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Sample records for polar transport inhibitor

  1. Differential effects of auxin polar transport inhibitors on rooting in some Crassulaceae species

    Directory of Open Access Journals (Sweden)

    Marian Saniewski

    2014-07-01

    Full Text Available Effects of auxin polar transport inhibitors, 2,3,5-triio-dobenzoic acid (TIBA, 1-N-naphthylphthalamic acid (NPA and methyl 2-chloro-9-hydroxyfluorene-9-carboxylate (morphactin IT 3456, as a lanolin paste, on root formation in cuttings of some species of Crassulaceae, such as Bryophyllum daigremontianum, B. calycinum, Kalanchoe blossfeldiana and K. tubiflora, were studied. Cuttings of these plants were easily rooted in water without any treatment. TIBA and morphactin IT 3456 completely inhibited root formation in the cuttings of these plants but NPA did not when these inhibitors were applied around the stem below the leaves. When TIBA and morphactin were applied around the stem near the top, but leaves were present below the treatment, the root formation was observed in B. calycinum and K. blossfeldiana but in a smaller degree than in control cuttings. These results strongly suggest that endogenous auxin is required for root formation in cuttings of Crassulaceae plants. The differential mode of action of NPA is discussed together with its effect on auxin polar transport.

  2. Increasing oral absorption of polar neuraminidase inhibitors: a prodrug transporter approach applied to oseltamivir analogue.

    Science.gov (United States)

    Gupta, Deepak; Varghese Gupta, Sheeba; Dahan, Arik; Tsume, Yasuhiro; Hilfinger, John; Lee, Kyung-Dall; Amidon, Gordon L

    2013-02-04

    compartment, indicating complete activation (hydrolysis) during transport. Intestinal rat jejunal permeability studies showed that l-valyl and l-isoleucyl prodrugs are highly permeable compared to the orally well absorbed metoprolol, while the parent drug had essentially zero permeability in the jejunum, consistent with its known poor low absorption. Prodrugs were rapidly converted to parent in cell homogenates, suggesting their ability to be activated endogenously in the epithelial cell, consistent with the transport studies. Additionally, l-valyl prodrug was found to be a substrate for valacyclovirase (K(m) = 2.37 mM), suggesting a potential cell activation mechanism. Finally we determined the oral bioavailability of our most promising candidate, GOC-l-Val, in mice to be 23% under fed conditions and 48% under fasted conditions. In conclusion, GOC-l-Val prodrug was found to be a very promising antiviral agent for oral delivery. These findings indicate that the carrier-mediated prodrug approach is an excellent strategy for improving oral absorption of polar neuraminidase inhibitors. These promising results demonstrate that the oral peptide transporter-mediated prodrug strategy has enormous promise for improving the oral mucosal cell membrane permeability of polar, poorly absorbed antiviral agents and treating influenza via the oral route of administration.

  3. Inhibitors of plant hormone transport

    Czech Academy of Sciences Publication Activity Database

    Klíma, Petr; Laňková, Martina; Zažímalová, Eva

    2016-01-01

    Roč. 253, č. 6 (2016), s. 1391-1404 ISSN 0033-183X R&D Projects: GA MŠk(CZ) LD15088 Institutional support: RVO:61389030 Keywords : polar auxin transport * acid-binding protein * gnom arf-gef * equilibrative nucleoside transporter * efflux carrier polarity * plasma-membrane-protein * cultured tobacco cells * arabidopsis-thaliana * gravitropic response * brefeldin-a * Plant hormones * Transport * Inhibitors * Auxin * Cytokinins * Strigolactones * Abscisic acid * Cell biology Subject RIV: ED - Physiology Impact factor: 2.870, year: 2016

  4. Polar transport in plants mediated by membrane transporters: focus on mechanisms of polar auxin transport.

    Science.gov (United States)

    Naramoto, Satoshi

    2017-12-01

    Directional cell-to-cell transport of functional molecules, called polar transport, enables plants to sense and respond to developmental and environmental signals. Transporters that localize to plasma membranes (PMs) in a polar manner are key components of these systems. PIN-FORMED (PIN) auxin efflux carriers, which are the most studied polar-localized PM proteins, are implicated in the polar transport of auxin that in turn regulates plant development and tropic growth. In this review, the regulatory mechanisms underlying polar localization of PINs, control of auxin efflux activity, and PIN abundance at PMs are considered. Up to date information on polar-localized nutrient transporters that regulate directional nutrient movement from soil into the root vasculature is also discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Polarized photon transport through fog

    Science.gov (United States)

    Farmer, Jonathan; Persons, Christopher M.; DeSilva, Robert; Kirkland, James H.; Finney, Greg A.; Fuller, Kirk A.; Hokr, Brett H.

    2017-09-01

    Anyone who has driven through fog understands the detrimental effect scattering can have on your ability to see. When light interacts with a scattering center, in this case a fog droplet, it is scattered into a new direction, ultimately turning the world around you into a dull gray haze. In some fogs, visibility can be less than 100 meters. It would be possible to see through turbid media like fog if you can separate the scattered light from the unscattered, or ballistic, light; however, we must understand the light transport properties of the atmosphere to determine the optimum scheme. Here, we present an end-to-end simulation for polarized light transport through fog. Our approach can be summarized in three steps: compute the Mueller matrix for a single scattering interaction, ensemble average a distribution of sizes and shapes, and solve the light transport using a Monte Carlo simulation. For small spherical particles, such as fog, we use Mie theory to calculate the single scattering Mueller matrix, but this approach can be generalized to non-spherical particles using ray tracing for large particles or a T-matrix approach for smaller particles. Through this simulation, we are able to determine a backscattering Mueller matrix and a forward scattering Mueller matrix response function for the atmosphere as a function of position and detection angle.

  6. Molecular modeling of auxin transport inhibitors

    International Nuclear Information System (INIS)

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

    1990-01-01

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

  7. Polarized Neutron Reflectometry of Nickel Corrosion Inhibitors.

    Science.gov (United States)

    Wood, Mary H; Welbourn, Rebecca J L; Zarbakhsh, Ali; Gutfreund, Philipp; Clarke, Stuart M

    2015-06-30

    Polarized neutron reflectometry has been used to investigate the detailed adsorption behavior and corrosion inhibition mechanism of two surfactants on a nickel surface under acidic conditions. Both the corrosion of the nickel surface and the structure of the adsorbed surfactant layer could be monitored in situ by the use of different solvent contrasts. Layer thicknesses and roughnesses were evaluated over a range of pH values, showing distinctly the superior corrosion inhibition of one negatively charged surfactant (sodium dodecyl sulfate) compared to a positively charged example (dodecyl trimethylammonium bromide) due to its stronger binding interaction with the surface. It was found that adequate corrosion inhibition occurs at significantly less than full surface coverage.

  8. Diffusion equation and spin drag in spin-polarized transport

    DEFF Research Database (Denmark)

    Flensberg, Karsten; Jensen, Thomas Stibius; Mortensen, Asger

    2001-01-01

    We study the role of electron-electron interactions for spin-polarized transport using the Boltzmann equation, and derive a set of coupled transport equations. For spin-polarized transport the electron-electron interactions are important, because they tend to equilibrate the momentum of the two-s...

  9. Polar auxin transport: controlling where and how much

    Science.gov (United States)

    Muday, G. K.; DeLong, A.; Brown, C. S. (Principal Investigator)

    2001-01-01

    Auxin is transported through plant tissues, moving from cell to cell in a unique polar manner. Polar auxin transport controls important growth and developmental processes in higher plants. Recent studies have identified several proteins that mediate polar auxin transport and have shown that some of these proteins are asymmetrically localized, paving the way for studies of the mechanisms that regulate auxin transport. New data indicate that reversible protein phosphorylation can control the amount of auxin transport, whereas protein secretion through Golgi-derived vesicles and interactions with the actin cytoskeleton might regulate the localization of auxin efflux complexes.

  10. Charge transport in non-polar and semi-polar III-V nitride heterostructures

    International Nuclear Information System (INIS)

    Konar, Aniruddha; Verma, Amit; Fang, Tian; Zhao, Pei; Jana, Raj; Jena, Debdeep

    2012-01-01

    Compared to the intense research focus on the optical properties, the transport properties in non-polar and semi-polar III-nitride semiconductors remain relatively unexplored to date. The purpose of this paper is to discuss charge-transport properties in non-polar and semi-polar orientations of GaN in a comparative fashion to what is known for transport in polar orientations. A comprehensive approach is adopted, starting from an investigation of the differences in the electronic bandstructure along different polar orientations of GaN. The polarization fields along various orientations are then discussed, followed by the low-field electron and hole mobilities. A number of scattering mechanisms that are specific to non-polar and semi-polar GaN heterostructures are identified, and their effects are evaluated. Many of these scattering mechanisms originate due to the coupling of polarization with disorder and defects in various incarnations depending on the crystal orientation. The effect of polarization orientation on carrier injection into quantum-well light-emitting diodes is discussed. This paper ends with a discussion of orientation-dependent high-field charge-transport properties including velocity saturation, instabilities and tunneling transport. Possible open problems and opportunities are also discussed. (paper)

  11. Alkoxy-auxins are selective inhibitors of auxin transport mediated by PIN, ABCB, and AUX1 transporters.

    Science.gov (United States)

    Tsuda, Etsuko; Yang, Haibing; Nishimura, Takeshi; Uehara, Yukiko; Sakai, Tatsuya; Furutani, Masahiko; Koshiba, Tomokazu; Hirose, Masakazu; Nozaki, Hiroshi; Murphy, Angus S; Hayashi, Ken-ichiro

    2011-01-21

    Polar auxin movement is a primary regulator of programmed and plastic plant development. Auxin transport is highly regulated at the cellular level and is mediated by coordinated transport activity of plasma membrane-localized PIN, ABCB, and AUX1/LAX transporters. The activity of these transporters has been extensively analyzed using a combination of pharmacological inhibitors, synthetic auxins, and knock-out mutants in Arabidopsis. However, efforts to analyze auxin-dependent growth in other species that are less tractable to genetic manipulation require more selective inhibitors than are currently available. In this report, we characterize the inhibitory activity of 5-alkoxy derivatives of indole 3-acetic acid and 7-alkoxy derivatives of naphthalene 1-acetic acid, finding that the hexyloxy and benzyloxy derivatives act as potent inhibitors of auxin action in plants. These alkoxy-auxin analogs inhibit polar auxin transport and tropic responses associated with asymmetric auxin distribution in Arabidopsis and maize. The alkoxy-auxin analogs inhibit auxin transport mediated by AUX1, PIN, and ABCB proteins expressed in yeast. However, these analogs did not inhibit or activate SCF(TIR1) auxin signaling and had no effect on the subcellular trafficking of PIN proteins. Together these results indicate that alkoxy-auxins are inactive auxin analogs for auxin signaling, but are recognized by PIN, ABCB, and AUX1 auxin transport proteins. Alkoxy-auxins are powerful new tools for analyses of auxin-dependent development.

  12. Alkoxy-auxins Are Selective Inhibitors of Auxin Transport Mediated by PIN, ABCB, and AUX1 Transporters*

    Science.gov (United States)

    Tsuda, Etsuko; Yang, Haibing; Nishimura, Takeshi; Uehara, Yukiko; Sakai, Tatsuya; Furutani, Masahiko; Koshiba, Tomokazu; Hirose, Masakazu; Nozaki, Hiroshi; Murphy, Angus S.; Hayashi, Ken-ichiro

    2011-01-01

    Polar auxin movement is a primary regulator of programmed and plastic plant development. Auxin transport is highly regulated at the cellular level and is mediated by coordinated transport activity of plasma membrane-localized PIN, ABCB, and AUX1/LAX transporters. The activity of these transporters has been extensively analyzed using a combination of pharmacological inhibitors, synthetic auxins, and knock-out mutants in Arabidopsis. However, efforts to analyze auxin-dependent growth in other species that are less tractable to genetic manipulation require more selective inhibitors than are currently available. In this report, we characterize the inhibitory activity of 5-alkoxy derivatives of indole 3-acetic acid and 7-alkoxy derivatives of naphthalene 1-acetic acid, finding that the hexyloxy and benzyloxy derivatives act as potent inhibitors of auxin action in plants. These alkoxy-auxin analogs inhibit polar auxin transport and tropic responses associated with asymmetric auxin distribution in Arabidopsis and maize. The alkoxy-auxin analogs inhibit auxin transport mediated by AUX1, PIN, and ABCB proteins expressed in yeast. However, these analogs did not inhibit or activate SCFTIR1 auxin signaling and had no effect on the subcellular trafficking of PIN proteins. Together these results indicate that alkoxy-auxins are inactive auxin analogs for auxin signaling, but are recognized by PIN, ABCB, and AUX1 auxin transport proteins. Alkoxy-auxins are powerful new tools for analyses of auxin-dependent development. PMID:21084292

  13. TRANSPORT CORRIDOR "URAL INDUSTRIAL – URAL POLAR": PROBLEMS, EVOLUTION PATHS

    Directory of Open Access Journals (Sweden)

    N.V. Tabakov

    2007-06-01

    Full Text Available The article deals with the theoretic and methodological questions regarding the formation of a transport corridor "Urals industrial – Urals Polar". Analyzed are the main factors that affect the formation of the transport infrastructure. A big effect is centered around the world-view problem, which has to do with the occupation of a human, and the effect of it on nature. Put forth is the possibility to look upon the question of the formation of ma transport corridor "Urals industrial – Urals Polar" in the frame of the forming of the Ural-West-Siberian TPK, taking into account the global transport web.

  14. TWISTED DWARF1 Mediates the Action of Auxin Transport Inhibitors on Actin Cytoskeleton Dynamics

    Science.gov (United States)

    Bailly, Aurelien; Zwiewka, Marta; Sovero, Valpuri; Ge, Pei; Aryal, Bibek; Hao, Pengchao; Linnert, Miriam; Burgardt, Noelia Inés; Lücke, Christian; Weiwad, Matthias; Michel, Max; Weiergräber, Oliver H.; Pollmann, Stephan; Azzarello, Elisa; Fukao, Yoichiro; Hoffmann, Céline; Wedlich-Söldner, Roland

    2016-01-01

    Plant growth and architecture is regulated by the polar distribution of the hormone auxin. Polarity and flexibility of this process is provided by constant cycling of auxin transporter vesicles along actin filaments, coordinated by a positive auxin-actin feedback loop. Both polar auxin transport and vesicle cycling are inhibited by synthetic auxin transport inhibitors, such as 1-N-naphthylphthalamic acid (NPA), counteracting the effect of auxin; however, underlying targets and mechanisms are unclear. Using NMR, we map the NPA binding surface on the Arabidopsis thaliana ABCB chaperone TWISTED DWARF1 (TWD1). We identify ACTIN7 as a relevant, although likely indirect, TWD1 interactor, and show TWD1-dependent regulation of actin filament organization and dynamics and that TWD1 is required for NPA-mediated actin cytoskeleton remodeling. The TWD1-ACTIN7 axis controls plasma membrane presence of efflux transporters, and as a consequence act7 and twd1 share developmental and physiological phenotypes indicative of defects in auxin transport. These can be phenocopied by NPA treatment or by chemical actin (de)stabilization. We provide evidence that TWD1 determines downstream locations of auxin efflux transporters by adjusting actin filament debundling and dynamizing processes and mediating NPA action on the latter. This function appears to be evolutionary conserved since TWD1 expression in budding yeast alters actin polarization and cell polarity and provides NPA sensitivity. PMID:27053424

  15. The actin cytoskeleton may control the polar distribution of an auxin transport protein

    Science.gov (United States)

    Muday, G. K.; Hu, S.; Brady, S. R.; Davies, E. (Principal Investigator)

    2000-01-01

    The gravitropic bending of plants has long been linked to the changes in the transport of the plant hormone auxin. To understand the mechanism by which gravity alters auxin movement, it is critical to know how polar auxin transport is initially established. In shoots, polar auxin transport is basipetal (i.e., from the shoot apex toward the base). It is driven by the basal localization of the auxin efflux carrier complex. One mechanism for localizing this efflux carrier complex to the basal membrane may be through attachment to the actin cytoskeleton. The efflux carrier protein complex is believed to consist of several polypeptides, including a regulatory subunit that binds auxin transport inhibitors, such as naphthylphthalamic acid (NPA). Several lines of experimentation have been used to determine if the NPA binding protein interacts with actin filaments. The NPA binding protein has been shown to partition with the actin cytoskeleton during detergent extraction. Agents that specifically alter the polymerization state of the actin cytoskeleton change the amount of NPA binding protein and actin recovered in these cytoskeletal pellets. Actin-affinity columns were prepared with polymers of actin purified from zucchini hypocotyl tissue. NPA binding activity was eluted in a single peak from the actin filament column. Cytochalasin D, which fragments the actin cytoskeleton, was shown to reduce polar auxin transport in zucchini hypocotyls. The interaction of the NPA binding protein with the actin cytoskeleton may localize it in one plane of the plasma membrane, and thereby control the polarity of auxin transport.

  16. Convergent evolution of shoots in land plants: lack of auxin polar transport in moss shoots.

    Science.gov (United States)

    Fujita, Tomomichi; Sakaguchi, Hisako; Hiwatashi, Yuji; Wagstaff, Steven J; Ito, Motomi; Deguchi, Hironori; Sato, Toshiyuki; Hasebe, Mitsuyasu

    2008-01-01

    The shoot is a repeated structure made up of stems and leaves and is the basic body plan in land plants. Vascular plants form a shoot in the diploid generation, whereas nonvascular plants such as mosses form a shoot in the haploid generation. It is not clear whether all land plants use similar molecular mechanisms in shoot development or how the genetic networks for shoot development evolved. The control of auxin distribution, especially by polar auxin transport, is essential for shoot development in flowering plants. We did not detect polar auxin transport in the gametophytic shoots of several mosses, but did detect it in the sporophytes of mosses without shoot structure. Treatment with auxin transport inhibitors resulted in abnormal embryo development, as in flowering plants, but did not cause any morphological changes in the haploid shoots. We fused the soybean auxin-inducible promoter GH3 with a GUS reporter gene and used it to indirectly detect auxin distribution in the moss Physcomitrella patens. An auxin transport inhibitor NPA did not cause any changes in the putative distribution of auxin in the haploid shoot. These results indicate that polar auxin transport is not involved in haploid shoot development in mosses and that shoots in vascular plants and mosses are most likely regulated differently during development.

  17. IPOLE - semi-analytic scheme for relativistic polarized radiative transport

    Science.gov (United States)

    Mościbrodzka, M.; Gammie, C. F.

    2018-03-01

    We describe IPOLE, a new public ray-tracing code for covariant, polarized radiative transport. The code extends the IBOTHROS scheme for covariant, unpolarized transport using two representations of the polarized radiation field: In the coordinate frame, it parallel transports the coherency tensor; in the frame of the plasma it evolves the Stokes parameters under emission, absorption, and Faraday conversion. The transport step is implemented to be as spacetime- and coordinate- independent as possible. The emission, absorption, and Faraday conversion step is implemented using an analytic solution to the polarized transport equation with constant coefficients. As a result, IPOLE is stable, efficient, and produces a physically reasonable solution even for a step with high optical depth and Faraday depth. We show that the code matches analytic results in flat space, and that it produces results that converge to those produced by Dexter's GRTRANS polarized transport code on a complicated model problem. We expect IPOLE will mainly find applications in modelling Event Horizon Telescope sources, but it may also be useful in other relativistic transport problems such as modelling for the IXPE mission.

  18. Transport phenomena of polar biomolecules and colloids : perspectives through simulation

    OpenAIRE

    Terämä, Emma

    2007-01-01

    The thesis focuses on the transport of polar biomolecules and colloid particles studied through atomistic and coarse-grained simulation techniques. The thesis is comprised of two themes complementing one another. First we concentrate on the structural and dynamical aspects of alcohol molecules in lipid bilayers with varying degree of unsaturation. Second, the thesis employs dielectrophoresis to elucidate the non-equilibrium transport phenomena of nano-sized colloidal particles. The former is ...

  19. Concentration polarization: Electrodeposition and transport phenomena at overlimiting current

    DEFF Research Database (Denmark)

    Nielsen, Christoffer Peder

    . Secondly, we investigate concentration polarization in a microchannel with charged walls. We provide full numerical solutions to the transport problem, including the effects of advection and surface conduction in the electric double layers. We show that in large areas of the relevant parameter space...... the transport can be understood in terms of a group of simple analytical models. Some of these are generalizations of a previously published analytical model. In addition to the full numerical model, we employ a numerical boundary layer model with a slip velocity. By carefully comparing the full model...... and the boundary layer model, we reveal a number of issues, which invalidate most previous attempts at modeling microchannel concentration polarization using a slip model. Returning to concentration polarization in a bulk system, we study the effects of water splitting at a permselective membrane. We investigate...

  20. TRANSPORT CORRIDOR "URAL INDUSTRIAL – URAL POLAR": PROBLEMS, EVOLUTION PATHS

    OpenAIRE

    N.V. Tabakov

    2007-01-01

    The article deals with the theoretic and methodological questions regarding the formation of a transport corridor "Urals industrial – Urals Polar". Analyzed are the main factors that affect the formation of the transport infrastructure. A big effect is centered around the world-view problem, which has to do with the occupation of a human, and the effect of it on nature. Put forth is the possibility to look upon the question of the formation of ma transport corridor "Urals industrial – Urals P...

  1. Auxin response, but not its polar transport, plays a role in hydrotropism of Arabidopsis roots.

    Science.gov (United States)

    Kaneyasu, Tomoko; Kobayashi, Akie; Nakayama, Mayumi; Fujii, Nobuharu; Takahashi, Hideyuki; Miyazawa, Yutaka

    2007-01-01

    Plants are sessile in nature, and need to detect and respond to many environmental cues in order to regulate their growth and orientation. Indeed, plants sense numerous environmental cues and respond via appropriate tropisms, and it is widely accepted that auxin plays an important role in these responses. Recent analyses using Arabidopsis have emphasized the importance of polar auxin transport and differential auxin responses to gravitropism. Even so, the involvement of auxin in hydrotropism remains unclear. To clarify whether or not auxin is involved in the hydrotropic response, Arabidopsis seedlings were treated with inhibitors of auxin influx (3-chloro-4-hydroxyphenylacetic acid), efflux (1-naphthylphthalemic acid and 2,3,5-triiodobenzoic acid), and response (p-chlorophenoxyisobutylacetic acid), and their effects were examined on both hydrotropic and gravitropic responses. In agreement with previous reports, gravitropism was inhibited by all the chemicals tested. By contrast, only an inhibitor of the auxin response (p-chlorophenoxyisobutylacetic acid) reduced hydrotropism, whereas inhibitors for influx or efflux of auxin had no effect. These results suggest that auxin response, apart from its polar transport, plays a definite role in hydrotropic response, and will evoke a new concept for the auxin-mediated regulation of tropisms.

  2. Polar transport and accumulation of indole-3-acetic acid during root regeneration by Pinus lambertiana embryos.

    Science.gov (United States)

    Greenwood, M S; Goldsmith, M H

    1970-12-01

    The relation of indoleacetic acid (IAA) transport to accumulation of auxin at the base of cuttings and to polar root formation was investigated with small cuttings from germinating embryos of Pinus lambertiana.The transport of endogenous auxin participates in regeneration of roots. This is shown by the facts that (1) more than 40% of the cuttings rooted without addition of exogenous indoleacetic acid; (2) the first regeneration always occurred at the basal tip of a slanting cut; and (3) 2,3,5-triiodobenzoic acid (TIBA), a specific inhibitor of auxin transport, totally inhibited rooting. Addition of IAA to the medium increased the number of roots formed per rooting hypocotyl.Sections of hypocotyls excised from dormant embryos and tested immediately after 2 h hydration were capable of polar transport of IAA. This polarity increased during the first 3 days of culture because of a marked increase in basipetal transport. Culturing the cuttings in 1 μM IAA for 3-5 days doubled both the basipetal transport of 1-(14)C-IAA by hypocotyl segments and the accumulation of radioactivity at the base of cuttings.The extent of the accumulation at the base of cuttings was similar at early (2 days, first mitoses) and late stages (5 days, organized meristem) of regeneration and was not affected by removal of the regenerating region immediately prior to uptake and transport of (14)C-IAA. The accumulation was inhibited by TIBA. In terms of increase in wet and dry weight and mitotic activity, the cotyledons rather than the regenerating root meristems were the most actively growing region of the cuttings. The upper part of the hypocotyl elongated more than the region of the slanting cut where regeneration was occurring.These results provide no support for the idea that the regenerating root controls the direction of polar transport by acting as a sink. The results are consistent with the view that polar auxin transport delivers auxin to the base of the cutting and raises the local

  3. Brassinosteroids stimulate plant tropisms through modulation of polar auxin transport in Brassica and Arabidopsis.

    Science.gov (United States)

    Li, Li; Xu, Jian; Xu, Zhi-Hong; Xue, Hong-Wei

    2005-10-01

    Brassinosteroids (BRs) are important plant growth regulators in multiple developmental processes. Previous studies have indicated that BR treatment enhanced auxin-related responses, but the underlying mechanisms remain unknown. Using (14)C-labeled indole-3-acetic acid and Arabidopsis thaliana plants harboring an auxin-responsive reporter construct, we show that the BR brassinolide (BL) stimulates polar auxin transport capacities and modifies the distribution of endogenous auxin. In plants treated with BL or defective in BR biosynthesis or signaling, the transcription of PIN genes, which facilitate functional auxin transport in plants, was differentially regulated. In addition, BL enhanced plant tropistic responses by promoting the accumulation of the PIN2 protein from the root tip to the elongation zone and stimulating the expression and dispersed localization of ROP2 during tropistic responses. Constitutive overexpression of ROP2 results in enhanced polar accumulation of PIN2 protein in the root elongation region and increased gravitropism, which is significantly affected by latrunculin B, an inhibitor of F-actin assembly. The ROP2 dominant negative mutants (35S-ROP2-DA/DN) show delayed tropistic responses, and this delay cannot be reversed by BL addition, strongly supporting the idea that ROP2 modulates the functional localization of PIN2 through regulation of the assembly/reassembly of F-actins, thereby mediating the BR effects on polar auxin transport and tropistic responses.

  4. Heme and non-heme iron transporters in non-polarized and polarized cells

    Directory of Open Access Journals (Sweden)

    Yasui Yumiko

    2010-06-01

    Full Text Available Abstract Background Heme and non-heme iron from diet, and recycled iron from hemoglobin are important products of the synthesis of iron-containing molecules. In excess, iron is potentially toxic because it can produce reactive oxygen species through the Fenton reaction. Humans can absorb, transport, store, and recycle iron without an excretory system to remove excess iron. Two candidate heme transporters and two iron transporters have been reported thus far. Heme incorporated into cells is degraded by heme oxygenases (HOs, and the iron product is reutilized by the body. To specify the processes of heme uptake and degradation, and the reutilization of iron, we determined the subcellular localizations of these transporters and HOs. Results In this study, we analyzed the subcellular localizations of 2 isoenzymes of HOs, 4 isoforms of divalent metal transporter 1 (DMT1, and 2 candidate heme transporters--heme carrier protein 1 (HCP1 and heme responsive gene-1 (HRG-1--in non-polarized and polarized cells. In non-polarized cells, HCP1, HRG-1, and DMT1A-I are located in the plasma membrane. In polarized cells, they show distinct localizations: HCP1 and DMT1A-I are located in the apical membrane, whereas HRG-1 is located in the basolateral membrane and lysosome. 16Leu at DMT1A-I N-terminal cytosolic domain was found to be crucial for plasma membrane localization. HOs are located in smooth endoplasmic reticulum and colocalize with NADPH-cytochrome P450 reductase. Conclusions HCP1 and DMT1A-I are localized to the apical membrane, and HRG-1 to the basolateral membrane and lysosome. These findings suggest that HCP1 and DMT1A-I have functions in the uptake of dietary heme and non-heme iron. HRG-1 can transport endocytosed heme from the lysosome into the cytosol. These localization studies support a model in which cytosolic heme can be degraded by HOs, and the resulting iron is exported into tissue fluids via the iron transporter ferroportin 1, which is

  5. Effects of auxin transport inhibitors on gibberellins in pea

    International Nuclear Information System (INIS)

    Ross, J.J.

    1998-01-01

    The effects of the auxin transport inhibitors 2,3,5-triiodobenzoic acid (TIBA), 9-hydroxyfluorene-9-carboxylic acid (HFCA), and 1-N-naphthylphthalamic acid (NPA) on gibberellins (GAs) in the garden pea (Pisum sativum L.) were studied. Application of these compounds to elongating internodes of intact wild type plants reduced markedly the endogenous level of the bioactive gibberellin A1. (GA1) below the application site. Indole-3-acetic acid (IAA) levels were also reduced, as was internode elongation. The auxin transport inhibitors did not affect the level of endogenous GA1 above the application site markedly, nor that of GA1 precursors above or below it. When plants were treated with [13C,3H]GA20, TIBA reduced dramatically the level of [13C,3H]GA1 recovered below the TIBA application site. The internodes treated with auxin transport inhibitors appeared to be still in the phase where endogenous GA1 affects elongation, as indicated by the strong response to applied GA1 by internodes of a GA1-deficient line at the same stage of expansion. On the basis of the present results it is suggested that caution be exercised when attributing the developmental effects of auxin transport inhibitors to changes in IAA level alone

  6. Regulation of renal peripheral benzodiazepine receptors by anion transport inhibitors

    Energy Technology Data Exchange (ETDEWEB)

    Basile, A.S.; Lueddens, W.M.; Skolnick, P.

    1988-01-01

    The in vitro and in vivo regulation of (/sup 3/H)Ro 5-4864 binding to peripheral benzodiazepine receptors (PBR) by ion transport/exchange inhibitors was studied in the kidney. The potencies of 9-anthroic acid, furosemide, bumetanide, hydrochlorothiazide and SITS as inhibitors of (/sup 3/H)Ro 5-4864 binding to renal membranes were consistent with their actions as anion transport inhibitors (Ki approx. = 30 - 130 ..mu..M). In contrast, spironolactone, amiloride, acetazolamide, and ouabain were less potent (Ki=100-1000 ..mu..M). Administration of furosemide to rats for five days resulted in a profound diuresis accompanied by a significant increase in PBR density (43%) that was apparent by the fifth day of treatment. Administration of hydrochlorothiazide or Ro 5-4864 for five days also caused diuresis and increased renal PBR density. Both the diuresis and increased density of PBR produced by Ro 5-4864 were blocked by coadministration of PK 11195, which alone had no effect on either PBR density or urine volume. The equilibrium binding constants of (/sup 3/H)Ro 5-4864 to cardiac membranes were unaffected by administration of any of these drugs. These findings suggest that renal PBR may be selectively modulated in vivo and in vitro by administration of ion transport/exchange inhibitors. 36 references, 4 tables.

  7. Modeling hydrate formation conditions in the presence of electrolytes and polar inhibitor solutions

    International Nuclear Information System (INIS)

    Osfouri, Shahriar; Azin, Reza; Gholami, Reza; Izadpanah, Amir Abbas

    2015-01-01

    Highlights: • A new predictive model is proposed for prediction of hydrate formation pressures. • A new local composition model was used to evaluate water activity in the presence of electrolyte. • MEG, DEG and TEG were used to test ability of the proposed model in the presence of polar inhibitors. • Cage occupancies by methane for the small cage were higher than carbon dioxide for gas mixtures. • The proposed model gives better match with experimental data in mixed electrolyte solutions. - Abstract: In this paper, a new predictive model is proposed for prediction of gas hydrate formation conditions in the presence of single and mixed electrolytes and solutions containing both electrolyte and a polar inhibitor such as monoethylene glycol (MEG), diethylene glycol (DEG) and triethylene glycol (TEG). The proposed model is based on the γ–φ approach, which uses modified Patel–Teja equation of state (VPT EOS) for characterizing the vapor phase, the solid solution theory by van der Waals and Platteeuw for modeling the hydrate phase, the non-electrolyte NRTL-NRF local composition model and Pitzer–Debye–Huckel equation as short-range and long-range contributions to calculate water activity in single electrolyte solutions. Also, the Margules equation was used to determine the activity of water in solutions containing polar inhibitor (glycols). The model predictions are in acceptable agreement with experimental data. For single electrolyte solutions, the model predictions are similar to available models, while for mixtures of electrolytes and mixtures of electrolytes and inhibitors, the proposed model gives significantly better predictions. In addition, the absolute average deviation of hydrate formation pressures (AADP) for 144 experimental data in solutions containing single electrolyte is 5.86% and for 190 experimental data in mixed electrolytes solutions is 5.23%. Furthermore, the proposed model has an AADP of 14.13%, 5.82% and 5.28% in solutions

  8. The polar warhead of a TRIM24 bromodomain inhibitor rearranges a water-mediated interaction network.

    Science.gov (United States)

    Liu, Jiuyang; Li, Fudong; Bao, Hongyu; Jiang, Yiyang; Zhang, Shuya; Ma, Rongsheng; Gao, Jia; Wu, Jihui; Ruan, Ke

    2017-04-01

    Tripartite motif-containing protein 24 (TRIM24) is closely correlated with multiple cancers, and a recent study demonstrated that the bromodomain of TRIM24 is essential for the proliferation of lethal castration-resistant prostate cancer. Here, we identify three new inhibitors of the TRIM24 bromodomain using NMR fragment-based screening. The crystal structures of two new inhibitors in complex with the TRIM24 bromodomain reveal that the water-bridged interaction network is conserved in the same fashion as those for known benzoimidazolone inhibitors. Interestingly, the polar substitution on the warhead of one new inhibitor pulls the whole ligand approximately 2 Å into the inner side pocket of the TRIM24 bromodomain, and thus exhibits a binding mode significantly different from other known bromodomain ligands. This mode provides a useful handle for further hit-to-lead evolution toward novel inhibitors of the TRIM24 bromodomain. Structural data are available in the PDB under the accession numbers 5H1T, 5H1U, and 5H1V. © 2017 Federation of European Biochemical Societies.

  9. Reduced naphthylphthalamic acid binding in the tir3 mutant of Arabidopsis is associated with a reduction in polar auxin transport and diverse morphological defects

    Science.gov (United States)

    Ruegger, M.; Dewey, E.; Hobbie, L.; Brown, D.; Bernasconi, P.; Turner, J.; Muday, G.; Estelle, M.

    1997-01-01

    Polar auxin transport plays a key role in the regulation of plant growth and development. To identify genes involved in this process, we have developed a genetic procedure to screen for mutants of Arabidopsis that are altered in their response to auxin transport inhibitors. We recovered a total of 16 independent mutants that defined seven genes, called TRANSPORT INHIBITOR RESPONSE (TIR) genes. Recessive mutations in one of these genes, TIR3, result in altered responses to transport inhibitors, a reduction in polar auxin transport, and a variety of morphological defects that can be ascribed to changes in indole-3-acetic acid distribution. Most dramatically, tir3 seedlings are strongly deficient in lateral root production, a process that is known to depend on polar auxin transport from the shoot into the root. In addition, tir3 plants display a reduction in apical dominance as well as decreased elongation of siliques, pedicels, roots, and the inflorescence. Biochemical studies indicate that tir3 plants have a reduced number of N-1-naphthylphthalamic (NPA) binding sites, suggesting that the TIR3 gene is required for expression, localization, or stabilization of the NPA binding protein (NBP). Alternatively, the TIR3 gene may encode the NBP. Because the tir3 mutants have a substantial defect in NPA binding, their phenotype provides genetic evidence for a role for the NBP in plant growth and development.

  10. The phosphodiesterase-5 inhibitor vardenafil is a potent inhibitor of ABCB1/P-glycoprotein transporter.

    Directory of Open Access Journals (Sweden)

    Pei-Rong Ding

    Full Text Available One of the major causes of chemotherapy failure in cancer treatment is multidrug resistance (MDR which is mediated by the ABCB1/P-glycoprotein. Previously, through the use of an extensive screening process, we found that vardenafil, a phosphodiesterase 5 (PDE-5 inhibitor significantly reverses MDR in ABCB1 overexpressing cancer cells, and its efficacy was greater than that of tadalafil, another PDE-5 inhibitor. The present study was designed to determine the reversal mechanisms of vardenafil and tadalafil on ABC transporters-mediated MDR. Vardenafil or tadalafil alone, at concentrations up to 20 µM, had no significant toxic effects on any of the cell lines used in this study, regardless of their membrane transporter status. However, vardenafil when used in combination with anticancer substrates of ABCB1, significantly potentiated their cytotoxicity in ABCB1 overexpressing cells in a concentration-dependent manner, and this effect was greater than that of tadalafil. The sensitivity of the parenteral cell lines to cytotoxic anticancer drugs was not significantly altered by vardenafil. The differential effects of vardenafil and tadalafil appear to be specific for the ABCB1 transporter as both vardenafil and tadalafil had no significant effect on the reversal of drug resistance conferred by ABCC1 (MRP1 and ABCG2 (BCRP transporters. Vardenafil significantly increased the intracellular accumulation of [(3H]-paclitaxel in the ABCB1 overexpressing KB-C2 cells. In addition, vardenafil significantly stimulated the ATPase activity of ABCB1 and inhibited the photolabeling of ABCB1 with [(125I]-IAAP. Furthermore, Western blot analysis indicated the incubation of cells with either vardenafil or tadalafil for 72 h did not alter ABCB1 protein expression. Overall, our results suggest that vardenafil reverses ABCB1-mediated MDR by directly blocking the drug efflux function of ABCB1.

  11. Auxin transport inhibitors impair vesicle motility and actin cytoskeleton dynamics in diverse eukaryotes

    NARCIS (Netherlands)

    Dhonukshe, P.; Grigoriev, I.; Fischer, R.; Tominaga, M.; Robinson, D.G.; Hašek, J.; Paciorek, T.; Petrášek, J.; Seifertová, D.; Tejos, R.; Meisel, L.A.; Zažímalová, E.; Gadella (jr.), T.W.J.; Stierhof, Y.-D.; Ueda, T.; Oiwa, K.; Akhmanova, A.; Brock, R.; Spang, A.; Friml, J.

    2008-01-01

    Many aspects of plant development, including patterning and tropisms, are largely dependent on the asymmetric distribution of the plant signaling molecule auxin. Auxin transport inhibitors (ATIs), which interfere with directional auxin transport, have been essential tools in formulating this

  12. Auxin transport inhibitors impair vesicle motility and actin cytoskeleton dynamics in diverse eukaryotes

    NARCIS (Netherlands)

    P. Dhonukshe (Pankaj); I. Grigoriev (Ilya); R. Fischer (Rainer); M. Tominaga (Motoki); D.G. Robinson (David); J. Hašek (Jiří); T. Paciorek (Tomasz); J. Petrášek (Jan); D. Seifertová (Daniela); R. Tejos (Ricardo); L.A. Meisel (Lee); E. Zažímalová (Eva); T.W.J. Gadella (Theodorus); Y.D. Stierhof; T. Ueda (Takashi); K. Oiwa (Kazuhiro); A.S. Akhmanova (Anna); R. Brock (Roland); A. Spang (Anne); J. Friml (Jiří)

    2008-01-01

    textabstractMany aspects of plant development, including patterning and tropisms, are largely dependent on the asymmetric distribution of the plant signaling molecule auxin. Auxin transport inhibitors (ATIs), which interfere with directional auxin transport, have been essential tools in formulating

  13. Auxin transport inhibitors impair vesicle motility and actin cytoskeleton dynamics in diverse eukaryotes.

    NARCIS (Netherlands)

    Dhonukshe, P.; Grigoriev, I.; Fischer, R.; Tominaga, M.; Robinson, D.G.; Hasek, J.; Paciorek, T.; Petrasek, J.; Seifertova, D.; Tejos, R.; Meisel, L.A.; Zazimalova, E.; Gadella, T.W.; Stierhof, Y.D.; Ueda, T.; Oiwa, K.; Akhmanova, A.; Brock, R.E.; Spang, A.; Friml, J.

    2008-01-01

    Many aspects of plant development, including patterning and tropisms, are largely dependent on the asymmetric distribution of the plant signaling molecule auxin. Auxin transport inhibitors (ATIs), which interfere with directional auxin transport, have been essential tools in formulating this

  14. Polar auxin transport is essential for gall formation by Pantoea agglomerans on Gypsophila.

    Science.gov (United States)

    Chalupowicz, Laura; Weinthal, Dan; Gaba, Victor; Sessa, Guido; Barash, Isaac; Manulis-Sasson, Shulamit

    2013-02-01

    The virulence of the bacterium Pantoea agglomerans pv. gypsophilae (Pag) on Gypsophila paniculata depends on a type III secretion system (T3SS) and its effectors. The hypothesis that plant-derived indole-3-acetic acid (IAA) plays a major role in gall formation was examined by disrupting basipetal polar auxin transport with the specific inhibitors 2,3,5-triiodobenzoic acid (TIBA) and N-1-naphthylphthalamic acid (NPA). On inoculation with Pag, galls developed in gypsophila stems above but not below lanolin rings containing TIBA or NPA, whereas, in controls, galls developed above and below the rings. In contrast, TIBA and NPA could not inhibit tumour formation in tomato caused by Agrobacterium tumefaciens. The colonization of gypsophila stems by Pag was reduced below, but not above, the lanolin-TIBA ring. Following Pag inoculation and TIBA treatment, the expression of hrpL (a T3SS regulator) and pagR (a quorum-sensing transcriptional regulator) decreased four-fold and that of pthG (a T3SS effector) two-fold after 24 h. Expression of PIN2 (a putative auxin efflux carrier) increased 35-fold, 24 h after Pag inoculation. However, inoculation with a mutant in the T3SS effector pthG reduced the expression of PIN2 by two-fold compared with wild-type infection. The results suggest that pthG might govern the elevation of PIN2 expression during infection, and that polar auxin transport-derived IAA is essential for gall initiation. © 2012 THE AUTHORS. MOLECULAR PLANT PATHOLOGY © 2012 BSPP AND BLACKWELL PUBLISHING LTD.

  15. Design of a TW-SLIM Module for Dual Polarity Confinement, Transport, and Reactions

    Science.gov (United States)

    Garimella, Sandilya V. B.; Webb, Ian K.; Prabhakaran, Aneesh; Attah, Isaac K.; Ibrahim, Yehia M.; Smith, Richard D.

    2017-07-01

    Here we describe instrumental approaches for performing dual polarity ion confinement, transport, ion mobility separations, and reactions in structures for lossless ion manipulations (SLIM). Previous means of ion confinement in SLIM, based upon rf-generated pseudopotentials and DC fields for lateral confinement, cannot trap ions of opposite polarity simultaneously. Here we explore alternative approaches to provide simultaneous lateral confinement of both ion polarities. Traveling wave ion mobility (IM) separations experienced in such SLIM cause ions of both polarities to migrate in the same directions and exhibit similar separations. The ion motion (and relative motion of the two polarities) under both surfing and IM separation conditions are discussed. In surfing conditions the two polarities are transported losslessly and non-reactively in their respective potential minima (higher absolute voltage regions confine negative polarities, and lower absolute potential regions are populated by positive polarities). In separation mode, where ions roll over an overtaking traveling wave, the two polarities can interact during the rollovers. Strategies to minimize overlap of the two ion populations to prevent reactive losses during separations are presented. A theoretical treatment of the time scales over which two populations (injected into a DC field-free region of the dual polarity SLIM device) interact is considered, and SLIM designs for allowing ion/ion interactions and other manipulations with dual polarities at 4 Torr are presented.

  16. Flavonoids and Auxin Transport Inhibitors Rescue Symbiotic Nodulation in the Medicago truncatula Cytokinin Perception Mutant cre1

    Science.gov (United States)

    Ng, Jason Liang Pin; Hassan, Samira; Truong, Thy T.; Hocart, Charles H.; Laffont, Carole; Frugier, Florian; Mathesius, Ulrike

    2015-01-01

    Initiation of symbiotic nodules in legumes requires cytokinin signaling, but its mechanism of action is largely unknown. Here, we tested whether the failure to initiate nodules in the Medicago truncatula cytokinin perception mutant cre1 (cytokinin response1) is due to its altered ability to regulate auxin transport, auxin accumulation, and induction of flavonoids. We found that in the cre1 mutant, symbiotic rhizobia cannot locally alter acro- and basipetal auxin transport during nodule initiation and that these mutants show reduced auxin (indole-3-acetic acid) accumulation and auxin responses compared with the wild type. Quantification of flavonoids, which can act as endogenous auxin transport inhibitors, showed a deficiency in the induction of free naringenin, isoliquiritigenin, quercetin, and hesperetin in cre1 roots compared with wild-type roots 24 h after inoculation with rhizobia. Coinoculation of roots with rhizobia and the flavonoids naringenin, isoliquiritigenin, and kaempferol, or with the synthetic auxin transport inhibitor 2,3,5,-triiodobenzoic acid, rescued nodulation efficiency in cre1 mutants and allowed auxin transport control in response to rhizobia. Our results suggest that CRE1-dependent cytokinin signaling leads to nodule initiation through the regulation of flavonoid accumulation required for local alteration of polar auxin transport and subsequent auxin accumulation in cortical cells during the early stages of nodulation. PMID:26253705

  17. The arabidopsis thaliana AGRAVITROPIC 1 gene encodes a component of the polar-auxin-transport efflux carrier

    Science.gov (United States)

    Chen, R.; Hilson, P.; Sedbrook, J.; Rosen, E.; Caspar, T.; Masson, P. H.

    1998-01-01

    Auxins are plant hormones that mediate many aspects of plant growth and development. In higher plants, auxins are polarly transported from sites of synthesis in the shoot apex to their sites of action in the basal regions of shoots and in roots. Polar auxin transport is an important aspect of auxin functions and is mediated by cellular influx and efflux carriers. Little is known about the molecular identity of its regulatory component, the efflux carrier [Estelle, M. (1996) Current Biol. 6, 1589-1591]. Here we show that mutations in the Arabidopsis thaliana AGRAVITROPIC 1 (AGR1) gene involved in root gravitropism confer increased root-growth sensitivity to auxin and decreased sensitivity to ethylene and an auxin transport inhibitor, and cause retention of exogenously added auxin in root tip cells. We used positional cloning to show that AGR1 encodes a putative transmembrane protein whose amino acid sequence shares homologies with bacterial transporters. When expressed in Saccharomyces cerevisiae, AGR1 promotes an increased efflux of radiolabeled IAA from the cells and confers increased resistance to fluoro-IAA, a toxic IAA-derived compound. AGR1 transcripts were localized to the root distal elongation zone, a region undergoing a curvature response upon gravistimulation. We have identified several AGR1-related genes in Arabidopsis, suggesting a global role of this gene family in the control of auxin-regulated growth and developmental processes.

  18. A fluorescence polarization based screening assay for identification of small molecule inhibitors of the PICK1 PDZ domain

    DEFF Research Database (Denmark)

    Thorsen, Thor S; Madsen, Kenneth L; Dyhring, Tino

    2011-01-01

    PDZ (PSD-95/Discs-large/ZO-1 homology) domains represent putative targets in several diseases including cancer, stroke, addiction and neuropathic pain. Here we describe the application of a simple and fast screening assay based on fluorescence polarization (FP) to identify inhibitors of the PDZ...

  19. Polarized protein transport and lumen formation during epithelial tissue morphogenesis.

    Science.gov (United States)

    Blasky, Alex J; Mangan, Anthony; Prekeris, Rytis

    2015-01-01

    One of the major challenges in biology is to explain how complex tissues and organs arise from the collective action of individual polarized cells. The best-studied model of this process is the cross talk between individual epithelial cells during their polarization to form the multicellular epithelial lumen during tissue morphogenesis. Multiple mechanisms of apical lumen formation have been proposed. Some epithelial lumens form from preexisting polarized epithelial structures. However, de novo lumen formation from nonpolarized cells has recently emerged as an important driver of epithelial tissue morphogenesis, especially during the formation of small epithelial tubule networks. In this review, we discuss the latest findings regarding the mechanisms and regulation of de novo lumen formation in vitro and in vivo.

  20. Effect of the degree of polar mismatching on traffic jam formation in fast axonal transport.

    Science.gov (United States)

    Kuznetsov, A V

    2010-12-01

    This paper simulates an axon with a region of reversed microtubule (MT) polarity, and investigates how the degree of polar mismatching in this region affects the formation of organelle traps in the axon. The model is based on modified Smith-Simmons equations governing molecular-motor-assisted transport in neurons. It is established that the structure that develops as a result of a region with disoriented MTs consists of two organelle traps, the trap to the left of this region accumulates plus-end-oriented organelles and the trap to the right of this region accumulates minus-end-oriented organelles. The presence of such a structure is shown to inhibit the transport of organelles down the axon. The degree by which the transport of organelles is inhibited depends on the degree of polar mismatching of MTs in the region between MT traps. Four cases with a different degree of polar mismatching are investigated.

  1. Polarized recombination of acoustically transported carriers in GaAs nanowires

    Science.gov (United States)

    Möller, Michael; Hernández-Mínguez, Alberto; Breuer, Steffen; Pfüller, Carsten; Brandt, Oliver; de Lima, Mauricio M.; Cantarero, Andrés; Geelhaar, Lutz; Riechert, Henning; Santos, Paulo V.

    2012-05-01

    The oscillating piezoelectric field of a surface acoustic wave (SAW) is employed to transport photoexcited electrons and holes in GaAs nanowires deposited on a SAW delay line on a LiNbO3 crystal. The carriers generated in the nanowire by a focused light spot are acoustically transferred to a second location where they recombine. We show that the recombination of the transported carriers occurs in a zinc blende section on top of the predominant wurtzite nanowire. This allows contactless control of the linear polarized emission by SAWs which is governed by the crystal structure. Additional polarization-resolved photoluminescence measurements were performed to investigate spin conservation during transport.

  2. Flavonoids Are Inhibitors of Human Organic Anion Transporter 1 (OAT1)–Mediated Transport

    Science.gov (United States)

    An, Guohua; Wang, Xiaodong

    2014-01-01

    Organic anion transporter 1 (OAT1) has been reported to be involved in the nephrotoxicity of many anionic xenobiotics. As current clinically used OAT1 inhibitors are often associated with safety issues, identifying potent OAT1 inhibitors with little toxicity is of great value in reducing OAT1-mediated drug nephrotoxicity. Flavonoids are a class of polyphenolic compounds with exceptional safety records. Our objective was to evaluate the effects of 18 naturally occurring flavonoids, and some of their glycosides, on the uptake of para-aminohippuric acid (PAH) in both OAT1-expressing and OAT1-negative LLC-PK1 cells. Most flavonoid aglycones produced substantial decreases in PAH uptake in OAT1-expressing cells. Among the flavonoids screened, fisetin, luteolin, morin, and quercetin exhibited the strongest effect and produced complete inhibition of OAT1-mediated PAH uptake at a concentration of 50 μM. Further concentration-dependent studies revealed that both morin and luteolin are potent OAT1 inhibitors, with IC50 values of flavonoid aglycones, all flavonoid glycosides had negligible or small effects on OAT1. In addition, the role of OAT1 in the uptake of fisetin, luteolin, morin, and quercetin was investigated and fisetin was found to be a substrate of OAT1. Taken together, our results indicate that flavonoids are a novel class of OAT1 modulators. Considering the high consumption of flavonoids in the diet and in herbal products, OAT1-mediated flavonoid-drug interactions may be clinically relevant. Further investigation is warranted to evaluate the nephroprotective role of flavonoids in relation to drug-induced nephrotoxicity mediated by the OAT1 pathway. PMID:25002746

  3. Velocity barrier-controlled of spin-valley polarized transport in monolayer WSe2 junction

    Science.gov (United States)

    Qiu, Xuejun; Lv, Qiang; Cao, Zhenzhou

    2018-05-01

    In this work, we have theoretically investigated the influence of velocity barrier on the spin-valley polarized transport in monolayer (ML) WSe2 junction with a large spin-orbit coupling (SOC). Both the spin-valley resolved transmission probabilities and conductance are strong dependent on the velocity barrier, as the velocity barrier decreases to 0.06, a spin-valley polarization of exceeding 90% is observed, which is distinct from the ML MoS2 owing to incommensurable SOC. In addition, the spin-valley polarization is further increased above 95% in a ML WSe2 superlattice, in particular, it's found many extraordinary velocity barrier-dependent transport gaps for multiple barrier due to evanescent tunneling. Our results may open an avenue for the velocity barrier-controlled high-efficiency spin and valley polarizations in ML WSe2-based electronic devices.

  4. Investigation of Beam Emittance and Beam Transport Line Optics on Polarization

    Energy Technology Data Exchange (ETDEWEB)

    Fiedler, Andrew [Northern Illinois U.; Syphers, Michael [Fermilab

    2017-10-06

    Effects of beam emittance, energy spread, optical parameters and magnet misalignment on beam polarization through particle transport systems are investigated. Particular emphasis will be placed on the beam lines being used at Fermilab for the development of the muon beam for the Muon g-2 experiment, including comparisons with the natural polarization resulting from pion decay, and comments on the development of systematic correlations among phase space variables.

  5. Valley-polarized quantum transport generated by gauge fields in graphene

    DEFF Research Database (Denmark)

    Settnes, Mikkel; Garcia, Jose H; Roche, Stephan

    2017-01-01

    We report on the possibility to simultaneously generate in graphene a bulk valley-polarized dissipative transport and a quantum valley Hall effect by combining strain-induced gauge fields and real magnetic fields. Such unique phenomenon results from a ‘resonance/anti-resonance’ effect driven...... by the superposition/cancellation of superimposed gauge fields which differently affect time reversal symmetry. The onset of a valley-polarized Hall current concomitant to a dissipative valley-polarized current flow in the opposite valley is revealed by a Hall conductivity plateau. We employ efficient linear scaling...

  6. Aspergillus myosin-V supports polarized growth in the absence of microtubule-based transport.

    Directory of Open Access Journals (Sweden)

    Jun Zhang

    Full Text Available In the filamentous fungus Aspergillus nidulans, both microtubules and actin filaments are important for polarized growth at the hyphal tip. Less clear is how different microtubule-based and actin-based motors work together to support this growth. Here we examined the role of myosin-V (MYOV in hyphal growth. MYOV-depleted cells form elongated hyphae, but the rate of hyphal elongation is significantly reduced. In addition, although wild type cells without microtubules still undergo polarized growth, microtubule disassembly abolishes polarized growth in MYOV-depleted cells. Thus, MYOV is essential for polarized growth in the absence of microtubules. Moreover, while a triple kinesin null mutant lacking kinesin-1 (KINA and two kinesin-3s (UNCA and UNCB undergoes hyphal elongation and forms a colony, depleting MYOV in this triple mutant results in lethality due to a severe defect in polarized growth. These results argue that MYOV, through its ability to transport secretory cargo, can support a significant amount of polarized hyphal tip growth in the absence of any microtubule-based transport. Finally, our genetic analyses also indicate that KINA (kinesin-1 rather than UNCA (kinesin-3 is the major kinesin motor that supports polarized growth in the absence of MYOV.

  7. Energy transport, polar amplification, and ITCZ shifts in the GeoMIP G1 ensemble

    Directory of Open Access Journals (Sweden)

    R. D. Russotto

    2018-02-01

    Full Text Available The polar amplification of warming and the ability of the Intertropical Convergence Zone (ITCZ to shift to the north or south are two very important problems in climate science. Examining these behaviors in global climate models (GCMs running solar geoengineering experiments is helpful not only for predicting the effects of solar geoengineering but also for understanding how these processes work under increased carbon dioxide (CO2. Both polar amplification and ITCZ shifts are closely related to the meridional transport of moist static energy (MSE by the atmosphere. This study examines changes in MSE transport in 10 fully coupled GCMs in experiment G1 of the Geoengineering Model Intercomparison Project (GeoMIP, in which the solar constant is reduced to compensate for the radiative forcing from abruptly quadrupled CO2 concentrations. In G1, poleward MSE transport decreases relative to preindustrial conditions in all models, in contrast to the Coupled Model Intercomparison Project phase 5 (CMIP5 abrupt4xCO2 experiment, in which poleward MSE transport increases. We show that since poleward energy transport decreases rather than increases, and local feedbacks cannot change the sign of an initial temperature change, the residual polar amplification in the G1 experiment must be due to the net positive forcing in the polar regions and net negative forcing in the tropics, which arise from the different spatial patterns of the simultaneously imposed solar and CO2 forcings. However, the reduction in poleward energy transport likely plays a role in limiting the polar warming in G1. An attribution study with a moist energy balance model shows that cloud feedbacks are the largest source of uncertainty regarding changes in poleward energy transport in midlatitudes in G1, as well as for changes in cross-equatorial energy transport, which are anticorrelated with ITCZ shifts.

  8. Energy transport, polar amplification, and ITCZ shifts in the GeoMIP G1 ensemble

    Science.gov (United States)

    Russotto, Rick D.; Ackerman, Thomas P.

    2018-02-01

    The polar amplification of warming and the ability of the Intertropical Convergence Zone (ITCZ) to shift to the north or south are two very important problems in climate science. Examining these behaviors in global climate models (GCMs) running solar geoengineering experiments is helpful not only for predicting the effects of solar geoengineering but also for understanding how these processes work under increased carbon dioxide (CO2). Both polar amplification and ITCZ shifts are closely related to the meridional transport of moist static energy (MSE) by the atmosphere. This study examines changes in MSE transport in 10 fully coupled GCMs in experiment G1 of the Geoengineering Model Intercomparison Project (GeoMIP), in which the solar constant is reduced to compensate for the radiative forcing from abruptly quadrupled CO2 concentrations. In G1, poleward MSE transport decreases relative to preindustrial conditions in all models, in contrast to the Coupled Model Intercomparison Project phase 5 (CMIP5) abrupt4xCO2 experiment, in which poleward MSE transport increases. We show that since poleward energy transport decreases rather than increases, and local feedbacks cannot change the sign of an initial temperature change, the residual polar amplification in the G1 experiment must be due to the net positive forcing in the polar regions and net negative forcing in the tropics, which arise from the different spatial patterns of the simultaneously imposed solar and CO2 forcings. However, the reduction in poleward energy transport likely plays a role in limiting the polar warming in G1. An attribution study with a moist energy balance model shows that cloud feedbacks are the largest source of uncertainty regarding changes in poleward energy transport in midlatitudes in G1, as well as for changes in cross-equatorial energy transport, which are anticorrelated with ITCZ shifts.

  9. Calcium- and BTB domain protein-modulated PINOID kinase directs polar auxin transport

    NARCIS (Netherlands)

    Robert-Boisivon, Hélène S.

    2008-01-01

    Plant architecture is determined by tightly regulated developmental processes that largely depend on the action of the plant hormone auxin. A major determinant in auxin action, besides its signaling pathway, is its polar cell-to-cell transport (PAT) throughout the plant. The direction on this

  10. Spin-polarized transport in a two-dimensional electron gas with interdigital-ferromagnetic contacts

    DEFF Research Database (Denmark)

    Hu, C.-M.; Nitta, Junsaku; Jensen, Ane

    2001-01-01

    Ferromagnetic contacts on a high-mobility, two-dimensional electron gas (2DEG) in a narrow gap semiconductor with strong spin-orbit interaction are used to investigate spin-polarized electron transport. We demonstrate the use of magnetized contacts to preferentially inject and detect specific spi...

  11. Identification of IAA transport inhibitors including compounds affecting cellular PIN trafficking by two chemical screening approaches using maize coleoptile systems.

    Science.gov (United States)

    Nishimura, Takeshi; Matano, Naoyuki; Morishima, Taichi; Kakinuma, Chieko; Hayashi, Ken-Ichiro; Komano, Teruya; Kubo, Minoru; Hasebe, Mitsuyasu; Kasahara, Hiroyuki; Kamiya, Yuji; Koshiba, Tomokazu

    2012-10-01

    The monocot coleoptile tip region has been generally supposed to be the source of IAA to supply IAA to basal parts by the polar IAA transport system, which results in gravi- and phototropic curvature of coleoptiles. Based on this IAA transport system and gravitropism of maize coleoptiles, we have developed two screening methods to identify small molecules from a large chemical library that inhibit IAA transport. The methods detect molecules that affect (i) gravitropic curvature of coleoptiles; and (ii) the amount of IAA transported from the tip. From 10,000 chemicals, eight compounds were identified and categorized into two groups. Four chemicals in group A decreased IAA transport from the tip, and increased endogenous IAA levels in the tip. The structures of two compounds resembled that of 1-N-naphthylphthalamic acid (NPA), but those of the other two differed from structures of known IAA transport inhibitors. Four chemicals in group B strongly inhibited IAA transport from the tip, but IAA levels at the tip were only slightly affected. At higher concentrations, group B compounds inhibited germination of Arabidopsis, similarly to brefeldin A (BFA). Analysis of the cellular distribution of PIN2-green fluorescent protein (GFP) and PIN1-GFP in Arabidopsis revealed that one of the four chemicals in group B induced internalization of PIN1 and PIN2 proteins into vesicles smaller than BFA bodies, suggesting that this compound affects cellular vesicle trafficking systems related to PIN trafficking. The eight chemicals identified here will be a useful tool for understanding the mechanisms of IAA transport in plants.

  12. Spin-polarized quantum transport properties through flexible phosphorene

    Science.gov (United States)

    Chen, Mingyan; Yu, Zhizhou; Xie, Yiqun; Wang, Yin

    2016-10-01

    We report a first-principles study on the tunnel magnetoresistance (TMR) and spin-injection efficiency (SIE) through phosphorene with nickel electrodes under the mechanical tension and bending on the phosphorene region. Both the TMR and SIE are largely improved under these mechanical deformations. For the uniaxial tension (ɛy) varying from 0% to 15% applied along the armchair transport (y-)direction of the phosphorene, the TMR ratio is enhanced with a maximum of 107% at ɛy = 10%, while the SIE increases monotonously from 8% up to 43% with the increasing of the strain. Under the out-of-plane bending, the TMR overall increases from 7% to 50% within the bending ratio of 0%-3.9%, and meanwhile the SIE is largely improved to around 70%, as compared to that (30%) of the flat phosphorene. Such behaviors of the TMR and SIE are mainly affected by the transmission of spin-up electrons in the parallel configuration, which is highly dependent on the applied mechanical tension and bending. Our results indicate that the phosphorene based tunnel junctions have promising applications in flexible electronics.

  13. Charge transport by inverse micelles in non-polar media

    Science.gov (United States)

    Strubbe, Filip; Neyts, Kristiaan

    2017-11-01

    Charged inverse micelles play an important role in the electrical charging and the electrodynamics of nonpolar colloidal dispersions relevant for applications such as electronic ink displays and liquid toner printing. This review examines the properties and the behavior of charged inverse micelles in microscale devices in the absence of colloidal particles. It is discussed how charge in nonpolar liquids is stabilized in inverse micelles and how conductivity depends on the inverse micelle size, water content and ionic impurities. Frequently used nonpolar surfactant systems are investigated with emphasis on aerosol-OT (AOT) and poly-isobutylene succinimide (PIBS) in dodecane. Charge generation in the bulk by disproportionation is studied from measurements of conductivity as a function of surfactant concentration and from generation currents in quasi steady-state. When a potential difference is applied, the steady-state situation can show electric field screening or complete charge separation. Different regimes of charge transport are identified when a voltage step is applied. It is shown how the transient and steady-state currents depend on the rate of bulk generation, on insulating layers and on the sticking or non-sticking behavior of charged inverse micelles at interfaces. For the cases of AOT and PIBS in dodecane, the magnitude of the generation rate and the type of interaction at the interface are very different.

  14. Understanding the effects of electronic polarization and delocalization on charge-transport levels in oligoacene systems

    KAUST Repository

    Sutton, Christopher

    2017-06-13

    Electronic polarization and charge delocalization are important aspects that affect the charge-transport levels in organic materials. Here, using a quantum mechanical/ embedded-charge (QM/EC) approach based on a combination of the long-range corrected omega B97X-D exchange-correlation functional (QM) and charge model 5 (CM5) point-charge model (EC), we evaluate the vertical detachment energies and polarization energies of various sizes of crystalline and amorphous anionic oligoacene clusters. Our results indicate that QM/EC calculations yield vertical detachment energies and polarization energies that compare well with the experimental values obtained from ultraviolet photoemission spectroscopy measurements. In order to understand the effect of charge delocalization on the transport levels, we considered crystalline naphthalene systems with QM regions including one or five-molecules. The results for these systems show that the delocalization and polarization effects are additive; therefore, allowing for electron delocalization by increasing the size of the QM region leads to the additional stabilization of the transport levels. Published by AIP Publishing.

  15. Identification of the first highly selective inhibitor of human GABA transporter GAT3

    DEFF Research Database (Denmark)

    Damgaard, Maria; Al-Khawaja, Anas; Vogensen, Stine B.

    2015-01-01

    Screening a library of small-molecule compounds using a cell line expressing human GABA transporter 3 (hGAT3) in a [(3)H]GABA uptake assay identified isatin derivatives as a new class of hGAT3 inhibitors. A subsequent structure-activity relationship (SAR) study led to the identification of hGAT3-...... site that matched the observed selectivity, inhibition kinetics, and SAR of the compound series. These compounds are the most potent GAT3 inhibitors reported to date that provide selectivity for GAT3 over other GABA transporter subtypes....

  16. Inhibitors

    Science.gov (United States)

    ... Icon View public health webinars on blood disorders Inhibitors Language: English (US) Español (Spanish) Recommend on Facebook ... because treatment of bleeds becomes less effective. About Inhibitors People with hemophilia, and many with VWD type ...

  17. Heterocyclic Analogues of Modafinil as Novel, Atypical Dopamine Transporter Inhibitors.

    Science.gov (United States)

    Kalaba, Predrag; Aher, Nilima Y; Ilić, Marija; Dragačević, Vladimir; Wieder, Marcus; Miklosi, Andras G; Zehl, Martin; Wackerlig, Judith; Roller, Alexander; Beryozkina, Tetyana; Radoman, Bojana; Saroja, Sivaprakasam R; Lindner, Wolfgang; Gonzalez, Eduardo Perez; Bakulev, Vasiliy; Leban, Johann Jakob; Sitte, Harald H; Urban, Ernst; Langer, Thierry; Lubec, Gert

    2017-11-22

    Modafinil is a wake promoting compound with high potential for cognitive enhancement. It is targeting the dopamine transporter (DAT) with moderate selectivity, thereby leading to reuptake inhibition and increased dopamine levels in the synaptic cleft. A series of modafinil analogues have been reported so far, but more target-specific analogues remain to be discovered. It was the aim of this study to synthesize and characterize such analogues and, indeed, a series of compounds were showing higher activities on the DAT and a higher selectivity toward DAT versus serotonin and norepinephrine transporters than modafinil. This was achieved by substituting the amide moiety by five- and six-membered aromatic heterocycles. In vitro studies indicated binding to the cocaine pocket on DAT, although molecular dynamics revealed binding different from that of cocaine. Moreover, no release of dopamine was observed, ruling out amphetamine-like effects. The absence of neurotoxicity of a representative analogue may encourage further preclinical studies of the above-mentioned compounds.

  18. Luminal nucleotides are tonic inhibitors of renal tubular transport

    DEFF Research Database (Denmark)

    Leipziger, Jens Georg

    2011-01-01

    PURPOSE OF REVIEW: Extracellular ATP is an essential local signaling molecule in all organ systems. In the kidney, purinergic signaling is involved in an array of functions and this review highlights those of relevance for renal tubular transport. RECENT FINDINGS: Purinergic receptors are expressed...... in all renal tubular segments and their stimulation generally leads to transport inhibition. Recent evidence has identified the tubular lumen as a restricted space for purinergic signaling. The concentrations of ATP in the luminal fluids are sufficiently high to inflict a tonic inhibition of renal...... tubular absorption via P2 receptors. The apical P2Y2 receptor plays a crucial role in this process. ATP is released continuously into the tubular lumen. The release is augmented in response to an increase of tubular flow and after stimulation of G-protein-coupled receptors. The primary cilium appears...

  19. Discovery of PF-06928215 as a high affinity inhibitor of cGAS enabled by a novel fluorescence polarization assay

    Energy Technology Data Exchange (ETDEWEB)

    Hall, Justin; Brault, Amy; Vincent, Fabien; Weng, Shawn; Wang, Hong; Dumlao, Darren; Aulabaugh, Ann; Aivazian, Dikran; Castro, Dana; Chen, Ming; Culp, Jeffrey; Dower, Ken; Gardner, Joseph; Hawrylik, Steven; Golenbock, Douglas; Hepworth, David; Horn, Mark; Jones, Lyn; Jones, Peter; Latz, Eicke; Li, Jing; Lin, Lih-Ling; Lin, Wen; Lin, David; Lovering, Frank; Niljanskul, Nootaree; Nistler, Ryan; Pierce, Betsy; Plotnikova, Olga; Schmitt, Daniel; Shanker, Suman; Smith, James; Snyder, William; Subashi, Timothy; Trujillo, John; Tyminski, Edyta; Wang, Guoxing; Wong, Jimson; Lefker, Bruce; Dakin, Leslie; Leach, Karen (UMASS, MED); (Pfizer)

    2017-09-21

    Cyclic GMP-AMP synthase (cGAS) initiates the innate immune system in response to cytosolic dsDNA. After binding and activation from dsDNA, cGAS uses ATP and GTP to synthesize 2', 3' -cGAMP (cGAMP), a cyclic dinucleotide second messenger with mixed 2'-5' and 3'-5' phosphodiester bonds. Inappropriate stimulation of cGAS has been implicated in autoimmune disease such as systemic lupus erythematosus, thus inhibition of cGAS may be of therapeutic benefit in some diseases; however, the size and polarity of the cGAS active site makes it a challenging target for the development of conventional substrate-competitive inhibitors. We report here the development of a high affinity (KD = 200 nM) inhibitor from a low affinity fragment hit with supporting biochemical and structural data showing these molecules bind to the cGAS active site. We also report a new high throughput cGAS fluorescence polarization (FP)-based assay to enable the rapid identification and optimization of cGAS inhibitors. This FP assay uses Cy5-labelled cGAMP in combination with a novel high affinity monoclonal antibody that specifically recognizes cGAMP with no cross reactivity to cAMP, cGMP, ATP, or GTP. Given its role in the innate immune response, cGAS is a promising therapeutic target for autoinflammatory disease. Our results demonstrate its druggability, provide a high affinity tool compound, and establish a high throughput assay for the identification of next generation cGAS inhibitors.

  20. Spin-polarized transport in a δ-doped magnetic-barrier nanostructure

    Energy Technology Data Exchange (ETDEWEB)

    Li, Shuai; Lu, Mao-Wang, E-mail: maowanglu@126.com; Jiang, Ya-Qing; Chen, Sai-Yan

    2014-09-05

    We theoretically investigate the electron spin transport properties through a δ-doped magnetic-barrier nanostructure, which can be realized experimentally by depositing two identical ferromagnetic stripes with the opposite in-plane magnetization on the top of a semiconductor heterostructure in parallel configuration and by using atomic layer doping technique. The δ-doping dependent transmission, conductance and spin polarization are calculated exactly by analytically solving Schrödinger equation of the spin electron. It is found that the electronic spin-polarized behavior in this device can be manipulated by changing the weight and/or the position of the δ-doping. Therefore, such a device can be used as a controllable spin filter, which may be helpful for spintronics applications. - Highlights: • Spin-polarized transport in a δ-doped magnetic-barrier nanostructure is explored. • Both magnitude and sign of spin polarization depend on the δ-doping. • A controllable spin filter can be achieved for spintronics applications.

  1. Convergences and divergences in polar auxin transport and shoot development in land plant evolution

    OpenAIRE

    Fujita, Tomomichi; Hasebe, Mitsuyasu

    2009-01-01

    A shoot is a reiterated structure consisting of stems and leaves and is the prevailing body plan in most land plant lineages. Vascular plants form shoots in the diploid generation, whereas mosses do so in the haploid generation.1 However, whether these plants use similar molecular mechanisms in shoot development and how the genetic networks for shoot development evolved is not clear. In our recent paper,2 we examined polar auxin transport in several mosses, which is essential for shoot develo...

  2. Disruption of the polar auxin transport system in cotton seedlings following treatment with the defoliant thidiazuron

    International Nuclear Information System (INIS)

    Suttle, J.C.

    1988-01-01

    The effect of the defoliant thidiazuron (TDZ) on basipetal auxin transport in petiole segments isolated from cotton (Gossypium hirsutum L. cv LG102) seedlings was examined using the donor/receiver agar block technique. Treatment of intact seedlings with TDZ at concentrations of 1 micromolar or greater resulted in a dose-dependent inhibition of 14 C-IAA transport in petiole segment isolated 1 or 2 days after treatment. Using 100 micromolar TDZ, the inhibition was detectable 19 hours after treatment and was complete by 27 hours. Both leaves and petiole segments exhibited a marked increase in ethylene production following treatment with TDZ at concentrations of 0.1 micromolar or greater. The involvement of ethylene in this TDA response was evaluated by examining the effects of two inhibitors of ethylene action: silver thiosulfate, 2,5-norbornadiene. One day after treatment, both inhibitors effectively antagonized the TDZ-induced inhibition of auxin transport. Two days after TDZ treatment both inhibitors were ineffective. The decrease in IAA transport in TDZ treated tissues was associated with increased metabolism of IAA. The transport of 14 C-2,4-dichlorophenoxyacetic acid was also inhibited by TDZ treatment. This inhibition was not accompanied by increased metabolism. Incorporation of TDZ into the receiver blocks had no effect on auxin transport. The ability of the phytotropin N-1-naphthylphthalamic acid to stimulate IAA uptake from a bathing medium was reduced in TDZ-treated tissues. This reduction is thought to reflect a decline in the auxin efflux system following TDZ treatment

  3. Spin-polarized transport properties of a pyridinium-based molecular spintronics device

    Science.gov (United States)

    Zhang, J.; Xu, B.; Qin, Z.

    2018-05-01

    By applying a first-principles approach based on non-equilibrium Green's functions combined with density functional theory, the transport properties of a pyridinium-based "radical-π-radical" molecular spintronics device are investigated. The obvious negative differential resistance (NDR) and spin current polarization (SCP) effect, and abnormal magnetoresistance (MR) are obtained. Orbital reconstruction is responsible for novel transport properties such as that the MR increases with bias and then decreases and that the NDR being present for both parallel and antiparallel magnetization configurations, which may have future applications in the field of molecular spintronics.

  4. Evidence for regulation of polar auxin transport at the efflux carrier in maize coleoptile sections

    International Nuclear Information System (INIS)

    Vesper, M.J.

    1989-01-01

    Previously we have shown that conditions which result in an increased auxin-induced growth response in maize (Zea mays L.) coleoptile sections also result in a decrease in the velocity of polar auxin transport. Coleoptile sections given conditions which result in slower transport of IAA have different kinetics for net IAA accumulation compared to sections given conditions which result in faster transport. In further experiments, sections were loaded with 30 nM ( 3 H)IAA in the presence of increasing unlabeled IAA at low pH. Efflux of ( 3 H)IAA was then followed as a function of unlabeled IAA. Saturation of efflux appears to occur at a lower conc. of IAA in sections showing slower transport

  5. The organic anion transport inhibitor probenecid increases brain concentrations of the NKCC1 inhibitor bumetanide.

    Science.gov (United States)

    Töllner, Kathrin; Brandt, Claudia; Römermann, Kerstin; Löscher, Wolfgang

    2015-01-05

    Bumetanide is increasingly being used for experimental treatment of brain disorders, including neonatal seizures, epilepsy, and autism, because the neuronal Na-K-Cl cotransporter NKCC1, which is inhibited by bumetanide, is implicated in the pathophysiology of such disorders. However, use of bumetanide for treatment of brain disorders is associated with problems, including poor brain penetration and systemic adverse effects such as diuresis, hypokalemic alkalosis, and hearing loss. The poor brain penetration is thought to be related to its high ionization rate and plasma protein binding, which restrict brain entry by passive diffusion, but more recently brain efflux transporters have been involved, too. Multidrug resistance protein 4 (MRP4), organic anion transporter 3 (OAT3) and organic anion transporting polypeptide 2 (OATP2) were suggested to mediate bumetanide brain efflux, but direct proof is lacking. Because MRP4, OAT3, and OATP2 can be inhibited by probenecid, we studied whether this drug alters brain levels of bumetanide in mice. Probenecid (50 mg/kg) significantly increased brain levels of bumetanide up to 3-fold; however, it also increased its plasma levels, so that the brain:plasma ratio (~0.015-0.02) was not altered. Probenecid markedly increased the plasma half-life of bumetanide, indicating reduced elimination of bumetanide most likely by inhibition of OAT-mediated transport of bumetanide in the kidney. However, the diuretic activity of bumetanide was not reduced by probenecid. In conclusion, our study demonstrates that the clinically available drug probenecid can be used to increase brain levels of bumetanide and decrease its elimination, which could have therapeutic potential in the treatment of brain disorders. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. The Isomeric Preference of an Atypical Dopamine Transporter Inhibitor Contributes to Its Selection of the Transporter Conformation

    DEFF Research Database (Denmark)

    Abramyan, Ara M.; Stolzenberg, Sebastian; Li, Zheng

    2017-01-01

    Cocaine, a widely abused psychostimulant, inhibits the dopamine transporter (DAT) by trapping the protein in an outward-open conformation, whereas atypical DAT inhibitors such as benztropine have low abuse liability and prefer less outward-open conformations. Here, we use a spectrum of computatio......Cocaine, a widely abused psychostimulant, inhibits the dopamine transporter (DAT) by trapping the protein in an outward-open conformation, whereas atypical DAT inhibitors such as benztropine have low abuse liability and prefer less outward-open conformations. Here, we use a spectrum...... in binding to DAT compared to that of a cocaine derivative, CFT. To further investigate the different inhibition mechanisms of DAT, we carried out MD simulations in combination with Markov state modeling analysis of wild-type and Y156F DAT in the absence of any ligand or the presence of CFT or JHW007. Our...

  7. Generation and Characterization of Anti-VGLUT Nanobodies Acting as Inhibitors of Transport.

    Science.gov (United States)

    Schenck, Stephan; Kunz, Laura; Sahlender, Daniela; Pardon, Els; Geertsma, Eric R; Savtchouk, Iaroslav; Suzuki, Toshiharu; Neldner, Yvonne; Štefanić, Saša; Steyaert, Jan; Volterra, Andrea; Dutzler, Raimund

    2017-08-01

    The uptake of glutamate by synaptic vesicles is mediated by vesicular glutamate transporters (VGLUTs). The central role of these transporters in excitatory neurotransmission underpins their importance as pharmacological targets. Although several compounds inhibit VGLUTs, highly specific inhibitors were so far unavailable, thus limiting applications to in vitro experiments. Besides their potential in pharmacology, specific inhibitors would also be beneficial for the elucidation of transport mechanisms. To overcome this shortage, we generated nanobodies (Nbs) by immunization of a llama with purified rat VGLUT1 and subsequent selection of binders from a phage display library. All identified Nbs recognize cytosolic epitopes, and two of the binders greatly reduced the rate of uptake of glutamate by reconstituted liposomes and subcellular fractions enriched with synaptic vesicles. These Nbs can be expressed as functional green fluorescent protein fusion proteins in the cytosol of HEK cells for intracellular applications as immunocytochemical and biochemical agents. The selected binders thus provide valuable tools for cell biology and neuroscience.

  8. Proton pump inhibitors inhibit metformin uptake by organic cation transporters (OCTs.

    Directory of Open Access Journals (Sweden)

    Anne T Nies

    Full Text Available Metformin, an oral insulin-sensitizing drug, is actively transported into cells by organic cation transporters (OCT 1, 2, and 3 (encoded by SLC22A1, SLC22A2, or SLC22A3, which are tissue specifically expressed at significant levels in various organs such as liver, muscle, and kidney. Because metformin does not undergo hepatic metabolism, drug-drug interaction by inhibition of OCT transporters may be important. So far, comprehensive data on the interaction of proton pump inhibitors (PPIs with OCTs are missing although PPIs are frequently used in metformin-treated patients. Using in silico modeling and computational analyses, we derived pharmacophore models indicating that PPIs (i.e. omeprazole, pantoprazole, lansoprazole, rabeprazole, and tenatoprazole are potent OCT inhibitors. We then established stably transfected cell lines expressing the human uptake transporters OCT1, OCT2, or OCT3 and tested whether these PPIs inhibit OCT-mediated metformin uptake in vitro. All tested PPIs significantly inhibited metformin uptake by OCT1, OCT2, and OCT3 in a concentration-dependent manner. Half-maximal inhibitory concentration values (IC(50 were in the low micromolar range (3-36 µM and thereby in the range of IC(50 values of other potent OCT drug inhibitors. Finally, we tested whether the PPIs are also transported by OCTs, but did not identify PPIs as OCT substrates. In conclusion, PPIs are potent inhibitors of the OCT-mediated metformin transport in vitro. Further studies are needed to elucidate the clinical relevance of this drug-drug interaction with potential consequences on metformin disposition and/or efficacy.

  9. Spin transport at the international linear collider and its impact on the measurement of polarization

    Energy Technology Data Exchange (ETDEWEB)

    Beckmann, Moritz

    2013-12-15

    At the planned International Linear Collider (ILC), the longitudinal beam polarization needs to be determined with an unprecedented precision. For that purpose, the beam delivery systems (BDS) are equipped with two laser Compton polarimeters each, which are foreseen to achieve a systematic uncertainty of {<=} 0.25 %. The polarimeters are located 1.6 km upstream and 150 m downstream of the e{sup +}e{sup -} interaction point (IP). The average luminosity-weighted longitudinal polarization P{sup lumi}{sub z}, which is the decisive quantity for the experiments, has to be determined from these measurements with the best possible precision. Therefore, a detailed understanding of the spin transport in the BDS is mandatory to estimate how precise the longitudinal polarization at the IP is known from the polarimeter measurements. The envisaged precision for the propagation of the measurement value is {<=} 0.1 %. This thesis scrutinizes the spin transport in view of the achievable precision. A detailed beamline simulation for the BDS has been developed, including the simulation of the beam-beam collisions at the IP. The following factors which might limit the achievable precision is investigated: a variation of the beam parameters, the beam alignment precision at the polarimeters and the IP, the bunch rotation at the IP, the detector magnets, the beam-beam collisions, the emission of synchrotron radiation and misalignments of the beamline elements. In absence of collisions, a precision of 0.085% on the propagation of the measured longitudinal polarization has been found achievable. This result however depends mainly on the presumed precisions for the parallel alignment of the beam at the polarimeters and for the alignment of polarization vector. In presence of collisions, the measurement at the downstream polarimeter depends strongly on the intensity of the collision and the size of the polarimeter laser spot. Therefore, a more detailed study of the laser-bunch interaction is

  10. Natriuretic Hormones, Endogenous Ouabain, and Related Sodium Transport Inhibitors

    Directory of Open Access Journals (Sweden)

    John eHamlyn

    2014-12-01

    Full Text Available The work of deWardener and colleagues stimulated longstanding interest in natriuretic hormones (NH. In addition to the atrial peptides (APs, the circulation contains unidentified physiologically-relevant NHs. One NH is controlled by the central nervous system (CNS and likely secreted by the pituitary. Its circulating activity is modulated by salt intake and the prevailing sodium concentration of the blood and intracerebroventricular fluid, and contributes to postprandial and dehydration natriuresis. The other NH, mobilized by atrial stretch, promotes natriuresis by increasing the production of intrarenal dopamine and/or nitric oxide. Both NHs have short (<35 minutes circulating half lives, depress renotubular sodium transport, and neither requires the renal nerves. The search for NHs led to endogenous cardiotonic steroids (CTS including ouabain-, digoxin-, and bufadienolide-like materials. These CTS, given acutely in high nanomole to micromole amounts into the general or renal circulations, inhibit sodium pumps and are natriuretic. Among these CTS, only bufalin is cleared sufficiently rapidly to qualify for an NH-like role. Ouabain-like CTS are cleared slowly, and when given chronically in low daily nanomole amounts, promote sodium retention, augment arterial myogenic tone, reduce renal blood flow and glomerular filtration, suppress nitric oxide in the renal vasa recta, and increase sympathetic nerve activity and blood pressure. Moreover, lowering total body sodium raises circulating endogenous ouabain. Thus, ouabain-like CTS have physiological actions that, like aldosterone, support renal sodium retention and blood pressure. In conclusion, the mammalian circulation contains two non-AP NHs. Identification of the CNS NH should be a priority.

  11. Cytoplasmic Dynein Transports Axonal Microtubules in a Polarity-Sorting Manner

    Directory of Open Access Journals (Sweden)

    Anand N. Rao

    2017-06-01

    Full Text Available Axonal microtubules are predominantly organized into a plus-end-out pattern. Here, we tested both experimentally and with computational modeling whether a motor-based polarity-sorting mechanism can explain this microtubule pattern. The posited mechanism centers on cytoplasmic dynein transporting plus-end-out and minus-end-out microtubules into and out of the axon, respectively. When cytoplasmic dynein was acutely inhibited, the bi-directional transport of microtubules in the axon was disrupted in both directions, after which minus-end-out microtubules accumulated in the axon over time. Computational modeling revealed that dynein-mediated transport of microtubules can establish and preserve a predominantly plus-end-out microtubule pattern as per the details of the experimental findings, but only if a kinesin motor and a static cross-linker protein are also at play. Consistent with the predictions of the model, partial depletion of TRIM46, a protein that cross-links axonal microtubules in a manner that influences their polarity orientation, leads to an increase in microtubule transport.

  12. Adenosine kinase inhibitors: polar 7-substitutent of pyridopyrimidine derivatives improving their locomotor selectivity.

    Science.gov (United States)

    Zheng, Guo Zhu; Mao, Yue; Lee, Chih-Hung; Pratt, John K; Koenig, John R; Perner, Richard J; Cowart, Marlon D; Gfesser, Gregory A; McGaraughty, Steve; Chu, Katharine L; Zhu, Chang; Yu, Haixia; Kohlhaas, Kathy; Alexander, Karen M; Wismer, Carol T; Mikusa, Joseph; Jarvis, Michael F; Kowaluk, Elizabeth A; Stewart, Andrew O

    2003-09-15

    We have discovered that polar 7-substituents of pyridopyrimidine derivatives affect not only whole cell AK inhibitory potency, but also selectivity in causing locomotor side effects in vivo animal models. We have identified compound, 1o, which has potent whole cell AK inhibitory potency, analgesic activity and minimal reduction of locomotor activity.

  13. Dark states in spin-polarized transport through triple quantum dot molecules

    Science.gov (United States)

    Wrześniewski, K.; Weymann, I.

    2018-02-01

    We study the spin-polarized transport through a triple-quantum-dot molecule weakly coupled to ferromagnetic leads. The analysis is performed by means of the real-time diagrammatic technique, including up to the second order of perturbation expansion with respect to the tunnel coupling. The emphasis is put on the impact of dark states on spin-resolved transport characteristics. It is shown that the interplay of coherent population trapping and cotunneling processes results in a highly nontrivial behavior of the tunnel magnetoresistance, which can take negative values. Moreover, a super-Poissonian shot noise is found in transport regimes where the current is blocked by the formation of dark states, which can be additionally enhanced by spin dependence of tunneling processes, depending on the magnetic configuration of the device. The mechanisms leading to those effects are thoroughly discussed.

  14. Transport Through a Precessing Spin Coupled to Noncollinearly Polarized Ferromagnetic Leads

    International Nuclear Information System (INIS)

    Wang Xianchao; Xin Zihua; Feng Liya

    2010-01-01

    The quantum electronic transport through a precessing magnetic spin coupled to noncollinearly polarized ferromagnetic leads (F-MS-F) has been studied in this paper. The nonequilibrium Green function approach is used to calculate local density of states (LDOS) and current in the presence of external bias. The characters of LDOS and the electronic current are obtained. The tunneling current is investigated for different precessing angle and different configurations of the magnetization of the leads. The investigation reveals that when the precessing angle takes θ < π/2 and negative bias is applied, the resonant tunneling current appears, otherwise, it appears when positive bias is applied. When the leads are totally polarized and the precessing angel takes 0, the tunneling current changes with the configuration of two leads; and it becomes zero when the two leads are antiparallel. (condensed matter: electronic structure, electrical, magnetic, and optical properties)

  15. Aquaglyceroporin-null trypanosomes display glycerol transport defects and respiratory-inhibitor sensitivity.

    Directory of Open Access Journals (Sweden)

    Laura Jeacock

    2017-03-01

    Full Text Available Aquaglyceroporins (AQPs transport water and glycerol and play important roles in drug-uptake in pathogenic trypanosomatids. For example, AQP2 in the human-infectious African trypanosome, Trypanosoma brucei gambiense, is responsible for melarsoprol and pentamidine-uptake, and melarsoprol treatment-failure has been found to be due to AQP2-defects in these parasites. To further probe the roles of these transporters, we assembled a T. b. brucei strain lacking all three AQP-genes. Triple-null aqp1-2-3 T. b. brucei displayed only a very moderate growth defect in vitro, established infections in mice and recovered effectively from hypotonic-shock. The aqp1-2-3 trypanosomes did, however, display glycerol uptake and efflux defects. They failed to accumulate glycerol or to utilise glycerol as a carbon-source and displayed increased sensitivity to salicylhydroxamic acid (SHAM, octyl gallate or propyl gallate; these inhibitors of trypanosome alternative oxidase (TAO can increase intracellular glycerol to toxic levels. Notably, disruption of AQP2 alone generated cells with glycerol transport defects. Consistent with these findings, AQP2-defective, melarsoprol-resistant clinical isolates were sensitive to the TAO inhibitors, SHAM, propyl gallate and ascofuranone, relative to melarsoprol-sensitive reference strains. We conclude that African trypanosome AQPs are dispensable for viability and osmoregulation but they make important contributions to drug-uptake, glycerol-transport and respiratory-inhibitor sensitivity. We also discuss how the AQP-dependent inverse sensitivity to melarsoprol and respiratory inhibitors described here might be exploited.

  16. Euglycaemic diabetic ketoacidosis in patients using sodium-glucose co-transporter 2 inhibitors.

    Science.gov (United States)

    Isaacs, Michelle; Tonks, Katherine T; Greenfield, Jerry R

    2017-06-01

    Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are an increasingly prescribed class of medication for type 2 diabetes mellitus. Euglycaemic diabetic ketoacidosis (euDKA) has been reported in association with SGLT2i use. Clinicians need to understand how to recognise and treat this complication. We describe three cases of euDKA in patients treated with SGLT2i. © 2017 Royal Australasian College of Physicians.

  17. Small molecule peptidomimetic inhibitors of importin α/β mediated nuclear transport

    Science.gov (United States)

    Ambrus, Géza; Whitby, Landon R.; Singer, Eric L.; Trott, Oleg; Choi, Euna; Olson, Arthur J.; Boger, Dale L.; Gerace, Larry

    2010-01-01

    Nucleocytoplasmic transport of macromolecules is a fundamental process of eukaryotic cells. Translocation of proteins and many RNAs between the nucleus and cytoplasm is carried out by shuttling receptors of the β-karyopherin family, also called importins and exportins. Leptomycin B, a small molecule inhibitor of the exportin CRM1, has proved to be an invaluable tool for cell biologists, but up to now no small molecule inhibitors of nuclear import have been described. We devised a microtiter plate based permeabilized cell screen for small molecule inhibitors of the importin α/β pathway. By analyzing peptidomimetic libraries, we identified β-turn and α-helix peptidomimetic compounds that selectively inhibit nuclear import by importin α/β but not by transportin. Structure-activity relationship analysis showed that large aromatic residues and/or a histidine side chain are required for effective import inhibition by these compounds. Our validated inhibitors can be useful for in vitro studies of nuclear import, and can also provide a framework for synthesis of higher potency nuclear import inhibitors. PMID:20869252

  18. Phosphodiesterase type 5 inhibitors increase Herceptin transport and treatment efficacy in mouse metastatic brain tumor models.

    Directory of Open Access Journals (Sweden)

    Jinwei Hu

    2010-04-01

    Full Text Available Chemotherapeutic drugs and newly developed therapeutic monoclonal antibodies are adequately delivered to most solid and systemic tumors. However, drug delivery into primary brain tumors and metastases is impeded by the blood-brain tumor barrier (BTB, significantly limiting drug use in brain cancer treatment.We examined the effect of phosphodiesterase 5 (PDE5 inhibitors in nude mice on drug delivery to intracranially implanted human lung and breast tumors as the most common primary tumors forming brain metastases, and studied underlying mechanisms of drug transport. In vitro assays demonstrated that PDE5 inhibitors enhanced the uptake of [(14C]dextran and trastuzumab (Herceptin, a humanized monoclonal antibody against HER2/neu by cultured mouse brain endothelial cells (MBEC. The mechanism of drug delivery was examined using inhibitors for caveolae-mediated endocytosis, macropinocytosis and coated pit/clathrin endocytosis. Inhibitor analysis strongly implicated caveolae and macropinocytosis endocytic pathways involvement in the PDE5 inhibitor-enhanced Herceptin uptake by MBEC. Oral administration of PDE5 inhibitor, vardenafil, to mice with HER2-positive intracranial lung tumors led to an increased tumor permeability to high molecular weight [(14C]dextran (2.6-fold increase and to Herceptin (2-fold increase. Survival time of intracranial lung cancer-bearing mice treated with Herceptin in combination with vardenafil was significantly increased as compared to the untreated, vardenafil- or Herceptin-treated mice (p0.05.These findings suggest that PDE5 inhibitors may effectively modulate BTB permeability, and enhance delivery and therapeutic efficacy of monoclonal antibodies in hard-to-treat brain metastases from different primary tumors that had metastasized to the brain.

  19. Validation of inhibitors of an ABC transporter required to transport lipopolysaccharide to the cell surface in Escherichia coli

    Science.gov (United States)

    Sherman, David J.; Okuda, Suguru; Denny, William A.; Kahne, Daniel

    2013-01-01

    The presence of lipopolysaccharide (LPS) in the outer leaflet of the outer membrane (OM) of Gram-negative bacteria creates a permeability barrier that prevents the entry of most currently available antibiotics. The seven lipopolysaccharide transport (Lpt) proteins involved in transporting and assembling this glycolipid are essential for growth and division in Escherichia coli; therefore, inhibiting their functions leads to cell death. LptB, the ATPase that provides energy for LPS transport and assembly, forms a complex with three other inner membrane (IM) components, LptC, F, and G. We demonstrate that inhibitors of pure LptB can also inhibit the full IM complex, LptBFGC, purified in detergent. We also compare inhibition of LptB and the LptBFGC complex with the antibiotic activity of these compounds. Our long-term goal is to develop tools to study inhibitors of LPS biogenesis that could serve as potentiators by disrupting the OM permeability barrier, facilitating entry of clinically used antibiotics not normally used to treat Gram-negative infections, or that can serve as antibiotics themselves. PMID:23665139

  20. The exocyst complex contributes to PIN auxin efflux carrier recycling and polar auxin transport in Arabidopsis

    Czech Academy of Sciences Publication Activity Database

    Drdová, Edita; Synek, Lukáš; Pečenková, Tamara; Hála, Michal; Kulich, I.; Fowler, J.E.; Murphy, A.S.; Žárský, Viktor

    2013-01-01

    Roč. 73, č. 5 (2013), s. 709-719 ISSN 0960-7412 R&D Projects: GA ČR GPP501/11/P853; GA ČR(CZ) GAP305/11/1629; GA MŠk(CZ) LC06034; GA AV ČR KJB600380802 Grant - others:GA MŠk(CZ) ME10033 Institutional research plan: CEZ:AV0Z50380511 Keywords : exocyst * polar auxin transport * PIN recycling Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 6.815, year: 2013

  1. 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

  2. Transport-driven formation of a polar ozone layer on Mars

    Science.gov (United States)

    Montmessin, Franck; Lefèvre, Franck

    2013-11-01

    Since the seasonal and spatial distribution of ozone on Mars was detected by the ultraviolet spectrometer onboard the spacecraft Mariner 7, our understanding has evolved considerably thanks to parallel efforts in observations and modelling. At low-to-mid latitudes, martian ozone is distributed vertically in two main layers, a near-surface layer and a layer at an altitude between 30 and 60km (ref. ). Here we report evidence from the SPICAM UV spectrometer onboard the Mars Express orbiter for the existence of a previously overlooked ozone layer that emerges in the southern polar night at 40-60km in altitude, with no counterpart observed at the north pole. Comparisons with global climate simulations for Mars indicate that this layer forms as a result of the large-scale transport of oxygen-rich air from sunlit latitudes to the poles, where the oxygen atoms recombine to form ozone during the polar night. However, transport-driven ozone formation is counteracted in our simulations by the destruction of ozone by reactions with hydrogen radicals, whose concentrations vary seasonally on Mars, reflecting seasonal variations of water vapour. We conclude that the observed dichotomy between the ozone layers of the two poles, with a significantly richer layer in the southern hemisphere, can be explained by the interplay of these mechanisms.

  3. Tunable spin-polarized edge transport in inverted quantum-well junctions

    Science.gov (United States)

    Nanclares, Dimy; Lima, Leandro R. F.; Lewenkopf, Caio H.; da Silva, Luis G. G. V. Dias

    2017-10-01

    Inverted HgTe/CdTe quantum wells have been used as a platform for the realization of two-dimensional topological insulators, bulk insulator materials with spin-helical metallic edge states protected by time-reversal symmetry. This paper investigates the spectrum and the charge transport in HgTe/CdTe quantum well junctions both in the topological regime and in the absence of time-reversal symmetry. We model the system using the Bernevig-Hughes-Zhang effective Hamiltonian and compute the transport properties using recursive Green's functions with a finite differences' method. Specifically, we have studied the material's spatially resolved conductance in a setup with a gated central region, forming monopolar (n -n'-n ) and heteropolar (n -p -n , n -TI-n ) double junctions, which have been recently realized in experiments. We find regimes in which the edge states carry spin-polarized currents in the central region even in the presence of a small magnetic field, which breaks time-reversal symmetry. More interestingly, the conductance displays spin-dependent, Fabry-Perót-like oscillations as a function of the central gate voltage producing tunable, fully spin-polarized currents through the device.

  4. Spectroscopic imaging studies of nanoscale polarity and mass transport phenomena in self-assembled organic nanotubes.

    Science.gov (United States)

    Xu, Hao; Nagasaka, Shinobu; Kameta, Naohiro; Masuda, Mitsutoshi; Ito, Takashi; Higgins, Daniel A

    2017-08-02

    Synthetic organic nanotubes self-assembled from bolaamphiphile surfactants are now being explored for use as drug delivery vehicles. In this work, several factors important to their implementation in drug delivery are explored. All experiments are performed with the nanotubes immersed in ethanol. First, Nile Red (NR) and a hydroxylated Nile Red derivative (NR-OH) are loaded into the nanotubes and spectroscopic fluorescence imaging methods are used to determine the apparent dielectric constant of their local environment. Both are found in relatively nonpolar environments, with the NR-OH molecules preferring regions of relatively higher dielectric constant compared to NR. Unique two-color imaging fluorescence correlation spectroscopy (imaging FCS) measurements are then used along with the spectroscopic imaging results to deduce the dielectric properties of the environments sensed by mobile and immobile populations of probe molecules. The results reveal that mobile NR molecules pass through less polar regions, likely within the nanotube walls, while immobile NR molecules are found in more polar regions, possibly near the nanotube surfaces. In contrast, mobile and immobile NR-OH molecules are found to locate in environments of similar polarity. The imaging FCS results also provide quantitative data on the apparent diffusion coefficient for each dye. The mean diffusion coefficient for the NR dye was approximately two-fold larger than that of NR-OH. Slower diffusion by the latter could result from its additional hydrogen bonding interactions with polar triglycine, amine, and glucose moieties near the nanotube surfaces. The knowledge gained in these studies will allow for the development of nanotubes that are better engineered for applications in the controlled transport and release of uncharged, dipolar drug molecules.

  5. Auxin transport inhibitors impair vesicle motility and actin cytoskeleton dynamics in diverse eukaryotes.

    Science.gov (United States)

    Dhonukshe, Pankaj; Grigoriev, Ilya; Fischer, Rainer; Tominaga, Motoki; Robinson, David G; Hasek, Jirí; Paciorek, Tomasz; Petrásek, Jan; Seifertová, Daniela; Tejos, Ricardo; Meisel, Lee A; Zazímalová, Eva; Gadella, Theodorus W J; Stierhof, York-Dieter; Ueda, Takashi; Oiwa, Kazuhiro; Akhmanova, Anna; Brock, Roland; Spang, Anne; Friml, Jirí

    2008-03-18

    Many aspects of plant development, including patterning and tropisms, are largely dependent on the asymmetric distribution of the plant signaling molecule auxin. Auxin transport inhibitors (ATIs), which interfere with directional auxin transport, have been essential tools in formulating this concept. However, despite the use of ATIs in plant research for many decades, the mechanism of ATI action has remained largely elusive. Using real-time live-cell microscopy, we show here that prominent ATIs such as 2,3,5-triiodobenzoic acid (TIBA) and 2-(1-pyrenoyl) benzoic acid (PBA) inhibit vesicle trafficking in plant, yeast, and mammalian cells. Effects on micropinocytosis, rab5-labeled endosomal motility at the periphery of HeLa cells and on fibroblast mobility indicate that ATIs influence actin cytoskeleton. Visualization of actin cytoskeleton dynamics in plants, yeast, and mammalian cells show that ATIs stabilize actin. Conversely, stabilizing actin by chemical or genetic means interferes with endocytosis, vesicle motility, auxin transport, and plant development, including auxin transport-dependent processes. Our results show that a class of ATIs act as actin stabilizers and advocate that actin-dependent trafficking of auxin transport components participates in the mechanism of auxin transport. These studies also provide an example of how the common eukaryotic process of actin-based vesicle motility can fulfill a plant-specific physiological role.

  6. Biaryls as potent, tunable dual neurokinin 1 receptor antagonists and serotonin transporter inhibitors.

    Science.gov (United States)

    Degnan, Andrew P; Tora, George O; Han, Ying; Rajamani, Ramkumar; Bertekap, Robert; Krause, Rudolph; Davis, Carl D; Hu, Joanna; Morgan, Daniel; Taylor, Sarah J; Krause, Kelly; Li, Yu-Wen; Mattson, Gail; Cunningham, Melissa A; Taber, Matthew T; Lodge, Nicholas J; Bronson, Joanne J; Gillman, Kevin W; Macor, John E

    2015-08-01

    Depression is a serious illness that affects millions of patients. Current treatments are associated with a number of undesirable side effects. Neurokinin 1 receptor (NK1R) antagonists have recently been shown to potentiate the antidepressant effects of serotonin-selective reuptake inhibitors (SSRIs) in a number of animal models. Herein we describe the optimization of a biaryl chemotype to provide a series of potent dual NK1R antagonists/serotonin transporter (SERT) inhibitors. Through the choice of appropriate substituents, the SERT/NK1R ratio could be tuned to afford a range of target selectivity profiles. This effort culminated in the identification of an analog that demonstrated oral bioavailability, favorable brain uptake, and efficacy in the gerbil foot tap model. Ex vivo occupancy studies with compound 58 demonstrated the ability to maintain NK1 receptor saturation (>88% occupancy) while titrating the desired level of SERT occupancy (11-84%) via dose selection. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Spectral Induced Polarization approaches to characterize reactive transport parameters and processes

    Science.gov (United States)

    Schmutz, M.; Franceschi, M.; Revil, A.; Peruzzo, L.; Maury, T.; Vaudelet, P.; Ghorbani, A.; Hubbard, S. S.

    2017-12-01

    For almost a decade, geophysical methods have explored the potential for characterization of reactive transport parameters and processes relevant to hydrogeology, contaminant remediation, and oil and gas applications. Spectral Induced Polarization (SIP) methods show particular promise in this endeavour, given the sensitivity of the SIP signature to geological material electrical double layer properties and the critical role of the electrical double layer on reactive transport processes, such as adsorption. In this presentation, we discuss results from several recent studies that have been performed to quantify the value of SIP parameters for characterizing reactive transport parameters. The advances have been realized through performing experimental studies and interpreting their responses using theoretical and numerical approaches. We describe a series of controlled experimental studies that have been performed to quantify the SIP responses to variations in grain size and specific surface area, pore fluid geochemistry, and other factors. We also model chemical reactions at the interface fluid/matrix linked to part of our experimental data set. For some examples, both geochemical modelling and measurements are integrated into a SIP physico-chemical based model. Our studies indicate both the potential of and the opportunity for using SIP to estimate reactive transport parameters. In case of well sorted granulometry of the samples, we find that the grain size characterization (as well as the permeabililty for some specific examples) value can be estimated using SIP. We show that SIP is sensitive to physico-chemical conditions at the fluid/mineral interface, including the different pore fluid dissolved ions (Na+, Cu2+, Zn2+, Pb2+) due to their different adsorption behavior. We also showed the relevance of our approach to characterize the fluid/matrix interaction for various organic contents (wetting and non-wetting oils). We also discuss early efforts to jointly

  8. Caffeine intake enhances the benefits of sodium glucose transporter 2 inhibitor.

    Science.gov (United States)

    Hashimoto, Yoshitaka; Tanaka, Muhei; Yamazaki, Masahiro; Nakano, Koji; Ushigome, Emi; Okada, Hiroshi; Oda, Yohei; Nakamura, Naoto; Fukui, Michiaki

    2016-10-01

    The effect of sodium glucose transporter 2 (SGLT-2) inhibitors is dependent on the glomerular filtration rate. It has been reported that caffeine intake increases glomerular filtration rate. However, the effect of caffeine intake on urinary glucose excretion in patients who take SGLT-2 inhibitors is unclear. Six patients with type 2 diabetes took part in a randomized, open-label, crossover pilot study. The patients took SGLT-2 inhibitors (ipragliflozin) for 9 days. On day 3, 6 and 9, the patients were assigned to one of three studies: Water 500, patients drank 500 mL of water in 3 h; Water 1500, patients drank 1500 mL of water in 3 h; and Caffeine 500, patients drank 500 mL of water with 400 mg of caffeine in 3 h. In all of the studies, the patients' urine was collected over a 6-h period. In addition, we enrolled 60 patients with type 2 diabetes who newly took SGLT-2 inhibitors in a 3-month follow-up cohort study to investigate the effect of caffeine intake on glucose control. Caffeine intake was evaluated using questionnaires. The 6-h median (interquartile range) urinary glucose excretion was 9.5 (8.5-9.7) g in Water 500, 12.2 (10.3-27.2) g in Water 1500 and 15.7 (11.4-21.4) g in Caffeine 500 (p = 0.005 vs Water 500). In the cohort study, multiple regression analysis demonstrated that log (caffeine intake) was associated with a change in HbA 1c (β = -0.299, p = 0.043) after adjusting for covariates. Caffeine intake enhanced the effect of SGLT-2 inhibitors. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  9. Trafficking Ion Transporters to the Apical Membrane of Polarized Intestinal Enterocytes.

    Science.gov (United States)

    Engevik, Amy Christine; Goldenring, James R

    2018-01-02

    Epithelial cells lining the gastrointestinal tract require distinct apical and basolateral domains to function properly. Trafficking and insertion of enzymes and transporters into the apical brush border of intestinal epithelial cells is essential for effective digestion and absorption of nutrients. Specific critical ion transporters are delivered to the apical brush border to facilitate fluid and electrolyte uptake. Maintenance of these apical transporters requires both targeted delivery and regulated membrane recycling. Examination of altered apical trafficking in patients with Microvillus Inclusion disease caused by inactivating mutations in MYO5B has led to insights into the regulation of apical trafficking by elements of the apical recycling system. Modeling of MYO5B loss in cell culture and animal models has led to recognition of Rab11a and Rab8a as critical regulators of apical brush border function. All of these studies show the importance of apical membrane trafficking dynamics in maintenance of polarized epithelial cell function. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.

  10. The cytotoxic styryl lactone goniothalamin is an inhibitor of nucleocytoplasmic transport.

    Science.gov (United States)

    Wach, Jean-Yves; Güttinger, Stephan; Kutay, Ulrike; Gademann, Karl

    2010-05-01

    An in vivo nuclear export assay (immunostaining of Rio2 in HeLa cells) demonstrated that (R)-goniothalamin is an inhibitor of nucleocytoplasmic transport above 500 nM, which was rationalized also by molecular modeling. The cytotoxic styryl lactone natural product was prepared via an enantioselective Cr(III) catalyzed hetero Diels-Alder reaction and a Sonogashira coupling. A series of analogs was synthesized and only the oxidized goniothalamin derivative featuring an alkyne spacer was found active. Unsaturated lactones of natural origin other than leptomycin (LMB) are thus suggested to operate via a similar mechanism targeting the CRM1 nuclear receptor. 2010 Elsevier Ltd. All rights reserved.

  11. Discovery of the first selective inhibitor of excitatory amino acid transporter subtype 1

    DEFF Research Database (Denmark)

    Jensen, Anders Asbjørn; Erichsen, Mette Navy; Nielsen, Christina Wøhlk

    2009-01-01

    The discovery of the first class of subtype-selective inhibitors of the human excitatory amino acid transporter subtype 1 (EAAT1) and its rat orthologue GLAST is reported. An opening structure-activity relationship of 25 analogues is presented that addresses the influence of substitutions at the 4......- and 7-positions of the parental skeleton 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile. The most potent analogue 1o displays high nanomolar inhibitory activity at EAAT1 and a >400-fold selectivity over EAAT2 and EAAT3, making it a highly valuable pharmacological tool....

  12. Magnetic adatoms in two and four terminal graphene nanoribbons: A comparison between their spin polarized transport

    Science.gov (United States)

    Ganguly, Sudin; Basu, Saurabh

    2018-04-01

    We study the charge and spin transport in two and four terminal graphene nanoribbons (GNR) decorated with random distribution of magnetic adatoms. The inclusion of the magnetic adatoms generates only the z-component of the spin polarized conductance via an exchange bias in the absence of Rashba spin-orbit interaction (SOI), while in presence of Rashba SOI, one is able to create all the three (x, y and z) components. This has important consequences for possible spintronic applications. The charge conductance shows interesting behaviour near the zero of the Fermi energy. Where in presence of magnetic adatoms the familiar plateau at 2e2 / h vanishes, thereby transforming a quantum spin Hall insulating phase to an ordinary insulator. The local charge current and the local spin current provide an intuitive idea on the conductance features of the system. We found that, the local charge current is independent of Rashba SOI, while the three components of the local spin currents are sensitive to Rashba SOI. Moreover the fluctuations of the spin polarized conductance are found to be useful quantities as they show specific trends, that is, they enhance with increasing adatom densities. A two terminal GNR device seems to be better suited for possible spintronic applications.

  13. Extracellular loop 3 of the noradrenaline transporter contributes to substrate and inhibitor selectivity

    DEFF Research Database (Denmark)

    Lynagh, Timothy; Khamu, Tina S.; Bryan-Lluka, Lesley J.

    2014-01-01

    The human noradrenaline transporter (NET) and 5-hydroxytryptamine (5-HT) transporter (SERT) are inhibited by antidepressants and psychoactive drugs such as cocaine. Both substrates and inhibitors bind in the transmembrane core of the protein, but molecular divergence at the binding site...... is not sufficient to account for the NET-selective and SERT-selective inhibition of the antidepressants, desipramine and citalopram, respectively. We considered that the poorly conserved third extracellular loop may contribute to these differences. We substituted single amino acid residues of the third...... extracellular loop in NET for equivalents from SERT, transiently transfected COS-7 cells with WT NET, 13 mutant NETs and WT SERT, and measured [ 3H]noradrenaline uptake, [3H]nisoxetine binding and [ 3H]5-HT uptake. Mutants F299W, Y300Q, R301K and K303L, at the C-terminal end of EL3, all showed significantly...

  14. Inhibitors of Apoptosis Protein Antagonists (Smac Mimetic Compounds Control Polarization of Macrophages during Microbial Challenge and Sterile Inflammatory Responses

    Directory of Open Access Journals (Sweden)

    Vinod Nadella

    2018-01-01

    Full Text Available Apoptosis is a physiological cell death process essential for development, tissue homeostasis, and for immune defense of multicellular animals. Inhibitors of apoptosis proteins (IAPs regulate apoptosis in response to various cellular assaults. Using both genetic and pharmacological approaches we demonstrate here that the IAPs not only support opportunistic survival of intracellular human pathogens like Chlamydia pneumoniae but also control plasticity of iNOS+ M1 macrophage during the course of infection and render them refractory for immune stimulation. Treatment of Th1 primed macrophages with birinapant (IAP-specific antagonist inhibited NO generation and relevant proteins involved in innate immune signaling. Accordingly, birinapant promoted hypoxia, angiogenesis, and tumor-induced M2 polarization of iNOS+ M1 macrophages. Interestingly, birinapant-driven changes in immune signaling were accompanied with changes in the expression of various proteins involved in the metabolism, and thus revealing the new role of IAPs in immune metabolic reprogramming in committed macrophages. Taken together, our study reveals the significance of IAP targeting approaches (Smac mimetic compounds for the management of infectious and inflammatory diseases relying on macrophage plasticity.

  15. Monitoring transport and equilibrium of heavy metals in soil using induced polarization

    Science.gov (United States)

    Shalem, T.; Huisman, J. A.; Zimmermann, E.; Furman, A.

    2017-12-01

    Soil and groundwater pollution in general, and by heavy metals in particular, is a major threat to human health, and especially in rapidly developing regions, such as China. Fast, accurate and low-cost measurement of heavy metal contamination is of high desire. Spectral induced polarization (SIP) may be an alternative to the tedious sampling techniques typically used. In the SIP method, an alternating current at a range of low frequencies is injected into the soil and the resultant potential is measured along the current's path. SIP is a promising method for monitoring heavy metals, because it is sensitive to the chemical composition of both the absorbed ions on the soil minerals and the pore fluid and to the interface between the two. The high sorption affinity of heavy metals suggests that their electrical signature may be significant, even at relatively low concentrations. The goal of this research is to examine the electrical signature of soil contaminated by heavy metals and of the pollution transport and remediation processes, in a non-tomographic fashion. Specifically, we are looking at the SIP response of various heavy metals in several settings: 1) at equilibrium state in batch experiments; 2) following the progress of a pollution front along a soil column through flow experiments and 3) monitoring the extraction of the contaminant by a chelating agent. Using the results, we develop and calibrate a multi-Cole-Cole model to separate the electrochemical and the interfacial components of the polarization. Last, we compare our results to the electrical signature of contaminated soil from southern China. Results of single metals from both batch and flow experiments display a shift of the relaxation time and a decrease in the phase response of the soil with increase of the metal concentration, suggesting strong sorption of the metals on the stern layer. Preliminary results also show evidence of electrodic polarization, assuming to be related to the formation of

  16. Model of polar auxin transport coupled to mechanical forces retrieves robust morphogenesis along the Arabidopsis root

    Science.gov (United States)

    Romero-Arias, J. Roberto; Hernández-Hernández, Valeria; Benítez, Mariana; Alvarez-Buylla, Elena R.; Barrio, Rafael A.

    2017-03-01

    Stem cells are identical in many scales, they share the same molecular composition, DNA, genes, and genetic networks, yet they should acquire different properties to form a functional tissue. Therefore, they must interact and get some external information from their environment, either spatial (dynamical fields) or temporal (lineage). In this paper we test to what extent coupled chemical and physical fields can underlie the cell's positional information during development. We choose the root apical meristem of Arabidopsis thaliana to model the emergence of cellular patterns. We built a model to study the dynamics and interactions between the cell divisions, the local auxin concentration, and physical elastic fields. Our model recovers important aspects of the self-organized and resilient behavior of the observed cellular patterns in the Arabidopsis root, in particular, the reverse fountain pattern observed in the auxin transport, the PIN-FORMED (protein family of auxin transporters) polarization pattern and the accumulation of auxin near the region of maximum curvature in a bent root. Our model may be extended to predict altered cellular patterns that are expected under various applied auxin treatments or modified physical growth conditions.

  17. Sodium-glucose co-transporter type 2 inhibitors reduce evening home blood pressure in type 2 diabetes with nephropathy.

    Science.gov (United States)

    Takenaka, Tsuneo; Kishimoto, Miyako; Ohta, Mari; Tomonaga, Osamu; Suzuki, Hiromichi

    2017-05-01

    The effects of sodium-glucose co-transporter type 2 inhibitors on home blood pressure were examined in type 2 diabetes with nephropathy. The patients with diabetic nephropathy were screened from medical records in our hospitals. Among them, 52 patients who measured home blood pressure and started to take sodium-glucose co-transporter type 2 inhibitors were selected. Clinical parameters including estimated glomerular filtration rate, albuminuria and home blood pressure for 6 months were analysed. Sodium-glucose co-transporter type 2 inhibitors (luseogliflozin 5 mg/day or canagliflozin 100 mg/day) reduced body weight, HbA1c, albuminuria, estimated glomerular filtration rate and office blood pressure. Although sodium-glucose co-transporter type 2 inhibitors did not alter morning blood pressure, it reduced evening systolic blood pressure. Regression analyses revealed that decreases in evening blood pressure predicted decrements in albuminuria. The present data suggest that sodium-glucose co-transporter type 2 inhibitors suppress sodium overload during daytime to reduce evening blood pressure and albuminuria.

  18. The electron transport system of the anaerobic Propionibacterium shermanii: cytochrome and inhibitor studies.

    Science.gov (United States)

    Schwartz, A C; Sporkenbach, J

    1975-03-10

    1. Electron transport particles obtained from cell-free extracts of Propionibacterium shermanii by centrifugation at 105000 times g for 3 hrs oxidized NADH, D,L-lactate, L-glycerol-3-phosphate and succinate with oxygen and, except for succinate, with fumarate, too. 2. Spectral investigation of the electron transport particles revealed the presence of cytochromes b, d and o, and traces of cytochrome alpha1 and a c-type cytochrome. Cytochrome b was reduced by succinate to about 50%, and by NADH, lactate or glycerol-3-phosphate to 80--90%. 3. The inhibitory effects of amytal and rotenone on NADH oxidation, but not on the oxidation of the other substrates, indicated the presence of the NADH dehydrogenase complex, or "site I region", in the electron transport system of P. shermanii. 4. NQNO inhibited substrate oxidations by oxygen and fumarate, as well as equilibration of the flavoproteins of the substrate dehydrogenases by way of menaquinone. The inhibition occurred at low concentrations of the inhibitor and reached 80--100%, depending on the substrate tested. The site of inhibition of the respiratory activity was located between menaquinone and cytochrome b. In addition, inhibition of flavoprotein equilibration suggested that NQNO acted upon the electron transfer directed from menaquinol towards the acceptor to be reduced, either cytochrome b or the flavoproteins, which would include fumarate reductase. 5. In NQNO-inhibited particles, cytochrome b was not oxidized by oxygen-free fumarate, but readily oxidized by oxygen. It was concluded from this and the above evidence that the branching-point of the electron transport chain towards fumarate reductase was located at the menaquinone in P. shermanii. It was further concluded that all cytochromes were situated in the oxygen-linked branch of the chain, which formed a dead end of the system under anaerobic conditions. 6. Antimycin A inhibited only oxygen-linked reactions of the particles to about 50% at high concentrations

  19. Potent human uric acid transporter 1 inhibitors: in vitro and in vivo metabolism and pharmacokinetic studies

    Directory of Open Access Journals (Sweden)

    Wempe MF

    2012-11-01

    Full Text Available Michael F Wempe,1 Janet W Lightner,2 Bettina Miller,1 Timothy J Iwen,1 Peter J Rice,1 Shin Wakui,3 Naohiko Anzai,4 Promsuk Jutabha,4 Hitoshi Endou51Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; 2Department of Pharmacology, East Tennessee State University, Johnson City, TN, USA; 3Department of Toxicology, Azabu University School of Veterinary Medicine, Chuo Sagamihara, Kanagawa, Japan; 4Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine, Mibu, Shimotsuga, Tochigi, Japan; 5Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Mitaka, Tokyo, JapanAbstract: Human uric acid transporter 1 (hURAT1; SLC22A12 is a very important urate anion exchanger. Elevated urate levels are known to play a pivotal role in cardiovascular diseases, chronic renal disease, diabetes, and hypertension. Therefore, the development of potent uric acid transport inhibitors may lead to novel therapeutic agents to combat these human diseases. The current study investigates small molecular weight compounds and their ability to inhibit 14C-urate uptake in oocytes expressing hURAT1. Using the most promising drug candidates generated from our structure–activity relationship findings, we subsequently conducted in vitro hepatic metabolism and pharmacokinetic (PK studies in male Sprague-Dawley rats. Compounds were incubated with rat liver microsomes containing cofactors nicotinamide adenine dinucleotide phosphate and uridine 5'-diphosphoglucuronic acid. In vitro metabolism and PK samples were analyzed using liquid chromatography/mass spectrometry-mass spectrometry methods. Independently, six different inhibitors were orally (capsule dosing or intravenously (orbital sinus administered to fasting male Sprague-Dawley rats. Blood samples were collected and analyzed; these data were used to compare in vitro and in vivo metabolism and to

  20. Diphenyleneiodonium, an inhibitor of NOXes and DUOXes, is also an iodide-specific transporter

    Directory of Open Access Journals (Sweden)

    C. Massart

    2014-01-01

    Full Text Available NADPH oxidases (NOXes and dual oxidases (DUOXes generate O2.− and H2O2. Diphenyleneiodonium (DPI inhibits the activity of these enzymes and is often used as a specific inhibitor. It is shown here that DPI, at concentrations similar to those which inhibit the generation of O2 derivatives, activated the efflux of radioiodide but not of its analog 99mTcO4− nor of the K+ cation mimic 86Rb+ in thyroid cells, in the PCCl3 rat thyroid cell line and in COS cell lines expressing the iodide transporter NIS. Effects obtained with DPI, especially in thyroid cells, should therefore be interpreted with caution.

  1. Nitrobenzylthioinosine (NBT), a nucleoside transport inhibitor, protects against Shiga toxin cytotoxicity in human microvascular endothelial cells.

    Science.gov (United States)

    Ohmi, K; Kiyokawa, N; Sekino, T; Suzuki, T; Mimori, K; Taguchi, T; Nakajima, H; Katagiri, Y U; Fujimoto, J; Nakao, H; Takeda, T

    2001-01-01

    Infections with Shiga toxin (Stx)-producing Escherichia coli (STEC) cause microvascular endothelial cell damage, resulting in hemorrhagic colitis and hemolytic uremic syndrome. The prevention of endothelial cell damage is therefore a crucial step in overcoming this disorder. Here, we report that nitrobenzylthioinosine (NBT), a nucleoside transport inhibitor, has a protective effect against the cytotoxicity of Stxs in human microvascular endothelial cells (HMVECs). The relative viability of cells treated with 1.5-15 pM of Stx1 was reduced to 10-20% of that without Stx1. However, the viability of cells treated with NBT (10-100 microM) remained higher than 80%, even in the presence of Stx1. NBT also protected against Stx1 cytotoxicity in sodium butyrate-treated hypersensitive HMVECs. The protective effect of NBT against Stx cytotoxicity may be due to the depletion of ATP in the cells, thereby inhibiting the entry of Stx1.

  2. Sodium-glucose co-transporter-2 inhibitors and euglycemic ketoacidosis: Wisdom of hindsight

    Directory of Open Access Journals (Sweden)

    Awadhesh Kumar Singh

    2015-01-01

    Full Text Available Sodium-glucose co-transporter-2 inhibitors (SGLT-2i are newly approved class of oral anti-diabetic drugs, in the treatment of type 2 diabetes, which reduces blood glucose through glucouresis via the kidney, independent, and irrespective of available pancreatic beta-cells. Studies conducted across their clinical development program found, a modest reduction in glycated hemoglobin ranging from −0.5 to −0.8%, without any significant hypoglycemia. Moreover, head-to-head studies versus active comparators yielded comparable efficacy. Interestingly, weight and blood pressure reduction were additionally observed, which was not only consistent but significantly superior to active comparators, including metformin, sulfonylureas, and dipeptydylpeptide-4 inhibitors. Indeed, these additional properties makes this class a promising oral anti-diabetic drug. Surprisingly, a potentially fatal unwanted side effect of diabetic ketoacidosis has been noted with its widespread use, albeit rarely. Nevertheless, this has created a passé among the clinicians. This review is an attempt to pool those ketosis data emerging with SGLT-2i, and put a perspective on its implicated mechanism.

  3. A fluorescence polarization based screening assay for identification of small molecule inhibitors of the PICK1 PDZ domain

    DEFF Research Database (Denmark)

    Thorsen, Thor S; Madsen, Kenneth L; Dyhring, Tino

    2011-01-01

    domain in PICK1 (protein interacting with C kinase 1). We screened 43,380 compounds for their ability to inhibit binding of an Oregon Green labeled C-terminal dopamine transporter peptide (OrG-DAT C13) to purified PICK1 in solution. The assay was highly reliable with excellent screening assay parameters...... (Z'˜0.7 and Z˜0.6). Out of ~200 compounds that reduced FP to less than 80% of the control wells, six compounds were further characterized. The apparent affinities of the compounds were determined in FP competition binding experiments and ranged from ~5.0 µM to ~193 µM. Binding to the PICK1 PDZ domain...... to fluorescence resonance energy transfer (FRET) experiments capable of inhibiting the interaction between the C-terminus of the GluR2 subunit of the AMPA-type glutamate receptor and PICK1 in live cells. Additional experiments suggested that CSC-03 most likely is an irreversible inhibitor but with specificity...

  4. Atypical dopamine transporter inhibitors attenuate compulsive-like methamphetamine self-administration in rats.

    Science.gov (United States)

    Tunstall, Brendan J; Ho, Chelsea P; Cao, Jianjing; Vendruscolo, Janaína C M; Schmeichel, Brooke E; Slack, Rachel D; Tanda, Gianluigi; Gadiano, Alexandra J; Rais, Rana; Slusher, Barbara S; Koob, George F; Newman, Amy H; Vendruscolo, Leandro F

    2018-03-15

    Methamphetamine (METH) is a highly addictive drug, but no pharmacological treatment is yet available for METH use disorders. Similar to METH, the wake-promoting drug (R)-modafinil (R-MOD) binds to the dopamine transporter (DAT). Unlike METH, R-MOD is not a substrate for transport by DAT and has low abuse potential. We tested the hypothesis that the atypical DAT inhibitor R-MOD and compounds that are derived from modafinil would decrease METH intake by reducing the actions of METH at the DAT. We tested the effects of systemic injections of R-MOD and four novel modafinil-derived ligands with increased DAT affinity (JJC8-016, JJC8-088, JJC8-089, and JJC8-091) on intravenous (i.v.) METH self-administration in rats that were allowed short access (ShA; 1 h) or long access (LgA; 6 h) to the drug. ShA rats exhibited stable METH intake over sessions, whereas LgA rats exhibited an escalation of drug intake. R-MOD decreased METH self-administration in ShA and LgA rats (in the 1st hour only). JJC8-091 and JJC8-016 decreased METH self-administration in both ShA and LgA rats. JJC8-089 decreased METH self-administration in LgA rats only, whereas JJC8-088 had no effect on METH self-administration in either ShA or LgA rats. These findings support the potential of atypical DAT inhibitors for the treatment of METH use disorders and suggest several novel compounds as candidate drugs. Published by Elsevier Ltd.

  5. Reduced Sodium Transport With Nasal Administration of the Prostasin Inhibitor Camostat in Subjects With Cystic Fibrosis

    Science.gov (United States)

    Reeves, Ginger; Hathorne, Heather; Solomon, G. Martin; Abbi, Smita; Renard, Didier; Lock, Ruth; Zhou, Ping; Danahay, Henry; Clancy, John P.; Waltz, David A.

    2013-01-01

    Background: Prostasin, a trypsin-like serine protease, is a channel-activating protease and major regulator of epithelial sodium channel-mediated sodium absorption. Its direct inhibition by camostat represents a potential approach to inhibiting sodium transport in cystic fibrosis (CF). Methods: To determine whether a topical formulation of camostat represents an efficacious and tolerable approach to reducing Na+ transport in the CF airway, we conducted a two-part randomized, double-blind, placebo-controlled, crossover, ascending single-dose study to evaluate the pharmacodynamics, safety, and pharmacokinetics of camostat administered through a nasal spray pump in subjects with CF. Nasal potential difference (PD) was measured before and after treatment, and safety and pharmacokinetics were assessed by a standardized approach. Results: In part 1, nine subjects were enrolled, and six completed crossover dosing at the maximally tolerated dose. The change in maximal (most polarizing) basal PD 2 h following administration of camostat was +13.1 mV (1.6-mg dose group) compared with −8.6 mV following placebo (P < .005). Intrasubject change in Ringer and amiloride-sensitive PDs exhibited similar and consistent responses. Bayesian analysis in an additional six subjects in part 2 estimated a dose of 18 μg/mL to provide 50% of the maximum effect. There was no significant change in chloride transport or total nasal symptom score, nasal examination rating, and laboratory parameters. Conclusions: This study establishes the proof of concept that a reduction in sodium transport in the human CF airway can be achieved through inhibition of prostasin activity, identifying a potential therapeutic target in the disease. Trial registration: ClinicalTrials.gov; No.: NCT00506792; URL: www.clinicaltrials.gov PMID:23412700

  6. Polarization of electron-beam irradiated LDPE films: contribution to charge generation and transport

    Science.gov (United States)

    Banda, M. E.; Griseri, V.; Teyssèdre, G.; Le Roy, S.

    2018-04-01

    Electron-beam irradiation is an alternative way to generate charges in insulating materials, at controlled position and quantity, in order to monitor their behaviour in regard to transport phenomena under the space charge induced electric field or external field applied. In this study, low density polyethylene (LDPE) films were irradiated by a 80 keV electron-beam with a flux of 1 nA cm‑2 during 10 min in an irradiation chamber under vacuum conditions, and were then characterized outside the chamber using three experimental methods. The electrical behaviour of the irradiated material was assessed by space charge measurements using the pulsed electro-acoustic (PEA) method under dc stress. The influence of the applied electric field polarity and amplitude has been tested in order to better understand the charge behaviour after electron-beam irradiation. Fourier transform infra-red spectroscopy (FTIR) and photoluminescence (PL) measurements were performed to evaluate the impact of the electron beam irradiation, i.e. deposited charges and energy, on the chemical structure of the irradiated samples. The present results show that the electrical behaviour in LDPE after irradiation is mostly driven by charges, i.e. by physical process functions of the electric field, and that changes in the chemical structure seems to be mild.

  7. Spin-polarized transport through single-molecule magnet Mn6 complexes

    KAUST Repository

    Cremades, Eduard

    2013-01-01

    The coherent transport properties of a device, constructed by sandwiching a Mn6 single-molecule magnet between two gold surfaces, are studied theoretically by using the non-equilibrium Green\\'s function approach combined with density functional theory. Two spin states of such Mn6 complexes are explored, namely the ferromagnetically coupled configuration of the six MnIII cations, leading to the S = 12 ground state, and the low S = 4 spin state. For voltages up to 1 volt the S = 12 ground state shows a current one order of magnitude larger than that of the S = 4 state. Furthermore this is almost completely spin-polarized, since the Mn6 frontier molecular orbitals for S = 12 belong to the same spin manifold. As such the high-anisotropy Mn6 molecule appears as a promising candidate for implementing, at the single molecular level, both spin-switches and low-temperature spin-valves. © 2013 The Royal Society of Chemistry.

  8. Spin-polarized transport in manganite-based magnetic nano structures

    International Nuclear Information System (INIS)

    Granada, Mara

    2007-01-01

    Giant magnetoresistance (G M R) and tunnel magnetoresistance are spin polarized transport phenomena which are observed in magnetic multilayers.They consist in a large variation of the electrical resistivity of the system depending on whether the magnetizations of the magnetic layers are aligned parallel or anti-parallel to each other. In order to be able to align the magnetic layers by means of an external magnetic field, they must not be strongly ferromagnetically coupled.The extrinsic magnetoresistance effects in magnetic multilayers, either G M R in the case of a metallic spacer, or T M R in the case of an insulating spacer, are observed at low magnetic fields, which makes these phenomena interesting for technological applications.We studied the possibility of using the ferromagnetic manganite La 0 ,75Sr 0 ,25MnO 3 (L S M O) in magneto resistive devices, with different materials as a spacer layer.As the main result of this work, we report G M R and T M R measurements in L S M O/LaNiO 3 /L S M O and L S M O/CaMnO 3 /L S M O tri layers, respectively, observed for the first time in these systems.This work included the deposition of films and multilayers by sputtering, the structural characterization of the samples and the study of their magnetic and electric transport properties.Our main interest was the study of G M R in L S M O/LaNiO 3 /L S M O tri layers.It was necessary to firstly characterize the magnetic coupling of L S M O layers through the L N O spacer. After that, we performed electric transport measurements with the current in the plane of the samples.We measured a G M R contribution of ∼ 0,55 % at T = 83 K.We designed a procedure for patterning the samples by e-beam lithography for electric transport measurements with the current perpendicular to the plane. We also performed the study of L S M O/CaMnO 3 /L S M O tri layers with an insulating spacer.We studied the magnetic coupling, as in the previous case.Then we fabricated a tunnel junction for

  9. Effect of secretin and inhibitors of HCO3-/H+ transport on the membrane voltage of rat pancreatic duct cells

    DEFF Research Database (Denmark)

    Novak, I; Pahl, C

    1993-01-01

    The aim of the present study was to study the effect of secretin on the electrophysiological response of pancreatic ducts. Furthermore, we investigated the effects of lipid-soluble buffers and inhibitors of HCO3-/H+ transport. Ducts obtained from fresh rat pancreas were perfused in vitro. Secretin...

  10. Influence of intrinsic spin-flip processes on spin-polarized transport through quantum dots in the cotunneling regime

    International Nuclear Information System (INIS)

    Weymann, I.; Barnas, J.

    2006-01-01

    The influence of intrinsic spin relaxation on spin-polarized cotunneling through quantum dots coupled to ferromagnetic leads is analyzed theoretically. It is shown that the zero bias anomaly, which occurs due to the interplay of single-barrier and double-barrier cotunneling processes, becomes suppressed by spin relaxation processes on the dot. Diode-like features of the transport characteristics in the cotunneling regime have been found in asymmetrical systems. These features are also suppressed by the spin relaxation processes

  11. Differing effects of transport inhibitor on glutamate uptake by nerve terminals before and after exposure of rats to artificial gravity.

    Science.gov (United States)

    Borisova, T.; Krisanova, N.; Himmelreich, N.

    Glutamate is the major excitatory neurotransmitter in the brain. Subsequent to its release from glutamatergic neurons and activation of receptors, it is removed from extracellular space by high affinity Na^+-dependent glutamate transporters, which utilize the Na^+/K^+ electrochemical gradient as a driving force and located in nerve terminals and astrocytes. The glutamate transporters may modify the time course of synaptic events. Like glutamate itself, glutamate transporters are somehow involved in almost all aspects of normal and abnormal brain activity (e.g. cerebral ischemia, amyotrophic lateral sclerosis, Alzheimer's disease, traumatic brain injury, epilepsy and schizophrenia). The present study assessed transporter inhibitor for the ability to inhibit glutamate uptake by synaptosomes at the normal and hypergravity conditions (rats were rotated in a long-arm centrifuge at ten-G during one-hour period). DL-threo-beta-benzyloxyaspartate (DL-TBOA) is a newly developed competitive inhibitor of the high-affinity, Na^+-dependent glutamate transporters. As a potent, non- transported inhibitor of glutamate transporters, DL-TBOA promises to be a valuable new compound for the study of glutamatergic mechanisms. We demonstrated that DL-TBOA inhibited glutamate uptake ( 100 μM glutamate, 30 sec incubation period) in dose-dependent manner as in control as in hypergravity. The effect of this transport inhibitor on glutamate uptake by control synaptosomes and synaptosomes prepared of animals exposed to hypergravity was different. IC50 values calculated on the basis of curves of non-linear regression kinetic analysis was 18±2 μM and 11±2 μM ((P≤0,05) before and after exposure to artificial gravity, respectively. Inhibition caused by 10 μM DL-TBOA was significantly increased from 38,0±3,8 % in control group to 51,0±4,1 % in animals, exposed to hypergravity (P≤0,05). Thus, DL-TBOA had complex effect on glutamate uptake process and perhaps, became more potent under

  12. Substrate and Inhibitor-Specific Conformational Changes in the Human Serotonin Transporter Revealed by Voltage-Clamp Fluorometry

    DEFF Research Database (Denmark)

    Söderhielm, Pella C; Andersen, Jacob; Munro, Lachlan

    2015-01-01

    of TM6, Ala419 in the interface between TM8 and extracellular loop (EL) 4, and Leu481 in EL5. The reporter positions were used for time-resolved measurement of conformational changes during 5-HT transport and binding of cocaine and the selective serotonin reuptake inhibitors fluoxetine and escitalopram....... At all reporter positions, fluorescence changes observed upon substrate application were distinctly different from those observed upon inhibitor application, with respect to relative amplitude or direction. Furthermore, escitalopram, fluoxetine, and cocaine induced a very similar pattern of fluorescent...

  13. The endocannabinoid transport inhibitor AM404 differentially modulates recognition memory in rats depending on environmental aversiveness

    Science.gov (United States)

    Campolongo, Patrizia; Ratano, Patrizia; Manduca, Antonia; Scattoni, Maria L.; Palmery, Maura; Trezza, Viviana; Cuomo, Vincenzo

    2012-01-01

    Cannabinoid compounds may influence both emotional and cognitive processes depending on the level of environmental aversiveness at the time of drug administration. However, the mechanisms responsible for these responses remain to be elucidated. The present experiments investigated the effects induced by the endocannabinoid transport inhibitor AM404 (0.5–5 mg/kg, i.p.) on both emotional and cognitive performances of rats tested in a Spatial Open Field task and subjected to different experimental settings, named High Arousal (HA) and Low Arousal (LA) conditions. The two different experimental conditions influenced emotional reactivity independently of drug administration. Indeed, vehicle-treated rats exposed to the LA condition spent more time in the center of the arena than vehicle-treated rats exposed to the HA context. Conversely, the different arousal conditions did not affect the cognitive performances of vehicle-treated animals such as the capability to discriminate a spatial displacement of the objects or an object substitution. AM404 administration did not alter locomotor activity or emotional behavior of animals exposed to both environmental conditions. Interestingly, AM404 administration influenced the cognitive parameters depending on the level of emotional arousal: it impaired the capability of rats exposed to the HA condition to recognize a novel object while it did not induce any impairing effect in rats exposed to the LA condition. These findings suggest that drugs enhancing endocannabinoid signaling induce different effects on recognition memory performance depending on the level of emotional arousal induced by the environmental conditions. PMID:22454620

  14. Benzo- and cyclohexanomazindol analogues as potential inhibitors of the cocaine binding site at the dopamine transporter.

    Science.gov (United States)

    Houlihan, William J; Ahmad, Umer F; Koletar, Judith; Kelly, Lawrence; Brand, Leonard; Kopajtic, Theresa A

    2002-09-12

    A series of mazindol (1), homomazindol (2), and bishomomazindol (3) derivatives with a benzo or cyclohexano ring fused at various sites were prepared as part of an SAR study to determine the effect of increased aliphatic and aromatic lipophilicity on selected in vitro assays used to identify potential cocaine-like and cocaine antagonism activity. Very good (IC(50) = 2-3 nM) inhibition of [(3)H] WIN 35,428 and [(125)I] RTI-55 binding on rat or guinea pig striatal membranes and HEK cells expressing cDNA for the human dopamine transporter (HEK-hDAT) was shown by the 8,9-benzomazindol 25 and 9,10-benzohomomazindol 28. All new compounds were weaker inhibitors of [(3)H] DA uptake in HEK-hDAT cells than 1 and 2. No improvement in the binding selectivity ratio (SERT/DAT and NET/DAT) was found when compared to 2. Compounds 25and 28 showed a considerable increase versus 1 in uptake/binding discrimination ratios at the DAT (311.0 and 182.1 vs 0.9), SERT (33.6 and 127.3 vs 1.9), and NET (7.3 and 10.0 vs 0.3).

  15. Effect of Porosity and Concentration Polarization on Electrolyte Diffusive Transport Parameters through Ceramic Membranes with Similar Nanopore Size

    Directory of Open Access Journals (Sweden)

    Virginia Romero

    2014-08-01

    Full Text Available Diffusive transport through nanoporous alumina membranes (NPAMs produced by the two-step anodization method, with similar pore size but different porosity, is studied by analyzing membrane potential measured with NaCl solutions at different concentrations. Donnan exclusion of co-ions at the solution/membrane interface seem to exert a certain control on the diffusive transport of ions through NPAMs with low porosity, which might be reduced by coating the membrane surface with appropriated materials, as it is the case of SiO2. Our results also show the effect of concentration polarization at the membrane surface on ionic transport numbers (or diffusion coefficients for low-porosity and high electrolyte affinity membranes, which could mask values of those characteristic electrochemical parameters.

  16. The Great Solar Active Region NOAA 12192: Helicity Transport, Filament Formation, and Impact on the Polar Field

    Science.gov (United States)

    Petrie, Gordon; McMaken, Tyler C.

    2017-08-01

    The solar active region (AR), NOAA 12192, appeared in 2014 October as the largest AR in 24 years. Here we examine the counterintuitive nature of two diffusion-driven processes in the region: the role of helicity buildup in the formation of a major filament, and the relationship between the effects of supergranular diffusion and meridional flow on the AR and on the polar field. Quantitatively, calculations of current helicity and magnetic twist from Helioseismic and Magnetic Imager (HMI) vector magnetograms indicate that, though AR 12192 emerged with negative helicity, positive helicity from subsequent flux emergence, consistent with the hemispheric sign-preference of helicity, increased over time within large-scale, weak-field regions such as those near the polarity inversion line (PIL). Morphologically, Atmospheric Imaging Assembly observations of filament barbs, sigmoidal patterns, and bases of Fe xii stalks initially exhibited signatures of negative helicity, and the long filament that subsequently formed had a strong positive helicity consistent with the helicity buildup along the PIL. We find from full-disk HMI magnetograms that AR 12192's leading positive flux was initially closer to the equator but, owing either to the region’s magnetic surroundings or to its asymmetric flux density distribution, was transported poleward more quickly on average than its trailing negative flux, contrary to the canonical pattern of bipole flux transport. This behavior caused the AR to have a smaller effect on the polar fields than expected and enabled the formation of the very long neutral line where the filament formed.

  17. Investigation of the electronic transport in polarization-induced nanowires using conductive atomic force microscopy (AFM)

    Science.gov (United States)

    Selcu, Camelia; Carnevale, Santino C.; Kent, Thomas F.; Akyol, Fatih; Phillips, Patrick J.; Mills, Michael J.; Rajan, Siddharth; Pelz, Jonathan P.; Myers, Roberto C.

    2013-03-01

    In the search to improve short wavelength light emitting diodes (LED's), where the dislocations limit their performance and hole doping (Mg) is a fundamental challenge, the III-Nitride polarization-induced nanowire LED provides a promising system to address these problems. The new type of pn diode, polarization-induced nanowire LED (PINLED), was developed by linearly grading AlGaN composition of the nanowires (from GaN to AlN and back to GaN) from 0% to 100% and back to 0% Al (Carnevale et al, Nano Lett., 12, 915 (2012)). In III-Nitrides (Ga,Al/N), the effects of polarization are commonly observed at the surfaces and interfaces. Thus, in the case of the polarization-induced nanowire LEDs, taking advantage of the bound polarization charge, due to the grading of the AlGaN, the pn diodes are formed. The polarity of the nanowires determines the carrier type in each graded region, and therefore the diode orientation (n/p vs p/n). We used conductive AFM to investigate polarity of the PINLED's as well as hole conductivity in PINLED's made of AlGaN with and without acceptor doping. The results reveal that most of the wires are n-top/p-bottom (N-face), but some are p-top/n-bottom (Ga-face). Also, we found that the current density is 3 orders of magnitude larger in the case of the doped nanowires than the nanowires with no impurity doping.

  18. Relationship between conformational changes in the dopamine transporter and cocaine-like subjective effects of uptake inhibitors

    DEFF Research Database (Denmark)

    Løland, Claus Juul; Desai, Rajeev I; Zou, Mu-Fa

    2007-01-01

    Cocaine exerts its stimulatory effect by inhibiting the dopamine transporter (DAT). However, novel benztropine- and rimcazole-based inhibitors show reduced stimulant effects compared with cocaine, despite higher affinity and selectivity for DAT. To investigate possible mechanisms, we compared...... the extracellular transporter gate is open but inaccessible when it is closed. The data indicated that cocaine analogs bind an open conformation, whereas benztropine and rimcazole analogs bind a closed conformation. Next, we investigated the changes in inhibition potency of [(3)H]dopamine uptake of the compounds...... at a mutant DAT (Y335A) characterized by a global change in the conformational equilibrium. We observed a close relationship between the decrease in potencies of inhibitors at this mutant and cocaine-like responding in rats trained to discriminate cocaine from saline injections. Our data suggest...

  19. Effect of Known Inhibitors of Ion Transport on Pendrin (SLC26A4) Activity in a Human Kidney Cell Line

    OpenAIRE

    Emanuele Bernardinelli; Roberta Costa; Charity Nofziger; Markus Paulmichl; Silvia Dossena

    2016-01-01

    Background/Aims: Pendrin is a Cl-/I-/HCO3- exchanger playing a fundamental role in controlling blood pressure and airway function, therefore representing an attractive target for the treatment of hypertensive states and respiratory distresses. A review of the literature regarding the ability of some compounds (namely several known inhibitors of ion transport) to block pendrin activity revealed discordant findings. These incongruous findings may be due, in part, to the concentration of compoun...

  20. The Rho kinase inhibitor Fasudil up-regulates astrocytic glutamate transport subsequent to actin remodelling in murine cultured astrocytes

    DEFF Research Database (Denmark)

    Lau, Cl; O'Shea, Rd; Bischof, L

    2011-01-01

    activity and astrocytic morphology. EXPERIMENTAL APPROACH The functional activity of glutamate transport was determined in murine cultured astrocytes after exposure to the ROCK inhibitors Fasudil (HA-1077) and Y27632 using biochemical, molecular and morphological approaches. Cytochemical analyses assessed......BACKGROUND AND PURPOSE Glutamate transporters play a major role in maintaining brain homeostasis and the astrocytic transporters, EAAT1 and EAAT2, are functionally dominant. Astrocytic excitatory amino acid transporters (EAATs) play important roles in various neuropathologies wherein astrocytes...... changes in astrocytic morphology, F-/G-actin, and localizations of EAAT1/2. RESULTS Fasudil and Y27632 increased [(3) H]-d-aspartate (d-Asp) uptake into astrocytes, and the action of Fasudil was time-dependent and concentration-related. The rapid stellation of astrocytes (glial fibrillary acidic protein...

  1. Safety of Sodium-Glucose Co-Transporter 2 Inhibitors during Ramadan Fasting: Evidence, Perceptions and Guidelines

    Directory of Open Access Journals (Sweden)

    Salem A. Beshyah

    2016-06-01

    Full Text Available Sodium-glucose co-transporter 2 (SGLT2 inhibitors are a new glucose-lowering therapy for T2DM with documented benefits on blood glucose, hypertension, weight reduction and long term cardiovascular benefit. They have an inherent osmotic diuretic effect and lead to some volume loss and possible dehydration. There is some concern about the safety of using SGLT2 inhibitors in Muslim type 2 diabetes mellitus (T2DM patients during the fast during Ramadan. Currently, there is a dearth of research data to help guide physicians and reassure patients.  One study confirmed good glycemic control with less risk of hypoglycemia and no marked volume depletion. Data in the elderly and in combination with diuretics are reassuring of their safe to use in Ramadan in general. SGLT2 inhibitor-related diabetic ketoacidosis has not been reported during Ramadan and is unlikely to be relevant. Survey of physicians revealed that the majority felt that SGLT2 inhibitors are generally safe in T2DM patients during Ramadan fasting but should be discontinued in certain high risk patients. Some professional groups with interest in diabetes and Ramadan fasting included SGLT2 inhibitors in their guidelines on management of diabetes during Ramadan. They acknowledged the lack of trial data, recommended caution in high risk groups, advised regular monitoring and emphasized pre-Ramadan patients’ education. In conclusion, currently, knowledge, data and experience with SGLT2 inhibitors in Ramadan are limited. Nonetheless, stable patients with normal kidney function and low risk of dehydration may safely use the SGLT2 inhibitors therapy. Higher risk patients should be observed carefully and managed on individual basis.

  2. Effects of cholesterol transport inhibitor U18666A on APP metabolism in rat primary astrocytes.

    Science.gov (United States)

    Yang, Hongyan; Wang, Yanlin; Kar, Satyabrata

    2017-11-01

    Amyloid β (Aβ) peptides generated from the amyloid precursor protein (APP) play an important role in the degeneration of neurons and development of Alzheimer's disease (AD). Current evidence indicates that high levels of cholesterol-which increase the risk of developing AD-can influence Aβ production in neurons. However, it remains unclear how altered level/subcellular distribution of cholesterol in astrocytes can influence APP metabolism. In this study, we evaluated the effects of cholesterol transport inhibitor U18666A-a class II amphiphile that triggers redistribution of cholesterol within the endosomal-lysosomal (EL) system-on APP levels and metabolism in rat primary cultured astrocytes. Our results revealed that U18666A increased the levels of the APP holoprotein and its cleaved products (α-/β-/η-CTFs) in cultured astrocytes, without altering the total levels of cholesterol or cell viability. The cellular levels of Aβ 1-40 were also found to be markedly increased, while secretory levels of Aβ 1-40 were decreased in U18666A-treated astrocytes. We further report a corresponding increase in the activity of the enzymes regulating APP processing, such as α-secretase, β-secretase, and γ-secretase as a consequence of U18666A treatment. Additionally, APP-cleaved products are partly accumulated in the lysosomes following cholesterol sequestration within EL system possibly due to decreased clearance. Interestingly, serum delipidation attenuated enhanced levels of APP and its cleaved products following U18666A treatment. Collectively, these results suggest that cholesterol sequestration within the EL system in astrocytes can influence APP metabolism and the accumulation of APP-cleaved products including Aβ peptides, which can contribute to the development of AD pathology. © 2017 Wiley Periodicals, Inc.

  3. The organic anion transporter OAT3 enhances the glucosuric effect of the SGLT2 inhibitor empagliflozin.

    Science.gov (United States)

    Fu, Yiling; Breljak, Davorka; Onishi, Akira; Batz, Falk; Patel, Rohit; Huang, Winnie; Song, Panai; Freeman, Brent; Mayoux, Eric; Koepsell, Hermann; Anzai, Naohiko; Nigam, Sanjay K; Sabolić, Ivan; Vallon, Volker

    2018-02-07

    The SGLT2 inhibitor empagliflozin (plasma protein binding ~88%) may reach its target in the brush border of the early proximal tubule by glomerular filtration and tubular secretion. Here we determined whether empagliflozin is secreted by renal tubules, and whether genetic knockout of the basolateral organic anion transporter Oat3 (-/-) affects its tubular secretion or glucosuric effect. Renal clearance studies in wild-type (WT) mice showed that tubular secretion accounted for 50-70% of empagliflozin urinary excretion. Immunostaining indicated that SGLT2 and OAT3 localization partially overlapped in proximal tubule S1 and S2 segments. Glucosuria in metabolic cage studies was reduced in Oat3-/- vs. WT mice for acute empagliflozin doses of 1, 3, and 10mg/kg, whereas 30mg/kg induced similar maximal glucosuria in both genotypes. Chronic application of empagliflozin (~25mg kg-1 day-1) in Oat3-/- mice was associated with lower urinary glucose to creatinine ratios despite maintaining slightly higher blood glucose levels than WT. On a whole kidney level, renal secretion of empagliflozin was largely unchanged in Oat3-/- mice. However, the absence of OAT3 attenuated the influence of empagliflozin on fractional glucose excretion; higher levels of plasma or filtered empagliflozin were needed to induce similar increases in fractional renal glucose excretion. We conclude that empagliflozin is excreted into the urine to similar extent by glomerular filtration and tubular secretion. The latter can occur largely independent of OAT3. However, OAT3 increases the glucosuric effect of empagliflozin, which may relate to the partial overlap of its localization with SGLT2 and OAT3-mediated tubular secretion of empagliflozin in the early proximal tubule.

  4. Inositol Trisphosphate-Induced Ca2+ Signaling Modulates Auxin Transport and PIN Polarity

    Czech Academy of Sciences Publication Activity Database

    Zhang, J.; Vanneste, S.; Brewer, P. B.; Michniewicz, M.; Grones, P.; Kleine-Vehn, J.; Löfke, Ch.; Teichmann, T.; Bielach, A.; Cannoot, B.; Hoyerová, Klára; Chen, X.; Xue, H. W.; Benková, E.; Zažímalová, Eva; Friml, J.

    2011-01-01

    Roč. 20, č. 6 (2011), s. 855-866 ISSN 1534-5807 Institutional research plan: CEZ:AV0Z50380511 Keywords : PIN polarity * auxin distribution * Inositol trisphosphate Subject RIV: ED - Physiology Impact factor: 14.030, year: 2011

  5. Pore Polarity and Charge Determine Differential Block of Kir1.1 and Kir7.1 Potassium Channels by Small-Molecule Inhibitor VU590.

    Science.gov (United States)

    Kharade, Sujay V; Sheehan, Jonathan H; Figueroa, Eric E; Meiler, Jens; Denton, Jerod S

    2017-09-01

    VU590 was the first publicly disclosed, submicromolar-affinity (IC 50 = 0.2 μ M), small-molecule inhibitor of the inward rectifier potassium (Kir) channel and diuretic target, Kir1.1. VU590 also inhibits Kir7.1 (IC 50 ∼ 8 μ M), and has been used to reveal new roles for Kir7.1 in regulation of myometrial contractility and melanocortin signaling. Here, we employed molecular modeling, mutagenesis, and patch clamp electrophysiology to elucidate the molecular mechanisms underlying VU590 inhibition of Kir1.1 and Kir7.1. Block of both channels is voltage- and K + -dependent, suggesting the VU590 binding site is located within the pore. Mutagenesis analysis in Kir1.1 revealed that asparagine 171 (N171) is the only pore-lining residue required for high-affinity block, and that substituting negatively charged residues (N171D, N171E) at this position dramatically weakens block. In contrast, substituting a negatively charged residue at the equivalent position in Kir7.1 enhances block by VU590, suggesting the VU590 binding mode is different. Interestingly, mutations of threonine 153 (T153) in Kir7.1 that reduce constrained polarity at this site (T153C, T153V, T153S) make wild-type and binding-site mutants (E149Q, A150S) more sensitive to block by VU590. The Kir7.1-T153C mutation enhances block by the structurally unrelated inhibitor VU714 but not by a higher-affinity analog ML418, suggesting that the polar side chain of T153 creates a barrier to low-affinity ligands that interact with E149 and A150. Reverse mutations in Kir1.1 suggest that this mechanism is conserved in other Kir channels. This study reveals a previously unappreciated role of membrane pore polarity in determination of Kir channel inhibitor pharmacology. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  6. In vivo and in vitro evaluations of intestinal gabapentin absorption: effect of dose and inhibitors on carrier-mediated transport.

    Science.gov (United States)

    Larsen, Malte Selch; Frølund, Sidsel; Nøhr, Martha Kampp; Nielsen, Carsten Uhd; Garmer, Mats; Kreilgaard, Mads; Holm, René

    2015-03-01

    Gabapentin exhibits saturable absorption kinetics, however, it remains unclear which transporters that are involved in the intestinal transport of gabapentin. Thus, the aim of the current study was to explore the mechanistic influence of transporters on the intestinal absorption of gabapentin by both in vivo and in vitro investigations Pharmacokinetic parameters were determined following a range of intravenous (5-100 mg/kg) and oral doses (10-200 mg/kg) in rats. Transepithelial transport (50 μM-50 mM) and apical uptake of gabapentin (0.01-50 mM) were investigated in Caco-2 cells. The effect of co-application of the LAT-inhibitor, BCH, and the b(0,+)-substrate, L-lysine, on intestinal transport of gabapentin was evaluated in vivo and in vitro. Gabapentin showed dose-dependent oral absorption kinetics and dose-independent disposition kinetics. Co-application of BCH inhibited intestinal absorption in vivo and apical uptake in vitro, whereas no effect was observed following co-application of L-lysine. The present study shows for the first time that BCH was capable of inhibiting intestinal absorption of gabapentin in vivo. Furthermore, in Caco-2 cell experiments BCH inhibited apical uptake of gabapentin. These findings may imply that a BCH-sensitive transport-system was involved in the apical and possibly the basolateral transport of gabapentin across the intestinal wall.

  7. Insight into electronic, mechanical and transport properties of quaternary CoVTiAl: Spin-polarized DFT + U approach

    Energy Technology Data Exchange (ETDEWEB)

    Yousuf, Saleem, E-mail: nengroosaleem17@gmail.com; Gupta, D.C., E-mail: sosfizix@gmail.com

    2017-07-15

    Highlights: • 100% spin-polarized material important for the application in spintronics. • It is ferromagnetic and ductile in nature. • Shows semiconducting behavior with a band gap of 1.06 eV. • Possibly efficient high temperature thermoelectric material. - Abstract: We present a preliminary investigation of band structure and thermoelectric properties of new quaternary CoVTiAl Heusler alloy. Structural, magnetic property and 100% spin polarization of equiatomic CoVTiAl predicts ferromagnetic stable ground state. Band profile outlines the indirect semiconducting behavior in spin down channel with band gap of 1.06 eV, and the magnetic moment of 3 µ{sub B} in accordance with Slater-Pauling rule. To evaluate the accuracy of different approximations in predicting thermoelectric properties, the comparison with available experimental data is made which shows fair agreement for the transport coefficients. The high temperature (800 K) positive Seebeck coefficient of 73.71 µV/K describes the p-type character of the material with high efficiency due to highly influential semiconducting behavior around the Fermi level. Considering the combination of 100% spin-polarization, high Seebeck coefficient and large figure of merit, ferromagnetic semiconducting CoVTiAl may prove as a potential candidate for high temperature thermoelectrics and an ideal spin source material for spintronic applications.

  8. Development and potential role of type-2 sodium-glucose transporter inhibitors for management of type 2 diabetes.

    Science.gov (United States)

    Hardman, Timothy Colin; Dubrey, Simon William

    2011-09-01

    There is a recognized need for new treatment options for type 2 diabetes mellitus (T2DM). Recovery of glucose from the glomerular filtrate represents an important mechanism in maintaining glucose homeostasis and represents a novel target for the management of T2DM. Recovery of glucose from the glomerular filtrate is executed principally by the type 2 sodium-glucose cotransporter (SGLT2). Inhibition of SGLT2 promotes glucose excretion and normalizes glycemia in animal models. First reports of specifically designed SGLT2 inhibitors began to appear in the second half of the 1990s. Several candidate SGLT2 inhibitors are currently under development, with four in the later stages of clinical testing. The safety profile of SGLT2 inhibitors is expected to be good, as their target is a highly specific membrane transporter expressed almost exclusively within the renal tubules. One safety concern is that of glycosuria, which could predispose patients to increased urinary tract infections. So far the reported safety profile of SGLT2 inhibitors in clinical studies appears to confirm that the class is well tolerated. Where SGLT2 inhibitors will fit in the current cascade of treatments for T2DM has yet to be established. The expected favorable safety profile and insulin-independent mechanism of action appear to support their use in combination with other antidiabetic drugs. Promotion of glucose excretion introduces the opportunity to clear calories (80-90 g [300-400 calories] of glucose per day) in patients that are generally overweight, and is expected to work synergistically with weight reduction programs. Experience will most likely lead to better understanding of which patients are likely to respond best to SGLT2 inhibitors, and under what circumstances.

  9. 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

  10. 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.

  11. The role of human equilibrative nucleoside transporter 1 on the cellular transport of the DNA methyltransferase inhibitors 5-azacytidine and CP-4200 in human leukemia cells.

    Science.gov (United States)

    Hummel-Eisenbeiss, Johanna; Hascher, Antje; Hals, Petter-Arnt; Sandvold, Marit Liland; Müller-Tidow, Carsten; Lyko, Frank; Rius, Maria

    2013-09-01

    The nucleoside analog 5-azacytidine is an archetypical drug for epigenetic cancer therapy, and its clinical effectiveness has been demonstrated in the treatment of myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). However, therapy resistance in patients with MDS/AML remains a challenging issue. Membrane proteins that are involved in drug uptake are potential mediators of drug resistance. The responsible proteins for the transport of 5-azacytidine into MDS/AML cells are unknown. We have now systematically analyzed the expression and activity of various nucleoside transporters. We identified the human equilibrative nucleoside transporter 1 (hENT1) as the most abundant nucleoside transporter in leukemia cell lines and in AML patient samples. Transport assays using [¹⁴C]5-azacytidine demonstrated Na⁺-independent uptake of the drug into the cells, which was inhibited by S-(4-nitrobenzyl)-6-thioinosine (NBTI), a hENT1 inhibitor. The cellular toxicity of 5-azacytidine and its DNA demethylating activity were strongly reduced after hENT1 inhibition. In contrast, the cellular activity of the 5-azacytidine derivative 5-azacytidine-5'-elaidate (CP-4200), a nucleoside transporter-independent drug, persisted after hENT1 inhibition. A strong dependence of 5-azacytidine-induced DNA demethylation on hENT1 activity was also confirmed by array-based DNA methylation profiling, which uncovered hundreds of loci that became demethylated only when hENT1-mediated transport was active. Our data establish hENT1 as a key transporter for the cellular uptake of 5-azacytidine in leukemia cells and raise the possibility that hENT1 expression might be a useful biomarker to predict the efficiency of 5-azacytidine treatments. Furthermore, our data suggest that CP-4200 may represent a valuable compound for the modulation of transporter-related 5-azacytidine resistances.

  12. The Great Solar Active Region NOAA 12192: Helicity Transport, Filament Formation, and Impact on the Polar Field

    Energy Technology Data Exchange (ETDEWEB)

    McMaken, Tyler C. [National Solar Observatory REU Program, 3665 Discovery Drive, 3rd Floor, Boulder, CO 80303 (United States); Petrie, Gordon J. D., E-mail: tmcmaken@gmail.com, E-mail: gpetrie@noao.edu [National Solar Observatory, 3665 Discovery Drive, 3rd Floor, Boulder, CO 80303 (United States)

    2017-05-10

    The solar active region (AR), NOAA 12192, appeared in 2014 October as the largest AR in 24 years. Here we examine the counterintuitive nature of two diffusion-driven processes in the region: the role of helicity buildup in the formation of a major filament, and the relationship between the effects of supergranular diffusion and meridional flow on the AR and on the polar field. Quantitatively, calculations of current helicity and magnetic twist from Helioseismic and Magnetic Imager (HMI) vector magnetograms indicate that, though AR 12192 emerged with negative helicity, positive helicity from subsequent flux emergence, consistent with the hemispheric sign-preference of helicity, increased over time within large-scale, weak-field regions such as those near the polarity inversion line (PIL). Morphologically, Atmospheric Imaging Assembly observations of filament barbs, sigmoidal patterns, and bases of Fe xii stalks initially exhibited signatures of negative helicity, and the long filament that subsequently formed had a strong positive helicity consistent with the helicity buildup along the PIL. We find from full-disk HMI magnetograms that AR 12192's leading positive flux was initially closer to the equator but, owing either to the region’s magnetic surroundings or to its asymmetric flux density distribution, was transported poleward more quickly on average than its trailing negative flux, contrary to the canonical pattern of bipole flux transport. This behavior caused the AR to have a smaller effect on the polar fields than expected and enabled the formation of the very long neutral line where the filament formed.

  13. Transport Properties of Spin-Polarized Atomic Hydrogen Using Generalized Scattering Theory

    Science.gov (United States)

    Joudeh, B. R.; Sandouqa, A. S.

    2018-02-01

    Our results for the scattering and thermophysical properties of spin-polarized atomic hydrogen (H{\\downarrow }) have been presented in the temperature range 0.01-10 K using the Galitskii-Migdal-Feynman formalism. These results include the quantum second virial coefficient, the average total and viscosity cross sections, the viscosity, the diffusion coefficient, and the thermal conductivity. The calculations have been undertaken using three triplet-state potentials: Morse-type, Silvera and Born-Oppenheimer potentials. The Morse potential is less attractive and very simple, but less accurate to describe spin-polarized atomic hydrogen. That explains the differences between it and the other two potentials, which are clearly better. From the results of the average total cross sections, it is concluded the H{\\downarrow } remains a gas even at low temperature. The viscosity, the thermal conductivity, and the diffusion coefficients of H{\\downarrow } increase in all cases with increasing temperature.

  14. Spin-wave propagation and spin-polarized electron transport in single-crystal iron films

    Science.gov (United States)

    Gladii, O.; Halley, D.; Henry, Y.; Bailleul, M.

    2017-11-01

    The techniques of propagating spin-wave spectroscopy and current-induced spin-wave Doppler shift are applied to a 20-nm-thick Fe/MgO(001) film. The magnetic parameters extracted from the position of the spin-wave resonance peaks are very close to those tabulated for bulk iron. From the zero-current propagating wave forms, a group velocity of 4 km/s and an attenuation length of about 6 μ m are extracted for 1.6-μ m -wavelength spin wave at 18 GHz. From the measured current-induced spin-wave Doppler shift, we extract a surprisingly high degree of spin polarization of the current of 83 % , which constitutes the main finding of this work. This set of results makes single-crystalline iron a promising candidate for building devices utilizing high-frequency spin waves and spin-polarized currents.

  15. Temperature-Dependent Polarization in Field-Effect Transport and Photovoltaic Measurements of Methylammonium Lead Iodide.

    Science.gov (United States)

    Labram, John G; Fabini, Douglas H; Perry, Erin E; Lehner, Anna J; Wang, Hengbin; Glaudell, Anne M; Wu, Guang; Evans, Hayden; Buck, David; Cotta, Robert; Echegoyen, Luis; Wudl, Fred; Seshadri, Ram; Chabinyc, Michael L

    2015-09-17

    While recent improvements in the reported peak power conversion efficiency (PCE) of hybrid organic-inorganic perovskite solar cells have been truly astonishing, there are many fundamental questions about the electronic behavior of these materials. Here we have studied a set of electronic devices employing methylammonium lead iodide ((MA)PbI3) as the active material and conducted a series of temperature-dependent measurements. Field-effect transistor, capacitor, and photovoltaic cell measurements all reveal behavior consistent with substantial and strongly temperature-dependent polarization susceptibility in (MA)PbI3 at temporal and spatial scales that significantly impact functional behavior. The relative PCE of (MA)PbI3 photovoltaic cells is observed to reduce drastically with decreasing temperature, suggesting that such polarization effects could be a prerequisite for high-performance device operation.

  16. Sodium-glucose co-transporter 2 (SGLT2 inhibitors: a growing class of anti-diabetic agents

    Directory of Open Access Journals (Sweden)

    Eva M Vivian

    2014-12-01

    Full Text Available Although several treatment options are available to reduce hyperglycemia, only about half of individuals with diagnosed diabetes mellitus (DM achieve recommended glycemic targets. New agents that reduce blood glucose concentrations by novel mechanisms and have acceptable safety profiles are needed to improve glycemic control and reduce the complications associated with type 2 diabetes mellitus (T2DM. The renal sodium-glucose co-transporter 2 (SGLT2 is responsible for reabsorption of most of the glucose filtered by the kidney. Inhibitors of SGLT2 lower blood glucose independent of the secretion and action of insulin by inhibiting renal reabsorption of glucose, thereby promoting the increased urinary excretion of excess glucose. Canagliflozin, dapagliflozin, and empagliflozin are SGLT2 inhibitors approved as treatments for T2DM in the United States, Europe, and other countries. Canagliflozin, dapagliflozin, and empagliflozin increase renal excretion of glucose and improve glycemic parameters in patients with T2DM when used as monotherapy or in combination with other antihyperglycemic agents. Treatment with SGLT2 inhibitors is associated with weight reduction, lowered blood pressure, and a low intrinsic propensity to cause hypoglycemia. Overall, canagliflozin, dapagliflozin, and empagliflozin are well tolerated. Cases of genital infections and, in some studies, urinary tract infections have been more frequent in canagliflozin-, dapagliflozin-, and empagliflozin-treated patients compared with those receiving placebo. Evidence from clinical trials suggests that SGLT2 inhibitors are a promising new treatment option for T2DM.

  17. Polar Processes in a 50-year Simulation of Stratospheric Chemistry and Transport

    Science.gov (United States)

    Kawa, S.R.; Douglass, A. R.; Patrick, L. C.; Allen, D. R.; Randall, C. E.

    2004-01-01

    The unique chemical, dynamical, and microphysical processes that occur in the winter polar lower stratosphere are expected to interact strongly with changing climate and trace gas abundances. Significant changes in ozone have been observed and prediction of future ozone and climate interactions depends on modeling these processes successfully. We have conducted an off-line model simulation of the stratosphere for trace gas conditions representative of 1975-2025 using meteorology from the NASA finite-volume general circulation model. The objective of this simulation is to examine the sensitivity of stratospheric ozone and chemical change to varying meteorology and trace gas inputs. This presentation will examine the dependence of ozone and related processes in polar regions on the climatological and trace gas changes in the model. The model past performance is base-lined against available observations, and a future ozone recovery scenario is forecast. Overall the model ozone simulation is quite realistic, but initial analysis of the detailed evolution of some observable processes suggests systematic shortcomings in our description of the polar chemical rates and/or mechanisms. Model sensitivities, strengths, and weaknesses will be discussed with implications for uncertainty and confidence in coupled climate chemistry predictions.

  18. Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Aβ Levels Mediated by Brain Shuttle Transport

    Directory of Open Access Journals (Sweden)

    Nadine Ruderisch

    2017-10-01

    Full Text Available Therapeutic approaches to fight Alzheimer's disease include anti-Amyloidβ (Aβ antibodies and secretase inhibitors. However, the blood-brain barrier (BBB limits the brain exposure of biologics and the chemical space for small molecules to be BBB permeable. The Brain Shuttle (BS technology is capable of shuttling large molecules into the brain. This allows for new types of therapeutic modalities engineered for optimal efficacy on the molecular target in the brain independent of brain penetrating properties. To this end, we designed BACE1 peptide inhibitors with varying lipid modifications with single-digit picomolar cellular potency. Secondly, we generated active-exosite peptides with structurally confirmed dual binding mode and improved potency. When fused to the BS via sortase coupling, these BACE1 inhibitors significantly reduced brain Aβ levels in mice after intravenous administration. In plasma, both BS and non-BS BACE1 inhibitor peptides induced a significant time- and dose-dependent decrease of Aβ. Our results demonstrate that the BS is essential for BACE1 peptide inhibitors to be efficacious in the brain and active-exosite design of BACE1 peptide inhibitors together with lipid modification may be of therapeutic relevance.

  19. In vitro evidence for the brain glutamate efflux hypothesis: brain endothelial cells cocultured with astrocytes display a polarized brain-to-blood transport of glutamate.

    Science.gov (United States)

    Helms, Hans Christian; Madelung, Rasmus; Waagepetersen, Helle Sønderby; Nielsen, Carsten Uhd; Brodin, Birger

    2012-05-01

    The concentration of the excitotoxic amino acid, L-glutamate, in brain interstitial fluid is tightly regulated by uptake transporters and metabolism in astrocytes and neurons. The aim of this study was to investigate the possible role of the blood-brain barrier endothelium in brain L-glutamate homeostasis. Transendothelial transport- and accumulation studies of (3) H-L-glutamate, (3) H-L-aspartate, and (3) H-D-aspartate in an electrically tight bovine endothelial/rat astrocyte blood-brain barrier coculture model were performed. After 6 days in culture, the endothelium displayed transendothelial resistance values of 1014 ± 70 Ω cm(2) , and (14) C-D-mannitol permeability values of 0.88 ± 0.13 × 10(-6) cm s(-1) . Unidirectional flux studies showed that L-aspartate and L-glutamate, but not D-aspartate, displayed polarized transport in the brain-to-blood direction, however, all three amino acids accumulated in the cocultures when applied from the abluminal side. The transcellular transport kinetics were characterized with a K(m) of 69 ± 15 μM and a J(max) of 44 ± 3.1 pmol min(-1) cm(-2) for L-aspartate and a K(m) of 138 ± 49 μM and J(max) of 28 ± 3.1 pmol min(-1) cm(-2) for L-glutamate. The EAAT inhibitor, DL-threo-ß-Benzyloxyaspartate, inhibited transendothelial brain-to-blood fluxes of L-glutamate and L-aspartate. Expression of EAAT-1 (Slc1a3), -2 (Slc1a2), and -3 (Slc1a1) mRNA in the endothelial cells was confirmed by conventional PCR and localization of EAAT-1 and -3 in endothelial cells was shown with immunofluorescence. Overall, the findings suggest that the blood-brain barrier itself may participate in regulating brain L-glutamate concentrations. Copyright © 2012 Wiley Periodicals, Inc.

  20. Manipulating NiFe/AlOx interfacial chemistry for the spin-polarized electrons transport

    International Nuclear Information System (INIS)

    Zhao, Chong-Jun; Sun, Li; Ding, Lei; Li, Jian-Wei; Zhang, Jing-Yan; Cao, Yi; Yu, Guang-Hua

    2013-01-01

    Through vacuum annealing, interfacial chemical composition of sputter-deposited AlO x /NiFe/AlO x can be controlled for electron transport manipulation. Chemical status change at the NiFe/AlO x interface was quantified by X-ray photoelectron spectroscopy and correlated to the structure and electron transport properties of the heterostructure. It is found that elemental Al existed in the insulting AlO x after annealing at intermediate temperature can improve the AlO x /NiFe interface and thus favor the electronic transport. Annealing at higher temperature will result in native AlO x formation and degrade transport properties due to the NiFe/AlO x interfaces deterioration caused by significant difference in thermal expansion coefficients of the two materials.

  1. Extracellular concentration of homocysteine in human cell lines is influenced by specific inhibitors of cyst(e)ine transport.

    Science.gov (United States)

    Hultberg, Björn

    2004-04-01

    Despite the growing evidence that plasma homocysteine is a cardiovascular risk factor, the mechanism behind the vascular injuries is still unknown. Studies of the cellular uptake systems for homocysteine are scarce, but membrane transporters of cyst(e)ine seem to be involved. In the present study the cellular uptake of extracellular homocysteine in HeLa and hepatoma cell lines is investigated by using several different transport inhibitors for cellular uptake of cyst(e)ine. It is shown that systems A and Xc- are the main transport systems for homocysteine uptake in HeLa cells. It is also confirmed that the magnitude of homocysteine uptake in hepatoma cells is lower than in HeLa cells. However, in the presence of high amounts of extracellular homocysteine both cell types exhibited a high elimination of homocysteine, which was inhibited by the presence of inhibitors of systems A or Xc-. It is possible that there is normally a high turnover of homocysteine in cell cultures, which is not detected by occasional determinations of homocysteine concentrations. The complex pattern of homocysteine production, release, uptake and distribution between different cells in the body is important to examine further in order to possibly be able to modulate the elimination of homocysteine from circulation and thereby lower the risk of cardiovascular disease.

  2. Importance of the Extracellular Loop 4 in the Human Serotonin Transporter for Inhibitor Binding and Substrate Translocation.

    Science.gov (United States)

    Rannversson, Hafsteinn; Wilson, Pamela; Kristensen, Kristina Birch; Sinning, Steffen; Kristensen, Anders Skov; Strømgaard, Kristian; Andersen, Jacob

    2015-06-05

    The serotonin transporter (SERT) terminates serotonergic neurotransmission by performing reuptake of released serotonin, and SERT is the primary target for antidepressants. SERT mediates the reuptake of serotonin through an alternating access mechanism, implying that a central substrate site is connected to both sides of the membrane by permeation pathways, of which only one is accessible at a time. The coordinated conformational changes in SERT associated with substrate translocation are not fully understood. Here, we have identified a Leu to Glu mutation at position 406 (L406E) in the extracellular loop 4 (EL4) of human SERT, which induced a remarkable gain-of-potency (up to >40-fold) for a range of SERT inhibitors. The effects were highly specific for L406E relative to six other mutations in the same position, including the closely related L406D mutation, showing that the effects induced by L406E are not simply charge-related effects. Leu(406) is located >10 Å from the central inhibitor binding site indicating that the mutation affects inhibitor binding in an indirect manner. We found that L406E decreased accessibility to a residue in the cytoplasmic pathway. The shift in equilibrium to favor a more outward-facing conformation of SERT can explain the reduced turnover rate and increased association rate of inhibitor binding we found for L406E. Together, our findings show that EL4 allosterically can modulate inhibitor binding within the central binding site, and substantiates that EL4 has an important role in controlling the conformational equilibrium of human SERT. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria

    Science.gov (United States)

    Chino, Yukihiro; Samukawa, Yoshishige; Sakai, Soichi; Nakai, Yasuhiro; Yamaguchi, Jun-ichi; Nakanishi, Takeo; Tamai, Ikumi

    2014-01-01

    Sodium glucose cotransporter 2 (SGLT2) inhibitors have been reported to lower the serum uric acid (SUA) level. To elucidate the mechanism responsible for this reduction, SUA and the urinary excretion rate of uric acid (UEUA) were analysed after the oral administration of luseogliflozin, a SGLT2 inhibitor, to healthy subjects. After dosing, SUA decreased, and a negative correlation was observed between the SUA level and the UEUA, suggesting that SUA decreased as a result of the increase in the UEUA. The increase in UEUA was correlated with an increase in urinary d-glucose excretion, but not with the plasma luseogliflozin concentration. Additionally, in vitro transport experiments showed that luseogliflozin had no direct effect on the transporters involved in renal UA reabsorption. To explain that the increase in UEUA is likely due to glycosuria, the study focused on the facilitative glucose transporter 9 isoform 2 (GLUT9ΔN, SLC2A9b), which is expressed at the apical membrane of the kidney tubular cells and transports both UA and d-glucose. It was observed that the efflux of [14C]UA in Xenopus oocytes expressing the GLUT9 isoform 2 was trans-stimulated by 10 mm d-glucose, a high concentration of glucose that existed under SGLT2 inhibition. On the other hand, the uptake of [14C]UA by oocytes was cis-inhibited by 100 mm d-glucose, a concentration assumed to exist in collecting ducts. In conclusion, it was demonstrated that the UEUA could potentially be increased by luseogliflozin-induced glycosuria, with alterations of UA transport activity because of urinary glucose. PMID:25044127

  4. Fatty acid transport protein-2 inhibitor Grassofermata/CB5 protects cells against lipid accumulation and toxicity

    International Nuclear Information System (INIS)

    Saini, Nipun; Black, Paul N.; Montefusco, David; DiRusso, Concetta C.

    2015-01-01

    The inhibition of the fatty acid uptake into non-adipose tissues provides an attractive target for prevention of lipotoxicity leading to obesity-associated non-alcoholic fatty liver disease and type 2 diabetes. Fatty acid transport proteins (FATPs) are bifunctional proteins involved in the uptake and activation of fatty acids by esterification with coenzyme A. Here we characterize Grassofermata/CB5, previously identified as a fatty acid uptake inhibitor directed against HsFATP2. The compound was effective in inhibiting the uptake of fatty acids in the low micro-molar range (IC 50 8–11 μM) and prevented palmitate-mediated lipid accumulation and cell death in cell lines that are models for intestines, liver, muscle and pancreas. In adipocytes, uptake inhibition was less effective (IC 50 58 μM). Inhibition was specific for long chain fatty acids and was ineffective toward medium chain fatty acids, which are transported by diffusion. Kinetic analysis of Grassofermata-dependent FA transport inhibition verified a non-competitive mechanism. By comparison with Grassofermata, several atypical antipsychotic drugs previously implicated as inhibitors of FA uptake were ineffectual. In mice Grassofermata decreased absorption of 13 C-oleate demonstrating its potential as a therapeutic agent. - Highlights: • Grassofermata is a small compound inhibitor of FATP2. • Uptake inhibition is specific for long chain fatty acids. • Uptake kinetics shows low specificity for adipocytes compared to other cell types. • Inhibition is by a non-competitive mechanism. • Atypical antipsychotics do not inhibit FA uptake by comparison with Grassofermata

  5. Fatty acid transport protein-2 inhibitor Grassofermata/CB5 protects cells against lipid accumulation and toxicity

    Energy Technology Data Exchange (ETDEWEB)

    Saini, Nipun; Black, Paul N.; Montefusco, David; DiRusso, Concetta C., E-mail: cdirusso2@unl.edu

    2015-09-25

    The inhibition of the fatty acid uptake into non-adipose tissues provides an attractive target for prevention of lipotoxicity leading to obesity-associated non-alcoholic fatty liver disease and type 2 diabetes. Fatty acid transport proteins (FATPs) are bifunctional proteins involved in the uptake and activation of fatty acids by esterification with coenzyme A. Here we characterize Grassofermata/CB5, previously identified as a fatty acid uptake inhibitor directed against HsFATP2. The compound was effective in inhibiting the uptake of fatty acids in the low micro-molar range (IC{sub 50} 8–11 μM) and prevented palmitate-mediated lipid accumulation and cell death in cell lines that are models for intestines, liver, muscle and pancreas. In adipocytes, uptake inhibition was less effective (IC{sub 50} 58 μM). Inhibition was specific for long chain fatty acids and was ineffective toward medium chain fatty acids, which are transported by diffusion. Kinetic analysis of Grassofermata-dependent FA transport inhibition verified a non-competitive mechanism. By comparison with Grassofermata, several atypical antipsychotic drugs previously implicated as inhibitors of FA uptake were ineffectual. In mice Grassofermata decreased absorption of {sup 13}C-oleate demonstrating its potential as a therapeutic agent. - Highlights: • Grassofermata is a small compound inhibitor of FATP2. • Uptake inhibition is specific for long chain fatty acids. • Uptake kinetics shows low specificity for adipocytes compared to other cell types. • Inhibition is by a non-competitive mechanism. • Atypical antipsychotics do not inhibit FA uptake by comparison with Grassofermata.

  6. Evolutionarily conserved sites in yeast tropomyosin function in cell polarity, transport and contractile ring formation

    Directory of Open Access Journals (Sweden)

    Susanne Cranz-Mileva

    2015-08-01

    Full Text Available Tropomyosin is a coiled-coil protein that binds and regulates actin filaments. The tropomyosin gene in Schizosaccharomyces pombe, cdc8, is required for formation of actin cables, contractile rings, and polar localization of actin patches. The roles of conserved residues were investigated in gene replacement mutants. The work validates an evolution-based approach to identify tropomyosin functions in living cells and sites of potential interactions with other proteins. A cdc8 mutant with near-normal actin affinity affects patch polarization and vacuole fusion, possibly by affecting Myo52p, a class V myosin, function. The presence of labile residual cell attachments suggests a delay in completion of cell division and redistribution of cell patches following cytokinesis. Another mutant with a mild phenotype is synthetic negative with GFP-fimbrin, inferring involvement of the mutated tropomyosin sites in interaction between the two proteins. Proteins that assemble in the contractile ring region before actin do so in a mutant cdc8 strain that cannot assemble condensed actin rings, yet some cells can divide. Of general significance, LifeAct-GFP negatively affects the actin cytoskeleton, indicating caution in its use as a biomarker for actin filaments.

  7. Shot noise as a probe of spin-polarized transport through single atoms

    DEFF Research Database (Denmark)

    Burtzlaff, Andreas; Weismann, Alexander; Brandbyge, Mads

    2015-01-01

    Single atoms on Au(111) surfaces have been contacted with the Au tip of a low temperature scanning tunneling microscope. The shot noise of the current through these contacts has been measured up to frequencies of 120 kHz and Fano factors have been determined to characterize the transport channels...

  8. Transport-limited water splitting at ion-selective interfaces during concentration polarization

    DEFF Research Database (Denmark)

    Nielsen, Christoffer Peder; Bruus, Henrik

    2014-01-01

    We present an analytical model of salt- and water-ion transport across an ion-selective interface based on an assumption of local equilibrium of the water-dissociation reaction. The model yields current-voltage characteristics and curves of water-ion current versus salt-ion current, which are in ...

  9. Novel and High Affinity 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues as Atypical Dopamine Transporter Inhibitors

    DEFF Research Database (Denmark)

    Cao, Jianjing; Slack, Rachel D.; Bakare, Oluyomi M.

    2016-01-01

    pharmacological profiles in animal models of cocaine and methamphetamine abuse. Herein, we report a series of modafinil analogues that have an atypical DAT inhibitor profile. We extended SAR by chemically manipulating the oxidation states of the sulfoxide and the amide functional groups, halogenating the phenyl...

  10. A one dimensional model study of the mechanism of halogen liberation and vertical transport in the polar troposphere

    Directory of Open Access Journals (Sweden)

    E. Lehrer

    2004-01-01

    Full Text Available Sudden depletions of tropospheric ozone during spring were reported from the Arctic and also from Antarctic coastal sites. Field studies showed that those depletion events are caused by reactive halogen species, especially bromine compounds. However the source and seasonal variation of reactive halogen species is still not completely understood. There are several indications that the halogen mobilisation from the sea ice surface of the polar oceans may be the most important source for the necessary halogens. Here we present a one dimensional model study aimed at determining the primary source of reactive halogens. The model includes gas phase and heterogeneous bromine and chlorine chemistry as well as vertical transport between the surface and the top of the boundary layer. The autocatalytic Br release by photochemical processes (bromine explosion and subsequent rapid bromine catalysed ozone depletion is well reproduced in the model and the major source of reactive bromine appears to be the sea ice surface. The sea salt aerosol alone is not sufficient to yield the high levels of reactive bromine in the gas phase necessary for fast ozone depletion. However, the aerosol efficiently 'recycles' less reactive bromine species (e.g. HBr and feeds them back into the ozone destruction cycle. Isolation of the boundary layer air from the free troposphere by a strong temperature inversion was found to be critical for boundary layer ozone depletion to happen. The combination of strong surface inversions and presence of sunlight occurs only during polar spring.

  11. Zeeman- and electric-field control of spin- and valley-polarized transport through biased magnetic junctions on WSe2

    Science.gov (United States)

    Tahir, M.; Krstajić, P. M.; Vasilopoulos, P.

    2017-04-01

    The electronic properties of WSe2 comprise a huge spin-orbit coupling, a wide direct band gap, and especially a strong anisotropic lifting of the degeneracy of the valley degree of freedom in a magnetic field. We study ballistic electron transport through single or double junctions on monolayer WSe2 in the presence of spin M s and valley M v Zeeman fields and of an electric potential U. The conductance vs. the field M s or M v decreases in a fluctuating manner. For a single junction the spin P s and valley P v polarizations rise with M=M_v=2Ms , reach a value of more than 70%, and become perfect above U≈ 90 \\text{meV} while for a double junction this change can occur for U≈ 50 \\text{meV} and M≥ 10 \\text{meV} . P v increases with U and both polarizations oscillate with the junction width. The results may render WSe2 a promising candidate for new spintronic and valleytronic devices.

  12. Magnetic and electric control of spin- and valley-polarized transport across tunnel junctions on monolayer WSe2

    Science.gov (United States)

    Tahir, M.; Krstajić, P. M.; Vasilopoulos, P.

    2017-06-01

    The recent experimental realization of high-quality WSe2 leads to the possibility of an efficient manipulation of its spin and valley degrees of freedom. Its electronic properties comprise a huge spin-orbit coupling, a direct band gap, and a strong anisotropic lifting of the degeneracy of the valley degree of freedom in a magnetic field. We evaluate its band structure and study ballistic electron transport through single and double junctions (or barriers) on monolayer WSe2 in the presence of spin Ms and valley Mv Zeeman fields and of an electric potential U . The conductance versus the field Ms or Mv decreases in a fluctuating manner. For a single junction, the spin Ps and valley Pv polarizations rise with M =Mv=2 Ms , reach a value of more than 55 % , and become perfect above U ≈45 meV while for a double junction this change can occur for U ≥50 meV and M ≥5 meV. In certain regions of the (M ,U ) plane Pv becomes perfect. The conductance gc, its spin-up and spin-down components, and both polarizations oscillate with the barrier width d . The ability to isolate various carrier degrees of freedom in WSe2 may render it a promising candidate for new spintronic and valleytronic devices.

  13. Spin-polarized charge transport in HgTe/CdTe quantum well topological insulator under a ferromagnetic metal strip

    Science.gov (United States)

    Wu, Zhenhua; Luo, Kun; Yu, Jiahan; Wu, Xiaobo; Lin, Liangzhong

    2018-02-01

    Electron tunneling through a single magnetic barrier in a HgTe topological insulator has been theoretically investigated. We find that the perpendicular magnetic field would not lead to spin-flip of the edge states due to the conservation of the angular moment. By tuning the magnetic field and the Fermi energy, the edge channels can be transited from switch-on states to switch-off states and the current from unpolarized states can be filtered to fully spin polarized states. These features offer us an efficient way to control charge/spin transport in a HgTe/CdTe quantum well, and pave a way to construct the nanoelectronic devices utilizing the topological edge states.

  14. Polarization effects in coherent and incoherent photon scattering: survey of measurements and theory relevant to radiation transport calculations

    International Nuclear Information System (INIS)

    Hubbell, J.H.

    1993-01-01

    This report reviews available information on polarization effects arising when photons in the X-ray and gamma-ray energy regime undergo coherent (Rayleigh) scattering and incoherent (Compton) scattering by atomic electrons. In addition to descriptions and discussions of these effects, including estimates of their magnitudes as they apply to radiation transport calculations, an annotated bibliography of 102 selected works covering the period 1905-1991 is provided, with particularly relevant works for the purpose of this report flagged with asterisks (*). A major resource for this report is a 1948 unpublished informal report by L.V. Spencer which has been quoted here almost in its entirety, since, of all the works cited in the annotated bibliography, it appears to be the only one which explicitly and directly addresses the purpose of this report. Hence this valuable material should be re-introduced into the available and current literature. (author). 119 refs., 7 figs

  15. Pharmacology of Glutamate Transport in the CNS: Substrates and Inhibitors of Excitatory Amino Acid Transporters (EAATs) and the Glutamate/Cystine Exchanger System x c -

    Science.gov (United States)

    Bridges, Richard J.; Patel, Sarjubhai A.

    As the primary excitatory neurotransmitter in the mammalian CNS, l-glutamate participates not only in standard fast synaptic communication, but also contributes to higher order signal processing, as well as neuropathology. Given this variety of functional roles, interest has been growing as to how the extracellular concentrations of l-glutamate surrounding neurons are regulated by cellular transporter proteins. This review focuses on two prominent systems, each of which appears capable of influencing both the signaling and pathological actions of l-glutamate within the CNS: the sodium-dependent excitatory amino acid transporters (EAATs) and the glutamate/cystine exchanger, system x c - (Sx c -). While the family of EAAT subtypes limit access to glutamate receptors by rapidly and efficiently sequestering l-glutamate in neurons and glia, Sxc - provides a route for the export of glutamate from cells into the extracellular environment. The primary intent of this work is to provide an overview of the inhibitors and substrates that have been developed to delineate the pharmacological specificity of these transport systems, as well as be exploited as probes with which to selectively investigate function. Particular attention is paid to the development of small molecule templates that mimic the structural properties of the endogenous substrates, l-glutamate, l-aspartate and l-cystine and how strategic control of functional group position and/or the introduction of lipophilic R-groups can impact multiple aspects of the transport process, including: subtype selectivity, inhibitory potency, and substrate activity.

  16. Metabolism of ATP-binding cassette drug transporter inhibitors: complicating factor for multidrug resistance.

    NARCIS (Netherlands)

    Cnubben, N.H.; Wortelboer, H.M.; Zanden, J.J. van; Rietjens, I.M.; Bladeren, P.J. van

    2005-01-01

    Membrane transport proteins belonging to the ATP-binding cassette (ABC) family of transport proteins play a central role in the defence of organisms against toxic compounds, including anticancer drugs. However, for compounds that are designed to display a toxic effect, this defence system diminishes

  17. Analgesic effect of GT-0198, a structurally novel glycine transporter 2 inhibitor, in a mouse model of neuropathic pain

    Directory of Open Access Journals (Sweden)

    Yu Omori

    2015-03-01

    Full Text Available This study was conducted to identify the characteristic pharmacological features of GT-0198 that is phenoxymethylbenzamide derivatives. GT-0198 inhibited the function of glycine transporter 2 (GlyT2 in human GlyT2-expressing HEK293 cells and did not bind various major transporters or receptors of neurotransmitters in a competitive manner. Thus, GT-0198 is considered to be a comparatively selective GlyT2 inhibitor. Intravenous, oral, and intrathecal injections of GT-0198 decreased the pain-related response in a model of neuropathic pain with partial sciatic nerve ligation. This result suggests that GT-0198 has an analgesic effect. The analgesic effect of GT-0198 was abolished by the intrathecal injection of strychnine, a glycine receptor antagonist. Therefore, GT-0198 is considered to exhibit its analgesic effect via the activation of a glycine receptor by glycine following presynaptic GlyT2 inhibition in the spinal cord. In summary, GT-0198 is a structurally novel GlyT2 inhibitor bearing a phenoxymethylbenzamide moiety with in vivo efficacy in behavioral models of neuropathic pain.

  18. Unexpected effects of azole transporter inhibitors on antifungal susceptibility in Candida glabrata and other pathogenic Candida species.

    Science.gov (United States)

    Nagayoshi, Yohsuke; Miyazaki, Taiga; Shimamura, Shintaro; Nakayama, Hironobu; Minematsu, Asuka; Yamauchi, Shunsuke; Takazono, Takahiro; Nakamura, Shigeki; Yanagihara, Katsunori; Kohno, Shigeru; Mukae, Hiroshi; Izumikawa, Koichi

    2017-01-01

    The pathogenic fungus Candida glabrata is often resistant to azole antifungal agents. Drug efflux through azole transporters, such as Cdr1 and Cdr2, is a key mechanism of azole resistance and these genes are under the control of the transcription factor Pdr1. Recently, the monoamine oxidase A (MAO-A) inhibitor clorgyline was shown to inhibit the azole efflux pumps, leading to increased azole susceptibility in C. glabrata. In the present study, we have evaluated the effects of clorgyline on susceptibility of C. glabrata to not only azoles, but also to micafungin and amphotericin B, using wild-type and several mutant strains. The addition of clorgyline to the culture media increased fluconazole susceptibility of a C. glabrata wild-type strain, whereas micafungin and amphotericin B susceptibilities were markedly decreased. These phenomena were also observed in other medically important Candida species, including Candida albicans, Candida parapsilosis, Candida tropicalis, and Candida krusei. Expression levels of CDR1, CDR2 and PDR1 mRNAs and an amount of Cdr1 protein in the C. glabrata wild-type strain were highly increased in response to the treatment with clorgyline. However, loss of Cdr1, Cdr2, Pdr1, and a putative clorgyline target (Fms1), which is an ortholog of human MAO-A, or overexpression of CDR1 did not affect the decreased susceptibility to micafungin and amphotericin B in the presence of clorgyline. The presence of other azole efflux pump inhibitors including milbemycin A4 oxime and carbonyl cyanide 3-chlorophenylhydrazone also decreased micafungin susceptibility in C. glabrata wild-type, Δcdr1, Δcdr2, and Δpdr1 strains. These findings suggest that azole efflux pump inhibitors increase azole susceptibility but concurrently induce decreased susceptibility to other classes of antifungals independent of azole transporter functions.

  19. Probenecid, an organic anion transporter 1 and 3 inhibitor, increases plasma and brain exposure of N-acetylcysteine.

    Science.gov (United States)

    Hagos, Fanuel T; Daood, Monica J; Ocque, Jacob A; Nolin, Thomas D; Bayir, Hulya; Poloyac, Samuel M; Kochanek, Patrick M; Clark, Robert S B; Empey, Philip E

    2017-04-01

    1. N-acetylcysteine (NAC) is being investigated as an antioxidant for several conditions including traumatic brain injury, but the mechanism by which it crosses membrane barriers is unknown. We have attempted to understand how the transporter inhibitor, probenecid, affects NAC pharmacokinetics and to evaluate the interaction of NAC with transporters. 2. Juvenile Sprague-Dawley rats were administered NAC alone or in combination with probenecid intraperitoneally. Plasma and brain samples were collected serially and NAC concentrations were measured. Transporter studies were conducted with human embryonic kidney-293 cells that overexpress organic anion transporter (OAT)1 or OAT3 and with human multi-drug resistance-associated protein (MRP)1 or MRP4 membrane vesicles. 3. NAC area under the curve was increased in plasma (1.65-fold) and brain (2.41-fold) by probenecid. The apparent plasma clearance was decreased by 65%. Time- and concentration-dependent NAC uptake that was inhibitable by probenecid was observed with OAT1 and OAT3. No uptake of NAC was observed with MRP1 or MRP4. 4. Our results indicate for the first time that NAC is substrate for OAT1 and OAT3 and that probenecid increases NAC plasma and brain exposure in vivo. These data provide insight regarding how NAC crosses biological barriers and suggest a promising therapeutic strategy to increase NAC exposure.

  20. Detection of inhibitors of Candida albicans Cdr transporters using a diS-C3(3 fluorescence

    Directory of Open Access Journals (Sweden)

    Joanna eSzczepaniak

    2015-03-01

    Full Text Available Candida albicans is a major cause of opportunistic and life-threatening, systemic fungal infections. Hence new antifungal agents, as well as new methods to treat fungal infections, are still needed. The application of inhibitors of drug-efflux pumps may increase the susceptibility of C. albicans to drugs. We developed a new fluorescence method that allows the in vivo activity evaluation of compounds inhibiting of C. albicans transporters. We show that the potentiometric dye 3,3′-dipropylthiacarbocyanine iodide diS-C3(3 is pumped out by both Cdr1 and Cdr2 transporters. The fluorescence labeling with diS-C3(3 enables a real-time observation of the activity of C. albicans Cdr1 and Cdr2 transporters. We demonstrate that enniatin A and beauvericin show different specificities toward these transporters. Enniatin A inhibits diS-C3(3 efflux by Cdr1 while beauvericin inhibits both Cdr1p and Cdr2p.

  1. A Note on the Radiative and Collisional Branching Ratios in Polarized Radiation Transport with Coherent Scattering

    Science.gov (United States)

    Casini, R.; del Pino Alemán, T.; Manso Sainz, R.

    2017-02-01

    We discuss the implementation of physically meaningful branching ratios between the CRD and partial redistribution contributions to the emissivity of a polarized multi-term atom in the presence of both inelastic and elastic collisions. Our derivation is based on a recent theoretical formulation of partially coherent scattering, and it relies on a heuristic diagrammatic analysis of the various radiative and collisional processes to determine the proper form of the branching ratios. The expression we obtain for the emissivity is {\\boldsymbol{\\varepsilon }}=[{{\\boldsymbol{\\varepsilon }}}(1)-{{\\boldsymbol{\\varepsilon }}}{{f}.{{s}}.}(2)]+{{\\boldsymbol{\\varepsilon }}}(2), where {{\\boldsymbol{\\varepsilon }}}(1) and {{\\boldsymbol{\\varepsilon }}}(2) are the emissivity terms for the redistributed and partially coherent radiation, respectively, and where “f.s.” implies that the corresponding term must be evaluated assuming a flat-spectrum average of the incident radiation. This result is shown to be in agreement with prior literature on the subject in the limit of the unpolarized multi-level atom.

  2. Three-Component Aminoalkylations Yielding Dihydronaphthoxazine-Based Sirtuin Inhibitors: Scaffold Modification and Exploration of Space for Polar Side-Chains.

    Science.gov (United States)

    Vojacek, Steffen; Beese, Katja; Alhalabi, Zayan; Swyter, Sören; Bodtke, Anja; Schulzke, Carola; Jung, Manfred; Sippl, Wolfgang; Link, Andreas

    2017-07-01

    Nonpolar derivatives of heterocyclic aromatic screening hits like the non-selective sirtuin inhibitor splitomicin tend to be poorly soluble in biological fluids. Unlike sp 3 -rich natural products, flat aromatic compounds are prone to stacking and often difficult to optimize into leads with activity in cellular systems. The aim of this work was to identify anchor points for the introduction of sp 3 -rich fragments with polar functional groups into the newly discovered active (IC 50  = 5 μM) but nonpolar scaffold 1,2-dihydro-3H-naphth[1,2-e][1,3]oxazine-3-thione by a molecular modeling approach. Docking studies were conducted with structural data from crystallized human SIRT2 enzyme. Subsequent evaluation of the in silico hypotheses through synthesis and biological evaluation of the designed structures was accomplished with the aim to discover new SIRT2 inhibitors with improved aqueous solubility. Derivatives of 8-bromo-1,2-dihydro-3H-naphth[1,2-e][1,3]oxazine-3-thione N-alkylated with a hydrophilic morpholino-alkyl chain at the thiocarbamate group intended for binding in the acetyl-lysine pocket of the enzyme appeared to be promising. Both the sulfur of the thiocarbamate and the bromo substituent were assumed to result in favorable hydrophobic interactions and the basic morpholino-nitrogen was predicted to build a hydrogen bond with the backbone Ile196. While the brominated scaffold showed moderately improved activity (IC 50  = 1.8 μM), none of the new compounds displayed submicromolar activity. Synthesis and characterization of the new compounds are reported and the possible reasons for the outcome are discussed. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Piezoelectric polarization and quantum size effects on the vertical transport in AlGaN/GaN resonant tunneling diodes

    International Nuclear Information System (INIS)

    Dakhlaoui, H; Almansour, S

    2016-01-01

    In this work, the electronic properties of resonant tunneling diodes (RTDs) based on GaN-Al x Ga (1−x) N double barriers are investigated by using the non-equilibrium Green functions formalism (NEG). These materials each present a wide conduction band discontinuity and a strong internal piezoelectric field, which greatly affect the electronic transport properties. The electronic density, the transmission coefficient, and the current–voltage characteristics are computed with considering the spontaneous and piezoelectric polarizations. The influence of the quantum size on the transmission coefficient is analyzed by varying GaN quantum well thickness, Al x Ga (1−x) N width, and the aluminum concentration x Al . The results show that the transmission coefficient more strongly depends on the thickness of the quantum well than the barrier; it exhibits a series of resonant peaks and valleys as the quantum well width increases. In addition, it is found that the negative differential resistance (NDR) in the current–voltage ( I – V) characteristic strongly depends on aluminum concentration x Al . It is shown that the peak-to-valley ratio (PVR) increases with x Al value decreasing. These findings open the door for developing vertical transport nitrides-based ISB devices such as THz lasers and detectors. (paper)

  4. Piezoelectric polarization and quantum size effects on the vertical transport in AlGaN/GaN resonant tunneling diodes

    Science.gov (United States)

    H, Dakhlaoui; S, Almansour

    2016-06-01

    In this work, the electronic properties of resonant tunneling diodes (RTDs) based on GaN-Al x Ga(1-x)N double barriers are investigated by using the non-equilibrium Green functions formalism (NEG). These materials each present a wide conduction band discontinuity and a strong internal piezoelectric field, which greatly affect the electronic transport properties. The electronic density, the transmission coefficient, and the current-voltage characteristics are computed with considering the spontaneous and piezoelectric polarizations. The influence of the quantum size on the transmission coefficient is analyzed by varying GaN quantum well thickness, Al x Ga(1-x)N width, and the aluminum concentration x Al. The results show that the transmission coefficient more strongly depends on the thickness of the quantum well than the barrier; it exhibits a series of resonant peaks and valleys as the quantum well width increases. In addition, it is found that the negative differential resistance (NDR) in the current-voltage (I-V) characteristic strongly depends on aluminum concentration x Al. It is shown that the peak-to-valley ratio (PVR) increases with x Al value decreasing. These findings open the door for developing vertical transport nitrides-based ISB devices such as THz lasers and detectors. Project supported by the Deanship of Scientific Research of University of Dammam (Grant No. 2014137).

  5. Effects of inhibitors of protein synthesis and intracellular transport on the gamma-aminobutyric acid agonist-induced functional differentiation of cultured cerebellar granule cells

    DEFF Research Database (Denmark)

    Belhage, B; Hansen, Gert Helge; Meier, E

    1990-01-01

    an intracellular and a plasma membrane localization of the receptors. In all experiments cultures treated with THIP alone served as controls. The inhibitors of protein synthesis totally abolished the ability of THIP to induce low-affinity GABA receptors. In contrast, the inhibitors of intracellular transport......The effect of inhibitors of protein synthesis (actinomycin D, cycloheximide), proteases (leupeptin), and intracellular transport (colchicine, monensin) on the gamma-aminobutyric acid (GABA) agonist [4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP)]-induced changes in morphological...... as well as the protease inhibitor did not affect this parameter. However, studies of effects of GABA on transmitter release from monensin-treated cultures showed that transmitter release could not be inhibited by GABA in these cells in spite of the presence of low-affinity GABA receptors in the membrane...

  6. Influence of the electric polarization on carrier transport and recombinaton dynamics in ZnO-based heterostructures

    Energy Technology Data Exchange (ETDEWEB)

    Brandt, Matthias

    2010-08-16

    The present thesis deals with the influence of the electric polarization on properties of free carriers in ZnO-based semiconductor heterostructures. Thereby especially transport properties of free carriers as well as their recombination dynamics are studied. The thesis treats four main topics. The first main topic lies on the phsical properties of the applied materials, here the connection of the band gap and the lattice constant of thin Mg{sub x}Zn{sub 1-x}O films and their magnesium content is described. Furthermore the morphology of such films is discussed. Different substrates and deposition conditions are thereby detailedly considered. The second main topic treats the properties of undoped and phosphorus doped thin ZnO and Mg{sub x}Zn{sub 1-x}O films. The structural, transport, and luminescence properties are here compared and conclusions drawn on the growth conditions. In the third main topic quantum effects on ZnO/Mg{sub x}Zn{sub 1-x}O interfaces are treated. Hereby especially the influence of the electric polarization is considered. The presence of a two-dimensional electron gas is proved, and the necessary conditions for the generation of the so-called confined Stark effect are explained. Especially the growth-relevant parameters are considered. The fourth main topic represent coupling phenomena in ZnO/BaTiO{sub 3} heterostructures. Thereby first the experimentally observed properties of different heterostructures are shown, which were grown on different substrates. Here structural and transport properties hold the spotlight. A model for the description of the formation of space-charge zones in such heterostructures is introduced and applied for the description of the experimental results. The usefulness of the ferroelectric properties of the material BaTiO{sub 3} in combination with semiconducting ZnO were studied. For this ferroelectric field effect transistors were fabricated under application of both materials. The principle suitedness of the

  7. Flozins, inhibitors of type 2 renal sodium-glucose co-transporter – not only antihyperglycemic drugs

    Directory of Open Access Journals (Sweden)

    Mizerski Grzegorz

    2015-09-01

    Full Text Available The kidneys play a crucial role in the regulation of the carbohydrate metabolism. In normal physiological conditions, the glucose that filters through the renal glomeruli is subsequently nearly totally reabsorbed in the proximal renal tubules. Two transporters are engaged in this process: sodium-glucose co-transporter type 1 (SGLT1, and sodium-glucose co-transporter type type 2 (SGLT2 - this being located in the luminal membrane of the renal tubular epithelial cells. It was found that the administration of dapagliflozin, a selective SGLT2 inhibitor, in patients with type 2 diabetes, is associated with the reduction of HbA1c concentration by 0.45-1.11%. Additional benefits from the treatment with dapagliflozin are the reduction of arterial blood pressure and a permanent reduction of body weight. This outcome is related to the effect of osmotic diuresis and to the considerable loss of the glucose load by way of urine excretion. Dapagliflozin may be successfully applied in type 2 diabetes monotherapy, as well as in combined therapy (including insulin, where it is equally effective as other oral anti-diabetic drugs. Of note: serious adverse effects of dapagliflozin administration are rarely observed. What is more, episodes of severe hypoglycaemia related with the treatment occur only sporadically, most often in the course of diabetes polytherapy. The most frequent effects of the SGLT2 inhibitors are inseparably associated with the mechanism of their action (the glucuretic effect, and cover urogenital infections with a mild clinical course. At present, clinical trials are being continued of the administration of several subsequent drugs from this group, the most advanced of these being the use of canagliflozin and empagliflozin.

  8. Spectra and Charge Transport of Polar Molecular Photoactive Layers Used for Solar Cells

    Directory of Open Access Journals (Sweden)

    Yuanzuo Li

    2015-01-01

    Full Text Available The ground state structures, HOMO and LUMO energy levels, band gaps ΔH-L, ionization potentials (IP, and electron affinities (EA of three types of copolymer P1 and its derivatives P2, P3, and PBDT-BTA were investigated by using density functional theory (DFT with B3LYP and 6-31G (d basis set. On the base of optimized structures of ground states, their absorption spectra were obtained by using TD-DFT//Cam-B3LYP/6-31 G (d. Research shows that with the increasing conjugated units, HOMO energy levels increased, LUMO energy levels decreased, and band gaps decreased gradually. Moreover, their ionization potentials decreased and electron affinities increased along with the increase of conjugated chains, and absorption spectra red-shifted. In addition, the side chain has a significant effect on the properties of ground and excited states. In order to investigate the influence of conjugated units and side chain on the charge transport, their hole and electron reorganization energies were calculated, and the results indicated that Pb have a good hole transport capability. Considering the practical application, the HOMO and LUMO energy levels, band gaps, and absorption spectra under external electric field were studied, and the results proved that the external electric field has an effect on the optical and electronic properties.

  9. Methods comparison, transport and distribution of polar herbicides in the Baltic Sea.

    Science.gov (United States)

    Skeff, Wael; Orlikowska, Anna; Schulz-Bull, Detlef E

    2017-01-30

    Two LC-MS/MS methods including different sample preparation and quantitative processes showed a good agreement for analysis of the herbicides MCPA, mecoprop, isoproturon, bentazon and chloridazon, and the metabolite chloridazon-methyl-desphenyl (CMD) in estuarine waters. Due to different sensitivity of the methods only one could be used to analyze marine samples. The transport of these compounds to the Baltic Sea via ten German estuaries and their distribution between coastal water and sediments was studied. The results showed that all selected compounds can be transported to the Baltic Sea (0.9-747ng/L). Chloridazon, bentazon, isoproturon and CMD were detected (0.9-8.9ng/L) in the coastal waters and chloridazon and isorproturon in the sediments (5-136pg/g d.w.). Levels of contaminants in the sediments could be influenced by the total organic carbon content. Concentrations observed in the Baltic Sea are most likely not high enough to cause acute effects, but long term effect studies are strongly recommended. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. In vivo evaluation of carbon-11-labelled non-sarcosine-based glycine transporter 1 inhibitors in mice and conscious monkeys

    Energy Technology Data Exchange (ETDEWEB)

    Toyohara, Jun [Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan 260-8670 (Japan); Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 173-0022 (Japan); Ishiwata, Kiichi; Sakata, Muneyuki [Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan 173-0022 (Japan); Wu, Jin [Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan 260-8670 (Japan); Nishiyama, Shingo; Tsukada, Hideo [Central Research Laboratory, Hamamatsu Photonics K.K., Shizuoka, Japan 434-8601 (Japan); Hashimoto, Kenji, E-mail: hashimoto@faculty.chiba-u.j [Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan 260-8670 (Japan)

    2011-05-15

    Introduction: Glycine transporter 1 (GlyT-1) is an attractive target in positron emission tomography (PET) studies. Here, we report the in vivo evaluation of three carbon-11-labelled non-sarcosine-type GlyT-1 inhibitors - [{sup 11}C]SA1, [{sup 11}C]SA2 and [{sup 11}C]SA3 - as novel PET tracers for GlyT-1. Methods: The regional brain distributions of the three compounds in mice were studied at baseline and under receptor-blockade conditions with co-injection of carrier loading or pretreatment with an excess of selective GlyT-1 inhibitors (ALX-5407 and SSR504734). Metabolic stability was investigated by radio high-performance liquid chromatography. Dynamic PET scans in conscious monkeys were performed with/without selective GlyT-1 inhibitors. Results: The IC{sub 50} values of SA1, SA2 and SA3 were 9.0, 6400 and 39.7 nM, respectively. The regional brain uptakes of [{sup 11}C]SA1 and [{sup 11}C]SA3 in mice were heterogeneous and consistent with the known distribution of GlyT-1. [{sup 11}C]SA2 showed low and homogeneous uptake in the brain. Most radioactivity in the brain was detected in unchanged form, although peripherally these compounds were degraded. Carrier loading decreased the uptake of [{sup 11}C]SA1 in GlyT-1-rich regions. However, similar reductions were not observed with [{sup 11}C]SA3. Pretreatment with ALX-5407 decreased the uptake of [{sup 11}C]SA1 in GlyT-1-rich regions. In the monkey at baseline, regional brain uptake of [{sup 11}C]SA1 was heterogeneous and consistent with the known GlyT-1 distribution. Pretreatment with selective GlyT-1 inhibitors significantly decreased the distribution volume ratio of [{sup 11}C] SA1 in GlyT-1-rich regions. Conclusions: [{sup 11}C]SA1 has the most suitable profile among the three carbon-11-labelled GlyT-1 inhibitors. Lead optimization of [{sup 11}C]SA1 structure will be required to achieve in vivo selective GlyT-1 imaging.

  11. In vivo evaluation of carbon-11-labelled non-sarcosine-based glycine transporter 1 inhibitors in mice and conscious monkeys

    International Nuclear Information System (INIS)

    Toyohara, Jun; Ishiwata, Kiichi; Sakata, Muneyuki; Wu, Jin; Nishiyama, Shingo; Tsukada, Hideo; Hashimoto, Kenji

    2011-01-01

    Introduction: Glycine transporter 1 (GlyT-1) is an attractive target in positron emission tomography (PET) studies. Here, we report the in vivo evaluation of three carbon-11-labelled non-sarcosine-type GlyT-1 inhibitors - [ 11 C]SA1, [ 11 C]SA2 and [ 11 C]SA3 - as novel PET tracers for GlyT-1. Methods: The regional brain distributions of the three compounds in mice were studied at baseline and under receptor-blockade conditions with co-injection of carrier loading or pretreatment with an excess of selective GlyT-1 inhibitors (ALX-5407 and SSR504734). Metabolic stability was investigated by radio high-performance liquid chromatography. Dynamic PET scans in conscious monkeys were performed with/without selective GlyT-1 inhibitors. Results: The IC 50 values of SA1, SA2 and SA3 were 9.0, 6400 and 39.7 nM, respectively. The regional brain uptakes of [ 11 C]SA1 and [ 11 C]SA3 in mice were heterogeneous and consistent with the known distribution of GlyT-1. [ 11 C]SA2 showed low and homogeneous uptake in the brain. Most radioactivity in the brain was detected in unchanged form, although peripherally these compounds were degraded. Carrier loading decreased the uptake of [ 11 C]SA1 in GlyT-1-rich regions. However, similar reductions were not observed with [ 11 C]SA3. Pretreatment with ALX-5407 decreased the uptake of [ 11 C]SA1 in GlyT-1-rich regions. In the monkey at baseline, regional brain uptake of [ 11 C]SA1 was heterogeneous and consistent with the known GlyT-1 distribution. Pretreatment with selective GlyT-1 inhibitors significantly decreased the distribution volume ratio of [ 11 C] SA1 in GlyT-1-rich regions. Conclusions: [ 11 C]SA1 has the most suitable profile among the three carbon-11-labelled GlyT-1 inhibitors. Lead optimization of [ 11 C]SA1 structure will be required to achieve in vivo selective GlyT-1 imaging.

  12. Metformin + Sodium-glucose Co-transporter-2 Inhibitor: Salutogenic Lifestyle Mimetics in a Tablet?

    Directory of Open Access Journals (Sweden)

    Sanjay Kalra

    2018-01-01

    Full Text Available Salutogenesis is an accepted approach for chronic disease management. Calorie restriction and exercise are two evidence based salutogenic interventions in diabetes treatment. Calorie restriction mimetics and exercise mimetics may be used as pharmacological tools to help manage diabetes in a sulutogenic manner. This article discusses the biochemical basis and pharmacology of metformin and sodium glucose cotransporter 2 inhibitors. It describes how a combination of these drugs can be used as a calories restriction and exercise mimetic, to help improve diabetes control.

  13. Identification of Small-Molecule Inhibitors of the HuR/RNA Interaction Using a Fluorescence Polarization Screening Assay Followed by NMR Validation.

    Directory of Open Access Journals (Sweden)

    Zhonghua Wang

    Full Text Available The human antigen R (HuR stabilizes many mRNAs of proto-oncogene, transcription factors, cytokines and growth factors by recognizing AU-rich elements (AREs presented in their 3' or 5' untranslated region (UTR. Multiple lines of experimental evidence suggest that this process plays a key role in cancer development. Thus, destabilizing HuR/RNA interaction by small molecules presents an opportunity for cancer treatment/prevention. Here we present an integrated approach to identify inhibitors of HuR/RNA interaction using a combination of fluorescence-based and NMR-based high throughput screening (HTS. The HTS assay with fluorescence polarization readout and Z'-score of 0.8 was used to perform a screen of the NCI diversity set V library in a 384 well plate format. An NMR-based assay with saturation transfer difference (STD detection was used for hits validation. Protein NMR spectroscopy was used to demonstrate that some hit compounds disrupt formation of HuR oligomer, whereas others block RNA binding. Thus, our integrated high throughput approach provides a new avenue for identification of small molecules targeting HuR/RNA interaction.

  14. Probenecid interferes with renal oxidative metabolism: A potential pitfall in its use as an inhibitor of drug transport

    Science.gov (United States)

    Masereeuw, Rosalinde; van Pelt, Ard P; van Os, Sandra H G; Willems, Peter H G M; Smits, Paul; Russel, Frans G M

    2000-01-01

    The anionic drug probenecid has been traditionally used as an inhibitor of renal organic anion transport. More recently the drug was found to inhibit organic cation transport as well, and it is used to retain intracellularly loaded fluorophores. In these investigations it is implicitly assumed that probenecid performs its activity through competition for transport. Here we studied the possibility that probenecid provokes its effect through inhibition of cellular oxidative metabolism. Oxygen consumption was measured in isolated rat kidney cortex mitochondria. At concentrations of 1 mM or higher, probenecid increased the resting state (state 4) and decreased the ADP-stimulated respiration (state 3). A complete loss in respiratory control was observed at 10 mM probenecid. After incubating isolated rat kidney proximal tubular cells (PTC) for 30 min with probenecid a concentration-dependent reduction in ATP content was observed, which was significant at concentrations of 1 mM and higher. Using digital image fluorescence microscopy the membrane potential in PTC was measured with bisoxonol. The mitochondrial effects of probenecid were paralleled by a depolarization of the plasma membrane, immediately after drug addition. All events are likely to be a result of membrane disordering due to the lipophilic character of probenecid, and may explain, at least in part, the various inhibitory effects found for the drug. We recommend to be cautious with applying probenecid in cellular research. PMID:10960069

  15. Amino acid derivatives are substrates or non-transported inhibitors of the amino acid transporter PAT2 (slc36a2).

    Science.gov (United States)

    Edwards, Noel; Anderson, Catriona M H; Gatfield, Kelly M; Jevons, Mark P; Ganapathy, Vadivel; Thwaites, David T

    2011-01-01

    The H(+)-coupled amino acid transporter PAT2 (SLC36A2) transports the amino acids proline, glycine, alanine and hydroxyproline. A physiological role played by PAT2 in amino acid reabsorption in the renal proximal tubule is demonstrated by mutations in SLC36A2 that lead to an iminoglycinuric phenotype (imino acid and glycine uria) in humans. A number of proline, GABA and tryptophan derivatives were examined to determine if they function either as transported substrates or non-transported inhibitors of PAT2. The compounds were investigated following heterologous expression of rat PAT2 in Xenopus laevis oocytes. PAT2 function was characterised by: radiotracer uptake and competition (cis-inhibition) studies; radiotracer efflux and trans-stimulation; and measurement of substrate-induced positive inward current by two-electrode voltage-clamp. In general, the proline derivatives appeared to be transported substrates and the relative ability to induce current flow was closely related to the inhibitory effects on PAT2-mediated l-[(3)H]proline uptake. In contrast, certain heterocyclic GABA derivatives (e.g. l-pipecolic acid) were translocated only slowly. Finally, the tryptophan derivatives inhibited PAT2 function but did not undergo transport. l-Proline uptake was inhibited by 5-hydroxy-l-tryptophan (IC(50) 1.6±0.4mM), α-methyl-d,l-tryptophan (3.5±1.5mM), l-tryptophan, 1-methyl-l-tryptophan and indole-3-propionic acid. Although neither 5-hydroxy-l-tryptophan nor α-methyl-d,l-tryptophan were able to elicit inward current in PAT2-expressing oocytes both reduced the current evoked by l-proline. 5-Hydroxy-l-tryptophan and α-methyl-d,l-tryptophan were unable to trans-stimulate l-proline efflux from PAT2-expressing oocytes, confirming that the two compounds act as non-transported blockers of PAT2. These two tryptophan derivatives should prove valuable experimental tools in future investigations of the physiological roles of PAT2. Copyright © 2010 Elsevier B.V. All rights

  16. Early Discontinuation of Metformin in Individuals Treated with Inhibitors of Transporters of Metformin

    DEFF Research Database (Denmark)

    Stage, Tore Bjerregaard; Lee, Moa P; Hallas, Jesper

    2016-01-01

    The aim of this study was to examine the risk of early discontinuation of metformin as a proxy for intolerance, associated with use of drugs known to inhibit transporters involved in metformin distribution. We analysed all incident users of metformin in Denmark between 2000 and 2012 (n = 132......,221) and in a cohort of US patients (n = 296,903). Risk of early discontinuation of metformin was assessed using adjusted logistic regression for 28 drugs putatively inhibiting metformin transporters and four negative controls. Increased odds ratio of early discontinuation of metformin was only associated with codeine...

  17. Effects of inhibitors of protein synthesis and intracellular transport on the gamma-aminobutyric acid agonist-induced functional differentiation of cultured cerebellar granule cells

    DEFF Research Database (Denmark)

    Belhage, B; Hansen, Gert Helge; Meier, E

    1990-01-01

    The effect of inhibitors of protein synthesis (actinomycin D, cycloheximide), proteases (leupeptin), and intracellular transport (colchicine, monensin) on the gamma-aminobutyric acid (GABA) agonist [4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP)]-induced changes in morphological differenti......The effect of inhibitors of protein synthesis (actinomycin D, cycloheximide), proteases (leupeptin), and intracellular transport (colchicine, monensin) on the gamma-aminobutyric acid (GABA) agonist [4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP)]-induced changes in morphological...

  18. GDP-mannose transporter paralogues play distinct roles in polarized growth of Aspergillus nidulans.

    Science.gov (United States)

    Jackson-Hayes, Loretta; Hill, Terry W; Loprete, Darlene M; Gordon, Barbara S; Groover, Chassidy J; Johnson, Laura R; Martin, Stuart A

    2010-01-01

    GDP-mannose transporters (GMT) carry GDP-mannose nucleotide sugars from the cytosol across the Golgi apparatus membrane for use as substrates in protein glycosylation in plants, animals and fungi. Genomes of some fungal species, such as the yeast Saccharomyces cerevisiae, contain only one gene encoding a GMT, while others, including Aspergillus nidulans, contain two (gmtA and gmtB). We previously showed that cell wall integrity and normal hyphal morphogenesis in A. nidulans depend upon the function of GmtA and that GmtA localizes to a Golgi-like compartment. Cells bearing the calI11 mutation in gmtA also have reduced cell surface mannosylation. Here we show that GmtB colocalizes with GmtA, suggesting that the role of GmtB is similar to that of GmtA, although the respective transcript levels differ during spore germination and early development. Transcript levels of gmtB are high in ungerminated spores and remain so throughout the first 16 h of germination. In contrast, transcript levels of gmrtA are negligible in ungerminated spores but increase to levels comparable to those of gmtB during germination. These observations suggest that although GmtA and GmtB reside within the same subcellular compartments, they nevertheless perform distinct functions at different stages of development.

  19. Extracellular ATP inhibits root gravitropism at concentrations that inhibit polar auxin transport

    Science.gov (United States)

    Tang, Wenqiang; Brady, Shari R.; Sun, Yu; Muday, Gloria K.; Roux, Stanley J.

    2003-01-01

    Raising the level of extracellular ATP to mM concentrations similar to those found inside cells can block gravitropism of Arabidopsis roots. When plants are grown in Murashige and Skoog medium supplied with 1 mM ATP, their roots grow horizontally instead of growing straight down. Medium with 2 mM ATP induces root curling, and 3 mM ATP stimulates lateral root growth. When plants are transferred to medium containing exogenous ATP, the gravity response is reduced or in some cases completely blocked by ATP. Equivalent concentrations of ADP or inorganic phosphate have slight but usually statistically insignificant effects, suggesting the specificity of ATP in these responses. The ATP effects may be attributable to the disturbance of auxin distribution in roots by exogenously applied ATP, because extracellular ATP can alter the pattern of auxin-induced gene expression in DR5-beta-glucuronidase transgenic plants and increase the response sensitivity of plant roots to exogenously added auxin. The presence of extracellular ATP also decreases basipetal auxin transport in a dose-dependent fashion in both maize (Zea mays) and Arabidopsis roots and increases the retention of [(3)H]indole-3-acetic acid in root tips of maize. Taken together, these results suggest that the inhibitory effects of extracellular ATP on auxin distribution may happen at the level of auxin export. The potential role of the trans-plasma membrane ATP gradient in auxin export and plant root gravitropism is discussed.

  20. myo-Inositol-1-phosphate synthase is required for polar auxin transport and organ development

    KAUST Repository

    Chen, Hao

    2010-06-01

    myo-Inositol-1-phosphate synthase is a conserved enzyme that catalyzes the first committed and rate-limiting step in inositol biosynthesis. Despite its wide occurrence in all eukaryotes, the role of myo-inositol-1-phosphate synthase and de novo inositol biosynthesis in cell signaling and organism development has been unclear. In this study, we isolated loss-of-function mutants in the Arabidopsis MIPS1 gene from different ecotypes. It was found that all mips1 mutants are defective in embryogenesis, cotyledon venation patterning, root growth, and root cap development. The mutant roots are also agravitropic and have reduced basipetal auxin transport. mips1 mutants have significantly reduced levels of major phosphatidylinositols and exhibit much slower rates of endocytosis. Treatment with brefeldin A induces slower PIN2 protein aggregation in mips1, indicating altered PIN2 trafficking. Our results demonstrate that MIPS1 is critical for maintaining phosphatidylinositol levels and affects pattern formation in plants likely through regulation of auxin distribution. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. Empagliflozin: a new sodium-glucose co-transporter 2 (SGLT2 inhibitor for the treatment of type 2 diabetes

    Directory of Open Access Journals (Sweden)

    Joshua J Neumiller

    2014-06-01

    Full Text Available Type 2 diabetes is increasing in prevalence worldwide, and hyperglycemia is often poorly controlled despite a number of therapeutic options. Unlike previously available agents, sodium-glucose co-transporter 2 (SGLT2 inhibitors offer an insulin-independent mechanism for improving blood glucose levels, since they promote urinary glucose excretion (UGE by inhibiting glucose reabsorption in the kidney. In addition to glucose control, SGLT2 inhibitors are associated with weight loss and blood pressure reductions, and do not increase the risk of hypoglycemia. Empagliflozin is a selective inhibitor of SGLT2, providing dose-dependent UGE increases in healthy volunteers, with up to 90 g of glucose excreted per day. It can be administered orally, and studies of people with renal or hepatic impairment indicated empagliflozin needed no dose adjustment based on pharmacokinetics. In Phase II trials in patients with type 2 diabetes, empagliflozin provided improvements in glycosylated hemoglobin (HbA1c and other measures of glycemic control when given as monotherapy or add-on to metformin, as well as reductions in weight and systolic blood pressure. As add-on to basal insulin, empagliflozin not only improved HbA1c levels but also reduced insulin doses. Across studies, empagliflozin was generally well tolerated with a similar rate of hypoglycemia to placebo; however, patients had a slightly increased frequency of genital infections, but not urinary tract infections, versus placebo. Phase III studies have also reported a good safety profile along with significant improvements in HbA1c, weight and blood pressure, with no increased risk of hypoglycemia versus placebo. Based on available data, it appears that empagliflozin may be a useful option in a range of patients; however, clinical decisions will be better informed by the results of ongoing studies, in particular, a large cardiovascular outcome study (EMPA-REG OUTCOME™.

  2. Rapid chemoenzymatic route to glutamate transporter inhibitor L-TFB-TBOA and related amino acids

    NARCIS (Netherlands)

    Fu, Haigen; Younes, Sabry H. H.; Saifuddin, Mohammad; Tepper, Pieter G.; Zhang, Jielin; Keller, Erik; Heeres, Andre; Szymanski, Wiktor; Poelarends, Gerrit J.

    2017-01-01

    The complex amino acid (L-threo)-3-[3-[4-(trifluoromethyl) benzoylamino] benzyloxy] aspartate (L-TFB-TBOA) and its derivatives are privileged compounds for studying the roles of excitatory amino acid transporters (EAATs) in regulation of glutamatergic neurotransmission, animal behavior, and in the

  3. Risk stratification of patients with diabetes and the role of sodium glucose co-transporter inhibitors 2 during Ramadan fasting.

    Science.gov (United States)

    Adnan, Zaina

    2017-09-01

    The month of Ramadan represents a golden opportunity for better management of patients with diabetes not only during Ramadan month, but also through the entire year. Pre Ramadan period is crucial for evaluating and preparing patients with diabetes intending to Fast Ramadan. The risk stratification categories should take into consideration patients with diabetes having specific conditions such as nephrotic syndrome who are predisposed to thrombosis independent to their estimated glomerular filtration rate and glycated haemoglobin. Furthermore, population-specific conditions such as nomadic Bedouins living in remote areas should be considered as part of the very high risk category for fasting Ramadan. Published data regarding the use of sodium glucose co-transporter 2 inhibitors during Ramadan is very limited. Dapagliflozin was the only agent studied during Ramadan. Therefore, it is suggested to categorize this group of agents differently from other agents such as metformin and incretin based therapy studied vastly during Ramadan. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. A new structural class of subtype-selective inhibitor of cloned excitatory amino acid transporter, EAAT2

    DEFF Research Database (Denmark)

    Bräuner-Osborne, Hans; Hermit, M B; Nielsen, B

    2000-01-01

    We have studied the pharmacological effects of (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) and the enantiomers of (RS)-2-amino-3-(3-hydroxy-1,2, 5-thiadiazol-4-yl)propionic acid (TDPA) on cloned human excitatory amino acid transporter subtypes 1, 2 and 3 (EAAT1......-3) expressed in Cos-7 cells. Whereas AMPA and (R)-TDPA were both inactive as inhibitors of [3H]-(R)-aspartic acid uptake on all three EAAT subtypes, (S)-TDPA was shown to selectively inhibit uptake by EAAT2 with a potency equal to that of the endogenous ligand (S)-glutamic acid. (S)-TDPA thus represents a new...

  5. Benefits and Harms of Sodium-Glucose Co-Transporter 2 Inhibitors in Patients with Type 2 Diabetes

    DEFF Research Database (Denmark)

    Storgaard, Heidi; Gluud, Lise L; Bennett, Cathy

    2016-01-01

    OBJECTIVE: Sodium-glucose co-transporter 2 inhibitors (SGLT2-i) are a novel drug class for the treatment of diabetes. We aimed at describing the maximal benefits and risks associated with SGLT2-i for patients with type 2 diabetes. DESIGN: Systematic review and meta-analysis. DATA SOURCES AND STUDY......, ketoacidosis and CVD. Secondary outcomes were fasting plasma glucose, body weight, blood pressure, heart rate, lipids, liver function tests, creatinine and adverse events including infections. The quality of the evidence was assessed using GRADE. RESULTS: Meta-analysis of 34 RCTs with 9,154 patients showed...... increased risk in non-serious adverse events. The analyses may overestimate the intervention benefit due bias....

  6. A highly conserved sequence of the viral TAP inhibitor ICP47 is required for freezing of the peptide transport cycle.

    Science.gov (United States)

    Matschulla, Tony; Berry, Richard; Gerke, Carolin; Döring, Marius; Busch, Julia; Paijo, Jennifer; Kalinke, Ulrich; Momburg, Frank; Hengel, Hartmut; Halenius, Anne

    2017-06-07

    The transporter associated with antigen processing (TAP) translocates antigenic peptides into the endoplasmic reticulum (ER) lumen for loading onto MHC class I molecules. This is a key step in the control of viral infections through CD8+ T-cells. The herpes simplex virus type-1 encodes an 88 amino acid long species-specific TAP inhibitor, ICP47, that functions as a high affinity competitor for the peptide binding site on TAP. It has previously been suggested that the inhibitory function of ICP47 resides within the N-terminal region (residues 1-35). Here we show that mutation of the highly conserved 50 PLL 52 motif within the central region of ICP47 attenuates its inhibitory capacity. Taking advantage of the human cytomegalovirus-encoded TAP inhibitor US6 as a luminal sensor for conformational changes of TAP, we demonstrated that the 50 PLL 52 motif is essential for freezing of the TAP conformation. Moreover, hierarchical functional interaction sites on TAP dependent on 50 PLL 52 could be defined using a comprehensive set of human-rat TAP chimeras. This data broadens our understanding of the molecular mechanism underpinning TAP inhibition by ICP47, to include the 50 PLL 52 sequence as a stabilizer that tethers the TAP-ICP47 complex in an inward-facing conformation.

  7. Polar Localization of the NIP5;1 Boric Acid Channel Is Maintained by Endocytosis and Facilitates Boron Transport in Arabidopsis Roots.

    Science.gov (United States)

    Wang, Sheliang; Yoshinari, Akira; Shimada, Tomoo; Hara-Nishimura, Ikuko; Mitani-Ueno, Namiki; Feng Ma, Jian; Naito, Satoshi; Takano, Junpei

    2017-04-01

    Boron uptake in Arabidopsis thaliana is mediated by nodulin 26-like intrinsic protein 5;1 (NIP5;1), a boric acid channel that is located preferentially on the soil side of the plasma membrane in root cells. However, the mechanism underlying this polar localization is poorly understood. Here, we show that the polar localization of NIP5;1 in epidermal and endodermal root cells is mediated by the phosphorylation of Thr residues in the conserved TPG (ThrProGly) repeat in the N-terminal region of NIP5;1. Although substitutions of Ala for three Thr residues in the TPG repeat did not affect lateral diffusion in the plasma membrane, these substitutions inhibited endocytosis and strongly compromised the polar localization of GFP-NIP5;1. Consistent with this, the polar localization was compromised in µ subunit mutants of the clathrin adaptor AP2. The Thr-to-Ala substitutions did not affect the boron transport activity of GFP-NIP5;1 in Xenopus laevis oocytes but did inhibit the ability to complement boron translocation to shoots and rescue growth defects in nip5;1-1 mutant plants under boron-limited conditions. These results demonstrate that the polar localization of NIP5;1 is maintained by clathrin-mediated endocytosis, is dependent on phosphorylation in the TPG repeat, and is necessary for the efficient transport of boron in roots. © 2017 American Society of Plant Biologists. All rights reserved.

  8. The effect of vapor transport of acidic aerosols on salt speciation in Antarctic soils collected near the polar plateau

    Science.gov (United States)

    Graly, J. A.; Licht, K.; Kaplan, M. R.; Druschel, G.

    2017-12-01

    Vapor is the primary phase in which water is transported through soils where temperatures rarely, if ever, reach the melting point. In terrestrial settings, such as Antarctica, these cold, dry soils accumulate appreciable quantities of salts, primarily derived from atmospheric aerosols. Past studies have often analyzed the transport of salts to depth using solubility parameters, which assumes liquid water can percolate through porous media. We analyzed the distribution of salts in an Antarctic blue ice moraine, located near the polar plateau (84˚S, 163˚E). Here moraine soils are progressively older with distance from active ice, the oldest soils dating to several hundred ka. Changes in salt content were analyzed both with depth and with soil age. Of atmospheric salts analyzed, chloride and fluoride salts are fluxed to greatest depth, followed by nitrate salts. Sulfate and borate salts are both relatively immobile in the soil and are not detected below the top several cm. This distribution runs counter to the solubility of the salt species, with borate having high solubility and fluoride and nitrate both being relatively insoluble. Instead, the vapor pressures of the acids from which the salts form correspond very strongly with the relative abundance of the salts at depth. This suggests that percolation of liquid water plays a minimal role in moving salts to depth. Instead salts move to depth as vapors of acidic aerosols. With soil age, surface concentrations of the more mobile salts (nitrate, chloride, and fluoride) show logarithmic or power-law increases in concentrations, whereas boron and sulfate increase linearly. This is consistent with the former's progressive flux to depth. An exception to this pattern occurs in a few of the oldest soils, where substantially higher concentrations of the mobile salts are found in the top soils. This suggests that the direction of net vapor flux may reverse once sufficient salt concentration is developed at depth, though

  9. Effects of SM-20550, a selective Na+-H+ exchange inhibitor, on the ion transport of myocardial mitochondria.

    Science.gov (United States)

    Hotta, Y; Ishikawa, N; Ohashi, N; Matsui, K

    2001-03-01

    The effect of a novel Na+-H+ exchange inhibitor, SM-20550 [N-(aminoiminomethyl)-1,4-dimethyl-1H-indole-2-carboxamide methanesulfonate] (SM) on the ion transport of myocardial mitochondria was studied using ion fluorometry and superfusion techniques. Isolated mitochondria from the guinea-pig heart were pre-loaded with fluoroprobes of either BCECF AM for H+, SBFI AM for Na+ or fura-2 AM for Ca2+. Initially, the treated mitochondria were superfused with a normal medium (MOPS-buffer, pH 7.4, 24 degrees C), subsequently fluorometric experiments on the Na+, H+, Ca2+ mobilization across the mitochondrial membrane were performed. The intramitochondrial pH (pHm) was increased by the superfusion of Na+ at physiological cytosolic concentrations of 10 mM, indicating the existence of a Na+-H+ exchange in mitochondrial membranes. The Na+ induced elevation of pH was dose-dependently inhibited by SM 1 microM (delta pHm; 45% as drug-free 100%), and 10 microM (delta pHm; 70%), as observed in our experiments with the myocardial sarcolemmal membrane. The selective Na+-H+ exchange inhibitor SM reduced such pHm elevations more markedly than that of EIPA [5-(N-ethyl-N-isopropyl) amiloride]. The Na+-H+ exchange inhibitors, SM and EIPA suppressed the intramitochondrial Ca2+ elevation ([Ca2+]m) brought on by external Ca2+ concentration changes: The pretreatment with SM 1 microM, 10 microM and EIPA 10 microM reduced the [Ca2+]m influx by 28.3, 56.5 and 63%, respectively. Additionally, the [Ca2+]m elevation induced by acidification of the perfusate was reduced by the prior infusion of SM and EIPA. Pretreatment of mitochondria with SM or EIPA which had beneficial effects on the left ventricular developed pressure (LVDP) in the ischemia-reperfusion injury of Langendorff hearts, reduced the intramitochondrial Na+ and pHm levels, indicating interplay of the inhibitory mechanism of Ca2+-uptake into mitochondria coupled with Na+-H+ exchange. These findings suggested that protective effects of Na

  10. Effects of polarization field on vertical transport in GaN/AlGaN resonant tunneling diodes

    International Nuclear Information System (INIS)

    Park, Seoung-Hwan; Shim, Jong-In

    2012-01-01

    Polarization-field effects on the vertical transport in GaN/AlGaN resonant tunneling diodes (RTDs) were theoretically investigated by using the transfer matrix formalism. The self-consistent model shows that the resonant peaks are shifted toward higher energies with increasing Al composition in the AlGaN barrier, and the transmission probability values are shown to decrease rapidly. In the case of the flat-band model, on the other hand, the shift of the resonant peaks is smaller than it is for the self-consistent model and the variation of transmission probability values with increasing Al composition is relatively smaller than that of the self-consistent model. The current voltage characteristics of the self-consistent model are asymmetric while those of the flat-band model are symmetric for positive and negative current directions. The peak-to-valley ratio (PVR) of the self-consistent model is shown to be slightly smaller than that of the flat-band model for Al = 0.3.

  11. VLN2 Regulates Plant Architecture by Affecting Microfilament Dynamics and Polar Auxin Transport in Rice[OPEN

    Science.gov (United States)

    Wu, Shengyang; Xie, Yurong; Guo, Xiuping; Sheng, Peike; Wang, Juan; Wu, Chuanyin; Wang, Haiyang; Wan, Jianmin

    2015-01-01

    As a fundamental and dynamic cytoskeleton network, microfilaments (MFs) are regulated by diverse actin binding proteins (ABPs). Villins are one type of ABPs belonging to the villin/gelsolin superfamily, and their function is poorly understood in monocotyledonous plants. Here, we report the isolation and characterization of a rice (Oryza sativa) mutant defective in VILLIN2 (VLN2), which exhibits malformed organs, including twisted roots and shoots at the seedling stage. Cellular examination revealed that the twisted phenotype of the vln2 mutant is mainly caused by asymmetrical expansion of cells on the opposite sides of an organ. VLN2 is preferentially expressed in growing tissues, consistent with a role in regulating cell expansion in developing organs. Biochemically, VLN2 exhibits conserved actin filament bundling, severing and capping activities in vitro, with bundling and stabilizing activity being confirmed in vivo. In line with these findings, the vln2 mutant plants exhibit a more dynamic actin cytoskeleton network than the wild type. We show that vln2 mutant plants exhibit a hypersensitive gravitropic response, faster recycling of PIN2 (an auxin efflux carrier), and altered auxin distribution. Together, our results demonstrate that VLN2 plays an important role in regulating plant architecture by modulating MF dynamics, recycling of PIN2, and polar auxin transport. PMID:26486445

  12. Dune field pattern formation and recent transporting winds in the Olympia Undae Dune Field, north polar region of Mars

    Science.gov (United States)

    Ewing, Ryan C.; Peyret, Aymeric-Pierre B.; Kocurek, Gary; Bourke, Mary

    2010-08-01

    High-Resolution Imaging Science Experiment (HiRISE) imagery of the central Olympia Undae Dune Field in the north polar region of Mars shows a reticulate dune pattern consisting of two sets of nearly orthogonal dune crestlines, with apparent slipfaces on the primary crests, ubiquitous wind ripples, areas of coarse-grained wind ripples, and deflated interdune areas. Geomorphic evidence and dune field pattern analysis of dune crest length, spacing, defect density, and orientation indicates that the pattern is complex, representing two constructional generations of dunes. The oldest and best-organized generation forms the primary crestlines and is transverse to circumpolar easterly winds. Gross bed form-normal analysis of the younger pattern of crestlines indicates that it emerged with both circumpolar easterly winds and NE winds and is reworking the older pattern. Mapping of secondary flow fields over the dunes indicates that the most recent transporting winds were from the NE. The younger pattern appears to represent an influx of sediment to the dune field associated with the development of the Olympia Cavi reentrant, with NE katabatic winds channeling through the reentrant. A model of the pattern reformation based upon the reconstructed primary winds and resulting secondary flow fields shows that the development of the secondary pattern is controlled by the boundary condition of the older dune topography.

  13. 9-Deazapurines as Broad-Spectrum Inhibitors of the ABC Transport Proteins P-Glycoprotein, Multidrug Resistance-Associated Protein 1, and Breast Cancer Resistance Protein.

    Science.gov (United States)

    Stefan, Katja; Schmitt, Sven Marcel; Wiese, Michael

    2017-11-09

    P-Glycoprotein (P-gp, ABCB1), multidrug resistance-associated protein 1 (MRP1, ABCC1), and breast cancer resistance protein (BCRP, ABCG2) are the three major ABC transport proteins conferring resistance to many structurally diverse anticancer agents, leading to the phenomenon called multidrug resistance (MDR). Much effort has been put into the development of clinically useful compounds to reverse MDR. Broad-spectrum inhibitors of ABC transport proteins can be of great use in cancers that simultaneously coexpress two or three transporters. In this work, we continued our effort to generate new, potent, nontoxic, and multiply effective inhibitors of the three major ABC transporters. The best compound was active in a very low micromolar concentration range against all three transporters and restored sensitivity toward daunorubicin (P-gp and MRP1) and SN-38 (BCRP) in A2780/ADR (P-gp), H69AR (MRP1), and MDCK II BCRP (BCRP) cells. Additionally, the compound is a noncompetitive inhibitor of daunorubicin (MRP1), calcein AM (P-gp), and pheophorbide A (BCRP) transport.

  14. Effect of Known Inhibitors of Ion Transport on Pendrin (SLC26A4) Activity in a Human Kidney Cell Line.

    Science.gov (United States)

    Bernardinelli, Emanuele; Costa, Roberta; Nofziger, Charity; Paulmichl, Markus; Dossena, Silvia

    2016-01-01

    Pendrin is a Cl-/I-/HCO3- exchanger playing a fundamental role in controlling blood pressure and airway function, therefore representing an attractive target for the treatment of hypertensive states and respiratory distresses. A review of the literature regarding the ability of some compounds (namely several known inhibitors of ion transport) to block pendrin activity revealed discordant findings. These incongruous findings may be due, in part, to the concentration of compound and/or the nature of the model system used in the study. Pendrin activity was evaluated by measuring pendrin-dependent iodide influx following overexpression of the transporter in a human kidney cell line, in the presence of selected test compounds or the respective vehicles. Pendrin activity was significantly hampered by 0.1 mM 5-nitro-2-[(3-phenylpropyl)amino]benzoic acid (NPPB), niflumic acid and tenidap, but was resistant to 0.1 mM 4, 4'-diisothiocyano-2, 2'-stilbene-disulfonic acid (DIDS), furosemide and probenecid. The results of the present study indicate that clinically effective non-steroidal anti-inflammatory drugs (niflumic acid and tenidap) directly inhibit pendrin activity. © 2016 The Author(s) Published by S. Karger AG, Basel.

  15. Effect of Known Inhibitors of Ion Transport on Pendrin (SLC26A4 Activity in a Human Kidney Cell Line

    Directory of Open Access Journals (Sweden)

    Emanuele Bernardinelli

    2016-05-01

    Full Text Available Background/Aims: Pendrin is a Cl-/I-/HCO3- exchanger playing a fundamental role in controlling blood pressure and airway function, therefore representing an attractive target for the treatment of hypertensive states and respiratory distresses. A review of the literature regarding the ability of some compounds (namely several known inhibitors of ion transport to block pendrin activity revealed discordant findings. These incongruous findings may be due, in part, to the concentration of compound and/or the nature of the model system used in the study. Methods: Pendrin activity was evaluated by measuring pendrin-dependent iodide influx following overexpression of the transporter in a human kidney cell line, in the presence of selected test compounds or the respective vehicles. Results: Pendrin activity was significantly hampered by 0.1 mM 5-nitro-2-[(3-phenylpropylamino]benzoic acid (NPPB, niflumic acid and tenidap, but was resistant to 0.1 mM 4, 4′-diisothiocyano-2, 2′-stilbene-disulfonic acid (DIDS, furosemide and probenecid. Conclusions: The results of the present study indicate that clinically effective non-steroidal anti-inflammatory drugs (niflumic acid and tenidap directly inhibit pendrin activity.

  16. Use of Silica Tubes as Nanocontainers for Corrosion Inhibitor Storage

    Directory of Open Access Journals (Sweden)

    Cesia Ávila-Gonzalez

    2011-01-01

    Full Text Available A new alkyd paint anticorrosion smart coating was developed by using silica nanoparticles as corrosion inhibitor nanocontainers. Silica particles were mixed with the paint at different concentrations to study their performance and ensure their free transportation to the damaged metal. The filling up of silica particles was done preparing three solutions: distilled water, acetone, and a mixture of both, with Fe(NO33 and silica particles immersed in each of the solutions to adsorb the inhibitor. Acetone solution was the best alternative determined by weight gain analysis made with the inhibitor adsorbed in silica nanocontainers. Steel samples were painted with inhibitor silica nanocontainer coatings and immersed in an aqueous solution of 3% sodium chloride. Polarization curves and electrochemical noise techniques were used to evaluate the corrosion inhibitor system behavior. Good performance was obtained in comparison with samples without inhibitor nanocontainer coating.

  17. Beta-Sulfonamido Functionalized Aspartate Analogs as Excitatory Amino Acid Transporter Inhibitors: Distinct Subtype-Selectivity Profiles Arising from Subtle Structural Differences

    DEFF Research Database (Denmark)

    Hansen, Jacob Christian; Bjørn-Yoshimoto, Walden Emil; Bisballe, Niels

    2016-01-01

    EAAT inhibitors displaying IC50 values ∼1 μM at all three subtypes, this elaborate structure-activity relationship also identified analogues exhibiting distinct preferences or selectivities for specific transporter subtypes. Introduction of two fluorine atoms on the phenyl ring yielded analogue 4y...

  18. [Changes in polarization of myometrial cells plasma and internal mitochondrial membranes under calixarenes action as inhibitors of plasma membrane Na+, K+-ATPase].

    Science.gov (United States)

    Danylovych, H V; Danylovych, Iu V; Kolomiiets', O V; Kosterin, S O; Rodik, R V; Cherenok, S O; Kal'chenko, V I; Chunikhin, O Iu; Horchev, V F; Karakhim, S O

    2012-01-01

    The influence of supramolecular macrocyclic compounds--calix[4]arenes C-97, C-99, C-107, which are ouabainomymetic high affinity inhibitors of Na+, K(+)-ATPase, on the polarization level of plasmic and mitochondrial membranes of rat uterine smooth muscle cells was investigated. The influence of these compounds on the myocytes characteristic size was studied. By using a confocal microscopy and specific for mitochondrial MitoTracker Orange CM-H2TMRos dye it was proved that the potential-sensitive fluorescent probe DiOC6(3) interacts with mitochondria. Artificial potential collapse of plasmic membrane in this case was modeled by myocytes preincubation with ouabain (1 mM). Further experiments performed using the method of flow cytometry with DiOC6(3) have shown that the compounds C-97, C-99 and C-107 at concentration 50-100 nM caused depolarization of the plasma membrane (at the level of 30% relative to control values) in conditions of artificial collapse of mitochondrial potential by myocytes preincubation in the presence of 5 mM of sodium azide. Under artificial sarcolemma depolarization by ouabain, calixarenes C-97, C-99 and C-107 at 100 nM concentrations caused a transient increase of mitochondrial membrane potential, that is 40% of the control level and lasted about 5 minutes. Calixarenes C-99 and C-107 caused a significant increase in fluorescence of myocytes in these conditions, which was confirmed by confocal microscopy too. It was proved by photon correlation spectroscopy method that the C-99 and C-107 caused an increase of characteristic size of myocytes.

  19. Single-molecule interrogation of a bacterial sugar transporter allows the discovery of an extracellular inhibitor

    Science.gov (United States)

    Kong, Lingbing; Harrington, Leon; Li, Qiuhong; Cheley, Stephen; Davis, Benjamin G.; Bayley, Hagan

    2013-08-01

    Capsular polysaccharides form the outermost protective layer around many Gram-negative bacteria. Antibiotics aimed directly at weakening this layer are not yet available. In pathogenic Escherichia coli E69, a protein, Wza, forms a pore in the outer membrane that transports K30 capsular polysaccharide from its site of synthesis to the outside of the cell. This therefore represents a prospective antibiotic target. Here we test a variety of grommet-like mimics of K30 capsular polysaccharide on wild-type Wza and on mutant open forms of the pore by electrical recording in planar lipid bilayers. The most effective glycomimetic was the unnatural cyclic octasaccharide octakis(6-deoxy-6-amino)cyclomaltooctaose (am8γCD), which blocks the α-helix barrel of Wza, a site that is directly accessible from the external medium. This glycomimetic inhibited K30 polysaccharide transport in live E. coli E69. With the protective outer membrane disrupted, the bacteria can be recognized and killed by the human immune system.

  20. The effects of Rashba spin-orbit coupling on spin-polarized transport in hexagonal graphene nano-rings and flakes

    Science.gov (United States)

    Laghaei, M.; Heidari Semiromi, E.

    2018-03-01

    Quantum transport properties and spin polarization in hexagonal graphene nanostructures with zigzag edges and different sizes were investigated in the presence of Rashba spin-orbit interaction (RSOI). The nanostructure was considered as a channel to which two semi-infinite armchair graphene nanoribbons were coupled as input and output leads. Spin transmission and spin polarization in x, y, and z directions were calculated through applying Landauer-Buttiker formalism with tight binding model and the Green's function to the system. In these quantum structures it is shown that changing the size of system, induce and control the spin polarized currents. In short, these graphene systems are typical candidates for electrical spintronic devices as spin filtering.

  1. Probenecid, an inhibitor of transmembrane organic anion transporters, alters tissue distribution of DNA adducts in 1-hydroxymethylpyrene-treated rats.

    Science.gov (United States)

    Monien, Bernhard H; Müller, Carolin; Bakhiya, Nadiya; Donath, Claudia; Frank, Heinz; Seidel, Albrecht; Glatt, Hansruedi

    2009-07-28

    1-Methylpyrene (1-MP), an abundant alkylated polycyclic aromatic hydrocarbon, is activated by side-chain hydroxylation to 1-hydroxymethylpyrene (1-HMP) and subsequent sulfo-conjugation to electrophilic 1-sulfooxymethylpyrene (1-SMP). In rats, this activation mainly occurs in liver. 1-SMP may react with hepatic DNA or be exported into the blood circulation to reach other tissues, in particular kidneys. Findings with recombinant cell lines suggest that renal 1-SMP uptake proceeds via organic anion transporters (OATs). Here, we tested the hypothesis that probenecid, a characteristic OAT inhibitor, interferes with kidney damage brought about by 1-SMP formed in rats. 1-HMP was administered intraperitoneally to 30 rats, half of which were co-treated with probenecid. The tissue distribution of DNA adducts was analyzed using (32)P-postlabeling and isotope dilution LC-MS/MS for the detection of the adducts N(2)-(1-methylpyrenyl)-2'-deoxyguanosine and N(6)-(1-methylpyrenyl)-2'-deoxyadenosine. In rats treated solely with 1-HMP, adduct levels in kidney tissue were about 3-fold and 8-fold higher than those in liver and lung, respectively. After co-treatment with probenecid, hepatic and pulmonary adduct levels were 12-fold and 4-fold elevated, respectively, whereas renal adduct levels were slightly lower compared to those of rats receiving 1-HMP alone. Moreover, serum levels of 1-SMP were increased 23-fold in animals pre-treated with probenecid. The differential effects on hepatic and pulmonary adduct levels suggest that not only renal OATs, but also additional anion transporters, e.g. those mediating the hepatic export of 1-SMP into the bile, were inhibited. Thus, transmembrane transport proteins play a crucial role in the distribution of reactive phase II metabolites, and thereby in tissue allocation of DNA adducts.

  2. Halogenated mazindol analogs as potential inhibitors of the cocaine binding site at the dopamine transporter.

    Science.gov (United States)

    Houlihan, W J; Boja, J W; Parrino, V A; Kopajtic, T A; Kuhar, M J

    1996-12-06

    A series of halogenated (F, Cl, Br, I), pyrimido and diazepino homologs of mazindol were prepared and evaluated for their ability to displace [3H]WIN 35,428 binding and to inhibit uptake of [3H]dopamine (DA) in rat striatal tissue. All of the compounds except for the 2'-chloro (6) and 2'-bromo (16) analogs of mazindol displaced [3H]WIN 35,428 binding and inhibited [3H]DA uptake more effectively than (R)-cocaine. Structure-activity studies indicated that best inhibition of [3H]WIN 35,428 binding occurred in the imidazo series with compounds containing one or two Cl or Br atoms in the 3'- or 4'-position of the free phenyl group. Replacement of the imidazo ring by a pyrimido or diazepino ring enhanced binding inhibition. The most potent inhibitors of [3H]WIN 35,428 binding and [3H]DA uptake were 6-(3'-chlorophenyl)-2,3,4,6-tetrahydropyrimido[2,1-alpha]isoind ol-6-ol (23; IC50 1.0 nM; 8 x mazindol) and 7-(3',4'-dichlorophenyl)-2,3,4,5-tetrahydro-7H-diazepino[2,1-alpha ]isoindol-7-ol (28; IC50 0.26 nM; 32 x mazindol), respectively. No significant differences was found between binding and uptake inhibition. Mazindol and the pyrimido and diazepino homologs 24 and 27 showed a selectivity for the DA uptake over the serotonin (5-HT) uptake site of 5-, 250-, and 465-fold, respectively, and displayed weak or no affinity for a variety of neurotransmitter receptor sites.

  3. Phenylglycine analogs are inhibitors of the neutral amino acid transporters ASCT1 and ASCT2 and enhance NMDA receptor-mediated LTP in rat visual cortex slices.

    Science.gov (United States)

    Foster, Alan C; Rangel-Diaz, Natalie; Staubli, Ursula; Yang, Jia-Ying; Penjwini, Mahmud; Viswanath, Veena; Li, Yong-Xin

    2017-11-01

    The N-methyl-d-aspartate receptor (NMDA) co-agonist d-serine is a substrate for the neutral amino acid transporters ASCT1 (SLC1A4) and ASCT2 (SLC1A5). We identified l-phenylglycine (PG) and its analogs as inhibitors of ASCT1 and ASCT2. PG analogs were shown to be non-substrate inhibitors of ASCT1 and ASCT2 with a range of activities relative to other amino acid transport systems, including sodium-dependent glutamate transporters, the sodium-independent d-serine transporter asc-1 and system L. L-4-chloroPG was the most potent and selective ASCT1/2 inhibitor identified. The PG analogs facilitated theta-burst induced long-term potentiation in rat visual cortex slices in a manner that was dependent on extracellular d-serine. For structurally-related PG analogs, there was an excellent correlation between ASCT1/2 transport inhibition and enhancement of LTP which was not the case for inhibition of asc-1 or system L. The ability of PG analogs to enhance LTP is likely due to inhibition of d-serine transport by ASCT1/2, leading to elevated extracellular levels of d-serine and increased NMDA receptor activity. These results suggest that ASCT1/2 may play an important role in regulating extracellular d-serine and NMDA receptor-mediated physiological effects and that ASCT1/2 inhibitors have the potential for therapeutic benefit. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Mazindol analogues as potential inhibitors of the cocaine binding site at the dopamine transporter.

    Science.gov (United States)

    Houlihan, William J; Kelly, Lawrence; Pankuch, Jessica; Koletar, Judith; Brand, Leonard; Janowsky, Aaron; Kopajtic, Theresa A

    2002-09-12

    A series of mazindol (2) and homomazindol (3) analogues with a variety of electron-donating and electron-withdrawing groups in the pendant aryl group and the benzo ring C, as well as H, methoxy, and alkyl groups replacing the hydroxyl group were synthesized, and their binding affinities at the dopamine transporter (DAT) on rat or guinea pig striatal membranes were determined. Several active analogues were also evaluated for their ability to block uptake of DA, 5-HT, and NE and inhibit binding of [(125)I] RTI-55 at HEK-hDAT, HEK-hSERT, and HEK-hNET cells. Mazindane (26) was found to be a pro-drug, oxidizing (5-H --> 5-OH) to mazindol on rat striatal membranes and HEK-hDAT cells. The 4',7,8-trichloro analogue (38) of mazindol was the most potent and selective ligand for HEK-hDAT cells (DAT K(i) = 1.1 nM; SERT/DAT = 1283 and NET/DAT = 38). Experimental results strongly favor the cyclic or ol tautomers of 2 and 3 to bind more tightly at the DAT than the corresponding keto tautomers.

  5. A Novel Dopamine Transporter Inhibitor CE-123 Improves Cognitive Flexibility and Maintains Impulsivity in Healthy Male Rats

    Directory of Open Access Journals (Sweden)

    Agnieszka Nikiforuk

    2017-11-01

    Full Text Available Reduced cognitive abilities are often characterized by an impairment of flexibility, i.e., the ability to switch from learned rules or categories that were important in certain contexts to different new modalities that rule the task. Drugs targeting the dopamine transporter (DAT are widely used for their potential to enhance cognitive abilities. However, commercially available drugs are of limited specificity for DAT, blocking also noradrenaline and serotonine transporters, that can lead to unwanted side effects in healthy subjects. Therefore, we tested a newly synthetized compound (CE-123 with higher specificity for DAT in male rats in an attentional set-shifting task (ASST, that proves for cognitive flexibility and a 5-choice serial-reaction time task (5-CSRTT assessing visuospatial attention and impulsivity. Treated rats at a dose of 0.3 and 1.0 but not 0.1 mg/kg bodyweight showed reduced extra-dimensional shifts in the ASST compared to controls indicating increased cognitive flexibility. Rats treated with R-Modafinil, a commercially available DAT inhibitor at a dose of 10 mg/kg bodyweight showed increased premature responses, an indicator of increased impulsivity, during a 10 s but not a 2.5, 5, or 7.5 s intertrial interval when compared to vehicle-treated rats in the 5-CSRTT. This was not found in rats treated with CE-123 at the same dose as for R-Modafinil. Visuospatial attention, except premature responses, did not differ between R-Modafinil and CE-123-treated rats and their respective controls. Thus, CE-123 increased cognitive flexibility with diminished impulsivity.

  6. Renal accumulation of [{sup 111}In]DOTATOC in rats: influence of inhibitors of the organic ion transport and diuretics

    Energy Technology Data Exchange (ETDEWEB)

    Stahl, A.R. [Technische Universitaet Muenchen, Klinikum rechts der Isar, Department of Nuclear Medicine, Munich (Germany); Universitaetsklinikum Essen, Department of Radiology, Essen (Germany); Wagner, B.; Heemann, U.; Lutz, J. [Technische Universitaet Muenchen, Klinikum rechts der Isar, Department of Nephrology, Munich (Germany); Poethko, T.; Perutka, M.; Wester, H.J.; Essler, M.; Schwaiger, M. [Technische Universitaet Muenchen, Klinikum rechts der Isar, Department of Nuclear Medicine, Munich (Germany)

    2007-12-15

    Radiation exposure to the kidney limits therapy with radiometal labelled DOTATOC. This study evaluates the organic anion and cation transport (inhibitors: probenecid and cimetidine/dexamethason) as well as diuresis (furosemide and mannitol) regarding renal uptake of [{sup 111}In]DOTATOC. One hundred eight male Fisher rats were injected with [{sup 111}In]DOTATOC via the tail vein. Prior to activity injection a total of 84 rats underwent injection with probenecid vs. sodium chloride 0.9% (48 rats), cimetidine vs. dexamethasone vs. sodium chloride 0.9% (18 rats), and furosemide vs. mannitol vs. sodium chloride 0.9% (18 rats). Rats were sacrificed at predetermined time points up to 48 h after activity injection. Kidneys, adrenal glands, pancreas, spleen, blood, liver, and muscle were harvested and injected activity per gram tissue was determined. Autoradiographic images of the kidneys were acquired in a total of 24 rats. Probenecid led to a reduction in renal uptake by up to 30% while not significantly changing the activity accumulation in the other organs investigated. This reduction was attributable to the renal cortex (ratio cortex/medulla 1.72 vs. 1.99; p = 0.006). Cimetidine and dexamethasone had no effect in any of the organs. Furosemide led to a 44% increase in renal activity accumulation attributable to enhanced renal medullary uptake (ratio cortex/medulla 1.44 versus 1.69; p = 0.006). Mannitol had no effect on renal activity uptake. Inhibition of the organic anion transport by probenecid may help reduce renal uptake regarding therapy with radiometal labelled DOTATOC. The enhancing effect of furosemide may be unfavourable for therapy. The results must be confirmed by human studies. (orig.)

  7. 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.

  8. A non-local-thermodynamic equilibrium formulation of the transport equation for polarized light in the presence of weak magnetic fields. Doctoral thesis

    International Nuclear Information System (INIS)

    McNamara, D.J.

    1977-01-01

    The present work is motivated by the desire to better understand solar magnetism. Just as stellar astrophysics and radiative transfer have been coupled in the history of research in physics, so too has the study of radiative transfer of polarized light in magnetic fields and solar magnetism been a history of mutual growth. The Stokes parameters characterize the state of polarization of a beam of radiation. The author considers the changes in polarization, and therefore in the Stokes parameters, due to the transport of a beam through an optically thick medium in a weak magnetic field. The transport equation is derived from a general density matrix equation of motion. This allows the possibility of interference effects arising from the mixing of atomic sublevels in a weak magnetic field to be taken into account. The statistical equilibrium equations are similarly derived. Finally, the coupled system of equations is presented, and the order of magnitude of the interference effects, shown. Collisional effects are not considered. The magnitude of the interference effects in magnetic field measurements of the sun may be evaluated

  9. The Atypical Stimulant and Nootropic Modafinil Interacts with the Dopamine Transporter in a Different Manner than Classical Cocaine-Like Inhibitors

    Science.gov (United States)

    Schmitt, Kyle C.; Reith, Maarten E. A.

    2011-01-01

    Modafinil is a mild psychostimulant with pro-cognitive and antidepressant effects. Unlike many conventional stimulants, modafinil has little appreciable potential for abuse, making it a promising therapeutic agent for cocaine addiction. The chief molecular target of modafinil is the dopamine transporter (DAT); however, the mechanistic details underlying modafinil's unique effects remain unknown. Recent studies suggest that the conformational effects of a given DAT ligand influence the magnitude of the ligand's reinforcing properties. For example, the atypical DAT inhibitors benztropine and GBR12909 do not share cocaine's notorious addictive liability, despite having greater binding affinity. Here, we show that the binding mechanism of modafinil is different than cocaine and similar to other atypical inhibitors. We previously established two mutations (W84L and D313N) that increase the likelihood that the DAT will adopt an outward-facing conformational state—these mutations increase the affinity of cocaine-like inhibitors considerably, but have little or opposite effect on atypical inhibitor binding. Thus, a compound's WT/mutant affinity ratio can indicate whether the compound preferentially interacts with a more outward- or inward-facing conformational state. Modafinil displayed affinity ratios similar to those of benztropine, GBR12909 and bupropion (which lack cocaine-like effects in humans), but far different than those of cocaine, β-CFT or methylphenidate. Whereas treatment with zinc (known to stabilize an outward-facing transporter state) increased the affinity of cocaine and methylphenidate two-fold, it had little or no effect on the binding of modafinil, benztropine, bupropion or GBR12909. Additionally, computational modeling of inhibitor binding indicated that while β-CFT and methylphenidate stabilize an “open-to-out” conformation, binding of either modafinil or bupropion gives rise to a more closed conformation. Our findings highlight a mechanistic

  10. The atypical stimulant and nootropic modafinil interacts with the dopamine transporter in a different manner than classical cocaine-like inhibitors.

    Directory of Open Access Journals (Sweden)

    Kyle C Schmitt

    Full Text Available Modafinil is a mild psychostimulant with pro-cognitive and antidepressant effects. Unlike many conventional stimulants, modafinil has little appreciable potential for abuse, making it a promising therapeutic agent for cocaine addiction. The chief molecular target of modafinil is the dopamine transporter (DAT; however, the mechanistic details underlying modafinil's unique effects remain unknown. Recent studies suggest that the conformational effects of a given DAT ligand influence the magnitude of the ligand's reinforcing properties. For example, the atypical DAT inhibitors benztropine and GBR12909 do not share cocaine's notorious addictive liability, despite having greater binding affinity. Here, we show that the binding mechanism of modafinil is different than cocaine and similar to other atypical inhibitors. We previously established two mutations (W84L and D313N that increase the likelihood that the DAT will adopt an outward-facing conformational state--these mutations increase the affinity of cocaine-like inhibitors considerably, but have little or opposite effect on atypical inhibitor binding. Thus, a compound's WT/mutant affinity ratio can indicate whether the compound preferentially interacts with a more outward- or inward-facing conformational state. Modafinil displayed affinity ratios similar to those of benztropine, GBR12909 and bupropion (which lack cocaine-like effects in humans, but far different than those of cocaine, β-CFT or methylphenidate. Whereas treatment with zinc (known to stabilize an outward-facing transporter state increased the affinity of cocaine and methylphenidate two-fold, it had little or no effect on the binding of modafinil, benztropine, bupropion or GBR12909. Additionally, computational modeling of inhibitor binding indicated that while β-CFT and methylphenidate stabilize an "open-to-out" conformation, binding of either modafinil or bupropion gives rise to a more closed conformation. Our findings highlight a

  11. Health effects from long-range transported contaminants in Arctic top predators: An integrated review based on studies of polar bears and relevant model species.

    Science.gov (United States)

    Sonne, Christian

    2010-07-01

    The aim of this review is to provide a thorough overview of the health effects from the complexed biomagnified mixture of long-range transported industrial organochlorines (OCs), polybrominated diphenyl ethers (PBDEs), perfluorinated compounds (PFCs) and mercury (Hg) on polar bear (Ursus maritimus) health. Multiple scientific studies of polar bears indicate negative relationships between exposure to these contaminants and health parameters; however, these are all of a correlative nature and do not represent true cause-and-effects. Therefore, information from controlled studies of farmed Norwegian Arctic foxes (Vulpes lagopus) and housed East and West Greenland sledge dogs (Canis familiaris) were included as supportive weight of evidence in the clarification of contaminant exposure and health effects in polar bears. The review showed that hormone and vitamin concentrations, liver, kidney and thyroid gland morphology as well as reproductive and immune systems of polar bears are likely to be influenced by contaminant exposure. Furthermore, exclusively based on polar bear contaminant studies, bone density reduction and neurochemical disruption and DNA hypomethylation of the brain stem seemed to occur. The range of tissue concentration, at which these alterations were observed in polar bears, were ca. 1-70,000 ng/g lw for OCs (blood plasma concentrations of some PCB metabolites even higher), ca. 1-1000 ng/g lw for PBDEs and for PFCs and Hg 114-3052 ng/g ww and 0.1-50 microg/g ww, respectively. Similar concentrations were found in farmed foxes and housed sledge dogs while the lack of dose response designs did not allow an estimation of threshold levels for oral exposure and accumulated tissue concentrations. Nor was it possible to pinpoint a specific group of contaminants being more important than others nor analyze their interactions. For East Greenland polar bears the corresponding daily SigmaOC and SigmaPBDE oral exposure was estimated to be 35 and 0.34 microg/kg body

  12. A role for accumbal glycine receptors in modulation of dopamine release by the glycine transporter-1 inhibitor Org25935

    Directory of Open Access Journals (Sweden)

    Helga eHöifödt Lidö

    2011-03-01

    Full Text Available AbstractAccumbal glycine modulates basal and ethanol-induced dopamine levels in the nucleus accumbens (nAc as well as voluntary ethanol consumption. Also, systemic administration of the glycine transporter-1 inhibitor Org25935 elevates dopamine levels in nAc, prevents a further ethanol-induced dopamine elevation and robustly and dose-dependently decreases ethanol consumption in rats. Here we investigated whether Org25935 applied locally in nAc modulates dopamine release, and whether accumbal glycine receptors or NMDA receptors are involved in this tentative effect. We also addressed whether Org25935 and ethanol applied locally in nAc interact with dopamine levels, as seen after systemic administration. We used in vivo microdialysis coupled to HPLC-ED in freely moving male Wistar rats to monitor dopamine output in nAc after local perfusion of Org25935 alone, with ethanol, or Org25935-perfusion after pre-treatment with the glycine receptor antagonist strychnine or the NMDA receptor glycine site antagonist L-701.324. Local Org25935 increased extracellular dopamine levels in a subpopulation of rats. Local strychnine, but not systemic L-701.324, antagonized the dopamine-activating effect of Org25935. Ethanol failed to induce a dopamine overflow in the subpopulation responding to Org25935 with a dopamine elevation. The study supports a role for accumbal glycine receptors rather than NMDA receptor signaling in the dopamine-activating effect of Org25935. The results further indicate that the previously reported systemic Org25935-ethanol interaction with regard to accumbal dopamine is localized to the nAc. This adds to the growing evidence for the glycine receptor as an important player in the dopamine reward circuitry and in ethanol’s effects within this system.

  13. Polarization and charge-transfer effect on the transport properties in two-dimensional electron gases/LaNiO3 heterostructure

    Science.gov (United States)

    Chen, M. J.; Ning, X. K.; Wang, Z. J.; Liu, P.; Wang, S. F.; Wang, J. L.; Fu, G. S.; Ma, S.; Liu, W.; Zhang, Z. D.

    2018-01-01

    The film thickness dependent transport properties of the LaNiO3 (LNO) layer epitaxially grown on LaAlO3/SrTiO3 (LAO) 2-dimensional electronic gas (2DEG) have been investigated. The ultrathin LNO films grown on the 2DEG have a sheet resistance below the values of h/e2 in all temperature ranges. The electron density is enhanced by more than one order of magnitude by capping LNO films. X-ray photoelectron spectroscopy shows that the interface undergoes unambiguous charge transfer and electronic reconstruction, leading to modulation doping of such atomically engineered complex oxide heterointerfaces. The polar-catastrophe of the 2DEG is directly linked to the electronic structure and transport properties of the LNO. The transport properties can be well modulated by the thickness of the LAO in the 2DEG, and the data can be well fitted with the polar-catastrophe scenario. These results suggest a general approach to tunable functional films in oxide heterostructures with the 2DEG.

  14. A transportable hybrid antenna-transmitter system for the generation of elliptically polarized waves for NVIS propagation research

    NARCIS (Netherlands)

    Witvliet, Ben A.; Laanstra, Geert J.; van Maanen, Erik; Alsina-Pagès, Rosa M.; Bentum, Marinus Jan; Slump, Cornelis H.; Schiphorst, Roelof

    2016-01-01

    For empirical research on Near Vertical Incidence Skywave (NVIS) characteristic wave propagation, a beacon transmitter system is needed that can be programmed to emit precisely defined elliptically and circularly polarized waves at high elevation angles. This paper proposes a novel hybrid

  15. Importance of uncharged polar residues and proline in the proximal two-thirds (Pro107–Ser128 of the highly conserved region of mouse ileal Na+-dependent bile acid transporter, Slc10a2, in transport activity and cellular expression

    Directory of Open Access Journals (Sweden)

    Saeki Tohru

    2013-02-01

    Full Text Available Abstract Background SLC10A2-mediated reabsorption of bile acids at the distal end of the ileum is the first step in enterohepatic circulation. Because bile acids act not only as detergents but also as signaling molecules in lipid metabolism and energy production, SLC10A2 is important as the key transporter for understanding the in vivo kinetics of bile acids. SLC10A family members and the homologous genes of various species share a highly conserved region corresponding to Gly104–Pro142 of SLC10A2. The functional importance of this region has not been fully elucidated. Results To elucidate the functional importance of this region, we previously performed mutational analysis of the uncharged polar residues and proline in the distal one-third (Thr130–Pro142 of the highly conserved region in mouse Slc10a2. In this study, proline and uncharged polar residues in the remaining two-thirds of this region in mouse Slc10a2 were subjected to mutational analysis, and taurocholic acid uptake and cell surface localization were examined. Cell surface localization of Slc10a2 is necessary for bile acid absorption. Mutants in which Asp or Leu were substituted for Pro107 (P107N or P107L were abundantly expressed, but their cell surface localization was impaired. The S126A mutant was completely impaired in cellular expression. The T110A and S128A mutants exhibited remarkably enhanced membrane expression. The S112A mutant was properly expressed at the cell surface but transport activity was completely lost. Replacement of Tyr117 with various amino acids resulted in reduced transport activity. The degree of reduction roughly depended on the van der Waals volume of the side chains. Conclusions The functional importance of proline and uncharged polar residues in the highly conserved region of mouse Slc10a2 was determined. This information will contribute to the design of bile acid-conjugated prodrugs for efficient drug delivery or SLC10A2 inhibitors for

  16. Identification of Selective Inhibitors of the Plasmodium falciparum Hexose Transporter PfHT by Screening Focused Libraries of Anti-Malarial Compounds.

    Directory of Open Access Journals (Sweden)

    Diana Ortiz

    Full Text Available Development of resistance against current antimalarial drugs necessitates the search for novel drugs that interact with different targets and have distinct mechanisms of action. Malaria parasites depend upon high levels of glucose uptake followed by inefficient metabolic utilization via the glycolytic pathway, and the Plasmodium falciparum hexose transporter PfHT, which mediates uptake of glucose, has thus been recognized as a promising drug target. This transporter is highly divergent from mammalian hexose transporters, and it appears to be a permease that is essential for parasite viability in intra-erythrocytic, mosquito, and liver stages of the parasite life cycle. An assay was developed that is appropriate for high throughput screening against PfHT based upon heterologous expression of PfHT in Leishmania mexicana parasites that are null mutants for their endogenous hexose transporters. Screening of two focused libraries of antimalarial compounds identified two such compounds that are high potency selective inhibitors of PfHT compared to human GLUT1. Additionally, 7 other compounds were identified that are lower potency and lower specificity PfHT inhibitors but might nonetheless serve as starting points for identification of analogs with more selective properties. These results further support the potential of PfHT as a novel drug target.

  17. In vitro assay shows that PCB metabolites completely saturate thyroid hormone transport capacity in blood of wild polar bears (Ursus maritimus).

    Science.gov (United States)

    Gutleb, Arno C; Cenijn, Peter; Velzen, Martin van; Lie, Elisabeth; Ropstad, Erik; Skaare, Janneche Utne; Malmberg, Tina; Bergman, Ake; Gabrielsen, Geir W; Legler, Juliette

    2010-04-15

    Persistent chemicals accumulate in the arctic environment due to their chemical reactivity and physicochemical properties and polychlorinated biphenyls (PCBs) are the most concentrated pollutant class in polar bears (Ursus maritimus). Metabolism of PCB and polybrominated biphenyl ether (PBDE) flame-retardants alter their toxicological properties and these metabolites are known to interfere with the binding of thyroid hormone (TH) to transthyretin (TTR) in rodents and humans. In polar bear plasma samples no binding of [125I]-T(4) to TTR was observed after incubation and PAGE separation. Incubation of the plasma samples with [14C]-4-OH-CB107, a compound with a higher binding affinity to TTR than the endogenous ligand T(4) resulted in competitive binding as proven by the appearance of a radio labeled TTR peak in the gel. Plasma incubation with T(4) up to 1 mM, a concentration that is not physiologically relevant anymore did not result in any visible competition. These results give evidence that the binding sites on TTR for T(4) in wild living polar bears are completely saturated. Such saturation of binding sites can explain observed lowered levels of THs and could lead to contaminant transport into the developing fetus.

  18. Transporter-Mediated Drug Interaction Strategy for 5-Aminolevulinic Acid (ALA-Based Photodynamic Diagnosis of Malignant Brain Tumor: Molecular Design of ABCG2 Inhibitors

    Directory of Open Access Journals (Sweden)

    Toshihisa Ishikawa

    2011-09-01

    Full Text Available Photodynamic diagnosis (PDD is a practical tool currently used in surgical operation of aggressive brain tumors, such as glioblastoma. PDD is achieved by a photon-induced physicochemical reaction which is induced by excitation of protoporphyrin IX (PpIX exposed to light. Fluorescence-guided gross-total resection has recently been developed in PDD, where 5-aminolevulinic acid (ALA or its ester is administered as the precursor of PpIX. ALA induces the accumulation of PpIX, a natural photo-sensitizer, in cancer cells. Recent studies provide evidence that adenosine triphosphate (ATP-binding cassette (ABC transporter ABCG2 plays a pivotal role in regulating the cellular accumulation of porphyrins in cancer cells and thereby affects the efficacy of PDD. Protein kinase inhibitors are suggested to potentially enhance the PDD efficacy by blocking ABCG2-mediated porphyrin efflux from cancer cells. It is of great interest to develop potent ABCG2-inhibitors that can be applied to PDD for brain tumor therapy. This review article addresses a pivotal role of human ABC transporter ABCG2 in PDD as well as a new approach of quantitative structure-activity relationship (QSAR analysis to design potent ABCG2-inhibitors.

  19. Insights into the molecular mechanism of action of Celastraceae sesquiterpenes as specific, non-transported inhibitors of human P-glycoprotein.

    Science.gov (United States)

    Muñoz-Martínez, Francisco; Reyes, Carolina P; Pérez-Lomas, Antonio L; Jiménez, Ignacio A; Gamarro, Francisco; Castanys, Santiago

    2006-01-01

    Dihydro-beta-agarofuran sesquiterpenes from Celastraceae have been recently shown to bind to human P-glycoprotein (Pgp), functioning as specific, mixed-type inhibitors of its drug transport activity, as well as multidrug resistance (MDR) modulators in vitro. However, nothing is known about whether such compounds are themselves transported by Pgp, or whether they affect Pgp expression as well as its activity, or about the location of their binding site within the protein. We performed transport experiments with a newly synthesized fluorescent sesquiterpene derivative, which retains the anti-Pgp activity of its natural precursor. This probe was poorly transported by Pgp, MRP1, MRP2 and BCRP transporters, compared with classical MDR substrates. Moreover, Pgp did not confer cross-resistance to the most potent dihydro-beta-agarofurans, which did not affect Pgp expression levels in several MDR cell lines. Finally, we observed competitive and non-competitive interactions between one of such dihydro-beta-agarofurans (Mama12) and classical Pgp modulators such as cyclosporin A, verapamil, progesterone, vinblastine and GF120918. These findings suggest that multidrug ABC transporters do not confer resistance to dihydro-beta-agarofurans and could not affect their absorption and biodistribution in the body. Moreover, we mapped their binding site(s) within Pgp, which may prove useful for the rational design of improved modulators based on the structure of dihydro-beta-agarofurans.

  20. Dune field pattern formation and recent transporting winds in the Olympia Undae Dune Field, north polar region of Mars

    OpenAIRE

    Ewing, Ryan C.; Peyret, Aymeric-Pierre B.; Kocurek, Gary; Bourke, Mary

    2010-01-01

    High-Resolution Imaging Science Experiment (HiRISE) imagery of the central Olympia Undae Dune Field in the north polar region of Mars shows a reticulate dune pattern consisting of two sets of nearly orthogonal dune crestlines, with apparent slipfaces on the primary crests, ubiquitous wind ripples, areas of coarse-grained wind ripples, and deflated interdune areas. Geomorphic evidence and dune field pattern analysis of dune crest length, spacing, defect density, and orientation indicates that ...

  1. Polarization Optics

    OpenAIRE

    Fressengeas, Nicolas

    2010-01-01

    The physics of polarization optics *Polarized light propagation *Partially polarized light; DEA; After a brief introduction to polarization optics, this lecture reviews the basic formalisms for dealing with it: Jones Calculus for totally polarized light and Stokes parameters associated to Mueller Calculus for partially polarized light.

  2. Discovery of Indazoles as Potent, Orally Active Dual Neurokinin 1 Receptor Antagonists and Serotonin Transporter Inhibitors for the Treatment of Depression.

    Science.gov (United States)

    Degnan, Andrew P; Tora, George O; Huang, Hong; Conlon, David A; Davis, Carl D; Hanumegowda, Umesh M; Hou, Xiaoping; Hsiao, Yi; Hu, Joanna; Krause, Rudolph; Li, Yu-Wen; Newton, Amy E; Pieschl, Rick L; Raybon, Joseph; Rosner, Thorsten; Sun, Jung-Hui; Taber, Matthew T; Taylor, Sarah J; Wong, Michael K; Zhang, Huiping; Lodge, Nicholas J; Bronson, Joanne J; Macor, John E; Gillman, Kevin W

    2016-12-21

    Combination studies of neurokinin 1 (NK1) receptor antagonists and serotonin-selective reuptake inhibitors (SSRIs) have shown promise in preclinical models of depression. Such a combination may offer important advantages over the current standard of care. Herein we describe the discovery and optimization of an indazole-based chemotype to provide a series of potent dual NK1 receptor antagonists/serotonin transporter (SERT) inhibitors to overcome issues of ion channel blockade. This effort culminated in the identification of compound 9, an analogue that demonstrated favorable oral bioavailability, excellent brain uptake, and robust in vivo efficacy in a validated depression model. Over the course of this work, a novel heterocycle-directed asymmetric hydrogenation was developed to facilitate installation of the key stereogenic center.

  3. The use of LeuT as a model in elucidating binding sites for substrates and inhibitors in neurotransmitter transporters

    DEFF Research Database (Denmark)

    Løland, Claus Juul

    2015-01-01

    Background: The mammalian neurotransmitter transporters are complex proteins playing a central role in synaptic transmission between neurons by rapid reuptake of neurotransmitters. The proteins which transport dopamine, noradrenaline and serotonin belong to the Neurotransmitter:Sodium Symporters...

  4. [Sodium-glucose co-transporter-2 inhibitors: from the bark of apple trees and familial renal glycosuria to the treatment of type 2 diabetes mellitus].

    Science.gov (United States)

    Mauricio, Dídac

    2013-09-01

    The therapeutic armamentarium for the treatment of hyperglycemia in type 2 diabetes mellitus is still inadequate. We are currently witnessing the introduction of a new mode of hypoglycemic treatment through induction of glycosuria to decrease the availability of the metabolic substrate, i.e. glucose. Clinical trials have shown that sodium-glucose co-transporter-2 (SGLT2) inhibitors are as efficacious as other oral hypoglycemic drugs. This article discusses the basic features of this new treatment concept and the efficacy and safety of this new drug group. Copyright © 2013 Elsevier España, S.L. All rights reserved.

  5. A virtual high-throughput screening approach to the discovery of novel inhibitors of the bacterial leucine transporter, LeuT

    DEFF Research Database (Denmark)

    Simmons, Katie J; Gotfryd, Kamil; Billesbølle, Christian B

    2013-01-01

    Abstract Membrane proteins are intrinsically involved in both human and pathogen physiology, and are the target of 60% of all marketed drugs. During the past decade, advances in the studies of membrane proteins using X-ray crystallography, electron microscopy and NMR-based techniques led to the e...... this is a virtual high-throughput screening (vHTS) technique initially developed for soluble proteins. This paper describes application of this technique to the discovery of inhibitors of the leucine transporter (LeuT), a member of the neurotransmitter:sodium symporter (NSS) family....

  6. Identification of novel natural inhibitor for NorM - a multidrug and toxic compound extrusion transporter - an insilico molecular modeling and simulation studies.

    Science.gov (United States)

    Kesherwani, Manish; Michael Gromiha, M; Fukui, Kazuhiko; Velmurugan, Devadasan

    2017-01-01

    The emergence of bacterial multidrug resistance is an increasing problem in treatment of infectious diseases. An important cause for the multidrug resistance of bacteria is the expression of multidrug efflux transporters. The multidrug and toxic compound extrusion (MATE) transporters are most recently recognized as unique efflux system for extrusion of antimicrobials and therapeutic drugs due to energy stored in either Na + or H + electrochemical gradient. In the present study, high throughput virtual screening of natural compound collections against NorM - a MATE transporter from Neisseria gonorrhea (NorM-NG) has been carried out followed by flexible docking. The molecular simulation in membrane environment has been performed for understanding the stability and binding energetic of top lead compounds. Results identified a compound from the Indian medicinal plant "Terminalia chebula" which has good binding free energy compared to substrates (rhodamine 6 g, ethidium) and more favorable interactions with the central cavity forming active site residues. The compound has restricted movement in TM7, TM8, and TM1, thus blocking the disruption of Na+ - coordination along with equilibrium state bias towards occlude state of NorM transporter. Thus, this compound blocks the effluxing pathway of antimicrobial drugs and provides as a natural bioactive lead inhibitor against NorM transporter in drug-resistant gonorrhea.

  7. Discovery of substituted 3,4-diphenyl-thiazoles as a novel class of monoamine transporter inhibitors through 3-D pharmacophore search using a new pharmacophore model derived from mazindol.

    Science.gov (United States)

    Enyedy, Istvan J; Wang, Jiansuo; Zaman, Wahiduz A; Johnson, Kenneth M; Wang, Shaomeng

    2002-07-08

    Substituted 3,4-diphenyl-1,3-thiazols were identified as a class of novel and potent monoamine transporter inhibitors through a 3-D pharmacophore search using a new pharmacophore model derived from mazindol. The most potent compound (13) has K(i) values of 24 and 23 nM in binding to dopamine transporter and inhibition of dopamine reuptake, respectively.

  8. The influence of firn air transport processes and radiocarbon production on gas records from polar firn and ice

    DEFF Research Database (Denmark)

    Buizert, Christo

    in Northern Greenland (77.45 o N 51.06 o W). The depthdiffusivity relationship needs to be reconstructed using reference tracers of known atmospheric history. We present a novel method of characterizing the firn transport using ten tracers simultaneously, thus constraining the effective diffusivity better...... does not vanish completely in the lock-in zone, as is commonly assumed. Six state-of-the-art firn air transport models are tuned to the NEEM site; all models successfully reproduce the data within a 1 Gaussian distribution. We present the first intercomparison study of firn air models, where we...

  9. Transport of spin-labeled compounds across the erythrocyte membrane. 1. Effect of noncovalent inhibitors and gamma radiation

    Energy Technology Data Exchange (ETDEWEB)

    Gwozdzinski, K. (Lodz Univ. (Poland))

    1984-03-01

    Effect of phloretin and phlorizin on the transport of two spin-labeled non-electrolytes: TEMPO /2,2,6,6-tetramethylpiperidine-1-oxyl/ and TEMPOL /4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl/ was studied in gamma-irradiated human erythrocytes by ESR technique. Phloretin inhibited TEMPO and TEMPOL transport in gamma-irradiated erythrocytes while phlorizin inhibited TEMPOL and accelerated TEMPO transport.

  10. Blockade of the high-affinity noradrenaline transporter (NET) by the selective 5-HT reuptake inhibitor escitalopram: an in vivo microdialysis study in mice

    Science.gov (United States)

    Nguyen, Hai T; Guiard, Bruno P; Bacq, Alexandre; David, Denis J; David, Indira; Quesseveur, Gaël; Gautron, Sophie; Sanchez, Connie; Gardier, Alain M

    2013-01-01

    BACKGROUND AND PURPOSE Escitalopram, the S(+)-enantiomer of citalopram is the most selective 5-HT reuptake inhibitor approved. Although all 5-HT selective reuptake inhibitors (SSRIs) increase extracellular levels of 5-HT ([5-HT]ext). some also enhance, to a lesser extent, extracellular levels of noradrenaline ([NA]ext). However, the mechanisms by which SSRIs activate noradrenergic transmission in the brain remain to be determined. EXPERIMENTAL APPROACH This study examined the effects of escitalopram, on both [5-HT]ext and [NA]ext in the frontal cortex (FCx) of freely moving wild-type (WT) and mutant mice lacking the 5-HT transporter (SERT−/−) by using intracerebral microdialysis. We explored the possibilities that escitalopram enhances [NA]ext, either by a direct mechanism involving the inhibition of the low- or high-affinity noradrenaline transporters, or by an indirect mechanism promoted by [5-HT]ext elevation. The forced swim test (FST) was used to investigate whether enhancing cortical [5-HT]ext and/or [NA]ext affected the antidepressant-like activity of escitalopram. KEY RESULTS In WT mice, a single systemic administration of escitalopram produced a significant increase in cortical [5-HT]ext and [NA]ext. As expected, escitalopram failed to increase cortical [5-HT]ext in SERT−/− mice, whereas its neurochemical effects on [NA]ext persisted in these mutants. In WT mice subjected to the FST, escitalopram increased swimming parameters without affecting climbing behaviour. Finally, escitalopram, at relevant concentrations, failed to inhibit cortical noradrenaline and 5-HT uptake mediated by low-affinity monoamine transporters. CONCLUSIONS AND IMPLICATIONS These experiments suggest that escitalopram enhances, although moderately, cortical [NA]extin vivo by a direct mechanism involving the inhibition of the high-affinity noradrenaline transporter (NET). PMID:22233336

  11. Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3).

    Science.gov (United States)

    Liang, Xiaomin; Chien, Huan-Chieh; Yee, Sook Wah; Giacomini, Marilyn M; Chen, Eugene C; Piao, Meiling; Hao, Jia; Twelves, Jolyn; Lepist, Eve-Irene; Ray, Adrian S; Giacomini, Kathleen M

    2015-12-07

    The biguanide metformin is widely used as first-line therapy for the treatment of type 2 diabetes. Predominately a cation at physiological pH's, metformin is transported by membrane transporters, which play major roles in its absorption and disposition. Recently, our laboratory demonstrated that organic cation transporter 1, OCT1, the major hepatic uptake transporter for metformin, was also the primary hepatic uptake transporter for thiamine, vitamin B1. In this study, we tested the reverse, i.e., that metformin is a substrate of thiamine transporters (THTR-1, SLC19A2, and THTR-2, SLC19A3). Our study demonstrated that human THTR-2 (hTHTR-2), SLC19A3, which is highly expressed in the small intestine, but not hTHTR-1, transports metformin (Km = 1.15 ± 0.2 mM) and other cationic compounds (MPP(+) and famotidine). The uptake mechanism for hTHTR-2 was pH and electrochemical gradient sensitive. Furthermore, metformin as well as other drugs including phenformin, chloroquine, verapamil, famotidine, and amprolium inhibited hTHTR-2 mediated uptake of both thiamine and metformin. Species differences in the substrate specificity of THTR-2 between human and mouse orthologues were observed. Taken together, our data suggest that hTHTR-2 may play a role in the intestinal absorption and tissue distribution of metformin and other organic cations and that the transporter may be a target for drug-drug and drug-nutrient interactions.

  12. Gram-scale solution-phase synthesis of selective sodium bicarbonate Co-transport Inhibitor S0859

    DEFF Research Database (Denmark)

    Larsen, Ann Møller; Krogsgaard-Larsen, Niels; Lauritzen, Gitte

    2012-01-01

    Na+-coupled HCO3- transporters (NBCs) mediate the transport of bicarbonate ions across cell membranes and are thus ubiquitous regulators of intracellular pH. NBC dysregulation is associated with a range of diseases; for instance, NBCn1 is strongly up-regulated in a model of ErbB2-dependent breast...

  13. Transcriptional Responses of Escherichia coli to a Small-Molecule Inhibitor of LolCDE, an Essential Component of the Lipoprotein Transport Pathway

    Science.gov (United States)

    Lorenz, Christian; Dougherty, Thomas J.

    2016-01-01

    ABSTRACT In Gram-negative bacteria, a dedicated machinery consisting of LolABCDE components targets lipoproteins to the outer membrane. We used a previously identified small-molecule inhibitor of the LolCDE complex of Escherichia coli to assess the global transcriptional consequences of interference with lipoprotein transport. Exposure of E. coli to the LolCDE inhibitor at concentrations leading to minimal and significant growth inhibition, followed by transcriptome sequencing, identified a small group of genes whose transcript levels were decreased and a larger group whose mRNA levels increased 10- to 100-fold compared to those of untreated cells. The majority of the genes whose mRNA concentrations were reduced were part of the flagellar assembly pathway, which contains an essential lipoprotein component. Most of the genes whose transcript levels were elevated encode proteins involved in selected cell stress pathways. Many of these genes are involved with envelope stress responses induced by the mislocalization of outer membrane lipoproteins. Although several of the genes whose RNAs were induced have previously been shown to be associated with the general perturbation of the cell envelope by antibiotics, a small subset was affected only by LolCDE inhibition. Findings from this work suggest that the efficiency of the Lol system function may be coupled to a specific monitoring system, which could be exploited in the development of reporter constructs suitable for use for screening for additional inhibitors of lipoprotein trafficking. IMPORTANCE Inhibition of the lipoprotein transport pathway leads to E. coli death and subsequent lysis. Early significant changes in the levels of RNA for a subset of genes identified to be associated with some periplasmic and envelope stress responses were observed. Together these findings suggest that disruption of this key pathway can have a severe impact on balanced outer membrane synthesis sufficient to affect viability. PMID

  14. Transcriptional Responses of Escherichia coli to a Small-Molecule Inhibitor of LolCDE, an Essential Component of the Lipoprotein Transport Pathway.

    Science.gov (United States)

    Lorenz, Christian; Dougherty, Thomas J; Lory, Stephen

    2016-12-01

    In Gram-negative bacteria, a dedicated machinery consisting of LolABCDE components targets lipoproteins to the outer membrane. We used a previously identified small-molecule inhibitor of the LolCDE complex of Escherichia coli to assess the global transcriptional consequences of interference with lipoprotein transport. Exposure of E. coli to the LolCDE inhibitor at concentrations leading to minimal and significant growth inhibition, followed by transcriptome sequencing, identified a small group of genes whose transcript levels were decreased and a larger group whose mRNA levels increased 10- to 100-fold compared to those of untreated cells. The majority of the genes whose mRNA concentrations were reduced were part of the flagellar assembly pathway, which contains an essential lipoprotein component. Most of the genes whose transcript levels were elevated encode proteins involved in selected cell stress pathways. Many of these genes are involved with envelope stress responses induced by the mislocalization of outer membrane lipoproteins. Although several of the genes whose RNAs were induced have previously been shown to be associated with the general perturbation of the cell envelope by antibiotics, a small subset was affected only by LolCDE inhibition. Findings from this work suggest that the efficiency of the Lol system function may be coupled to a specific monitoring system, which could be exploited in the development of reporter constructs suitable for use for screening for additional inhibitors of lipoprotein trafficking. Inhibition of the lipoprotein transport pathway leads to E. coli death and subsequent lysis. Early significant changes in the levels of RNA for a subset of genes identified to be associated with some periplasmic and envelope stress responses were observed. Together these findings suggest that disruption of this key pathway can have a severe impact on balanced outer membrane synthesis sufficient to affect viability. Copyright © 2016 Lorenz et al.

  15. Importance of the Extracellular Loop 4 in the Human Serotonin Transporter for Inhibitor Binding and Substrate Translocation

    DEFF Research Database (Denmark)

    Rannversson, Hafsteinn; Wilson, Pamela; Kristensen, Kristina

    2015-01-01

    ) in the extracellular loop 4 (EL4) of human SERT, which induced a remarkable gain-of-potency (up to >40-fold) for a range of SERT inhibitors. The effects were highly specific for L406E relative to six other mutations in the same position, including the closely related L406D mutation, showing that the effects induced...... has an important role in controlling the conformational equilibrium of human SERT....

  16. Temporal trends and transport within and around the Antarctic polar vortex during the formation of the 1987 Antarctic ozone hole

    Science.gov (United States)

    Proffitt, M. H.; Powell, J. A.; Tuck, A. F.; Fahey, D. W.; Kelly, K. K.; Loewenstein, M.; Podolske, J. R.; Chan, K. Roland

    1988-01-01

    During AAOE in 1987 an ER-2 high altitude aircraft made twelve flights out of Punta Arenas, Chile (53 S, 71 W) into the Antarctic polar vortex. The aircraft was fitted with fast response instruments for in situ measurements of many trace species including O3, ClO, BrO, NO sub y, NO, H2O, and N2O. Grab samples of long-lived tracers were also taken and a scanning microwave radiometer measured temperatures above and below the aircraft. Temperature, pressure, and wind measurements were also made on the flight tracks. Most of these flights were flown to 72 S, at a constant potential temperature, followed by a dip to a lower altitude and again assuming a sometimes different potential temperature for the return leg. The potential temperature chosen was 425 K (17 to 18 km) on 12 of the flight legs, and 5 of the flight legs were flown at 450 K (18 to 19 km). The remaining 7 legs of the 12 flights were not flown on constant potential temperature surfaces. Tracer data have been analyzed for temporal trends. Data from the ascents out of Punta Arenas, the constant potential temperature flight legs, and the dips within the vortex are used to compare tracer values inside and outside the vortex, both with respect to constant potential temperature and constant N2O. The time trend during the one-month period of August 23 through September 22, 1987, shows that ozone decreased by 50 percent or more at altitudes form 15 to 19 km. This trend is evident whether analyzed with respect to constant potential temperature or constant N2O. The trend analysis for ozone outside the vortex shows no downward trend during this period. The analysis for N2O at a constant potential temperature indicates no significant trend either inside or outside the vortex; however, a decrease in N2O with an increase in latitude is evident.

  17. 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

  18. Soybean polar lipids differently impact adipose tissue inflammation and the endotoxin transporters LBP and sCD14 in flaxseed vs. palm oil-rich diets.

    Science.gov (United States)

    Lecomte, Manon; Couëdelo, Leslie; Meugnier, Emmanuelle; Loizon, Emmanuelle; Plaisancié, Pascale; Durand, Annie; Géloën, Alain; Joffre, Florent; Vaysse, Carole; Michalski, Marie-Caroline; Laugerette, Fabienne

    2017-05-01

    Obesity and type 2 diabetes are nutritional pathologies, characterized by a subclinical inflammatory state. Endotoxins are now well recognized as an important factor implicated in the onset and maintain of this inflammatory state during fat digestion in high-fat diet. As a preventive strategy, lipid formulation could be optimized to limit these phenomena, notably regarding fatty acid profile and PL emulsifier content. Little is known about soybean polar lipid (SPL) consumption associated to oils rich in saturated FA vs. anti-inflammatory omega-3 FA such as α-linolenic acid on inflammation and metabolic endotoxemia. We then investigated in mice the effect of different synthetic diets enriched with two different oils, palm oil or flaxseed oil and containing or devoid of SPL on adipose tissue inflammation and endotoxin receptors. In both groups containing SPL, adipose tissue (WAT) increased compared with groups devoid of SPL and an induction of MCP-1 and LBP was observed in WAT. However, only the high-fat diet in which flaxseed oil was associated with SPL resulted in both higher WAT inflammation and higher circulating sCD14 in plasma. In conclusion, we have demonstrated that LPS transporters LBP and sCD14 and adipose tissue inflammation can be modulated by SPL in high fat diets differing in oil composition. Notably high-flaxseed oil diet exerts a beneficial metabolic impact, however blunted by PL addition. Our study suggests that nutritional strategies can be envisaged by optimizing dietary lipid sources in manufactured products, including fats/oils and polar lipid emulsifiers, in order to limit the inflammatory impact of palatable foods. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Tensammetric Studies on Corrosion Inhibitors

    Indian Academy of Sciences (India)

    Tensammetric Studies on Corrosion Inhibitors-I 277 paralleled potential data and corrosion data given in the next section. The only chemicals which bring about increased polarization of the steel speci- mens are sodium nitrite, dicyclohexylamine nitrite, cyclohexylamine and morpholine. The extent of polarization follows the ...

  20. 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.)

  1. A new multi-gas constrained model of trace gas non-homogeneous transport in firn: evaluation and behaviour at eleven polar sites

    Directory of Open Access Journals (Sweden)

    E. Witrant

    2012-12-01

    Full Text Available Insoluble trace gases are trapped in polar ice at the firn-ice transition, at approximately 50 to 100 m below the surface, depending primarily on the site temperature and snow accumulation. Models of trace gas transport in polar firn are used to relate firn air and ice core records of trace gases to their atmospheric history. We propose a new model based on the following contributions. First, the firn air transport model is revised in a poromechanics framework with emphasis on the non-homogeneous properties and the treatment of gravitational settling. We then derive a nonlinear least square multi-gas optimisation scheme to calculate the effective firn diffusivity (automatic diffusivity tuning. The improvements gained by the multi-gas approach are investigated (up to ten gases for a single site are included in the optimisation process. We apply the model to four Arctic (Devon Island, NEEM, North GRIP, Summit and seven Antarctic (DE08, Berkner Island, Siple Dome, Dronning Maud Land, South Pole, Dome C, Vostok sites and calculate their respective depth-dependent diffusivity profiles. Among these different sites, a relationship is inferred between the snow accumulation rate and an increasing thickness of the lock-in zone defined from the isotopic composition of molecular nitrogen in firn air (denoted δ15N. It is associated with a reduced diffusivity value and an increased ratio of advective to diffusive flux in deep firn, which is particularly important at high accumulation rate sites. This has implications for the understanding of δ15N of N2 records in ice cores, in relation with past variations of the snow accumulation rate. As the snow accumulation rate is clearly a primary control on the thickness of the lock-in zone, our new approach that allows for the estimation of the lock-in zone width as a function of accumulation may lead to a better constraint on the age difference between the ice and entrapped gases.

  2. Polarized scintillator targets

    Science.gov (United States)

    van den Brandt, B.; Bunyatova, E. I.; Hautle, P.; Konter, J. A.; Mango, S.

    2000-05-01

    The hydrogen nuclei in an organic scintillator have been polarized to more than 80% and the deuterons in its fully deuterated version to 24%. The scintillator, doped with TEMPO, has been polarized dynamically in a field of 2.5 T in a vertical dilution refrigerator in which a plastic lightguide transports the scintillation light from the sample in the mixing chamber to a photomultiplier outside the cryostat. Sizeable solid samples with acceptable optical properties and light output have been prepared and successfully operated as "live" polarized targets in nuclear physics experiments.

  3. Polarized scintillator targets

    Energy Technology Data Exchange (ETDEWEB)

    Brandt, B. van den E-mail: vandenbrandt@psi.ch; Bunyatova, E.I.; Hautle, P.; Konter, J.A.; Mango, S

    2000-05-21

    The hydrogen nuclei in an organic scintillator have been polarized to more than 80% and the deuterons in its fully deuterated version to 24%. The scintillator, doped with TEMPO, has been polarized dynamically in a field of 2.5 T in a vertical dilution refrigerator in which a plastic lightguide transports the scintillation light from the sample in the mixing chamber to a photomultiplier outside the cryostat. Sizeable solid samples with acceptable optical properties and light output have been prepared and successfully operated as 'live' polarized targets in nuclear physics experiments.

  4. Preventative and therapeutic effects of a GABA transporter 1 inhibitor administered systemically in a mouse model of paclitaxel-induced neuropathic pain

    Directory of Open Access Journals (Sweden)

    Willias Masocha

    2016-12-01

    Full Text Available Background There is a dearth of drugs to manage a dose-limiting painful peripheral neuropathy induced by paclitaxel in some patients during the treatment of cancer. Gamma-aminobutyric acid transporter-1 (GAT-1 whose expression is increased in the brain and spinal cord during paclitaxel-induced neuropathic pain (PINP might be a potential therapeutic target for managing PINP. Thus, our aim was to evaluate if systemic administration of a GAT-1 inhibitor ameliorates PINP. Methods The reaction latency to thermal stimuli (hot plate test; at 55 °C and cold stimuli (cold plate test; at 4 °C of female BALB/c mice was recorded before and after intraperitoneal treatment with paclitaxel, its vehicle, and/or a selective GAT-1 inhibitor NO-711. The effects of NO-711 on motor coordination were evaluated using the rotarod test at a constant speed of 4 rpm or accelerating mode from 4 rpm to 40 rpm over 5 min. Results The coadministration of paclitaxel with NO-711 3 mg/kg prevented the development of paclitaxel-induced thermal hyperalgesia and cold allodynia at day 7 after drug treatment. NO-711 at 3 mg/kg produced antihyperalgesic activity up to 1 h and antiallodynic activity up to 2 h in mice with established paclitaxel-induced thermal hyperalgesia and cold allodynia. No motor deficits were observed with NO-711 at a dose of 3 mg/kg, whereas a higher dose 5 mg/kg caused motor impairment and reduced mean time spent on the rotarod at a constant speed of 4 rpm. However, at a rotarod accelerating mode from 4 rpm to 40 rpm over 5 min, NO-711 3 mg/kg caused motor impairment up to 1 h, but had recovered by 2 h. Conclusions These results show that systemic administration of the GAT-1 inhibitor NO-711 has preventative and therapeutic activity against paclitaxel-induced thermal hyperalgesia and cold allodynia. NO-711’s antiallodynic effects, but not antihyperalgesic effects, were independent of its motor impairment/sedation properties. Thus, low doses of GAT-1

  5. Discovery of Flexible Naphthyltriazolylmethane-based Thioacetic Acids as Highly Active Uric Acid Transporter 1 (URAT1) Inhibitors for the Treatment of Hyperuricemia of Gout.

    Science.gov (United States)

    Zhang, Xiansheng; Wu, Jingwei; Liu, Wei; Liu, Yuqiang; Xie, Yafei; Shang, Qian; Zhou, Zhixing; Xu, Weiren; Tang, Lida; Wang, Jianwu; Zhao, Guilong

    2017-01-01

    Gout is the most common inflammatory arthritis, which, if left untreated or inadequately treated, will lead to joint destruction, bone erosion and disability due to the crystal deposition. Uric acid transporter 1 (URAT1) was the promising therapeutic target for urate-lowering therapy. The goal of this work is to understand the structure-activity relationship (SAR) of a potent lesinurad-based hit, sodium 2-((5-bromo-4-((4-cyclopropyl-naphth-1-yl)methyl)-4H-1,2,4-triazol-3- yl)thio)acetate (1c), and based on that discover a more potent URAT1 inhibitor. The SAR of 1c was systematically explored and the in vitro URAT1 inhibitory activity of synthesized compounds 1a-1t was determined by the inhibition of URAT1-mediated [8-14C]uric acid uptake by human embryonic kidney 293 (HEK293) cells stably expressing human URAT1. Twenty compounds 1a-1t were synthesized. SAR analysis was performed. Two highly active URAT1 inhibitors, sodium 2-((5-bromo-4-((4-n-propylnaphth-1-yl)methyl)-4H-1,2,4-triazol-3- yl)thio)acetate (1j) and sodium 2-((5-bromo-4-((4-bromonaphth-1-yl)methyl)-4H-1,2,4-triazol-3- yl)thio)acetate (1m), were identified, which were 78- and 76-fold more active than parent lesinurad in in vitro URAT1 inhibitory assay, respectively (IC50 values for 1j and 1m were 0.092 μM and 0.094 μM, respectively, against human URAT1 vs 7.18 μM for lesinurad). Two highly active URAT1 inhibitors were discovered. The SAR exploration also identified more flexible naphthyltriazolylmethane as a novel molecular skeleton that will be valuable for the design of URAT1 inhibitors, as indicated by the observation that many of the synthesized naphthyltriazolylmethane- bearing derivatives (1b-1d, 1g, 1j and 1m) showed significantly improved UART1 inhibitory activity (sub-micromolar IC50 values) as compared with lesinurad which has the rigid naphthyltriazole skeleton. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  6. Interaction Potential of the Multitargeted Receptor Tyrosine Kinase Inhibitor Dovitinib with Drug Transporters and Drug Metabolising Enzymes Assessed in Vitro

    Directory of Open Access Journals (Sweden)

    Johanna Weiss

    2014-12-01

    Full Text Available Dovitinib (TKI-258 is under development for the treatment of diverse cancer entities. No published information on its pharmacokinetic drug interaction potential is available. Thus, we assessed its interaction with important drug metabolising enzymes and drug transporters and its efficacy in multidrug resistant cells in vitro. P-glycoprotein (P-gp, MDR1, ABCB1 inhibition was evaluated by calcein assay, inhibition of breast cancer resistance protein (BCRP, ABCG2 by pheophorbide A efflux, and inhibition of organic anion transporting polypeptides (OATPs by 8-fluorescein-cAMP uptake. Inhibition of cytochrome P450 3A4, 2C19, and 2D6 was assessed by using commercial kits. Induction of transporters and enzymes was quantified by real-time RT-PCR. Possible aryl hydrocarbon receptor (AhR activating properties were assessed by a reporter gene assay. Substrate characteristics were evaluated by growth inhibition assays in cells over-expressing P-gp or BCRP. Dovitinib weakly inhibited CYP2C19, CYP3A4, P-gp and OATPs. The strongest inhibition was observed for BCRP (IC50 = 10.3 ± 4.5 μM. Among the genes investigated, dovitinib only induced mRNA expression of CYP1A1, CYP1A2, ABCC3 (coding for multidrug resistance-associated protein 3, and ABCG2 and suppressed mRNA expression of some transporters and drug metabolising enzymes. AhR reporter gene assay demonstrated that dovitinib is an activator of this nuclear receptor. Dovitinib retained its efficacy in cell lines over-expressing P-gp or BCRP. Our analysis indicates that dovitinib will most likely retain its efficacy in tumours over-expressing P-gp or BCRP and gives first evidence that dovitinib might act as a perpetrator drug in pharmacokinetic drug–drug interactions.

  7. Synthesis of L-rhamnose derived chiral bicyclic triazoles as novel sodium-glucose transporter (SGLT) inhibitors.

    Science.gov (United States)

    Putapatri, Siddamal Reddy; Kanwal, Abhinav; Sridhar, Balasubramanian; Banerjee, Sanjay K; Kantevari, Srinivas

    2014-11-14

    Herein we describe the synthesis of a series of novel fused bicyclic 1,2,3-triazoles from commercially available, natural deoxy sugar, L-rhamnose. The key reactions involved are (i) Zn(OTf)2 catalyzed enantioselective alkynylation of L-rhamnose derived azidoaldehyde and (ii) deprotection of the acid sensitive 1,2-isopropylidene group followed by in situ intramolecular click-cycloaddition of azidoalkynols. Some compounds exhibit excellent sodium-glucose transporter (SGLT1 and SGLT2) inhibition activity.

  8. Theoretical Analysis of Thermal Transport in Graphene Supported on Hexagonal Boron Nitride: The Importance of Strong Adhesion Due to π -Bond Polarization

    Science.gov (United States)

    Pak, Alexander J.; Hwang, Gyeong S.

    2016-09-01

    One important attribute of graphene that makes it attractive for high-performance electronics is its inherently large thermal conductivity (κ ) for the purposes of thermal management. Using a combined density-functional theory and classical molecular-dynamics approach, we predict that the κ of graphene supported on hexagonal boron nitride (h -BN) can be as large as 90% of the κ of suspended graphene, in contrast to the significant suppression of κ (more than 70% reduction) on amorphous silica. Interestingly, we find that this enhanced thermal transport is largely attributed to increased lifetimes of the in-plane acoustic phonon modes, which is a notable contrast from the dominant contribution of out-of-plane acoustic modes in suspended graphene. This behavior is possible due to the charge polarization throughout graphene that induces strong interlayer adhesion between graphene and h -BN. These findings highlight the potential benefit of layered dielectric substrates such as h -BN for graphene-based thermal management, in addition to their electronic advantages. Furthermore, our study brings attention to the importance of understanding the interlayer interactions of graphene with layered dielectric materials which may offer an alternative technological platform for substrates in electronics.

  9. 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, Douglas; 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...

  10. The effect of organic anion transporter 3 inhibitor probenecid on bumetanide levels in the brain: an integrated in vivo microdialysis study in the rat.

    Science.gov (United States)

    Donovan, Maria D; O'Brien, Fionn E; Boylan, Geraldine B; Cryan, John F; Griffin, Brendan T

    2015-04-01

    Recent data highlight the potential of bumetanide as a treatment for neonatal seizures and autism, as it facilitates the excitatory to inhibitory switch in gamma-aminobutyric acid signalling. This study examines the extent of blood-brain barrier (BBB) permeation of bumetanide, a key determinant of the efficacy of centrally acting drugs. Furthermore, the impact of efflux transporter organic anion transporter 3 (oat3) inhibition on bumetanide pharmacokinetics was investigated. Bumetanide levels in extracellular fluid (ECF) and plasma in the presence and absence of oat3 inhibitor probenecid were monitored using integrated microdialysis. Following a bumetanide bolus/continuous infusion of 10 mg/kg and 6 mg/kg/h, bumetanide was detected in hippocampal ECF at the estimated concentration of 131 ± 55 ng/ml. Plasma bumetanide levels were ∼20 mg/l at steady state. Coadministration of probenecid resulted in an increase in bumetanide levels in both ECF and plasma, indicating that oat3 inhibition influences the pharmacokinetics of bumetanide primarily in the periphery. Although bumetanide reached detectable levels in hippocampal ECF, bumetanide concentration in ECF was low relative to systemic concentration. Oat3 inhibition by probenecid resulted in increased bumetanide concentrations in brain and plasma. As an acute treatment in neonatal seizures, the bumetanide/probenecid combination may hold therapeutic potential. © 2014 Royal Pharmaceutical Society.

  11. Inhibitor mechanisms in the S1 binding site of the dopamine transporter defined by multi-site molecular tethering of photoactive cocaine analogs.

    Science.gov (United States)

    Krout, Danielle; Pramod, Akula Bala; Dahal, Rejwi Acharya; Tomlinson, Michael J; Sharma, Babita; Foster, James D; Zou, Mu-Fa; Boatang, Comfort; Newman, Amy Hauck; Lever, John R; Vaughan, Roxanne A; Henry, L Keith

    2017-10-15

    Dopamine transporter (DAT) blockers like cocaine and many other abused and therapeutic drugs bind and stabilize an inactive form of the transporter inhibiting reuptake of extracellular dopamine (DA). The resulting increases in DA lead to the ability of these drugs to induce psychomotor alterations and addiction, but paradoxical findings in animal models indicate that not all DAT antagonists induce cocaine-like behavioral outcomes. How this occurs is not known, but one possibility is that uptake inhibitors may bind at multiple locations or in different poses to stabilize distinct conformational transporter states associated with differential neurochemical endpoints. Understanding the molecular mechanisms governing the pharmacological inhibition of DAT is therefore key for understanding the requisite interactions for behavioral modulation and addiction. Previously, we leveraged complementary computational docking, mutagenesis, peptide mapping, and substituted cysteine accessibility strategies to identify the specific adduction site and binding pose for the crosslinkable, photoactive cocaine analog, RTI 82, which contains a photoactive azide attached at the 2β position of the tropane pharmacophore. Here, we utilize similar methodology with a different cocaine analog N-[4-(4-azido-3-I-iodophenyl)-butyl]-2-carbomethoxy-3-(4-chlorophenyl)tropane, MFZ 2-24, where the photoactive azide is attached to the tropane nitrogen. In contrast to RTI 82, which crosslinked into residue Phe319 of transmembrane domain (TM) 6, our findings show that MFZ 2-24 adducts to Leu80 in TM1 with modeling and biochemical data indicating that MFZ 2-24, like RTI 82, occupies the central S1 binding pocket with the (+)-charged tropane ring nitrogen coordinating with the (-)-charged carboxyl side chain of Asp79. The superimposition of the tropane ring in the three-dimensional binding poses of these two distinct ligands provides strong experimental evidence for cocaine binding to DAT in the S1 site

  12. N,N-bis(cyclohexanol)amine aryl esters: a new class of highly potent transporter-dependent multidrug resistance inhibitors.

    Science.gov (United States)

    Martelli, Cecilia; Alderighi, Daniela; Coronnello, Marcella; Dei, Silvia; Frosini, Maria; Le Bozec, Bénédicte; Manetti, Dina; Neri, Annalisa; Romanelli, Maria Novella; Salerno, Milena; Scapecchi, Serena; Mini, Enrico; Sgaragli, Giampietro; Teodori, Elisabetta

    2009-02-12

    A new series of Pgp-dependent MDR inhibitors having a N,N-bis(cyclohexanol)amine scaffold was designed on the basis of the frozen analogue approach. The scaffold chosen gives origin to different geometrical isomers. The new compounds showed a wide range of potencies and efficacies on doxorubicin-resistant erythroleukemia K562 cells in the pirarubicin uptake assay. The most interesting compounds (isomers of 3) were studied further evaluating their action on the ATPase activity present in rat small intestine membrane vesicles and doxorubicin cytotoxicity potentiation on K562 cells. The latter assay was performed also on the isomers of 4. The four isomers of each set present different behavior in each of these tests. Compound 3d shows the most promising properties as it was able to completely reverse Pgp-dependent pirarubicin extrusion at low nanomolar concentration, inhibited ATPase activity at 5 x 10(-9) and increased the cytotoxicity of doxorubicin with a reversal fold (RF) of 36.4 at 3 microM concentration.

  13. Selective GABA transporter inhibitors tiagabine and EF1502 exhibit mechanistic differences in their ability to modulate the ataxia and anticonvulsant action of the extrasynaptic GABA(A) receptor agonist gaboxadol

    DEFF Research Database (Denmark)

    Madsen, Karsten Kirkegaard; Ebert, Bjarke; Clausen, Rasmus Prætorius

    2011-01-01

    Modulation of the extracellular levels of GABA via inhibition of the synaptic GABA transporter GAT1 by the clinically effective and selective GAT1 inhibitor tiagabine [(R)-N-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]nipecotic acid; Gabitril] has proven to be an effective treatment strategy for focal...

  14. Common selective serotonin reuptake inhibitor side effects in older adults associated with genetic polymorphisms in the serotonin transporter and receptors: data from a randomized controlled trial.

    Science.gov (United States)

    Garfield, Lauren D; Dixon, David; Nowotny, Petra; Lotrich, Francis E; Pollock, Bruce G; Kristjansson, Sean D; Doré, Peter M; Lenze, Eric J

    2014-10-01

    Antidepressant side effects are a significant public health issue, associated with poor adherence, premature treatment discontinuation, and, rarely, significant harm. Older adults assume the largest and most serious burden of medication side effects. We investigated the association between antidepressant side effects and genetic variation in the serotonin system in anxious, older adults participating in a randomized, placebo-controlled trial of the selective serotonin reuptake inhibitor (SSRI) escitalopram. Adults (N = 177) aged ≥ 60 years were randomized to active treatment or placebo for 12 weeks. Side effects were assessed using the Udvalg fur Kliniske Undersøgelser side-effect rating scale. Genetic polymorphisms were putative functional variants in the promoters of the serotonin transporter and 1A and 2A receptors (5-HTTLPR [L/S + rs25531], HTR1A rs6295, HTR2A rs6311, respectively). Four significant drug-placebo side-effect differences were found: increased duration of sleep, dry mouth, diarrhea, and diminished sexual desire. Analyses using putative high- versus low-transcription genotype groupings revealed six pharmacogenetic effects: greater dry mouth and decreased sexual desire for the low- and high-expressing serotonin transporter genotypes, respectively, and greater diarrhea with the 1A receptor low-transcription genotype. Diminished sexual desire was experienced significantly more by high-expressing genotypes in the serotonin transporter, 1A, or 2A receptors. There was not a significant relationship between drug concentration and side effects nor a mean difference in drug concentration between low- and high-expressing genotypes. Genetic variation in the serotonin system may predict who develops common SSRI side effects and why. More work is needed to further characterize this genetic modulation and to translate research findings into strategies useful for more personalized patient care. Published by Elsevier Inc.

  15. Transport of the Two Natural Auxins, Indole-3-Butyric Acid and Indole-3-Acetic Acid, in Arabidopsis1

    Science.gov (United States)

    Rashotte, Aaron M.; Poupart, Julie; Waddell, Candace S.; Muday, Gloria K.

    2003-01-01

    Polar transport of the natural auxin indole-3-acetic acid (IAA) is important in a number of plant developmental processes. However, few studies have investigated the polar transport of other endogenous auxins, such as indole-3-butyric acid (IBA), in Arabidopsis. This study details the similarities and differences between IBA and IAA transport in several tissues of Arabidopsis. In the inflorescence axis, no significant IBA movement was detected, whereas IAA is transported in a basipetal direction from the meristem tip. In young seedlings, both IBA and IAA were transported only in a basipetal direction in the hypocotyl. In roots, both auxins moved in two distinct polarities and in specific tissues. The kinetics of IBA and IAA transport appear similar, with transport rates of 8 to 10 mm per hour. In addition, IBA transport, like IAA transport, is saturable at high concentrations of auxin, suggesting that IBA transport is protein mediated. Interestingly, IAA efflux inhibitors and mutations in genes encoding putative IAA transport proteins reduce IAA transport but do not alter IBA movement, suggesting that different auxin transport protein complexes are likely to mediate IBA and IAA transport. Finally, the physiological effects of IBA and IAA on hypocotyl elongation under several light conditions were examined and analyzed in the context of the differences in IBA and IAA transport. Together, these results present a detailed picture of IBA transport and provide the basis for a better understanding of the transport of these two endogenous auxins. PMID:14526119

  16. Transport of the two natural auxins, indole-3-butyric acid and indole-3-acetic acid, in Arabidopsis

    Science.gov (United States)

    Rashotte, Aaron M.; Poupart, Julie; Waddell, Candace S.; Muday, Gloria K.; Brown, C. S. (Principal Investigator)

    2003-01-01

    Polar transport of the natural auxin indole-3-acetic acid (IAA) is important in a number of plant developmental processes. However, few studies have investigated the polar transport of other endogenous auxins, such as indole-3-butyric acid (IBA), in Arabidopsis. This study details the similarities and differences between IBA and IAA transport in several tissues of Arabidopsis. In the inflorescence axis, no significant IBA movement was detected, whereas IAA is transported in a basipetal direction from the meristem tip. In young seedlings, both IBA and IAA were transported only in a basipetal direction in the hypocotyl. In roots, both auxins moved in two distinct polarities and in specific tissues. The kinetics of IBA and IAA transport appear similar, with transport rates of 8 to 10 mm per hour. In addition, IBA transport, like IAA transport, is saturable at high concentrations of auxin, suggesting that IBA transport is protein mediated. Interestingly, IAA efflux inhibitors and mutations in genes encoding putative IAA transport proteins reduce IAA transport but do not alter IBA movement, suggesting that different auxin transport protein complexes are likely to mediate IBA and IAA transport. Finally, the physiological effects of IBA and IAA on hypocotyl elongation under several light conditions were examined and analyzed in the context of the differences in IBA and IAA transport. Together, these results present a detailed picture of IBA transport and provide the basis for a better understanding of the transport of these two endogenous auxins.

  17. Kaempferol 3-O-rhamnoside-7-O-rhamnoside is an endogenous flavonol inhibitor of polar auxin transport in Arabidopsis shoots

    Czech Academy of Sciences Publication Activity Database

    Yin, R.H.; Han, K.; Heller, W.; Albert, A.; Dobrev, Petre; Zažímalová, Eva; Schaffner, A.R.

    2014-01-01

    Roč. 201, č. 2 (2014), s. 466-475 ISSN 1469-8137 R&D Projects: GA ČR(CZ) GAP305/11/0797 Institutional support: RVO:61389030 Keywords : Arabidopsis thaliana * flavonol biosynthesis * flavonol glycoside Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 6.545, year: 2013

  18. Flavonoids act as negative regulators of auxin transport in vivo in arabidopsis

    Science.gov (United States)

    Brown, D. E.; Rashotte, A. M.; Murphy, A. S.; Normanly, J.; Tague, B. W.; Peer, W. A.; Taiz, L.; Muday, G. K.

    2001-01-01

    Polar transport of the plant hormone auxin controls many aspects of plant growth and development. A number of synthetic compounds have been shown to block the process of auxin transport by inhibition of the auxin efflux carrier complex. These synthetic auxin transport inhibitors may act by mimicking endogenous molecules. Flavonoids, a class of secondary plant metabolic compounds, have been suggested to be auxin transport inhibitors based on their in vitro activity. The hypothesis that flavonoids regulate auxin transport in vivo was tested in Arabidopsis by comparing wild-type (WT) and transparent testa (tt4) plants with a mutation in the gene encoding the first enzyme in flavonoid biosynthesis, chalcone synthase. In a comparison between tt4 and WT plants, phenotypic differences were observed, including three times as many secondary inflorescence stems, reduced plant height, decreased stem diameter, and increased secondary root development. Growth of WT Arabidopsis plants on naringenin, a biosynthetic precursor to those flavonoids with auxin transport inhibitor activity in vitro, leads to a reduction in root growth and gravitropism, similar to the effects of synthetic auxin transport inhibitors. Analyses of auxin transport in the inflorescence and hypocotyl of independent tt4 alleles indicate that auxin transport is elevated in plants with a tt4 mutation. In hypocotyls of tt4, this elevated transport is reversed when flavonoids are synthesized by growth of plants on the flavonoid precursor, naringenin. These results are consistent with a role for flavonoids as endogenous regulators of auxin transport.

  19. Polarized Scintillating Targets at Psi

    Science.gov (United States)

    van den Brandt, B.; Bunyatova, E. I.; Hautle, P.; Konter, J. A.; Mango, S.

    2001-02-01

    Scintillating polarized targets are now routinely available: blocks of 18×18×5 mm scintillating organic polymer, doped with TEMPO, polarized dynamically in a field of 2.5 T in a vertical 3He-4He dilution refrigerator. A 19 mm diameter plastic lightguide transports the scintillation light from the sample in the mixing chamber to a photomultiplier outside the cryostat.

  20. Probing for improved potency and in vivo bioavailability of excitatory amino acid transporter subtype 1 inhibitors UCPH-101 and UCPH-102: Design, synthesis and pharmacological evaluation of substituted 7-biphenyl analogs

    DEFF Research Database (Denmark)

    Erichsen, Mette Norman; Hansen, J; Artacho Ruiz, Jose

    2014-01-01

    Uptake of the major excitatory neurotransmitter in the CNS, (S)-glutamate, is mediated by a family of excitatory amino acid transporters (EAAT). Previously we have explored the structure-activity relationship (SAR) of a series of EAAT1 selective inhibitors, leading to the development of the potent...... lipophilic binding pocket in EAAT1 for the aromatic 7-substituent in these ligands. In conclusion, while we have not succeeded in developing UCPH-101/102 analogs possessing improved bioavailability properties, this study does offer interesting SAR information about this inhibitor class, and analog 1d seems...

  1. The Sodium-Glucose Co-Transporter 2 Inhibitor, Empagliflozin, Protects against Diabetic Cardiomyopathy by Inhibition of the Endoplasmic Reticulum Stress Pathway

    Directory of Open Access Journals (Sweden)

    Yang Zhou

    2017-05-01

    Full Text Available Background/Aims: This study aimed to determine whether or not the sodium-glucose co-transporter 2 inhibitor, empagliflozin (EMPA, can protect against diabetic cardiomyopathy (DCM and to elucidate the related mechanism. Methods: Rats were divided into the following four groups: a non-diabetic group; diabetic cardiomyopathy rats without EMPA treatment; and diabetic cardiomyopathy rats with EMPA treatment (low- and high-dose EMPA. Hemodynamic measurements were performed to evaluate left ventricular systolic and diastolic function. The histopathology of the heart was examined with hematoxylin-eosin staining. Expression of glucose-regulated protein (GRP78, enhancer-binding protein homologous protein (CHOP, and caspase-12 was detected by Western blot, and the mRNA levels of XBP1, ATF4, and TRAF2 were analysed by real-time PCR. Results: EMPA significantly decreased the blood glucose level when compared with vehicle. EMPA strongly improved cardiac function based on hemodynamic and histopathologic analyses. Moreover, EMPA can significantly down-regulate the expression of GRP78, CHOP, and caspase-12 (P < 0.01. Additionally, the mRNA levels of XBP1, ATF4, and TRAF2 were markedly decreased by administration of EMPA (P < 0.01. Conclusion: EMPA protects against DCM by inactivating the endoplasmic reticulum stress pathway.

  2. Safe and pragmatic use of sodium–glucose co-transporter 2 inhibitors in type 2 diabetes mellitus: South Asian Federation of Endocrine Societies consensus statement

    Directory of Open Access Journals (Sweden)

    Sanjay Kalra

    2017-01-01

    Full Text Available Diabetes prevalence shows a continuous increasing trend in South Asia. Although well-established treatment modalities exist for type 2 diabetes mellitus (T2DM management, they are limited by their side effect profile. Sodium–glucose co-transporter 2 inhibitors (SGLT2i with their novel insulin-independent renal action provide improved glycemic control, supplemented by reduction in weight and blood pressure, and cardiovascular safety. Based on the clinical outcomes with SGLT2i in patients with T2DM, treatment strategies that make a “good clinical sense” are desirable. Considering the peculiar lifestyle, body types, dietary patterns (long duration religious fasts, and the hot climate of the South Asian population, a unanimous decision was taken to design specific, customized guidelines for T2DM treatment strategies in these regions. The panel met for a discussion three times so as to get a consensus for the guidelines, and only unanimous consensus was included. After careful consideration of the quality and strength of the available evidence, the executive summary of this consensus statement was developed based on the American Association of Clinical Endocrinologists/American College of Endocrinology protocol.

  3. Expression of glutamate transporter, GABRA6, serine proteinase inhibitor 2 and low levels of glutamate and GABA in the brain of knock-out mouse for Canavan disease.

    Science.gov (United States)

    Surendran, Sankar; Rady, Peter L; Michals-Matalon, Kimberlee; Quast, Michael J; Rassin, David K; Campbell, Gerald A; Ezell, Ed L; Wei, Jingna; Tyring, Stephen K; Szucs, Sylvia; Matalon, Reuben

    2003-08-30

    Canavan disease (CD) is an autosomal recessive leukodystrophy characterized by spongy degeneration of the brain. The clinical features of CD are hypotonia, megalencephaly, and mental retardation leading to early death. While aspartoacylase (ASPA) activity increases with age in the wild type mouse brain, there is no ASPA activity in the CD mouse brain. So far ASPA deficiency and elevated NAA have been ascribed with the CD. Other factors affecting the brain that result from ASPA deficiency may lead pathophysiology of CD. The NMR spectra and amino acid analysis showed lower levels of glutamate and gamma-aminobutyric acid in the CD mouse brain compared to the wild type. Microarray gene expression on CD mouse brain showed glutamate transporter-EAAT4 and gamma-aminobutyric acid-A receptor, subunit alpha6 (GABRA6) were lower 9.7- and 119.1-fold, respectively. Serine proteinase inhibitor 2 (Spi2) was 29.9-fold higher in the CD mouse brain compared to the wild type. The decrease of GABRA6 and high expression of Spi2 in CD mouse brain were also confirmed by real-time RT-PCR. This first report showing abnormal expression of EAAT4, GABRA6, Spi2 combined with lower levels of glutamate and GABA are likely to be associated with the pathophysiology of CD.

  4. Evaluation of drug-drug interaction between henagliflozin, a novel sodium-glucose co-transporter 2 inhibitor, and metformin in healthy Chinese males.

    Science.gov (United States)

    Wang, Liupeng; Wu, Chunyong; Shen, Lu; Liu, Haiyan; Chen, Ying; Liu, Fang; Wang, Youqun; Yang, Jin

    2016-08-01

    1. Henagliflozin is a novel sodium-glucose transporter 2 inhibitor and presents a complementary therapy to metformin for patients with T2DM due to its insulin-independent mechanism of action. This study evaluated the potential pharmacokinetic drug-drug interaction between henagliflozin and metformin in healthy Chinese male subjects. 2. In open-label, single-center, single-arm, two-period, three-treatment self-control study, 12 subjects received 25 mg henagliflozin, 1000 mg metformin or the combination. Lack of PK interaction was defined as the ratio of geometric means and 90% confidence interval (CI) for combination: monotherapy being within the range of 0.80-1.25. 3. Co-administration of henagliflozin with metformin had no effect on henagliflozin area under the plasma concentration-time curve (AUC0-24) (GRM: 1.08; CI: 1.05, 1.10) and peak plasma concentration (Cmax) (GRM: 0.99; CI: 0.92, 1.07). Reciprocally, co-administration of metformin with henagliflozin had no clinically significant on metformin AUC0-24 (GRM: 1.09, CI: 1.02, 1.16) although there was an 11% increase in metformin Cmax (GRM 1.12; CI 1.02, 1.23). All monotherapies and combination therapy were well tolerated. 4. Henagliflozin can be co-administered with metformin without dose adjustment of either drug.

  5. Differential sensitivity to NaCl for inhibitors and substrates that recognize mutually exclusive binding sites on the neuronal transporter of dopamine in rat striatal membranes.

    Science.gov (United States)

    Tidjane Corera, A; Do-Régo, J C; Costentin, J; Bonnet, J J

    2001-03-01

    Addition of NaCl (90--290 mM) to a 10 mM Na(+) medium did not significantly modify B(max) and K(d) values for [3H]mazindol binding to the dopamine neuronal transporter (DAT) studied on rat striatal membranes at 20 degrees C. Addition of NaCl differentially affected the ability of other uptake inhibitors and substrates to block the [3H]mazindol binding. Ratios of 50% inhibiting concentrations calculated for 290 and 90 mM NaCl allowed to distinguish three groups of agents: substrates which were more potent in the presence of 290 mM NaCl (group 1; ratio mazindol, benztropine, nomifensine). However, agents from these three groups recognize mutually exclusive binding sites since in interaction studies the presence of WIN 35,428 (group 2) or mazindol (group 3) increased the 50% inhibiting concentrations of D-amphetamine (group 1) and WIN 35,428 on the [3H]mazindol binding to theoretical values expected for a competition of all of these compounds for the same binding domain on the DAT.

  6. Muscle symptoms in statin users, associations with cytochrome P450, and membrane transporter inhibitor use: a subanalysis of the USAGE study.

    Science.gov (United States)

    Ito, Matthew K; Maki, Kevin C; Brinton, Eliot A; Cohen, Jerome D; Jacobson, Terry A

    2014-01-01

    Drug interactions have been identified as a risk factor for muscle-related side effects in statin users. The aim was to assess whether use of medications that inhibit cytochrome P450 (CYP450) isozymes, organic anion transporting polypeptide 1B1 (OATP1B1), or P-glycoprotein (P-gp) are associated with muscle-related symptoms among current and former statin users. Persons (n = 10,138) from the Understanding Statin Use in America and Gaps in Education (USAGE) internet survey were categorized about whether they ever reported new or worsening muscle pain while taking a statin (n = 2935) or ever stopped a statin because of muscle pain (n = 1516). Univariate and multivariate logistic regression models were used to assess associations between use of concomitant therapies that inhibit CYP450 isozymes, OATP1B1, P-gp, or a combination and muscle-related outcomes. In multivariate analyses, concomitant use of a CYP450 inhibitor was associated with increased odds for new or worse muscle pain (odds ratio [OR] = 1.42; P reducing statin drug interactions. Copyright © 2014 National Lipid Association. All rights reserved.

  7. Polarization developments

    International Nuclear Information System (INIS)

    Prescott, C.Y.

    1993-07-01

    Recent developments in laser-driven photoemission sources of polarized electrons have made prospects for highly polarized electron beams in a future linear collider very promising. This talk discusses the experiences with the SLC polarized electron source, the recent progress with research into gallium arsenide and strained gallium arsenide as a photocathode material, and the suitability of these cathode materials for a future linear collider based on the parameters of the several linear collider designs that exist

  8. Lack of Contribution of Multidrug Resistance-associated Protein and Organic Anion-transporting Polypeptide to Pharmacokinetics of Regorafenib, a Novel Multi-Kinase Inhibitor, in Rats.

    Science.gov (United States)

    Hotta, Kazuo; Ueyama, Jun; Tatsumi, Yasuaki; Tsukiyama, Ikuto; Sugiura, Yuka; Saito, Hiroko; Matsuura, Katsuhiko; Hasegawa, Takaaki

    2015-09-01

    We investigated whether hepatic multidrug resistance-associated protein 2 (ABCC2) is involved in the hepatobiliary excretion of regorafenib, a novel multi-kinase inhibitor, using Sprague-Dawley (SD) rats and Eisai hyperbilirubinemic rats (EHBR) lacking the efflux transporter ABCC2. The involvement of organic anion-transporting polypeptide 1 (OATP1; OATP in humans) and OATP2 in the hepatic uptake of regorafenib and their protein levels in the liver were also investigated in the two rat groups. When regorafenib (5 mg/kg) was administered intravenously, the plasma concentrations of regorafenib were higher in EHBR than those in SD rats. However, the slope of the plasma concentration-time curves was the same for the two groups. Although the apparent biliary clearance of regorafenib in EHBR was lower than that of SD rats, no significant difference in the biliary excretion rate was observed between them, suggesting that regorafenib is not a substrate for ABCC2 and is not excreted into bile by ABCC2. It was also found that the contribution of biliary excretion to the systemic elimination of regorafenib is small. The protein-binding profiles of regorafenib were found to be linear in both rat groups. The binding potency, which was very high in both rat groups (>99.5%), was significantly higher in EHBR than that in SD rats. No significant differences in the plasma concentrations of unbound regorafenib were observed between the two rat groups, suggesting that the differences observed in the pharmacokinetic behaviors of regorafenib between the two rat groups were due to differences in protein-binding. When the protein levels of hepatic OATP1 and OATP2 were measured by immunoblot analysis, the expression of both transporters in EHBR was less than 40% of that in SD rats. The present results suggest that regorafenib is not a substrate for OATP1 and OATP2. These findings suggest the possibility that ABCC2-mediated hepatobiliary excretion and OATP1/OATP2-mediated hepatic uptake do

  9. Effects of antidiabetic drugs on the incidence of macrovascular complications and mortality in type 2 diabetes mellitus: a new perspective on sodium-glucose co-transporter 2 inhibitors.

    Science.gov (United States)

    Rahelić, Dario; Javor, Eugen; Lucijanić, Tomo; Skelin, Marko

    2017-02-01

    Elevated hemoglobin A 1c (HbA 1c ) values correlate with microvascular and macrovascular complications. Thus, patients with type 2 diabetes mellitus (T2DM) are at an increased risk of developing macrovascular events. Treatment of T2DM should be based on a multifactorial approach because of its evidence regarding reduction of macrovascular complications and mortality in T2DM. It is well known that intensive glucose control reduces the risk of microvascular complications in T2DM, but the effects of antidiabetic drugs on macrovascular complications and mortality in T2DM are less clear. The results of recent trials have demonstrated clear evidence that empagliflozin and liraglutide reduce cardiovascular (CV) and all-cause mortality in T2DM, an effect that is absent in other members of antidiabetic drugs. Empagliflozin is a member of a novel class of antidiabetic drugs, the sodium-glucose co-transporter 2 (SGLT2) inhibitors. Two ongoing randomized clinical trials involving other SGLT2 inhibitors, canagliflozin and dapagliflozin, will provide additional evidence of the beneficial effects of SGLT2 inhibitors in T2DM population. The aim of this paper is to systematically present the latest evidence regarding the usage of antidiabetic drugs, and the reduction of macrovascular complications and mortality. A special emphasis is put on the novel class of antidiabetic drugs, of SGLT2 inhibitors. Key messages Macrovascular complications and mortality are best clinical trial endpoints for evaluating the efficacy of antidiabetic drugs. The first antidiabetic drug that demonstrated a reduction in mortality in the treatment of type 2 diabetes mellitus (T2DM) was empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor. SGLT2 inhibitors are novel class of antidiabetic drugs that play a promising role in the treatment of T2DM.

  10. Polarization, political

    NARCIS (Netherlands)

    Wojcieszak, M.; Mazzoleni, G.; Barnhurst, K.G.; Ikeda, K.; Maia, R.C.M.; Wessler, H.

    2015-01-01

    Polarization has been studied in three different forms: on a social, group, and individual level. This entry first focuses on the undisputed phenomenon of elite polarization (i.e., increasing adherence of policy positions among the elites) and also outlines different approaches to assessing mass

  11. In vitro assay shows that PCB metabolites completely saturate thyroid hormone transport capacity in blood of wild polar bears (Ursus maritimus)

    NARCIS (Netherlands)

    Gutleb, A.C.; Cenijn, P.H.; van Velzen, P.; Lie, E.; Ropstad, E.; Skaare, J.U.; Malmberg, T.; Bergman, A.; Gabrielsen, G. W.; Legler, J.

    2010-01-01

    Persistent chemicals accumulate in the arctic environment due to their chemical reactivity and physicochemical properties and polychlorinated biphenyls (PCBs) are the most concentrated pollutant class in polar bears (Ursus maritimus). Metabolism of PCB and polybrominated biphenyl ether (PBDE)

  12. Polarization holography

    DEFF Research Database (Denmark)

    Nikolova, L.; Ramanujam, P.S.

    Current research into holography is concerned with applications in optically storing, retrieving, and processing information. Polarization holography has many unique properties compared to conventional holography. It gives results in high efficiency, achromaticity, and special polarization...... properties. This books reviews the research carried out in this field over the last 15 years. The authors provide basic concepts in polarization and the propagation of light through anisotropic materials, before presenting a sound theoretical basis for polarization holography. The fabrication...... and characterization of azobenzene based materials, which remain the most efficient for the purpose, is described in detail. This is followed by a description of other materials that are used in polarization holography. An in-depth description of various applications, including display holography and optical storage...

  13. Sodium glucose co-transporter 2 inhibitors for glycemic control in type 2 diabetes mellitus: Quality of reporting of randomized controlled trials

    Directory of Open Access Journals (Sweden)

    Niti Mittal

    2016-01-01

    Full Text Available Background: Sodium glucose co-transporter 2 inhibitors represent a novel class of antidiabetic drugs. The reporting quality of the trials evaluating the efficacy of these agents for glycemic control in type 2 diabetes mellitus has not been explored. Our aim was to assess the reporting quality of such randomized controlled trials (RCTs and to identify the predictors of reporting quality. Materials and Methods: A systematic literature search was conducted for RCTs published till 12 June 2014. Two independent investigators carried out the searches and assessed the reporting quality on three parameters: Overall quality score (OQS using Consolidated Standards of Reporting Trials (CONSORT 2010 statement, Jadad score and intention to treat analysis. Inter-rater agreements were compared using Cohen's weighted kappa statistic. Multivariable linear regression analysis was used to identify the predictors. Results: Thirty-seven relevant RCTs were included in the present analysis. The median OQS was 17 with a range from 8 to 21. On Jadad scale, the median score was three with a range from 0 to 5. Complete details about allocation concealment and blinding were present in 21 and 10 studies respectively. Most studies lacked an elaborate discussion on trial limitations and generalizability. Among the factors identified as significantly associated with reporting quality were the publishing journal and region of conduct of RCT. Conclusions: The key methodological items remain poorly reported in most studies. Strategies like stricter adherence to CONSORT guidelines by journals, access to full trial protocols to gain valuable information and full collaboration among investigators and methodologists might prove helpful in improving the quality of published RCT reports.

  14. Effects of rifampin, cyclosporine A, and probenecid on the pharmacokinetic profile of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in healthy participants.

    Science.gov (United States)

    Devineni, Damayanthi; Vaccaro, Nicole; Murphy, Joe; Curtin, Christopher; Mamidi, Rao N V S; Weiner, Sveta; Wang, Shean-Sheng; Ariyawansa, Jay; Stieltjes, Hans; Wajs, Ewa; Di Prospero, Nicholas A; Rothenberg, Paul

    2015-02-01

    Canagliflozin, a sodium-glucose co-transporter 2 inhibitor, approved for the treatment of type-2 diabetes mellitus (T2DM), is metabolized by uridine diphosphate-glucuronosyltransferases (UGT) 1A9 and UGT2B4, and is a substrate of P-glycoprotein (P-gp). Canagliflozin exposures may be affected by coadministration of drugs that induce (e.g., rifampin for UGT) or inhibit (e.g. probenecid for UGT; cyclosporine A for P-gp) these pathways. The primary objective of these three independent studies (single-center, open-label, fixed-sequence) was to evaluate the effects of rifampin (study 1), probenecid (study 2), and cyclosporine A (study 3) on the pharmacokinetics of canagliflozin in healthy participants. Participants received; in study 1: canagliflozin 300 mg (days 1 and 10), rifampin 600 mg (days 4-12); study 2: canagliflozin 300 mg (days 1-17), probenecid 500 mg twice daily (days 15-17); and study 3: canagliflozin 300 mg (days 1-8), cyclosporine A 400 mg (day 8). Pharmacokinetics were assessed at prespecified intervals on days 1 and 10 (study 1); on days 14 and 17 (study 2), and on days 2-8 (study 3). Rifampin decreased the maximum plasma canagliflozin concentration (Cmax) by 28% and its area under the curve (AUC) by 51%. Probenecid increased the Cmax by 13% and the AUC by 21%. Cyclosporine A increased the AUC by 23% but did not affect the Cmax. Coadministration of canagliflozin with rifampin, probenecid, and cyclosporine A was well-tolerated. No clinically meaningful interactions were observed for probenecid or cyclosporine A, while rifampin coadministration modestly reduced canagliflozin plasma concentrations and could necessitate an appropriate monitoring of glycemic control.

  15. Quinine dimers are potent inhibitors of the Plasmodium falciparum chloroquine resistance transporter and are active against quinoline-resistant P. falciparum.

    Science.gov (United States)

    Hrycyna, Christine A; Summers, Robert L; Lehane, Adele M; Pires, Marcos M; Namanja, Hilda; Bohn, Kelsey; Kuriakose, Jerrin; Ferdig, Michael; Henrich, Philipp P; Fidock, David A; Kirk, Kiaran; Chmielewski, Jean; Martin, Rowena E

    2014-03-21

    Chloroquine (CQ) resistance in the human malaria parasite Plasmodium falciparum is primarily conferred by mutations in the "chloroquine resistance transporter" (PfCRT). The resistance-conferring form of PfCRT (PfCRT(CQR)) mediates CQ resistance by effluxing the drug from the parasite's digestive vacuole, the acidic compartment in which CQ exerts its antiplasmodial effect. PfCRT(CQR) can also decrease the parasite's susceptibility to other quinoline drugs, including the current antimalarials quinine and amodiaquine. Here we describe interactions between PfCRT(CQR) and a series of dimeric quinine molecules using a Xenopus laevis oocyte system for the heterologous expression of PfCRT and using an assay that detects the drug-associated efflux of H(+) ions from the digestive vacuole in parasites that harbor different forms of PfCRT. The antiplasmodial activities of dimers 1 and 6 were also examined in vitro (against drug-sensitive and drug-resistant strains of P. falciparum) and in vivo (against drug-sensitive P. berghei). Our data reveal that the quinine dimers are the most potent inhibitors of PfCRT(CQR) reported to date. Furthermore, the lead compounds (1 and 6) were not effluxed by PfCRT(CQR) from the digestive vacuole but instead accumulated to very high levels within this organelle. Both 1 and 6 exhibited in vitro antiplasmodial activities that were inversely correlated with CQ. Moreover, the additional parasiticidal effect exerted by 1 and 6 in the drug-resistant parasites was attributable, at least in part, to their ability to inhibit PfCRT(CQR). This highlights the potential for devising new antimalarial therapies that exploit inherent weaknesses in a key resistance mechanism of P. falciparum.

  16. Peptide Inhibitor of Complement C1 (PIC1) demonstrates antioxidant activity via single electron transport (SET) and hydrogen atom transfer (HAT).

    Science.gov (United States)

    Gregory Rivera, Magdielis; Hair, Pamela S; Cunnion, Kenji M; Krishna, Neel K

    2018-01-01

    Reactive oxygen species (ROS) are natural byproducts of oxidative respiration that are toxic to organs and tissues. To mitigate ROS damage, organisms have evolved a variety of antioxidant systems to counteract these harmful molecules, however in certain pathological conditions these protective mechanisms can be overwhelmed. We have recently demonstrated that Peptide Inhibitor of Complement C1 (PIC1) mitigates peroxidase activity of the heme bearing proteins myeloperoxidase, hemoglobin, and myoglobin through a reversible process. To determine if this property of PIC1 was antioxidant in nature, we tested PIC1 in a number of well-established antioxidant assays. PIC1 showed dose-dependent antioxidant activity in a total antioxidant (TAC) assay, hydroxyl radical antioxidant capacity (HORAC) assay, oxygen radical antioxidant capacity (ORAC) assay as well as the thiobarbituric acid reactive substances (TBARS) assay to screen for PIC1 antioxidant activity in human plasma. The antioxidant activity of PIC1 in the TAC assay, as well as the HORAC/ORAC assay demonstrated that this peptide acts via the single electron transport (SET) and hydrogen atom transfer (HAT) mechanisms, respectively. Consistent with this mechanism of action, PIC1 did not show activity in a metal chelating activity (MCA) assay. PIC1 contains two vicinal cysteine residues and displayed similar antioxidant activity to the well characterized cysteine-containing tripeptide antioxidant molecule glutathione (GSH). Consistent with the role of the cysteine residues in the antioxidant activity of PIC1, oxidation of these residues significantly abrogated antioxidant activity. These results demonstrate that in addition to its described complement inhibiting activity, PIC1 displays in vitro antioxidant activity.

  17. Prenatal serotonin reuptake inhibitor (SRI antidepressant exposure and serotonin transporter promoter genotype (SLC6A4 influence executive functions at 6 years of age

    Directory of Open Access Journals (Sweden)

    Whitney eWeikum

    2013-10-01

    Full Text Available Prenatal exposure to serotonin reuptake inhibitor (SRI antidepressants and maternal depression may affect prefrontal cognitive skills (executive functions; EFs including self-control, working memory and cognitive flexibility. We examined long-term effects of prenatal SRI exposure on EFs to determine whether effects are moderated by maternal mood and/or genetic variations in SLC6A4 (a gene that codes for the serotonin transporter [5-HTT] central to the regulation of synaptic serotonin levels and behavior. Children who were exposed to SRIs prenatally (SRI-exposed N=26 and non-exposed (N=38 were studied at age 6 years (M=6.3 SD=0.5 using the Hearts & Flowers task (H&F to assess EFs. Maternal mood was measured during pregnancy (3rd trimester and when the child was age 6 years (Hamilton Depression Scale. Parent reports of child behavior were also obtained (MacArthur Health & Behavior Questionnaire. Parents of prenatally SRI-exposed children reported fewer child externalizing and inattentive (ADHD behaviors. Generalized estimate equation modeling showed a significant 3-way interaction between prenatal SRI exposure, SLC6A4 variant, and maternal mood at the 6-year time-point on H&F accuracy. For prenatally SRI-exposed children, regardless of maternal mood, the H&F accuracy of children with reduced 5HTT expression (a short [S] allele remained stable. Even with increasing maternal depressive symptoms (though all below clinical threshold, EFs of children with at least one short allele were comparable to children with the same genotype whose mothers reported few if any depressive symptoms – in this sense they showed resilience. Children with two long (L alleles were more sensitive to context. When their mothers had few depressive symptoms, LL children showed extremely good EF performance – better than any other group. When their mothers reported more depressive symptoms, LL children’s EF performance was worse than that of any other group.

  18. Polar Bears

    Science.gov (United States)

    Amstrup, Steven C.; Douglas, David C.; Reynolds, Patricia E.; Rhode, E.B.

    2002-01-01

    Polar bears (Ursus maritimus) are hunted throughout most of their range. In addition to hunting polar bears of the Beaufort Sea region are exposed to mineral and petroleum extraction and related human activities such as shipping road-building, and seismic testing (Stirling 1990).Little was known at the start of this project about how polar bears move about in their environment, and although it was understood that many bears travel across political borders, the boundaries of populations had not been delineated (Amstrup 1986, Amstrup et al. 1986, Amstrup and DeMaster 1988, Garner et al. 1994, Amstrup 1995, Amstrup et al. 1995, Amstrup 2000).As human populations increase and demands for polar bears and other arctic resources escalate, managers must know the sizes and distributions of the polar bear populations. Resource managers also need reliable estimates of breeding rates, reproductive intervals, litter sizes, and survival of young and adults.Our objectives for this research were 1) to determine the seasonal and annual movements of polar bears in the Beaufort Sea, 2) to define the boundaries of the population(s) using this region, 3) to determine the size and status of the Beaufort Sea polar bear population, and 4) to establish reproduction and survival rates (Amstrup 2000).

  19. A lunar polar expedition

    Science.gov (United States)

    Dowling, Richard; Staehle, Robert L.; Svitek, Tomas

    1992-09-01

    Advanced exploration and development in harsh environments require mastery of basic human survival skill. Expeditions into the lethal climates of Earth's polar regions offer useful lessons for tommorrow's lunar pioneers. In Arctic and Antarctic exploration, 'wintering over' was a crucial milestone. The ability to establish a supply base and survive months of polar cold and darkness made extensive travel and exploration possible. Because of the possibility of near-constant solar illumination, the lunar polar regions, unlike Earth's may offer the most hospitable site for habitation. The World Space Foundation is examining a scenario for establishing a five-person expeditionary team on the lunar north pole for one year. This paper is a status report on a point design addressing site selection, transportation, power, and life support requirements.

  20. Recognition of benztropine by the dopamine transporter (DAT) differs from that of the classical dopamine uptake inhibitors cocaine, methylphenidate, and mazindol as a function of a DAT transmembrane 1 aspartic acid residue.

    Science.gov (United States)

    Ukairo, Okechukwu T; Bondi, Corry D; Newman, Amy Hauck; Kulkarni, Santosh S; Kozikowski, Alan P; Pan, Stephen; Surratt, Christopher K

    2005-08-01

    Binding of cocaine to the dopamine transporter (DAT) protein blocks synaptic dopamine clearance, triggering the psychoactive effects associated with the drug; the discrete drug-protein interactions, however, remain poorly understood. A longstanding postulate holds that cocaine inhibits DAT-mediated dopamine transport via competition with dopamine for formation of an ionic bond with the DAT transmembrane aspartic acid residue D79. In the present study, DAT mutations of this residue were generated and assayed for translocation of radiolabeled dopamine and binding of radiolabeled DAT inhibitors under identical conditions. When feasible, dopamine uptake inhibition potency and apparent binding affinity K(i) values were determined for structurally diverse DAT inhibitors. The glutamic acid substitution mutant (D79E) displayed values indistinguishable from wild-type DAT in both assays for the charge-neutral cocaine analog 8-oxa-norcocaine, a finding not supportive of the D79 "salt bridge" ligand-docking model. In addressing whether the D79 side chain contributes to the DAT binding sites of other portions of the cocaine pharmacophore, only inhibitors with modifications of the tropane ring C-3 substituent, i.e., benztropine and its analogs, displayed a substantially altered dopamine uptake inhibition potency as a function of the D79E mutation. A single conservative amino acid substitution thus differentiated structural requirements for benztropine function relative to those for all other classical DAT inhibitors. Distinguishing the precise mechanism of action of this DAT inhibitor with relatively low abuse liability from that of cocaine may be attainable using DAT mutagenesis and other structure-function studies, opening the door to rational design of therapeutic agents for cocaine abuse.

  1. PH-DEPENDENT PROTON PERMEABILITY OF THE PLASMA-MEMBRANE IN A REGULATING MECHANISM OF POLAR TRANSPORT THROUGH THE SUBMERGED LEAVES OF POTAMOGETON-LUCENS

    NARCIS (Netherlands)

    MIEDEMA, H; PRINS, HBA

    Recently it has been hypothesized that light-induced polarity in leaves of the submerged angiosperms Potamogeton and Elodea results in part from a pH-dependent change in the permeability of the plasma membrane for protons. It is assumed that the proton permeability increases at high pH. In this

  2. Update of the Polar SWIFT model for polar stratospheric ozone loss (Polar SWIFT version 2)

    Science.gov (United States)

    Wohltmann, Ingo; Lehmann, Ralph; Rex, Markus

    2017-07-01

    The Polar SWIFT model is a fast scheme for calculating the chemistry of stratospheric ozone depletion in polar winter. It is intended for use in global climate models (GCMs) and Earth system models (ESMs) to enable the simulation of mutual interactions between the ozone layer and climate. To date, climate models often use prescribed ozone fields, since a full stratospheric chemistry scheme is computationally very expensive. Polar SWIFT is based on a set of coupled differential equations, which simulate the polar vortex-averaged mixing ratios of the key species involved in polar ozone depletion on a given vertical level. These species are O3, chemically active chlorine (ClOx), HCl, ClONO2 and HNO3. The only external input parameters that drive the model are the fraction of the polar vortex in sunlight and the fraction of the polar vortex below the temperatures necessary for the formation of polar stratospheric clouds. Here, we present an update of the Polar SWIFT model introducing several improvements over the original model formulation. In particular, the model is now trained on vortex-averaged reaction rates of the ATLAS Chemistry and Transport Model, which enables a detailed look at individual processes and an independent validation of the different parameterizations contained in the differential equations. The training of the original Polar SWIFT model was based on fitting complete model runs to satellite observations and did not allow for this. A revised formulation of the system of differential equations is developed, which closely fits vortex-averaged reaction rates from ATLAS that represent the main chemical processes influencing ozone. In addition, a parameterization for the HNO3 change by denitrification is included. The rates of change of the concentrations of the chemical species of the Polar SWIFT model are purely chemical rates of change in the new version, whereas in the original Polar SWIFT model, they included a transport effect caused by the

  3. The Influence of Active Transport Systems on Morphine -6-Glucuronide Transport in MDCKII and MDCK-PGP Cells

    Directory of Open Access Journals (Sweden)

    SO. Mashayekhi

    2011-12-01

    Full Text Available Background and the purpose of the study: Morphine-6-glucuronide (M6G is a potent metabolite of morphine which has high penetration into the brain despite its high polarity, which could be the result of an active transport system involved in M6G transport through blood brain barrier. Examples of such transporters are p-glycoprotein (PGP, probenecid-sensitive transport mechanism, multidrug resistance related protein 1-3, the organic anion transporter family, and the organic anion transporter polypeptide family. The aim of present study was to elucidate the mechanisms involved in transporting morphine's potent metabolite, M6G.Methods: M6G permeability via two cell lines; MDCKII and MDCK-PGP, was compared with that of sucrose. M6G transport was examined in different concentrations and in the presence of inhibitors of different transport systems such as cyclosporine, digoxin and probenecid. M6G concentration was measured using ELISA assay. The method was sensitive, reliable and reproducible.Results: The results confirmed that M6G could cross a layer of MDCK II or MDR-PGP cells more than sucrose could. It was also observed that M6G is a PGP transporter substrate. Its permeability was increased by the use of a PGP expressed cell line, and also in the presence of a strong PGP inhibitor. Digoxin related transporters such as Oatp2 may also involved in transport of M6G. M6G seemed to be a glucose transporter 1 substrate, but was not a substrate to probenecid sensitive transporters.Major conclusion: It is concluded that different transporters are responsible for M6G transports via different membrane, which could have effects on its pharmacokinetics or pharmacodynamics.

  4. Political polarization

    OpenAIRE

    Dixit, Avinash K.; Weibull, Jörgen W.

    2007-01-01

    Failures of government policies often provoke opposite reactions from citizens; some call for a reversal of the policy, whereas others favor its continuation in stronger form. We offer an explanation of such polarization, based on a natural bimodality of preferences in political and economic contexts and consistent with Bayesian rationality.

  5. Political polarization.

    Science.gov (United States)

    Dixit, Avinash K; Weibull, Jörgen W

    2007-05-01

    Failures of government policies often provoke opposite reactions from citizens; some call for a reversal of the policy, whereas others favor its continuation in stronger form. We offer an explanation of such polarization, based on a natural bimodality of preferences in political and economic contexts and consistent with Bayesian rationality.

  6. Titan Polar Landscape Evolution

    Science.gov (United States)

    Moore, Jeffrey M.

    2016-01-01

    With the ongoing Cassini-era observations and studies of Titan it is clear that the intensity and distribution of surface processes (particularly fluvial erosion by methane and Aeolian transport) has changed through time. Currently however, alternate hypotheses substantially differ among specific scenarios with respect to the effects of atmospheric evolution, seasonal changes, and endogenic processes. We have studied the evolution of Titan's polar region through a combination of analysis of imaging, elevation data, and geomorphic mapping, spatially explicit simulations of landform evolution, and quantitative comparison of the simulated landscapes with corresponding Titan morphology. We have quantitatively evaluated alternate scenarios for the landform evolution of Titan's polar terrain. The investigations have been guided by recent geomorphic mapping and topographic characterization of the polar regions that are used to frame hypotheses of process interactions, which have been evaluated using simulation modeling. Topographic information about Titan's polar region is be based on SAR-Topography and altimetry archived on PDS, SAR-based stereo radar-grammetry, radar-sounding lake depth measurements, and superposition relationships between geomorphologic map units, which we will use to create a generalized topographic map.

  7. New insights into the structure-activity-relationship of selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitors UCPH-101 and UCPH-102

    DEFF Research Database (Denmark)

    Hansen, Stinne Wessel; Erichsen, Mette Norman; Huynh, T.H.V.

    2016-01-01

    In the present study, we made further investigations on the structure-activity requirements of the selective excitatory amino acid transporter 1 (EAAT1) inhibitor, 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101), by exploring 15 diffe...... as EAAT1 inhibitors. A study of the stereochemical stability of the four pure stereoisomers 14 g-A-D showed that epimerization takes places at C7 via a ring-opening, C-C bond rotation, ring-closing mechanism....

  8. Basipetal auxin transport is required for gravitropism in roots of Arabidopsis

    Science.gov (United States)

    Rashotte, A. M.; Brady, S. R.; Reed, R. C.; Ante, S. J.; Muday, G. K.; Davies, E. (Principal Investigator)

    2000-01-01

    Auxin transport has been reported to occur in two distinct polarities, acropetally and basipetally, in two different root tissues. The goals of this study were to determine whether both polarities of indole-3-acetic acid (IAA) transport occur in roots of Arabidopsis and to determine which polarity controls the gravity response. Global application of the auxin transport inhibitor naphthylphthalamic acid (NPA) to roots blocked the gravity response, root waving, and root elongation. Immediately after the application of NPA, the root gravity response was completely blocked, as measured by an automated video digitizer. Basipetal [(3)H]IAA transport in Arabidopsis roots was inhibited by NPA, whereas the movement of [(14)C]benzoic acid was not affected. Inhibition of basipetal IAA transport by local application of NPA blocked the gravity response. Inhibition of acropetal IAA transport by application of NPA at the root-shoot junction only partially reduced the gravity response at high NPA concentrations. Excised root tips, which do not receive auxin from the shoot, exhibited a normal response to gravity. The Arabidopsis mutant eir1, which has agravitropic roots, exhibited reduced basipetal IAA transport but wild-type levels of acropetal IAA transport. These results support the hypothesis that basipetally transported IAA controls root gravitropism in Arabidopsis.

  9. Investigating the enteroenteric recirculation of apixaban, a factor Xa inhibitor: administration of activated charcoal to bile duct-cannulated rats and dogs receiving an intravenous dose and use of drug transporter knockout rats.

    Science.gov (United States)

    Zhang, Donglu; Frost, Charles E; He, Kan; Rodrigues, A David; Wang, Xiaoli; Wang, Lifei; Goosen, Theunis C; Humphreys, W Griffith

    2013-04-01

    The study described here investigated the impact of intestinal excretion (IE; excretion of drug directly from circulation to intestinal lumen), enteroenteric recirculation (EER), and renal tubule recirculation (RTR) on apixaban pharmacokinetics and disposition. The experimental approaches involve integrating apixaban elimination pathways with pharmacokinetic profiles obtained from bile duct-cannulated (BDC) rats and dogs receiving i.v. doses together with oral administration of activated charcoal (AC). Additionally, the role of P-gp (P-glycoprotein; abcb1) and BCRP (breast cancer resistance protein; abcg2) in apixaban disposition was evaluated in experiments using transporter inhibitors and transporter knockout (KO) rats. Approximately 20-50% of an apixaban i.v. dose was found in feces of BDC rats and dogs, suggesting IE leading to fecal elimination and intestinal clearance (IC). The fecal elimination, IC, and systemic clearance of apixaban were increased upon AC administration in both BDC rats and dogs and were decreased in BDC rats dosed with GF-120918, a dual BCRP and P-gp inhibitor). BCRP appeared to play a more important role for absorption and intestinal and renal elimination of apixaban than P-gp in transporter-KO rats after oral and i.v. dosing, which led to a higher level of active renal excretion in rat than other species. These data demonstrate that apixaban undergoes IE, EER, and RTR that are facilitated by efflux transporters. Intestinal reabsorption of apixaban could be interrupted by AC even at 3 hours post-drug dose in dogs (late charcoal effect). This study demonstrates that the intestine is an organ for direct clearance and redistribution of apixaban. The IE, EER, and RTR contribute to overall pharmacokinetic profiles of apixaban. IE as a clearance pathway, balanced with metabolism and renal excretion, helps decrease the impacts of intrinsic (renal or hepatic impairment) and extrinsic (drug-drug interactions) factors on apixaban disposition.

  10. Sodium glucose co-transporter inhibitors for the management of diabetes mellitus: an opinion paper from the Endocrine and Metabolism Practice and Research Network of the American College of Clinical Pharmacy.

    Science.gov (United States)

    Clements, Jennifer N; Whitley, Heather P; D'Souza, Jennifer J; Gross, Benjamin; Hess, Rick; Reece, Sara; Gentry, Chad; Shealy, Kayce

    2015-01-01

    Type 2 diabetes mellitus (T2DM) carries a high prevalence in the United States and worldwide. Therefore, the number of medication classes being developed and studied has grown. The individualized management of diabetes is accomplished by evaluating a medication's efficacy, safety, and cost, along with the patient's preference and tolerance to the medication. Sodium glucose co-transporter 2 inhibitors are a new therapeutic class indicated for the treatment of diabetes and have a unique mechanism of action, independent of beta-cell function. The first agent approved by the Food and Drug Administration (FDA) was canagliflozin in March 2013. Two agents - dapagliflozin and empagliflozin - were FDA-approved in January and July 2014, respectively. A clear understanding of the new class is needed to identify its appropriate use in clinical practice. Members of the American College of Clinical Pharmacy Endocrine and Metabolism Practice and Research Network reviewed available literature regarding this therapeutic class. The article addresses the advantages, disadvantages, emerging role, and patient education for sodium glucose co-transporter 2 inhibitors. Key limitations for this article include limited access to clinical trial data not published by the pharmaceutical company and limited data on products produced outside the United States.

  11. Episodes of Cross-Polar Transport in the Arctic Troposphere During July 2008 as Seen from Models, Satellite, and Aircraft Observations

    Science.gov (United States)

    Sodemann, H.; Pommier, M.; Arnold, S. R.; Monks, S. A.; Stebel, K.; Burkhart, J. F.; Hair, J. W.; Diskin, G. S.; Clerbaux, C.; Coheur, P.-F.; hide

    2011-01-01

    During the POLARCAT summer campaign in 2008, two episodes (2 5 July and 7 10 July 2008) occurred where low-pressure systems traveled from Siberia across the Arctic Ocean towards the North Pole. The two cyclones had extensive smoke plumes from Siberian forest fires and anthropogenic sources in East Asia embedded in their associated air masses, creating an excellent opportunity to use satellite and aircraft observations to validate the performance of atmospheric transport models in the Arctic, which is a challenging model domain due to numerical and other complications. Here we compare transport simulations of carbon monoxide (CO) from the Lagrangian transport model FLEXPART and the Eulerian chemical transport model TOMCAT with retrievals of total column CO from the IASI passive infrared sensor onboard the MetOp-A satellite. The main aspect of the comparison is how realistic horizontal and vertical structures are represented in the model simulations. Analysis of CALIPSO lidar curtains and in situ aircraft measurements provide further independent reference points to assess how reliable the model simulations are and what the main limitations are. The horizontal structure of mid-latitude pollution plumes agrees well between the IASI total column CO and the model simulations. However, finer-scale structures are too quickly diffused in the Eulerian model. Applying the IASI averaging kernels to the model data is essential for a meaningful comparison. Using aircraft data as a reference suggests that the satellite data are biased high, while TOMCAT is biased low. FLEXPART fits the aircraft data rather well, but due to added background concentrations the simulation is not independent from observations. The multi-data, multi-model approach allows separating the influences of meteorological fields, model realisation, and grid type on the plume structure. In addition to the very good agreement between simulated and observed total column CO fields, the results also highlight the

  12. Strategic Polarization.

    Science.gov (United States)

    Kalai, Adam; Kalai, Ehud

    2001-08-01

    In joint decision making, similarly minded people may take opposite positions. Consider the example of a marriage in which one spouse gives generously to charity while the other donates nothing. Such "polarization" may misrepresent what is, in actuality, a small discrepancy in preferences. It may be that the donating spouse would like to see 10% of their combined income go to charity each year, while the apparently frugal spouse would like to see 8% donated. A simple game-theoretic analysis suggests that the spouses will end up donating 10% and 0%, respectively. By generalizing this argument to a larger class of games, we provide strategic justification for polarization in many situations such as debates, shared living accommodations, and disciplining children. In some of these examples, an arbitrarily small disagreement in preferences leads to an arbitrarily large loss in utility for all participants. Such small disagreements may also destabilize what, from game-theoretic point of view, is a very stable equilibrium. Copyright 2001 Academic Press.

  13. Evaluation of the endothelin receptor antagonists ambrisentan, bosentan, macitentan, and sitaxsentan as hepatobiliary transporter inhibitors and substrates in sandwich-cultured human hepatocytes.

    Directory of Open Access Journals (Sweden)

    Eve-Irene Lepist

    Full Text Available Inhibition of the transporter-mediated hepatobiliary elimination of bile salts is a putative mechanism for liver toxicity observed with some endothelin receptor antagonists (ERAs.Sandwich-cultured human hepatocytes were used to study the hepatobiliary distribution and accumulation of exogenous taurocholate, ERAs and endogenous bile acids. The molecular mechanisms for findings in hepatocytes or clinical observations were further explored using either vesicular assays (efflux transporters or transfected cell-lines (uptake transporters. Inhibition constants (IC50 were measured for the human hepatobiliary transporters bile salt export pump (BSEP, sodium taurocholate cotransporting polypeptide (NTCP, multidrug resistance protein 2 (MRP2, P-glycoprotein (Pgp, breast cancer resistance protein (BCRP, organic anion-transporting polypeptide 1B1 (OATP1B1 and OATP1B3.The ERAs showed dose-dependent reductions in exogenous taurocholate cellular accumulation in human hepatocytes, with macitentan having the greatest effect. Consistent with their effects on bile acids, the ERAs inhibited bile transporters. IC50 values for OATP1B1 and OATP1B3 ranged from 2 µM for macitentan to 47 µM for ambrisentan. Macitentan and bosentan also inhibited NTCP with IC50 values of 10 and 36 µM, respectively. Similar to previously reported findings with sitaxsentan, BSEP inhibition was observed for bosentan and macitentan with IC50 values of 42 and 12 µM, respectively. In contrast, ambrisentan showed little or no inhibition of these transporters. Other transporters tested were weakly inhibited by the ERAs. Accumulation in hepatocytes was also a factor in the effects on bile transport. Macitentan demonstrated the greatest accumulation in human hepatocytes (∼100x followed by sitaxsentan (∼40x, bosentan (∼20x and ambrisentan (∼2x.Significant differences in the inhibition of hepatic transporters were observed between the evaluated ERAs in vitro. Macitentan had the highest

  14. Modeling of hole transport in poly[2-methoxy-5-(2´-ethylhexyloxy)-p-phenylene vinylene] doped with polar additives

    Czech Academy of Sciences Publication Activity Database

    Toman, Petr; Nešpůrek, Stanislav

    2008-01-01

    Roč. 496, - (2008), s. 25-38 ISSN 1542-1406. [International Conference on Electronic Processes in Organic Materials /7./. Lviv, 26.05.2008-30.05.2008] R&D Projects: GA ČR GA203/06/0285; GA AV ČR IAA401770601; GA AV ČR 1ET400500402 Institutional research plan: CEZ:AV0Z40500505 Keywords : charge transport * conjugated polymers * marcus theory Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 0.537, year: 2008

  15. Mn concentration and quantum size effects on spin-polarized transport through CdMnTe based magnetic resonant tunneling diode.

    Science.gov (United States)

    Mnasri, S; Abdi-Ben Nasrallahl, S; Sfina, N; Lazzari, J L; Saïd, M

    2012-11-01

    Theoretical studies on spin-dependent transport in magnetic tunneling diodes with giant Zeeman splitting of the valence band are carried out. The studied structure consists of two nonmagnetic layers CdMgTe separated by a diluted magnetic semiconductor barrier CdMnTe, the hole is surrounded by two p-doped CdTe layers. Based on the parabolic valence band effective mass approximation and the transfer matrix method, the magnetization and the current densities for holes with spin-up and spin-down are studied in terms of the Mn concentration, the well and barrier thicknesses as well as the voltage. It is found that, the current densities depend strongly on these parameters and by choosing suitable values; this structure can be a good spin filter. Such behaviors are originated from the enhancement and suppression in the spin-dependent resonant states.

  16. Sodium-glucose co-transporter-2 inhibitor use and dietary carbohydrate intake in Japanese individuals with type 2 diabetes: A randomized, open-label, 3-arm parallel comparative, exploratory study.

    Science.gov (United States)

    Yabe, Daisuke; Iwasaki, Masahiro; Kuwata, Hitoshi; Haraguchi, Takuya; Hamamoto, Yoshiyuki; Kurose, Takeshi; Sumita, Kiminobu; Yamazato, Hitoshi; Kanada, Shigeto; Seino, Yutaka

    2017-05-01

    This study investigated the safety and efficacy of the sodium-glucose co-transporter-2 (SGLT2) inhibitor luseogliflozin with differing carbohydrate intakes in Japanese individuals with type 2 diabetes (T2D). Participants were randomly assigned to 3 carbohydrate-adjusted meals for 14 days (days 1-14; a high carbohydrate [HC; 55% total energy carbohydrate] and high glycaemic index [HGI] meal; an HC [55% total energy carbohydrate] and low glycaemic index [LGI] meal; or a low carbohydrate [LC; 40% total energy carbohydrate] and HGI meal). All participants received luseogliflozin for the last 7 days (days 8-14), continuous glucose monitoring (CGM) before and after luseogliflozin treatment (days 5-8 and days 12-15) and blood tests on days 1, 8 and 15. Luseogliflozin significantly decreased the area under the curve and mean of CGM values in all 3 groups similarly. Fasting plasma glucose, insulin and glucagon were similar at all time points. Ketone bodies on day 15 were significantly higher in the LC-HGI group compared with the HC-HGI and HC-LGI groups. In conclusion, luseogliflozin has similar efficacy and safety in Japanese people with T2D when meals contain 40% to 55% total energy carbohydrate, but a strict LC diet on this class of drug should be avoided to prevent SGLT2 inhibitor-associated diabetic ketoacidosis. © 2016 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

  17. Precessing deuteron polarization

    International Nuclear Information System (INIS)

    Sitnik, I.M.; Volkov, V.I.; Kirillov, D.A.; Piskunov, N.M.; Plis, Yu.A.

    2002-01-01

    The feasibility of the acceleration in the Nuclotron of deuterons polarized in the horizontal plane is considered. This horizontal polarization is named precessing polarization. The effects of the main magnetic field and synchrotron oscillations are included. The precessing polarization is supposed to be used in studying the polarization parameters of the elastic dp back-scattering and other experiments

  18. Affects of organic amine inhibitors on elastomers

    International Nuclear Information System (INIS)

    Ray, T.W.; Ivey, C.E.

    1984-01-01

    The inhibitive properties of long chain, high molecular weight polar materials have permitted long term operation of oil and gas wells which otherwise might not have been economical to keep in production. It is a well known fact that as these inhibitors are introduced into the well, they can attack fluoroelastomer seals which are otherwise very chemical resistant. This paper presents data concerning the attack of these inhibitors on certain elastomers

  19. Physiologically based pharmacokinetic-pharmacodynamic modeling to predict concentrations and actions of sodium-dependent glucose transporter 2 inhibitor canagliflozin in human intestines and renal tubules.

    Science.gov (United States)

    Mori, Kazumi; Saito, Ryuta; Nakamaru, Yoshinobu; Shimizu, Makiko; Yamazaki, Hiroshi

    2016-11-01

    Canagliflozin is a recently developed sodium-glucose cotransporter (SGLT) 2 inhibitor that promotes renal glucose excretion and is considered to inhibit renal SGLT2 from the luminal side of proximal tubules. Canagliflozin reportedly inhibits SGLT1 weakly and suppresses postprandial plasma glucose, suggesting that it also inhibits intestinal SGLT1. However, it is difficult to measure the drug concentrations of these assumed sites of action directly. The pharmacokinetic-pharmacodynamic (PK/PD) relationships of canagliflozin remain poorly characterized. Therefore, a physiologically based pharmacokinetic (PBPK) model of canagliflozin was developed based on clinical data from healthy volunteers and it was used to simulate luminal concentrations in intestines and renal tubules. In small intestine simulations, the inhibition ratios for SGLT1 were predicted to be 40%-60% after the oral administration of clinical doses (100-300 mg/day). In contrast, inhibition ratios of canagliflozin for renal SGLT2 and SGLT1 were predicted to be approximately 100% and 0.2%-0.4%, respectively. These analyses suggest that canagliflozin only inhibits SGLT2 in the kidney. Using the simulated proximal tubule luminal concentrations of canagliflozin, the urinary glucose excretion rates in canagliflozin-treated diabetic patients were accurately predicted using the renal glucose reabsorption model as a PD model. Because the simulation of canagliflozin pharmacokinetics was successful, this PBPK methodology was further validated by successfully simulating the pharmacokinetics of dapagliflozin, another SGLT2 inhibitor. The present results suggest the utility of this PBPK/PD model for predicting canagliflozin concentrations at target sites and help to elucidate the pharmacological effects of SGLT1/2 inhibition in humans. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  20. Polare maskuliniteter

    Directory of Open Access Journals (Sweden)

    Marit Anne Hauan

    2012-05-01

    Full Text Available In this paper my aim is to read and understand the journal of Gerrit de Veer from the last journey of William Barents to the Arctic Regions in 1596 and the journal of captain Junge on his hunting trip from Tromsø to Svalbard in 1834.It is nearly 240 years between this to voyages. The first journal is known as the earliest report from the arctic era. Gerrit de Veer adds instructive copper engravings to his text and give us insight in the crews meeting with this new land. Captain Junges journal is found together with his dead crew in a house in a fjord nearby Ny-Ålesund and has no drawings, but word. Both of these journals may be read as sources of the knowledge and understanding of the polar region. They might also unveil the ideas of how to deal with and survive under the challenges that is given. In addition one can ask if the sources can tell us more about how men describe their challenges. Can the way they expressed themselves in the journals give us an understanding of masculinity? And not least help us to create good questions of the change in the ideas of masculinities which is said to follow the change in understanding of the wilderness.

  1. Modeling diffusion coefficients in binary mixtures of polar and non-polar compounds

    DEFF Research Database (Denmark)

    Medvedev, Oleg; Shapiro, Alexander

    2005-01-01

    The theory of transport coefficients in liquids, developed previously, is tested on a description of the diffusion coefficients in binary polar/non-polar mixtures, by applying advanced thermodynamic models. Comparison to a large set of experimental data shows good performance of the model. Only...

  2. Fluoroethoxy-1,4-diphenethylpiperidine and piperazine derivatives: Potent and selective inhibitors of [3H]dopamine uptake at the vesicular monoamine transporter-2.

    Science.gov (United States)

    Hankosky, Emily R; Joolakanti, Shyam R; Nickell, Justin R; Janganati, Venumadhav; Dwoskin, Linda P; Crooks, Peter A

    2017-12-15

    A small library of fluoroethoxy-1,4-diphenethyl piperidine and fluoroethoxy-1,4-diphenethyl piperazine derivatives were designed, synthesized and evaluated for their ability to inhibit [ 3 H]dopamine (DA) uptake at the vesicular monoamine transporter-2 (VMAT2) and dopamine transporter (DAT), [ 3 H]serotonin (5-HT) uptake at the serotonin transporter (SERT), and [ 3 H]dofetilide binding at the human-ether-a-go-go-related gene (hERG) channel. The majority of the compounds exhibited potent inhibition of [ 3 H]DA uptake at VMAT2, Ki changes in the nanomolar range (K i  = 0.014-0.073 µM). Compound 15d exhibited the highest affinity (K i  = 0.014 µM) at VMAT2, and had 160-, 5-, and 60-fold greater selectivity for VMAT2 vs. DAT, SERT and hERG, respectively. Compound 15b exhibited the greatest selectivity (>60-fold) for VMAT2 relative to all the other targets evaluated, and 15b had high affinity for VMAT2 (K i  = 0.073 µM). Compound 15b was considered the lead compound from this analog series due to its high affinity and selectivity for VMAT2. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Gram-scale solution-phase synthesis of selective sodium bicarbonate co-transport inhibitor S0859: in vitro efficacy studies in breast cancer cells.

    Science.gov (United States)

    Larsen, Ann M; Krogsgaard-Larsen, Niels; Lauritzen, Gitte; Olesen, Christina W; Honoré Hansen, Steen; Boedtkjer, Ebbe; Pedersen, Stine F; Bunch, Lennart

    2012-10-01

    Na(+)-coupled HCO(3)(-) transporters (NBCs) mediate the transport of bicarbonate ions across cell membranes and are thus ubiquitous regulators of intracellular pH. NBC dysregulation is associated with a range of diseases; for instance, NBCn1 is strongly up-regulated in a model of ErbB2-dependent breast cancer, a malignant and widespread cancer with no targeted treatment options, and single-nucleotide polymorphisms in NBCn1 genetically link to breast cancer development and hypertension. The N-cyanosulfonamide S0859 has been shown to selectively inhibit NBCs, and its availability on the gram scale is therefore of significant interest to the scientific community. Herein we describe a short and efficient synthesis of S0859 with an overall yield of 45 % from commercially available starting materials. The inhibitory effect of S0859 on recovery of intracellular pH after an acid load was verified in human and murine cancer cell lines in Ringer solutions. However, S0859 binds very strongly to components in plasma, and accordingly, measurements on isolated murine tissues showed no effect of S0859 at concentrations up to 50 μM. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. PSI: Very slow polarized muons

    International Nuclear Information System (INIS)

    Anon.

    1994-01-01

    At the 'pion factory' of the Swiss Paul Scherrer Institute, a collaboration of PSI, Heidelberg and Zurich (ETH) has recently produced intense beams of positive muons which have kinetic energies as low as 10 eV and with complete polarization (spin orientation). The new results were achieved at a surface muon channel, transporting positive muons from the decay of positive pions stopped at the surface of a pion production target. Surface muons with 4 MeV kinetic energy were transported by a conventional secondary beam channel and partially stopped in a moderator consisting of a layer of solidified noble gas deposited on a cold metallic substrate

  5. Inhibitor for the Corrosion of Mild Steel in H SO

    African Journals Online (AJOL)

    NJD

    KEYWORDS. Terminalia chebula, acid corrosion inhibitor, electrochemical polarization, electrochemical impedance spectroscopy, mild steel. 1. Introduction. Large amounts of sulphuric acid are used in the chemical in- dustry for the removal of undesired scale and rust. The addition of corrosion inhibitors effectively protects ...

  6. The glutamate transport inhibitor DL-Threo-β-Benzyloxyaspartic acid (DL-TBOA) differentially affects SN38- and oxaliplatin-induced death of drug-resistant colorectal cancer cells

    International Nuclear Information System (INIS)

    Pedraz-Cuesta, Elena; Christensen, Sandra; Jensen, Anders A.; Jensen, Niels Frank; Bunch, Lennart; Romer, Maria Unni; Brünner, Nils; Stenvang, Jan; Pedersen, Stine Falsig

    2015-01-01

    Colorectal cancer (CRC) is a leading cause of cancer death globally and new biomarkers and treatments are severely needed. Here, we employed HCT116 and LoVo human CRC cells made resistant to either SN38 or oxaliplatin, to investigate whether altered expression of the high affinity glutamate transporters Solute Carrier (SLC)-1A1 and -1A3 (EAAT3, EAAT1) is associated with the resistant phenotypes. Analyses included real-time quantitative PCR, immunoblotting and immunofluorescence analyses, radioactive tracer flux measurements, and biochemical analyses of cell viability and glutathione content. Results were evaluated using one- and two-way ANOVA and Students two-tailed t-test, as relevant. In SN38-resistant HCT116 and LoVo cells, SLC1A1 expression was down-regulated ~60 % and up-regulated ~4-fold, respectively, at both mRNA and protein level, whereas SLC1A3 protein was undetectable. The changes in SLC1A1 expression were accompanied by parallel changes in DL-Threo-β-Benzyloxyaspartic acid (TBOA)-sensitive, UCPH101-insensitive [ 3 H]-D-Aspartate uptake, consistent with increased activity of SLC1A1 (or other family members), yet not of SLC1A3. DL-TBOA co-treatment concentration-dependently augmented loss of cell viability induced by SN38, while strongly counteracting that induced by oxaliplatin, in both HCT116 and LoVo cells. This reflected neither altered expression of the oxaliplatin transporter Cu 2+ -transporter-1 (CTR1), nor changes in cellular reduced glutathione (GSH), although HCT116 cell resistance per se correlated with increased cellular GSH. DL-TBOA did not significantly alter cellular levels of p21, cleaved PARP-1, or phospho-Retinoblastoma protein, yet altered SLC1A1 subcellular localization, and reduced chemotherapy-induced p53 induction. SLC1A1 expression and glutamate transporter activity are altered in SN38-resistant CRC cells. Importantly, the non-selective glutamate transporter inhibitor DL-TBOA reduces chemotherapy-induced p53 induction and augments

  7. Recovery of dopamine neuronal transporter but lack of change of its mRNA in substantia nigra after inactivation by a new irreversible inhibitor characterized in vitro and ex vivo in the rat

    Science.gov (United States)

    Do Régo, Jean-Claude; Syringas, Maria; Leblond, Bertrand; Costentin, Jean; Bonnet, Jean-Jacques

    1999-01-01

    In vitro, the ability of DEEP-NCS {1-[2-(diphenylmethoxy)ethyl]-4-[2-(4-isothiocyanatophenyl)ethyl]-piperazine} to inhibit [3H]-dopamine uptake by rat striatal synaptosomes was concentration-dependent and inversely related to the protein concentration. This inhibition was irreversible and resulted from changes in Vmax and KM. DEEP-NCS was less potent on noradrenaline, serotonin and choline transport. One day after intrastriatal injections of DEEP-NCS (100 and 1000 pmol) in 20% dimethylsulphoxide, moderate decreases in the ex vivo dopamine uptake were observed in synaptosomes obtained from striatum injected with DEEP-NCS or solvent, and the contralateral uninjected striatum. In similar conditions, 300 pmol DEEP-NCS in 45% 2 hydroxypropyl-γ-cyclodextrin–0.5% dimethylsulphoxide solution sub-totally reduced ex vivo dopamine uptake and mazindol binding, and moderately decreased choline and serotonin transport. These reductions were specific to DEEP-NCS-injected striata. A clomipramine pretreatment (16 mg kg−1 i.p. 1 h before) was performed in following experiments, since it reduced the DEEP-NCS-elicited decrease in serotonin uptake without affecting other indices. One day after intrastriatal injection, DEEP-NCS elicited similar dose-dependent decreases in ex vivo dopamine uptake and mazindol binding (ID50=6.9-8 ng striatum−1). Changes in KM and Vmax for ex vivo dopamine transport produced by DEEP-NCS disappeared according to similar time-courses. The t½ for transporter recovery was 6.1 days. This value should correspond to its actual turnover rate in vivo, since no change in transporter mRNA level was observed in substantia nigra ipsilateral to 300 pmol DEEP-NCS-injected striatum. The results indicate that DEEP-NCS behaves as a potent, quite selective, irreversible inhibitor of the DAT, in vitro and in vivo. Its use in vivo suggests that the physiological half-life of the rat striatal DAT is close to 6 days. PMID:10498834

  8. Quinine Dimers Are Potent Inhibitors of the Plasmodium falciparum Chloroquine Resistance Transporter and Are Active against Quinoline-Resistant P. falciparum

    Science.gov (United States)

    Hrycyna, Christine A.; Summers, Robert L.; Lehane, Adele M.; Pires, Marcos M.; Namanja, Hilda; Bohn, Kelsey; Kuriakose, Jerrin; Ferdig, Michael; Henrich, Philipp P.; Fidock, David A.; Kirk, Kiaran; Chmielewski, Jean; Martin, Rowena E.

    2014-01-01

    Chloroquine (CQ) resistance in the human malaria parasite Plasmodium falciparum is primarily conferred by mutations in the “chloroquine resistance transporter” (PfCRT). The resistance-conferring form of PfCRT (PfCRTCQR) mediates CQ resistance by effluxing the drug from the parasite’s digestive vacuole, the acidic compartment in which CQ exerts its antiplasmodial effect. PfCRTCQR can also decrease the parasite’s susceptibility to other quinoline drugs, including the current antimalarials quinine and amodiaquine. Here we describe interactions between PfCRTCQR and a series of dimeric quinine molecules using a Xenopus laevis oocyte system for the heterologous expression of PfCRT and using an assay that detects the drug-associated efflux of H+ ions from the digestive vacuole in parasites that harbor different forms of PfCRT. The antiplasmodial activities of dimers 1 and 6 were also examined in vitro (against drug-sensitive and drug-resistant strains of P. falciparum) and in vivo (against drug-sensitive P. berghei). Our data reveal that the quinine dimers are the most potent inhibitors of PfCRTCQR reported to date. Furthermore, the lead compounds (1 and 6) were not effluxed by PfCRTCQR from the digestive vacuole but instead accumulated to very high levels within this organelle. Both 1 and 6 exhibited in vitro antiplasmodial activities that were inversely correlated with CQ. Moreover, the additional parasiticidal effect exerted by 1 and 6 in the drug-resistant parasites was attributable, at least in part, to their ability to inhibit PfCRTCQR. This highlights the potential for devising new antimalarial therapies that exploit inherent weaknesses in a key resistance mechanism of P. falciparum. PMID:24369685

  9. Polarized nuclei in plastic scintillators: a new class of polarized targets

    Science.gov (United States)

    van den Brandt, B.; Bunyatova, E. I.; Hautle, P.; Konter, J. A.; Mango, S.; Nemchonok, I. B.

    2001-06-01

    Polarized scintillating targets are now routinely available: protons, deuterons or other nuclei in blocks of scintillating organic polymer, doped with the free radical TEMPO, are polarized dynamically in a field of 2.5 T in a vertical 3He-4He dilution refrigerator. A 19 mm diameter plastic lightguide transports the scintillation light from the sample in the mixing chamber to a photomultiplier outside the cryostat. Sizeable nuclear polarizations have been achieved newly in boron enriched polystyrene-based scintillating material. A scintillator target with high detection sensitivity for low energy neutrons has been so made available, in which both protons and boron nuclei are polarized. .

  10. α-Ketoglutarate-related inhibitors of HIF prolyl hydroxylases are substrates of renal organic anion transporters 1 (OAT1) and 4 (OAT4).

    Science.gov (United States)

    Hagos, Yohannes; Schley, Gunnar; Schödel, Johannes; Krick, Wolfgang; Burckhardt, Gerhard; Willam, Carsten; Burckhardt, Birgitta C

    2012-10-01

    2-Oxoglutarate or α-ketoglutarate (αKG) is a substrate of HIF prolyl hydroxylases 1-3 that decrease cellular levels of the hypoxia-inducible factor 1α (HIF-1α) in the presence of oxygen. αKG analogs are applied to stabilize HIF-1α even in the presence of oxygen and thus provide a novel therapeutic option in treating kidney diseases. In the kidneys, the organic anion transporters 1 and 3 (OAT1 and OAT3, respectively) in cooperation with the sodium-dependent dicarboxylate transporter 3 (NaDC3) and the OAT4 might be responsible for the uptake of αKG analogs into and the efflux out of the tubular cells. Using the radiolabelled substrates p-aminohippurate (PAH, OAT1), estrone-3-sulfate (ES; OAT3, OAT4), and succinate (NaDC3), N-oxalylglycine (NOG), dimethyloxalyl glycine (DMOG), 2,4-diethylpyridine dicarboxylate (2,4-DPD), and pyridine-2,4-dicarboxylic acid (PDCA) were tested in cis-inhibition and trans-stimulation experiments. None of these αKG analogs interacted with NaDC3. 2,4-DPD and PDCA inhibited ES uptake by OAT3 moderately. NOG, 2,4-DPD and PDCA, but not DMOG, inhibited PAH uptake by OAT1 significantly. trans-Stimulation experiments and experiments demonstrating stabilization of HIF-1α revealed that NOG and PDCA, but not 2,4-DPD, are translocated by OAT1. All compounds trans-stimulated ES uptake by OAT4, but only PDCA stabilized HIF-1α. The data suggest that OAT1 is involved in the uptake of NOG and PDCA across the basolateral membrane of proximal tubule cells, whereas OAT4 may release these compounds into the primary urine.

  11. Polarized electron sources

    Energy Technology Data Exchange (ETDEWEB)

    Prepost, R. [Univ. of Wisconsin, Madison, WI (United States)

    1994-12-01

    The fundamentals of polarized electron sources are described with particular application to the Stanford Linear Accelerator Center. The SLAC polarized electron source is based on the principle of polarized photoemission from Gallium Arsenide. Recent developments using epitaxially grown, strained Gallium Arsenide cathodes have made it possible to obtain electron polarization significantly in excess of the conventional 50% polarization limit. The basic principles for Gallium and Arsenide polarized photoemitters are reviewed, and the extension of the basic technique to strained cathode structures is described. Results from laboratory measurements of strained photocathodes as well as operational results from the SLAC polarized source are presented.

  12. Mercury biomagnification in polar bears ( Ursus maritimus)

    Science.gov (United States)

    Horton, T. W.; Blum, J. D.; Xie, Z.; Hren, M.; Chamberlain, C. P.

    2007-12-01

    Mercury biomagnification occurs in a variety of ecosystems resulting in greater potential for toxicological effects in higher-level trophic feeders. However, Hg transport pathways through different foodweb channels are not well known, particularly in high-latitude systems affected by atmospheric Hg deposition associated with snow and ice. Stable carbon and nitrogen isotope ratios and Hg concentrations determined for 26 late 19th and early 20th century polar bear hair specimens collected from cataloged museum collections elucidate relationships between high latitude marine foodweb structure and Hg transport pathways. Nitrogen and carbon isotopic compositions suggest that polar bears derive nutrition from both open water (pelagic) and ice associated (sympagic) foodweb channels. Correlation between Hg concentrations and nitrogen isotope compositions indicate mercury biomagnification occurred in most of the polar bears investigated. Interpretation of stable isotope based foodweb structure in concert with Hg concentrations further suggests that Hg biomagnification occurred to a greater degree in polar bears participating in pelagic foodweb channels.

  13. Polarization versus Temperature in Pyridinium Ionic Liquids

    DEFF Research Database (Denmark)

    Chaban, V. V.; Prezhdo, O. V.

    2014-01-01

    Electronic polarization and charge transfer effects play a crucial role in thermodynamic, structural, and transport properties of room-temperature ionic liquids (RTILs). These nonadditive interactions constitute a useful tool for tuning physical chemical behavior of RTILs. Polarization and charge...... electronic density description for a cationanion pair. Atom-centered density matrix propagation molecular dynamics, supplemented by a weak coupling to an external bath, is used to simulate the temperature impact on system properties. We show that, quite surprisingly, nonadditivity in the cationanion...

  14. Azorhodanine derivatives as inhibitors for acidic corrosion of nickel.

    Science.gov (United States)

    Fouda, Abd El-Aziz S; Al-Sarawy, Ahmed A; Omar, Tark M

    2005-01-01

    Azorhodanine derivatives (HL1-HL5) were tested as corrosion inhibitors for nickel in 2M HNO3 solution using weight loss and galvanostatic polarization techniques. The results showed that these derivatives act as inhibitors for nickel in this medium. The inhibition was assumed to occur via adsorption of the inhibitor molecule on the metal surface. Polarization measurements indicated that these compounds act as mixed-type inhibitors, but the cathode is more polarized when an external current was applied. This means that these compounds retard the rate of hydrogen evolution and the rate of dissolution of the metal. Results showed that azorhodanine derivatives are adsorbed on the nickel surface following Temkin's adsorption isotherm. The activation energy and thermodynamic parameters were calculated and discussed at different temperatures (30-45 degrees C).

  15. Geographical Income Polarization

    DEFF Research Database (Denmark)

    Azhar, Hussain; Jonassen, Anders Bruun

    inter municipal income inequality. Counter factual simulations show that rising property prices to a large part explain the rise in polarization. One side-effect of polarization is tendencies towards a parallel polarization of residence location patterns, where low skilled individuals tend to live......In this paper we estimate the degree, composition and development of geographical income polarization based on data at the individual and municipal level in Denmark from 1984 to 2002. Rising income polarization is reconfirmed when applying new polarization measures, the driving force being greater...

  16. Polymorphism of rs3813034 in Serotonin Transporter Gene SLC6A4 Is Associated With the Selective Serotonin and Serotonin-Norepinephrine Reuptake Inhibitor Response in Depressive Disorder: Sequencing Analysis of SLC6A4.

    Science.gov (United States)

    Nonen, Shinpei; Kato, Masaki; Takekita, Yoshiteru; Wakeno, Masataka; Sakai, Shiho; Serretti, Alessandro; Kinoshita, Toshihiko

    2016-02-01

    Selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRI/SNRI) are commonly used for treating major depression. Regretfully, significant heterogeneity exists regarding the benefits of SSRI/SNRI in individual cases. We previously reported that a polymorphism located in the serotonin transporter linked promoter region (5-HTT LPR) is associated with an interindividual difference in SSRI treatment efficacy. However, this explains only a small part of the variation of this complex phenotype. Other 5-HTT variants in the coding regions, 3' untranslated region (3' UTR), and introns adjacent to each exon could also contribute to treatment response. Therefore, we performed a sequencing analysis of the SLC6A4 gene (coding for 5-HTT) and investigated the association between variants detected in this study and the antidepressant response to SSRI/SNRI in 201 Japanese depressive patients. Seventeen novel mutations were identified by sequencing analysis. We found that the polymorphism G2563T (rs3813034) as a tag single-nucleotide polymorphism of IVS9 A-90G (rs140701), G2356T (rs1042173), and A3641C (rs7224199) is associated with interindividual variability of SSRI/SNRI efficacy at week 6, independent from clinical variables and effect of 5-HTT LPR (P depressive patients in combination with 5-HTT LPR.

  17. Intra- and inter-subject variability for increases in serum ketone bodies in patients with type 2 diabetes treated with the sodium glucose co-transporter 2 inhibitor canagliflozin.

    Science.gov (United States)

    Polidori, David; Iijima, Hiroaki; Goda, Maki; Maruyama, Nobuko; Inagaki, Nobuya; Crawford, Peter A

    2018-01-17

    Sodium glucose co-transporter 2 (SGLT2) inhibitors have been associated with increased serum ketone body levels in patients with type 2 diabetes mellitus (T2DM). In the present analysis we evaluated serum ketone body levels and variability in 1278 Japanese patients with T2DM treated with canagliflozin 100 or 200 mg. Similar mean increases in ketone body concentrations of ~2-fold were seen with both canagliflozin doses. The median (interquartile range) percent change from baseline was 62% (0;180) for acetoacetate and 78% (2;236) for β-hydroxybutyrate. Approximately two-thirds of the variability in each ketone measure was attributed to intra-subject variability. Intra-subject variability was higher for serum ketones than other metabolites. Patients in the lowest response tertile exhibited no increase in ketones. Those in the highest response tertile tended to be male and have higher fasting plasma glucose levels, lower insulin levels, and longer T2DM duration at baseline. Moreover, changes in serum ketones were not fully explained by changes in plasma fatty acids, suggesting downstream effects of SGLT2 inhibition on hepatic metabolism that favour ketogenesis. In summary, increases in serum ketone bodies with canagliflozin were greater and more variable than changes in other metabolic measures in Japanese patients with T2DM. © 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

  18. Evaluation of corrosion inhibitor simulating conditions of operation

    Science.gov (United States)

    Gómez, O.; Aponte, H.; Vera, E.; Pineda, Y.

    2017-12-01

    Operating conditions at the head of oil wells are critical, in addition to injecting water to increase the pressure while maintaining production cause deterioration in the metallic structures that transport fluids. One way to maintain integrity is the injection of inhibitors which plays an important role in protecting the pipes. In this study a molecule N-PHENYL NITRONE was obtained, which was evaluated by electrochemical tests (LPR) and Tafel Polarization Curves in a reactor controlling environments containing different dosages, pressure values, temperatures and flow velocity using working electrodes tubing API N 80, the reactor was connected to a potentiostat to determine corrosion rates, allowing the analysis of the influence of each variable on the protective behaviour of the inhibitor, and its efficiency against the decrease of the deterioration of the pipes. Corrosion products are analysed by X-Ray Diffraction (XRD). Photographic records of the surface verify the formation of iron carbonate (FeCO3). In addition, a mathematical analysis of the independent variables is performed to evaluate the effect that it has on the efficiency of corrosion inhibition.

  19. Polarized Light Corridor Demonstrations.

    Science.gov (United States)

    Davies, G. R.

    1990-01-01

    Eleven demonstrations of light polarization are presented. Each includes a brief description of the apparatus and the effect demonstrated. Illustrated are strain patterns, reflection, scattering, the Faraday Effect, interference, double refraction, the polarizing microscope, and optical activity. (CW)

  20. Identification of the cells involved in auxin transport in maize mesocotyl

    International Nuclear Information System (INIS)

    Jones, A.M.

    1989-01-01

    A study was undertaken to identify by a direct method the cells involved in auxin transport through maize mesocotyl tissue. The auxin photoaffinity labeling agent, 7-[ 3 H], 5-azidoindole 3-acetic acid (N 3 IAA), was loaded into excised stem tissue from a cut end. Polar transport of this analog was demonstrated over 4 hours by comparing uptake into tissue loaded with N 3 IAA from the apical vs. the basal end. Triiodobenzoic acid, an auxin transport inhibitor, inhibited N 3 IAA uptake into tissue. Tissue which had taken up the photoaffinity labeling agent was photolyzed to covalently fix the radioisotope within cells. This tissue was sectioned and subjected to in situ autoradiography. The outermost cell of epidermal tissue and certain files of cells in vascular tissue were densely labeled indicating that on a per cell basis these two cell types are most actively transporting auxin

  1. Corrosion inhibitors

    International Nuclear Information System (INIS)

    El Ashry, El Sayed H.; El Nemr, Ahmed; Esawy, Sami A.; Ragab, Safaa

    2006-01-01

    The corrosion inhibition efficiencies of some triazole, oxadiazole and thiadiazole derivatives for steel in presence of acidic medium have been studied by using AM1, PM3, MINDO/3 and MNDO semi-empirical SCF molecular orbital methods. Geometric structures, total negative charge on the molecule (TNC), highest occupied molecular energy level (E HOMO ), lowest unoccupied molecular energy level (E LUMO ), core-core repulsion (CCR), dipole moment (μ) and linear solvation energy terms, molecular volume (V i ) and dipolar-polarization (π *), were correlated to corrosion inhibition efficiency. Four equations were proposed to calculate corrosion inhibition efficiency. The agreement with the experimental data was found to be satisfactory; the standard deviations between the calculated and experimental results ranged between ±0.03 and ±4.18. The inhibition efficiency was closely related to orbital energies (E HOMO and E LUMO ) and μ. The correlation between quantum parameters and experimental inhibition efficiency has been validated by single point calculations for the semi-empirical AM1 structures using B3LYP/6-31G** as a higher level of theory. The proposed equations were applied to predict the corrosion inhibition efficiency of some related structures to select molecules of possible activity from a presumable library of compounds

  2. ABC Transporters in Cancer Stem Cells: Beyond Chemoresistance.

    Science.gov (United States)

    Begicevic, Romana-Rea; Falasca, Marco

    2017-11-08

    The efficacy of chemotherapy is one of the main challenges in cancer treatment and one of the major obstacles to overcome in achieving lasting remission and a definitive cure in patients with cancer is the emergence of cancer resistance. Indeed, drug resistance is ultimately accountable for poor treatment outcomes and tumour relapse. There are various molecular mechanisms involved in multidrug resistance, such as the change in the activity of membrane transporters primarily belonging to the ATP binding cassette (ABC) transporter family. In addition, it has been proposed that this common feature could be attributed to a subpopulation of slow-cycling cancer stem cells (CSCs), endowed with enhanced tumorigenic potential and multidrug resistance. CSCs are characterized by the overexpression of specific surface markers that vary in different cancer cell types. Overexpression of ABC transporters has been reported in several cancers and more predominantly in CSCs. While the major focus on the role played by ABC transporters in cancer is polarized by their involvement in chemoresistance, emerging evidence supports a more active role of these proteins, in which they release specific bioactive molecules in the extracellular milieu. This review will outline our current understanding of the role played by ABC transporters in CSCs, how their expression is regulated and how they support the malignant metabolic phenotype. To summarize, we suggest that the increased expression of ABC transporters in CSCs may have precise functional roles and provide the opportunity to target, particularly these cells, by using specific ABC transporter inhibitors.

  3. ABC Transporters in Cancer Stem Cells: Beyond Chemoresistance

    Directory of Open Access Journals (Sweden)

    Romana-Rea Begicevic

    2017-11-01

    Full Text Available The efficacy of chemotherapy is one of the main challenges in cancer treatment and one of the major obstacles to overcome in achieving lasting remission and a definitive cure in patients with cancer is the emergence of cancer resistance. Indeed, drug resistance is ultimately accountable for poor treatment outcomes and tumour relapse. There are various molecular mechanisms involved in multidrug resistance, such as the change in the activity of membrane transporters primarily belonging to the ATP binding cassette (ABC transporter family. In addition, it has been proposed that this common feature could be attributed to a subpopulation of slow-cycling cancer stem cells (CSCs, endowed with enhanced tumorigenic potential and multidrug resistance. CSCs are characterized by the overexpression of specific surface markers that vary in different cancer cell types. Overexpression of ABC transporters has been reported in several cancers and more predominantly in CSCs. While the major focus on the role played by ABC transporters in cancer is polarized by their involvement in chemoresistance, emerging evidence supports a more active role of these proteins, in which they release specific bioactive molecules in the extracellular milieu. This review will outline our current understanding of the role played by ABC transporters in CSCs, how their expression is regulated and how they support the malignant metabolic phenotype. To summarize, we suggest that the increased expression of ABC transporters in CSCs may have precise functional roles and provide the opportunity to target, particularly these cells, by using specific ABC transporter inhibitors.

  4. Polarized Moessbauer transitions

    International Nuclear Information System (INIS)

    Barb, D.

    1975-01-01

    Theoretical aspects of the emission, absorption and scattering of polarized gamma rays are reviewed for a general case of combined magnetic and electric hyperfine interactions; various possibilities of obtaining polarized gamma sources are described and examples are given of the applications of Moessbauer spectroscopy with polarized gamma rays in solving problems of solid state physics. (A.K.)

  5. The Physics of Polarization

    Science.gov (United States)

    Landi Degl'Innocenti, Egidio

    2015-10-01

    The introductory lecture that has been delivered at this Symposium is a condensed version of an extended course held by the author at the XII Canary Island Winter School from November 13 to November 21, 2000. The full series of lectures can be found in Landi Degl'Innocenti (2002). The original reference is organized in 20 Sections that are here itemized: 1. Introduction, 2. Description of polarized radiation, 3. Polarization and optical devices: Jones calculus and Muller matrices, 4. The Fresnel equations, 5. Dichroism and anomalous dispersion, 6. Polarization in everyday life, 7. Polarization due to radiating charges, 8. The linear antenna, 9. Thomson scattering, 10. Rayleigh scattering, 11. A digression on Mie scattering, 12. Bremsstrahlung radiation, 13. Cyclotron radiation, 14. Synchrotron radiation, 15. Polarization in spectral lines, 16. Density matrix and atomic polarization, 17. Radiative transfer and statistical equilibrium equations, 18. The amplification condition in polarized radiative transfer, and 19. Coupling radiative transfer and statistical equilibrium equations.

  6. Development of green vapour corrosion inhibitor

    Science.gov (United States)

    Asmara, Y. P.; Suraj, V.; Siregar, J. P.; Kurniawan, T.; Bachtiar, D.; Mohamed, N. M. Z. N.

    2017-10-01

    Corrosion control using inhibitor is an effective method to protect carbon steel from corrosion. Due to environmental toxicity of chemical inorganic corrosion inhibitors (synthetic), green inhibitors are potentially to develop. In atmospheric conditions, green vapour corrosion inhibitors are the best solutions to replace the uses of inorganic corrosion inhibitors. This research used chemical acid extraction from the key lime (citrus aurantiifolia) leaves and seeds. They are used as the main ingredients to produce this effective green corrosion inhibitor. The experiments investigated effects of corrosion inhibition on corrosion rate of low carbon steel in 3% NaCl solution using both fog salt chamber and electrochemical cell. Using salt fog chamber to represent atmospheric conditions, and corrosion rates are evaluated visually and calculated using weight loss methods. Corrosion rate on electrochemical cell were calculated using linear polarization resistance (LPR) methods. All of the experiments were set in natural conditions at pH 7. Using weight loss for three days exposure time, the efficiency of the inhibitor reached 82.39%.

  7. The Sodium-Glucose Co-Transporter 2 Inhibitor Empagliflozin Improves Diabetes-Induced Vascular Dysfunction in the Streptozotocin Diabetes Rat Model by Interfering with Oxidative Stress and Glucotoxicity

    Science.gov (United States)

    Welschof, Philipp; Jansen, Thomas; Hausding, Michael; Mikhed, Yuliya; Stamm, Paul; Mader, Michael; Zinßius, Elena; Agdauletova, Saule; Gottschlich, Anna; Steven, Sebastian; Schulz, Eberhard; Bottari, Serge P.; Mayoux, Eric; Münzel, Thomas; Daiber, Andreas

    2014-01-01

    Objective In diabetes, vascular dysfunction is characterized by impaired endothelial function due to increased oxidative stress. Empagliflozin, as a selective sodium-glucose co-transporter 2 inhibitor (SGLT2i), offers a novel approach for the treatment of type 2 diabetes by enhancing urinary glucose excretion. The aim of the present study was to test whether treatment with empagliflozin improves endothelial dysfunction in type I diabetic rats via reduction of glucotoxicity and associated vascular oxidative stress. Methods Type I diabetes in Wistar rats was induced by an intravenous injection of streptozotocin (60 mg/kg). One week after injection empagliflozin (10 and 30 mg/kg/d) was administered via drinking water for 7 weeks. Vascular function was assessed by isometric tension recording, oxidative stress parameters by chemiluminescence and fluorescence techniques, protein expression by Western blot, mRNA expression by RT-PCR, and islet function by insulin ELISA in serum and immunohistochemical staining of pancreatic tissue. Advanced glycation end products (AGE) signaling was assessed by dot blot analysis and mRNA expression of the AGE-receptor (RAGE). Results Treatment with empagliflozin reduced blood glucose levels, normalized endothelial function (aortic rings) and reduced oxidative stress in aortic vessels (dihydroethidium staining) and in blood (phorbol ester/zymosan A-stimulated chemiluminescence) of diabetic rats. Additionally, the pro-inflammatory phenotype and glucotoxicity (AGE/RAGE signaling) in diabetic animals was reversed by SGLT2i therapy. Conclusions Empagliflozin improves hyperglycemia and prevents the development of endothelial dysfunction, reduces oxidative stress and improves the metabolic situation in type 1 diabetic rats. These preclinical observations illustrate the therapeutic potential of this new class of antidiabetic drugs. PMID:25402275

  8. The sodium-glucose co-transporter 2 inhibitor empagliflozin improves diabetes-induced vascular dysfunction in the streptozotocin diabetes rat model by interfering with oxidative stress and glucotoxicity.

    Directory of Open Access Journals (Sweden)

    Matthias Oelze

    Full Text Available OBJECTIVE: In diabetes, vascular dysfunction is characterized by impaired endothelial function due to increased oxidative stress. Empagliflozin, as a selective sodium-glucose co-transporter 2 inhibitor (SGLT2i, offers a novel approach for the treatment of type 2 diabetes by enhancing urinary glucose excretion. The aim of the present study was to test whether treatment with empagliflozin improves endothelial dysfunction in type I diabetic rats via reduction of glucotoxicity and associated vascular oxidative stress. METHODS: Type I diabetes in Wistar rats was induced by an intravenous injection of streptozotocin (60 mg/kg. One week after injection empagliflozin (10 and 30 mg/kg/d was administered via drinking water for 7 weeks. Vascular function was assessed by isometric tension recording, oxidative stress parameters by chemiluminescence and fluorescence techniques, protein expression by Western blot, mRNA expression by RT-PCR, and islet function by insulin ELISA in serum and immunohistochemical staining of pancreatic tissue. Advanced glycation end products (AGE signaling was assessed by dot blot analysis and mRNA expression of the AGE-receptor (RAGE. RESULTS: Treatment with empagliflozin reduced blood glucose levels, normalized endothelial function (aortic rings and reduced oxidative stress in aortic vessels (dihydroethidium staining and in blood (phorbol ester/zymosan A-stimulated chemiluminescence of diabetic rats. Additionally, the pro-inflammatory phenotype and glucotoxicity (AGE/RAGE signaling in diabetic animals was reversed by SGLT2i therapy. CONCLUSIONS: Empagliflozin improves hyperglycemia and prevents the development of endothelial dysfunction, reduces oxidative stress and improves the metabolic situation in type 1 diabetic rats. These preclinical observations illustrate the therapeutic potential of this new class of antidiabetic drugs.

  9. Electrochemical regulation of budding yeast polarity.

    Directory of Open Access Journals (Sweden)

    Armin Haupt

    2014-12-01

    Full Text Available Cells are naturally surrounded by organized electrical signals in the form of local ion fluxes, membrane potential, and electric fields (EFs at their surface. Although the contribution of electrochemical elements to cell polarity and migration is beginning to be appreciated, underlying mechanisms are not known. Here we show that an exogenous EF can orient cell polarization in budding yeast (Saccharomyces cerevisiae cells, directing the growth of mating projections towards sites of hyperpolarized membrane potential, while directing bud emergence in the opposite direction, towards sites of depolarized potential. Using an optogenetic approach, we demonstrate that a local change in membrane potential triggered by light is sufficient to direct cell polarization. Screens for mutants with altered EF responses identify genes involved in transducing electrochemical signals to the polarity machinery. Membrane potential, which is regulated by the potassium transporter Trk1p, is required for polarity orientation during mating and EF response. Membrane potential may regulate membrane charges through negatively charged phosphatidylserines (PSs, which act to position the Cdc42p-based polarity machinery. These studies thus define an electrochemical pathway that directs the orientation of cell polarization.

  10. Coast Guard Polar Icebreaker Modernization: Background and Issues for Congress

    Science.gov (United States)

    2016-05-27

    subcommittee of the House Transportation and Infrastructure Committee, Vice Admiral John P. Currier, the Vice Commandant of the Coast Guard, testified...55 Calvin Biesecker, “Coast Guard Requests Information On Heavy Polar Icebreaker,” Defense...

  11. Monoamine Reuptake Inhibitors in Parkinson's Disease

    Science.gov (United States)

    Huot, Philippe; Fox, Susan H.; Brotchie, Jonathan M.

    2015-01-01

    The motor manifestations of Parkinson's disease (PD) are secondary to a dopamine deficiency in the striatum. However, the degenerative process in PD is not limited to the dopaminergic system and also affects serotonergic and noradrenergic neurons. Because they can increase monoamine levels throughout the brain, monoamine reuptake inhibitors (MAUIs) represent potential therapeutic agents in PD. However, they are seldom used in clinical practice other than as antidepressants and wake-promoting agents. This review article summarises all of the available literature on use of 50 MAUIs in PD. The compounds are divided according to their relative potency for each of the monoamine transporters. Despite wide discrepancy in the methodology of the studies reviewed, the following conclusions can be drawn: (1) selective serotonin transporter (SERT), selective noradrenaline transporter (NET), and dual SERT/NET inhibitors are effective against PD depression; (2) selective dopamine transporter (DAT) and dual DAT/NET inhibitors exert an anti-Parkinsonian effect when administered as monotherapy but do not enhance the anti-Parkinsonian actions of L-3,4-dihydroxyphenylalanine (L-DOPA); (3) dual DAT/SERT inhibitors might enhance the anti-Parkinsonian actions of L-DOPA without worsening dyskinesia; (4) triple DAT/NET/SERT inhibitors might exert an anti-Parkinsonian action as monotherapy and might enhance the anti-Parkinsonian effects of L-DOPA, though at the expense of worsening dyskinesia. PMID:25810948

  12. [Review] Polarization and Polarimetry

    Science.gov (United States)

    Trippe, Sascha

    2014-02-01

    Polarization is a basic property of light and is fundamentally linked to the internal geometry of a source of radiation. Polarimetry complements photometric, spectroscopic, and imaging analyses of sources of radiation and has made possible multiple astrophysical discoveries. In this article I review (i) the physical basics of polarization: electromagnetic waves, photons, and parameterizations; (ii) astrophysical sources of polarization: scattering, synchrotron radiation, active media, and the Zeeman, Goldreich-Kylafis, and Hanle effects, as well as interactions between polarization and matter (like birefringence, Faraday rotation, or the Chandrasekhar-Fermi effect); (iii) observational methodology: on-sky geometry, influence of atmosphere and instrumental polarization, polarization statistics, and observational techniques for radio, optical, and X/γ wavelengths; and (iv) science cases for astronomical polarimetry: solar and stellar physics, planetary system bodies, interstellar matter, astrobiology, astronomical masers, pulsars, galactic magnetic fields, gamma-ray bursts, active galactic nuclei, and cosmic microwave background radiation.

  13. Hybrid Streamers for Polar Seismic

    Science.gov (United States)

    Gifford, C. M.; Agah, A.; Tsoflias, G. P.

    2006-12-01

    We propose a new hybrid streamer seismic approach for polar regions that incorporates insertion of spiked geophones, the land streamer method of transportation, and mobile robotics. Current land streamers do not plant the geophone spike at each node location on the streamer(s) nor use robotic control. This approach combines the two methods, and is therefore termed "Hybrid Streamers". Land seismic 3D surveying is costly and time consuming due to manual handling of geophones and cables. Multiple streamers make this process simpler by allowing efficient deployment of large numbers of geophones. Hybrid streamers go further to robotically insert the geophone spike at each node location to achieve higher frequency and better resolution seismic images. For deployment and retrieval, the geophone spikes are drilled into the ground, or inserted using heat. This can be accomplished by modifying the geophone spike to be similar to a threaded screw or similar to a soldering iron for polar environments. Heat could help melt the ice during deployment, which would refreeze around the geophone for firm coupling. Heat could also be used to make polar geophone retrieval easier. By ensuring that the towing robots are robust and effective, the problem of single point of failure can be less of an issue. Polar rovers have proven useful in harsh environments, and could be utilized in polar seismic applications. Towing geophone nodes in a tethered fashion not only provides all nodes with power to operate the onboard equipment, but also gives them a medium to transfer data to the towing rover. Hybrid streamers could be used in several ways. One or more hybrid streamers could be tethered and towed by a single robot. Several robots could be used to form a single grid, working in conjunction to image larger areas in three dimensions. Such an approach could speed up entire missions and make efficient use of seismic source ignitions. The reduction of human involvement by use of mobile robots

  14. Polarization feedback laser stabilization

    Science.gov (United States)

    Esherick, P.; Owyoung, A.

    1987-09-28

    A system for locking two Nd:YAG laser oscillators includes an optical path for feeding the output of one laser into the other with different polarizations. Elliptical polarization is incorporated into the optical path so that the change in polarization that occurs when the frequencies coincide may be detected to provide a feedback signal to control one laser relative to the other. 4 figs.

  15. Polarization in Sagittarius A*

    OpenAIRE

    Bower, Geoffrey C.

    2000-01-01

    We summarize the current state of polarization observations of Sagittarius A*, the compact radio source and supermassive black hole candidate in the Galactic Center. These observations are providing new tools for understanding accretion disks, jets and their environments. Linear polarization observations have shown that Sgr A* is unpolarized at frequencies as high as 86 GHz. However, recent single-dish observations indicate that Sgr A* may have strong linear polarization at frequencies higher...

  16. Application of response surface methodology method in designing corrosion inhibitor

    Science.gov (United States)

    Asmara, Y. P.; Athirah; Siregar, J. P.; Kurniawan, T.; Bachtiar, D.

    2017-10-01

    In oil and gas pipelines and offshore structure, inhibitors have been considered to be the first choice to reduce corrosion rate. There are many corrosion inhibitor compositions available in the market. To produce the best corrosion inhibitor requires many experimental data which is not efficient. These experiments used response surface methodology (RSM) to select corrosion inhibitor compositions. The experiments investigated effects of corrosion inhibition on corrosion rate of low carbon steel in 3% NaCl solution with different concentrations of selected main inhibitor compositions which are ethyl acetate (EA), ethylene glycol (EG) and sodium benzoate (SB). Corrosion rate were calculated using linear polarization resistance (LPR). All of the experiments were set in natural conditions at pH 7. MINITAB® version 15 was used for data analysis. It is shown that a quadratic model is a representative model can predict best corrosion inhibitor composition comprehensibly.

  17. Airborne Laser Polarization Sensor

    Science.gov (United States)

    Kalshoven, James, Jr.; Dabney, Philip

    1991-01-01

    Instrument measures polarization characteristics of Earth at three wavelengths. Airborne Laser Polarization Sensor (ALPS) measures optical polarization characteristics of land surface. Designed to be flown at altitudes of approximately 300 m to minimize any polarizing or depolarizing effects of intervening atmosphere and to look along nadir to minimize any effects depending on look angle. Data from measurements used in conjunction with data from ground surveys and aircraft-mounted video recorders to refine mathematical models used in interpretation of higher-altitude polarimetric measurements of reflected sunlight.

  18. Polarization at SLC

    International Nuclear Information System (INIS)

    Swartz, M.L.

    1988-07-01

    The SLAC Linear Collider has been designed to readily accommodate polarized electron beams. Considerable effort has been made to implement a polarized source, a spin rotation system, and a system to monitor the beam polarization. Nearly all major components have been fabricated. At the current time, several source and polarimeter components have been installed. The installation and commissioning of the entire system will take place during available machine shutdown periods as the commissioning of SLC progresses. It is expected that a beam polarization of 45% will be achieved with no loss in luminosity. 13 refs., 15 figs

  19. RHIC Polarized proton operation

    International Nuclear Information System (INIS)

    Huang, H.; Ahrens, L.; Alekseev, I.G.; Aschenauer, E.; Atoian, G.; Bai, M.; Bazilevsky, A.; Blaskiewicz, M.; Brennan, J.M.; Brown, K.A.; Bruno, D.; Connolly, R.; Dion, A.; D'Ottavio, T.; Drees, K.A.; Fischer, W.; Gardner, C.; Glenn, J.W.; Gu, X.; Harvey, M.; Hayes, T.; Hoff, L.; Hulsart, R.L.; Laster, J.; Liu, C.; Luo, Y.; MacKay, W.W.; Makdisi, Y.; Marr, G.J.; Marusic, A.; Meot, F.; Mernick, K.; Michnoff, R.; Minty, M.; Montag, C.; Morris, J.; Nemesure, S.; Poblaguev, A.; Ptitsyn, V.; Ranjibar, V.; Robert-Demolaize, G.; Roser, T.; Schmidke, B.; Schoefer, V.; Severino, F.; Smirnov, D.; Smith, K.; Steski, D.; Svirida, D.; Tepikian, S.; Trbojevic, D.; Tsoupas, N.; Tuozzolo, J.E.; Wang, G.; Wilinski, M.; Yip, K.; Zaltsman, A.; Zelenski, A.; Zeno, K.; Zhang, S.Y.

    2011-01-01

    The Relativistic Heavy Ion Collider (RHIC) operation as the polarized proton collider presents unique challenges since both luminosity(L) and spin polarization(P) are important. With longitudinally polarized beams at the experiments, the figure of merit is LP 4 . A lot of upgrades and modifications have been made since last polarized proton operation. A 9 MHz rf system is installed to improve longitudinal match at injection and to increase luminosity. The beam dump was upgraded to increase bunch intensity. A vertical survey of RHIC was performed before the run to get better magnet alignment. The orbit control is also improved this year. Additional efforts are put in to improve source polarization and AGS polarization transfer efficiency. To preserve polarization on the ramp, a new working point is chosen such that the vertical tune is near a third order resonance. The overview of the changes and the operation results are presented in this paper. Siberian snakes are essential tools to preserve polarization when accelerating polarized beams to higher energy. At the same time, the higher order resonances still can cause polarization loss. As seen in RHIC, the betatron tune has to be carefully set and maintained on the ramp and during the store to avoid polarization loss. In addition, the orbit control is also critical to preserve polarization. The higher polarization during this run comes from several improvements over last run. First we have a much better orbit on the ramp. The orbit feedback brings down the vertical rms orbit error to 0.1mm, much better than the 0.5mm last run. With correct BPM offset and vertical realignment, this rms orbit error is indeed small. Second, the jump quads in the AGS improved input polarization for RHIC. Third, the vertical tune was pushed further away from 7/10 snake resonance. The tune feedback maintained the tune at the desired value through the ramp. To calibrate the analyzing power of RHIC polarimeters at any energy above

  20. RHIC Polarized proton operation

    Energy Technology Data Exchange (ETDEWEB)

    Huang, H.; Ahrens, L.; Alekseev, I.G.; Aschenauer, E.; Atoian, G.; Bai, M.; Bazilevsky, A.; Blaskiewicz, M.; Brennan, J.M.; Brown, K.A.; Bruno, D.; Connolly, R.; Dion, A.; D' Ottavio, T.; Drees, K.A.; Fischer, W.; Gardner, C.; Glenn, J.W.; Gu, X.; Harvey, M.; Hayes, T.; Hoff, L.; Hulsart, R.L.; Laster, J.; Liu, C.; Luo, Y.; MacKay, W.W.; Makdisi, Y.; Marr, G.J.; Marusic, A.; Meot, F.; Mernick, K.; Michnoff, R,; Minty, M.; Montag, C.; Morris, J.; Nemesure, S.; Poblaguev, A.; Ptitsyn, V.; Ranjibar, V.; Robert-Demolaize, G.; Roser, T.; J.; Severino, F.; Schmidke, B.; Schoefer, V.; Severino, F.; Smirnov, D.; Smith, K.; Steski, D.; Svirida, D.; Tepikian, S.; Trbojevic, D.; Tsoupas, N.; Tuozzolo, J. Wang, G.; Wilinski, M.; Yip, K.; Zaltsman, A.; Zelenski, A.; Zeno, K.; Zhang, S.Y.

    2011-03-28

    The Relativistic Heavy Ion Collider (RHIC) operation as the polarized proton collider presents unique challenges since both luminosity(L) and spin polarization(P) are important. With longitudinally polarized beams at the experiments, the figure of merit is LP{sup 4}. A lot of upgrades and modifications have been made since last polarized proton operation. A 9 MHz rf system is installed to improve longitudinal match at injection and to increase luminosity. The beam dump was upgraded to increase bunch intensity. A vertical survey of RHIC was performed before the run to get better magnet alignment. The orbit control is also improved this year. Additional efforts are put in to improve source polarization and AGS polarization transfer efficiency. To preserve polarization on the ramp, a new working point is chosen such that the vertical tune is near a third order resonance. The overview of the changes and the operation results are presented in this paper. Siberian snakes are essential tools to preserve polarization when accelerating polarized beams to higher energy. At the same time, the higher order resonances still can cause polarization loss. As seen in RHIC, the betatron tune has to be carefully set and maintained on the ramp and during the store to avoid polarization loss. In addition, the orbit control is also critical to preserve polarization. The higher polarization during this run comes from several improvements over last run. First we have a much better orbit on the ramp. The orbit feedback brings down the vertical rms orbit error to 0.1mm, much better than the 0.5mm last run. With correct BPM offset and vertical realignment, this rms orbit error is indeed small. Second, the jump quads in the AGS improved input polarization for RHIC. Third, the vertical tune was pushed further away from 7/10 snake resonance. The tune feedback maintained the tune at the desired value through the ramp. To calibrate the analyzing power of RHIC polarimeters at any energy above

  1. Blood pressure, intraerythrocyte content, and transmembrane fluxes of sodium during normal and high salt intake in subjects with and without a family history of hypertension: evidence against a sodium transport inhibitor.

    Science.gov (United States)

    Gudmundsson, O; Andersson, O; Herlitz, H; Jonsson, O; Nauclér, J; Wikstrand, J; Berglund, G

    1984-01-01

    Seventeen young normotensive men with a family history of hypertension in two generations (H) and 15 age-matched control subjects (C) were studied with respect to blood pressure (BP), intraerythrocyte sodium content (IeNa), sodium influx, and rate of sodium efflux. The investigations were done during normal salt intake and after 4 weeks of ordinary intake plus 12 g NaCl daily. BP did not increase significantly in either of the two groups during increased salt intake. During normal salt intake H had a significantly (p less than 0.01) higher IeNa (9.5 +/- 1.5 mmol/L) compared with C (8.2 +/- 1.4 mmol/L). During high salt intake IeNa in H decreased significantly to 8.1 +/- 1.2 mmol/L, the difference from C (7.6 +/- 1.2 mmol/L) not being significant. While the Na influx was similar in the two groups, the rate constant for Na efflux was significantly lower during normal salt intake in H (0.23 +/- 0.08 vs 0.29 +/- 0.1 h-1, p less than 0.05). Salt intake increased the efflux rate constant significantly in H (0.28 +/- 0.08 h-1, p less than 0.05), while it did not change significantly in C (0.32 +/- 0.08 h-1) compared with the value for normal salt intake. Our results suggest that young men with a hereditary predisposition to hypertension have a higher IeNa secondary to a lower rate of Na efflux, while a normal Na influx indicates normal cell permeability to Na. The findings in H during high Na intake--a decreased IeNa and an increased efflux rate of Na--do not favor the existence of a sodium transport inhibitor, in subjects predisposed to hypertension, increasing during high salt intake and volume expansion and acting through inhibition of the Na efflux.

  2. Our Polar Past

    Science.gov (United States)

    Clary, Renee; Wandersee, James

    2009-01-01

    The study of polar exploration is fascinating and offers students insights into the history, culture, and politics that affect the developing sciences at the farthest ends of Earth. Therefore, the authors think there is value in incorporating polar exploration accounts within modern science classrooms, and so they conducted research to test their…

  3. Terahertz polarization imaging

    NARCIS (Netherlands)

    Van der Valk, N.C.J.; Van der Marel, W.A.M.; Planken, P.C.M.

    2005-01-01

    We present a new method to measure the polarization state of a terahertz pulse by using a modified electrooptic sampling setup. To illustrate the power of this method, we show two examples in which the knowledge of the polarization of the terahertz pulse is essential for interpreting the results:

  4. Polarized proton beams

    International Nuclear Information System (INIS)

    Roser, T.

    1995-01-01

    The acceleration of polarized proton beams in circular accelerators is complicated by the presence of numerous depolarizing spin resonances. Careful and tedious minimization of polarization loss at each of these resonances allowed acceleration of polarized proton beams up to 22 GeV. It has been the hope that Siberian Snakes, which are local spin rotators inserted into ring accelerators, would eliminate these resonances and allow acceleration of polarized beams with the same ease and efficiency that is now routine for unpolarized beams. First tests at IUCF with a full Siberian Snake showed that the spin dynamics with a Snake can be understood in detail. The author now has results of the first tests of a partial Siberian Snake at the AGS, accelerating polarized protons to an energy of about 25 GeV. These successful tests of storage and acceleration of polarized proton beams open up new possibilities such as stored polarized beams for internal target experiments and high energy polarized proton colliders

  5. Polar Science Is Cool!

    Science.gov (United States)

    Weeks, Sophie

    2012-01-01

    Children are fascinated by the fact that polar scientists do research in extremely cold and dangerous places. In the Arctic they might be viewed as lunch by a polar bear. In the Antarctic, they could lose toes and fingers to frostbite and the wind is so fast it can rip skin off. They camp on ice in continuous daylight, weeks from any form of…

  6. Efficient polarization analysis for focusing neutron instruments

    Science.gov (United States)

    Stahn, Jochen; Glavic, Artur

    2017-06-01

    Polarized neutrons are a powerful probe to investigate magnetism in condensed matter on length scales from single atomic distances to micrometers. With the ongoing advancement of neutron optics, that allow to transport beams with increased divergence, the demands on neutron polarizes and analyzers have grown as well. The situation becomes especially challenging for new instruments at pulsed sources, where a large wavelength band needs to be polarized to make efficient use of the time structure of the beam. Here we present a polarization analysis concept for highly focused neutron beams that is based on transmission supermirrors that are bend in the shape of equiangular spirals. The method allows polarizations above 95% and good transmission, without negative impact on other beam characteristics. An example of a compact polarizing device already tested on the AMOR reflectometer is presented as well as the concept for the next generation implementation of the technique that will be installed on the Estia instrument being build for the European Spallation Source.

  7. Magnetoresistance through spin-polarized p states

    International Nuclear Information System (INIS)

    Papanikolaou, Nikos

    2003-01-01

    We present a theoretical study of the ballistic magnetoresistance in Ni contacts using first-principles, atomistic, electronic structure calculations. In particular we investigate the role of defects in the contact region with the aim of explaining the recently observed spectacular magnetoresistance ratio. Our results predict that the possible presence of spin-polarized oxygen in the contact region could explain conductance changes by an order of magnitude. Electronic transport essentially occurs through spin-polarized oxygen p states, and this mechanism gives a much higher magnetoresistance than that obtained assuming clean atomically sharp domain walls alone

  8. Precision Polarization of Neutrons

    Science.gov (United States)

    Martin, Elise; Barron-Palos, Libertad; Couture, Aaron; Crawford, Christopher; Chupp, Tim; Danagoulian, Areg; Estes, Mary; Hona, Binita; Jones, Gordon; Klein, Andi; Penttila, Seppo; Sharma, Monisha; Wilburn, Scott

    2009-05-01

    Determining polarization of a cold neutron beam to high precision is required for the next generation neutron decay correlation experiments at the SNS, such as the proposed abBA and PANDA experiments. Precision polarimetry measurements were conducted at Los Alamos National Laboratory with the goal of determining the beam polarization to the level of 10-3 or better. The cold neutrons from FP12 were polarized using optically polarized ^3He gas as a spin filter, which has a highly spin-dependent absorption cross section. A second ^ 3He spin filter was used to analyze the neutron polarization after passing through a resonant RF spin rotator. A discussion of the experiment and results will be given.

  9. Optically polarized 3He

    Science.gov (United States)

    Gentile, T. R.; Nacher, P. J.; Saam, B.; Walker, T. G.

    2018-01-01

    This article reviews the physics and technology of producing large quantities of highly spin-polarized 3He nuclei using spin-exchange (SEOP) and metastability-exchange (MEOP) optical pumping. Both technical developments and deeper understanding of the physical processes involved have led to substantial improvements in the capabilities of both methods. For SEOP, the use of spectrally narrowed lasers and K-Rb mixtures has substantially increased the achievable polarization and polarizing rate. For MEOP nearly lossless compression allows for rapid production of polarized 3He and operation in high magnetic fields has likewise significantly increased the pressure at which this method can be performed, and revealed new phenomena. Both methods have benefitted from development of storage methods that allow for spin-relaxation times of hundreds of hours, and specialized precision methods for polarimetry. SEOP and MEOP are now widely applied for spin-polarized targets, neutron spin filters, magnetic resonance imaging, and precision measurements. PMID:29503479

  10. Optically polarized 3He

    Science.gov (United States)

    Gentile, T. R.; Nacher, P. J.; Saam, B.; Walker, T. G.

    2017-10-01

    This article reviews the physics and technology of producing large quantities of highly spin-polarized 3He nuclei using spin-exchange (SEOP) and metastability-exchange (MEOP) optical pumping. Both technical developments and deeper understanding of the physical processes involved have led to substantial improvements in the capabilities of both methods. For SEOP, the use of spectrally narrowed lasers and K-Rb mixtures has substantially increased the achievable polarization and polarizing rate. For MEOP nearly lossless compression allows for rapid production of polarized 3He and operation in high magnetic fields has likewise significantly increased the pressure at which this method can be performed, and revealed new phenomena. Both methods have benefitted from development of storage methods that allow for spin-relaxation times of hundreds of hours, and specialized precision methods for polarimetry. SEOP and MEOP are now widely applied for spin-polarized targets, neutron spin filters, magnetic resonance imaging, and precision measurements.

  11. Parallel Polarization State Generation.

    Science.gov (United States)

    She, Alan; Capasso, Federico

    2016-05-17

    The control of polarization, an essential property of light, is of wide scientific and technological interest. The general problem of generating arbitrary time-varying states of polarization (SOP) has always been mathematically formulated by a series of linear transformations, i.e. a product of matrices, imposing a serial architecture. Here we show a parallel architecture described by a sum of matrices. The theory is experimentally demonstrated by modulating spatially-separated polarization components of a laser using a digital micromirror device that are subsequently beam combined. This method greatly expands the parameter space for engineering devices that control polarization. Consequently, performance characteristics, such as speed, stability, and spectral range, are entirely dictated by the technologies of optical intensity modulation, including absorption, reflection, emission, and scattering. This opens up important prospects for polarization state generation (PSG) with unique performance characteristics with applications in spectroscopic ellipsometry, spectropolarimetry, communications, imaging, and security.

  12. Proton pump inhibitors

    Science.gov (United States)

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

  13. Polarization at the SLC

    Energy Technology Data Exchange (ETDEWEB)

    Moffeit, K.C.

    1988-10-01

    The Stanford Linear collider was designed to accommodate polarized electron beams. Longitudinally polarized electrons colliding with unpolarized positrons at a center of mass energy near the Z/sup 0/ mass can be used as novel and sensitive probes of the electroweak process. A gallium arsenide based photon emission source will provide a beam of longitudinally polarized electrons of about 45 percent polarization. A system of bend magnets and a superconducting solenoid will be used to rotate the spins so that the polarization is preserved while the 1.21 GeV electrons are stored in the damping ring. Another set of bend magnets and two superconducting solenoids orient the spin vectors so that longitudinal polarization of the electrons is achieved at the collision point with the unpolarized positrons. A system to monitor the polarization based on Moller and Compton scattering will be used. Nearly all major components have been fabricated and tested. Subsystems of the source and polarimeters have been installed, and studies are in progress. The installation and commissioning of the entire system will take place during available machine shutdown periods as the commissioning of SLC progresses. 8 refs., 16 figs., 1 tab.

  14. Polarized atomic beams for targets

    International Nuclear Information System (INIS)

    Grueebler, W.

    1984-01-01

    The basic principle of the production of polarized atomic hydrogen and deuterium beams are reviewed. The status of the present available polarization, density and intensity are presented. The improvement of atomic beam density by cooling the hydrogen atoms to low velocity is discussed. The possible use of polarized atomic beams as targets in storage rings is shown. It is proposed that polarized atomic beams can be used to produce polarized gas targets with high polarization and greatly improved density

  15. Heidelberg polarized alkali source

    International Nuclear Information System (INIS)

    Kraemer, D.; Steffens, E.; Jaensch, H.; Philipps Universitaet, Marburg, Germany)

    1984-01-01

    A new atomic beam type polarized alkali ion source has been installed at Heidelberg. In order to improve the beam polarization considerably optical pumping is applied in combination with an adiabatic medium field transition which results in beams in single hyperfine sublevels. The m state population is determined by laser-induced fluorescence spectroscopy. Highly polarized beams (P/sub s/ > 0.9, s = z, zz) with intensities of 30 to 130 μA can be extracted for Li + and Na + , respectively

  16. Polarized Cell Division of Chlamydia trachomatis.

    Directory of Open Access Journals (Sweden)

    Yasser Abdelrahman

    2016-08-01

    Full Text Available Bacterial cell division predominantly occurs by a highly conserved process, termed binary fission, that requires the bacterial homologue of tubulin, FtsZ. Other mechanisms of bacterial cell division that are independent of FtsZ are rare. Although the obligate intracellular human pathogen Chlamydia trachomatis, the leading bacterial cause of sexually transmitted infections and trachoma, lacks FtsZ, it has been assumed to divide by binary fission. We show here that Chlamydia divides by a polarized cell division process similar to the budding process of a subset of the Planctomycetes that also lack FtsZ. Prior to cell division, the major outer-membrane protein of Chlamydia is restricted to one pole of the cell, and the nascent daughter cell emerges from this pole by an asymmetric expansion of the membrane. Components of the chlamydial cell division machinery accumulate at the site of polar growth prior to the initiation of asymmetric membrane expansion and inhibitors that disrupt the polarity of C. trachomatis prevent cell division. The polarized cell division of C. trachomatis is the result of the unipolar growth and FtsZ-independent fission of this coccoid organism. This mechanism of cell division has not been documented in other human bacterial pathogens suggesting the potential for developing Chlamydia-specific therapeutic treatments.

  17. Polarization measurement in the COMPASS polarized target

    CERN Document Server

    Kondo, K; Baum, G; Berglund, P; Doshita, N; Gautheron, F; Görtz, S; Hasegawa, T; Horikawa, N; Ishimoto, S; Iwata, T; Kisselev, Yu V; Koivuniemi, J H; Le Goff, J M; Magnon, A; Meyer, W; Reicherz, G; Matsuda, T

    2004-01-01

    Continuous wave nuclear magnetic resonance (NMR) is used to determine the target polarization in the COMPASS experiment. The system is made of the so-called Liverpool Q-meters, Yale-cards, and VME modules for data taking and system controlling. In 2001 the NMR coils were embedded in the target material, while in 2002 and 2003 the coils were mounted on the outer surface of the target cells to increase the packing factor of the material. Though the error of the measurement became larger with the outer coils than with the inner coils, we have performed stable measurements throughout the COMPASS run time for 3 years. The maximum polarization was +57% and -53% as the average in the target cells.

  18. Polarization Shaping for Control of Nonlinear Propagation.

    Science.gov (United States)

    Bouchard, Frédéric; Larocque, Hugo; Yao, Alison M; Travis, Christopher; De Leon, Israel; Rubano, Andrea; Karimi, Ebrahim; Oppo, Gian-Luca; Boyd, Robert W

    2016-12-02

    We study the nonlinear optical propagation of two different classes of light beams with space-varying polarization-radially symmetric vector beams and Poincaré beams with lemon and star topologies-in a rubidium vapor cell. Unlike Laguerre-Gauss and other types of beams that quickly experience instabilities, we observe that their propagation is not marked by beam breakup while still exhibiting traits such as nonlinear confinement and self-focusing. Our results suggest that, by tailoring the spatial structure of the polarization, the effects of nonlinear propagation can be effectively controlled. These findings provide a novel approach to transport high-power light beams in nonlinear media with controllable distortions to their spatial structure and polarization properties.

  19. Workshop on the Polar Regions of Mars: Geology, Glaciology, and Climate History, part 1

    Science.gov (United States)

    Clifford, S. M. (Editor); Howard, A. D. (Editor); Paterson, W. S. B. (Editor)

    1992-01-01

    Papers and abstract of papers presented at the workshop are presented. Some representative titles are as follows: Glaciation in Elysium; Orbital, rotational, and climatic interactions; Water on Mars; Rheology of water-silicate mixtures at low temperatures; Evolution of the Martian atmosphere (the role of polar caps); Is CO2 ice permanent; Dust transport into Martian polar latitudes; Mars observer radio science (MORS) observations in polar regions; and Wind transport near the poles of Mars (timescales of changes in deposition and erosion).

  20. Dynamic nuclear spin polarization

    Energy Technology Data Exchange (ETDEWEB)

    Stuhrmann, H.B. [GKSS-Forschungszentrum Geesthacht GmbH (Germany)

    1996-11-01

    Polarized neutron scattering from dynamic polarized targets has been applied to various hydrogenous materials at different laboratories. In situ structures of macromolecular components have been determined by nuclear spin contrast variation with an unprecedented precision. The experiments of selective nuclear spin depolarisation not only opened a new dimension to structural studies but also revealed phenomena related to propagation of nuclear spin polarization and the interplay of nuclear polarisation with the electronic spin system. The observation of electron spin label dependent nuclear spin polarisation domains by NMR and polarized neutron scattering opens a way to generalize the method of nuclear spin contrast variation and most importantly it avoids precontrasting by specific deuteration. It also likely might tell us more about the mechanism of dynamic nuclear spin polarisation. (author) 4 figs., refs.

  1. Time Domain Induced Polarization

    DEFF Research Database (Denmark)

    Fiandaca, Gianluca; Auken, Esben; Christiansen, Anders Vest

    2012-01-01

    Time-domain-induced polarization has significantly broadened its field of reference during the last decade, from mineral exploration to environmental geophysics, e.g., for clay and peat identification and landfill characterization. Though, insufficient modeling tools have hitherto limited the use...... of time-domaininduced polarization for wider purposes. For these reasons, a new forward code and inversion algorithm have been developed using the full-time decay of the induced polarization response, together with an accurate description of the transmitter waveform and of the receiver transfer function......%. Furthermore, the presence of low-pass filters in time-domain-induced polarization instruments affects the early times of the acquired decays (typically up to 100 ms) and has to be modeled in the forward response to avoid significant loss of resolution. The developed forward code has been implemented in a 1D...

  2. Polarized proton colliders

    International Nuclear Information System (INIS)

    Roser, T.

    1995-01-01

    High energy polarized beam collisions will open up the unique physics opportunities of studying spin effects in hard processes. This will allow the study of the spin structure of the proton and also the verification of the many well documented expectations of spin effects in perturbative QCD and parity violation in W and Z production. Proposals for polarized proton acceleration for several high energy colliders have been developed. A partial Siberian Snake in the AGS has recently been successfully tested and full Siberian Snakes, spin rotators, and polarimeters for RHIC are being developed to make the acceleration of polarized beams to 250 GeV possible. This allows for the unique possibility of colliding two 250 GeV polarized proton beams at luminosities of up to 2 x 10 32 cm -2 s -1

  3. Transport of Indole-3-Butyric Acid and Indole-3-Acetic Acid in Arabidopsis Hypocotyls Using Stable Isotope Labeling1[C][W][OA

    Science.gov (United States)

    Liu, Xing; Barkawi, Lana; Gardner, Gary; Cohen, Jerry D.

    2012-01-01

    The polar transport of the natural auxins indole-3-butyric acid (IBA) and indole-3-acetic acid (IAA) has been described in Arabidopsis (Arabidopsis thaliana) hypocotyls using radioactive tracers. Because radioactive assays alone cannot distinguish IBA from its metabolites, the detected transport from applied [3H]IBA may have resulted from the transport of IBA metabolites, including IAA. To test this hypothesis, we used a mass spectrometry-based method to quantify the transport of IBA in Arabidopsis hypocotyls by following the movement of [13C1]IBA and the [13C1]IAA derived from [13C1]IBA. We also assayed [13C6]IAA transport in a parallel control experiment. We found that the amount of transported [13C1]IBA was dramatically lower than [13C6]IAA, and the IBA transport was not reduced by the auxin transport inhibitor N-1-naphthylphthalamic acid. Significant amounts of the applied [13C1]IBA were converted to [13C1]IAA during transport, but [13C1]IBA transport was independent of IBA-to-IAA conversion. We also found that most of the [13C1]IBA was converted to ester-linked [13C1]IBA at the apical end of hypocotyls, and ester-linked [13C1]IBA was also found in the basal end at a level higher than free [13C1]IBA. In contrast, most of the [13C6]IAA was converted to amide-linked [13C6]IAA at the apical end of hypocotyls, but very little conjugated [13C6]IAA was found in the basal end. Our results demonstrate that the polar transport of IBA is much lower than IAA in Arabidopsis hypocotyls, and the transport mechanism is distinct from IAA transport. These experiments also establish a method for quantifying the movement of small molecules in plants using stable isotope labeling. PMID:22323783

  4. Plasma polarization spectroscopy

    International Nuclear Information System (INIS)

    Iwamae, Atsushi; Horimoto, Yasuhiro; Fujimoto, Takashi; Hasegawa, Noboru; Sukegawa, Kouta; Kawachi, Tetsuya

    2005-01-01

    The electron velocity distribution function (EVDF) in plasma can be anisotropic in laser-produced plasmas. We have developed a new technique to evaluate the polarization degree of the emission lines in the extreme vacuum ultra violet wavelength region. The polarization of the emission lines and the continuums from the lithium-like nitrogen and from helium- and hydrogen-like carbon in recombining plasma is evaluated. Particle simulation in the velocity space gives the time scale for relaxation of anisotropic EVDFs. (author)

  5. Ultracold Polar Molecules

    Science.gov (United States)

    2016-04-01

    AFRL-AFOSR-UK-TR-2016-0005 Ultracold Polar Molecules Jeremy Hutson UNIVERSITY OF DURHAM Final Report 04/01/2016 DISTRIBUTION A: Distribution approved...DATES COVERED (From - To) 15-Jan-2010 to 14-Jul-2015 4. TITLE AND SUBTITLE Final Report on Grant FA8655-10-1-3033 on Ultracold Polar Molecules 5a...formation of ultracold 87RbCs molecules in their rovibrational ground state by magnetoassociation followed by STIRAP, resulting in 14 papers acknowledging

  6. Astrocytic GABA Transporters

    DEFF Research Database (Denmark)

    Schousboe, Arne; Wellendorph, Petrine; Frølund, Bente

    2017-01-01

    , and several of these compounds have been shown to exhibit pronounced anticonvulsant activity in a variety of animal seizure models. As proof of concept of the validity of this drug development approach, one GABA-transport inhibitor, tiagabine, has been developed as a clinically active antiepileptic drug...

  7. Hsp Polarization Verification

    Science.gov (United States)

    Bless, Robert

    1991-07-01

    This proposal defines the procedure for determining the instrumental polarization of the polarimetric IDT (IDT#1, POL) on the HSP. 1 of 2 unpolarized standard stars wil be observed using various filter-polarizer combinations. These observations will permit the instrumental polarization to be calibrated. The instrumental polarization must be determined to a high precision in order to vectoriallly remove it from HSP polarization observations to determine the actual astronomical polarization. Final run of proposal will look at one of 2 possible stars previously observed to get another look at the throughput. Revision History: Mark H. Slovak 8/30/88 Translated to V2 proposal instructions (RPSS V6.2) S. Laurent 1/20/89 Updated: Sally Laurent 2/24/89, 3/20/89, 4/13/89, 5/12/89 Modified: P. Stanley 1/15/90 - change to use CTA selected targets only; Fixes for aberration problem - SALM 7/30/90; Based on SV/HSP 1386. New submission changed targets and revised scheduling strategy. Revised: 26 Aug 92 J. Dolan, L. Walter, P. Reppert want to re-run the proposal (3985) one last time to bring down errors.

  8. Polarized Light Microscopy

    Science.gov (United States)

    Frandsen, Athela F.

    2016-01-01

    Polarized light microscopy (PLM) is a technique which employs the use of polarizing filters to obtain substantial optical property information about the material which is being observed. This information can be combined with other microscopy techniques to confirm or elucidate the identity of an unknown material, determine whether a particular contaminant is present (as with asbestos analysis), or to provide important information that can be used to refine a manufacturing or chemical process. PLM was the major microscopy technique in use for identification of materials for nearly a century since its introduction in 1834 by William Fox Talbot, as other techniques such as SEM (Scanning Electron Microscopy), FTIR (Fourier Transform Infrared spectroscopy), XPD (X-ray Powder Diffraction), and TEM (Transmission Electron Microscopy) had not yet been developed. Today, it is still the only technique approved by the Environmental Protection Agency (EPA) for asbestos analysis, and is often the technique first applied for identification of unknown materials. PLM uses different configurations in order to determine different material properties. With each configuration additional clues can be gathered, leading to a conclusion of material identity. With no polarizing filter, the microscope can be used just as a stereo optical microscope, and view qualities such as morphology, size, and number of phases. With a single polarizing filter (single polars), additional properties can be established, such as pleochroism, individual refractive indices, and dispersion staining. With two polarizing filters (crossed polars), even more can be deduced: isotropy vs. anisotropy, extinction angle, birefringence/degree of birefringence, sign of elongation, and anomalous polarization colors, among others. With the use of PLM many of these properties can be determined in a matter of seconds, even for those who are not highly trained. McCrone, a leader in the field of polarized light microscopy, often

  9. The apical actin fringe contributes to localized cell wall deposition and polarized growth in the lily pollen tube.

    Science.gov (United States)

    Rounds, Caleb M; Hepler, Peter K; Winship, Lawrence J

    2014-09-01

    In lily (Lilium formosanum) pollen tubes, pectin, a major component of the cell wall, is delivered through regulated exocytosis. The targeted transport and secretion of the pectin-containing vesicles may be controlled by the cortical actin fringe at the pollen tube apex. Here, we address the role of the actin fringe using three different inhibitors of growth: brefeldin A, latrunculin B, and potassium cyanide. Brefeldin A blocks membrane trafficking and inhibits exocytosis in pollen tubes; it also leads to the degradation of the actin fringe and the formation of an aggregate of filamentous actin at the base of the clear zone. Latrunculin B, which depolymerizes filamentous actin, markedly slows growth but allows focused pectin deposition to continue. Of note, the locus of deposition shifts frequently and correlates with changes in the direction of growth. Finally, potassium cyanide, an electron transport chain inhibitor, briefly stops growth while causing the actin fringe to completely disappear. Pectin deposition continues but lacks focus, instead being delivered in a wide arc across the pollen tube tip. These data support a model in which the actin fringe contributes to the focused secretion of pectin to the apical cell wall and, thus, to the polarized growth of the pollen tube. © 2014 American Society of Plant Biologists. All Rights Reserved.

  10. A study of the first and second polar bodies in mouse oogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Evsikov, A.V.; Evsikov, S.V. [Institute of Molecular Biology and Genetics, Kiev (Ukraine)

    1995-05-01

    The possibility of using a polar body for biopsy of human oocytes and early embryos has recently been shown. Genetic analysis of polar bodies can also provide additional information about the mechanisms underlying oocyte maturation. The first polar body is extremely unstable: in mouse oocytes, it disintegrates within several hours. Thus, the possibilities for its analysis are limited. We obtained karyoplasts of mouse eggs that contained the metaphase II spindle. By using them as a model for the first polar body, we studied the causes of its rapid disintegration. The rates of disintegration of the karyoplasts treated with various inhibitors of the cytoskeleton indicate that disintegration of the first polar body may be due to interaction between the actin cytoskeleton, chromatin, and the plasma membrane. The second polar body is found in mouse embryos until the blastocyst stage. Fusion of the second polar body with the enucleated zygote allowed analysis of its chromosomes. 22 refs., 5 figs., 1 tab.

  11. The evolution of tensor polarization

    International Nuclear Information System (INIS)

    Huang, H.; Lee, S.Y.; Ratner, L.

    1993-01-01

    By using the equation of motion for the vector polarization, the spin transfer matrix for spin tensor polarization, the spin transfer matrix for spin tensor polarization is derived. The evolution equation for the tensor polarization is studied in the presence of an isolate spin resonance and in the presence of a spin rotor, or snake

  12. Polarized Electrons at Jefferson Laboratory

    Energy Technology Data Exchange (ETDEWEB)

    Sinclair, C.K.

    1997-12-31

    The CEBAF accelerator at Jefferson laboratory can deliver CW electron beams to three experimental halls simultaneously. A large fraction of the approved scientific program at the lab requires polarized electron beams. Many of these experiments, both polarized and unpolarized, require high average beam current as well. Since all electrons delivered to the experimental halls originate from the same cathode, delivery of polarized beam to a single hall requires using the polarized source to deliver beam to all experiments in simultaneous operation. The polarized source effort at Jefferson Lab is directed at obtaining very long polarized source operational lifetimes at high average current and beam polarization; at developing the capability to deliver all electrons leaving the polarized source to the experimental halls; and at delivering polarized beam to multiple experimental halls simultaneously.initial operational experience with the polarized source will be presented.

  13. Polarized electrons at Jefferson laboratory

    International Nuclear Information System (INIS)

    The CEBAF accelerator at Jefferson laboratory can deliver CW electron beams to three experimental halls simultaneously. A large fraction of the approved scientific program at the lab requires polarized electron beams. Many of these experiments, both polarized and unpolarized, require high average beam current as well. Since all electrons delivered to the experimental halls originate from the same cathode, delivery of polarized beam to a single hall requires using the polarized source to deliver beam to all experiments in simultaneous operation. The polarized source effort at Jefferson Lab is directed at obtaining very long polarized source operational lifetimes at high average current and beam polarization; at developing the capability to deliver all electrons leaving the polarized source to the experimental halls; and at delivering polarized beam to multiple experimental halls simultaneously. Initial operational experience with the polarized source will be presented

  14. Ginger extract as green corrosion inhibitor of mild steel in hydrochloric acid solution

    Science.gov (United States)

    Fidrusli, A.; Suryanto; Mahmood, M.

    2018-01-01

    Ginger extract as corrosion inhibitor from natural resources was studied to prevent corrosion of mild steel in acid media. Ginger rhizome was extracted to produce green corrosion inhibitor (G-1) while ginger powder bought at supermarket was also extract to form green corrosion inhibitor (G-2). Effectiveness of inhibitor in preventing corrosion process of mild steel was studied in 1.0 M of hydrochloric acid. The experiment of weight loss method and polarization technique were conducted to measure corrosion rate and inhibition efficiency of mild steel in solution containing 1.0 M of hydrochloric acid with various concentration of inhibitor at room temperature. The results showed that, the rate of corrosion dropped from 8.09 mmpy in solution containing no inhibitor to 0.72 mmpy in solution containing 150g/l inhibitor while inhibition efficiency up to 91% was obtained. The polarization curve in polarization experiments shows that the inhibition efficiency is 86% with high concentration of inhibitor. The adsorption of ginger extract on the surface of mild steel was observed by using optical microscope and the characterization analysis was done by using pH measurement method. When high concentration of green inhibitor in the acid solution is used, the pH at the surface of steel is increasing.

  15. Polar low monitoring

    Science.gov (United States)

    Bobylev, Leonid; Zabolotskikh, Elizaveta; Mitnik, Leonid

    2010-05-01

    Polar lows are intense mesoscale atmospheric low pressure weather systems, developing poleward of the main baroclinic zone and associated with high surface wind speeds. Small size and short lifetime, sparse in-situ observations in the regions of their development complicate polar low study. Our knowledge of polar lows and mesocyclones has come almost entirely during the period of satellite remote sensing since, by virtue of their small horizontal scale, it was rarely possible to analyse these lows on conventional weather charts using only the data from the synoptic observing network. However, the effects of intense polar lows have been felt by coastal communities and seafarers since the earliest times. These weather systems are thought to be responsible for the loss of many small vessels over the centuries, although the nature of the storms was not understood and their arrival could not be predicted. The actuality of the polar low research is stipulated by their high destructive power: they are a threat to such businesses as oil and gas exploration, fisheries and shipping. They could worsen because of global warming: a shrinking of sea ice around the North Pole, which thawed to its record minimum in the summer of 2007, is likely to give rise to more powerful storms that form only over open water and can cause hurricane-strength winds. Therefore, study of polar lows, their timely detection, tracking and forecasting represents a challenge for today meteorology. Satellite passive microwave data, starting from Special Sensor Microwave Imager (SSM/I) onboard Defense Meteorological Satellite Program (DMSP) satellite, remain invaluable source of regularly available remotely sensed data to study polar lows. The sounding in this spectral range has several advantages in comparison with observations in visible and infrared ranges and Synthetic Aperture Radar (SAR) data: independence on day time and clouds, regularity and high temporal resolution in Polar Regions. Satellite

  16. Polarized protons at RHIC

    International Nuclear Information System (INIS)

    Tannenbaum, M.J.

    1990-12-01

    The Physics case is presented for the use of polarized protons at RHIC for one or two months each year. This would provide a facility with polarizations of approx-gt 50% high luminosity ∼2.0 x 10 32 cm -2 s -1 , the possibility of both longitudinal and transverse polarization at the interaction regions, and frequent polarization reversal for control of systematic errors. The annual integrated luminosity for such running (∼10 6 sec per year) would be ∫ Ldt = 2 x 10 38 cm -2 -- roughly 20 times the total luminosity integrated in ∼ 10 years of operation of the CERN Collider (∼10 inverse picobarns, 10 37 cm -2 ). This facility would be unique in the ability to perform parity-violating measurements and polarization test of QCD. Also, the existence of p-p collisions in a new energy range would permit the study of ''classical'' reactions like the total cross section and elastic scattering, etc., and serve as a complement to measurements from p-bar p colliders. 11 refs

  17. The Bochum Polarized Target

    International Nuclear Information System (INIS)

    Reicherz, G.; Goertz, S.; Harmsen, J.; Heckmann, J.; Meier, A.; Meyer, W.; Radtke, E.

    2001-01-01

    The Bochum 'Polarized Target' group develops the target material 6 LiD for the COMPASS experiment at CERN. Several different materials like alcohols, alcanes and ammonia are under investigation. Solid State Targets are polarized in magnetic fields higher than B=2.5T and at temperatures below T=1K. For the Dynamic Nuclear Polarization process, paramagnetic centers are induced chemically or by irradiation with ionizing beams. The radical density is a critical factor for optimization of polarization and relaxation times at adequate magnetic fields and temperatures. In a high sensitive EPR--apparatus, an evaporator and a dilution cryostat with a continuous wave NMR--system, the materials are investigated and optimized. To improve the polarization measurement, the Liverpool NMR-box is modified by exchanging the fixed capacitor for a varicap diode which not only makes the tuning very easy but also provides a continuously tuned circuit. The dependence of the signal area upon the circuit current is measured and it is shown that it follows a linear function

  18. In-line Fiber Polarizer

    OpenAIRE

    Perumalsamy, Priya

    1998-01-01

    Polarizers and polarization devices are important components in fiber optic communication and sensor systems. There is a growing need for efficient low loss components that are compatible with optical fibers. An all fiber in-line polarizer is a more desirable alternative that could be placed at appropriate intervals along communication links. An in-line fiber polarizer was fabricated and tested. The in-line fiber polarizer operates by coupling optical energy propagatin...

  19. Political Competition and Polarization

    DEFF Research Database (Denmark)

    Schultz, Christian

    This paper considers political competition and the consequences of political polarization when parties are better informed about how the economy functions than voters are. Specifically, parties know the cost producing a public good, voters do not. An incumbent's choice of policy acts like a signa...... for costs before an upcoming election. It is shown that the more polarized the political parties the more distorted the incumbent's policy choice.......This paper considers political competition and the consequences of political polarization when parties are better informed about how the economy functions than voters are. Specifically, parties know the cost producing a public good, voters do not. An incumbent's choice of policy acts like a signal...

  20. Physics of polarized targets

    CERN Document Server

    Niinikoski, Tapio

    2014-01-01

    For developing, building and operating solid polarized targets we need to understand several fields of physics that have seen sub stantial advances during the last 50 years. W e shall briefly review a selection of those that are important today. These are: 1) quantum statistical methods to describe saturation and relaxation in magnetic resonance; 2) equal spin temperature model for dy namic nuclear polarization; 3 ) weak saturation during NMR polarization measurement; 4 ) refrigeration using the quantum fluid properties of helium isotopes. These, combined with superconducting magnet technologies, permit today to reach nearly complete pola rization of almost any nuclear spins. Targets can be operated in frozen spin mode in rather low and inhomogeneous field of any orientation, and in DNP mode in beams of high intensity. Beyond such experiments of nuclear and particle physics, applications a re also emerging in macromolecular chemistry and in magnetic resonance imaging. This talk is a tribute to Michel Borghini...

  1. No More Polarization, Please!

    DEFF Research Database (Denmark)

    Hansen, Mia Reinholt

    The organizational science literature on motivation has for long been polarized into two main positions; the organizational economic position focusing on extrinsic motivation and the organizational behavior position emphasizing intrinsic motivation. With the rise of the knowledge economy...... and the increasing levels of complexities it entails, such polarization is not fruitful in the attempt to explain motivation of organizational members. This paper claims that a more nuanced perspective on motivation, acknowledging the co-existence of intrinsic and extrinsic motivation, the possible interaction...... between the two as well as different types of motivations filling in the gap between the two polar types, is urgently needed in the organizational science literature. By drawing on the research on intrinsic and extrinsic motivation conducted in social psychology and combining this with contributions from...

  2. Polarized source upgrading

    International Nuclear Information System (INIS)

    Clegg, T.B.; Rummel, R.L.; Carter, E.P.; Westerfeldt, C.R.; Lovette, A.W.; Edwards, S.E.

    1985-01-01

    The decision was made this past year to move the Lamb-shift polarized ion source which was first installed in the laboratory in 1970. The motivation was the need to improve the flexibility of spin-axis orientation by installing the ion source with a new Wien-filter spin precessor which is capable of rotating physically about the beam axis. The move of the polarized source was accomplished in approximately two months, with the accelerator being turned off for experiments during approximately four weeks of this time. The occasion of the move provided the opportunity to rewire completely the entire polarized ion source frame and to rebuild approximately half of the electronic chassis on the source. The result is an ion source which is now logically wired and carefully documented. Beams obtained from the source are much more stable than those previously available

  3. Polarization simulations in the RHIC run 15 lattice

    Energy Technology Data Exchange (ETDEWEB)

    Meot, F. [Brookhaven National Lab. (BNL), Upton, NY (United States). Collider-Accelerator Dept.; Huang, H. [Brookhaven National Lab. (BNL), Upton, NY (United States). Collider-Accelerator Dept.; Luo, Y. [Brookhaven National Lab. (BNL), Upton, NY (United States). Collider-Accelerator Dept.; Ranjbar, V. [Brookhaven National Lab. (BNL), Upton, NY (United States). Collider-Accelerator Dept.; Robert-Demolaize, G. [Brookhaven National Lab. (BNL), Upton, NY (United States). Collider-Accelerator Dept.; White, S. [Brookhaven National Lab. (BNL), Upton, NY (United States). Collider-Accelerator Dept.

    2015-05-03

    RHIC polarized proton Run 15 uses a new acceleration ramp optics, compared to RHIC Run 13 and earlier runs, in relation with electron-lens beam-beam compensation developments. The new optics induces different strengths in the depolarizing snake resonance sequence, from injection to top energy. As a consequence, polarization transport along the new ramp has been investigated, based on spin tracking simulations. Sample results are reported and discussed.

  4. POLARIZED NEUTRONS IN RHIC

    Energy Technology Data Exchange (ETDEWEB)

    COURANT,E.D.

    1998-04-27

    There does not appear to be any obvious way to accelerate neutrons, polarized or otherwise, to high energies by themselves. To investigate the behavior of polarized neutrons the authors therefore have to obtain them by accelerating them as components of heavier nuclei, and then sorting out the contribution of the neutrons in the analysis of the reactions produced by the heavy ion beams. The best neutron carriers for this purpose are probably {sup 3}He nuclei and deuterons. A polarized deuteron is primarily a combination of a proton and a neutron with their spins pointing in the same direction; in the {sup 3}He nucleus the spins of the two protons are opposite and the net spin (and magnetic moment) is almost the same as that of a free neutron. Polarized ions other than protons may be accelerated, stored and collided in a ring such as RHIC provided the techniques proposed for polarized proton operation can be adapted (or replaced by other strategies) for these ions. To accelerate polarized particles in a ring, one must make provisions for overcoming the depolarizing resonances that occur at certain energies. These resonances arise when the spin tune (ratio of spin precession frequency to orbit frequency) resonates with a component present in the horizontal field. The horizontal field oscillates with the vertical motion of the particles (due to vertical focusing); its frequency spectrum is dominated by the vertical oscillation frequency and its modulation by the periodic structure of the accelerator ring. In addition, the magnet imperfections that distort the closed orbit vertically contain all integral Fourier harmonics of the orbit frequency.

  5. Dark Polar Dunes

    Science.gov (United States)

    2005-01-01

    20 January 2004 This Mars Global Surveyor (MGS) Mars Orbiter Camera (MOC) image, acquired during northern summer in December 2004, shows dark, windblown sand dunes in the north polar region of Mars. A vast sea of sand dunes nearly surrounds the north polar cap. These landforms are located near 80.3oN, 144.1oW. Light-toned features in the image are exposures of the substrate that underlies the dune field. The image covers an area about 3 km (1.9 mi) wide and is illuminated by sunlight from the lower left.

  6. Imaging with Polarized Neutrons

    Directory of Open Access Journals (Sweden)

    Nikolay Kardjilov

    2018-01-01

    Full Text Available Owing to their zero charge, neutrons are able to pass through thick layers of matter (typically several centimeters while being sensitive to magnetic fields due to their intrinsic magnetic moment. Therefore, in addition to the conventional attenuation contrast image, the magnetic field inside and around a sample can be visualized by detecting changes of polarization in a transmitted beam. The method is based on the spatially resolved measurement of the cumulative precession angles of a collimated, polarized, monochromatic neutron beam that traverses a magnetic field or sample.

  7. The polar mesosphere

    International Nuclear Information System (INIS)

    Morris, Ray; Murphy, Damian

    2008-01-01

    The mesosphere region, which lies at the edge of space, contains the coldest layer of the Earth's atmosphere, with summer temperatures as low as minus 130 °C. In this extreme environment ice aerosol layers have appeared since the dawn of industrialization—whose existence may arguably be linked to human influence—on yet another layer of the Earth's fragile atmosphere. Ground-based and space-based experiments conducted in the Arctic and Antarctic during the International Polar Year (IPY) aim to address limitations in our knowledge and to advance our understanding of thermal and dynamical processes at play in the polar mesosphere

  8. Internal polarized targets

    Energy Technology Data Exchange (ETDEWEB)

    Kinney, E.R.; Coulter, K.; Gilman, R.; Holt, R.J.; Kowalczyk, R.S.; Napolitano, J.; Potterveld, D.H.; Young, L. (Argonne National Lab., IL (USA)); Mishnev, S.I.; Nikolenko, D.M.; Popov, S.G.; Rachek, I.A.; Temnykh, A.B.; Toporkov, D.K.; Tsentalovich, E.P.; Wojtsekhowski, B.B. (AN SSSR, Novosibirsk (USSR). Inst. Yadernoj Fiziki)

    1989-01-01

    Internal polarized targets offer a number of advantages over external targets. After a brief review of the basic motivation and principles behind internal polarized targets, the technical aspects of the atomic storage cell will be discussed in particular. Sources of depolarization and the means by which their effects can be ameliorated will be described, especially depolarization by the intense magnetic fields arising from the circulating particle beam. The experience of the Argonne Novosibirsk collaboration with the use of a storage cell in a 2 GeV electron storage ring will be the focus of this technical discussion. 17 refs., 11 figs.

  9. AGS polarized H- source

    International Nuclear Information System (INIS)

    Kponou, A.; Alessi, J.G.; Sluyters, T.

    1985-01-01

    The AGS polarized H - source is now operational. During a month-long experimental physics run in July 1984, pulses equivalent to 15 μA x 300 μs (approx. 3 x 10 10 protons) were injected into the RFQ preaccelerator. Beam polarization, measured at 200 MeV, was approx. 75%. After the run, a program to increase the H - yield of the source was begun and significant progress has been made. The H - current is now frequently 20 to 30 μA. A description of the source and some details of our operating experience are given. We also briefly describe the improvement program

  10. Synthesis of poly[N-(2-hydroxypropyl)methacrylamide] conjugates of inhibitors of the ABC transporter that overcome multidrug resistance in doxorubicin-resistant P388 cells in vitro

    Czech Academy of Sciences Publication Activity Database

    Šubr, Vladimír; Sivák, Ladislav; Koziolová, Eva; Braunová, Alena; Pechar, Michal; Strohalm, Jiří; Kabešová, Martina; Říhová, Blanka; Ulbrich, Karel; Kovář, Marek

    2014-01-01

    Roč. 15, č. 8 (2014), s. 3030-3043 ISSN 1525-7797 R&D Projects: GA ČR GAP301/12/1254; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:61389013 ; RVO:61388971 Keywords : N-(2-hydroxypropyl)methacrylamide copolymers * multidrug resistance * P-glycoprotein inhibitors Subject RIV: CD - Macromolecular Chemistry; FD - Oncology ; Hematology (MBU-M) Impact factor: 5.750, year: 2014

  11. Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic)

    DEFF Research Database (Denmark)

    Birkeland, Kåre I.; Jørgensen, Marit E.; Carstensen, Bendix

    2017-01-01

    , and atrial fibrillation. We also assessed incidence of severe hypoglycaemia. Findings Matched SGLT2 inhibitor (n=22 830) and other glucose-lowering drug (n=68 490) groups were well balanced at baseline, with a mean follow-up of 0·9 (SD 4·1) years (80 669 patient-years) and mean age of 61 (12·0) years; 40...... with the results of clinical trials in patients at high cardiovascular risk. Funding AstraZeneca....

  12. Phosphatidylserine improves axonal transport by inhibition of HDAC and has potential in treatment of neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Shiran Naftelberg

    2017-01-01

    Full Text Available Familial dysautonomia (FD is a rare children neurodegenerative disease caused due to a point mutation in the IKBKAP gene that results in decreased IKK complex-associated protein (IKAP protein production. The disease affects mostly the dorsal root ganglion (DRG and the sympathetic ganglion. Recently, we found that the molecular mechanisms underlying neurodegeneration in FD patients are defects in axonal transport of nerve growth factors and microtubule stability in the DRG. Neurons are highly polarized cells with very long axons. In order to survive and maintain proper function, neurons depend on transport of proteins and other cellular components from the neuronal body along the axons. We further demonstrated that IKAP is necessary for axon maintenance and showed that phosphatidylserine acts as an HDAC6 inhibitor to rescue neuronal function in FD cells. In this review, we will highlight our latest research findings.

  13. DPP-4 inhibitors

    DEFF Research Database (Denmark)

    Deacon, Carolyn F.

    2016-01-01

    Dipeptidyl peptidase (DPP)-4 inhibitors inhibit the activity of the enzyme responsible for the initial rapid degradation of the incretin hormones, thereby enhancing their antihyperglycemic effects.......Dipeptidyl peptidase (DPP)-4 inhibitors inhibit the activity of the enzyme responsible for the initial rapid degradation of the incretin hormones, thereby enhancing their antihyperglycemic effects....

  14. The physics of polarization

    Science.gov (United States)

    Landi Degl'Innocenti, Egidio

    This course is intended to give a description of the basic physical concepts which underlie the study and the interpretation of polarization phenomena. Apart from a brief historical introduction (Sect. 1), the course is organized in three parts. A first part (Sects. 2 - 6) covers the most relevant facts about the polarization phenomena that are typically encountered in laboratory applications and in everyday life. In Sect. 2, the modern description of polarization in terms of the Stokes parameters is recalled, whereas Sect. 3 is devoted to introduce the basic tools of laboratory polarimetry, such as the Jones calculus and the Mueller matrices. The polarization phenomena which are met in the reflection and refraction of a beam of radiation at the separation surface between two dielectrics, or between a dielectric and a metal, are recalled in Sect. 4. Finally, Sect. 5 gives an introduction to the phenomena of dichroism and of anomalous dispersion and Sect. 6 summarizes the polarization phenomena that are commonly encountered in everyday life. The second part of this course (Sects. 7-14) deals with the description, within the formalism of classical physics, of the spectro-polarimetric properties of the radiation emitted by accelerated charges. Such properties are derived by taking as starting point the Liénard and Wiechert equations that are recalled and discussed in Sect. 7 both in the general case and in the non-relativistic approximation. The results are developed to find the percentage polarization, the radiation diagram, the cross-section and the spectral characteristics of the radiation emitted in different phenomena particularly relevant from the astrophysical point of view. The emission of a linear antenna is derived in Sect. 8. The other Sections are devoted to Thomson scattering (Sect. 9), Rayleigh scattering (Sect. 10), Mie scattering (Sect. 11), bremsstrahlung radiation (Sect. 12), cyclotron radiation (Sect. 13), and synchrotron radiation (Sect. 14

  15. Polarized Proton Collisions at RHIC

    CERN Document Server

    Bai, Mei; Alekseev, Igor G; Alessi, James; Beebe-Wang, Joanne; Blaskiewicz, Michael; Bravar, Alessandro; Brennan, Joseph M; Bruno, Donald; Bunce, Gerry; Butler, John J; Cameron, Peter; Connolly, Roger; De Long, Joseph; Drees, Angelika; Fischer, Wolfram; Ganetis, George; Gardner, Chris J; Glenn, Joseph; Hayes, Thomas; Hseuh Hsiao Chaun; Huang, Haixin; Ingrassia, Peter; Iriso, Ubaldo; Laster, Jonathan S; Lee, Roger C; Luccio, Alfredo U; Luo, Yun; MacKay, William W; Makdisi, Yousef; Marr, Gregory J; Marusic, Al; McIntyre, Gary; Michnoff, Robert; Montag, Christoph; Morris, John; Nicoletti, Tony; Oddo, Peter; Oerter, Brian; Osamu, Jinnouchi; Pilat, Fulvia Caterina; Ptitsyn, Vadim; Roser, Thomas; Satogata, Todd; Smith, Kevin T; Svirida, Dima; Tepikian, Steven; Tomas, Rogelio; Trbojevic, Dejan; Tsoupas, Nicholaos; Tuozzolo, Joseph; Vetter, Kurt; Wilinski, Michelle; Zaltsman, Alex; Zelenski, Anatoli; Zeno, Keith; Zhang, S Y

    2005-01-01

    The Relativistic Heavy Ion Collider~(RHIC) provides not only collisions of ions but also collisions of polarized protons. In a circular accelerator, the polarization of polarized proton beam can be partially or fully lost when a spin depolarizing resonance is encountered. To preserve the beam polarization during acceleration, two full Siberian snakes were employed in RHIC to avoid depolarizing resonances. In 2003, polarized proton beams were accelerated to 100~GeV and collided in RHIC. Beams were brought into collisions with longitudinal polarization at the experiments STAR and PHENIX by using spin rotators. RHIC polarized proton run experience demonstrates that optimizing polarization transmission efficiency and improving luminosity performance are significant challenges. Currently, the luminosity lifetime in RHIC is limited by the beam-beam effect. The current state of RHIC polarized proton program, including its dedicated physics run in 2005 and efforts to optimize luminosity production in beam-beam limite...

  16. Some like it cold: microbial transformations of mercury in polar regions

    DEFF Research Database (Denmark)

    Barkay, Tamar; Kroer, Niels A.; Poulain, Alexandre J.

    2011-01-01

    The contamination of polar regions with mercury that is transported from lower latitudes as inorganic mercury has resulted in the accumulation of methylmercury (MeHg) in food chains, risking the health of humans and wildlife. While production of MeHg has been documented in polar marine and terres......The contamination of polar regions with mercury that is transported from lower latitudes as inorganic mercury has resulted in the accumulation of methylmercury (MeHg) in food chains, risking the health of humans and wildlife. While production of MeHg has been documented in polar marine...

  17. Lobbying and political polarization

    OpenAIRE

    Ursprung, Heinrich W.

    2002-01-01

    Standard spatial models of political competition give rise to equilibria in which the competing political parties or candidates converge to a common position. In this paper I show how political polarization can be generated in models that focus on the nexus between pre-election interest group lobbying and electoral competition.

  18. Fluorescence confocal polarizing microscopy

    Indian Academy of Sciences (India)

    Much of the modern understanding of orientational order in liquid crystals (LCs) is based on polarizing microscopy (PM). A PM image bears only two-dimensional (2D) information, integrating the 3D pattern of optical birefringence over the path of light. Recently, we proposed a technique to image 3D director patterns by ...

  19. Polarization of Bremsstrahlung

    International Nuclear Information System (INIS)

    Miller, J.

    1957-01-01

    The numerical results for the polarization of Bremsstrahlung are presented. The multiple scattering of electrons in the target is taken into account. The angular-and photon energy dependences are seen on the curves for an incident 25 MeV electron energy. (Author) [fr

  20. DESY: HERA polarization

    International Nuclear Information System (INIS)

    Anon.

    1992-01-01

    The new HERA electron-proton collider at DESY in Hamburg achieved the first luminosity for electron-proton collisions on 19 October last year. Only one month later, on 20 November, HERA passed another important milestone with the observation of transverse electron polarization

  1. Graphics of polar figure

    International Nuclear Information System (INIS)

    Macias B, L.R.

    1991-11-01

    The objective of this work, is that starting from a data file coming from a spectra that has been softened, and of the one that have been generated its coordinates to project it in stereographic form, to create the corresponding polar figure making use of the Cyber computer of the ININ by means of the GRAPHOS package. This work only requires a Beta, Fi and Intensity (I) enter data file. It starts of the existence of a softened spectra of which have been generated already with these data, making use of some language that in this case was FORTRAN for the Cyber computer, a program is generated supported in the Graphos package that allows starting of a reading of the Beta, Fi, I file, to generate the points in a stereographic projection and that it culminates with the graph of the corresponding polar figure. The program will request the pertinent information that is wanted to capture in the polar figure just as: date, name of the enter file, indexes of the polar figure, number of levels, radio of the stereographic projection (cms.), crystalline system to which belongs the sample, name the neuter graph file by create and to add the own general data. (Author)

  2. Polarity-Driven Geometrical Cluster Growth Model of Budding Yeast

    Science.gov (United States)

    Cabral, Reniel B.; Lim, May T.

    We present a polarity-driven activator-inhibitor model of budding yeast in a two-dimensional medium wherein impeding metabolites secretion (or growth inhibitors) and growth directionality are determined by the local nutrient level. We found that colony size and morphological features varied with nutrient concentration. A branched-type morphology is associated with high impeding metabolite concentration together with a high fraction of distal budding, while opposite conditions (low impeding metabolite concentration, high fraction of proximal budding) promote Eden-type patterns. Increasing the anisotropy factor (or polarity) produced other spatial patterns akin to the electrical breakdown under varying electric field. Rapid changes in the colony morphology, which we conjecture to be equivalent to a transition from an inactive quiescent state to an active budding state, appeared when nutrients were limited.

  3. Characteristics of volume polarization holography with linear polarization light

    Science.gov (United States)

    Zang, Jinliang; Wu, An'an; Liu, Ying; Wang, Jue; Lin, Xiao; Tan, Xiaodi; Shimura, Tsutomu; Kuroda, Kazuo

    2015-10-01

    Volume polarization holographic recording in phenanthrenequinone-doped poly(methyl methacrylate) (PQ-PMMA) photopolymer with linear polarized light is obtained. The characteristics of the volume polarization hologram are experimentally investigated. It is found that beyond the paraxial approximation the polarization states of the holographic reconstruction light are generally different from the signal light. Based on vector wave theoretical analyses and material properties, the special exposure condition for correctly holographic reconstruction is obtained and experimentally demonstrated.

  4. Experiments with Fermilab polarized proton and polarized antiproton beams

    International Nuclear Information System (INIS)

    Yokosawa, A.

    1990-01-01

    We summarize activities concerning the Fermilab polarized beams. They include a brief description of the polarized-beam facility, measurements of beam polarization by polarimeters, asymmetry measurements in the π degree production at high p perpendicular and in the Λ (Σ degree), π ± , π degree production at large x F , and Δσ L (pp, bar pp) measurements. 18 refs

  5. NUCLEON POLARIZATION IN 3-BODY MODELS OF POLARIZED LI-6

    NARCIS (Netherlands)

    SCHELLINGERHOUT, NW; KOK, LP; COON, SA; ADAM, RM

    1993-01-01

    Just as He-3 --> can be approximately characterized as a polarized neutron target, polarized Li-6D has been advocated as a good isoscalar nuclear target for the extraction of the polarized gluon content of the nucleon. The original argument rests upon a presumed ''alpha + deuteron'' picture of Li-6,

  6. Geomagnetic polarity transitions

    Science.gov (United States)

    Merrill, Ronald T.; McFadden, Phillip L.

    1999-05-01

    The top of Earth's liquid outer core is nearly 2900 km beneath Earth's surface, so we will never be able to observe it directly. This hot, dense, molten iron-rich body is continuously in motion and is the source of Earth's magnetic field. One of the most dynamic manifestations at Earth's surface of this fluid body is, perhaps, a reversal of the geomagnetic field. Unfortunately, the most recent polarity transition occurred at about 780 ka, so we have never observed a transition directly. It seems that a polarity transition spans many human lifetimes, so no human will ever witness the phenomenon in its entirety. Thus we are left with the tantalizing prospect that paleomagnetic records of polarity transitions may betray some of the secrets of the deep Earth. Certainly, if there are systematics in the reversal process and they can be documented, then this will reveal substantial information about the nature of the lowermost mantle and of the outer core. Despite their slowness on a human timescale, polarity transitions occur almost instantaneously on a geological timescale. This rapidity, together with limitations in the paleomagnetic recording process, prohibits a comprehensive description of any reversal transition both now and into the foreseeable future, which limits the questions that may at this stage be sensibly asked. The natural model for the geomagnetic field is a set of spherical harmonic components, and we are not able to obtain a reliable model for even the first few harmonic terms during a transition. Nevertheless, it is possible, in principle, to make statements about the harmonic character of a geomagnetic polarity transition without having a rigorous spherical harmonic description of one. For example, harmonic descriptions of recent geomagnetic polarity transitions that are purely zonal can be ruled out (a zonal harmonic does not change along a line of latitude). Gleaning information about transitions has proven to be difficult, but it does seem

  7. Polarized electron beams at SLAC

    International Nuclear Information System (INIS)

    Moffeit, K.C.

    1992-11-01

    SLAC has successfully accelerated high energy polarized electrons for the Stanford Linear Collider and fixed polarized nuclear target experiments. The polarized electron beams at SLAC use a gallium arsenide (GaAlAs for E-142) photon emission source to provide the beam of polarized electrons with polarization of approximately 28% (41% for E-142). While the beam emittance is reduced in the damping ring for SLC operation a system of bend magnets and superconducting solenoids preserve and orient the spin direction for maximum longitudinal polarization at the collision point. The electron polarization is monitored with a Compton scattering polarimeter, and was typically 22% at the e+e- collision point for the 1992 run. Improvements are discussed to increase the source polarization and to reduce the depolarization effects between the source and the collision point

  8. Analytical polarization calculations beyond SLIM

    International Nuclear Information System (INIS)

    Barber, D.P.

    1989-01-01

    A comparison is made between the theories of Bell and Leinaas and of Derbenev and Kondratenko for the spin polarization in electron storage rings. A calculation of polarization in HERA using the program SMILE of Mane is presented

  9. Mining the epigenetic landscape of tissue polarity in search of new targets for cancer therapy.

    Science.gov (United States)

    Atrian, Farzaneh; Lelièvre, Sophie A

    2015-01-01

    The epigenetic nature of cancer encourages the development of inhibitors of epigenetic pathways. Yet, the clinical use for solid tumors of approved epigenetic drugs is meager. We argue that this situation might improve upon understanding the coinfluence between epigenetic pathways and tissue architecture. We present emerging information on the epigenetic control of the polarity axis, a central feature of epithelial architecture created by the orderly distribution of multiprotein complexes at cell-cell and cell-extracellular matrix contacts and altered upon cancer onset (with apical polarity loss), invasive progression (with basolateral polarity loss) and metastatic development (with basoapical polarity imbalance). This information combined with the impact of polarity-related proteins on epigenetic mechanisms of cancer enables us to envision how to guide the choice of drugs specific for distinct epigenetic modifiers, in order to halt cancer development and counter the consequences of polarity alterations.

  10. On Determinants of Political Polarization

    OpenAIRE

    Grechyna, Daryna

    2015-01-01

    Political polarization has been shown to significantly influence a country's economic performance. However, little is known about the drivers of political polarization. In this article, we aim to identify the main determinants of political polarization using Bayesian Model Averaging to overcome the problem of model uncertainty. We find that the level of trust within a country and the degree of income inequality are the most robust determinants of political polarization.

  11. Polarization Shaping for Control of Nonlinear Propagation

    Science.gov (United States)

    Bouchard, Frédéric; Larocque, Hugo; Yao, Alison M.; Travis, Christopher; De Leon, Israel; Rubano, Andrea; Karimi, Ebrahim; Oppo, Gian-Luca; Boyd, Robert W.

    2016-12-01

    We study the nonlinear optical propagation of two different classes of light beams with space-varying polarization—radially symmetric vector beams and Poincaré beams with lemon and star topologies—in a rubidium vapor cell. Unlike Laguerre-Gauss and other types of beams that quickly experience instabilities, we observe that their propagation is not marked by beam breakup while still exhibiting traits such as nonlinear confinement and self-focusing. Our results suggest that, by tailoring the spatial structure of the polarization, the effects of nonlinear propagation can be effectively controlled. These findings provide a novel approach to transport high-power light beams in nonlinear media with controllable distortions to their spatial structure and polarization properties.

  12. Polarized electrogowdy spacetimes censored

    Energy Technology Data Exchange (ETDEWEB)

    Nungesser, Ernesto, E-mail: ernesto.nungesser@aei.mpg.d [Max-Planck-Institut fuer Gravitationsphysik, Albert-Einstein-Institut, Am Muehlenberg 1, 14476 Potsdam (Germany)

    2010-05-01

    A sketch of the proof of strong cosmic censorship is presented for a class of solutions of the Einstein-Maxwell equations, those with polarized Gowdy symmetry. A key element of the argument is the observation that by means of a suitable choice of variables the central equations in this problem can be written in a form where they are identical to the central equations for general (i.e. non-polarized) vacuum Gowdy spacetimes. Using this it is seen that the results of Ringstroem on strong cosmic censorship in the vacuum case have implications for the Einstein-Maxwell case. Working out the geometrical meaning of these analytical results leads to the main conclusion.

  13. Novel Histone Deacetylase Inhibitors

    National Research Council Canada - National Science Library

    Strobl, Jeannie

    2001-01-01

    The research goal is to demonstrate HDACl is a new chemotherapeutic target for human breast tumor cells and to identify new HDACl inhibitors on the basis of the structure of quinoline antimalarials...

  14. PEPPo: Using a Polarized Electron Beam to Produce Polarized Positrons

    Energy Technology Data Exchange (ETDEWEB)

    Adeyemi, Adeleke H. [Hampton Univ., Hampton, VA (United States); et al.

    2015-09-01

    Polarized positron beams have been identified as either an essential or a significant ingredient for the experimental program of both the present and next generation of lepton accelerators (JLab, Super KEK B, ILC, CLIC). An experiment demonstrating a new method for producing polarized positrons has been performed at the Continuous Electron Beam Accelerator Facility at Jefferson Lab. The PEPPo (Polarized Electrons for Polarized Positrons) concept relies on the production of polarized e⁻/e⁺ pairs from the bremsstrahlung radiation of a longitudinally polarized electron beam interacting within a high-Z conversion target. PEPPo demonstrated the effective transfer of spin-polarization of an 8.2 MeV/c polarized (P~85%) electron beam to positrons produced in varying thickness tungsten production targets, and collected and measured in the range of 3.1 to 6.2 MeV/c. In comparison to other methods this technique reveals a new pathway for producing either high-energy or thermal polarized positron beams using a relatively low polarized electron beam energy (~10MeV) .This presentation will describe the PEPPo concept, the motivations of the experiment and high positron polarization achieved.

  15. Polarization induced doped transistor

    Science.gov (United States)

    Xing, Huili; Jena, Debdeep; Nomoto, Kazuki; Song, Bo; Zhu, Mingda; Hu, Zongyang

    2016-06-07

    A nitride-based field effect transistor (FET) comprises a compositionally graded and polarization induced doped p-layer underlying at least one gate contact and a compositionally graded and doped n-channel underlying a source contact. The n-channel is converted from the p-layer to the n-channel by ion implantation, a buffer underlies the doped p-layer and the n-channel, and a drain underlies the buffer.

  16. Polar bears, Ursus maritimus

    Science.gov (United States)

    Rode, Karyn D.; Stirling, Ian

    2017-01-01

    Polar bears are the largest of the eight species of bears found worldwide and are covered in a pigment-free fur giving them the appearance of being white. They are the most carnivorous of bear species consuming a high-fat diet, primarily of ice-associated seals and other marine mammals. They range throughout the circumpolar Arctic to the southernmost extent of seasonal pack ice.

  17. Polarized advanced fuel reactors

    International Nuclear Information System (INIS)

    Kulsrud, R.M.

    1987-07-01

    The d- 3 He reaction has the same spin dependence as the d-t reaction. It produces no neutrons, so that if the d-d reactivity could be reduced, it would lead to a neutron-lean reactor. The current understanding of the possible suppression of the d-d reactivity by spin polarization is discussed. The question as to whether a suppression is possible is still unresolved. Other advanced fuel reactions are briefly discussed. 11 refs

  18. On polarization in biomembranes

    DEFF Research Database (Denmark)

    Zecchi, Karis Amata

    close to physiological conditions, making these effects biologically relevant. In this work, we consider the case of asymmetric membranes which can display spontaneous polarization in the absence of a field. Close to the phase transition, we find that the membrane displays piezoelectric, flexoelectric...... on different geometries point in the direction of a flexoelectric mechanism behind current rectification in lipid bilayers. Finally, we suggest that our updated equivalent circuit should be included in the interpretation of elctrophysiological data....

  19. Multifrequency Behaviour of Polars

    Directory of Open Access Journals (Sweden)

    K. Reinsch

    2015-02-01

    Full Text Available Cataclysmic variables emit over a wide range of the electromagnetic spectrum. In this paper I will review observations of polars in relevant passbands obtained during the last decade and will discuss their diagnostical potential to access the physics of the main components within the binary systems. This will include a discussion of intrinsic source variability and the quest for simultaneous multi-frequency observations.

  20. Polar Business Design

    Directory of Open Access Journals (Sweden)

    Sébastien Caisse

    2014-02-01

    Full Text Available Polar business design aims to enable entrepreneurs, managers, consultants, researchers, and business students to better tackle model-based analysis, creation, and transformation of businesses, ventures, and, more generically, collective endeavors of any size and purpose. It is based on a systems-thinking approach that builds on a few interrelated core concepts to create holistic visual frameworks. These core concepts act as poles linked by meaningful dyads, flows, and faces arranged in geometric shapes. The article presents two such polar frameworks as key findings in an ongoing analytic autoethnography: the three-pole Value−Activity−Stakeholder (VAS triquetra and the four-pole Offer−Creation−Character−Stakeholder (OCCS tetrahedron. The VAS triquetra is a more aggregated model of collective endeavors. The OCCS tetrahedron makes a trade-off between a steeper learning curve and deeper, richer representation potential. This article discusses how to use these two frameworks as well as their limits, and explores the potential that polar business design offers for future research.

  1. Development of Non-GAT1-Selective Inhibitors

    DEFF Research Database (Denmark)

    Damgaard, Maria; Haugaard, Anne Stæhr; Kickinger, Stefanie

    2017-01-01

    explored transporter due to its high abundance in the brain and the existence of selective and potent GAT1 inhibitors. Consequently, less is known about the role and therapeutic potential of the non-GAT1 subtypes. Emerging pharmacological evidence suggests that some of these transporters pose interesting...... targets in several brain disorders. Pharmacological non-GAT1-selective tool compounds are important to further investigate the involvement of GATs in different pathological conditions. Extensive medicinal chemistry efforts have been put into the development of subtype-selective inhibitors, but truly...... selective and potent inhibitors of non-GAT1 subtypes are still limited. This review covers the advances within the medicinal chemistry area and the structural basis for obtaining non-GAT1-selective inhibitors....

  2. The p38 mitogen-activated protein kinase inhibitor SB203580 reduces glucose turnover by the glucose transporter-4 of 3T3-L1 adipocytes in the insulin-stimulated state

    NARCIS (Netherlands)

    Bazuine, Merlijn; Carlotti, Françoise; Rabelink, Martijn J. W. E.; Vellinga, Jort; Hoeben, Rob C.; Maassen, J. Antonie

    2005-01-01

    Insulin induces a profound increase in glucose uptake in 3T3-L1 adipocytes through the activity of the glucose transporter-4 (GLUT4). Apart from GLUT4 translocation toward the plasma membrane, there is also an insulin-induced p38 MAPK-dependent step involved in the regulation of glucose uptake.

  3. Clays valorization as corrosion inhibitors for E400 reinforcing steel

    Directory of Open Access Journals (Sweden)

    Gassama Diadioly

    2016-06-01

    Full Text Available The behavior of E400 steel, a constructional steel widely used in Senegal, was studied in aqueous NaCl solution in the presence of two types of clay: volcanic tuffs, and sedimentary montmorillonite. The protection efficiency of these compounds were electrochemically assessed (corrosion potential variation curves, polarization curves and electrochemical impedance spectroscopy at various inhibitor contents. The results obtained showed that these inhibitors present an inhibitory efficacy of about 70% for an optimal concentration of 0.60% for the tuffs and 62% for a maximum content of 0.50% for montmorillonite.

  4. Concentration polarization, surface currents, and bulk advection in a microchannel

    DEFF Research Database (Denmark)

    Nielsen, Christoffer Peder; Bruus, Henrik

    2014-01-01

    We present a comprehensive analysis of salt transport and overlimiting currents in a microchannel during concentration polarization. We have carried out full numerical simulations of the coupled Poisson-Nernst-Planck-Stokes problem governing the transport and rationalized the behavior of the syst...... as in the limit of negligible surface charge. By including the effects of diffusion and advection in the diffuse part of the electric double layers, we extend a recently published analytical model of overlimiting current due to surface conduction....

  5. ST-segment resolution with bivalirudin versus heparin and routine glycoprotein IIb/IIIa inhibitors started in the ambulance in ST-segment elevation myocardial infarction patients transported for primary percutaneous coronary intervention

    DEFF Research Database (Denmark)

    Van't Hof, Arnoud; Giannini, Francesco; Ten Berg, Jurrien

    2017-01-01

    resolution either before or after the index procedure. CONCLUSIONS: Pre-hospital treatment with bivalirudin is non-inferior to pre-hospital heparin + GPI with regard to residual ST-segment deviation or ST-segment resolution, reflecting comparable myocardial reperfusion with the two strategies.......BACKGROUND: Myocardial reperfusion after primary percutaneous coronary intervention (PCI) can be assessed by the extent of post-procedural ST-segment resolution. The European Ambulance Acute Coronary Syndrome Angiography (EUROMAX) trial compared pre-hospital bivalirudin and pre-hospital heparin...... or enoxaparin with or without GPIIb/IIIa inhibitors (GPIs) in primary PCI. This nested substudy was performed in centres routinely using pre-hospital GPI in order to compare the impact of randomized treatments on ST-resolution after primary PCI. METHODS: Residual cumulative ST-segment deviation on the single...

  6. Development of Ecofriendly Corrosion Inhibitors for Application in Acidization of Petroleum Oil Well

    Directory of Open Access Journals (Sweden)

    M. Yadav

    2013-01-01

    Full Text Available In the present investigation the protective ability of 1-(2-aminoethyl-2-octadecylimidazoline (AEODI and 1-(2-octadecylamidoethyl-2-octadecylimidazoline (ODAEODI as corrosion inhibitors for N80 steel in 15% hydrochloric acid has been studied, which may find application as ecofriendly corrosion inhibitors in acidizing processes in petroleum industry. Different concentration of synthesized inhibitors AEODI and ODAEODI was added to test solution (15% HCl, and corrosion inhibition of N80 steel was tested by weight loss, potentiodynamic polarization, and AC impedance measurements. Influence of temperature (298 to 323 K on the inhibition behaviour was studied. Surface studies were performed by using SEM. It was found that both the inhibitors were effective inhibitors, and their inhibition efficiency was significantly increased with increasing their concentration. Polarization curves revealed that the used inhibitors represent mixed-type inhibitors. The adsorption of used inhibitors led to a reduction in the double-layer capacitance and an increase in the charge transfer resistance. The adsorption of used compounds was found to obey Langmuir isotherm. The adsorption of the corrosion inhibitors at the surface of N80 steel is the root cause of corrosion inhibition.

  7. The role of polarization current in magnetic island evolution

    International Nuclear Information System (INIS)

    Connor, J.W.; Waelbroeck, F.L.; Wilson, H.R.

    2001-01-01

    The polarization current plays an important role in the evolution of magnetic islands with a width comparable to the characteristic ion orbit width. Understanding the evolution of such small magnetic islands is important for two reasons: (1) to investigate the threshold mechanisms for growth of large-scale islands (e.g., neoclassical tearing modes), and (2) to describe the drive mechanisms for small-scale magnetic turbulence and consequent transport. This article presents a two-fluid, cold ion, collisional analysis of the role of the polarization current in magnetic island evolution in slab geometry. It focuses on the role played by the conjunction of parallel electron dynamics and perpendicular transport (particle diffusion and viscosity) in determining the island rotation frequency and the distribution of the polarization current within the island

  8. Multiple scattering of polarized light in a turbid medium

    International Nuclear Information System (INIS)

    Gorodnichev, E. E.; Kuzovlev, A. I.; Rogozkin, D. B.

    2007-01-01

    It is shown that multiple scattering of polarized light in a turbid medium can be represented as independent propagation of three basic modes: intensity and linearly and circularly polarized modes. Weak interaction between the basic modes can be described by perturbation theory and gives rise to 'overtones' (additional polarization modes). Transport equations for the basic and additional modes are derived from a vector radiative transfer equation. Analytical solutions to these equations are found in the practically important cases of diffusive light propagation and small-angle multiple scattering. The results obtained are in good agreement with experimental and numerical results and provide an explanation for the experimentally observed difference in depolarization between linearly and circularly polarized waves

  9. Spin-polarized current generated by magneto-electrical gating

    International Nuclear Information System (INIS)

    Ma Minjie; Jalil, Mansoor Bin Abdul; Tan, Seng Ghee

    2012-01-01

    We theoretically study spin-polarized current through a single electron tunneling transistor (SETT), in which a quantum dot (QD) is coupled to non-magnetic source and drain electrodes via tunnel junctions, and gated by a ferromagnetic (FM) electrode. The I–V characteristics of the device are investigated for both spin and charge currents, based on the non-equilibrium Green's function formalism. The FM electrode generates a magnetic field, which causes a Zeeman spin-splitting of the energy levels in the QD. By tuning the size of the Zeeman splitting and the source–drain bias, a fully spin-polarized current is generated. Additionally, by modulating the electrical gate bias, one can effect a complete switch of the polarization of the tunneling current from spin-up to spin-down current, or vice versa. - Highlights: ► The spin polarized transport through a single electron tunneling transistor is systematically studied. ► The study is based on Keldysh non-equilibrium Green's function and equation of motion method. ► A fully spin polarized current is observed. ► We propose to reverse current polarization by the means of gate voltage modulation. ► This device can be used as a bi-polarization current generator.

  10. Rotational inertia of continents: A proposed link between polar wandering and plate tectonics

    Science.gov (United States)

    Kane, M.F.

    1972-01-01

    A mechanism is proposed whereby displacement between continents and the earth's pole of rotation (polar wandering) gives rise to latitudinal transport of continental plates (continental drift) because of their relatively greater rotational inertia. When extended to short-term polar wobble, the hypothesis predicts an energy change nearly equivalent to the seismic energy rate.

  11. Circularly polarized antennas

    CERN Document Server

    Gao, Steven; Zhu, Fuguo

    2013-01-01

    This book presents a comprehensive insight into the design techniques for different types of CP antenna elements and arrays In this book, the authors address a broad range of topics on circularly polarized (CP) antennas. Firstly, it introduces to the reader basic principles, design techniques and characteristics of various types of CP antennas, such as CP patch antennas, CP helix antennas, quadrifilar helix antennas (QHA), printed quadrifilar helix antennas (PQHA), spiral antenna, CP slot antennas, CP dielectric resonator antennas, loop antennas, crossed dipoles, monopoles and CP horns. Adva

  12. Plasma polarization spectroscopy

    CERN Document Server

    Iwamae, Atsushi

    2008-01-01

    Plasma Polarization Spectroscopy (PPS) is now becoming a standard diagnostic technique for working with laboratory plasmas. This new area needs a comprehensive framework, both experimental and theoretical. This book reviews the historical development of PPS, develops a general theoretical formulation to deal with this phenomenon, along with an overview of relevant cross sections, and reports on laboratory experiments so far performed. It also includes various facets that are interesting from this standpoint, e.g. X-ray lasers and effects of microwave irradiation. It also offers a timely discussion of instrumentation that is quite important in a practical PPS experiment.

  13. System for measuring the proton polarization in a polarized target

    International Nuclear Information System (INIS)

    Karnaukhov, I.M.; Lukhanin, A.A.; Telegin, Yu.N.; Trotsenko, V.I.; Chechetenko, V.F.

    1984-01-01

    The system for measuring the proton polarization in a polarized target representing the high-sensitivity nuclear magnetic resonance (NMR) is described Q-meter with series connection and a circuit for measuring system resonance characteristic is used for NMR-absorption signal recording. Measuring coil is produced of a strip conductor in order to obtain uniform system sensitivity to polarization state in all target volume and improve signal-to-noise ratio. Polarization measuring system operates ion-line with the M-6000 computer. The total measuring error for the value of free proton polarization in target taking into account the error caused by local depolarization of working substance under irradiation by high-intense photon beam is <= 6%. Long-term application of the described system for measuring the proton polarization in the LUEh-20000 accelerator target used in the pion photoproduction experiments has demonstrated its high reliability

  14. The Apical Actin Fringe Contributes to Localized Cell Wall Deposition and Polarized Growth in the Lily Pollen Tube1[W][OPEN

    Science.gov (United States)

    Rounds, Caleb M.; Hepler, Peter K.; Winship, Lawrence J.

    2014-01-01

    In lily (Lilium formosanum) pollen tubes, pectin, a major component of the cell wall, is delivered through regulated exocytosis. The targeted transport and secretion of the pectin-containing vesicles may be controlled by the cortical actin fringe at the pollen tube apex. Here, we address the role of the actin fringe using three different inhibitors of growth: brefeldin A, latrunculin B, and potassium cyanide. Brefeldin A blocks membrane trafficking and inhibits exocytosis in pollen tubes; it also leads to the degradation of the actin fringe and the formation of an aggregate of filamentous actin at the base of the clear zone. Latrunculin B, which depolymerizes filamentous actin, markedly slows growth but allows focused pectin deposition to continue. Of note, the locus of deposition shifts frequently and correlates with changes in the direction of growth. Finally, potassium cyanide, an electron transport chain inhibitor, briefly stops growth while causing the actin fringe to completely disappear. Pectin deposition continues but lacks focus, instead being delivered in a wide arc across the pollen tube tip. These data support a model in which the actin fringe contributes to the focused secretion of pectin to the apical cell wall and, thus, to the polarized growth of the pollen tube. PMID:25037212

  15. EDITORIAL: Non-polar and semipolar nitride semiconductors Non-polar and semipolar nitride semiconductors

    Science.gov (United States)

    Han, Jung; Kneissl, Michael

    2012-02-01

    topics including growth and heteroepitaxy, bulk GaN substrates, theory and modelling, optical properties, laser diodes and LEDs as well as transport properties and electronics. Farrell et al review materials and growth issues for high-performance non- and semipolar light-emitting devices, and Scholz provides an overview of heteroepitaxial growth of semipolar GaN. Okada et al review growth mechanisms of non- and semipolar GaN layers on patterned sapphire substrates, and Vennéguès discusses defect reduction methods for heteroepitaxially grown non- and semipolar III-nitride films. Leung et al explain how kinetic Wulff plots can be used to design and control non-polar and semipolar GaN heteroepitaxy, and a contribution by Sawaki et al explores the impurity incorporation in (1-101) GaN grown on Si substrates. In the area of bulk crystal growth Kucharski et al review non- and semipolar GaN substrates by ammonothermal growth, and Chichibu et al discuss the challenges for epitaxial growth of InGaN on free-standing m-plane GaN substrates. Calculation of semipolar orientations for wurtzitic semiconductor heterostructures and their application to nitrides and oxides are reviewed by Bigenwald et al, and Ito et al present an ab initio approach to reconstruction, adsorption, and incorporation on GaN surfaces. Finally, the theoretical description of non-polar and semipolar nitride semiconductor quantum-well structures is presented by Ahn et al. In a discussion of the optical properties, Kisin et al discuss the effect of the quantum well population on the optical characteristics of polar, semipolar and non-polar III-nitride light emitters, and Jönen et al investigate the indium incorporation and optical properties of non- and semipolar GaInN QW structures. Wernicke et al explore the emission wavelength of polar, non-polar, and semipolar InGaN quantum wells and the incorporation of indium. In a contribution by Melo et al, the gain in polar and non-polar/semipolar gallium

  16. The efficiency of a corrosion inhibitor on steel in a simulated concrete environment

    International Nuclear Information System (INIS)

    Gartner, Nina; Kosec, Tadeja; Legat, Andraž

    2016-01-01

    The aim of the present work was to characterize the efficiency of a corrosion inhibitor on steel in a simulated concrete pore solution. Laboratory measurements were performed at various chloride and inhibitor concentrations in order to simulate different applications of the inhibitor when used for the protection or rehabilitation of steel reinforcement in concrete. Two electrochemical techniques, i.e. potentiodynamic polarization scans and electrochemical impedance spectroscopy, were used for this study. The exposed surfaces of the steel specimens were subsequently investigated by Raman spectroscopy and scanning electron microscopy. It was found that the inhibitor can efficiently retard the corrosion of steel in a simulated concrete pore solution at concentrations of the inhibitor >2.0% and of chlorides <0.3% at a pH 10.5. On the other hand, when these conditions are not fulfilled, localized corrosion was observed. The results of the Raman and SEM/EDS analysis showed various morphologies of corrosion products and different types of corrosion attack depending on the pH of the pore solution, and the applied concentrations of the chlorides and the inhibitor. - Highlights: • Electrochemical studies performed at various Cl − and inhibitor concentrations. • Exposed steel surfaces investigated by Raman spectroscopy and SEM. • Cl − /inhibitor ratio is important parameter for the inhibitor's efficiency. • The corrosion can re-occur if the concentration of the inhibitor is reduced. • Different corrosion behaviour and oxides in the presence of inhibitor and/or Cl − .

  17. Polar drive on OMEGA

    Directory of Open Access Journals (Sweden)

    Radha P.B.

    2013-11-01

    Full Text Available High-convergence polar-drive experiments are being conducted on OMEGA [T. R. Boehly et al., Opt. Commum. 133, 495 (1997] using triple-picket laser pulses. The goal of OMEGA experiments is to validate modeling of oblique laser deposition, heat conduction in the presence of nonradial thermal gradients in the corona, and implosion energetics in the presence of laser–plasma interactions such as crossed-beam energy transfer. Simulated shock velocities near the equator, where the beams are obliquely incident, are within 5% of experimentally inferred values in warm plastic shells, well within the required accuracy for ignition. High, near-one-dimensional areal density is obtained in warm-plastic-shell implosions. Simulated backlit images of the compressing core are in good agreement with measured images. Outstanding questions that will be addressed in the future relate to the role of cross-beam transfer in polar drive irradiation and increasing the energy coupled into the target by decreasing beam obliquity.

  18. Cathepsin D inhibitors

    Directory of Open Access Journals (Sweden)

    M. Gacko

    2007-11-01

    Full Text Available Inhibitors of cathepsin D belong to chemical compounds that estrify carboxyl groups of the Asp33 and Asp231residues of its catalytic site, penta-peptides containing statin, i.e. the amino acid similar in structure to the tetraedric indirectproduct, and polypeptides found in the spare organs of many plants and forming permanent noncovalent complexes withcathepsin. Cathepsin D activity is also inhibited by alpha2-macroglobulin and antibodies directed against this enzyme.Methods used to determine the activity and concentration of these inhibitors and their analytical, preparative and therapeuticapplications are discussed.

  19. Aminocyclopentanols - Potential glycosidase inhibitors

    DEFF Research Database (Denmark)

    Lauritsen, Marie

    Recently several aminocyclopentanols having the aminogroup adjacent to a carbon sidechain, proved to be potent and anomer-selective glycosidase inhibitors.1 The bicyclic lactone 1, which has been synthesised in our group from sugar-derived starting materials, was found to be suited for further...... in the desired position, 3 and 4 were easily converted into the aminocyclopentanols 5 and 6. Other aminocyclopentanols, which have been synthesised from 1, will be presented, and their activities and specificities as glycosidase inhibitors will be discussed....

  20. Polarized proton collider at RHIC

    Energy Technology Data Exchange (ETDEWEB)

    Alekseev, I.; Allgower, C.; Bai, M.; Batygin, Y.; Bozano, L.; Brown, K.; Bunce, G.; Cameron, P.; Courant, E.; Erin, S.; Escallier, J.; Fischer, W.; Gupta, R.; Hatanaka, K.; Huang, H.; Imai, K.; Ishihara, M.; Jain, A.; Lehrach, A.; Kanavets, V.; Katayama, T.; Kawaguchi, T.; Kelly, E.; Kurita, K.; Lee, S.Y.; Luccio, A.; MacKay, W.W. E-mail: mackay@bnl.govhttp://www.rhichome.bnl.gov/People/waldowaldo@bnl.gov; Mahler, G.; Makdisi, Y.; Mariam, F.; McGahern, W.; Morgan, G.; Muratore, J.; Okamura, M.; Peggs, S.; Pilat, F.; Ptitsin, V.; Ratner, L.; Roser, T.; Saito, N.; Satoh, H.; Shatunov, Y.; Spinka, H.; Syphers, M.; Tepikian, S.; Tominaka, T.; Tsoupas, N.; Underwood, D.; Vasiliev, A.; Wanderer, P.; Willen, E.; Wu, H.; Yokosawa, A.; Zelenski, A.N

    2003-03-01

    In addition to heavy ion collisions (RHIC Design Manual, Brookhaven National Laboratory), RHIC will also collide intense beams of polarized protons (I. Alekseev, et al., Design Manual Polarized Proton Collider at RHIC, Brookhaven National Laboratory, 1998, reaching transverse energies where the protons scatter as beams of polarized quarks and gluons. The study of high energy polarized protons beams has been a long term part of the program at BNL with the development of polarized beams in the Booster and AGS rings for fixed target experiments. We have extended this capability to the RHIC machine. In this paper we describe the design and methods for achieving collisions of both longitudinal and transverse polarized protons in RHIC at energies up to {radical}s=500 GeV.

  1. Spin exchange in polarized deuterium

    International Nuclear Information System (INIS)

    Przewoski, B. von; Meyer, H.O.; Balewski, J.; Doskow, J.; Ibald, R.; Pollock, R.E.; Rinckel, T.; Wellinghausen, A.; Whitaker, T.J.; Daehnick, W.W.; Haeberli, W.; Schwartz, B.; Wise, T.; Lorentz, B.; Rathmann, F.; Pancella, P.V.; Saha, Swapan K.; Thoerngren-Engblom, P.

    2003-01-01

    We have measured the vector and tensor polarization of an atomic deuterium target as a function of the target density. The polarized deuterium was produced in an atomic beam source and injected into a storage cell. For this experiment, the atomic beam source was operated without rf transitions, in order to avoid complications from the unknown efficiency of these transitions. In this mode, the atomic beam is vector and tensor polarized and both polarizations can be measured simultaneously. We used a 1.2-cm-diam and 27-cm-long storage cell, which yielded an average target density between 3 and 9x10 11 at/cm 3 . We find that the tensor polarization decreases with increasing target density while the vector polarization remains constant. The data are in quantitative agreement with the calculated effect of spin exchange between deuterium atoms at low field

  2. Electron Transport in Si Nanowires

    Energy Technology Data Exchange (ETDEWEB)

    Ramayya, E [Arizona State University, Tempe, AZ (United States); Vasileska, D [Arizona State University, Tempe, AZ (United States); Goodnick, S M [Arizona State University, Tempe, AZ (United States); Knezevic, I [University of Wisconsin, Madison, WI (United States)

    2006-05-15

    We investigate electron transport in silicon nanowires taking into account acoustic, non-polar optical phonons and surface/interface roughness scattering. We find that at very high transverse fields the reduced density of final states to which the carriers can scatter into gives rise to a reduced influence of interface-roughness scattering, which is promising result from a fabrication point of view.

  3. Linear polarization of BY Draconis

    International Nuclear Information System (INIS)

    Koch, R.H.; Pfeiffer, R.J.

    1976-01-01

    Linear polarization measurements are reported in four bandpasses for the flare star BY Dra. The red polarization is intrinsically variable at a confidence level greater than 99 percent. On a time scale of many months, the variability is not phase-locked to either a rotational or a Keplerian ephemeris. The observations of the three other bandpasses are useful principally to indicate a polarization spectrum rising toward shorter wavelengths

  4. Polarity in Mammalian Epithelial Morphogenesis

    OpenAIRE

    Roignot, Julie; Peng, Xiao; Mostov, Keith

    2013-01-01

    Cell polarity is fundamental for the architecture and function of epithelial tissues. Epithelial polarization requires the intervention of several fundamental cell processes, whose integration in space and time is only starting to be elucidated. To understand what governs the building of epithelial tissues during development, it is essential to consider the polarization process in the context of the whole tissue. To this end, the development of three-dimensional organotypic cell culture model...

  5. Blue tetrazolium as a novel corrosion inhibitor for cold rolled steel in hydrochloric acid solution

    International Nuclear Information System (INIS)

    Li Xianghong; Deng Shuduan; Fu Hui

    2010-01-01

    The inhibition effect of blue tetrazolium (BT) on the corrosion of cold rolled steel (CRS) in 1.0 M HCl solution at 20 o C was investigated by weight loss, potentiodynamic polarization, electrochemical impedance spectroscopy (EIS), and scanning electron microscopy (SEM) methods. The results show that BT is a very good inhibitor, and the adsorption of BT on CRS surface obeys Langmuir adsorption isotherm. Polarization curves reveal that BT acts as a mixed-type inhibitor. EIS spectra exhibit one capacitive loop and confirm the inhibitive ability. The inhibition action of BT is also evidenced by SEM images.

  6. A polarized alkali ion source

    International Nuclear Information System (INIS)

    Boettger, R.; Tungate, G.; Bauer, B.; Egelhof, P.; Moebius, K.H.; Steffens, E.

    1978-01-01

    The beam foil technique has been applied to detect nuclear vector polarization of a 10 keV 23 Na + beam. The result was about 70% of the atomic beam polarization thus limiting the depolarization by the surface ionizer to at most 30%. In a Coulomb excitation experiment with a tensor polarized 42 MeV 23 Na 7+ beam an effect of 0.011 +- 0.003 was measured yielding a value of t 20 approx. 0.04 for the beam polarization. The depolarization during the acceleration process can be estimated to be about 0.8. (orig.) [de

  7. The SLAC polarized electron source

    International Nuclear Information System (INIS)

    Tang, H.; Alley, R.; Frisch, J.

    1995-06-01

    The SLAC polarized electron source employs a photocathode DC high voltage gun with a loadlock and a YAG pumped Ti:sapphire laser system for colliding beam experiments or a flash lamp pumped Ti:sapphire laser for fixed target experiments. It uses a thin, strained GaAs(100) photocathode, and is capable of producing a pulsed beam with a polarization of ≥80% and a peak current exceeding 10 A. Its operating efficiency has reached 99%. The physics and technology of producing high polarization electron beams from a GaAs photocathode will be reviewed. The prospects of realizing a polarized electron source for future linear colliders will also be discussed

  8. Endocannabinoid transport revisited.

    Science.gov (United States)

    Nicolussi, Simon; Gertsch, Jürg

    2015-01-01

    Endocannabinoids are arachidonic acid-derived endogenous lipids that activate the endocannabinoid system which plays a major role in health and disease. The primary endocannabinoids are anandamide (AEA, N-arachidonoylethanolamine) and 2-arachidonoyl glycerol. While their biosynthesis and metabolism have been studied in detail, it remains unclear how endocannabinoids are transported across the cell membrane. In this review, we critically discuss the different models of endocannabinoid trafficking, focusing on AEA cellular uptake which is best studied. The evolution of the current knowledge obtained with different AEA transport inhibitors is reviewed and the confusions caused by the lack of their specificity discussed. A comparative summary of the most important AEA uptake inhibitors and the studies involving their use is provided. Based on a comprehensive literature analysis, we propose a model of facilitated AEA membrane transport followed by intracellular shuttling and sequestration. We conclude that novel and more specific probes will be essential to identify the missing targets involved in endocannabinoid membrane transport. © 2015 Elsevier Inc. All rights reserved.

  9. Empagliflozin (an SGLT2 inhibitor), alone or in combination with linagliptin (a DPP-4 inhibitor), prevents steatohepatitis in a novel mouse model of non-alcoholic steatohepatitis and diabetes

    OpenAIRE

    Jojima, Teruo; Tomotsune, Takanori; Iijima, Toshie; Akimoto, Kazumi; Suzuki, Kunihiro; Aso, Yoshimasa

    2016-01-01

    Background Sodium-glucose co-transporter-2 (SGLT2) inhibitors are new oral antidiabetic drugs that reduce hyperglycemia by promoting urinary glucose excretion. Glycosuria produced by SGLT2 inhibitors is associated with weight loss, mainly due to reduced fat volume. We investigated the effects of empagliflozin (selective SGLT2 inhibitor) and linagliptin (DPP-4 inhibitor) on steatohepatitis and fibrosis in a mouse model of non-alcoholic steatohepatitis (NASH) with diabetes. Methods A novel NASH...

  10. Transport of N-acetyl-S-pentachloro-1,3-butadienylcysteine by rat renal cortex

    Energy Technology Data Exchange (ETDEWEB)

    Lock, E.A.; Odum, J.; Ormond, P.

    1986-05-01

    N-acetyl-S-pentachloro-1,3-butadienyl-L-cysteine (PCBD-NAC) is a postulated metabolite derived from glutathione conjugation of hexachloro-1,3-butadiene and is nephrotoxic in the rat. Because PCBD-NAC causes selective necrosis to the pars recta of the proximal tubule, and is an organic anion it might be expected to be transported by the renal organic anion transport system. Rat renal cortical slices were used to characterise the transport. /sup 14/C-PCBD-NAC uptake was temperature dependent and reduced by the metabolic inhibitors cyanide and iodoacetate. Probenecid and sulphinpyrazone, specific competitive inhibitors of the anion transport system, and dinitrophenol, a metabolic inhibitor as well as a competitive inhibitor of anion transport, reduced PCBD-NAC transport. Organic cations or uric acid transport inhibitors did not alter PCBD-NAC accumulation by the slices. These data are consistent with the transport of PCBD-NAC by the renal organic anion secretory system.

  11. Cuminum cyminum Extracts as Eco-Friendly Corrosion Inhibitor for Mild Steel in Seawater

    OpenAIRE

    Sribharathy, V.; Rajendran, Susai

    2013-01-01

    The inhibitive effect of Jeera (Cuminum cyminum) plant extracts on the corrosion of mild steel in an aqueous solution of seawater was investigated using potentiodynamic polarization and electrochemical impedance spectroscopy (EIS) techniques. The stability of the inhibition efficiency of Jeera extracts was examined by weight-loss method. Potentiodynamic polarization curves indicated that the Jeera extract behaves as an anodic type inhibitor. EIS measurements showed that the dissolution proces...

  12. Transglutaminase inhibitor from milk

    NARCIS (Netherlands)

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

    2003-01-01

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

  13. Phosphodiesterase 4 inhibitors.

    Science.gov (United States)

    Zebda, Rema; Paller, Amy S

    2018-03-01

    Historically, drugs available for treating atopic dermatitis (AD) have been limited to topical corticosteroids and topical calcineurin inhibitors, with systemic immunosuppressants and phototherapy reserved for severe AD. Despite their efficacy and infrequent adverse events, phobia about the use of topical steroids and calcineurin inhibitors has limited their use. More targeted options with fewer systemic and cutaneous side effects are needed for treating AD. Phosphodiesterase 4 (PDE4) is involved in the regulation of proinflammatory cytokines via the degradation of cyclic adenosine monophosphate. PDE4 activity is increased in the inflammatory cells of patients with AD, leading to increased production of proinflammatory cytokines and chemokines. Targeting PDE4 reduces the production of these proinflammatory mediators in AD. Both topical and oral PDE4 inhibitors have a favorable safety profile. Crisaborole 2% ointment, a topical PDE4, is now US Food and Drug Administration-approved for children older than 2 years and adults in the treatment of AD. Crisaborole 2% ointment shows early and sustained improvement in disease severity and pruritus and other AD symptoms, with burning and/or stinging upon application as the only related adverse event. Other PDE4 inhibitors are currently in trials with promising efficacy and safety. Copyright © 2017. Published by Elsevier Inc.

  14. Inhibitors of histone deacetylase

    DEFF Research Database (Denmark)

    2015-01-01

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

  15. Inhibitors of histone demethylases

    DEFF Research Database (Denmark)

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

    2011-01-01

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

  16. HIV protease inhibitor resistance

    NARCIS (Netherlands)

    Wensing, Annemarie M.J.; Fun, Axel; Nijhuis, Monique

    2017-01-01

    HIV protease is pivotal in the viral replication cycle and directs the formation of mature infectious virus particles. The development of highly specific HIV protease inhibitors (PIs), based on thorough understanding of the structure of HIV protease and its substrate, serves as a prime example of

  17. Assessment of caffeine adsorption onto mild steel surface as an eco-friendly corrosion inhibitor

    OpenAIRE

    Souza, Fernando S. de; Gonçalves, Reinaldo S.; Spinelli, Almir

    2014-01-01

    The adsorption and corrosion-inhibition properties of caffeine as an eco-friendly corrosion inhibitor for mild steel in acid medium were investigated by electrochemical and spectroscopic techniques. Polarization experiments indicated that caffeine behaves as a cathodic-type inhibitor. Impedance data showed that surface coverage increased with caffeine concentration in the range of 1.0 to 10.0 mmol L-1. The maximum inhibition efficiency obtained was 92.4%. The adsorption of the corrosion inhib...

  18. Staminate Flower of Cocos Nucifera as Green Inhibitor for Mild Steel in HCl Medium

    OpenAIRE

    Rajalakshmi, R.; Safina, A. S.

    2012-01-01

    Corrosion control methods, especially the use of inhibitors, have gained monumental importance in the present scenario of expunging corrosion and the quest for eco-friendly reasons continues. To arrive at an inexpensive non-toxic, eco-friendly inhibitor formulations the present study on the use of Staminate Flower extract of Cocos Nucifera has been carried out by the classical weight loss measurements and electrochemical polarization measurements. The acid extract could bring out a maximum of...

  19. Regulation of vesicle transport and cell motility by Golgi-localized Dbs

    Science.gov (United States)

    Fitzpatrick, Ethan R; Hu, Tinghui; Ciccarelli, Bryan T; Whitehead, Ian P

    2014-01-01

    DBS/MCF2L has been recently identified as a risk locus for osteoarthritis. It encodes a guanine nucleotide exchange factor (Dbs) that has been shown to regulate both normal and tumor cell motility. In the current study, we have determined that endogenous Dbs is predominantly expressed as 2 isoforms, a 130 kDa form (Dbs-130) that is localized to the Golgi complex, and an 80 kDa form (Dbs-80) that is localized to the endoplasmic reticulum (ER). We have previously described an inhibitor that binds to the RhoGEF domain of Dbs and blocks its transforming activity. Here we show that the inhibitor localizes to the Golgi, where it specifically interacts with Dbs-130. Inhibition of endogenous Dbs-130 activity is associated with reduced levels of activated Cdc42, enlarged Golgi, and resistance to Brefeldin A-mediated Golgi dispersal, suggesting a role for Dbs in vesicle transport. Cells treated with the inhibitor exhibit normal protein transport from the ER to the Golgi, but are defective in transport from the Golgi to the plasma membrane. Inhibition of Dbs-130 in MDA-MB-231 human breast tumor cells limits motility in both transwell and wound healing assays, but appears to have no effect on the organization of the microtubule cytoskeleton. The reduced motility is associated with a failure to reorient the Golgi toward the leading edge. This is consistent with the Golgi localization, and suggests that the Dbs-130 regulates aspects of the secretory pathway that are required to support cell polarization during directed migration. PMID:25483302

  20. Inhibitors of proprotein convertases.

    Science.gov (United States)

    Basak, Ajoy

    2005-11-01

    The discovery of mammalian subtilases, proprotein convertases (PCs) or subtilisin-like proprotein convertases (SPCs), in 1990 was a result of sustained efforts in searching for enzyme/s responsible for maturation of inactive protein precursors. Since then, seven PCs have so far been discovered that cleave at the carboxy-terminal of a basic amino acid characterized by the consensus sequence Arg/Lys/His-X-X/Lys/Arg-Arg downward arrow, where X denotes any amino acid other than Cys. Two additional PC subtypes--called subtilisin kexin isozyme 1 (SKI-1) or site 1 protease (S1P) and neural apoptosis regulated convertase 1 (NARC-1), also known as PCSK9--that cleave at the carboxy terminus of nonbasic amino acids were discovered later. Numerous studies revealed various important functional roles of PCs in health and diseases such as tumorigenesis, diabetes, viral infections, bacterial pathogenesis, atherosclerosis, and neurodegenarative diseases such as Alzheimer's. Owing to these findings, PCs became a promising frontier for treatment of diverse pathologies. Thus modulation of PC activity with designed inhibitors is an attractive proposition not only for intervention of diseases, but also for biochemical characterization of these enzymes. Various physiological and bioengineered proteins as well as small molecules such as peptide, peptidomimetic, and nonpeptide compounds as inhibitors of PCs have been described in the literature. Among the strategies used for design of PC inhibitors, the most successful is the one based on bioengineered serpin proteins, of which the best example is alpha1-PDX, the double mutant variant of alpha1-antitrypsin (from A(355)IPM(358) to R(355)IPR(358)). Others include small peptide inhibitors with C-terminal carboxyl function modified with a potent neucleophile or those containing pseudo or isosteric peptide bond at the scissile site of a suitable peptide substrate. Among nonpeptide PC inhibitors, the number is very limited. So far, these include

  1. Bivalirudin is superior to heparins alone with bailout GP IIb/IIIa inhibitors in patients with ST-segment elevation myocardial infarction transported emergently for primary percutaneous coronary intervention

    DEFF Research Database (Denmark)

    Zeymer, Uwe; van 't Hof, Arnoud; Adgey, Jennifer

    2014-01-01

    in comparison with heparins only with GPI used as bailout. METHODS AND RESULTS: In the EUROMAX study, 2198 patients with ST-segment elevation myocardial infarction (STEMI) were randomized during transport for primary PCI to bivalirudin or to heparins with optional GPI. Primary and principal outcome...... outcome death and major bleeding occurred in 5.1% with bivalirudin, 7.6% with heparin plus routine GPI (HR 0.67 and 95% CI 0.46-0.97, P = 0.034), and 9.8% with heparins plus bailout GPI (HR 0.52 and 95% CI 0.35-0.75, P = 0.006). Following adjustment by logistic regression, bivalirudin was still associated...

  2. The glutamate transport inhibitor DL-Threo-β-Benzyloxyaspartic acid (DL-TBOA) differentially affects SN38- and oxaliplatin-induced death of drug-resistant colorectal cancer cells

    DEFF Research Database (Denmark)

    Cuesta, Elena Pedraz; Christensen, Sandra; Jensen, Anders A.

    2015-01-01

    cell resistance per se correlated with increased cellular GSH. DL-TBOA did not significantly alter cellular levels of p21, cleaved PARP-1, or phospho-Retinoblastoma protein, yet altered SLC1A1 subcellular localization, and reduced chemotherapy-induced p53 induction. CONCLUSIONS: SLC1A1 expression...... affinity glutamate transporters Solute Carrier (SLC)-1A1 and -1A3 (EAAT3, EAAT1) is associated with the resistant phenotypes. Analyses included real-time quantitative PCR, immunoblotting and immunofluorescence analyses, radioactive tracer flux measurements, and biochemical analyses of cell viability...... and glutathione content. Results were evaluated using one- and two-way ANOVA and Students two-tailed t-test, as relevant. RESULTS: In SN38-resistant HCT116 and LoVo cells, SLC1A1 expression was down-regulated ~60 % and up-regulated ~4-fold, respectively, at both mRNA and protein level, whereas SLC1A3 protein...

  3. Peculiarities of spin polarization inversion at a thiophene/cobalt interface

    KAUST Repository

    Wang, Xuhui

    2013-03-20

    We perform ab initio calculations to investigate the spin polarization at the interface between a thiophene molecule and cobalt substrate. We find that the reduced symmetry in the presence of a sulfur atom (in the thiophene molecule) leads to a strong spatial dependence of the spin polarization of the molecule. The two carbon atoms far from the sulfur acquire a polarization opposite to that of the substrate, while the carbon atoms bonded directly to sulfur possess the same polarization as the substrate. We determine the origin of this peculiar spin interface property as well as its impact on the spin transport.

  4. Polarization spectroscopy on laser-produced plasmas and Z-pinch plasmas

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Dong E. [POSTECH, Kyungbuk (Korea); Baronova, Elena O. [RRC Kurchatov Institute, Nuclear Fusion Institute, Moscow (Russian Federation); Jakubowski, Lech [Soltan Institute for Nuclear Studies, Swierk-Otwock (Poland)

    2002-08-01

    PPS experiments on laser-produced plasmas are reviewed. Polarization is interpreted in terms of the anisotropic velocity distribution of electrons due to non-local transport. The polarization of an x-ray laser, and recent results regarding the recombining plasma are also presented. X-ray polarization spectroscopy experiments on heliumlike ion lines from a vacuum spark and from a plasma focus are presented: in both cases, the resonance line of the heliumlike ions shows polarization in the direction perpendicular to the discharge axis. Two possible interpretations are suggested. (author)

  5. Optical Polarization Modulation and Gain Anisotropy in an Electrically Injected Spin Laser

    Science.gov (United States)

    Basu, D.; Saha, D.; Bhattacharya, P.

    2009-03-01

    The effects of spin-induced gain anisotropy on output polarization and threshold current reduction of electrically pumped spin-polarized lasers have been studied. Analytical forms of these parameters are derived by considering diffusive transport from the spin injector to the active region. The calculated values of the parameter are in excellent agreement with values obtained from measurements made at 200 K on an InAs/GaAs quantum dot spin-polarized vertical cavity surface-emitting laser. Electrical modulation of the output polarization of the laser is demonstrated with a peak modulation index of 0.6.

  6. Polar Biomedical Research - An Assessment.

    Science.gov (United States)

    1982-10-01

    to grow more crops in subpolar Alaska. The severity of the polar conditions in Antarctica allow no practical method for providing volumes of plant food...for an expanded population. Any experiments in polar regions in food production involving geothermal heat, solar energy, hydroponics , or aquaculture

  7. Create a Polarized Light Show.

    Science.gov (United States)

    Conrad, William H.

    1992-01-01

    Presents a lesson that introduces students to polarized light using a problem-solving approach. After illustrating the concept using a slinky and poster board with a vertical slot, students solve the problem of creating a polarized light show using Polya's problem-solving methods. (MDH)

  8. Carbon nanotube fiber terahertz polarizer

    Energy Technology Data Exchange (ETDEWEB)

    Zubair, Ahmed [Department of Electrical and Computer Engineering, Rice University, Houston, Texas 77005 (United States); Tsentalovich, Dmitri E.; Young, Colin C. [Department of Chemical and Biomolecular Engineering, Rice University, Houston, Texas 77005 (United States); Heimbeck, Martin S. [Charles M. Bowden Laboratory, Aviation & Missile Research, Development, and Engineering Center (AMRDEC), Redstone Arsenal, Alabama 35898 (United States); Everitt, Henry O. [Department of Electrical and Computer Engineering, Rice University, Houston, Texas 77005 (United States); Charles M. Bowden Laboratory, Aviation & Missile Research, Development, and Engineering Center (AMRDEC), Redstone Arsenal, Alabama 35898 (United States); Pasquali, Matteo [Department of Chemical and Biomolecular Engineering, Rice University, Houston, Texas 77005 (United States); Department of Chemistry, Rice University, Houston, Texas 77005 (United States); Department of Materials Science and NanoEngineering, Rice University, Houston, Texas 77005 (United States); Kono, Junichiro, E-mail: kono@rice.edu [Department of Electrical and Computer Engineering, Rice University, Houston, Texas 77005 (United States); Department of Materials Science and NanoEngineering, Rice University, Houston, Texas 77005 (United States); Department of Physics and Astronomy, Rice University, Houston, Texas 77005 (United States)

    2016-04-04

    Conventional, commercially available terahertz (THz) polarizers are made of uniformly and precisely spaced metallic wires. They are fragile and expensive, with performance characteristics highly reliant on wire diameters and spacings. Here, we report a simple and highly error-tolerant method for fabricating a freestanding THz polarizer with nearly ideal performance, reliant on the intrinsically one-dimensional character of conduction electrons in well-aligned carbon nanotubes (CNTs). The polarizer was constructed on a mechanical frame over which we manually wound acid-doped CNT fibers with ultrahigh electrical conductivity. We demonstrated that the polarizer has an extinction ratio of ∼−30 dB with a low insertion loss (<0.5 dB) throughout a frequency range of 0.2–1.1 THz. In addition, we used a THz ellipsometer to measure the Müller matrix of the CNT-fiber polarizer and found comparable attenuation to a commercial metallic wire-grid polarizer. Furthermore, based on the classical theory of light transmission through an array of metallic wires, we demonstrated the most striking difference between the CNT-fiber and metallic wire-grid polarizers: the latter fails to work in the zero-spacing limit, where it acts as a simple mirror, while the former continues to work as an excellent polarizer even in that limit due to the one-dimensional conductivity of individual CNTs.

  9. Polarization-preserving holey fibers

    DEFF Research Database (Denmark)

    Broeng, Jes; Mogilevtsev, Dmitri; Libori, Stig E. Barkou

    2001-01-01

    In this work we suggest and discuss a microstructure of air capillaries with elliptical cross-section in a tread of glass that gives opportunity for Creation of polarization-preserving fiber with very small beat length between the fundamental modes of different polarization...

  10. UV Coatings, Polarization, and Coronagraphy

    Science.gov (United States)

    Bolcar, Matthew R.; Quijada, Manuel; West, Garrett; Balasubramanian, Bala; Krist, John; Martin, Stefan; Sabatke, Derek

    2016-01-01

    Presenation for the Large UltraViolet Optical Infrared (LUVOIR) and Habitable Exoplanet Imager (HabEx) Science and Technology Definition Teams (STDT) on technical considerations regarding ultraviolet coatings, polarization, and coronagraphy. The presentations review the state-of-the-art in ultraviolet coatings, how those coatings generate polarization aberrations, and recent study results from both the LUVOIR and HabEx teams.

  11. Polarization Imaging and Insect Vision

    Science.gov (United States)

    Green, Adam S.; Ohmann, Paul R.; Leininger, Nick E.; Kavanaugh, James A.

    2010-01-01

    For several years we have included discussions about insect vision in the optics units of our introductory physics courses. This topic is a natural extension of demonstrations involving Brewster's reflection and Rayleigh scattering of polarized light because many insects heavily rely on optical polarization for navigation and communication.…

  12. Climate Drives Polar Bear Origins

    Science.gov (United States)

    In their provocative analysis of northern bears (“Nuclear genomic sequences reveal that polar bears are an old and distinct bear lineage,” Reports, 20 April, p. 344), F. Hailer et al. use independent nuclear loci to show that polar bears originated during the middle Pleistocene, rather than during t...

  13. Spin-polarized inelastic tunneling through insulating barriers.

    Science.gov (United States)

    Lu, Y; Tran, M; Jaffrès, H; Seneor, P; Deranlot, C; Petroff, F; George, J-M; Lépine, B; Ababou, S; Jézéquel, G

    2009-05-01

    Spin-conserving hopping transport through chains of localized states has been evidenced by taking benefit of the high degree of spin-polarization of CoFeB-MgO-CoFeB magnetic tunnel junctions. In particular, our data show that relatively thick MgO barriers doped with boron favor the activation of spin-conserving inelastic channels through a chain of three localized states and leading to reduced magnetoresistance effects. We propose an extension of the Glazman-Matveev theory to the case of ferromagnetic reservoirs to account for spin-polarized inelastic tunneling through nonmagnetic localized states embedded in an insulating barrier.

  14. Integrins and epithelial cell polarity.

    Science.gov (United States)

    Lee, Jessica L; Streuli, Charles H

    2014-08-01

    Cell polarity is characterised by differences in structure, composition and function between at least two poles of a cell. In epithelial cells, these spatial differences allow for the formation of defined apical and basal membranes. It has been increasingly recognised that cell-matrix interactions and integrins play an essential role in creating epithelial cell polarity, although key gaps in our knowledge remain. This Commentary will discuss the mounting evidence for the role of integrins in polarising epithelial cells. We build a model in which both inside-out signals to polarise basement membrane assembly at the basal surface, and outside-in signals to control microtubule apical-basal orientation and vesicular trafficking are required for establishing and maintaining the orientation of epithelial cell polarity. Finally, we discuss the relevance of the basal integrin polarity axis to cancer. This article is part of a Minifocus on Establishing polarity. © 2014. Published by The Company of Biologists Ltd.

  15. Hyperon polarization: An experimental overview

    International Nuclear Information System (INIS)

    Lach, J.

    1992-12-01

    The fact that inclusively produced hyperons are produced with significant polarization was first discovered at Fermilab about seventeen years ago. This and subsequent experiments showed that Λ degree were produced polarized while bar Λ degree had no polarization in the same kinematical region. This set the stage for many experiments which showed that most hyperons are produced polarized. Recent Fermilab experiments have showed that this phenomena is even more complex than previously thought and theoretical understanding is still lacking. Nevertheless polarized hyperon beams have been an extremely useful experimental tool in measuring hyperon magnetic moments and hyperon β-decay. Recently, hyperon radiative decays have been studied and magnetic moment precession of channeled particles in bent crystals has been observed

  16. A review of polarized ion sources

    International Nuclear Information System (INIS)

    Schmor, P.W.

    1995-06-01

    The two main types of polarized ion sources in use on accelerators today are the Atomic Beam Polarized Ion Source (ABIS) source and the Optically Pumped Polarized Ion Source (OPPIS). Both types can provide beams of nuclearly polarized light ions which are either positively or negatively charged. Heavy ion polarized ion sources for accelerators are being developed. (author). 35 refs., 1 tab

  17. Polar cap hot patches: Enhanced density structures different from the classical patches in the ionosphere

    Science.gov (United States)

    Zhang, Q.-H.; Ma, Y.-Z.; Jayachandran, P. T.; Moen, J.; Lockwood, M.; Zhang, Y.-L.; Foster, J. C.; Zhang, S.-R.; Wang, Y.; Themens, D. R.; Zhang, B.-C.; Xing, Z. Y.

    2017-08-01

    Based on in situ and ground-based observations, a new type of "polar cap hot patch" has been identified that is different from the classical polar cap enhanced density structure (cold patches). Comparing with the classical polar cap patches, which are transported from the dayside sunlit region with dense and cold plasma, the polar cap hot patches are associated with particle precipitations (therefore field-aligned currents), ion upflows, and flow shears. The hot patches may have the same order of density enhancement as classical patches in the topside ionosphere, suggesting that the hot patches may be produced by transported photoionization plasma into flow channels. Within the flow channels, the hot patches have low-energy particle precipitation and/or ion upflows associated with field-aligned currents and flow shears. Corresponding Global Navigation Satellite System (GNSS) signal scintillation measurements indicate that hot patches may produce slightly stronger radio signal scintillation in the polar cap region than classical patches. A new type of polar cap patches, "polar cap hot patches," is identified to differentiate enhanced density structures from classical patches. Hot patches are associated with particle precipitations, ion upflows, field-aligned currents, and shear flows in the polar cap. Hot patches may lead to slightly stronger ionospheric scintillations of GNSS signals in the polar cap region than classical patches.

  18. Promoting Diversity Through Polar Interdisciplinary Coordinated Education (Polar ICE)

    Science.gov (United States)

    McDonnell, J. D.; Hotaling, L. A.; Garza, C.; Van Dyk, P. B.; Hunter-thomson, K. I.; Middendorf, J.; Daniel, A.; Matsumoto, G. I.; Schofield, O.

    2017-12-01

    Polar Interdisciplinary Coordinated Education (ICE) is an education and outreach program designed to provide public access to the Antarctic and Arctic regions through polar data and interactions with the scientists. The program provides multi-faceted science communication training for early career scientists that consist of a face-to face workshop and opportunities to apply these skills. The key components of the scientist training workshop include cultural competency training, deconstructing/decoding science for non-expert audiences, the art of telling science stories, and networking with members of the education and outreach community and reflecting on communication skills. Scientists partner with educators to provide professional development for K-12 educators and support for student research symposia. Polar ICE has initiated a Polar Literacy initiative that provides both a grounding in big ideas in polar science and science communication training designed to underscore the importance of the Polar Regions to the public while promoting interdisciplinary collaborations between scientists and educators. Our ultimate objective is to promote STEM identity through professional development of scientists and educators while developing career awareness of STEM pathways in Polar science.

  19. Radiation Transport

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-06-15

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

  20. Auxin transport sites are visualized in planta using fluorescent auxin analogs

    Science.gov (United States)

    Hayashi, Ken-ichiro; Nakamura, Shouichi; Fukunaga, Shiho; Nishimura, Takeshi; Jenness, Mark K.; Murphy, Angus S.; Motose, Hiroyasu; Nozaki, Hiroshi; Furutani, Masahiko; Aoyama, Takashi

    2014-01-01

    The plant hormone auxin is a key morphogenetic signal that controls many aspects of plant growth and development. Cellular auxin levels are coordinately regulated by multiple processes, including auxin biosynthesis and the polar transport and metabolic pathways. The auxin concentration gradient determines plant organ positioning and growth responses to environmental cues. Auxin transport systems play crucial roles in the spatiotemporal regulation of the auxin gradient. This auxin gradient has been analyzed using SCF-type E3 ubiquitin-ligase complex-based auxin biosensors in synthetic auxin-responsive reporter lines. However, the contributions of auxin biosynthesis and metabolism to the auxin gradient have been largely elusive. Additionally, the available information on subcellular auxin localization is still limited. Here we designed fluorescently labeled auxin analogs that remain active for auxin transport but are inactive for auxin signaling and metabolism. Fluorescent auxin analogs enable the selective visualization of the distribution of auxin by the auxin transport system. Together with auxin biosynthesis inhibitors and an auxin biosensor, these analogs indicated a substantial contribution of local auxin biosynthesis to the formation of auxin maxima at the root apex. Moreover, fluorescent auxin analogs mainly localized to the endoplasmic reticulum in cultured cells and roots, implying the presence of a subcellular auxin gradient in the cells. Our work not only provides a useful tool for the plant chemical biology field but also demonstrates a new strategy for imaging the distribution of small-molecule hormones. PMID:25049419

  1. Use of low-dose clinical pharmacodynamic and pharmacokinetic data to establish an occupational exposure limit for dapagliflozin, a potent inhibitor of the renal sodium glucose co-transporter 2.

    Science.gov (United States)

    Gould, Janet C; Kasichayanula, Sreeneeranj; Shepperly, David C; Boulton, David W

    2013-10-01

    Classical risk assessment models for setting safe occupational exposure limits (OEL) have used multiple uncertainty factors (UF) applied to a point of departure (POD), e.g., a No Observed Effect Level (NOEL), which in some cases is the pharmacological effect. Dapagliflozin promotes glucosuria by inhibiting the renal sodium-glucose cotransporter-2 transporter. The initial OEL for dapagliflozin (0.002mg/m(3)) was calculated when low dose clinical data was not available to identify a NOEL resulting in the need to use excessive UFs. To reduce the UFs from the OEL, a clinical pharmacodynamic [glucosuria and urinary glucose dipstick (UGD)] and pharmacokinetic study was conducted with single oral doses of 0.001, 0.01, 0.1, 0.3, 1.0 or 2.5mg administered to 36 healthy subjects. Dose-related dapagliflozin systemic exposures were observed at doses ⩾0.1mg and glucosuria was observed at doses ⩾0.3mg and corroborated by UGD. The NOEL was therefore 0.1mg for glucosuria. For setting the new OEL, no UFs were required. Dividing the POD by 10m(3) (the volume of air an adult inhales in a workday), the resulting OEL was 0.01mg/m(3). In conclusion, low-dose clinical pharmacodynamic and pharmacokinetic data can allow the OEL to be adjusted to the highest safe level. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Molecular pharmacokinetic determinants of anticancer kinase inhibitors in humans

    Directory of Open Access Journals (Sweden)

    Julie Scholler

    2011-06-01

    Full Text Available This review presents the published data regarding the molecular determinants (drug metabolizing enzymes, drug transporters and orphan nuclear receptors of approved anticancer kinase inhibitors pharmacokinetics in humans. The clinical impact of these determinants (drug disposition and drug–drug interactions is also discussed.

  3. An enhancement of spin polarization by multiphoton pumping in semiconductors

    Energy Technology Data Exchange (ETDEWEB)

    Miah, M. Idrish, E-mail: m.miah@griffith.edu.au [Queensland Micro- and Nanotechnology Centre, Griffith University, Nathan, Brisbane, QLD 4111 (Australia); Department of Physics, University of Chittagong, Chittagong 4331 (Bangladesh)

    2011-08-15

    Highlights: {yields} Multiphoton pumping and spin generation in semiconductors. {yields} Optical selection rules for inter-band transitions. {yields} Calculations of spin polarization using band-energy model and the second order perturbation theory. {yields} Enhancement of the electronic spin polarization. - Abstract: A pump-probe spectroscopic study has been carried out in zinc-blende bulk semiconductors. In the semiconductor samples, a spin-polarized carrier population is produced by the absorption of a monochromatic circularly polarized light beam with two-photon energy above the direct band gap in bulk semiconductors. The production of a carrier population with a net spin is a consequence of the optical selection rules for the heavy-hole and light-hole valence-to-conduction band transitions. This production is probed by the spin-dependent transmission of the samples in the time domain. The spin polarization of the conduction-band-electrons in dependences of delay of the probe beam as well as of pumping photon energy is estimated. The spin polarization is found to depolarize rapidly for pumping energy larger than the energy gap of the split-off band to the conduction band. From the polarization decays, the spin relaxation times are also estimated. Compared to one-photon pumping, the results, however, show that an enhancement of the spin-polarization is achieved by multiphoton excitation of the samples. The experimental results are compared with those obtained in calculations using second order perturbation theory of the spin transport model. A good agreement between experiment and theory is obtained. The observed results are discussed in details.

  4. An enhancement of spin polarization by multiphoton pumping in semiconductors

    International Nuclear Information System (INIS)

    Miah, M. Idrish

    2011-01-01

    Highlights: → Multiphoton pumping and spin generation in semiconductors. → Optical selection rules for inter-band transitions. → Calculations of spin polarization using band-energy model and the second order perturbation theory. → Enhancement of the electronic spin polarization. - Abstract: A pump-probe spectroscopic study has been carried out in zinc-blende bulk semiconductors. In the semiconductor samples, a spin-polarized carrier population is produced by the absorption of a monochromatic circularly polarized light beam with two-photon energy above the direct band gap in bulk semiconductors. The production of a carrier population with a net spin is a consequence of the optical selection rules for the heavy-hole and light-hole valence-to-conduction band transitions. This production is probed by the spin-dependent transmission of the samples in the time domain. The spin polarization of the conduction-band-electrons in dependences of delay of the probe beam as well as of pumping photon energy is estimated. The spin polarization is found to depolarize rapidly for pumping energy larger than the energy gap of the split-off band to the conduction band. From the polarization decays, the spin relaxation times are also estimated. Compared to one-photon pumping, the results, however, show that an enhancement of the spin-polarization is achieved by multiphoton excitation of the samples. The experimental results are compared with those obtained in calculations using second order perturbation theory of the spin transport model. A good agreement between experiment and theory is obtained. The observed results are discussed in details.

  5. POLARIZED LIGHT IN PHYSIOTHERAPY

    Directory of Open Access Journals (Sweden)

    L. D. Tondiy

    2015-12-01

    Full Text Available The data on polarized light (PS - a new promising treatment, rehabilitation and prevention, which took its deserved place among the known therapeutic physical factors and may even compete with laser radiation of low and LED therapy. It is reflected the significant contribution of domestic scientists in the study of aircraft action on the body, its introduction in the treatment, rehabilitation and prevention of grippe, ARI. These action's mechanisms of the aircraft on the electro-physiological processes in the body that have the leading role in the regulation of its life. The new moment in the study of aircraft on the body is the evidence of its positive impact on the mechanisms of self body - its different units: the disease's banning - a revitalization of the stress-protective, stress-limiting system antioxidial, detoxification and other protection systems, the formation by the body antiviral and antimicrobial specific substances (interferon and lysozyme, activation of the immune system, phagocytosis, protective functions of skin. The protective and mobilizing role of the second link is studied: which is triggered in case of occurrence of disease or preexisting diseases: PL mobilized processes of restitution, reparations, compensation, immunity and microcirculation. The authors studied the possibility of aircraft's using to enhance performance, reduce side effects of physical factors, which are often used in the treatment (electric methods, treatment by sound, fresh and mineral water, etc..

  6. A novel class of small molecule inhibitors of HDAC6.

    Science.gov (United States)

    Inks, Elizabeth S; Josey, Benjamin J; Jesinkey, Sean R; Chou, C James

    2012-02-17

    Histone deacetylases (HDACs) are a family of enzymes that play significant roles in numerous biological processes and diseases. HDACs are best known for their repressive influence on gene transcription through histone deacetylation. Mapping of nonhistone acetylated proteins and acetylation-modifying enzymes involved in various cellular pathways has shown protein acetylation/deacetylation also plays key roles in a variety of cellular processes including RNA splicing, nuclear transport, and cytoskeletal remodeling. Studies of HDACs have accelerated due to the availability of small molecule HDAC inhibitors, most of which contain a canonical hydroxamic acid or benzamide that chelates the metal catalytic site. To increase the pool of unique and novel HDAC inhibitor pharmacophores, a pharmacological active compound screen was performed. Several unique HDAC inhibitor pharmacophores were identified in vitro. One class of novel HDAC inhibitors, with a central naphthoquinone structure, displayed a selective inhibition profile against HDAC6. Here we present the results of a unique class of HDAC6 inhibitors identified using this compound library screen. In addition, we demonstrated that treatment of human acute myeloid leukemia cell line MV4-11 with the selective HDAC6 inhibitors decreases levels of mutant FLT-3 and constitutively active STAT5 and attenuates Erk phosphorylation, all of which are associated with the inhibitor's selective toxicity against leukemia.

  7. Chamber transport

    International Nuclear Information System (INIS)

    Olson, Craig L.

    2001-01-01

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

  8. Inhibitin: a specific inhibitor of sodium/sodium exchange in erythrocytes.

    OpenAIRE

    Morgan, K; Brown, R C; Spurlock, G; Southgate, K; Mir, M A

    1986-01-01

    An inhibitor of ouabain-insensitive sodium/sodium exchange in erythrocytes has been isolated from leukemic promyelocytes. To explore the specific effects of this inhibitor, named inhibitin, sodium transport experiments were carried out in human erythrocytes. Inhibitin reduced ouabain-insensitive bidirectional sodium transport. It did not change net sodium fluxes, had no significant effect on rubidium influx, and did not inhibit sodium-potassium-ATPase activity. The inhibitory effect of inhibi...

  9. Nuclear physics with polarized particles

    CERN Document Server

    Paetz gen Schieck, Hans

    2012-01-01

    The measurement of spin-polarization observables in reactions of nuclei and particles is of great utility and advantage when the effects of single-spin sub-states are to be investigated. Indeed, the unpolarized differential cross-section encompasses the averaging over the spin states of the particles, and thus loses details of the interaction process. This introductory text combines, in a single volume, course-based lecture notes on spin physics and on polarized-ion sources with the aim of providing a concise yet self-contained starting point for newcomers to the field, as well as for lecturers in search of suitable material for their courses and seminars. A significant part of the book is devoted to introducing the formal theory-a description of polarization and of nuclear reactions with polarized particles. The remainder of the text describes the physical basis of methods and devices necessary to perform experiments with polarized particles and to measure polarization and polarization effects in nuclear rea...

  10. Few-body experiments with polarized beams and polarized targets

    International Nuclear Information System (INIS)

    Simmons, J.E.

    1983-01-01

    A survey is presented concerning recent polarization experiments in the elastic p-d, p- 3 He, and p- 4 He systems. Mention is made of selected neutron experiments. The nominal energy range is 10 to 1000 MeV. Recent results and interpretations of the p-d system near 10 MeV are discussed. New experiments on the energy dependence of back angle p-d tensor polarization are discussed with respect to resolution of discrepancies and difficulty of theoretical interpretation. Progress is noted concerning multiple scattering interpretation of forward p-d deuteron polarization. Some new results are presented concerning the p- 3 He system and higher energy p- 4 He polarization experiments. 52 references

  11. Elite Polarization and Public Opinion

    DEFF Research Database (Denmark)

    Robison, Joshua; Mullinix, Kevin

    2016-01-01

    Elite polarization has reshaped American politics and is an increasingly salient aspect of news coverage within the United States. As a consequence, a burgeoning body of research attempts to unravel the effects of elite polarization on the mass public. However, we know very little about how...... attitudes. In our first study, we show that criticism of polarization leads partisans to more positively evaluate the argument offered by their non-preferred party, increases support for bi-partisanship, but ultimately does not change the extent to which partisans follow their party’s policy endorsements...

  12. Acceleration of polarized proton beams

    International Nuclear Information System (INIS)

    Roser, T.

    1998-01-01

    The acceleration of polarized beams in circular accelerators is complicated by the numerous depolarizing spin resonances. Using a partial Siberian snake and a rf dipole that ensure stable adiabatic spin motion during acceleration has made it possible to accelerate polarized protons to 25 GeV at the Brookhaven AGS. Full Siberian snakes are being developed for RHIC to make the acceleration of polarized protons to 250 GeV possible. A similar scheme is being studied for the 800 GeV HERA proton accelerator

  13. Polarimetry with azimuthally polarized light

    Science.gov (United States)

    de Sande, Juan Carlos González; Piquero, Gemma; Santarsiero, Massimo

    2018-03-01

    Nonuniformly polarized light can be used for Mueller polarimetry of homogeneous linear samples. In this work, a set up based on using azimuthally polarized input light and a modified commercial light polarimeter is proposed and developed. With this set up, a Mueller submatrix of a sample can be obtained by measuring the Stokes parameters at only three different positions across the output beam section. Symmetry constraints for linear deterministic samples allow the complete Mueller matrix to be deduced for this kind of specimens. The experimental results obtained for phase plates and for a linear polarizer confirm the validity of the proposed method.

  14. Polarized deuteron elastic scattering from a polarized proton target

    International Nuclear Information System (INIS)

    Schmelzer, R.; Kuiper, H.; Schoeberl, M.; Berber, S.; Hilmert, H.; Koeppel, R.; Pferdmenges, R.; Zankel, H.

    1983-01-01

    Measurements are reported of the spin correlation parameter Cy,y for the elastic scattering of 10.0 MeV vector polarized deuterons from a polarized proton target at five CM angles (76 0 ,85 0 ,98 0 ,115 0 ,132 0 ). The experimental results are compared with different predictions. A Faddeev type calculation on the basis of local potentials also including approximate Coulomb distortion is favoured by our experimental results. (orig.)

  15. PolarHub: A Global Hub for Polar Data Discovery

    Science.gov (United States)

    Li, W.

    2014-12-01

    This paper reports the outcome of a NSF project in developing a large-scale web crawler PolarHub to discover automatically the distributed polar dataset in the format of OGC web services (OWS) in the cyberspace. PolarHub is a machine robot; its goal is to visit as many webpages as possible to find those containing information about polar OWS, extract this information and store it into the backend data repository. This is a very challenging task given huge data volume of webpages on the Web. Three unique features was introduced in PolarHub to make it distinctive from earlier crawler solutions: (1) a multi-task, multi-user, multi-thread support to the crawling tasks; (2) an extensive use of thread pool and Data Access Object (DAO) design patterns to separate persistent data storage and business logic to achieve high extendibility of the crawler tool; (3) a pattern-matching based customizable crawling algorithm to support discovery of multi-type geospatial web services; and (4) a universal and portable client-server communication mechanism combining a server-push and client pull strategies for enhanced asynchronous processing. A series of experiments were conducted to identify the impact of crawling parameters to the overall system performance. The geographical distribution pattern of all PolarHub identified services is also demonstrated. We expect this work to make a major contribution to the field of geospatial information retrieval and geospatial interoperability, to bridge the gap between data provider and data consumer, and to accelerate polar science by enhancing the accessibility and reusability of adequate polar data.

  16. Characterization of Encapsulated Corrosion Inhibitors for Environmentally Friendly Smart Coatings

    Science.gov (United States)

    Pearman, B. P.; Calle, L. M.; Zhang, X.; Li, W.; Buhrow, J. W.; Johnsey, M. N.; Montgomery, E. L.; Fitzpatrick, L.; Surma, J. M.

    2015-01-01

    The NASA Kennedy Space Center's Corrosion Technology Lab at the Kennedy Space Center in Florida, U.S.A. has been developing multifunctional smart coatings based on the microencapsulation of environmentally friendly corrosion indicators, inhibitors and self-healing agents. This allows the incorporation of autonomous corrosion control functionalities, such as corrosion detection and inhibition as well as the self-healing of mechanical damage, into coatings. This paper presents technical details on the characterization of inhibitor-containing particles and their corrosion inhibitive effects using electrochemical and mass loss methods. Three organic environmentally friendly corrosion inhibitors were encapsulated in organic microparticles that are compatible with desired coatings. The release of the inhibitors from the microparticles in basic solution was studied. Fast release, for immediate corrosion protection, as well as long-term release for continued protection, was observed. The inhibition efficacy of the inhibitors, incorporated directly and in microparticles, on carbon steel was evaluated. Polarization curves and mass loss measurements showed that, in the case of 2MBT, its corrosion inhibition effectiveness was greater when it was delivered from microparticles.

  17. Seasonal erosion and restoration of Mars' northern polar dunes.

    Science.gov (United States)

    Hansen, C J; Bourke, M; Bridges, N T; Byrne, S; Colon, C; Diniega, S; Dundas, C; Herkenhoff, K; McEwen, A; Mellon, M; Portyankina, G; Thomas, N

    2011-02-04

    Despite radically different environmental conditions, terrestrial and martian dunes bear a strong resemblance, indicating that the basic processes of saltation and grainfall (sand avalanching down the dune slipface) operate on both worlds. Here, we show that martian dunes are subject to an additional modification process not found on Earth: springtime sublimation of Mars' CO(2) seasonal polar caps. Numerous dunes in Mars' north polar region have experienced morphological changes within a Mars year, detected in images acquired by the High-Resolution Imaging Science Experiment on the Mars Reconnaissance Orbiter. Dunes show new alcoves, gullies, and dune apron extension. This is followed by remobilization of the fresh deposits by the wind, forming ripples and erasing gullies. The widespread nature of these rapid changes, and the pristine appearance of most dunes in the area, implicates active sand transport in the vast polar erg in Mars' current climate.

  18. Lonafarnib is a potential inhibitor for neovascularization.

    Directory of Open Access Journals (Sweden)

    Linlin Sun

    Full Text Available Atherosclerosis is a common cardiovascular disease that involves the build-up of plaque on the inner walls of the arteries. Intraplaque neovacularization has been shown to be essential in the pathogenesis of atherosclerosis. Previous studies showed that small-molecule compounds targeting farnesyl transferase have the ability to prevent atherosclerosis in apolipoprotein E-deficient mice, but the underlying mechanism remains to be elucidated. In this study, we found that lonafarnib, a specific inhibitor of farnesyl transferase, elicits inhibitory effect on vascular endothelial capillary assembly in vitro in a dose-dependent manner. In addition, we showed that lonafarnib treatment led to a dose-dependent decrease in scratch wound closure in vitro, whereas it had little effect on endothelial cell proliferation. These data indicate that lonafarnib inhibits neovascularization via directly targeting endothelial cells and disturbing their motility. Moreover, we demonstrated that pharmacological inhibition of farnesyl transferase by lonafarnib significantly impaired centrosome reorientation toward the leading edge of endothelial cells. Mechanistically, we found that the catalytic β subunit of farnesyl transferase associated with a cytoskeletal protein important for the establishment and maintenance of cell polarity. Additionally, we showed that lonafarnib remarkably inhibited the expression of the cytoskeletal protein and interrupted its interaction with farnesyl transferase. Our findings thus offer novel mechanistic insight into the protective effect of farnesyl transferase inhibitors on atherosclerosis and provide encouraging evidence for the potential use of this group of agents in inhibiting plaque neovascularization.

  19. Inhibitor for the Corrosion of Mild Steel in H 2 SO 4 | Patel | South ...

    African Journals Online (AJOL)

    An extract of Terminalia chebula fruits was investigated as a corrosion inhibitor of mild steel in 0.5 M H2SO4 by means of conventional mass loss, electrochemical polarization, electrochemical impedance spectroscopy and scanning electron microscopy. The mass loss results showed that the extract of Terminalia chebula is ...

  20. Extract of Combretum micranthum as corrosion inhibitor for Al – Si ...

    African Journals Online (AJOL)

    The calculated values of activation energy, enthalpy of activation entropy of activation, free energy of process is by physical adsorption. Equally, methanol extract CM is a good adsorption inhibitor for the corrosion of Al-Si-Mg in 3.5wt% NaCl solution. Tafel polarization analysis indicates that the studied plant extract is a ...