori, Osamu; Clark, John B; Heales, Simon J R

    2008-09-01

    The accumulation of oxidatively modified proteins has been shown to be a characteristic feature of many neurodegenerative disorders and its regulation requires efficient proteolytic processing. One component of the mitochondrial proteolytic system is Lon, an ATP-dependent protease that has been shown to degrade oxidatively modified aconitase in vitro and may thus play a role in defending against the accumulation of oxidized matrix proteins in mitochondria. Using an assay system that allowed us to distinguish between basal and ATP-stimulated Lon protease activity, we have shown in isolated non-synaptic rat brain mitochondria that Lon protease is highly susceptible to oxidative inactivation by peroxynitrite (ONOO(-)). This susceptibility was more pronounced with regard to ATP-stimulated activity, which was inhibited by 75% in the presence of a bolus addition of 1mM ONOO(-), whereas basal unstimulated activity was inhibited by 45%. Treatment of mitochondria with a range of peroxynitrite concentrations (10-1000 microM) revealed that a decline in Lon protease activity preceded electron transport chain (ETC) dysfunction (complex I, II-III and IV) and that ATP-stimulated activity was approximately fivefold more sensitive than basal Lon protease activity. Furthermore, supplementation of mitochondrial matrix extracts with reduced glutathione, following ONOO(-) exposure, resulted in partial restoration of basal and ATP-stimulated activity, thus suggesting possible redox regulation of this enzyme complex. Taken together these findings suggest that Lon protease may be particularly vulnerable to inactivation in conditions associated with GSH depletion and elevated oxidative stress.

  1. Harmonizing carbon footprint calculation for freight transport chains

    NARCIS (Netherlands)

    Lewis, A.; Ehrler, V.; Auvinen, H.; Maurer, H.; Davydenko, I.; Burmeister, A.; Seidel, S.; Lischke, A.; Kiel, J.

    2016-01-01

    The European Commission has set as a target a reduction of 60% in transport greenhouse gas emissions by 2050 [EC 11]. This includes freight transport emissions, which present a particular challenge due to the forecast increase in goods transport linked to future economic growth, the current trend of

  2. Behavioral Logistics - Analysis of behavioral routines and governance structures in the interorganizational maritime transport chain

    Directory of Open Access Journals (Sweden)

    2010-09-01

    Full Text Available The strong improvements in information and communication systems as well as better transshipment technologies provide the platform for more efficient transport within interorganizational transport chains. Nevertheless these technologies do not automatically optimize systems based on routines and behavioral patterns, established over the last decades. Logisticians - in theory and practice - have to consider the field of behavioral science to describe and analyse transport problems regarding to involved actors' strategic behavior and social embeddedness, too. The objective of this paper is to illustrate behavioral aspects of supposed technical problems in interorganizational transport chains. Therefore, this paper analyses behavioral routines and governance structures in the interorganizational maritime transport chain using a case study, dealing with the generation and circulation of transport information at the earliest point available, so called "estimated time of arrival" (ETA.

  3. A decision support system for transportation infrastructure and supply chain system planning.

    Science.gov (United States)

    2013-07-01

    This project makes the results (models and methodology) of the research and development efforts on freight movement modeling (FMM) and supply chain design carried out by faculty at OSU and OU available to transportation and logistics professionals. A...

  4. Characterizing the tradeoffs and costs associated with transportation congestion in supply chains.

    Science.gov (United States)

    2010-01-21

    We consider distribution and location-planning models for supply chains that explicitly : account for traffic congestion effects. The majority of facility location and transportation : planning models in the operations research literature consider fa...

  5. Cost optimization of biofuel production – The impact of scale, integration, transport and supply chain configurations

    NARCIS (Netherlands)

    de Jong, S.A.|info:eu-repo/dai/nl/41200836X; Hoefnagels, E.T.A.|info:eu-repo/dai/nl/313935998; Wetterlund, Elisabeth; Pettersson, Karin; Faaij, André; Junginger, H.M.|info:eu-repo/dai/nl/202130703

    2017-01-01

    This study uses a geographically-explicit cost optimization model to analyze the impact of and interrelation between four cost reduction strategies for biofuel production: economies of scale, intermodal transport, integration with existing industries, and distributed supply chain configurations

  6. RYBP Is a K63-Ubiquitin-Chain-Binding Protein that Inhibits Homologous Recombination Repair

    Directory of Open Access Journals (Sweden)

    Mohammad A.M. Ali

    2018-01-01

    Full Text Available Summary: Ring1-YY1-binding protein (RYBP is a member of the non-canonical polycomb repressive complex 1 (PRC1, and like other PRC1 members, it is best described as a transcriptional regulator. However, several PRC1 members were recently shown to function in DNA repair. Here, we report that RYBP preferentially binds K63-ubiquitin chains via its Npl4 zinc finger (NZF domain. Since K63-linked ubiquitin chains are assembled at DNA double-strand breaks (DSBs, we examined the contribution of RYBP to DSB repair. Surprisingly, we find that RYBP is K48 polyubiquitylated by RNF8 and rapidly removed from chromatin upon DNA damage by the VCP/p97 segregase. High expression of RYBP competitively inhibits recruitment of BRCA1 repair complex to DSBs, reducing DNA end resection and homologous recombination (HR repair. Moreover, breast cancer cell lines expressing high endogenous RYBP levels show increased sensitivity to DNA-damaging agents and poly ADP-ribose polymerase (PARP inhibition. These data suggest that RYBP negatively regulates HR repair by competing for K63-ubiquitin chain binding. : Ali et al. find that RYBP binds K63-linked ubiquitin chains and is removed from DNA damage sites. This K63-ubiquitin binding allows RYBP to hinder the recruitment of BRCA1 and Rad51 to DNA double-strand breaks, thus inhibiting homologous recombination repair. Accordingly, cancer cells expressing high RYBP are more sensitive to DNA-damaging therapies. Keywords: DNA damage response, homologous recombination, ubiquitylation, RYBP, polycomb proteins, double-strand break repair, chromatin, histone modification

  7. Spin-polarized transport properties of Fe atomic chain adsorbed on zigzag graphene nanoribbons

    International Nuclear Information System (INIS)

    Zhang, Z L; Chen, Y P; Xie, Y E; Zhang, M; Zhong, J X

    2011-01-01

    The spin-polarized transport properties of Fe atomic chain adsorbed on zigzag graphene nanoribbons (ZGNRs) are investigated using the density-functional theory in combination with the nonequilibrium Green's function method. We find that the Fe chain has drastic effects on spin-polarized transport properties of ZGNRs compared with a single Fe atom adsorbed on the ZGNRs. When the Fe chain is adsorbed on the centre of the ZGNR, the original semiconductor transforms into metal, showing a very wide range of spin-polarized transport. Particularly, the spin polarization around the Fermi level is up to 100%. This is because the adsorbed Fe chain not only induces many localized states but also has effects on the edge states of ZGNR, which can effectively modulate the spin-polarized transports. The spin polarization of ZGNRs is sensitive to the adsorption site of the Fe chain. When the Fe chain is adsorbed on the edge of ZGNR, the spin degeneracy of conductance is completely broken. The spin polarization is found to be more pronounced because the edge state of one edge is destroyed by the additional Fe chain. These results have direct implications for the control of the spin-dependent conductance in ZGNRs with the adsorption of Fe chains.

  8. Interference of a short-chain phospholipid with ion transport pathways in frog skin

    DEFF Research Database (Denmark)

    Unmack, M A; Frederiksen, O; Willumsen, N J

    1997-01-01

    The effects of mucosal application of the short-chain phospholipid didecanoyl-L-alpha-phosphatidylcholine (DDPC; with two saturated 10-carbon acyl chains) on active Na+ transport and transepithelial conductance (G) in the frog skin (Rana temporaria) were investigated. Active Na+ transport...... of the frog skin epithelium and opens a paracellular tight junction pathway. Both effects may be caused by incorporation of DDPC in the apical cell membrane....

  9. The Role of Transport Activities in Logistics Chain

    OpenAIRE

    Robert Chira

    2014-01-01

    The operation of transportation determines the efficiency of moving products. The progress in techniques and management principles improves the moving load, delivery speed, service quality, operation costs, the usage of facilities and energy saving. Transportation takes a crucial part in the manipulation of logistic. Reviewing the current condition, a strong system needs a clear frame of logistics and a proper transport implements and techniques to link the producing procedures. The objective...

  10. Transverse transport in coupled strongly correlated electronic chains

    International Nuclear Information System (INIS)

    Capponi, S.; Poilblanc, D.

    1997-01-01

    One-particle interchain hopping in a system of coupled Luttinger liquids is investigated by use of exact diagonalizations techniques. We give numerical evidence that inter-chain coherent hopping (defined by a non-vanishing splitting) can be totally suppressed for the Luttinger liquid exponent α ∝ 0.4 or even smaller α values. The transverse conductivity is shown to exhibit a strong incoherent part even when coherent inter-chain hopping is believed to occur. Implications for the optical experiments in quasi-1D organic or high-T c superconductors is outlined. (orig.)

  11. Transport properties for carbon chain sandwiched between heteroatom-doped carbon nanotubes with different doping sites

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Wenjiang [Big Data and Information Engineering College of Guizhou University, Guiyang 550025 (China); Guizhou University of Finance and Economics, Guiyang 550025 (China); Deng, Xiaoqing, E-mail: xq-deng@163.com, E-mail: caish@mail.gufe.edu.cn [School of Physics and Electronic Science, Changsha University of Science and Technology, Changsha 410114 (China); Cai, Shaohong, E-mail: xq-deng@163.com, E-mail: caish@mail.gufe.edu.cn [Guizhou University of Finance and Economics, Guiyang 550025 (China)

    2016-07-15

    The First-principles calculation is used to investigate the transport properties of a carbon chain connected with N-and/or B-doped caped carbon nanotube acting as electrodes. The I-V curves of the carbon chain are affected by the N/B doping sites, and rectifying behavior can be obtained distinctly when the carbon chain is just connected onto two doping atom sites (N- chain-B), and a weak rectification occurs when N (B) doping at other sites. Interestingly, the spin-filtering effects exist in the junction when it is doped at other sites, undoped system, or N-terminal carbon chains. However, no this behavior is found in N-chain-B and B-chain-B systems. The analysis on the transmission spectra, PDOS, LDOS, spin density, and the electron transmission pathways give an insight into the observed results for the system.

  12. Transport properties for carbon chain sandwiched between heteroatom-doped carbon nanotubes with different doping sites

    International Nuclear Information System (INIS)

    Liu, Wenjiang; Deng, Xiaoqing; Cai, Shaohong

    2016-01-01

    The First-principles calculation is used to investigate the transport properties of a carbon chain connected with N-and/or B-doped caped carbon nanotube acting as electrodes. The I-V curves of the carbon chain are affected by the N/B doping sites, and rectifying behavior can be obtained distinctly when the carbon chain is just connected onto two doping atom sites (N- chain-B), and a weak rectification occurs when N (B) doping at other sites. Interestingly, the spin-filtering effects exist in the junction when it is doped at other sites, undoped system, or N-terminal carbon chains. However, no this behavior is found in N-chain-B and B-chain-B systems. The analysis on the transmission spectra, PDOS, LDOS, spin density, and the electron transmission pathways give an insight into the observed results for the system.

  13. The inhibition performance of long-chain alkyl-substituted benzimidazole derivatives for corrosion of mild steel in HCl

    International Nuclear Information System (INIS)

    Zhang, Dongqin; Tang, Yongming; Qi, Sijun; Dong, Dawei; Cang, Hui; Lu, Gang

    2016-01-01

    Highlights: • Inhibition performance of long-chain alkyl-substituted benzimidazole. • Benzimidazole segment donating electrons to metal surface. • Non-polar long chain enhancing inhibition by the barrier effect. • Molecular form of DBI more tightly adsorbs on the steel than its protonated form. - Abstract: The corrosion inhibition of a new benzimidazole derivative, 6-(dodecyloxy)-1H-benzo[d]imidazole (DBI), for mild steel in 1 M HCl was investigated in this paper. Computational chemistry was performed to explore the adsorption of DBI on metal surface. Inhibition performance of DBI is attributed to both the direct interaction of benzimidazole segment with iron surface and the barrier effect of the non-polar long chain against aggressive solution. Compared to the protonated form, the molecular form of DBI could more tightly interact with iron surface. These results show that the long-chain alkyl-substituted benzimidazole derivative is of great potential application as corrosion inhibitor.

  14. Modelling of the radionuclide transport through terrestrial food chains

    International Nuclear Information System (INIS)

    Hanusik, V.

    1991-01-01

    The paper presents a terrestrial food chains model for computing potential human intake of radionuclides released into the atmosphere during normal NPP operation. Attention is paid to the choice of model parameter values. Results obtained by our approach are compared to those applied in current methodology. (orig.) [de

  15. Augmenting transport versus increasing cold storage to improve vaccine supply chains.

    Science.gov (United States)

    Haidari, Leila A; Connor, Diana L; Wateska, Angela R; Brown, Shawn T; Mueller, Leslie E; Norman, Bryan A; Schmitz, Michelle M; Paul, Proma; Rajgopal, Jayant; Welling, Joel S; Leonard, Jim; Chen, Sheng-I; Lee, Bruce Y

    2013-01-01

    When addressing the urgent task of improving vaccine supply chains, especially to accommodate the introduction of new vaccines, there is often a heavy emphasis on stationary storage. Currently, donations to vaccine supply chains occur largely in the form of storage equipment. This study utilized a HERMES-generated detailed, dynamic, discrete event simulation model of the Niger vaccine supply chain to compare the impacts on vaccine availability of adding stationary cold storage versus transport capacity at different levels and to determine whether adding stationary storage capacity alone would be enough to relieve potential bottlenecks when pneumococcal and rotavirus vaccines are introduced by 2015. Relieving regional level storage bottlenecks increased vaccine availability (by 4%) more than relieving storage bottlenecks at the district (1% increase), central (no change), and clinic (no change) levels alone. Increasing transport frequency (or capacity) yielded far greater gains (e.g., 15% increase in vaccine availability when doubling transport frequency to the district level and 18% when tripling). In fact, relieving all stationary storage constraints could only increase vaccine availability by 11%, whereas doubling the transport frequency throughout the system led to a 26% increase and tripling the frequency led to a 30% increase. Increasing transport frequency also reduced the amount of stationary storage space needed in the supply chain. The supply chain required an additional 61,269L of storage to relieve constraints with the current transport frequency, 55,255L with transport frequency doubled, and 51,791L with transport frequency tripled. When evaluating vaccine supply chains, it is important to understand the interplay between stationary storage and transport. The HERMES-generated dynamic simulation model showed how augmenting transport can result in greater gains than only augmenting stationary storage and can reduce stationary storage needs.

  16. Augmenting Transport versus Increasing Cold Storage to Improve Vaccine Supply Chains

    Science.gov (United States)

    Haidari, Leila A.; Connor, Diana L.; Wateska, Angela R.; Brown, Shawn T.; Mueller, Leslie E.; Norman, Bryan A.; Schmitz, Michelle M.; Paul, Proma; Rajgopal, Jayant; Welling, Joel S.; Leonard, Jim; Chen, Sheng-I; Lee, Bruce Y.

    2013-01-01

    Background When addressing the urgent task of improving vaccine supply chains, especially to accommodate the introduction of new vaccines, there is often a heavy emphasis on stationary storage. Currently, donations to vaccine supply chains occur largely in the form of storage equipment. Methods This study utilized a HERMES-generated detailed, dynamic, discrete event simulation model of the Niger vaccine supply chain to compare the impacts on vaccine availability of adding stationary cold storage versus transport capacity at different levels and to determine whether adding stationary storage capacity alone would be enough to relieve potential bottlenecks when pneumococcal and rotavirus vaccines are introduced by 2015. Results Relieving regional level storage bottlenecks increased vaccine availability (by 4%) more than relieving storage bottlenecks at the district (1% increase), central (no change), and clinic (no change) levels alone. Increasing transport frequency (or capacity) yielded far greater gains (e.g., 15% increase in vaccine availability when doubling transport frequency to the district level and 18% when tripling). In fact, relieving all stationary storage constraints could only increase vaccine availability by 11%, whereas doubling the transport frequency throughout the system led to a 26% increase and tripling the frequency led to a 30% increase. Increasing transport frequency also reduced the amount of stationary storage space needed in the supply chain. The supply chain required an additional 61,269L of storage to relieve constraints with the current transport frequency, 55,255L with transport frequency doubled, and 51,791L with transport frequency tripled. Conclusions When evaluating vaccine supply chains, it is important to understand the interplay between stationary storage and transport. The HERMES-generated dynamic simulation model showed how augmenting transport can result in greater gains than only augmenting stationary storage and can reduce

  17. Transportation as an Untapped Potential for Competitive Supply Chain Management Advantage

    DEFF Research Database (Denmark)

    Borgström, Benedikte

    2017-01-01

    This article argues that top managers and supply chain managers need to become involved in transport and logistics policy making and include it in the strategic development of supply chain management processes. Under the assumption that these operations are outsourced, the crucial “top-down” task...... is to realize the trade-offs in designing and operating logistics systems and make sure that the ongoing task of making transport and logistics choices is aligned to the strategic direction set out for supply chain management business process development....

  18. The multiplicity of dehydrogenases in the electron transport chain of plant mitochondria

    DEFF Research Database (Denmark)

    Rasmusson, Allan G; Geisler, Daniela A; Møller, Ian Max

    2008-01-01

    The electron transport chain in mitochondria of different organisms contains a mixture of common and specialised components. The specialised enzymes form branches to the universal electron path, especially at the level of ubiquinone, and allow the chain to adjust to different cellular and metabolic...... and their consequences for the understanding of electron transport and redundancy of electron paths...... requirements. In plants, specialised components have been known for a long time. However, recently, the known number of plant respiratory chain dehydrogenases has increased, including both components specific to plants and those with mammalian counterparts. This review will highlight the novel branches...

  19. 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.

  20. Development of natural gas ocean transportation chain by means of natural gas hydrate (NGH)

    International Nuclear Information System (INIS)

    Nogami, T.; Oya, N.; Ishida, H.; Matsumoto, H.

    2008-01-01

    Recent studies in Japan have suggested that natural gas hydrate (NGH) transportation of natural gas is more economical than liquefied natural gas (LNG) transportation systems for small, medium and remote gas fields. Researchers in Japan have built a 600 kg per day NGH production and pelletizing plant and regasification facility. This paper discussed feasibility studies conducted in southeast Asia to determine the unit's commercialization potential with large natural gas-related businesses including shipping companies and electric power utilities. The total supply chain was compared with the corresponding liquefied natural gas (LNG) and compressed natural gas (CNG) supply chains. The study also examined natural gas reserves, energy policies, the positioning of natural gas supplies, and future forecasts of natural gas demand. A conceptual design for an NGH supply chain in Indonesia was presented. Results of the study have demonstrated that the NGH chain is an appropriate and economically feasible transportation method for many areas in southeast Asia. 8 refs., 10 figs

  1. Only adding stationary storage to vaccine supply chains may create and worsen transport bottlenecks.

    Science.gov (United States)

    Haidari, Leila A; Connor, Diana L; Wateska, Angela R; Brown, Shawn T; Mueller, Leslie E; Norman, Bryan A; Schmitz, Michelle M; Paul, Proma; Rajgopal, Jayant; Welling, Joel S; Leonard, Jim; Claypool, Erin G; Weng, Yu-Ting; Chen, Sheng-I; Lee, Bruce Y

    2013-01-01

    Although vaccine supply chains in many countries require additional stationary storage and transport capacity to meet current and future needs, international donors tend to donate stationary storage devices far more often than transport equipment. To investigate the impact of only adding stationary storage equipment on the capacity requirements of transport devices and vehicles, we used HERMES (Highly Extensible Resource for Modeling Supply Chains) to construct a discrete event simulation model of the Niger vaccine supply chain. We measured the transport capacity requirement for each mode of transport used in the Niger vaccine cold chain, both before and after adding cold rooms and refrigerators to relieve all stationary storage constraints in the system. With the addition of necessary stationary storage, the average transport capacity requirement increased from 88% to 144% for cold trucks, from 101% to 197% for pickup trucks, and from 366% to 420% for vaccine carriers. Therefore, adding stationary storage alone may worsen or create new transport bottlenecks as more vaccines flow through the system, preventing many vaccines from reaching their target populations. Dynamic modeling can reveal such relationships between stationary storage capacity and transport constraints.

  2. In silico analysis of the regulation of the photosynthetic electron transport chain in C3 plants

    NARCIS (Netherlands)

    Morales Sierra, A.; Yin, Xinyou; Harbinson, Jeremy; Driever, Steven Michiel; Molenaar, Jaap; Kramer, David M.; Struik, Paul

    2018-01-01

    We present a new simulation model of the reactions in the photosynthetic electron transport chain of C3 species. We show that including recent insights about the regulation of the thylakoid proton motive force, ATP/NADPH balancing mechanisms (cyclic and non-cyclic alternative electron transport),

  3. 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.

  4. Direct measurement of superdiffusive energy transport in disordered granular chains.

    Science.gov (United States)

    Kim, Eunho; Martínez, Alejandro J; Phenisee, Sean E; Kevrekidis, P G; Porter, Mason A; Yang, Jinkyu

    2018-02-13

    Energy transport properties in heterogeneous materials have attracted scientific interest for more than half of a century, and they continue to offer fundamental and rich questions. One of the outstanding challenges is to extend Anderson theory for uncorrelated and fully disordered lattices in condensed-matter systems to physical settings in which additional effects compete with disorder. Here we present the first systematic experimental study of energy transport and localization properties in simultaneously disordered and nonlinear granular crystals. In line with prior theoretical studies, we observe in our experiments that disorder and nonlinearity-which individually favor energy localization-can effectively cancel each other out, resulting in the destruction of wave localization. We also show that the combined effect of disorder and nonlinearity can enable manipulation of energy transport speed in granular crystals. Specifically, we experimentally demonstrate superdiffusive transport. Furthermore, our numerical computations suggest that subdiffusive transport should be attainable by controlling the strength of the system's external precompression force.

  5. Increased expression of electron transport chain genes in uterine leiomyoma.

    Science.gov (United States)

    Tuncal, Akile; Aydin, Hikmet Hakan; Askar, Niyazi; Ozkaya, Ali Burak; Ergenoglu, Ahmet Mete; Yeniel, Ahmet Ozgur; Akdemir, Ali; Ak, Handan

    2014-01-01

    The etiology and pathophysiology of uterine leiomyomas, benign smooth muscle tumors of the uterus, are not well understood. To evaluate the role of mitochondria in uterine leiomyoma, we compared electron transport gene expressions of uterine leiomyoma tissue with myometrium tissue in six uterine leiomyoma patients by RT-PCR array. Our results showed an average of 1.562 (±0.445) fold increase in nuclear-encoded electron transport genes. These results might suggest an increase in size, number, or activity of mitochondria in uterine leiomyoma that, to our knowledge, has not been previously reported. © 2014 by the Association of Clinical Scientists, Inc.

  6. The occurrence and control of nitric oxide generation by the plant mitochondrial electron transport chain.

    Science.gov (United States)

    Alber, Nicole A; Sivanesan, Hampavi; Vanlerberghe, Greg C

    2017-07-01

    The plant mitochondrial electron transport chain (ETC) is bifurcated such that electrons from ubiquinol are passed to oxygen via the usual cytochrome path or through alternative oxidase (AOX). We previously showed that knockdown of AOX in transgenic tobacco increased leaf concentrations of nitric oxide (NO), implying that an activity capable of generating NO had been effected. Here, we identify the potential source of this NO. Treatment of leaves with antimycin A (AA, Q i -site inhibitor of Complex III) increased NO amount more than treatment with myxothiazol (Myxo, Q o -site inhibitor) despite both being equally effective at inhibiting respiration. Comparison of nitrate-grown wild-type with AOX knockdown and overexpression plants showed a negative correlation between AOX amount and NO amount following AA. Further, Myxo fully negated the ability of AA to increase NO amount. With ammonium-grown plants, neither AA nor Myxo strongly increased NO amount in any plant line. When these leaves were supplied with nitrite alongside the AA or Myxo, then the inhibitor effects across lines mirrored that of nitrate-grown plants. Hence the ETC, likely the Q-cycle of Complex III generates NO from nitrite, and AOX reduces this activity by acting as a non-energy-conserving electron sink upstream of Complex III. © 2016 John Wiley & Sons Ltd.

  7. Assessment of mitochondrial electron transport chain function in a primary astrocyte cell model of hyperhomocystinaemia.

    Science.gov (United States)

    Turkes, Fiona; Murphy, Elaine; Land, John; Demiray, Berna; Duberley, Kate; Briddon, Antony; Hargreaves, Iain

    2013-07-01

    Elevated plasma homocysteine (Hcy) has been detected in patients with various neurodegenerative conditions. Studies on neurones and cerebral tissue have revealed that hyperhomocystinaemia may inhibit mitochondrial electron transport chain (ETC) enzyme activity resulting in neuronal morbidity. As astrocytes convey a protective and supportive role towards neurones, we postulated that Hcy-induced astrocytic ETC inhibition may contribute to neurological dysfunction. In order to investigate this hypothesis, we established a cellular model of hyperhomocystinaemia using primary rat astrocytes. Which were incubated were incubated with 200 µM, 500 µM Hcy and the Hcy metabolite, thiolactone (10 µM). Following 96 h of incubation with 200 µM and 500 µM Hcy, an approximate two-fold (1.11 nmol/mg) and three-fold (1.45 nmol/mg) increase in mitochondrial levels of Hcy, respectively, were detected compared to control levels (0.54 nmol/mg). However, on exposure to Hcy (200 or 500 µM) and Hcy-thiolactone (10 µM), the activities of astrocytic ETC complex I, II-III and IV were found to be comparable to control levels. In addition, the extracellular lactate:pyruvate ratio and the intracellular glutathione status of primary rat astrocytes were not significantly different between Hcy (200 or 500 µM) treated and controls. In conclusion, the results of this study suggest that Hcy induced impairment of astrocytic ETC function may not contribute to the pathophysiology of hyperhomocystinaemia.

  8. Electron transport chains in organohalide-respiring bacteria and bioremediation implications.

    Science.gov (United States)

    Wang, Shanquan; Qiu, Lan; Liu, Xiaowei; Xu, Guofang; Siegert, Michael; Lu, Qihong; Juneau, Philippe; Yu, Ling; Liang, Dawei; He, Zhili; Qiu, Rongliang

    2018-04-06

    In situ remediation employing organohalide-respiring bacteria represents a promising solution for cleanup of persistent organohalide pollutants. The organohalide-respiring bacteria conserve energy by utilizing H 2 or organic compounds as electron donors and organohalides as electron acceptors. Reductive dehalogenase (RDase), a terminal reductase of the electron transport chain in organohalide-respiring bacteria, is the key enzyme that catalyzes halogen removal. Accumulating experimental evidence thus far suggests that there are distinct models for respiratory electron transfer in organohalide-respirers of different lineages, e.g., Dehalococcoides, Dehalobacter, Desulfitobacterium and Sulfurospirillum. In this review, to connect the knowledge in organohalide-respiratory electron transport chains to bioremediation applications, we first comprehensively review molecular components and their organization, together with energetics of the organohalide-respiratory electron transport chains, as well as recent elucidation of intramolecular electron shuttling and halogen elimination mechanisms of RDases. We then highlight the implications of organohalide-respiratory electron transport chains in stimulated bioremediation. In addition, major challenges and further developments toward understanding the organohalide-respiratory electron transport chains and their bioremediation applications are identified and discussed. Copyright © 2018 Elsevier Inc. All rights reserved.

  9. The magnetism and spin-dependent electronic transport properties of boron nitride atomic chains

    International Nuclear Information System (INIS)

    An, Yipeng; Zhang, Mengjun; Wang, Tianxing; Jiao, Zhaoyong; Wu, Dapeng; Fu, Zhaoming; Wang, Kun

    2016-01-01

    Very recently, boron nitride atomic chains were successively prepared and observed in experiments [O. Cretu et al., ACS Nano 8, 11950 (2015)]. Herein, using a first-principles technique, we study the magnetism and spin-dependent electronic transport properties of three types of BN atomic chains whose magnetic moment is 1 μ B for B n N n−1 , 2 μ B for B n N n , and 3 μ B for B n N n+1 type atomic chains, respectively. The spin-dependent electronic transport results demonstrate that the short B n N n+1 chain presents an obvious spin-filtering effect with high spin polarization ratio (>90%) under low bias voltages. Yet, this spin-filtering effect does not occur for long B n N n+1 chains under high bias voltages and other types of BN atomic chains (B n N n−1 and B n N n ). The proposed short B n N n+1 chain is predicted to be an effective low-bias spin filters. Moreover, the length-conductance relationships of these BN atomic chains were also studied.

  10. Lateral electron transport in monolayers of short chains at interfaces: A Monte Carlo study

    International Nuclear Information System (INIS)

    George, Christopher B.; Szleifer, Igal; Ratner, Mark A.

    2010-01-01

    Graphical abstract: Electron hopping between electroactive sites in a monolayer composed of redox-active and redox-passive molecules. - Abstract: Using Monte Carlo simulations, we study lateral electronic diffusion in dense monolayers composed of a mixture of redox-active and redox-passive chains tethered to a surface. Two charge transport mechanisms are considered: the physical diffusion of electroactive chains and electron hopping between redox-active sites. Results indicate that by varying the monolayer density, the mole fraction of electroactive chains, and the electron hopping range, the dominant charge transport mechanism can be changed. For high density monolayers in a semi-crystalline phase, electron diffusion proceeds via electron hopping almost exclusively, leading to static percolation behavior. In fluid monolayers, the diffusion of chains may contribute more to the overall electronic diffusion, reducing the observed static percolation effects.

  11. Transportation flow analysis in a centralised supply chain at Toyota Material Handling Europe

    OpenAIRE

    Gustavsson, Styrbjörn; Öberg, Mikael

    2010-01-01

    This report is the result of a Master Thesis written at Toyota Material Handling Europe (TMHE), with the purpose to map the existing spare part supply chain structure and to analyse future suggested supply chain structures with a focus on transportation flows. TMHE is one of the world’s largest producing forklift distributers with large market shares throughout Europe. Besides the main activity of forklifts the aftermarket of distributing spare parts is a major business. With a current decent...

  12. Livestock transport from the perspective of the pre-slaughter logistic chain: a review.

    Science.gov (United States)

    Miranda-de la Lama, G C; Villarroel, M; María, G A

    2014-09-01

    New developments in livestock transport within the pre-slaughter chain are discussed in terms of three logistic nodes: origin, stopovers and slaughterhouse. Factors as transport cost, haulier, truck specifications, micro-environment conditions, loading density, route planning, vehicle accidents and journey length are discussed as well as causes of morbidity, mortality, live weight and carcass damage. Taking into account current trends towards increased transport times, logistics stopovers and mixed transport, there is a need to develop systems of evaluation and decision-making that provide tools and protocols that can minimize the biological cost to animals, which may have been underestimated in the past. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. Data Envelopment Analysis of Helsinki-Tallinn Transportation Chains

    Directory of Open Access Journals (Sweden)

    Olli-Pekka Hilmola

    2013-12-01

    Full Text Available The Baltic Sea shipping is at a crossroads as sulphur regulation will lead to excessive cost increases from the year 2015 onwards and CO2 emission trading is planned to be implemented for the entire shipping sector within the EU area. Therefore, shipping is going to be minimized and hinterland transportation (road and rail will act as substitute. This research analyzes the situation on one of the highest volume general cargo transportation routes of Finland (operating between Helsinki, Finland and Tallinn, Estonia, including loading and unloading at seaports and short sea shipping activity in between. Based on the efficiency evaluation results, it seems that containers should be favoured over semi-trailers – containers could be carried efficiently either in container ships or even at currently favoured RoRo or RoPax ships. Our research illustrates that pure container shipping with larger container ships within the analyzed route is not entirely out of question, but lead time and hinterland operations should receive more attention. Alternatively, RoRo and RoPax ships can also do something to increase their competitiveness in environmental harm caused and diesel consumption – higher cargo loads and utilization levels are short-term key for continued dominance.

  14. Optical transport and statistics of radiative losses in disordered chains of microspheres

    International Nuclear Information System (INIS)

    Deng Chaosheng; Xu Hui; Deych, Lev

    2010-01-01

    Optical transport in a one-dimensional chain of microspherical resonators with size disorder is studied in the spectral range of high-Q whispering gallery modes. An ab initio approach is used to develop a theoretical framework for analysis of steady-state transport parameters with main emphasis on properly defined radiative loss coefficient. Probability distribution and scaling properties of the latter are established and explained.

  15. Therapeutic activity of multiple common γ-chain cytokine inhibition in acute and chronic GVHD.

    Science.gov (United States)

    Hechinger, Anne-Kathrin; Smith, Benjamin A H; Flynn, Ryan; Hanke, Kathrin; McDonald-Hyman, Cameron; Taylor, Patricia A; Pfeifer, Dietmar; Hackanson, Björn; Leonhardt, Franziska; Prinz, Gabriele; Dierbach, Heide; Schmitt-Graeff, Annette; Kovarik, Jiri; Blazar, Bruce R; Zeiser, Robert

    2015-01-15

    The common γ chain (CD132) is a subunit of the interleukin (IL) receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Because levels of several of these cytokines were shown to be increased in the serum of patients developing acute and chronic graft-versus-host disease (GVHD), we reasoned that inhibition of CD132 could have a profound effect on GVHD. We observed that anti-CD132 monoclonal antibody (mAb) reduced acute GVHD potently with respect to survival, production of tumor necrosis factor, interferon-γ, and IL-6, and GVHD histopathology. Anti-CD132 mAb afforded protection from GVHD partly via inhibition of granzyme B production in CD8 T cells, whereas exposure of CD8 T cells to IL-2, IL-7, IL-15, and IL-21 increased granzyme B production. Also, T cells exposed to anti-CD132 mAb displayed a more naive phenotype in microarray-based analyses and showed reduced Janus kinase 3 (JAK3) phosphorylation upon activation. Consistent with a role of JAK3 in GVHD, Jak3(-/-) T cells caused less severe GVHD. Additionally, anti-CD132 mAb treatment of established chronic GVHD reversed liver and lung fibrosis, and pulmonary dysfunction characteristic of bronchiolitis obliterans. We conclude that acute GVHD and chronic GVHD, caused by T cells activated by common γ-chain cytokines, each represent therapeutic targets for anti-CD132 mAb immunomodulation. © 2015 by The American Society of Hematology.

  16. Using Adobe Flash animations of electron transport chain to teach and learn biochemistry.

    Science.gov (United States)

    Teplá, Milada; Klímová, Helena

    2015-01-01

    Teaching the subject of the electron transport chain is one of the most challenging aspects of the chemistry curriculum at the high school level. This article presents an educational program called "Electron Transport Chain" which consists of 14 visual animations including a biochemistry quiz. The program was created in the Adobe Flash CS3 Professional animation program and is designed for high school chemistry students. Our goal is to develop educational materials that facilitate the comprehension of this complex subject through dynamic animations which show the course of the electron transport chain and simultaneously explain its nature. We record the process of the electron transport chain, including connections with oxidative phosphorylation, in such a way as to minimize the occurrence of discrepancies in interpretation. The educational program was evaluated in high schools through the administration of a questionnaire, which contained 12 opened-ended items and which required participants to evaluate the graphics of the animations, chemical content, student preferences, and its suitability for high school biochemistry teaching. © 2015 The International Union of Biochemistry and Molecular Biology.

  17. Electronic structure and transport of a carbon chain between graphene nanoribbon leads

    International Nuclear Information System (INIS)

    Zhang, G P; Fang, X W; Yao, Y X; Wang, C Z; Ho, K M; Ding, Z J

    2011-01-01

    The electronic structure and transport property of a carbon chain between two graphene nanoribbon leads are studied using an ab initio tight-binding (TB) model and Landauer's formalism combined with a non-equilibrium Green's function. The TB Hamiltonian and overlap matrices are extracted from first-principles density functional calculations through the quasi-atomic minimal basis orbital scheme. The accuracy of the TB model is demonstrated by comparing the electronic structure from the TB model with that from first-principles density functional theory. The results of electronic transport on a carbon atomic chain connected to armchair and zigzag graphene ribbon leads, such as different transport characters near the Fermi level and at most one quantized conductance, reveal the effect of the electronic structure of the leads and the scattering from the atomic chain. In addition, bond length alternation and an interesting transmission resonance are observed in the atomic chain connected to zigzag graphene ribbon leads. Our approach provides a promising route to quantitative investigation of both the electronic structure and transport property of large systems.

  18. Basic regulatory principles of Escherichia coli's electron transport chain for varying oxygen conditions

    NARCIS (Netherlands)

    Henkel, S.G.; Ter Beek, A.S.; Steinsiek, S.; Stagge, S.; Bettenbrock, K.; Teixeira De Mattos, M.J.; Sauter, T.; Sawodny, O.; Ederer, M.

    2014-01-01

    For adaptation between anaerobic, micro-aerobic and aerobic conditions Escherichia coli's metabolism and in particular its electron transport chain (ETC) is highly regulated. Although it is known that the global transcriptional regulators FNR and ArcA are involved in oxygen response it is unclear

  19. Targeting the Mitochondrial Electron Transport Chain Complexes for the Induction of Apoptosis and Cancer Treatment

    Czech Academy of Sciences Publication Activity Database

    Rohlena, Jakub; Dong, L. F.; Neužil, Jiří

    2013-01-01

    Roč. 14, č. 3 (2013), s. 377-389 ISSN 1389-2010 Institutional research plan: CEZ:AV0Z50520701 Keywords : Cancer * mitochondria * electron transport chain Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.511, year: 2013

  20. A disaggregate freight transport model of transport chain and shipment size choice

    NARCIS (Netherlands)

    Windisch, E.; De Jong, G.C.; Van Nes, R.; Hoogendoorn, S.P.

    2010-01-01

    The field of freight transport modelling is relatively young compared to passenger transport modelling. However, some key issues in freight policy, like growing freight shares on the road, advanced logistics concepts or emerging strict freight transport regulations, have been creating increasing

  1. Charge Injection and Transport in Metal/Polymer Chains/Metal Sandwich Structure

    International Nuclear Information System (INIS)

    Hai-Hong, Li; Dong-Mei, Li; Yuan, Li; Kun, Gao; De-Sheng, Liu; Shi-Jie, Xie

    2008-01-01

    Using the tight-binding Su–Schrieffer–Heeger model and a nonadiabatic dynamic evolution method, we study the dynamic processes of the charge injection and transport in a metal/two coupled conjugated polymer chains/metal structure. It is found that the charge interchain transport is determined by the strength of the electric field and the magnitude of the voltage bias applied on the metal electrode. The stronger electric field and the larger voltage bias are both in favour of the charge interchain transport. (condensed matter: electronic structure, electrical, magnetic, and optical properties)

  2. Heat transport in the XXZ spin chain: from ballistic to diffusive regimes and dephasing enhancement

    International Nuclear Information System (INIS)

    Mendoza-Arenas, J J; Al-Assam, S; Clark, S R; Jaksch, D

    2013-01-01

    In this work we study the heat transport in an XXZ spin-1/2 Heisenberg chain with homogeneous magnetic field, incoherently driven out of equilibrium by reservoirs at the boundaries. We focus on the effect of bulk dephasing (energy-dissipative) processes in different parameter regimes of the system. The non-equilibrium steady state of the chain is obtained by simulating its evolution under the corresponding Lindblad master equation, using the time evolving block decimation method. In the absence of dephasing, the heat transport is ballistic for weak interactions, while being diffusive in the strongly interacting regime, as evidenced by the heat current scaling with the system size. When bulk dephasing takes place in the system, diffusive transport is induced in the weakly interacting regime, with the heat current monotonically decreasing with the dephasing rate. In contrast, in the strongly interacting regime, the heat current can be significantly enhanced by dephasing for systems of small size. (paper)

  3. A Select Subset of Electron Transport Chain Genes Associated with Optic Atrophy Link Mitochondria to Axon Regeneration in Caenorhabditis elegans.

    Science.gov (United States)

    Knowlton, Wendy M; Hubert, Thomas; Wu, Zilu; Chisholm, Andrew D; Jin, Yishi

    2017-01-01

    The role of mitochondria within injured neurons is an area of active interest since these organelles are vital for the production of cellular energy in the form of ATP. Using mechanosensory neurons of the nematode Caenorhabditis elegans to test regeneration after neuronal injury in vivo , we surveyed genes related to mitochondrial function for effects on axon regrowth after laser axotomy. Genes involved in mitochondrial transport, calcium uptake, mitophagy, or fission and fusion were largely dispensable for axon regrowth, with the exception of eat-3/Opa1 . Surprisingly, many genes encoding components of the electron transport chain were dispensable for regrowth, except for the iron-sulfur proteins gas-1, nduf-2.2, nduf-7 , and isp-1 , and the putative oxidoreductase rad-8 . In these mutants, axonal development was essentially normal and axons responded normally to injury by forming regenerative growth cones, but were impaired in subsequent axon extension. Overexpression of nduf-2.2 or isp-1 was sufficient to enhance regrowth, suggesting that mitochondrial function is rate-limiting in axon regeneration. Moreover, loss of function in isp-1 reduced the enhanced regeneration caused by either a gain-of-function mutation in the calcium channel EGL-19 or overexpression of the MAP kinase DLK-1. While the cellular function of RAD-8 remains unclear, our genetic analyses place rad-8 in the same pathway as other electron transport genes in axon regeneration. Unexpectedly, rad-8 regrowth defects were suppressed by altered function in the ubiquinone biosynthesis gene clk-1 . Furthermore, we found that inhibition of the mitochondrial unfolded protein response via deletion of atfs-1 suppressed the defective regrowth in nduf-2.2 mutants. Together, our data indicate that while axon regeneration is not significantly affected by general dysfunction of cellular respiration, it is sensitive to the proper functioning of a select subset of electron transport chain genes, or to the

  4. The Agr quorum-sensing system regulates fibronectin binding but not hemolysis in the absence of a functional electron transport chain.

    Science.gov (United States)

    Pader, Vera; James, Ellen H; Painter, Kimberley L; Wigneshweraraj, Sivaramesh; Edwards, Andrew M

    2014-10-01

    Staphylococcus aureus is responsible for numerous chronic and recurrent infections, which are frequently associated with the emergence of small-colony variants (SCVs) that lack a functional electron transport chain. SCVs exhibit enhanced expression of fibronectin-binding protein (FnBP) and greatly reduced hemolysin production, although the basis for this is unclear. One hypothesis is that these phenotypes are a consequence of the reduced Agr activity of SCVs, while an alternative is that the lack of a functional electron transport chain and the resulting reduction in ATP production are responsible. Disruption of the electron transport chain of S. aureus genetically (hemB and menD) or chemically, using 2-n-heptyl-4-hydroxyquinoline N-oxide (HQNO), inhibited both growth and Agr activity and conferred an SCV phenotype. Supplementation of the culture medium with synthetic autoinducing peptide (sAIP) significantly increased Agr expression in both hemB mutant strains and S. aureus grown with HQNO and significantly reduced staphylococcal adhesion to fibronectin. However, sAIP did not promote hemolysin expression in hemB mutant strains or S. aureus grown with HQNO. Therefore, while Agr regulates fibronectin binding in SCVs, it cannot promote hemolysin production in the absence of a functional electron transport chain. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  5. The sporulation of the green alga Ulva prolifera is controlled by changes in photosynthetic electron transport chain.

    Science.gov (United States)

    Wang, Hui; Lin, Apeng; Gu, Wenhui; Huan, Li; Gao, Shan; Wang, Guangce

    2016-04-22

    Sporulation and spore release are essential phases of the life cycle in algae and land plants. Ulva prolifera, which is an ideal organism for studying sporulation and spore release, was used as the experimental material in the present study. The determination of photosynthetic parameters, combined with microscopic observation, treatment with photosynthetic inhibitors, limitation of carbon acquisition, and protein mass spectrometry, was employed in this experiment. Cycle electron transport (CEF) was found enhanced at the onset of sporangia formation. The inhibition effect of dibromothymoquinone (DBMIB) towards sporulation was always strong during the sporulation process whereas the inhibition effect of 3-(3',4'-dichlorophenyl)-1,1-dimethylurea (DCMU) was continuously declined accompanied with the progress of sporulation. The changes of photosynthesis resulted from the limitation of CO2 acquisition could stimulate sporulation onset. Quantitative protein analysis showed that enzymes involved in carbon fixation, including RUBISCO and pyruvate orthophosphate dikinase, declined during sporogenesis, while proteins involved in sporulation, including tubulin and centrin, increased. These results suggest that enhanced cyclic electron flow (CEF) and oxidation of the plastoquinone pool are essential for sporangia formation onset, and changes in photosynthetic electron transport chain have significant impacts on sporulation of the green algae.

  6. Customized Transportation, Equity Participation, and Cooperation Performance within Logistics Supply Chains

    Directory of Open Access Journals (Sweden)

    Xudong Lin

    2015-01-01

    Full Text Available Customized transportation has received growing concerns by researchers and practitioners in recent years. Despite the fact that one consignor often holds partial ownership of its carrier within a supply chain, the existing interpretations behind them remain relatively unexplored. Based on the game models, we find that a simple take-or-pay contract is not likely to solve the low-efficient customized production problem, and equity participation mechanism plus simple contract may improve the cooperation performance of customized transportation. In the case of the owner-managed carrier, only when purchasing at par can it be ensured to obtain the socially optimal customization investment, but when purchasing at premium or discount, the optimal partial ownership selected by consignor cannot motivate the carrier to make the most efficient customization investment. With the optimal solutions, we also provide a theoretic foundation for calculating the optimal partial ownership and for interpreting why the interfirm share-holding ratios of the member-firms within the familial-type logistic supply chains are much larger than the ratios within the public-type logistic supply chains. Finally, our results show that the familial-type logistic supply chains may choose more efficient customized production level than public-type logistic supply chains.

  7. Finite speed heat transport in a quantum spin chain after quenched local cooling

    Science.gov (United States)

    Fries, Pascal; Hinrichsen, Haye

    2017-04-01

    We study the dynamics of an initially thermalized spin chain in the quantum XY-model, after sudden coupling to a heat bath of lower temperature at one end of the chain. In the semi-classical limit we see an exponential decay of the system-bath heatflux by exact solution of the reduced dynamics. In the full quantum description however, we numerically find the heatflux to reach intermediate plateaus where it is approximately constant—a phenomenon that we attribute to the finite speed of heat transport via spin waves.

  8. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain.

    Science.gov (United States)

    Owen, M R; Doran, E; Halestrap, A P

    2000-06-15

    Although metformin is widely used for the treatment of non-insulin-dependent diabetes, its mode of action remains unclear. Here we provide evidence that its primary site of action is through a direct inhibition of complex 1 of the respiratory chain. Metformin(50 microM) inhibited mitochondrial oxidation of glutamate+malate in hepatoma cells by 13 and 30% after 24 and 60 h exposure respectively, but succinate oxidation was unaffected. Metformin also caused time-dependent inhibition of complex 1 in isolated mitochondria, whereas in sub-mitochondrial particles inhibition was immediate but required very high metformin concentrations (K(0.5),79 mM). These data are compatible with the slow membrane-potential-driven accumulation of the positively charged drug within the mitochondrial matrix leading to inhibition of complex 1. Metformin inhibition of gluconeogenesis from L-lactate in isolated rat hepatocytes was also time- and concentration-dependent, and accompanied by changes in metabolite levels similar to those induced by other inhibitors of gluconeogenesis acting on complex 1. Freeze-clamped livers from metformin-treated rats exhibited similar changes in metabolite concentrations. We conclude that the drug's pharmacological effects are mediated, at least in part, through a time-dependent, self-limiting inhibition of the respiratory chain that restrains hepatic gluconeogenesis while increasing glucose utilization in peripheral tissues. Lactic acidosis, an occasional side effect, canal so be explained in this way.

  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. The Impact of Green Supply Chain Management on Transportation Cost Reduction in Turkey

    Directory of Open Access Journals (Sweden)

    Mehmet SARIDOGAN

    2012-01-01

    Full Text Available Supply chain management (SCM has become an important competitive approach for organizations. The issue of green supply chain management is critical for the successful implementation of industrial ecosystems and industrial ecology. Organizations have a number of reasons for implementing these green supply chain policies, from reactive regulatory reasons, to proactive strategic and competitive advantage reasons. From an overall environmental and organizational perspective, it is important to understand the situation and what issues exist in this field. Many organizations worldwide have already experienced globalization and a shifting focus to competition among networks of companies in this environment. Multinational enterprises have established global networks of suppliers that take advantage of country-industry specific characteristics to build this competitive advantage. To success having this competitive advantage, logistics and supply chain managers have to balance efforts to reduce costs and innovate while maintaining good environmental (ecological performance (Pagell et al., 2004. Therefore, today, competition is not between companies, between supply chains. This study brings us the effect of Green Supply Chain Management (GSCM on the Transportation Cost Reduction (TCR.

  12. Entanglement of conjugated polymer chains influences molecular self-assembly and carrier transport

    KAUST Repository

    Zhao, Kui

    2013-06-26

    The influence of polymer entanglement on the self-assembly, molecular packing structure, and microstructure of low-Mw (lightly entangled) and high-Mw (highly entangled) poly (3-hexylthiophene) (P3HT), and the carrier transport in thin-film transistors, are investigated. The polymer chains are gradually disentangled in a marginal solvent via ultrasonication of the polymer solution, and demonstrate improved diffusivity of precursor species (coils, aggregates, and microcrystallites), enhanced nucleation and crystallization of P3HT in solution, and self-assembly of well-ordered and highly textured fibrils at the solid-liquid interface. In low-Mw P3HT, reducing chain entanglement enhances interchain and intrachain ordering, but reduces the interconnectivity of ordered domains (tie molecules) due to the presence of short chains, thus deteriorating carrier transport even in the face of improving crystallinity. Reducing chain entanglement in high-Mw P3HT solutions increases carrier mobility up to ≈20-fold, by enhancing interchain and intrachain ordering while maintaining a sufficiently large number of tie molecules between ordered domains. These results indicate that charge carrier mobility is strongly governed by the balancing of intrachain and interchain ordering, on the one hand, and interconnectivity of ordered domains, on the other hand. In high-Mw P3HT, intrachain and interchain ordering appear to be the key bottlenecks to charge transport, whereas in low-Mw P3HT, the limited interconnectivity of the ordered domains acts as the primary bottleneck to charge transport. Conjugated polymer chains of poly(3-hexylthiophene) (P3HT) are gradually disentangled in solution and trends in carrier transport mechanisms in organic thin film transistors for low- and high-molecular weight P3HT are investigated. While intrachain and interchain ordering within ordered domains are the key bottlenecks to charge transport in high-Mw P3HT films, the limited interconnectivity of ordered

  13. Entanglement of conjugated polymer chains influences molecular self-assembly and carrier transport

    KAUST Repository

    Zhao, Kui; Khan, Hadayat Ullah; Li, Ruipeng; Su, Yisong; Amassian, Aram

    2013-01-01

    The influence of polymer entanglement on the self-assembly, molecular packing structure, and microstructure of low-Mw (lightly entangled) and high-Mw (highly entangled) poly (3-hexylthiophene) (P3HT), and the carrier transport in thin-film transistors, are investigated. The polymer chains are gradually disentangled in a marginal solvent via ultrasonication of the polymer solution, and demonstrate improved diffusivity of precursor species (coils, aggregates, and microcrystallites), enhanced nucleation and crystallization of P3HT in solution, and self-assembly of well-ordered and highly textured fibrils at the solid-liquid interface. In low-Mw P3HT, reducing chain entanglement enhances interchain and intrachain ordering, but reduces the interconnectivity of ordered domains (tie molecules) due to the presence of short chains, thus deteriorating carrier transport even in the face of improving crystallinity. Reducing chain entanglement in high-Mw P3HT solutions increases carrier mobility up to ≈20-fold, by enhancing interchain and intrachain ordering while maintaining a sufficiently large number of tie molecules between ordered domains. These results indicate that charge carrier mobility is strongly governed by the balancing of intrachain and interchain ordering, on the one hand, and interconnectivity of ordered domains, on the other hand. In high-Mw P3HT, intrachain and interchain ordering appear to be the key bottlenecks to charge transport, whereas in low-Mw P3HT, the limited interconnectivity of the ordered domains acts as the primary bottleneck to charge transport. Conjugated polymer chains of poly(3-hexylthiophene) (P3HT) are gradually disentangled in solution and trends in carrier transport mechanisms in organic thin film transistors for low- and high-molecular weight P3HT are investigated. While intrachain and interchain ordering within ordered domains are the key bottlenecks to charge transport in high-Mw P3HT films, the limited interconnectivity of ordered

  14. Effect of backbone structure on charge transport along isolated conjugated polymer chains

    International Nuclear Information System (INIS)

    Siebbeles, Laurens D.A.; Grozema, Ferdinand C.; Haas, Matthijs P. de; Warman, John M.

    2005-01-01

    Fast charge transport in conjugated polymers is essential for their application in opto-electronic devices. In the present paper, measurements and theoretical modeling of the mobility of excess charges along isolated chains of conjugated polymers in dilute solution are presented. Charge carriers were produced by irradiation of the polymer solution with 3-MeV electrons from a Van de Graaff accelerator. The mobilities of the charges along the polymer chains were obtained from time-resolved microwave conductivity measurements. The mobilities are strongly dependent on the chemical nature of the polymer backbone. Comparison of the experimental data with results from ab initio quantum mechanical calculations shows that the measured mobilities are strongly limited by torsional disorder, chemical defects and chain ends. Improvement of the structure of polymer backbones is therefore expected to significantly enhance the performance of these materials in 'plastic electronics'

  15. First-principles study on electron transport properties of carbon-silicon mixed chains

    Science.gov (United States)

    Hu, Wei; Zhou, Qinghua; Liang, Yan; Liu, Wenhua; Wang, Tao; Wan, Haiqing

    2018-03-01

    In this paper, the transport properties of carbon-silicon mixed chains are studied by using the first-principles. We studied five atomic chain models. In these studies, we found that the equilibrium conductances of atomic chains appear to oscillate, the maximum conductance and the minimum conductance are more than twice the difference. Their I-V curves are linear and show the behavior of metal resistance, M5 system and M2 system current ratio is the largest in 0.9 V, which is 3.3, showing a good molecular switch behavior. In the case of bias, while the bias voltage increases, the transmission peaks move from the Fermi level. The resonance transmission peak height is reduced near the Fermi level. In the higher energy range, a large resonance transmission peak reappears, there is still no energy cut-off range.

  16. Chain segmentation for the Monte Carlo solution of particle transport problems

    International Nuclear Information System (INIS)

    Ragheb, M.M.H.

    1984-01-01

    A Monte Carlo approach is proposed where the random walk chains generated in particle transport simulations are segmented. Forward and adjoint-mode estimators are then used in conjunction with the firstevent source density on the segmented chains to obtain multiple estimates of the individual terms of the Neumann series solution at each collision point. The solution is then constructed by summation of the series. The approach is compared to the exact analytical and to the Monte Carlo nonabsorption weighting method results for two representative slowing down and deep penetration problems. Application of the proposed approach leads to unbiased estimates for limited numbers of particle simulations and is useful in suppressing an effective bias problem observed in some cases of deep penetration particle transport problems

  17. Functional size of photosynthetic electron transport chain determined by radiation inactivation

    International Nuclear Information System (INIS)

    Pan, R.S.; Chen, L.F.; Wang, M.Y.; Tsal, M.Y.; Pan, R.L.; Hsu, B.D.

    1987-01-01

    Radiation inactivation technique was employed to determine the functional size of photosynthetic electron transport chain of spinach chloroplasts. The functional size for photosystem I+II(H 2 O to methylviologen) was 623 +/- 37 kilodaltons; for photosystem II (H 2 O to dimethylquinone/ferricyanide), 174 +/- 11 kilodaltons; and for photosystem I (reduced diaminodurene to methylviologen), 190 +/- 11 kilodaltons. The difference between 364 +/- 22 (the sum of 174 +/- 11 and 190 +/- 11) kilodaltons and 623 +/- 37 kilodaltons is partially explained to be due to the presence of two molecules of cytochrome b 6 /f complex of 280 kilodaltons. The molecular mass for other partial reactions of photosynthetic electron flow, also measured by radiation inactivation, is reported. The molecular mass obtained by this technique is compared with that determined by other conventional biochemical methods. A working hypothesis for the composition, stoichiometry, and organization of polypeptides for photosynthetic electron transport chain is proposed

  18. Transport and selective chaining of bidisperse particles in a travelling wave potential.

    Science.gov (United States)

    Tierno, Pietro; Straube, Arthur V

    2016-05-01

    We combine experiments, theory and numerical simulation to investigate the dynamics of a binary suspension of paramagnetic colloidal particles dispersed in water and transported above a stripe-patterned magnetic garnet film. The substrate generates a one-dimensional periodic energy landscape above its surface. The application of an elliptically polarized rotating magnetic field causes the landscape to translate, inducing direct transport of paramagnetic particles placed above the film. The ellipticity of the applied field can be used to control and tune the interparticle interactions, from net repulsive to net attractive. When considering particles of two distinct sizes, we find that, depending on their elevation above the surface of the magnetic substrate, the particles feel effectively different potentials, resulting in different mobilities. We exploit this feature to induce selective chaining for certain values of the applied field parameters. In particular, when driving two types of particles, we force only one type to condense into travelling parallel chains. These chains confine the movement of the other non-chaining particles within narrow colloidal channels. This phenomenon is explained by considering the balance of pairwise magnetic forces between the particles and their individual coupling with the travelling landscape.

  19. Quasibound states and transport characteristics of Au chains with a substitutional S impurity

    International Nuclear Information System (INIS)

    Wawrzyniak-Adamczewska, M; Kostyrko, T

    2013-01-01

    Electronic transport properties of short gold atom chains with a single sulfur impurity were studied using density functional theory. It is found that the role of the impurity atom in the transport properties is twofold. First, it acts as a scattering center in the dominating 6s-orbital transmission channel and generally leads to a decrease of the transmission function in a wide energy region around the Fermi level. Second, it gives rise to a quasibound state manifesting as a peak near the Fermi level both in the partial density of states as well as in the transmission function. Because of the hybridization of the sulfur 3p and gold 5d orbitals in its formation, the quasibound state moves locally upward in the gold 5d transmission channel and brings about an enhancement of the transmission function in a narrow energy region near the Fermi level. The height of the peak of the quasibound state in the transmission function depends significantly on the position of the impurity in the chain and its energy varies with the bias voltage. The current–voltage (I–V) characteristics become asymmetric with a departure of the impurity from the central position in the chain and they are nonlinear for small values of the voltage (V < 0.1 V). It is proposed that a careful analysis of the I–V characteristics or the voltage dependence of the differential conductance may be used for unambiguous location of the light impurity in experiments with gold chains. (paper)

  20. Hydrogen is a preferred intermediate in the energy-conserving electron transport chain of Methanosarcina barkeri.

    Science.gov (United States)

    Kulkarni, Gargi; Kridelbaugh, Donna M; Guss, Adam M; Metcalf, William W

    2009-09-15

    Methanogens use an unusual energy-conserving electron transport chain that involves reduction of a limited number of electron acceptors to methane gas. Previous biochemical studies suggested that the proton-pumping F(420)H(2) dehydrogenase (Fpo) plays a crucial role in this process during growth on methanol. However, Methanosarcina barkeri Delta fpo mutants constructed in this study display no measurable phenotype on this substrate, indicating that Fpo plays a minor role, if any. In contrast, Delta frh mutants lacking the cytoplasmic F(420)-reducing hydrogenase (Frh) are severely affected in their ability to grow and make methane from methanol, and double Delta fpo/Delta frh mutants are completely unable to use this substrate. These data suggest that the preferred electron transport chain involves production of hydrogen gas in the cytoplasm, which then diffuses out of the cell, where it is reoxidized with transfer of electrons into the energy-conserving electron transport chain. This hydrogen-cycling metabolism leads directly to production of a proton motive force that can be used by the cell for ATP synthesis. Nevertheless, M. barkeri does have the flexibility to use the Fpo-dependent electron transport chain when needed, as shown by the poor growth of the Delta frh mutant. Our data suggest that the rapid enzymatic turnover of hydrogenases may allow a competitive advantage via faster growth rates in this freshwater organism. The mutant analysis also confirms the proposed role of Frh in growth on hydrogen/carbon dioxide and suggests that either Frh or Fpo is needed for aceticlastic growth of M. barkeri.

  1. Triplet Transport to and Trapping by Acceptor End Groups on Conjugated Polyfluorene Chains

    Energy Technology Data Exchange (ETDEWEB)

    Sreearunothai, P.; Miller, J.; Estrada, A.; Asaoka, S.; Kowalczyk, M.; Jang, S.; Cook, A.R.; Preses, J.M.

    2011-08-31

    Triplet excited states created in polyfluorene (pF) molecules having average lengths up to 170 repeat units were transported to and captured by trap groups at the ends in less {approx}40 ns. Almost all of the triplets attached to the chains reached the trap groups, ruling out the presence of substantial numbers of defects that prevent transport. The transport yields a diffusion coefficient D of at least 3 x 10{sup -4} cm{sup 2} s{sup -1}, which is 30 times typical molecular diffusion and close to a value for triplet transport reported by Keller (J. Am. Chem. Soc.2011, 133, 11289-11298). The triplet states were created in solution by pulse radiolysis; time resolution was limited by the rate of attachment of triplets to the pF chains. Naphthylimide (NI) or anthraquinone (AQ) groups attached to the ends of the chains acted as traps for the triplets, although AQ would not have been expected to serve as a trap on the basis of triplet energies of the separate molecules. The depths of the NI and AQ triplet traps were determined by intermolecular triplet transfer equilibria and temperature dependence. The trap depths are shallow, just a few times thermal energy for both, so a small fraction of the triplets reside in the pF chains in equilibrium with the end-trapped triplets. Trapping by AQ appears to arise from charge transfer interactions between the pF chains and the electron-accepting AQ groups. Absorption bands of the end-trapped triplet states are similar in peak wavelength (760 nm) and shape to the 760 nm bands of triplets in the pF chains but have reduced intensities. When an electron donor, N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD), is added to the solution, it reacts with the end-trapped triplets to remove the 760 nm bands and to make the trapping irreversible. New bands created upon reaction with TMPD may be due to charge transfer states.

  2. Cost-effective strategy to mitigate transportation disruptions in supply chain

    Science.gov (United States)

    Albertzeth, G.; Pujawan, I. N.

    2018-04-01

    Supply chain disruptions have gained significant attention by scholars. But, even though transportation plays a central role in supply chain, only few studies address transportation disruptions. This research demonstrates a real case of an order delivery process from a focal company (FC) to a single distributor, where transportation disruptions stochastically occurs. Considering the possibility of sales loss during the disruption duration, we proposed a redundant stock, flexible route, and combined flexibility-redundancy (ReFlex) as mitigation strategies and a base case as a risk acceptance strategy. The objective is to find out the best strategy that promotes cost-effectiveness against transportation disruptions. To fulfill this objective, we use simulation modeling and cost-effectiveness analysis (CEA) as our research method. We simulate the delivery process of 5 brands using each strategy to produce two different responses: loss of sales percentage and the incurred costs. Next, using these responses, we evaluate and compare the cost-effectiveness ratio of each strategy using CEA. We found that redundant stock gave the best effectiveness on all brands, ReFlex as the second best, while flexible route gave the least effectiveness. Finally, we recommend which strategy should be applied based on the decision maker willingness to pay.

  3. 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

  4. Ascorbate Biosynthesis in Mitochondria Is Linked to the Electron Transport Chain between Complexes III and IV1

    Science.gov (United States)

    Bartoli, Carlos G.; Pastori, Gabriela M.; Foyer, Christine H.

    2000-01-01

    Ascorbic acid is synthesized from galactono-γ-lactone (GL) in plant tissues. An improved extraction procedure involving ammonium sulfate precipitation of membrane proteins from crude leaf homogenates yielded a simple, quick method for determining tissue activities of galactono-γ-lactone dehydrogenase (GLDH). Total foliar ascorbate and GLDH activity decreased with leaf age. Subcellular fractionation experiments using marker enzymes demonstrated that 80% of the total GLDH activity was located on the inner mitochondrial membrane, and 20% in the microsomal fraction. Specific antibody raised against potato (Solanum tuberosum L.) tuber GLDH recognized a 56-kD polypeptide in extracts from the mitochondrial membranes but failed to detect the equivalent polypeptide in microsomes. We demonstrate that isolated intact mitochondria synthesize ascorbate in the presence of GL. GL stimulated mitochondrial electron transport rates. The respiration inhibitor antimycin A stimulated ascorbate biosynthesis, while cyanide inhibited both respiration and ascorbate production. GL-dependent oxygen uptake was observed in isolated intact mitochondria. This evidence suggests that GLDH delivers electrons to the mitochondrial electron transport chain between complexes III and IV. PMID:10806250

  5. Phosphorylation of Cytochrome c Threonine 28 Regulates Electron Transport Chain Activity in Kidney: IMPLICATIONS FOR AMP KINASE.

    Science.gov (United States)

    Mahapatra, Gargi; Varughese, Ashwathy; Ji, Qinqin; Lee, Icksoo; Liu, Jenney; Vaishnav, Asmita; Sinkler, Christopher; Kapralov, Alexandr A; Moraes, Carlos T; Sanderson, Thomas H; Stemmler, Timothy L; Grossman, Lawrence I; Kagan, Valerian E; Brunzelle, Joseph S; Salomon, Arthur R; Edwards, Brian F P; Hüttemann, Maik

    2017-01-06

    Mammalian cytochrome c (Cytc) plays a key role in cellular life and death decisions, functioning as an electron carrier in the electron transport chain and as a trigger of apoptosis when released from the mitochondria. However, its regulation is not well understood. We show that the major fraction of Cytc isolated from kidneys is phosphorylated on Thr 28 , leading to a partial inhibition of respiration in the reaction with cytochrome c oxidase. To further study the effect of Cytc phosphorylation in vitro, we generated T28E phosphomimetic Cytc, revealing superior behavior regarding protein stability and its ability to degrade reactive oxygen species compared with wild-type unphosphorylated Cytc Introduction of T28E phosphomimetic Cytc into Cytc knock-out cells shows that intact cell respiration, mitochondrial membrane potential (ΔΨ m ), and ROS levels are reduced compared with wild type. As we show by high resolution crystallography of wild-type and T28E Cytc in combination with molecular dynamics simulations, Thr 28 is located at a central position near the heme crevice, the most flexible epitope of the protein apart from the N and C termini. Finally, in silico prediction and our experimental data suggest that AMP kinase, which phosphorylates Cytc on Thr 28 in vitro and colocalizes with Cytc to the mitochondrial intermembrane space in the kidney, is the most likely candidate to phosphorylate Thr 28 in vivo We conclude that Cytc phosphorylation is mediated in a tissue-specific manner and leads to regulation of electron transport chain flux via "controlled respiration," preventing ΔΨ m hyperpolarization, a known cause of ROS and trigger of apoptosis. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  6. Phosphorylation of Cytochrome c Threonine 28 Regulates Electron Transport Chain Activity in Kidney: IMPLICATIONS FOR AMP KINASE

    Energy Technology Data Exchange (ETDEWEB)

    Mahapatra, Gargi; Varughese, Ashwathy; Ji, Qinqin; Lee, Icksoo; Liu, Jenney; Vaishnav, Asmita; Sinkler, Christopher; Kapralov, Alexandr A.; Moraes, Carlos T.; Sanderson, Thomas H.; Stemmler, Timothy L.; Grossman, Lawrence I.; Kagan, Valerian E.; Brunzelle, Joseph S.; Salomon, Arthur R.; Edwards, Brian F. P.; Hüttemann, Maik

    2016-10-07

    Mammalian cytochrome c (Cytc) plays a key role in cellular life and death decisions, functioning as an electron carrier in the electron transport chain and as a trigger of apoptosis when released from the mitochondria. However, its regulation is not well understood. We show that the major fraction of Cytc isolated from kidneys is phosphorylated on Thr28, leading to a partial inhibition of respiration in the reaction with cytochrome c oxidase. To further study the effect of Cytc phosphorylation in vitro, we generated T28E phosphomimetic Cytc, revealing superior behavior regarding protein stability and its ability to degrade reactive oxygen species compared with wild-type unphosphorylated Cytc. Introduction of T28E phosphomimetic Cytc into Cytc knock-out cells shows that intact cell respiration, mitochondrial membrane potential (ΔΨm), and ROS levels are reduced compared with wild type. As we show by high resolution crystallography of wild-type and T28E Cytc in combination with molecular dynamics simulations, Thr28 is located at a central position near the heme crevice, the most flexible epitope of the protein apart from the N and C termini. Finally, in silico prediction and our experimental data suggest that AMP kinase, which phosphorylates Cytc on Thr28 in vitro and colocalizes with Cytc to the mitochondrial intermembrane space in the kidney, is the most likely candidate to phosphorylate Thr28 in vivo. We conclude that Cytc phosphorylation is mediated in a tissue-specific manner and leads to regulation of electron transport chain flux via “controlled respiration,” preventing ΔΨm hyperpolarization, a known cause of ROS and trigger of apoptosis.

  7. Electronic transport in large systems through a QUAMBO-NEGF approach: Application to atomic carbon chains

    International Nuclear Information System (INIS)

    Fang, X.W.; Zhang, G.P.; Yao, Y.X.; Wang, C.Z.; Ding, Z.J.; Ho, K.M.

    2011-01-01

    The conductance of single-atom carbon chain (SACC) between two zigzag graphene nanoribbons (GNR) is studied by an efficient scheme utilizing tight-binding (TB) parameters generated via quasi-atomic minimal basis set orbitals (QUAMBOs) and non-equilibrium Green's function (NEGF). Large systems (SACC contains more than 50 atoms) are investigated and the electronic transport properties are found to correlate with SACC's parity. The SACCs provide a stable off or on state in broad energy region (0.1-1 eV) around Fermi energy. The off state is not sensitive to the length of SACC while the corresponding energy region decreases with the increase of the width of GNR. -- Highlights: → Graphene has many superior electronic properties. → First-principles calculation are accurate but limited to system size. → QUAMBOs construct tight-binding parameters with spatial localization, and then use divide-and-conquer method. → SACC (single carbon atom chain): structure and transport show even-odd parity, and long chains are studied.

  8. Electronic transport through a quantum dot chain with strong dot-lead coupling

    International Nuclear Information System (INIS)

    Liu, Yu; Zheng, Yisong; Gong, Weijiang; Gao, Wenzhu; Lue, Tianquan

    2007-01-01

    By means of the non-equilibrium Green function technique, the electronic transport through an N-quantum-dot chain is theoretically studied. By calculating the linear conductance spectrum and the local density of states in quantum dots, we find the resonant peaks in the spectra coincides with the eigen-energies of the N-quantum-dot chain when the dot-lead coupling is relatively weak. With the increase of the dot-lead coupling, such a correspondence becomes inaccurate. When the dot-lead coupling exceeds twice the interdot coupling, such a mapping collapses completely. The linear conductance turn to reflect the eigen-energies of the (N-2)- or (N-1)-quantum dot chain instead. The two peripheral quantum dots do not manifest themselves in the linear conductance spectrum. More interestingly, with the further increase of the dot-lead coupling, the system behaves just like an (N-2)- or (N-1)-quantum dot chain in weak dot-lead coupling limit, since the resonant peaks becomes narrower with the increase of dot-lead coupling

  9. Reversal of local spins in transport of electrons through a one-dimensional chain

    International Nuclear Information System (INIS)

    Hu, D.-S.; Xiong, S.-J.

    2003-01-01

    We investigate the spin reversal of two coupled magnetic impurities in the transport processes of electrons in a one-dimensional chain. The impurities are side coupled to the chain and the electrons are injected and tunneling through it. The transmission coefficient of electrons and the polarization of impurities are calculated by the use of the equivalent single-particle network method for the correlated system. It is found that both the transmission coefficient and the polarization of impurities depend on the initial state of impurities and the impurity spins can be converted into the direction of electron spin if the injected electrons are polarized and the number of electrons is large enough. The evolution of the spin-reversal processes is studied in details

  10. CASCADER: An M-chain gas-phase radionuclide transport and fate model

    International Nuclear Information System (INIS)

    Lindstrom, F.T.; Cawlfield, D.E.; Emer, D.F.; Shott, G.J.; Donahue, M.E.

    1993-02-01

    Chemicals and radionuclides move either in the gas-phase, liquid-phase, or both phases in soils. They may be acted upon by either biological or abiotic processes through advection and diffusion. Furthermore, parent and daughter radionuclides may decay as they are transported in the soil. CASCADER is a gas-phase, one-space dimensional transport and fate model for M-chain radionuclides in very dry homogeneous or heterogeneous soil. This model contains barometric pressure-induced advection and diffusion together with linear irreversible and linear reversible sorption for each radionuclide. The advection velocity is derived from an embedded air-pumping submodel. The air-pumping submodel is based on an assumption of isothermal conditions, which is driven by barometric pressure. CASCADER allows the concentration of source radionuclides to decay via the classical Bateman chain of simple, first-order kinetic processes. The transported radionuclides also decay via first-order processes while in the soil. A mass conserving, flux-type inlet and exit set of boundary conditions are used. The user must supply the initial distribution for the parent radionuclide in the soil. The initial daughter distribution is found using equilibrium rules. The model is user friendly as it uses a prompt-driven, free-form input. The code is ANSI standard Fortran 77

  11. CASCADER: An m-chain gas-phase radionuclide transport and fate model

    International Nuclear Information System (INIS)

    Lindstrom, F.T.; Cawlfield, D.E.; Emer, D.F.; Shott, G.J.; Donahue, M.E.

    1992-06-01

    Chemicals and radionuclides move either in the gas-phase, liquid-phase, or both phases in soils. They may be acted upon by either biological or abiotic processes as they are advected and/or dispersed. Furthermore, parent and daughter radionuclides may decay as they are transported in the soil. CASCADER is a gas-phase, one space dimensional transport and fate model for an m-chain of radionuclides in very dry soil. This model contains barometric pressure-induced advection and diffusion together with linear irreversible and linear reversible sorption for each radionuclide. The advocation velocity is derived from an embedded air-pumping submodel. The airpumping submodel is based on an assumption of isothermal conditions and is barometric pressure driven. CASCADER allows the concentration of source radionuclides to decay via the classical Bateman chain of simple, first-order kinetic processes. The transported radionuclides also decay via first-order processes while in the soil. A mass conserving, flux-type inlet and exit set of boundary conditions is used. The user must supply the initial distribution for the parent radionuclide in the soil. The initial daughter distribution is found using equilibrium rules. The model is user friendly as it uses a prompt-driven, free-form input. The code is ANSI standard Fortran 77

  12. Chemical genetics analysis of an aniline mustard anticancer agent reveals complex I of the electron transport chain as a target.

    Science.gov (United States)

    Fedeles, Bogdan I; Zhu, Angela Y; Young, Kellie S; Hillier, Shawn M; Proffitt, Kyle D; Essigmann, John M; Croy, Robert G

    2011-09-30

    The antitumor agent 11β (CAS 865070-37-7), consisting of a DNA-damaging aniline mustard linked to an androgen receptor (AR) ligand, is known to form covalent DNA adducts and to induce apoptosis potently in AR-positive prostate cancer cells in vitro; it also strongly prevents growth of LNCaP xenografts in mice. The present study describes the unexpectedly strong activity of 11β against the AR-negative HeLa cells, both in cell culture and tumor xenografts, and uncovers a new mechanism of action that likely explains this activity. Cellular fractionation experiments indicated that mitochondria are the major intracellular sink for 11β; flow cytometry studies showed that 11β exposure rapidly induced oxidative stress, mitochondria being an important source of reactive oxygen species (ROS). Additionally, 11β inhibited oxygen consumption both in intact HeLa cells and in isolated mitochondria. Specifically, 11β blocked uncoupled oxygen consumption when mitochondria were incubated with complex I substrates, but it had no effect on oxygen consumption driven by substrates acting downstream of complex I in the mitochondrial electron transport chain. Moreover, 11β enhanced ROS generation in isolated mitochondria, suggesting that complex I inhibition is responsible for ROS production. At the cellular level, the presence of antioxidants (N-acetylcysteine or vitamin E) significantly reduced the toxicity of 11β, implicating ROS production as an important contributor to cytotoxicity. Collectively, our findings establish complex I inhibition and ROS generation as a new mechanism of action for 11β, which supplements conventional DNA adduct formation to promote cancer cell death.

  13. Thermal generation and mobility of charge carriers in collective proton transport in hydrogen-bonded chains

    International Nuclear Information System (INIS)

    Peyrard, M.; Boesch, R.; Kourakis, I.

    1991-01-01

    The transport of protons in hydrogen-bonded systems is a long standing problem which has not yet obtained a satisfactorily theoretical description. Although this problem was examined first for ice, it is relevant in many systems and in particular in biology for the transport along proteins or for proton conductance across membranes, an essential process in cell life. The broad relevance makes the study of proton conduction very appealing. Since the original work of Bernal and Fowler on ice, the idea that the transport occurs through chains of hydrogen bonds has been well accepted. Such ''proton wires'' were invoked by Nagle and Morowitz for proton transport across membranes proteins and more recently across lipid bilayers. In this report, we assume the existence of such an hydrogen-bonded chain and discuss its consequences on the dynamics of the charge carriers. We show that this assumption leads naturally to the idea of soliton transport and we put a special emphasis on the role of the coupling between the protons and heavy ions motions. The model is presented. We show how the coupling affects strongly the dynamics of the charge carriers and we discuss the role it plays in the thermal generation of carriers. The work presented has been performed in 1986 and 87 with St. Pnevmatikos and N. Flyzanis and was then completed in collaboration with D. Hochstrasser and H. Buettner. Therefore the results presented in this part are not new but we think that they are appropriate in the context of this multidisciplinary workshop because they provide a rather complete example of the soliton picture for proton conduction. This paper discusses the thermal generation of the charge carriers when the coupling between the protons and heavy ions dynamics is taken into account. The results presented in this part are very recent and will deserve further analysis but they already show that the coupling can assist for the formation of the charge carriers

  14. Green supply chain management using the queuing theory to handle congestion and reduce energy consumption and emissions from supply chain transportation fleet

    Directory of Open Access Journals (Sweden)

    Arvin Aziziankohan

    2017-05-01

    Full Text Available Purpose: Nowadays, governments and people pay more attention to use green products due to environmental pollution, irreplaceable energy and shortage of resources. Green products are resulted from the application of green supply chain management strategies to the organizations' performance strategies, so that we can reduce environmental pollutants and wastes and take a step towards saving energy with limited resources. Methodology:  In this paper, the effect of reducing energy consumption in green supply chain is examined by using queuing theory and transportation models. Data was generated and solved by a commercial optimization epackage. Findings:  The findings indicate that suitable assignment of existing transportation fleet with specified capacity, and using queueing theory in a closed-loop network to reduce the queue length and handle congestion, can cause a reduction in energy consumption by optimizing transportation and waiting times in a green supply chain. Originality/value: Adopting investment strategy in improving the environmental performance of the supply chain, will yield in many advantages and benefits. This article investigates the effect of queuing theory on reducing waiting time, optimizing energy consumption in green supply chain, and consequently decreasing pollution.

  15. Green supply chain management using the queuing theory to handle congestion and reduce energy consumption and emissions from supply chain transportation fleet

    International Nuclear Information System (INIS)

    Aziziankohan, A.; Jolai, F.; Khalilzadeh, M.; Soltani, R.; Tavakkoli-Moghaddam, R.

    2017-01-01

    Purpose: Nowadays, governments and people pay more attention to use green products due to environmental pollution, irreplaceable energy and shortage of resources. Green products are resulted from the application of green supply chain management strategies to the organizations' performance strategies, so that we can reduce environmental pollutants and wastes and take a step towards saving energy with limited resources. Methodology: In this paper, the effect of reducing energy consumption in green supply chain is examined by using queuing theory and transportation models. Data was generated and solved by a commercial optimization epackage. Findings: The findings indicate that suitable assignment of existing transportation fleet with specified capacity, and using queueing theory in a closed-loop network to reduce the queue length and handle congestion, can cause a reduction in energy consumption by optimizing transportation and waiting times in a green supply chain. Originality/value: Adopting investment strategy in improving the environmental performance of the supply chain, will yield in many advantages and benefits. This article investigates the effect of queuing theory on reducing waiting time, optimizing energy consumption in green supply chain, and consequently decreasing pollution.

  16. Green supply chain management using the queuing theory to handle congestion and reduce energy consumption and emissions from supply chain transportation fleet

    Energy Technology Data Exchange (ETDEWEB)

    Aziziankohan, A.; Jolai, F.; Khalilzadeh, M.; Soltani, R.; Tavakkoli-Moghaddam, R.

    2017-07-01

    Purpose: Nowadays, governments and people pay more attention to use green products due to environmental pollution, irreplaceable energy and shortage of resources. Green products are resulted from the application of green supply chain management strategies to the organizations' performance strategies, so that we can reduce environmental pollutants and wastes and take a step towards saving energy with limited resources. Methodology: In this paper, the effect of reducing energy consumption in green supply chain is examined by using queuing theory and transportation models. Data was generated and solved by a commercial optimization epackage. Findings: The findings indicate that suitable assignment of existing transportation fleet with specified capacity, and using queueing theory in a closed-loop network to reduce the queue length and handle congestion, can cause a reduction in energy consumption by optimizing transportation and waiting times in a green supply chain. Originality/value: Adopting investment strategy in improving the environmental performance of the supply chain, will yield in many advantages and benefits. This article investigates the effect of queuing theory on reducing waiting time, optimizing energy consumption in green supply chain, and consequently decreasing pollution.

  17. 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...

  18. Transport and supply logistics of biomass fuels: Vol. 1. Supply chain options for biomass fuels

    Energy Technology Data Exchange (ETDEWEB)

    Allen, J; Browne, M; Palmer, H; Hunter, A; Boyd, J

    1996-10-01

    The study which forms part of a wider project funded by the Department of Trade and Industry, looks at the feasibility of generating electricity from biomass-fuelled power stations. Emphasis is placed on supply availabilty and transport consideration for biomass fuels such as wood wastes from forestry, short rotation coppice products, straw, miscanthus (an energy crop) and farm animal slurries. The study details the elements of the supply chain for each fuel from harvesting to delivery at the power station. The delivered cost of each fuel, the environmental impact of the biomass fuel supply and other relevant non-technical issues are addressed. (UK)

  19. 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...

  20. 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.

  1. SWIFT, 3-D Fluid Flow, Heat Transfer, Decay Chain Transport in Geological Media

    International Nuclear Information System (INIS)

    Cranwell, R.M.; Reeves, M.

    2003-01-01

    1 - Description of problem or function: SWIFT solves the coupled or individual equations governing fluid flow, heat transport, brine displacement, and radionuclide displacement in geologic media. Fluid flow may be transient or steady-state. One, two, or three dimensions are available and transport of radionuclides chains is possible. 4. Method of solution: Finite differencing is used to discretize the partial differential equations in space and time. The user may choose centered or backward spatial differencing, coupled with either central or backward temporal differencing. The matrix equations may be solved iteratively (two line successive-over-relaxation) or directly (special matrix banding and Gaussian elimination). 5. Restrictions on the complexity of the problem: On the CDC7600 in direct solution mode, the maximum number of grid blocks allowed is approximately 1400

  2. Specific Interaction between Redox Phospholipid Polymers and Plastoquinone in Photosynthetic Electron Transport Chain.

    Science.gov (United States)

    Tanaka, Kenya; Kaneko, Masahiro; Ishikawa, Masahito; Kato, Souichiro; Ito, Hidehiro; Kamachi, Toshiaki; Kamiya, Kazuhide; Nakanishi, Shuji

    2017-04-19

    Redox phospholipid polymers added in culture media are known to be capable of extracting electrons from living photosynthetic cells across bacterial cell membranes with high cytocompatibility. In the present study, we identify the intracellular redox species that transfers electrons to the polymers. The open-circuit electrochemical potential of an electrolyte containing the redox polymer and extracted thylakoid membranes shift to positive (or negative) under light irradiation, when an electron transport inhibitor specific to plastoquinone is added upstream (or downstream) in the photosynthetic electron transport chain. The same trend is also observed for a medium containing living photosynthetic cells of Synechococcus elongatus PCC7942. These results clearly indicate that the phospholipid redox polymers extract photosynthetic electrons mainly from plastoquinone. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Supply Chain Model with Stochastic Lead Time, Trade-Credit Financing, and Transportation Discounts

    Directory of Open Access Journals (Sweden)

    Sung Jun Kim

    2017-01-01

    Full Text Available This model extends a two-echelon supply chain model by considering the trade-credit policy, transportations discount to make a coordination mechanism between transportation discounts, trade-credit financing, number of shipments, quality improvement of products, and reduced setup cost in such a way that the total cost of the whole system can be reduced, where the supplier offers trade-credit-period to the buyer. For buyer, the backorder rate is considered as variable. There are two investments to reduce setup cost and to improve quality of products. The model assumes lead time-dependent backorder rate, where the lead time is stochastic in nature. By using the trade-credit policy, the model gives how the credit-period would be determined to achieve the win-win outcome. An iterative algorithm is designed to obtain the global optimum results. Numerical example and sensitivity analysis are given to illustrate the model.

  4. 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

  5. Revisiting Temporal Markov Chains for Continuum modeling of Transport in Porous Media

    Science.gov (United States)

    Delgoshaie, A. H.; Jenny, P.; Tchelepi, H.

    2017-12-01

    The transport of fluids in porous media is dominated by flow­-field heterogeneity resulting from the underlying permeability field. Due to the high uncertainty in the permeability field, many realizations of the reference geological model are used to describe the statistics of the transport phenomena in a Monte Carlo (MC) framework. There has been strong interest in working with stochastic formulations of the transport that are different from the standard MC approach. Several stochastic models based on a velocity process for tracer particle trajectories have been proposed. Previous studies have shown that for high variances of the log-conductivity, the stochastic models need to account for correlations between consecutive velocity transitions to predict dispersion accurately. The correlated velocity models proposed in the literature can be divided into two general classes of temporal and spatial Markov models. Temporal Markov models have been applied successfully to tracer transport in both the longitudinal and transverse directions. These temporal models are Stochastic Differential Equations (SDEs) with very specific drift and diffusion terms tailored for a specific permeability correlation structure. The drift and diffusion functions devised for a certain setup would not necessarily be suitable for a different scenario, (e.g., a different permeability correlation structure). The spatial Markov models are simple discrete Markov chains that do not require case specific assumptions. However, transverse spreading of contaminant plumes has not been successfully modeled with the available correlated spatial models. Here, we propose a temporal discrete Markov chain to model both the longitudinal and transverse dispersion in a two-dimensional domain. We demonstrate that these temporal Markov models are valid for different correlation structures without modification. Similar to the temporal SDEs, the proposed model respects the limited asymptotic transverse spreading of

  6. Physiological Evidence for Isopotential Tunneling in the Electron Transport Chain of Methane-Producing Archaea.

    Science.gov (United States)

    Duszenko, Nikolas; Buan, Nicole R

    2017-09-15

    Many, but not all, organisms use quinones to conserve energy in their electron transport chains. Fermentative bacteria and methane-producing archaea (methanogens) do not produce quinones but have devised other ways to generate ATP. Methanophenazine (MPh) is a unique membrane electron carrier found in Methanosarcina species that plays the same role as quinones in the electron transport chain. To extend the analogy between quinones and MPh, we compared the MPh pool sizes between two well-studied Methanosarcina species, Methanosarcina acetivorans C2A and Methanosarcina barkeri Fusaro, to the quinone pool size in the bacterium Escherichia coli We found the quantity of MPh per cell increases as cultures transition from exponential growth to stationary phase, and absolute quantities of MPh were 3-fold higher in M. acetivorans than in M. barkeri The concentration of MPh suggests the cell membrane of M. acetivorans , but not of M. barkeri , is electrically quantized as if it were a single conductive metal sheet and near optimal for rate of electron transport. Similarly, stationary (but not exponentially growing) E. coli cells also have electrically quantized membranes on the basis of quinone content. Consistent with our hypothesis, we demonstrated that the exogenous addition of phenazine increases the growth rate of M. barkeri three times that of M. acetivorans Our work suggests electron flux through MPh is naturally higher in M. acetivorans than in M. barkeri and that hydrogen cycling is less efficient at conserving energy than scalar proton translocation using MPh. IMPORTANCE Can we grow more from less? The ability to optimize and manipulate metabolic efficiency in cells is the difference between commercially viable and nonviable renewable technologies. Much can be learned from methane-producing archaea (methanogens) which evolved a successful metabolic lifestyle under extreme thermodynamic constraints. Methanogens use highly efficient electron transport systems and

  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. I-V characteristic of electronic transport through a quantum dot chain: The role of antiresonance

    International Nuclear Information System (INIS)

    Liu Yu; Zheng Yisong; Gong Weijiang; Lue Tianquan

    2006-01-01

    The I-V spectrum of electronic transport through a quantum dot chain is calculated by means of the nonequilibrium Green function technique. In such a system, two arbitrary quantum dots are connected with two electron reservoirs through leads. When the dot-lead coupling is very weak, a series of discrete resonant peaks in electron transmission function cause staircase-like I-V characteristic. On the contrary, in the relatively strong dot-lead coupling regime, stairs in the I-V spectrum due to resonance vanish. However, when there are some dangling quantum dots in the chain outside two leads, the antiresonance which corresponds to the zero points of electron transmission function brings about novel staircase characteristic in the I-V spectrum. Moreover, two features in the I-V spectrum arising from the antiresonance are pointed out, which are significant for possible device applications. One is the multiple negative differential conductance regions, and another is regarding to create a highly spin-polarized current through the quantum dot chain by the interplay of the resonance and antiresonance. Finally, we focus on the role that the many-body effect plays on the antiresonance. Our result is that the antiresonance remains when the electron interaction is considered to the second order approximation

  9. Non-adiabatic quantum state preparation and quantum state transport in chains of Rydberg atoms

    Science.gov (United States)

    Ostmann, Maike; Minář, Jiří; Marcuzzi, Matteo; Levi, Emanuele; Lesanovsky, Igor

    2017-12-01

    Motivated by recent progress in the experimental manipulation of cold atoms in optical lattices, we study three different protocols for non-adiabatic quantum state preparation and state transport in chains of Rydberg atoms. The protocols we discuss are based on the blockade mechanism between atoms which, when excited to a Rydberg state, interact through a van der Waals potential, and rely on single-site addressing. Specifically, we discuss protocols for efficient creation of an antiferromagnetic GHZ state, a class of matrix product states including a so-called Rydberg crystal and for the state transport of a single-qubit quantum state between two ends of a chain of atoms. We identify system parameters allowing for the operation of the protocols on timescales shorter than the lifetime of the Rydberg states while yielding high fidelity output states. We discuss the effect of positional disorder on the resulting states and comment on limitations due to other sources of noise such as radiative decay of the Rydberg states. The proposed protocols provide a testbed for benchmarking the performance of quantum information processing platforms based on Rydberg atoms.

  10. Low-temperature transport in out-of-equilibrium XXZ chains

    Science.gov (United States)

    Bertini, Bruno; Piroli, Lorenzo

    2018-03-01

    We study the low-temperature transport properties of out-of-equilibrium XXZ spin-1/2 chains. We consider the protocol where two semi-infinite chains are prepared in two thermal states at small but different temperatures and suddenly joined together. We focus on the qualitative and quantitative features of the profiles of local observables, which at large times t and distances x from the junction become functions of the ratio \\zeta=x/t . By means of the generalized hydrodynamic equations, we analyse the rich phenomenology arising by considering different regimes of the phase diagram. In the gapped phases, variations of the profiles are found to be exponentially small in the temperatures, but described by non-trivial functions of ζ. We provide analytical formulae for the latter, which give accurate results also for small but finite temperatures. In the gapless regime, we show how the three-step conformal predictions for the profiles of energy density and energy current are naturally recovered from the hydrodynamic equations. Moreover, we also recover the recent non-linear Luttinger liquid predictions for low-temperature transport: universal peaks of width \

  11. Stochastic analysis of contaminant transport in porous media: analysis of a two-member radionuclide chain

    International Nuclear Information System (INIS)

    Bonano, E.J.; Shipers, L.R.

    1987-01-01

    In this study the authors extend previous stochastic analyses of contaminant transport in geologic media for a single species to a chain of two species. The authors particular application is the quantification of uncertainties due to lack of characterization of the spatial variability of hydrologic parameters on transport of radionuclides from a high-level waste repository to the biosphere. Radionuclide chains can have a significant impact on demonstrating compliance (or violation) of standards regulating the release to the environment accessible to humans. Two approaches for determining the cross-covariance terms in the mean concentration equations are presented. One uses a Taylor expansion to obtain the cross-covariance between the velocity and concentration fluctuations, while the other is based on a Fourier-Laplace double transform method. For the conditions of interest here, the difference between these two approaches are expected to be small. In addition, the variances are calculated in a unique way by solving another associated partial differential equation. A parametric study is carried out to examine the sensitivity of the mean concentration of the two species and their corresponding variances and cross-covariance on the parameters associated with the structure of the stochastic velocity field. It is found that the dependent variables are most sensitive to the intensity and correlation length of the velocity fluctuations. The magnitude of the variances and cross-covariance of the concentrations are proportional to the magnitude of the mean concentrations which depend on inlet concentration boundary conditions

  12. 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.

  13. Nonpoint source solute transport normal to aquifer bedding in heterogeneous, Markov chain random fields

    Science.gov (United States)

    Zhang, Hua; Harter, Thomas; Sivakumar, Bellie

    2006-06-01

    Facies-based geostatistical models have become important tools for analyzing flow and mass transport processes in heterogeneous aquifers. Yet little is known about the relationship between these latter processes and the parameters of facies-based geostatistical models. In this study, we examine the transport of a nonpoint source solute normal (perpendicular) to the major bedding plane of an alluvial aquifer medium that contains multiple geologic facies, including interconnected, high-conductivity (coarse textured) facies. We also evaluate the dependence of the transport behavior on the parameters of the constitutive facies model. A facies-based Markov chain geostatistical model is used to quantify the spatial variability of the aquifer system's hydrostratigraphy. It is integrated with a groundwater flow model and a random walk particle transport model to estimate the solute traveltime probability density function (pdf) for solute flux from the water table to the bottom boundary (the production horizon) of the aquifer. The cases examined include two-, three-, and four-facies models, with mean length anisotropy ratios for horizontal to vertical facies, ek, from 25:1 to 300:1 and with a wide range of facies volume proportions (e.g., from 5 to 95% coarse-textured facies). Predictions of traveltime pdfs are found to be significantly affected by the number of hydrostratigraphic facies identified in the aquifer. Those predictions of traveltime pdfs also are affected by the proportions of coarse-textured sediments, the mean length of the facies (particularly the ratio of length to thickness of coarse materials), and, to a lesser degree, the juxtapositional preference among the hydrostratigraphic facies. In transport normal to the sedimentary bedding plane, traveltime is not lognormally distributed as is often assumed. Also, macrodispersive behavior (variance of the traveltime) is found not to be a unique function of the conductivity variance. For the parameter range

  14. 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

  15. Electronic and transport properties of a carbon-atom chain in the core of semiconducting carbon nanotubes

    International Nuclear Information System (INIS)

    Chen Jiangwei; Yang Linfeng; Yang Huatong; Dong Jinming

    2003-01-01

    Using the tight-binding calculations, we have studied electronic and transport properties of the semiconducting single-walled carbon nanotubes (SSWNTs) doped by a chain of carbon-atoms, which can be well controlled by density of the encapsulated carbon atoms. When it is lower, weak coupling between the chain atoms and the tube produces flat bands near the Fermi level, which means a great possibility of superconductivity and ferromagnetism for the combined system. The weak coupling also leads to a significant conductance at the Fermi level, which is contributed by both of the tube and the encapsulated carbon-atom chain. Increasing density of the chain carbon atoms, the flat bands near the Fermi level disappear, and the current may be carried only by the carbon-atom chain, thus making the system become an ideal one-dimensional quantum wire with its conducting chain enclosed by a SWNT insulator

  16. Doxorubicin in vivo rapidly alters expression and translation of myocardial electron transport chain genes, leads to ATP loss and caspase 3 activation.

    Directory of Open Access Journals (Sweden)

    Amy V Pointon

    2010-09-01

    Full Text Available Doxorubicin is one of the most effective anti-cancer drugs but its use is limited by cumulative cardiotoxicity that restricts lifetime dose. Redox damage is one of the most accepted mechanisms of toxicity, but not fully substantiated. Moreover doxorubicin is not an efficient redox cycling compound due to its low redox potential. Here we used genomic and chemical systems approaches in vivo to investigate the mechanisms of doxorubicin cardiotoxicity, and specifically test the hypothesis of redox cycling mediated cardiotoxicity.Mice were treated with an acute dose of either doxorubicin (DOX (15 mg/kg or 2,3-dimethoxy-1,4-naphthoquinone (DMNQ (25 mg/kg. DMNQ is a more efficient redox cycling agent than DOX but unlike DOX has limited ability to inhibit gene transcription and DNA replication. This allowed specific testing of the redox hypothesis for cardiotoxicity. An acute dose was used to avoid pathophysiological effects in the genomic analysis. However similar data were obtained with a chronic model, but are not specifically presented. All data are deposited in the Gene Expression Omnibus (GEO. Pathway and biochemical analysis of cardiac global gene transcription and mRNA translation data derived at time points from 5 min after an acute exposure in vivo showed a pronounced effect on electron transport chain activity. This led to loss of ATP, increased AMPK expression, mitochondrial genome amplification and activation of caspase 3. No data gathered with either compound indicated general redox damage, though site specific redox damage in mitochondria cannot be entirely discounted.These data indicate the major mechanism of doxorubicin cardiotoxicity is via damage or inhibition of the electron transport chain and not general redox stress. There is a rapid response at transcriptional and translational level of many of the genes coding for proteins of the electron transport chain complexes. Still though ATP loss occurs with activation caspase 3 and these

  17. The impacts of phosphorus deficiency on the photosynthetic electron transport chain

    DEFF Research Database (Denmark)

    Carstensen, Andreas; Herdean, Andrei; Schmidt, Sidsel Birkelund

    2018-01-01

    light conditions. Under P deficiency, the enhanced electron flow through PSI increases the levels of NADPH, whereas ATP production remains restricted and hence reduces CO2 fixation. In parallel, lumen acidification activates the qE component of the non-photochemical quenching (NPQ) mechanism......Phosphorus (P) is an essential macronutrient, and P deficiency limits plant productivity. Recent work showed that P deficiency affects electron transport to photosystem I (PSI), but the underlying mechanisms are unknown. Here, we present a comprehensive biological model describing how P deficiency...... accumulate in the thylakoids and cause lumen acidification, which inhibits linear electron flow. Limited plastoquinol (PQH2) oxidation retards electron transport to the cytochrome (Cyt) b6f complex, yet the electron transfer rate of PSI is increased under steady-state growth light and is limited under high...

  18. Critical role of mitochondrial ROS is dependent on their site of production on the electron transport chain in ischemic heart.

    Science.gov (United States)

    Madungwe, Ngonidzashe B; Zilberstein, Netanel F; Feng, Yansheng; Bopassa, Jean C

    2016-01-01

    Reactive oxygen species (ROS) generation has been implicated in many pathologies including ischemia/reperfusion (I/R) injury. This led to multiple studies on antioxidant therapies to treat cardiovascular diseases but paradoxically, results have so far been mixed as ROS production can be beneficial as a signaling mechanism and in cardiac protection via preconditioning interventions. We investigated whether the differential impact of increased ROS in injury as well as in protection could be explained by their site of production on the mitochondrial electron transport chain. Using amplex red to measure ROS production, we found that mitochondria isolated from hearts after I/R produced more ROS than non-ischemic when complex I substrate (glutamate/malate) was used. Interestingly, the substrates of complex II (succinate) and ubiquinone (sn-glycerol 3-phosphate, G3P) produced less ROS in mitochondria from I/R hearts compared to normal healthy hearts. The inhibitors of complex I (rotenone) and complex III (antimycin A) increased ROS production when glutamate/malate and G3P were used; in contrast, they reduced ROS production when the complex II substrate was used. Mitochondrial calcium retention capacity required to induce mitochondrial permeability transition pore (mPTP) opening was measured using calcium green fluorescence and was found to be higher when mitochondria were treated with G3P and succinate compared to glutamate/malate. Furthermore, Langendorff hearts treated with glutamate/malate exhibited reduced cardiac functional recovery and increased myocardial infarct size compared to hearts treated with G3P. Thus, ROS production by the stimulated respiratory chain complexes I and III has opposite roles: cardio-deleterious when produced in complex I and cardio-protective when produced in complex III. The mechanism of these ROS involves the inhibition of the mPTP opening, a key event in cell death following ischemia/reperfusion injury.

  19. The role of sea ports in end-to-end maritime transport chain emissions

    International Nuclear Information System (INIS)

    Gibbs, David; Rigot-Muller, Patrick; Mangan, John; Lalwani, Chandra

    2014-01-01

    This paper's purpose is to investigate the role of sea ports in helping to mitigate the GHG emissions associated with the end-to-end maritime transport chain. The analysis is primarily focused on the UK, but is international in application. The paper is based on both the analysis of secondary data and information on actions taken by ports to reduce their emissions, with the latter data collected for the main UK ports via their published reports and/or via interviews. Only a small number of ports (representing 32% of UK port activity) actually measure and report their carbon emissions in the UK context. The emissions generated by ships calling at these ports are analysed using a method based on Department for Transport Maritime Statistics Data. In addition, a case example (Felixstowe) of emissions associated with HGV movements to and from ports is presented, and data on vessel emissions at berth are also considered. Our analyses indicate that emissions generated by ships during their voyages between ports are of a far greater magnitude than those generated by the port activities. Thus while reducing the ports' own emissions is worthwhile, the results suggest that ports might have more impact through focusing their efforts on reducing shipping emissions. - Highlights: • Investigates role of ports in mitigating GHG emissions in the end-to-end maritime transport chain. • Emissions generated both by ports and by ships calling at ports are analysed. • Shipping's emissions are far greater than those generated by port activities. • Ports may have more impact through focusing efforts on reducing shipping's emissions. • Options for ports to support and drive change in the maritime sector also considered

  20. 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).

  1. 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

  2. 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...

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

    Science.gov (United States)

    Griffiths, Lisa A; Flatters, Sarah J L

    2015-10-01

    Paclitaxel is an effective first-line chemotherapeutic with the major dose-limiting side effect of painful neuropathy. Mitochondrial dysfunction and oxidative stress have been implicated in paclitaxel-induced painful neuropathy. Here we show the effects of pharmacological modulation of mitochondrial sites that produce reactive oxygen species using systemic rotenone (complex I inhibitor) or antimycin A (complex III inhibitor) on the maintenance and development of paclitaxel-induced mechanical hypersensitivity in adult male Sprague Dawley rats. The maximally tolerated dose (5 mg/kg) of rotenone inhibited established paclitaxel-induced mechanical hypersensitivity. However, some of these inhibitory effects coincided with decreased motor coordination; 3 mg/kg rotenone also significantly attenuated established paclitaxel-induced mechanical hypersensitivity without any motor impairment. The maximally tolerated dose (.6 mg/kg) of antimycin A reversed established paclitaxel-induced mechanical hypersensitivity without any motor impairment. Seven daily doses of systemic rotenone or antimycin A were given either after paclitaxel administration or before and during paclitaxel administration. Rotenone had no significant effect on the development of paclitaxel-induced mechanical hypersensitivity. However, antimycin A significantly inhibited the development of paclitaxel-induced mechanical hypersensitivity when given before and during paclitaxel administration but had no effect when given after paclitaxel administration. These studies provide further evidence of paclitaxel-evoked mitochondrial dysfunction in vivo, suggesting that complex III activity is instrumental in paclitaxel-induced pain. This study provides further in vivo evidence that mitochondrial dysfunction is a key contributor to the development and maintenance of chemotherapy-induced painful neuropathy. This work also indicates that selective modulation of the electron transport chain can induce antinociceptive

  4. 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.

  5. In Silico Analysis of the Regulation of the Photosynthetic Electron Transport Chain in C3 Plants.

    Science.gov (United States)

    Morales, Alejandro; Yin, Xinyou; Harbinson, Jeremy; Driever, Steven M; Molenaar, Jaap; Kramer, David M; Struik, Paul C

    2018-02-01

    We present a new simulation model of the reactions in the photosynthetic electron transport chain of C3 species. We show that including recent insights about the regulation of the thylakoid proton motive force, ATP/NADPH balancing mechanisms (cyclic and noncyclic alternative electron transport), and regulation of Rubisco activity leads to emergent behaviors that may affect the operation and regulation of photosynthesis under different dynamic environmental conditions. The model was parameterized with experimental results in the literature, with a focus on Arabidopsis ( Arabidopsis thaliana ). A dataset was constructed from multiple sources, including measurements of steady-state and dynamic gas exchange, chlorophyll fluorescence, and absorbance spectroscopy under different light intensities and CO 2 , to test predictions of the model under different experimental conditions. Simulations suggested that there are strong interactions between cyclic and noncyclic alternative electron transport and that an excess capacity for alternative electron transport is required to ensure adequate redox state and lumen pH. Furthermore, the model predicted that, under specific conditions, reduction of ferredoxin by plastoquinol is possible after a rapid increase in light intensity. Further analysis also revealed that the relationship between ATP synthesis and proton motive force was highly regulated by the concentrations of ATP, ADP, and inorganic phosphate, and this facilitated an increase in nonphotochemical quenching and proton motive force under conditions where metabolism was limiting, such as low CO 2 , high light intensity, or combined high CO 2 and high light intensity. The model may be used as an in silico platform for future research on the regulation of photosynthetic electron transport. © 2018 American Society of Plant Biologists. All Rights Reserved.

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

    International Nuclear Information System (INIS)

    Dietrich, C.P.; Nader, H.B.; Buonassisi, V.; Colburn, P.

    1988-01-01

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

  7. A conserved WW domain-like motif regulates invariant chain-dependent cell-surface transport of the NKG2D ligand ULBP2

    DEFF Research Database (Denmark)

    Uhlenbrock, Franziska Katharina; van Andel, Esther; Andresen, Lars

    2015-01-01

    that the NKG2D ligand ULBP2 traffics over an invariant chain (Ii)-dependent pathway to the cell surface. This study set out to elucidate how Ii regulates ULBP2 cell-surface transport: We discovered conserved tryptophan (Trp) residues in the primary protein sequence of ULBP1-6 but not in the related MICA....../B. Substitution of Trp to alanine resulted in cell-surface inhibition of ULBP2 in different cancer cell lines. Moreover, the mutated ULBP2 constructs were retained and not degraded inside the cell, indicating a crucial role of this conserved Trp-motif in trafficking. Finally, overexpression of Ii increased...... surface expression of wt ULBP2 while Trp-mutants could not be expressed, proposing that this Trp-motif is required for an Ii-dependent cell-surface transport of ULBP2. Aberrant soluble ULBP2 is immunosuppressive. Thus, targeting a distinct protein module on the ULBP2 sequence could counteract...

  8. 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.

  9. Supply chain and innovation activity in transport related enterprises in Eastern Poland

    Directory of Open Access Journals (Sweden)

    Giuseppe Ioppolo

    2016-12-01

    Full Text Available  Background: One of the development strategies uses R&D activity as the main source of innovation, which is often carried out in cooperation with other units, but in particular in the supply chain, and therefore applies to cooperation between enterprises and their customers and suppliers. The aim of the study was to identify the variable determinants of the impact of the character of relationships among enterprises and their suppliers and customers on their innovative performance, within regional industrial systems and to define the constraints for a model regional structure of innovation network tailored to the needs of Poland and its regions. Methods: 167 enterprises belonging to the transport sector and operating in the area of Eastern Poland took part. In order to determine the impact of relationships with suppliers and customers on innovation activity, models based on probability analysis - probit models - were used. Results: It can be clearly stated that the cooperation of industrial enterprises in the transport sector with customers and suppliers activates innovation activity and its specified attributes. However, the probability varies depending on the test variable adopted. Conclusions: The cooperation with suppliers and customers is the cognitive aspect in the development of innovation activity in industrial enterprises representing the transport-related sector. Such cooperation has a stimulating effect on expenditures on innovation activity and on the implementation of innovative solutions in the field of technological innovation (products and processes.  

  10. 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

  11. 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.

  12. Nature of the elements transporting long-chain fatty acids through the red cell membrane

    DEFF Research Database (Denmark)

    Bojesen, Inge Norby; Bojesen, Eigil

    1998-01-01

    Docosahexaenoic acid, linoleic acid, red cell membrane, transporting elements, transport kinetics, fatty acid transport......Docosahexaenoic acid, linoleic acid, red cell membrane, transporting elements, transport kinetics, fatty acid transport...

  13. Metformin inhibits Branched Chain Amino Acid (BCAA) derived ketoacidosis and promotes metabolic homeostasis in MSUD.

    Science.gov (United States)

    S Sonnet, Davis; N O'Leary, Monique; A Gutierrez, Mark; M Nguyen, Steven; Mateen, Samiha; Hsu, Yuehmei; P Mitchell, Kylie; J Lopez, Antonio; Vockley, Jerry; K Kennedy, Brian; Ramanathan, Arvind

    2016-07-04

    Maple Syrup Urine Disease (MSUD) is an inherited disorder caused by the dysfunction in the branched chain keto-acid dehydrogenase (BCKDH) enzyme. This leads to buildup of branched-chain keto-acids (BCKA) and branched-chain amino acids (BCAA) in body fluids (e.g. keto-isocaproic acid from the BCAA leucine), leading to numerous clinical features including a less understood skeletal muscle dysfunction in patients. KIC is an inhibitor of mitochondrial function at disease relevant concentrations. A murine model of intermediate MSUD (iMSUD) shows significant skeletal muscle dysfunction as by judged decreased muscle fiber diameter. MSUD is an orphan disease with a need for novel drug interventions. Here using a 96-well plate (liquid chromatography- mass spectrometry (LC-MS) based drug-screening platform we show that Metformin, a widely used anti-diabetic drug, reduces levels of KIC in patient-derived fibroblasts by 20-50%. This Metformin-mediated effect was conserved in vivo; Metformin-treatment significantly reduced levels of KIC in the muscle (by 69%) and serum (by 56%) isolated from iMSUD mice, and restored levels of mitochondrial metabolites (e.g. AMP and other TCA). The drug also decreased the expression of mitochondrial branched chain amino transferase (BCAT) which produces KIC in skeletal muscle. This suggests that Metformin can restore skeletal muscle homeostasis in MSUD by decreasing mitochondrial KIC production.

  14. Molecularly imprinted nanoparticles for inhibiting ribonuclease in reverse transcriptase polymerase chain reaction

    DEFF Research Database (Denmark)

    Feng, Xiaotong; Ashley, Jon; Zhou, Tongchang

    2018-01-01

    Molecularly imprinted nanoparticles (nanoMIPs) are synthesized via a solid-phase approach using RNase as the template. The feasibility of employing the nanoMIPs as RNase inhibitor is successfully demonstrated in reverse transcriptase polymerase chain reaction (RT-PCR) assays, suggesting the tailor...

  15. Nonequilibrium spin transport in integrable spin chains: Persistent currents and emergence of magnetic domains

    Science.gov (United States)

    De Luca, Andrea; Collura, Mario; De Nardis, Jacopo

    2017-07-01

    We construct exact steady states of unitary nonequilibrium time evolution in the gapless XXZ spin-1/2 chain where integrability preserves ballistic spin transport at long times. We characterize the quasilocal conserved quantities responsible for this feature and introduce a computationally effective way to evaluate their expectation values on generic matrix product initial states. We employ this approach to reproduce the long-time limit of local observables in all quantum quenches which explicitly break particle-hole or time-reversal symmetry. We focus on a class of initial states supporting persistent spin currents and our predictions remarkably agree with numerical simulations at long times. Furthermore, we propose a protocol for this model where interactions, even when antiferromagnetic, are responsible for the unbounded growth of a macroscopic magnetic domain.

  16. Electromagnetic probes of molecular motors in the electron transport chains of mitochondria and chloroplasts

    Science.gov (United States)

    Miller, J. H., Jr.; Nawarathna, D.; Vajrala, V.; Gardner, J.; Widger, W. R.

    2005-12-01

    We report on measurements of harmonics generated by whole cells, mitochondria, and chloroplasts in response to applied sinusoidal electric fields. The frequency- and amplitude-dependence of the induced harmonics exhibit features that correlate with physiological processes. Budding yeast (S. cerevisiae) cells produce numerous harmonics, the amplitudes of which depend strongly on frequency. When the second or third harmonic amplitude is plotted vs. applied frequency, we observe two peaks, around 3 kHz and 12 kHz, which are suppressed by respiratory inhibitors. We observe similar peaks when measuring the harmonic response of B. indicas, a relative of the mitochondrial ancestor. In uncoupled mitochondria, in which most of the electron transport chain is active but the ATP-synthase molecular turbine is inactive, only one (lower frequency) of the two peaks is present. Finally, we find that harmonics generated by chloroplasts depend dramatically on incident light, and vanish in the absence of light.

  17. Tunable long-distance light transportation along Au nanoparticle chains: promising for optical interconnect

    Science.gov (United States)

    Lin, Z.; Li, X. D.; Chen, T. P.

    2014-10-01

    Tunable light resonance transportation along a single long Au hemisphere nanoparticles (NPs) chain was studied. The realistic experimentally determined gold dielectric function was used for the simulation of Au localized surface plasmon polariton (LSPPs) effect. The resonance light energy with minimized attenuation and its bandwidth were quantitatively analyzed by inducing the effective mass which was observed to increase only with the length of Au NPs between the source and the test point. The geometric ratio g/ r of NP size and gap were investigated at 5 µm far of NPs with different gaps from 0 to 70 nm. Strongest resonance can be achieved with g/ r = 1.2 by the factor of 1.5 than the connected NPs. This resonance mode falls in the wavelength λ = 555 nm (green light), which is exactly the maximum sensitivity of a light-adapted eye of human beings.

  18. Radiocesium transport in the pasture-cow-milk food chain; and reply

    Energy Technology Data Exchange (ETDEWEB)

    Lassey, K R [Department of Scientific and Industrial Research, Lower Hutt (New Zealand). Inst. of Nuclear Sciences; Matthies, M [Gesellschaft fuer Strahlen- und Umweltforschung m.b.H. Muenchen, Neuherberg (Germany, F.R.)

    1982-11-01

    In this letter Lassey comments on the model analysis of radiocesium transport through the pasture-cow-milk food chain, presented by Matthies et al. This 5-compartmental model extends by one one compartment-soil surface (S), the model, TERMOD, used by Lassey. Matthies model fails to take account of radiocesium 'fixed' for many years in the upper few cm of untilled soil and unavailable for root uptake. This soil sink compartment (D) should really be two compartments, one for 'leached' and one for 'fixed' radiocesium. Matthies replies that radioecological model predictions have a degree of uncertainty because of the large biological variabilities of transfer processes involved, and the results of his stochastic model calculations provide more information than those of Lassey's more deterministic methods.

  19. Environmental assessment of passenger transportation should include infrastructure and supply chains

    International Nuclear Information System (INIS)

    Chester, Mikhail V; Horvath, Arpad

    2009-01-01

    To appropriately mitigate environmental impacts from transportation, it is necessary for decision makers to consider the life-cycle energy use and emissions. Most current decision-making relies on analysis at the tailpipe, ignoring vehicle production, infrastructure provision, and fuel production required for support. We present results of a comprehensive life-cycle energy, greenhouse gas emissions, and selected criteria air pollutant emissions inventory for automobiles, buses, trains, and airplanes in the US, including vehicles, infrastructure, fuel production, and supply chains. We find that total life-cycle energy inputs and greenhouse gas emissions contribute an additional 63% for onroad, 155% for rail, and 31% for air systems over vehicle tailpipe operation. Inventorying criteria air pollutants shows that vehicle non-operational components often dominate total emissions. Life-cycle criteria air pollutant emissions are between 1.1 and 800 times larger than vehicle operation. Ranges in passenger occupancy can easily change the relative performance of modes.

  20. WD60/FAP163 is a dynein intermediate chain required for retrograde intraflagellar transport in cilia

    Science.gov (United States)

    Patel-King, Ramila S.; Gilberti, Renée M.; Hom, Erik F. Y.; King, Stephen M.

    2013-01-01

    Retrograde intraflagellar transport (IFT) is required for assembly of cilia. We identify a Chlamydomonas flagellar protein (flagellar-associated protein 163 [FAP163]) as being closely related to the D1bIC(FAP133) intermediate chain (IC) of the dynein that powers this movement. Biochemical analysis revealed that FAP163 is present in the flagellar matrix and is actively trafficked by IFT. Furthermore, FAP163 copurified with D1bIC(FAP133) and the LC8 dynein light chain, indicating that it is an integral component of the retrograde IFT dynein. To assess the functional role of FAP163, we generated an RNA interference knockdown of the orthologous protein (WD60) in planaria. The Smed-wd60(RNAi) animals had a severe ciliary assembly defect that dramatically compromised whole-organism motility. Most cilia were present as short stubs that had accumulated large quantities of IFT particle–like material between the doublet microtubules and the membrane. The few remaining approximately full-length cilia had a chaotic beat with a frequency reduced from 24 to ∼10 Hz. Thus WD60/FAP163 is a dynein IC that is absolutely required for retrograde IFT and ciliary assembly. PMID:23864713

  1. Lysine desuccinylase SIRT5 binds to cardiolipin and regulates the electron transport chain.

    Science.gov (United States)

    Zhang, Yuxun; Bharathi, Sivakama S; Rardin, Matthew J; Lu, Jie; Maringer, Katherine V; Sims-Lucas, Sunder; Prochownik, Edward V; Gibson, Bradford W; Goetzman, Eric S

    2017-06-16

    SIRT5 is a lysine desuccinylase known to regulate mitochondrial fatty acid oxidation and the urea cycle. Here, SIRT5 was observed to bind to cardiolipin via an amphipathic helix on its N terminus. In vitro , succinyl-CoA was used to succinylate liver mitochondrial membrane proteins. SIRT5 largely reversed the succinyl-CoA-driven lysine succinylation. Quantitative mass spectrometry of SIRT5-treated membrane proteins pointed to the electron transport chain, particularly Complex I, as being highly targeted for desuccinylation by SIRT5. Correspondingly, SIRT5 -/- HEK293 cells showed defects in both Complex I- and Complex II-driven respiration. In mouse liver, SIRT5 expression was observed to localize strictly to the periportal hepatocytes. However, homogenates prepared from whole SIRT5 -/- liver did show reduced Complex II-driven respiration. The enzymatic activities of Complex II and ATP synthase were also significantly reduced. Three-dimensional modeling of Complex II suggested that several SIRT5-targeted lysine residues lie at the protein-lipid interface of succinate dehydrogenase subunit B. We postulate that succinylation at these sites may disrupt Complex II subunit-subunit interactions and electron transfer. Lastly, SIRT5 -/- mice, like humans with Complex II deficiency, were found to have mild lactic acidosis. Our findings suggest that SIRT5 is targeted to protein complexes on the inner mitochondrial membrane via affinity for cardiolipin to promote respiratory chain function. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  2. Inhibition of the neutrophil oxidative burst by sphingoid long-chain bases: role of protein kinase C in the activation of the burst

    International Nuclear Information System (INIS)

    Wilson, E.; Olcott, M.C.; Bell, R.M.; Merrill, A.H.; Lambeth, J.D.

    1986-01-01

    The neutrophil oxidative burst is triggered by a variety of both particulate (opsonized zymosan) and soluble agonists [formylmethionylleucylphenylalanine (FMLP), arachidonate, short-chained diacylglycerols (DAG) and phorbol myristate acetate (PMA)]. The authors show that the long-chain lipid bases sphinganine and sphingosine block activation of the burst in human neutrophils. Inhibition is reversible, does not alter cell viability, and does not affect phagocytosis. The inhibition affects the activation mechanism rather than the NADPH-oxidase enzyme. The structural requirements for inhibition include a hydrophobic carbon chain and an amino-containing headgroup, and the naturally occurring erythro sphinganine was more potent than the threo isomer. Activation of the oxidative burst by a variety of agonists was blocked by the same concentration of sphinganine indicating a common inhibited step. The authors suggest that the common step is protein kinase C, as evidenced by the following: 1) long-chain bases inhibit PKC in a micelle reconstituted system, 2) PMA-induced phophorylation is inhibited by sphinganine, and 3) sphinganine competes with ( 3 H)-phorbol dibutyrate for its cytosolic receptor (i.e. protein kinase C). The authors suggest that sphingoid long-chain bases play a role in the cellular regulations

  3. 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.

  4. Coherent transport in a system of periodic linear chain of quantum dots situated between two parallel quantum wires

    International Nuclear Information System (INIS)

    Petrosyan, Lyudvig S

    2016-01-01

    We study coherent transport in a system of periodic linear chain of quantum dots situated between two parallel quantum wires. We show that the resonant-tunneling conductance between the wires exhibits a Rabi splitting of the resonance peak as a function of Fermi energy in the wires. This effect is an electron transport analogue of the Rabi splitting in optical spectra of two interacting systems. The conductance peak splitting originates from the anticrossing of Bloch bands in a periodic system that is caused by a strong coupling between the electron states in the quantum dot chain and quantum wires. (paper)

  5. Mechanism of action of anions on the electron transport chain in thylakoid membranes of higher plants.

    Science.gov (United States)

    Singh-Rawal, Pooja; Zsiros, Ottó; Bharti, Sudhakar; Garab, Gyozo; Jajoo, Anjana

    2011-04-01

    With an aim to improve our understanding of the mechanisms behind specific anion effects in biological membranes, we have studied the effects of sodium salts of anions of varying valency in thylakoid membranes. Rates of electron transport of PS II and PS I, 77K fluorescence emission and excitation spectra, cyclic electron flow around PS I and circular dichroism (CD) spectra were measured in thylakoid membranes in order to elucidate a general mechanism of action of inorganic anions on photosynthetic electron transport chain. Re-distribution of absorbed excitation energy has been observed as a signature effect of inorganic anions. In the presence of anions, such as nitrite, sulphate and phosphate, distribution of absorbed excitation energy was found to be more in favor of Photosystem I (PS I). The amount of energy distributed towards PS I depended on the valency of the anion. In this paper, we propose for the first time that energy re-distribution and its valence dependence may not be the effect of anions per se. The entry of negative charge (anion) is accompanied by influx of positive charge (protons) to maintain a balance of charge across the thylakoid membranes. As reflected by the CD spectra, the observed energy re-distribution could be a result of structural rearrangements of the protein complexes of PS II caused by changes in the ionic environment of the thylakoid lumen.

  6. Clarifying the supercomplex: the higher-order organization of the mitochondrial electron transport chain.

    Science.gov (United States)

    Letts, James A; Sazanov, Leonid A

    2017-10-05

    The oxidative phosphorylation electron transport chain (OXPHOS-ETC) of the inner mitochondrial membrane is composed of five large protein complexes, named CI-CV. These complexes convert energy from the food we eat into ATP, a small molecule used to power a multitude of essential reactions throughout the cell. OXPHOS-ETC complexes are organized into supercomplexes (SCs) of defined stoichiometry: CI forms a supercomplex with CIII 2 and CIV (SC I+III 2 +IV, known as the respirasome), as well as with CIII 2 alone (SC I+III 2 ). CIII 2 forms a supercomplex with CIV (SC III 2 +IV) and CV forms dimers (CV 2 ). Recent cryo-EM studies have revealed the structures of SC I+III 2 +IV and SC I+III 2 . Furthermore, recent work has shed light on the assembly and function of the SCs. Here we review and compare these recent studies and discuss how they have advanced our understanding of mitochondrial electron transport.

  7. Model-based confirmation of alternative substrates of mitochondrial electron transport chain.

    Science.gov (United States)

    Kleessen, Sabrina; Araújo, Wagner L; Fernie, Alisdair R; Nikoloski, Zoran

    2012-03-30

    Discrimination of metabolic models based on high throughput metabolomics data, reflecting various internal and external perturbations, is essential for identifying the components that contribute to the emerging behavior of metabolic processes. Here, we investigate 12 different models of the mitochondrial electron transport chain (ETC) in Arabidopsis thaliana during dark-induced senescence in order to elucidate the alternative substrates to this metabolic pathway. Our findings demonstrate that the coupling of the proposed computational approach, based on dynamic flux balance analysis, with time-resolved metabolomics data results in model-based confirmations of the hypotheses that, during dark-induced senescence in Arabidopsis, (i) under conditions where the main substrate for the ETC are not fully available, isovaleryl-CoA dehydrogenase and 2-hydroxyglutarate dehydrogenase are able to donate electrons to the ETC, (ii) phytanoyl-CoA does not act even as an indirect substrate of the electron transfer flavoprotein/electron-transfer flavoprotein:ubiquinone oxidoreductase complex, and (iii) the mitochondrial γ-aminobutyric acid transporter has functional significance in maintaining mitochondrial metabolism. Our study provides a basic framework for future in silico studies of alternative pathways in mitochondrial metabolism under extended darkness whereby the role of its components can be computationally discriminated based on available molecular profile data.

  8. Medium-chain fatty acids inhibit mitochondrial metabolism in astrocytes promoting astrocyte-neuron lactate and ketone body shuttle systems.

    Science.gov (United States)

    Thevenet, Jonathan; De Marchi, Umberto; Domingo, Jaime Santo; Christinat, Nicolas; Bultot, Laurent; Lefebvre, Gregory; Sakamoto, Kei; Descombes, Patrick; Masoodi, Mojgan; Wiederkehr, Andreas

    2016-05-01

    Medium-chain triglycerides have been used as part of a ketogenic diet effective in reducing epileptic episodes. The health benefits of the derived medium-chain fatty acids (MCFAs) are thought to result from the stimulation of liver ketogenesis providing fuel for the brain. We tested whether MCFAs have direct effects on energy metabolism in induced pluripotent stem cell-derived human astrocytes and neurons. Using single-cell imaging, we observed an acute pronounced reduction of the mitochondrial electrical potential and a concomitant drop of the NAD(P)H signal in astrocytes, but not in neurons. Despite the observed effects on mitochondrial function, MCFAs did not lower intracellular ATP levels or activate the energy sensor AMP-activated protein kinase. ATP concentrations in astrocytes were unaltered, even when blocking the respiratory chain, suggesting compensation through accelerated glycolysis. The MCFA decanoic acid (300 μM) promoted glycolysis and augmented lactate formation by 49.6%. The shorter fatty acid octanoic acid (300 μM) did not affect glycolysis but increased the rates of astrocyte ketogenesis 2.17-fold compared with that of control cells. MCFAs may have brain health benefits through the modulation of astrocyte metabolism leading to activation of shuttle systems that provide fuel to neighboring neurons in the form of lactate and ketone bodies.-Thevenet, J., De Marchi, U., Santo Domingo, J., Christinat, N., Bultot, L., Lefebvre, G., Sakamoto, K., Descombes, P., Masoodi, M., Wiederkehr, A. Medium-chain fatty acids inhibit mitochondrial metabolism in astrocytes promoting astrocyte-neuron lactate and ketone body shuttle systems. © FASEB.

  9. 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

  10. Branched Chain Amino Acids Cause Liver Injury in Obese/Diabetic Mice by Promoting Adipocyte Lipolysis and Inhibiting Hepatic Autophagy.

    Science.gov (United States)

    Zhang, Fuyang; Zhao, Shihao; Yan, Wenjun; Xia, Yunlong; Chen, Xiyao; Wang, Wei; Zhang, Jinglong; Gao, Chao; Peng, Cheng; Yan, Feng; Zhao, Huishou; Lian, Kun; Lee, Yan; Zhang, Ling; Lau, Wayne Bond; Ma, Xinliang; Tao, Ling

    2016-11-01

    The Western meat-rich diet is both high in protein and fat. Although the hazardous effect of a high fat diet (HFD) upon liver structure and function is well recognized, whether the co-presence of high protein intake contributes to, or protects against, HF-induced hepatic injury remains unclear. Increased intake of branched chain amino acids (BCAA, essential amino acids compromising 20% of total protein intake) reduces body weight. However, elevated circulating BCAA is associated with non-alcoholic fatty liver disease and injury. The mechanisms responsible for this quandary remain unknown; the role of BCAA in HF-induced liver injury is unclear. Utilizing HFD or HFD+BCAA models, we demonstrated BCAA supplementation attenuated HFD-induced weight gain, decreased fat mass, activated mammalian target of rapamycin (mTOR), inhibited hepatic lipogenic enzymes, and reduced hepatic triglyceride content. However, BCAA caused significant hepatic damage in HFD mice, evidenced by exacerbated hepatic oxidative stress, increased hepatic apoptosis, and elevated circulation hepatic enzymes. Compared to solely HFD-fed animals, plasma levels of free fatty acids (FFA) in the HFD+BCAA group are significantly further increased, due largely to AMPKα2-mediated adipocyte lipolysis. Lipolysis inhibition normalized plasma FFA levels, and improved insulin sensitivity. Surprisingly, blocking lipolysis failed to abolish BCAA-induced liver injury. Mechanistically, hepatic mTOR activation by BCAA inhibited lipid-induced hepatic autophagy, increased hepatic apoptosis, blocked hepatic FFA/triglyceride conversion, and increased hepatocyte susceptibility to FFA-mediated lipotoxicity. These data demonstrated that BCAA reduces HFD-induced body weight, at the expense of abnormal lipolysis and hyperlipidemia, causing hepatic lipotoxicity. Furthermore, BCAA directly exacerbate hepatic lipotoxicity by reducing lipogenesis and inhibiting autophagy in the hepatocyte. Copyright © 2016. Published by Elsevier

  11. Branched Chain Amino Acids Cause Liver Injury in Obese/Diabetic Mice by Promoting Adipocyte Lipolysis and Inhibiting Hepatic Autophagy

    Directory of Open Access Journals (Sweden)

    Fuyang Zhang

    2016-11-01

    Full Text Available The Western meat-rich diet is both high in protein and fat. Although the hazardous effect of a high fat diet (HFD upon liver structure and function is well recognized, whether the co-presence of high protein intake contributes to, or protects against, HF-induced hepatic injury remains unclear. Increased intake of branched chain amino acids (BCAA, essential amino acids compromising 20% of total protein intake reduces body weight. However, elevated circulating BCAA is associated with non-alcoholic fatty liver disease and injury. The mechanisms responsible for this quandary remain unknown; the role of BCAA in HF-induced liver injury is unclear. Utilizing HFD or HFD + BCAA models, we demonstrated BCAA supplementation attenuated HFD-induced weight gain, decreased fat mass, activated mammalian target of rapamycin (mTOR, inhibited hepatic lipogenic enzymes, and reduced hepatic triglyceride content. However, BCAA caused significant hepatic damage in HFD mice, evidenced by exacerbated hepatic oxidative stress, increased hepatic apoptosis, and elevated circulation hepatic enzymes. Compared to solely HFD-fed animals, plasma levels of free fatty acids (FFA in the HFD + BCAA group are significantly further increased, due largely to AMPKα2-mediated adipocyte lipolysis. Lipolysis inhibition normalized plasma FFA levels, and improved insulin sensitivity. Surprisingly, blocking lipolysis failed to abolish BCAA-induced liver injury. Mechanistically, hepatic mTOR activation by BCAA inhibited lipid-induced hepatic autophagy, increased hepatic apoptosis, blocked hepatic FFA/triglyceride conversion, and increased hepatocyte susceptibility to FFA-mediated lipotoxicity. These data demonstrated that BCAA reduces HFD-induced body weight, at the expense of abnormal lipolysis and hyperlipidemia, causing hepatic lipotoxicity. Furthermore, BCAA directly exacerbate hepatic lipotoxicity by reducing lipogenesis and inhibiting autophagy in the hepatocyte.

  12. Ethanol and Other Short-Chain Alcohols Inhibit NLRP3 Inflammasome Activation through Protein Tyrosine Phosphatase Stimulation

    Science.gov (United States)

    Hoyt, Laura R.; Ather, Jennifer L.; Randall, Matthew J.; DePuccio, Daniel P.; Landry, Christopher C.; Wewers, Mark D.; Gavrilin, Mikhail A.; Poynter, Matthew E.

    2016-01-01

    Immunosuppression is a major complication of alcoholism that contributes to increased rates of opportunistic infections and sepsis in alcoholics. The NLRP3 inflammasome, a multi-protein intracellular pattern recognition receptor complex that facilitates the cleavage and secretion of the pro-inflammatory cytokines IL-1β and IL-18, can be inhibited by ethanol and we sought to better understand the mechanism through which this occurs and whether chemically similar molecules exert comparable effects. We show that ethanol can specifically inhibit activation of the NLRP3 inflammasome, resulting in attenuated IL-1β and caspase-1 cleavage and secretion, as well as diminished ASC speck formation, without affecting potassium efflux, in a mouse macrophage cell line (J774), mouse bone marrow derived dendritic cells, mouse neutrophils, and human PBMCs. The inhibitory effects on the Nlrp3 inflammasome were independent of GABAA receptor activation or NMDA receptor inhibition, but was associated with decreased oxidant production. Ethanol treatment markedly decreased cellular tyrosine phosphorylation, while administration of the tyrosine phosphatase inhibitor sodium orthovanadate prior to ethanol restored tyrosine phosphorylation and IL-1β secretion subsequent to ATP stimulation. Furthermore, sodium orthovanadate-induced phosphorylation of ASC Y144, necessary and sufficient for Nlrp3 inflammasome activation, and secretion of phosphorylated ASC, were inhibited by ethanol. Finally, multiple alcohol-containing organic compounds exerted inhibitory effects on the Nlrp3 inflammasome, whereas 2-methylbutane (isopentane), the analogous alkane of the potent inhibitor isoamyl alcohol (isopentanol), did not. Our results demonstrate that ethanol antagonizes the NLRP3 inflammasome at an apical event in its activation through the stimulation of protein tyrosine phosphatases, an effect shared by other short-chain alcohols. PMID:27421477

  13. Long distance bioenergy logistics. An assessment of costs and energy consumption for various biomass energy transport chains

    International Nuclear Information System (INIS)

    Suurs, R.

    2002-01-01

    In order to create the possibility of obtaining an insight in the key factors of the title system, a model has been developed, taking into account different production systems, pretreatment operations and transport options. Various transport chains were constructed, which were subjected to a sensitivity analysis with respect to factors like transport distance, fuel prices and equipment operation times. Scenarios are analysed for Latin-America and Europe for which the distinguishing parameters were assumed to be the transport distances and biomass prices. For both regions the analysis concerns a situation where ship transports are applied for a coastal and for an inland biomass supply. For European biomass a train transport was considered as well. In order to explore possibilities for improvement, the effects of these variables on costs and energy consumption within a chain, were assessed. Delivered biomass can be converted to power or methanol. Model results are as follows: Total costs for European bioenergy range from 11.2-21.2 euro/GJ MeOH for methanol and 17.4-28.0 euro/GJ e for electricity. For Latin-America, costs ranges are 11.3-21.8 euro/GJ MeOH for methanol and 17.4-28.7 euro/GJ e for electricity. The lower end of these ranges is represented by transport chains that are characterised by the use of high density energy carriers such as logs, pellets or liquid fuels (these are the most attractive for all scenarios considered). The transport of chips should be avoided categorically due to their low density and high production costs. Transport chains based on the early production of liquid energy carriers such as methanol or pyrolysis oil seem to be promising alternatives as well. With respect to energy consumption, the transport of chips is highly unfavourable for the same reasons as stated above. The use of pelletizing operations implies a high energy input, however due to energy savings as a result of more efficient transport operations, this energy loss is

  14. Strategies for recovering inhibition caused by long chain fatty acids on anaerobic thermophilic biogas reactors

    DEFF Research Database (Denmark)

    Palatsi, J.; Laureni, M.; Andres, M.V.

    2009-01-01

    patterns, dilution and addition of adsorbents, in order to determine the most appropriate strategy for fast recovery of the reactor activity in manure based plants inhibited by LCFA. Dilution with active inoculum for increasing the biomass/LCFA ratio, or addition of adsorbents for adsorbing the LCFA...... biomass to an inhibitory concentration of LCFA improved the recovery ability of the system, indicated as increasing degradation rates from 0.04 to 0.16 g COD_CH4/g VS day. The incubation time between subsequent pulses, or discontinuous LCFA pulses, seems to be a decisive process parameter to tackle LCFA...

  15. Learning How the Electron Transport Chain Works: Independent and Interactive Effects of Instructional Strategies and Learners' Characteristics

    Science.gov (United States)

    Darabi, Aubteen; Arrastia-Lloyd, Meagan C.; Nelson, David W.; Liang, Xinya; Farrell, Jennifer

    2015-01-01

    In order to develop an expert-like mental model of complex systems, causal reasoning is essential. This study examines the differences between forward and backward instructional strategies in terms of efficiency, students' learning and progression of their mental models of the electronic transport chain in an undergraduate metabolism course…

  16. Analyzing the environmental impact of transportation in reengineered supply chains: a case study from a leather upholstery company

    NARCIS (Netherlands)

    Yazan, Devrim Murat; Yazan, Devrim; Petruzzelli, Antonio Messeni; Albino, Vito

    2011-01-01

    This paper examines the impact of process disaggregation and specialization on the environmental performance of the supply chain of a leather upholstery company. An enterprise input–output model that relates geographical information with production processes and transportation routes is developed.

  17. Role of colonic short-chain fatty acid transport in diarrhea.

    Science.gov (United States)

    Binder, Henry J

    2010-01-01

    Short-chain fatty acids (SCFA) are the major anion in stool and are synthesized from nonabsorbed carbohydrate by the colonic microbiota. Nonabsorbed carbohydrate are not absorbed in the colon and induce an osmotically mediated diarrhea; in contrast, SCFA are absorbed by colonic epithelial cells and stimulate Na-dependent fluid absorption via a cyclic AMP-independent process involving apical membrane Na-H, SCFA-HCO(3), and Cl-SCFA exchanges. SCFA production represents an adaptive process to conserve calories, fluid, and electrolytes. Inhibition of SCFA synthesis by antibiotics and administration of PEG, a substance that is not metabolized by colonic microbiota, both result in diarrhea. In contrast, increased production of SCFA as a result of providing starch that is relatively resistant to amylase digestion [so-called resistant starch (RS)] to oral rehydration solution (RS-ORS) improves the efficacy of ORS and represents an important approach to improve the effectiveness of ORS in the treatment of acute diarrhea in children under five years of age.

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

    Science.gov (United States)

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

    1980-11-25

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

  19. Modeling of anaerobic degradation of solid slaughterhouse waste: inhibition effects of long-chain fatty acids or ammonia.

    Science.gov (United States)

    Lokshina, L Y; Vavilin, V A; Salminen, E; Rintala, J

    2003-01-01

    The anaerobic bioconversion of solid poultry slaughterhouse wastes was kinetically investigated. The modified version of simulation model was applied for description of experimental data in mesophilic laboratory digester and assays. Additionally, stages of formation and consumption of long chain fatty acids (LCFA) were included in the model. Batch data on volatile solids, ammonium, acetate, butyrate, propionate, LCFA concentrations, pH level, cumulative volume, and methane partial pressure were used for model calibration. As a reference, the model was used to describe digestion of solid sorted household waste. Simulation results showed that an inhibition of polymer hydrolysis by volatile fatty acids and acetogenesis by NH3 or LCFA could be responsible for the complex system dynamics during degradation of lipid- and protein-rich wastes.

  20. 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

  1. Variability in dose estimates associated with the food-chain transport and ingestion of selected radionuclides

    International Nuclear Information System (INIS)

    Hoffman, F.O.; Gardner, R.H.; Eckerman, K.F.

    1982-06-01

    Dose predictions for the ingestion of 90 Sr and 137 Cs, using aquatic and terrestrial food chain transport models similar to those in the Nuclear Regulatory Commission's Regulatory Guide 1.109, are evaluated through estimating the variability of model parameters and determining the effect of this variability on model output. The variability in the predicted dose equivalent is determined using analytical and numerical procedures. In addition, a detailed discussion is included on 90 Sr dosimetry. The overall estimates of uncertainty are most relevant to conditions where site-specific data is unavailable and when model structure and parameter estimates are unbiased. Based on the comparisons performed in this report, it is concluded that the use of the generic default parameters in Regulatory Guide 1.109 will usually produce conservative dose estimates that exceed the 90th percentile of the predicted distribution of dose equivalents. An exception is the meat pathway for 137 Cs, in which use of generic default values results in a dose estimate at the 24th percentile. Among the terrestrial pathways of exposure, the non-leafy vegetable pathway is the most important for 90 Sr. For 90 Sr, the parameters for soil retention, soil-to-plant transfer, and internal dosimetry contribute most significantly to the variability in the predicted dose for the combined exposure to all terrestrial pathways. For 137 Cs, the meat transfer coefficient the mass interception factor for pasture forage, and the ingestion dose factor are the most important parameters. The freshwater finfish bioaccumulation factor is the most important parameter for the dose prediction of 90 Sr and 137 Cs transported over the water-fish-man pathway

  2. 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

  3. Mitochondrial electron transport chain is involved in microcystin-RR induced tobacco BY-2 cells apoptosis.

    Science.gov (United States)

    Huang, Wenmin; Li, Dunhai; Liu, Yongding

    2014-09-01

    Microcystin-RR (MC-RR) has been suggested to induce apoptosis in tobacco BY-2 cells through mitochondrial dysfunction including the loss of mitochondrial membrane potential (ΔΨm). To further elucidate the mechanisms involved in MC-RR induced apoptosis in tobacco BY-2 cells, we have investigated the role of mitochondrial electron transport chain (ETC) as a potential source for reactive oxygen species (ROS). Tobacco BY-2 cells after exposure to MC-RR (60mg/L) displayed apoptotic changes in association with an increased production of ROS and loss of ΔΨm. All of these adverse effects were significantly attenuated by ETC inhibitors including Rotenone (2μmol/L, complex I inhibitor) and antimycin A (0.01μmol/L, complex III inhibitor), but not by thenoyltrifluoroacetone (5μmol/L, complex II inhibitor). These results suggest that mitochondrial ETC plays a key role in mediating MC-RR induced apoptosis in tobacco BY-2 cells through an increased mitochondrial production of ROS. Copyright © 2014. Published by Elsevier B.V.

  4. Effects of molecular structure on microscopic heat transport in chain polymer liquids

    International Nuclear Information System (INIS)

    Matsubara, Hiroki; Kikugawa, Gota; Ohara, Taku; Bessho, Takeshi; Yamashita, Seiji

    2015-01-01

    In this paper, we discuss the molecular mechanism of the heat conduction in a liquid, based on nonequilibrium molecular dynamics simulations of a systematic series of linear- and branched alkane liquids, as a continuation of our previous study on linear alkane [T. Ohara et al., J. Chem. Phys. 135, 034507 (2011)]. The thermal conductivities for these alkanes in a saturated liquid state at the same reduced temperature (0.7T c ) obtained from the simulations are compared in relation to the structural difference of the liquids. In order to connect the thermal energy transport characteristics with molecular structures, we introduce the new concept of the interatomic path of heat transfer (atomistic heat path, AHP), which is defined for each type of inter- and intramolecular interaction. It is found that the efficiency of intermolecular AHP is sensitive to the structure of the first neighbor shell, whereas that of intramolecular AHP is similar for different alkane species. The dependence of thermal conductivity on different lengths of the main and side chain can be understood from the natures of these inter- and intramolecular AHPs

  5. Mitochondrial electron transport chain functions in long-lived Ames dwarf mice

    Science.gov (United States)

    Choksi, Kashyap B.; Nuss, Jonathan E.; DeFord, James H.; Papaconstantinou, John

    2011-01-01

    The age-associated decline in tissue function has been attributed to ROS-mediated oxidative damage due to mitochondrial dysfunction. The long-lived Ames dwarf mouse exhibits resistance to oxidative stress, a physiological characteristic of longevity. It is not known, however, whether there are differences in the electron transport chain (ETC) functions in Ames tissues that are associated with their longevity. In these studies we analyzed enzyme activities of ETC complexes, CI-CV and the coupled CI-CII and CII-CIII activities of mitochondria from several tissues of young, middle aged and old Ames dwarf mice and their corresponding wild type controls to identify potential mitochondrial prolongevity functions. Our studies indicate that post-mitotic heart and skeletal muscle from Ames and wild-type mice show similar changes in ETC complex activities with aging, with the exception of complex IV. Furthermore, the kidney, a slowly proliferating tissue, shows dramatic differences in ETC functions unique to the Ames mice. Our data show that there are tissue specific mitochondrial functions that are characteristic of certain tissues of the long-lived Ames mouse. We propose that this may be a factor in the determination of extended lifespan of dwarf mice. PMID:21934186

  6. Effects of molecular structure on microscopic heat transport in chain polymer liquids

    Energy Technology Data Exchange (ETDEWEB)

    Matsubara, Hiroki, E-mail: matsubara@microheat.ifs.tohoku.ac.jp; Kikugawa, Gota; Ohara, Taku [Institute of Fluid Science, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577 (Japan); Bessho, Takeshi; Yamashita, Seiji [Higashifuji Technical Center, Toyota Motor Corporation, 1200 Mishuku, Susono, Shizuoka 410-1193 (Japan)

    2015-04-28

    In this paper, we discuss the molecular mechanism of the heat conduction in a liquid, based on nonequilibrium molecular dynamics simulations of a systematic series of linear- and branched alkane liquids, as a continuation of our previous study on linear alkane [T. Ohara et al., J. Chem. Phys. 135, 034507 (2011)]. The thermal conductivities for these alkanes in a saturated liquid state at the same reduced temperature (0.7T{sub c}) obtained from the simulations are compared in relation to the structural difference of the liquids. In order to connect the thermal energy transport characteristics with molecular structures, we introduce the new concept of the interatomic path of heat transfer (atomistic heat path, AHP), which is defined for each type of inter- and intramolecular interaction. It is found that the efficiency of intermolecular AHP is sensitive to the structure of the first neighbor shell, whereas that of intramolecular AHP is similar for different alkane species. The dependence of thermal conductivity on different lengths of the main and side chain can be understood from the natures of these inter- and intramolecular AHPs.

  7. Proteome Imbalance of Mitochondrial Electron Transport Chain in Brown Adipocytes Leads to Metabolic Benefits.

    Science.gov (United States)

    Masand, Ruchi; Paulo, Esther; Wu, Dongmei; Wang, Yangmeng; Swaney, Danielle L; Jimenez-Morales, David; Krogan, Nevan J; Wang, Biao

    2018-03-06

    Brown adipose tissue (BAT) thermogenesis is critical for thermoregulation and contributes to total energy expenditure. However, whether BAT has non-thermogenic functions is largely unknown. Here, we describe that BAT-specific liver kinase b1 knockout (Lkb1 BKO ) mice exhibited impaired BAT mitochondrial respiration and thermogenesis but reduced adiposity and liver triglyceride accumulation under high-fat-diet feeding at room temperature. Importantly, these metabolic benefits were also present in Lkb1 BKO mice at thermoneutrality, where BAT thermogenesis was not required. Mechanistically, decreased mRNA levels of mtDNA-encoded electron transport chain (ETC) subunits and ETC proteome imbalance led to defective BAT mitochondrial respiration in Lkb1 BKO mice. Furthermore, reducing mtDNA gene expression directly in BAT by removing mitochondrial transcription factor A (Tfam) in BAT also showed ETC proteome imbalance and the trade-off between BAT thermogenesis and systemic metabolism at room temperature and thermoneutrality. Collectively, our data demonstrate that ETC proteome imbalance in BAT regulates systemic metabolism independently of thermogenesis. Copyright © 2018 Elsevier Inc. All rights reserved.

  8. Supercomplexes of the mitochondrial electron transport chain decline in the aging rat heart.

    Science.gov (United States)

    Gómez, Luis A; Monette, Jeffrey S; Chavez, Juan D; Maier, Claudia S; Hagen, Tory M

    2009-10-01

    Accumulation of mitochondrial electron transport chain (ETC) defects is a recognized hallmark of the age-associated decline in cardiac bioenergetics; however, the molecular events involved are only poorly understood. In the present work, we hypothesized that age-related ETC deterioration stemmed partly from disassociation of large solid-state macromolecular assemblies termed "supercomplexes". Mitochondrial proteins from young and old rat hearts were separated by blue native-PAGE, protein bands analyzed by LC-MALDI-MS/MS, and protein levels quantified by densitometry. Results showed that supercomplexes comprised of various stoichiometries of complexes I, III and IV were observed, and declined significantly (p<0.05, n=4) with age. Supercomplexes displaying the highest molecular masses were the most severely affected. Considering that certain diseases (e.g. Barth Syndrome) display similar supercomplex destabilization as our results for aging, the deterioration in ETC supercomplexes may be an important underlying factor for both impaired mitochondrial function and loss of cardiac bioenergetics with age.

  9. Composition of the mitochondrial electron transport chain in acanthamoeba castellanii: structural and evolutionary insights.

    Science.gov (United States)

    Gawryluk, Ryan M R; Chisholm, Kenneth A; Pinto, Devanand M; Gray, Michael W

    2012-11-01

    The mitochondrion, derived in evolution from an α-proteobacterial progenitor, plays a key metabolic role in eukaryotes. Mitochondria house the electron transport chain (ETC) that couples oxidation of organic substrates and electron transfer to proton pumping and synthesis of ATP. The ETC comprises several multiprotein enzyme complexes, all of which have counterparts in bacteria. However, mitochondrial ETC assemblies from animals, plants and fungi are generally more complex than their bacterial counterparts, with a number of 'supernumerary' subunits appearing early in eukaryotic evolution. Little is known, however, about the ETC of unicellular eukaryotes (protists), which are key to understanding the evolution of mitochondria and the ETC. We present an analysis of the ETC proteome from Acanthamoeba castellanii, an ecologically, medically and evolutionarily important member of Amoebozoa (sister to Opisthokonta). Data obtained from tandem mass spectrometric (MS/MS) analyses of purified mitochondria as well as ETC complexes isolated via blue native polyacrylamide gel electrophoresis are combined with the results of bioinformatic queries of sequence databases. Our bioinformatic analyses have identified most of the ETC subunits found in other eukaryotes, confirming and extending previous observations. The assignment of proteins as ETC subunits by MS/MS provides important insights into the primary structures of ETC proteins and makes possible, through the use of sensitive profile-based similarity searches, the identification of novel constituents of the ETC along with the annotation of highly divergent but phylogenetically conserved ETC subunits. © 2012 Elsevier B.V. All rights reserved.

  10. Alternative oxidase: a respiratory electron transport chain pathway essential for maintaining photosynthetic performance during drought stress.

    Science.gov (United States)

    Vanlerberghe, Greg C; Martyn, Greg D; Dahal, Keshav

    2016-07-01

    Photosynthesis and respiration are the hubs of energy metabolism in plants. Drought strongly perturbs photosynthesis as a result of both diffusive limitations resulting from stomatal closure, and in some cases biochemical limitations that are associated with a reduced abundance of key photosynthetic components. The effects of drought on respiration, particularly respiration in the light (RL ), are less understood. The plant mitochondrial electron transport chain includes a non-energy conserving terminal oxidase called alternative oxidase (AOX). Several studies have shown that drought increases AOX transcript, protein and maximum capacity. Here we review recent studies comparing wild-type (WT) tobacco to transgenic lines with altered AOX protein amount. Specifically during drought, RL was compromised in AOX knockdown plants and enhanced in AOX overexpression plants, compared with WT. Significantly, these differences in RL were accompanied by dramatic differences in photosynthetic performance. Knockdown of AOX increased the susceptibility of photosynthesis to drought-induced biochemical limitations, while overexpression of AOX delayed the development of such biochemical limitations, compared with WT. Overall, the results indicate that AOX is essential to maintaining RL during drought, and that this non-energy conserving respiration maintains photosynthesis during drought by promoting energy balance in the chloroplast. This review also outlines several areas for future research, including the possibility that enhancement of non-energy conserving respiratory electron sinks may be a useful biotechnological approach to increase plant performance during stress. © 2016 Scandinavian Plant Physiology Society.

  11. Regulated production of free radicals by the mitochondrial electron transport chain: Cardiac ischemic preconditioning.

    Science.gov (United States)

    Matsuzaki, Satoshi; Szweda, Pamela A; Szweda, Luke I; Humphries, Kenneth M

    2009-11-30

    Excessive production of free radicals by mitochondria is associated with, and likely contributes to, the progression of numerous pathological conditions. Nevertheless, the production of free radicals by the mitochondria may have important biological functions under normal or stressed conditions by activating or modulating redox-sensitive cellular signaling pathways. This raises the intriguing possibility that regulated mitochondrial free radical production occurs via mechanisms that are distinct from pathologies associated with oxidative damage. Indeed, the capacity of mitochondria to produce free radicals in a limited manner may play a role in ischemic preconditioning, the phenomenon whereby short bouts of ischemia protect from subsequent prolonged ischemia and reperfusion. Ischemic preconditioning can thus serve as an important model system for defining regulatory mechanisms that allow for transient, signal-inducing, production of free radicals by mitochondria. Defining how these mechanism(s) occur will provide insight into therapeutic approaches that minimize oxidative damage without altering normal cellular redox biology. The aim of this review is to present and discuss evidence for the regulated production of superoxide by the electron transport chain within the ischemic preconditioning paradigm of redox regulation.

  12. Complementation of mitochondrial electron transport chain by manipulation of the NAD+/NADH ratio.

    Science.gov (United States)

    Titov, Denis V; Cracan, Valentin; Goodman, Russell P; Peng, Jun; Grabarek, Zenon; Mootha, Vamsi K

    2016-04-08

    A decline in electron transport chain (ETC) activity is associated with many human diseases. Although diminished mitochondrial adenosine triphosphate production is recognized as a source of pathology, the contribution of the associated reduction in the ratio of the amount of oxidized nicotinamide adenine dinucleotide (NAD(+)) to that of its reduced form (NADH) is less clear. We used a water-forming NADH oxidase from Lactobacillus brevis (LbNOX) as a genetic tool for inducing a compartment-specific increase of the NAD(+)/NADH ratio in human cells. We used LbNOX to demonstrate the dependence of key metabolic fluxes, gluconeogenesis, and signaling on the cytosolic or mitochondrial NAD(+)/NADH ratios. Expression of LbNOX in the cytosol or mitochondria ameliorated proliferative and metabolic defects caused by an impaired ETC. The results underscore the role of reductive stress in mitochondrial pathogenesis and demonstrate the utility of targeted LbNOX for direct, compartment-specific manipulation of redox state. Copyright © 2016, American Association for the Advancement of Science.

  13. Short chain and polyunsaturated fatty acids in host gut health and foodborne bacterial pathogen inhibition.

    Science.gov (United States)

    Peng, Mengfei; Biswas, Debabrata

    2017-12-12

    As a major source of microbes and their numerous beneficial effects, the gut microflora/microbiome is intimately linked to human health and disease. The exclusion of enteric pathogens by these commensal microbes partially depends upon the production of bioactive compounds such as short-chain fatty acids (SCFAs) and polyunsaturated fatty acids (PUFAs). These key intestinal microbial byproducts are crucial to the maintenance of a healthy gut microbial community. Moreover, SCFAs and PUFAs play multiple critical roles in host defense and immunity, including anti-cancer, anti-inflammation, and anti-oxidant activities, as well as out-competition of enteric bacterial pathogens. In this review article, we hereby aim to highlight the importance of SCFAs and PUFAs and the microbes involved in production of these beneficial intestinal components, and their biological functions, specifically as to their immunomodulation and interactions with enteric bacterial pathogens. Finally, we also advance potential applications of these fatty acids with regards to food safety and human gut health.

  14. Sorafenib targets the mitochondrial electron transport chain complexes and ATP synthase to activate the PINK1-Parkin pathway and modulate cellular drug response.

    Science.gov (United States)

    Zhang, Conggang; Liu, Zeyu; Bunker, Eric; Ramirez, Adrian; Lee, Schuyler; Peng, Yinghua; Tan, Aik-Choon; Eckhardt, S Gail; Chapnick, Douglas A; Liu, Xuedong

    2017-09-08

    Sorafenib (Nexavar) is a broad-spectrum multikinase inhibitor that proves effective in treating advanced renal-cell carcinoma and liver cancer. Despite its well-characterized mechanism of action on several established cancer-related protein kinases, sorafenib causes variable responses among human tumors, although the cause for this variation is unknown. In an unbiased screening of an oncology drug library, we found that sorafenib activates recruitment of the ubiquitin E3 ligase Parkin to damaged mitochondria. We show that sorafenib inhibits the activity of both complex II/III of the electron transport chain and ATP synthase. Dual inhibition of these complexes, but not inhibition of each individual complex, stabilizes the serine-threonine protein kinase PINK1 on the mitochondrial outer membrane and activates Parkin. Unlike the protonophore carbonyl cyanide m -chlorophenylhydrazone, which activates the mitophagy response, sorafenib treatment triggers PINK1/Parkin-dependent cellular apoptosis, which is attenuated upon Bcl-2 overexpression. In summary, our results reveal a new mechanism of action for sorafenib as a mitocan and suggest that high Parkin activity levels could make tumor cells more sensitive to sorafenib's actions, providing one possible explanation why Parkin may be a tumor suppressor gene. These insights could be useful in developing new rationally designed combination therapies with sorafenib. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  15. A conjugate of an anti-midkine single-chain variable fragment to doxorubicin inhibits tumor growth

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Shuli [Immunology and Reproductive Biology Laboratory, Medical School & State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing (China); Nanjing Affiliated First Hospital, Nanjing Medical University, Nanjing (China); Zhao, Guangfeng; Xie, Hao; Huang, Yahong [Immunology and Reproductive Biology Laboratory, Medical School & State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing (China); Hou, Yayi [Immunology and Reproductive Biology Laboratory, Medical School & State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing (China); Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing (China)

    2012-01-27

    Doxorubicin (DOX) was conjugated to a single-chain variable fragment (scFv) against human midkine (MK), and the conjugate (scFv-DOX) was used to target the chemotherapeutic agent to a mouse solid tumor model in which the tumor cells expressed high levels of human MK. The His-tagged recombinant scFv was expressed in bacteria, purified by metal affinity chromatography, and then conjugated to DOX using oxidative dextran (Dex) as a linker. The molecular formula of this immunoconjugate was scFv(Dex){sub 1.3}(DOX){sub 20}. In vitro apoptosis assays showed that the scFv-DOX conjugate was more cytotoxic against MK-transfected human adenocarcinoma cells (BGC823-MK) than untransfected cells (55.3 ± 2.4 vs 22.4 ± 3.8%) for three independent experiments. Nude mice bearing BGC823-MK solid tumors received scFv-DOX or equivalent doses of scFv + DOX for 2 weeks and tumor growth was more effectively inhibited by the scFv-DOX conjugate than by scFv + DOX (51.83% inhibition vs 40.81%). Histological analysis of the tumor tissues revealed that the highest levels of DOX accumulated in tumors from mice treated with scFv-DOX and this resulted in more extensive tumor cell death than in animals treated with the equivalent dose of scFv + DOX. These results show that the scFv-DOX conjugate effectively inhibited tumor growth in vivo and suggest that antigen-specific scFv may be competent drug-carriers.

  16. A conjugate of an anti-midkine single-chain variable fragment to doxorubicin inhibits tumor growth

    International Nuclear Information System (INIS)

    Zhao, Shuli; Zhao, Guangfeng; Xie, Hao; Huang, Yahong; Hou, Yayi

    2012-01-01

    Doxorubicin (DOX) was conjugated to a single-chain variable fragment (scFv) against human midkine (MK), and the conjugate (scFv-DOX) was used to target the chemotherapeutic agent to a mouse solid tumor model in which the tumor cells expressed high levels of human MK. The His-tagged recombinant scFv was expressed in bacteria, purified by metal affinity chromatography, and then conjugated to DOX using oxidative dextran (Dex) as a linker. The molecular formula of this immunoconjugate was scFv(Dex) 1.3 (DOX) 20 . In vitro apoptosis assays showed that the scFv-DOX conjugate was more cytotoxic against MK-transfected human adenocarcinoma cells (BGC823-MK) than untransfected cells (55.3 ± 2.4 vs 22.4 ± 3.8%) for three independent experiments. Nude mice bearing BGC823-MK solid tumors received scFv-DOX or equivalent doses of scFv + DOX for 2 weeks and tumor growth was more effectively inhibited by the scFv-DOX conjugate than by scFv + DOX (51.83% inhibition vs 40.81%). Histological analysis of the tumor tissues revealed that the highest levels of DOX accumulated in tumors from mice treated with scFv-DOX and this resulted in more extensive tumor cell death than in animals treated with the equivalent dose of scFv + DOX. These results show that the scFv-DOX conjugate effectively inhibited tumor growth in vivo and suggest that antigen-specific scFv may be competent drug-carriers

  17. 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.

  18. 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

  19. Aspirin and salicylate bind to immunoglobulin heavy chain binding protein (BiP) and inhibit its ATPase activity in human fibroblasts.

    Science.gov (United States)

    Deng, W G; Ruan, K H; Du, M; Saunders, M A; Wu, K K

    2001-11-01

    Salicylic acid (SA), an endogenous signaling molecule of plants, possesses anti-inflammatory and anti-neoplastic actions in human. Its derivative, aspirin, is the most commonly used anti-inflammatory and analgesic drug. Aspirin and sodium salicylate (salicylates) have been reported to have multiple pharmacological actions. However, it is unclear whether they bind to a cellular protein. Here, we report for the first time the purification from human fibroblasts of a approximately 78 kDa salicylate binding protein with sequence identity to immunoglobulin heavy chain binding protein (BiP). The Kd values of SA binding to crude extract and to recombinant BiP were 45.2 and 54.6 microM, respectively. BiP is a chaperone protein containing a polypeptide binding site recognizing specific heptapeptide sequence and an ATP binding site. A heptapeptide with the specific sequence displaced SA binding in a concentration-dependent manner whereas a control heptapeptide did not. Salicylates inhibited ATPase activity stimulated by this specific heptapeptide but did not block ATP binding or induce BiP expression. These results indicate that salicylates bind specifically to the polypeptide binding site of BiP in human cells that may interfere with folding and transport of proteins important in inflammation.

  20. 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.

  1. 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.

  2. 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

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. Basic regulatory principles of Escherichia coli's electron transport chain for varying oxygen conditions.

    Science.gov (United States)

    Henkel, Sebastian G; Ter Beek, Alexander; Steinsiek, Sonja; Stagge, Stefan; Bettenbrock, Katja; de Mattos, M Joost Teixeira; Sauter, Thomas; Sawodny, Oliver; Ederer, Michael

    2014-01-01

    For adaptation between anaerobic, micro-aerobic and aerobic conditions Escherichia coli's metabolism and in particular its electron transport chain (ETC) is highly regulated. Although it is known that the global transcriptional regulators FNR and ArcA are involved in oxygen response it is unclear how they interplay in the regulation of ETC enzymes under micro-aerobic chemostat conditions. Also, there are diverse results which and how quinones (oxidised/reduced, ubiquinone/other quinones) are controlling the ArcBA two-component system. In the following a mathematical model of the E. coli ETC linked to basic modules for substrate uptake, fermentation product excretion and biomass formation is introduced. The kinetic modelling focusses on regulatory principles of the ETC for varying oxygen conditions in glucose-limited continuous cultures. The model is based on the balance of electron donation (glucose) and acceptance (oxygen or other acceptors). Also, it is able to account for different chemostat conditions due to changed substrate concentrations and dilution rates. The parameter identification process is divided into an estimation and a validation step based on previously published and new experimental data. The model shows that experimentally observed, qualitatively different behaviour of the ubiquinone redox state and the ArcA activity profile in the micro-aerobic range for different experimental conditions can emerge from a single network structure. The network structure features a strong feed-forward effect from the FNR regulatory system to the ArcBA regulatory system via a common control of the dehydrogenases of the ETC. The model supports the hypothesis that ubiquinone but not ubiquinol plays a key role in determining the activity of ArcBA in a glucose-limited chemostat at micro-aerobic conditions.

  8. Hypoxic augmentation of Ca2+ channel currents requires a functional electron transport chain.

    Science.gov (United States)

    Brown, Stephen T; Scragg, Jason L; Boyle, John P; Hudasek, Kristin; Peers, Chris; Fearon, Ian M

    2005-06-10

    The incidence of Alzheimer disease is increased following ischemic episodes, and we previously demonstrated that following chronic hypoxia (CH), amyloid beta (Abeta) peptide-mediated increases in voltage-gated L-type Ca(2+) channel activity contribute to the Ca(2+) dyshomeostasis seen in Alzheimer disease. Because in certain cell types mitochondria are responsible for detecting altered O(2) levels we examined the role of mitochondrial oxidant production in the regulation of recombinant Ca(2+) channel alpha(1C) subunits during CH and exposure to Abeta-(1-40). In wild-type (rho(+)) HEK 293 cells expressing recombinant L-type alpha(1C) subunits, Ca(2+) currents were enhanced by prolonged (24 h) exposure to either CH (6% O(2)) or Abeta-(1-40) (50 nm). By contrast the response to CH was absent in rho(0) cells in which the mitochondrial electron transport chain (ETC) was depleted following long term treatment with ethidium bromide or in rho(+) cells cultured in the presence of 1 microm rotenone. CH was mimicked in rho(0) cells by the exogenous production of O2(-.). by xanthine/xanthine oxidase. Furthermore Abeta-(1-40) enhanced currents in rho(0) cells to a degree similar to that seen in cells with an intact ETC. The antioxidants ascorbate (200 microm) and Trolox (500 microm) ablated the effect of CH in rho(+) cells but were without effect on Abeta-(1-40)-mediated augmentation of Ca(2+) current in rho(0) cells. Thus oxidant production in the mitochondrial ETC is a critical factor, acting upstream of amyloid beta peptide production in the up-regulation of Ca(2+) channels in response to CH.

  9. Inhibition of nuclear T3 binding by fatty acids: dependence on chain length, unsaturated bonds, cis-trans configuration and esterification

    NARCIS (Netherlands)

    Wiersinga, W. M.; Platvoet-ter Schiphorst, M.

    1990-01-01

    1. Fatty acids have the capacity for inhibition of nuclear T3 binding (INB). The present studies were undertaken to describe the INB-activity of fatty acids as a function of chain length, unsaturated bonds, cis-trans configuration, and esterification. 2. Isolated rat liver nuclei were incubated with

  10. 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.

  11. Double path integral method for obtaining the mobility of the one-dimensional charge transport in molecular chain.

    Science.gov (United States)

    Yoo-Kong, Sikarin; Liewrian, Watchara

    2015-12-01

    We report on a theoretical investigation concerning the polaronic effect on the transport properties of a charge carrier in a one-dimensional molecular chain. Our technique is based on the Feynman's path integral approach. Analytical expressions for the frequency-dependent mobility and effective mass of the carrier are obtained as functions of electron-phonon coupling. The result exhibits the crossover from a nearly free particle to a heavily trapped particle. We find that the mobility depends on temperature and decreases exponentially with increasing temperature at low temperature. It exhibits large polaronic-like behaviour in the case of weak electron-phonon coupling. These results agree with the phase transition (A.S. Mishchenko et al., Phys. Rev. Lett. 114, 146401 (2015)) of transport phenomena related to polaron motion in the molecular chain.

  12. Nuclide transport of decay chain in the fractured rock medium: a model using continuous time Markov process

    International Nuclear Information System (INIS)

    Younmyoung Lee; Kunjai Lee

    1995-01-01

    A model using continuous time Markov process for nuclide transport of decay chain of arbitrary length in the fractured rock medium has been developed. Considering the fracture in the rock matrix as a finite number of compartments, the transition probability for nuclide from the transition intensity between and out of the compartments is represented utilizing Chapman-Kolmogorov equation, with which the expectation and the variance of nuclide distribution for the fractured rock medium could be obtained. A comparison between continuous time Markov process model and available analytical solutions for the nuclide transport of three decay chains without rock matrix diffusion has been made showing comparatively good agreement. Fittings with experimental breakthrough curves obtained with nonsorbing materials such as NaLS and uranine in the artificial fractured rock are also made. (author)

  13. A control volume scheme for three-dimensional transport: buffer and matrix effect on a decay chain transport in the repository

    International Nuclear Information System (INIS)

    Lee, Y. M.; Hwang, Y. S.; Kim, S. G.; Kang, C. H.

    2002-01-01

    Using a three-dimensional numerical code, B3R developed for nuclide transport of an arbitrary length of decay chain in the buffer between the canister and adjacent rock in a high-level radioactive waste repository by adopting a finite difference method utilizing the control-volume scheme, some illustrative calculations have been done. A linear sorption isotherm, nuclide transport due to diffusion in the buffer and the rock matrix, and advection and dispersion along thin rigid parallel fractures existing in a saturated porous rock matrix as well as diffusion through the fracture wall into the matrix is assumed. In such kind of repository, buffer and rock matrix are known to be important physico-chemical barriers in nuclide retardation. To show effects of buffer and rock matrix on nuclide transport in HLW repository and also to demonstrate usefulness of B3R, several cases of breakthrough curves as well as three-dimensional plots of concentration isopleths associated with these two barriers are introduced for a typical case of decay chain of 234 U→ 230 Th→ 226 Ra, which is the most important chain as far as the human environment is concerned

  14. 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

  15. 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

  16. A Comparative Proteome Profile of Female Mouse Gonads Suggests a Tight Link between the Electron Transport Chain and Meiosis Initiation.

    Science.gov (United States)

    Shen, Cong; Li, Mingrui; Zhang, Pan; Guo, Yueshuai; Zhang, Hao; Zheng, Bo; Teng, Hui; Zhou, Tao; Guo, Xuejiang; Huo, Ran

    2018-01-01

    Generation of haploid gametes by meiosis is a unique property of germ cells and is critical for sexual reproduction. Leaving mitosis and entering meiosis is a key step in germ cell development. Several inducers or intrinsic genes are known to be important for meiotic initiation, but the regulation of meiotic initiation, especially at the protein level, is still not well understood. We constructed a comparative proteome profile of female mouse fetal gonads at specific time points (11.5, 12.5, and 13.5 days post coitum), spanning a critical window for initiation of meiosis in female germ cells. We identified 3666 proteins, of which 473 were differentially expressed. Further bioinformatics analysis showed that these differentially expressed proteins were enriched in the mitochondria, especially in the electron transport chain and, notably, 9 proteins in electron transport chain Complex I were differentially expressed. We disrupted the mitochondrial electron transport chain function by adding the complex I inhibitor, rotenone to 11.5 days post coitum female gonads cultured in vitro. This treatment resulted in a decreased proportion of meiotic germ cells, as assessed by staining for histone γH2AX. Rotenone treatment also caused decreased ATP levels, increased reactive oxygen species levels and failure of the germ cells to undergo premeiotic DNA replication. These effects were partially rescued by adding Coenzyme Q10. Taken together, our results suggested that a functional electron transport chain is important for meiosis initiation. Our characterization of the quantitative proteome of female gonads provides an inventory of proteins, useful for understanding the mechanisms of meiosis initiation and female fertility. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  17. Managing in-country transportation risks in humanitarian supply chains by logistics service providers: Insights from the 2015 Nepal earthquake

    OpenAIRE

    Baharmand, Hossein; Comes, Tina; Lauras, Matthieu

    2017-01-01

    Humanitarian supply chains (HSCs) play a central role in effective and efficient disaster relief operations. Transportation has a critical share in HSCs and managing its risks helps to avoid further disruptions in relief operations. However, there is no common approach to or culture of risk management that its applicability has been studied through recent cases. This paper incorporates an empirical research design and makes a threefold contribution: first, it identifies in-country transportat...

  18. Charge photogeneration and transport in side-chain carbazole polymers and co-polymers

    KAUST Repository

    Li, Huawei; Termine, Roberto; Godbert, Nicolas; Angiolini, Luigi; Giorgini, Loris; Golemme, Attilio

    2011-01-01

    The photoconductivity, hole mobility and charge photogeneration efficiency of a series of side-chain carbazole homopolymers and copolymers (with azo side-chains) have been investigated. Cyclic voltammetry measurement of frontier orbitals energies show that the HOMO energy is determined by the nature and the position of attachment of the linker between the main chain and the carbazole, the azo-moiety being not relevant in this respect. Hole mobility is not influenced by the HOMO energy but seems to depend on the degree of conformational mobility of the side-chains, reaching values of the order of 10-3cm2V-1s-1 in the best cases. The HOMO energy is instead extremely important when considering photogeneration efficiency, that can change by 10 orders of magnitude depending on the density of the carbazole side-chains in co-polymers and on the linker nature and attachment position. © 2011 Elsevier B.V. All rights reserved.

  19. Charge photogeneration and transport in side-chain carbazole polymers and co-polymers

    KAUST Repository

    Li, Huawei

    2011-07-01

    The photoconductivity, hole mobility and charge photogeneration efficiency of a series of side-chain carbazole homopolymers and copolymers (with azo side-chains) have been investigated. Cyclic voltammetry measurement of frontier orbitals energies show that the HOMO energy is determined by the nature and the position of attachment of the linker between the main chain and the carbazole, the azo-moiety being not relevant in this respect. Hole mobility is not influenced by the HOMO energy but seems to depend on the degree of conformational mobility of the side-chains, reaching values of the order of 10-3cm2V-1s-1 in the best cases. The HOMO energy is instead extremely important when considering photogeneration efficiency, that can change by 10 orders of magnitude depending on the density of the carbazole side-chains in co-polymers and on the linker nature and attachment position. © 2011 Elsevier B.V. All rights reserved.

  20. Inhibition of serine palmitoyltransferase in vitro and long-chain base biosynthesis in intact Chinese hamster ovary cells by β-chloroalanine

    International Nuclear Information System (INIS)

    Medlock, K.A.; Merrill, A.H. Jr.

    1988-01-01

    The effects of β-chloroalanine (β-Cl-alanine) on the serine palmitoyltransferase activity and the de novo biosynthesis of sphinganine and sphingenine were investigated in vitro with rat liver microsomes and in vivo with intact Chinese hamster ovary (CHO) cells. The inhibition in vitro was rapid, irreversible, and concentration and time dependent and apparently involved the active site because inactivation only occurred with β-Cl-L-alanine and was blocked by L-serine. These are characteristics of mechanism-based (suicide) inhibition. Serine palmitoyltransferase (SPT) was also inhibited when intact CHO cells were incubated with β-Cl-alanine and this treatment inhibited [ 14 C]serine incorporation into long-chain bases by intact cells. The concentration dependence of the loss of SPT activity and of long-chain base synthesis was identical. The effects of β-Cl-alanine appeared to occur with little perturbation of other cell functions: the cells exhibited no loss in cell viability, [ 14 C]serine uptake was not blocked, total lipid biosynthesis from [ 14 C]acetic acid was not decreased (nor was the appearance of radiolabel in cholesterol and phosphatidylcholine), and [ 3 H]thymidine incorporation into DNA was not affected. There appeared to be little effect on protein synthesis based on the incorporation of [ 3 H]leucine, which was only decreased by 14%. Although β-Cl-L-alanine is known to inhibit other pyridoxal 5'-phosphate dependent enzymes, alanine and aspartate transaminases were not inhibited under these conditions. These results establish the close association between the activity of serine palmitoyltransferase and the cellular rate of long-chain base formation and indicate that β-Cl-alanine and other mechanism-based inhibitors might be useful to study alterations in cellular long-chain base synthesis

  1. Selective downregulation of mitochondrial electron transport chain activity and increased oxidative stress in human atrial fibrillation.

    Science.gov (United States)

    Emelyanova, Larisa; Ashary, Zain; Cosic, Milanka; Negmadjanov, Ulugbek; Ross, Gracious; Rizvi, Farhan; Olet, Susan; Kress, David; Sra, Jasbir; Tajik, A Jamil; Holmuhamedov, Ekhson L; Shi, Yang; Jahangir, Arshad

    2016-07-01

    Mitochondria are critical for maintaining normal cardiac function, and a deficit in mitochondrial energetics can lead to the development of the substrate that promotes atrial fibrillation (AF) and its progression. However, the link between mitochondrial dysfunction and AF in humans is still not fully defined. The aim of this study was to elucidate differences in the functional activity of mitochondrial oxidative phosphorylation (OXPHOS) complexes and oxidative stress in right atrial tissue from patients without (non-AF) and with AF (AF) who were undergoing open-heart surgery and were not significantly different for age, sex, major comorbidities, and medications. The overall functional activity of the electron transport chain (ETC), NADH:O2 oxidoreductase activity, was reduced by 30% in atrial tissue from AF compared with non-AF patients. This was predominantly due to a selective reduction in complex I (0.06 ± 0.007 vs. 0.09 ± 0.006 nmol·min(-1)·citrate synthase activity(-1), P = 0.02) and II (0.11 ± 0.012 vs. 0.16 ± 0.012 nmol·min(-1)·citrate synthase activity(-1), P = 0.003) functional activity in AF patients. Conversely, complex V activity was significantly increased in AF patients (0.21 ± 0.027 vs. 0.12 ± 0.01 nmol·min(-1)·citrate synthase activity(-1), P = 0.005). In addition, AF patients exhibited a higher oxidative stress with increased production of mitochondrial superoxide (73 ± 17 vs. 11 ± 2 arbitrary units, P = 0.03) and 4-hydroxynonenal level (77.64 ± 30.2 vs. 9.83 ± 2.83 ng·mg(-1) protein, P = 0.048). Our findings suggest that AF is associated with selective downregulation of ETC activity and increased oxidative stress that can contribute to the progression of the substrate for AF. Copyright © 2016 the American Physiological Society.

  2. Global production chains in the fast fashion sector, transports and logistics: the case of the Spanish retailer Inditex

    Directory of Open Access Journals (Sweden)

    Ana Isabel Escalona Orcao

    2014-01-01

    Full Text Available Recent geographical analyses of global production networks in different economic sectors demonstrate that little attention has been paid to the logistical and transport systems through which networks are fully integrated. This paper on Inditex, a leading firm in the fast fashion sector, addresses this lack of attention and analyses how transport and logistics fit into the production network and provide the firm with one of its most notable competitive advantages. We describe the network of shops and manufacturing, present the principles of the logistical model, and provide details of the procedures applied for the functional and geographical integration of the chain of production of Zara, the best known of the company’s 11 brands. The analysis highlights the growing use of air transport in supplying chains of high-fashion-content products manufactured in distant countries and in the distribution of garments to distant markets. The conclusion of the paper is that logistics and transport strategies must be considered because the geographical configuration of global fashion networks increasingly depends on how rapidly the major fashion retailers are able to meet the needs of time-sensitive customers and the appropriate organisational and logistical strategies they adopt for that purpose.

  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. Alkylation of amide linkages and cleavage of the C chain in the enzyme-activated-substrate inhibition of alpha-chymotrypsin with N-nitrosamides

    International Nuclear Information System (INIS)

    Donadio, S.; Perks, H.M.; Tsuchiya, K.; White, E.H.

    1985-01-01

    Active-site-directed N-nitrosamides inhibit alpha-chymotrypsin through an enzyme-activated-substrate mechanism. In this work, the activation results in the release--in the active site--of benzyl carbonium ions, which alkylate and inhibit the enzyme. The final ratio of benzyl groups to enzyme molecules is 1.0, but the alkyl groups are scattered over a number of sites. Reduction and alkylation of the inhibited enzyme generate peptides insoluble in most media. Guanidine hydrochloride at 6 M proved a good solvent, and its use as an eluant on G-75 Sephadex permitted separation of the peptides. In the case of 14 C-labeled enzyme, such an approach has shown that all of the alkylation occurs on the C chain of the enzyme, the chain of which the active site is constructed. Chemical modification of the peptides with ethylenediamine and N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide rendered them soluble in dilute acid, permitting high-performance liquid chromatographic separation. Model studies have shown that the benzyl carbonium ions are highly reactive, alkylating amide linkages at both oxygen and nitrogen. Chromatography of this mixture and also 13 C NMR spectroscopy of the intact inhibited enzyme have shown that three major N-alkylations have occurred. Tryptic digestion of the C chain of chymotrypsin, which contains all of the alkylation sites, provides evidence that the stable N sites are principally located between residue 216 and residue 230

  6. Selección de cadenas para equipos de transporte continuo. // Chain selection software for continuous conveyors.

    Directory of Open Access Journals (Sweden)

    F. Aguilar Parés

    2003-01-01

    Full Text Available El diseño de transportadores y elevadores, que usan cadenas como órgano motor, es algo común en la industria. Unelemento esencial para el buen funcionamiento del equipo es seleccionar correctamente la cadena. Los fabricantes decadenas disponen de una amplia gama de cadenas y aditamentos para satisfacer cualquier requerimiento del equipodiseñado, pero precisamente ante tal universo de cadenas es que surge la necesidad de establecer un procedimiento quecontemple:· Tipo de equipo diseñado (transportador de tablillas o de rastrillos o elevador de cangilones.· Requerimientos de transportación (capacidad, velocidad de transportación, características del material, etc..· Condiciones de transportación (sobrecarga, condiciones de operación, horas de trabajo, etc..El procedimiento antes descrito resulta ser engorroso porque hay etapas en que una decisión implica ajustes a cálculosanteriores y porque como en cualquier proceso de diseño se puede obtener mas de una solución. Por tal motivo se acometióla realización del programa de computación SELCAD. El programa está concebido para que se obtengan resultados porpersonas que no son expertas en el diseño y selección de equipos de transporte continuo, pudiéndose usar también paravalorar si una cadena dada está bien empleada. La base de datos fue obtenida de un catálogo de la Link Belt IndustrialChain Division en que se valoran el uso de 14 tipos de cadenas, con un promedio de 15 modelos por tipo de cadena, lascuales disponen de 40 tipos de aditamentos diferentes. Algunas características del programa son:· Ambiente fácil para el usuario (programado en Visual Basic versión 5.· Sistema de ayudas a lo largo del programa.· Brinda las características del órgano portador y de la rueda motriz.· Permite visualizar, mediante fotos, la forma real de la cadena y del aditamento seleccionado.· Análisis rápido de variantes diferentesPalabras claves Cadenas de transportaci

  7. A conserved WW domain-like motif regulates invariant chain-dependent cell-surface transport of the NKG2D ligand ULBP2.

    Science.gov (United States)

    Uhlenbrock, Franziska; van Andel, Esther; Andresen, Lars; Skov, Søren

    2015-08-01

    Malignant cells expressing NKG2D ligands on their cell surface can be directly sensed and killed by NKG2D-bearing lymphocytes. To ensure this immune recognition, accumulating evidence suggests that NKG2D ligands are trafficed via alternative pathways to the cell surface. We have previously shown that the NKG2D ligand ULBP2 traffics over an invariant chain (Ii)-dependent pathway to the cell surface. This study set out to elucidate how Ii regulates ULBP2 cell-surface transport: We discovered conserved tryptophan (Trp) residues in the primary protein sequence of ULBP1-6 but not in the related MICA/B. Substitution of Trp to alanine resulted in cell-surface inhibition of ULBP2 in different cancer cell lines. Moreover, the mutated ULBP2 constructs were retained and not degraded inside the cell, indicating a crucial role of this conserved Trp-motif in trafficking. Finally, overexpression of Ii increased surface expression of wt ULBP2 while Trp-mutants could not be expressed, proposing that this Trp-motif is required for an Ii-dependent cell-surface transport of ULBP2. Aberrant soluble ULBP2 is immunosuppressive. Thus, targeting a distinct protein module on the ULBP2 sequence could counteract this abnormal expression of ULBP2. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. Long chain fatty acids (LCFA) evolution for inhibition forecasting during anaerobic treatment of lipid-rich wastes: Case of milk-fed veal slaughterhouse waste.

    Science.gov (United States)

    Rodríguez-Méndez, R; Le Bihan, Y; Béline, F; Lessard, P

    2017-09-01

    A detailed study of a solid slaughterhouse waste (SHW) anaerobic treatment is presented. The waste used in this study is rich in lipids and proteins residue. Long chain fatty acids (LCFA), coming from the hydrolysis of lipids were inhibitory to anaerobic processes at different degrees. Acetogenesis and methanogenesis processes were mainly affected by inhibition whereas disintegration and hydrolysis processes did not seem to be affected by high LCFA concentrations. Nevertheless, because of the high energy content, this kind of waste is very suitable for anaerobic digestion but strict control of operating conditions is required to prevent inhibition. For that, two inhibition indicators were identified in this study. Those two indicators, LCFA dynamics and LCFA/VS biomass ratio proved to be useful to predict and to estimate the process inhibition degree. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Contaminant transport in fractured porous media: analytical solution for a two-member decay chain in a single fracture

    International Nuclear Information System (INIS)

    Sudicky, E.A.; Frind, E.O.

    1984-01-01

    An analytical solution is presented for the problem of radionuclide chain decay during transport through a discrete fracture situated in a porous rock matrix. The solution takes into account advection along the fracture, molecular diffusion from the fracture to the porous matrix, adsorption on the fracture face, adsorption in the rock matrix, and radioactive decay. The solution for the daughter product is in the form of a double integral which is evaluated by Gauss-Legendre quadrature. Results show that the daughter product tends to advance ahead of the parent nuclide even when the half-life of the parent is larger. This is attributed to the effect of chain decay in the matrix, which tends to reduce the diffusive loss of the daughter along the fracture. The examples also demonstrate that neglecting the parent nuclide and modeling its daughter as a single species can result in significant overestimation of arrival times at some point along the fracture. Although the analytical solution is restricted to a two-member chain for practical reasons, it represents a more realistic description of nuclide transport along a fracture than available single-species models. The solution may be of use for application to other contaminants undergoing different types of first-order transformation reactions

  10. Toxicity of ricin A chain is reduced in mammalian cells by inhibiting its interaction with the ribosome

    Energy Technology Data Exchange (ETDEWEB)

    Jetzt, Amanda E. [Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901-8520 (United States); Li, Xiao-Ping; Tumer, Nilgun E. [Department of Plant Biology and Pathology, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901-8520 (United States); Cohick, Wendie S., E-mail: cohick@aesop.rutgers.edu [Department of Animal Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901-8520 (United States)

    2016-11-01

    Ricin is a potent ribotoxin that is considered a bioterror threat due to its ease of isolation and possibility of aerosolization. In yeast, mutation of arginine residues away from the active site results in a ricin toxin A chain (RTA) variant that is unable to bind the ribosome and exhibits reduced cytotoxicity. The goal of the present work was to determine if these residues contribute to ribosome binding and cytotoxicity of RTA in mammalian cells. The RTA mutant R193A/R235A did not interact with mammalian ribosomes, while a G212E variant with a point mutation near its active site bound ribosomes similarly to wild-type (WT) RTA. R193A/R235A retained full catalytic activity on naked RNA but had reduced activity on mammalian ribosomes. To determine the effect of this mutant in intact cells, pre R193A/R235A containing a signal sequence directing it to the endoplasmic reticulum and mature R193A/R235A that directly targeted cytosolic ribosomes were each expressed. Depurination and protein synthesis inhibition were reduced by both pre- and mature R193A/R235A relative to WT. Protein synthesis inhibition was reduced to a greater extent by R193A/R235A than by G212E. Pre R193A/R235A caused a greater reduction in caspase activation and loss of mitochondrial membrane potential than G212E relative to WT RTA. These findings indicate that an RTA variant with reduced ribosome binding is less toxic than a variant with less catalytic activity but normal ribosome binding activity. The toxin-ribosome interaction represents a novel target for the development of therapeutics to prevent or treat ricin intoxication. - Highlights: • Arginines 193 and 235 of RTA are critical for binding to the mammalian ribosome. • R193A/R235A has full catalytic activity on RNA but not on mammalian ribosomes. • R193A/R235A is less toxic than a mutant that targets the active site. • The toxin-ribosome interaction is a therapeutic target for ricin intoxication.

  11. 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....

  12. Modelling the effect of nonplanarity on charge transport along conjugated polymer chains

    International Nuclear Information System (INIS)

    Correia, Helena M.G.; Ramos, Marta M.D.

    2007-01-01

    Conjugated polymers show interesting properties that make them appropriated for nanoelectronics. Several studies of poly(p-phenylene vinylene) (PPV) have suggested that each polymer chain consists of several planar segments, with conjugation length of nanoscale dimension, linked by twists or kinks. A pronounced twist between two planar segments in a PPV chain not only causes loss of main-chain conjugation but it may also alter electron and hole mobility along the chain, which has further implications for the percolation of charge through the polymer film. We used self-consistent quantum molecular dynamics calculations to provide information on the electric field needed to move the injected charges (either electrons or holes) along the planar segments of PPV and to cross the twist between two planar segments perpendicular to each other. Field-dependent charge mobility was also estimated for conjugated segments of various lengths. Our results suggest that electrons can cross the twist between adjacent planar segments for lower applied electric fields than holes if there is no more than one electronic charge (electron or hole) on the PPV chain, otherwise similar fields are needed

  13. TCR¿ is transported to and retained in the Golgi apparatus independently of other TCR chains: implications for TCR assembly

    DEFF Research Database (Denmark)

    Dietrich, J; Kastrup, J; Lauritsen, Jens Peter Holst

    1999-01-01

    . This study focused on the intracellular localization and transport of partially assembled TCR complexes as determined by confocal microscopy analyses. We found that none of the TCR chains except for TCRzeta were allowed to exit the ER in T cell variants in which the hexameric CD3gammaepsilonTi alphabetaCD3...... deltaepsilon complex was not formed. Interestingly, TCRzeta was exported from the ER independently of other TCR chains and was predominantly located in a compartment identified as the Golgi apparatus. Furthermore, in the TCRzeta-negative cell line MA5.8, the hexameric CD3gammaepsilonTi alphabetaCD3...... the ER to the Golgi apparatus independently of each other and that these partial TCR complexes are unable to be efficiently expressed at the cell surface suggest that final TCR assembly occurs in the Golgi apparatus....

  14. Low-intensity laser irradiation at 660 nm stimulates transcription of genes involved in the electron transport chain.

    Science.gov (United States)

    Masha, Roland T; Houreld, Nicolette N; Abrahamse, Heidi

    2013-02-01

    Low-intensity laser irradiation (LILI) has been shown to stimulate cellular functions leading to increased adenosine triphosphate (ATP) synthesis. This study was undertaken to evaluate the effect of LILI on genes involved in the mitochondrial electron transport chain (ETC, complexes I-IV) and oxidative phosphorylation (ATP synthase). Four human skin fibroblast cell models were used in this study: normal non-irradiated cells were used as controls while wounded, diabetic wounded, and ischemic cells were irradiated. Cells were irradiated with a 660 nm diode laser with a fluence of 5 J/cm(2) and gene expression determined by quantitative real-time reverse transcription (RT) polymerase chain reaction (PCR). LILI upregulated cytochrome c oxidase subunit VIb polypeptide 2 (COX6B2), cytochrome c oxidase subunit VIc (COX6C), and pyrophosphatase (inorganic) 1 (PPA1) in diabetic wounded cells; COX6C, ATP synthase, H+transporting, mitochondrial Fo complex, subunit B1 (ATP5F1), nicotinamide adenine dinucleotide (NADH) dehydrogenase (ubiquinone) 1 alpha subcomplex, 11 (NDUFA11), and NADH dehydrogenase (ubiquinone) Fe-S protein 7 (NDUFS7) in wounded cells; and ATPase, H+/K+ exchanging, beta polypeptide (ATP4B), and ATP synthase, H+ transporting, mitochondrial Fo complex, subunit C2 (subunit 9) (ATP5G2) in ischemic cells. LILI at 660 nm stimulates the upregulation of genes coding for subunits of enzymes involved in complexes I and IV and ATP synthase.

  15. SLC25 Family Member Genetic Interactions Identify a Role for HEM25 in Yeast Electron Transport Chain Stability.

    Science.gov (United States)

    Dufay, J Noelia; Fernández-Murray, J Pedro; McMaster, Christopher R

    2017-06-07

    The SLC25 family member SLC25A38 (Hem25 in yeast) was recently identified as a mitochondrial glycine transporter that provides substrate to initiate heme/hemoglobin synthesis. Mutations in the human SLC25A38 gene cause congenital sideroblastic anemia. The full extent to which SLC25 family members coregulate heme synthesis with other mitochondrial functions is not clear. In this study, we surveyed 29 nonessential SLC25 family members in Saccharomyces cerevisiae for their ability to support growth in the presence and absence of HEM25 Six SLC25 family members were identified that were required for growth or for heme synthesis in cells lacking Hem25 function. Importantly, we determined that loss of function of the SLC25 family member Flx1, which imports FAD into mitochondria, together with loss of function of Hem25, resulted in inability to grow on media that required yeast cells to supply energy using mitochondrial respiration. We report that specific components of complexes of the electron transport chain are decreased in the absence of Flx1 and Hem25 function. In addition, we show that mitochondria from flx1 Δ hem25 Δ cells contain uncharacterized Cox2-containing high molecular weight aggregates. The functions of Flx1 and Hem25 provide a facile explanation for the decrease in heme level, and in specific electron transport chain complex components. Copyright © 2017 Dufay et al.

  16. SLC25 Family Member Genetic Interactions Identify a Role for HEM25 in Yeast Electron Transport Chain Stability

    Directory of Open Access Journals (Sweden)

    J. Noelia Dufay

    2017-06-01

    Full Text Available The SLC25 family member SLC25A38 (Hem25 in yeast was recently identified as a mitochondrial glycine transporter that provides substrate to initiate heme/hemoglobin synthesis. Mutations in the human SLC25A38 gene cause congenital sideroblastic anemia. The full extent to which SLC25 family members coregulate heme synthesis with other mitochondrial functions is not clear. In this study, we surveyed 29 nonessential SLC25 family members in Saccharomyces cerevisiae for their ability to support growth in the presence and absence of HEM25. Six SLC25 family members were identified that were required for growth or for heme synthesis in cells lacking Hem25 function. Importantly, we determined that loss of function of the SLC25 family member Flx1, which imports FAD into mitochondria, together with loss of function of Hem25, resulted in inability to grow on media that required yeast cells to supply energy using mitochondrial respiration. We report that specific components of complexes of the electron transport chain are decreased in the absence of Flx1 and Hem25 function. In addition, we show that mitochondria from flx1Δ hem25Δ cells contain uncharacterized Cox2-containing high molecular weight aggregates. The functions of Flx1 and Hem25 provide a facile explanation for the decrease in heme level, and in specific electron transport chain complex components.

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

    Science.gov (United States)

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

    2013-01-01

    Verrucosidin (VCD) belongs to a group of fungal metabolites that were identified in screening programs to detect molecules that preferentially kill cancer cells under glucose-deprived conditions. Its mode of action was proposed to involve inhibition of increased GRP78 (glucose regulated protein 78) expression during hypoglycemia. Because GRP78 plays an important role in tumorigenesis, inhibitors such as VCD might harbor cancer therapeutic potential. We therefore sought to characterize VCD’s anticancer activity in vitro. Triple-negative breast cancer cell lines MDA-MB-231 and MDA-MB-468 were treated with VCD under different conditions known to trigger increased expression of GRP78, and a variety of cellular processes were analyzed. We show that VCD was highly cytotoxic only under hypoglycemic conditions, but not in the presence of normal glucose levels, and VCD blocked GRP78 expression only when glycolysis was impaired (due to hypoglycemia or the presence of the glycolysis inhibitor 2-deoxyglucose), but not when GRP78 was induced by other means (hypoxia, thapsigargin, tunicamycin). However, VCD’s strictly hypoglycemia-specific toxicity was not due to the inhibition of GRP78. Rather, VCD blocked mitochondrial energy production via inhibition of complex I of the electron transport chain. As a result, cellular ATP levels were quickly depleted under hypoglycemic conditions, and common cellular functions, including general protein synthesis, deteriorated and resulted in cell death. Altogether, our study identifies mitochondria as the primary target of VCD. The possibility that other purported GRP78 inhibitors (arctigenin, biguanides, deoxyverrucosidin, efrapeptin, JBIR, piericidin, prunustatin, pyrvinium, rottlerin, valinomycin, versipelostatin) might act in a similar GRP78-independent fashion will be discussed. PMID:23755268

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

    Directory of Open Access Journals (Sweden)

    Simmy Thomas

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

  19. 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...

  20. Factors influencing the transport rate of short-chain alcohols through mesoporous y-alumina membranes

    NARCIS (Netherlands)

    Roy Chowdhury, Sankhanilay; Roy Chowdhury, S.; Blank, David H.A.; ten Elshof, Johan E.

    2005-01-01

    The pressure-driven transport of water, ethanol, and 1-propanol through supported -alumina membranes with different pore diameters is reported. Water and alcohols had similar permeabilities when they were transported through y-alumina membranes with average pore diameters of 4.4 and 6.0 nm, and the

  1. THE PERSPECTIVES OF MARITIME TRANSPORT IN EU AND ITS INTEGRATION IN THE SUPPLY CHAIN MANAGEMENT

    Directory of Open Access Journals (Sweden)

    Voicu-Dorobantu Roxana

    2010-12-01

    Full Text Available In a globalised economy transport is one of the most important factors linking the national economies and maritime transport is the main way to deliver goods in international trade. For any international company, choosing the appropriate transportation as part of the logistic solution is vital for its competitiveness. In the context of the economic crisis, CEE strategic location factors play an important role for regional companies which adapt and change their logistic services by developing new scenarios for the shipping industry in order to obtain a better position on the global market. In addition to a favourable geographical location CEE has several other important arguments, like sufficient harbours for developing container terminals to launch extensive container transport transit. The most important recent trends in logistics are shown, as well as the framework of the EU maritime transport.

  2. Phonon transport in a one-dimensional harmonic chain with long-range interaction and mass disorder

    Science.gov (United States)

    Zhou, Hangbo; Zhang, Gang; Wang, Jian-Sheng; Zhang, Yong-Wei

    2016-11-01

    Atomic mass and interatomic interaction are the two key quantities that significantly affect the heat conduction carried by phonons. Here, we study the effects of long-range (LR) interatomic interaction and mass disorder on the phonon transport in a one-dimensional harmonic chain with up to 105 atoms. We find that while LR interaction reduces the transmission of low-frequency phonons, it enhances the transmission of high-frequency phonons by suppressing the localization effects caused by mass disorder. Therefore, LR interaction is able to boost heat conductance in the high-temperature regime or in the large size regime, where the high-frequency modes are important.

  3. Colloid-facilitated radionuclide transport in the fractured rock: effects of decay chain and limited matrix diffusion

    International Nuclear Information System (INIS)

    Park, J. B.; Park, J. W.; Lee, E. Y.; Kim, C. R.

    2002-01-01

    Colloid-facilitated radionuclide transport in the fractured rock is studies by considering radioactive decay chain and limited matrix diffusion into surrounding porous media. Semi-analytical solution in the Laplace domain is obtained from the mass balance equation of radionuclides and colloid particles. Numerical inversion of the Laplace solution is used to get the concentration profiles both in a fracture and in rock matrix. There issues are analyzed for the radionuclide concentration in a fracture by 1) formation constant of pseudo-colloid, 2) filtration coefficient of radio-colloid and 3) effective diffusion depth into the surrounding porous rock media

  4. Global supply chain management/transportation : building a global network of scholars and educators : phase I

    Science.gov (United States)

    2008-01-01

    During the project period two conferences--1st Symposium and Workshop in Global : Supply Chain (http://www.business.utoledo.edu/scm) at University of Toledo, Toledo, : OH, USA (October 6-7, 2007) and 2nd Symposium and Workshop in Global Supply : Chai...

  5. Connecting Structural and Transport Properties of Ionic Liquids with Cationic Oligoether Chains

    Energy Technology Data Exchange (ETDEWEB)

    Lall-Ramnarine, Sharon I.; Zhao, Man; Rodriguez, Chanele; Fernandez, Rahonel; Zmich, Nicole; Fernandez, Eddie D.; Dhiman, Surajdevprakash B.; Castner, Edward W.; Wishart, James F.

    2017-01-01

    X-ray diffraction and molecular dynamics simulations were used to probe the structures of two families of ionic liquids containing oligoether tails on the cations. Imidazolium and pyrrolidinium bis(trifluoromethylsulfonyl)amide ILs with side chains ranging from 4 to 10 atoms in length, including both linear alkyl and oligo-ethylene oxide tails, were prepared. Their physical properties, such as viscosity, conductivity and thermal profile, were measured and compared for systematic trends. Consistent with earlier literature, a single ether substituent substantially decreases the viscosity of pyrrolidinium and imidazolium ILs compared to their alkyl congeners. Remarkably, as the number of ether units in the pyrrolidinium ILs increases there is hardly any increase in the viscosity, in contrast to alkylpyrrolidinium ILs where the viscosity increases steadily with chain length. Viscosities of imidazolium ether ILs increase with chain length but always remain well below their alkyl congeners. To complement the experimentally determined properties, molecular dynamics simulations were run on the two ILs with the longest ether chains. The results point to specific aspects that could be useful for researchers designing ILs for specific applications.

  6. The Herbaspirillum seropedicae SmR1 Fnr orthologs controls the cytochrome composition of the electron transport chain.

    Science.gov (United States)

    Batista, Marcelo B; Sfeir, Michelle Z T; Faoro, Helisson; Wassem, Roseli; Steffens, Maria B R; Pedrosa, Fábio O; Souza, Emanuel M; Dixon, Ray; Monteiro, Rose A

    2013-01-01

    The transcriptional regulatory protein Fnr, acts as an intracellular redox sensor regulating a wide range of genes in response to changes in oxygen levels. Genome sequencing of Herbaspirillum seropedicae SmR1 revealed the presence of three fnr-like genes. In this study we have constructed single, double and triple fnr deletion mutant strains of H. seropedicae. Transcriptional profiling in combination with expression data from reporter fusions, together with spectroscopic analysis, demonstrates that the Fnr1 and Fnr3 proteins not only regulate expression of the cbb3-type respiratory oxidase, but also control the cytochrome content and other component complexes required for the cytochrome c-based electron transport pathway. Accordingly, in the absence of the three Fnr paralogs, growth is restricted at low oxygen tensions and nitrogenase activity is impaired. Our results suggest that the H. seropedicae Fnr proteins are major players in regulating the composition of the electron transport chain in response to prevailing oxygen concentrations.

  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. Non-motorised modes in transport systems: a multimodal chain perspective for The Netherlands

    Energy Technology Data Exchange (ETDEWEB)

    Rietveld, P. [Vrije Universiteit, Amsterdam (Netherlands). Faculty of Economics

    2000-01-01

    Non-motorised transport modes such as walking and biking are environmentally friendly, cheap and reasonably fast alternatives for trips up to a distance of some 3.5 km. Their importance for longer trips follows when a multimodal perspective is used: the use of the car implies short walking trips to a parking place. For public transport the same holds true for walking and biking to a public transport stop. Recognition of the multimodal character of these trips means that the number of moves made by pedestrians increases with a factor of about 6; the increase in distance is about 40%. Implications are discussed for average travel speeds, daily travel-time budgets, parking policies and policies to stimulate public transport. (author)

  10. INFLUENCE OF TRANSPORT FACTOR ON STOCKS IN LOGISTICS CHAINS OF RESOURCE BEHAVIOU

    Directory of Open Access Journals (Sweden)

    I. A. Lebedeva

    2011-01-01

    Full Text Available The paper considers behaviour of material flows at stages of complicated  logistic industrial and transport systems. Key parameters of logistic delivery schemes are analyzed in the paper. The paper estimates an influence of a time parameter on the level of transport and logistics costs and, as a consequence, on  a final finished product.While determining a stock level it is necessary to know not only an intensity of material resource consumption by manufacturing process  for a concrete period of time, but also a probability of non-observance of   transport service terms and cost of stock storage. Stocks of mass cargoes are basically formed at first stages of industrial and transport system and cost of their storage is relatively insignificant. However deficit presence of the given resources influences on functioning of all subsequent interrelated stages of the industrial and transport system.Thus, a risk of deficit occurrence of the given resources can be probably reduced by creating a high stock rate. There is a processing of hi-tech component items (or half-finished products at last stages of the industrial and transport system. Expenses on storage of such resources  are usually high and possibility of their substitution by analogous ones is insignificant. At last stages a mobilization of facilities for provision of on-time delivery is more profitable that allows to save on stock arrangement.

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

    DEFF Research Database (Denmark)

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

    2010-01-01

    ) (polyethylene glycol-catalase) or by NADPH-oxidase inhibition (apocynin). Also, the K(+) channel inhibitors tetraethylammonium (nonselective), diphenyl phosphine oxide-1 (voltage-gated K(+) channel 1.5), glibenclamide (ATP-sensitive K(+) channel), iberiotoxin (large-conductance Ca(2+)-activated K(+) channel...

  12. Current transport properties and phase diagram of a Kitaev chain with long-range pairing

    Science.gov (United States)

    Giuliano, Domenico; Paganelli, Simone; Lepori, Luca

    2018-04-01

    We describe a method to probe the quantum phase transition between the short-range topological phase and the long-range topological phase in the superconducting Kitaev chain with long-range pairing, both exhibiting subgap modes localized at the edges. The method relies on the effects of the finite mass of the subgap edge modes in the long-range regime (which survives in the thermodynamic limit) on the single-particle scattering coefficients through the chain connected to two normal leads. Specifically, we show that, when the leads are biased at a voltage V with respect to the superconducting chain, the Fano factor is either zero (in the short-range correlated phase) or 2 e (in the long-range correlated phase). As a result, we find that the Fano factor works as a directly measurable quantity to probe the quantum phase transition between the two phases. In addition, we note a remarkable "critical fractionalization effect" in the Fano factor, which is exactly equal to e along the quantum critical line. Finally, we note that a dual implementation of our proposed device makes it suitable as a generator of large-distance entangled two-particle states.

  13. Learning Electron Transport Chain Process in Photosynthesis Using Video and Serious Game

    Science.gov (United States)

    Espinoza Morales, Cecilia

    This research investigates students' learning about the electron transport chain (ETC) process in photosynthesis by watching a video followed by playing a serious board game-Electron Chute- that models the ETC process. To accomplish this goal, several learning outcomes regarding the misconceptions students' hold about photosynthesis and the ETC process in photosynthesis were defined. Middle school students need opportunities to develop cohesive models that explain the mechanistic processes of biological systems to support their learning. A six-week curriculum on photosynthesis included a one day learning activity using an ETC video and the Electron Chute game to model the ETC process. The ETC model explained how sunlight energy was converted to chemical energy (ATP) at the molecular level involving a flow of electrons. The learning outcomes and the experiences were developed based on the Indiana Academic Standards for biology and the Next Generation Science Standards (NGSS) for the life sciences. Participants were 120 eighth grade science students from an urban public school. The participants were organized into six classes based on their level of academic readiness, regular and challenge, by the school corporation. Four classes were identified as regular classes and two of them as challenge classes. Students in challenge classes had the opportunity to be challenged with more difficult content knowledge and required higher level thinking skills. The regular classes were the mainstream at school. A quasi-experimental design known as non-equivalent group design (NEGD) was used in this study. This experimental design consisted of a pretest-posttest experiment in two similar groups to begin with-the video only and video+game treatments. Intact classes were distributed into the treatments. The video only watched the ETC video and the video+game treatment watched the ETC video and played the Electron Chute game. The instrument (knowledge test) consisted of a multiple

  14. Solute transport in a single fracture involving an arbitrary length decay chain with rock matrix comprising different geological layers.

    Science.gov (United States)

    Mahmoudzadeh, Batoul; Liu, Longcheng; Moreno, Luis; Neretnieks, Ivars

    2014-08-01

    A model is developed to describe solute transport and retention in fractured rocks. It accounts for advection along the fracture, molecular diffusion from the fracture to the rock matrix composed of several geological layers, adsorption on the fracture surface, adsorption in the rock matrix layers and radioactive decay-chains. The analytical solution, obtained for the Laplace-transformed concentration at the outlet of the flowing channel, can conveniently be transformed back to the time domain by the use of the de Hoog algorithm. This allows one to readily include it into a fracture network model or a channel network model to predict nuclide transport through channels in heterogeneous fractured media consisting of an arbitrary number of rock units with piecewise constant properties. More importantly, the simulations made in this study recommend that it is necessary to account for decay-chains and also rock matrix comprising at least two different geological layers, if justified, in safety and performance assessment of the repositories for spent nuclear fuel. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. A liquefied energy chain for transport and utilization of natural gas for power production with CO2 capture and storage - Part 4: Sensitivity analysis of transport pressures and benchmarking with conventional technology for gas transport

    International Nuclear Information System (INIS)

    Aspelund, Audun; Gundersen, Truls

    2009-01-01

    A novel energy and cost effective transport chain for stranded natural gas utilized for power production with CO 2 capture and storage is developed. It includes an offshore section, a combined gas carrier and an integrated receiving terminal. In the offshore section, natural gas (NG) is liquefied to LNG by liquid carbon dioxide (LCO 2 ) and liquid inert nitrogen (LIN), which are used as cold carriers. In the onshore process, the cryogenic exergy in the LNG is utilized to cool and liquefy the cold carriers, LCO 2 and LIN. The transport pressures for LNG, LIN and LCO 2 will influence the thermodynamic efficiency as well as the ship utilization; hence sensitivity analyses are performed, showing that the ship utilization for the payload will vary between 58% and 80%, and the transport chain exergy efficiency between 48% and 52%. A thermodynamically optimized process requires 319 kWh/tonne LNG. The NG lost due to power generation needed to operate the LEC processes is roughly one third of the requirement in a conventional transport chain for stranded NG gas with CO 2 capture and sequestration (CCS)

  16. 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.

  17. PATHWAY: a simulation model of radionuclide-transport through agricultural food chains

    International Nuclear Information System (INIS)

    Kirchner, T.B.; Whicker, F.W.; Otis, M.D.

    1982-01-01

    PATHWAY simulates the transport of radionuclides from fallout through an agricultural ecosystem. The agro-ecosystem is subdivided into several land management units, each of which is used either for grazing animals, for growing hay, or for growing food crops. The model simulates the transport of radionuclides by both discrete events and continuous, time-dependent processes. The discrete events include tillage of soil, harvest and storage of crops,and deposition of fallout. The continuous processes include the transport of radionuclides due to resuspension, weathering, rain splash, percolation, leaching, adsorption and desorption of radionuclides in the soil, root uptake, foliar absorption, growth and senescence of vegetation, and the ingestion assimilation, and excretion of radionuclides by animals. Preliminary validation studies indicate that the model dynamics and simulated values of radionuclide concentrations in several agricultural products agree well with measured values when the model is driven with site specific data on deposition from world-wide fallout

  18. Creating prospective value chains for renewable road transport energy sources up to 2050 in Nordic Countries

    DEFF Research Database (Denmark)

    Wessberg, Nina; Leinonen, Anna; Tuominen, Anu

    2013-01-01

    If the Nordic energy and transport sectors are to meet the 2050 energy and climate policy targets, major systemic changes are necessary. Along with new technologies, changes are required also in other societal functions such as business models and consumer habits. The transition requires...... cooperation between public and private actors. This paper discusses the paradigm change towards 2050 Nordic road transport system based on renewable energy. More precisely, it proposes an approach for creation and analysis of prospective value networks up to the year 2050. The value networks arise from three...... application with a set of practical tools to support development of implementation strategies and policy programmes in the fields of energy and transport....

  19. 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

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

    Science.gov (United States)

    Gomes, Marcelo Pedrosa; Juneau, Philippe

    2016-11-01

    We investigated the physiological responses of Lemna minor plants exposed to glyphosate. The deleterious effects of this herbicide on photosynthesis, respiration, and pigment concentrations were related to glyphosate-induced oxidative stress through hydrogen peroxide (H 2 O 2 ) accumulation. By using photosynthetic and respiratory electron transport chain (ETC) inhibitors we located the primary site of reactive oxygen species (ROS) production in plants exposed to 500 mg glyphosate l -1 . Inhibition of mitochondrial ETC Complex I by rotenone reduced H 2 O 2 concentrations in glyphosate-treated plants. Complex III activity was very sensitive to glyphosate which appears to act much like antimycin A (an inhibitor of mitochondrial ETC Complex III) by shunting electrons from semiquinone to oxygen, with resulting ROS formation. Confocal evaluations for ROS localization showed that ROS are initially produced outside of the chloroplasts upon initial glyphosate exposure. Our results indicate that in addition to interfering with the shikimate pathway, glyphosate can induce oxidative stress in plants through H 2 O 2 formation by targeting the mitochondrial ETC, which would explain its observed effects on non-target organisms. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Improving the Value Chain of Biofuel Manufacturing Operations by Enhancing Coproduct Transportation and Logistics

    Science.gov (United States)

    Biofuels, including corn-based ethanol, can partially meet the increasing demand for transportation fuels. The production of ethanol in the U.S. has dramatically increased; so too has the quantity of manufacturing coproducts. These nonfermentable residues (i.e., proteins, fibers, oils) are sold as...

  2. Long Distance Bioenergy Logistics: An assessment of costs and energy consumption for various biomass transport chains

    NARCIS (Netherlands)

    Suurs, R.A.A.

    2002-01-01

    This study gives an analysis of costs and energy consumption, associated with long distance bioenergy transport systems. In order to create the possibility of obtaining an insight in the system’s key factors, a model has been developed, taking into account different production systems,

  3. Non-motorised modes in transport systems: a multimodel chain perspective for the Netherlands

    NARCIS (Netherlands)

    Rietveld, P.

    2000-01-01

    Non-motorised transport modes such as walking and biking are environmentally friendly, cheap and reasonably fast alternatives for trips up to a distance of some 3.5 km. Their importance for longer trips follows when a multimodal perspective is used: the use of the car implies short walking trips to

  4. Direct interaction between linear electron transfer chains and solute transport systems in bacteria

    NARCIS (Netherlands)

    Elferink, Marieke G.L.; Hellingwerf, Klaas J.; Belkum, Marco J. van; Poolman, Bert; Konings, Wil N.

    1984-01-01

    In studies on alanine and lactose transport in Rhodopseudomonas sphaeroides we have demonstrated that the rate of solute uptake in this phototrophic bacterium is regulated by the rate of light-induced cyclic electron transfer. In the present paper the interaction between linear electron transfer

  5. 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.

  6. 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.

  7. In Silico Analysis of the Regulation of the Photosynthetic Electron Transport Chain in C3 Plants1[OPEN

    Science.gov (United States)

    Kramer, David M.

    2018-01-01

    We present a new simulation model of the reactions in the photosynthetic electron transport chain of C3 species. We show that including recent insights about the regulation of the thylakoid proton motive force, ATP/NADPH balancing mechanisms (cyclic and noncyclic alternative electron transport), and regulation of Rubisco activity leads to emergent behaviors that may affect the operation and regulation of photosynthesis under different dynamic environmental conditions. The model was parameterized with experimental results in the literature, with a focus on Arabidopsis (Arabidopsis thaliana). A dataset was constructed from multiple sources, including measurements of steady-state and dynamic gas exchange, chlorophyll fluorescence, and absorbance spectroscopy under different light intensities and CO2, to test predictions of the model under different experimental conditions. Simulations suggested that there are strong interactions between cyclic and noncyclic alternative electron transport and that an excess capacity for alternative electron transport is required to ensure adequate redox state and lumen pH. Furthermore, the model predicted that, under specific conditions, reduction of ferredoxin by plastoquinol is possible after a rapid increase in light intensity. Further analysis also revealed that the relationship between ATP synthesis and proton motive force was highly regulated by the concentrations of ATP, ADP, and inorganic phosphate, and this facilitated an increase in nonphotochemical quenching and proton motive force under conditions where metabolism was limiting, such as low CO2, high light intensity, or combined high CO2 and high light intensity. The model may be used as an in silico platform for future research on the regulation of photosynthetic electron transport. PMID:28924017

  8. Inhibition of serine palmitoyltransferase in vitro and long-chain base biosynthesis in intact Chinese hamster ovary cells by β-Cl-alanine

    International Nuclear Information System (INIS)

    Medlock, K.A.; Merrill, A.H. Jr.

    1987-01-01

    Serine palmitoyltransferase (SPT) is a pyridoxal-5'-phosphate dependent enzyme that catalyzes the first committed step of long-chain base (LCB) synthesis. Inhibition of SPT activity and de novo biosynthesis of sphinganine and sphingosine was observed in vitro and in intact Chinese hamster ovary cells (CHO). In vitro studies revealed that inhibition was irreversible and concentration- and time-dependent, which are characteristics of suicide inhibition. Incubation of intact CHO cells with 5 mM β-Cl-alanine for 15 min completely inhibited SPT activity and LCB synthesis from [ 14 C]serine. The concentration dependences of inhibition of SPT activity and LCB formation were identical. There was no loss of viability of recovery of SPT activity over the 2 hour time course of these experiments. The synthesis of several other lipids was not affected by the same treatment. These results establish the association between the activity of SPT and the cellular rate of LCB formation and indicate that β-Cl-alanine can be used to study alterations in cellular LCB synthesis

  9. The ABC transporter Rv1272c of Mycobacterium tuberculosis enhances the import of long-chain fatty acids in Escherichia coli.

    Science.gov (United States)

    Martin, Audrey; Daniel, Jaiyanth

    2018-02-05

    Mycobacterium tuberculosis (Mtb), which causes tuberculosis, is capable of accumulating triacylglycerol (TAG) by utilizing fatty acids from host cells. ATP-binding cassette (ABC) transporters are involved in transport processes in all organisms. Among the classical ABC transporters in Mtb none have been implicated in fatty acid import. Since the transport of fatty acids from the host cell is important for dormancy-associated TAG synthesis in the pathogen, mycobacterial ABC transporter(s) could potentially be involved in this process. Based on sequence identities with a bacterial ABC transporter that mediates fatty acid import for TAG synthesis, we identified Rv1272c, a hitherto uncharacterized ABC-transporter in Mtb that also shows sequence identities with a plant ABC transporter involved in fatty acid transport. We expressed Rv1272c in E. coli and show that it enhances the import of radiolabeled fatty acids. We also show that Rv1272c causes a significant increase in the metabolic incorporation of radiolabeled long-chain fatty acids into cardiolipin, a tetra-acylated phospholipid, and phosphatidylglycerol in E. coli. This is the first report on the function of Rv1272c showing that it displays a long-chain fatty acid transport function. Copyright © 2018 Elsevier Inc. All rights reserved.

  10. Harvesting and transport operations to optimise biomass supply chain and industrial biorefinery processes

    Directory of Open Access Journals (Sweden)

    Robert Matindi

    2018-10-01

    Full Text Available In Australia, Bioenergy plays an important role in modern power systems, where many biomass resources provide greenhouse gas neutral and electricity at a variety of scales. By 2050, the Biomass energy is projected to have a 40-50 % share as an alternative source of energy. In addition to conversion of biomass, barriers and uncertainties in the production, supply may hinder biomass energy development. The sugarcane is an essential ingredient in the production of Bioenergy, across the whole spectrum ranging from the first generation to second generation, e.g., production of energy from the lignocellulosic component of the sugarcane initially regarded as waste (bagasse and cane residue. Sustainable recovery of the Lignocellulosic component of sugarcane from the field through a structured process is largely unknown and associated with high capital outlay that have stifled the growth of bioenergy sector. In this context, this paper develops a new scheduler to optimise the recovery of lignocellulosic component of sugarcane and cane, transport and harvest systems with reducing the associated costs and operational time. An Optimisation Algorithm called Limited Discrepancy Search has been adapted and integrated with the developed scheduling transport algorithms. The developed algorithms are formulated and coded by Optimization Programming Language (OPL to obtain the optimised cane and cane residues transport schedules. Computational experiments demonstrate that high-quality solutions are obtainable for industry-scale instances. To provide insightful decisions, sensitivity analysis is conducted in terms of different scenarios and criteria.

  11. Microemulsions containing long-chain oil ethyl oleate improve the oral bioavailability of piroxicam by increasing drug solubility and lymphatic transportation simultaneously.

    Science.gov (United States)

    Xing, Qiao; Song, Jia; You, Xiuhua; Xu, Dongling; Wang, Kexin; Song, Jiaqi; Guo, Qin; Li, Pengyu; Wu, Chuanbin; Hu, Haiyan

    2016-09-25

    Drug solubility and lymphatic transport enhancements are two main pathways to improve drug oral bioavailability for microemulsions. However, it is not easy to have both achieved simultaneously because excipients used for improving lymphatic transport were usually insufficient in forming microemulsions and solubilizing drugs. Our research is to explore whether ethyl oleate, an oil effective in developing microemulsions with desired solubilizing capability, could increase bioavailability to a higher extent by enhancing lymphatic transport. As a long-chain oil, ethyl oleate won larger microemulsion area than short-chain tributyrin and medium-chain GTCC. In contrast, long-chain soybean oil failed to prepare microemulsions. The solubility of piroxicam in ethyl oleate microemulsions (ME-C) increased by about 30 times than in water. ME-C also won significantly higher AUC0-t compared with tributyrin microemulsions (ME-A) and GTCC microemulsions (ME-B). Oral bioavailability in ME-C decreased by 38% after lymphatic transport was blocked by cycloheximide, severer than those in ME-A and ME-B (8% and 34%). These results suggest that improving lymphatic transport and solubility simultaneously might be a novel strategy to increase drug oral bioavailability to a higher extent than increasing solubility only. Ethyl oleate is a preferred oil candidate due to its integrated advantages of high solubilizing capability, large microemulsion area and effective lymphatic transport. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. A Comprehensive study of the Effects of Chain Morphology on the Transport Properties of Amorphous Polymer Films

    Science.gov (United States)

    Mendels, Dan; Tessler, Nir

    2016-07-01

    Organic semiconductors constitute one of the main components underlying present-day paradigm shifting optoelectronic applications. Among them, polymer based semiconductors are deemed particularly favorable due to their natural compatibility with low-cost device fabrication techniques. In light of recent advances in the syntheses of these classes of materials, yielding systems exhibiting charge mobilities comparable with those found in organic crystals, a comprehensive study of their charge transport properties is presented. Among a plethora of effects arising from these systems morphological and non morphological attributes, it is shown that a favorable presence of several of these attributes, including that of rapid on-chain carrier propagation and the presence of elongated conjugation segments, can lead to an enhancement of the system’s mobility by more than 5 orders of magnitude with respect to ‘standard’ amorphous organic semiconductors. New insight for the formulation of new engineering strategies for next generation polymer based semiconductors is thus gathered.

  13. Modeling generator power plant portfolios and pollution taxes in electric power supply chain networks: a transportation network equilibrium transformation

    International Nuclear Information System (INIS)

    Kai Wu; Nagurney, A.; University of Massachusetts, Amherst, MA; Zugang Liu; Stranlund, J.K.

    2006-01-01

    Global climate change and fuel security risks have encouraged international and regional adoption of pollution/carbon taxes. A major portion of such policy interventions is directed at the electric power industry with taxes applied according to the type of fuel used by the power generators in their power plants. This paper proposes an electric power supply chain network model that captures the behavior of power generators faced with a portfolio of power plant options and subject to pollution taxes. We demonstrate that this general model can be reformulated as a transportation network equilibrium model with elastic demands and qualitatively analyzed and solved as such. The connections between these two different modeling schemas is done through finite-dimensional variational inequality theory. The numerical examples illustrate how changes in the pollution/carbon taxes affect the equilibrium electric power supply chain network production outputs, the transactions between the various decision-makers the demand market prices, as well as the total amount of carbon emissions generated. (author)

  14. CASCADER: An m-chain gas-phase radionuclide transport and fate model

    International Nuclear Information System (INIS)

    Cawlfield, D.E.; Been, K.B.; Emer, D.F.; Lindstrom, F.T.; Shott, G.J.

    1993-06-01

    Chemicals and radionuclides move either in the gas-phase, liquid-phase, or both phases in soils. They may be acted upon by either biological or abiotic processes through advection and/or diffusion. Furthermore, parent and daughter radionuclides may decay as they are transported in the soil. This is volume two to the CASCADER series, titled CASCADR8. It embodies the concepts presented in volume one of this series. To properly understand how the CASCADR8 model works, the reader should read volume one first. This volume presents the input and output file structure for CASCADR8, and a set of realistic scenarios for buried sources of radon gas

  15. CASCADER: An M-chain gas-phase radionuclide transport and fate model

    International Nuclear Information System (INIS)

    Cawlfield, D.E.; Emer, D.F.; Lindstrom, F.T.; Shott, G.J.

    1993-09-01

    Chemicals and radionuclides move either in the gas-phase, liquid-phase, or both phases in soils. They may be acted upon by either biological or abiotic processes through advection and/or dispersion. Additionally during the transport of parent and daughter radionuclides in soil, radionuclide decay may occur. This version of CASCADER called CASCADR9 starts with the concepts presented in volumes one and three of this series. For a proper understanding of how the model works, the reader should read volume one first. Also presented in this volume is a set of realistic scenarios for buried sources of radon gas, and the input and output file structure for CASCADER9

  16. Resistor-network anomalies in the heat transport of random harmonic chains.

    Science.gov (United States)

    Weinberg, Isaac; de Leeuw, Yaron; Kottos, Tsampikos; Cohen, Doron

    2016-06-01

    We consider thermal transport in low-dimensional disordered harmonic networks of coupled masses. Utilizing known results regarding Anderson localization, we derive the actual dependence of the thermal conductance G on the length L of the sample. This is required by nanotechnology implementations because for such networks Fourier's law G∝1/L^{α} with α=1 is violated. In particular we consider "glassy" disorder in the coupling constants and find an anomaly which is related by duality to the Lifshitz-tail regime in the standard Anderson model.

  17. Inactivation of brain mitochondrial Lon protease by peroxynitrite precedes electron transport chain dysfunction

    DEFF Research Database (Denmark)

    Stanyer, Lee; Jørgensen, Wenche; Hori, Osamu

    2008-01-01

    shown to degrade oxidatively modified aconitase in vitro and may thus play a role in defending against the accumulation of oxidized matrix proteins in mitochondria. Using an assay system that allowed us to distinguish between basal and ATP-stimulated Lon protease activity, we have shown in isolated non......-synaptic rat brain mitochondria that Lon protease is highly susceptible to oxidative inactivation by peroxynitrite (ONOO(-)). This susceptibility was more pronounced with regard to ATP-stimulated activity, which was inhibited by 75% in the presence of a bolus addition of 1mM ONOO(-), whereas basal unstimulated...... more sensitive than basal Lon protease activity. Furthermore, supplementation of mitochondrial matrix extracts with reduced glutathione, following ONOO(-) exposure, resulted in partial restoration of basal and ATP-stimulated activity, thus suggesting possible redox regulation of this enzyme complex...

  18. 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.

  19. Analysis of multistage chains in public transport: The case of Quito, Ecuador

    Energy Technology Data Exchange (ETDEWEB)

    Bastidas Zelaya, E.

    2016-07-01

    Because of the growth of cities in size and population, people get used to perform several stage trips involving transfers due to advantages such as time or price paid, being multistage trips more attractive compared to single stage trips. In Quito, Ecuador, nowadays multistage trips represent one third of total daily trips. This paper seeks to identify main characteristics of multistage trips as well as find relationships and inferences that allow recommendations regarding best practices to policy makers and transport managers. The information used belong to the data collected in the Household Survey Mobility held in Quito in 2011. Based on these data, the present work starts using an analysis with descriptive statistics. The next phase of this research involves the search for a methodology in order to identify correlations between demographic, socioeconomic and transport variables related with traveler´s choice for making or not a transfer. Best methodology found was the use of Binary Logistic Regression (Logit) and specific computer software, with which different statistic's models were performed to find the strongest correlation. The paper ends with conclusions and recommendations as well as suggestions for future research. (Author)

  20. Electronic torsional sound in linear atomic chains: Chemical energy transport at 1000 km/s

    Energy Technology Data Exchange (ETDEWEB)

    Kurnosov, Arkady A.; Rubtsov, Igor V.; Maksymov, Andrii O.; Burin, Alexander L., E-mail: aburin@tulane.edu [Department of Chemistry, Tulane University, New Orleans, Louisiana 70118 (United States)

    2016-07-21

    We investigate entirely electronic torsional vibrational modes in linear cumulene chains. The carbon nuclei of a cumulene are positioned along the primary axis so that they can participate only in the transverse and longitudinal motions. However, the interatomic electronic clouds behave as a torsion spring with remarkable torsional stiffness. The collective dynamics of these clouds can be described in terms of electronic vibrational quanta, which we name torsitons. It is shown that the group velocity of the wavepacket of torsitons is much higher than the typical speed of sound, because of the small mass of participating electrons compared to the atomic mass. For the same reason, the maximum energy of the torsitons in cumulenes is as high as a few electronvolts, while the minimum possible energy is evaluated as a few hundred wavenumbers and this minimum is associated with asymmetry of zero point atomic vibrations. Theory predictions are consistent with the time-dependent density functional theory calculations. Molecular systems for experimental evaluation of the predictions are proposed.

  1. Markov Chain-Based Stochastic Modeling of Chloride Ion Transport in Concrete Bridges

    Directory of Open Access Journals (Sweden)

    Yan Zhang

    2018-03-01

    Full Text Available Over the last decade, there has been an increasing interest in models for the evaluation and prediction of the condition of bridges in Canada due to their large number in an advanced state of deterioration. The models are used to develop optimal maintenance and replacement strategies to extend service life and optimally allocate financial and technical resources. The main process of deterioration of concrete bridges in Canada is corrosion of the reinforcing steel due to the widespread use of de-icing salts. In this article, numerical models of the diffusion process and chemical reactions of chloride ions in concrete are used to estimate the time to initiation of corrosion and for the progression of corrosion. The analyses are performed for a range of typical concrete properties, exposure and climatic conditions. The results from these simulations are used to develop parametric surrogate Markov chain models of increasing states of deterioration. The surrogate models are more efficient than physical models for the portfolio analysis of a large number of structures. The procedure provides an alternative to Markov models derived from condition ratings when historical inspection data is limited.

  2. Electronic torsional sound in linear atomic chains: Chemical energy transport at 1000 km/s

    Science.gov (United States)

    Kurnosov, Arkady A.; Rubtsov, Igor V.; Maksymov, Andrii O.; Burin, Alexander L.

    2016-07-01

    We investigate entirely electronic torsional vibrational modes in linear cumulene chains. The carbon nuclei of a cumulene are positioned along the primary axis so that they can participate only in the transverse and longitudinal motions. However, the interatomic electronic clouds behave as a torsion spring with remarkable torsional stiffness. The collective dynamics of these clouds can be described in terms of electronic vibrational quanta, which we name torsitons. It is shown that the group velocity of the wavepacket of torsitons is much higher than the typical speed of sound, because of the small mass of participating electrons compared to the atomic mass. For the same reason, the maximum energy of the torsitons in cumulenes is as high as a few electronvolts, while the minimum possible energy is evaluated as a few hundred wavenumbers and this minimum is associated with asymmetry of zero point atomic vibrations. Theory predictions are consistent with the time-dependent density functional theory calculations. Molecular systems for experimental evaluation of the predictions are proposed.

  3. 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...

  4. Influence of lattice vibrations on the field driven electronic transport in chains with correlated disorder

    Science.gov (United States)

    da Silva, L. D.; Sales, M. O.; Ranciaro Neto, A.; Lyra, M. L.; de Moura, F. A. B. F.

    2016-12-01

    We investigate electronic transport in a one-dimensional model with four different types of atoms and long-ranged correlated disorder. The latter was attained by choosing an adequate distribution of on-site energies. The wave-packet dynamics is followed by taking into account effects due to a static electric field and electron-phonon coupling. In the absence of electron-phonon coupling, the competition between correlated disorder and the static electric field promotes the occurrence of wave-packet oscillations in the regime of strong correlations. When the electron-lattice coupling is switched on, phonon scattering degrades the Bloch oscillations. For weak electron-phonon couplings, a coherent oscillatory-like dynamics of the wave-packet centroid persists for short periods of time. For strong couplings the wave-packet acquires a diffusive-like displacement and spreading. A slower sub-diffusive spreading takes place in the regime of weak correlations.

  5. Use of Short Chained Alkylphenols (SCAP in Analysis of Transport Behaviour of Oil Contaminated Groundwater

    Directory of Open Access Journals (Sweden)

    M. Sauter

    2002-06-01

    Full Text Available Shortchained alkylphenols (SCAP represent a main constituent of crude oil and coal liquefaction products. Due to their specific oil/water partitioning behaviour and high aqueous solubility they can be detected in oil exploitation waters and groundwaters affected by various spills near oil pipelines, oil exploitation sites and coal liquefaction plants. New efficient and powerful analytical techniques have been developed that allow the identification of all 34 individual compounds (C0-C3 without derivatisation and in complex matrices. Due to the different physico-chemical properties of the SCAP, differential transport behaviour in groundwater can be observed, changing the relative concentrations of SCAP downgradient in space and time. These characteristic ratios can be employed to derive information on migration direction and the ageing of the source of contamination. A case study is presented to illustrate the use of this new tool.

  6. Evaluation of the participation of ferredoxin in oxygen reduction in the photosynthetic electron transport chain of isolated pea thylakoids.

    Science.gov (United States)

    Kozuleva, Marina A; Ivanov, Boris N

    2010-07-01

    The contribution to reduction of oxygen by ferredoxin (Fd) to the overall reduction of oxygen in isolated pea thylakoids was studied in the presence of Fd versus Fd + NADP(+). The overall rate of electron transport was measured using a determination of Photosystem II quantum yield from chlorophyll fluorescence parameters, and the rate of oxidation of Fd was measured from the light-induced redox changes of Fd. At low light intensity, increasing Fd concentration from 5 to 30 microM in the absence of NADP(+) increased the proportion of oxygen reduction by Fd from 25-35 to 40-60% in different experiments. This proportion decreased with increasing light intensity. When NADP(+) was added in the presence of 15 microM Fd, which was optimal for the NADP(+) reduction rate, the participation of Fd in the reduction of oxygen was low, no more than 10%, and it also decreased with increasing light intensity. At high light intensity, the overall oxygen reduction rates in the presence of Fd + NADP(+) and in the presence of Fd alone were comparable. The significance of reduction of dioxygen either by water-soluble Fd or by the membrane-bound carriers of the photosynthetic electron transport chain for redox signaling under different light intensities is discussed.

  7. Mitochondrial pharmacology: electron transport chain bypass as strategies to treat mitochondrial dysfunction.

    Science.gov (United States)

    Atamna, Hani; Mackey, Jeanette; Dhahbi, Joseph M

    2012-01-01

    Mitochondrial dysfunction (primary or secondary) is detrimental to intermediary metabolism. Therapeutic strategies to treat/prevent mitochondrial dysfunction could be valuable for managing metabolic and age-related disorders. Here, we review strategies proposed to treat mitochondrial impairment. We then concentrate on redox-active agents, with mild-redox potential, who shuttle electrons among specific cytosolic or mitochondrial redox-centers. We propose that specific redox agents with mild redox potential (-0.1 V; 0.1 V) improve mitochondrial function because they can readily donate or accept electrons in biological systems, thus they enhance metabolic activity and prevent reactive oxygen species (ROS) production. These agents are likely to lack toxic effects because they lack the risk of inhibiting electron transfer in redox centers. This is different from redox agents with strong negative (-0.4 V; -0.2 V) or positive (0.2 V; 0.4 V) redox potentials who alter the redox status of redox-centers (i.e., become permanently reduced or oxidized). This view has been demonstrated by testing the effect of several redox active agents on cellular senescence. Methylene blue (MB, redox potential ≅10 mV) appears to readily cycle between the oxidized and reduced forms using specific mitochondrial and cytosolic redox centers. MB is most effective in delaying cell senescence and enhancing mitochondrial function in vivo and in vitro. Mild-redox agents can alter the biochemical activity of specific mitochondrial components, which then in response alters the expression of nuclear and mitochondrial genes. We present the concept of mitochondrial electron-carrier bypass as a potential result of mild-redox agents, a method to prevent ROS production, improve mitochondrial function, and delay cellular aging. Thus, mild-redox agents may prevent/delay mitochondria-driven disorders. Copyright © 2012 International Union of Biochemistry and Molecular Biology, Inc.

  8. Electronic and transport properties of noncollinear magnetic monatomic Mn chains: Fano resonances in the superlattice of noncollinear magnetic barriers and magnetic anisotropic bands

    International Nuclear Information System (INIS)

    Dai, C.J.; Yan, X.H.; Xiao, Y.; Guo, Y.D.

    2015-01-01

    By means of the density functional theory combined with non-equilibrium Green's function method, ballistic transport properties of one-dimensional noncollinear magnetic monatomic chains were investigated using the single-atomic Mn chains as a model system. Fano resonances are found to exist in the monatomic Mn chains with spin-spiral structure. Furthermore, in the monatomic Mn chains with magnetic soliton lattice, Fano resonances are enhanced and cause the conductance splitting in the transmission spectra. The Fano resonances in the noncollinear magnetic single-atomic Mn chains are arising from the coupling of the localized d-states and the extended states of the quantum channels. By constructing a theoretical model and calculating its conductance, it is found that the phenomena of Fano resonances and the accompanying conductance splitting exist universally in the superlattice of one-dimensional noncollinear magnetic barriers, due to the interference of the incident waves and reflected waves by the interfaces between the neighboring barriers. Moreover, the band structures of the ferromagnetic and spin-spiral monatomic Mn chains exhibit a strong dependence on the spatial arrangement of the magnetic moments of Mn atoms when spin–orbit coupling is considered. - Highlights: • Transport properties of noncollinear magnetic monatomic Mn chains are studied. • Fano resonances are found in the noncollinear magnetic monatomic Mn chains. • Magnetic soliton lattice leads to conductance splitting in the transmission curve. • Fano resonances exist in the superlattice of noncollinear magnetic barriers. • Effect of SOC on the band structure of FM and spin-spiral Mn chains are studied

  9. Meta-iodobenzylguanidine inhibits complex I and III of the respiratory chain in the human cell line Molt-4

    NARCIS (Netherlands)

    Cornelissen, J.; Wanders, R. J.; van Gennip, A. H.; van den Bogert, C.; Voûte, P. A.; van Kuilenburg, A. B.

    1995-01-01

    In this paper we report the effects of meta-iodobenzylguanidine (MIBG), a structural analogue of norepinephrine, on cell proliferation and several parameters related to mitochondrial respiration in Molt-4 cells. In micromolar concentrations, MIBG completely inhibited the proliferation of Molt-4

  10. Identification and Characterization of a Novel IL-4 Receptor α Chain (IL-4Rα Antagonist to Inhibit IL-4 Signalling

    Directory of Open Access Journals (Sweden)

    Nayyar Ahmed

    2015-05-01

    Full Text Available Background/Aims: In recent times, allergy has become a financial, physical and psychological burden to the society as a whole. In allergic cascades, cytokine IL-4 binds to IL-4 receptor (IL-4R, consequently producing allergen-specific IgE antibodies by B cells. In addition, among other functions, IL-4 is also responsible for B and T cell proliferation and differentiation. Hence, characterization of novel antagonists that inhibit IL-4 signalling forms the overall aim of this study. Methods: Phage display was used to screen a random 12-mer synthetic peptide library with a human IL-4Rα to identify peptide candidates. Once identified, the peptides were commercially synthesized and used for in vitro immunoassays. Results: We have successfully used phage display to identify M13 phage clones that demonstrated specific binding to IL-4Rα. The peptide N1 was synthesized for use in ELISA, demonstrating significant binding to IL-4Rα and inhibiting interaction with cytokine IL-4. Furthermore, the peptide was tested in a transfected HEK-Blue IL-4 reporter cell line model, which produces alkaline phosphatase (AP. QUANTI-Blue, a substrate, breaks down in the presence of AP producing a blue coloration. Using this colorimetric analysis, >50% inhibition of IL-4 signalling was achieved. Conclusion: We have successfully identified and characterised a synthetic peptide antagonist against IL-4Rα, which effectively inhibits IL-4 interaction with the IL-4Rα in vitro. Since IL-4 interaction with IL-4Rα is a common pathway for many allergies, a prophylactic treatment can be devised by inhibiting this interaction for future treatment of allergies.

  11. 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.

  12. A liquefied energy chain for transport and utilization of natural gas for power production with CO2 capture and storage - Part 1

    International Nuclear Information System (INIS)

    Aspelund, Audun; Gundersen, Truls

    2009-01-01

    A novel transport chain for stranded natural gas utilized for power production with CO 2 capture and storage is developed. It includes an offshore section, a combined gas carrier, and an onshore integrated receiving terminal. Due to utilization of the cold exergy both in the offshore and onshore processes, and combined use of the gas carrier, the transport chain is both energy and cost effective. In this paper, the liquefied energy chain (LEC) is explained, including novel processes for both the offshore field site and onshore market site. In the offshore section, natural gas (NG) is liquefied to LNG by liquid carbon dioxide (LCO 2 ) and liquid inert nitrogen (LIN), which are used as cold carriers. The LNG is transported in a combined gas carrier to the receiving terminal where it is used as a cooling agent to liquefy CO 2 and nitrogen. The LCO 2 and LIN are transported offshore using the same combined carrier. Pinch and Exergy Analyses are used to determine the optimal offshore and onshore processes and the best transport conditions. The exergy efficiency for a thermodynamically optimized process is 87% and 71% for the offshore and onshore processes, respectively, yielding a total efficiency of 52%. The offshore process is self-supported with power and can operate with few units of rotating equipment and without flammable refrigerants. The loss of natural gas due to power generation for the energy requirements in the LEC processes is roughly one third of the loss in a conventional transport chain for stranded natural gas with CO 2 sequestration. The LEC has several configurations and can be used for small scale ( 5 MTPA LNG) transport. In the example in this paper, the total costs for the simple LEC including transport of natural gas to a 400 MW net power plant and return of 85% of the corresponding carbon as CO 2 for a total sailing distance of 24 h are 58.1 EUR/tonne LNG excluding or including the cost of power. The total power requirements are 319 k

  13. 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....

  14. 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.

  15. Updated model for radionuclide transport in the near-surface till at Forsmark - Implementation of decay chains and sensitivity analyses

    International Nuclear Information System (INIS)

    Pique, Angels; Pekala, Marek; Molinero, Jorge; Duro, Lara; Trinchero, Paolo; Vries, Luis Manuel de

    2013-02-01

    overestimate radionuclide concentrations at the discharge zone). Specifically, examination of the modelling results indicates that: 1. The implementation of the revised till stratigraphy has an overall small impact on the modelling results: despite distinctly different groundwater flow patterns, tracer arrival at the discharge zone is similar between the previous and current till models. 2. Of the radionuclides studied only 226 Ra is significantly affected by radioactive chain decay dynamics. 3. The values of geochemical parameters used in the Base Case reactive transport calculations produce conservative results. 4. The model is largely insensitive to significant variations in dispersivity of the till and an alternative definition of the shallow groundwater inflow, although the elimination of vertical stratification in hydraulic conductivity has the effect to speed up radionuclide transport. 5. Over saturation with barite is not reached under any of the considered scenarios hence Ra coprecipitation with barite does not contribute to 226 Ra retardation under the assumptions of the model. In contrast, Sr co-precipitation with calcite is an important retention mechanism for 90 Sr

  16. Updated model for radionuclide transport in the near-surface till at Forsmark - Implementation of decay chains and sensitivity analyses

    Energy Technology Data Exchange (ETDEWEB)

    Pique, Angels; Pekala, Marek; Molinero, Jorge; Duro, Lara; Trinchero, Paolo; Vries, Luis Manuel de [Amphos 21 Consulting S.L., Barcelona (Spain)

    2013-02-15

    tendency to overestimate radionuclide concentrations at the discharge zone). Specifically, examination of the modelling results indicates that: 1. The implementation of the revised till stratigraphy has an overall small impact on the modelling results: despite distinctly different groundwater flow patterns, tracer arrival at the discharge zone is similar between the previous and current till models. 2. Of the radionuclides studied only {sup 226}Ra is significantly affected by radioactive chain decay dynamics. 3. The values of geochemical parameters used in the Base Case reactive transport calculations produce conservative results. 4. The model is largely insensitive to significant variations in dispersivity of the till and an alternative definition of the shallow groundwater inflow, although the elimination of vertical stratification in hydraulic conductivity has the effect to speed up radionuclide transport. 5. Over saturation with barite is not reached under any of the considered scenarios hence Ra coprecipitation with barite does not contribute to {sup 226}Ra retardation under the assumptions of the model. In contrast, Sr co-precipitation with calcite is an important retention mechanism for {sup 90}Sr.

  17. Bond length and electric current oscillation of long linear carbon chains: Density functional theory, MpB model, and quantum spin transport studies

    International Nuclear Information System (INIS)

    Oeiras, R. Y.; Silva, E. Z. da

    2014-01-01

    Carbon linear atomic chains attached to graphene have experimentally been produced. Motivated by these results, we study the nature of the carbon bonds in these nanowires and how it affects their electrical properties. In the present study we investigate chains with different numbers of atoms and we observe that nanowires with odd number of atoms present a distinct behavior than the ones with even numbers. Using graphene nanoribbons as leads, we identify differences in the quantum transport of the chains with the consequence that even and odd numbered chains have low and high electrical conduction, respectively. We also noted a dependence of current with the wire size. We study this unexpected behavior using a combination of first principles calculations and simple models based on chemical bond theory. From our studies, the electrons of carbon nanowires present a quasi-free electron behavior and this explains qualitatively the high electrical conduction and the bond lengths with unexpected values for the case of odd nanowires. Our study also allows the understanding of the electric conduction dependence with the number of atoms and their parity in the chain. In the case of odd number chains a proposed π-bond (MpB) model describes unsaturated carbons that introduce a mobile π-bond that changes dramatically the structure and transport properties of these wires. Our results indicate that the nature of bonds plays the main role in the oscillation of quantum electrical conduction for chains with even and odd number of atoms and also that nanowires bonded to graphene nanoribbons behave as a quasi-free electron system, suggesting that this behavior is general and it could also remain if the chains are bonded to other materials

  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. Reduced coupling of oxidative phosphorylation in vivo precedes electron transport chain defects due to mild oxidative stress in mice.

    Directory of Open Access Journals (Sweden)

    Michael P Siegel

    Full Text Available Oxidative stress and mitochondrial function are at the core of many degenerative conditions. However, the interaction between oxidative stress and in vivo mitochondrial function is unclear. We used both pharmacological (2 week paraquat (PQ treatment of wild type mice and transgenic (mice lacking Cu, Zn-superoxide dismutase (SOD1(-/- models to test the effect of oxidative stress on in vivo mitochondrial function in skeletal muscle. Magnetic resonance and optical spectroscopy were used to measure mitochondrial ATP and oxygen fluxes and cell energetic state. In both models of oxidative stress, coupling of oxidative phosphorylation was significantly lower (lower P/O at rest in vivo in skeletal muscle and was dose-dependent in the PQ model. Despite this reduction in efficiency, in vivo mitochondrial phosphorylation capacity (ATPmax was maintained in both models, and ex vivo mitochondrial respiration in permeabilized muscle fibers was unchanged following PQ treatment. In association with the reduced P/O, PQ treatment led to a dose-dependent reduction in PCr/ATP ratio and increased phosphorylation of AMPK. These results indicate that oxidative stress uncouples oxidative phosphorylation in vivo and results in energetic stress in the absence of defects in the mitochondrial electron transport chain.

  2. Electronic structure and transport properties of monatomic Fe chains in a vacuum and anchored to a graphene nanoribbon

    International Nuclear Information System (INIS)

    Nguyen, N B; Lebon, A; Vega, A; García-Fuente, A; Gallego, L J

    2012-01-01

    The electronic structure and transport properties of monatomic Fe wires of different characteristics are studied within the density functional theory. In both equidistant and dimerized (more stable) isolated wires, magnetism plays an important role since it leads to different shapes of the transmission coefficients for each spin component. In equidistant wires, electron localization around the Fermi level leads to symmetry breaking between d xy and d x 2 -y 2 bands. The main effect of the structural dimerization is to decrease the number of channels available for the minority spin component. When anchored to the edges of a graphene nanoribbon, the dimerization of the chain is preserved, despite the hybridization of the d states of Fe with the C atoms which gives way to a reduction in the number of d channels around the Fermi level. Most conduction is then led by an electronic channel from the ribbon and the sp z bands from the Fe wires. Suggestions to improve the spintronic ability of Fe wires are proposed.

  3. Structure of the Zymomonas mobilis respiratory chain: oxygen affinity of electron transport and the role of cytochrome c peroxidase.

    Science.gov (United States)

    Balodite, Elina; Strazdina, Inese; Galinina, Nina; McLean, Samantha; Rutkis, Reinis; Poole, Robert K; Kalnenieks, Uldis

    2014-09-01

    The genome of the ethanol-producing bacterium Zymomonas mobilis encodes a bd-type terminal oxidase, cytochrome bc1 complex and several c-type cytochromes, yet lacks sequences homologous to any of the known bacterial cytochrome c oxidase genes. Recently, it was suggested that a putative respiratory cytochrome c peroxidase, receiving electrons from the cytochrome bc1 complex via cytochrome c552, might function as a peroxidase and/or an alternative oxidase. The present study was designed to test this hypothesis, by construction of a cytochrome c peroxidase mutant (Zm6-perC), and comparison of its properties with those of a mutant defective in the cytochrome b subunit of the bc1 complex (Zm6-cytB). Disruption of the cytochrome c peroxidase gene (ZZ60192) caused a decrease of the membrane NADH peroxidase activity, impaired the resistance of growing culture to exogenous hydrogen peroxide and hampered aerobic growth. However, this mutation did not affect the activity or oxygen affinity of the respiratory chain, or the kinetics of cytochrome d reduction. Furthermore, the peroxide resistance and membrane NADH peroxidase activity of strain Zm6-cytB had not decreased, but both the oxygen affinity of electron transport and the kinetics of cytochrome d reduction were affected. It is therefore concluded that the cytochrome c peroxidase does not terminate the cytochrome bc1 branch of Z. mobilis, and that it is functioning as a quinol peroxidase. © 2014 The Authors.

  4. Effects of selected electron transport chain inhibitors on 24-h hydrogen production by Synechocystis sp. PCC 6803.

    Science.gov (United States)

    Burrows, Elizabeth H; Chaplen, Frank W R; Ely, Roger L

    2011-02-01

    One factor limiting biosolar hydrogen (H(2)) production from cyanobacteria is electron availability to the hydrogenase enzyme. In order to optimize 24-h H(2) production this study used Response Surface Methodology and Q2, an optimization algorithm, to investigate the effects of five inhibitors of the photosynthetic and respiratory electron transport chains of Synechocystis sp. PCC 6803. Over 3 days of diurnal light/dark cycling, with the optimized combination of 9.4 mM KCN (3.1 μmol 10(10) cells(-1)) and 1.5 mM malonate (0.5 μmol 10(10) cells(-1)) the H(2) production was 30-fold higher, in EHB-1 media previously optimized for nitrogen (N), sulfur (S), and carbon (C) concentrations (Burrows et al., 2008). In addition, glycogen concentration was measured over 24 h with two light/dark cycling regimes in both standard BG-11 and EHB-1 media. The results suggest that electron flow as well as glycogen accumulation should be optimized in systems engineered for maximal H(2) output. Copyright © 2010 Elsevier Ltd. All rights reserved.

  5. The Mechanisms of Oxygen Reduction in the Terminal Reducing Segment of the Chloroplast Photosynthetic Electron Transport Chain.

    Science.gov (United States)

    Kozuleva, Marina A; Ivanov, Boris N

    2016-07-01

    The review is dedicated to ascertainment of the roles of the electron transfer cofactors of the pigment-protein complex of PSI, ferredoxin (Fd) and ferredoxin-NADP reductase in oxygen reduction in the photosynthetic electron transport chain (PETC) in the light. The data regarding oxygen reduction in other segments of the PETC are briefly analyzed, and it is concluded that their participation in the overall process in the PETC under unstressful conditions should be insignificant. Data concerning the contribution of Fd to the oxygen reduction in the PETC are examined. A set of collateral evidence as well as results of direct measurements of the involvement of Fd in this process in the presence of isolated thylakoids led to the inference that this contribution in vivo is negligible. The increase in oxygen reduction rate in the isolated thylakoids in the presence of either Fd or Fd plus NADP + under increasing light intensity was attributed to the increase in oxygen reduction executed by the membrane-bound oxygen reductants. Data are presented which imply that a main reductant of the O 2 molecule in the terminal reducing segment of the PETC is the electron transfer cofactor of PSI, phylloquinone. The physiological significance of characteristic properties of oxygen reductants in this segment of the PETC is discussed. © The Author 2016. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  6. Learning how the electron transport chain works: independent and interactive effects of instructional strategies and learners' characteristics.

    Science.gov (United States)

    Darabi, Aubteen; Arrastia-Lloyd, Meagan C; Nelson, David W; Liang, Xinya; Farrell, Jennifer

    2015-12-01

    In order to develop an expert-like mental model of complex systems, causal reasoning is essential. This study examines the differences between forward and backward instructional strategies' in terms of efficiency, students' learning and progression of their mental models of the electronic transport chain in an undergraduate metabolism course (n = 151). Additionally, the participants' cognitive flexibility, prior knowledge, and mental effort in the learning process are also investigated. The data were analyzed using a series of general linear models to compare the strategies. Although the two strategies did not differ significantly in terms of mental model progression and learning outcomes, both groups' mental models progressed significantly. Mental effort and prior knowledge were identified as significant predictors of mental model progression. An interaction between instructional strategy and cognitive flexibility revealed that the backward instruction was more efficient than the conventional (forward) strategy for students with lower cognitive flexibility, whereas the conventional instruction was more efficient for students with higher cognitive flexibility. The results are discussed and suggestions for future research on the possible moderating role of cognitive flexibility in the area of health education are presented.

  7. The homeobox protein CEH-23 mediates prolonged longevity in response to impaired mitochondrial electron transport chain in C. elegans.

    Directory of Open Access Journals (Sweden)

    Ludivine Walter

    2011-06-01

    Full Text Available Recent findings indicate that perturbations of the mitochondrial electron transport chain (METC can cause extended longevity in evolutionarily diverse organisms. To uncover the molecular basis of how altered METC increases lifespan in C. elegans, we performed an RNAi screen and revealed that three predicted transcription factors are specifically required for the extended longevity of mitochondrial mutants. In particular, we demonstrated that the nuclear homeobox protein CEH-23 uniquely mediates the longevity but not the slow development, reduced brood size, or resistance to oxidative stress associated with mitochondrial mutations. Furthermore, we showed that ceh-23 expression levels are responsive to altered METC, and enforced overexpression of ceh-23 is sufficient to extend lifespan in wild-type background. Our data point to mitochondria-to-nucleus communications to be key for longevity determination and highlight CEH-23 as a novel longevity factor capable of responding to mitochondrial perturbations. These findings provide a new paradigm for how mitochondria impact aging and age-dependent diseases.

  8. Antioxidant and oxidative stress parameters in brain of Heteropneustes fossilis under air exposure condition; role of mitochondrial electron transport chain.

    Science.gov (United States)

    Paital, Biswaranjan

    2013-09-01

    Many fishes are exposed to air in their natural habitat or during their commercial handling. In natural habitat or during commercial handling, the cat fish Heteropneustes fossilis is exposed to air for >24h. Data on its oxidative metabolism in the above condition are not available. Oxidative stress (OS) indices (lipid and protein oxidation), toxic reactive oxygen species (ROS: H2O2) generation, antioxidative status (levels of superoxide dismutase, catalase, glutathione peroxidase and reductase, ascorbic acid and non-protein sulfhydryl) and activities of electron transport chain (ETC) enzymes (complex I-IV) were investigated in brain tissue of H. fossilis under air exposure condition (0, 3, 6, 12 and 18 h at 25°C). Decreased activities of antioxidant (except catalase) and ETC enzymes (except complex II) with increased H2O2 and OS levels were observed in the tissue under water deprivation condition. Positive correlation was observed for complex II activity and non-protein thiol groups with time period of air exposure. The critical time period to induce OS and to reduce most of the studied antioxidant level in brain was found to be 3-6h air exposure. The data can be useful to minimize the stress generated during commercial handling of the live fishes those exposed to air in general and H. fossilis in particular. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. 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.

  10. Occurrence, bioaccumulation and long-range transport of short-chain chlorinated paraffins on the Fildes Peninsula at King George Island, Antarctica.

    Science.gov (United States)

    Li, Huijuan; Fu, Jianjie; Zhang, Aiqian; Zhang, Qinghua; Wang, Yawei

    2016-09-01

    As a candidate persistent organic pollutant of the Stockholm Convention, short-chain chlorinated paraffins (SCCPs) have recently received particular attention. In this study, we investigated, for the first time, the concentrations of SCCPs in biota samples collected from the Fildes Peninsula at King George Island and Ardley Island, Antarctica. The concentrations of SCCPs ranged from 3.5 to 256.6ng/g (dry weight, dw), with a mean of 76.6±61.8ng/g dw, which was lower than those detected in mid- and low-latitude regions. The long-range transport behaviour of SCCPs was confirmed by both the detection of SCCPs in Antarctic remote areas and their special congener profiles. Short carbon chain (C10) congeners predominated in the Antarctic samples, which accounted for 56.1% of the total SCCP contamination. Such enrichment of C10 congeners indicated the high potential for the long-range transport of shorter chain congeners. In addition, SCCPs tended to be enriched in the species with high lipid contents. The biomagnification potential of SCCPs was found between Archeogastropoda (Agas) and Neogastropoda (Ngas), and the biomagnification factors of shorter chain congeners of SCCPs were higher than that of the longer chain ones. Considering that the endemic species in polar regions may be sensitive and vulnerable to the adverse effects of environmental contaminants, more attention should be paid on the bioaccumulation and toxicological risks of SCCPs in polar environments. Copyright © 2016. Published by Elsevier Ltd.

  11. Long-chain fatty acids inhibition and adaptation process in anaerobic thermophilic digestion: Batch tests, microbial community structure and mathematical modelling

    DEFF Research Database (Denmark)

    Paltsi, Jordi; Illa, J.; Prenafeta-Boldu, F.X.

    2010-01-01

    Biomass samples taken during the continuous operation of thermophilic anaerobic digestors fed with manure and exposed to successive inhibitory pulses of long-chain fatty acids (LCFA) were characterized in terms of specific metabolic activities and 16S rDNA DGGE profiling of the microbial community....... Population profiles of eubacterial and archaeal 16S rDNA genes revealed that no significant shift on microbial community composition took place upon biomass exposure to LCFA. DNA sequencing of predominant DGGE bands showed close phylogenetic affinity to ribotypes characteristic from specific beta...... kinetics considering the relation between LCFA inhibitory substrate concentration and specific biomass content, as an approximation to the adsorption process, improved the model fitting and provided a better insight on the physical nature of the LCFA inhibition process. (C) 2009 Elsevier Ltd. All rights...

  12. 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.

  13. 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.

  14. Metformin-induced inhibition of the mitochondrial respiratory chain increases FGF21 expression via ATF4 activation

    International Nuclear Information System (INIS)

    Kim, Kook Hwan; Jeong, Yeon Taek; Kim, Seong Hun; Jung, Hye Seung; Park, Kyong Soo; Lee, Hae-Youn; Lee, Myung-Shik

    2013-01-01

    Highlights: •Metformin induces FGF21 expression in an AMPK independent manner. •Metformin enhances FGF21 expression by inhibiting mitochondrial complex I activity. •The PERK-eIF2α-ATF4 axis is required for metformin-induced FGF21 expression. •Metformin activates the ATF4-FGF21 axis in the liver of mouse. •Metformin increases serum FGF21 level in diabetic human subjects. -- Abstract: Fibroblast growth factor 21 (FGF21) is an endocrine hormone that exhibits anti-obesity and anti-diabetes effects. Because metformin is widely used as a glucose-lowering agent in patients with type 2 diabetes (T2D), we investigated whether metformin modulates FGF21 expression in cell lines, and in mice or human subjects. We found that metformin increased the expression and release of FGF21 in a diverse set of cell types, including rat hepatoma FaO, primary mouse hepatocytes, and mouse embryonic fibroblasts (MEFs). Intriguingly, AMP-activated protein kinase (AMPK) was dispensable for the induction of FGF21 by metformin. Mammalian target of rapamycin complex 1 (mTORC1) and peroxisome proliferator-activated receptor α (PPARα), which are additional targets of metformin, were not involved in metformin-induced FGF21 expression. Importantly, inhibition of mitochondrial complex I activity by metformin resulted in FGF21 induction through PKR-like ER kinase (PERK)-eukaryotic translation factor 2α (eIF2α)-activating transcription factor 4 (ATF4). We showed that metformin activated ATF4 and increased FGF21 expression in the livers of mice, which led to increased serum levels of FGF21. We also found that serum FGF21 level was increased in human subjects with T2D after metformin therapy for 6 months. In conclusion, our results indicate that metformin induced expression of FGF21 through an ATF4-dependent mechanism by inhibiting mitochondrial respiration independently of AMPK. Therefore, FGF21 induction by metformin might explain a portion of the beneficial metabolic effects of metformin

  15. Metformin-induced inhibition of the mitochondrial respiratory chain increases FGF21 expression via ATF4 activation

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kook Hwan [Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135-710 (Korea, Republic of); Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135-710 (Korea, Republic of); Jeong, Yeon Taek [Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135-710 (Korea, Republic of); Kim, Seong Hun [Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135-710 (Korea, Republic of); Jung, Hye Seung; Park, Kyong Soo [Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-dong Chongno-gu, Seoul 110-744 (Korea, Republic of); Lee, Hae-Youn [Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135-710 (Korea, Republic of); Lee, Myung-Shik, E-mail: mslee0923@skku.edu [Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135-710 (Korea, Republic of); Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-gu, Seoul 135-710 (Korea, Republic of)

    2013-10-11

    Highlights: •Metformin induces FGF21 expression in an AMPK independent manner. •Metformin enhances FGF21 expression by inhibiting mitochondrial complex I activity. •The PERK-eIF2α-ATF4 axis is required for metformin-induced FGF21 expression. •Metformin activates the ATF4-FGF21 axis in the liver of mouse. •Metformin increases serum FGF21 level in diabetic human subjects. -- Abstract: Fibroblast growth factor 21 (FGF21) is an endocrine hormone that exhibits anti-obesity and anti-diabetes effects. Because metformin is widely used as a glucose-lowering agent in patients with type 2 diabetes (T2D), we investigated whether metformin modulates FGF21 expression in cell lines, and in mice or human subjects. We found that metformin increased the expression and release of FGF21 in a diverse set of cell types, including rat hepatoma FaO, primary mouse hepatocytes, and mouse embryonic fibroblasts (MEFs). Intriguingly, AMP-activated protein kinase (AMPK) was dispensable for the induction of FGF21 by metformin. Mammalian target of rapamycin complex 1 (mTORC1) and peroxisome proliferator-activated receptor α (PPARα), which are additional targets of metformin, were not involved in metformin-induced FGF21 expression. Importantly, inhibition of mitochondrial complex I activity by metformin resulted in FGF21 induction through PKR-like ER kinase (PERK)-eukaryotic translation factor 2α (eIF2α)-activating transcription factor 4 (ATF4). We showed that metformin activated ATF4 and increased FGF21 expression in the livers of mice, which led to increased serum levels of FGF21. We also found that serum FGF21 level was increased in human subjects with T2D after metformin therapy for 6 months. In conclusion, our results indicate that metformin induced expression of FGF21 through an ATF4-dependent mechanism by inhibiting mitochondrial respiration independently of AMPK. Therefore, FGF21 induction by metformin might explain a portion of the beneficial metabolic effects of metformin.

  16. 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....

  17. 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

  18. 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

  19. 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.

  20. 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.

  1. 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,…

  2. 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,

  3. Arg9 facilitates the translocation and downstream signal inhibition of an anti-HER2 single chain antibody

    Directory of Open Access Journals (Sweden)

    Hu Yi

    2012-07-01

    Full Text Available Abstract Background HER2 plays a critical role in the pathogenesis of many cancers and is linked to poor prognosis or cancer metastases. Monoclonal antibodies, such as Herceptin against HER2-overexpressing cancers, have showed satisfactory clinical therapeutic effect. However, they have difficulty to surmount obstacles to enter cells or blood–brain barrier. Results In this study, a cell-penetrating peptide Arg9 was linked to the C-terminus of anti-HER2 single chain antibody (MIL5scFv. Flow cytometry, confocal microscopy and electron microscopy analysis all revealed that Arg9 peptide facilitated the penetration of MIL5scFv into HER2-negative cell line NIH3T3 and orientate in mitochondria. More interestingly, Western blot assay showed the potential enhanced bioactivity of MIL5scFv-Arg9 in HER2+ cell line SKOV3, indicating that Arg9 could help large molecules (e.g. antibody to penetrate into cells and therefore enhance its anti-neoplastic function. Conclusions Our work represented an attractive by preliminary strategy to enhance the therapeutic effect of existing antibodies by entering cells easier, or more desirable, surmounting the physical barriers, especially in hard-to-reach cancers such as brain metastases cases.

  4. Identification of mitochondrial electron transport chain-mediated NADH radical formation by EPR spin-trapping techniques.

    Science.gov (United States)

    Matsuzaki, Satoshi; Kotake, Yashige; Humphries, Kenneth M

    2011-12-20

    The mitochondrial electron transport chain (ETC) is a major source of free radical production. However, due to the highly reactive nature of radical species and their short lifetimes, accurate detection and identification of these molecules in biological systems is challenging. The aim of this investigation was to determine the free radical species produced from the mitochondrial ETC by utilizing EPR spin-trapping techniques and the recently commercialized spin-trap, 5-(2,2-dimethyl-1,3-propoxycyclophosphoryl)-5-methyl-1-pyrroline N-oxide (CYPMPO). We demonstrate that this spin-trap has the preferential quality of having minimal mitochondrial toxicity at concentrations required for radical detection. In rat heart mitochondria and submitochondrial particles supplied with NADH, the major species detected under physiological pH was a carbon-centered radical adduct, indicated by markedly large hyperfine coupling constant with hydrogen (a(H) > 2.0 mT). In the presence of the ETC inhibitors, the carbon-centered radical formation was increased and exhibited NADH concentration dependency. The same carbon-centered radical could also be produced with the NAD biosynthesis precursor, nicotinamide mononucleotide, in the presence of a catalytic amount of NADH. The results support the conclusion that the observed species is a complex I derived NADH radical. The formation of the NADH radical could be blocked by hydroxyl radical scavengers but not SOD. In vitro experiments confirmed that an NADH-radical is readily formed by hydroxyl radical but not superoxide anion, further implicating hydroxyl radical as an upstream mediator of NADH radical production. These findings demonstrate the identification of a novel mitochondrial radical species with potential physiological significance and highlight the diverse mechanisms and sites of production within the ETC.

  5. 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...

  6. 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.

  7. 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.

  8. 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.

  9. 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...

  10. 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.

  11. 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.

  12. 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...

  13. 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…

  14. 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.

  15. Effect of side chain length on charge transport, morphology, and photovoltaic performance of conjugated polymers in bulk heterojunction solar cells

    NARCIS (Netherlands)

    Duan, C.; Willems, R.E.M.; van Franeker, J.J.; Bruijnaers, B.J.; Wienk, M.M.; Janssen, R.A.J.

    2016-01-01

    The effect of side chain length on the photovoltaic properties of conjugated polymers is systematically investigated with two sets of polymers that bear different alkyl side chain lengths based on benzodithiophene and benzo[2,1,3]thiadiazole or 5,6-difluorobenzo[2,1,3]thiadiazole. Characterization

  16. 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

  17. 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....

  18. 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.

  19. Enabling high-mobility, ambipolar charge-transport in a DPP-benzotriazole copolymer by side-chain engineering

    DEFF Research Database (Denmark)

    Gruber, Mathias; Jung, Seok-Heon; Schott, Sam

    2015-01-01

    In this article we discuss the synthesis of four new low band-gap co-polymers based on the diketopyrrolopyrrole (DPP) and benzotriazole (BTZ) monomer unit. We demonstrate that the BTZ unit allows for additional solubilizing side-chains on the co-monomer and show that the introduction of a linear...... side-chain on the DPP-unit leads to an increase in thin-film order and charge-carrier mobility if a sufficiently solubilizing, branched, side chain is attached to the BTZ. We compare two different synthetic routes, direct arylation and Suzuki-polycondensation, by a direct comparison of polymers...

  20. 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.

  1. Analysis of the LIV system of Campylobacter jejuni reveals alternative roles for LivJ and LivK in commensalism beyond branched-chain amino acid transport.

    Science.gov (United States)

    Ribardo, Deborah A; Hendrixson, David R

    2011-11-01

    Campylobacter jejuni is a leading cause of diarrheal disease in humans and an intestinal commensal in poultry and other agriculturally important animals. These zoonotic infections result in significant amounts of C. jejuni present in the food supply to contribute to disease in humans. We previously found that a transposon insertion in Cjj81176_1038, encoding a homolog of the Escherichia coli LivJ periplasmic binding protein of the leucine, isoleucine, and valine (LIV) branched-chain amino acid transport system, reduced the commensal colonization capacity of C. jejuni 81-176 in chicks. Cjj81176_1038 is the first gene of a six-gene locus that encodes homologous components of the E. coli LIV system. By analyzing mutants with in-frame deletions of individual genes or pairs of genes, we found that this system constitutes a LIV transport system in C. jejuni responsible for a high level of leucine acquisition and, to a lesser extent, isoleucine and valine acquisition. Despite each LIV protein being required for branched-chain amino acid transport, only the LivJ and LivK periplasmic binding proteins were required for wild-type levels of commensal colonization of chicks. All LIV permease and ATPase components were dispensable for in vivo growth. These results suggest that the biological functions of LivJ and LivK for colonization are more complex than previously hypothesized and extend beyond a role for binding and acquiring branched-chain amino acids during commensalism. In contrast to other studies indicating a requirement and utilization of other specific amino acids for colonization, acquisition of branched-chain amino acids does not appear to be a determinant for C. jejuni during commensalism.

  2. Very-long-chain fatty acid biosynthesis is inhibited by cafenstrole, N,N-diethyl-3-mesitylsulfonyl-1H-1,2,4-triazole-1-carboxamide and its analogs

    International Nuclear Information System (INIS)

    Takahashi, H.; Ohki, A.; Sato, Y.; Wakabayashi, K.; Tanaka, A.; Matthes, B.; Boeger, P.

    2001-01-01

    The rice herbicide cafenstrole and its analogs inhibited the incorporation of [1- 14 C]-oleate and [2- 14 C]-malonate into very-long-chain fatty acids (VLCFAs), using Scenedesmus cells and leek microsomes from Allium porrum. Although the precise mode of interaction of cafenstrole at the molecular level is not completely clarified by the present study, it is concluded that cafenstrole acts as a specific inhibitor of the microsomal elongase enzyme involved in the biosynthesis of fatty acids with alkyl chains longer than C 18 . For a strong VLCFA biosynthesis inhibition an -SO 2 - linkage of the 1,2,4-triazole-1-carboxamides was required. Furthermore, N,N-dialkyl substitution of the carbamoyl nitrogen and electron-donating groups such as methyl at the benzene ring of 1,2,4-triazole-1-carboxamides produced a strong inhibition of VLCFA formation. A correlation was found between the phytotoxic effect against barnyardgrass (Echinochloa oryzicola) and impaired VLCFA formation. (orig.)

  3. 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.

  4. 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

  5. (99m)Tc-labeled gastrins of varying peptide chain length: Distinct impact of NEP/ACE-inhibition on stability and tumor uptake in mice.

    Science.gov (United States)

    Kaloudi, Aikaterini; Nock, Berthold A; Lymperis, Emmanouil; Krenning, Eric P; de Jong, Marion; Maina, Theodosia

    2016-06-01

    In situ inhibition of neutral endopeptidase (NEP) has been recently shown to impressively increase the bioavailability and tumor uptake of biodegradable gastrin radioligands. Furthermore, angiotensin converting enzyme (ACE) has been previously shown to cleave gastrin analogs in vitro. In the present study, we have assessed the effects induced by single or dual NEP/ACE-inhibition on the pharmacokinetic profile of three (99m)Tc-labeled gastrins of varying peptide chain length: [(99m)Tc]SG6 ([(99m)Tc-N4-Gln(1)]gastrin(1-17)), [(99m)Tc]DG2 ([(99m)Tc-N4-Gly(4),DGlu(5)]gastrin(4-17)) and [(99m)Tc]DG4 ([(99m)Tc-N4-DGlu(10)]gastrin(10-17)). Mouse blood samples were collected 5min after injection of each of [(99m)Tc]SG6/DG2/DG4 together with: a) vehicle, b) the NEP-inhibitor phosphoramidon (PA), c) the ACE-inhibitor lisinopril (Lis), or d) PA plus Lis and were analyzed by RP-HPLC for radiometabolite detection. Biodistribution was studied in SCID mice bearing A431-CCK2R(+/-) xenografts at 4h postinjection (pi). [(99m)Tc]SG6 or [(99m)Tc]DG4 was coinjected with either vehicle or the above described NEP/ACE-inhibitor regimens; for [(99m)Tc]DG2 control and PA animal groups were only included. Treatment of mice with PA induced significant stabilization of (99m)Tc-radiotracers in peripheral blood, while treatment with Lis or Lis+PA affected the stability of des(Glu)5 [(99m)Tc]DG4 only. In line with these findings, PA coinjection led to notable amplification of tumor uptake of radiopeptides compared to controls (PTc]DG4 profited by single Lis (2.06±0.39%ID/g vs 0.99±0.13%ID/g in controls) or combined Lis+PA coinjection (8.91±1.61%ID/g vs 4.89±1.33%ID/g in PA-group). Furthermore, kidney uptake remained favourably low and unaffected by PA and/or Lis coinjection only in the case of [(99m)Tc]DG4 (Tc-radioligands based on different-length gastrins. Truncated [(99m)Tc]DG4 exhibited overall the most attractive profile during combined NEP/ACE-inhibition in mouse models, providing new

  6. 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.

  7. Effects of chronic Akt/mTOR inhibition by rapamycin on mechanical overload-induced hypertrophy and myosin heavy chain transition in masseter muscle.

    Science.gov (United States)

    Umeki, Daisuke; Ohnuki, Yoshiki; Mototani, Yasumasa; Shiozawa, Kouichi; Fujita, Takayuki; Nakamura, Yoshiki; Saeki, Yasutake; Okumura, Satoshi

    2013-01-01

    To examine the effects of the Akt/mammalian target of rapamycin (mTOR) pathway on masseter muscle hypertrophy and myosin heavy chain (MHC) transition in response to mechanical overload, we analyzed the effects of bite-opening (BO) on the hypertrophy and MHC composition of masseter muscle of BO-rats treated or not treated with rapamycin (RAPA), a selective mTOR inhibitor. The masseter muscle weight in BO-rats was significantly greater than that in controls, and this increase was attenuated by RAPA treatment. Expression of slow-twitch MHC isoforms was significantly increased in BO-rats with/without RAPA treatment, compared with controls, but the magnitude of the increase was much smaller in RAPA-treated BO-rats. Phosphorylation of p44/42 MAPK (ERK1/2), which preserves fast-twitch MHC isoforms in skeletal muscle, was significantly decreased in BO-rats, but the decrease was abrogated by RAPA treatment. Calcineurin signaling is known to be important for masseter muscle hypertrophy and fast-to-slow MHC isoform transition, but expression of known calcineurin activity modulators was unaffected by RAPA treatment. Taken together, these results indicate that the Akt/mTOR pathway is involved in both development of masseter muscle hypertrophy and fast-to-slow MHC isoform transition in response to mechanical overload with inhibition of the ERK1/2 pathway and operates independently of the calcineurin pathway.

  8. Medium-chain triglycerides promote macrophage reverse cholesterol transport and improve atherosclerosis in ApoE-deficient mice fed a high-fat diet.

    Science.gov (United States)

    Zhang, Xinsheng; Zhang, Yong; Liu, Yinghua; Wang, Jin; Xu, Qing; Yu, Xiaoming; Yang, Xueyan; Liu, Zhao; Xue, Changyong

    2016-09-01

    We previously observed that medium-chain triglycerides (MCTs) could reduce body fat mass and improve the metabolism of cholesterol. We hypothesized that MCTs can improve atherosclerosis by promoting the reverse cholesterol transport (RCT) process. Therefore, the objective of this study was to investigate the roles of MCTs in macrophage RCT and the progression of atherosclerosis. To test this hypothesis, 30 4-week-old ApoE-deficient (ApoE(-/-)) mice were randomly divided into 2 groups and fed a diet of 2% MCTs or long-chain triglycerides (LCTs) for 16 weeks. Ten age- and sex-matched C57BL/6J mice were fed a diet of 2% LCTs as the control. Macrophage-to-feces RCT was assessed in vivo by intraperitoneal injection of RAW 264.7 macrophages containing (3)H-labeled cholesterol, and atherosclerotic plaques were measured. The mRNA and protein expressions were determined by reverse transcriptase polymerase chain reaction and Western blot analyses, respectively. There was a greater decrease in body fat mass, atherosclerotic plaques, and an improvement in serum lipid profiles. In addition, the MCT mice group showed an increase in (3)H-tracer in the feces and a decrease in the liver. Significantly higher levels of mRNA and protein expression of hepatic ATP-binding cassette transporter A1, ATP-binding cassette transporter G5, cholesterol 7α-hydroxylase, and intestinal ATP-binding cassette transporter G8, as well as lower levels of expression of intestinal Niemann-Pick C1-like 1, were found in the MCT group. These results suggest that MCTs could obviously promote macrophage RCT and improve atherosclerosis in ApoE(-/-) mice, indicating that MCTs have the potential to prevent cardiovascular disease. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. 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

  10. 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.

  11. Transport of a Two-Member Decay Chain of Radionuclides Through a Discrete Fracture in a Porous Rock Matrix in the Presence of Colloids

    International Nuclear Information System (INIS)

    Tien, N.-C.; Li Shihhai

    2002-01-01

    Many physical and chemical processes dominate the transport of radionuclides in groundwater. Among these processes, the decay chain process of radionuclides was frequently disregarded in previous research. However, the daughter products may travel much farther than their parents along the fracture. Therefore, some models neglecting the effect of the decay chain may underestimate the transport radionuclide concentration in geological media. The transport of radionuclides in groundwater is also controlled by colloidal particles. The radionuclides may be enhanced or retarded by the colloids, according to the mobility of these colloidal particles. This work describes a novel model of the transport of a two-member decay chain of radionuclides through a discrete fracture in a porous rock matrix in the presence of colloids. The model addresses the following processes: (a) advective transport in the fracture, (b) mechanical dispersion and molecular diffusion along the fracture, (c) molecular diffusion from the fracture to the rock matrix, (d) adsorption onto the fracture wall, (e) adsorption in the rock matrix, and (f) radioactive decay. Furthermore, colloids are assumed to be excluded from the matrix pores because of their size. A fully developed concentration profile system with nonreactive colloids is used to understand the effect of colloidal sizes by using hydrodynamic chromatography. The external forces acting on the colloid surface, such as the inertial, the van der Waals attractive force, the double layer force, and the gravitational force are accounted for. The parameters, the average velocity of the colloid, the dispersion coefficient of the colloid, and the distribution coefficient of radionuclides with colloids are modified according to the colloidal size. The transport equations for the parent radionuclides are solved analytically using the Laplace transformation and inversion method. However, for the transformed solution of the daughter products along the

  12. 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.

  13. 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...

  14. 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

  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. Analysis of the transport of Chernobyl fallout nuclides through the pasture-cow-milk food chain using a time-dependent model

    International Nuclear Information System (INIS)

    Kirchner, G.

    1989-01-01

    Following the Chernobyl accident, activity concentrations in grass from a pasture situated near Bremen and in milk from one particular cow grazing there were analyzed continuously in order to monitor the time-dependent transfer via the grass-cow-milk food chain. From these data weathering half lives on grass are calculated. Using a three compartment model, transfer rates for the transport of I-131 and Cs-137 into milk are determined. Transfer coefficients from feed to milk for use with equilibrium food chain models are derived. Generally, results are in the range of transfer data reported in the literature. Calculated weathering half lives, however, are in the lower range of values previously reported. (orig.)

  17. 99mTc-labeled gastrins of varying peptide chain length: Distinct impact of NEP/ACE-inhibition on stability and tumor uptake in mice

    International Nuclear Information System (INIS)

    Kaloudi, Aikaterini; Nock, Berthold A.; Lymperis, Emmanouil; Krenning, Eric P.; Jong, Marion de; Maina, Theodosia

    2016-01-01

    Introduction: In situ inhibition of neutral endopeptidase (NEP) has been recently shown to impressively increase the bioavailability and tumor uptake of biodegradable gastrin radioligands. Furthermore, angiotensin converting enzyme (ACE) has been previously shown to cleave gastrin analogs in vitro. In the present study, we have assessed the effects induced by single or dual NEP/ACE-inhibition on the pharmacokinetic profile of three 99m Tc-labeled gastrins of varying peptide chain length: [ 99m Tc]SG6 ([ 99m Tc-N 4 -Gln 1 ]gastrin(1–17)), [ 99m Tc]DG2 ([ 99m Tc-N 4 -Gly 4 ,DGlu 5 ]gastrin(4–17)) and [ 99m Tc]DG4 ([ 99m Tc-N 4 -DGlu 10 ]gastrin(10–17)). Methods: Mouse blood samples were collected 5 min after injection of each of [ 99m Tc]SG6/DG2/DG4 together with: a) vehicle, b) the NEP-inhibitor phosphoramidon (PA), c) the ACE-inhibitor lisinopril (Lis), or d) PA plus Lis and were analyzed by RP-HPLC for radiometabolite detection. Biodistribution was studied in SCID mice bearing A431-CCK2R(+/−) xenografts at 4 h postinjection (pi). [ 99m Tc]SG6 or [ 99m Tc]DG4 was coinjected with either vehicle or the above described NEP/ACE-inhibitor regimens; for [ 99m Tc]DG2 control and PA animal groups were only included. Results: Treatment of mice with PA induced significant stabilization of 99m Tc-radiotracers in peripheral blood, while treatment with Lis or Lis + PA affected the stability of des(Glu) 5 [ 99m Tc]DG4 only. In line with these findings, PA coinjection led to notable amplification of tumor uptake of radiopeptides compared to controls (P < 0.01). Only [ 99m Tc]DG4 profited by single Lis (2.06 ± 0.39%ID/g vs 0.99 ± 0.13%ID/g in controls) or combined Lis + PA coinjection (8.91 ± 1.61%ID/g vs 4.89 ± 1.33%ID/g in PA-group). Furthermore, kidney uptake remained favourably low and unaffected by PA and/or Lis coinjection only in the case of [ 99m Tc]DG4 (< 1.9%ID/g) resulting in the most optimal tumor-to-kidney ratios. Conclusions: In situ NEP/ACE-inhibition

  18. A 19-kDa C-terminal tryptic fragment of the α chain of Na/K-ATPase is essential for occlusion and transport of cations

    International Nuclear Information System (INIS)

    Karlish, S.J.D.; Goldshleger, R.; Stein, W.D.

    1990-01-01

    Tryptic digestion of pig renal Na/K-ATPase in the presence of Rb and absence of Ca ions removes about half of the protein but leaves a stable 19-kDa membrane-embedded fragment derived from the α chain, a largely intact β chain, and essentially normal Rb- and Na-occlusion capacity. Subsequent digestion with trypsin in the presence of Ca or absence of Rb ions leads to rapid loss of the 19-kDa fragment and a parallel loss of Rb occlusion, demonstrating that the fragment is essential for occlusion. The N-terminal sequence of the 19-kDa fragment is Asn-Pro-Lys-Thr-Asp-Lys-Leu-Val-Asn-Glu-Arg-Leu-Ile-Ser-Met-Ala, beginning at residue 830 and extending toward the C terminus. Membranes containing the 19-kDa fragment have the following functional properties. (i) ATP-dependent functions are absent. (ii) The apparent affinity for occluding Rb is unchanged, the affinity for Na is lower than in the control enzyme, and activation is now strongly sigmoidal rather than hyperbolic. (iii) Membranes containing the 19-kDa fragment can be reconstituted into phospholipid vesicles and sustain slow Rb-Rb exchange. Thus the transport pathway is retained. The authors conclude that cation occlusion sites and the transport pathway within transmembrane segments are quite separate from the ATP binding sites, located on the cytoplasmic domain of the α chain. Interactions between cation and ATP sites, the heart of active transport, must be indirect - mediated, presumably, by conformational changes of the protein

  19. A 19-kDa C-terminal tryptic fragment of the. alpha. chain of Na/K-ATPase is essential for occlusion and transport of cations

    Energy Technology Data Exchange (ETDEWEB)

    Karlish, S.J.D.; Goldshleger, R. (Weizmann Institute of Science, Rehovot (Israel)); Stein, W.D. (Hebrew Univ. Jerusalem (Israel))

    1990-06-01

    Tryptic digestion of pig renal Na/K-ATPase in the presence of Rb and absence of Ca ions removes about half of the protein but leaves a stable 19-kDa membrane-embedded fragment derived from the {alpha} chain, a largely intact {beta} chain, and essentially normal Rb- and Na-occlusion capacity. Subsequent digestion with trypsin in the presence of Ca or absence of Rb ions leads to rapid loss of the 19-kDa fragment and a parallel loss of Rb occlusion, demonstrating that the fragment is essential for occlusion. The N-terminal sequence of the 19-kDa fragment is Asn-Pro-Lys-Thr-Asp-Lys-Leu-Val-Asn-Glu-Arg-Leu-Ile-Ser-Met-Ala, beginning at residue 830 and extending toward the C terminus. Membranes containing the 19-kDa fragment have the following functional properties. (i) ATP-dependent functions are absent. (ii) The apparent affinity for occluding Rb is unchanged, the affinity for Na is lower than in the control enzyme, and activation is now strongly sigmoidal rather than hyperbolic. (iii) Membranes containing the 19-kDa fragment can be reconstituted into phospholipid vesicles and sustain slow Rb-Rb exchange. Thus the transport pathway is retained. The authors conclude that cation occlusion sites and the transport pathway within transmembrane segments are quite separate from the ATP binding sites, located on the cytoplasmic domain of the {alpha} chain. Interactions between cation and ATP sites, the heart of active transport, must be indirect - mediated, presumably, by conformational changes of the protein.

  20. 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.

  1. 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.

  2. EVALUATION OF THE FREQUENCY OF DIAGNOSTICS OF COMPONENTS AND ASSEMBLIES FOR TRANSPORT AND TECHNOLOGICAL MACHINES ON THE BASIS OF HIDDEN MARKOV CHAINS

    Directory of Open Access Journals (Sweden)

    Andrey Borisovich Nikolaev

    2017-05-01

    Full Text Available In this article a statistical analysis of supply volumes of spare parts, components and accessories was carried out, with some persistent patterns and laws of distribution of failures of major components revealed. There are suggested evaluation models of components and assemblies reliability for the formation of order management procedures of spare parts, components and accessories for the maintenance and repair of transport and technological machines. For the purpose of identification of components operational condition there is proposed a model of hidden Markov chain which allows to classify the condition by indirect evidence, based on the collected statistics.

  3. MASCOT user's guide--Version 2.0: Analytical solutions for multidimensional transport of a four-member radionuclide decay chain in ground water

    International Nuclear Information System (INIS)

    Gureghian, A.B.

    1988-07-01

    The MASCOT code computes the two- and three-dimensional space-time dependent convective-dispersive transport of a four-member radionuclide decay chain in unbounded homogeneous porous media, for constant and radionuclide-dependent release, and assuming steady- state isothermal ground-water flow and parallel streamlines. The model can handle a single or multiple finite line source or a Gaussian distributed source in the two-dimensional case, and a single or multiple patch source or bivariate-normal distributed source in the three-dimensional case. The differential equations are solved by Laplace and Fourier transforms and a Gauss-Legendre integration scheme. 33 figs., 3 tabs

  4. Structure activity correlations in the inhibition of brain synaptosomal 3H-norepinephrine uptake by phenethylamine analogs. The role of α-alkyl side chain and methoxyl ring substitutions

    International Nuclear Information System (INIS)

    Makriyannis, A.; Bowerman, D.; Sze, P.Y.; Fournier, D.; Jong, A.P. de

    1982-01-01

    α-Ethylphenethylamine proved to be a weaker inhibitor of rat brain synaptosomal [ 3 H]norepinephrine ([ 3 H]NE) uptake than amphetamine, while 2-amino-tetralin and 2-amino-1,2-dihydronaphtalene, compounds in which the α-side chain ethyl group is tied to the aromatic ring have a similar inhibiting potency as amphetamine. Hallucinogenic polymethoxy substituted phenethylamine analogs have very low inhibitory potencies indicating that inhibition of NE-reuptake in brain noradrenergic neurons is not associated with the drug-induced hallucinogenic syndrome. (Auth.)

  5. 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

  6. Enabling congestion avoidance and reduction in the Michigan-Ohio transportation network to improve supply chain efficiency : freight ATIS.

    Science.gov (United States)

    2010-01-01

    We consider dynamic vehicle routing under milk-run tours with time windows in congested : transportation networks for just-in-time (JIT) production. The arc travel times are considered : stochastic and time-dependent. The problem integrates TSP with ...

  7. 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

  8. Use of MICRAS code on the evaluation of the maximum radionuclides concentrations due to transport/migration of decay chain in groundwaters

    International Nuclear Information System (INIS)

    Aquino Branco, O.E. de

    1995-01-01

    This paper presents a methodology for the evaluation of the maximum radionuclides concentrations in groundwaters, due to the transport/migration of decay chains. Analytical solution of the equations system is difficult, even if only three elements of the decay chain are considered. Therefore, a numerical solution is most convenient. An application of the MICRAS code, developed to assess maximum concentrations of each radionuclide, starting with the initial concentrations, is presented. The maximum concentration profile for 226 Ra, calculated using MICRAS, is compared with the results obtained through an analytical and a numerical model. The fitness of results is considered good. Simplified models, like the one represented by the application of MICRAS, are largely employed in the section in the selection and characterization of sites for radioactive wastes repositories and in studies of safety evaluation for the same purpose. A detailed analysis of the transport/migration of contaminants in aquifers requires a large quantify of data from the site and from the installation as well, which makes this analysis expensive and inviable during the preliminary phases of the studies. (author). 6 refs, 1 fig, 1 tab

  9. Alkaline Ceramidase 3 (ACER3) Hydrolyzes Unsaturated Long-chain Ceramides, and Its Down-regulation Inhibits Both Cell Proliferation and Apoptosis*

    OpenAIRE

    Hu, Wei; Xu, Ruijuan; Sun, Wei; Szulc, Zdzislaw M.; Bielawski, Jacek; Obeid, Lina M.; Mao, Cungui

    2010-01-01

    Ceramides with different fatty acyl chains may vary in their physiological or pathological roles; however, it remains unclear how cellular levels of individual ceramide species are regulated. Here, we demonstrate that our previously cloned human alkaline ceramidase 3 (ACER3) specifically controls the hydrolysis of ceramides carrying unsaturated long acyl chains, unsaturated long-chain (ULC) ceramides. In vitro, ACER3 only hydrolyzed C18:1-, C20:1-, C20:4-ceramides, dihydroceramides, and phyto...

  10. Long branch-chains of amylopectin with B-type crystallinity in rice seed with inhibition of starch branching enzyme I and IIb resist in situ degradation and inhibit plant growth during seedling development : Degradation of rice starch with inhibition of SBEI/IIb during seedling development.

    Science.gov (United States)

    Pan, Ting; Lin, Lingshang; Wang, Juan; Liu, Qiaoquan; Wei, Cunxu

    2018-01-08

    Endosperm starch provides prime energy for cereal seedling growth. Cereal endosperm with repression of starch branching enzyme (SBE) has been widely studied for its high resistant starch content and health benefit. However, in barley and maize, the repression of SBE changes starch component and amylopectin structure which affects grain germination and seedling establishment. A high resistant starch rice line (TRS) has been developed through inhibiting SBEI/IIb, and its starch has very high resistance to in vitro hydrolysis and digestion. However, it is unclear whether the starch resists in situ degradation in seed and influences seedling growth after grain germination. In this study, TRS and its wild-type rice cultivar Te-qing (TQ) were used to investigate the seedling growth, starch property changes, and in situ starch degradation during seedling growth. The slow degradation of starch in TRS seed restrained the seedling growth. The starch components including amylose and amylopectin were simultaneously degraded in TQ seeds during seedling growth, but in TRS seeds, the amylose was degraded faster than amylopectin and the amylopectin long branch-chains with B-type crystallinity had high resistance to in situ degradation. TQ starch was gradually degraded from the proximal to distal region of embryo and from the outer to inner in endosperm. However, TRS endosperm contained polygonal, aggregate, elongated and hollow starch from inner to outer. The polygonal starch similar to TQ starch was completely degraded, and the other starches with long branch-chains of amylopectin and B-type crystallinity were degraded faster at the early stage of seedling growth but had high resistance to in situ degradation during TRS seedling growth. The B-type crystallinity and long branch-chains of amylopectin in TRS seed had high resistance to in situ degradation, which inhibited TRS seedling growth.

  11. A Novel Application of a Hybrid Delphi-Analytic Hierarchy Process (AHP) Technique: Identifying Key Success Factors in the Strategic Alignment of Collaborative Heterarchical Transportation Networks for Supply Chains

    OpenAIRE

    Yasanur Kayikci; Volker Stix; Larry J. LeBlanc; Michael R. Bartolacci

    2014-01-01

    This research studies heterarchical collaboration in logistical transport. Specifically, it utilizes a hybrid Delphi-Analytic Hierarchy Process (AHP) approach to explore the relevant criteria for the formation and maintenance of a strategic alignment for heterarchical transport collaboration. The importance of this work is that it applies a novel hybrid approach for identifying criteria for success to a little-studied form of supply chain collaboration: heterarchical collaborative transport. ...

  12. 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...

  13. Multiple mobility edges in a 1D Aubry chain with Hubbard interaction in presence of electric field: Controlled electron transport

    Science.gov (United States)

    Saha, Srilekha; Maiti, Santanu K.; Karmakar, S. N.

    2016-09-01

    Electronic behavior of a 1D Aubry chain with Hubbard interaction is critically analyzed in presence of electric field. Multiple energy bands are generated as a result of Hubbard correlation and Aubry potential, and, within these bands localized states are developed under the application of electric field. Within a tight-binding framework we compute electronic transmission probability and average density of states using Green's function approach where the interaction parameter is treated under Hartree-Fock mean field scheme. From our analysis we find that selective transmission can be obtained by tuning injecting electron energy, and thus, the present model can be utilized as a controlled switching device.

  14. Altered expression of mitochondrial electron transport chain proteins and improved myocardial energetic state during late ischemic preconditioning

    NARCIS (Netherlands)

    J.A. Cabrera (Jesús); E.A. Ziemba (Elizabeth); L.H. Colbert (Lisa); L.B. Anderson (Lorraine); W.J. Sluiter (Wim); D.J.G.M. Duncker (Dirk); T.A. Butterick (Tammy); J. Sikora (Joseph); H.B. Ward (Herbert B.); R.F. Kelly (Rosemary); E.O. McFalls (Edward)

    2012-01-01

    textabstractAltered expression of mitochondrial electron transport proteins has been shown in early preconditioned myocardial tissue. We wished to determine whether these alterations persist in the Second Window of Protection (SWOP) and if so, whether a favorable energetic state is facilitated

  15. Experimental Study of the Thermal Transport in CsNiF3 - An S=1 Quantum Chain

    Czech Academy of Sciences Publication Activity Database

    Tkáč, V.; Orendáčová, A.; Orendáč, M.; Legut, Dominik; Tibenská, K.; Feher, A.; Poirier, M.; Meisel, M. W.

    2012-01-01

    Roč. 121, 5-6 (2012), s. 1098-1101 ISSN 0587-4246. [European Conference on Physics of Magnetism (PM). Poznaň, 27.06.2011-01.07.2011] Institutional support: RVO:68081723 Keywords : thermal transport * lattice specif heat * phonons * ab initio * Debye model Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 0.531, year: 2012

  16. 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

  17. Peroxisome protein transportation affects metabolism of branched-chain fatty acids that critically impact growth and development of C. elegans.

    Directory of Open Access Journals (Sweden)

    Rencheng Wang

    Full Text Available The impact of specific lipid molecules, including fatty acid variants, on cellular and developmental regulation is an important research subject that remains under studied. Monomethyl branched-chain fatty acids (mmBCFAs are commonly present in multiple organisms including mammals, however our understanding of mmBCFA functions is very limited. C. elegans has been the premier model system to study the functions of mmBCFAs and their derived lipids, as mmBCFAs have been shown to play essential roles in post-embryonic development in this organism. To understand more about the metabolism of mmBCFAs in C. elegans, we performed a genetic screen for suppressors of the L1 developmental arrest phenotype caused by mmBCFA depletion. Extensive characterization of one suppressor mutation identified prx-5, which encodes an ortholog of the human receptor for the type-1 peroxisomal targeting signal protein. Our study showed that inactivating prx-5 function compromised the peroxisome protein import, resulting in an increased level of branched-chain fatty acid C17ISO in animals lacking normal mmBCFA synthesis, thereby restoring wild-type growth and development. This work reveals a novel connection between peroxisomal functions and mmBCFA metabolism.

  18. Response of Lemna minor L. to short-term cobalt exposure: The effect on photosynthetic electron transport chain and induction of oxidative damage

    Energy Technology Data Exchange (ETDEWEB)

    Begović, Lidija, E-mail: lbegovic@biologija.unios.hr [Josip Juraj Strossmayer University of Osijek, Department of Biology, Ulica cara Hadrijana 8/A, H R -31000 Osijek (Croatia); Mlinarić, Selma, E-mail: smlinaric@biologija.unios.hr [Josip Juraj Strossmayer University of Osijek, Department of Biology, Ulica cara Hadrijana 8/A, H R -31000 Osijek (Croatia); Antunović Dunić, Jasenka, E-mail: jantunovic@biologija.unios.hr [Josip Juraj Strossmayer University of Osijek, Department of Biology, Ulica cara Hadrijana 8/A, H R -31000 Osijek (Croatia); Katanić, Zorana, E-mail: zkatanic@biologija.unios.hr [Josip Juraj Strossmayer University of Osijek, Department of Biology, Ulica cara Hadrijana 8/A, H R -31000 Osijek (Croatia); Lončarić, Zdenko, E-mail: zdenko.loncaric@pfos.hr [Faculty of Agriculture, Josip Juraj Strossmayer University of Osijek, Ulica kralja Petra Svačića 1d, H R -31000 Osijek (Croatia); Lepeduš, Hrvoje, E-mail: hlepedus@yahoo.com [Faculty of Humanities and Social Sciences, Josip Juraj Strossmayer University of Osijek, Lorenza Jägera 9, HR-31000 Osijek (Croatia); Cesar, Vera, E-mail: vcesarus@yahoo.com [Josip Juraj Strossmayer University of Osijek, Department of Biology, Ulica cara Hadrijana 8/A, H R -31000 Osijek (Croatia)

    2016-06-15

    Highlights: • Cobalt (Co{sup 2+}) impaired the function of oxygen evolving complex (OEC) in L. minor L. • Electron transport through PSII components varied depending on Co{sup 2+} concentration. • K-band was proven to be suitable parameter for investigation of Co{sup 2+} toxicity. • Increased lipid peroxidation level showed early oxidative damage induced by Co{sup 2+}. - Abstract: The effect of two concentrations of cobalt (Co{sup 2+}) on photosynthetic activity and antioxidative response in Lemna minor L. were assessed 24, 48 and 72 h after the start of the exposure. Higher concentration of cobalt (1 mM) induced growth inhibition while lower concentration (0.01 mM) increased photosynthetic pigments content. Analysis of chlorophyll a fluorescence transients revealed high sensitivity of photosystem II primary photochemistry to excess of Co{sup 2+} especially at the higher concentration where decreased electron transport beyond primary quinone acceptor Q{sub A}{sup −} and impaired function of oxygen evolving complex (OEC) was observed. Due to impairment of OEC, oxygen production was decreased at higher Co{sup 2+} concentration. Activity of superoxide dismutase was mainly inhibited while lipid peroxidation increased, at both concentrations, indicating that cobalt-induced oxidative damage after short exposure and moreover, susceptibility of the membranes in the cell to cobalt toxicity. Results obtained in this study suggest possible application of used parameters as tools in assessment of early damage caused by metals.

  19. Response of Lemna minor L. to short-term cobalt exposure: The effect on photosynthetic electron transport chain and induction of oxidative damage

    International Nuclear Information System (INIS)

    Begović, Lidija; Mlinarić, Selma; Antunović Dunić, Jasenka; Katanić, Zorana; Lončarić, Zdenko; Lepeduš, Hrvoje; Cesar, Vera

    2016-01-01

    Highlights: • Cobalt (Co"2"+) impaired the function of oxygen evolving complex (OEC) in L. minor L. • Electron transport through PSII components varied depending on Co"2"+ concentration. • K-band was proven to be suitable parameter for investigation of Co"2"+ toxicity. • Increased lipid peroxidation level showed early oxidative damage induced by Co"2"+. - Abstract: The effect of two concentrations of cobalt (Co"2"+) on photosynthetic activity and antioxidative response in Lemna minor L. were assessed 24, 48 and 72 h after the start of the exposure. Higher concentration of cobalt (1 mM) induced growth inhibition while lower concentration (0.01 mM) increased photosynthetic pigments content. Analysis of chlorophyll a fluorescence transients revealed high sensitivity of photosystem II primary photochemistry to excess of Co"2"+ especially at the higher concentration where decreased electron transport beyond primary quinone acceptor Q_A"− and impaired function of oxygen evolving complex (OEC) was observed. Due to impairment of OEC, oxygen production was decreased at higher Co"2"+ concentration. Activity of superoxide dismutase was mainly inhibited while lipid peroxidation increased, at both concentrations, indicating that cobalt-induced oxidative damage after short exposure and moreover, susceptibility of the membranes in the cell to cobalt toxicity. Results obtained in this study suggest possible application of used parameters as tools in assessment of early damage caused by metals.

  20. 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.

  1. Designing E-learning Model to Learn About Transportation Management System to Support Supply Chain Management with Simulation Problems

    OpenAIRE

    Wiyono, Didiek Sri; Pribadi, Sidigdoyo; Permana, Ryan

    2011-01-01

    Focus of this research is designing Transportation Management System (TMS) as e-learning media for logistic education. E-learning is the use of Internet technologies to enhance knowledge and performance. E-learning technologies offer learners control over content, learning sequence, pace of learning, time, and often media, allowing them to tailor their experiences to meet their personal learning objectives. E-learning appears to be at least as effective as classical lectures. Students do not ...

  2. Characterizing Oregon's supply chains.

    Science.gov (United States)

    2013-03-01

    In many regions throughout the world, freight models are used to aid infrastructure investment and : policy decisions. Since freight is such an integral part of efficient supply chains, more realistic : transportation models can be of greater assista...

  3. Supply chain components

    OpenAIRE

    Vieraşu, T.; Bălăşescu, M.

    2011-01-01

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

  4. Supply chain components

    Directory of Open Access Journals (Sweden)

    Vieraşu, T.

    2011-01-01

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

  5. Opinion: the red-light response of stomatal movement is sensed by the redox state of the photosynthetic electron transport chain.

    Science.gov (United States)

    Busch, Florian A

    2014-02-01

    Guard cells regulate CO2 uptake and water loss of a leaf by controlling stomatal movement in response to environmental factors such as CO2, humidity, and light. The mechanisms by which stomata respond to red light are actively debated in the literature, and even after decades of research it is still controversial whether stomatal movement is related to photosynthesis or not. This review summarizes the current knowledge of the red-light response of stomata. A comparison of published evidence suggests that stomatal movement is controlled by the redox state of photosynthetic electron transport chain components, in particular the redox state of plastoquinone. Potential consequences for the modeling of stomatal conductance are discussed.

  6. 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...

  7. Absence of high-temperature ballistic transport in the spin-1/2 XXX chain within the grand-canonical ensemble

    Science.gov (United States)

    Carmelo, J. M. P.; Prosen, T.

    2017-01-01

    Whether in the thermodynamic limit, vanishing magnetic field h → 0, and nonzero temperature the spin stiffness of the spin-1/2 XXX Heisenberg chain is finite or vanishes within the grand-canonical ensemble remains an unsolved and controversial issue, as different approaches yield contradictory results. Here we provide an upper bound on the stiffness and show that within that ensemble it vanishes for h → 0 in the thermodynamic limit of chain length L → ∞, at high temperatures T → ∞. Our approach uses a representation in terms of the L physical spins 1/2. For all configurations that generate the exact spin-S energy and momentum eigenstates such a configuration involves a number 2S of unpaired spins 1/2 in multiplet configurations and L - 2 S spins 1/2 that are paired within Msp = L / 2 - S spin-singlet pairs. The Bethe-ansatz strings of length n = 1 and n > 1 describe a single unbound spin-singlet pair and a configuration within which n pairs are bound, respectively. In the case of n > 1 pairs this holds both for ideal and deformed strings associated with n complex rapidities with the same real part. The use of such a spin 1/2 representation provides useful physical information on the problem under investigation in contrast to often less controllable numerical studies. Our results provide strong evidence for the absence of ballistic transport in the spin-1/2 XXX Heisenberg chain in the thermodynamic limit, for high temperatures T → ∞, vanishing magnetic field h → 0 and within the grand-canonical ensemble.

  8. Absence of high-temperature ballistic transport in the spin-1/2 XXX chain within the grand-canonical ensemble

    Directory of Open Access Journals (Sweden)

    J.M.P. Carmelo

    2017-01-01

    Full Text Available Whether in the thermodynamic limit, vanishing magnetic field h→0, and nonzero temperature the spin stiffness of the spin-1/2 XXX Heisenberg chain is finite or vanishes within the grand-canonical ensemble remains an unsolved and controversial issue, as different approaches yield contradictory results. Here we provide an upper bound on the stiffness and show that within that ensemble it vanishes for h→0 in the thermodynamic limit of chain length L→∞, at high temperatures T→∞. Our approach uses a representation in terms of the L physical spins 1/2. For all configurations that generate the exact spin-S energy and momentum eigenstates such a configuration involves a number 2S of unpaired spins 1/2 in multiplet configurations and L−2S spins 1/2 that are paired within Msp=L/2−S spin–singlet pairs. The Bethe-ansatz strings of length n=1 and n>1 describe a single unbound spin–singlet pair and a configuration within which n pairs are bound, respectively. In the case of n>1 pairs this holds both for ideal and deformed strings associated with n complex rapidities with the same real part. The use of such a spin 1/2 representation provides useful physical information on the problem under investigation in contrast to often less controllable numerical studies. Our results provide strong evidence for the absence of ballistic transport in the spin-1/2 XXX Heisenberg chain in the thermodynamic limit, for high temperatures T→∞, vanishing magnetic field h→0 and within the grand-canonical ensemble.

  9. 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.

  10. Very-long-chain fatty acid biosynthesis is inhibited by cafenstrole, N,N-diethyl-3-mesitylsulfonyl-1H-1,2,4-triazole-1-carboxamide and its analogs

    Energy Technology Data Exchange (ETDEWEB)

    Takahashi, H.; Ohki, A.; Sato, Y.; Wakabayashi, K. [Tamagawa Univ., Tokyo (Japan). Graduate School of Agricultural Science; Kanzaki, M. [Regulatory Affairs Dept., Chugai Pharmaceutical Co. Ltd., Tokyo (Japan); Tanaka, A. [Showa Univ., Tokyo (Japan). School of Pharmaceutical Sciences; Matthes, B.; Boeger, P. [Konstanz Univ. (Germany). Lehrstuhl fuer Physiologie und Biochemie der Pflanzen

    2001-10-01

    The rice herbicide cafenstrole and its analogs inhibited the incorporation of [1-{sup 14}C]-oleate and [2-{sup 14}C]-malonate into very-long-chain fatty acids (VLCFAs), using Scenedesmus cells and leek microsomes from Allium porrum. Although the precise mode of interaction of cafenstrole at the molecular level is not completely clarified by the present study, it is concluded that cafenstrole acts as a specific inhibitor of the microsomal elongase enzyme involved in the biosynthesis of fatty acids with alkyl chains longer than C{sub 18}. For a strong VLCFA biosynthesis inhibition an -SO{sub 2}- linkage of the 1,2,4-triazole-1-carboxamides was required. Furthermore, N,N-dialkyl substitution of the carbamoyl nitrogen and electron-donating groups such as methyl at the benzene ring of 1,2,4-triazole-1-carboxamides produced a strong inhibition of VLCFA formation. A correlation was found between the phytotoxic effect against barnyardgrass (Echinochloa oryzicola) and impaired VLCFA formation. (orig.)

  11. 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.)

  12. 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.

  13. 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.

  14. Electronic Interactions of n-Doped Perylene Diimide Groups Appended to Polynorbornene Chains: Implications for Electron Transport in Organic Electronics.

    Science.gov (United States)

    Nguyen, Minh T; Biberdorf, Joshua D; Holliday, Bradley J; Jones, Richard A

    2017-11-01

    A polymer consisting of a polynorbornene backbone with perylene diimide (PDI) pendant groups on each monomeric unit is synthesized via ring opening metathesis polymerization. The PDI pendant groups along the polymer backbone, studied by UV-vis absorption, fluorescence emission, and electron paramagnetic resonance spectroscopy in addition to electrochemical methods, show evidence of molecular aggregation and corresponding electronic coupling with neighboring groups, which forms pathways for efficient electron transport from one group to another in a specific reduced form. When n-doped, the title polymer shows redox conductivity of 5.4 × 10 -3 S cm -1 , comparable with crystalline PDI materials, and is therefore a promising material for use in organic electronics. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  15. Component identification of electron transport chains in curdlan-producing Agrobacterium sp. ATCC 31749 and its genome-specific prediction using comparative genome and phylogenetic trees analysis.

    Science.gov (United States)

    Zhang, Hongtao; Setubal, Joao Carlos; Zhan, Xiaobei; Zheng, Zhiyong; Yu, Lijun; Wu, Jianrong; Chen, Dingqiang

    2011-06-01

    Agrobacterium sp. ATCC 31749 (formerly named Alcaligenes faecalis var. myxogenes) is a non-pathogenic aerobic soil bacterium used in large scale biotechnological production of curdlan. However, little is known about its genomic information. DNA partial sequence of electron transport chains (ETCs) protein genes were obtained in order to understand the components of ETC and genomic-specificity in Agrobacterium sp. ATCC 31749. Degenerate primers were designed according to ETC conserved sequences in other reported species. DNA partial sequences of ETC genes in Agrobacterium sp. ATCC 31749 were cloned by the PCR method using degenerate primers. Based on comparative genomic analysis, nine electron transport elements were ascertained, including NADH ubiquinone oxidoreductase, succinate dehydrogenase complex II, complex III, cytochrome c, ubiquinone biosynthesis protein ubiB, cytochrome d terminal oxidase, cytochrome bo terminal oxidase, cytochrome cbb (3)-type terminal oxidase and cytochrome caa (3)-type terminal oxidase. Similarity and phylogenetic analyses of these genes revealed that among fully sequenced Agrobacterium species, Agrobacterium sp. ATCC 31749 is closest to Agrobacterium tumefaciens C58. Based on these results a comprehensive ETC model for Agrobacterium sp. ATCC 31749 is proposed.

  16. 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.

  17. 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...

  18. Response of Lemna minor L. to short-term cobalt exposure: The effect on photosynthetic electron transport chain and induction of oxidative damage.

    Science.gov (United States)

    Begović, Lidija; Mlinarić, Selma; Antunović Dunić, Jasenka; Katanić, Zorana; Lončarić, Zdenko; Lepeduš, Hrvoje; Cesar, Vera

    2016-06-01

    The effect of two concentrations of cobalt (Co(2+)) on photosynthetic activity and antioxidative response in Lemna minor L. were assessed 24, 48 and 72h after the start of the exposure. Higher concentration of cobalt (1mM) induced growth inhibition while lower concentration (0.01mM) increased photosynthetic pigments content. Analysis of chlorophyll a fluorescence transients revealed high sensitivity of photosystem II primary photochemistry to excess of Co(2+) especially at the higher concentration where decreased electron transport beyond primary quinone acceptor QA(-) and impaired function of oxygen evolving complex (OEC) was observed. Due to impairment of OEC, oxygen production was decreased at higher Co(2+) concentration. Activity of superoxide dismutase was mainly inhibited while lipid peroxidation increased, at both concentrations, indicating that cobalt-induced oxidative damage after short exposure and moreover, susceptibility of the membranes in the cell to cobalt toxicity. Results obtained in this study suggest possible application of used parameters as tools in assessment of early damage caused by metals. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. 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

  20. 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.

  1. Metastasis-associated protein Mts1 (S100A4) inhibits CK2-mediated phosphorylation and self-assembly of the heavy chain of nonmuscle myosin

    DEFF Research Database (Denmark)

    Kriajevska, M; Bronstein, I B; Scott, D J

    2000-01-01

    a regulatory role in the myosin assembly. In the presence of calcium, Mts1 binds at the C-terminal end of the myosin heavy chain close to the site of phosphorylation by protein kinase CK2 (Ser1944). In the present study, we have shown that interaction of Mts1 with the human platelet myosin or C...

  2. Shewanella oneidensis MR-1 chemotaxis proteins and electron-transport chain components essential for congregation near insoluble electron acceptors.

    Science.gov (United States)

    Harris, H Wayne; El-Naggar, Mohamed Y; Nealson, Kenneth H

    2012-12-01

    Shewanella oneidensis MR-1 cells utilize a behaviour response called electrokinesis to increase their speed in the vicinity of IEAs (insoluble electron acceptors), including manganese oxides, iron oxides and poised electrodes [Harris, El-Naggar, Bretschger, Ward, Romine, Obraztsova and Nealson (2010) Proc. Natl. Acad. Sci. U.S.A. 107, 326-331]. However, it is not currently understood how bacteria remain in the vicinity of the IEA and accumulate both on the surface and in the surrounding medium. In the present paper, we provide results indicating that cells that have contacted the IEAs swim faster than those that have not recently made contact. In addition, fast-swimming cells exhibit an enhancement of swimming reversals leading to rapid non-random accumulation of cells on, and adjacent to, mineral particles. We call the observed accumulation near IEAs 'congregation'. Congregation is eliminated by the loss of a critical gene involved with EET (extracellular electron transport) (cymA, SO_4591) and is altered or eliminated in several deletion mutants of homologues of genes that are involved with chemotaxis or energy taxis in Escherichia coli. These genes include chemotactic signal transduction protein (cheA-3, SO_3207), methyl-accepting chemotaxis proteins with the Cache domain (mcp_cache, SO_2240) or the PAS (Per/Arnt/Sim) domain (mcp_pas, SO_1385). In the present paper, we report studies of S. oneidensis MR-1 that lend some insight into how microbes in this group can 'sense' the presence of a solid substrate such as a mineral surface, and maintain themselves in the vicinity of the mineral (i.e. via congregation), which may ultimately lead to attachment and biofilm formation.

  3. Anisotropic Transport of Electrons in a Novel FET Channel with Chains of InGaAs Nano-Islands Embedded along Quasi-Periodic Multi-Atomic Steps on Vicinal (111)B GaAs

    International Nuclear Information System (INIS)

    Akiyama, Y.; Kawazu, T.; Noda, T.; Sakaki, H.

    2010-01-01

    We have studied electron transport in n-AlGaAs/GaAs heterojunction FET channels, in which chains of InGaAs nano-islands are embedded along quasi-periodic steps. By using two samples, conductance G para (V g ) parallel to the steps and G perp (V g ) perpendicular to them were measured at 80 K as functions of gate voltage V g . At sufficiently high V g , G para at 80 K is several times as high as G perp , which manifests the anisotropic two-dimensional transport of electrons. When V g is reduced to -0.7 V, G perp almost vanishes, while Gpara stays sizable unless V g is set below -0.8 V. These results indicate that 'inter-chain' barriers play stronger roles than 'intra-chain' barriers.

  4. Editorial: Supply Chain Management

    Directory of Open Access Journals (Sweden)

    Dimitrios Aidonis

    2017-05-01

    Full Text Available This special issue has followed up the 3rd Olympus International Conference on Supply Chains held on Athens Metropolitan Expo, November 7 & 8 2015, Greece. The Conference was organized by the Department of Logistics Technological Educational Institute of Central Macedonia, in collaboration with the: a Laboratory of Quantitative Analysis, Logistics and Supply Chain Management of the Department of Mechanical Engineering, Aristotle University of Thessaloniki (AUTH, b Greek Association of Supply Chain Management (EEL of Northern Greece and the c Supply Chain & Logistics Journal. During the 2-Days Conference more than 60 research papers were presented covering the following thematic areas: (i Transportation, (ii Best Practices in Logistics, (iii Information and Communication Technologies in Supply Chain Management, (iv Food Logistics, (v New Trends in Business Logistics, and (vi Green Supply Chain Management. Three keynote invited speakers addressed interesting issues for the Operational Research, the Opportunities and Prospects of Greek Ports chaired Round Tables with other Greek and Foreign Scientists and Specialists.

  5. 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.

  6. 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

  7. THE DURATION OF BORDER CONTROL PROCEDURES RELATED TO THE HANDLING OF FREIGHT TRANSPORTED BY MEANS OF SEA-ROAD TRANSPORT CHAINS AS A COMPONENT IN COMPETITIVENESS OF THE POLISH SEAPORTS

    Directory of Open Access Journals (Sweden)

    Michał Pluciński

    2017-09-01

    Full Text Available The duration of border control procedures related to the handling of freight transported by means of sea-road transport chains has become a significant component in competitiveness of seaports. The situation in this regard, existing in the Polish seaports, which was unfavourable against the background of other seaports providing services to the same supply base, resulted in the fact that a significant part of freight, i.e. mainly general containerized cargo, was handled outside the Polish seaports. The situation began to change when amendments to the regulations related to VAT (2011 and the so called “Porty 24” Package (2014 were adopted. In majority of the customs offices located in the biggest Polish seaports both the duration of services provided in relation to customs declaration and the duration of the so called “collective customs clearance” were reduced. The number of customs declarations under the simplified procedure also rose significantly. Between 2007 and 2015 customs duties and taxes in relation to the sea-land handling in Gdańsk, Gdynia, Szczecin and Świnoujście rose more than threefold.

  8. 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.

  9. Sex hormones reduce NNK detoxification through inhibition of short-chain dehydrogenases/reductases and aldo-keto reductases in vitro.

    Science.gov (United States)

    Stapelfeld, Claudia; Maser, Edmund

    2017-10-01

    Carbonyl reduction is an important metabolic pathway for endogenous and xenobiotic substances. The tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, nicotine-derived nitrosamine ketone) is classified as carcinogenic to humans (IARC, Group 1) and considered to play the most important role in tobacco-related lung carcinogenesis. Detoxification of NNK through carbonyl reduction is catalyzed by members of the AKR- and the SDR-superfamilies which include AKR1B10, AKR1C1, AKR1C2, AKR1C4, 11β-HSD1 and CBR1. Because some reductases are also involved in steroid metabolism, five different hormones were tested for their inhibitory effect on NNK carbonyl reduction. Two of those hormones were estrogens (estradiol and ethinylestradiol), another two hormones belong to the gestagen group (progesterone and drospirenone) and the last tested hormone was an androgen (testosterone). Furthermore, one of the estrogens (ethinylestradiol) and one of the gestagens (drospirenone) are synthetic hormones, used as hormonal contraceptives. Five of six NNK reducing enzymes (AKR1B10, AKR1C1, AKR1C2, AKR1C4 and 11β-HSD1) were significantly inhibited by the tested sex hormones. Only NNK reduction catalyzed by CBR1 was not significantly impaired. In the case of the other five reductases, gestagens had remarkably stronger inhibitory effects at a concentration of 25 μM (progesterone: 66-88% inhibition; drospirenone: 26-87% inhibition) in comparison to estrogens (estradiol: 17-51% inhibition; ethinylestradiol: 14-79% inhibition) and androgens (14-78% inhibition). Moreover, in most cases the synthetic hormones showed a greater ability to inhibit NNK reduction than the physiologic derivatives. These results demonstrate that male and female sex hormones have different inhibitory potentials, thus indicating that there is a varying detoxification capacity of NNK in men and women which could result in a different risk for developing lung cancer. Copyright © 2017 Elsevier B

  10. Roles of the twin-arginine translocase and associated chaperones in the biogenesis of the electron transport chains of the human pathogen Campylobacter jejuni.

    Science.gov (United States)

    Hitchcock, Andrew; Hall, Stephen J; Myers, Jonathan D; Mulholland, Francis; Jones, Michael A; Kelly, David J

    2010-10-01

    The zoonotic pathogen Campylobacter jejuni NCTC 11168 uses a complex set of electron transport chains to ensure growth with a variety of electron donors and alternative electron acceptors, some of which are known to be important for host colonization. Many of the key redox proteins essential for electron transfer in this bacterium have N-terminal twin-arginine translocase (TAT) signal sequences that ensure their transport across the cytoplasmic membrane in a folded state. By comparisons of 2D gels of periplasmic extracts, gene fusions and specific enzyme assays in wild-type, tatC mutant and complemented strains, we experimentally verified the TAT dependence of 10 proteins with an N-terminal twin-arginine motif. NrfH, which has a TAT-like motif (LRRKILK), was functional in nitrite reduction in a tatC mutant, and was correctly rejected as a TAT substrate by the tatfind and TatP prediction programs. However, the hydrogenase subunit HydA is also rejected by tatfind, but was shown to be TAT-dependent experimentally. The YedY homologue Cj0379 is the only TAT translocated molybdoenzyme of unknown function in C. jejuni; we show that a cj0379c mutant is deficient in chicken colonization and has a nitrosative stress phenotype, suggestive of a possible role for Cj0379 in the reduction of reactive nitrogen species in the periplasm. Only two potential TAT chaperones, NapD and Cj1514, are encoded in the genome. Surprisingly, despite homology to TorD, Cj1514 was shown to be specifically required for the activity of formate dehydrogenase, not trimethylamine N-oxide reductase, and was designated FdhM.

  11. 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.

  12. 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.

  13. A liquefied energy chain for transport and utilization of natural gas for power production with CO2 capture and storage - Part 2: The offshore and the onshore processes

    International Nuclear Information System (INIS)

    Aspelund, Audun; Gundersen, Truls

    2009-01-01

    A novel energy and cost effective transport chain for stranded natural gas utilized for power production with CO 2 capture and storage is developed. It includes an offshore section, a combined gas carrier, and an integrated receiving terminal. In the offshore process, natural gas (NG) is liquefied to LNG by liquid carbon dioxide (LCO 2 ) and liquid inert nitrogen (LIN), which are used as cold carriers. The offshore process is self-supported with power, hot and cold utilities and can operate with little rotating equipment and without flammable refrigerants. In the onshore process, the cryogenic exergy in LNG is used to cool and liquefy the cold carriers, which reduces the power requirement to 319 kWh/tonne LNG. Pinch and exergy analyses are used to determine thermodynamically optimized offshore and onshore processes with exergy efficiencies of 87% and 71%, respectively. There are very low emissions from the processes. The estimated specific costs for the offshore and onshore process are 8.0 and 14.6 EUR per tonne LNG, respectively, excluding energy costs. With an electricity price of 100 EUR per MWh, the specific cost of energy in the onshore process is 31.9 EUR per tonne LNG

  14. Electron transport chain dysfunction by H(2)O (2) is linked to increased reactive oxygen species production and iron mobilization by lipoperoxidation: studies using Saccharomyces cerevisiae mitochondria.

    Science.gov (United States)

    Cortés-Rojo, Christian; Estrada-Villagómez, Mirella; Calderón-Cortés, Elizabeth; Clemente-Guerrero, Mónica; Mejía-Zepeda, Ricardo; Boldogh, Istvan; Saavedra-Molina, Alfredo

    2011-04-01

    The mitochondrial electron transport chain (ETC) contains thiol groups (-SH) which are reversibly oxidized to modulate ETC function during H(2)O(2) overproduction. Since deleterious effects of H(2)O(2) are not limited to -SH oxidation, due to the formation of other H(2)O(2)-derived species, some processes like lipoperoxidation could enhance the effects of H(2)O(2) over ETC enzymes, disrupt their modulation by -SH oxidation and increase superoxide production. To verify this hypothesis, we tested the effects of H(2)O(2) on ETC activities, superoxide production and iron mobilization in mitochondria from lipoperoxidation-resistant native yeast and lipoperoxidation-sensitized yeast. Only complex III activity from lipoperoxidation-sensitive mitochondria exhibited a higher susceptibility to H(2)O(2) and increased superoxide production. The recovery of ETC activity by the thiol reductanct β-mercaptoethanol (BME) was also altered at complex III, and a role was attributed to lipoperoxidation, the latter being also responsible for iron release. A hypothetical model linking lipoperoxidation, increased complex III damage, superoxide production and iron release is given.

  15. Initiation of electron transport chain activity in the embryonic heart coincides with the activation of mitochondrial complex 1 and the formation of supercomplexes.

    Science.gov (United States)

    Beutner, Gisela; Eliseev, Roman A; Porter, George A

    2014-01-01

    Mitochondria provide energy in form of ATP in eukaryotic cells. However, it is not known when, during embryonic cardiac development, mitochondria become able to fulfill this function. To assess this, we measured mitochondrial oxygen consumption and the activity of the complexes (Cx) 1 and 2 of the electron transport chain (ETC) and used immunoprecipitation to follow the generation of mitochondrial supercomplexes. We show that in the heart of mouse embryos at embryonic day (E) 9.5, mitochondrial ETC activity and oxidative phosphorylation (OXPHOS) are not coupled, even though the complexes are present. We show that Cx-1 of the ETC is able to accept electrons from the Krebs cycle, but enzyme assays that specifically measure electron flow to ubiquinone or Cx-3 show no activity at this early embryonic stage. At E11.5, mitochondria appear functionally more mature; ETC activity and OXPHOS are coupled and respond to ETC inhibitors. In addition, the assembly of highly efficient respiratory supercomplexes containing Cx-1, -3, and -4, ubiquinone, and cytochrome c begins at E11.5, the exact time when Cx-1 becomes functional activated. At E13.5, ETC activity and OXPHOS of embryonic heart mitochondria are indistinguishable from adult mitochondria. In summary, our data suggest that between E9.5 and E11.5 dramatic changes occur in the mitochondria of the embryonic heart, which result in an increase in OXPHOS due to the activation of complex 1 and the formation of supercomplexes.

  16. Developmental and hormone-induced changes of mitochondrial electron transport chain enzyme activities during the last instar larval development of maize stem borer, Chilo partellus (Lepidoptera: Crambidae).

    Science.gov (United States)

    VenkatRao, V; Chaitanya, R K; Naresh Kumar, D; Bramhaiah, M; Dutta-Gupta, A

    2016-12-01

    The energy demand for structural remodelling in holometabolous insects is met by cellular mitochondria. Developmental and hormone-induced changes in the mitochondrial respiratory activity during insect metamorphosis are not well documented. The present study investigates activities of enzymes of mitochondrial electron transport chain (ETC) namely, NADH:ubiquinone oxidoreductase or complex I, Succinate: ubiquinone oxidoreductase or complex II, Ubiquinol:ferricytochrome c oxidoreductase or complex III, cytochrome c oxidase or complex IV and F 1 F 0 ATPase (ATPase), during Chilo partellus development. Further, the effect of juvenile hormone (JH) analog, methoprene, and brain and corpora-allata-corpora-cardiaca (CC-CA) homogenates that represent neurohormones, on the ETC enzyme activities was monitored. The enzymatic activities increased from penultimate to last larval stage and thereafter declined during pupal development with an exception of ATPase which showed high enzyme activity during last larval and pupal stages compared to the penultimate stage. JH analog, methoprene differentially modulated ETC enzyme activities. It stimulated complex I and IV enzyme activities, but did not alter the activities of complex II, III and ATPase. On the other hand, brain homogenate declined the ATPase activity while the injected CC-CA homogenate stimulated complex I and IV enzyme activities. Cumulatively, the present study is the first to show that mitochondrial ETC enzyme system is under hormone control, particularly of JH and neurohormones during insect development. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Acidic pH and short-chain fatty acids activate Na+ transport but differentially modulate expression of Na+/H+ exchanger isoforms 1, 2, and 3 in omasal epithelium.

    Science.gov (United States)

    Lu, Zhongyan; Yao, Lei; Jiang, Zhengqian; Aschenbach, Jörg R; Martens, Holger; Shen, Zanming

    2016-01-01

    Low sodium content in feed and large amounts of salivary sodium secretion are essential requirements to efficient sodium reabsorption in the dairy cow. It is already known that Na(+)/H(+) exchange (NHE) of the ruminal epithelium plays a key role in Na(+) absorption, and its function is influenced by the presence of short-chain fatty acids (SCFA) and mucosal pH. By contrast, the functional role and regulation of NHE in omasal epithelium have not been completely understood. In the present study, we used model studies in small ruminants (sheep and goats) to investigate NHE-mediated Na(+) transport and the effects of pH and SCFA on NHE activity in omasal epithelium and on the expression of NHE isoform in omasal epithelial cells. Conventional Ussing chamber technique, primary cell culture, quantitative PCR, and Western blot were used. In native omasal epithelium of sheep, the Na(+) transport was electroneutral, and it was inhibited by the specific NHE3 inhibitor 3-[2-(3-guanidino-2-methyl-3-oxo-propenyl)-5-methyl-phenyl]-N-isopropylidene-2-methyl-acrylamide dihydrochloride, which decreased mucosal-to-serosal, serosal-to-mucosal, and net flux rates of Na(+) by 80% each. The application of low mucosal pH (6.4 or 5.8) in the presence of SCFA activated the Na(+) transport across omasal epithelium of sheep compared with that at pH 7.4. In cultured omasal epithelial cells of goats, mRNA and protein of NHE1, NHE2, and NHE3 were detected. The application of SCFA increased NHE1 mRNA and protein expression, which was most prominent when the culture medium pH decreased from 7.4 to 6.8. At variance, the mRNA and protein expression of NHE2 and NHE3 were decreased with low pH and SCFA, which was contrary to the published data from ruminal epithelial studies. In conclusion, this paper shows that (1) NHE1, NHE2, and NHE3 are expressed in omasal epithelium; (2) NHE3 mediates the major portion of transepithelial Na(+) transport in omasal epithelium; and (3) SCFA and acidic pH acutely

  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. L-tryptophan-induced electron transport across supported lipid bilayers: an alkyl-chain tilt-angle, and bilayer-symmetry dependence.

    Science.gov (United States)

    Sarangi, Nirod Kumar; Patnaik, Archita

    2012-12-21

    Molecular orientation-dependent electron transport across supported 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) lipid bilayers (SLBs) on semiconducting indium tin oxide (ITO) is reported with an aim towards potential nanobiotechnological applications. A bifunctional strategy is adopted to form symmetric and asymmetric bilayers of DPPC that interact with L-tryptophan, and are analyzed by surface manometry and atomic force microscopy. Polarization-dependent real-time Fourier transform infrared reflection absorption spectroscopy (FT-IRRAS) analysis of these SLBs reveals electrostatic, hydrogen-bonding, and cation-π interactions between the polar head groups of the lipid and the indole side chains. Consequently, a molecular tilt arises from the effective interface dipole, facilitating electron transport across the ITO-anchored SLBs in the presence of an internal Fe(CN)(6)(4-/3-) redox probe. The incorporation of tryptophan enhances the voltammetric features of the SLBs. The estimated electron-transfer rate constants for symmetric and asymmetric bilayers (k(s) = 2.0×10(-2) and 2.8×10(-2) s(-1)) across the two-dimensional (2D) ordered DPPC/tryptophan SLBs are higher compared to pure DPPC SLBs (k(s) = 3.2×10(-3) and 3.9×10(-3) s(-1)). In addition, they are molecular tilt-dependent, as it is the case with the standard apparent rate constants k(app)(0), estimated from electrochemical impedance spectroscopy and bipotentiostatic experiments with a Pt ultramicroelectrode. Lower magnitudes of k(s) and k(app)(0) imply that electrochemical reactions across the ITO-SLB electrodes are kinetically limited and consequently governed by electron tunneling across the SLBs. Standard theoretical rate constants (k(th)(0)) accrued upon electron tunneling comply with the potential-independent electron-tunneling coefficient β = 0.15 Å(-1). Insulator-semiconductor transitions moving from a liquid-expanded to a condensed 2D-phase state of the SLBs are noted, adding a new dimension

  20. A monoclonal antibody against PDGF B-chain inhibits PDGF-induced DNA synthesis in C3H fibroblasts and prevents binding of PDGF to its receptor.

    Science.gov (United States)

    Vassbotn, F S; Langeland, N; Hagen, I; Holmsen, H

    1990-09-01

    A monoclonal antibody (MAb 6D11) against platelet-derived growth factor (PDGF) was studied. We found that the MAb 6D11 in concentrations equimolar to PDGF blocked the [3H]thymidine incorporation in C3H/10T1/2 C18 fibroblasts stimulated by PDGF B-B and PDGF A-B. This inhibition was overcome by high doses of PDGF. The [3H]thymidine incorporation stimulated by other growth factors (aFGF, bFGF and bombesin) was not inhibited by the antibody. The MAb 6D11 blocked receptor binding of PDGF B-B, but not PDGF A-A. These findings suggest that the MAb 6D11 abolishes PDGF-induced DNA synthesis by blocking PDGF receptor binding. In this communication we demonstrate an isoform-specific monoclonal antibody against PDGF.

  1. 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.

  2. 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

  3. Intermodal Supply Chain Risk Management

    OpenAIRE

    Maslarić, Marinko; Brnjac, Nikolina; Bago, Drago

    2016-01-01

    Efficient and secure global supply chains contribute to the Improvement of the competitiveness of the products traded on international markets by reducing their costs and delivery time while increasing the reliability and security. Global supply chains are unthinkable without transport integration, which is usually accomplished through the form of intermodal transport systems. Intermodal transport systems are much more complex than the unimodal ones due to the number of stakeholders, included...

  4. 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.

  5. 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....

  6. 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.

  7. 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

  8. 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...

  9. 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

  10. 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

  11. 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...

  12. 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.

  13. 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.

  14. 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.

  15. Reduced expression of mitochondrial electron transport chain proteins from hibernating hearts relative to ischemic preconditioned hearts in the second window of protection.

    Science.gov (United States)

    Cabrera, Jesús A; Butterick, Tammy A; Long, Eric K; Ziemba, Elizabeth A; Anderson, Lorraine B; Duffy, Cayla M; Sluiter, Willem; Duncker, Dirk J; Zhang, Jianyi; Chen, Yingjie; Ward, Herbert B; Kelly, Rosemary F; McFalls, Edward O

    2013-07-01

    Although protection against necrosis has been observed in both hibernating (HIB) and ischemic preconditioned hearts in the second window of protection (SWOP), a comparison of the mitochondrial proteome between the two entities has not been previously performed. Anesthetized swine underwent instrumentation with a fixed constrictor around the LAD artery and were followed for 12 weeks (HIB; N=7). A second group of anesthetized swine underwent ischemic preconditioning by inflating a balloon within the LAD artery 10 times for 2 min, each separated by 2 min reperfusion and were sacrificed 24h later (SWOP; N=7). Myocardial blood flow and high-energy nucleotides were obtained in the LAD region and normalized to remote regions. Post-sacrifice, protein content as measured with iTRAQ was compared in isolated mitochondria from the LAD area of a Sham heart. Basal regional blood flow in the LAD region when normalized to the remote region was 0.86±0.04 in HIB and 1.02±0.02 in SWOP tissue (Pregional blood flows in HIB hearts, ATP content in the LAD region, when normalized to the remote region was similar in HIB versus SWOP (1.06±0.06 and 1.02±0.05 respectively; NS) as was the transmural phosphocreatine (PCr) to ATP ratio (2.1±0.2 and 2.2±0.2 respectively; NS). Using iTRAQ, 64 common proteins were identified in HIB and SWOP hearts. Compared with SWOP, the relative abundance of mitochondrial proteins involved with electron transport chain (ETC) were reduced in HIB including NADH dehydrogenase, Cytochrome c reductase and oxidase, ATP synthase, and nicotinamide nucleotide transhydrogenase. Within chronically HIB heart tissue with reduced blood flow, the relative abundance of mitochondrial ETC proteins is decreased when compared with SWOP tissue. These data support the concept that HIB heart tissue subjected to chronically reduced blood flow is associated with a down-regulation in the expression of key mitochondrial proteins involved in electron transport. Published by Elsevier

  16. Modulation of redox regulatory molecules and electron transport chain activity in muscle of air breathing fish Heteropneustes fossilis under air exposure stress.

    Science.gov (United States)

    Paital, Biswaranjan

    2014-01-01

    Responses of redox regulatory system to long-term survival (>18 h) of the catfish Heteropneustes fossilis in air are not yet understood. Lipid and protein oxidation level, oxidant (H2O2) generation, antioxidative status (levels of superoxide dismutase, catalase, glutathione peroxidase and reductase, ascorbic acid and non-protein sulfhydryl) and activities of respiratory complexes (I, II, III and IV) in mitochondria were investigated in muscle of H. fossilis under air exposure condition (0, 3, 6, 12 and 18 h at 25 °C). The increased levels of both H2O2 and tissue oxidation were observed due to the decreased activities of antioxidant enzymes in muscle under water deprivation condition. However, ascorbic acid and non-protein thiol groups were the highest at 18 h air exposure time. A linear increase in complex II activity with air exposure time and an increase up to 12 h followed by a decrease in activity of complex I at 18 h were observed. Negative correlation was observed for complex III and V activity with exposure time. Critical time to modulate the above parameters was found to be 3 h air exposure. Dehydration induced oxidative stress due to modulation of electron transport chain and redox metabolizing enzymes in muscle of H. fossilis was clearly observed. Possible contribution of redox regulatory system in muscle tissue of the fish for long-term survival in air is elucidated. Results of the present study may be useful to understand the redox metabolism in muscle of fishes those are exposed to air in general and air breathing fishes in particular.

  17. Electron Transport Chain Is Biochemically Linked to Pilus Assembly Required for Polymicrobial Interactions and Biofilm Formation in the Gram-Positive Actinobacterium Actinomyces oris

    Directory of Open Access Journals (Sweden)

    Belkys C. Sanchez

    2017-06-01

    Full Text Available The Gram-positive actinobacteria Actinomyces spp. are key colonizers in the development of oral biofilms due to the inherent ability of Actinomyces to adhere to receptor polysaccharides on the surface of oral streptococci and host cells. This receptor-dependent bacterial interaction, or coaggregation, requires a unique sortase-catalyzed pilus consisting of the pilus shaft FimA and the coaggregation factor CafA forming the pilus tip. While the essential role of the sortase machine SrtC2 in pilus assembly, biofilm formation, and coaggregation has been established, little is known about trans-acting factors contributing to these processes. We report here a large-scale Tn5 transposon screen for mutants defective in Actinomyces oris coaggregation with Streptococcus oralis. We obtained 33 independent clones, 13 of which completely failed to aggregate with S. oralis, and the remainder of which exhibited a range of phenotypes from severely to weakly defective coaggregation. The former had Tn5 insertions in fimA, cafA, or srtC2, as expected; the latter were mapped to genes coding for uncharacterized proteins and various nuo genes encoding the NADH dehydrogenase subunits. Electron microscopy and biochemical analyses of mutants with nonpolar deletions of nuo genes and ubiE, a menaquinone C-methyltransferase-encoding gene downstream of the nuo locus, confirmed the pilus and coaggregation defects. Both nuoA and ubiE mutants were defective in oxidation of MdbA, the major oxidoreductase required for oxidative folding of pilus proteins. Furthermore, supplementation of the ubiE mutant with exogenous menaquinone-4 rescued the cell growth and pilus defects. Altogether, we propose that the A. oris electron transport chain is biochemically linked to pilus assembly via oxidative protein folding.

  18. Pre-silencing of genes involved in the electron transport chain (ETC) pathway is associated with responsiveness to abatacept in rheumatoid arthritis.

    Science.gov (United States)

    Derambure, C; Dzangue-Tchoupou, G; Berard, C; Vergne, N; Hiron, M; D'Agostino, M A; Musette, P; Vittecoq, O; Lequerré, T

    2017-05-25

    In the current context of personalized medicine, one of the major challenges in the management of rheumatoid arthritis (RA) is to identify biomarkers that predict drug responsiveness. From the European APPRAISE trial, our main objective was to identify a gene expression profile associated with responsiveness to abatacept (ABA) + methotrexate (MTX) and to understand the involvement of this signature in the pathophysiology of RA. Whole human genome microarrays (4 × 44 K) were performed from a first subset of 36 patients with RA. Data validation by quantitative reverse-transcription (qRT)-PCR was performed from a second independent subset of 32 patients with RA. Gene Ontology and WikiPathways database allowed us to highlight the specific biological mechanisms involved in predicting response to ABA/MTX. From the first subset of 36 patients with RA, a combination including 87 transcripts allowed almost perfect separation between responders and non-responders to ABA/MTX. Next, the second subset of patients 32 with RA allowed validation by qRT-PCR of a minimal signature with only four genes. This latter signature categorized 81% of patients with RA with 75% sensitivity, 85% specificity and 85% negative predictive value. This combination showed a significant enrichment of genes involved in electron transport chain (ETC) pathways. Seven transcripts from ETC pathways (NDUFA6, NDUFA4, UQCRQ, ATP5J, COX7A2, COX7B, COX6A1) were significantly downregulated in responders versus non-responders to ABA/MTX. Moreover, dysregulation of these genes was independent of inflammation and was specific to ABA response. Pre-silencing of ETC genes is associated with future response to ABA/MTX and might be a crucial key to susceptibility to ABA response.

  19. Falling chains

    OpenAIRE

    Wong, Chun Wa; Yasui, Kosuke

    2005-01-01

    The one-dimensional fall of a folded chain with one end suspended from a rigid support and a chain falling from a resting heap on a table is studied. Because their Lagrangians contain no explicit time dependence, the falling chains are conservative systems. Their equations of motion are shown to contain a term that enforces energy conservation when masses are transferred between subchains. We show that Cayley's 1857 energy nonconserving solution for a chain falling from a resting heap is inco...

  20. Effect of alkyl chain length of imidazolium cations on the electron transport and recombination kinetics in ionic gel electrolytes based quasi-solid-state dye-sensitized solar cells

    International Nuclear Information System (INIS)

    Huo, Zhipeng; Tao, Li; Wang, Lu; Zhu, Jun; Chen, Shuanghong; Zhang, Changneng; Dai, Songyuan; Zhang, Bing

    2015-01-01

    Highlights: •A series of novel IGEs based on 12-hydroxystearicacid as LMOG were prepared. •The QS-DSSCs exhibit excellent stability during the accelerated aging tests. •The influence of Im + alkyl chain length on the electron kinetic process is investigated. -- Abstract: A series of stable quasi-solid-state dye-sensitized solar cells (QS-DSSCs) are prepared by the 12-hydroxystearicacid as low molecular mass organogelator (LMOG) to gelate the ionic liquid with different alkyl chain lengths (3, 4, and 7). The influence of alkyl chain length of imidazolium cations (Im + ) on the kinetic processes of electron transport and recombination are investigated by Electrochemical impedance spectroscopy (EIS) and intensity-modulated photocurrent spectroscopy/intensity-modulated photovoltage spectroscopy (IMPS/IMVS). It is found that the ionic gel electrolytes (IGEs) with different alkyl chain lengths of Im + can influence the competitive adsorption effects of imidazolium cations (Im + ) and Li + , and further affect the charge diffusion, the electron recombination/transport processes, the shift of TiO 2 conduction band edge and surface states distribution. The IGE with longer alkyl chain length of Im + can prolong the electron recombination lifetime, promote the incidental photon-to-electron conversion efficiency (IPCE) and the short circuit photocurrent density (J sc ). An excellent QS-DSSC based on the IGE with the longer alkyl chain of Im + gives the highest photoelectric conversion efficiency. Moreover, all the QS-DSSCs based on IGEs exhibit excellent durability without losing their photovoltaic performances during the accelerated thermal and light–soaking test. These results are very important to the researches on the electrochemical mechanism and application of QS-DSSCs based on IGEs

  1. Formation of nitrosyl non-heme iron-sulphur complexes of a mitrochondria electron-transport chain in a liver and kidneys under prolonged permanent action of radiation contamination in the Chernobyl region

    International Nuclear Information System (INIS)

    Sidorik, E.P.; Burlaka, A.P.; Druzhina, N.A.

    1995-01-01

    No-complexes with iron-sulfur protein of the N-type (EPR signal g=2.03 at 77 K) have been revealed in a mitochondria electron transport chain in a liver and kidneys of animals which were hold for 1.5 years in the Chernobyl area under action of low intensity ionizing radiation as a result of incorporated radionuclides. These alterations in protein give evidence of changes in oxidation and phosphorylation in tissues

  2. 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...

  3. 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

  4. 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

  5. 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.

  6. Editorial: Supply Chain Management

    Directory of Open Access Journals (Sweden)

    Aidonis, D.

    2012-01-01

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

  7. Ionizing radiation induces mitochondrial reactive oxygen species production accompanied by upregulation of mitochondrial electron transport chain function and mitochondrial content under control of the cell cycle checkpoint.

    Science.gov (United States)

    Yamamori, Tohru; Yasui, Hironobu; Yamazumi, Masayuki; Wada, Yusuke; Nakamura, Yoshinari; Nakamura, Hideo; Inanami, Osamu

    2012-07-15

    Whereas ionizing radiation (Ir) instantaneously causes the formation of water radiolysis products that contain some reactive oxygen species (ROS), ROS are also suggested to be released from biological sources in irradiated cells. It is now becoming clear that these ROS generated secondarily after Ir have a variety of biological roles. Although mitochondria are assumed to be responsible for this Ir-induced ROS production, it remains to be elucidated how Ir triggers it. Therefore, we conducted this study to decipher the mechanism of Ir-induced mitochondrial ROS production. In human lung carcinoma A549 cells, Ir (10 Gy of X-rays) induced a time-dependent increase in the mitochondrial ROS level. Ir also increased mitochondrial membrane potential, mitochondrial respiration, and mitochondrial ATP production, suggesting upregulation of the mitochondrial electron transport chain (ETC) function after Ir. Although we found that Ir slightly enhanced mitochondrial ETC complex II activity, the complex II inhibitor 3-nitropropionic acid failed to reduce Ir-induced mitochondrial ROS production. Meanwhile, we observed that the mitochondrial mass and mitochondrial DNA level were upregulated after Ir, indicating that Ir increased the mitochondrial content of the cell. Because irradiated cells are known to undergo cell cycle arrest under control of the checkpoint mechanisms, we examined the relationships between cell cycle and mitochondrial content and cellular oxidative stress level. We found that the cells in the G2/M phase had a higher mitochondrial content and cellular oxidative stress level than cells in the G1 or S phase, regardless of whether the cells were irradiated. We also found that Ir-induced accumulation of the cells in the G2/M phase led to an increase in cells with a high mitochondrial content and cellular oxidative stress level. This suggested that Ir upregulated mitochondrial ETC function and mitochondrial content, resulting in mitochondrial ROS production, and that

  8. Inhibition of post-traumatic septic proteolysis and ureagenesis and stimulation of hepatic acute-phase protein production by branched-chain amino acid TPN.

    Science.gov (United States)

    Chiarla, C; Siegel, J H; Kidd, S; Coleman, B; Mora, R; Tacchino, R; Placko, R; Gum, M; Wiles, C E; Belzberg, H

    1988-08-01

    Previous studies have shown that severe sepsis after major trauma results in the reprioritization of release of hepatic acute-phase proteins (APP). They suggest competition for leucine for nutritional utilization may be responsible. To test this hypothesis, a branched-chain enriched (46.6%) amino acid mixture (BCAA) was administered on a prospective randomized basis with standard TPN therapy to 16 septic post-trauma patients. After sepsis was diagnosed, a randomized therapy (control-TPN or BCAA-TPN) was given for 12 days, or until death occurred. Total calories and amino acid nitrogen (N) administered were not different in the two groups (t-test) and q 8 h (347 study periods) amino acid clearances, urinary