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Sample records for alkylaminocarbene ligand leads

  1. Nanopore-Based Sensors for Ligand-Receptor Lead Optimization.

    Science.gov (United States)

    Luan, Binquan; Huynh, Tien; Zhou, Ruhong

    2015-02-01

    Developing a low-cost and high-efficacy method to optimize prescreened or designed drug candidates will facilitate drug discovery and biomedical research in general. Current methods of drug screening usually involve tedious sample preparation and costly biological/chemical assays. Here, through all-atom molecular dynamics simulations, we propose a new drug optimization method, based on the nanopore force spectroscopy, to electrically detect the binding strength between a drug molecule and a target protein. Simulation results demonstrate that the drug-protein complex can be electrophoretically driven into a nanopore, which is followed by the rupture of the complex at a critical biasing voltage. The latter determines the binding strength of the tested drug molecule. It is expected that the application of this single-molecule technology could help to accelerate the drug discovery, particularly for processes of the narrow screening and further lead optimization. PMID:26261942

  2. In vivo evaluation of a lead-labeled monoclonal antibody using the DOTA ligand

    International Nuclear Information System (INIS)

    The aim of this study was to assess the utility of a radioimmunoconjugate containing a lead radionuclide for therapy and scintigraphy applications. The radioimmunoconjugate evaluated consisted of a bifunctional DOTA ligand and monoclonal antibody (MAb) B72.3 using athymic mice bearing LS-174T tumors, human colon carcinoma xenografts. In the studies reported here, the lead-203-DOTA complex itself was first demonstrated to have in vivo stability. MAb B72.3 was then conjugated with the DOTA ligand and labeled with 203Pb, and the immunoreactivity of B72.3 was maintained. The localization of the radioimmunoconjugate to tumor tissue and other select organs paralleled that of DOTA-125I-B72.3, suggesting a similar metabolic pattern of the two radioimmunoconjugates. Thus, the DOTA-metal complex does not alter the behavior of the radioimmunoconjugate. Tumor localization of the 203Pb-DOTA-B72.3 conjugate was demonstrated with biodistribution studies as well as immunoscintigraphy studies. Such data highlight the stability of a lead radionuclide in the DOTA ligand. The suitability of this chelation chemistry for labeling radioimmunoconjugates with a lead radionuclide now makes its application in nuclear medicine a feasible proposition. (orig.)

  3. Urgent percutaneous coronary intervention leads to a decrease in serum concentrations of soluble CD40 ligand

    Directory of Open Access Journals (Sweden)

    Ratković Nenad

    2010-01-01

    Full Text Available Background/Aim. Inflammation as a consequence of vascular injury after percutaneous coronary intervention (PCI is a pathological substrate of restenosis and of its complications. The aim of the study was to examine perprocedural inflammatory response expressed by soluble CD40 ligand (sCD40L and C-reactive protein (CRP in patients treated with PCI and dual antiplatelet therapy. Methods. The experimental group included 52 patients (80.8% men, age 60 ± 9 years with angina pectoris treated by PCI (22 urgent PCI with stent implantation, and dual antiplatelet therapy (tienopiridins and aspirin, according to the current recommendations for the execution of the intervention. The control group consisted of 8 patients (70.5% men, age 59 ± 7 years with angina pectoris, who had undergone coronarography taking aspirin 3 days prior to it. In all the patients 24 hours before and after the PCI concentrations of CRP and sCD40L in the blood were determined. Results. In the experimental group, the concentration of sCD40L was lower as compared to the control (p < 0.02. In 34 (65% patients postprocedural decrease in sCD40L was recorded, in 18 (34.6% of them increase, while in 50 (96% patients there was a rise in CRP. The patients with postprocedural fall in sCD40L hod greater preprocedural concentration of sCD40L (p < 0.001, and less postprocedural concentration of sCD40L (p < 0.001, compared to the group with an increase in sCD40L after the PCI, while CRP levels tients treated with emergency PCI compared to elective patietns had a postprocedural decrease in sCD40L (p = 0.02. Increase in the level of CRP was higher in the group with emergency PCI in relation to elective PCI (p < 0.01. Conclusion. Emergency PCI procedures in the treatment of patients with unstable angina pectoris lead to a postprocedural fall in the serum concentration of sCD40L. Dual antiplate therapy with tienopiridins and aspirin inhibits the release of sCD40L. Regardless a clinical presentation

  4. Lead(II) complexes with some SNO and ONO tridentate Schiff base ligands and their evaluation as lead(II) sensors

    Energy Technology Data Exchange (ETDEWEB)

    Saadeh, Salman M., E-mail: hazemona1@yahoo.co.uk [Chemistry Department, College of Sciences, Islamic University of Gaza, Gaza (Palestinian Territory, Occupied); Abu Shawish, Hazem M., E-mail: hazemona1@yahoo.co.uk [Chemistry Department, College of Sciences, Al-Aqsa University, Gaza (Palestinian Territory, Occupied); Dalloul, Hany M. [Chemistry Department, College of Sciences, Al-Aqsa University, Gaza (Palestinian Territory, Occupied); EL-Halabi, Nabil M.; Kh. Daher, Baha [Chemistry Department, College of Sciences, Islamic University of Gaza, Gaza (Palestinian Territory, Occupied)

    2012-04-01

    New Pb(II) complexes of the general formula PbL{sub 2} where HL 2-acetylthiophene benzoylhydrazone, 2-acetylfuran benzoylhydrazone, 2-carboxaldehydethiophene benzoylhydrazone and 2-carboxaldehydefuran benzoylhydrazone were synthesized by reaction of lead(II) acetate with the ligands in methanol in lead to ligand ratio of 1: 2. The complexes are insoluble in common organic solvents but soluble in DMF and DMSO. The measured molar conductance values in DMF indicate that, the complexes are non-electrolytes in nature. In view of analytical and spectral (IR, UV-vis and NMR) studies, it has been concluded that, all the metal complexes possess octahedral geometry in which the ligand is coordinated to lead(II) through azomethine nitrogen, benzoyl oxygen and thiophene sulfur or furan oxygen atom via deprotonation. These complexes were tested as ionophores for lead(II) determination. Pb(ATBH){sub 2} gave the best response with two plasticizers Doph and DOS were fully characterized. Their detection limit were 3.9 Multiplication-Sign 10{sup -7} mol L{sup -1}, 7.9 Multiplication-Sign 10{sup -7} mol L{sup -1}, concentration range 5.9 Multiplication-Sign 10{sup -7} -1.0 Multiplication-Sign 10{sup -2} mol L{sup -1}, 9.1 Multiplication-Sign 10{sup -7}-1.0 Multiplication-Sign 10{sup -2} mol L{sup -1} response time {approx} 8-10 sec and pH range 6.2-7.8. The proposed sensors show a reasonable discrimination ability towards Pb(II) in comparison to some alkali, alkaline earth, transition heavy metal ions. The modified electrodes were applied as an indicator electrode and successfully used to determine Pb(II) in synthesized polluted water samples giving satisfactory results. - Highlights: Black-Right-Pointing-Pointer Preparation and characterization of lead complexes of some SNO and NNO tridentate ligands. Black-Right-Pointing-Pointer New chemically modified carbon paste electrodes (CMCPEs) for lead(II) were designed. Black-Right-Pointing-Pointer Lead complexes were used as sensing

  5. Lead(II) complexes with some SNO and ONO tridentate Schiff base ligands and their evaluation as lead(II) sensors

    International Nuclear Information System (INIS)

    New Pb(II) complexes of the general formula PbL2 where HL 2-acetylthiophene benzoylhydrazone, 2-acetylfuran benzoylhydrazone, 2-carboxaldehydethiophene benzoylhydrazone and 2-carboxaldehydefuran benzoylhydrazone were synthesized by reaction of lead(II) acetate with the ligands in methanol in lead to ligand ratio of 1: 2. The complexes are insoluble in common organic solvents but soluble in DMF and DMSO. The measured molar conductance values in DMF indicate that, the complexes are non-electrolytes in nature. In view of analytical and spectral (IR, UV–vis and NMR) studies, it has been concluded that, all the metal complexes possess octahedral geometry in which the ligand is coordinated to lead(II) through azomethine nitrogen, benzoyl oxygen and thiophene sulfur or furan oxygen atom via deprotonation. These complexes were tested as ionophores for lead(II) determination. Pb(ATBH)2 gave the best response with two plasticizers Doph and DOS were fully characterized. Their detection limit were 3.9 × 10−7 mol L−1, 7.9 × 10−7 mol L−1, concentration range 5.9 × 10−7 -1.0 × 10−2 mol L−1, 9.1 × 10−7–1.0 × 10−2 mol L−1 response time ∼ 8–10 sec and pH range 6.2–7.8. The proposed sensors show a reasonable discrimination ability towards Pb(II) in comparison to some alkali, alkaline earth, transition heavy metal ions. The modified electrodes were applied as an indicator electrode and successfully used to determine Pb(II) in synthesized polluted water samples giving satisfactory results. - Highlights: ► Preparation and characterization of lead complexes of some SNO and NNO tridentate ligands. ► New chemically modified carbon paste electrodes (CMCPEs) for lead(II) were designed. ► Lead complexes were used as sensing material in preparation of lead-CMCPEs. ► Modifies carbon paste electrodes are unique in surface renewal and ease of use. ► These electrodes are useful in determination of lead(II) in polluted water samples.

  6. Extraction of uranium and lead from mixed waste debris using a variety of metal/ligand complexes

    International Nuclear Information System (INIS)

    To ensure the safety of our Nation's nuclear stockpile, Los Alamos National Laboratory is in the process of constructing the DARHT (Dual Axis Radiographic Hydrodynamic Test) facility. DARHT will examine the effects of aging and the stability of our stockpile. Contained testing will be phased in to reduce the impact of these tests, which contain depleted uranium, on our environment. The main focus of this research is to develop a treatment scheme for the recovery of depleted uranium and lead from shot debris that will result from these tests. The goals of this research are to optimize the conditions on a bench scale using a commercially available water soluble polymer to bind the lead and a variety of metal/ligand complexes such as 4,5-dihydroxy-1,3-benzene-disulfonic acid, dithionite, sodium carbonate/bicarbonate, and sodium hypochlorite to bind the uranium. Studies were conducted on a mixture of debris, such as wood, cable, paper towels, and tubing that contained both uranium and lead ranging in concentration from 10-1000's of ppm of contaminants. Experiments were done varying combinations and successions of extractant solutions as well as a number of sequential extractions. Studies show that a mixture of sodium hypochlorite and carbonate removed 90+% of both uranium and lead. We then focused on a separation scheme for the lead and uranium

  7. Three modified activated carbons by different ligands for the solid phase extraction of copper and lead

    International Nuclear Information System (INIS)

    In the presented work, 5,5-diphenylimidazolidine-2,4-dione (phenytoin) (DFTD), 5,5-diphenylimidazolidine-2-thione-,4-one (thiophenytoin) (DFID) and 2-(4'-methoxy-benzylidenimine) thiophenole (MBIP) modified activated carbons have been used for the solid phase extraction of copper and lead ions prior to their flame atomic absorption spectrometric determinations. The influences of the various analytical parameters including pH, amounts of reagent, sample volume and eluent type, etc. on the recovery efficiencies of copper and lead ions were investigated. The influences of alkaline, earth alkaline and some transition metals on the adsorption of the analytes were also examined. The detection limits by three sigma for analyte ions were 0.65 and 0.42 μg L-1 using activated carbon modified with DFID; 0.52 and 0.37 μg L-1 using activated carbon modified with DFTD and 0.46 and 0.31 μg L-1 using activated carbon modified with MBIP for Pb(II) and Cu(II), respectively. The procedure was applied to the determination of analytes in natural waters, soil, and blood samples with satisfactory results (recoveries greater than 95%, R.S.D.'s lower than 4%)

  8. From the dual function lead AP2238 to AP2469, a multi-target-directed ligand for the treatment of Alzheimer's disease

    OpenAIRE

    Tarozzi, Andrea; Bartolini, Manuela; Piazzi, Lorna; Valgimigli, Luca; Amorati, Riccardo; Bolondi, Cecilia; Djemil, Alice; Mancini, Francesca; Andrisano, Vincenza; Rampa, Angela

    2014-01-01

    The development of drugs with different pharmacological properties appears to be an innovative therapeutic approach for Alzheimer's disease. In this article, we describe a simple structural modification of AP2238, a first dual function lead, in particular the introduction of the catechol moiety performed in order to search for multi-target ligands. The new compound AP2469 retains anti-acetylcholinesterase (AChE) and beta-site amyloid precursor protein cleaving enzyme (BACE)1 activities compar...

  9. Coordination chemistry of two heavy metals: I, Ligand preferences in lead(II) complexation, toward the development of therapeutic agents for lead poisoning: II, Plutonium solubility and speciation relevant to the environment

    International Nuclear Information System (INIS)

    The coordination chemistry and solution behavior of the toxic ions lead(II) and plutonium(IV, V, VI) have been investigated. The ligand pKas and ligand-lead(II) stability constants of one hydroxamic acid and four thiohydroaxamic acids were determined. Solution thermodynamic results indicate that thiohydroxamic acids are more acidic and slightly better lead chelators than hydroxamates, e.g., N-methylthioaceto-hydroxamic acid, pKa = 5.94, logβ120 = 10.92; acetohydroxamic acid, pKa = 9.34, logβl20 = 9.52. The syntheses of lead complexes of two bulky hydroxamate ligands are presented. The X-ray crystal structures show the lead hydroxamates are di-bridged dimers with irregular five-coordinate geometry about the metal atom and a stereochemically active lone pair of electrons. Molecular orbital calculations of a lead hydroxamate and a highly symmetric pseudo octahedral lead complex were performed. The thermodynamic stability of plutonium(IV) complexes of the siderophore, desferrioxamine B (DFO), and two octadentate derivatives of DFO were investigated using competition spectrophotometric titrations. The stability constant measured for the plutonium(IV) complex of DFO-methylterephthalamide is logβ110 = 41.7. The solubility limited speciation of 242Pu as a function of time in near neutral carbonate solution was measured. Individual solutions of plutonium in a single oxidation state were added to individual solutions at pH = 6.0, T = 30.0, 1.93 mM dissolved carbonate, and sampled over intervals up to 150 days. Plutonium solubility was measured, and speciation was investigated using laser photoacoustic spectroscopy and chemical methods

  10. Coordination chemistry of two heavy metals: I, Ligand preferences in lead(II) complexation, toward the development of therapeutic agents for lead poisoning: II, Plutonium solubility and speciation relevant to the environment

    Energy Technology Data Exchange (ETDEWEB)

    Neu, M.P. [Lawrence Berkeley Lab., CA (United States)

    1993-11-01

    The coordination chemistry and solution behavior of the toxic ions lead(II) and plutonium(IV, V, VI) have been investigated. The ligand pK{sub a}s and ligand-lead(II) stability constants of one hydroxamic acid and four thiohydroaxamic acids were determined. Solution thermodynamic results indicate that thiohydroxamic acids are more acidic and slightly better lead chelators than hydroxamates, e.g., N-methylthioaceto-hydroxamic acid, pK{sub a} = 5.94, log{beta}{sub 120} = 10.92; acetohydroxamic acid, pK{sub a} = 9.34, log{beta}{sub l20} = 9.52. The syntheses of lead complexes of two bulky hydroxamate ligands are presented. The X-ray crystal structures show the lead hydroxamates are di-bridged dimers with irregular five-coordinate geometry about the metal atom and a stereochemically active lone pair of electrons. Molecular orbital calculations of a lead hydroxamate and a highly symmetric pseudo octahedral lead complex were performed. The thermodynamic stability of plutonium(IV) complexes of the siderophore, desferrioxamine B (DFO), and two octadentate derivatives of DFO were investigated using competition spectrophotometric titrations. The stability constant measured for the plutonium(IV) complex of DFO-methylterephthalamide is log{beta}{sub 110} = 41.7. The solubility limited speciation of {sup 242}Pu as a function of time in near neutral carbonate solution was measured. Individual solutions of plutonium in a single oxidation state were added to individual solutions at pH = 6.0, T = 30.0, 1.93 mM dissolved carbonate, and sampled over intervals up to 150 days. Plutonium solubility was measured, and speciation was investigated using laser photoacoustic spectroscopy and chemical methods.

  11. Synthesis, characterization and electrochemical characterization of lead selenide sub-micron particles capped with a benzoate ligand and prepared at different temperatures

    International Nuclear Information System (INIS)

    Semiconductor materials offer several potential benefits as active elements in the development of harvesting-energy conversion technologies. In particular, lead selenide (PbSe) semiconductors have been used and proposed to design solar energy harvesting devices, IR sensors, FET devices, etc. Lead salts have drawn particular attention from the applied and fundamental research communities due to their exceptionally strong quantum confinement effects. Several syntheses of PbSe have been proposed using long chain surfactants to allow the formation of particles and nanoparticles. Here we present a synthesis using benzoic acid as the capping ligand in ambient atmosphere. Although the particles are not in nanometric size, we compare the crystal structure (using x-ray powder diffraction data), the near infrared and mid-infrared absorption properties of PbSe using oleic acid as the capping ligand with PbSe using benzoic acid as the capping ligand. The new synthetized particles were shown to have similar crystal structure and absorb light in the near infrared region at 1410 nm. We also performed cyclic voltammetry of these particles drop-casted in the surface of a glassy carbon electrode. The particles showed electrochemical behavior with an oxidation peak near (−402 ± 5 mV) versus Ag/AgCl reference electrode. The particles seem to form a polymeric film at the surface of a glassy carbon electrode. (paper)

  12. Lead

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1998-12-31

    This is one of a series of reports made on industrial pollutants by the Expert Panel on Air Quality Standards to advise the United Kingdom Government on air quality standards. It describes the main sources of lead exposure, including the relative contribution of lead in the air and lead in the diet, and the methods by which it is measured in air. The Panel also considers the airborne concentrations recorded to date in the United Kingdom, ways in which lead is handled in by the body, and its toxic effects on people. The dominant source of airborne lead is petrol combustion. Other source include coal combustion, the production of non-ferrous metals and waste treatment and disposal. The justification of an air quality standard for lead is set down. The Panel recommends an air quality standard for lead in the United Kingdom of 0.25 {mu}g/m{sup 3} measured as an annual average. This is intended to protect young children, the group most vulnerable to impairment of brain function. 17 refs., 3 figs., 2 tabs.

  13. Organic-ligand-assisted supercritical hydrothermal synthesis of titanium oxide nanocrystals leading to perfectly dispersed titanium oxide nanoparticle in organic phase

    International Nuclear Information System (INIS)

    Titanium oxide (TiO2) nanocyrstals which are perfectly dispersed in organic solvents are synthesized by organic-ligand-assisted supercritical hydrothermal synthesis. The addition of hexaldehyde to the supercritical hydrothermal synthesis of TiO2 leads to the in-situ surface modification, which enables the synthsized TiO2 nanocrystals to be perfectly dispersed in iso-octane because of its hydrophobic nature. Further, the one-pot synthesis of hybrid materials results in the significant reduction of the particles size, probably due to the capping effect of hexaldehyde to suppress the particles growth

  14. Organic-ligand-assisted supercritical hydrothermal synthesis of titanium oxide nanocrystals leading to perfectly dispersed titanium oxide nanoparticle in organic phase

    Energy Technology Data Exchange (ETDEWEB)

    Mousavand, Tahereh; Zhang Jing; Ohara, Satoshi; Umetsu, Mitsuo; Naka, Takashi; Adschiri, Tadafumi [Tohoku University, Institute of Multidisciplinary Research for Advanced Materials (Japan)], E-mail: ajiri@tagen.tohoku.ac.jp

    2007-12-15

    Titanium oxide (TiO{sub 2}) nanocyrstals which are perfectly dispersed in organic solvents are synthesized by organic-ligand-assisted supercritical hydrothermal synthesis. The addition of hexaldehyde to the supercritical hydrothermal synthesis of TiO{sub 2} leads to the in-situ surface modification, which enables the synthsized TiO{sub 2} nanocrystals to be perfectly dispersed in iso-octane because of its hydrophobic nature. Further, the one-pot synthesis of hybrid materials results in the significant reduction of the particles size, probably due to the capping effect of hexaldehyde to suppress the particles growth.

  15. A Saccharomyces cerevisiae Assay System to Investigate Ligand/AdipoR1 Interactions That Lead to Cellular Signaling

    KAUST Repository

    Aouida, Mustapha

    2013-06-07

    Adiponectin is a mammalian hormone that exerts anti-diabetic, anti-cancer and cardioprotective effects through interaction with its major ubiquitously expressed plasma membrane localized receptors, AdipoR1 and AdipoR2. Here, we report a Saccharomyces cerevisiae based method for investigating agonist-AdipoR interactions that is amenable for high-throughput scale-up and can be used to study both AdipoRs separately. Agonist-AdipoR1 interactions are detected using a split firefly luciferase assay based on reconstitution of firefly luciferase (Luc) activity due to juxtaposition of its N- and C-terminal fragments, NLuc and CLuc, by ligand induced interaction of the chimeric proteins CLuc-AdipoR1 and APPL1-NLuc (adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif 1-NLuc) in a S. cerevisiae strain lacking the yeast homolog of AdipoRs (Izh2p). The assay monitors the earliest known step in the adiponectin-AdipoR anti-diabetic signaling cascade. We demonstrate that reconstituted Luc activity can be detected in colonies or cells using a CCD camera and quantified in cell suspensions using a microplate reader. AdipoR1-APPL1 interaction occurs in absence of ligand but can be stimulated specifically by agonists such as adiponectin and the tobacco protein osmotin that was shown to have AdipoR-dependent adiponectin-like biological activity in mammalian cells. To further validate this assay, we have modeled the three dimensional structures of receptor-ligand complexes of membrane-embedded AdipoR1 with cyclic peptides derived from osmotin or osmotin-like plant proteins. We demonstrate that the calculated AdipoR1-peptide binding energies correlate with the peptides\\' ability to behave as AdipoR1 agonists in the split luciferase assay. Further, we demonstrate agonist-AdipoR dependent activation of protein kinase A (PKA) signaling and AMP activated protein kinase (AMPK) phosphorylation in S. cerevisiae, which are homologous to

  16. A Saccharomyces cerevisiae assay system to investigate ligand/AdipoR1 interactions that lead to cellular signaling.

    Directory of Open Access Journals (Sweden)

    Mustapha Aouida

    Full Text Available Adiponectin is a mammalian hormone that exerts anti-diabetic, anti-cancer and cardioprotective effects through interaction with its major ubiquitously expressed plasma membrane localized receptors, AdipoR1 and AdipoR2. Here, we report a Saccharomyces cerevisiae based method for investigating agonist-AdipoR interactions that is amenable for high-throughput scale-up and can be used to study both AdipoRs separately. Agonist-AdipoR1 interactions are detected using a split firefly luciferase assay based on reconstitution of firefly luciferase (Luc activity due to juxtaposition of its N- and C-terminal fragments, NLuc and CLuc, by ligand induced interaction of the chimeric proteins CLuc-AdipoR1 and APPL1-NLuc (adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain and leucine zipper motif 1-NLuc in a S. cerevisiae strain lacking the yeast homolog of AdipoRs (Izh2p. The assay monitors the earliest known step in the adiponectin-AdipoR anti-diabetic signaling cascade. We demonstrate that reconstituted Luc activity can be detected in colonies or cells using a CCD camera and quantified in cell suspensions using a microplate reader. AdipoR1-APPL1 interaction occurs in absence of ligand but can be stimulated specifically by agonists such as adiponectin and the tobacco protein osmotin that was shown to have AdipoR-dependent adiponectin-like biological activity in mammalian cells. To further validate this assay, we have modeled the three dimensional structures of receptor-ligand complexes of membrane-embedded AdipoR1 with cyclic peptides derived from osmotin or osmotin-like plant proteins. We demonstrate that the calculated AdipoR1-peptide binding energies correlate with the peptides' ability to behave as AdipoR1 agonists in the split luciferase assay. Further, we demonstrate agonist-AdipoR dependent activation of protein kinase A (PKA signaling and AMP activated protein kinase (AMPK phosphorylation in S. cerevisiae, which are

  17. 1. Medicinal chemistry of a small molecule drug lead: Tamoxilog 2. Electronic communication through ruthenium nanoparticles: Synthesis of custom ligands and nanoparticles

    Science.gov (United States)

    Zuckerman, Nathaniel Benjamin

    1. Compound NSC-670224, previously shown to be toxic to Saccharomyces cerevisiae at low micromolar concentrations, potentially acts via a mechanism of action related to that of tamoxifen (NSC 180973), a widely utilized breast cancer drug. The structure of NSC-670224, previously thought to be a 2,4-dichloro arene, was established as the 3,4-dichloro arene, and a focused library of analogues were synthesized and biologically evaluated in conjunction with the UCSC Chemical Screening Center. The synthesis of a biotinylated affinity probe was also completed in order to extract the protein target(s) of NSC-670224 from yeast and human cell lines in collaboration with the Hartzog lab (UCSC MCD Biology) 2. Stabilization of ruthenium nanoparticles (Ru NPs) through carbene bound ligands has led to a simple and effective means to generate new materials with unique optoelectronic properties. The affinity of freshly prepared Ru NPs to diazo compounds, specifically octyl diazoacetate (ODA), provides a robust nanostructure that can be further functionalized via metathesis of terminal olefins to generate these unique materials. Carbene-stabilized Ru NPs have provided insights into the nature of extended conjugation and intraparticle charge delocalization through covalently bound probes (e.g., ferrocene and pyrene). The growing interest to study electronic communication through Ru NPs has lead to collaborative, multidisciplinary efforts between analytical (Shaowei Chen lab, UCSC), theoretical (Haobin Wang Lab, NMSU), and synthetic organic chemists (Konopelski Lab, UCSC). With this powerful collaboration, new methods to generate stabilized Ru NPs, testing theory with experiment, and efficient means to functionalize NPs have been investigated. The syntheses of custom ligands and their applications to nanoparticle-mediated electronic communication are reported.

  18. Forced Homo- and Heterodimerization of All gp130-Type Receptor Complexes Leads to Constitutive Ligand-independent Signaling and Cytokine-independent Growth

    OpenAIRE

    Suthaus, Jan; Tillmann, Anna; Lorenzen, Inken; Bulanova, Elena; Rose-John, Stefan; Scheller, Jürgen

    2010-01-01

    Naturally ligand independent constitutively active gp130 variants were described to be responsible for inflammatory hepatocellular adenomas. Recently, we genetically engineered a ligand-independent constitutively active gp130 variant based on homodimerization of Jun leucine zippers. Because also heterodimeric complexes within the gp130 family may have tumorigenic potential, we seek to generate ligand-independent constitutively active heterodimers for all known gp130-receptor complexes based o...

  19. Ligand less temperature-controlled ionic liquid-phase microextraction of lead(II) ion prior to its determination by FAAS

    International Nuclear Information System (INIS)

    We describe the application of temperature-controlled ionic liquid based microextraction (TC-IL-ME) of lead(II) ion. The method does not require the use of an organic solvent or a ligand. Rather, the IL is directly added to the aqueous sample containing Pb(II) in a centrifuge tube, and the mixture is heated to 80 °C for 4 min. After cooling at 0 °C, the solution turns cloudy due to the formation of fine droplets of the IL containing Pb(II). The IL is separated by centrifugation, acidified, and directly submitted to FAAS by microinjection. The effects of pH value, volume of IL, extraction time, temperature, sample volume and matrix were optimized to result in a preconcentration factor of 30, a detection limit of 5.8 μg L−1, and a limit of quantification of 19.3 μg L−1. The method was validated by analyzing a certified reference material (NCSZC81002B; hair). A recovery test performed with spiked samples gave values between 102 % and 105 %. The method was also used to determine Pb(II) in hair samples. (author)

  20. 1D coordination polymers formed by tetranuclear lead(II) building blocks with carboxylate ligands: In situ isomerization of itaconic acid

    International Nuclear Information System (INIS)

    The synthesis of two new lead(II) coordination polymers, [Pb2(mpic)4(H2O)]·0.5H2O (1) and [Pb2(phen)2(cit)(mes)]·2H2O (2) has been reported, where mpic=3-methyl picolinate, phen=o-phenanthroline, H2cit=citraconic acid, H2mes mesaconic acid. X-ray single crystal diffraction analyses showed that the complexes comprise topologically different 1D polymeric chains stabilized by weak interactions and both containing tetranuclear Pb4 units connected by carboxylate groups. In compound 1 3-methylpicolinic acid is formed in situ from 3-methyl piconitrile, and mesaconate and citraconate anions were surprisingly formed from itaconic acid during the synthesis of 2. The photoluminescence and thermal properties of the complexes have been studied. - Graphical abstract: Two new topologically different 1D coordination polymers formed by Pb4 clusters have been synthesized and characterized by X-ray analysis. The luminescence and thermal properties have been studied. Display Omitted - Highlights: • Both the complexes, made up of different ligands, forms topologycally different 1D polymeric chains containing Pb4 clusters. • The final structures are stabilized by weak interactions (H-bond, π∙∙∙π stacking). • In complex 1, the 3-methylpicolinic acid is generated in situ from 3-methyl piconitrile. • Mesaconate and citraconate anions are surprisingly formed in situ from itaconic acid during the synthesis of complex 2, indicating an exceptional transformation

  1. Holo- and hemidirected lead(II) in the polymeric [Pb(4)(mu-3,4-TDTA)2(H2O)2]*4H2O complex. N,N,N',N'-tetraacetate ligands derived from o-phenylenediamines as sequestering agents for lead(II).

    Science.gov (United States)

    Sanchiz, Joaquín; Esparza, Pedro; Villagra, Diego; Domínguez, Sixto; Mederos, Alfredo; Brito, Felipe; Araujo, Lorena; Sánchez, Agustin; Arrieta, Juan Manuel

    2002-11-18

    The coordinating ability of the ligands 3,4-toluenediamine-N,N,N',N'-tetraacetate (3,4-TDTA), o-phenylenediamine-N,N,N',N'-tetraacetate (o-PhDTA), and 4-chloro-1,2-phenylenediamine-N,N,N',N'-tetraacetate (4-Cl-o-PhDTA) (H4L acids) toward lead(II) is studied by potentiometry (25 degrees C, I = 0.5 mol x dm(-3) in NaClO4), UV-vis spectrophotometry, and 207Pb NMR spectrometry. The stability constants of the complex species formed were determined. X-ray diffraction structural analysis of the complex [Pb4(mu-3,4-TDTA)4(H2O)2]*4H2O (1) revealed that 1 has a 2-D structure. The layers are built up by the polymerization of centrosymmetric [Pb4L2(H2O)2] tetranuclear units. The neutral layers have the aromatic rings of the ligands pointing to the periphery, whereas the metallic ions are located in the central part of the layers. In compound 1, two types of six-coordinate lead(II) environments are produced. The Pb(1) is coordinated to two nitrogen atoms and four carboxylate oxygens from the ligand, whereas Pb(2) has an O6 trigonally distorted octahedral surrounding. The lead(II) ion is surrounded by five carboxylate oxygens and a water molecule. The carboxylate oxygens belong to four different ligands that are also joined to four other Pb(1) ions. The selective uptake of lead(II) was analyzed by means of chemical speciation diagrams as well as the so-called conditional or effective formation constants K(Pb)eff. The results indicate that, in competition with other ligands that are strong complexing agents for lead(II), our ligands are better sequestering agents in acidic media. PMID:12425632

  2. Color tunable and near white-light emission of two solvent-induced 2D lead(II) coordination networks based on a rigid ligand 1-tetrazole-4-imidazole-benzene.

    Science.gov (United States)

    Chen, Jun; Zhang, Qing; Liu, Zhi-Fa; Wang, Shuai-Hua; Xiao, Yu; Li, Rong; Xu, Jian-Gang; Zhao, Ya-Ping; Zheng, Fa-Kun; Guo, Guo-Cong

    2015-06-01

    Two new lead(II) coordination polymers, [Pb(NO3)(tzib)]n (1) and [Pb(tzib)2]n (2), were successfully synthesized from the reaction of a rigid ligand 1-tetrazole-4-imidazole-benzene (Htzib) and lead(II) nitrate in different solvents. The obtained polymers have been characterized by single-crystal X-ray diffraction analyses, which show that both polymers feature 2D layer structures. The inorganic anion nitrate in 1 shows a μ2-κO3:κO3 bridging mode to connect adjacent lead ions into a zigzag chain, and then the organic ligands tzib(-) join the neighboring chains into a 2D layer by a μ3-κN1:κN2:κN6 connection mode. In 2, there are two different bridging modes of the tzib(-) ligand: μ3-κN1:κN2:κN6 and μ3-κN1:κN6 to coordinate the lead ions into a 2D layer structure. Interestingly, both polymers displayed broadband emissions covering the entire visible spectra, which could be tunable to near white-light emission by varying excitation wavelengths. PMID:25952460

  3. Ligand exchange leads to efficient triplet energy transfer to CdSe/ZnS Q-dots in a poly(N-vinylcarbazole) matrix nanocomposite

    Science.gov (United States)

    Khetubol, Adis; Van Snick, Sven; Hassinen, Antti; Fron, Eduard; Firdaus, Yuliar; Pandey, Lesley; David, Charlotte C.; Duerinckx, Karel; Dehaen, Wim; Hens, Zeger; Van der Auweraer, Mark

    2013-02-01

    Upon exchanging long chain alkylamine ligands with a carbazole terminated fatty acid as 6-(N-carbazolyl)-hexanoic acid (C6) and 11-(N-carbazolyl) undecanoic acid (C11), efficient photoluminescence (PL) of CdSe/ZnS colloidal quantum dots (QDs) was observed upon excitation in the absorption band of the carbazole moiety at 330 nm. This effect, which occurred both in solution and in a poly(N-vinylcarbazole) (PVK) matrix doped with the QDs, is attributed to sensitization of the QDs by PVK and the ligands. More efficient energy transfer was observed in solution for the shorter ligand (C6) capped QDs, due to a shorter average distance between the donor (carbazole) and the acceptor (QD). The binding of C6 and C11 to the QDs was confirmed by 1H solution nuclear magnetic resonance, which showed line broadening of the carbazole signal due to a decrease of the mobility of the carbazoles upon binding to the QDs compared with the sharp lines observed for the free molecules in solution. In doped PVK films, the significant enhancement of the energy transfer to the QD core could also be related to a better miscibility between the QDs and the PVK as confirmed by optical transmission and confocal microscopy images. In contrast to the experiment in solution, the overall energy transfer in the doped films was found more efficient for QDs capped with C11. To study in more detail the energy transfer between the carbazole moieties and the QDs, time-resolved fluorescence measurements were performed for solutions of C6 and C11, capped QDs and PVK films doped with the QDs. In contrast to the large enhancement of the QD emission indicated by steady-state PL spectra, the latter experiments suggested only a relatively low efficiency (19.6% and 10.8%) for singlet transfer from the carbazole ligands to the QDs. This suggests that the enhancement of the QD emission must be largely due to triplet transfer.

  4. Photoconductivity of CdTe Nanocrystal-Based Thin Films. Te2- Ligands Lead To Charge Carrier Diffusion Lengths Over 2 Micrometers

    Energy Technology Data Exchange (ETDEWEB)

    Crisp, Ryan W. [National Renewable Energy Lab. (NREL), Golden, CO (United States); Callahan, Rebecca [National Renewable Energy Lab. (NREL), Golden, CO (United States); Reid, Obadiah G. [Univ. of Colorado, Boulder, CO (United States); Dolzhnikov, Dmitriy S. [Univ. of Chicago, IL (United States); Talapin, Dmitri V. [Univ. of Chicago, IL (United States); Rumbles, Garry [National Renewable Energy Lab. (NREL), Golden, CO (United States); Luther, Joseph M. [National Renewable Energy Lab. (NREL), Golden, CO (United States); Kopidakis, Nikos [National Renewable Energy Lab. (NREL), Golden, CO (United States)

    2015-11-16

    We report on photoconductivity of films of CdTe nanocrystals (NCs) using time-resolved microwave photoconductivity (TRMC). Spherical and tetrapodal CdTe NCs with tunable size-dependent properties are studied as a function of surface ligand (including inorganic molecular chalcogenide species) and annealing temperature. Relatively high carrier mobility is measured for films of sintered tetrapod NCs (4 cm2/(V s)). Our TRMC findings show that Te2- capped CdTe NCs show a marked improvement in carrier mobility (11 cm2/(V s)), indicating that NC surface termination can be altered to play a crucial role in charge-carrier mobility even after the NC solids are sintered into bulk films.

  5. Synthesis and characterization of mixed ligand chiral nanoclusters

    OpenAIRE

    Güven, Zekiye Pelin; Guven, Zekiye Pelin; Üstbaş, Burçin; Ustbas, Burcin; Harkness, Kellen M.; Coşkun, Hikmet; Coskun, Hikmet; Joshi, Chakra P.; Besong, Tabot M. D.; Stellacci, Francesco; Bakr, Osman M.; Akbulut, Özge; Akbulut, Ozge

    2015-01-01

    Chiral mixed ligand silver nanoclusters were synthesized in the presence of a chiral and an achiral ligand. The ratio of the ligands was changed to track the formation of these clusters. While the chiral ligand lead to nanoparticles, Presence of the achiral ligand induced the formation of nanoclusters with chiral properties.

  6. Cloud point extraction for determination of lead in blood samples of children, using different ligands prior to analysis by flame atomic absorption spectrometry: A multivariate study

    International Nuclear Information System (INIS)

    Highlights: → Trace levels of lead in blood samples of healthy children and with different kidney disorders → Pre-concentration of Pb+2 in acid digested blood samples after chelating with two complexing reagents. → Multivariate technique was used for screening of significant factors that influence the CPE of Pb+2 → The level of Pb+2 in diseased children was significantly higher than referents of same age group. - Abstract: The phase-separation phenomenon of non-ionic surfactants occurring in aqueous solution was used for the extraction of lead (Pb2+) from digested blood samples after simultaneous complexation with ammonium pyrrolidinedithiocarbamate (APDC) and diethyldithiocarbamate (DDTC) separately. The complexed analyte was quantitatively extracted with octylphenoxypolyethoxyethanol (Triton X-114). The multivariate strategy was applied to estimate the optimum values of experimental factors. Acidic ethanol was added to the surfactant-rich phase prior to its analysis by flame atomic absorption spectrometer (FAAS). The detection limit value of Pb2+ for the preconcentration of 10 mL of acid digested blood sample was 1.14 μg L-1. The accuracy of the proposed methods was assessed by analyzing certified reference material (whole blood). Under the optimized conditions of both CPE methods, 10 mL of Pb2+ standards (10 μg L-1) complexed with APDC and DDTC, permitted the enhancement factors of 56 and 42, respectively. The proposed method was used for determination of Pb2+ in blood samples of children with kidney disorders and healthy controls.

  7. Cloud point extraction for determination of lead in blood samples of children, using different ligands prior to analysis by flame atomic absorption spectrometry: A multivariate study

    Energy Technology Data Exchange (ETDEWEB)

    Shah, Faheem, E-mail: shah_ceac@yahoo.com [National Center of Excellence in Analytical Chemistry, University of Sindh, Jamshoro 76080 (Pakistan); Kazi, Tasneem Gul, E-mail: tgkazi@yahoo.com [National Center of Excellence in Analytical Chemistry, University of Sindh, Jamshoro 76080 (Pakistan); Afridi, Hassan Imran, E-mail: hassanimranafridi@yahoo.com [National Center of Excellence in Analytical Chemistry, University of Sindh, Jamshoro 76080 (Pakistan); Naeemullah, E-mail: khannaeemullah@ymail.com [National Center of Excellence in Analytical Chemistry, University of Sindh, Jamshoro 76080 (Pakistan); Arain, Muhammad Balal, E-mail: bilal_ku2004@yahoo.com [Department of Chemistry, University of Science and Technology, Bannu, KPK (Pakistan); Baig, Jameel Ahmed, E-mail: jab_mughal@yahoo.com [National Center of Excellence in Analytical Chemistry, University of Sindh, Jamshoro 76080 (Pakistan)

    2011-09-15

    Highlights: {yields} Trace levels of lead in blood samples of healthy children and with different kidney disorders {yields} Pre-concentration of Pb{sup +2} in acid digested blood samples after chelating with two complexing reagents. {yields} Multivariate technique was used for screening of significant factors that influence the CPE of Pb{sup +2} {yields} The level of Pb{sup +2} in diseased children was significantly higher than referents of same age group. - Abstract: The phase-separation phenomenon of non-ionic surfactants occurring in aqueous solution was used for the extraction of lead (Pb{sup 2+}) from digested blood samples after simultaneous complexation with ammonium pyrrolidinedithiocarbamate (APDC) and diethyldithiocarbamate (DDTC) separately. The complexed analyte was quantitatively extracted with octylphenoxypolyethoxyethanol (Triton X-114). The multivariate strategy was applied to estimate the optimum values of experimental factors. Acidic ethanol was added to the surfactant-rich phase prior to its analysis by flame atomic absorption spectrometer (FAAS). The detection limit value of Pb{sup 2+} for the preconcentration of 10 mL of acid digested blood sample was 1.14 {mu}g L{sup -1}. The accuracy of the proposed methods was assessed by analyzing certified reference material (whole blood). Under the optimized conditions of both CPE methods, 10 mL of Pb{sup 2+} standards (10 {mu}g L{sup -1}) complexed with APDC and DDTC, permitted the enhancement factors of 56 and 42, respectively. The proposed method was used for determination of Pb{sup 2+} in blood samples of children with kidney disorders and healthy controls.

  8. Ylide Ligands

    OpenAIRE

    Esteban P. Urriolabeitia

    2010-01-01

    The use of ylides of P, N, As, or S as ligands toward transition metals is still a very active research area in organometallic chemistry. This fact is mainly due to the nucleophilic character of the ylides and to their particular bonding properties and coordination modes. They can behave as monodentate or bidentate chelate or bridging species, they can be used as chiral auxiliary reagents, and they are interesting reaction intermediates or useful starting materials in a wide ...

  9. Handling ligands with Coot

    OpenAIRE

    Debreczeni, Judit É.; Emsley, Paul

    2012-01-01

    Coot is a molecular-graphics application primarily aimed to assist in model building and validation of biological macromolecules. Recently, tools have been added to work with small molecules. The newly incorporated tools for the manipulation and validation of ligands include interaction with PRODRG, subgraph isomorphism-based tools, representation of ligand chemistry, ligand fitting and analysis, and are described here.

  10. Metal-ligand cooperation.

    Science.gov (United States)

    Khusnutdinova, Julia R; Milstein, David

    2015-10-12

    Metal-ligand cooperation (MLC) has become an important concept in catalysis by transition metal complexes both in synthetic and biological systems. MLC implies that both the metal and the ligand are directly involved in bond activation processes, by contrast to "classical" transition metal catalysis where the ligand (e.g. phosphine) acts as a spectator, while all key transformations occur at the metal center. In this Review, we will discuss examples of MLC in which 1) both the metal and the ligand are chemically modified during bond activation and 2) bond activation results in immediate changes in the 1st coordination sphere involving the cooperating ligand, even if the reactive center at the ligand is not directly bound to the metal (e.g. via tautomerization). The role of MLC in enabling effective catalysis as well as in catalyst deactivation reactions will be discussed. PMID:26436516

  11. Synthesis, biophysical, and pharmacological evaluation of the melanocortin agonist AST3-88: modifications of peptide backbone at Trp 7 position lead to a potent, selective, and stable ligand of the melanocortin 4 receptor (MC4R).

    Science.gov (United States)

    Singh, Anamika; Dirain, Marvin L; Wilczynski, Andrzej; Chen, Chi; Gosnell, Blake A; Levine, Allen S; Edison, Arthur S; Haskell-Luevano, Carrie

    2014-10-15

    The melanocortin-3 (MC3R) and melanocortin-4 (MC4R) receptors are expressed in the brain and are implicated in the regulation of food intake and energy homeostasis. The endogenous agonist ligands for these receptors (α-, β-, γ-MSH and ACTH) are linear peptides with limited receptor subtype selectivity and metabolic stability, thus minimizing their use as probes to characterize the overlapping pharmacological and physiological functions of the melanocortin receptor subtypes. In the present study, an engineered template, in which the peptide backbone was modified by a heterocyclic reverse turn mimetic at the Trp(7) residue, was synthesized using solid phase peptide synthesis and characterized by a β-galactosidase cAMP based reporter gene assay. The functional assay identified a ∼5 nM mouse MC4R agonist (AST3-88) with more than 50-fold selectivity over the mMC3R. Biophysical studies (2D (1)H NMR spectroscopy and molecular dynamics) of AST3-88 identified a type VIII β-turn secondary structure spanning the pharmacophore domain stabilized by the intramolecular interactions between the side chains of the His and Trp residues. Enzymatic studies of AST3-88 revealed enhanced stability of AST3-88 over the α-MSH endogenous peptide in rat serum. Upon central administration of AST3-88 into rats, a decreased food intake response was observed. This is the first study to probe the in vivo physiological activity of this engineered peptide-heterocycle template. These findings advance the present knowledge of pharmacophore design for potent, selective, and metabolically stable melanocortin ligands. PMID:25141170

  12. Autocrine signal transmission with extracellular ligand degradation

    International Nuclear Information System (INIS)

    Traveling waves of cell signaling in epithelial layers orchestrate a number of important processes in developing and adult tissues. These waves can be mediated by positive feedback autocrine loops, a mode of cell signaling where binding of a diffusible extracellular ligand to a cell surface receptor can lead to further ligand release. We formulate and analyze a biophysical model that accounts for ligand-induced ligand release, extracellular ligand diffusion and ligand–receptor interaction. We focus on the case when the main mode for ligand degradation is extracellular and analyze the problem with the sharp threshold positive feedback nonlinearity. We derive expressions that link the speed of propagation and other characteristics of traveling waves to the parameters of the biophysical processes, such as diffusion rates, receptor expression level, etc. Analyzing the derived expressions we found that traveling waves in such systems can exhibit a number of unusual properties, e.g. non-monotonic dependence of the speed of propagation on ligand diffusivity. Our results for the fully developed traveling fronts can be used to analyze wave initiation from localized perturbations, a scenario that frequently arises in the in vitro models of epithelial wound healing, and guide future modeling studies of cell communication in epithelial layers

  13. Ligand modeling and design

    Energy Technology Data Exchange (ETDEWEB)

    Hay, B.P. [Pacific Northwest National Lab., Richland, WA (United States)

    1997-10-01

    The purpose of this work is to develop and implement a molecular design basis for selecting organic ligands that would be used in the cost-effective removal of specific radionuclides from nuclear waste streams. Organic ligands with metal ion specificity are critical components in the development of solvent extraction and ion exchange processes that are highly selective for targeted radionuclides. The traditional approach to the development of such ligands involves lengthy programs of organic synthesis and testing, which in the absence of reliable methods for screening compounds before synthesis, results in wasted research effort. The author`s approach breaks down and simplifies this costly process with the aid of computer-based molecular modeling techniques. Commercial software for organic molecular modeling is being configured to examine the interactions between organic ligands and metal ions, yielding an inexpensive, commercially or readily available computational tool that can be used to predict the structures and energies of ligand-metal complexes. Users will be able to correlate the large body of existing experimental data on structure, solution binding affinity, and metal ion selectivity to develop structural design criteria. These criteria will provide a basis for selecting ligands that can be implemented in separations technologies through collaboration with other DOE national laboratories and private industry. The initial focus will be to select ether-based ligands that can be applied to the recovery and concentration of the alkali and alkaline earth metal ions including cesium, strontium, and radium.

  14. LEADING WITH LEADING INDICATORS

    International Nuclear Information System (INIS)

    This paper documents Fluor Hanford's use of Leading Indicators, management leadership, and statistical methodology in order to improve safe performance of work. By applying these methods, Fluor Hanford achieved a significant reduction in injury rates in 2003 and 2004, and the improvement continues today. The integration of data, leadership, and teamwork pays off with improved safety performance and credibility with the customer. The use of Statistical Process Control, Pareto Charts, and Systems Thinking and their effect on management decisions and employee involvement are discussed. Included are practical examples of choosing leading indicators. A statistically based color coded dashboard presentation system methodology is provided. These tools, management theories and methods, coupled with involved leadership and employee efforts, directly led to significant improvements in worker safety and health, and environmental protection and restoration at one of the nation's largest nuclear cleanup sites

  15. LEADING WITH LEADING INDICATORS

    Energy Technology Data Exchange (ETDEWEB)

    PREVETTE, S.S.

    2005-01-27

    This paper documents Fluor Hanford's use of Leading Indicators, management leadership, and statistical methodology in order to improve safe performance of work. By applying these methods, Fluor Hanford achieved a significant reduction in injury rates in 2003 and 2004, and the improvement continues today. The integration of data, leadership, and teamwork pays off with improved safety performance and credibility with the customer. The use of Statistical Process Control, Pareto Charts, and Systems Thinking and their effect on management decisions and employee involvement are discussed. Included are practical examples of choosing leading indicators. A statistically based color coded dashboard presentation system methodology is provided. These tools, management theories and methods, coupled with involved leadership and employee efforts, directly led to significant improvements in worker safety and health, and environmental protection and restoration at one of the nation's largest nuclear cleanup sites.

  16. Ligand modeling and design

    Energy Technology Data Exchange (ETDEWEB)

    Hay, B. [Pacific Northwest Lab., Richland, WA (United States)

    1996-10-01

    The purpose of this work is to develop and implement a molecular design basis for selecting organic ligands that would be used tin applications for the cost-effective removal of specific radionuclides from nuclear waste streams.

  17. Predicting Nanocrystal Shape through Consideration of Surface-Ligand Interactions

    KAUST Repository

    Bealing, Clive R.

    2012-03-27

    Density functional calculations for the binding energy of oleic acid-based ligands on Pb-rich {100} and {111} facets of PbSe nanocrystals determine the surface energies as a function of ligand coverage. Oleic acid is expected to bind to the nanocrystal surface in the form of lead oleate. The Wulff construction predicts the thermodynamic equilibrium shape of the PbSe nanocrystals. The equilibrium shape is a function of the ligand surface coverage, which can be controlled by changing the concentration of oleic acid during synthesis. The different binding energy of the ligand on the {100} and {111} facets results in different equilibrium ligand coverages on the facets, and a transition in the equilibrium shape from octahedral to cubic is predicted when increasing the ligand concentration during synthesis. © 2012 American Chemical Society.

  18. Lead Poisoning

    Science.gov (United States)

    Lead is a metal that occurs naturally in the earth's crust. Lead can be found in all parts of our ... from human activities such as mining and manufacturing. Lead used to be in paint; older houses may ...

  19. Glutamate receptor ligands

    DEFF Research Database (Denmark)

    Guldbrandt, Mette; Johansen, Tommy N; Frydenvang, Karla Andrea; Bräuner-Osborne, Hans; Stensbøl, Tine B; Nielsen, Birgitte; Karla, Rolf; Santi, Flavio; Krogsgaard-Larsen, Povl; Madsen, Ulf

    2002-01-01

    Homologation and substitution on the carbon backbone of (S)-glutamic acid [(S)-Glu, 1], as well as absolute stereochemistry, are structural parameters of key importance for the pharmacological profile of (S)-Glu receptor ligands. We describe a series of methyl-substituted 2-aminoadipic acid (AA...

  20. AMPA receptor ligands

    DEFF Research Database (Denmark)

    Strømgaard, Kristian; Mellor, Ian

    2004-01-01

    polyamines are known to modulate the function of these receptors in vivo. In this study, recent developments in the medicinal chemistry of polyamine-based ligands are given, particularly focusing on the use of solid-phase synthesis (SPS) as a tool for the facile generation of libraries of polyamine toxin...

  1. Analysis of macromolecules, ligands and macromolecule-ligand complexes

    Science.gov (United States)

    Von Dreele, Robert B.

    2008-12-23

    A method for determining atomic level structures of macromolecule-ligand complexes through high-resolution powder diffraction analysis and a method for providing suitable microcrystalline powder for diffraction analysis are provided. In one embodiment, powder diffraction data is collected from samples of polycrystalline macromolecule and macromolecule-ligand complex and the refined structure of the macromolecule is used as an approximate model for a combined Rietveld and stereochemical restraint refinement of the macromolecule-ligand complex. A difference Fourier map is calculated and the ligand position and points of interaction between the atoms of the macromolecule and the atoms of the ligand can be deduced and visualized. A suitable polycrystalline sample of macromolecule-ligand complex can be produced by physically agitating a mixture of lyophilized macromolecule, ligand and a solvent.

  2. Ligand-Receptor Interactions

    CERN Document Server

    Bongrand, Pierre

    2008-01-01

    The formation and dissociation of specific noncovalent interactions between a variety of macromolecules play a crucial role in the function of biological systems. During the last few years, three main lines of research led to a dramatic improvement of our understanding of these important phenomena. First, combination of genetic engineering and X ray cristallography made available a simultaneous knowledg of the precise structure and affinity of series or related ligand-receptor systems differing by a few well-defined atoms. Second, improvement of computer power and simulation techniques allowed extended exploration of the interaction of realistic macromolecules. Third, simultaneous development of a variety of techniques based on atomic force microscopy, hydrodynamic flow, biomembrane probes, optical tweezers, magnetic fields or flexible transducers yielded direct experimental information of the behavior of single ligand receptor bonds. At the same time, investigation of well defined cellular models raised the ...

  3. Radiobiology with DNA ligands

    International Nuclear Information System (INIS)

    The paper deals with the following topics: labelling of DNA ligands and other tumour-affinic compounds with 4.15-d 124I, radiotoxicity of Hoechst 33258 and 33342 and of iodinated Hoechst 33258 in cell cultures, preparation of 76Br-, 123I-, and 221At-labelled 5-halo-2'-deoxyuridine, chemical syntheses of boron derivatives of Hoechst 33258.III., Gadolinium neutron capture therapy

  4. Imidazoline receptors ligands

    Directory of Open Access Journals (Sweden)

    Agbaba Danica

    2012-01-01

    Full Text Available Extensive biochemical and pharmacological studies have determined three different subtypes of imidazoline receptors: I1-imidazoline receptors (I1-IR involved in central inhibition of sympathicus that produce hypotensive effect; I2-imidazoline receptors (I2-IR modulate monoamine oxidase B activity (MAO-B; I3-imidazoline receptors (I3-IR regulate insulin secretion from pancreatic β-cells. Therefore, the I1/I2/I3 imidazoline receptors are selected as new, interesting targets for drug design and discovery. Novel selective I1/I2/I3 agonists and antagonists have been recently developed. In the present review, we provide a brief update to the field of imidazoline research, highlighting some of the chemical diversity and progress made in the 2D-QSAR, 3D-QSAR and quantitative pharmacophore development studies of I1-IR and I2-IR imidazoline receptor ligands. Theoretical studies of I3-IR ligands are not yet performed because of insufficient number of synthesized I3-IR ligands.

  5. Metal-ligand cooperation in H2 activation with iron complexes bearing hemilabile bis(diphenylphosphino)amine ligands.

    Science.gov (United States)

    Frank, Nicolas; Hanau, Katharina; Langer, Robert

    2014-10-20

    The octahedral transition-metal complex [(dppa)Fe(Ph2P-N-PPh2)2] (1) [dppa = bis(diphenylphosphino)amine] with homofunctional bidentate ligands is described. The ligand exhibits hemilability due to its small bite angle and the steric repulsion of the coordinated donor groups. As the {Ph2P-N-PPh2}(-) ligand can act as an internal base, heterolytic cleavage of dihydrogen by complex 1 leads to the formation of the hydride complex [(dppa)(Ph2P-N-PPh2)Fe(H)(κ(1)-Ph2P-NH-PPh2)2] (2), representing an example of cooperative bond activation with a homofunctional hemilabile ligand. This study demonstrates that hemilability of homofunctionalized ligands can be affected by careful adjustment of geometric parameters. PMID:25290535

  6. KLIFS: a knowledge-based structural database to navigate kinase-ligand interaction space.

    Science.gov (United States)

    van Linden, Oscar P J; Kooistra, Albert J; Leurs, Rob; de Esch, Iwan J P; de Graaf, Chris

    2014-01-23

    Protein kinases regulate the majority of signal transduction pathways in cells and have become important targets for the development of designer drugs. We present a systematic analysis of kinase-ligand interactions in all regions of the catalytic cleft of all 1252 human kinase-ligand cocrystal structures present in the Protein Data Bank (PDB). The kinase-ligand interaction fingerprints and structure database (KLIFS) contains a consistent alignment of 85 kinase ligand binding site residues that enables the identification of family specific interaction features and classification of ligands according to their binding modes. We illustrate how systematic mining of kinase-ligand interaction space gives new insights into how conserved and selective kinase interaction hot spots can accommodate the large diversity of chemical scaffolds in kinase ligands. These analyses lead to an improved understanding of the structural requirements of kinase binding that will be useful in ligand discovery and design studies. PMID:23941661

  7. Lead poisoning

    Science.gov (United States)

    ... free solder, lead is still found in some modern faucets. Soil contaminated by decades of car exhaust ... NOT store wine, spirits, or vinegar-based salad dressings in lead crystal decanters for long periods of ...

  8. Lead Toxicity

    Science.gov (United States)

    ... in children over time may lead to reduced IQ, slow learning, Attention Deficit Hyperactivity Disorder (ADHD), or ... avoid exposure to soil. Is there a medical test for lead exposure? • Blood samples can be tested ...

  9. Improved ligand geometries in crystallographic refinement using AFITT in PHENIX.

    Science.gov (United States)

    Janowski, Pawel A; Moriarty, Nigel W; Kelley, Brian P; Case, David A; York, Darrin M; Adams, Paul D; Warren, Gregory L

    2016-09-01

    Modern crystal structure refinement programs rely on geometry restraints to overcome the challenge of a low data-to-parameter ratio. While the classical Engh and Huber restraints work well for standard amino-acid residues, the chemical complexity of small-molecule ligands presents a particular challenge. Most current approaches either limit ligand restraints to those that can be readily described in the Crystallographic Information File (CIF) format, thus sacrificing chemical flexibility and energetic accuracy, or they employ protocols that substantially lengthen the refinement time, potentially hindering rapid automated refinement workflows. PHENIX-AFITT refinement uses a full molecular-mechanics force field for user-selected small-molecule ligands during refinement, eliminating the potentially difficult problem of finding or generating high-quality geometry restraints. It is fully integrated with a standard refinement protocol and requires practically no additional steps from the user, making it ideal for high-throughput workflows. PHENIX-AFITT refinements also handle multiple ligands in a single model, alternate conformations and covalently bound ligands. Here, the results of combining AFITT and the PHENIX software suite on a data set of 189 protein-ligand PDB structures are presented. Refinements using PHENIX-AFITT significantly reduce ligand conformational energy and lead to improved geometries without detriment to the fit to the experimental data. For the data presented, PHENIX-AFITT refinements result in more chemically accurate models for small-molecule ligands. PMID:27599738

  10. Relational Leading

    DEFF Research Database (Denmark)

    Larsen, Mette Vinther; Rasmussen, Jørgen Gulddahl

    2015-01-01

    This first chapter presents the exploratory and curious approach to leading as relational processes – an approach that pervades the entire book. We explore leading from a perspective that emphasises the unpredictable challenges and triviality of everyday life, which we consider an interesting......, relevant and realistic way to examine leading. The chapter brings up a number of concepts and contexts as formulated by researchers within the field, and in this way seeks to construct a first understanding of relational leading....

  11. Molecular path for ligand search

    Institute of Scientific and Technical Information of China (English)

    Tao Lu; Yuan Yuan Qiao; Pan Wen Shen

    2011-01-01

    A ligand is a small molecule bind to several residues of a receptor. We adapt the concept of molecular path for effective ligand search with its contacting residues. Additionally, we allow wild type definitions on atoms and bonds of molecular paths for fuzzy algorithms on structural match. We choose hydrogen bond interactions to characterize the binding mode of a ligand by several proper molecular paths and use them to query the deposited ligands in PDBe that interact with their residues in the same way. Expression of molecular path and format of database entries are described with examples. Our molecular path provides a new approach to explore the ligand-receptor interactions and to provide structural framework reference on new ligand design.

  12. Macrocyclic G-quadruplex ligands

    DEFF Research Database (Denmark)

    Nielsen, M C; Ulven, Trond

    2010-01-01

    G-quadruplex stabilizing compounds have recently received increased interest due to their potential application as anticancer therapeutics. A significant number of structurally diverse G-quadruplex ligands have been developed. Some of the most potent and selective ligands currently known are...... macrocyclic structures which have been modeled after the natural product telomestatin or from porphyrin-based ligands discovered in the late 1990s. These two structural classes of G-quadruplex ligands are reviewed here with special attention to selectivity and structure-activity relationships, and with focus...

  13. Lead poisoning

    Science.gov (United States)

    ... help if this information is not immediately available. Poison Control If someone has severe symptoms from possible ... be caused by lead poisoning, call your local poison control center. Your local poison center can be ...

  14. Lead Test

    Science.gov (United States)

    ... Other potential lead sources include imported foods, candy, cosmetics, costume jewelry, brass keys, and toys or household ... Health Professionals ©2001 - by American Association for Clinical Chemistry • Contact Us | Terms of Use | Privacy We comply ...

  15. Lead Poisoning

    Science.gov (United States)

    ... has also been associated with juvenile delinquency and criminal behavior. In adults, lead can increase blood pressure ... and-forth manner, but rather from left to right (or vise-versa), or from the top of ...

  16. Serum concentrations of Flt-3 ligand in rheumatic diseases.

    Science.gov (United States)

    Nakamura, Kayo; Nakatsuka, Noriko; Jinnin, Masatoshi; Makino, Takamitsu; Kajihara, Ikko; Makino, Katsunari; Honda, Noritoshi; Inoue, Kuniko; Fukushima, Satoshi; Ihn, Hironobu

    2015-10-01

    Fms-like tyrosine kinase 3 (Flt-3) is a cytokine receptor expressed on the surface of bone-marrow progenitor of hematopoietic cells. Flt-3 ligands are produced by peripheral blood mononuclear cells, and found in various human body fluids. Flt-3 signal is involved in the regulation of vessel formation as well as B cell differentiation, suggesting that Flt-3 signal contributes to the pathogenesis of vascular abnormalities and immune dysregulation in rheumatic diseases. The aim of the present study is to examine serum Flt-3 ligand levels in patients with various rheumatic diseases, and to evaluate the possibility that serum Flt-3 ligand levels can be a useful disease marker. Sera were obtained from 20 dermatomyositis (DM) patients, 36 systemic sclerosis (SSc) patients, 10 systemic lupus erythematosus (SLE) patients, 10 scleroderma spectrum disorder (SSD) patients, 4 mixed connective tissue disease (MCTD) patients, and 12 normal subjects. Flt-3 ligand levels were determined with ELISA. Serum Flt-3 ligand levels were significantly elevated in patients with DM, SSc, SSD and MCTD compared to those in normal subjects. DM patients with elevated Flt-3 ligand levels were accompanied with significantly increased CRP levels and increased frequency of heliotrope rash than those with normal levels. In addition, SSc patients with elevated Flt-3 ligand levels showed significantly reduced frequency of nailfold bleeding. Serum Flt-3 ligand levels can be a marker of cutaneous manifestation in DM and a marker of microangiopathy in SSc. Clarifying the role of Flt-3 ligand in rheumatic diseases may lead to further understanding of these diseases and new therapeutic approaches. PMID:26559027

  17. Database of ligand-induced domain movements in enzymes

    Directory of Open Access Journals (Sweden)

    Hayward Steven

    2009-03-01

    Full Text Available Abstract Background Conformational change induced by the binding of a substrate or coenzyme is a poorly understood stage in the process of enzyme catalysed reactions. For enzymes that exhibit a domain movement, the conformational change can be clearly characterized and therefore the opportunity exists to gain an understanding of the mechanisms involved. The development of the non-redundant database of protein domain movements contains examples of ligand-induced domain movements in enzymes, but this valuable data has remained unexploited. Description The domain movements in the non-redundant database of protein domain movements are those found by applying the DynDom program to pairs of crystallographic structures contained in Protein Data Bank files. For each pair of structures cross-checking ligands in their Protein Data Bank files with the KEGG-LIGAND database and using methods that search for ligands that contact the enzyme in one conformation but not the other, the non-redundant database of protein domain movements was refined down to a set of 203 enzymes where a domain movement is apparently triggered by the binding of a functional ligand. For these cases, ligand binding information, including hydrogen bonds and salt-bridges between the ligand and specific residues on the enzyme is presented in the context of dynamical information such as the regions that form the dynamic domains, the hinge bending residues, and the hinge axes. Conclusion The presentation at a single website of data on interactions between a ligand and specific residues on the enzyme alongside data on the movement that these interactions induce, should lead to new insights into the mechanisms of these enzymes in particular, and help in trying to understand the general process of ligand-induced domain closure in enzymes. The website can be found at: http://www.cmp.uea.ac.uk/dyndom/enzymeList.do

  18. Targeting Selectins and Their Ligands in Cancer.

    Science.gov (United States)

    Natoni, Alessandro; Macauley, Matthew S; O'Dwyer, Michael E

    2016-01-01

    Aberrant glycosylation is a hallmark of cancer cells with increased evidence pointing to a role in tumor progression. In particular, aberrant sialylation of glycoproteins and glycolipids has been linked to increased immune cell evasion, drug evasion, drug resistance, tumor invasiveness, and vascular dissemination, leading to metastases. Hypersialylation of cancer cells is largely the result of overexpression of sialyltransferases (STs). Differentially, humans express twenty different STs in a tissue-specific manner, each of which catalyzes the attachment of sialic acids via different glycosidic linkages (α2-3, α2-6, or α2-8) to the underlying glycan chain. One important mechanism whereby overexpression of STs contributes to an enhanced metastatic phenotype is via the generation of selectin ligands. Selectin ligand function requires the expression of sialyl-Lewis X and its structural isomer sialyl-Lewis A, which are synthesized by the combined action of alpha α1-3-fucosyltransferases, α2-3-sialyltransferases, β1-4-galactosyltranferases, and N-acetyl-β-glucosaminyltransferases. The α2-3-sialyltransferases ST3Gal4 and ST3Gal6 are critical to the generation of functional E- and P-selectin ligands and overexpression of these STs have been linked to increased risk of metastatic disease in solid tumors and poor outcome in multiple myeloma. Thus, targeting selectins and their ligands as well as the enzymes involved in their generation, in particular STs, could be beneficial to many cancer patients. Potential strategies include ST inhibition and the use of selectin antagonists, such as glycomimetic drugs and antibodies. Here, we review ongoing efforts to optimize the potency and selectivity of ST inhibitors, including the potential for targeted delivery approaches, as well as evaluate the potential utility of selectin inhibitors, which are now in early clinical development. PMID:27148485

  19. Leading men

    DEFF Research Database (Denmark)

    Bekker-Nielsen, Tønnes

    2016-01-01

    Through a systematic comparison of c. 50 careers leading to the koinarchate or high priesthood of Asia, Bithynia, Galatia, Lycia, Macedonia and coastal Pontus, as described in funeral or honorary inscriptions of individual koinarchs, it is possible to identify common denominators but also...

  20. Lead grids

    CERN Multimedia

    1974-01-01

    One of the 150 lead grids used in the multiwire proportional chamber g-ray detector. The 0.75 mm diameter holes are spaced 1 mm centre to centre. The grids were made by chemical cutting techniques in the Godet Workshop of the SB Physics.

  1. Lead Poisoning

    Science.gov (United States)

    ... Environment Kids Health Kids Environment Kids Health Topics Environment & Health Healthy Living Pollution Reduce, Reuse, Recycle Science – How ... poisoning is still one of the most important health issues in the United States ... in housing built before 1946 have elevated blood lead levels. These ...

  2. Protecting Ligands Enhance Selective Targeting of Multivalent Nanoparticles

    CERN Document Server

    Angioletti-Uberti, Stefano

    2016-01-01

    Nanoparticles functionalized with multiple ligands can be programmed to bind biological targets, e.g. cells, depending on the receptors they express, providing a general platform for the development of different technologies, from selective drug-delivery to biosensing. In order to be highly selective ligands should exclusively bind to specific targeted receptors, since formation of bonds with other, untargeted ones would lead to non-specific binding and potentially harmful behaviour. This poses a particular problem for multivalent nanoparticles, because even very weak bonds can collectively lead to strong binding. A statistical mechanical model is presented here to describe the extent to which bond strength and nanoparticle valency can induce non-selective adsorption. The same model is used to describe a possible solution: functionalization of the nanoparticles with "protective" receptors. The latter compete with cell receptors for the targeting ligands, and can be optimized to strongly reduce the effect of u...

  3. Porphyrin-based design of bioinspired multitarget quadruplex ligands.

    Science.gov (United States)

    Laguerre, Aurélien; Desbois, Nicolas; Stefan, Loic; Richard, Philippe; Gros, Claude P; Monchaud, David

    2014-09-01

    Secondary nucleic acid structures, such as DNA and RNA quadruplexes, are potential targets for cancer therapies. Ligands that interact with these targets could thus find application as anticancer agents. Synthetic G-quartets have recently found numerous applications, including use as bioinspired G-quadruplex ligands. Herein, the design, synthesis and preliminary biophysical evaluation of a new prototype multitarget G-quadruplex ligand, (PNA)PorphySQ, are reported, where peptidic nucleic acid guanine ((PNA)G) was incorporated in the porphyrin-templated synthetic G-quartet (PorphySQ). Using fluorescence resonance energy transfer (FRET)-melting experiments, PorphySQ was shown to possess enhanced quadruplex-interacting properties thanks to the presence of four positively charged (PNA)G residues that improve its electrostatic interactions with the binding site of both DNA and RNA quadruplexes (i.e., their negatively charged and accessible G-quartets), thereby making (PNA)PorphySQ an interesting prototype of a multitarget ligand. Both the chemical stability and water solubility of (PNA)PorphySQ are improved over the non-PNA derivative (PorphySQ), which are desirable properties for drug development, and while improvements remain to be made, this ligand is a promising lead for the further development of multitarget G-quadruplex ligands. PMID:24678052

  4. The therapeutic potential of allosteric ligands for free fatty acid sensitive GPCRs

    DEFF Research Database (Denmark)

    Hudson, Brian D; Ulven, Trond; Milligan, Graeme

    2013-01-01

    identifying allosteric leads and their often flat or confusing SAR. The present review will consider the advantages and challenges associated with allosteric GPCR ligands, and examine how the particular properties of these ligands may be exploited to uncover the therapeutic potential for free fatty acid...

  5. Released ligand fluoroimmunoassay

    International Nuclear Information System (INIS)

    Radioimmunoassay (RIA) is one of the most sensitive and specific methods for analysis of proteins, drugs and other substances commonly found in biological fluids. Because of the limited stability and problems in handling radioisotopes (particularly 125I), there has been a continuous effort in recent years to develop non-isotopic immunoassays. Fluoroimmunoassay is one of the more promising alternatives to RIA, but has relatively low sensitivity due to background fluorescence from other substances in biological fluids. The authors have proposed an alternative type of fluoroimmunoassay, released ligand fluoroimmunoassay (RLFIA), wherein the fluorophore is released from the analyte and analyzed separately, thus reducing the problems of background fluorescence. 1-(4-(3-(2,3-dihydroxy-1-carboxyethyl))-phenyl)-3-(3-(7-diethylamino-4-methylcoumarinyl)) thiourea (IX), a fluorescent coumarin derivative with a periodate cleavable vic-glycol linkage, was synthesized and employed to demonstrate the principle of RLFIA. The principle of the RLFIA was tested by comparison with a commercially available kit Immuno-Fluor IgG Assay. Because of the lower quantum yield of the fluorophore used, the sensitivity of the resulting RLFIA was only one tenth that of the commercial kit. As an outgrowth of this project, a series of analogs of compound IX, having electron donating and withdrawing groups at the phenyl ring, were synthesized in order to study the effect of substituent on fluorescence yield. An interactive computer graphics system, Chemical Structure Drawing 2-Dimensional (CSD2D), developed by the author mainly for the generation of publication quality structure drawings is also described

  6. Nutraceuticals as Ligands of PPARγ

    OpenAIRE

    Meera Penumetcha; Nalini Santanam

    2012-01-01

    Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors that respond to several exogenous and endogenous ligands by modulating genes related to lipid, glucose, and insulin homeostasis. PPARγ, expressed in adipose tissue and liver, regulates lipid storage and glucose metabolism and is the target of type 2 diabetes drugs, thiazolidinediones (TZDs). Due to high levels of toxicity associated with the first generation TZDs, troglitazone (Rezulin), rosiglitazone (...

  7. Validity of Ligand Efficiency Metrics

    OpenAIRE

    Murray, Christopher W; Erlanson, Daniel A.; Hopkins, Andrew L.; Keserü, György M; Leeson, Paul D.; Rees, David C.; Reynolds, Charles H.; Richmond, Nicola J.

    2014-01-01

    A recent viewpoint article (Improving the plausibility of success with inefficient metrics. ACS Med. Chem. Lett.2014, 5, 2–5) argued that the standard definition of ligand efficiency (LE) is mathematically invalid. In this viewpoint, we address this criticism and show categorically that the definition of LE is mathematically valid. LE and other metrics such as lipophilic ligand efficiency (LLE) can be useful during the multiparameter optimization challenge faced by med...

  8. Ligand Identification Scoring Algorithm (LISA)

    Science.gov (United States)

    Zheng, Zheng; Merz, Kenneth M.

    2011-01-01

    A central problem in de novo drug design is determining the binding affinity of a ligand with a receptor. A new scoring algorithm is presented that estimates the binding affinity of a protein-ligand complex given a three-dimensional structure. The method, LISA (Ligand Identification Scoring Algorithm), uses an empirical scoring function to describe the binding free energy. Interaction terms have been designed to account for van der Waals (VDW) contacts, hydrogen bonding, desolvation effects and metal chelation to model the dissociation equilibrium constants using a linear model. Atom types have been introduced to differentiate the parameters for VDW, H-bonding interactions and metal chelation between different atom pairs. A training set of 492 protein-ligand complexes was selected for the fitting process. Different test sets have been examined to evaluate its ability to predict experimentally measured binding affinities. By comparing with other well known scoring functions, the results show that LISA has advantages over many existing scoring functions in simulating protein-ligand binding affinity, especially metalloprotein-ligand binding affinity. Artificial Neural Network (ANN) was also used in order to demonstrate that the energy terms in LISA are well designed and do not require extra cross terms. PMID:21561101

  9. Hindered rotation in a novel 1,2,4-triazinyl phenanthroline (T-Phen) ligand leading to improved separation of Am3+ and Eu3+ vis-a-vis 1,2,4-triazinyl bipyridine (T-Bipy): synthesis and computational validation of the experimental results

    International Nuclear Information System (INIS)

    A novel nitrogen donor ligand having more pre-organized structure, 1,2,4-triazinyl phenanthroline (T-phen), was synthesized and evaluated for lanthanide - actinide separation. The extraction and selectivity for Am3+ over Eu3+ was found to be improved with T-phen as compared to the analogous 1,2,4-triazinyl bipyridine bipy, which was explained by analyzing their conformational energies and energy differences between the frontier orbitals (highest occupied molecular orbital (HOMO) and lowest unoccupied molecular (LUMO) with the help of ab initio molecular orbital calculations. Higher covalence in Am3+ complexes compared to the Eu3+ complexes were indicated by more shared electrons between Am3+ and bonded 'N' atoms, shorter 'Am-N' bonds and higher overlap between the orbitals of Am3+ and ligands in the frontier orbitals complexes in case of both the ligands. The separation factor values with T-phen and T-bipy are given at varying pH values. The results suggest more efficient separation with T-phen as compared to T-bipy which is attributed to hindered rotation of the former ligand

  10. Controlling Nanocrystal Superlattice Symmetry and Shape-Anisotropic Interactions through Variable Ligand Surface Coverage

    KAUST Repository

    Choi, Joshua J.

    2011-03-09

    The assembly of colloidal nanocrystals (NCs) into superstructures with long-range translational and orientational order is sensitive to the molecular interactions between ligands bound to the NC surface. We illustrate how ligand coverage on colloidal PbS NCs can be exploited as a tunable parameter to direct the self-assembly of superlattices with predefined symmetry. We show that PbS NCs with dense ligand coverage assemble into face-centered cubic (fcc) superlattices whereas NCs with sparse ligand coverage assemble into body-centered cubic (bcc) superlattices which also exhibit orientational ordering of NCs in their lattice sites. Surface chemistry characterization combined with density functional theory calculations suggest that the loss of ligands occurs preferentially on {100} than on reconstructed {111} NC facets. The resulting anisotropic ligand distribution amplifies the role of NC shape in the assembly and leads to the formation of superlattices with translational and orientational order. © 2011 American Chemical Society.

  11. Targeting Protein-Protein Interactions with Trimeric Ligands: High Affinity Inhibitors of the MAGUK Protein Family

    DEFF Research Database (Denmark)

    Nissen, Klaus B; Kedström, Linda Maria Haugaard; Wilbek, Theis S;

    2015-01-01

    related MAGUK proteins contain three consecutive PDZ domains, hence we envisioned that targeting all three PDZ domains simultaneously would lead to more potent and potentially more specific interactions with the MAGUK proteins. Here we describe the design, synthesis and characterization of a series of...... trimeric ligands targeting all three PDZ domains of PSD-95 and the related MAGUK proteins, PSD-93, SAP-97 and SAP-102. Using our dimeric ligands targeting the PDZ1-2 tandem as starting point, we designed novel trimeric ligands by introducing a PDZ3-binding peptide moiety via a cysteine-derivatized NPEG...... linker. The trimeric ligands generally displayed increased affinities compared to the dimeric ligands in fluorescence polarization binding experiments and optimized trimeric ligands showed low nanomolar inhibition towards the four MAGUK proteins, thus being the most potent inhibitors described. Kinetic...

  12. Improving Grubbs' II type ruthenium catalysts by appropriately modifying the N-heterocyclic carbene ligand.

    Science.gov (United States)

    Vieille-Petit, Ludovic; Luan, Xinjun; Gatti, Michele; Blumentritt, Sascha; Linden, Anthony; Clavier, Hervé; Nolan, Steven P; Dorta, Reto

    2009-07-01

    The introduction of N-heterocyclic carbene ligands that incorporate correctly substituted naphthyl side chains leads to increased activity and stability in second generation ruthenium metathesis catalysts. PMID:19557281

  13. Visualization of Metal-to-Ligand and Ligand-to-Ligand Charge Transfer in Metal-Ligand Complexes

    Institute of Scientific and Technical Information of China (English)

    Yong Ding; Jian-xiu Guo; Xiang-si Wang; Sha-sha Liu; Feng-cai Ma

    2009-01-01

    Three methods including the atomic resolved density of state, charge difference density, and the transition density matrix are used to visualize metal to ligand charge transfer (MLCT) in ruthenium(Ⅱ) ammine complex. The atomic resolved density of state shows that there is density of Ru on the HOMOs. All the density is localized on the ammine, which reveals that the excited electrons in the Ru complex are delocalized over the ammine ligand. The charge difference density shows that all the holes are localized on the Ru and the electrons on the ammine. The localization explains the MLCT on excitation. The transition density matrix shows that there is electron-hole coherence between Ru and ammine. These methods are also used to examine the MLCT in Os(bpy)(p0p)Cl ("Osp0p"; bpy=2,2'-bipyridyl; p0p=4,4'-bipyridyl) and the ligand-to-ligand charge transfer (LLCT) in Alq3. The calculated results show that these methods are powerful to examine MLCT and LLCT in the metal-ligand system.

  14. Memetic algorithms for ligand expulsion from protein cavities

    Science.gov (United States)

    Rydzewski, J.; Nowak, W.

    2015-09-01

    Ligand diffusion through a protein interior is a fundamental process governing biological signaling and enzymatic catalysis. A complex topology of channels in proteins leads often to difficulties in modeling ligand escape pathways by classical molecular dynamics simulations. In this paper, two novel memetic methods for searching the exit paths and cavity space exploration are proposed: Memory Enhanced Random Acceleration (MERA) Molecular Dynamics (MD) and Immune Algorithm (IA). In MERA, a pheromone concept is introduced to optimize an expulsion force. In IA, hybrid learning protocols are exploited to predict ligand exit paths. They are tested on three protein channels with increasing complexity: M2 muscarinic G-protein-coupled receptor, enzyme nitrile hydratase, and heme-protein cytochrome P450cam. In these cases, the memetic methods outperform simulated annealing and random acceleration molecular dynamics. The proposed algorithms are general and appropriate in all problems where an accelerated transport of an object through a network of channels is studied.

  15. Docking Screens for Novel Ligands Conferring New Biology.

    Science.gov (United States)

    Irwin, John J; Shoichet, Brian K

    2016-05-12

    It is now plausible to dock libraries of 10 million molecules against targets over several days or weeks. When the molecules screened are commercially available, they may be rapidly tested to find new leads. Although docking retains important liabilities (it cannot calculate affinities accurately nor even reliably rank order high-scoring molecules), it can often can distinguish likely from unlikely ligands, often with hit rates above 10%. Here we summarize the improvements in libraries, target quality, and methods that have supported these advances, and the open access resources that make docking accessible. Recent docking screens for new ligands are sketched, as are the binding, crystallographic, and in vivo assays that support them. Like any technique, controls are crucial, and key experimental ones are reviewed. With such controls, docking campaigns can find ligands with new chemotypes, often revealing the new biology that may be docking's greatest impact over the next few years. PMID:26913380

  16. Memetic algorithms for ligand expulsion from protein cavities

    CERN Document Server

    Rydzewski, Jakub

    2015-01-01

    Ligand diffusion through a protein interior is a fundamental process governing biological signaling and enzymatic catalysis. A complex topology of channels in proteins leads often to difficulties in modeling ligand escape pathways by classical molecular dynamics simulations. In this paper two novel memetic methods for searching the exit paths and cavity space exploration are proposed: Memory Enhanced Random Acceleration (MERA) Molecular Dynamics and Immune Algorithm (IA). In MERA, a pheromone concept is introduced to optimize an expulsion force. In IA, hybrid learning protocols are exploited to predict ligand exit paths. They are tested on three protein channels with increasing complexity: M2 muscarinic GPCR receptor, enzyme nitrile hydratase and heme-protein cytochrome P450cam. In these cases, the memetic methods outperform Simulated Annealing and Random Acceleration Molecular Dynamics. The proposed algorithms are general and appropriate in all problems where an accelerated transport of an object through a n...

  17. Why mercury prefers soft ligands

    Energy Technology Data Exchange (ETDEWEB)

    Riccardi, Demian M [ORNL; Guo, Hao-Bo [ORNL; Gu, Baohua [ORNL; Parks, Jerry M [ORNL; Summers, Anne [University of Georgia, Athens, GA; Miller, S [University of California, San Francisco; Liang, Liyuan [ORNL; Smith, Jeremy C [ORNL

    2013-01-01

    Mercury (Hg) is a major global pollutant arising from both natural and anthropogenic sources. Defining the factors that determine the relative affinities of different ligands for the mercuric ion, Hg2+, is critical to understanding its speciation, transformation, and bioaccumulation in the environment. Here, we use quantum chemistry to dissect the relative binding free energies for a series of inorganic anion complexes of Hg2+. Comparison of Hg2+ ligand interactions in the gaseous and aqueous phases shows that differences in interactions with a few, local water molecules led to a clear periodic trend within the chalcogenide and halide groups and resulted in the well-known experimentally observed preference of Hg2+ for soft ligands such as thiols. Our approach establishes a basis for understanding Hg speciation in the biosphere.

  18. Theoretical study of 'Mixed' ligands superhalogens: Cl-M-NO3 (M = Li, Na, K)

    Science.gov (United States)

    Zhao, Xinghua; Liu, Weihui; Wang, Jiesheng; Li, Chun; Yuan, Guang

    2016-08-01

    MCl2-, M(NO3)2-, and (Cl-M-NO3)- (M = Li, Na, K) species are systematically investigated using the density functional theory. In all the cases studied, the vertical detachment energies (VDEs) exceed the electron affinity of chlorine atom, leading to the conclusion that MCl2-, M(NO3)2- and (Cl-M-NO3)- are superhalogens. The VDEs of (Cl-M-NO3)- are between that of MCl2- and M(NO3)2-, showing that replacing one ligand with a larger electronegative ligand leads to the higher VDE. Superhalogens with suitable VDEs can be built by using different ligands.

  19. NKG2D ligands mediate immunosurveillance of senescent cells.

    Science.gov (United States)

    Sagiv, Adi; Burton, Dominick G A; Moshayev, Zhana; Vadai, Ezra; Wensveen, Felix; Ben-Dor, Shifra; Golani, Ofra; Polic, Bojan; Krizhanovsky, Valery

    2016-02-01

    Cellular senescence is a stress response mechanism that limits tumorigenesis and tissue damage. Induction of cellular senescence commonly coincides with an immunogenic phenotype that promotes self-elimination by components of the immune system, thereby facilitating tumor suppression and limiting excess fibrosis during wound repair. The mechanisms by which senescent cells regulate their immune surveillance are not completely understood. Here we show that ligands of an activating Natural Killer (NK) cell receptor (NKG2D), MICA and ULBP2 are consistently up-regulated following induction of replicative senescence, oncogene-induced senescence and DNA damage - induced senescence. MICA and ULBP2 proteins are necessary for efficient NK-mediated cytotoxicity towards senescent fibroblasts. The mechanisms regulating the initial expression of NKG2D ligands in senescent cells are dependent on a DNA damage response, whilst continuous expression of these ligands is regulated by the ERK signaling pathway. In liver fibrosis, the accumulation of senescent activated stellate cells is increased in mice lacking NKG2D receptor leading to increased fibrosis. Overall, our results provide new insights into the mechanisms regulating the expression of immune ligands in senescent cells and reveal the importance of NKG2D receptor-ligand interaction in protecting against liver fibrosis. PMID:26878797

  20. Predicting Electrophoretic Mobility of Protein-Ligand Complexes for Ligands from DNA-Encoded Libraries of Small Molecules.

    Science.gov (United States)

    Bao, Jiayin; Krylova, Svetlana M; Cherney, Leonid T; Hale, Robert L; Belyanskaya, Svetlana L; Chiu, Cynthia H; Shaginian, Alex; Arico-Muendel, Christopher C; Krylov, Sergey N

    2016-05-17

    Selection of target-binding ligands from DNA-encoded libraries of small molecules (DELSMs) is a rapidly developing approach in drug-lead discovery. Methods of kinetic capillary electrophoresis (KCE) may facilitate highly efficient homogeneous selection of ligands from DELSMs. However, KCE methods require accurate prediction of electrophoretic mobilities of protein-ligand complexes. Such prediction, in turn, requires a theory that would be applicable to DNA tags of different structures used in different DELSMs. Here we present such a theory. It utilizes a model of a globular protein connected, through a single point (small molecule), to a linear DNA tag containing a combination of alternating double-stranded and single-stranded DNA (dsDNA and ssDNA) regions of varying lengths. The theory links the unknown electrophoretic mobility of protein-DNA complex with experimentally determined electrophoretic mobilities of the protein and DNA. Mobility prediction was initially tested by using a protein interacting with 18 ligands of various combinations of dsDNA and ssDNA regions, which mimicked different DELSMs. For all studied ligands, deviation of the predicted mobility from the experimentally determined value was within 11%. Finally, the prediction was tested for two proteins and two ligands with a DNA tag identical to those of DELSM manufactured by GlaxoSmithKline. Deviation between the predicted and experimentally determined mobilities did not exceed 5%. These results confirm the accuracy and robustness of our model, which makes KCE methods one step closer to their practical use in selection of drug leads, and diagnostic probes from DELSMs. PMID:27119259

  1. Coordination chemistry of lanthanides(III) ions with oxygen nitrogen tripodal ligands

    International Nuclear Information System (INIS)

    This work aims at demonstrating the great potentialities of flexible tripodal ligands in various fields of applications of the coordination chemistry of lanthanide(III) ions. The coordination properties of different tripodal ligands with Ln(III) ions are reported. The ligand trenphen acts as a nona-dentate ligand for the Ln(III) ions independently to the ion size. The solid-state crystal structure and the rigid solution structure of the isostructural [Ln(trenphen)](OTt)3 complexes have been determined. Solvent extraction studies of lanthanides(III) and actinides(III) shows that the ligand trenphen is a selective complexant of actinides(III), thus confirming the interest of tripodal ligand containing soft nitrogen atoms for the selective extraction of actinides(III). The high number of coordination sites and the likely presence of interstrand interactions in the potentially dodeca-dentate ligand trenterpy prevent the formation of mononuclear complexes. In presence of lanthanum triflate, this ligand leads to the self-assembly of a discrete trinuclear complex. The use of tripodal ligands is a possible way to generate polynuclear arrays. We also report the synthesis and the structural properties of the Ln(III) complexes of the hepta-dentate ligand tpaa. Three types of crystal structures have been found for these complexes along the series which differ in their nuclearity and in the coordination number of the metal (10, 9 and 8). This flexible podate leads to a Gd complex with a relaxivity remarkably higher than those of the currently used contrast agents for MRI based on complexes of octa-dentate ligands. A shorter water proton-Gd(III) bond distance associated with a probable water coordination equilibrium appear to be at the origin of the high relaxivity of the Gd complex. This complex also displays a fast exchange rate of the coordinated water. Renee, the use of carefully tailored podates could prove to be a very efficient way to achieve optimized relaxivity

  2. Polypharmacology of dopamine receptor ligands.

    Science.gov (United States)

    Butini, S; Nikolic, K; Kassel, S; Brückmann, H; Filipic, S; Agbaba, D; Gemma, S; Brogi, S; Brindisi, M; Campiani, G; Stark, H

    2016-07-01

    Most neurological diseases have a multifactorial nature and the number of molecular mechanisms discovered as underpinning these diseases is continuously evolving. The old concept of developing selective agents for a single target does not fit with the medical need of most neurological diseases. The development of designed multiple ligands holds great promises and appears as the next step in drug development for the treatment of these multifactorial diseases. Dopamine and its five receptor subtypes are intimately involved in numerous neurological disorders. Dopamine receptor ligands display a high degree of cross interactions with many other targets including G-protein coupled receptors, transporters, enzymes and ion channels. For brain disorders like Parkinsońs disease, schizophrenia and depression the dopaminergic system, being intertwined with many other signaling systems, plays a key role in pathogenesis and therapy. The concept of designed multiple ligands and polypharmacology, which perfectly meets the therapeutic needs for these brain disorders, is herein discussed as a general ligand-based concept while focusing on dopaminergic agents and receptor subtypes in particular. PMID:27234980

  3. Determination of Lead by Electrochemistry

    Institute of Scientific and Technical Information of China (English)

    HE YuFeng; ZHANG Zhang; MA YongJun; KANG JingWan

    2001-01-01

    @@ Lead is one of the poisonous trace element for human body. It is important to find a way for measuring content of lead. Deternination of lead by electrochemistry is one of a method[1]. In this paper, lead is determined by single-sweep polarography. The absorption behavior of meso-tetra (4-sulfonylphenyl) porphyrin (H2TPPS4) complex with lead ion has also been studied.In Na2B4O7-NaOH solution with pH=l 0.5, the reduction peaks of the ligand are P1 (Ep1=-0.38V), P2 (Ep2=-1.04V), which potentials are obtained vs. S.C.E. When lead ion has been added into above solution. The peak current of P1 and P2 decrease, and a new reduction peak P3 (Ep3=-1.10 V) appears. It shows that the TPPS4-Pb(Ⅱ) complex forms,and this method can be applied to study the complex.

  4. Determination of Lead by Electrochemistry

    Institute of Scientific and Technical Information of China (English)

    HE; YuFeng

    2001-01-01

    Lead is one of the poisonous trace element for human body. It is important to find a way for measuring content of lead. Deternination of lead by electrochemistry is one of a method[1]. In this paper, lead is determined by single-sweep polarography. The absorption behavior of meso-tetra (4-sulfonylphenyl) porphyrin (H2TPPS4) complex with lead ion has also been studied.In Na2B4O7-NaOH solution with pH=l 0.5, the reduction peaks of the ligand are P1 (Ep1=-0.38V), P2 (Ep2=-1.04V), which potentials are obtained vs. S.C.E. When lead ion has been added into above solution. The peak current of P1 and P2 decrease, and a new reduction peak P3 (Ep3=-1.10 V) appears. It shows that the TPPS4-Pb(Ⅱ) complex forms,and this method can be applied to study the complex.……

  5. Crystallization of protein–ligand complexes

    International Nuclear Information System (INIS)

    Methods presented for growing protein–ligand complexes fall into the categories of co-expression of the protein with the ligands of interest, use of the ligands during protein purification, cocrystallization and soaking the ligands into existing crystals. Obtaining diffraction-quality crystals has long been a bottleneck in solving the three-dimensional structures of proteins. Often proteins may be stabilized when they are complexed with a substrate, nucleic acid, cofactor or small molecule. These ligands, on the other hand, have the potential to induce significant conformational changes to the protein and ab initio screening may be required to find a new crystal form. This paper presents an overview of strategies in the following areas for obtaining crystals of protein–ligand complexes: (i) co-expression of the protein with the ligands of interest, (ii) use of the ligands during protein purification, (iii) cocrystallization and (iv) soaks

  6. Solvent fluctuations induce non-Markovian kinetics in hydrophobic pocket-ligand binding

    CERN Document Server

    Weiß, R Gregor; Dzubiella, Joachim

    2016-01-01

    We investigate the impact of water fluctuations on the key-lock association kinetics of a hydrophobic ligand (key) binding to a hydrophobic pocket (lock) by means of a minimalistic stochastic model system. It describes the collective hydration behavior of the pocket by bimodal fluctuations of a water-pocket interface that dynamically couples to the diffusive motion of the approaching ligand via the hydrophobic interaction. This leads to a set of overdamped Langevin equations in 2D-coordinate-space, that is Markovian in each dimension. Numerical simulations demonstrate locally increased friction of the ligand, decelerated binding kinetics, and local non-Markovian (memory) effects in the ligand's reaction coordinate as found previously in explicit-water molecular dynamics studies of model hydrophobic pocket-ligand binding [1,2]. Our minimalistic model elucidates the origin of effectively enhanced friction in the process that can be traced back to long-time decays in the force-autocorrelation function induced by...

  7. Learn about Lead

    Science.gov (United States)

    ... US EPA US Environmental Protection Agency Search Search Lead Share Facebook Twitter Google+ Pinterest Contact Us You ... EPA Home » Lead » Learn about Lead Learn about Lead General Lead Information Read more about lead in ...

  8. Ligand chain length conveys thermochromism.

    Science.gov (United States)

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

    2014-08-14

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

  9. Presentation of Ligands on Hydroxylapatite

    Science.gov (United States)

    Chu, Barbara C. F.; Orgel, Leslie E.

    1997-01-01

    Conjugates of biotin with the decamer of glutamic acid (glu(sub 10)) and the trimer of D,L-2-amino-5-phosphonovaleric acid (I) have been synthesized, and it has been shown that they mediate the binding of avidin to hydroxylapatite. In a similar way a conjugate of methotrexate with glu(sub 10) mediates the binding of dihydrofolate reductase to the mineral. The presentation of ligands on the hydroxylapatite component of bone may find applications in clinical medicine.

  10. Privileged chiral ligands and catalysts

    CERN Document Server

    Zhou, Qi-Lin

    2011-01-01

    This ultimate ""must have"" and long awaited reference for every chemist working in the field of asymmetric catalysis starts with the core structure of the catalysts, explaining why a certain ligand or catalyst is so successful. It describes in detail the history, the basic structural characteristics, and the applications of these ""privileged catalysts"". A novel concept that gives readers a much deeper insight into the topic.

  11. Tumor targeting via integrin ligands

    Directory of Open Access Journals (Sweden)

    HorstKessler

    2013-08-01

    Full Text Available Selective and targeted delivery of drugs to tumors is a major challenge for an effective cancer therapy and also to overcome the side effects associated with current treatments. Overexpression of various receptors on tumor cells is a characteristic structural and biochemical aspect of tumors and distinguishes them from physiologically normal cells. This abnormal feature is therefore suitable for selectively directing anticancer molecules to tumors by using ligands that can preferentially recognize such receptors. Several subtypes of integrin receptors that are crucial for cell adhesion, cell signaling, cell viability and motility have been shown to have an upregulated expression on cancer cells. Thus, ligands that recognize specific integrin subtypes represent excellent candidates to be conjugated to drugs or drug carrier systems and be targeted to tumors. In this regard, integrins recognizing the RGD cell adhesive sequence have been extensively targeted for tumor specific drug delivery. Here we review key recent examples on the presentation of RGD-based integrin ligands by means of distinct drug delivery systems, and discuss the prospects of such therapies to specifically target tumor cells.

  12. Radioiodinated ligands for dopamine receptors

    International Nuclear Information System (INIS)

    The dopamine receptor system is important for normal brain function; it is also the apparent action site for various neuroleptic drugs for the treatment of schizophrenia and other metal disorders. In the past few years radioiodinated ligands for single photon emission tomography (SPECT) have been successfully developed and tested in humans: [123I]TISCH for D1 dopamine receptors; [123I]IBZM, epidepride, IBF and FIDA2, four iodobenzamide derivatives, for D2/D3 dopamine receptors. In addition, [123I]β-CIT (RTI-55) and IPT, cocaine derivatives, for the dopamine reuptake site are potentially useful for diagnosis of loss of dopamine neurons. The first iodinated ligand, (R)trans-7-OH-PIPAT, for D3 dopamine receptors, was synthesized and characterized with cloned cell lines (Spodoptera frugiperda, Sf9) expressing the D2 and D3 dopamine receptors and with rat basal forebrain membrane preparations. Most of the known iodobenzamides displayed similar potency in binding to both D2 and D3 dopamine receptors expressed in the cell lines. Initial studies appear to suggest that by fine tuning the structures it may be possible to develop agents specific for D2 and D3 dopamine receptors. It is important to investigate D2/D3 selectivity for this series of potent ligands

  13. Understanding the shape effect on the plasmonic response of small ligand coated nanoparticles

    Science.gov (United States)

    Chen, Xing; Jensen, Lasse

    2016-07-01

    The plasmonic properties of metallic nanoparticles typically depend strongly on their shapes and local environment. However, not much is known about the shape effects on the plasmonic response in small metallic nanoparticles when quantum size effects become important. In this work, we use atomistic electrodynamics models incorporated with quantum size effects to study the optical properties of both bare and ligand coated Ag nanoparticles in different shapes. Using classical electrodynamics, we find that the plasmonic response of bare metallic nanoparticles depends strongly on the morphology of the nanoparticles due to the presence of higher-order plasmon modes. By including quantum size effects in the simulations, we find a significant blue-shift of the dipole plasmon as well as the smearing-out of the multipole plasmon modes, and both lead to a weak shape dependence. The ligand effects on the nanoparticles cause a significant red-shift of the plasmon resonance arising from the reduction of the conductivity of the Ag atoms where the ligands bind. In contrast to the bare nanoparticles, we find several higher-order plasmon modes in the ligand coated nanoparticles, that are likely caused by the weak electron spill-out effect and the symmetry breaking at the surface in the presence of the ligands. Furthermore, we show that the ligand layer strongly modify the near-field distribution due to the screening of the ligands. This work highlights the importance of quantum size and ligand effects on the optical properties of small metallic nanoparticles.

  14. An approach to rational ligand-design based on a thermodynamic analysis.

    Science.gov (United States)

    Ui, Mihoko; Tsumoto, Kouhei

    2010-11-01

    Thermodynamic analysis is an effective tool in screening of lead-compounds for development of potential drug candidates. In most cases, a ligand achieve high affinity and specificity to a target protein by means of both favorable enthalpy and entropy terms, which can be reflected in binding profiles of Isothermal Titration Calorimetry (ITC). A favorable enthalpy change suggests the contribution of noncovalent contacts such as hydrogen bonding and van der Waals interaction between a ligand and its target protein. In general, optimization of binding enthalpy is more difficult than that of entropies in ligand-design; therefore, it is desirable to choose firstly a lead-compound based on its binding enthalpic gain. In this paper, we demonstrate the utility of thermodynamic approach to ligand screening using anti-ciguatoxin antibody 10C9 as a model of a target protein which possesses a large hydrophobic pocket. As a result of this screening, we have identified three compounds that could bind to the antigen-binding pocket of 10C9 with a few kcal/mol of favorable binding enthalpy. Comparison of their structure with the proper antigen ciguatoxin CTX3C revealed that 10C9 rigorously identifies their cyclic structure and a characteristic hydroxyl group. ITC measurement might be useful and powerful for a rational ligand screening and the optimization of the ligand; the enthalpic gain is an effective index for ligand-design studies. PMID:21171955

  15. Contrasting roles for TLR ligands in HIV-1 pathogenesis.

    Directory of Open Access Journals (Sweden)

    Beda Brichacek

    Full Text Available The first line of a host's response to various pathogens is triggered by their engagement of cellular pattern recognition receptors (PRRs. Binding of microbial ligands to these receptors leads to the induction of a variety of cellular factors that alter intracellular and extracellular environment and interfere directly or indirectly with the life cycle of the triggering pathogen. Such changes may also affect any coinfecting microbe. Using ligands to Toll-like receptors (TLRs 5 and 9, we examined their effect on human immunodeficiency virus (HIV-1 replication in lymphoid tissue ex vivo. We found marked differences in the outcomes of such treatment. While flagellin (TLR5 agonist treatment enhanced replication of CC chemokine receptor 5 (CCR 5-tropic and CXC chemokine receptor 4 (CXCR4-tropic HIV-1, treatment with oligodeoxynucleotide (ODN M362 (TLR9 agonist suppressed both viral variants. The differential effects of these TLR ligands on HIV-1 replication correlated with changes in production of CC chemokines CCL3, CCL4, CCL5, and of CXC chemokines CXCL10, and CXCL12 in the ligand-treated HIV-1-infected tissues. The nature and/or magnitude of these changes were dependent on the ligand as well as on the HIV-1 viral strain. Moreover, the tested ligands differed in their ability to induce cellular activation as evaluated by the expression of the cluster of differentiation markers (CD 25, CD38, CD39, CD69, CD154, and human leukocyte antigen D related (HLA-DR as well as of a cell proliferation marker, Ki67, and of CCR5. No significant effect of the ligand treatment was observed on apoptosis and cell death/loss in the treated lymphoid tissue ex vivo. Our results suggest that binding of microbial ligands to TLRs is one of the mechanisms that mediate interactions between coinfected microbes and HIV-1 in human tissues. Thus, the engagement of appropriate TLRs by microbial molecules or their mimetic might become a new strategy for HIV therapy or prevention.

  16. Differential effects of EGFR ligands on endocytic sorting of the receptor

    DEFF Research Database (Denmark)

    Roepstorff, Kirstine; Grandal, Michael Vibo; Henriksen, Lasse;

    2009-01-01

    signalling and is a more potent mitogen than EGF. In addition to EGF and TGF-alpha, five EGFR ligands have been identified. Although many of these ligands are upregulated in cancers, very little is known about their effect on EGFR trafficking. We have compared the effect of six different ligands on endocytic...... trafficking of EGFR. We find that, whereas they all stimulate receptor internalization, they have very diverse effects on endocytic sorting. Heparin-binding EGF-like growth factor and Betacellulin target all EGFRs for lysosomal degradation. In contrast, TGF-alpha and epiregulin lead to complete receptor...

  17. Ultrafast Electron Trapping in Ligand-Exchanged Quantum Dot Assemblies

    Science.gov (United States)

    Kikkawa, J. M.; Turk, M. E.; Vora, P. M.; Fafarman, A. T.; Diroll, B. T.; Murray, C. B.; Kagan, C. R.

    2015-03-01

    We use time-integrated and time-resolved photoluminescence and absorption to characterize the low-temperature (10 K) optical properties of CdSe quantum dot (QD) solids with different ligand and annealing preparation. Close-packed CdSe quantum dot solids are prepared with native aliphatic ligands and with thiocyanate with and without thermal annealing. Using sub-picosecond, broadband time-resolved photoluminescence and absorption, we find that ligand exchange increases the rate of carrier surface trapping. We further determine that holes within the QD core, rather than electrons, can bleach the band-edge transition in these samples at low temperature, a finding that comes as a surprise given what is known about the surface treatment in these QDs. We find that our ligand treatments lead to faster electron trapping to the quantum dot surface, a greater proportion of surface photoluminescence, and an increased rate of nonradiative decay due to enhanced interparticle coupling upon exchange and annealing. All aspects of this work supported by the U.S. Department of Energy Office of Basic Energy Sciences, Division of Materials Science and Engineering, under Award No. DE-SC0002158.

  18. Colloidal-quantum-dot photovoltaics using atomic-ligand passivation

    KAUST Repository

    Tang, Jiang

    2011-09-18

    Colloidal-quantum-dot (CQD) optoelectronics offer a compelling combination of solution processing and spectral tunability through quantum size effects. So far, CQD solar cells have relied on the use of organic ligands to passivate the surface of the semiconductor nanoparticles. Although inorganic metal chalcogenide ligands have led to record electronic transport parameters in CQD films, no photovoltaic device has been reported based on such compounds. Here we establish an atomic ligand strategy that makes use of monovalent halide anions to enhance electronic transport and successfully passivate surface defects in PbS CQD films. Both time-resolved infrared spectroscopy and transient device characterization indicate that the scheme leads to a shallower trap state distribution than the best organic ligands. Solar cells fabricated following this strategy show up to 6% solar AM1.5G power-conversion efficiency. The CQD films are deposited at room temperature and under ambient atmosphere, rendering the process amenable to low-cost, roll-by-roll fabrication. © 2011 Macmillan Publishers Limited. All rights reserved.

  19. Ligand-directed trafficking of receptor stimulus.

    Science.gov (United States)

    Chilmonczyk, Zdzisław; Bojarski, Andrzej J; Sylte, Ingebrigt

    2014-12-01

    GPCRs are seven transmembrane-spanning receptors that convey specific extracellular stimuli to intracellular signalling. They represent the largest family of cell surface proteins that are therapeutically targeted. According to the traditional two-state model of receptor theory, GPCRs were considered as operating in equilibrium between two functional conformations, an active (R*) and inactive (R) state. Thus, it was assumed that a GPCR can exist either in an "off" or "on" conformation causing either no activation or equal activation of all its signalling pathways. Over the past several years it has become evident that this model is too simple and that GPCR signalling is far more complex. Different studies have presented a multistate model of receptor activation in which ligand-specific receptor conformations are able to differentiate between distinct signalling partners. Recent data show that beside G proteins numerous other proteins, such as β-arrestins and kinases, may interact with GPCRs and activate intracellular signalling pathways. GPCR activation may therefore involve receptor desensitization, coupling to multiple G proteins, Gα or Gβγ signalling, and pathway activation that is independent of G proteins. This latter effect leads to agonist "functional selectivity" (also called ligand-directed receptor trafficking, stimulus trafficking, biased agonism, biased signalling), and agonist intervention with functional selectivity may improve the therapy. Many commercially available drugs with beneficial efficacy also show various undesirable side effects. Further studies of biased signalling might facilitate our understanding of the side effects of current drugs and take us to new avenues to efficiently design pathway-specific medications. PMID:25443729

  20. Ligand switch in photoinduced copper-mediated polymerization: synthesis of methacrylate-acrylate block copolymers

    OpenAIRE

    CHUANG, Ya-Mi; Wenn, Benjamin; Gielen, Sam; Ethirajan, Anitha; Junkers, Thomas

    2015-01-01

    The use of photo-induced copper-mediated radical polymerization (photoCMP) to synthesize mixed acrylate/methacrylate (methyl acrylate, MA and methyl methacrylate, MMA) block copolymers is investigated. Reactions in which only one type of ligand (Me6TREN) is used lead to unsuccessful outcomes of polymerization due to a mismatch in reactivity of the two monomers. A ligand exchange to PMDETA for methacrylate is required to obtain good block structures. Due to insufficient re-initiation of polyac...

  1. Improved thermal stability of oxide-supported naked gold nanoparticles by ligand-assisted pinning

    Energy Technology Data Exchange (ETDEWEB)

    Moreno, C [Universitat Politecnica de Catalunya, Barcelona, Spain; Divins, N. J. [Universitat Politecnica de Catalunya, Barcelona, Spain; Gazquez, Jaume [UCM, Dept Fis Aplicada 3, Madrid, Spain; Varela, Maria [UCM, Dept Fis Aplicada 3, Madrid, Spain; Angurell, I [Universitat de Barcelona; Llorca, J [Universitat Politecnica de Catalunya, Barcelona, Spain

    2012-01-01

    We report a method to improve the thermal stability, up to 900 C, of bare-metal (naked) gold nanoparticles supported on top of SiO{sub 2} and SrTiO{sub 3} substrates via ligand-assisted pinning. This approach leads to monodisperse naked gold nanoparticles without significant sintering after thermal annealing in air at 900 C. The ligand-assisted pinning mechanism is described.

  2. A Series of Diamagnetic Pyridine Monoimine Rhenium Complexes with Different Degrees of Metal-to-Ligand Charge Transfer: Correlating (13) C NMR Chemical Shifts with Bond Lengths in Redox-Active Ligands.

    Science.gov (United States)

    Sieh, Daniel; Kubiak, Clifford P

    2016-07-18

    A set of pyridine monoimine (PMI) rhenium(I) tricarbonyl chlorido complexes with substituents of different steric and electronic properties was synthesized and fully characterized. Spectroscopic (NMR and IR) and single-crystal X-ray diffraction analyses of these complexes showed that the redox-active PMI ligands are neutral and that the overall electronic structure is little affected by the choices of the substituent at the ligand backbone. One- and two-electron reduction products were prepared from selected starting compounds and could also be characterized by multiple spectroscopic methods and X-ray diffraction. The final product of a one-electron reduction in THF is a diamagnetic metal-metal-bonded dimer after loss of the chlorido ligand. Bond lengths in and NMR chemical shifts of the PMI ligand backbone indicate partial electron transfer to the ligand. Two-electron reduction in THF also leads to the loss of the chlorido ligand and a pentacoordinate complex is obtained. The comparison with reported bond lengths and (13) C NMR chemical shifts of doubly reduced free pyridine monoaldimine ligands indicates that both redox equivalents in the doubly reduced rhenium complex investigated here are located in the PMI ligand. With diamagnetic complexes varying over three formal reduction stages at the PMI ligand we were, for the first time, able to establish correlations of the (13) C NMR chemical shifts with the relevant bond lengths in redox-active ligands over a full redox series. PMID:27319753

  3. Ligand placement based on prior structures: the guided ligand-replacement method

    Energy Technology Data Exchange (ETDEWEB)

    Klei, Herbert E. [Lawrence Berkeley National Laboratory, Berkeley, CA 94720 (United States); Bristol-Myers Squibb, Princeton, NJ 08543-4000 (United States); Moriarty, Nigel W., E-mail: nwmoriarty@lbl.gov; Echols, Nathaniel [Lawrence Berkeley National Laboratory, Berkeley, CA 94720 (United States); Terwilliger, Thomas C. [Los Alamos National Laboratory, Los Alamos, NM 87545-0001 (United States); Baldwin, Eric T. [Bristol-Myers Squibb, Princeton, NJ 08543-4000 (United States); Natural Discovery LLC, Princeton, NJ 08542-0096 (United States); Pokross, Matt; Posy, Shana [Bristol-Myers Squibb, Princeton, NJ 08543-4000 (United States); Adams, Paul D. [Lawrence Berkeley National Laboratory, Berkeley, CA 94720 (United States); University of California at Berkeley, Berkeley, CA 94720-1762 (United States)

    2014-01-01

    A new module, Guided Ligand Replacement (GLR), has been developed in Phenix to increase the ease and success rate of ligand placement when prior protein-ligand complexes are available. The process of iterative structure-based drug design involves the X-ray crystal structure determination of upwards of 100 ligands with the same general scaffold (i.e. chemotype) complexed with very similar, if not identical, protein targets. In conjunction with insights from computational models and assays, this collection of crystal structures is analyzed to improve potency, to achieve better selectivity and to reduce liabilities such as absorption, distribution, metabolism, excretion and toxicology. Current methods for modeling ligands into electron-density maps typically do not utilize information on how similar ligands bound in related structures. Even if the electron density is of sufficient quality and resolution to allow de novo placement, the process can take considerable time as the size, complexity and torsional degrees of freedom of the ligands increase. A new module, Guided Ligand Replacement (GLR), was developed in Phenix to increase the ease and success rate of ligand placement when prior protein–ligand complexes are available. At the heart of GLR is an algorithm based on graph theory that associates atoms in the target ligand with analogous atoms in the reference ligand. Based on this correspondence, a set of coordinates is generated for the target ligand. GLR is especially useful in two situations: (i) modeling a series of large, flexible, complicated or macrocyclic ligands in successive structures and (ii) modeling ligands as part of a refinement pipeline that can automatically select a reference structure. Even in those cases for which no reference structure is available, if there are multiple copies of the bound ligand per asymmetric unit GLR offers an efficient way to complete the model after the first ligand has been placed. In all of these applications, GLR

  4. Ligand photo-isomerization triggers conformational changes in iGluR2 ligand binding domain.

    Directory of Open Access Journals (Sweden)

    Tino Wolter

    Full Text Available Neurological glutamate receptors bind a variety of artificial ligands, both agonistic and antagonistic, in addition to glutamate. Studying their small molecule binding properties increases our understanding of the central nervous system and a variety of associated pathologies. The large, oligomeric multidomain membrane protein contains a large and flexible ligand binding domains which undergoes large conformational changes upon binding different ligands. A recent application of glutamate receptors is their activation or inhibition via photo-switchable ligands, making them key systems in the emerging field of optochemical genetics. In this work, we present a theoretical study on the binding mode and complex stability of a novel photo-switchable ligand, ATA-3, which reversibly binds to glutamate receptors ligand binding domains (LBDs. We propose two possible binding modes for this ligand based on flexible ligand docking calculations and show one of them to be analogues to the binding mode of a similar ligand, 2-BnTetAMPA. In long MD simulations, it was observed that transitions between both binding poses involve breaking and reforming the T686-E402 protein hydrogen bond. Simulating the ligand photo-isomerization process shows that the two possible configurations of the ligand azo-group have markedly different complex stabilities and equilibrium binding modes. A strong but slow protein response is observed after ligand configuration changes. This provides a microscopic foundation for the observed difference in ligand activity upon light-switching.

  5. Ruthenium Cumulenylidene Complexes Bearing Heteroscorpionate Ligands

    OpenAIRE

    Strinitz, Frank

    2014-01-01

    In previous work of the BURZLAFF group, the design of suitable N,N,O ligands for a wide variety of applications ranging from catalysis to bioinorganic model compounds has been extensively investigated. Especially the methyl substituted bis(3,5-dimethylpyrazol-1-yl) acetate (bdmpza) ligand has shown manifold chemistry, comparable to the anionic cyclopentadienyl (Cp) and hydridotris(pyrazol-1-yl)borato (Tp) ligand. In the first part of this thesis the new tricarbonylmanganese(I) complexes be...

  6. Phenotypic spandrel: absolute discrimination and ligand antagonism

    OpenAIRE

    François, Paul; Johnson, Kyle A.; Saunders, Laura N.

    2015-01-01

    We consider the general problem of absolute discrimination between categories of ligands irrespective of their concentration. An instance of this problem is immune discrimination between self and not-self. We connect this problem to biochemical adaptation, and establish that ligand antagonism - the ability of sub threshold ligands to negatively impact response - is a necessary consequence of absolute discrimination.Thus antagonism constitutes a "phenotypic spandrel": a phenotype existing as a...

  7. From Widely Accepted Concepts in Coordination Chemistry to Inverted Ligand Fields.

    Science.gov (United States)

    Hoffmann, Roald; Alvarez, Santiago; Mealli, Carlo; Falceto, Andrés; Cahill, Thomas J; Zeng, Tao; Manca, Gabriele

    2016-07-27

    We begin with a brief historical review of the development of our understanding of the normal ordering of nd orbitals of a transition metal interacting with ligands, the most common cases being three below two in an octahedral environment, two below three in tetrahedral coordination, and four below one in a square-planar environment. From the molecular orbital construction of these ligand field splittings evolves a strategy for inverting the normal order: the obvious way to achieve this is to raise the ligand levels above the metal d's; that is, make the ligands better Lewis bases. However, things are not so simple, for such metal/ligand level placement may lead to redox processes. For 18-electron octahedral complexes one can create the inverted situation, but it manifests itself in the makeup of valence orbitals (are they mainly on metal or ligands?) rather than energy. One can also see the effect, in small ways, in tetrahedral Zn(II) complexes. We construct several examples of inverted ligand field systems with a hypothetical but not unrealistic AlCH3 ligand and sketch the consequences of inversion on reactivity. Special attention is paid to the square-planar case, exemplified by [Cu(CF3)4](-), in which Snyder had the foresight to see a case of an inverted field, with the empty valence orbital being primarily ligand centered, the dx2-y2 orbital heavily occupied, in what would normally be called a Cu(III) complex. For [Cu(CF3)4](-) we provide theoretical evidence from electron distributions, geometry of the ligands, thermochemistry of molecule formation, and the energetics of abstraction of a CF3 ligand by a base, all consistent with oxidation of the ligands in this molecule. In [Cu(CF3)4](-), and perhaps more complexes on the right side of the transition series than one has imagined, some ligands are σ-noninnocent. Exploration of inverted ligand fields helps us see the continuous, borderless transition from transition metal to main group bonding. We also give

  8. Clinical Use of PPARγ Ligands in Cancer

    Directory of Open Access Journals (Sweden)

    Jennifer L. Hatton

    2008-01-01

    Full Text Available The role of PPARγ in adipocyte differentiation has fueled intense interest in the function of this steroid nuclear receptor for regulation of malignant cell growth and differentiation. Given the antiproliferative and differentiating effects of PPARγ ligands on liposarcoma cells, investigation of PPARγ expression and ligand activation in other solid tumors such as breast, colon, and prostate cancers ensued. The anticancer effects of PPARγ ligands in cell culture and rodent models of a multitude of tumor types suggest broad applicability of these agents to cancer therapy. This review focuses on the clinical use of PPARγ ligands, specifically the thiazolidinediones, for the treatment and prevention of cancer.

  9. Development of immobilized ligands for actinide separations

    International Nuclear Information System (INIS)

    Primary goals during this grant period were to (1) synthesize new bifunctional chelating ligands, (2) characterize the structural features of the Ln and An coordination complexes formed by these ligands, (3) use structural data to iteratively design new classes of multifunctional ligands, and (4) explore additional routes for attachment of key ligands to solid supports that could be useful for chromatographic separations. Some highlights of recently published work as well as a summary of submitted, unpublished and/or still in progress research are outlined

  10. Ligand Exchange Reaction of Au(I) R-N-Heterocyclic Carbene Complexes with Cysteine.

    Science.gov (United States)

    Dos Santos, H F; Vieira, M A; Sánchez Delgado, G Y; Paschoal, D

    2016-04-14

    The chemotherapy with gold complexes has been attempted since the 90s after the clinical success of auranofin, a gold(I) coordination complex. Currently, the organometallics compounds have shown promise in cancer therapy, mainly in those complexes containing N-heterocylic carbenes (NHC) as a ligand. The present study shows a kinetic analysis of the reaction of six alkyl-substituted NHC with cysteine (Cys), which is taken as an important bionucleophile representative. The first and second ligand exchange processes were analyzed with the complete description of the mechanism and energy profiles. For the first reaction step, which is the rate-limiting step of the whole substitution reaction, the activation enthalpy follows the order 1/Me2 order is correlated with the r(Au-S) calculated for the transition state structures where S is the sulfur ligand from the Cys entering group. This means that longer r(Au-S) leads to higher activation enthalpy and is consistent with the effectiveness of gold shielding from nucleophile attack by bulkier alkyl-substituted NHC ligand. When electronic effect was addressed we found that higher activation barrier was predicted for strongly electron-donating NHC ligand, represented by the eigenvalue of σ-HOMO orbital of the free ligands. The molecular interpretation of the electronic effects is that strong donating NHC forms strong metal-ligand bond. For the second reaction step, similar structure-reactivity relationships were obtained, however the activation energies are less sensitive to the structure. PMID:27010796

  11. Direct Measure of Metal-Ligand Bonding Replacing the Tolman Electronic Parameter.

    Science.gov (United States)

    Setiawan, Dani; Kalescky, Robert; Kraka, Elfi; Cremer, Dieter

    2016-03-01

    The Tolman electronic parameter (TEP) derived from the A1-symmetrical CO stretching frequency of nickel-tricarbonyl complexes L-Ni(CO)3 with varying ligands L is misleading as (i) it is not based on a mode decoupled CO stretching frequency and (ii) a generally applicable and quantitatively correct or at least qualitatively reasonable relationship between the TEP and the metal-ligand bond strength does not exist. This is shown for a set of 181 nickel-tricarbonyl complexes using both experimental and calculated TEP values. Even the use of mode-mode decoupled CO stretching frequencies (L(ocal)TEPs) does not lead to a reliable description of the metal-ligand bond strength. This is obtained by introducing a new electronic parameter that is directly based on the metal-ligand local stretching force constant. For the test set of 181 nickel complexes, a direct metal-ligand electronic parameter (MLEP) in the form of a bond strength order is derived, which reveals that phosphines and related ligands (amines, arsines, stibines, bismuthines) are bonded to Ni both by σ-donation and π-back-donation. The strongest Ni-L bonds are identified for carbenes and cationic ligands. The new MLEP quantitatively assesses electronic and steric factors. PMID:26900632

  12. Facile ligand oxidation and ring nitration in ruthenium complexes derived from a ligand with dicarboxamide-N and phosphine-P donors.

    Science.gov (United States)

    Fry, Nicole L; Rose, Michael J; Nyitray, Crystal; Mascharak, Pradip K

    2008-12-15

    The reaction of the tetradentate dicarboxamide ligand 1,2-bis-N-[2'(diphenylphosphanyl)benzoyl]diaminobenzene (dppbH(2)) with RuCl(3) in DMF or ethanol results in metal-mediated ligand oxidation and formation of the diamagnetic Ru(II) complex [(dppQ)Ru(Cl)(2)] (1) with N(2)P(2) chromophore. The o-phenylenedicarboxamide portion of the dppb(2-) ligand is oxidized to a o-benzoquinonediimine (bqdi) moiety in [(dppQ)Ru(Cl)(2)]. Presence of oxygen accelerates the ligand oxidation process. Unlike other tetradentate dicarboxamide ligands with pyridine-N, phenolato-O, or thiolato-S donors, dppb(2-) provides stability to the +2 oxidation state of ruthenium and facilitates oxidation of the coordinated ligand frame. Results of spectroscopic and redox studies strongly support the +2 oxidation state of Ru in 1. Exposure of 1 to NO(g) does not lead to formation of any metal nitrosyl; instead, the bqdi ring is nitrated to afford [(NO(2)dppQ)Ru(Cl)(2)] (2). PMID:19006289

  13. Ligand-specific conformational changes in the alpha1 glycine receptor ligand-binding domain

    DEFF Research Database (Denmark)

    Pless, Stephan Alexander; Lynch, Joseph W

    2009-01-01

    residue responded differently to glycine and strychnine, thus underlining the importance of loop C in ligand discrimination. These results provide an important step toward mapping the domains crucial for ligand discrimination in the ligand-binding domain of glycine receptors and possibly other Cys loop...

  14. Lead levels - blood

    Science.gov (United States)

    Blood lead levels ... is used to screen people at risk for lead poisoning. This may include industrial workers and children ... also used to measure how well treatment for lead poisoning is working. Lead is common in the ...

  15. Lead Poisoning Prevention Tips

    Science.gov (United States)

    ... or removed safely. How are children exposed to lead? Lead-based paint and lead contaminated dust are ... What can be done to prevent exposure to lead? It is important to determine the construction year ...

  16. Lead for radiation shields

    International Nuclear Information System (INIS)

    Fabrication programme lead in radiation protection: lead bricks, radiation protection tables and windows, locks, lead containers, vaults and bunkers, radiation protection capsules as well as lead fillings for reactor aggregates. (RW/LH)

  17. Reductive Cleavage of CO2 by Metal-Ligand-Cooperation Mediated by an Iridium Pincer Complex.

    Science.gov (United States)

    Feller, Moran; Gellrich, Urs; Anaby, Aviel; Diskin-Posner, Yael; Milstein, David

    2016-05-25

    A unique mode of stoichiometric CO2 activation and reductive splitting based on metal-ligand-cooperation is described. The novel Ir hydride complexes [((t)Bu-PNP*)Ir(H)2] (2) ((t)Bu-PNP*, deprotonated (t)Bu-PNP ligand) and [((t)Bu-PNP)Ir(H)] (3) react with CO2 to give the dearomatized complex [((t)Bu-PNP*)Ir(CO)] (4) and water. Mechanistic studies have identified an adduct in which CO2 is bound to the ligand and metal, [((t)Bu-PNP-COO)Ir(H)2] (5), and a di-CO2 iridacycle [((t)Bu-PNP)Ir(H)(C2O4-κC,O)] (6). DFT calculations confirm the formation of 5 and 6 as reversibly formed side products, and suggest an η(1)-CO2 intermediate leading to the thermodynamic product 4. The calculations support a metal-ligand-cooperation pathway in which an internal deprotonation of the benzylic position by the η(1)-CO2 ligand leads to a carboxylate intermediate, which further reacts with the hydride ligand to give complex 4 and water. PMID:27124097

  18. Internalization mechanisms of the epidermal growth factor receptor after activation with different ligands.

    Directory of Open Access Journals (Sweden)

    Lasse Henriksen

    Full Text Available The epidermal growth factor receptor (EGFR regulates normal growth and differentiation, but dysregulation of the receptor or one of the EGFR ligands is involved in the pathogenesis of many cancers. There are eight ligands for EGFR, however most of the research into trafficking of the receptor after ligand activation focuses on the effect of epidermal growth factor (EGF and transforming growth factor-α (TGF-α. For a long time it was believed that clathrin-mediated endocytosis was the major pathway for internalization of the receptor, but recent work suggests that different pathways exist. Here we show that clathrin ablation completely inhibits internalization of EGF- and TGF-α-stimulated receptor, however the inhibition of receptor internalization in cells treated with heparin-binding EGF-like growth factor (HB-EGF or betacellulin (BTC was only partial. In contrast, clathrin knockdown fully inhibits EGFR degradation after all ligands tested. Furthermore, inhibition of dynamin function blocked EGFR internalization after stimulation with all ligands. Knocking out a number of clathrin-independent dynamin-dependent pathways of internalization had no effect on the ligand-induced endocytosis of the EGFR. We suggest that EGF and TGF-α lead to EGFR endocytosis mainly via the clathrin-mediated pathway. Furthermore, we suggest that HB-EGF and BTC also lead to EGFR endocytosis via a clathrin-mediated pathway, but can additionally use an unidentified internalization pathway or better recruit the small amount of clathrin remaining after clathrin knockdown.

  19. Macrocyclic ligands for uranium complexation

    International Nuclear Information System (INIS)

    A highly preorganized 24-macrocycle containing biuret, thiobiuret and pyridine subunits has been prepared by high dilution ring-closure procedures. Intermediate products to this macrocycle have been utilized to extend this synthetic route to include further representatives where solubility and stability will be influenced by substituent variation. A 1:1 complex has been formed from uranyl acetate and a quinquepyridine derivative, this representing a new type of ligand for the uranyl ion. A very convenient synthetic procedure that will allow the incorporation of these macrocycles into polymeric systems has been developed for the introduction of a vinyl substituent into the 4-position of the pyridine ring. Using triflate, vinyltributyltin and Pd0 chemistry, this procedure should make a variety of substituted 4-vinylpyridines available for the first time. 3 refs

  20. Natural products as tools for studies of ligand-gated ion channels

    DEFF Research Database (Denmark)

    Strømgaard, Kristian

    2005-01-01

    in the brain. Historically, natural products have been used extensively in biomedical studies and ultimately as drugs or leads for drug design. In studies of ligand-gated ion channels, natural products have been essential for the understanding of their structure and function. In the following a short......Ligand-gated ion channels, or ionotropic receptors, constitute a group of membrane-bound proteins that regulate the flux of ions across the cell membrane. In the brain, ligand-gated ion channels mediate fast neurotransmission. They are crucial for normal brain function and involved in many diseases...... survey of natural products and their use in studies of ligand-gated ion channels is given....

  1. Colloidal metal oxide nanocrystal catalysis by sustained chemically driven ligand displacement

    Science.gov (United States)

    de Roo, Jonathan; van Driessche, Isabel; Martins, José C.; Hens, Zeger

    2016-05-01

    Surface chemistry is a key enabler for colloidal nanocrystal applications. In this respect, metal oxide nanocrystals (NCs) stand out from other NCs as carboxylic acid ligands adsorb on their surface by dissociation to carboxylates and protons, the latter proving essential in electron transfer reactions. Here, we show that this binding motif sets the stage for chemically driven ligand displacement where the binding of amines or alcohols to HfO2 NCs is promoted by the conversion of a bound carboxylic acid into a non-coordinating amide or ester. Furthermore, the sustained ligand displacement, following the addition of excess carboxylic acid, provides a catalytic pathway for ester formation, whereas the addition of esters leads to NC-catalysed transesterification. Because sustained, chemically driven ligand displacement leaves the NCs--including their surface composition--unchanged and preserves colloidal stability, metal oxide nanocrystals are thus turned into effective nanocatalysts that bypass the tradeoff between colloidal stability and catalytic activity.

  2. Design and synthesis of carborane-containing estrogen receptor-beta (ERβ)-selective ligands.

    Science.gov (United States)

    Ohta, Kiminori; Ogawa, Takumi; Oda, Akifumi; Kaise, Asako; Endo, Yasuyuki

    2015-10-01

    Candidates for highly selective estrogen receptor-beta (ERβ) ligands (6a-c, 7a-c, 8a and 8b) were designed and synthesized based on carborane-containing ER ligands 1 and 2 as lead compounds. Among them, p-carboranylcyclohexanol derivatives 8a and 8b exhibited high ERβ selectivity in competitive binding assay: for example, 8a showed 56-fold selectivity for ERβ over ERα. Docking studies of 8a and 8b with the ERα and ERβ ligand-binding domains (LBDs) suggested that the p-carborane cage of the ligands is located close to key amino acid residues that influence ER-subtype selectivity, that is, Leu384 in the ERα LBD and Met336 in the ERβ LBD. The p-carborane cage in 8a and 8b appears to play a crucial role in the increased ERβ selectivity. PMID:26298498

  3. Ligand-receptor Interactions by NMR Spectroscopy

    Directory of Open Access Journals (Sweden)

    Novak. P.

    2008-04-01

    Full Text Available Today NMR spectroscopy is a method of choice for elucidation of interactions between biomolecules and the potential ligands. Knowledge on these interactions is an essential prerequisite for the rational drug design. The most important contribution of NMR to drug design a few years ago was the 3D structure determination of proteins. Besides delivering the 3D structures of the free proteins as a raw material for the modeling studies on ligand binding, NMR can directly yield valuable experimental data on the biologically important protein-ligand complexes. In addition to X-ray diffraction, NMR spectroscopy can provide information on the internal protein dynamics ordynamics of intermolecular interactions. Changes in NMR parameters allow us to detect ("SAR by NMR" and quantitatively determine binding affinities (titration, diffusion NMR experiments, etc. of potential ligands. Also, it is possible to determine the binding site and conformations of ligands, receptors and receptor-ligand complexes with the help of NMR methods such as tr-NOESY. Epitopes or functional groups responsible for binding of ligands to the receptor can be identified by employing STD or WaterLOGSY experiments. In this review are described some of the most frequent NMR methods for the characterization of the interactions between biomolecules and ligands, together with their advantages and disadvantages.

  4. Magnetic nanoparticles linked to a ligand

    OpenAIRE

    Penadés, Soledad; Martín-Lomas, Manuel; Martínez de la Fuente, Jesús; Rademacher, Thomas W.

    2006-01-01

    Materials and methods for making small magnetic particles, e.g. clusters of metal atoms, which can be employed as a substrate for immobilising a plurality of ligands. Also disclosed are uses of these magnetic nanoparticles as therapeutic and diagnostic reagents, and in the study of ligand-mediated interactions.

  5. Electrochemistry of complex combinations with organic ligands

    International Nuclear Information System (INIS)

    The electrochemical behaviour of Cd(2), Ni(2), Fe(2), Fe(3), In(3), Pb(2) complexes with organic bi-and polydentate ligands have been studied by methods of classical and alternating current polarography. Cadmium and indium complexing depending on pH value and the nature of the ligands (bipyridyl isomers, phosphoric acid esters) is discussed

  6. Ligand sphere conversions in terminal carbide complexes

    DEFF Research Database (Denmark)

    Morsing, Thorbjørn Juul; Reinholdt, Anders; Sauer, Stephan P. A.; Bendix, Jesper

    2016-01-01

    Metathesis is introduced as a preparative route to terminal carbide complexes. The chloride ligands of the terminal carbide complex [RuC(Cl)2(PCy3)2] (RuC) can be exchanged, paving the way for a systematic variation of the ligand sphere. A series of substituted complexes, including the first exam...

  7. Influence of the ligand field on slow magnetization relaxation versus spin crossover in mononuclear cobalt complexes.

    Science.gov (United States)

    Habib, Fatemah; Luca, Oana R; Vieru, Veacheslav; Shiddiq, Muhandis; Korobkov, Ilia; Gorelsky, Serge I; Takase, Michael K; Chibotaru, Liviu F; Hill, Stephen; Crabtree, Robert H; Murugesu, Muralee

    2013-10-18

    The electronic and magnetic properties of the complexes [Co(terpy)Cl2 ] (1), [Co(terpy)(NCS)2 ] (2), and [Co(terpy)2 ](NCS)2 (3) were investigated. The coordination environment around Co(II) in 1 and 2 leads to a high-spin complex at low temperature and single-molecule magnet properties with multiple relaxation pathways. Changing the ligand field and geometry with an additional terpy ligand leads to spin-crossover behavior in 3 with a gradual transition from high spin to low spin. PMID:24009214

  8. Passivating ligand and solvent contributions to the electronic properties of semiconductor nanocrystals

    Energy Technology Data Exchange (ETDEWEB)

    Fischer, S.; Crotty, A.; Kilina, S.; Ivanov, I.; Tretiak, S

    2012-01-01

    We examine in detail the impact of passivating ligands (i.e., amines, phosphines, phosphine oxides and pyridines) on the electronic and optical spectra of Cd{sub 33}Se{sub 33} quantum dots (QDs) using density functional theory (DFT) and time-dependent DFT (TDDFT) quantum-chemical methodologies. Most ligand orbitals are found deep inside in the valence and conduction bands of the QD, with pyridine being an exception by introducing new states close to the conduction band edge. Importantly, all ligands contribute states which are highly delocalized over both the QD surface and ligands, forming hybridized orbitals rather than ligand-localized trap states. In contrast, the states close to the band gap are delocalized over the QD atoms only and define the lower energy absorption spectra. The random detachment of one of ligands from the QD surface results in the appearance of a highly localized unoccupied state inside the energy gap of the QD. Such changes in the electronic structure are correlated with the respective QD-ligand binding energy and steric ligand-ligand interactions. Polar solvent significantly reduces both effects leading to delocalization and stabilization of the surface states. Thus, trap and surface states are substantially eliminated by the solvent. Polar solvent also blue-shifts (e.g., 0.3-0.4 eV in acetonitrile) the calculated absorption spectra. This shift increases with an increase of the dielectric constant of the solvent. We also found that the approximate single-particle Kohn-Sham (KS) approach is adequate for calculating the absorption spectra of the ligated QDs. Besides a systematic blue-shift, the KS spectra are in very good agreement with their respective counterparts calculated with the more accurate TDDFT method.

  9. Protein-ligand-based pharmacophores: generation and utility assessment in computational ligand profiling.

    Science.gov (United States)

    Meslamani, Jamel; Li, Jiabo; Sutter, Jon; Stevens, Adrian; Bertrand, Hugues-Olivier; Rognan, Didier

    2012-04-23

    Ligand profiling is an emerging computational method for predicting the most likely targets of a bioactive compound and therefore anticipating adverse reactions, side effects and drug repurposing. A few encouraging successes have already been reported using ligand 2-D similarity searches and protein-ligand docking. The current study describes the use of receptor-ligand-derived pharmacophore searches as a tool to link ligands to putative targets. A database of 68,056 pharmacophores was first derived from 8,166 high-resolution protein-ligand complexes. In order to limit the number of queries, a maximum of 10 pharmacophores was generated for each complex according to their predicted selectivity. Pharmacophore search was compared to ligand-centric (2-D and 3-D similarity searches) and docking methods in profiling a set of 157 diverse ligands against a panel of 2,556 unique targets of known X-ray structure. As expected, ligand-based methods outperformed, in most of the cases, structure-based approaches in ranking the true targets among the top 1% scoring entries. However, we could identify ligands for which only a single method was successful. Receptor-ligand-based pharmacophore search is notably a fast and reliable alternative to docking when few ligand information is available for some targets. Overall, the present study suggests that a workflow using the best profiling method according to the protein-ligand context is the best strategy to follow. We notably present concrete guidelines for selecting the optimal computational method according to simple ligand and binding site properties. PMID:22480372

  10. Lead and the Romans

    Science.gov (United States)

    Reddy, Aravind; Braun, Charles L.

    2010-01-01

    Lead poisoning has been a problem since early history and continues into modern times. An appealing characteristic of lead is that many lead salts are sweet. In the absence of cane and beet sugars, early Romans used "sugar of lead" (lead acetate) to sweeten desserts, fruits, and sour wine. People most at risk would have been those who consumed the…

  11. Novel bispidine ligands with a possible application in nuclear medicine

    International Nuclear Information System (INIS)

    Due to our current way of life and the environmental influences we are exposed in the industrial nations, cancer diseases turn out to be a more and more serious threat to our civilization. The ongoing research during the last decades leads to a better insight in cancer diseases and enables an earlier recognition of developing carcinoma. The detection of pathological tissue changes at an early stage increases the patients' chances of cure. Magnetic resonance tomography (MRT) and computed tomography (CT) as well as radiopharmaceutically assisted imaging techniques, like positron emission tomography (PET) and scintigraphy are an indispensable clinical tool in the oncological early diagnosis. By the development of multimodality imaging agents that combine the benefits of several imaging techniques, the early recognition of tumors can be more efficient and in consequence a matching therapy can be applied. This thesis deals with the synthesis of novel bispidine based ligands and their transition metal complexes as potential mono- and bimodal imaging agents for a 64Cu-assisted radiopharmaceutical application in positron emission tomography (PET) and optical imaging (OI). The synthesized ligands L and LOH are offering the opportunity to build up a ruthenium(II) polypyridine complex by one of the ligand's donor sets, to act as a fluorescence dye for optical imaging (OI), and to coordinate 64CuII by the ligand's vacant cavity for positron emission tomography (PET). The RuII complex exhibits two different fluorescence activities with two different lifetimes and only one of the two fluorescences is quenched by subsequent complexation of CuII. The calculated CuII stability constant of L and LOH is similar to that of the isomeric ligand N2py2 which has been already evaluated as a 64Cu-radiotracer. Further transition metal complexes of FeII, FeIII and MnII are dealing with interesting structural properties like pentagonal bipyramidal geometries. For the development of stable and

  12. Iron-Catalyzed Hydroboration: Unlocking Reactivity through Ligand Modulation.

    Science.gov (United States)

    Espinal-Viguri, Maialen; Woof, Callum R; Webster, Ruth L

    2016-08-01

    Iron-catalyzed hydroboration (HB) of alkenes and alkynes is reported. A simple change in ligand structure leads to an extensive change in catalyst activity. Reactions proceed efficiently over a wide range of challenging substrates including activated, unactivated and sterically encumbered motifs. Conditions are mild and do not require the use of reducing agents or other additives. Large excesses of borating reagent are not required, allowing control of chemo- and regioselectivity in the presence of multiple double bonds. Mechanistic insight reveals that the reaction is likely to proceed via a highly reactive iron hydride intermediate. PMID:27321704

  13. Statistical removal of background signals from high-throughput 1H NMR line-broadening ligand-affinity screens

    International Nuclear Information System (INIS)

    NMR ligand-affinity screens are vital to drug discovery, are routinely used to screen fragment-based libraries, and used to verify chemical leads from high-throughput assays and virtual screens. NMR ligand-affinity screens are also a highly informative first step towards identifying functional epitopes of unknown proteins, as well as elucidating the biochemical functions of protein–ligand interaction at their binding interfaces. While simple one-dimensional 1H NMR experiments are capable of indicating binding through a change in ligand line shape, they are plagued by broad, ill-defined background signals from protein 1H resonances. We present an uncomplicated method for subtraction of protein background in high-throughput ligand-based affinity screens, and show that its performance is maximized when phase-scatter correction is applied prior to subtraction

  14. Ligand-Controlled Synthesis of Azoles via Ir-Catalyzed Reactions of Sulfoxonium Ylides with 2-Amino Heterocycles.

    Science.gov (United States)

    Phelps, Alicia M; Chan, Vincent S; Napolitano, José G; Krabbe, Scott W; Schomaker, Jennifer M; Shekhar, Shashank

    2016-05-20

    An iridium-catalyzed method was developed for the synthesis of imidazo-fused pyrrolopyrazines. The presence or absence of a nitrogenated ligand controlled the outcome of the reaction, leading to simple β-keto amine products in the absence of added ligand and the cyclized 7- and 8-substituted-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine products in the presence of ligand. This catalyst control was conserved across a variety of ylide and amine coupling partners. The substrate was shown to act as a ligand for the iridium catalyst in the absence of other ligands via NMR spectroscopy. Kinetic studies indicated that formation of the Ir-carbene was reversible and the slow step of the reaction. These mechanistic investigations suggest that the β-keto amine products form via an intramolecular carbene N-H insertion, and the imidazopyrrolopyrazines form via an intermolecular carbene N-H insertion. PMID:27104299

  15. Statistical removal of background signals from high-throughput {sup 1}H NMR line-broadening ligand-affinity screens

    Energy Technology Data Exchange (ETDEWEB)

    Worley, Bradley; Sisco, Nicholas J.; Powers, Robert, E-mail: rpowers3@unl.edu [University of Nebraska-Lincoln, Department of Chemistry (United States)

    2015-09-15

    NMR ligand-affinity screens are vital to drug discovery, are routinely used to screen fragment-based libraries, and used to verify chemical leads from high-throughput assays and virtual screens. NMR ligand-affinity screens are also a highly informative first step towards identifying functional epitopes of unknown proteins, as well as elucidating the biochemical functions of protein–ligand interaction at their binding interfaces. While simple one-dimensional {sup 1}H NMR experiments are capable of indicating binding through a change in ligand line shape, they are plagued by broad, ill-defined background signals from protein {sup 1}H resonances. We present an uncomplicated method for subtraction of protein background in high-throughput ligand-based affinity screens, and show that its performance is maximized when phase-scatter correction is applied prior to subtraction.

  16. Jinde Lead lead smelting project starts construction

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    <正>On Dec.20,the lead smelting project of Jiangxi Jinde Lead started construction in Dexin as a technical renovation project on environmental treatment of Jiangxi Metallurgical Group.The project is the one with the largest investment of Provincial Metallurgical Group in non-ferrous

  17. Pacemaker lead design masquerading as lead fracture

    OpenAIRE

    Madhu Gangadhara; Charles Peebles; James Gnanapragasam

    2015-01-01

    Performing chest X-ray is an important annual investigation to check pacemaker lead integrity during follow-up of patients with pacemakers. Understanding lead design is vital to the correct interpretation of X-rays to prevent inappropriate interventions for patients as highlighted in this case.

  18. Improving protein-ligand docking with flexible interfacial water molecules using SWRosettaLigand.

    Science.gov (United States)

    Li, Linqing; Xu, Weiwei; Lü, Qiang

    2015-11-01

    Computational protein-ligand docking is of great importance in drug discovery and design. Conformational changes greatly affect the results of protein-ligand docking, especially when water molecules take part in mediating protein ligand interactions or when large conformational changes are observed in the receptor backbone interface. We have developed an improved protocol, SWRosettaLigand, based on the RosettaLigand protocol. This approach incorporates the flexibility of interfacial water molecules and modeling of the interface of the receptor into the original RosettaLigand. In a coarse sampling step, SWRosettaLigand pre-optimizes the initial position of the water molecules, docks the ligand to the receptor with explicit water molecules, and minimizes the predicted structure with water molecules. The receptor backbone interface is treated as a loop and perturbed and refined by kinematic closure, or cyclic coordinate descent algorithm, with the presence of the ligand. In two cross-docking test sets, it was identified that for 8 out of 14, and 16 out of 22, test instances, the top-ranked structures by SWRosettaLigand achieved better accuracy than other protocols. PMID:26515196

  19. Synthetic and Thermodynamic Investigations of Ancillary Ligand Influence on Catalytic Organometallic Systems. Final Report

    Energy Technology Data Exchange (ETDEWEB)

    Nolan, Steven

    2003-03-20

    During the grant period we have been involved in synthesizing and experimentally determining solution enthalpy values associated with partially fluorinated ligands. This has lead to the publication of manuscripts dealing with synthetic, calorimetric and catalytic behavior of partially fluorinated ligands. The collaboration with Los Alamos researchers has lead to the publication of catalytic results in sc CO{sub 2} which have proven very interesting. Furthermore, we have also examined ligands that behave as phosphine mimics. The N-heterocyclic carbenes have been explored as alternatives for tertiary phosphines and have resulted in the design and construction of efficient palladium and nickel system capable of performing C-C and C-N cross coupling reactions. The initial studies in this areas were made possible by exploratory work conducted under the DOE/EPSCoR grant.

  20. New Proton-Ionizable, Calixarene-Based Ligands for Selective Metal Ion Separations

    Energy Technology Data Exchange (ETDEWEB)

    Bartsch, Richard A.

    2012-06-04

    The project objective was the discovery of new ligands for performing metal ion separations. The research effort entailed the preparation of new metal ion complexing agents and polymers and their evaluation in metal ion separation processes of solvent extraction, synthetic liquid membrane transport, and sorption. Structural variations in acyclic, cyclic, and bicyclic organic ligands were used to probe their influence upon the efficiency and selectivity with which metal ion separations can be performed. A unifying feature of the ligand structures is the presence of one (or more) side arm with a pendent acidic function. When a metal ion is complexed within the central cavity of the ligand, ionization of the side arm(s) produces the requisite anion(s) for formation of an overall electroneutral complex. This markedly enhances extraction/transport efficiency for separations in which movement of aqueous phase anions of chloride, nitrate, or sulfate into an organic medium would be required. Through systematic structural variations, new ligands have been developed for efficient and selective separations of monovalent metal ions (e.g., alkali metal, silver, and thallium cations) and of divalent metal ion species (e.g., alkaline earth metal, lead, and mercury cations). Research results obtained in these fundamental investigations provide important insight for the design and development of ligands suitable for practical metal ion separation applications.

  1. Are superhalogens without halogen ligand capable of transcending traditional halogen-based superhalogens? Ab initio case study of binuclear anions based on pseudohalogen ligand

    International Nuclear Information System (INIS)

    The superhalogen properties of polynuclear structures without halogen ligand are theoretically explored here for several [M2(CN)5]−1 (M =  Ca, Be) clusters. At CCSD(T) level, these clusters have been confirmed to be superhalogens due to their high vertical electron detachment energies (VDE). The largest one is 9.70 eV for [Ca2(CN)5]−1 which is even higher than those of corresponding traditional structures based on fluorine or chlorine ligands. Therefore the superhalogens stronger than the traditional halogen-based structures could be realized by ligands other than halogen atoms. Compared with CCSD(T), outer valence Green’s function (OVGF) method either overestimates or underestimates the VDEs for different structures while MP2 results are generally consistent in the aspect of relative values. The extra electrons of the highest VDE anions here aggregate on the bridging CN units with non-negligible distribution occurring on other CN units too. These two features lower both the potential and kinetic energies of the extra electron respectively and thus lead to high VDE. Besides superhalogen properties, the structures, relative stabilities and thermodynamic stabilities with respect to the detachment of cyanide ligand were also investigated. The sum of these results identifies the potential of polynuclear structures with pseudohalogen ligand as suitable candidates with enhanced superhalogens properties

  2. Ligand Exchange Processes on Solvated Lithium Cations

    OpenAIRE

    Pasgreta, Ewa Maria

    2007-01-01

    In this work the solvation process of Li+ ion, as well as solvent and ligand exchange reactions on Li+ ion were studied. Li+ ions possess interesting properties and like other alkali metal ions are known to form complexes with macrocyclic ligands called cryptands. In this summary, an overview over the insights gained in the factors that control the reactivity of Li+ complexes with respect to the solvent and cryptand properties is presented. Three main questions were addressed: • How does the ...

  3. Chemistry of Marine Ligands and Siderophores

    OpenAIRE

    Vraspir, Julia M.; Butler, Alison

    2009-01-01

    Marine microorganisms are presented with unique challenges to obtain essential metal ions required to survive and thrive in the ocean. The production of organic ligands to complex transition metal ions is one strategy to both facilitate uptake of specific metals, such as iron, and to mitigate the potential toxic effects of other metal ions, such as copper. A number of important trace metal ions are complexed by organic ligands in seawater, including iron, cobalt, nickel, copper, zinc, and cad...

  4. Fas ligand deficiency in HIV disease

    OpenAIRE

    Sieg, Scott; Smith, Dawn; Yildirim, Zafer; Kaplan, David

    1997-01-01

    Apoptosis is postulated to be involved as an anti-viral immune mechanism by killing infected cells before viral replication has occurred. The Fas–Fas ligand interaction is a powerful regulator of T cell apoptosis and could potentially act as a potent anti-viral immune mechanism against T cell tropic virus such as human immunodeficiency virus (HIV). We investigated the status of Fas ligand in peripheral blood mononuclear cells (PBMCs) obtained from persons infected with HIV. We found that mono...

  5. Vesicular Stomatitis Virus Infection Promotes Immune Evasion by Preventing NKG2D-Ligand Surface Expression

    DEFF Research Database (Denmark)

    Jensen, Helle; Andresen, Lars; Nielsen, Jens; Christensen, Jan Pravsgaard; Skov, Søren

    2011-01-01

    leads to a robust induction of MICA mRNA expression, however the subsequent surface expression is potently hindered. Thus, VSV lines up with human cytomegalovirus (HCMV) and adenovirus, which actively subvert the immune system by negatively affecting NKG2D-ligand surface expression. VSV infection caused...

  6. Minireview: More than just a hammer: ligand "bias" and pharmaceutical discovery.

    Science.gov (United States)

    Luttrell, Louis M

    2014-03-01

    Conventional orthosteric drug development programs targeting G protein-coupled receptors (GPCRs) have focused on the concepts of agonism and antagonism, in which receptor structure determines the nature of the downstream signal and ligand efficacy determines its intensity. Over the past decade, the emerging paradigms of "pluridimensional efficacy" and "functional selectivity" have revealed that GPCR signaling is not monolithic, and that ligand structure can "bias" signal output by stabilizing active receptor states in different proportions than the native ligand. Biased ligands are novel pharmacologic entities that possess the unique ability to qualitatively change GPCR signaling, in effect creating "new receptors" with distinct efficacy profiles driven by ligand structure. The promise of biased agonism lies in this ability to engender "mixed" effects not attainable using conventional agonists or antagonists, promoting therapeutically beneficial signals while antagonizing deleterious ones. Indeed, arrestin pathway-selective agonists for the type 1 parathyroid hormone and angiotensin AT1 receptors, and G protein pathway-selective agonists for the GPR109A nicotinic acid and μ-opioid receptors, have demonstrated unique, and potentially therapeutic, efficacy in cell-based assays and preclinical animal models. Conversely, activating GPCRs in "unnatural" ways may lead to downstream biological consequences that cannot be predicted from prior knowledge of the actions of the native ligand, especially in the case of ligands that selectively activate as-yet poorly characterized G protein-independent signaling networks mediated via arrestins. Although much needs to be done to realize the clinical potential of functional selectivity, biased GPCR ligands nonetheless appear to be important new additions to the pharmacologic toolbox. PMID:24433041

  7. Construction of dinuclear complexes using multidentate ligands

    International Nuclear Information System (INIS)

    This work details the synthesis of novel copper(I), copper(II), nickel(II) and zinc(II) dinuclear complexes. Attempts have been made to control the co-ordination architectures of the metal centres by using bis-bidentate and tridentate chelating N,S- and N-donor ligands to generate dinuclear systems. The ligands were both symmetrically and asymmetrically disubstituted pyridazine-based and pyridine-based ligands consisting of a mixture of N-only and mixed N,S-donors. The study using the pyridazine-based ligands continues previous research in our group using 3,6-bis disubstituted pyridazine-based ligands to form complexes with copper(l) and copper(II). The pyridazine-based ligands have been seen to be bis-bidentate upon co-ordination of copper. The pyridazine-based ligands could be envisaged to generate dinuclear complexes by directly bridging between two metal ions. This study involved the formation of copper(l), nickel(II) and zinc(II) complexes with these ligands. The structural properties of two particular complexes have been explored using X-ray crystallography and spectroscopic techniques. Pyridine-based ligands have also been used previously in our group as tridentate chelating ligands. They have been seen to form dinuclear complexes with copper(I) and copper(II) when reacted with an additional bridging ligand e.g. 4,4'-bipyridine. This provides an alternative method for generating dinuclear complexes. Chapter 1 presents an introduction to the area of supramolecular chemistry from which we can learn the principles of polymer formation and them 'in reverse' to generate discrete dinuclear systems. Chapter 2 details the synthesis of the pyridazine and pyridine-based ligands including a detailed nmr study of the ligands. Since the ligands were synthesised using cyclic thioamides as terminal groups it has been found that thiol-thione tautomerisation occurred during synthesis giving rise to two possible ligand conformations. The nmr study has been used to try and

  8. Visualizing ligand molecules in twilight electron density

    International Nuclear Information System (INIS)

    A software script is presented for facilitating the analysis and visual inspection of ligand molecules in the context of the electron-density maps calculated from experimental data associated with protein structures determined by X-ray crystallography. Three-dimensional models of protein structures determined by X-ray crystallography are based on the interpretation of experimentally derived electron-density maps. The real-space correlation coefficient (RSCC) provides an easily comprehensible, objective measure of the residue-based fit of atom coordinates to electron density. Among protein structure models, protein–ligand complexes are of special interest, given their contribution to understanding the molecular underpinnings of biological activity and to drug design. For consumers of such models, it is not trivial to determine the degree to which ligand-structure modelling is biased by subjective electron-density interpretation. A standalone script, Twilight, is presented for the analysis, visualization and annotation of a pre-filtered set of 2815 protein–ligand complexes deposited with the PDB as of 15 January 2012 with ligand RSCC values that are below a threshold of 0.6. It also provides simplified access to the visualization of any protein–ligand complex available from the PDB and annotated by the Uppsala Electron Density Server. The script runs on various platforms and is available for download at http://www.ruppweb.org/twilight//

  9. Designer TGFβ superfamily ligands with diversified functionality.

    Directory of Open Access Journals (Sweden)

    George P Allendorph

    Full Text Available Transforming Growth Factor--beta (TGFβ superfamily ligands, including Activins, Growth and Differentiation Factors (GDFs, and Bone Morphogenetic Proteins (BMPs, are excellent targets for protein-based therapeutics because of their pervasiveness in numerous developmental and cellular processes. We developed a strategy termed RASCH (Random Assembly of Segmental Chimera and Heteromer, to engineer chemically-refoldable TGFβ superfamily ligands with unique signaling properties. One of these engineered ligands, AB208, created from Activin-βA and BMP-2 sequences, exhibits the refolding characteristics of BMP-2 while possessing Activin-like signaling attributes. Further, we find several additional ligands, AB204, AB211, and AB215, which initiate the intracellular Smad1-mediated signaling pathways more strongly than BMP-2 but show no sensitivity to the natural BMP antagonist Noggin unlike natural BMP-2. In another design, incorporation of a short N-terminal segment from BMP-2 was sufficient to enable chemical refolding of BMP-9, without which was never produced nor refolded. Our studies show that the RASCH strategy enables us to expand the functional repertoire of TGFβ superfamily ligands through development of novel chimeric TGFβ ligands with diverse biological and clinical values.

  10. LigandRFs: random forest ensemble to identify ligand-binding residues from sequence information alone

    KAUST Repository

    Chen, Peng

    2014-12-03

    Background Protein-ligand binding is important for some proteins to perform their functions. Protein-ligand binding sites are the residues of proteins that physically bind to ligands. Despite of the recent advances in computational prediction for protein-ligand binding sites, the state-of-the-art methods search for similar, known structures of the query and predict the binding sites based on the solved structures. However, such structural information is not commonly available. Results In this paper, we propose a sequence-based approach to identify protein-ligand binding residues. We propose a combination technique to reduce the effects of different sliding residue windows in the process of encoding input feature vectors. Moreover, due to the highly imbalanced samples between the ligand-binding sites and non ligand-binding sites, we construct several balanced data sets, for each of which a random forest (RF)-based classifier is trained. The ensemble of these RF classifiers forms a sequence-based protein-ligand binding site predictor. Conclusions Experimental results on CASP9 and CASP8 data sets demonstrate that our method compares favorably with the state-of-the-art protein-ligand binding site prediction methods.

  11. Fully Flexible Docking of Medium Sized Ligand Libraries with RosettaLigand

    Science.gov (United States)

    DeLuca, Samuel; Khar, Karen; Meiler, Jens

    2015-01-01

    RosettaLigand has been successfully used to predict binding poses in protein-small molecule complexes. However, the RosettaLigand docking protocol is comparatively slow in identifying an initial starting pose for the small molecule (ligand) making it unfeasible for use in virtual High Throughput Screening (vHTS). To overcome this limitation, we developed a new sampling approach for placing the ligand in the protein binding site during the initial ‘low-resolution’ docking step. It combines the translational and rotational adjustments to the ligand pose in a single transformation step. The new algorithm is both more accurate and more time-efficient. The docking success rate is improved by 10–15% in a benchmark set of 43 protein/ligand complexes, reducing the number of models that typically need to be generated from 1000 to 150. The average time to generate a model is reduced from 50 seconds to 10 seconds. As a result we observe an effective 30-fold speed increase, making RosettaLigand appropriate for docking medium sized ligand libraries. We demonstrate that this improved initial placement of the ligand is critical for successful prediction of an accurate binding position in the ‘high-resolution’ full atom refinement step. PMID:26207742

  12. Syntheses of chelating tetrazole-containing ligands and studies of their palladium (II) and ruthenium (II) complexes

    International Nuclear Information System (INIS)

    Eleven chelating tetrazole-containing ligands have been synthesized, and their complexes with palladium (II) and ruthenium (II) prepared. Proton n.m.r. spectroscopy, electronic absorption spectroscopy and cyclic voltametry have been used to study the nature of the metal-ligand interactions in these complexes. The negatively charged tetrazolate group is shown to be a strong electron donor with very different properties to those of the protonated or alkylated tetrazole group. This leads to pH control of the properties of transition metal complexes containing such ligands. 13 refs., 2 tabs., 3 figs.,ill

  13. Syntheses of chelating tetrazole-containing ligands and studies of their palladium (II) and ruthenium (II) complexes

    Energy Technology Data Exchange (ETDEWEB)

    Downard, A.J.; Steel, P.J.; Steenwijk, J. [Canterbury Univ., Christchurch (New Zealand). Dept. of Chemistry

    1995-12-31

    Eleven chelating tetrazole-containing ligands have been synthesized, and their complexes with palladium (II) and ruthenium (II) prepared. Proton n.m.r. spectroscopy, electronic absorption spectroscopy and cyclic voltametry have been used to study the nature of the metal-ligand interactions in these complexes. The negatively charged tetrazolate group is shown to be a strong electron donor with very different properties to those of the protonated or alkylated tetrazole group. This leads to pH control of the properties of transition metal complexes containing such ligands. 13 refs., 2 tabs., 3 figs.,ill.

  14. Lead inclusions in aluminium

    International Nuclear Information System (INIS)

    Ion implantation at room temperature of lead into aluminum leads to spontaneous phase separation and formation of lead precipitates growing topotactically with the matrix. Unlike the highly pressurized (∼ 1-5 GPa) solid inclusions formed after noble gas implantations, the pressure in the lead precipitates is found to be less than 0.12 GPa. Recently the authors have observed the result that the lead inclusions in aluminum exhibit both superheating and supercooling. In this paper they review and elaborate on these results. Small implantation-induced lead precipitates embedded in an aluminum matrix were studied by x-ray diffraction

  15. Coronary Sinus Lead Extraction.

    Science.gov (United States)

    Cronin, Edmond M; Wilkoff, Bruce L

    2015-12-01

    Expanded indications for cardiac resynchronization therapy and the increasing incidence of cardiac implantable electronic device infection have led to an increased need for coronary sinus (CS) lead extraction. The CS presents unique anatomical obstacles to successful lead extraction. Training and facility requirements for CS lead extraction should mirror those for other leads. Here we review the indications, technique, and results of CS lead extraction. Published success rates and complications are similar to those reported for other leads, although multiple techniques may be required. Re-implantation options may be limited, which should be incorporated into pre-procedural decision making. PMID:26596810

  16. Lead (in the Workplace)

    Science.gov (United States)

    ... to Z Index Contact Us FAQs What's New Lead Health Effects Exposure and Controls General Resources Enforcement ... section of this webpage. Who is Exposed to Lead? OSHA estimates that approximately 804,000 workers in ...

  17. Rapid Lead Screening Test

    Science.gov (United States)

    ... Medical Procedures In Vitro Diagnostics Lab Tests Rapid Lead Screening Test Share Tweet Linkedin Pin it More ... reducing the need for a follow-up visit. Lead Risk Links Centers for Disease Control and Prevention ( ...

  18. Leading Causes of Blindness

    Science.gov (United States)

    ... Issue Past Issues Feature: Vision Leading Causes of Blindness Past Issues / Summer 2008 Table of Contents For ... have cataracts. They are the leading cause of blindness in the world. By age 80, more than ...

  19. VOLUMETRIC LEAD ASSAY

    International Nuclear Information System (INIS)

    This report describes a system for handling and radioassay of lead, consisting of a robot, a conveyor, and a gamma spectrometer. The report also presents a cost-benefit analysis of options: radioassay and recycling lead vs. disposal as waste

  20. Lead and tap water

    Science.gov (United States)

    Water contaminated with lead ... The Environmental Protection Agency (EPA) monitors drinking water in the United States. It requires water suppliers to produce annual water quality reports. These reports include information about lead amounts, and they ...

  1. Lead and tap water

    Science.gov (United States)

    Water contaminated with lead ... The Environmental Protection Agency (EPA) monitors drinking water and requires water suppliers to produce annual water quality reports. These reports, which include information about lead amounts, are available to consumers. For ...

  2. Immobilisation of ligands by radio-derivatized polymers; Immobilisering av ligander med radioderiverte polymerer

    Energy Technology Data Exchange (ETDEWEB)

    Varga, J.M.; Fritsch, P.

    1995-01-30

    The invention relates to radio-derivatized polymers and a method of producing them by contacting non-polymerizable conjugands with radiolysable polymers in the presence of irradiation. The resulting radio-derivatized polymers can be further linked with ligand of organic or inorganic nature to immobilize such ligands. 2 figs., 5 tabs.

  3. NA49: lead-lead collision

    CERN Multimedia

    1996-01-01

    This is an image of an actual lead ion collision taken from tracking detectors on the NA49 experiment, part of the heavy ion project at CERN. These collisions produce a very complicated array of hadrons as the heavy ions break up. It is hoped that one of these collisions will eventually create a new state of matter known as quark-gluon plasma.

  4. An in Vitro and in Vivo Investigation of Bivalent Ligands That Display Preferential Binding and Functional Activity for Different Melanocortin Receptor Homodimers.

    Science.gov (United States)

    Lensing, Cody J; Freeman, Katie T; Schnell, Sathya M; Adank, Danielle N; Speth, Robert C; Haskell-Luevano, Carrie

    2016-04-14

    Pharmacological probes for the melanocortin receptors have been utilized for studying various disease states including cancer, sexual function disorders, Alzheimer's disease, social disorders, cachexia, and obesity. This study focused on the design and synthesis of bivalent ligands to target melanocortin receptor homodimers. Lead ligands increased binding affinity by 14- to 25-fold and increased cAMP signaling potency by 3- to 5-fold compared to their monovalent counterparts. Unexpectedly, different bivalent ligands showed preferences for particular melanocortin receptor subtypes depending on the linker that connected the binding scaffolds, suggesting structural differences between the various dimer subtypes. Homobivalent compound 12 possessed a functional profile that was unique from its monovalent counterpart providing evidence of the discrete effects of bivalent ligands. Lead compound 7 significantly decreased feeding in mice after intracerebroventricular administration. To the best of our knowledge, this is the first report of a melanocortin bivalent ligand's in vivo physiological effects. PMID:26959173

  5. Lead Poisoning (For Parents)

    Science.gov (United States)

    ... Story" 5 Things to Know About Zika & Pregnancy Lead Poisoning KidsHealth > For Parents > Lead Poisoning Print A ... Family en español La intoxicación por plomo About Lead Poisoning If you have young kids, it's important ...

  6. Organotellurium ligands - designing and complexation reactions

    Indian Academy of Sciences (India)

    Ajai K Singh

    2002-08-01

    A variety of tellurium ligands has been designed and studied for their complexation reactions in the last decade. Of these hybrid telluroethers, halotellurium ligands and polytellurides are the most notable ones. RTe- and polytelluride ions have also been used to design clusters. Ligation of ditelluroethers and several hybrid telluroethers is extensively studied in our laboratories. The ditelluroether ligand RTeCH2TeR (where R = 4-MeOC6H4) (1), similar to dppm [1,2-bis(diphenylphosphino) methane], has been synthesized in good yield (∼80 %) by reacting CHCl3 with RTe- (generated in situ by borohydride reduction of R2Te2). Iodine reacts with 1 to give tetra-iodo derivative, which has intermolecular Te$\\cdots$I interactions resulting in a macro structure containing rectangular Te-I$\\cdots$Te bridges. 1 readily forms four membered rings with Pd(II) and Ru(II). On the formation of this chelate ring, the signal in 125Te NMR spectra shifts significantly upfield (50-60 ppm). The bridging mode of 1 has been shown in [Ru(-cymene)Cl2](-1)[Ru(-cymene)Cl2]. The hybrid telluroether ligands explored are of the types (Te, S), (Te, N) and (Te, O). The tellurium donor site has strong trans influence, which is manifested more strongly in square planar complexes of palladium(II). The morpholine N-donor site has been found to have weaker donor characteristics in (Te, N) ligands than pyridine and alkylamine donor sites of analogous ligands. The singlet oxygen readily oxidises the coordinated Te. This oxidation follows first order kinetics. The complexation reaction of RuCl3.H2O with N-[2-(4-methoxyphenyltelluro)ethyl]phthalimide (2) results in a novel (Te, N, O)-heterocycle, Te-chloro,Te-anisyl-1a-aza-4-oxa-3-tellura-1H, 2H, 4aH-9 fluorenone. The (Te, O) ligands can be used as hemilabile ligands, the oxygen atom temporarily protects the vacant coordination site before the arrival of the substrate. The chelate shifts observed in 125Te NMR spectra of metal complexes of Te-ligands have

  7. Sliding tethered ligands add topological interactions to the toolbox of ligand-receptor design

    Science.gov (United States)

    Bauer, Martin; Kékicheff, Patrick; Iss, Jean; Fajolles, Christophe; Charitat, Thierry; Daillant, Jean; Marques, Carlos M.

    2015-09-01

    Adhesion in the biological realm is mediated by specific lock-and-key interactions between ligand-receptor pairs. These complementary moieties are ubiquitously anchored to substrates by tethers that control the interaction range and the mobility of the ligands and receptors, thus tuning the kinetics and strength of the binding events. Here we add sliding anchoring to the toolbox of ligand-receptor design by developing a family of tethered ligands for which the spacer can slide at the anchoring point. Our results show that this additional sliding degree of freedom changes the nature of the adhesive contact by extending the spatial range over which binding may sustain a significant force. By introducing sliding tethered ligands with self-regulating length, this work paves the way for the development of versatile and reusable bio-adhesive substrates with potential applications for drug delivery and tissue engineering.

  8. A new class of PN3-pincer ligands for metal–ligand cooperative catalysis

    KAUST Repository

    Li, Huaifeng

    2014-12-01

    Work on a new class of PN3-pincer ligands for metal-ligand cooperative catalysis is reviewed. While the field of the pyridine-based PN3-transition metal pincer complexes is still relatively young, many important applications of these complexes have already emerged. In several cases, the PN3-pincer complexes for metal-ligand cooperative catalysis result in significantly improved or unprecedented activities. The synthesis and coordination chemistry of PN3-pincer ligands are briefly summarized first to cover the synthetic routes for their preparation, followed by a focus review on their applications in catalysis. A specific emphasis is placed on the later section about the role of PN3-pincer ligands\\' dearomatization-rearomatization steps during the catalytic cycles. The mechanistic insights from density functional theory (DFT) calculations are also discussed.

  9. Impact of receptor clustering on ligand binding

    Directory of Open Access Journals (Sweden)

    Caré Bertrand R

    2011-03-01

    Full Text Available Abstract Background Cellular response to changes in the concentration of different chemical species in the extracellular medium is induced by ligand binding to dedicated transmembrane receptors. Receptor density, distribution, and clustering may be key spatial features that influence effective and proper physical and biochemical cellular responses to many regulatory signals. Classical equations describing this kind of binding kinetics assume the distributions of interacting species to be homogeneous, neglecting by doing so the impact of clustering. As there is experimental evidence that receptors tend to group in clusters inside membrane domains, we investigated the effects of receptor clustering on cellular receptor ligand binding. Results We implemented a model of receptor binding using a Monte-Carlo algorithm to simulate ligand diffusion and binding. In some simple cases, analytic solutions for binding equilibrium of ligand on clusters of receptors are provided, and supported by simulation results. Our simulations show that the so-called "apparent" affinity of the ligand for the receptor decreases with clustering although the microscopic affinity remains constant. Conclusions Changing membrane receptors clustering could be a simple mechanism that allows cells to change and adapt its affinity/sensitivity toward a given stimulus.

  10. Ligand identification using electron-density map correlations

    International Nuclear Information System (INIS)

    An automated ligand-fitting procedure is applied to (Fo − Fc)exp(iϕc) difference density for 200 commonly found ligands from macromolecular structures in the Protein Data Bank to identify ligands from density maps. A procedure for the identification of ligands bound in crystal structures of macromolecules is described. Two characteristics of the density corresponding to a ligand are used in the identification procedure. One is the correlation of the ligand density with each of a set of test ligands after optimization of the fit of that ligand to the density. The other is the correlation of a fingerprint of the density with the fingerprint of model density for each possible ligand. The fingerprints consist of an ordered list of correlations of each the test ligands with the density. The two characteristics are scored using a Z-score approach in which the correlations are normalized to the mean and standard deviation of correlations found for a variety of mismatched ligand-density pairs, so that the Z scores are related to the probability of observing a particular value of the correlation by chance. The procedure was tested with a set of 200 of the most commonly found ligands in the Protein Data Bank, collectively representing 57% of all ligands in the Protein Data Bank. Using a combination of these two characteristics of ligand density, ranked lists of ligand identifications were made for representative (Fo − Fc)exp(iϕc) difference density from entries in the Protein Data Bank. In 48% of the 200 cases, the correct ligand was at the top of the ranked list of ligands. This approach may be useful in identification of unknown ligands in new macromolecular structures as well as in the identification of which ligands in a mixture have bound to a macromolecule

  11. Lead encephalopathy in adults

    Directory of Open Access Journals (Sweden)

    Janapareddy Vijaya Bhaskara Rao

    2014-01-01

    Full Text Available Lead poisoning is a common occupational health hazard in developing countries. We report the varied clinical presentation, diagnostic and management issues in two adult patients with lead encephalopathy. Both patients worked in a battery manufacturing unit. Both patients presented with seizures and one patient also complained of abdominal colic and vomiting. Both were anemic and a lead line was present. Blood lead level in both the patients was greater than 25 µg/dl. Magnetic resonance imaging of brain revealed bilateral symmetric involvement of the thalamus, lentiform nucleus in both patients and also the external capsules, sub-cortical white matter in one patient. All these changes, seen as hyperintensities in T2-weighted images suggested demyelination. They were advised avoidance of further exposure to lead and were treated with anti-epileptics; one patient also received D-penicillamine. They improved well on follow-up. Lead encephalopathy is an uncommon but important manifestation of lead toxicity in adults.

  12. Major advances in the development of histamine H4 receptor ligands.

    Science.gov (United States)

    Smits, Rogier A; Leurs, Rob; de Esch, Iwan J P

    2009-08-01

    The search for new and potent histamine H4 receptor ligands is leading to a steadily increasing number of scientific publications and patent applications. Several interesting and structurally diverse compounds have been found, but fierce IP competition for a preferred 2-aminopyrimidine scaffold is becoming apparent. Recent investigations into the role of the histamine H(4)R in (patho)physiology and the use of H4R ligands in in vivo disease models reveal enormous potential in the field of inflammation and allergy, among others. The development of ligands that display activity at two or more histamine receptor (HR) subtypes is another clinical opportunity that is currently being explored. Taken together, the histamine H4R field is gearing up for clinical studies and has the potential to deliver another generation of blockbuster drugs. PMID:19477292

  13. Histamine H4 receptor ligands: future applications and state of art.

    Science.gov (United States)

    Corrêa, Michelle Fidelis; dos Santos Fernandes, João Paulo

    2015-04-01

    Histamine is a chemical transmitter found practically in whole organism and exerts its effects through the interaction with H1 to H4 histaminergic receptors. Specifically, H4 receptors are found mainly in immune cells and blood-forming tissues, thus are involved in inflammatory and immune processes, as well as some actions in central nervous system. Therefore, H4 receptor ligands can have applications in the treatment of chronic inflammatory and immune diseases and may be novel therapeutic option in these conditions. Several H4 receptor ligands have been described from early 2000's until nowadays, being imidazole, indolecarboxamide, 2-aminopyrimidine, quinazoline, and quinoxaline scaffolds the most explored and discussed in this review. Moreover, several studies of molecular modeling using homology models of H4 receptor and QSAR data of the ligands are summarized. The increasing and promising therapeutic applications are leading these compounds to clinical trials, which probably will be part of the next generation of blockbuster drugs. PMID:25228262

  14. Interaction between ligands in ternary complexes of cadmium(II) with phenanthroline and phenylalkylmalonates in solution

    International Nuclear Information System (INIS)

    The formation and stability of the ternary complexes of cadmium(II) with phenanthroline and malonate, phenylmalonate, benzylmalonate, 2-phenylethylmalonate, and 3-phenylpropylmalonate are studied by the potentiometric pH-titration technique in 40% (v/v) dioxane-water at 25 C and 0.1 mol/l ionic strength (NaNO3). In all systems, there are stable ternary complexes. The complexes possess enhanced stability relative to their statistical values. The possible reasons that lead to these results are discussed in terms of π-electron back donation from metal ions to ligands and the intramolecular ligand-ligand aromatic ring stacking interaction. 1H NMR measurements are used to demonstrate the aromatic ring-stacking interaction. The relative contribution of each interactions to the enhanced stability is also estimated

  15. Effects of PPARγ Ligands on Leukemia

    Directory of Open Access Journals (Sweden)

    Yoko Tabe

    2012-01-01

    Full Text Available Peroxisome proliferator-activated receptors (PPARs and retinoic acid receptors (RARs, members of the nuclear receptor superfamily, are transcription factors that regulate a variety of important cellular functions. PPARs form heterodimers retinoid X receptor (RXR, an obligate heterodimeric partner for other nuclear receptors. Several novel links between retinoid metabolism and PPAR responses have been identified, and activation of PPAR/RXR expression has been shown to increase response to retinoids. PPARγ has emerged as a key regulator of cell growth and survival, whose activity is modulated by a number of synthetic and natural ligands. While clinical trials in cancer patients with thiazolidinediones (TZD have been disappointing, novel structurally different PPARγ ligands, including triterpenoids, have entered clinical arena as therapeutic agents for epithelial and hematopoietic malignancies. Here we shall review the antitumor advances of PPARγ, alone and in combination with RARα ligands in control of cell proliferation, differentiation, and apoptosis and their potential therapeutic applications in hematological malignancies.

  16. Flexible Ligand Docking Using Evolutionary Algorithms

    DEFF Research Database (Denmark)

    Thomsen, Rene

    2003-01-01

    search spaces effectively and is one of the commonly used methods for flexible ligand docking. During the last decade, several EAs using different variation operators have been introduced, such as the ones provided with the AutoDock program. In this paper we evaluate the performance of different EA......The docking of ligands to proteins can be formulated as a computational problem where the task is to find the most favorable energetic conformation among the large space of possible protein–ligand complexes. Stochastic search methods such as evolutionary algorithms (EAs) can be used to sample large...... settings such as choice of variation operators, population size, and usage of local search. The comparison is performed on a suite of six docking problems previously used to evaluate the performance of search algorithms provided with the AutoDock program package. The results from our investigation confirm...

  17. Flexible Ligand Docking Using Differential Evolution

    DEFF Research Database (Denmark)

    Thomsen, René

    2003-01-01

    Molecular docking of biomolecules is becoming an increasingly important part in the process of developing new drugs, as well as searching compound databases for promising drug candidates. The docking of ligands to proteins can be formulated as an optimization problem where the task is to find the...... most favorable energetic conformation among the large space of possible protein-ligand complexes. Stochastic search methods, such as evolutionary algorithms (EAs), can be used to sample large search spaces effectively and is one of the preferred methods for flexible ligand docking. The differential...... evolution algorithm (DE) is applied to the docking problem using the AutoDock program. The introduced DockDE algorithm is compared with the Lamarckian GA (LGA) provided with AutoDock, and the DockEA previously found to outperform the LGA. The comparison is performed on a suite of six commonly used docking...

  18. ALICE: Simulated lead-lead collision

    CERN Multimedia

    2003-01-01

    This track is an example of simulated data modelled for the ALICE detector on the Large Hadron Collider (LHC) at CERN, which will begin taking data in 2008. ALICE will focus on the study of collisions between nuclei of lead, a heavy element that produces many different particles when collided. It is hoped that these collisions will produce a new state of matter known as the quark-gluon plasma, which existed billionths of a second after the Big Bang.

  19. NA49: lead-lead collisions

    CERN Multimedia

    1996-01-01

    This is an image of an actual lead ion collision taken from tracking detectors on the NA49 experiment, part of the heavy ion project at CERN. These collisions produce a very complicated array of hadrons as the heavy ions break up. It is hoped that one of these collisions will eventually create a new state of matter known as the quark-gluon plasma.

  20. Ligands for Ionotropic Glutamate Receptors

    Science.gov (United States)

    Swanson, Geoffrey T.; Sakai, Ryuichi

    Marine-derived small molecules and peptides have played a central role in elaborating pharmacological specificities and neuronal functions of mammalian ionotropic glutamate receptors (iGluRs), the primary mediators of excitatory syn-aptic transmission in the central nervous system (CNS). As well, the pathological sequelae elicited by one class of compounds (the kainoids) constitute a widely-used animal model for human mesial temporal lobe epilepsy (mTLE). New and existing molecules could prove useful as lead compounds for the development of therapeutics for neuropathologies that have aberrant glutamatergic signaling as a central component. In this chapter we discuss natural source origins and pharmacological activities of those marine compounds that target ionotropic glutamate receptors.

  1. Supramolecular architectures constructed using angular bipyridyl ligands

    International Nuclear Information System (INIS)

    This work details the synthesis and characterization of a series of coordination frameworks that are formed using bidentate angular N-donor ligands. Pyrimidine was reacted with metal(ll) nitrate salts. Reactions using Cd(NO3)2 receive particular focus and the analogous reactions using the linear ligand, pyrazine, were studied for comparison. In all cases, two-dimensional coordination networks were prepared. Structural diversity is observed for the Cd(ll) centres including metal-nitrate bridging. In contrast, first row transition metal nitrates form isostructural one-dimensional chains with only the bridging N-donor ligands generating polymeric propagation. The angular ligand, 2,4-bis(4-pyridyl)-1,3,5-triazine (dpt), was reacted with Cd(NO3)2 and Zn(NO3)2. Whereas Zn(NO3)2 compounds exhibit solvent mediated polymorphism, a range of structures were obtained for the reactions with Cd(NO3)2, including the first example of a doubly parallel interpenetrated 4.82 net. 4,7-phenanthroline, was reacted with various metal(ll) nitrates as well as cobalt(ll) and copper(ll) halides. The ability of 4,7-phenanthroline to act as both a N-donor ligand and a hydrogen bond acceptor has been discussed. Reactions of CuSCN with pyrimidine yield an unusual three-dimensional structure in which polymeric propagation is not a result of ligand bridging. The reaction of CuSCN with dpt yielded structural supramolecular isomers. (author)

  2. The first scorpionate ligand based on diazaphosphole.

    Science.gov (United States)

    Mlateček, Martin; Dostál, Libor; Růžičková, Zdeňka; Honzíček, Jan; Holubová, Jana; Erben, Milan

    2015-12-14

    The reaction of PhBCl2 with 1H-1,2,4-λ(3)-diazaphosphole in the presence of NEt3 gives a new scorpionate ligand, phenyl-tris(1,2,4-diazaphospholyl)borate (PhTdap). The coordination behaviour of this ligand toward transition and non-transition metals has been comprehensively studied. In the thallium(I) complex, Tl(PhTdap), κ(2)-N,N bonding supported with intramolecular η(3)-phenyl coordination has been observed in the solid state. Tl(PhTdap) also shows unusual intermolecular π-interactions between five-membered diazaphosphole rings and the thallium atom giving infinite molecular chains in the crystal. In the square planar complex [Pd(C,N-C6H4CH2NMe2)(PhTdap)], κ(2)-bonded scorpionate has been detected in both solution and in the solid state. For other studied compounds with the central metal ion Ti(IV), Mo(II), Mn(I), Fe(II), Ru(II), Co(II), Co(III), Ni(II) and Cd(II), the κ(3)-N,N,N coordination pattern was observed. Electronic properties of PhTdap and its ligand-field strength were elucidated from UV-Vis spectra of transition-metal species. The CH/P replacement on going from tris(pyrazolyl)borate to the ligand PhTdap causes a slight increase in electronic density rendered to the central metal atom. The following order of ligand-field strength has been established: HB(3,5-Me2pz)3 PhB(pz)3 PhB(1,2,4-triazolyl) < PhTdap. The crystal structures of ten metal complexes bearing the new ligand are reported. The possibility of PhTdap coordination through the phosphorus atom is also briefly discussed. PMID:26537349

  3. Nephrotoxicity of cadmium & lead.

    Science.gov (United States)

    Gonick, H C

    2008-10-01

    Cadmium and lead are divalent cations with a propensity to settle in the proximal tubule of the nephron, leading to nephrotoxicity. The pathophysiological results, however, tend to diverge. Cadmium in sufficient cumulative dosage leads to the production of the Fanconi syndrome, a generalized proximal tubular reabsorptive defect thought to be related to inhibition of both ATP production and Na-K-ATPase activity. On the other hand, lead accumulation in the proximal tubule leads to hyperuricaemia and gout, presumably by inhibiting uric acid secretion, and diminished glomerular filteration rate (GFR). Fanconi syndrome is seen unusually only in children and experimental animals. Cadmium nephrotoxicity is heralded by increased excretion of beta2-microglobulin, retinol binding protein and alpha1-microglobulin, indicative of decreased proximal tubule function. Beta2-microglobulinuria is not found in lead nephropathy. In lead nephropathy albuminuria is absent or minimal whereas in cadmium nephropathy albuminuria is variable. From the standpoint of pathology, both entities are characterized by tubulointerstitial disease and fibrosis, but only early lead nephropathy is characterized by the presence of proximal tubule nuclear inclusion bodies, due to the combination of lead with a lead binding-protein. PMID:19106433

  4. Cationic ruthenium alkylidene catalysts bearing phosphine ligands

    OpenAIRE

    Endo, Koji; Grubbs, Robert H.

    2016-01-01

    The discovery of highly active catalysts and the success of ionic liquid immobilized systems have accelerated attention to a new class of cationic metathesis catalysts. We herein report the facile syntheses of cationic ruthenium catalysts bear-ing bulky phosphine ligands. Simple ligand exchange using silver(I) salts of non-coordinating or weakly coordinating anions pro-vided either PPh3 or chelating Ph2P(CH2)nPPh2 (n = 2 or 3) ligated cationic catalysts. The structures of these newly reported...

  5. Ligand Intermediates in Metal-Catalyzed Reactions

    Energy Technology Data Exchange (ETDEWEB)

    Gladysz, John A.

    1999-07-31

    The longest-running goal of this project has been the synthesis, isolation, and physical chemical characterization of homogeneous transition metal complexes containing ligand types believed to be intermediates in the metal-catalyzed conversion of CO/H{sub 2}, CO{sub 2}, CH{sub 4}, and similar raw materials to organic fuels, feedstocks, etc. In the current project period, complexes that contain unusual new types of C{sub x}(carbide) and C{sub x}O{sub y} (carbon oxide) ligands have been emphasized. A new program in homogeneous fluorous phase catalysis has been launched as described in the final report.

  6. LiCABEDS II. Modeling of ligand selectivity for G-protein-coupled cannabinoid receptors.

    Science.gov (United States)

    Ma, Chao; Wang, Lirong; Yang, Peng; Myint, Kyaw Z; Xie, Xiang-Qun

    2013-01-28

    The cannabinoid receptor subtype 2 (CB2) is a promising therapeutic target for blood cancer, pain relief, osteoporosis, and immune system disease. The recent withdrawal of Rimonabant, which targets another closely related cannabinoid receptor (CB1), accentuates the importance of selectivity for the development of CB2 ligands in order to minimize their effects on the CB1 receptor. In our previous study, LiCABEDS (Ligand Classifier of Adaptively Boosting Ensemble Decision Stumps) was reported as a generic ligand classification algorithm for the prediction of categorical molecular properties. Here, we report extension of the application of LiCABEDS to the modeling of cannabinoid ligand selectivity with molecular fingerprints as descriptors. The performance of LiCABEDS was systematically compared with another popular classification algorithm, support vector machine (SVM), according to prediction precision and recall rate. In addition, the examination of LiCABEDS models revealed the difference in structure diversity of CB1 and CB2 selective ligands. The structure determination from data mining could be useful for the design of novel cannabinoid lead compounds. More importantly, the potential of LiCABEDS was demonstrated through successful identification of newly synthesized CB2 selective compounds. PMID:23278450

  7. Multifunctionality and mechanism of ligand binding in a mosquito antiinflammatory protein

    Energy Technology Data Exchange (ETDEWEB)

    Calvo, Eric; Mans, Ben J.; Ribeiro, José M.C.; Andersen, John F.; (NIH)

    2009-04-07

    The mosquito D7 salivary proteins are encoded by a multigene family related to the arthropod odorant-binding protein (OBP) superfamily. Forms having either one or two OBP domains are found in mosquito saliva. Four single-domain and one two-domain D7 proteins from Anopheles gambiae and Aedes aegypti (AeD7), respectively, were shown to bind biogenic amines with high affinity and with a stoichiometry of one ligand per protein molecule. Sequence comparisons indicated that only the C-terminal domain of AeD7 is homologous to the single-domain proteins from A. gambiae, suggesting that the N-terminal domain may bind a different class of ligands. Here, we describe the 3D structure of AeD7 and examine the ligand-binding characteristics of the N- and C-terminal domains. Isothermal titration calorimetry and ligand complex crystal structures show that the N-terminal domain binds cysteinyl leukotrienes (cysLTs) with high affinities (50-60 nM) whereas the C-terminal domain binds biogenic amines. The lipid chain of the cysLT binds in a hydrophobic pocket of the N-terminal domain, whereas binding of norepinephrine leads to an ordering of the C-terminal portion of the C-terminal domain into an alpha-helix that, along with rotations of Arg-176 and Glu-268 side chains, acts to bury the bound ligand.

  8. Lead-Free Piezoelectrics

    CERN Document Server

    Nahm, Sahn

    2012-01-01

    Ecological restrictions in many parts of the world are demanding the elimination of Pb from all consumer items. At this moment in the piezoelectric ceramics industry, there is no issue of more importance than the transition to lead-free materials. The goal of Lead-Free Piezoelectrics is to provide a comprehensive overview of the fundamentals and developments in the field of lead-free materials and products to leading researchers in the world. The text presents chapters on demonstrated applications of the lead-free materials, which will allow readers to conceptualize the present possibilities and will be useful for both students and professionals conducting research on ferroelectrics, piezoelectrics, smart materials, lead-free materials, and a variety of applications including sensors, actuators, ultrasonic transducers and energy harvesters.

  9. Design and synthesis of novel bivalent ligands (MOR and DOR) by conjugation of enkephalin analogues with 4-anilidopiperidine derivatives.

    Science.gov (United States)

    Deekonda, Srinivas; Wugalter, Lauren; Rankin, David; Largent-Milnes, Tally M; Davis, Peg; Wang, Yue; Bassirirad, Neemah M; Lai, Josephine; Kulkarni, Vinod; Vanderah, Todd W; Porreca, Frank; Hruby, Victor J

    2015-10-15

    We describe the design and synthesis of novel bivalent ligands based on the conjugation of 4-anilidopiperidine derivatives with enkephalin analogues. The design of non-peptide analogues is explored with 5-amino substituted (tetrahydronaphthalen-2yl) methyl containing 4-anilidopiperidine derivatives, while non-peptide-peptide ligands are explored by conjugating the C-terminus of enkephalin analogues (H-Xxx-DAla-Gly-Phe-OH) to the amino group of 4-anilidopiperidine small molecule derivatives with and without a linker. These novel bivalent ligands are evaluated for biological activities at μ and δ opioid receptors. They exhibit very good affinities at μ and δ opioid receptors, and potent agonist activities in MVD and GPI assays. Among these the lead bivalent ligand 17 showed excellent binding affinities (0.1 nM and 0.5 nM) at μ and δ opioid receptors respectively, and was found to have very potent agonist activities in MVD (56 ± 5.9 nM) and GPI (4.6 ± 1.9 nM) assays. In vivo the lead bivalent ligand 17 exhibited a short duration of action (<15 min) comparable to 4-anilidopiperidine derivatives, and moderate analgesic activity. The ligand 17 has limited application against acute pain but may have utility in settings where a highly reversible analgesic is required. PMID:26323872

  10. Lead Poison Detection

    Science.gov (United States)

    1976-01-01

    With NASA contracts, Whittaker Corporations Space Science division has developed an electro-optical instrument to mass screen for lead poisoning. Device is portable and detects protoporphyrin in whole blood. Free corpuscular porphyrins occur as an early effect of lead ingestion. Also detects lead in urine used to confirm blood tests. Test is inexpensive and can be applied by relatively unskilled personnel. Similar Whittaker fluorometry device called "drug screen" can measure morphine and quinine in urine much faster and cheaper than other methods.

  11. A review of monoamine transporter-ligand interactions.

    Science.gov (United States)

    Immadisetty, Kalyan; Madura, Jeffry D

    2013-12-01

    Transporters of the monoamines serotonin, dopamine, and norepinephrine are plasma membrane proteins belonging to the neurotransmitter sodium symporter family (NSS). Monoamine transporters (MATs) by facilitating reuptake of neurotransmitters from the synapse into the presynaptic nerve terminal, regulate neurotransmitter chemical signaling and maintain homeostasis. MATs are targets for several psychostimulants such as cocaine and amphetamine; and also for drugs treating several psychiatric disorders such as depression, attention deficit hyperactivity disorder, Parkinson's disease, and schizophrenia. Since, currently available treatment has several limitations and side effects, novel treatment is highly desired. Efforts to develop better treatment have been hampered by the lack of crystal structures for MATs. However, leucine transporter (LeuTAa), a bacterial protein from Aquifex aeolicus, belonging to the same NSS family as MATs has recently been crystallized. LeuTAa is used as a template to develop homology models of MATs, which facilitates understanding of the structure, function and pharmacology of MATs. Experimental methods for drug discovery demand a significant amount of time, effort and money. Efficient utilization of computational techniques hastens the process of drug discovery and also significantly reduces the cost. Assessing the binding affinity of drugs to the receptors is a key aspect of drug design. Free energy calculations compliment the experiment by quantitatively assessing the affinity of ligands to receptors. These methods are highly beneficial in the lead identification and optimization stages of rational drug design. We review the currently available free energy methods to treat protein-ligand interactions along with several free energy studies performed on MATs. PMID:24138394

  12. Mimicking nature: Phosphopeptide enrichment using combinatorial libraries of affinity ligands.

    Science.gov (United States)

    Batalha, Iris L; Zhou, Houjiang; Lilley, Kathryn; Lowe, Christopher R; Roque, Ana C A

    2016-07-29

    Phosphorylation is a reversible post-translational modification of proteins that controls a plethora of cellular processes and triggers specific physiological responses, for which there is a need to develop tools to characterize phosphorylated targets efficiently. Here, a combinatorial library of triazine-based synthetic ligands comprising 64 small molecules has been rationally designed, synthesized and screened for the enrichment of phosphorylated peptides. The lead candidate (coined A8A3), composed of histidine and phenylalanine mimetic components, showed high binding capacity and selectivity for binding mono- and multi-phosphorylated peptides at pH 3. Ligand A8A3 was coupled onto both cross-linked agarose and magnetic nanoparticles, presenting higher binding capacities (100-fold higher) when immobilized on the magnetic support. The magnetic adsorbent was further screened against a tryptic digest of two phosphorylated proteins (α- and β-caseins) and one non-phosphorylated protein (bovine serum albumin, BSA). The MALDI-TOF mass spectra of the eluted peptides allowed the identification of nine phosphopeptides, comprising both mono- and multi-phosphorylated peptides. PMID:27345211

  13. Efficient synthesis of hexahydroindenopyridines and their potential as melatoninergic ligands.

    Science.gov (United States)

    Párraga, Javier; Moreno, Laura; Diaz, Amelia; El Aouad, Noureddine; Galán, Abraham; Sanz, María Jesús; Caignard, Daniel-Henri; Figadère, Bruno; Cabedo, Nuria; Cortes, Diego

    2014-10-30

    Hexahydroindenopyridine (HHIP) is an interesting tricyclic piperidine nucleus that is structurally related to melatonin, a serotonin-derived neurohormone. Melatonin receptor ligands have applications in several cellular, neuroendocrine and neurophysiological disorders, including depression and/or insomnia. We report herein an efficient two-step method to prepare new HHIP via enamine C-alkylation-cyclization. The influence of substituents on the benzene ring and the nitrogen atom on melatoninergic receptors has been studied. Among the 25 synthesized HHIPs, some of them containing methylenedioxy (series 2) and 8-chloro-7-methoxy substituents (series 4) on the benzene ring revealed affinity for the MT1 and/or the MT2 receptors within the nanomolar range or low micromolar. Similar activities were also encountered for those presenting urea (4g), N-aryl (2e) and N-alkyl (2f) acetamide functions. Therefore, new synthesized compounds with a HHIP nucleus have emerged as new promising leads towards the discovery of melatoninergic ligands which could provide new therapeutic agents. PMID:25232966

  14. Lead and the skin

    Energy Technology Data Exchange (ETDEWEB)

    Allen, B.R.; Moore, M.R.; Hunter, J.A.A.

    1975-01-01

    The increasing use of lead will continue to give rise to problems of toxicity. Protective measures have resulted in florid lead poisoning becoming rare. Attention has recently turned to the possibility of prolonged exposure to low doses of lead causing morbidity in the absence of the classical clinical features of poisoning. Lead is absorbed mostly through the lungs and gastrointestinal tract. Some is also absorbed through the skin but with inorganic compounds the amount is small. Shortly after the most widely used compound, tetraethyl lead, was first manufactured, cases of toxicity began to occur. Manufacture was forbidden until plant design produced greater safety. Significant absorption can occur through the skin. The hazard to those handling leaded gasoline in a normal manner is probably small, mainly because 95 percent of a dose applied to the open skin surface evaporates. Hair has been used as a biopsy material to assess lead exposure. The biological effects of lead poisoning are discussed, including the synergistic effects of lead and agents provoking porphyria.

  15. Chronic lead poisoning

    Energy Technology Data Exchange (ETDEWEB)

    Hess, K.; Straub, P.W.

    1974-02-19

    A detailed description is given of the complex pathological picture observed in the case of a worker with 30 years' occupational exposure to lead in an accumulator factory (evolution of the disease, clinical findings, autopsy). In spite of a typical clinical picture, lead is not held responsible for the terminal encephalopathy, in view of the fact that Alzheimer's syndrome was discovered at autopsy. However, the neurovegetative asthenia and progressive kidney disease without hypertonia, but with uraemia, which preceded the encephalopathy are in all probability due to chronic lead poisoning. The article discusses the diagnosis and symptomatology of chronic lead poisoning, encephalopathy and kidney disease.

  16. REVIEW ARTICLE:Future of Lead Chelation – Distribution and Treatment

    Directory of Open Access Journals (Sweden)

    Venkatesh Thuppil

    2012-01-01

    Full Text Available Lead is the major environmental toxin resulting in the ill health and deleterious effect on almost all organs in the human body in a slow and effective manner. The best treatment for lead poisoning is chelation therapy which is next only to prevention. The authors describe the disruption of homeostasis of the human body by lead in various tissues like blood, bones, liver, kidneys and brain; and the ability of lead to enter the cell using calcium channels and calcium receptors like Ca++ dependant K+ ion channels, transient receptor potential channels, T-tubules, calmodulin receptors, inositol trisphosphate receptors and ryanodine receptors. We report a few novel chelating agents like ionophores, decadentate ligands, picolinate ligands, octadentate ligand, allicin, thiamine, that show good potential for being used in chelation therapy. Future of leadpoisoning is a challenge to all and it needs to be meticulously studies to have an economic and health approach.

  17. A versatile dinucleating ligand containing sulfonamide groups

    DEFF Research Database (Denmark)

    Sundberg, Jonas; Witt, Hannes; Cameron, Lisa;

    2014-01-01

    Copper, iron, and gallium coordination chemistries of the new pentadentate bis-sulfonamide ligand 2,6-bis(N-2-pyridylmethylsulfonamido)-4-methylphenol (psmpH3) were investigated. PsmpH3 is capable of varying degrees of deprotonation, and notably, complexes containing the fully trideprotonated...

  18. Supramolecular architectures constructed using angular bipyridyl ligands

    CERN Document Server

    Barnett, S A

    2003-01-01

    This work details the synthesis and characterization of a series of coordination frameworks that are formed using bidentate angular N-donor ligands. Pyrimidine was reacted with metal(ll) nitrate salts. Reactions using Cd(NO sub 3) sub 2 receive particular focus and the analogous reactions using the linear ligand, pyrazine, were studied for comparison. In all cases, two-dimensional coordination networks were prepared. Structural diversity is observed for the Cd(ll) centres including metal-nitrate bridging. In contrast, first row transition metal nitrates form isostructural one-dimensional chains with only the bridging N-donor ligands generating polymeric propagation. The angular ligand, 2,4-bis(4-pyridyl)-1,3,5-triazine (dpt), was reacted with Cd(NO sub 3) sub 2 and Zn(NO sub 3) sub 2. Whereas Zn(NO sub 3) sub 2 compounds exhibit solvent mediated polymorphism, a range of structures were obtained for the reactions with Cd(NO sub 3) sub 2 , including the first example of a doubly parallel interpenetrated 4.8 sup...

  19. Constitutive and ligand-induced TCR degradation

    DEFF Research Database (Denmark)

    von Essen, Marina; Bonefeld, Charlotte Menné; Siersma, Volkert;

    2004-01-01

    divergent models for TCR down-regulation and degradation have been suggested. The aims of this study were to determine the rate constants for constitutive and ligand-induced TCR degradation and to determine whether the TCR subunits segregate or are processed as an intact unit during TCR down-regulation and...

  20. Ligand iron catalysts for selective hydrogenation

    Science.gov (United States)

    Casey, Charles P.; Guan, Hairong

    2010-11-16

    Disclosed are iron ligand catalysts for selective hydrogenation of aldehydes, ketones and imines. A catalyst such as dicarbonyl iron hydride hydroxycyclopentadiene) complex uses the OH on the five member ring and hydrogen linked to the iron to facilitate hydrogenation reactions, particularly in the presence of hydrogen gas.

  1. Identification of ligands for bacterial sensor proteins.

    Science.gov (United States)

    Fernández, Matilde; Morel, Bertrand; Corral-Lugo, Andrés; Rico-Jiménez, Miriam; Martín-Mora, David; López-Farfán, Diana; Reyes-Darias, José Antonio; Matilla, Miguel A; Ortega, Álvaro; Krell, Tino

    2016-02-01

    Bacteria have evolved a variety of different signal transduction mechanisms. However, the cognate signal molecule for the very large amount of corresponding sensor proteins is unknown and their functional annotation represents a major bottleneck in the field of signal transduction. The knowledge of the signal molecule is an essential prerequisite to understand the signalling mechanisms. Recently, the identification of signal molecules by the high-throughput protein screening of commercially available ligand collections using differential scanning fluorimetry has shown promise to resolve this bottleneck. Based on the analysis of a significant number of different ligand binding domains (LBDs) in our laboratory, we identified two issues that need to be taken into account in the experimental design. Since a number of LBDs require the dimeric state for ligand recognition, it has to be assured that the protein analysed is indeed in the dimeric form. A number of other examples demonstrate that purified LBDs can contain bound ligand which prevents further binding. In such cases, the apo-form can be generated by denaturation and subsequent refolding. We are convinced that this approach will accelerate the functional annotation of sensor proteins which will help to understand regulatory circuits in bacteria. PMID:26511375

  2. Circulating amounts of osteoprotegerin and RANK ligand

    DEFF Research Database (Denmark)

    Abrahamsen, Bo; Hjelmborg, Jacob Vb; Kostenuik, Paul;

    2005-01-01

    UNLABELLED: Osteoprotegerin (OPG) is a circulating receptor that inhibits osteoclastogenesis by binding to RANK ligand (RANKL). OPG knock-out animals develop severe osteoporosis. Treatment with OPG lowers bone resorption and increases BMD. OPG production is influenced by a wide range of hormones ...

  3. Developmental immunotoxicology of lead

    International Nuclear Information System (INIS)

    The heavy metal, lead, is a known developmental immunotoxicant that has been shown to produce immune alterations in humans as well as other species. Unlike many compounds that exert adverse immune effects, lead exposure at low to moderate levels does not produce widespread loss of immune cells. In contrast, changes resulting from lead exposure are subtle at the immune cell population level but, nevertheless, can be functionally dramatic. A hallmark of lead-induced immunotoxicity is a pronounced shift in the balance in T helper cell function toward T helper 2 responses at the expense of T helper 1 functions. This bias alters the nature and range of immune responses that can be produced thereby influencing host susceptibility to various diseases. Immunotoxic responses to lead appear to differ across life stages not only quantitatively with regard to dose response, but also qualitatively in terms of the spectrum of immune alterations. Experimental studies in several lab animal species suggest the latter stages of gestation are a period of considerable sensitivity for lead-induced immunotoxicity. This review describes the basic characteristics of lead-induced immunotoxicity emphasizing experimental animal results. It also provides a framework for the consideration of toxicant exposure effects across life stages. The existence of and probable basis for developmental windows of immune hyper-susceptibility are presented. Finally, the potential for lead to serve as a perinatal risk factor for childhood asthma as well as other diseases is considered

  4. LEAD IN CANDLE EMISSIONS

    Science.gov (United States)

    The candle-using public should be made aware that the core of candle wicks may contain lead. Used as a stiffening agent to keep the wick out of the molten wax, lead can be emitted as particulate to the air and then deposited on indoor surfaces. To define the problem, 100 sets of ...

  5. Leading Educational Change Wisely

    Science.gov (United States)

    Forrester, Gillian

    2011-01-01

    In this article, the author reviews Christopher Branson's book entitled "Leading Educational Change Wisely". The book provides an alternative and engaging perspective on leading educational change. Branson utilises "wisdom" as its central conceptual device to present a thought-provoking and philosophical account on how leaders are able to build a…

  6. Decontaminating radioactive lead solids

    International Nuclear Information System (INIS)

    Lead has been and continues to be used extensively at nuclear facilities and DOE/DOD sites to shield workers from ionizing radiation. Because it is often used in highly contaminated areas, the lead itself often becomes radioactively contaminated, thus creating a Mixed Waste. If the lead is contaminated above specified limits, it must be decontaminated prior to release for unrestricted use. In most cases, where the lead cannot be decontaminated using conventional methods, the lead is stored until a viable decontamination method and/or disposal alternative is determined. At many facilities, large quantities of stored lead are creating a significant problem. The U.S. EPA treatment standard for radioactive lead is, 'Macroencapsulafion with surface coating materials such as polymeric organics (e.g. resins and plastics) or with a jacket of inert inorganic materials to substantially reduce surface exposure to potential leaching media'. Since the Toxicity Characteristic Leaching Procedure (TCLP) requires size reduction to less than 9.5 mm particles for solid waste, macroencapsulation is not a practical or economically feasible option for processing lead. The U.S. EPA originally proposed 'Surface Deactivation' as the treatment standard. Because there exists no demonstrated available technology, this method was dropped from the final treatment standard. (author)

  7. Studies on ligand exchange reaction of functionalized mercaptothiadiazole compounds onto citrate capped gold nanoparticles

    International Nuclear Information System (INIS)

    Mercaptothiadiazole ligands functionalized with thiol (2,5-dimercapto-1,3,4-thiadiazole (DMT)) and methyl (5-methyl-2-mercapto-1,3,4-thiadiazole (MMT)) groups capped onto citrate capped gold nanoparticles (C-AuNPs) by ligand exchange reaction was investigated by UV-vis spectroscopy, FT-IR spectroscopy and transmission electron microscopy (TEM) techniques. The surface plasmon resonance band at 522 nm for C-AuNPs was shifted to 530 nm after capping with DMT whereas an additional band was observed at 630 nm due to aggregation in addition to a shift in the band at 522 nm after capping of MMT onto C-AuNPs. Thus, capping of DMT onto C-AuNPs leads to the formation of stable AuNPs while capping of MMT leads to the formation of unstable AuNPs. FT-IR studies show that the citrate ions were completely replaced by both DMT and MMT ligands from the AuNPs. TEM images indicate that the size and shape of the AuNPs remain same after capping of these ligands.

  8. Tuning the spin state of iron phthalocyanine by ligand adsorption

    Energy Technology Data Exchange (ETDEWEB)

    Isvoranu, C; Ataman, E; Knudsen, J; Andersen, J N; Schnadt, J [Division of Synchrotron Radiation Research, Department of Physics, Lund University, Box 118, SE-221 00 Lund (Sweden); Wang, B; Bocquet, M L [Laboratoire de chimie, Ecole normale superieure de Lyon, 46 Allee d' Italie, F-69364 Lyon Cedex 07 (France); Schulte, K, E-mail: joachim.schnadt@sljus.lu.s [MAX-lab, Lund University, Box 118, SE-221 00 Lund (Sweden)

    2010-12-01

    The future use of single-molecule magnets in applications will require the ability to control and manipulate the spin state and magnetization of the magnets by external means. There are different approaches to this control, one being the modification of the magnets by adsorption of small ligand molecules. In this paper we use iron phthalocyanine supported by an Au(111) surface as a model compound and demonstrate, using x-ray photoelectron spectroscopy and density functional theory, that the spin state of the molecule can be tuned to different values (S {approx} 0, 1/2, 1) by adsorption of ammonia, pyridine, carbon monoxide or nitric oxide on the iron ion. The interaction also leads to electronic decoupling of the iron phthalocyanine from the Au(111) support. (fast track communication)

  9. Ammonia formation by metal-ligand cooperative hydrogenolysis of a nitrido ligand

    Science.gov (United States)

    Askevold, Bjorn; Nieto, Jorge Torres; Tussupbayev, Samat; Diefenbach, Martin; Herdtweck, Eberhardt; Holthausen, Max C.; Schneider, Sven

    2011-07-01

    Bioinspired hydrogenation of N2 to ammonia at ambient conditions by stepwise nitrogen protonation/reduction with metal complexes in solution has experienced remarkable progress. In contrast, the highly desirable direct hydrogenation with H2 remains difficult. In analogy to the heterogeneously catalysed Haber-Bosch process, such a reaction is conceivable via metal-centred N2 splitting and unprecedented hydrogenolysis of the nitrido ligands to ammonia. We report the synthesis of a ruthenium(IV) nitrido complex. The high nucleophilicity of the nitrido ligand is demonstrated by unusual N-C coupling with π-acidic CO. Furthermore, the terminal nitrido ligand undergoes facile hydrogenolysis with H2 at ambient conditions to produce ammonia in high yield. Kinetic and quantum chemical examinations of this reaction suggest cooperative behaviour of a phosphorus-nitrogen-phosphorus pincer ligand in rate-determining heterolytic hydrogen splitting.

  10. Substrate coated with receptor and labelled ligand for assays

    International Nuclear Information System (INIS)

    Improvements in the procedures for assaying ligands are described. The assay consists of a polystyrene tube on which receptors are present for both the ligand to be assayed and a radioactively labelled form of the ligand. The receptors on the bottom portion of the tube are also coated with labelled ligands, thus eliminating the necessity for separate addition of the labelled ligand and sample during an assay. Examples of ligands to which this method is applicable include polypeptides, nucleotides, nucleosides and proteins. Specific examples are given in which the ligand to be assayed is digoxin, the labelled form of the ligand is 3-0-succinyl digoxyigenin tyrosine (125I) and the receptor is digoxin antibody. (U.K.)

  11. Role of ligand-ligand vs. core-core interactions in gold nanoclusters.

    Science.gov (United States)

    Milowska, Karolina Z; Stolarczyk, Jacek K

    2016-05-14

    The controlled assembly of ligand-coated gold nanoclusters (NCs) into larger structures paves the way for new applications ranging from electronics to nanomedicine. Here, we demonstrate through rigorous density functional theory (DFT) calculations employing novel functionals accounting for van der Waals forces that the ligand-ligand interactions determine whether stable assemblies can be formed. The study of NCs with different core sizes, symmetry forms, ligand lengths, mutual crystal orientations, and in the presence of a solvent suggests that core-to-core van der Waals interactions play a lesser role in the assembly. The dominant interactions originate from combination of steric effects, augmented by ligand bundling on NC facets, and related to them changes in electronic properties induced by neighbouring NCs. We also show that, in contrast to standard colloidal theory approach, DFT correctly reproduces the surprising experimental trends in the strength of the inter-particle interaction observed when varying the length of the ligands. The results underpin the importance of understanding NC interactions in designing gold NCs for a specific function. PMID:27097887

  12. Ligand binding was acquired during evolution of nuclear receptors

    OpenAIRE

    Escriva, Hector; Safi, Rachid; Hänni, Catherine; Langlois, Marie-Claire; Saumitou-Laprade, Pierre; Stehelin, Dominique; Capron, André; Pierce, Raymond; Laudet, Vincent

    1997-01-01

    The nuclear receptor (NR) superfamily comprises, in addition to ligand-activated transcription factors, members for which no ligand has been identified to date. We demonstrate that orphan receptors are randomly distributed in the evolutionary tree and that there is no relationship between the position of a given liganded receptor in the tree and the chemical nature of its ligand. NRs are specific to metazoans, as revealed by a screen of NR-related sequences in early- and non-metazoan organism...

  13. LEADS-PEP

    DEFF Research Database (Denmark)

    Hauser, Alexander Sebastian; Windshügel, Björn

    2016-01-01

    tools, an independently constructed benchmark data set is urgently needed. Here we present the LEADS-PEP benchmark data set for assessing peptide docking performance. Using a rational and unbiased workflow, 53 protein-peptide complexes with peptide lengths ranging from 3 to 12 residues were selected....... The data set is publicly accessible at www.leads-x.org . In a second step we evaluated several small molecule docking programs for their potential to reproduce peptide conformations as present in LEADS-PEP. While most tested programs were capable to generate native-like binding modes of small peptides...

  14. {beta}-adrenergic receptor density and adenylate cyclase activity in lead-exposed rat brain after cessation of lead exposure

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Huoy-Rou [I-Shou University, Department of Biomedical Engineering, Dashu Shiang, Kaohsiung County (Taiwan); Tsao, Der-An [Fooyin University of Technology, Department of Medical Technology (Taiwan); Yu, Hsin-Su [Taiwan University, Department of Dermatology, College of Medicine (Taiwan); Ho, Chi-Kung [Kaohsiung Medical University, Occupational Medicine (Taiwan); Kaohsiung Medical University, Graduate Institute of Medicine, Research Center for Occupational Disease (Taiwan)

    2005-01-01

    To understanding the reversible or irreversible harm to the {beta}-adrenergic system in the brain of lead-exposed rats, this study sets up an animal model to estimate the change in the sympathetic nervous system of brain after lead exposure was withdrawn. We address the following topics in this study: (a) the relationship between withdrawal time of lead exposure and brain {beta}-adrenergic receptor, blood lead level, and brain lead level in lead-exposed rats after lead exposure was stopped; and (b) the relationship between lead level and {beta}-adrenergic receptor and cyclic AMP (c-AMP) in brain. Wistar rats were chronically fed with 2% lead acetate and water for 2 months. Radioligand binding was assayed by a method that fulfilled strict criteria of {beta}-adrenergic receptor using the ligand [{sup 125}I]iodocyanopindolol. The levels of lead were determined by electrothermal atomic absorption spectrometry. The c-AMP level was determined by radioimmunoassay. The results showed a close relationship between decreasing lead levels and increasing numbers of brain {beta}-adrenergic receptors and brain adenylate cyclase activity after lead exposure was withdrawn. The effect of lead exposure on the {beta}-adrenergic system of the brain is a partly reversible condition. (orig.)

  15. Lead User Innovation

    DEFF Research Database (Denmark)

    Brem, Alexander; Larsen, Henry

    2015-01-01

    User innovation and especially the integration of lead users is a key topic in the innovation management literature of recent years. This paper contributes by providing a rare perspective into what easily could be seen as innovation failure, shown from two perspectives. We show how a lack of shared...... imagination hampers participation and kills innovation between interdependent stakeholders at the threshold between invention and innovation in practice. We present a first case in the fun-sport industry where an external lead user and diverse firm representatives in different functions fail to create......, deliver and capture the value of an innovatively new device together. From the perspective of the lead user, we show antecedents and effects of social interaction between organizational actors and the lead user on the development of social capital, especially trust and shared imagination. The second case...

  16. Compressor leading edges

    OpenAIRE

    Goodhand, Martin

    2011-01-01

    Compressor blades often have a small 'spike' in the surface pressure distribution at the leading edge. This may result from blade erosion, manufacture defects or compromises made in the original design process. In this thesis it is shown that these spikes will increase the loss generated by a blade only when they become large enough to initiate boundary layer transition at the leading edge through a separation bubble; this process increases profile loss by about 30%. A criterion is presen...

  17. Lead poisoning in dogs

    International Nuclear Information System (INIS)

    Lead poisoning was diagnosed and studied in 60 dogs. It was found that lead poisoning is a common disease of young dogs, especially in the summer and fall, and is related to their chewing and eating habits resulting in the ingestion of paint, linoleum, or other lead-containing materials. The signs were characterized by gastrointestinal dysfunction (colic, vomiting, and diarrhea) and nervous disorders (convulsions, hysteria, nervousness, behavioral changes). The blood findings, which the authors consider nearly pathognomonic, consisted of numerous stippled and immature (especially nucleated) erythrocytes in the absence of severe anemia. Protein and casts were frequently found in the urine. Radiography sometimes revealed lead-containing particles in the gastro-intestinal tract, and lead lines were occasionally detected in the metaphysis of long bones in immature dogs. Treatment with calcium ethylenediamine-tetraacetic acid resulted in rapid and often dramatic recoveries in nearly all instances. Removal of lead from the gastrointestinal tract and treatment to relieve pronounced central nervous disorders was sometimes necessary. 40 references, 6 figures, 7 tables

  18. Coordination- and Redox-Noninnocent Behavior of Ambiphilic Ligands Containing Antimony.

    Science.gov (United States)

    Jones, J Stuart; Gabbaï, François P

    2016-05-17

    transition metals. Although coordinated to a metal, the antimony centers in these complexes retain residual Lewis acidity, as evidenced by their ability to participate in anion binding. Anion binding events at the antimony center have been shown by structural, spectroscopic, and theoretical studies to perturb the antimony-transition metal interaction and in some cases to trigger reactivity at the metal center. Coordinated Sb(III) centers in polydentate ligands have also been found to readily undergo two-electron oxidation, generating strongly Lewis acidic Sb(V) centers in the coordination sphere of the metal. Theoretical studies suggest that oxidation of the coordinated antimony center induces an umpolung of the antimony-metal bond, resulting in depletion of electron density at the metal center. In addition to elucidating the fundamental coordination and redox chemistry of antimony-containing ambiphilic ligands, our work has demonstrated that these unusual behaviors show promise for use in a variety of applications. The ability of coordinated antimony centers to bind anions has been exploited for sensing applications, in which anion coordination at antimony leads to a colorimetric response via a change in the geometry about the metal center. In addition, the capacity of antimony Lewis acids to modulate the electron density of coordinated metals has proved to be key in facilitating photochemical activation of M-X bonds as well as antimony-centered redox-controlled catalysis. PMID:27092722

  19. Mechanistic Characterization and Designing Possible Molecular Ligand Interactions with RdRp from CHIKV

    Directory of Open Access Journals (Sweden)

    D. P. Jobidhas

    2013-04-01

    Full Text Available To date, no suitable vaccine or specific antiviral drug is available to treat Chikungunya viral (CHIKV fever. Hence, it is essential to identify drug candidates that could potentially impede CHIKV infection. The present study focused with the development of Designing Possible Docking and Molecular Ligand Interactions with RdRp from CHIK-V protein based on the crystal structure. When, Rifapentine was interact with RdRp viral protein which were clearly showed the significantly excellent glide score of -5.690530 (Kcal/mol as well as poor glide score of 2.874727 (Kcal/mol. The docking results showed that among the four ligand molecules Efavirenz have the lowest binding values among the other ligands because it has residue contact with total of 13 residues. Two of them were Glut-31, Glut-46, which are catalytic site residues. It is expected that this ligand could prevented the catalytic process. Rimantadine peptide has hydrogen bond interaction with five other residues and them binded with GLU-28, ASP-38 and ILE-45. Based on docking result visualization, it is known that Rifapentine and Rifampin peptide ligand was bound with RdRp enzyme inside the cavity also viral RNA entry when it covets to begin initiation and elongation process. From this study clearly revealed, the ligands such as Rifapentine, Rifampin and Rimantadine may inhibit the RNA dependent RNA polymerase protein activity in chikungunya virus. Furthermore, the backbone structural scaffolds of these four lead compounds could serve as building blocks when designing drug-like molecules for the treatment of Chikungunya viral fever.

  20. Prospects for Thermal Atomic Layer Etching Using Sequential, Self-Limiting Fluorination and Ligand-Exchange Reactions.

    Science.gov (United States)

    George, Steven M; Lee, Younghee

    2016-05-24

    Thermal atomic layer etching (ALE) of Al2O3 and HfO2 using sequential, self-limiting fluorination and ligand-exchange reactions was recently demonstrated using HF and tin acetylacetonate (Sn(acac)2) as the reactants. This new thermal pathway for ALE represents the reverse of atomic layer deposition (ALD) and should lead to isotropic etching. Atomic layer deposition and ALE can together define the atomic layer growth and removal steps required for advanced semiconductor fabrication. The thermal ALE of many materials should be possible using fluorination and ligand-exchange reactions. The chemical details of ligand-exchange can lead to selective ALE between various materials. Thermal ALE could produce conformal etching in high-aspect-ratio structures. Thermal ALE could also yield ultrasmooth thin films based on deposit/etch-back methods. Enhancement of ALE rates and possible anisotropic ALE could be achieved using radicals or ions together with thermal ALE. PMID:27216115

  1. Magnesium Diboride Current Leads

    Science.gov (United States)

    Panek, John

    2010-01-01

    A recently discovered superconductor, magnesium diboride (MgB2), can be used to fabricate conducting leads used in cryogenic applications. Dis covered to be superconducting in 2001, MgB2 has the advantage of remaining superconducting at higher temperatures than the previously used material, NbTi. The purpose of these leads is to provide 2 A of electricity to motors located in a 1.3 K environment. The providing environment is a relatively warm 17 K. Requirements for these leads are to survive temperature fluctuations in the 5 K and 11 K heat sinks, and not conduct excessive heat into the 1.3 K environment. Test data showed that each lead in the assembly could conduct 5 A at 4 K, which, when scaled to 17 K, still provided more than the required 2 A. The lead assembly consists of 12 steelclad MgB2 wires, a tensioned Kevlar support, a thermal heat sink interface at 4 K, and base plates. The wires are soldered to heavy copper leads at the 17 K end, and to thin copper-clad NbTi leads at the 1.3 K end. The leads were designed, fabricated, and tested at the Forschungszentrum Karlsruhe - Institut foer Technische Physik before inclusion in Goddard's XRS (X-Ray Spectrometer) instrument onboard the Astro-E2 spacecraft. A key factor is that MgB2 remains superconducting up to 30 K, which means that it does not introduce joule heating as a resistive wire would. Because the required temperature ranges are 1.3-17 K, this provides a large margin of safety. Previous designs lost superconductivity at around 8 K. The disadvantage to MgB2 is that it is a brittle ceramic, and making thin wires from it is challenging. The solution was to encase the leads in thin steel tubes for strength. Previous designs were so brittle as to risk instrument survival. MgB2 leads can be used in any cryogenic application where small currents need to be conducted at below 30 K. Because previous designs would superconduct only at up to 8 K, this new design would be ideal for the 8-30 K range.

  2. Leaching behavior of butanedionedioxime as gold ligand

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Butanedionedioxime, a small organic compound with low-toxicity and good chemical stability, has been proposed as an effective gold ligand in gold extraction. The result of experiment shows that: 1) highly effective gold lixiviantcan be composed of butanedionedioxime (BDM) with many oxidants, especially potassium permanganate; 2)in the leaching system of BD M- K M nO4 the suitable Ox/Lig(ratio of oxidants to gold ligands) tange is 0.20 ~ 0. 50, optimally 0.25 ~0.45 at the pH range of 7 ~ 11; 3) BDM-KMnO4 extraction of gold from an oxide ore is similar to cyanide(cyanide-O2)extraction, but the leaching rate of gold by BDM-KMnO4 is faster than that by cyanide-O2; 4) gold may readily be recov-ered by carbon adsorption and zinc precipitation

  3. Environmental lead in Mexico

    Energy Technology Data Exchange (ETDEWEB)

    Albert, L.A.; Badillo, F. (Centro de Ecodesarrollo (Mexico))

    1991-01-01

    From the data presented here, it can be concluded that environmental exposure to lead is a particularly severe problem in Mexico. As has been shown, there are very important sources of exposure to this metal: (a) for rural populations who manufacture and/or utilize lead-glazed pottery, (b) for urban populations who are exposed to high air lead concentrations due to the continued use of lead fuel additives, (c) for workers of several industries, mainly those of batteries and pigments, (d) for consumers who routinely eat canned foods such as hot peppers and fruit products, and (e) for the general population living in the vicinity of smelters, refineries and other industries that emit lead. Therefore, in Mexico only those native populations living in very primitive communities, far away from all civilized life, could be expected to be free from this exposure. At the same time, and despite the relatively few data available, it can be stated that the exposure to lead of populations in Mexico could be approaching levels that might be highly hazardous, in particular for the neuropsychological health of children. Regarding the presence of lead in the environment, despite the fact that the available studies are not enough, it is evident that pollution by this metal is widespread and that there is a serious lack of studies for most regions of the country, including several that might be expected to be highly polluted. At the same time, it is evident that the official attention paid to the problem, either in regulations, support of further studies, or implementation of effective control measures has been far from the level needed according to the available data.

  4. Natural ligands of nuclear receptors. Isolation, design, synthesis, biochemical decodification and potential therapeutic applications.

    OpenAIRE

    Ummarino, Raffaella

    2013-01-01

    Natural products have historically been a rich source of lead compounds in drug discovery. The biochemical investigation of marine organisms, through the deep collaboration between chemists and pharmacologists, focused on searching of new biologically active compounds, is a central issue of this kind of studies. My research work, described in this PhD thesis, has been developed in this research area and was addressed to the identification of new ligands of nuclear receptors, discovering ...

  5. Bone marrow transplantation for CD40 ligand deficiency: a single centre experience

    OpenAIRE

    Khawaja, K; Gennery, A; Flood, T; Abinun, M; CANT, A.

    2001-01-01

    BACKGROUND—CD40 ligand (CD40L) deficiency is a rare X linked immunodeficiency disorder leading to recurrent bacterial infection, with cryptosporidial enteritis and subsequent hepatic cirrhosis. Bone marrow transplantation offers the only cure.
OBJECTIVE—To analyse retrospectively the outcome of bone marrow transplantation for this condition in one centre.
DESIGN—A retrospective case note analysis was performed, identifying all patients with CD40L deficiency who had und...

  6. Selective oxoanion separation using a tripodal ligand

    Energy Technology Data Exchange (ETDEWEB)

    Custelcean, Radu; Moyer, Bruce A.; Rajbanshi, Arbin

    2016-02-16

    The present invention relates to urea-functionalized crystalline capsules self-assembled by sodium or potassium cation coordination and by hydrogen-bonding water bridges to selectively encapsulate tetrahedral divalent oxoanions from highly competitive aqueous alkaline solutions and methods using this system for selective anion separations from industrial solutions. The method involves competitive crystallizations using a tripodal tris(urea) functionalized ligand and, in particular, provides a viable approach to sulfate separation from nuclear wastes.

  7. Polyfluoroalkylated tripyrazolylmethane ligands: Synthesis and complexes

    Czech Academy of Sciences Publication Activity Database

    Skalická, V.; Rybáčková, M.; Skalický, M.; Kvíčalová, Magdalena; Cvačka, Josef; Březinová, Anna; Čejka, J.; Kvíčala, J.

    2011-01-01

    Roč. 132, č. 7 (2011), s. 434-440. ISSN 0022-1139 R&D Projects: GA MŠk ME 857; GA MŠk ME09114 Institutional research plan: CEZ:AV0Z40320502; CEZ:AV0Z40550506 Keywords : tripyrazolylmethane * Tpm * tripyrazolylethanol * fluorinated * perfluoroalkylation * ligand Subject RIV: CC - Organic Chemistry Impact factor: 2.033, year: 2011

  8. Predictors of DMSA chelatable lead, tibial lead, and blood lead in 802 Korean lead workers

    OpenAIRE

    Todd, A; Lee, B; Lee, G.; Ahn, K; Moshier, E; Schwartz, B.

    2001-01-01

    OBJECTIVES—To examine the interrelations among chelatable lead (by dimercaptosuccinic acid, DMSA), tibial lead, and blood lead concentrations in 802 Korean workers with occupational exposure to lead and 135 employed controls with only environmental exposure to lead.
METHODS—This was a cross sectional study wherein tibial lead, DMSA chelatable lead, and blood lead were measured. Linear regression was used to identify predictors of the three lead biomarkers, evaluating the influence of age, job...

  9. PENCIL LEAD FIELD EMITTER

    OpenAIRE

    Khairnar, R.; Joag, D.

    1989-01-01

    Field electron emission from 2H and HB grades of pencil lead has been studied. The pencil lead field emitter is found to obey the Fowler-Nordheim characteristics. The emission current fluctuations are found to increase with the residual gas pressure and the emission current. The current density of the order of 106 amp/cm2 could be drawn from these emitters. The emission stability over the operation of six hours has been found to be reasonably good. The field ion microscopy of the 2H and HB gr...

  10. Magnesite growth inhibition by organic ligands: An experimental study at 100, 120 and 146 °C

    Science.gov (United States)

    Gautier, Quentin; Bénézeth, Pascale; Schott, Jacques

    2016-05-01

    It has been proposed that simple organic ligands, which accelerate Mg-silicates dissolution, could be used to accelerate CO2 mineral sequestration through mineral carbonation. The influence of these ligands on magnesite growth has however never been quantified. In this work, we investigated the influence of three organic ligands: oxalate, citrate and EDTA on magnesite growth in alkaline conditions and at hydrothermal temperatures (100, 120 and 146 °C) using mixed flow reactors. We show that the studied carboxylates decrease magnesite growth rates, due to two converging mechanisms: Complexation of Mg2+ in solution, which decreases the saturation state of the solution. This effect was carefully taken into account by using a thermodynamic database relevant for the studied system. EDTA being the stronger chelate of the three investigated ligands, it has the strongest influence on solution saturation state. Adsorption of the ligand on magnesite surface growth sites, which decreases the kinetic rate constant of magnesite growth. We observed the following inhibition effectiveness of investigated organic ligands: citrate > EDTA > oxalate. While citrate exerts the strongest growth inhibition due to adsorption, it does not apparently lead to a complete interruption of magnesite growth. Preliminary adsorption experiments suggest that citrate adsorbs to active growth sites at the mineral surface with a much higher affinity than for the bulk of the surface. Using experimentally retrieved magnesite growth rate laws and published forsterite (Mg2SiO4) dissolution rate law, we performed simple numerical simulations to estimate the overall influence of the investigated ligands on the carbonation rates of forsterite. We observe that all ligands will clearly be detrimental to forsterite carbonation rates in typical conditions foreseen for Mg-silicates mineral carbonation. Their use may be positive for the carbonation of less reactive Mg-silicate minerals, but the delayed formation of

  11. Total contribution of airborne lead to blood lead.

    OpenAIRE

    Manton, W I

    1985-01-01

    A nine year study of blood lead concentrations and isotope ratios carried out on a married couple shows that pulmonary deposition cannot account for all the airborne lead in blood; that lead from bone may comprise 70% of blood lead; and that during pregnancy blood lead may double due to mobilisation of lead from bone.

  12. Leading by Interviewing

    Science.gov (United States)

    Sorenson, Richard D.

    2007-01-01

    While the interview remains the most relevant process by which information about an applicant can be obtained, the effective school administrator must recognize that the interview process is much more than exploring an applicant's qualifications, skills, and experiences. The interview must also be utilized as a means of leading. In other words,…

  13. Change, Lead, Succeed

    Science.gov (United States)

    Munger, Linda; von Frank, Valerie

    2010-01-01

    Redefine leadership in your school, and create capacity through school leadership teams that successfully coordinate professional learning. "Change, Lead, Succeed" shows school leaders and teachers in leadership roles what they need to know to effectively create a culture for change. Find out what distinguishes a school leadership team from other…

  14. Turning lead into gold

    DEFF Research Database (Denmark)

    Jensen, Steffen Moltrup Ernø

    For years the field of entrepreneurship has been blinded by the alchemical promise of turning lead into gold, of finding the ones most likely to become the next Branson, Zuckerberg or Gates. The promise has been created in the midst of political and scientific agendas where certain individuals, the...

  15. lead glass brick

    CERN Multimedia

    As well as accelerators to boost particles up to high energy, physicists need detectors to see what happens when those particles collide. This lead glass block is part of a CERN detector called OPAL. OPAL uses some 12 000 blocks of glass like this to measure particle energies.

  16. Girls Leading Outward

    Science.gov (United States)

    Hamed, Heather; Reyes, Jazmin; Moceri, Dominic C.; Morana, Laura; Elias, Maurice J.

    2011-01-01

    The authors describe a program implemented in Red Bank Middle School in New Jersey to help at-risk, minority middle school girls realize their leadership potential. The GLO (Girls Leading Outward) program was developed by the Developing Safe and Civil Schools Project at Rutgers University and is facilitated by university students. Selected middle…

  17. Relational Perspectives on Leading

    DEFF Research Database (Denmark)

    Relational Perspectives on Leading discusses leadership from a relational and social constructionism perspective as practiced on an everyday basis between people. The book pursues a fast growing, practice-based approach - particularly within the Anglo-Saxon parts of the world - to organization...

  18. Dissecting the chemistry of nicotinic receptor-ligand interactions with infrared difference spectroscopy.

    Science.gov (United States)

    Ryan, Stephen E; Hill, Danny G; Baenziger, John E

    2002-03-22

    The physical interactions that occur between the nicotinic acetylcholine receptor from Torpedo and the agonists carbamylcholine and tetramethylamine have been studied using both conventional infrared difference spectroscopy and a novel double-ligand difference technique. The latter was developed to isolate vibrational bands from residues in a membrane receptor that interact with individual functional groups on a small molecule ligand. The binding of either agonist leads to an increase in vibrational intensity at frequencies centered near 1663, 1655, 1547, 1430, and 1059 cm(-1) indicating that both induce a conformational change from the resting to the desensitized state. Vibrational shifts near 1580, 1516, 1455, 1334, and between 1300 and 1400 cm(-1) are assigned to structural perturbations of tyrosine and possibly both tryptophan and charged carboxylic acid residues upon the formation of receptor-quaternary amine interactions, with the relatively intense feature near 1516 cm(-1) indicating a key role for tyrosine. Other vibrational bands suggest the involvement of additional side chains in agonist binding. Two side-chain vibrational shifts from 1668 and 1605 cm(-1) to 1690 and 1620 cm(-1), respectively, could reflect the formation of a hydrogen bond between the ester carbonyl of carbamylcholine and an arginine residue. The results demonstrate the potential of the double-ligand difference technique for dissecting the chemistry of membrane receptor-ligand interactions and provide new insight into the nature of nicotinic receptor-agonist interactions. PMID:11782459

  19. Synthesis, Structures and Properties of Cobalt Thiocyanate Coordination Compounds with 4-(hydroxymethylpyridine as Co-ligand

    Directory of Open Access Journals (Sweden)

    Stefan Suckert

    2016-04-01

    Full Text Available Reaction of Co(NCS2 with 4-(hydroxymethylpyridine (hmpy leads to the formation of six new coordination compounds with the composition [Co(NCS2(hmpy4] (1, [Co(NCS2(hmpy4] × H2O (1-H2O, [Co(NCS2(hmpy2(EtOH2] (2, [Co(NCS2(hmpy2(H2O2] (3, [Co(NCS2(hmpy2]n∙4 H2O (4 and [Co(NCS2(hmpy2]n (5. They were characterized by single crystal and powder X-ray diffraction experiments, thermal and elemental analysis, IR and magnetic measurements. Compound 1 and 1-H2O form discrete complexes, in which the Co(II cations are octahedrally coordinated by two terminal thiocyanato anions and four 4-(hydroxymethylpyridine ligands. Discrete complexes were also observed for compounds 2 and 3 where two of the hmpy ligands were substituted by solvent, either water (3 or ethanol (2. In contrast, in compounds 4 and 5, the Co(II cations are linked into chains by bridging 4-(hydroxymethylpyridine ligands. The phase purity was checked with X-ray powder diffraction. Thermogravimetric measurements showed that compound 3 transforms into 5 upon heating, whereas the back transformation occurs upon resolvation. Magnetic measurements did not show any magnetic exchange via the hmpy ligand for compound 5.

  20. Identification of Novel Smoothened Ligands Using Structure-Based Docking

    Science.gov (United States)

    Torosyan, Hayarpi; Parathaman, Pranavan; Irwin, John J.; Shoichet, Brian K.

    2016-01-01

    The seven transmembrane protein Smoothened is required for Hedgehog signaling during embryonic development and adult tissue homeostasis. Inappropriate activation of the Hedgehog signalling pathway leads to cancers such as basal cell carcinoma and medulloblastoma, and Smoothened inhibitors are now available clinically to treat these diseases. However, resistance to these inhibitors rapidly develops thereby limiting their efficacy. The determination of Smoothened crystal structures enables structure-based discovery of new ligands with new chemotypes that will be critical to combat resistance. In this study, we docked 3.2 million available, lead-like molecules against Smoothened, looking for those with high physical complementarity to its structure; this represents the first such campaign against the class Frizzled G-protein coupled receptor family. Twenty-one high-ranking compounds were selected for experimental testing, and four, representing three different chemotypes, were identified to antagonize Smoothened with IC50 values better than 50 μM. A screen for analogs revealed another six molecules, with IC50 values in the low micromolar range. Importantly, one of the most active of the new antagonists continued to be efficacious at the D473H mutant of Smoothened, which confers clinical resistance to the antagonist vismodegib in cancer treatment. PMID:27490099

  1. Quantification of ligand bias for clinically relevant β2-adrenergic receptor ligands: implications for drug taxonomy.

    Science.gov (United States)

    van der Westhuizen, Emma T; Breton, Billy; Christopoulos, Arthur; Bouvier, Michel

    2014-03-01

    The concepts of functional selectivity and ligand bias are becoming increasingly appreciated in modern drug discovery programs, necessitating more informed approaches to compound classification and, ultimately, therapeutic candidate selection. Using the β2-adrenergic receptor as a model, we present a proof of concept study that assessed the bias of 19 β-adrenergic ligands, including many clinically used compounds, across four pathways [cAMP production, extracellular signal-regulated kinase 1/2 (ERK1/2) activation, calcium mobilization, and receptor endocytosis] in the same cell background (human embryonic kidney 293S cells). Efficacy-based clustering placed the ligands into five distinct groups with respect to signaling signatures. In some cases, apparent functional selectivity originated from off-target effects on other endogenously expressed adrenergic receptors, highlighting the importance of thoroughly assessing selectivity of the responses before concluding receptor-specific ligand-biased signaling. Eliminating the nonselective compounds did not change the clustering of the 10 remaining compounds. Some ligands exhibited large differences in potency for the different pathways, suggesting that the nature of the receptor-effector complexes influences the relative affinity of the compounds for specific receptor conformations. Calculation of relative effectiveness (within pathway) and bias factors (between pathways) for each of the compounds, using an operational model of agonism, revealed a global signaling signature for all of the compounds relative to isoproterenol. Most compounds were biased toward ERK1/2 activation over the other pathways, consistent with the notion that many proximal effectors converge on this pathway. Overall, we demonstrate a higher level of ligand texture than previously anticipated, opening perspectives for the establishment of pluridimensional correlations between signaling profiles, drug classification, therapeutic efficacy, and

  2. Landscape of protein-small ligand binding modes.

    Science.gov (United States)

    Kasahara, Kota; Kinoshita, Kengo

    2016-09-01

    Elucidating the mechanisms of specific small-molecule (ligand) recognition by proteins is a long-standing conundrum. While the structures of these molecules, proteins and ligands, have been extensively studied, protein-ligand interactions, or binding modes, have not been comprehensively analyzed. Although methods for assessing similarities of binding site structures have been extensively developed, the methods for the computational treatment of binding modes have not been well established. Here, we developed a computational method for encoding the information about binding modes as graphs, and assessing their similarities. An all-against-all comparison of 20,040 protein-ligand complexes provided the landscape of the protein-ligand binding modes and its relationships with protein- and chemical spaces. While similar proteins in the same SCOP Family tend to bind relatively similar ligands with similar binding modes, the correlation between ligand and binding similarities was not very high (R(2)  = 0.443). We found many pairs with novel relationships, in which two evolutionally distant proteins recognize dissimilar ligands by similar binding modes (757,474 pairs out of 200,790,780 pairs were categorized into this relationship, in our dataset). In addition, there were an abundance of pairs of homologous proteins binding to similar ligands with different binding modes (68,217 pairs). Our results showed that many interesting relationships between protein-ligand complexes are still hidden in the structure database, and our new method for assessing binding mode similarities is effective to find them. PMID:27327045

  3. HAIR LEAD CONCENTRATION IN NAKHLAK LEAD MINERS VERSUS CONTROL GROUP

    OpenAIRE

    Izadi, N.; K Montazeri

    2002-01-01

    Introduction. Lead poisoning is a major problem in environmental health. Exposure can occur via air, soil, food and water. Occupational exposure is the most common source of lead poisoning in adults. Lead miners are exposed to an additional source of poisoning in long term. Hair analysis may be used to evaluate chronic lead toxicity. This study compare the hair lead concentration in Nakhlak lead miners and Mohammadieh people who live 130 km far from the lead mine. Methods. Hair samples f...

  4. Leading Indicator Project : Lithuania

    OpenAIRE

    Everhart, Stephen S.; Duval-Hernandez, Robert

    2000-01-01

    The authors present a method for forecasting growth cycles in economic activity, measured as total industrial production. They construct a series which they aggregate into a composite leading indicator to predict the path of the economy in Lithuania. The cycle is the result of the economy's deviations from its long-term trend. A contractionary phase means a decline in the growth rate of the economy, not necessarily an absolute decline in economic activity. The indicator they select for econom...

  5. CMS lead tungstate crystals

    CERN Multimedia

    Laurent Guiraud

    2000-01-01

    These crystals are made from lead tungstate, a crystal that is as clear as glass yet with nearly four times the density. They have been produced in Russia to be used as scintillators in the electromagnetic calorimeter on the CMS experiment, part of the LHC project at CERN. When an electron, positron or photon passes through the calorimeter it will cause a cascade of particles that will then be absorbed by these scintillating crystals, allowing the particle's energy to be measured.

  6. Tungsten acetonitrile complexes, containing nitrosyl ligand

    International Nuclear Information System (INIS)

    Synthesized are tungsten acetonitrile derivatives, containing nitrosyl ligand. In a course of boiling W(CO)4(NO)I-(1) at the excess of acetonitrile there is formed bis-(acetonitrile)-dicarbonilenitrosyltungsteniod-(2): W(CO)4(NO)I+2CH3CN → 2CO+(CH3CN)2W(CO)2(NO)I-(2). Investigation in reactionary ability of compound (2) is carried out. It is shown that at the reaction of acetonitrile complex (2) with two equivalents of triphenylphosphine depending on reaction conditions formed is a number of products

  7. Transmutable nanoparticles with reconfigurable surface ligands

    Science.gov (United States)

    Kim, Youngeun; Macfarlane, Robert J.; Jones, Matthew R.; Mirkin, Chad A.

    2016-02-01

    Unlike conventional inorganic materials, biological systems are exquisitely adapted to respond to their surroundings. Proteins and other biological molecules can process a complex set of chemical binding events as informational inputs and respond accordingly via a change in structure and function. We applied this principle to the design and synthesis of inorganic materials by preparing nanoparticles with reconfigurable surface ligands, where interparticle bonding can be programmed in response to specific chemical cues in a dynamic manner. As a result, a nascent set of “transmutable nanoparticles” can be driven to crystallize along multiple thermodynamic trajectories, resulting in rational control over the phase and time evolution of nanoparticle-based matter.

  8. Scorpionates the coordination chemistry of polypyrazolylborate ligands

    CERN Document Server

    Trofimenko, Swiatoslaw

    1999-01-01

    This book deals with polypyrazolylborates (scorpionates), a class of ligands known since 1966, but becoming rapidly popular with inorganic, organometallic and coordination chemists since 1986, because of their versatility and user-friendliness. They can be readily modified sterically and electronically through appropriate substitution on the pyrazole ring and on boron, and have led to a number of firsts in coordination chemistry (first stable CuCO complex, first monomeric MgR complex, and many other such firsts). Their denticity can range from two to four, their "Bite" can be adjusted, and add

  9. Metal mediated template synthesis of ligands

    CERN Document Server

    Costisor, Otilia

    2004-01-01

    This book surveys the relatively new area of the synthesis of organic ligands when metal ions act as a template. In the last fifty years this field has undergone an explosive development, marked by a great amount of literature. The material in the book has been arranged according to the type of chemical reaction involved. In this frame, the basic principles of metal template reactions and the shape of the molecules are considered. Designed to satisfy the demands of students, young researchers doing their PhDs, and those working in the field of coordination chemistry, the book details the role

  10. Up-regulation of PD-L1 on Monocytes and Dendritic Cells by HIV-1 derived TLR Ligands

    OpenAIRE

    Meier, Angela; Bagchi, Aranya; Sidhu, Harlyn K.; Alter, Galit; Suscovich, Todd J.; Kavanagh, Daniel G.; Streeck, Hendrik; Brockman, Mark A.; LeGall, Sylvie; Hellman, Judith; Altfeld, Marcus

    2008-01-01

    Increased PD-L1 expression has been reported in HIV-1-infected individuals, but the mechanisms leading to PD-L1-up-regulation remain to be elucidated. Here we demonstrate that HIV-1-derived TLR7/8 ligands can induce MyD88-dependent up-regulation of PD-L1 on pDCs, mDCs and monocytes. These data suggest a mechanism through which HIV-1-derived TLR ligands might contribute to the functional impairment of virus-specific PD-1+ T cells by inducing the up-regulation of PD-L1 on antigen-presenting cells.

  11. Room temperature synthesis of PbSe quantum dots in aqueous solution: Stabilization by interactions with ligands

    OpenAIRE

    Primera-Pedrozo, Oliva M.; Arslan, Zikri; Rasulev, Bakhtiyor; Leszczynski, Jerzy

    2012-01-01

    An aqueous route of synthesis is described for rapid synthesis of lead selenide quantum dots (PbSe QDs) at room temperature in an attempt to produce water-soluble and stable nanocrystals. Several thiol-ligands, including thioglycolic acid (TGA), thioglycerol (TGC), 3-mercaptopropionic acid (MPA), 2-mercaptoethyleamine hydrochloride (MEA), 6-mercaptohexanoic acid (MHA), and L-cysteine (L-cys), were used for capping/stabilization of PbSe QDs. The effects of the ligands on the stability of PbSe ...

  12. Mixed ligand oxovanadium(IV) complexes with salicylic acid and N,N-bidentate ligands

    International Nuclear Information System (INIS)

    Two mixed-ligand oxovanadium(IV) complexes VO(A)(B) [where H2A=salicylic acid and B=2,2'-bipyridine or 1,10-phenanthroline (hereafter, bipy and phen respectively)] have been synthesized and characterized by magnetic moment and spectral (IR, UV/VIS and EPR) data. The A2- ion acts as a bidentate dinegative ligand while B ligands acts as a neutral bidentate. The magnetic susceptibility values indicate the existence of a small amount of antiferromagnetic interaction. The vanadium atoms in the complexes are hexacoordinated and the coordination sphere is of the type [VO(OO)(NN)], where O atoms are of oxo, carboxylic and phenolic type and N atoms are of pyridine type. The sixth coordination site is occupied by phenolic oxygen of the neighbouring molecule forming a bridge. The vv=o confirms the hexacoordination. All the complexes have dxy1 type axial EPR spectra and they exhibit two ligand field transitions at 740 and 440 nm. (author)

  13. Treatment of autoimmune inflammation by a TLR7 ligand regulating the innate immune system.

    Directory of Open Access Journals (Sweden)

    Tomoko Hayashi

    Full Text Available The Toll-like receptors (TLR have been advocated as attractive therapeutic targets because TLR signaling plays dual roles in initiating adaptive immune responses and perpetuating inflammation. Paradoxically, repeated stimulation of bone marrow mononuclear cells with a synthetic TLR7 ligand 9-benzyl-8-hydroxy-2-(2-methoxyethoxy adenine (called 1V136 leads to subsequent TLR hyporesponsiveness. Further studies on the mechanism of action of this pharmacologic agent demonstrated that the TLR7 ligand treatment depressed dendritic cell activation, but did not directly affect T cell function. To verify this mechanism, we utilized experimental allergic encephalitis (EAE as an in vivo T cell dependent autoimmune model. Drug treated SJL/J mice immunized with proteolipid protein (PLP(139-151 peptide had attenuated disease severity, reduced accumulation of mononuclear cells in the central nervous system (CNS, and limited demyelination, without any apparent systemic toxicity. Splenic T cells from treated mice produced less cytokines upon antigenic rechallenge. In the spinal cords of 1V136-treated EAE mice, the expression of chemoattractants was also reduced, suggesting innate immune cell hyposensitization in the CNS. Indeed, systemic 1V136 did penetrate the CNS. These experiments indicated that repeated doses of a TLR7 ligand may desensitize dendritic cells in lymphoid organs, leading to diminished T cell responses. This treatment strategy might be a new modality to treat T cell mediated autoimmune diseases.

  14. Investigation of Uranyl Nitrate Ion Pairs Complexed with Amide Ligands using Electrospray Ionization Ion Trap Mass Spectrometry and Density Functional Theory

    International Nuclear Information System (INIS)

    Ion populations formed from electrospray of uranyl nitrate solutions containing different amides vary depending on ligand nucleophilicity and steric crowding at the metal center. The most abundant species were ion pair complexes having the general formula (UO2(NO3)(amide)n=2,3)+, and complexes containing the amide conjugate base, reduced uranyl UO2+, and a 2+ charge were also formed. The formamide experiment produced the greatest diversity of species that stems from weaker amide binding leading to dissociation and subsequent solvent coordination or metal reduction. Experiments using methyl formamide, dimethyl formamide, acetamide, and methyl acetamide produced ion pair and doubly charged complexes that were more abundant, and less abundant complexes containing solvent or reduced uranyl. This pattern is reversed in the dimethylacetamide experiment, which displayed reduced doubly charged complexes and augmented reduced uranyl complexes. DFT investigations of the tris-amide ion pair complexes showed that inter-ligand repulsion distorts the amide ligands out of the uranyl equatorial plane, and that complex stabilities do not increase with increasing amide nucleophilicity. Elimination of an amide ligand largely relieves the interligand repulsion, and the remaining amide ligands become closely aligned with the equatorial plane in the structures of the bis-amide ligands. The studies show that the phenomenological distribution of coordination complexes in a metal-ligand electrospray experiment is a function of both ligand nucleophilicity and interligand repulsion, and that the latter factor begins exerting influence even in the case of relatively small ligands like the substituted methyl-formamide and methyl-acetamide ligands.

  15. Investigation of Uranyl Nitrate Ion Pairs Complexed with Amide Ligands using Electrospray Ionization Ion Trap Mass Spectrometry and Density Functional Theory

    Energy Technology Data Exchange (ETDEWEB)

    Gary S. Groenewold; Adriana Dinescu; Michael T. Benson; Garold L. Gresham; Michael J. van Stipdonk

    2011-04-01

    Ion populations formed from electrospray of uranyl nitrate solutions containing different amides vary depending on ligand nucleophilicity and steric crowding at the metal center. The most abundant species were ion pair complexes having the general formula [UO2(NO3)(amide)n=2,3]+, and complexes containing the amide conjugate base, reduced uranyl UO2+, and a 2+ charge were also formed. The formamide experiment produced the greatest diversity of species that stems from weaker amide binding leading to dissociation and subsequent solvent coordination or metal reduction. Experiments using methyl formamide, dimethyl formamide, acetamide, and methyl acetamide produced ion pair and doubly charged complexes that were more abundant, and less abundant complexes containing solvent or reduced uranyl. This pattern is reversed in the dimethylacetamide experiment, which displayed reduced doubly charged complexes and augmented reduced uranyl complexes. DFT investigations of the tris-amide ion pair complexes showed that inter-ligand repulsion distorts the amide ligands out of the uranyl equatorial plane, and that complex stabilities do not increase with increasing amide nucleophilicity. Elimination of an amide ligand largely relieves the interligand repulsion, and the remaining amide ligands become closely aligned with the equatorial plane in the structures of the bis-amide ligands. The studies show that the phenomenological distribution of coordination complexes in a metal-ligand electrospray experiment is a function of both ligand nucleophilicity and interligand repulsion, and that the latter factor begins exerting influence even in the case of relatively small ligands like the substituted methyl-formamide and –acetamide ligands.

  16. Dopaminergic receptor-ligand binding assays based on molecularly imprinted polymers on quartz crystal microbalance sensors.

    Science.gov (United States)

    Naklua, Wanpen; Suedee, Roongnapa; Lieberzeit, Peter A

    2016-07-15

    Molecularly imprinted polymers (MIPs) have been successfully applied as selective materials for assessing the binding activity of agonist and antagonist of dopamine D1 receptor (D1R) by using quartz crystal microbalance (QCM). In this study, D1R derived from rat hypothalamus was used as a template and thus self-organized on stamps. Those were pressed into an oligomer film consisting of acrylic acid: N-vinylpyrrolidone: N,N'-(1,2-dihydroxyethylene) bis-acrylamide in a ratio of 2:3:12 spin coated onto a dual electrode QCM. Such we obtained one D1R-MIP-QCM electrode, whereas the other electrode carried the non-imprinted control polymer (NIP) that had remained untreated. Successful imprinting of D1R was confirmed by AFM. The polymer can re-incorporate D1R leading to frequency responses of 100-1200Hz in a concentration range of 5.9-47.2µM. In a further step such frequency changes proved inherently useful for examining the binding properties of test ligands to D1R. The resulting mass-sensitive measurements revealed Kd of dopamine∙HCl, haloperidol, and (+)-SCH23390 at 0.874, 25.6, and 0.004nM, respectively. These results correlate well with the values determined in radio ligand binding assays. Our experiments revealed that D1R-MIP sensors are useful for estimating the strength of ligand binding to the active single site. Therefore, we have developed a biomimetic surface imprinting strategy for QCM studies of D1R-ligand binding and presented a new method to ligand binding assay for D1R. PMID:26926593

  17. Lead diffusion in monazite

    International Nuclear Information System (INIS)

    Proper knowledge of the diffusion rates of lead in monazite is necessary to understand the U-Th-Pb age anomalies of this mineral, which is one of the most used in geochronology after zircon. Diffusion experiments were performed in NdPO4 monocrystals and in Nd0.66Ca0.17Th0.17PO4 polycrystals from Nd0.66Pb0.17Th0.17PO4 thin films to investigate Pb2+ + Th4+ ↔ 2 Nd3+ and Pb2+ ↔ Ca2+ exchanges. Diffusion annealings were run between 1200 and 1500 Celsius degrees, at room pressure, for durations ranging from one hour to one month. The diffusion profiles were analysed using TEM (transmission electronic microscopy) and RBS (Rutherford backscattering spectroscopy). The diffusivities extracted for Pb2+ + Th4+ ↔ 2 Nd3+ exchange follow an Arrhenius law with parameters E equals 509 ± 24 kJ mol-1 and log(D0 (m2s-1)) equals -3.41 ± 0.77. Preliminary data for Pb2+ ↔ Ca2+ exchange are in agreement with this result. The extrapolation of our data to crustal temperatures yields very slow diffusivities. For instance, the time necessary for a 50 μm grain to lose all of its lead at 800 Celsius degrees is greater than the age of the Earth. From these results and other evidence from the literature, we conclude that most of the perturbations in U-Th-Pb ages of monazite cannot be attributed to lead diffusion, but rather to interactions with fluids. (author)

  18. The Dynamics of Ligand Barrier Crossing inside the Acetylcholinesterase Gorge

    OpenAIRE

    Bui, Jennifer M.; Henchman, Richard H.; McCammon, J. Andrew

    2003-01-01

    The dynamics of ligand movement through the constricted region of the acetylcholinesterase gorge is important in understanding how the ligand gains access to and is released from the active site of the enzyme. Molecular dynamics simulations of the simple ligand, tetramethylammonium, crossing this bottleneck region are conducted using umbrella potential sampling and activated flux techniques. The low potential of mean force obtained is consistent with the fast reaction rate of acetylcholineste...

  19. Quasielastic neutron scattering study of POSS ligand dynamics

    Energy Technology Data Exchange (ETDEWEB)

    Jalarvo, Niina H [ORNL; Tyagi, Madhusudan [NIST Center for Neutron Research (NCRN), Gaithersburg, MD; Crawford, Michael [DuPont Experimental Station

    2015-01-01

    Polyoligosilsesquioxanes are molecules having cage-like structures composed of silicon and oxygen. These molecules can have a wide variety of functional ligands attached to them. Depending on the nature of the ligand, interesting properties and applications are found. In this work we present results from quasielastic neutron scattering measurements of four different POSS molecules that illustrate the presence of strong coupling between the ligand dynamics and the POSS crystal structures.

  20. Rapid flexible docking using a stochastic rotamer library of ligands

    OpenAIRE

    Ding, Feng; Yin, Shuangye; Dokholyan, Nikolay V.

    2010-01-01

    Existing flexible docking approaches model the ligand and receptor flexibility either separately or in a loosely-coupled manner, which captures the conformational changes inefficiently. Here, we propose a flexible docking approach, MedusaDock, which models both ligand and receptor flexibility simultaneously with sets of discrete rotamers. We develop an algorithm to build the ligand rotamer library “on-the-fly” during docking simulations. MedusaDock benchmarks demonstrate a rapid sampling effi...

  1. Ligand Binding Analysis and Screening by Chemical Denaturation Shift

    OpenAIRE

    Sch n, Arne; Brown, Richard K; Hutchins, Burleigh M.; Freire, Ernesto

    2013-01-01

    The identification of small molecule ligands is an important first step in drug development, especially drugs that target proteins with no intrinsic activity. Towards this goal, it is important to have access to technologies that are able to measure binding affinities for a large number of potential ligands in a fast and accurate way. Since ligand binding stabilizes the protein structure in a manner dependent on concentration and binding affinity, the magnitude of the protein stabilization ef...

  2. Dynamic Presentation of Immobilized Ligands Regulated through Biomolecular Recognition

    OpenAIRE

    Liu, Bo; Liu, Yang; Riesberg, Jeremiah J.; Shen, Wei

    2010-01-01

    To mimic the dynamic regulation of signaling ligands immobilized on extracellular matrices or on the surfaces of neighboring cells for guidance of cell behavior and fate selection, we have harnessed biomolecular recognition in combination with polymer engineering to create dynamic surfaces on which the accessibility of immobilized ligands to cell surface receptors can be reversibly interconverted under physiological conditions. The cell-adhesive RGD peptide is chosen as a model ligand. RGD is...

  3. lead glass brick

    CERN Multimedia

    When you look through the glass at a picture behind, the picture appears raised up because light is slowed down in the dense glass. It is this density (4.06 gcm-3) that makes lead glass attractive to physicists. The refractive index of the glass is 1.708 at 400nm (violet light), meaning that light travels in the glass at about 58% its normal speed. At CERN, the OPAL detector uses some 12000 blocks of glass like this to measure particle energies.

  4. Do organic ligands affect calcite dissolution rates?

    Science.gov (United States)

    Oelkers, Eric H.; Golubev, Sergey V.; Pokrovsky, Oleg S.; Bénézeth, Pascale

    2011-04-01

    Steady state Iceland-spar calcite dissolution rates were measured at 25 °C in aqueous solutions containing 0.1 M NaCl and up to 0.05 M dissolved bicarbonate at pH from 7.9 to 9.1 in the presence of 13 distinct dissolved organic ligands in mixed-flow reactors. The organic ligands considered in this study include those most likely to be present in either (1) aquifers at the conditions pertinent to CO 2 sequestration or (2) soil/early diagenetic environments: acetate, phthalate, citrate, EDTA 4-, succinate, D-glucosaminate, L-glutamate, D-gluconate, 2,4-dihydroxybenzoate, 3,4-dihydroxybenzoate, fumarate, malonate, and gallate. Results show that the presence of extract, humic acid, pectin, and gum xanthan. In no case did the presence of <100 ppm of these organics change calcite dissolution rates by more than a factor of 2.5. Results obtained in this study suggest that the presence of aqueous organic anions negligibly affects calcite forward dissolution rates in most natural environments. Some effect on calcite reactivity may be observed, however, by the presence of organic anions if they change substantially the chemical affinity of the fluid with respect to calcite.

  5. The first nitro-substituted heteroscorpionate ligand.

    Science.gov (United States)

    Pellei, Maura; Benetollo, Franco; Lobbia, Giancarlo Gioia; Alidori, Simone; Santini, Carlo

    2005-02-21

    The new dihydridobis(3-nitro-1,2,4-triazolyl)borate ligand, [H2B(tzNO2)2]-, has been synthesized in dimethylacetamide solution, using 3-nitro-1,2,4-triazole and KBH4 through careful temperature control, and characterized as its potassium salt. The zinc(II) and cadmium(II) complexes, {M[H2B(tzNO2)2]Cl(H2O)2}, have been prepared by metathesis of [H2B(tzNO2)2]K with ZnCl2 and CdCl2, respectively. The complexes likely contain a metal core in which the ligand is coordinated to the metal ions in the K2-N,N' or K4-N,N',O,O' fashion. A single-crystal structural characterization is reported for the potassium dihydrobis(3-nitro-1,2,4-triazolyl)borate. The potassium salt is polymeric and shows several K...N and K...O interactions. PMID:15859260

  6. Riboswitch Structure: an Internal Residue Mimicking the Purine Ligand

    Energy Technology Data Exchange (ETDEWEB)

    Delfosse, V.; Bouchard, P; Bonneau, E; Dagenais, P; Lemay, J; Lafontaine, D; Legault, P

    2009-01-01

    The adenine and guanine riboswitches regulate gene expression in response to their purine ligand. X-ray structures of the aptamer moiety of these riboswitches are characterized by a compact fold in which the ligand forms a Watson-Crick base pair with residue 65. Phylogenetic analyses revealed a strict restriction at position 39 of the aptamer that prevents the G39-C65 and A39-U65 combinations, and mutational studies indicate that aptamers with these sequence combinations are impaired for ligand binding. In order to investigate the rationale for sequence conservation at residue 39, structural characterization of the U65C mutant from Bacillus subtilis pbuE adenine riboswitch aptamer was undertaken. NMR spectroscopy and X-ray crystallography studies demonstrate that the U65C mutant adopts a compact ligand-free structure, in which G39 occupies the ligand-binding site of purine riboswitch aptamers. These studies present a remarkable example of a mutant RNA aptamer that adopts a native-like fold by means of ligand mimicking and explain why this mutant is impaired for ligand binding. Furthermore, this work provides a specific insight into how the natural sequence has evolved through selection of nucleotide identities that contribute to formation of the ligand-bound state, but ensures that the ligand-free state remains in an active conformation.

  7. Single-incubation immunoassay for a multivalent ligand

    International Nuclear Information System (INIS)

    In a two-site immunoassay method for a multivalent ligand using a single incubation, the ligand, labelled receptor for the ligand and unlabelled receptor for the ligand covalently bound to a solid-phase support are incubated as a stable suspension to produce a solid and liquid phase. The solid and liquid phases are separated from each other and the labelled receptor in either phase is quantified. The method has particular application as an assay for human thyroid stimulating hormone using purified, radioactively labelled antibodies and unlabelled antibodies covalently bound to hydrolyzed polyacrylamide particles. (author)

  8. The Dynamics of Ligand Barrier Crossing Inside the Acetylcholinesterase Gorge

    Energy Technology Data Exchange (ETDEWEB)

    Bui, Jennifer M.(University of California, San Diego); Henchman, Richard H.(University of California, San Diego); Mccammon, Andy (University of California, San Diego)

    2003-10-01

    The dynamics of ligand movement through the constricted region of the acetylcholinesterase gorge is important in understanding how the ligand gains access to and is released from the active site of the enzyme. Molecular dynamics simulations of the simple ligand, tetramethylammonium, crossing this bottleneck region are conducted using umbrella potential sampling and activated .ux techniques. The low potential of mean force obtained is consistent with the fast reaction rate of acetylcholinesterase observed experimentally. From the results of the activated dynamics simulations, local conformational .uctuations of the gorge residues and larger scale collective motions of the protein are found to correlate highly with the ligand crossing.

  9. Ligand Release Pathways Obtained with WExplore: Residence Times and Mechanisms.

    Science.gov (United States)

    Dickson, Alex; Lotz, Samuel D

    2016-06-23

    The binding of ligands with their molecular receptors is of tremendous importance in biology. Although much emphasis has been placed on characterizing binding sites and bound poses that determine the binding thermodynamics, the pathway by which a ligand binds importantly determines the binding kinetics. The computational study of entire unbiased ligand binding and release pathways is still an emerging field, made possible only recently by advances in computational hardware and sampling methodologies. We have developed one such method (WExplore) that is based on a weighted ensemble of trajectories, which we apply to ligand release for the first time, using a set of three previously characterized interactions between low-affinity ligands and the protein FKBP-12 (FK-506 binding protein). WExplore is found to be more efficient that conventional sampling, even for the nanosecond-scale unbinding events observed here. From a nonequilibrium ensemble of unbinding trajectories, we obtain ligand residence times and release pathways without using biasing forces or a Markovian assumption of transitions between regions. We introduce a set of analysis tools for unbinding transition pathways, including using von Mises-Fisher distributions to model clouds of ligand exit points, which provide a quantitative proxy for ligand surface diffusion. Differences between the transition pathway ensembles of the three ligands are identified and discussed. PMID:27231969

  10. Spectra of fluorinated rare earth. beta. -diketonates with added ligands

    Energy Technology Data Exchange (ETDEWEB)

    Khomenko, V.S.; Lozinskij, M.O.; Fialkov, Yu.A.; Rasshinina, T.A.; Krasovskaya, L.I. (AN Belorusskoj SSR, Minsk. Inst. Fiziki; AN Ukrainskoj SSR, Kiev. Inst. Organicheskoj Khimii)

    1984-01-01

    Different-ligand rare earth complexes are synthesized. Fluorated ..beta..-diketones, triethylphosphine oxide and trifluoracetic acid are used as active ligands. Mass-spectra of low and high resolution are taken at the energy of ionizing electrons of 70 eV, as well as luminescence spectra of complexes. Fragmentation ways of complexes decomposition under electron shock are studied. A series of changing the bound strength of additional ligands with europium in mixed complexes is determined. It is shown that the introduction of additional ligands can purposefully change physical and chemical properties of complexes.

  11. Superior serum half life of albumin tagged TNF ligands

    International Nuclear Information System (INIS)

    Due to their immune stimulating and apoptosis inducing properties, ligands of the TNF family attract increasing interest as therapeutic proteins. A general limitation of in vivo applications of recombinant soluble TNF ligands is their notoriously rapid clearance from circulation. To improve the serum half life of the TNF family members TNF, TWEAK and TRAIL, we genetically fused soluble variants of these molecules to human serum albumin (HSA). The serum albumin-TNF ligand fusion proteins were found to be of similar bioactivity as the corresponding HSA-less counterparts. Upon intravenous injection (i.v.), serum half life of HSA-TNF ligand fusion proteins, as determined by ELISA, was around 15 h as compared to approximately 1 h for all of the recombinant control TNF ligands without HSA domain. Moreover, serum samples collected 6 or 24 h after i.v. injection still contained high TNF ligand bioactivity, demonstrating that there is only limited degradation/inactivation of circulating HSA-TNF ligand fusion proteins in vivo. In a xenotransplantation model, significantly less of the HSA-TRAIL fusion protein compared to the respective control TRAIL protein was required to achieve inhibition of tumor growth indicating that the increased half life of HSA-TNF ligand fusion proteins translates into better therapeutic action in vivo. In conclusion, our data suggest that genetic fusion to serum albumin is a powerful and generally applicable mean to improve bioavailability and in vivo activity of TNF ligands.

  12. Nonlinear scoring functions for similarity-based ligand docking and binding affinity prediction.

    Science.gov (United States)

    Brylinski, Michal

    2013-11-25

    A common strategy for virtual screening considers a systematic docking of a large library of organic compounds into the target sites in protein receptors with promising leads selected based on favorable intermolecular interactions. Despite a continuous progress in the modeling of protein-ligand interactions for pharmaceutical design, important challenges still remain, thus the development of novel techniques is required. In this communication, we describe eSimDock, a new approach to ligand docking and binding affinity prediction. eSimDock employs nonlinear machine learning-based scoring functions to improve the accuracy of ligand ranking and similarity-based binding pose prediction, and to increase the tolerance to structural imperfections in the target structures. In large-scale benchmarking using the Astex/CCDC data set, we show that 53.9% (67.9%) of the predicted ligand poses have RMSD of <2 Å (<3 Å). Moreover, using binding sites predicted by recently developed eFindSite, eSimDock models ligand binding poses with an RMSD of 4 Å for 50.0-39.7% of the complexes at the protein homology level limited to 80-40%. Simulations against non-native receptor structures, whose mean backbone rearrangements vary from 0.5 to 5.0 Å Cα-RMSD, show that the ratio of docking accuracy and the estimated upper bound is at a constant level of ∼0.65. Pearson correlation coefficient between experimental and predicted by eSimDock Ki values for a large data set of the crystal structures of protein-ligand complexes from BindingDB is 0.58, which decreases only to 0.46 when target structures distorted to 3.0 Å Cα-RMSD are used. Finally, two case studies demonstrate that eSimDock can be customized to specific applications as well. These encouraging results show that the performance of eSimDock is largely unaffected by the deformations of ligand binding regions, thus it represents a practical strategy for across-proteome virtual screening using protein models. eSimDock is freely

  13. Synthesis and Doping of Ligand-Protected Atomically-Precise Metal Nanoclusters

    KAUST Repository

    Aljuhani, Maha A.

    2016-05-01

    Rapidly expanding research in nanotechnology has led to exciting progress in a versatile array of applications from medical diagnostics to catalysis. This success resulted from the manipulation of the desired properties of nanomaterials by controlling their size, shape, and composition. Among the most thriving areas of research about nanoparticle is the synthesis and doping of the ligand-protected atomically-precise metal nanoclusters. In this thesis, we developed three different novel metal nanoclusters, such as doped Ag29 with five gold (Au) atoms leading to enhance its quantum yield with remarkable stability. We also developed half-doped (alloyed) cluster of Ni6 nanocluster with molybdenum (Mo). This enabled enhanced stability and better catalytic activity. The third metal nanocluster that we synthesized was Au28 nanocluster by using di-thiolate as the ligand stabilizer instead of mono-thiolate. The new metal clusters obtained have been characterized by spectroscopic, electrochemical and crystallographic methods.

  14. A ligand-independent integrin β1 mechanosensory complex guides spindle orientation.

    Science.gov (United States)

    Petridou, Nicoletta I; Skourides, Paris A

    2016-01-01

    Control of spindle orientation is a fundamental process for embryonic development, morphogenesis and tissue homeostasis, while defects are associated with tumorigenesis and other diseases. Force sensing is one of the mechanisms through which division orientation is determined. Here we show that integrin β1 plays a critical role in this process, becoming activated at the lateral regions of the cell cortex in a ligand-independent manner. This activation is force dependent and polar, correlating with the spindle capture sites. Inhibition of integrin β1 activation on the cortex and disruption of its asymmetric distribution leads to spindle misorientation, even when cell adhesion is β1 independent. Examining downstream targets reveals that a cortical mechanosensory complex forms on active β1, and regulates spindle orientation irrespective of cell context. We propose that ligand-independent integrin β1 activation is a conserved mechanism that allows cell responses to external stimuli. PMID:26952307

  15. Direct Comparison of Linear and Macrocyclic Compound Libraries as a Source of Protein Ligands

    Science.gov (United States)

    2015-01-01

    There has been much discussion of the potential desirability of macrocyclic molecules for the development of tool compounds and drug leads. But there is little experimental data comparing otherwise equivalent macrocyclic and linear compound libraries as a source of protein ligands. In this Letter, we probe this point in the context of peptoid libraries. Bead-displayed libraries of macrocyclic and linear peptoids containing four variable positions and 0–2 fixed residues, to vary the ring size, were screened against streptavidin and the affinity of every hit for the target was measured. The data show that macrocyclization is advantageous, but only when the ring contains 17 atoms, not 20 or 23 atoms. This technology will be useful for conducting direct comparisons between many different types of chemical libraries to determine their relative utility as a source of protein ligands. PMID:25623285

  16. PSMA Ligands for Radionuclide Imaging and Therapy of Prostate Cancer: Clinical Status.

    Science.gov (United States)

    Lütje, Susanne; Heskamp, Sandra; Cornelissen, Alexander S; Poeppel, Thorsten D; van den Broek, Sebastiaan A M W; Rosenbaum-Krumme, Sandra; Bockisch, Andreas; Gotthardt, Martin; Rijpkema, Mark; Boerman, Otto C

    2015-01-01

    Prostate cancer (PCa) is the most common malignancy in men worldwide, leading to substantial morbidity and mortality. At present, imaging of PCa has become increasingly important for staging, restaging, and treatment selection. Until recently, choline-based positron emission tomography/computed tomography (PET/CT) represented the state-of-the-art radionuclide imaging technique for these purposes. However, its application is limited to patients with high PSA levels and Gleason scores. Prostate-specific membrane antigen (PSMA) is a promising new target for specific imaging of PCa, because it is upregulated in the majority of PCa. Moreover, PSMA can serve as a target for therapeutic applications. Currently, several small-molecule PSMA ligands with excellent in vivo tumor targeting characteristics are being investigated for their potential in theranostic applications in PCa. Here, a review of the recent developments in PSMA-based diagnostic imaging and therapy in patients with PCa with radiolabeled PSMA ligands is provided. PMID:26681984

  17. Influence of ligands on the electronic and magnetic properties of Fe porphyrin in gas phase and on Cu(001)

    Energy Technology Data Exchange (ETDEWEB)

    Brena, Barbara; Herper, Heike C., E-mail: heike.herper@physics.uu.se [Department of Physics and Astronomy, Uppsala University, 75120 Uppsala (Sweden)

    2015-05-07

    A study of the adsorption of different axial ligands on Fe porphyrin (FeP), both isolated and adsorbed on Cu(001), was performed by means of Density Functional Theory. The electronic and magnetic properties of the adsorbed FeP resulted to be strongly influenced by the axial ligands considered, Cl and O. Cl induces an enhancement of the overall molecular magnetic moment of 3.0 μ{sub B} while O or O{sub 2} leave the spin state of the molecule unchanged. The influence of the Cl in the electronic states was moreover studied by means of theoretical NEXAFS N K-edge, where the spectra of isolated FeP and FeP with Cl ligand were calculated. The adsorption of the FeP molecules on Cu(001) leads in case of Cl to a further increase of the magnetic moment due to strong deformation of the Fe-N bond.

  18. Protozoacidal Trojan-Horse: use of a ligand-lytic peptide for selective destruction of symbiotic protozoa within termite guts.

    Directory of Open Access Journals (Sweden)

    Amit Sethi

    Full Text Available For novel biotechnology-based termite control, we developed a cellulose bait containing freeze-dried genetically engineered yeast which expresses a protozoacidal lytic peptide attached to a protozoa-recognizing ligand. The yeast acts as a 'Trojan-Horse' that kills the cellulose-digesting protozoa in the termite gut, which leads to the death of termites, presumably due to inefficient cellulose digestion. The ligand targets the lytic peptide specifically to protozoa, thereby increasing its protozoacidal efficiency while protecting non-target organisms. After ingestion of the bait, the yeast propagates in the termite's gut and is spread throughout the termite colony via social interactions. This novel paratransgenesis-based strategy could be a good supplement for current termite control using fortified biological control agents in addition to chemical insecticides. Moreover, this ligand-lytic peptide system could be used for drug development to selectively target disease-causing protozoa in humans or other vertebrates.

  19. Half-sandwich pentamethylcyclopentadienyl group 9 metal complexes of 2-aminopyridyl ligands: Synthesis, spectral and molecular study

    Indian Academy of Sciences (India)

    Mahesh Kalidasan; Scott Forbes; Yurij Mozharivskyj; Mohan Rao Kollipara

    2015-06-01

    Thereaction of [Cp*M(-Cl)Cl]2 (M = Rh, Ir) with 2-aminopyridyl based ligands lead to the formation of mononuclear neutral complexes of general formula [Cp*MCl2(L)] {where L1= 2-aminopyridine, L2= 2-amino-3-picoline, L3= 2-amino-3-nirtopyridine, and L4= 2-amino-3-pyridine carboxyaldehyde}. The complexes have been characterized by FT-IR, UV-Vis, 1H-13C NMR and mass spectroscopic methods. X-ray crystallographic studies of the complexes have shown typical piano-stool geometry around the metal centre in which 2-aminopyridyl ligand acts as an N-monodentate ligand and the amino functionality is not involved in metal coordination. The intra/intermolecular arrangement is due to hydrogen bonding.

  20. Enhancement and inhibition of iron photoreduction by individual ligands in open ocean seawater

    Science.gov (United States)

    Rijkenberg, Micha J. A.; Gerringa, Loes J. A.; Carolus, Vicky E.; Velzeboer, Ilona; de Baar, Hein J. W.

    2006-06-01

    In laboratory experiments, we investigated the effect of five individual Fe-binding ligands: phaeophytin, ferrichrome, desferrioxamine B (DFOB), inositol hexaphosphate (phytic acid), and protoporphyrin IX (PPIX) on the Fe(II) photoproduction using seawater of the open Southern Ocean. Addition of 10-100 nM Fe(III) to open Southern Ocean seawater without the model ligands and containing; 1.1 nM dissolved Fe(III), 1.75 ± 0.28 equivalents of nM Fe of natural ligands with a conditional stability constant (log K') of 21.75 ± 0.34 and a concentration DOC of 86.8 ± 1.13 μM C leads to the formation of amorphous Fe(III) hydroxides. These amorphous Fe(III) hydroxides are the major source for the photoproduction of Fe(II). The addition of the model ligands changed the Fe(II) photoproduction considerably and in various ways. Phaeophytin showed higher Fe(II) photoproduction than ferrichrome and the control, i.e., amorphous Fe(III) hydroxides. Additions of phytic acid between 65 and 105 nM increased the concentration of photoproduced Fe(II) with 0.16 nM Fe(II) per nM phytic acid, presumably due to the co-aggregation of Fe(III) and phytic acid leading via an increasing colloidal surface to an increasing photoreducible Fe(III) fraction. DFOB and PPIX strongly decreased the photoproduced Fe(II) concentration. The low Fe(II) photoproduction with DFOB confirmed reported observations that Fe(III) complexed to DFOB is photo-stable. The PPIX hardly binds Fe(III) in the open Southern Ocean seawater but decreased the photoproduced Fe(II) concentration by complexing the Fe(II) with a binding rate constant of kFe(II)PPIX = 1.04 × 10 -4 ± 1.53 × 10 -5 s -1 nM -1 PPIX. Subsequently, PPIX is suggested to act as a photosensitizing producer of superoxide, thus increasing the dark reduction of Fe(III) to Fe(II). Our research shows that the photochemistry of Fe(III) and the resulting photoproduced Fe(II) concentration is strongly depending on the identity of the Fe-binding organic ligands

  1. Stability constants of mercury(II), copper(II), lead(II) and uranium(II)dioxide complexes with pyruvate

    International Nuclear Information System (INIS)

    Potentiometric titration technique is applied to study the complexes of CuII, HgII, PbII and UIIO2 with pyruvate at different ionic strengths and temperatures. 1:1 metal to ligand complexes are formed with the bivalent copper, mercury and lead ions whereas uranyl ion forms 1:1 and 1:2 metal to ligand complexes. The thermodynamic functions, ΔG*, ΔH* and ΔS* are determined. (author)

  2. Lead Test Assembly program

    International Nuclear Information System (INIS)

    Implementation of the new/alternative fuel requires addressing all aspects of the fuel assembly design basis (mechanical, fuel handling, thermal-hydraulic, nuclear design, chemistry, safety analysis and licensing and including mix core effects. The scope of the work is minimized by implementing a Lead Test Assembly (LTA) program with a limited number of assemblies (6 or more), using approved designed features, and placing the LTAs in a unlimited core power location. The topics discussed in the contribution include plant licensing basis and regulatory requirements, plant interface review, compatibility with resident fuel and reactor environment, safety analysis, and post radiation examination. It is concluded that the LTA program is a prudent means of introducing new core designs into existing cores. (P.A.)

  3. Modification of diphenylamine-linked bis(oxazoline) ligands: Tuning of electronic effect and rigidity of ligand skeleton

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    The electronic effect of diphenylamine-linked bis(oxazoline) ligands was tuned through introduction of electron-withdrawing bromo and nitro substituents onto the 4 and 4′ position. The variation of the NH bond acidity was determined by the different chemical shifts of NH. The catalytic activity and enantioselectivity of the modified ligands were tested in the asymmetric Friedel-Crafts alkylation of indole with β-nitrostyrene. The effect of ligand skeleton rigidity was also investigated through the synthesis of iminodibenzyl-linked bis(oxazoline) ligands and evaluation of their catalytic activity in Friedel-Crafts alkylation.

  4. Characterizing mixed phosphonic acid ligand capping on CdSe/ZnS quantum dots using ligand exchange and NMR spectroscopy.

    Science.gov (United States)

    Davidowski, Stephen K; Lisowski, Carmen E; Yarger, Jeffery L

    2016-03-01

    The ligand capping of phosphonic acid functionalized CdSe/ZnS core-shell quantum dots (QDs) was investigated with a combination of solution and solid-state (31) P nuclear magnetic resonance (NMR) spectroscopy. Two phosphonic acid ligands were used in the synthesis of the QDs, tetradecylphosphonic acid and ethylphosphonic acid. Both alkyl phosphonic acids showed broad liquid and solid-state (31) P NMR resonances for the bound ligands, indicative of heterogeneous binding to the QD surface. In order to quantify the two ligand populations on the surface, ligand exchange facilitated by phenylphosphonic acid resulted in the displacement of the ethylphosphonic acid and tetradecylphosphonic acid and allowed for quantification of the free ligands using (31) P liquid-state NMR. After washing away the free ligand, two broad resonances were observed in the liquids' (31) P NMR corresponding to the alkyl and aromatic phosphonic acids. The washed samples were analyzed via solid-state (31) P NMR, which confirmed the ligand populations on the surface following the ligand exchange process. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26639792

  5. Calculating the mean time to capture for tethered ligands and its effect on the chemical equilibrium of bound ligand pairs.

    Science.gov (United States)

    Shen, Lu; Decker, Caitlin G; Maynard, Heather D; Levine, Alex J

    2016-09-01

    We present here the calculation of the mean time to capture of a tethered ligand to the receptor. This calculation is then used to determine the shift in the partitioning between (1) free, (2) singly bound, and (3) doubly bound ligands in chemical equilibrium as a function of the length of the tether. These calculations are used in the research article Fibroblast Growth Factor 2 Dimer with Superagonist in vitro Activity Improves Granulation Tissue Formation During Wound Healing (Decker et al., in press [1]) to explain quantitatively how changes in polymeric linker length in the ligand dimers modifies the efficacy of these molecules relative to that of free ligands. PMID:27408925

  6. Leading from the boardroom.

    Science.gov (United States)

    Lorsch, Jay W; Clark, Robert C

    2008-04-01

    These days, boards are working overtime to comply with Sarbanes-Oxley and other governance requirements meant to protect shareholders from executive wrongdoing. But as directors have become more hands-on with compliance, they've become more hands-off with long-range planning. That exposes corporations and their shareholders to another--perhaps even greater--risk, say professors Lorsch, of Harvard Business School, and Clark, of Harvard Law School. Boards are giving the long term short shrift for a number of reasons. Despite much heavier workloads, directors haven't rethought their patterns of operating - their meetings, committees, and other interactions. Compliance has changed their relationship with executives, however, turning directors into micromanagers who closely probe executives' actions instead of providing high-level guidance. Meanwhile, the pressure to meet quarterly expectations intensifies. Directors need to do a better job of balancing compliance with forward thinking. Boardroom effectiveness hinges most on the quality of directors and their interactions, the authors' research shows. Directors must apply their wisdom broadly, handling compliance work more efficiently and staying out of the weeds on strategic issues. Using their power with management to evangelize for long-term planning, they must take the lead on discussions about financial infrastructure, talent development, and strategy. Reserving sacrosanct time for such discussions, as Philips Electronics' board does at annual retreats, is an effective practice: After one recent retreat, Philips decided to exit the semiconductor business, where it was losing ground. Individual directors also must not shy away from asking tough questions and acting as catalysts on critical issues, such as grooming a successor to the CEO. In short, directors must learn to lead from the boardroom. PMID:18435010

  7. Synthesis, spectroscopic studies and inhibitory activity against bactria and fungi of acyclic and macrocyclic transition metal complexes containing a triamine coumarine Schiff base ligand

    Science.gov (United States)

    Abou-Hussein, A. A.; Linert, Wolfgang

    2015-04-01

    Two series of new mono and binuclear complexes with a Schiff base ligand derived from the condensation of 3-acetylcoumarine and diethylenetriamine, in the molar ratio 2:1 have been prepared. The ligand was characterized by elemental analysis, IR, UV-visible, 1H-NMR and mass spectra. The reaction of the Schiff base ligand with cobalt(II), nickel(II), copper(II), zinc(II) and oxovanadium(IV) lead to mono or binuclear species of cyclic or macrocyclic complexes, depending on the mole ratio of metal to ligand and as well as on the method of preparation. The Schiff base ligand behaves as a cyclic bidentate, tetradendate or pentaentadentae ligand. The formation of macrocyclic complexes depends significantly on the dimension of the internal cavity, the rigidity of the macrocycles, the nature of its donor atoms and on the complexing properties of the anion involved in the coordination. Electronic spectra and magnetic moments of the complexes indicate that the geometries of the metal centers are either square pyramidal or octahedral for acyclic or macro-cyclic complexes. The structures are consistent with the IR, UV-visible, ESR, 1H-NMR, mass spectra as well as conductivity and magnetic moment measurements. The Schiff base ligand and its metal complexes were tested against two pathogenic bacteria as Gram-positive and Gram-negative bacteria as well as one kind of fungi. Most of the complexes exhibit mild antibacterial and antifungal activities against these organisms.

  8. Use of Residual Dipolar Couplings in Structural Analysis of Protein-Ligand Complexes by Solution NMR Spectroscopy

    Science.gov (United States)

    Jain, Nitin U.

    Investigation of structure-function relationships in protein complexes, specifically protein-ligand interactions, carry great significance in elucidating the structural and mechanistic bases of molecular recognition events and their role in regulating cell processes. Nuclear magnetic resonance (NMR) spectroscopy is one of the leading structural and analytical techniques in in-depth studies of protein-ligand interactions. Recent advances in NMR methodology such as transverse relaxation-optimized spectroscopy (TROSY) and residual dipolar couplings (RDCs) measured in liquid crystalline alignment medium, offer a viable alternative to traditional nuclear Overhauser enhancement (NOE)-based approaches for structure determination of large protein complexes. RDCs provide a way to constrain the relative orientation of two molecules in complex with each other by aligning their independently determined order tensors. The potential for utilization of RDCs can be extended to proteins with multiple ligands or even multimeric protein-ligand complexes, where symmetry properties of the protein can be taken advantage of. Availability of effective RDC data collection and analysis protocols can certainly aid this process by their incorporation into structure calculation protocols using intramolecular and intermolecular orientational restraints. This chapter discusses in detail some of these protocols including methods for sample preparation in liquid crystalline media, NMR experiments for RDC data collection, as well as software tools for RDC data analysis and protein-ligand complex structure determination.

  9. Rational design of class I MHC ligands

    Science.gov (United States)

    Rognan, D.; Scapozza, L.; Folkers, G.; Daser, Angelika

    1995-04-01

    From the knowledge of the three-dimensional structure of a class I MHC protein, several non natural peptides were designed in order to either optimize the interactions of one secondary anchor amino acid with its HLA binding pocket or to substitute the non interacting part with spacer residues. All peptides were synthesized and tested for binding to the class I MHC protein in an in vitro reconstitution assay. As predicted, the non natural peptides present an enhanced binding to the HLA-B27 molecule with respect to their natural parent peptides. This study constitutes the first step towards the rational design of non peptidic MHC ligands that should be very promising tools for the selective immunotherapy of autoimmune diseases.

  10. Blockade of Death Ligand TRAIL Inhibits Renal Ischemia Reperfusion Injury

    International Nuclear Information System (INIS)

    Renal ischemia-reperfusion injury (IRI) is a leading cause of acute kidney injury (AKI). Many investigators have reported that cell death via apoptosis significantly contributed to the pathophysiology of renal IRI. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor superfamily, and induces apoptosis and inflammation. However, the role of TRAIL in renal IRI is unclear. Here, we investigated whether TRAIL contributes to renal IRI and whether TRAIL blockade could attenuate renal IRI. AKI was induced by unilateral clamping of the renal pedicle for 60 min in male FVB/N mice. We found that the expression of TRAIL and its receptors were highly upregulated in renal tubular cells in renal IRI. Neutralizing anti-TRAIL antibody or its control IgG was given 24 hr before ischemia and a half-dose booster injection was administered into the peritoneal cavity immediately after reperfusion. We found that TRAIL blockade inhibited tubular apoptosis and reduced the accumulation of neutrophils and macrophages. Furthermore, TRAIL blockade attenuated renal fibrosis and atrophy after IRI. In conclusion, our study suggests that TRAIL is a critical pathogenic factor in renal IRI, and that TRAIL could be a new therapeutic target for the prevention of renal IRI

  11. Cyclic porphyrin dimers as hosts for coordinating ligands

    Indian Academy of Sciences (India)

    G Vaijayanthimala; V Krishnan; S K Mandal

    2008-01-01

    Bicovalently linked tetraphenylporphyrins bearing dioxypentane groups at the opposite (transoid, H4A) and adjacent (cisoid, H4B) aryl groups have been synthesised. Protonation of the free-base porphyrins leads to fully protonated species H8A4+/H8A4+ accompanied by expansion of cavity size of the bisporphyrins. The electrochemical redox studies of these porphyrins and their Zinc(II) derivatives revealed that the first ring oxidation proceeds through a two-electron process while the second ring oxidation occurs at two distinct one-electron steps indicating unsymmetrical charge distribution in the oxidized intermediate. The axial ligation properties of the Zinc(Il) derivatives of H4A/H4B with DABCO and PMDA investigated by spectroscopic and single crystal X-ray diffraction studies showed predominant existence of 1 : I complex. The Zn2A.DABCO complex assumes an interesting eclipsed structure wherein DABCO is located inside the cavity between the two porphyrin planes with Zn-N distances at 2.08 and 2.22 Å. The Zn atoms are pulled into the cavity due to coordination towards nitrogen atoms of DABCO and deviate from the mean porphyrin plane by 0.35 Å. The electrochemical redox potentials of the axially ligated metal derivatives are found to be sensitive function of the relative coordinating ability of the ligands and the conformation of the hosts.

  12. HAIR LEAD CONCENTRATION IN NAKHLAK LEAD MINERS VERSUS CONTROL GROUP

    Directory of Open Access Journals (Sweden)

    N IZADI

    2002-03-01

    Full Text Available Introduction. Lead poisoning is a major problem in environmental health. Exposure can occur via air, soil, food and water. Occupational exposure is the most common source of lead poisoning in adults. Lead miners are exposed to an additional source of poisoning in long term. Hair analysis may be used to evaluate chronic lead toxicity. This study compare the hair lead concentration in Nakhlak lead miners and Mohammadieh people who live 130 km far from the lead mine. Methods. Hair samples from 24 Nakhlak lead miners and 26 adult men of Mohammadieh village were gathered, washed by detergent and distilled water and dissolved by wet digestion. Lead concentrations of the samples were measured by flame atomic absorption spectroscopy. Results. There was a significant difference between hair lead concentration of Nakhlak lead miners and Mohammadieh people (P < 0.001. The mean of lead concentrations were 52.43±27.7 µg/g (mean ± SD and 17.32±3.43 µg/g hair of the lead mine workers and the Mohammadieh people, respectively. There was also a significant regression between the number of exposure years and the lead concentration of hair in Nakhlak lead miners (P < 0.001, r=0.8. Discussion. Presence of lead compounds in work environment especially in the air may be an important factor for the difference between hair lead concentration of Nakhlak lead miners and Mohammadieh people. However, the hair lead concentration in Mohammadieh people is also reasonably high. It means that these people are also exposed to lead through the other sources e.g. food, soil, water and air.

  13. Functionalized pyrazines as ligands for minor actinide extraction and catalysis

    NARCIS (Netherlands)

    Nikishkin, N.

    2013-01-01

    The research presented in this thesis concerns the design of ligands for a wide range of applications, from nuclear waste treatment to catalysis. The strategies employed to design actinide-selective extractants, for instance, comprise the fine tuning of the ligand electronic properties as well as us

  14. Organopalladium complexes with bidentate phosphorus and nitrogen containing ligands

    NARCIS (Netherlands)

    Koten, G. van; Graaf, W. de; Harder, Sjoerd; Boersma, J.; Kanters, J.A.

    1988-01-01

    Organopalladium complexes containing the potentially P, N-bidentate ligands o-diphenylphosphino-N,N-dimethylbenzylamine (PN) and o-diphenylphosphino-@a-methyl-N,N-dimethylbenzylamine (PN}*{) have been studied. The palladium(0) complexes Pd(P@?N){3} (P@?N = PN or PN}*{) have been prepared: the ligand

  15. Polymerization catalysts containing electron-withdrawing amide ligands

    Science.gov (United States)

    Watkin, John G.; Click, Damon R.

    2002-01-01

    The present invention describes methods of making a series of amine-containing organic compounds which are used as ligands for group 3-10 and lanthanide metal compounds. The ligands have electron-withdrawing groups bonded to them. The metal compounds, when combined with a cocatalyst, are catalysts for the polymerization of olefins.

  16. Influence of the platform in multicoordinate ligands for actinide partitioning

    NARCIS (Netherlands)

    Dam, Henk H.; Reinhoudt, David N.; Verboom, Willem

    2007-01-01

    Multicoordinate ligands based on the trityl, C-pivot, and CTV platforms and the ligating groups CMPO, DGA, PICO, and MPMA were synthesized and studied for their extraction properties. The extraction efficiencies of these multicoordinate ligands are largely influenced by the properties of the platfor

  17. Immobilisation of ligands by radio-derivatized polymers

    International Nuclear Information System (INIS)

    The invention relates to radio-derivatized polymers and a method of producing them by contacting non-polymerizable conjugands with radiolysable polymers in the presence of irradiation. The resulting radio-derivatized polymers can be further linked with ligand of organic or inorganic nature to immobilize such ligands. 2 figs., 5 tabs

  18. Competitive antagonism of AMPA receptors by ligands of different classes

    DEFF Research Database (Denmark)

    Hogner, Anders; Greenwood, Jeremy R; Liljefors, Tommy;

    2003-01-01

    -(phosphonomethoxy)-4-isoxazolyl]propionic acid (ATPO) in complex with the ligand-binding core of the receptor. Comparison with the only previous structure of the ligand-binding core in complex with an antagonist, 6,7-dinitro-2,3-quinoxalinedione (DNQX) (Armstrong, N.; Gouaux, E. Neuron 2000, 28, 165-181), reveals...

  19. Mechanochemical synthesis of mixed-ligand europium β-diketonates with nitrogen-containing neutral ligands

    International Nuclear Information System (INIS)

    The solid-phase reaction between europium salts of β-diketones and nitrogen-containing neutral ligands in a planetary mill produces luminescent mixed-ligand compounds Eu(β-dic)3 · D, where β-dic stands for dibenzoylmethane, benzoylacetone, thenoyltrifluoroacetone, or benzoyltrifluoroacetone; and D stands for 1,10-phenanthroline, 2,2-dipyridyl, or diphenylguanidine. The mechanosynthesis and yield of lanthanide β-diketonates are studied as affected by the treatment parameters and the nature of the reagents. Powder X-ray diffraction demonstrates a staged course of the mechanochemical synthesis. Examination of formation-rate curves shows that grinding/stirring is the rate-controlling stage of the process. Thermogravimetric analysis shows that the mechanosynthesis can proceed in the self-propagation mode. The relative luminescence intensity is determined as a function of treatment time. Particles of the mechanically activated mixture have sizes of 10-100 μm

  20. Polymorphism of lead oxoborate

    Energy Technology Data Exchange (ETDEWEB)

    Tyulyupa, A.G. [Middle School, Sablinskoe, Stavropol region, 356322 (Russian Federation); Voronov, V.V. [A.M. Prokhorov General Physics Institute RAS, 38 Vavilov Street, Moscow 119991 (Russian Federation); Fedorov, P.P., E-mail: ppfedorov@yandex.ru [A.M. Prokhorov General Physics Institute RAS, 38 Vavilov Street, Moscow 119991 (Russian Federation)

    2015-07-20

    Highlights: • Pb{sub 4}B{sub 2}O{sub 7} melt undergoes statistical undercooling. • Orthorhombic nonlinear optical crystal Pb{sub 4}O(BO{sub 3}){sub 2} is the metastable γ-polymorph. • Temperature of metastable melting of γ-Pb{sub 4}O(BO{sub 3}){sub 2} is equal to 530 °C. - Abstract: The study of lead borate melt crystallization by differential thermal analysis (DTA) and X-ray diffraction analysis has shown that, for Pb{sub 4}O(BO{sub 3}){sub 2} (or 4PbO·B{sub 2}O{sub 3}) stoichiometric compound, its well-known orthorhombic modification (non-centrosymmetric Aba2 space symmetry group (SSG), a = 15.472(1), b = 10.802(1), c = 9.9486(6) Å unit cell parameters) is metastable. It forms from the undercooled melt and has a melting point of 530 ± 5 °C.

  1. A response calculus for immobilized T cell receptor ligands

    DEFF Research Database (Denmark)

    Andersen, P S; Menné, C; Mariuzza, R A;

    2001-01-01

    To address the molecular mechanism of T cell receptor (TCR) signaling, we have formulated a model for T cell activation, termed the 2D-affinity model, in which the density of TCR on the T cell surface, the density of ligand on the presenting surface, and their corresponding two-dimensional affini...... affinity in solution, are of optimal two-dimensional affinity thereby allowing effective TCR binding under physiological conditions, i.e. at low ligand densities in cellular interfaces....... determine the level of T cell activation. When fitted to T cell responses against purified ligands immobilized on plastic surfaces, the 2D-affinity model adequately simulated changes in cellular activation as a result of varying ligand affinity and ligand density. These observations further demonstrated the...

  2. Labeling of amine ligands with sup(99m)Tc in aqueous solutions by ligand exchange

    Energy Technology Data Exchange (ETDEWEB)

    Volkert, W.A.; Troutner, D.E.; Holmes, R.A. (Missouri Univ., Columbia (USA). Dept. of Radiology; Missouri Univ., Columbia (USA). Dept. of Chemistry; Harry S. Truman Memorial Veterans Hospital, Columbia, MO (USA). Nuclear Medicine Service)

    1982-10-01

    Cyclam, ethylenediamine (EN) and a linear tetraamine (TA) form structurally similar complexes in high yields when pertechnetate is reduced with Sn(II) in aqueous solutions. Efficient labeling of these amine ligands is also accomplished by transfer of sup(99m)Tc from its complexes with diethylenetriaminepentaacetate (DTPA) and citrate. The labeling yields of cyclam, TA and EN using (sup(99m)Tc)DTPA are greater than 95% after standing for 30 min at room temperature in 0.03 M solutions of the amine ligands at pH above 11, but less than 10% at pH below 9. Yields of greater than 90% are obtained using (sup(99m)Tc)citrate under similar conditions at pH 7 or greater. Ethylenediamine-N,N'-diacetic acid (ENDA) also forms a complex with sup(99m)Tc that exhibits pH dependent stability characteristics that are the same as those of (sup(99m)Tc)EN. The labeling efficiency of ENDA with sup(99m)Tc as a function of pH is nearly identical to that of the other amine ligands.

  3. Ligand Symmetry Modulation for Designing Mixed-Ligand Metal-Organic Frameworks: Gas Sorption and Luminescence Sensing Properties.

    Science.gov (United States)

    Chen, Di-Ming; Tian, Jia-Yue; Liu, Chun-Sen

    2016-09-01

    Herein, we report the synthesis of a new mixed-linker Zn(II)-based metal-organic framework (MOF), {[Zn2(atz)2(bpydb)](DMA)8}n (1) (atz = deprotonated 3-amino-1,2,4-triazole, bpydb = deprotonated 4,4'-(4,4'-bipyridine-2,6-diyl) dibenzoic acid, DMA = N,N-dimethylacetamide), through symmetry modulation of a triazole ligand. The desymmetrized triazole linkers not only bond to the Zn(II) ions to result in a new helical Zn-triazolate chain building unit but also lead to the formation of a highly porous framework (N2 uptake: 617 cm(3)/g; BET surface area: 2393 m(2)/g) with 1D helical channels. The adsorption properties of desolved 1 were investigated by H2, C2H2, CO2, and CH4 sorption experiments, which showed that 1 exhibited high uptake capacity for H2 at 77 K and C2H2 around room temperature. More importantly, the high C2H2 uptake capacity but low binding energy makes this MOF a promising candidate for effective C2H2 capture from C2H2/CO2 and C2H2/CH4 mixed gases with low regenerative energy cost. In addition, 1 shows potential application for the luminescence sensing of small aromatic molecules picric acid (PA) and p-xylene (PX). PMID:27494087

  4. Leading Your Leaders

    Science.gov (United States)

    Hale, Wayne N.

    2008-01-01

    life is good. More often when an unbelievably difficult test fails, we are left with a very long discussion of why and what was wrong in the design or execution of the test. Make sure that the test is well defined. Even then, it is important to explain to your leaders what inherent accuracy (or error) the test conditions or equipment have and what the assumptions or initial conditions were for the test. Test results without a good understanding of the test's accuracy or the pedigree of the test assumptions are worth very little. Finally, there is flight test data. Always limited, never at the edge of the envelope, it still shows how the real hardware works in a combined environment. Flight experience is dangerous because it typically doesn't show how close to the edge of the cliff the equipment is operating, but it does demonstrate how the hardware really works. A flight test is the ultimate test, again taken with the knowledge that it is probably not the extreme but something more like the middle of the environmental and systems performance. Good understanding of a problem and its solution always relies on a combination of all these methods. Be sure to lead your leaders by using all the tools you have at your disposal. At the end of the day, decisions in space flight always come down to a risk trade. Our business is not remotely safe, not in the sense that the public, the media, or our legislators use the term. Everything we do has a risk, cost, schedule, or performance trade-off. For your leaders to make an appropriate decision, you need to educate them, lead them, talk with them, and engage them in the discussion until full understanding takes place. It's your job. *

  5. Investigation of the Novel Lead of Melanocortin 1 Receptor for Pigmentary Disorders

    OpenAIRE

    Hsin-Chieh Tang; Calvin Yu-Chian Chen

    2014-01-01

    Knowing the role of MC1R in skin tanning can provide a brand new idea to resolve pigmentary disorders. α MSH has 13 amino acids and is the most essential pigmentary melanocortin responsible for melanin synthesis. One could utilize the compound library to find lead compounds by virtual screening from peptide database and traditional Chinese medicine (TCM) database@Taiwan. Computational simulation provided a convenient technology to survey potential lead. Ligand-based validation set up the reli...

  6. Regulation mechanisms of the FLT3-ligand after irradiation

    International Nuclear Information System (INIS)

    The hematopoietic compartment is one of the most severely damaged after chemotherapy, radiotherapy or accidental irradiations. Whatever its origin, the resulting damage to the bone marrow remains difficult to evaluate. Thus, it would be of great interest to get a biological indicator of residual hematopoiesis in order to adapt the treatment to each clinical situation. Recent results indicated that the plasma Flt3 ligand concentration was increased in patients suffering from either acquired or induced aplasia, suggesting that Flt3 ligand might be useful as a biological indicator of bone marrow status. We thus followed in a mouse model as well as in several clinical situations the variations in plasma Flt3 ligand concentration, after either homogeneous or heterogeneous irradiations. These variations were correlated to the number of hematopoietic progenitors and to other parameters such as duration and depth of pancytopenia. The results indicated that the concentration of Flt3 ligand in the blood reflects the bone marrow status, and that the follow-up of plasma Flt3 ligand concentration could give predictive information about the bone marrow function and the duration and severity of pancytopenia and thrombocytopenia. Nevertheless, the clinical use of Flt3 ligand as a biological indicator of bone marrow damage require the knowledge of the mechanisms regulating the variations in plasma Flt3 ligand concentration. We thus developed a study in the mouse model. The results indicated that the variations in plasma Flt3 ligand variations were not solely due to a balance between its production by lymphoid cells and its consumption by hematopoietic cells. Moreover, we showed that T lymphocytes are not the main regulator of plasma Flt3 ligand concentration as previously suggested, and that other cell types, possibly including bone marrow stromal cells, might be strongly implicated. These results also suggest that the Flt3 ligand is a main systemic regulator of hematopoiesis

  7. Metrical oxidation states of 2-amidophenoxide and catecholate ligands: structural signatures of metal-ligand π bonding in potentially noninnocent ligands.

    Science.gov (United States)

    Brown, Seth N

    2012-02-01

    Catecholates and 2-amidophenoxides are prototypical "noninnocent" ligands which can form metal complexes where the ligands are best described as being in the monoanionic (imino)semiquinone or neutral (imino)quinone oxidation state instead of their closed-shell dianionic form. Through a comprehensive analysis of structural data available for compounds with these ligands in unambiguous oxidation states (109 amidophenolates, 259 catecholates), the well-known structural changes in the ligands with oxidation state can be quantified. Using these correlations, an empirical "metrical oxidation state" (MOS) which gives a continuous measure of the apparent oxidation state of the ligand can be determined based on least-squares fitting of its C-C, C-O, and C-N bond lengths to this single parameter (a simple procedure for doing so is provided via a spreadsheet in the Supporting Information). High-valent d(0) metal complexes, particularly those of vanadium(V) and molybdenum(VI), have ligands with unexpectedly positive, and generally nonintegral, MOS values. The structural effects in these complexes are attributed not to electron transfer, but rather to amidophenoxide- or catecholate-to-metal π bonding, an interpretation supported by the systematic variation of the MOS values as a function of the degree of competition with the other π-donating groups in the structures. PMID:22260321

  8. Leading clever people.

    Science.gov (United States)

    Goffee, Rob; Jones, Gareth

    2007-03-01

    In an economy driven by ideas and intellectual know-how, top executives recognize the importance of employing smart, highly creative people. But if clever people have one defining characteristic, it's that they do not want to be led. So what is a leader to do? The authors conducted more than 100 interviews with leaders and their clever people at major organizations such as PricewaterhouseCoopers, Cisco Systems, Novartis, the BBC, and Roche. What they learned is that the psychological relationships effective leaders have with their clever people are very different from the ones they have with traditional followers. Those relationships can be shaped by seven characteristics that clever people share: They know their worth--and they know you have to employ them if you want their tacit skills. They are organizationally savvy and will seek the company context in which their interests are most generously funded. They ignore corporate hierarchy; although intellectual status is important to them, you can't lure them with promotions. They expect instant access to top management, and if they don't get it, they may think the organization doesn't take their work seriously. They are plugged into highly developed knowledge networks, which both increases their value and makes them more of a flight risk. They have a low boredom threshold, so you have to keep them challenged and committed. They won't thank you--even when you're leading them well. The trick is to act like a benevolent guardian: to grant them the respect and recognition they demand, protect them from organizational rules and politics, and give them room to pursue private efforts and even to fail. The payoff will be a flourishing crop of creative minds that will enrich your whole organization. PMID:17348171

  9. Supramolecular self-assembled polynuclear complexes from tritopic, tetratopic, and pentatopic ligands: structural, magnetic and surface studies.

    Science.gov (United States)

    Dey, Subrata K; Abedin, Tareque S M; Dawe, Louise N; Tandon, Santokh S; Collins, Julie L; Thompson, Laurence K; Postnikov, Andrei V; Alam, Mohammad S; Müller, Paul

    2007-09-17

    Polymetallic, highly organized molecular architectures can be created by "bottom-up" self-assembly methods using ligands with appropriately programmed coordination information. Ligands based on 2,6-picolyldihydrazone (tritopic and pentatopic) and 3,6-pyridazinedihydrazone (tetratopic) cores, with tridentate coordination pockets, are highly specific and lead to the efficient self-assembly of square [3 x 3] Mn9, [4 x 4] Mn16, and [5 x 5] Mn25 nanoscale grids. Subtle changes in the tritopic ligand composition to include bulky end groups can lead to a rectangular 3 x [1 x 3] Mn9 grid, while changing the central pyridazine to a more sterically demanding pyrazole leads to simple dinuclear copper complexes, despite the potential for binding four metal ions. The creation of all bidentate sites in a tetratopic pyridazine ligand leads to a dramatically different spiral Mn4 strand. Single-crystal X-ray structural data show metallic connectivity through both mu-O and mu-NN bridges, which leads to dominant intramolecular antiferromagnetic spin exchange in all cases. Surface depositions of the Mn9, Mn16, and Mn25 square grid molecules on graphite (HOPG) have been examined using STM/CITS imagery (scanning tunneling microscopy/current imaging tunneling spectroscopy), where tunneling through the metal d-orbital-based HOMO levels reveals the metal ion positions. CITS imagery of the grids clearly shows the presence of 9, 16, and 25 manganese ions in the expected square grid arrangements, highlighting the importance and power of this technique in establishing the molecular nature of the surface adsorbed species. Nanoscale, electronically functional, polymetallic assemblies of this sort, created by such a bottom-up synthetic approach, constitute important components for advanced molecule-based materials. PMID:17696336

  10. Gas adsorption and gas mixture separations using mixed-ligand MOF material

    Science.gov (United States)

    Hupp, Joseph T.; Mulfort, Karen L.; Snurr, Randall Q.; Bae, Youn-Sang

    2011-01-04

    A method of separating a mixture of carbon dioxiode and hydrocarbon gas using a mixed-ligand, metal-organic framework (MOF) material having metal ions coordinated to carboxylate ligands and pyridyl ligands.

  11. Tunable volatile organic compounds sensor by using thiolated ligand conjugation on MoS2.

    Science.gov (United States)

    Kim, Jong-Seon; Yoo, Hae-Wook; Choi, Hyung Ouk; Jung, Hee-Tae

    2014-10-01

    One of the most important issues in the development of gas sensors for breath analysis is the fabrication of gas sensor arrays that possess different responses for recognizing patterns for volatile organic compounds (VOCs). Here, we develop a high-performance chemiresistor with a tunable sensor response and high sensitivity for representative VOC groups by using molybdenum disulfide (MoS2) and by conjugating a thiolated ligand (mercaptoundecanoic acid (MUA)) to MoS2 surface. Primitive and MUA-conjugated MoS2 sensing channels exhibit distinctly different sensor responses toward VOCs. In particular, the primitive MoS2 sensor presents positive responses for oxygen-functionalized VOCs, while the MUA-conjugated MoS2 sensor presents negative responses for the same analytes. Such characteristic sensor responses demonstrate that ligand conjugation successfully adds functionality to a MoS2 matrix. Thus, this will be a promising approach to constructing a versatile sensor array, by conjugating a wide variety of thiolated ligands on the MoS2 surface. Furthermore, these MoS2 sensors in this study exhibit high sensitivity to representative VOCs down to a concentration of 1 ppm. This approach to fabricating a tunable and sensitive VOC sensor may lead to a valuable real-world application for lung cancer diagnosis by breath analysis. PMID:25191976

  12. Biomolecular ligands screening using radiation damping difference WaterLOGSY spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Sun Peng; Jiang Xianwang; Jiang Bin; Zhang Xu, E-mail: zhangxu@wipm.ac.cn; Liu Maili, E-mail: ml.liu@wipm.ac.cn [Chinese Academy of Sciences, Wuhan Center for Magnetic Resonance, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Institute of Physics and Mathematics (China)

    2013-07-15

    Water-ligand observed via gradient spectroscopy (WaterLOGSY) is a widely used nuclear magnetic resonance method for ligand screening. The crucial procedure for the effectiveness of WaterLOGSY is selective excitation of the water resonance. The selective excitation is conventionally achieved by using long selective pulse, which causes partial saturation of the water magnetization leading to reduction of sensitivity, in addition to time consuming and error prone. Therefore, many improvements have been made to enhance the sensitivity and robustness of the method. Here we propose an alternative selective excitation scheme for WaterLOGSY by utilizing radiation damping effect. The pulse scheme starts simply with a hard inversion pulse, instead of selective pulse or pulse train, followed by a pulse field gradient to control the radiation damping effect. The rest parts of the pulse scheme are similar to conventional WaterLOGSY. When the gradient pulse is applied immediately after the inversion pulse, the radiation damping effect is suppressed, and all of the magnetization is inversed. When the gradient pulse and the inversion pulse are about 10-20 ms apart, the radiation damping effect remains active and drives the water magnetization toward +z-axis, resulting in selective non-inversion of the water magnetization. By taking the differences of the spectra obtained under these two conditions, one should get the result of WaterLOGSY. The method is demonstrated to be simple, robust and sensitive for ligand screening.

  13. Biomolecular ligands screening using radiation damping difference WaterLOGSY spectroscopy.

    Science.gov (United States)

    Sun, Peng; Jiang, Xianwang; Jiang, Bin; Zhang, Xu; Liu, Maili

    2013-07-01

    Water-ligand observed via gradient spectroscopy (WaterLOGSY) is a widely used nuclear magnetic resonance method for ligand screening. The crucial procedure for the effectiveness of WaterLOGSY is selective excitation of the water resonance. The selective excitation is conventionally achieved by using long selective pulse, which causes partial saturation of the water magnetization leading to reduction of sensitivity, in addition to time consuming and error prone. Therefore, many improvements have been made to enhance the sensitivity and robustness of the method. Here we propose an alternative selective excitation scheme for WaterLOGSY by utilizing radiation damping effect. The pulse scheme starts simply with a hard inversion pulse, instead of selective pulse or pulse train, followed by a pulse field gradient to control the radiation damping effect. The rest parts of the pulse scheme are similar to conventional WaterLOGSY. When the gradient pulse is applied immediately after the inversion pulse, the radiation damping effect is suppressed, and all of the magnetization is inversed. When the gradient pulse and the inversion pulse are about 10-20 ms apart, the radiation damping effect remains active and drives the water magnetization toward +z-axis, resulting in selective non-inversion of the water magnetization. By taking the differences of the spectra obtained under these two conditions, one should get the result of WaterLOGSY. The method is demonstrated to be simple, robust and sensitive for ligand screening. PMID:23740293

  14. Synthesis of ligand-free CZTS nanoparticles via a facile hot injection route

    Science.gov (United States)

    Mirbagheri, N.; Engberg, S.; Crovetto, A.; Simonsen, S. B.; Hansen, O.; Lam, Y. M.; Schou, J.

    2016-05-01

    Single-phase, ligand-free Cu2ZnSnS4 (CZTS) nanoparticles that can be dispersed in polar solvents are desirable for thin film solar cell fabrication, since water can be used as the solvent for the nanoparticle ink. In this work, ligand-free nanoparticles were synthesized using a simple hot injection method and the precursor concentration in the reaction medium was tuned to control the final product. The as-synthesized nanoparticles were characterized using various techniques, and were found to have a near-stoichiometric composition and a phase-pure kesterite crystal structure. No secondary phases were detected with Raman spectroscopy or scanning transmission electron microscopy energy dispersive x-ray spectroscopy. Furthermore, high resolution transmission electron microscopy showed large-sized nanoparticles with an average diameter of 23 nm ± 11 nm. This approach avoids all organic materials and toxic solvents that otherwise could hinder grain growth and limit the deposition techniques. In addition the synthesis route presented here results in nanoparticles of a large size compared to other ligand-free CZTS nanoparticles, due to the high boiling point of the solvents selected. Large particle size in CZTS nanoparticle solar cells may lead to a promising device performance. The results obtained demonstrate the suitability of the synthesized nanoparticles for application in low cost thin film solar cells.

  15. Isolation of atomically precise mixed ligand shell PdAu24 clusters

    Science.gov (United States)

    Sels, Annelies; Barrabés, Noelia; Knoppe, Stefan; Bürgi, Thomas

    2016-05-01

    Exposure of PdAu24(2-PET)18 (2-PET: 2-phenylethylthiolate) to BINAS (1,1-binaphthyl-2,2-dithiol) leads to species of composition PdAu24(2-PET)18-2x(BINAS)x due to ligand exchange reactions. The BINAS adsorbs in a specific mode that bridges the apex and one core site of two adjacent S(R)-Au-S(R)-Au-S(R) units. Species with different compositions of the ligand shell can be separated by HPLC. Furthermore, site isomers can be separated. For the cluster with exactly one BINAS in its ligand shell only one isomer is expected due to the symmetry of the cluster, which is confirmed by High-Performance Liquid Chromatography (HPLC). Addition of a second BINAS to the ligand shell leads to several isomers. In total six distinguishable isomers are possible for PdAu24(2-PET)14(BINAS)2 including two pairs of enantiomers concerning the adsorption pattern. At least four distinctive isomers are separated by HPLC. Calculations indicate that one of the six possibilities is energetically disfavoured. Interestingly, diastereomers, which have an enantiomeric relationship concerning the adsorption pattern of chiral BINAS, have significantly different stabilities. The relative intensity of the observed peaks in the HPLC does not reflect the statistical weight of the different isomers. This shows, as supported by the calculations, that the first adsorbed BINAS molecule influences the adsorption of the second incoming BINAS ligand. In addition, experiments with the corresponding Pt doped gold cluster reveal qualitatively the same behaviour, however with slightly different relative abundances of the corresponding isomers. This finding points towards the influence of electronic effects on the isomer distribution. Even for clusters containing more than two BINAS ligands a limited number of isomers were found, which is in contrast to the corresponding situation for monothiols, where the number of possible isomers is much larger.Exposure of PdAu24(2-PET)18 (2-PET: 2-phenylethylthiolate) to BINAS (1

  16. Effects of Na/K-ATPase and its ligands on bone marrow stromal cell differentiation

    Directory of Open Access Journals (Sweden)

    Moustafa Sayed

    2014-07-01

    Full Text Available Endogenous ligands of Na/K-ATPase have been demonstrated to increase in kidney dysfunction and heart failure. It is also reported that Na/K-ATPase signaling function effects stem cell differentiation. This study evaluated whether Na/K-ATPase activation through its ligands and associated signaling functions affect bone marrow stromal cells (BMSCs, also known as bone marrow-derived mesenchymal stem cells differentiation capacity. BMSCs were isolated from male Sprague–Dawley rats and cultured in minimal essential medium alpha (MEM-α supplemented with 15% Fetal Bovine serum (FBS. The results showed that marinobufagenin (MBG, a specific Na/K-ATPase ligand, potentiated rosiglitazone-induced adipogenesis in these BMSCs. Meanwhile, it attenuated BMSC osteogenesis. Mechanistically, MBG increased CCAAT/enhancer binding protein alpha (C/EBPα protein expression through activation of an extracellular regulated kinase (ERK signaling pathway, which leads to enhanced rosiglitazone-induced adipogenesis. Inhibition of ERK activation by U0126 blocks the effect of MBG on C/EBPα expression and on rosiglitazone-induced adipogenesis. Reciprocally, MBG reduced runt-related transcription factor 2 (RunX2 expression, which resulted in the inhibition of osteogenesis induced by β-glycerophosphate/ascorbic acid. MBG also potentiated rosiglitazone-induced adipogenesis in 3T3-L1 cells and in mouse BMSCs. These results suggest that Na/K-ATPase and its signaling functions are involved in the regulation of BMSCs differentiation.

  17. Capillary bioreactors based on human purine nucleoside phosphorylase: a new approach for ligands identification and characterization.

    Science.gov (United States)

    de Moraes, Marcela Cristina; Ducati, Rodrigo Gay; Donato, Augusto José; Basso, Luiz Augusto; Santos, Diógenes Santiago; Cardoso, Carmen Lucia; Cass, Quezia Bezerra

    2012-04-01

    The enzyme purine nucleoside phosphorylase (PNP) is a target for the discovery of new lead compounds employed on the treatment severe T-cell mediated disorders. Within this context, the development of new, direct, and reliable methods for ligands screening is an important task. This paper describes the preparation of fused silica capillaries human PNP (HsPNP) immobilized enzyme reactor (IMER). The activity of the obtained IMER is monitored on line in a multidimensional liquid chromatography system, by the quantification of the product formed throughout the enzymatic reaction. The K(M) value for the immobilized enzyme was about twofold higher than that measured for the enzyme in solution (255 ± 29.2 μM and 133 ± 14.9 μM, respectively). A new fourth-generation immucillin derivative (DI4G; IC(50)=40.6 ± 0.36 nM), previously identified and characterized in HsPNP free enzyme assays, was used to validate the IMER as a screening method for HsPNP ligands. The validated method was also used for mechanistic studies with this inhibitor. This new approach is a valuable tool to PNP ligand screening, since it directly measures the hypoxanthine released by inosine phosphorolysis, thus furnishing more reliable results than those one used in a coupled enzymatic spectrophotometric assay. PMID:22099222

  18. Molecular evolution of a peptide GPCR ligand driven by artificial neural networks.

    Directory of Open Access Journals (Sweden)

    Sebastian Bandholtz

    Full Text Available Peptide ligands of G protein-coupled receptors constitute valuable natural lead structures for the development of highly selective drugs and high-affinity tools to probe ligand-receptor interaction. Currently, pharmacological and metabolic modification of natural peptides involves either an iterative trial-and-error process based on structure-activity relationships or screening of peptide libraries that contain many structural variants of the native molecule. Here, we present a novel neural network architecture for the improvement of metabolic stability without loss of bioactivity. In this approach the peptide sequence determines the topology of the neural network and each cell corresponds one-to-one to a single amino acid of the peptide chain. Using a training set, the learning algorithm calculated weights for each cell. The resulting network calculated the fitness function in a genetic algorithm to explore the virtual space of all possible peptides. The network training was based on gradient descent techniques which rely on the efficient calculation of the gradient by back-propagation. After three consecutive cycles of sequence design by the neural network, peptide synthesis and bioassay this new approach yielded a ligand with 70fold higher metabolic stability compared to the wild type peptide without loss of the subnanomolar activity in the biological assay. Combining specialized neural networks with an exploration of the combinatorial amino acid sequence space by genetic algorithms represents a novel rational strategy for peptide design and optimization.

  19. Electronic spectra and photophysics of platinum(II) complexes with alpha-diimine ligands - Solid-state effects. I - Monomers and ligand pi dimers

    Science.gov (United States)

    Miskowski, Vincent M.; Houlding, Virginia H.

    1989-01-01

    Two types of emission behavior for Pt(II) complexes containing alpha-diimine ligands have been observed in dilute solution. If the complex also has weak field ligands such as chloride, ligand field (d-d) excited states become the lowest energy excited states. If only strong field ligands are present, a diimine 3(pi-pi/asterisk/) state becomes the lowest. In none of the cases studied did metal-to-ligand charge transfer excited state lie lowest.

  20. Regulation mechanisms of the FLT3-ligand after irradiation; Mecanismes de regulation du FLT3-ligand apres irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Prat-Lepesant, M

    2005-06-15

    The hematopoietic compartment is one of the most severely damaged after chemotherapy, radiotherapy or accidental irradiations. Whatever its origin, the resulting damage to the bone marrow remains difficult to evaluate. Thus, it would be of great interest to get a biological indicator of residual hematopoiesis in order to adapt the treatment to each clinical situation. Recent results indicated that the plasma Flt3 ligand concentration was increased in patients suffering from either acquired or induced aplasia, suggesting that Flt3 ligand might be useful as a biological indicator of bone marrow status. We thus followed in a mouse model as well as in several clinical situations the variations in plasma Flt3 ligand concentration, after either homogeneous or heterogeneous irradiations. These variations were correlated to the number of hematopoietic progenitors and to other parameters such as duration and depth of pancytopenia. The results indicated that the concentration of Flt3 ligand in the blood reflects the bone marrow status, and that the follow-up of plasma Flt3 ligand concentration could give predictive information about the bone marrow function and the duration and severity of pancytopenia and thrombocytopenia. Nevertheless, the clinical use of Flt3 ligand as a biological indicator of bone marrow damage require the knowledge of the mechanisms regulating the variations in plasma Flt3 ligand concentration. We thus developed a study in the mouse model. The results indicated that the variations in plasma Flt3 ligand variations were not solely due to a balance between its production by lymphoid cells and its consumption by hematopoietic cells. Moreover, we showed that T lymphocytes are not the main regulator of plasma Flt3 ligand concentration as previously suggested, and that other cell types, possibly including bone marrow stromal cells, might be strongly implicated. These results also suggest that the Flt3 ligand is a main systemic regulator of hematopoiesis

  1. Lead pollution sources and Impacts

    International Nuclear Information System (INIS)

    Despite the medical awareness of lead toxicity, and despite legislation designed to reduce environmental contamination, lead is one of the most widely used heavy metals. Significant human exposure occurs from automobile exhaust fumes, cigarette smoking, lead-based paints and plumbing systems lead spread in the environment can take place in several ways, the most important of which is through the lead compounds released in automobile exhaust as a direct result of the addition of tetraethyl or tetraethyl lead to gasoline as octane boosting agents. Of special is the effect of lead pollution on children, which affects their behavioral and educational attributes considerably. The major channel through through which lead is absorbed is through inhalation of lead compounds in the atmosphere. Lead is a heavy metal characterized its malleability, ductility and poor conduction of electricity. So, it has a wide range of applications ranging from battery manufacturing to glazing ceramics. It is rarely found free in nature but is present in several minerals and compounds. The aim of this paper is to discuss natural and anthropogenic sources of lead together with its distribution and trends with emphasis on egypt. The effects of lead pollution on human health, vegetation and welfare are also presented. It could be concluded that, the excessive release of lead into the environment, especially through the atmosphere, can produce many detrimental and sometimes fatal effects on human, agriculture and zoological life. Besides, it is very plain that there is a serious problem of pollution lead in egypt and specially in cairo. 7 figs

  2. SOLUBLE CD40 LIGAND IN DEMENTIA

    OpenAIRE

    Giunta, B.; Figueroa, K P; Town, T.; Tan, J.

    2009-01-01

    Some 15–20% of the population over the age of 65 years suffer from dementia, currently one of the leading causes of death behind cardiovascular diseases, cancer and cerebrovascular diseases. The major forms of dementia share in common overactivation of the CD40-CD40-L complex, leading to high levels of proinflammatory cytokine production by immune cells of the central nervous system (CNS), including microglia and astrocytes. Consequently, both neuronal survival and signaling are negatively af...

  3. Lanthanide mixed ligand chelates for DNA profiling and latent fingerprint detection

    Science.gov (United States)

    Menzel, E. R.; Allred, Clay

    1997-02-01

    It is our aim to develop a universally applicable latent fingerprint detection method using lanthanide (rare-earth) complexes as a source of luminescence. Use of these lanthanide complexes offers advantages on several fronts, including benefits from large Stokes shifts, long luminescence lifetimes, narrow emissions, ability of sequential assembly of complexes, and chemical variability of the ligands. Proper exploitation of these advantages would lead to a latent fingerprint detection method superior to any currently available. These same characteristics also lend themselves to many of the problems associated with DNA processing in the forensic science context.

  4. Decontamination and coating of lead

    International Nuclear Information System (INIS)

    Technology is being developed to decontaminate lead used in shielding applications in contaminated environments for recycle as shieldings. Technology is also being developed to coat either decontaminated lead or new lead before it is used in contaminated environments. The surface of the coating is expected to be much easier to decontaminate than the original lead surface. If contamination becomes severely embedded in the coating and cannot be removed, it can be easily cut with a knife and removed from the lead. The used coating can be disposed of as radioactive (hot hazardous) waste. The lead can then be recoated for further use as a shielding material

  5. Leaded gasoline - an environmental problem

    International Nuclear Information System (INIS)

    In the European countries it is a clear trend towards the increasing consumption of unleaded gasolines. Driving force of this trend is, on the one hand the high toxicity of lead compounds and on the other, the necessity of purification of exhaust gases by catalytic converters, for which the lead represent a catalyst poison. In Macedonia, the limit lead content in the leaded gasolines is relatively high (0,6 g/l), as well as the consumption of the leaded gasolines. Rapid and complete transition to unleaded gasolines can be realized by the concept of step by step reduction of lead in our gasolines. (Original)

  6. Dopamine D3 receptor ligands for drug addiction treatment: update on recent findings.

    Science.gov (United States)

    Le Foll, Bernard; Collo, Ginetta; Rabiner, Eugenii A; Boileau, Isabelle; Merlo Pich, Emilio; Sokoloff, Pierre

    2014-01-01

    The dopamine D3 receptor is located in the limbic area and apparently mediates selective effects on motivation to take drugs and drug-seeking behaviors, so that there has been considerable interest on the possible use of D3 receptor ligands to treat drug addiction. However, only recently selective tools allowing studying this receptor have been developed. This chapter presents an overview of findings that were presented at a symposium on the conference Dopamine 2013 in Sardinia in May 2013. Novel neurobiological findings indicate that drugs of abuse can lead to significant structural plasticity in rodent brain and that this is dependent on the availability of functional dopamine D3 autoreceptor, whose activation increased phosphorylation in the ERK pathway and in the Akt/mTORC1 pathway indicating the parallel engagement of a series of intracellular signaling pathways all involved in cell growth and survival. Preclinical findings using animal models of drug-seeking behaviors confirm that D3 antagonists have a promising profile to treat drug addiction across drugs of abuse type. Imaging the D3 is now feasible in human subjects. Notably, the development of (+)-4-propyl-9-hydroxynaphthoxazine ligand used in positron emission tomography (PET) studies in humans allows to measure D3 and D2 receptors based on the area of the brain under study. This PET ligand has been used to confirm up-regulation of D3 sites in psychostimulant users and to reveal that tobacco smoking produces elevation of dopamine at the level of D3 sites. There are now novel antagonists being developed, but also old drugs such as buspirone, that are available to test the D3 hypothesis in humans. The first results of clinical investigations are now being provided. Overall, those recent findings support further exploration of D3 ligands to treat drug addiction. PMID:24968784

  7. Expression of mammalian GPCRs in C. elegans generates novel behavioural responses to human ligands

    Directory of Open Access Journals (Sweden)

    Jansen Gert

    2006-07-01

    Full Text Available Abstract Background G-protein-coupled receptors (GPCRs play a crucial role in many biological processes and represent a major class of drug targets. However, purification of GPCRs for biochemical study is difficult and current methods of studying receptor-ligand interactions involve in vitro systems. Caenorhabditis elegans is a soil-dwelling, bacteria-feeding nematode that uses GPCRs expressed in chemosensory neurons to detect bacteria and environmental compounds, making this an ideal system for studying in vivo GPCR-ligand interactions. We sought to test this by functionally expressing two medically important mammalian GPCRs, somatostatin receptor 2 (Sstr2 and chemokine receptor 5 (CCR5 in the gustatory neurons of C. elegans. Results Expression of Sstr2 and CCR5 in gustatory neurons allow C. elegans to specifically detect and respond to somatostatin and MIP-1α respectively in a robust avoidance assay. We demonstrate that mammalian heterologous GPCRs can signal via different endogenous Gα subunits in C. elegans, depending on which cells it is expressed in. Furthermore, pre-exposure of GPCR transgenic animals to its ligand leads to receptor desensitisation and behavioural adaptation to subsequent ligand exposure, providing further evidence of integration of the mammalian GPCRs into the C. elegans sensory signalling machinery. In structure-function studies using a panel of somatostatin-14 analogues, we identified key residues involved in the interaction of somatostatin-14 with Sstr2. Conclusion Our results illustrate a remarkable evolutionary plasticity in interactions between mammalian GPCRs and C. elegans signalling machinery, spanning 800 million years of evolution. This in vivo system, which imparts novel avoidance behaviour on C. elegans, thus provides a simple means of studying and screening interaction of GPCRs with extracellular agonists, antagonists and intracellular binding partners.

  8. Triazacyclononane Phosphinic Acids (TRAP) as ligands for 68Ga radiopharmaceuticals

    International Nuclear Information System (INIS)

    Gallium-68 radiopharmaceuticals are the most interesting alternatives to those based on 18-F. 68-Ga is produced in commercial 68-Ge/68-Ga generator for fraction of the 18-F price. As metal isotope, 68-Ga must be tightly complexed by a suitable ligand. Macrocyclic ligands are the most suitable ones as their Ga3+ complexes are thermodynamically stable and kinetically inert. Till now, 68-Ga radiopharmaceuticals have been based on DOTA and NOTA skeletons but these ligands exhibit non-optimal labelling properties (high excess of the ligand, long heating, narrow pH range etc.). 1,4,9-TRiAzacyclononane Phosphinic acids (TRAP ligands) have been suggested as ligands for the fast and efficient 68-Ga incorporation. Due to low basicity of the phosphinic acid moieties as well as the ring nitrogen atoms, full complexation is possible even in highly acidic solutions (down to pH 1, i.e. pH of the neat generator eluate). Presence of weakly complexing atoms outside the ligand cage (oxygen atoms e.g. in TRAP-Pr or TRAP-OH) facilitates metal isotope incorporation in highly diluted solutions (non-carrier-added conditions) due to increasing effective metal ion concentration close to the macrocyclic cage. As very low excess of the ligands/conjugates is necessary for complexation, very high specific activity can be obtained. Unusual out-of-cage complexes were observed in the Ga-TRAP-OH system where deprotonated P-CH2O- groups participate in the Ga3+ coordination. The efficiency of 68-Ga labelling is also govern by selectivity of the TRAP ligands for Ga3+ over the most common impurities, e.g. Zn2+ and Fe3+ ions. The article is illustrated by the molecular schemes of NOTA, DOTA, TRAP-Pr and TRAP-OH

  9. Niobium tetrahalide complexes with neutral diphosphine ligands.

    Science.gov (United States)

    Benjamin, Sophie L; Chang, Yao-Pang; Hector, Andrew L; Jura, Marek; Levason, William; Reid, Gillian; Stenning, Gavin

    2016-05-10

    The reactions of NbCl4 with diphosphine ligands o-C6H4(PMe2)2, Me2PCH2CH2PMe2 or Et2PCH2CH2PEt2 in a 1 : 2 molar ratio in MeCN solution produced eight-coordinate [NbCl4(diphosphine)2]. [NbBr4(diphosphine)2] (diphosphine = o-C6H4(PMe2)2 or Me2PCH2CH2PMe2) were made similarly from NbBr4. X-ray crystal structures show that [NbCl4{o-C6H4(PMe2)2}2] has a dodecahedral geometry, but the complexes with dimethylene-backboned diphosphines are distorted square antiprisms. The Nb-P distances and niobium tetrabromide, conveniently made from NbCl4 and BBr3, is a chain polymer with edge-linked NbBr6 octahedra and alternating long and short Nb-Nb distances, the latter ascribed to Nb-Nb bonds. PMID:27094082

  10. Synthesis characterization and biological evaluation of a novel mixed ligand 99mTc complex as potential brain imaging agent

    International Nuclear Information System (INIS)

    One approach in the design of neutral oxotechnetium complexes is based on the simultaneous substitution of a tridentate dianionic ligand and a monodentate monoanionic coligand on a [Tc(V)O]+3 precursor. Following this ''mixed ligand'' concept, a novel 99mTc complex with N,N-bis(2-mercaptoethyl)-N'N'-diethylethylenediamine as ligand and 1-octanethiol as coligand is prepared and evaluated as potential brain radiopharmaceutical. Preparation of the complex at tracer level was accomplished by using 99mTc-glucoheptonate as precursor. The substitution was optimized and a coligand/ligand ratio of 5 was selected. Under this conditions the labeling yield was over 80% and a major product (with radiochemical purity > 80%) was isolated by HPLC methods and used for biological evaluation. Chemical characterization at carrier level was developed using the corresponding rhenium complex as structural model. The Re complex was also prepared by substitution method and isolated as a crystalline product. The crystals were characterized by UV-vis and IR spectra and elemental analysis. Results were consistent with the expected ReOLC structure. X ray crystallographic study demonstrated that the complex adopts a distorted trigonal bipyramidal geometry. The basal plane is defined by the SS atoms of the ligand and the oxo group, while the N of the ligand and the S of the colligand occupy the two apical positions. All sulphur atoms underwent ionization leading to the formation of a neutral compound. 99Tc complex was also prepared. Although it was not isolated due to the small amount of reagents employed, the HPLC profile was identical to the one observed for the rhenium complex suggesting the same chemical structure. Biodistribution in mice demonstrated early brain uptake, fast blood clearance, excretion through hepatobiliary system and a brain/blood ratio that increased significantly with time. (author)

  11. Synthesis and study of new oxazoline-based ligands

    OpenAIRE

    Tilliet, Mélanie

    2008-01-01

    This thesis deals with the study of oxazoline-based ligands in metal-catalyzed asymmetric reactions. The first part describes the synthesis of six new bifunctinal pyridine-bis(oxazoline) ligands and their applications in asymmetric metal-catalysis. These ligands, in addition to a Lewis acid coordination site, are equipped with a Lewis basic part in the 4-position of the oxazoline rings. Dual activation by means of this system was probed in cyanide addition to aldehydes. The second part is con...

  12. Quasielastic neutron scattering study of POSS ligand dynamics

    International Nuclear Information System (INIS)

    Poly-oligo-silsesquioxanes (POSS) are relatively large (1-2 nm diameter) molecules, that are composed of Si8O12 cages to which a wide variety of possible ligands can be attached. Depending on the nature of the ligand, interesting properties and applications are found. In this work we present results from quasielastic neutron scattering measurements of four different POSS (M-POSS, IBU-POSS, TMS-POSS and DMS-POSS) molecules that illustrate the presence of strong coupling between the ligand dynamics and the POSS crystal structures. (authors)

  13. Secondary lead production in Malaysia

    Science.gov (United States)

    Phillips, M. J.; Lim, S. S.

    The increase in the number of vehicles and, subsequently, the volume of batteries made by manufacturers in Malaysia have seen a dramatic rise in lead demand over the last five years. Without any lead mines, the only source of lead in Malaysia has been from the recycling of lead/acid batteries. Metal Reclamation (Industries) has commenced the design of a new and advanced secondary lead plant at West Port, Malaysia to meet the increasing demand for lead and the increasingly stringent environmental regulations. The plant is designed to produce up to 75 000 t of lead and lead alloys per year. The plant will also produce, as by-products: polypropylene chips, wallboard-grade gypsum, non-leachable slag for use in construction. A discussion of the process and the products from the new secondary smelter is outlined.

  14. Common ECG Lead Placement Errors. Part I: Limb Lead Reversals

    Directory of Open Access Journals (Sweden)

    Allison V. Rosen

    2015-10-01

    Full Text Available Background: Electrocardiography (ECG is a very useful diagnostic tool. However, errors in placement of ECG leads can create artifacts, mimic pathologies, and hinder proper ECG interpretation. It is important for members of the health care team to be able to recognize the common patterns resulting from lead placement errors. Methods: 12-lead ECGs were recorded in a single male healthy subject in his mid 20s. Six different limb lead reversals were compared to ECG recordings from correct lead placement. Results: Classic ECG patterns were observed when leads were reversed. Methods of discriminating these ECG patterns from true pathologic findings were described. Conclusion: Correct recording and interpretation of ECGs is key to providing optimal patient care. It is therefore crucial to be able to recognize common ECG patterns that are indicative of lead reversals.

  15. International perspectives of lead exposure and lead toxicity.

    Science.gov (United States)

    Grandjean, P

    1993-01-01

    Three approaches have been used to examine how human body burdens of lead depend on different environments: (1) In paleopathologic studies, lead concentrations have been determined in well-preserved human bones or teeth, and pre-pollution samples generally show lead concentrations of about 1% of current levels in industrialized countries. (2) Geographic comparisons of blood-lead concentrations show low levels in, Nepal, Faroe Islands, and Sweden, while high levels occur in Mexico and Malta; average blood-lead levels may vary by a factor of 10 or more. (3) In analytical epidemiology, major exposure sources have been related to lead levels in blood, by either prospective or cross-sectional design. Increased blood-lead concentrations are related to smoking, drinking alcoholic beverages, eating vegetables for dinner, urban residence, and exposure from lead-using industries; average blood-lead values of subgroups within well-defined populations may vary by a factor of 3 or more. The dose-relationships for lead-induced neurotoxicity will depend on the sensitivity of the parameters chosen as indicators of lead exposure and of neurotoxicity. The temporal relationship between lead exposures and the development of deficits must be ascertained. Individual susceptibility and interacting factors must also be taken into account. Differences in addressing these issues impede the comparison between studies. Recently neonatal jaundice has been found to be a risk factor for subsequent neurobehavioral dysfunction in children with a birth weight above 2500 g, but only in children with increased lead exposure. Lead exposure may act in combination with several other factors and result in additive, or synergistic effects.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8247415

  16. Effect of size and conformation of the ligand on asialoglycoprotein receptor-mediated ligand internalization and degradation in rat hepatocytes

    International Nuclear Information System (INIS)

    The rates of internalization and degradation of 125-I-labeled desialylated cyanogen bromide fragment I of orosomucoid (AS-CNBr-I) and its reduced and carboxymethylated derivative (AS-RC-CNBr-I) were compared with those of 125I-labeled asialoorosomucoid (ASOR) in rat hepatocytes. At 30 nM the rates of internalization and degradation of 125I-AS-CNBr-I were greater than those of 125I-ASOR. 125I-AS-RC-CNBr-I also had a lower rate of internalization and degradation. In contrast to 125I-ASOR, when degradation was inhibited by 5 μM colchicine there was a significant intracellular accumulation of the smaller ligands. At 40C the hepatocytes were found to bind the fragmented ligands more than 125I-ASOR. Incubation of the cells with bound ligand at 370 indicated that diacytosis of 125I-ASOR was greater than the smaller ligands. Colchincine markedly enhanced diacytosis of 125I-ASOR. On the other hand, there were marked accumulation of the smaller ligands by colchicine. These results suggest that the rates of internalization, degradation and diacytosis of the ligand are affected by the size and conformation of the ligand through different rates of receptor binding and intracellular transport

  17. HybridDock: A Hybrid Protein-Ligand Docking Protocol Integrating Protein- and Ligand-Based Approaches.

    Science.gov (United States)

    Huang, Sheng-You; Li, Min; Wang, Jianxin; Pan, Yi

    2016-06-27

    Structure-based molecular docking and ligand-based similarity search are two commonly used computational methods in computer-aided drug design. Structure-based docking tries to utilize the structural information on a drug target like protein, and ligand-based screening takes advantage of the information on known ligands for a target. Given their different advantages, it would be desirable to use both protein- and ligand-based approaches in drug discovery when information for both the protein and known ligands is available. Here, we have presented a general hybrid docking protocol, referred to as HybridDock, to utilize both the protein structures and known ligands by combining the molecular docking program MDock and the ligand-based similarity search method SHAFTS, and evaluated our hybrid docking protocol on the CSAR 2013 and 2014 exercises. The results showed that overall our hybrid docking protocol significantly improved the performance in both binding affinity and binding mode predictions, compared to the sole MDock program. The efficacy of the hybrid docking protocol was further confirmed using the combination of DOCK and SHAFTS, suggesting an alternative docking approach for modern drug design/discovery. PMID:26317502

  18. Biomimetic macroporous hydrogels: protein ligand distribution and cell response to the ligand architecture in the scaffold.

    Science.gov (United States)

    Savina, Irina N; Dainiak, Maria; Jungvid, Hans; Mikhalovsky, Sergey V; Galaev, Igor Yu

    2009-01-01

    Macroporous hydrogels (MHs), cryogels, are a new type of biomaterials for tissue engineering that can be produced from any natural or synthetic polymer that forms a gel. Synthetic MHs are rendered bioactive by surface or bulk modifications with extracellular matrix components. In this study, cell response to the architecture of protein ligands, bovine type-I collagen (CG) and human fibrinogen (Fg), immobilised using different methods on poly(2-hydroxyethyl methacrylate) (pHEMA) macroporous hydrogels (MHs) was analysed. Bulk modification was performed by cross-linking cryo-co-polymerisation of HEMA and poly(ethylene glycol)diacrylate (PEGA) in the presence of proteins (CG/pHEMA and Fg/pHEMA MHs). The polymer surface was modified by covalent immobilisation of the proteins to the active epoxy (ep) groups present on pHEMA after hydrogel fabrication (CG-epHEMA and Fg-epHEMA MHs). The concentration of proteins in protein/pHEMA and protein-epHEMA MHs was 80-85 and 130-140 mug/ml hydrogel, respectively. It was demonstrated by immunostaining and confocal laser scanning microscopy that bulk modification resulted in spreading of CG in the polymer matrix and spot-like distribution of Fg. On the contrary, surface modification resulted in spot-like distribution of CG and uniform spreading of Fg, which evenly coated the surface. Proliferation rate of fibroblasts was higher on MHs with even distribution of the ligands, i.e., on Fg-epHEMA and CG/pHEMA. After 30 days of growth, fibroblasts formed several monolayers and deposited extracellular matrix filling the pores of these MHs. The best result in terms of cell proliferation was obtained on Fg-epHEMA. The ligands displayed on surface of these scaffolds were in native conformation, while in bulk-modified CG/pHEMA MHs most of the proteins were buried inside the polymer matrix and were less accessible for interactions with specific antibodies and cells. The method used for MH modification with bioligands strongly affects spatial

  19. Blood Test: Lead (For Parents)

    Science.gov (United States)

    ... Things to Know About Zika & Pregnancy Blood Test: Lead KidsHealth > For Parents > Blood Test: Lead Print A A A Text Size What's in ... Análisis de sangre: plomo What It Is A lead test is used to determine the amount of ...

  20. Lead toxicosis in a puppy.

    OpenAIRE

    Huerter, L

    2000-01-01

    After showing clinical and radiographic signs of a gastrointestinal foreign body, a 5-month-old puppy began head pressing, which progressed to convulsions. Hematological abnormalities suggested lead poisoning; serum lead was 2.61 mumol/L. The puppy made a complete recovery after intensive treatment for lead toxicosis.

  1. Lead in teeth from lead-dosed goats: Microdistribution and relationship to the cumulative lead dose

    OpenAIRE

    Bellis, David J.; Hetter, Katherine M.; Jones, Joseph; Amarasiriwardena, Dula; Parsons, Patrick J.

    2007-01-01

    Teeth are commonly used as a biomarker of long-term lead exposure. There appear to be few data, however, on the content or distribution of lead in teeth where data on specific lead intake (dose) are also available. This study describes the analysis of a convenience sample of teeth from animals that were dosed with lead for other purposes, i.e., a proficiency testing program for blood lead. Lead concentration of whole teeth obtained from 23 animals, as determined by atomic absorption spectrome...

  2. Series of dinuclear and tetranuclear lanthanide clusters encapsulated by salen-type and β-diketionate ligands: single-molecule magnet and fluorescence properties.

    Science.gov (United States)

    Sun, Wen-Bin; Han, Bing-Lu; Lin, Po-Heng; Li, Hong-Feng; Chen, Peng; Tian, Yong-Mei; Murugesu, Muralee; Yan, Peng-Fei

    2013-10-01

    Three dinuclear [Ln2H2OL(1)2(acac)2]·solvent (1, Ln = Gd, solvent = 2CH2Cl2; 2, Ln = Tb, no solvent; 3, Ln = Er, solvent = (C2H5)2O), and two tetranuclear lanthanide clusters [Ln4(μ3-OH)2L(2)2(acac)6]·2(solvent) (4, Ln = Tb, solvent = CH3OH; 5, Ln = Dy, solvent = CH3CN) were characterized in terms of structure, fluorescence and magnetism. The dinuclear lanthanide complexes were constructed by a rigid salen-type ligand H2L(1) = N,N'-bis(salicylidene)-o-phenylenediamine and β-diketonate (acac = acetylacetonate) ligands, while the tetranuclear clusters were formed from the flexible ligand H2L(2) = N,N'-bis(salicylidene)-1,2-ethanediamine. Crystal structure analysis indicates that the rigid ligand favors the double-decker sandwich structure (Ln2L(1)2), in which the two lanthanide ions have different coordination numbers and geometry, while the more flexible ligand (H2L(2)) leads to planar tetranuclear clusters. The relationship between their respective magnetic anisotropy and ligand-field geometries and their fluorescence properties was investigated. The Dy and Tb-containing clusters exhibit typical visible fluorescence properties, and single-molecule magnet behavior is seen in complex 5. PMID:23887476

  3. Modification of diphenylamine-linked bis(oxazoline)ligands:Tuning of electronic effect and rigidity of ligand skeleton

    Institute of Scientific and Technical Information of China (English)

    LIU Han; LI Wei; DU DaMing

    2009-01-01

    The electronic effect of diphenylamine-linked bis(oxazoline) ligands was tuned through introduction of electron-withdrawing bromo and nitro substituents onto the 4 and 4' position.The variation of the NH bond acidity was determined by the different chemical shifts of NH.The catalytic activity and enantioselectivity of the modified ligands were tested in the asymmetric FriedeI-Crafts alkylation of indole with β-nitrostyrene.The effect of iigand skeleton rigidity was also investigated through the synthesis of iminodibenzyl-linked bis(oxazoline) ligands and evaluation of their catalytic activity in Friedel-Crafts alkylation.

  4. Ligand-based reactivity of a platinum bisdithiolene: double diene addition yields a new C2-chiral chelate ligand.

    Science.gov (United States)

    Kerr, Mitchell J; Harrison, Daniel J; Lough, Alan J; Fekl, Ulrich

    2009-10-01

    The reaction of Pt(tfd)(2) [tfd = S(2)C(2)(CF(3))(2)] with excess 2,3-dimethyl-1,3-butadiene initially yields the expected 1:1 adduct, in which the diene has added across two sulfur atoms on separate tfd ligands. However, within 1 day at 50 degrees C, this kinetic product quantitatively converts into a thermodynamic product where two dienes have added to one tfd ligand via unprecedented addition across the dithiolene CS bonds. The new reaction is highly selective for the C(2)-symmetric diastereomer. A new chiral bisthioether chelate ligand has formed in the product, which has been characterized crystallographically. PMID:19634863

  5. Unique advantages of organometallic supporting ligands for uranium complexes

    Energy Technology Data Exchange (ETDEWEB)

    Diaconescu, Paula L. [Univ. of California, Los Angeles, CA (United States); Garcia, Evan [Univ. of California, Los Angeles, CA (United States)

    2014-05-31

    The objective of our research project was to study the reactivity of uranium complexes supported by ferrocene-based ligands. In addition, this research provides training of graduate students as the next generation of actinide scientists.

  6. Linkable thiocarbamoylbenzamidines as ligands for bioconjugation of Rhenium and Technetium

    International Nuclear Information System (INIS)

    Bioconjugation reactions with Rhenium and Technetium are of high importance for the development of novel radiopharmaceuticals for nuclear medicine. In this thesis the possibilities for bioconjugation using linkable Thiocarmbamoylbenzamidines as ligands for the complexation of Rhenium and Technetium were examined.

  7. Steered molecular dynamics simulations of protein-ligand interactions

    Institute of Scientific and Technical Information of China (English)

    XU Yechun; SHEN Jianhua; LUO Xiaomin; SHEN Xu; CHEN Kaixian; JIANG Hualiang

    2004-01-01

    Studies of protein-ligand interactions are helpful to elucidating the mechanisms of ligands, providing clues for rational drug design. The currently developed steered molecular dynamics (SMD) is a complementary approach to experimental techniques in investigating the biochemical processes occurring at microsecond or second time scale, thus SMD may provide dynamical and kinetic processes of ligand-receptor binding and unbinding, which cannot be accessed by the experimental methods. In this article, the methodology of SMD is described, and the applications of SMD simulations for obtaining dynamic insights into protein-ligand interactions are illustrated through two of our own examples. One is associated with the simulations of binding and unbinding processes between huperzine A and acetylcholinesterase, and the other is concerned with the unbinding process of α-APA from HIV-1 reverse transcriptase.

  8. Capacity of Diffusion-based Molecular Communication with Ligand Receptors

    CERN Document Server

    Einolghozati, Arash; Fekri, Faramarz

    2012-01-01

    A diffusion-based molecular communication system has two major components: the diffusion in the medium, and the ligand-reception. Information bits, encoded in the time variations of the concentration of molecules, are conveyed to the receiver front through the molecular diffusion in the medium. The receiver, in turn, measures the concentration of the molecules in its vicinity in order to retrieve the information. This is done via ligand-reception process. In this paper, we develop models to study the constraints imposed by the concentration sensing at the receiver side and derive the maximum rate by which a ligand-receiver can receive information. Therefore, the overall capacity of the diffusion channel with the ligand receptors can be obtained by combining the results presented in this paper with our previous work on the achievable information rate of molecular communication over the diffusion channel.

  9. A new fullerene complexation ligand: N-pyridylfulleropyrrolidine.

    Science.gov (United States)

    Tat, Fatma T; Zhou, Zhiguo; MacMahon, Shaun; Song, Fayi; Rheingold, Arnold L; Echegoyen, Luis; Schuster, David I; Wilson, Stephen R

    2004-07-01

    The subject of this paper is a new fullerene building block design with the potential for defined geometry and good electronic communication. The synthesis and characterization of a new pyridinofullerene ligand capable of forming axially symmetric complexes with metalloporphyrins is reported. X-ray structural and molecular modeling studies, (1)H NMR, UV-vis spectroscopy, electrochemistry studies, and fluorescence quenching data support the formation of a strong complex between the new ligand and the metal center of ZnTPP. On the basis of computational studies, the highest occupied molecular orbital (HOMO) of this ligand is significantly different from a model compound with insulating carbons between the pyridine and the fullerene. The N-pyridinium fulleropyrrolidine salts of the new ligand and model compound were also prepared and their spectral and electrochemical properties are reported. PMID:15230581

  10. Fpocket: An open source platform for ligand pocket detection

    Directory of Open Access Journals (Sweden)

    Le Guilloux Vincent

    2009-06-01

    Full Text Available Abstract Background Virtual screening methods start to be well established as effective approaches to identify hits, candidates and leads for drug discovery research. Among those, structure based virtual screening (SBVS approaches aim at docking collections of small compounds in the target structure to identify potent compounds. For SBVS, the identification of candidate pockets in protein structures is a key feature, and the recent years have seen increasing interest in developing methods for pocket and cavity detection on protein surfaces. Results Fpocket is an open source pocket detection package based on Voronoi tessellation and alpha spheres built on top of the publicly available package Qhull. The modular source code is organised around a central library of functions, a basis for three main programs: (i Fpocket, to perform pocket identification, (ii Tpocket, to organise pocket detection benchmarking on a set of known protein-ligand complexes, and (iii Dpocket, to collect pocket descriptor values on a set of proteins. Fpocket is written in the C programming language, which makes it a platform well suited for the scientific community willing to develop new scoring functions and extract various pocket descriptors on a large scale level. Fpocket 1.0, relying on a simple scoring function, is able to detect 94% and 92% of the pockets within the best three ranked pockets from the holo and apo proteins respectively, outperforming the standards of the field, while being faster. Conclusion Fpocket provides a rapid, open source and stable basis for further developments related to protein pocket detection, efficient pocket descriptor extraction, or drugablity prediction purposes. Fpocket is freely available under the GNU GPL license at http://fpocket.sourceforge.net.

  11. Dysprosium complexes with the tetraphenylporphyrin macrocyclic ligand

    International Nuclear Information System (INIS)

    In this report, the results obtained on the synthesis, characterization and study of the chemical behavior of dysprosium complex with the acetylacetone chelating agent (Hacac) and the tetraphenylporphyrin macrocyclic ligand (H2TFP) are given. Based on the literature but according to our necessities and interest, the appropriate methodology settled down from the synthesis of prime matters until the obtaining and characterization of the products. The acetyl acetonate complex was obtained of mono hydrated dysprosium [Dy(acac)3. H20] and trihydrated [Dy(acac)3 .3 H20], the mono tetra phenyl porphyrinate [Dy(TFP)(acac). 2 ac] the double sandwich of the dysprosium porphyrinate [Dy(TFP)2] and the triple sandwich of the dysprosium porphyrinate [Dy(TFP)3. 2 TCB] (TCB = trichlorobenzene). Its were characterized by their melting points, solubility, IR, UV, TGA and DTA both first and besides the techniques already mentioned for NMR'H, RPE and Magnetic susceptibility the three last complexes. From the spectroscopic point of view, IR and RPE its suggested the existence of a complex of inverse mixed valence [Dy(TFP)2- (TFP) 1-] for the Dy(TFP)2 as a result of the existence of the free radical (TFP' 1- and that it was not in none of the other porphyrin compounds. In the NMR'H spectra of the compounds were not observed signals in the region from 0 to 10 ppm that which shows that the dysprosium complexes in special those of the porphyrin type are highly paramagnetic and its could be used as displacement reagents, creators of images and contrast agents of great utility in these days in studies of NMR, technique today by today used in medical diagnoses. (Author)

  12. Increased CD40 ligand in patients with acute anterior uveitis

    DEFF Research Database (Denmark)

    Øgard, Carsten; Sørensen, Torben Lykke; Krogh, Erik

    2005-01-01

    The inflammatory response in acute anterior uveitis (AU) is believed to be primarily mediated by autoreactive T-cells. We wanted to evaluate whether the T-cell activation marker CD40 ligand is involved in the AU immunopathogenesis.......The inflammatory response in acute anterior uveitis (AU) is believed to be primarily mediated by autoreactive T-cells. We wanted to evaluate whether the T-cell activation marker CD40 ligand is involved in the AU immunopathogenesis....

  13. Force History Dependence of Receptor-Ligand Dissociation

    OpenAIRE

    Marshall, Bryan T.; Sarangapani, Krishna K.; Lou, Jizhong; McEver, Rodger P.; Zhu, Cheng

    2004-01-01

    Receptor-ligand bonds that mediate cell adhesion are often subjected to forces that regulate their dissociation via modulating off-rates. Off-rates control how long receptor-ligand bonds last and how much force they withstand. One should therefore be able to determine off-rates from either bond lifetime or unbinding force measurements. However, substantial discrepancies exist between the force dependence of off-rates derived from the two types of measurements even for the same interactions, e...

  14. Reversible Size Control of Silver Nanoclusters via Ligand-exchange

    KAUST Repository

    Bootharaju, Megalamane Siddaramappa

    2015-05-21

    The properties of atomically monodisperse noble metal nanoclusters (NCs) are intricately intertwined with their precise molecular formula. The vast majority of size-specific NC syntheses start from the reduction of the metal salt and thiol ligand mixture. Only in gold was it recently shown that ligand-exchange could induce the growth of NCs from one atomically precise species to another; a process of yet unknown reversibility. Here, we present a process for the ligand-exchange-induced growth of atomically precise silver NCs, in a biphasic liquid-liquid system, which is particularly of interest because of its complete reversibility and ability to occur at room temperature. We explore this phenomenon in-depth using Ag35(SG)18 [SG= glutathionate] and Ag44(4-FTP)30 [4-FTP= 4-fluorothiophenol] as model systems. We show that the ligand-exchange conversion of Ag35(SG)18 into Ag44(4-FTP)30 is rapid (< 5 min) and direct, while the reverse process proceeds slowly through intermediate cluster sizes. We adapt a recently developed theory of reverse Ostwald ripening to model the NCs’ interconvertibility. The model’s predictions are in good agreement with the experimental observations, and they highlight the importance of small changes in the ligand-metal binding energy in determining the final equilibrium NC size. Based on the insight provided by this model, we demonstrated experimentally that by varying the choice of ligands, ligand-exchange can be used to obtain different sized NCs. The findings in this work establish ligand-exchange as a versatile tool for tuning cluster sizes.

  15. Coordination chemistry of poly(thioether)borate ligands

    OpenAIRE

    Riordan, Charles G.

    2010-01-01

    This review traces the development and application of the tris(thioether)borate ligands, tripodal ligands with highly polarizable thioether donors. Areas of emphasis include the basic coordination chemistry of the mid-to-late first row transition metals (Fe, Ni, Co, Cu), and the role of the thioether substituent in directing complex formation, the modeling of zinc thiolate protein active sites, high-spin organo-iron and organo-cobalt chemistry, the preparation of monovalent complexes of Fe, C...

  16. Designer ligands: The search for metal ion selectivity

    OpenAIRE

    Perry T. Kaye

    2011-01-01

    The paper reviews research conducted at Rhodes University towards the development of metal-selective ligands. The research has focused on the rational design, synthesis and evaluation of novel ligands for use in the formation of copper complexes as biomimetic models of the metalloenzyme, tyrosinase, and for the selective extraction of silver, nickel and platinum group metal ions in the presence of contaminating metal ions. Attention has also been given to the development of efficient, metal-s...

  17. Synthesis and evaluation of potential ligands for nuclear waste processing

    OpenAIRE

    Iqbal, M.

    2012-01-01

    The research presented in this thesis deals with the synthesis and evaluation of new potential ligands for the complexation of actinide and lanthanide ions either for their extraction from bulk radioactive waste or their stripping from an extracted organic phase for final processing of the waste. In particular, the aim of the work described here is the development of new ligands with improved separation and extraction efficiency. Separation of actinides (An) and lanthanides (Ln) is a challeng...

  18. Ligand assisted cleavage of uranium oxo-clusters

    Energy Technology Data Exchange (ETDEWEB)

    Nocton, Gregory; Pecaut, Jacques; Mazzanti, Marinella [Laboratoire de Reconnaissance Ionique et Chimie de Coordination, Service de Chimie Inorganique et Biologique, UMR-E 3 CEA-UJF, CEA/DSM/INAC, CEA-Grenoble, 38054 Grenoble, Cedex 09 (France); Filinchuk, Yaroslav [Swiss Norwegian Beam Lines (SNBL) at the European Synchrotron Radiation Facility (ESRF), rue Jules Horowitz, 38043 Grenoble (France)

    2010-07-01

    Dibenzoylmethanate replaces the bridging triflate ligands in uranium triflate poly-oxo-clusters and cleaves the U{sub 12}O{sub 20} core yielding the new [U{sub 6}O{sub 4}(OH){sub 4}({eta}-dbm){sub 12}] dibenzoylmethanate (dbm{sup -}) cluster which slowly dissociates into a monomeric complex. This reactivity demonstrates the importance of bridging ligands in stabilizing uranium poly-oxo-clusters. (authors)

  19. Tetrapyrroles as Endogenous TSPO Ligands in Eukaryotes and Prokaryotes: Comparisons with Synthetic Ligands

    Science.gov (United States)

    Veenman, Leo; Vainshtein, Alex; Yasin, Nasra; Azrad, Maya; Gavish, Moshe

    2016-01-01

    The 18 kDa translocator protein (TSPO) is highly 0conserved in eukaryotes and prokaryotes. Since its discovery in 1977, numerous studies established the TSPO’s importance for life essential functions. For these studies, synthetic TSPO ligands typically are applied. Tetrapyrroles present endogenous ligands for the TSPO. Tetrapyrroles are also evolutionarily conserved and regulate multiple functions. TSPO and tetrapyrroles regulate each other. In animals TSPO-tetrapyrrole interactions range from effects on embryonic development to metabolism, programmed cell death, response to stress, injury and disease, and even to life span extension. In animals TSPOs are primarily located in mitochondria. In plants TSPOs are also present in plastids, the nuclear fraction, the endoplasmic reticulum, and Golgi stacks. This may contribute to translocation of tetrapyrrole intermediates across organelles’ membranes. As in animals, plant TSPO binds heme and protoporphyrin IX. TSPO-tetrapyrrole interactions in plants appear to relate to development as well as stress conditions, including salt tolerance, abscisic acid-induced stress, reactive oxygen species homeostasis, and finally cell death regulation. In bacteria, TSPO is important for switching from aerobic to anaerobic metabolism, including the regulation of photosynthesis. As in mitochondria, in bacteria TSPO is located in the outer membrane. TSPO-tetrapyrrole interactions may be part of the establishment of the bacterial-eukaryote relationships, i.e., mitochondrial-eukaryote and plastid-plant endosymbiotic relationships. PMID:27271616

  20. DOCLASP - Docking ligands to target proteins using spatial and electrostatic congruence extracted from a known holoenzyme and applying simple geometrical transformations

    Science.gov (United States)

    Chakraborty, Sandeep

    2016-01-01

    The ability to accurately and effectively predict the interaction between proteins and small drug-like compounds has long intrigued researchers for pedagogic, humanitarian and economic reasons. Protein docking methods (AutoDock, GOLD, DOCK, FlexX and Glide to name a few) rank a large number of possible conformations of protein-ligand complexes using fast algorithms. Previously, it has been shown that structural congruence leading to the same enzymatic function necessitates the congruence of electrostatic properties (CLASP). The current work presents a methodology for docking a ligand into a target protein, provided that there is at least one known holoenzyme with ligand bound - DOCLASP (Docking using CLASP). The contact points of the ligand in the holoenzyme defines a motif, which is used to query the target enzyme using CLASP. If there are significant matches, the holoenzyme and the target protein are superimposed based on congruent atoms. The same linear and rotational transformations are also applied to the ligand, thus creating a unified coordinate framework having the holoenzyme, the ligand and the target enzyme. In the current work, the dipeptidyl peptidase-IV inhibitor vildagliptin was docked to the PI-PLC structure complexed with myo-inositol using DOCLASP. Also, corroboration of the docking of phenylthiourea to the modelled structure of polyphenol oxidase (JrPPO1) from walnut is provided based on the subsequently solved structure of JrPPO1 (PDBid:5CE9). Analysis of the binding of the antitrypanosomial drug suramin to nine non-homologous proteins in the PDB database shows a diverse set of binding motifs, and multiple binding sites in the phospholipase A2-likeproteins from the Bothrops genus of pitvipers. The conformational changes in the suramin molecule on binding highlights the challenges in docking flexible ligands into an already ’plastic’ binding site. Thus, DOCLASP presents a method for ’soft docking’ ligands to proteins with low

  1. Determining lead sources in Mexico using the lead isotope ratio

    Directory of Open Access Journals (Sweden)

    Chaudhary-Webb Madhu

    2003-01-01

    Full Text Available OBJECTIVE: Lead poisoning can, in some cases, be traced to a specific route or source of exposure on the basis of the individual's blood lead isotope ratio. To assess the major source of lead exposure among women residing in Mexico City, we compared blood, ceramic, and gasoline lead isotope ratios. MATERIAL AND METHODS: The study population, randomly selected from participants of a large trial, (1/1996-12/1996 comprised of 16 women whose lead levels exceeded 10 µg/dl and who reported using lead-glazed ceramics. Lead isotope ratios were performed on a Perkin Elmer 5000 Inductively Coupled Plasma Mass Spectrometer (ICP-MS interfaced with a Perkin Elmer HGA-600MS Electrothermal Vaporization System (ETV. RESULTS: The isotope ratios (206Pb/204Pb, 207Pb/204Pb, and 208Pb/204Pb of both the blood specimens and their corresponding ceramic specimens were highly correlated, with r=0.9979, r²=0.9958, r=0.9957, r²=0.9915 and r=0.9945, r²=0.9890 values for the three isotope ratios, respectively, suggesting that the lead exposure most likely resulted from the use of these ceramic. Measurements of lead isotope ratios from leaded gasoline in use at the time of blood sampling, differed from those in blood and ceramics. CONCLUSIONS: Determining lead isotope ratios can be an efficient tool to identify a major source of lead exposure and to support the implementation of public health prevention and control measures.

  2. Distribution of lead-203 in human peripheral blood in vitro

    International Nuclear Information System (INIS)

    In-vitro experiments using 203Pb were performed to identify the lead binding components in human peripheral blood. The distribution of lead in plasma, in the red cell membrane, and within the red cell was also investigated. Studies of the distribution of 203Pb in the whole blood showed that at a lead concentration of 2.45 μmol/l (50 μg/100 ml) about 94% of lead had been incorporated by the erythrocytes and 6% remained in the plasma. After extraction of lipid by a methanol/chloroform mixture, about 75% of the lead was found to be associated with the protein fraction. The lipid contained about 21% of the 203Pb, the remainder being in the aqueous plasma. SDS polyacrylamide gel electrophoresis of blood plasma showed that almost 90% of the 203Pb was present in the albumin fraction; the remainder was likely to be associated with high molecular weight globulins. Several binding sites were identified on the erythrocyte membrane. The high molecular weight component, about 130 000-230 000, was the most important 203Pb binding site. Chemical modification of membrane proteins suggested that the carboxyl groups are the major ligand responsible for most of the lead binding. SH groups of the membrane may have a minor role, but amino groups did not appear to affect the lead binding. The binding of lead to erythrocytes was not confined to membranes, over 80% of lead in blood penetrates into erythrocytes and binds to intracellular components. Gel chromatography of the haemolysate showed that over 90% of the 203Pb was attached to the haemoglobin molecule. (author)

  3. Ligand and interfacial dynamics in a homodimeric hemoglobin

    Science.gov (United States)

    Gupta, Prashant Kumar; Meuwly, Markus

    2016-01-01

    The structural dynamics of dimeric hemoglobin (HbI) from Scapharca inaequivalvis in different ligand-binding states is studied from atomistic simulations on the μs time scale. The intermediates are between the fully ligand-bound (R) and ligand-free (T) states. Tertiary structural changes, such as rotation of the side chain of Phe97, breaking of the Lys96–heme salt bridge, and the Fe–Fe separation, are characterized and the water dynamics along the R-T transition is analyzed. All these properties for the intermediates are bracketed by those determined experimentally for the fully ligand-bound and ligand-free proteins, respectively. The dynamics of the two monomers is asymmetric on the 100 ns timescale. Several spontaneous rotations of the Phe97 side chain are observed which suggest a typical time scale of 50–100 ns for this process. Ligand migration pathways include regions between the B/G and C/G helices and, if observed, take place in the 100 ns time scale. PMID:26958581

  4. Predicting Efficient Antenna Ligands for Tb(III) Emission

    Energy Technology Data Exchange (ETDEWEB)

    Samuel, Amanda P.S.; Xu, Jide; Raymond, Kenneth

    2008-10-06

    A series of highly luminescent Tb(III) complexes of para-substituted 2-hydroxyisophthalamide ligands (5LI-IAM-X) has been prepared (X = H, CH{sub 3}, (C=O)NHCH{sub 3}, SO{sub 3}{sup -}, NO{sub 2}, OCH{sub 3}, F, Cl, Br) to probe the effect of substituting the isophthalamide ring on ligand and Tb(III) emission in order to establish a method for predicting the effects of chromophore modification on Tb(III) luminescence. The energies of the ligand singlet and triplet excited states are found to increase linearly with the {pi}-withdrawing ability of the substituent. The experimental results are supported by time-dependent density functional theory (TD-DFT) calculations performed on model systems, which predict ligand singlet and triplet energies within {approx}5% of the experimental values. The quantum yield ({Phi}) values of the Tb(III) complex increases with the triplet energy of the ligand, which is in part due to the decreased non-radiative deactivation caused by thermal repopulation of the triplet. Together, the experimental and theoretical results serve as a predictive tool that can be used to guide the synthesis of ligands used to sensitize lanthanide luminescence.

  5. Extracellular interactions and ligand degradation shape the nodal morphogen gradient

    Science.gov (United States)

    Wang, Yin; Wang, Xi; Wohland, Thorsten; Sampath, Karuna

    2016-01-01

    The correct distribution and activity of secreted signaling proteins called morphogens is required for many developmental processes. Nodal morphogens play critical roles in embryonic axis formation in many organisms. Models proposed to generate the Nodal gradient include diffusivity, ligand processing, and a temporal activation window. But how the Nodal morphogen gradient forms in vivo remains unclear. Here, we have measured in vivo for the first time, the binding affinity of Nodal ligands to their major cell surface receptor, Acvr2b, and to the Nodal inhibitor, Lefty, by fluorescence cross-correlation spectroscopy. We examined the diffusion coefficient of Nodal ligands and Lefty inhibitors in live zebrafish embryos by fluorescence correlation spectroscopy. We also investigated the contribution of ligand degradation to the Nodal gradient. We show that ligand clearance via degradation shapes the Nodal gradient and correlates with its signaling range. By computational simulations of gradient formation, we demonstrate that diffusivity, extra-cellular interactions, and selective ligand destruction collectively shape the Nodal morphogen gradient. DOI: http://dx.doi.org/10.7554/eLife.13879.001 PMID:27101364

  6. Serum albumin ligand binding volumes using high pressure denaturation

    International Nuclear Information System (INIS)

    Highlights: ► We use pressure shift assay to study the thermodynamics of decanoate and dodecanoate ligand binding to human serum albumin. ► Pressure shift assay provides information on ligand binding volumes. ► The ligands stabilized human serum albumin against both pressure and temperature denaturation. ► ANS is a strong human serum albumin stabilizer and competes with lipids for the same binding sites. - Abstract: The pressure shift assay (PSA, also termed either PressureFluor or differential pressure fluorimetry) was used to study the thermodynamics of decanoate and dodecanoate lipid binding to human serum albumin (HSA) in the temperature range from 25 °C to 80 °C and the pressure range from 0.1 MPa to 400 MPa. The ligands stabilized HSA against both pressure and temperature denaturation. The P–T phase diagram for HSA bound to saturated fatty acids is shown. Pressure induced HSA denaturation reversibility is demonstrated via either intrinsic tryptophan or extrinsic probe 1,8-anilinonaphthalene sulfonate (ANS) fluorescence. The effect of guanidinium in a PSA was studied. PSA provides information on ligand binding volumes. The volume changes from protein–ligand binding are thermodynamically important and could be used in designing compounds with specific volumetric binding properties.

  7. Acetate binding induces fluorescence enhancement in tryptophan ligands

    Energy Technology Data Exchange (ETDEWEB)

    Deka, Arup K.; Sarma, Rupam J., E-mail: rjs@gauhati.ac.in

    2014-03-15

    The anion coordination properties of bis-tryptophan dicarboxamide ligands 1–3 were investigated using fluorescence and {sup 1}H NMR spectroscopy. It was observed that the coordination of acetate anions to these ligands produced emissions at 381 nm with gradual enhancement of fluorescence. In comparison, fluoride produced minor enhancement, the addition of chloride, bromide and nitrate anions caused quenching of ligand fluorescence. {sup 1}H NMR studies revealed that the ligands coordinated to the acetate anions through the indole and amide NH groups. -- Highlights: • We have synthesized and characterized three tryptophan-based diamide ligands 1–3. • We have reported new polymorph of ligand 1 (Crystal structure) in this article. • The role of intramolecular hydrogen bonding (1 vs. 2) in anion binding was investigated. • We were able to identify the role amide/indole NH in anion binding using {sup 1}H NMR. • On the basis of {sup 1}H NMR, we have established role of aromatic CH–anion interactions during anion complexation.

  8. Narrow escape for a stochastically gated Brownian ligand.

    Science.gov (United States)

    Reingruber, Jürgen; Holcman, David

    2010-02-17

    Molecular activation in cellular microdomains is usually characterized by a forward binding rate, which is the reciprocal of the arrival time of a ligand to a key target. Upon chemical interactions or conformational changes, a Brownian ligand may randomly switch between different states, and when target activation is possible in a specific state only, switching can significantly alter the activation process. The main goal of this paper is to study the mean time for a switching ligand to activate a small substrate, modelled as the time to exit a microdomain through a small absorbing window on the surface. We present the equations for the mean sojourn times the ligand spends in each state, and study the escape process with switching between two states in dimension one and three. When the ligand can exit in only one of the two states, we find that switching always decreases its sojourn time in the state where it can exit. Moreover, the fastest exit is obtained when the ligand diffuses most of the time in the state with the maximal diffusion coefficient, although this may imply that it spends most of the time 'hidden' in the state where it cannot exit. We discuss the physical mechanisms responsible for this apparent paradox. In dimension three we confirm our results with Brownian simulations. Finally, we suggest possible applications in cellular biology. PMID:21389363

  9. Highly luminescent charge-neutral europium(iii) and terbium(iii) complexes with tridentate nitrogen ligands.

    Science.gov (United States)

    Senthil Kumar, Kuppusamy; Schäfer, Bernhard; Lebedkin, Sergei; Karmazin, Lydia; Kappes, Manfred M; Ruben, Mario

    2015-09-21

    We report on the synthesis of tridentate-nitrogen pyrazole-pyridine-tetrazole (L(1)H) and pyrazole-pyridine-triazole (L(2)H) ligands and their complexation with lanthanides (Ln = Gd(iii), Eu(iii) and Tb(iii)) resulting in stable, charge-neutral complexes Ln(L(1))3 and Ln(L(2))3, respectively. X-ray crystallographic analysis of the complexes with L(1) ligands revealed tricapped trigonal coordination geometry around the lanthanide ions. All complexes show bright photoluminescence (PL) in the solid state, indicating efficient sensitization of the lanthanide emission via the triplet states of the ligands. In particular, the terbium complexes show high PL quantum yields of 65 and 59% for L(1) and L(2), respectively. Lower PL efficiencies of the europium complexes (7.5 and 9%, respectively) are attributed to large energy gaps between the triplet states of the ligands and accepting levels of Eu(iii). The triplet state energy can be reduced by introducing an electron withdrawing (EW) group at the 4 position of the pyridine ring. Such substitution of L(1)H with a carboxylic ester (COOMe) EW group leads to a europium complex with increased PL quantum yield of 31%. A comparatively efficient PL of the complexes dissolved in ethanol indicates that the lanthanide ions are shielded against nonradiative deactivation via solvent molecules. PMID:26245980

  10. Fibrinogen, an endogenous ligand of Toll-like receptor 4, activates monocytes in pre-eclamptic patients.

    Science.gov (United States)

    Al-ofi, Ebtisam; Coffelt, Seth B; Anumba, Dilly O

    2014-06-01

    Pre-eclampsia (PE) remains the leading cause of pregnancy-associated mortality and morbidity, urging the need for a better understanding of its aetiology and pathophysiological progression. A key characteristic of PE is a systemic, exaggerated, inflammatory condition involving abnormal cytokine levels in serum, altered immune cell phenotype and Th1/Th2-type immunological imbalance. However, it is unknown how this heightened inflammatory condition manifests. We previously reported increased expression of the lipopolysaccharide receptor, Toll-like receptor 4 (TLR4), on monocytes from PE patients compared with normotensive, pregnant patients (NP). This upregulation of TLR4 on PE monocytes was accompanied by a hyper-responsiveness to bacterial TLR4 ligands. To determine whether non-microbial, endogenous TLR4 ligands also activate monocytes from PE patients, we investigated the expression of host-derived TLR4 ligands and the response of monocytes to these endogenous ligands. Plasma levels of fibrinogen - but not fibronectin or heparan sulphate - were higher in PE patients than in NP. Exposure to fibrinogen was associated with significantly increased production of inflammatory cytokines by monocytes from PE patients. Interestingly, this effect was not observed with NP monocytes. Our findings suggest that the fibrinogen-TLR4 axis might play an important role in the atypical activation of monocytes observed in PE patients that may contribute to the exaggerated inflammatory condition. PMID:24661950

  11. Ligands turning around in the midst of protein conformers: the origin of ligand-protein mating. A NMR view.

    Science.gov (United States)

    Pertinhez, T A; Spisni, A

    2011-01-01

    Protein-ligand binding is a puzzling process. Many theories have been devised since the pioneering key-and-lock hypothesis based on the idea that both the protein and the ligand have a rigid single conformation. Indeed, molecular motion is the essence of the universe. Consequently, not only proteins are characterized by an extraordinary conformational freedom, but ligands too can fluctuate in a rather vast conformational space. In this scenario, the quest to understand how do they match is fascinating. Recognizing that the inherent dynamics of molecules is the key factor controlling the success of the binding and, subsequently, their chemical/biological function, here we present a view of this process from the NMR stand point. A description of the most relevant NMR parameters that can provide insights, at atomic level, on the mechanisms of protein-ligand binding is provided in the final section. PMID:20939791

  12. Rule of five in 2015 and beyond: Target and ligand structural limitations, ligand chemistry structure and drug discovery project decisions.

    Science.gov (United States)

    Lipinski, Christopher A

    2016-06-01

    The rule of five (Ro5), based on physicochemical profiles of phase II drugs, is consistent with structural limitations in protein targets and the drug target ligands. Three of four parameters in Ro5 are fundamental to the structure of both target and drug binding sites. The chemical structure of the drug ligand depends on the ligand chemistry and design philosophy. Two extremes of chemical structure and design philosophy exist; ligands constructed in the medicinal chemistry synthesis laboratory without input from natural selection and natural product (NP) metabolites biosynthesized based on evolutionary selection. Exceptions to Ro5 are found mostly among NPs. Chemistry chameleon-like behavior of some NPs due to intra-molecular hydrogen bonding as exemplified by cyclosporine A is a strong contributor to NP Ro5 outliers. The fragment derived, drug Navitoclax is an example of the extensive expertise, resources, time and key decisions required for the rare discovery of a non-NP Ro5 outlier. PMID:27154268

  13. LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters.

    Science.gov (United States)

    Wolber, Gerhard; Langer, Thierry

    2005-01-01

    From the historically grown archive of protein-ligand complexes in the Protein Data Bank small organic ligands are extracted and interpreted in terms of their chemical characteristics and features. Subsequently, pharmacophores representing ligand-receptor interaction are derived from each of these small molecules and its surrounding amino acids. Based on a defined set of only six types of chemical features and volume constraints, three-dimensional pharmacophore models are constructed, which are sufficiently selective to identify the described binding mode and are thus a useful tool for in-silico screening of large compound databases. The algorithms for ligand extraction and interpretation as well as the pharmacophore creation technique from the automatically interpreted data are presented and applied to a rhinovirus capsid complex as application example. PMID:15667141

  14. A Ferrocene-Based Catecholamide Ligand: the Consequences of Ligand Swivel for Directed Supramolecular Self-Assembly

    Energy Technology Data Exchange (ETDEWEB)

    Mugridge, Jeffrey; Fiedler, Dorothea; Raymond, Kenneth

    2010-02-04

    A ferrocene-based biscatecholamide ligand was prepared and investigated for the formation of metal-ligand supramolecular assemblies with different metals. Reaction with Ge(IV) resulted in the formation of a variety of Ge{sub n}L{sub m} coordination complexes, including [Ge{sub 2}L{sub 3}]{sup 4-} and [Ge{sub 2}L{sub 2}({mu}-OMe){sub 2}]{sup 2-}. The ligand's ability to swivel about the ferrocenyl linker and adopt different conformations accounts for formation of many different Ge{sub n}L{sub m} species. This study demonstrates why conformational ligand rigidity is essential in the rational design and directed self-assembly of supramolecular complexes.

  15. Secondary ligand-directed assembly of Co(II) coordination polymers based on a pyridine carboxylate ligand

    International Nuclear Information System (INIS)

    To investigate the influence of hydrogen bonds and secondary ligands on the structures and properties of the resulting frameworks, five new Co(II) compounds have been synthesized by the reactions of Co(II) salts and 3,5-bis(pyridin-4-ylmethoxy)benzoic acid (HL) with four rationally selected dicarboxylic acid ligands. Without secondary ligand, we got one compound [CoL2(H2O)2]n·2nH2O (1), which possesses a 1D chain structure. In the presence of ancillary ligands, namely, 1,3-adamantanedicarboxylic acid (H2adbc), terephthalic acid (H2tpa), thiophene-2,5-dicarboxylic acid (H2tdc) and 1,4-benzenedithioacetic acid (H2bdtc), four 3D structures [Co2L2(adbc)]n·nH2O (2), [Co2L2(tpa)]n (3), [Co2L2(tdc)]n (4), [Co2L2(bdtc)(H2O)]n (5) were obtained, respectively. It can be observed from the architectures of 1–5 that hydrogen bonds and secondary ligands both have great effects on the spatial connective fashions, resulting in the formation of various dimensional compounds. The XRPD, TGA data of title polymers and the magnetic properties for 2 and 5 have also been investigated. - Graphical abstract: The structural differences show that the ancillary ligands have great effects on the spatial connective fashions, resulting in the formation of various dimensional compounds. - Highlights: • Five new Co(II) coordination polymers have been synthesized by solvothermal reactions based on 3,5-bis(pyridin-4-ylmethoxy)benzoic acid (HL). • The long-flexible ligand (HL) is a good candidate to produce interpenetrating architectures. • The secondary dicarboxylic acid ligands play important roles in the spatial connective fashions and the formation of various dimensional compounds. • The magnetism studies show that both 2 and 5 exhibit antiferromagnetic interactions

  16. Integration of screening and identifying ligand(s) from medicinal plant extracts based on target recognition by using NMR spectroscopy

    OpenAIRE

    sprotocols

    2015-01-01

    Authors: Yalin Tang, Qian Shang, Junfeng Xiang, Qianfan Yang, Qiuju Zhou, Lin Li, Hong Zhang, Qian Li, Hongxia Sun, Aijiao Guan, Wei Jiang & Wei Gai ### Abstract This protocol presents the screening of ligand(s) from medicinal plant extracts based on target recognition by using NMR spectroscopy. A detailed description of sample preparation and analysis process is provided. NMR spectroscopies described here are 1H NMR, diffusion-ordered spectroscopy (DOSY), relaxation-edited NMR, ...

  17. electronic Ligand Builder and Optimisation Workbench (eLBOW): A tool for ligand coordinate and restraint generation

    Energy Technology Data Exchange (ETDEWEB)

    Moriarty, Nigel; Grosse-Kunstleve, Ralf; Adams, Paul

    2009-07-01

    The electronic Ligand Builder and Optimisation Workbench (eLBOW) is a program module of the PHENIX suite of computational crystallographic software. It's designed to be a flexible procedure using simple and fast quantum chemical techniques to provide chemically accurate information for novel and known ligands alike. A variety of input formats and options allow for the attainment of a number of diverse goals including geometry optimisation and generation of restraints.

  18. Lead Levels in Utah Eagles

    Science.gov (United States)

    Arnold, Michelle

    2006-10-01

    Lead is a health hazard to most animals, causing adverse effects to the nervous and reproductive systems if in sufficient quantity. Found in most fishing jigs and sinkers, as well as some ammunition used in hunting, this metal can poison wildlife such as eagles. Eagles are raptors, or predatory birds, and their lead exposure would most likely comes from their food -- a fish which has swallowed a sinker or lead shot in carrion (dead animal matter). As part of an ongoing project to investigate the environment lead levels in Utah, the bone lead levels in the wing bones of eagles have been measured for eagle carcasses found throughout Utah. The noninvasive technique of x-ray fluorescence was used, consisting of a Cd-109 radioactive source to activate lead atoms and a HPGe detector with digital electronics to collect the gamma spectra. Preliminary results for the eagles measured to date will be presented.

  19. Accuracy and precision of protein–ligand interaction kinetics determined from chemical shift titrations

    International Nuclear Information System (INIS)

    NMR-monitored chemical shift titrations for the study of weak protein–ligand interactions represent a rich source of information regarding thermodynamic parameters such as dissociation constants (KD) in the micro- to millimolar range, populations for the free and ligand-bound states, and the kinetics of interconversion between states, which are typically within the fast exchange regime on the NMR timescale. We recently developed two chemical shift titration methods wherein co-variation of the total protein and ligand concentrations gives increased precision for the KD value of a 1:1 protein–ligand interaction (Markin and Spyracopoulos in J Biomol NMR 53: 125–138, 2012). In this study, we demonstrate that classical line shape analysis applied to a single set of 1H–15N 2D HSQC NMR spectra acquired using precise protein–ligand chemical shift titration methods we developed, produces accurate and precise kinetic parameters such as the off-rate (koff). For experimentally determined kinetics in the fast exchange regime on the NMR timescale, koff ∼ 3,000 s−1 in this work, the accuracy of classical line shape analysis was determined to be better than 5 % by conducting quantum mechanical NMR simulations of the chemical shift titration methods with the magnetic resonance toolkit GAMMA. Using Monte Carlo simulations, the experimental precision for koff from line shape analysis of NMR spectra was determined to be 13 %, in agreement with the theoretical precision of 12 % from line shape analysis of the GAMMA simulations in the presence of noise and protein concentration errors. In addition, GAMMA simulations were employed to demonstrate that line shape analysis has the potential to provide reasonably accurate and precise koff values over a wide range, from 100 to 15,000 s−1. The validity of line shape analysis for koff values approaching intermediate exchange (∼100 s−1), may be facilitated by more accurate KD measurements from NMR-monitored chemical shift

  20. mRAISE: an alternative algorithmic approach to ligand-based virtual screening.

    Science.gov (United States)

    von Behren, Mathias M; Bietz, Stefan; Nittinger, Eva; Rarey, Matthias

    2016-08-01

    Ligand-based virtual screening is a well established method to find new lead molecules in todays drug discovery process. In order to be applicable in day to day practice, such methods have to face multiple challenges. The most important part is the reliability of the results, which can be shown and compared in retrospective studies. Furthermore, in the case of 3D methods, they need to provide biologically relevant molecular alignments of the ligands, that can be further investigated by a medicinal chemist. Last but not least, they have to be able to screen large databases in reasonable time. Many algorithms for ligand-based virtual screening have been proposed in the past, most of them based on pairwise comparisons. Here, a new method is introduced called mRAISE. Based on structural alignments, it uses a descriptor-based bitmap search engine (RAISE) to achieve efficiency. Alignments created on the fly by the search engine get evaluated with an independent shape-based scoring function also used for ranking of compounds. The correct ranking as well as the alignment quality of the method are evaluated and compared to other state of the art methods. On the commonly used Directory of Useful Decoys dataset mRAISE achieves an average area under the ROC curve of 0.76, an average enrichment factor at 1 % of 20.2 and an average hit rate at 1 % of 55.5. With these results, mRAISE is always among the top performing methods with available data for comparison. To access the quality of the alignments calculated by ligand-based virtual screening methods, we introduce a new dataset containing 180 prealigned ligands for 11 diverse targets. Within the top ten ranked conformations, the alignment closest to X-ray structure calculated with mRAISE has a root-mean-square deviation of less than 2.0 Å for 80.8 % of alignment pairs and achieves a median of less than 2.0 Å for eight of the 11 cases. The dataset used to rate the quality of the calculated alignments is freely available

  1. Lead Directorship and Firm Performance

    OpenAIRE

    OuYang, Bo

    2013-01-01

    This paper empirically explores the role of the lead directors in the corporate governance system and strives to empirically examine the association between the lead directorship and firm performance. I measure firm performance by three empirical proxies: Tobin’s Q, returns on assets (ROA) and stock returns. I explore the research question on the relationship between lead directorship and firm performance in both cross-sectional and inter-temporal contexts. The sample consists of S & P 500 fi...

  2. Archives of Atmospheric Lead Pollution

    Science.gov (United States)

    Weiss, Dominik; Shotyk, William; Kempf, Oliver

    Environmental archives such as peat bogs, sediments, corals, trees, polar ice, plant material from herbarium collections, and human tissue material have greatly helped to assess both ancient and recent atmospheric lead deposition and its sources on a regional and global scale. In Europe detectable atmospheric lead pollution began as early as 6000years ago due to enhanced soil dust and agricultural activities, as studies of peat bogs reveal. Increased lead emissions during ancient Greek and Roman times have been recorded and identified in many long-term archives such as lake sediments in Sweden, ice cores in Greenland, and peat bogs in Spain, Switzerland, the United Kingdom, and the Netherlands. For the period since the Industrial Revolution, other archives such as corals, trees, and herbarium collections provide similar chronologies of atmospheric lead pollution, with periods of enhanced lead deposition occurring at the turn of the century and since 1950. The main sources have been industry, including coal burning, ferrous and nonferrous smelting, and open waste incineration until c.1950 and leaded gasoline use since 1950. The greatest lead emissions to the atmosphere all over Europe occurred between 1950 and 1980 due to traffic exhaust. A marked drop in atmospheric lead fluxes found in most archives since the 1980s has been attributed to the phasing out of leaded gasoline. The isotope ratios of lead in the various archives show qualitatively similar temporal changes, for example, the immediate response to the introduction and phasing out of leaded gasoline. Isotope studies largely confirm source assessments based on lead emission inventories and allow the contributions of various anthropogenic sources to be calculated.

  3. A thermal responsive affinity ligand for precipitation of sialylated proteins

    Directory of Open Access Journals (Sweden)

    Lindsay Arnold

    2016-01-01

    Full Text Available We report here the development of a thermal responsive affinity ligand specific to sialic acid, sialic acid containing oligosaccharides, glycoproteins, and other sialylated glycoconjugates. The ligand is a fusion protein of 40 repeats of pentapeptide of an elastin like polymer (ELP and the 21 kD sialic acid binding domain of a Vibrio cholera neuraminidase (VCNA. For cost-effective synthesis, the fusion protein was targeted to the periplasmic space of an E. coli lpp deletion mutant, resulting in its secretion to the growth medium. A pre-induction heat-shock step at 42 ˚C for 20 minutes was necessary to achieve high level expression of the ligand. Under optimized induction condition (18 ˚C, 0.1 mM IPTG and 48 hours of post-induction cultivation, the ligand was produced to about 100 mg/L. The ligand exhibited a transition temperature of 52 ˚C, which could be depressed to 37 ˚C with the addition of 0.5 M NaCl. Using fetuin as a model sialylated protein, the ligand was applied in an affinity precipitation process to illustrate its potential application in glycoprotein isolation. The ligand captured 100% fetuin from an aqueous solution when the molar ratio of ligand to fetuin was 10 to 1, which was lower than the expected for full titration of sialic acid on the glycoprotein by the lectin. Elution of fetuin from ligand was achieved with PBS buffer containing 2 mM sialic acid. To evaluate how protein and other contaminants influence the recovery of sialylated proteins, CHO medium was spiked into the fetuin solution. The predominant protein species in CHO medium was found to be albumin. Although its removal of over 94% was evident, purified fetuin contained some albumin due to its over-abundance. Additional experiments with albumin contaminant of varying concentrations showed that below 1 mg/L, albumin had no impact on the affinity precipitation, whereas above 10 mg/L, some albumin was co-purified with fetuin. However, even at 50 mg/ml, fetuin

  4. Recovery of indium and lead from lead bullion

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Lead and indium were recovered by electrolysis and nonequilibrium solvent extraction process from lead bullion.The effects of current density,electrolytic period and circle amnant of electrolyte on the electrochemical dissolution of lead and indium were investigated.The effects of extraction phase ratio and mixing time on solvent extraction of indium and striping phase ratio and stripping stage on the loaded organic phase stripping were also investigated.The experimental results indicate that under optimum conditions,the purity of lead deposited on cathode is 98.5% and the deposit rate of lead is 99.9%,the dissolution rate of indium is 94.28%,the extraction rate of indium is 98.69%,the stripping rate of indium is almost 100%,and the impurity elements,such as Zn,Fe and Sn can be removed.

  5. Safe leads and lead changes in competitive team sports

    Science.gov (United States)

    Clauset, A.; Kogan, M.; Redner, S.

    2015-06-01

    We investigate the time evolution of lead changes within individual games of competitive team sports. Exploiting ideas from the theory of random walks, the number of lead changes within a single game follows a Gaussian distribution. We show that the probability that the last lead change and the time of the largest lead size are governed by the same arcsine law, a bimodal distribution that diverges at the start and at the end of the game. We also determine the probability that a given lead is "safe" as a function of its size L and game time t . Our predictions generally agree with comprehensive data on more than 1.25 million scoring events in roughly 40 000 games across four professional or semiprofessional team sports, and are more accurate than popular heuristics currently used in sports analytics.

  6. Remnant Pacemaker Lead Tips after Lead Extractions in Pacemaker Infections

    Science.gov (United States)

    Kim, Daehoon; Baek, Yong-Soo; Lee, Misol; Uhm, Jae-Sun; Pak, Hui-Nam; Lee, Moon-Hyoung

    2016-01-01

    Complete hardware removal is recommended in the case of patients with cardiovascular implantable electronic device (CIED) infections. However, the complete extraction of chronically implanted leads is not always achieved. The outcomes and optimal management of CIED infections with retained material after lead extractions have not been elucidated. In this case report, we present five patients with CIED infections with remnant lead tips even after lead extractions. Two patients had localized pocket infections, and were managed with antibiotics for a period of more than two weeks. The other three patients had infective endocarditis, and were managed with antibiotics for a period of more than four weeks. In one patient, the lead tip migrated to the right pulmonary artery, but did not produce any symptoms or complications. Only one of five patients experienced a resurgence of an infection. PMID:27482268

  7. Safe Leads and Lead Changes in Competitive Team Sports

    CERN Document Server

    Clauset, A; Redner, S

    2015-01-01

    We investigate the time evolution of lead changes within individual games of competitive team sports. Exploiting ideas from the theory of random walks, the number of lead changes within a single game follows a Gaussian distribution. We show that the probability that the last lead change and the time of the largest lead size are governed by the same arcsine law, a bimodal distribution that diverges at the start and at the end of the game. We also determine the probability that a given lead is "safe" as a function of its size $L$ and game time $t$. Our predictions generally agree with comprehensive data on more than 1.25 million scoring events in roughly 40,000 games across four professional or semi-professional team sports, and are more accurate than popular heuristics currently used in sports analytics.

  8. Issues of lead coolant technology

    International Nuclear Information System (INIS)

    Starting from 1989 with the BREST-OD-300 reactor design development, some experimental studies related to lead coolant have been performed to provide feasibility of using liquid lead as a coolant in the closed circuit. Further comprehensive analytical and experimental studies are required to develop lead coolant technology for the BREST-OD-300 reactor design. General work program for justification of lead coolant technology are planned aiming at not only getting the information on the components required for the technology realization and their design features but also revealing the possibility of use of data obtained in the course of lead-bismuth circuit operation for the lead circuits. The main results performed so far for justification of BREST-OD-300 reactor coolant technology are presented in this paper. The results confirmed the possibility of using the experience gained on lead-bismuth coolant justification on the stage of the BREST-OD-300 reactor design development. In addition, the results provided directions for further justification of lead coolant technology based on experience gained on lead-bismuth coolant. (author)

  9. Decontaminating lead bricks and shielding

    International Nuclear Information System (INIS)

    Lead used for shielding is often surface contaminated with radionuclides and is therefore a Resource Conservation and Recovery Act (RCRA) D008 mixed waste. The technology-based standard for treatment is macroencapsulation. However, decontaminating and recycling the clean lead is a more attractive solution. Los Alamos National Lab. decontaminates material and equipment contaminated with radioisotopes. Decontaminating lead poses special problems because of the RCRA hazard classification and the size of the inventory, now about 100 metric tons and likely to grow substantially because of planned decommissioning operations. This lead, in the form of bricks and other shield shapes, is surface contaminated with fission products. One of the best methods for decontaminating lead is removing the thin superficial layer of contamination with an abrasive medium under pressure. For lead, a mixture of alumina with water and air at about 280 kPa (40 psig) rapidly and effectively decontaminates the lead. The abrasive medium is sprayed onto the lead in a sealed-off area. The slurry of abrasive and particles of lead falls through a floor grating and is collected in a pump. A pump sends the slurry mixture back to the spray gun, creating a continuous process

  10. Synthesis and enzymatic cleavage of dual-ligand quantum dots

    Energy Technology Data Exchange (ETDEWEB)

    Sewell, Sarah L. [Department of Biomedical Engineering, Vanderbilt University, Nashville, TN (United States); Giorgio, Todd D., E-mail: todd.d.giorgio@vanderbilt.edu [Department of Biomedical Engineering, Vanderbilt University, Nashville, TN (United States); Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN (United States)

    2009-05-05

    Site directed therapy promises to minimize treatment-limiting systemic effects associated with cytotoxic agents that have no specificity for pathologic tissues. One general strategy is to target cell surface receptors uniquely presented on particular tissues. Highly specific in vivo targeting of an emerging neoplasm through a single molecular recognition mechanism has not generally been successful. Nonspecific binding and specific binding to non-target cells compromise the therapeutic index of small molecule, ubiquitous cancer targeting ligands. In this work, we have designed and fabricated a nanoparticle (NP) construct that could potentially overcome the current limitations of targeted in vivo delivery. Quantum dots (QDs) were functionalized with a poly(ethylene glycol) (PEG) modified to enable specific cleavage by matrix metalloprotease-7 (MMP-7). The QDs were further functionalized with folic acid, a ligand for a cell surface receptor that is overexpressed in many tumors, but also expressed in some normal tissues. The nanomolecular construct is designed so that the PEG initially conceals the folate ligand and construct binding to cells is inhibited. MMP-7 activated peptide cleavage and subsequent unmasking of the folate ligand occurs only near tumor tissue, resulting in a proximity activated (PA) targeting system. QDs functionalized with both the MMP-7 cleavable substrate and folic acid were successfully synthesized and characterized. The proteolytic capability of the dual ligand QD construct was quantitatively assessed by fluorometric analysis and compared to a QD construct functionalized with only the PA ligand. The dual ligand PA nanoparticles studied here exhibit significant susceptibility to cleavage by MMP-7 at physiologically relevant conditions. The capacity to autonomously convert a biopassivated nanostructure to a tissue-specific targeted delivery agent in vivo represents a paradigm change for site-directed therapies.

  11. Synthesis and enzymatic cleavage of dual-ligand quantum dots

    International Nuclear Information System (INIS)

    Site directed therapy promises to minimize treatment-limiting systemic effects associated with cytotoxic agents that have no specificity for pathologic tissues. One general strategy is to target cell surface receptors uniquely presented on particular tissues. Highly specific in vivo targeting of an emerging neoplasm through a single molecular recognition mechanism has not generally been successful. Nonspecific binding and specific binding to non-target cells compromise the therapeutic index of small molecule, ubiquitous cancer targeting ligands. In this work, we have designed and fabricated a nanoparticle (NP) construct that could potentially overcome the current limitations of targeted in vivo delivery. Quantum dots (QDs) were functionalized with a poly(ethylene glycol) (PEG) modified to enable specific cleavage by matrix metalloprotease-7 (MMP-7). The QDs were further functionalized with folic acid, a ligand for a cell surface receptor that is overexpressed in many tumors, but also expressed in some normal tissues. The nanomolecular construct is designed so that the PEG initially conceals the folate ligand and construct binding to cells is inhibited. MMP-7 activated peptide cleavage and subsequent unmasking of the folate ligand occurs only near tumor tissue, resulting in a proximity activated (PA) targeting system. QDs functionalized with both the MMP-7 cleavable substrate and folic acid were successfully synthesized and characterized. The proteolytic capability of the dual ligand QD construct was quantitatively assessed by fluorometric analysis and compared to a QD construct functionalized with only the PA ligand. The dual ligand PA nanoparticles studied here exhibit significant susceptibility to cleavage by MMP-7 at physiologically relevant conditions. The capacity to autonomously convert a biopassivated nanostructure to a tissue-specific targeted delivery agent in vivo represents a paradigm change for site-directed therapies.

  12. Microassay for measurement of binding of radiolabelled ligands to cell surface molecules

    International Nuclear Information System (INIS)

    An improved technique for measuring the binding of radiolabelled ligands to cell surface molecules has been developed by modification of a procedure using centrifugation through a water-immiscible oil to separate free and cell-bound ligand. It maximises the percentage of ligand bound since cell-bound and free ligand can be separated easily and reproducibly even when very small reaction volumes are used. This permits low levels of ligand radiolabelling and relatively low numbers of cells to be used

  13. Role of the T cell receptor ligand affinity in T cell activation by bacterial superantigens

    DEFF Research Database (Denmark)

    Andersen, P S; Geisler, C; Buus, S; Mariuzza, R A; Karjalainen, K

    2001-01-01

    the SEC3 variants correlated with enhanced binding without any optimum in the binding range covered by native TCR ligands. Comparable studies using anti-TCR antibodies of known affinity confirmed these observations. By comparing the biological potency of the two sets of ligands, we found a significant...... correlation between ligand affinity and ligand potency indicating that it is the density of receptor-ligand complexes in the T cell contact area that determines TCR signaling strength....

  14. Lead-free primary explosives

    Science.gov (United States)

    Huynh, My Hang V.

    2010-06-22

    Lead-free primary explosives of the formula (cat).sub.Y[M.sup.II(T).sub.X(H.sub.2O).sub.6-X].sub.Z, where T is 5-nitrotetrazolate, and syntheses thereof are described. Substantially stoichiometric equivalents of the reactants lead to high yields of pure compositions thereby avoiding dangerous purification steps.

  15. Targeting Lead in Solid Waste

    OpenAIRE

    Sigman, Hilary

    2003-01-01

    This paper explores policy options for reducing lead in municipal solid waste. It focuses on policies that rely on economic incentives, such as taxes, deposit-refunds, and recycled content standards. The paper addresses the relative cost effectiveness of these approaches and also considers the overall desirability of government intervention to reduce lead disposal.

  16. Ligand Migration and Binding in Myoglobin Mutant L29W

    Science.gov (United States)

    Nienhaus, G. Ulrich; Waschipky, Robert; Nienhaus, Karin; Minkow, Oleksandr; Ostermann, Andreas; Parak, Fritz G.

    2001-09-01

    Myoglobin, a small globular heme protein that binds gaseous ligands such as O2, CO, and NO reversibly at the heme iron, has for many years been a paradigm for studying the effects of structure and dynamics on protein reactions. Time-resolved spectroscopic measurements after photodissociation of the ligand reveal a complex ligand binding reaction with multiple kinetic intermediates, resulting from protein relaxation and movements of the ligand within the protein. To observe structural changes induced by ligand dissociation, we have investigated carbonmonoxy myoglobin (MbCO) mutant L29W using time-resolved infrared spectroscopy in combination with x-ray crystallography. The presence of two distinct infrared stretch bands of the bound CO, AI at 1945 cm-1 and AII at 1955 cm-1, implies that L29W MbCO assumes two different conformations at neutral pH. Low-temperature flash photolysis experiments with monitoring of the absorption changes in the individual CO lines reveal markedly different rebinding properties. While recombination in AII is conceptually simple and well described by a two-state transition involving a distribution of enthalpy barriers, recombination in AI is more complicated: Besides a fast kinetic component, a second, slower kinetic component appears; its population grows with increasing temperature. X-ray crystallography of crystals illuminated below 180 K to photodissociate the CO reveals that the slow component arises from ligands that have migrated from their initial docking site to a remote site within the distal heme pocket. This process occurs in an essentially immobilized, frozen protein. Subsequently, ligands rebind by thermal activation over a barrier that is much higher than the barrier for recombination from the initial docking site. Upon photodissociation above 180 K, ligands escape from the distal pocket, aided by protein fluctuations that transiently open exit channels. The x-ray structure shows a large proportion of ligands in a cavity on

  17. Heterolytic Cleavage of H2 by Bifunctional Manganese(I) Complexes: Impact of Ligand Dynamics, Electrophilicity, and Base Positioning

    Energy Technology Data Exchange (ETDEWEB)

    Hulley, Elliott B.; Helm, Monte L.; Bullock, R. Morris

    2014-12-01

    We report the synthesis, characterization, and reactivity with H2 of a series of MnI complexes of the type [(P-P)Mn(L2)CO]+ (L2 = dppm, bppm, or (CO)2; P-P = PPhNMePPh or PPh2 NBn2 ) that bear pendant amine ligands designed to function as proton relays. The pendant amine was found to function as a hemilabile ligand; its binding strength is strongly affected by the ancillary ligand environment around Mn. Tuning the electrophilicity of the Mn center leads to systems capable of reversible heterolytic cleavage of the H-H bond. The strength of pendant amine binding can be balanced to protect the Mn center while still leading to facile reactivity with H2. Neutral amine-bearing MnIH species were found to react with one-electron oxidants and, after proton and electron transfer reactions, regenerate MnI cationic species. The reactivity presented herein indicate that the Mn complexes we have developed are a promising platform for Mn-based H2 oxidation electrocatalyst development. The research was supported as part of the Center for Molecular Electrocatalysis, an Energy Frontier Research Center funded by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences. Pacific Northwest National Laboratory is operated by Battelle for DOE.

  18. Variation in the relationship between blood lead and air lead

    Science.gov (United States)

    Snee, Ronald D.; Bailey, Steven P.; Fellner, William H.; Pfeifer, Charles G.

    Estimates of the slope of the relationship between blood lead (μg dl -1) and air lead (μg m -3) obtained in ten independent studies are compared. No significant differences were detected among the estimates which ranged from 0.6 to 3.1 μg dl -1 per μg m -3 and represented male adult, female adult and child populations. A single best estimate of 1.2 μg dl -1 per μg m -3 ( ± 0.2,95 per cent confidence limits) was obtained. It is concluded that, if the blood lead-air lead slope depends on various physical and biological factors, then studies providing more precise estimates are required to detect these differences.

  19. Structural analysis of prolyl oligopeptidases using molecular docking and dynamics: insights into conformational changes and ligand binding.

    Directory of Open Access Journals (Sweden)

    Swati Kaushik

    Full Text Available Prolyl oligopeptidase (POP is considered as an important pharmaceutical target for the treatment of numerous diseases. Despite enormous studies on various aspects of POPs structure and function still some of the questions are intriguing like conformational dynamics of the protein and interplay between ligand entry/egress. Here, we have used molecular modeling and docking based approaches to unravel questions like differences in ligand binding affinities in three POP species (porcine, human and A. thaliana. Despite high sequence and structural similarity, they possess different affinities for the ligands. Interestingly, human POP was found to be more specific, selective and incapable of binding to a few planar ligands which showed extrapolation of porcine POP in human context is more complicated. Possible routes for substrate entry and product egress were also investigated by detailed analyses of molecular dynamics (MD simulations for the three proteins. Trajectory analysis of bound and unbound forms of three species showed differences in conformational dynamics, especially variations in β-propeller pore size, which was found to be hidden by five lysine residues present on blades one and seven. During simulation, β-propeller pore size was increased by ∼2 Å in porcine ligand-bound form which might act as a passage for smaller product movement as free energy barrier was reduced, while there were no significant changes in human and A. thaliana POPs. We also suggest that these differences in pore size could lead to fundamental differences in mode of product egress among three species. This analysis also showed some functionally important residues which can be used further for in vitro mutagenesis and inhibitor design. This study can help us in better understanding of the etiology of POPs in several neurodegenerative diseases.

  20. Cloud computing for protein-ligand binding site comparison.

    Science.gov (United States)

    Hung, Che-Lun; Hua, Guan-Jie

    2013-01-01

    The proteome-wide analysis of protein-ligand binding sites and their interactions with ligands is important in structure-based drug design and in understanding ligand cross reactivity and toxicity. The well-known and commonly used software, SMAP, has been designed for 3D ligand binding site comparison and similarity searching of a structural proteome. SMAP can also predict drug side effects and reassign existing drugs to new indications. However, the computing scale of SMAP is limited. We have developed a high availability, high performance system that expands the comparison scale of SMAP. This cloud computing service, called Cloud-PLBS, combines the SMAP and Hadoop frameworks and is deployed on a virtual cloud computing platform. To handle the vast amount of experimental data on protein-ligand binding site pairs, Cloud-PLBS exploits the MapReduce paradigm as a management and parallelizing tool. Cloud-PLBS provides a web portal and scalability through which biologists can address a wide range of computer-intensive questions in biology and drug discovery. PMID:23762824

  1. Predicting protein ligand binding motions with the conformation explorer

    Directory of Open Access Journals (Sweden)

    Flores Samuel C

    2011-10-01

    Full Text Available Abstract Background Knowledge of the structure of proteins bound to known or potential ligands is crucial for biological understanding and drug design. Often the 3D structure of the protein is available in some conformation, but binding the ligand of interest may involve a large scale conformational change which is difficult to predict with existing methods. Results We describe how to generate ligand binding conformations of proteins that move by hinge bending, the largest class of motions. First, we predict the location of the hinge between domains. Second, we apply an Euler rotation to one of the domains about the hinge point. Third, we compute a short-time dynamical trajectory using Molecular Dynamics to equilibrate the protein and ligand and correct unnatural atomic positions. Fourth, we score the generated structures using a novel fitness function which favors closed or holo structures. By iterating the second through fourth steps we systematically minimize the fitness function, thus predicting the conformational change required for small ligand binding for five well studied proteins. Conclusions We demonstrate that the method in most cases successfully predicts the holo conformation given only an apo structure.

  2. Kinetics of Receptor-Ligand Interactions in Immune Responses

    Institute of Scientific and Technical Information of China (English)

    Mian Long; Shouqin Lü; Ganyun Sun

    2006-01-01

    Receptor-ligand interactions in blood flow are crucial to initiate the biological processes as inflammatory cascade,platelet thrombosis, as well as tumor metastasis. To mediate cell adhesions, the interacting receptors and ligands must be anchored onto two apposing surfaces of two cells or a cell and a substratum, i.e., the two-dimensional (2D) binding, which is different from the binding of a soluble ligand in fluid phase to a receptor, i.e., three-dimensional (3D) binding. While numerous works have been focused on 3D kinetics of receptor-ligand interactions in immune systems, 2D kinetics and its regulations have less been understood, since no theoretical framework and experimental assays have been established until 1993. Not only does the molecular structure dominate 2D binding kinetics, but the shear force in blood flow also regulates cell adhesions mediated by interacting receptors and ligands. Here we provided the overview of current progresses in 2D bindings and regulations. Relevant issues of theoretical frameworks, experimental measurements, kinetic rates and binding affinities, and force regulations,were discussed.

  3. Leading people and leading authentic self through online networking platforms

    OpenAIRE

    Korzynski, Pawel

    2012-01-01

    Online social networking is more and more important in leading people and leading oneself. Online platforms provide a low cost, highly accessible way of communication, which enable leaders to build personal brand, maintain relationship with people within and outside leaders' company as well as support task performing through online discussion, sharing knowledge and finding clients. Leaders should pay special attention not only to their operational or individual network but also to strategi...

  4. Chemical speciation of lead dust associated with primary lead smelting.

    OpenAIRE

    Spear, T M; Svee, W; Vincent, J H; Stanisich, N

    1998-01-01

    The research presented in this article assessed geochemical factors relating to dust produced during primary lead smelting. Bulk dust samples and size-selective airborne dust samples were collected from four areas of a primary lead smelter and analyzed by X-ray diffraction and sequential chemical extraction. X-ray diffraction showed that the smelter dusts were composed primarily of sulfides, oxides, sulfates, and silicates of metal ores, with galena being the primary dust component. Sequentia...

  5. Lead levels of Culex mosquito larvae inhabiting lead utilizing factory

    Institute of Scientific and Technical Information of China (English)

    Kitvatanachai; S; Apiwathnasorn; C; Leemingsawat; S; Wongwit; W; Overgaard; HJ

    2011-01-01

    Objective:To determine lead level primarily in Culex quinquefasciatus(Cx.quinquefasciatus), and Culex gelidus(Cx.gelidus) larvae inhabiting lead consuming factories,and to putatively estimate eco-toxicological impact of effluents from the firms.Methods:Third instars larvae were sampled by standard dipping method and lead concentrations in the larvae and their respective surrounding factory aquatic environments were determined through standard atomic absorption spectrophotometry(AAS).Results:Cx.quinquefasciatus was the most abundant species followed by Cx.gelidus.The levels of lead were higher in the Cx.quinquefasciatus(1.08-47.47μg/g),than in the wastewaters surface(0.01-0.78 μg/mL) from the factories or closer areas around factories. Other species were not reaching the.criteria for lead determination.Conclusions:The Cx. quinquefasciatus larvae can bio-accumulate the metal and can potentially serve as a biomarker of lead contamination,to complemente conventional techniques.

  6. Toward Quantitatively Accurate Calculation of the Redox-Associated Acid-Base and Ligand Binding Equilibria of Aquacobalamin.

    Science.gov (United States)

    Johnston, Ryne C; Zhou, Jing; Smith, Jeremy C; Parks, Jerry M

    2016-08-01

    Redox processes in complex transition metal-containing species are often intimately associated with changes in ligand protonation states and metal coordination number. A major challenge is therefore to develop consistent computational approaches for computing pH-dependent redox and ligand dissociation properties of organometallic species. Reduction of the Co center in the vitamin B12 derivative aquacobalamin can be accompanied by ligand dissociation, protonation, or both, making these properties difficult to compute accurately. We examine this challenge here by using density functional theory and continuum solvation to compute Co-ligand binding equilibrium constants (Kon/off), pKas, and reduction potentials for models of aquacobalamin in aqueous solution. We consider two models for cobalamin ligand coordination: the first follows the hexa, penta, tetra coordination scheme for Co(III), Co(II), and Co(I) species, respectively, and the second model features saturation of each vacant axial coordination site on Co(II) and Co(I) species with a single, explicit water molecule to maintain six directly interacting ligands or water molecules in each oxidation state. Comparing these two coordination schemes in combination with five dispersion-corrected density functionals, we find that the accuracy of the computed properties is largely independent of the scheme used, but including only a continuum representation of the solvent yields marginally better results than saturating the first solvation shell around Co throughout. PBE performs best, displaying balanced accuracy and superior performance overall, with RMS errors of 80 mV for seven reduction potentials, 2.0 log units for five pKas and 2.3 log units for two log Kon/off values for the aquacobalamin system. Furthermore, we find that the BP86 functional commonly used in corrinoid studies suffers from erratic behavior and inaccurate descriptions of Co-axial ligand binding, leading to substantial errors in predicted pKas and

  7. Anthranilic acid derivatives as nuclear receptor modulators--development of novel PPAR selective and dual PPAR/FXR ligands.

    Science.gov (United States)

    Merk, Daniel; Lamers, Christina; Weber, Julia; Flesch, Daniel; Gabler, Matthias; Proschak, Ewgenij; Schubert-Zsilavecz, Manfred

    2015-02-01

    Nuclear receptors, especially the peroxisome proliferator activated receptors (PPARs) and the farnesoid X receptor (FXR) fulfill crucial roles in metabolic balance. Their activation offers valuable therapeutic potential which has high clinical relevance with the fibrates and glitazones as PPAR agonistic drugs. With growing knowledge about the various functions of nuclear receptors in many disorders, new selective or dual ligands of these pharmaceutical targets are however still required. Here we report the class of anthranilic acid derivatives as novel selective PPAR or dual FXR/PPAR ligands. We identified distinct molecular determinants that govern selectivity for each PPAR subtype or FXR as well as the amplitude of activation of the respective receptors. We thereby discovered several lead compounds for further optimization and developed a highly potent dual PPARα/FXR partial agonist that might have a beneficial synergistic effect on lipid homeostasis by simultaneous activation of two nuclear receptors involved in lipid metabolism. PMID:25583100

  8. Analytical developments for screening of lanthanides/ligands interactions

    International Nuclear Information System (INIS)

    This work investigates the potential of hyphenated capillary electrophoresis and inductively coupled mass spectrometry to classify different ligands according to their europium binding affinity in a hydro-organic medium. On the one hand, this method enables to evaluate the affinity of phosphorus-containing ligands in less than two hours and using less than 15 ng of ligand. On the other hand, complexation constants could be determined. The results are in excellent agreement with the values obtained by spectrophotometric titrations.Moreover, a library of copolymers for solid/liquid extraction of europium is investigated. The extraction protocol enables to classify copolymers according to their europium affinity in a hydro-organic medium. This screening requires 60 mg of copolymers. For the most promising recognition properties and selectivity La3+/Eu3+/Lu3+ are evaluated. (author)

  9. The thermodynamic principles of ligand binding in chromatography and biology

    DEFF Research Database (Denmark)

    Mollerup, Jørgen

    2007-01-01

    In chromatography, macromolecules do not adsorb in the traditional sense of the word but bind to ligands that are covalently bonded to the surface of the porous bead. Therefore, the adsorption must be modelled as a process where protein molecules bind to the immobilised ligands. The paper discusses...... it is also observed in chromatography due to protein-protein interactions. Retention measurements on P-lactoglobulin A demonstrate this. A discussion of salt effects on hydrophobic interactions in precipitation and chromatography of proteins concludes the paper. (c) 2007 Elsevier B.V. All rights...... the general thermodynamic principles of ligand binding. Models of the multi-component adsorption in ion-exchange and hydrophobic chromatography, HIC and RPLC, are developed. The parameters in the models have a well-defined physical significance. The models are compared to the Langmuir model. In the...

  10. Chiroptical activity in colloidal quantum dots coated with achiral ligands.

    Science.gov (United States)

    Melnikau, Dzmitry; Savateeva, Diana; Gaponik, Nikolai; Govorov, Alexander O; Rakovich, Yury P

    2016-01-25

    We studied the chiroptical properties of colloidal solution of CdSe and CdSe/ZnS quantum dots (QDs) with a cubic lattice structure which were initially prepared without use of any chiral molecules and coated with achiral ligands. We demonstrate circular dichroism (CD) activity around first and second excitonic transition of these CdSe based nanocrystals. We consider that this chiroptical activity is caused by imbalance in racemic mixtures of QDs between the left and right handed nanoparticles, which appears as a result of the formation of various defects or incorporation of impurities into crystallographic structure during their synthesis. We demonstrate that optical activity of colloidal solution of CdSe QDs with achiral ligands weakly depends on the QDs size and number of ZnS monolayers, but does not depend on the nature of achiral ligands or polarity of the solution. PMID:26832599

  11. Ligand screening by saturation-transfer difference (STD) NMR spectroscopy.

    Energy Technology Data Exchange (ETDEWEB)

    Krishnan, V V

    2005-04-26

    NMR based methods to screen for high-affinity ligands have become an indispensable tool for designing rationalized drugs, as these offer a combination of good experimental design of the screening process and data interpretation methods, which together provide unprecedented information on the complex nature of protein-ligand interactions. These methods rely on measuring direct changes in the spectral parameters, that are often simpler than the complex experimental procedures used to study structure and dynamics of proteins. The goal of this review article is to provide the basic details of NMR based ligand-screening methods, with particular focus on the saturation transfer difference (STD) experiment. In addition, we provide an overview of other NMR experimental methods and a practical guide on how to go about designing and implementing them.

  12. Aryl hydrocarbon receptor ligands in cancer: friend and foe.

    Science.gov (United States)

    Murray, Iain A; Patterson, Andrew D; Perdew, Gary H

    2014-12-01

    The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that is best known for mediating the toxicity and tumour-promoting properties of the carcinogen 2,3,7,8-tetrachlorodibenzo-p-dioxin, commonly referred to as ‘dioxin’. AHR influences the major stages of tumorigenesis — initiation, promotion, progression and metastasis — and physiologically relevant AHR ligands are often formed during disease states or during heightened innate and adaptive immune responses. Interestingly, ligand specificity and affinity vary between rodents and humans. Studies of aggressive tumours and tumour cell lines show increased levels of AHR and constitutive localization of this receptor in the nucleus. This suggests that the AHR is chronically activated in tumours, thus facilitating tumour progression. This Review discusses the role of AHR in tumorigenesis and the potential for therapeutic modulation of its activity in tumours. PMID:25568920

  13. Lanthanide and actinide complexation studies with tetradentate 'N' donor ligands

    International Nuclear Information System (INIS)

    Because of their similar charge and chemical behaviour separation of trivalent actinides and lanthanides is an important and challenging task in nuclear fuel cycle. Soft (S,N) donor ligands show selectivity towards the trivalent actinides over the lanthanides. Out of various 'N' donor ligands studied, bis(1,2,4)triazinyl bipyridine (BTBP) and bis(1,2,4)triazinyl phenanthroline (BTPhen) were found to be most promising. In order to understand the separation behaviour of these ligands, their complexation studies with these 'f' block elements are essential. In the present work, complexation studies of various lanthanide ions (La3+, Eu3+ and Er3+) was studied with ethyl derivatives of BTBP (C2BTBP) and BTBPhen (C2BTPhen) and pentyl derivative of BTBP (C5BTBP) in acetonitrile medium using UV-Vis spectrophotometry, fluorescence spectroscopy and solution calorimetry. Computational studies were also carried out to understand the experimental results

  14. Oxoiron(IV) Complex of the Ethylene-Bridged Dialkylcyclam Ligand Me2EBC.

    Science.gov (United States)

    England, Jason; Prakash, Jai; Cranswick, Matthew A; Mandal, Debasish; Guo, Yisong; Münck, Eckard; Shaik, Sason; Que, Lawrence

    2015-08-17

    We report herein the first example of an oxoiron(IV) complex of an ethylene-bridged dialkylcyclam ligand, [Fe(IV)(O)(Me2EBC)(NCMe)](2+) (2; Me2EBC = 4,11-dimethyl-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane). Complex 2 has been characterized by UV-vis, (1)H NMR, resonance Raman, Mössbauer, and X-ray absorption spectroscopy as well as electrospray ionization mass spectrometry, and its properties have been compared with those of the closely related [Fe(IV)(O)(TMC)(NCMe)](2+) (3; TMC = 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane), the intensively studied prototypical oxoiron(IV) complex of the macrocyclic tetramethylcyclam ligand. Me2EBC has an N4 donor set nearly identical with that of TMC but possesses an ethylene bridge in place of the 1- and 8-methyl groups of TMC. As a consequence, Me2EBC is forced to deviate from the trans-I configuration typically found for Fe(IV)(O)(TMC) complexes and instead adopts a folded cis-V stereochemistry that requires the MeCN ligand to coordinate cis to the Fe(IV)═O unit in 2 rather than in the trans arrangement found in 3. However, switching from the trans geometry of 3 to the cis geometry of 2 did not significantly affect their ground-state electronic structures, although a decrease in ν(Fe═O) was observed for 2. Remarkably, despite having comparable Fe(IV/III) reduction potentials, 2 was found to be significantly more reactive than 3 in both oxygen-atom-transfer (OAT) and hydrogen-atom-transfer (HAT) reactions. A careful analysis of density functional theory calculations on the HAT reactivity of 2 and 3 revealed the root cause to be the higher oxyl character of 2, leading to a stronger O---H bond specifically in the quintet transition state. PMID:26244657

  15. Mapping the Conformational Dynamics of E-selectin upon Interaction with its Ligands

    KAUST Repository

    Aleisa, Fajr A

    2013-05-15

    Selectins are key adhesion molecules responsible for initiating a multistep process that leads a cell out of the blood circulation and into a tissue or organ. The adhesion of cells (expressing ligands) to the endothelium (expressing the selectin i.e.,E-selectin) occurs through spatio-temporally regulated interactions that are mediated by multiple intra- and inter-cellular components. The mechanism of cell adhesion is investigated primarily using ensemble-based experiments, which provides indirect information about how individual molecules work in such a complex system. Recent developments in single-molecule (SM) fluorescence detection allow for the visualization of individual molecules with a good spatio-temporal resolution nanometer spatial resolution and millisecond time resolution). Furthermore, advanced SM fluorescence techniques such as Förster Resonance Energy Transfer (FRET) and super-resolution microscopy provide unique opportunities to obtain information about nanometer-scale conformational dynamics of proteins as well as nano-scale architectures of biological samples. Therefore, the state-of-the-art SM techniques are powerful tools for investigating complex biological system such as the mechanism of cell adhesion. In this project, several constructs of fluorescently labeled E-selectin will be used to study the conformational dynamics of E-selectin binding to its ligand(s) using SM-FRET and combination of SM-FRET and force microscopy. These studies will be beneficial to fully understand the mechanistic details of cell adhesion and migration of cells using the established model system of hematopoietic stem cells (HSCs) adhesion to the selectin expressing endothelial cells (such as the E-selectin expressing endothelial cells in the bone marrow).

  16. Ligand scaffold hopping combining 3D maximal substructure search and molecular similarity

    Directory of Open Access Journals (Sweden)

    Petitjean Michel

    2009-08-01

    Full Text Available Abstract Background Virtual screening methods are now well established as effective to identify hit and lead candidates and are fully integrated in most drug discovery programs. Ligand-based approaches make use of physico-chemical, structural and energetics properties of known active compounds to search large chemical libraries for related and novel chemotypes. While 2D-similarity search tools are known to be fast and efficient, the use of 3D-similarity search methods can be very valuable to many research projects as integration of "3D knowledge" can facilitate the identification of not only related molecules but also of chemicals possessing distant scaffolds as compared to the query and therefore be more inclined to scaffolds hopping. To date, very few methods performing this task are easily available to the scientific community. Results We introduce a new approach (LigCSRre to the 3D ligand similarity search of drug candidates. It combines a 3D maximum common substructure search algorithm independent on atom order with a tunable description of atomic compatibilities to prune the search and increase its physico-chemical relevance. We show, on 47 experimentally validated active compounds across five protein targets having different specificities, that for single compound search, the approach is able to recover on average 52% of the co-actives in the top 1% of the ranked list which is better than gold standards of the field. Moreover, the combination of several runs on a single protein target using different query active compounds shows a remarkable improvement in enrichment. Such Results demonstrate LigCSRre as a valuable tool for ligand-based screening. Conclusion LigCSRre constitutes a new efficient and generic approach to the 3D similarity screening of small compounds, whose flexible design opens the door to many enhancements. The program is freely available to the academics for non-profit research at: http://bioserv.rpbs.univ-paris-diderot.fr/LigCSRre.html.

  17. Sequence diversity and ligand-induced structural rearrangements of viper hyaluronidase.

    Science.gov (United States)

    Bharathi, A Christian; Yadav, Pradeep Kumar; Syed Ibrahim, B

    2016-04-01

    Hyaluronidases (Hyals) are a class of carbohydrate-active enzyme involved in angiogenesis, cancer proliferation, tumour growth and venom spreading. Functionally significant Hyals are responsible for the fast spreading of venom to the target site of action. The absence of molecular diversity and the structural and functional behaviour of snake venom Hyals was the inspiration for the objective of this study. Echis pyramidum leakeyi hyaluronidase (EHY)-based phylogenetic analysis showed the existence of two functional groups of Hyals which had diverged from the coral snake (the ancestor). The structure was modelled and it was found that the E-loop region (211-224 AA) was only present in EHY compared to the templates which may account for the significant function of viper Hyal. The best interacting ligands were screened from the selected plant derivatives and MYR consisted of better pharmacophore features (AADDRRR) in comparison with other ligands. Furthermore, the HOMO, LUMO, and MO energies and energy gaps of CGA, MIM and MYR were calculated by DFT analysis. EHY-ligand complex stability and interactions were investigated through MD simulation and FEL analysis. These revealed that MIM and MYR or their derivative compounds could be prominent lead molecules for both EHY and other eukaryotic Hyals. PCA analysis of both the non-ligated and ligated forms confirmed that loop-III (86-96 AA) and E-loop region structural rearrangements were essential for the association and dissociation process of the substrate. Particularly, ARG92 and LYS219 are determined as important key residues from the conformational changes. These regions' dynamic behaviour can be associated with HA binding and the catalytic function of EHY. This result can extend our knowledge of viper Hyal functional behaviour and provides structural insight to target eukaryotic Hyals as forthcoming drug targets in cancer treatment and venom spreading. PMID:26867694

  18. Ligands for pheromone-sensing neurons are not conformationally activated odorant binding proteins.

    Science.gov (United States)

    Gomez-Diaz, Carolina; Reina, Jaime H; Cambillau, Christian; Benton, Richard

    2013-01-01

    Pheromones form an essential chemical language of intraspecific communication in many animals. How olfactory systems recognize pheromonal signals with both sensitivity and specificity is not well understood. An important in vivo paradigm for this process is the detection mechanism of the sex pheromone (Z)-11-octadecenyl acetate (cis-vaccenyl acetate [cVA]) in Drosophila melanogaster. cVA-evoked neuronal activation requires a secreted odorant binding protein, LUSH, the CD36-related transmembrane protein SNMP, and the odorant receptor OR67d. Crystallographic analysis has revealed that cVA-bound LUSH is conformationally distinct from apo (unliganded) LUSH. Recombinantly expressed mutant versions of LUSH predicted to enhance or diminish these structural changes produce corresponding alterations in spontaneous and/or cVA-evoked activity when infused into olfactory sensilla, leading to a model in which the ligand for pheromone receptors is not free cVA, but LUSH that is "conformationally activated" upon cVA binding. Here we present evidence that contradicts this model. First, we demonstrate that the same LUSH mutants expressed transgenically affect neither basal nor pheromone-evoked activity. Second, we compare the structures of apo LUSH, cVA/LUSH, and complexes of LUSH with non-pheromonal ligands and find no conformational property of cVA/LUSH that can explain its proposed unique activated state. Finally, we show that high concentrations of cVA can induce neuronal activity in the absence of LUSH, but not SNMP or OR67d. Our findings are not consistent with the model that the cVA/LUSH complex acts as the pheromone ligand, and suggest that pheromone molecules alone directly activate neuronal receptors. PMID:23637570

  19. New divalent manganese complex with pyridine carboxylate N-oxide ligand: Synthesis, structure and magnetic properties

    International Nuclear Information System (INIS)

    Two new manganese complexes, [Mn3(L1)4(NO3)2]n (1, HL1=nicotinate N-oxide acid) and [MnL2Cl]n (2, HL2=isonicotinate N-oxide acid)], have been hydrothermally synthesized and characterized by elemental analysis, IR and single-crystal X-ray diffraction. In 1, the L1 ligands take two different coordinated modes bridging four and three MnII ions. The nitrate anions take chelating coordination modes, leading one type of the MnII ions as a 4-connected node. The whole net can be viewed as a 3, 4, 6-connected 4-nodal net with Schlaefli notation {43}2{44; 62}4{46; 66; 83}. Complex 2 has a honeycomb layer mixed bridged by chlorine, N-oxide and carboxylate. The adjacent layers are linked by the phenyl ring of L2 ligand, giving a 3D framework with a {34; 54} {32;4;56;66} 4, 6-connect net. Magnetic studies indicate that 1 is an antiferromagnet with low-dimensional characteristic, in which a -J1J1J2- coupled alternating chain is predigested. Fitting the data of 1 gives the best parameters J1=-2.77, J2=-0.67 cm-1. The magnetic properties of complex 2 represent the character of the 2D honeycomb layer with the J1=-2.05 and J2=0.55 cm-1, which results in a whole antiferromagnetic state. - Graphical abstract: The synthesis, crystal structure and magnetic properties of two new MnII complexes with pyridyl-carboxylate N-oxide ligands are reported.

  20. PPAR{gamma} ligands induce growth inhibition and apoptosis through p63 and p73 in human ovarian cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Soyeon [Cancer Research Institute, Seoul National University College of Medicine and Hospital, Seoul (Korea, Republic of); Innovative Research Institute for Cell Therapy, Seoul National University College of Medicine and Hospital, Seoul (Korea, Republic of); Lee, Jae-Jung [Cancer Research Institute, Seoul National University College of Medicine and Hospital, Seoul (Korea, Republic of); Heo, Dae Seog, E-mail: heo1013@snu.ac.kr [Cancer Research Institute, Seoul National University College of Medicine and Hospital, Seoul (Korea, Republic of); Department of Internal Medicine, Seoul National University College of Medicine and Hospital, Seoul (Korea, Republic of); Innovative Research Institute for Cell Therapy, Seoul National University College of Medicine and Hospital, Seoul (Korea, Republic of)

    2011-03-18

    Research highlights: {yields} PPAR{gamma} ligands increased the rate of apoptosis and inhibition of proliferation in ovarian cancer cells. {yields} PPAR{gamma} ligands induced p63 and p73 expression, but not p53. {yields} p63 and p73 leads to an increase in p21 expression and apoptosis in ovarian cancer cells with treatment PPAR{gamma} ligands. {yields} These findings suggest that PPAR{gamma} ligands suppressed growth of ovarian cancer cells through upregulation of p63 and p73. -- Abstract: Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonists, including thiazolidinediones (TZDs), can induce anti-proliferation, differentiation, and apoptosis in various cancer cell types. This study investigated the mechanism of the anticancer effect of TZDs on human ovarian cancer. Six human ovarian cancer cell lines (NIH:OVCAR3, SKOV3, SNU-251, SNU-8, SNU-840, and 2774) were treated with the TZD, which induced dose-dependent inhibition of cell growth. Additionally, these cell lines exhibited various expression levels of PPAR{gamma} protein as revealed by Western blotting. Flow cytometry showed that the cell cycle was arrested at the G1 phase, as demonstrated by the appearance of a sub-G1 peak. This observation was corroborated by the finding of increased levels of Bax, p21, PARP, and cleaved caspase 3 in TGZ-treated cells. Interestingly, when we determined the effect of p53-induced growth inhibition in these three human ovarian cancer cells, we found that they either lacked p53 or contained a mutant form of p53. Furthermore, TGZ induced the expression of endogenous or exogenous p63 and p73 proteins and p63- or p73-directed short hairpin (si) RNAs inhibited the ability of TGZ to regulate expression of p21 in these cells. Thus, our results suggest that PPAR{gamma} ligands can induce growth suppression of ovarian cancer cells and mediate p63 and p73 expression, leading to enhanced growth inhibition and apoptosis. The tumor suppressive effects of PPAR{gamma} ligands

  1. PPARγ ligands induce growth inhibition and apoptosis through p63 and p73 in human ovarian cancer cells

    International Nuclear Information System (INIS)

    Research highlights: → PPARγ ligands increased the rate of apoptosis and inhibition of proliferation in ovarian cancer cells. → PPARγ ligands induced p63 and p73 expression, but not p53. → p63 and p73 leads to an increase in p21 expression and apoptosis in ovarian cancer cells with treatment PPARγ ligands. → These findings suggest that PPARγ ligands suppressed growth of ovarian cancer cells through upregulation of p63 and p73. -- Abstract: Peroxisome proliferator-activated receptor gamma (PPARγ) agonists, including thiazolidinediones (TZDs), can induce anti-proliferation, differentiation, and apoptosis in various cancer cell types. This study investigated the mechanism of the anticancer effect of TZDs on human ovarian cancer. Six human ovarian cancer cell lines (NIH:OVCAR3, SKOV3, SNU-251, SNU-8, SNU-840, and 2774) were treated with the TZD, which induced dose-dependent inhibition of cell growth. Additionally, these cell lines exhibited various expression levels of PPARγ protein as revealed by Western blotting. Flow cytometry showed that the cell cycle was arrested at the G1 phase, as demonstrated by the appearance of a sub-G1 peak. This observation was corroborated by the finding of increased levels of Bax, p21, PARP, and cleaved caspase 3 in TGZ-treated cells. Interestingly, when we determined the effect of p53-induced growth inhibition in these three human ovarian cancer cells, we found that they either lacked p53 or contained a mutant form of p53. Furthermore, TGZ induced the expression of endogenous or exogenous p63 and p73 proteins and p63- or p73-directed short hairpin (si) RNAs inhibited the ability of TGZ to regulate expression of p21 in these cells. Thus, our results suggest that PPARγ ligands can induce growth suppression of ovarian cancer cells and mediate p63 and p73 expression, leading to enhanced growth inhibition and apoptosis. The tumor suppressive effects of PPARγ ligands may have applications for the treatment of ovarian cancer.

  2. Secondary ligand-directed assembly of Co(II) coordination polymers based on a pyridine carboxylate ligand

    Science.gov (United States)

    Cao, Ke-Li; Zhang, Yi-Ping; Cai, Yi-Ni; Xu, Xiao-Wei; Feng, Yun-Long

    2014-07-01

    To investigate the influence of hydrogen bonds and secondary ligands on the structures and properties of the resulting frameworks, five new Co(II) compounds have been synthesized by the reactions of Co(II) salts and 3,5-bis(pyridin-4-ylmethoxy)benzoic acid (HL) with four rationally selected dicarboxylic acid ligands. Without secondary ligand, we got one compound [CoL2(H2O)2]n·2nH2O (1), which possesses a 1D chain structure. In the presence of ancillary ligands, namely, 1,3-adamantanedicarboxylic acid (H2adbc), terephthalic acid (H2tpa), thiophene-2,5-dicarboxylic acid (H2tdc) and 1,4-benzenedithioacetic acid (H2bdtc), four 3D structures [Co2L2(adbc)]n·nH2O (2), [Co2L2(tpa)]n (3), [Co2L2(tdc)]n (4), [Co2L2(bdtc)(H2O)]n (5) were obtained, respectively. It can be observed from the architectures of 1-5 that hydrogen bonds and secondary ligands both have great effects on the spatial connective fashions, resulting in the formation of various dimensional compounds. The XRPD, TGA data of title polymers and the magnetic properties for 2 and 5 have also been investigated.

  3. Conformational diversity of flexible ligand in metal-organic frameworks controlled by size-matching mixed ligands

    Science.gov (United States)

    Hua, Xiu-Ni; Qin, Lan; Yan, Xiao-Zhi; Yu, Lei; Xie, Yi-Xin; Han, Lei

    2015-12-01

    Hydrothermal reactions of N-auxiliary flexible exo-bidentate ligand 1,3-bis(4-pyridyl)propane (bpp) and carboxylates ligands naphthalene-2,6-dicarboxylic acid (2,6-H2ndc) or 4,4‧-(hydroxymethylene)dibenzoic acid (H2hmdb), in the presence of cadmium(II) salts have given rise to two novel metal-organic frameworks based on flexible ligands (FL-MOFs), namely, [Cd2(2,6-ndc)2(bpp)(DMF)]·2DMF (1) and [Cd3(hmdb)3(bpp)]·2DMF·2EtOH (2) (DMF=N,N-Dimethylformamide). Single-crystal X-ray diffraction analyses revealed that compound 1 exhibits a three-dimensional self-penetrating 6-connected framework based on dinuclear cluster second building unit. Compound 2 displays an infinite three-dimensional 'Lucky Clover' shape (2,10)-connected network based on the trinuclear cluster and V-shaped organic linkers. The flexible bpp ligand displays different conformations in 1 and 2, which are successfully controlled by size-matching mixed ligands during the self-assembly process.

  4. New formamidine ligands and their mixed ligand palladium(II) oxalate complexes: Synthesis, characterization, DFT calculations and in vitro cytotoxicity

    Science.gov (United States)

    Soliman, Ahmed A.; Alajrawy, Othman I.; Attabi, Fawzy A.; Shaaban, Mohamed R.; Linert, W.

    2016-01-01

    A series of new ternary palladium(II) complexes of the type [Pd(L1-4)ox]·xH2O where L = formamidine ligands and ox = oxalate, were synthesized and characterized by elemental analyses, magnetic susceptibility, UV-Vis, infrared (IR) and mass spectroscopy and thermal analysis. The spectroscopic data indicated that the formamidine ligands act as bidentate N2 donors and the oxalate as O2 ligand. The complexes (1-4) are diamagnetic and the optimization of their structures indicated that the geometry is distorted square planer with O-Pd-O and N-Pd-N bond angles ranged 82.70-83.87° and 88.21-95.02°; respectively which is acceptable for the heteroleptic complexes. The dipole moment of the complexes (13.97-18.77 Debye) indicating that the complexes are more polarized than the ligands (1.93-4.96 Debye). The complexes are thermally stable as shown from their relatively higher overall activation energies (441-688 kJ mol-1). The ligands and the complexes are proved to have good cytotoxicity with IC50 (μM) in the range of (0.011-0.168) against MCF-7, (0.012-0.150) against HCT-116, (0.042-0.094) against PC-3 and (0.006-0.222) against HepG-2 cell lines, which open the field for further application as antitumor compounds.

  5. A ligand channel through the G protein coupled receptor opsin.

    Directory of Open Access Journals (Sweden)

    Peter W Hildebrand

    Full Text Available The G protein coupled receptor rhodopsin contains a pocket within its seven-transmembrane helix (TM structure, which bears the inactivating 11-cis-retinal bound by a protonated Schiff-base to Lys296 in TM7. Light-induced 11-cis-/all-trans-isomerization leads to the Schiff-base deprotonated active Meta II intermediate. With Meta II decay, the Schiff-base bond is hydrolyzed, all-trans-retinal is released from the pocket, and the apoprotein opsin reloaded with new 11-cis-retinal. The crystal structure of opsin in its active Ops* conformation provides the basis for computational modeling of retinal release and uptake. The ligand-free 7TM bundle of opsin opens into the hydrophobic membrane layer through openings A (between TM1 and 7, and B (between TM5 and 6, respectively. Using skeleton search and molecular docking, we find a continuous channel through the protein that connects these two openings and comprises in its central part the retinal binding pocket. The channel traverses the receptor over a distance of ca. 70 A and is between 11.6 and 3.2 A wide. Both openings are lined with aromatic residues, while the central part is highly polar. Four constrictions within the channel are so narrow that they must stretch to allow passage of the retinal beta-ionone-ring. Constrictions are at openings A and B, respectively, and at Trp265 and Lys296 within the retinal pocket. The lysine enforces a 90 degrees elbow-like kink in the channel which limits retinal passage. With a favorable Lys side chain conformation, 11-cis-retinal can take the turn, whereas passage of the all-trans isomer would require more global conformational changes. We discuss possible scenarios for the uptake of 11-cis- and release of all-trans-retinal. If the uptake gate of 11-cis-retinal is assigned to opening B, all-trans is likely to leave through the same gate. The unidirectional passage proposed previously requires uptake of 11-cis-retinal through A and release of photolyzed all

  6. Electrical properties of lead orthovanadate

    International Nuclear Information System (INIS)

    When studying the complex of electrical properties (electric conductivity as function T, psub(Osub(2)); ion numbers of transfer) the analysis of defective structure of lead orthovanadate has been carried out. It is shown that Pb3V2O8 - is a mixed semiconductor of n-type where electron conductivity prevails. Oxygen vacancies and internodal lead are the main point defects in the structure

  7. Systematic study of ligand structures of metal oxide EUV nanoparticle photoresists

    KAUST Repository

    Jiang, Jing

    2015-03-19

    Ligand stabilized metal oxide nanoparticle resists are promising candidates for EUV lithography due to their high sensitivity for high-resolution patterning and high etching resistance. As ligand exchange is responsible for the patterning mechanism, we systematically studied the influence of ligand structures of metal oxide EUV nanoparticles on their sensitivity and dissolution behavior. ZrO2 nanoparticles were protected with various aromatic ligands with electron withdrawing and electron donating groups. These nanoparticles have lower sensitivity compared to those with aliphatic ligands suggesting the structures of these ligands is more important than their pka on resist sensitivity. The influence of ligand structure was further studied by comparing the nanoparticles’ solubility for a single type ligand to mixtures of ligands. The mixture of nanoparticles showed improved pattern quality. © (2015) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE). Downloading of the abstract is permitted for personal use only.

  8. Platinum(II) phenanthroimidazole G-quadruplex ligand induces selective telomere shortening in A549 cancer cells.

    Science.gov (United States)

    Mancini, Johanna; Rousseau, Philippe; Castor, Katherine J; Sleiman, Hanadi F; Autexier, Chantal

    2016-02-01

    Telomere maintenance, achieved by the binding of protective shelterin capping proteins to telomeres and by either telomerase or a recombination-based alternative lengthening of telomere (ALT) mechanism, is critical for cell proliferation and survival. Extensive telomere shortening or loss of telomere integrity activates DNA damage checkpoints, leading to cell senescence or death. Although telomerase upregulation is an attractive target for anti-cancer therapy, the lag associated with telomere shortening and the potential activation of ALT pose a challenge. An alternative approach is to modify telomere interactions with binding proteins (telomere uncapping). G-quadruplex ligands stabilize structures generated from single-stranded G-rich 3'-telomere end (G-quadruplex) folding, which in principle, cannot be elongated by telomerase, thus leading to telomere shortening. Ligands can also mediate rapid anti-proliferative effects by telomere uncapping. We previously reported that the G-quadruplex ligand, phenylphenanthroimidazole ethylenediamine platinum(II) (PIP), inhibits telomerase activity in vitro[47]. In the current study, a long-term seeding assay showed that PIP significantly inhibited the seeding capacity of A549 lung cancer cells and to a lesser extent primary MRC5 fibroblast cells. Importantly, treatment with PIP caused a significant dose- and time-dependent decrease in average telomere length of A549 but not MRC5 cells. Moreover, cell cycle analysis revealed a significant increase in G1 arrest upon treatment of A549 cells, but not MRC5 cells. Both apoptosis and cellular senescence may contribute to the anti-proliferative effects of PIP. Our studies validate the development of novel and specific therapeutic ligands targeting telomeric G-quadruplex structures in cancer cells. PMID:26724375

  9. European lead cooled system (ELSY)

    International Nuclear Information System (INIS)

    The international Generation IV (GEN IV) initiative has once more highlighted that fast reactors are indispensable for a sustainable development of the Nuclear Energy. Europe has historically a large experience in the field of sodium-cooled fast reactors and recently has made a big effort in the development of the Lead-Bismuth Eutectic (LBE) technology for use in the sub-critical reactors, starting from the Russian technology for the submarine propulsion programme. The evolution from the LBE technology towards the pure lead technology is a natural and logical way because lead is less expensive, less corrosive and of lesser radiological concern. Lead has chemical and neutronic characteristics which are unique for a safe fast reactor. Molten lead, namely, operates at low pressure and high temperature, is relatively inert to air and water. The ELSY consortium intends to design a Lead-cooled Fast Reactor (LFR) system that complies with all GEN IV goals and gives assurance of investment protection. The EC FP6-ELSY project aims to demonstrate that it is possible to design a competitive and safe fast critical reactor using simple engineered technical features. ELSY is a 36-months project (starting September 1, 2006) partially funded as a Specific Targeted Research Project entitled to the European Commission

  10. Sequestering agent for uranyl chelation: new bi-naphtyl ligands

    International Nuclear Information System (INIS)

    The synthesis of phosphonate, sulfocatecholamide (CAMS) and hydroxy-pyridinone (HOPO) bi-naphtyl ligands is presented. Their binding abilities for uranyl cation were determined by UV spectrophotometry in aqueous media versus pH. These titrations showed that the efficiency of these chelating agents depends on the nature of the chelating group. Each ligand shows a more or less pronounced affinity towards uranium. While the bis-phosphonate compound did not show any affinity towards the uranyl ion, the BINHOPO derivative exhibits significant affinity at acidic and neutral pH while the BINCAMS is more efficient at basic pH. (authors)

  11. Structural Basis of Cooperative Ligand Binding by the Glycine Riboswitch

    Energy Technology Data Exchange (ETDEWEB)

    E Butler; J Wang; Y Xiong; S Strobel

    2011-12-31

    The glycine riboswitch regulates gene expression through the cooperative recognition of its amino acid ligand by a tandem pair of aptamers. A 3.6 {angstrom} crystal structure of the tandem riboswitch from the glycine permease operon of Fusobacterium nucleatum reveals the glycine binding sites and an extensive network of interactions, largely mediated by asymmetric A-minor contacts, that serve to communicate ligand binding status between the aptamers. These interactions provide a structural basis for how the glycine riboswitch cooperatively regulates gene expression.

  12. Complexation of neptunium(V) by polyaminocarboxylate ligands

    International Nuclear Information System (INIS)

    The stability constants of complexes of NpO2+ ion with a series of polyaminocarboxylate, oxydiacetate (ODA) and thiodiacetate (TDA) ligands were determined using spectrophotometric and potentiometric techniques. The measurements were conducted at an ionic strength of 0.50 M (NaClO4). By contrast to lanthanide complexation, the interaction of the ether oxygen of ODA with NpO2+ cation is very small whereas TDA acts only as a monodentate ligand via one of the carboxylate groups. (orig.)

  13. Spectroscopic study of cadmium (II) complexes with heterocyclic dithiocarbamate ligands

    Energy Technology Data Exchange (ETDEWEB)

    Garcia-Fontan, S. (Departamento de Quimica Pura y Aplicada, Universidad de Vigo (Spain)); Rodriguez-Seoane, P. (Departamento de Quimica Pura y Aplicada, Universidad de Vigo (Spain)); Casas, J.S. (Departamento de Quimica Inorganica, Universidad de Santiago de Compostela (Spain)); Sordo, J. (Departamento de Quimica Inorganica, Universidad de Santiago de Compostela (Spain)); Jones, M.M. (Department of Chemistry and Center in Molecular Toxicology, Vanderbilt University, Nashville, TN (United States))

    1993-09-15

    Cadmium(II) dithiocarbamates Cd(dtc)[sub 2] (dtc=4-carboxamidopiperidine-1-carbodithioate, morpholine-1-carbodithioate or 4-(2-hydroxyethyl)piperazine-1-carbodithioate) and Cd(dtc)[sub 2].H[sub 2]O (dtc=4-hydroxypiperidine-1-carbodithioate)[r brace] have been prepared and characterized by thermal analysis and IR and NMR ([sup 13]C, [sup 113]Cd) spectrometry. Two of these ligands have previously been shown capable of removing cadmium from its aged in vivo storage sites. The use of solid state [sup 13]C NMR measurements to establish the coordination mode of the dithiocarbomate ligands is also examined and the difficulties which arise are discussed. (orig.)

  14. Two ligands for a GPCR, proton vs lysolipid

    Institute of Scientific and Technical Information of China (English)

    Dong-soon IM

    2005-01-01

    Recently, two different chemicals have been matched as ligands with the same Gprotein-coupled receptor (GPCR). Double-pairing of OGR1 family GPCRs with proton and lysolipid raises several questions. First, whether both are the real ligands for the GPCRs. Second, whether modulation of a GPCR by two chemicals could be possible. Third, one of the chemicals is proton. Proton-sensing not only is a new action mode of GPCR activation, but also it could be generalized in other GPCRs.In this review, I'd like to summarize the issue and discuss questions with pharmacological criteria.

  15. Ligand-assisted capillary electrophoresis separations of the lanthanides

    International Nuclear Information System (INIS)

    Capillary electrophoresis is used with simple organic ligands added to the electrolyte matrix to achieve separation of the individual lanthanide cations. Results for acetate (AC-) and malonate (MA-) yield good resolution for the lighter lanthanides, but not the heavier lanthanides. In contrast, α-hydroxyisobutyrate (HIB-) gives complete resolution for all of the lanthanide cations. These results are related to the complexation chemistry between the lanthanides and the ligands across the lanthanide series. In addition, preliminary results for lanthanide separations using AC- in mixed methanol:water solvent systems are provided. The presence of methanol improves resolution but slows the separation. (author)

  16. Identification of Physiologically Active Substances as Novel Ligands for MRGPRD

    OpenAIRE

    Makiko Uno; Satoko Nishimura; Keisuke Fukuchi; Yasuyuki Kaneta; Yoko Oda; Hironobu Komori; Shigeki Takeda; Tatsuya Haga; Toshinori Agatsuma; Futoshi Nara

    2012-01-01

    Mas-related G-protein coupled receptor member D (MRGPRD) is a G protein-coupled receptor (GPCR) which belongs to the Mas-related GPCRs expressed in the dorsal root ganglia (DRG). In this study, we investigated two novel ligands in addition to beta-alanine: (1) beta-aminoisobutyric acid, a physiologically active substance, with which possible relation to tumors has been seen together with beta-alanine; (2) diethylstilbestrol, a synthetic estrogen hormone. In addition to the novel ligands, we f...

  17. Designer ligands: The search for metal ion selectivity

    Directory of Open Access Journals (Sweden)

    Perry T. Kaye

    2011-03-01

    Full Text Available The paper reviews research conducted at Rhodes University towards the development of metal-selective ligands. The research has focused on the rational design, synthesis and evaluation of novel ligands for use in the formation of copper complexes as biomimetic models of the metalloenzyme, tyrosinase, and for the selective extraction of silver, nickel and platinum group metal ions in the presence of contaminating metal ions. Attention has also been given to the development of efficient, metal-selective molecular imprinted polymers.

  18. Coordination chemistry of poly(thioether)borate ligands.

    Science.gov (United States)

    Riordan, Charles G

    2010-08-01

    This review traces the development and application of the tris(thioether)borate ligands, tripodal ligands with highly polarizable thioether donors. Areas of emphasis include the basic coordination chemistry of the mid-to-late first row transition metals (Fe, Ni, Co, Cu), and the role of the thioether substituent in directing complex formation, the modeling of zinc thiolate protein active sites, high-spin organo-iron and organo-cobalt chemistry, the preparation of monovalent complexes of Fe, Co and Ni, and dioxygen and sulfur activation by monovalent nickel complexes. PMID:20607091

  19. A new dinuclear lead(II) complex of 2,3-diphenyl-tetrazole-5-thione: synthesis and characterization

    OpenAIRE

    ZHUANG, Rui Rui; JIAN, Fang Fang; WANG, Ke Fei

    2010-01-01

    The present work reports on the synthesis, crystal structure, fluorescence, electrochemical behavior, and thermogravimetric analysis of a new dinuclear lead(II) complex of 2,3-diphenyl-tetrazole-5-thione. Its structure was characterized by X-ray crystallography, IR spectroscopy, and elemental analysis. Each lead atom adopts a distorted octahedral geometry by coordinating to 2 sulfur atoms from 2 2,3-diphenyl-tetrazole-5-thione ligands and 4 oxygen atoms from 3 nitrates. The fluoresc...

  20. Molecular Docking Explains Atomic Interaction between Plant-originated Ligands and Oncogenic E7 Protein of High Risk Human Papillomavirus Type 16

    Directory of Open Access Journals (Sweden)

    Satish Kumar

    2014-12-01

    Full Text Available Cervical cancer caused by Human papillomavirus (HPV is one of the leading causes of cancer mortality in women worldwide, particularly in the developing countries. In the last few decades, various compounds from plant origin such as Curcumin, Epigallocatechin gallate (EGCG, Jaceosidin, Resveratrol etc. have been used as anti cancer therapeutic agents. Different studies have shown these plant-originated compounds are able to suppress HPV infection. The E6 and E7 oncoproteins of high-risk HPV play a key role in HPV related cancers. In this study, we explored these ligands from plants origin against E7 oncoprotein of high risk HPV 16, which is known to inactivate tumor suppressor pRb protein. A robust homology model of HPV 16 E7 was built to foresee the interaction mechanism of E7 oncoprotein with these ligands using structure-based drug designing approach. Docking studies demonstrate the interaction of these ligands with pRb binding site of E7 protein by residues Tyr52, Asn53, Val55, Phe57, Cys59, Ser63, Thr64, Thr72, Arg77, Glu80 and Asp81 and help restoration of pRb functioning. This in silico based atomic interaction between these ligands and E7 protein may assist in validating the plant-originated ligands as effective drugs against HPV.

  1. Leading to distraction: Driver distraction, lead car, and road environment.

    Science.gov (United States)

    Kountouriotis, G K; Merat, N

    2016-04-01

    Driver distraction is strongly associated with crashes and near-misses, and despite the attention this topic has received in recent years, the effect of different types of distracting task on driving performance remains unclear. In the case of non-visual distractions, such as talking on the phone or other engaging verbal tasks that do not require a visual input, a common finding is reduced lateral variability in steering and gaze patterns where participants concentrate their gaze towards the centre of the road and their steering control is less variable. In the experiments presented here, we examined whether this finding is more pronounced in the presence of a lead car (which may provide a focus point for gaze) and whether the behaviour of the lead car has any influence on the driver's steering control. In addition, both visual and non-visual distraction tasks were used, and their effect on different road environments (straight and curved roadways) was assessed. Visual distraction was found to increase variability in both gaze patterns and steering control, non-visual distraction reduced gaze and steering variability in conditions without a lead car; in the conditions where a lead car was present there was no significant difference from baseline. The lateral behaviour of the lead car did not have an effect on steering performance, a finding which indicates that a lead car may not necessarily be used as an information point. Finally, the effects of driver distraction were different for straight and curved roadways, indicating a stronger influence of the road environment in steering than previously thought. PMID:26785327

  2. Bending crystals. Solid state photomechanical properties of transition metal complexes containing semiquinonate ligands

    Indian Academy of Sciences (India)

    Cortlandt G Pierpont

    2002-08-01

    The properties of transition metal complexes containing catecholate and radical semiquinonate ligands have often been found to be unusual and unexpected. Crystals of Rh(CO)2(3,6-DBSQ), containing the 3,6-di-tert-butyl-1,2-semiquinonate ligand, form as long thin needles that are observed to bend reversibly upon irradiation with NIR light. Crystallographic characterization reveals a stacked solid state lattice with planar molecules aligned with metal atoms atop one another. Electronic spectra recorded in the solid state and in solution show an intense band at 1600 nm that maps the energy dependence of crystal bend angle. The transition is a property of the stacked assembly, rather than of an individual complex molecule, and appears associated with an MLCT process that transfers charge from an antibonding band formed by interacting Rh $d_{z}^{2}$ orbitals to the vacant quinone * orbital. Related observations have been made on the [Co(-pyz)(3,6-DBSQ)(3,6-DBCat)] polymer. Photomechanical properties appear associated with electronic transitions that lead to a physical change in axial length of a linear polymer, coupled with a soft solid state lattice that permits axial contraction/expansion without crystal fracture.

  3. LIGSITEcsc: predicting ligand binding sites using the Connolly surface and degree of conservation

    Directory of Open Access Journals (Sweden)

    Schroeder Michael

    2006-09-01

    Full Text Available Abstract Background Identifying pockets on protein surfaces is of great importance for many structure-based drug design applications and protein-ligand docking algorithms. Over the last ten years, many geometric methods for the prediction of ligand-binding sites have been developed. Results We present LIGSITEcsc, an extension and implementation of the LIGSITE algorithm. LIGSITEcsc is based on the notion of surface-solvent-surface events and the degree of conservation of the involved surface residues. We compare our algorithm to four other approaches, LIGSITE, CAST, PASS, and SURFNET, and evaluate all on a dataset of 48 unbound/bound structures and 210 bound-structures. LIGSITEcsc performs slightly better than the other tools and achieves a success rate of 71% and 75%, respectively. Conclusion The use of the Connolly surface leads to slight improvements, the prediction re-ranking by conservation to significant improvements of the binding site predictions. A web server for LIGSITEcsc and its source code is available at scoppi.biotec.tu-dresden.de/pocket.

  4. Design and synthesis of dual-ligand modified chitosan as a liver targeting vector.

    Science.gov (United States)

    Chen, Houxiang; Li, Min; Wan, Tao; Zheng, Qichang; Cheng, Mingrong; Huang, Shiqi; Wang, Yong

    2012-02-01

    Vector plays an important role in hepatic targeted drug delivery system. In this study, a novel material as a liver targeting vector, dual-ligand modified chitosan (GCGA) composed of chitosan (CTS), glycyrrhetinic acid (GA) and lactobionic acid (LA), was designed and synthesized by an orthogonal experiment with two-step synthesis under mild conditions. The synthesized final product was characterized and confirmed by FTIR and (1)H-NMR spectroscopy, and DS of GA and LA in CTS were measured to be 13.77 and 16.74 mol% using (1)H-NMR, respectively. The cytotoxicity of CTS and GCGA was concentration dependent which was inverse proportion to the cell viability by MTT assay using L929 cell line, and inhibitory concentration 50% (IC50) was 0.2 mg/ml for GCGA. The in vitro targeting efficiency and the in vitro cellular uptake were investigated. Compared with CTS NPs and GA-CTS NPs, GCGA NPs showed good cell specificity to BEL-7402 cells via the dual-ligand-receptor-mediated recognition, leading to a higher affinity to BEL-7402 cells. The results suggested that GCGA described here has the potential to be used as an effective vector for hepatic targeted drug therapy. PMID:22105225

  5. The Prelude on Novel Receptor and Ligand Targets Involved in the Treatment of Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Venu Gopal Jonnalagadda

    2014-05-01

    Full Text Available Metabolic disorders are a group of disorders, due to the disruption of the normal metabolic process at a cellular level. Diabetes Mellitus and Tyrosinaemia are the majorly reported metabolic disorders. Among them, Diabetes Mellitus is a one of the leading metabolic syndrome, affecting 5 to 7 % of the population worldwide and mainly characterised by elevated levels of glucose and is associated with two types of physiological event disturbances such as impaired insulin secretion and insulin resistance. Up to now, various treatment strategies are like insulin, alphaglucosidase inhibitors, biguanides, incretins were being followed. Concurrently, various novel therapeutic strategies are required to advance the therapy of Diabetes mellitus. For the last few decades, there has been an extensive research in understanding the metabolic pathways involved in Diabetes Mellitus at the cellular level and having the profound knowledge on cell-growth, cell-cycle, and apoptosis at a molecular level provides new targets for the treatment of Diabetes Mellitus. Receptor signalling has been involved in these mechanisms, to translate the information coming from outside. To understand the various receptors involved in these pathways, we must have a sound knowledge on receptors and ligands involved in it. This review mainly summarises the receptors and ligands which are involved the Diabetes Mellitus. Finally, researchers have to develop the alternative chemical moieties that retain their affinity to receptors and efficacy. Diabetes Mellitus being a metabolic disorder due to the glucose surfeit, demands the need for regular exercise along with dietary changes.

  6. E4 Butterfly Complexes (E=P, As) as Chelating Ligands.

    Science.gov (United States)

    Schwarzmaier, Christoph; Heinl, Sebastian; Balázs, Gábor; Scheer, Manfred

    2015-10-26

    The coordination properties of new types of bidentate phosphane and arsane ligands with a narrow bite angle are reported. The reactions of [{Cp'''Fe(CO)2 }2 (μ,η(1:1) -P4 )] (1 a) with the copper salt [Cu(CH3 CN)4 ][BF4 ] leads, depending on the stoichiometry, to the formation of the spiro compound [{{Cp'''Fe(CO)2 }2 (μ3 ,η(1:1:1:1) -P4 )}2 Cu](+) [BF4 ](-) (2) or the monoadduct [{Cp'''Fe(CO)2 }2 (μ3 ,η(1:1:2) -P4 ){Cu(MeCN)}](+) [BF4 ](-) (3). Similarly, the arsane ligand [{Cp'''Fe(CO)2 }2 (μ,η(1:1) -As4 )] (1 b) reacts with [Cu(CH3 CN)4 ][BF4 ] to give [{{Cp'''Fe(CO)2 }2 (μ3 ,η(1:1:1:1) -As4 )}2 Cu](+) [BF4 ](-) (5). Protonation of 1 a occurs at the "wing tip" phosphorus atoms, which is in line with the results of DFT calculations. The compounds are characterized by spectroscopic methods (heteronuclear NMR spectroscopy and IR spectrometry) and by single-crystal X-ray diffraction studies. PMID:26332191

  7. Improved ligand binding energies derived from molecular dynamics: replicate sampling enhances the search of conformational space.

    Science.gov (United States)

    Adler, Marc; Beroza, Paul

    2013-08-26

    Does a single molecular trajectory provide an adequate sample conformational space? Our calculations indicate that for Molecular Mechanics--Poisson-Boltzmann Surface Area (MM-PBSA) measurement of protein ligand binding, a single molecular dynamics trajectory does not provide a representative sampling of phase space. For a single trajectory, the binding energy obtained by averaging over a number of molecular dynamics frames in an equilibrated system will converge after an adequate simulation time. A separate trajectory with nearly identical starting coordinates (1% randomly perturbed by 0.001 Å), however, can lead to a significantly different calculated binding energy. Thus, even though the calculated energy converges for a single molecular dynamics run, the variation across separate runs implies that a single run inadequately samples the system. The divergence in the trajectories is reflected in the individual energy components, such as the van der Waals and the electrostatics terms. These results indicate that the trajectories sample different conformations that are not in rapid exchange. Extending the length of the dynamics simulation does not resolve the energy differences observed between different trajectories. By averaging over multiple simulations, each with a nearly equivalent starting structure, we find the standard deviation in the calculated binding energy to be ∼1.3 kcal/mol. The work presented here indicates that combining MM-PBSA with multiple samples of the initial starting coordinates will produce more precise and accurate estimates of protein/ligand affinity. PMID:23845109

  8. Synthesis, Crystal structure, and Hirshfeld Surface Analysis of a New Mixed Ligand Copper(II) Complex.

    Science.gov (United States)

    Shit, Shyamapada; Marschner, Christoph; Mitra, Samiran

    2016-01-01

    A new mixed ligand copper(II) complex, [Cu(2,4-pydc)(pic)(H(2)O)]∙H(2)O (1) (where 2,4-pydc = pyridine-2,4-dicarboxylate, pic = 2-picolylamine) has been synthesized and characterized by elemental analysis, FT-IR and UV-Vis spectroscopic and thermogravimetric methods. Single crystal X-ray diffraction analysis reveals that copper(II) atom in the title complex adopts distorted square pyramidal geometry. Structural characterization also reveals that interplay of O-H···O, N-H···O, C-H···O, and C-H···π interactions between lattice and coordinated water and ligands significantly contribute to the crystal packing leading to the formation and strengthening of three dimensional supramolecular assembly. Hirshfeld surface analysis employing 3D molecular surface contours and 2D fingerprint plots have been used to analyze intermolecular interactions present in the solid state of the crystal. PMID:26970797

  9. Multiple complexation of CO and related ligands to a main-group element.

    Science.gov (United States)

    Braunschweig, Holger; Dewhurst, Rian D; Hupp, Florian; Nutz, Marco; Radacki, Krzysztof; Tate, Christopher W; Vargas, Alfredo; Ye, Qing

    2015-06-18

    The ability of an atom or molecular fragment to bind multiple carbon monoxide (CO) molecules to form multicarbonyl adducts is a fundamental trait of transition metals. Transition-metal carbonyl complexes are vital to industry, appear naturally in the active sites of a number of enzymes (such as hydrogenases), are promising therapeutic agents, and have even been observed in interstellar dust clouds. Despite the wealth of established transition-metal multicarbonyl complexes, no elements outside groups 4 to 12 of the periodic table have yet been shown to react directly with two or more CO units to form stable multicarbonyl adducts. Here we present the synthesis of a borylene dicarbonyl complex, the first multicarbonyl complex of a main-group element prepared using CO. The compound is additionally stable towards ambient air and moisture. The synthetic strategy used--liberation of a borylene ligand from a transition metal using donor ligands--is broadly applicable, leading to a number of unprecedented monovalent boron species with different Lewis basic groups. The similarity of these compounds to conventional transition-metal carbonyl complexes is demonstrated by photolytic liberation of CO and subsequent intramolecular carbon-carbon bond activation. PMID:26085273

  10. Surface ligand dependent toxicity of zinc oxide nanoparticles in HepG2 cell model

    International Nuclear Information System (INIS)

    Physicochemical properties of nanoparticles (NP) strongly affect their influence on cell behaviour, but can be significantly distorted by interactions with the proteins present in biological solutions. In this study we show how different surface functionalities of zinc oxide (ZnO) NP lead to changes in the size distribution and dissolution of the NP in serum containing cell culture media and how this impacts on NP toxicity. NPs capped with weakly bound large proteins undergo substantial transformations due to the exchange of the original surface ligands to the components of the cell culture media. Conversely, NP capped with a tight monolayer of small organic molecules or with covalently conjugated proteins show significantly higher stability. These differences in ligand exchange also affect the toxicity of the NP to the HepG2 liver cell model, with the NP capped with small organic molecules being more toxic than those capped with large proteins. This study highlights the importance of characterising NPs in biological media and the effect the media has during in-vitro analysis.

  11. Multiple complexation of CO and related ligands to a main-group element

    Science.gov (United States)

    Braunschweig, Holger; Dewhurst, Rian D.; Hupp, Florian; Nutz, Marco; Radacki, Krzysztof; Tate, Christopher W.; Vargas, Alfredo; Ye, Qing

    2015-06-01

    The ability of an atom or molecular fragment to bind multiple carbon monoxide (CO) molecules to form multicarbonyl adducts is a fundamental trait of transition metals. Transition-metal carbonyl complexes are vital to industry, appear naturally in the active sites of a number of enzymes (such as hydrogenases), are promising therapeutic agents, and have even been observed in interstellar dust clouds. Despite the wealth of established transition-metal multicarbonyl complexes, no elements outside groups 4 to 12 of the periodic table have yet been shown to react directly with two or more CO units to form stable multicarbonyl adducts. Here we present the synthesis of a borylene dicarbonyl complex, the first multicarbonyl complex of a main-group element prepared using CO. The compound is additionally stable towards ambient air and moisture. The synthetic strategy used--liberation of a borylene ligand from a transition metal using donor ligands--is broadly applicable, leading to a number of unprecedented monovalent boron species with different Lewis basic groups. The similarity of these compounds to conventional transition-metal carbonyl complexes is demonstrated by photolytic liberation of CO and subsequent intramolecular carbon-carbon bond activation.

  12. A novel AhR ligand, 2AI, protects the retina from environmental stress

    Science.gov (United States)

    Gutierrez, Mark A.; Davis, Sonnet S.; Rosko, Andrew; Nguyen, Steven M.; Mitchell, Kylie P.; Mateen, Samiha; Neves, Joana; Garcia, Thelma Y.; Mooney, Shaun; Perdew, Gary H.; Hubbard, Troy D.; Lamba, Deepak A.; Ramanathan, Arvind

    2016-01-01

    Various retinal degenerative diseases including dry and neovascular age-related macular degeneration (AMD), retinitis pigmentosa, and diabetic retinopathy are associated with the degeneration of the retinal pigmented epithelial (RPE) layer of the retina. This consequently results in the death of rod and cone photoreceptors that they support, structurally and functionally leading to legal or complete blindness. Therefore, developing therapeutic strategies to preserve cellular homeostasis in the RPE would be a favorable asset in the clinic. The aryl hydrocarbon receptor (AhR) is a conserved, environmental ligand-dependent, per ARNT-sim (PAS) domain containing bHLH transcription factor that mediates adaptive response to stress via its downstream transcriptional targets. Using in silico, in vitro and in vivo assays, we identified 2,2′-aminophenyl indole (2AI) as a potent synthetic ligand of AhR that protects RPE cells in vitro from lipid peroxidation cytotoxicity mediated by 4-hydroxynonenal (4HNE) as well as the retina in vivo from light-damage. Additionally, metabolic characterization of this molecule by LC-MS suggests that 2AI alters the lipid metabolism of RPE cells, enhancing the intracellular levels of palmitoleic acid. Finally, we show that, as a downstream effector of 2AI-mediated AhR activation, palmitoleic acid protects RPE cells from 4HNE-mediated stress, and light mediated retinal degeneration in mice. PMID:27364765

  13. Glucagon-like peptide-1 receptor ligand interactions: structural cross talk between ligands and the extracellular domain.

    Directory of Open Access Journals (Sweden)

    Graham M West

    Full Text Available Activation of the glucagon-like peptide-1 receptor (GLP-1R in pancreatic β-cells potentiates insulin production and is a current therapeutic target for the treatment of type 2 diabetes mellitus (T2DM. Like other class B G protein-coupled receptors (GPCRs, the GLP-1R contains an N-terminal extracellular ligand binding domain. N-terminal truncations on the peptide agonist generate antagonists capable of binding to the extracellular domain, but not capable of activating full length receptor. The main objective of this study was to use Hydrogen/deuterium exchange (HDX to identify how the amide hydrogen bonding network of peptide ligands and the extracellular domain of GLP-1R (nGLP-1R were altered by binding interactions and to then use this platform to validate direct binding events for putative GLP-1R small molecule ligands. The HDX studies presented here for two glucagon-like peptide-1 receptor (GLP-1R peptide ligands indicates that the antagonist exendin-4[9-39] is significantly destabilized in the presence of nonionic detergents as compared to the agonist exendin-4. Furthermore, HDX can detect stabilization of exendin-4 and exendin-4[9-39] hydrogen bonding networks at the N-terminal helix [Val19 to Lys27] upon binding to the N-terminal extracellular domain of GLP-1R (nGLP-1R. In addition we show hydrogen bonding network stabilization on nGLP-1R in response to ligand binding, and validate direct binding events with the extracellular domain of the receptor for putative GLP-1R small molecule ligands.

  14. Secondary ligand-directed assembly of Co(II) coordination polymers based on a pyridine carboxylate ligand

    Energy Technology Data Exchange (ETDEWEB)

    Cao, Ke-Li; Zhang, Yi-Ping; Cai, Yi-Ni; Xu, Xiao-Wei; Feng, Yun-Long, E-mail: sky37@zjnu.cn

    2014-07-01

    To investigate the influence of hydrogen bonds and secondary ligands on the structures and properties of the resulting frameworks, five new Co(II) compounds have been synthesized by the reactions of Co(II) salts and 3,5-bis(pyridin-4-ylmethoxy)benzoic acid (HL) with four rationally selected dicarboxylic acid ligands. Without secondary ligand, we got one compound [CoL{sub 2}(H{sub 2}O){sub 2}]{sub n}·2nH{sub 2}O (1), which possesses a 1D chain structure. In the presence of ancillary ligands, namely, 1,3-adamantanedicarboxylic acid (H{sub 2}adbc), terephthalic acid (H{sub 2}tpa), thiophene-2,5-dicarboxylic acid (H{sub 2}tdc) and 1,4-benzenedithioacetic acid (H{sub 2}bdtc), four 3D structures [Co{sub 2}L{sub 2}(adbc)]{sub n}·nH{sub 2}O (2), [Co{sub 2}L{sub 2}(tpa)]{sub n} (3), [Co{sub 2}L{sub 2}(tdc)]{sub n} (4), [Co{sub 2}L{sub 2}(bdtc)(H{sub 2}O)]{sub n} (5) were obtained, respectively. It can be observed from the architectures of 1–5 that hydrogen bonds and secondary ligands both have great effects on the spatial connective fashions, resulting in the formation of various dimensional compounds. The XRPD, TGA data of title polymers and the magnetic properties for 2 and 5 have also been investigated. - Graphical abstract: The structural differences show that the ancillary ligands have great effects on the spatial connective fashions, resulting in the formation of various dimensional compounds. - Highlights: • Five new Co(II) coordination polymers have been synthesized by solvothermal reactions based on 3,5-bis(pyridin-4-ylmethoxy)benzoic acid (HL). • The long-flexible ligand (HL) is a good candidate to produce interpenetrating architectures. • The secondary dicarboxylic acid ligands play important roles in the spatial connective fashions and the formation of various dimensional compounds. • The magnetism studies show that both 2 and 5 exhibit antiferromagnetic interactions.

  15. Regulating Competing Supramolecular Interactions Using Ligand Concentration.

    Science.gov (United States)

    Teunissen, Abraham J P; Paffen, Tim F E; Ercolani, Gianfranco; de Greef, Tom F A; Meijer, E W

    2016-06-01

    The complexity of biomolecular systems inevitably leads to a degree of competition between the noncovalent interactions involved. However, the outcome of biological processes is generally very well-defined often due to the competition of these interactions. In contrast, specificity in synthetic supramolecular systems is usually based on the presence of a minimum set of alternative assembly pathways. While the latter might simplify the system, it prevents the selection of specific structures and thereby limits the adaptivity of the system. Therefore, artificial systems containing competing interactions are vital to stimulate the development of more adaptive and lifelike synthetic systems. Here, we present a detailed study on the self-assembly behavior of a C2v-symmetrical tritopic molecule, functionalized with three self-complementary ureidopyrimidinone (UPy) motifs. Due to a shorter linker connecting one of these UPys, two types of cycles with different stabilities can be formed, which subsequently dimerize intermolecularly via the third UPy. The UPy complementary 2,7-diamido-1,8-naphthyridine (NaPy) motif was gradually added to this mixture in order to examine its effect on the cycle distribution. As a result of the C2v-symmetry of the tritopic UPy, together with small differences in binding strength, the cycle ratio can be regulated by altering the concentration of NaPy. We show that this ratio can be increased to an extent where one type of cycle is formed almost exclusively. PMID:27163942

  16. Lead-vacancy-related hole centers in lead tungstate crystals

    Czech Academy of Sciences Publication Activity Database

    Laguta, Valentyn; Nikl, Martin; Zazubovich, S.

    2012-01-01

    Roč. 249, č. 11 (2012), s. 2161-2166. ISSN 0370-1972 R&D Projects: GA AV ČR IAA100100810 Institutional research plan: CEZ:AV0Z10100521 Keywords : hole centers * lead tungstate * thermally stimulated luminescence Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 1.489, year: 2012

  17. CAN FLUORIDATION AFFECT WATER LEAD LEVELS AND LEAD NEUROTOXICITY?

    Science.gov (United States)

    Recent reports have attempted to show that certain approaches to fluoridating potable water is linked to increased levels of lead(II) in the blood. We examine these claims in light of the established science and critically evaluate their significance. The completeness of nexafluo...

  18. New bisaminoethanethiol (BAT) ligands which form two interconvertible Tc-99m complexes

    International Nuclear Information System (INIS)

    structure-activity relationship studies may lead to the development of new radiopharmaceuticals based on these unique new ligands

  19. Water-soluble diphosphadiazacyclooctanes as ligands for aqueous organometallic catalysis

    KAUST Repository

    Boulanger, Jérôme

    2012-12-01

    Two new water-soluble diphosphacyclooctanes been synthesized and characterized by NMR and surface tension measurements. Both phosphanes proved to coordinate rhodium in a very selective way as well-defined bidentates were obtained. When used in Rh-catalyzed hydroformylation of terminal alkenes, both ligands positively impacted the reaction chemoselectivity. © 2012 Elsevier B.V.

  20. Optimal Overlay of Ligands with Flexible Bonds Using Differential Evolution

    DEFF Research Database (Denmark)

    Pedersen, Christian Storm; Kristensen, Thomas Greve

    When designing novel drugs, the need arise to screen databases for structures resembling active ligands, e.g. by generating a query meta-structure which summarizes these. We propose a flexible bond method for making a meta-structure and present Monte Carlo, Nelder-Mead and Differential Evolution...

  1. The imidazoline receptors and ligands in pain modulation

    Directory of Open Access Journals (Sweden)

    Nurcan Bektas

    2015-01-01

    Full Text Available Pain is an unpleasant experience and effects daily routine negatively. Although there are various drugs, many of them are not entirely successful in relieving pain, since pain modulation is a complex process involving numerous mediators and receptors. Therefore, it is a rational approach to identify the factors involved in the complex process and develop new agents that act on these pain producing mechanisms. In this respect, the involvement of the imidazoline receptors in pain modulation has drawn attention in recent years. In this review, it is aimed to focus on the imidazoline receptors and their ligands which contribute to the pain modulation. It is demonstrated that imidazoline-2 (I2 receptors are steady new drug targets for analgesics. Even if the mechanism of I2receptor is not well known in the modulation of pain, it is known that it plays a role in tonic and chronic pain but not in acute phasic pain. Moreover, the I2receptor ligands increase the analgesic effects of opioids in both acute and chronic pain and prevent the development of opioid tolerance. So, they are valuable for the chronic pain treatment and also therapeutic coadjuvants in the management of chronic pain with opiate drugs due to the attenuation of opioid tolerance and addiction. Thus, the use of the ligands which bind to the imidazoline receptors is an effective strategy for relieving pain. This educational forum exhibits the role of imidazoline receptors and ligands in pain process by utilizing experimental studies.

  2. Fluorescent ligands for studying neuropeptide receptors by confocal microscopy

    Directory of Open Access Journals (Sweden)

    A. Beaudet

    1998-11-01

    Full Text Available This paper reviews the use of confocal microscopy as it pertains to the identification of G-protein coupled receptors and the study of their dynamic properties in cell cultures and in mammalian brain following their tagging with specific fluorescent ligands. Principles that should guide the choice of suitable ligands and fluorophores are discussed. Examples are provided from the work carried out in the authors' laboratory using custom synthetized fluoresceinylated or BODIPY-tagged bioactive peptides. The results show that confocal microscopic detection of specifically bound fluorescent ligands permits high resolution appraisal of neuropeptide receptor distribution both in cell culture and in brain sections. Within the framework of time course experiments, it also allows for a dynamic assessment of the internalization and subsequent intracellular trafficking of bound fluorescent molecules. Thus, it was found that neurotensin, somatostatin and mu- and delta-selective opioid peptides are internalized in a receptor-dependent fashion and according to receptor-specific patterns into their target cells. In the case of neurotensin, this internalization process was found to be clathrin-mediated, to proceed through classical endosomal pathways and, in neurons, to result in a mobilization of newly formed endosomes from neural processes to nerve cell bodies and from the periphery of cell bodies towards the perinuclear zone. These mechanisms are likely to play an important role for ligand inactivation, receptor regulation and perhaps also transmembrane signaling.

  3. Synergistic Effects of PPARγ Ligands and Retinoids in Cancer Treatment

    Directory of Open Access Journals (Sweden)

    Masahito Shimizu

    2008-01-01

    Full Text Available Peroxisome proliferator-activated receptors (PPARs are members of the nuclear receptor superfamily. The activation of PPARs by their specific ligands is regarded as one of the promising strategies to inhibit cancer cell growth. However, recent clinical trials targeting several common cancers showed no beneficial effect when PPAR ligands are used as a monotherapy. Retinoid X receptors (RXRs, which play a critical role in normal cell proliferation as a master regulator for nuclear receptors, preferentially form heterodimers with PPARs. A malfunction of RXRα due to phosphorylation by the Ras/MAPK signaling pathway is associated with the development of certain types of human malignancies. The activation of PPARγ/RXR heterodimer by their respective ligands synergistically inhibits cell growth, while inducing apoptosis in human colon cancer cells when the phosphorylation of RXRα was inhibited. We herein review the synergistic antitumor effects produced by the combination of the PPAR, especially PPARγ, ligands plus other agents, especially retinoids, in a variety of human cancers. We also focus on the phosphorylation of RXRα because the inhibition of RXRα phosphorylation and the restoration of its physiological function may activate PPAR/RXR heterodimer and, therefore, be a potentially effective and critical strategy for the inhibition of cancer cell growth.

  4. The imidazoline receptors and ligands in pain modulation.

    Science.gov (United States)

    Bektas, Nurcan; Nemutlu, Dilara; Arslan, Rana

    2015-01-01

    Pain is an unpleasant experience and effects daily routine negatively. Although there are various drugs, many of them are not entirely successful in relieving pain, since pain modulation is a complex process involving numerous mediators and receptors. Therefore, it is a rational approach to identify the factors involved in the complex process and develop new agents that act on these pain producing mechanisms. In this respect, the involvement of the imidazoline receptors in pain modulation has drawn attention in recent years. In this review, it is aimed to focus on the imidazoline receptors and their ligands which contribute to the pain modulation. It is demonstrated that imidazoline-2 (I2) receptors are steady new drug targets for analgesics. Even if the mechanism of I2 receptor is not well known in the modulation of pain, it is known that it plays a role in tonic and chronic pain but not in acute phasic pain. Moreover, the I2 receptor ligands increase the analgesic effects of opioids in both acute and chronic pain and prevent the development of opioid tolerance. So, they are valuable for the chronic pain treatment and also therapeutic coadjuvants in the management of chronic pain with opiate drugs due to the attenuation of opioid tolerance and addiction. Thus, the use of the ligands which bind to the imidazoline receptors is an effective strategy for relieving pain. This educational forum exhibits the role of imidazoline receptors and ligands in pain process by utilizing experimental studies. PMID:26600633

  5. A Guided Inquiry Activity for Teaching Ligand Field Theory

    Science.gov (United States)

    Johnson, Brian J.; Graham, Kate J.

    2015-01-01

    This paper will describe a guided inquiry activity for teaching ligand field theory. Previous research suggests the guided inquiry approach is highly effective for student learning. This activity familiarizes students with the key concepts of molecular orbital theory applied to coordination complexes. Students will learn to identify factors that…

  6. Ligand Induced Spin Crossover in Penta-Coordinated Ferric Dithiocarbamates

    Science.gov (United States)

    Ganguli, P.; Iyer, R. M.

    1981-09-01

    On addition of lewis bases to Fe(dtc)2X, ligand exchange takes place through a SN2 mechanism, with a parallel spin crossover in the ferric ion. The two species (S = 3/2 and S = 5/2) formed are in dynamic chemical equilibrium, and a slow decomposition is then initiated.

  7. Ligand for neurotransmission SPECT in extra-pyramidal diseases

    International Nuclear Information System (INIS)

    It is now possible to study by scintigraphy some parameters of dopaminergic neurotransmission with iodinated ligands. Some clinical studies have shown the interest of this kind of exploration for the early diagnosis, the differential diagnosis and the follow-up of evolution and treatment of the different extra pyramidal pathologies. However, advances are still expected in several fields (tracers, cameras resolutions). (N.C.)

  8. Helquats as a new class of G-quadruplex ligands

    Czech Academy of Sciences Publication Activity Database

    Devadig, Pradeep; Kozák, Jaroslav; Kužmová, Erika; Hubálková, Pavla; Novotná, J.; Komárková, Veronika; Císařová, I.; Šaman, David; Pohl, Radek; Bednárová, Lucie; Urbanová, M.; Hájek, Miroslav; Teplý, Filip

    Praha: Czech Chemical Society, 2015. s. 66. [Liblice 2015. Advances in Organic , Bioorganic and Pharmaceutical Chemistry /50./. 06.11.2015-08.11.2015, Olomouc] R&D Projects: GA ČR GA13-19213S Institutional support: RVO:61388963 Keywords : helquats * G-quadruplex ligands Subject RIV: CC - Organic Chemistry

  9. Dependence of acridine adsorption on ligand hydration enthalpy

    Energy Technology Data Exchange (ETDEWEB)

    Matzner, R.; Bales, R.C. (Univ. of Arizona, Tucson, AZ (United States). Dept. of Hydrology and Water Resources)

    1994-11-01

    The environmental fate of acridine is of concern because of its toxic and teratogenic properties. It is found in tobacco smoke, air pollution source effluents, recent lake sediments, wood preservative wastewater, wastewater treatment plant biosludge, and contaminated groundwater. The effect of the aqueous solution pH and ligand type (H[sub 2]PO[sup [minus

  10. Selective Electrocatalytic Activity of Ligand Stabilized Copper Oxide Nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Kauffman, Douglas R; Ohodnicki, Paul R; Kail, Brian W; Matranga, Christopher

    2011-01-01

    Ligand stabilization can influence the surface chemistry of Cu oxide nanoparticles (NPs) and provide unique product distributions for electrocatalytic methanol (MeOH) oxidation and CO{sub 2} reduction reactions. Oleic acid (OA) stabilized Cu{sub 2}O and CuO NPs promote the MeOH oxidation reaction with 88% and 99.97% selective HCOH formation, respectively. Alternatively, CO{sub 2} is the only reaction product detected for bulk Cu oxides and Cu oxide NPs with no ligands or weakly interacting ligands. We also demonstrate that OA stabilized Cu oxide NPs can reduce CO{sub 2} into CO with a {approx}1.7-fold increase in CO/H{sub 2} production ratios compared to bulk Cu oxides. The OA stabilized Cu oxide NPs also show 7.6 and 9.1-fold increases in CO/H{sub 2} production ratios compared to weakly stabilized and non-stabilized Cu oxide NPs, respectively. Our data illustrates that the presence and type of surface ligand can substantially influence the catalytic product selectivity of Cu oxide NPs.

  11. Ligand and ensemble effects in adsorption on alloy surfaces

    DEFF Research Database (Denmark)

    Liu, Ping; Nørskov, Jens Kehlet

    2001-01-01

    Density functional theory is used to study the adsorption of carbon monoxide, oxygen and nitrogen on various Au/Pd(111) bimetallic alloy surfaces. By varying the Au content in the surface we are able to make a clear separation into geometrical (or ensemble) effects and electronic (or ligand......) effects determining the adsorption properties....

  12. Optimal Overlay of Ligands with Flexible Bonds Using Differential Evolution

    DEFF Research Database (Denmark)

    Kristensen, Thomas Greve; Pedersen, Christian Storm

    2009-01-01

    spatial alignment of a set of active ligands taking the flexibility of chemical bonds into account. We present two implementations of our method. One using Differential Evolution (DE) for numerical optimization, and one using the Nelder-Mead method for numerical optimization. We investigate the quality of...

  13. Group 4 Metal Complexes of Chelating Cyclopentadienyl-ketimide Ligands

    Czech Academy of Sciences Publication Activity Database

    Večeřa, M.; Varga, Vojtěch; Císařová, I.; Pinkas, Jiří; Kucharczyk, P.; Sedlařík, V.; Lamač, Martin

    2016-01-01

    Roč. 35, č. 5 (2016), s. 785-798. ISSN 0276-7333 R&D Projects: GA ČR(CZ) GA14-08531S; GA MŠk(CZ) LO1504 Institutional support: RVO:61388955 Keywords : group 4 metal complexes * cyclopentadienyl-ketimide ligands * metallocenes Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 4.126, year: 2014

  14. GluR2 ligand-binding core complexes

    DEFF Research Database (Denmark)

    Kasper, C; Lunn, M-L; Liljefors, T; Gouaux, E; Egebjerg, J; Kastrup, Jette Sandholm Jensen

    2002-01-01

    X-ray structures of the GluR2 ligand-binding core in complex with (S)-Des-Me-AMPA and in the presence and absence of zinc ions have been determined. (S)-Des-Me-AMPA, which is devoid of a substituent in the 5-position of the isoxazolol ring, only has limited interactions with the partly hydrophobic...

  15. Modeling of metal interaction geometries for protein-ligand docking.

    Science.gov (United States)

    Seebeck, Birte; Reulecke, Ingo; Kämper, Andreas; Rarey, Matthias

    2008-05-15

    The accurate modeling of metal coordination geometries plays an important role for structure-based drug design applied to metalloenzymes. For the development of a new metal interaction model, we perform a statistical analysis of metal interaction geometries that are relevant to protein-ligand complexes. A total of 43,061 metal sites of the Protein Data Bank (PDB), containing amongst others magnesium, calcium, zinc, iron, manganese, copper, cadmium, cobalt, and nickel, were evaluated according to their metal coordination geometry. Based on statistical analysis, we derived a model for the automatic calculation and definition of metal interaction geometries for the purpose of molecular docking analyses. It includes the identification of the metal-coordinating ligands, the calculation of the coordination geometry and the superposition of ideal polyhedra to identify the optimal positions for free coordination sites. The new interaction model was integrated in the docking software FlexX and evaluated on a data set of 103 metalloprotein-ligand complexes, which were extracted from the PDB. In a first step, the quality of the automatic calculation of the metal coordination geometry was analyzed. In 74% of the cases, the correct prediction of the coordination geometry could be determined on the basis of the protein structure alone. Secondly, the new metal interaction model was tested in terms of predicting protein-ligand complexes. In the majority of test cases, the new interaction model resulted in an improved docking accuracy of the top ranking placements. PMID:18041759

  16. NMR-based screening of membrane protein ligands.

    Science.gov (United States)

    Yanamala, Naveena; Dutta, Arpana; Beck, Barbara; van Vliet, Bart; van Fleet, Bart; Hay, Kelly; Yazbak, Ahmad; Ishima, Rieko; Doemling, Alexander; Klein-Seetharaman, Judith

    2010-03-01

    Membrane proteins pose problems for the application of NMR-based ligand-screening methods because of the need to maintain the proteins in a membrane mimetic environment such as detergent micelles: they add to the molecular weight of the protein, increase the viscosity of the solution, interact with ligands non-specifically, overlap with protein signals, modulate protein dynamics and conformational exchange and compromise sensitivity by adding highly intense background signals. In this article, we discuss the special considerations arising from these problems when conducting NMR-based ligand-binding studies with membrane proteins. While the use of (13)C and (15)N isotopes is becoming increasingly feasible, (19)F and (1)H NMR-based approaches are currently the most widely explored. By using suitable NMR parameter selection schemes independent of or exploiting the presence of detergent, (1)H-based approaches require least effort in sample preparation because of the high sensitivity and natural abundance of (1)H in both, ligand and protein. On the other hand, the (19)F nucleus provides an ideal NMR probe because of its similarly high sensitivity to that of (1)H and the lack of natural (19)F background in biologic systems. Despite its potential, the use of NMR spectroscopy is highly underdeveloped in the area of drug discovery for membrane proteins. PMID:20331645

  17. Synthesis and evaluation of potential ligands for nuclear waste processing

    NARCIS (Netherlands)

    Iqbal, M.

    2012-01-01

    The research presented in this thesis deals with the synthesis and evaluation of new potential ligands for the complexation of actinide and lanthanide ions either for their extraction from bulk radioactive waste or their stripping from an extracted organic phase for final processing of the waste. In

  18. Synthesis and Characterization of Metal Complexes with Schiff Base Ligands

    Science.gov (United States)

    Wilkinson, Shane M.; Sheedy, Timothy M.; New, Elizabeth J.

    2016-01-01

    In order for undergraduate laboratory experiments to reflect modern research practice, it is essential that they include a range of elements, and that synthetic tasks are accompanied by characterization and analysis. This intermediate general chemistry laboratory exercise runs over 2 weeks, and involves the preparation of a Schiff base ligand and…

  19. Organoosmium complexes of imidazole-containing chelate acceptor ligands

    Czech Academy of Sciences Publication Activity Database

    Sarper, O.; Sarkar, B.; Fiedler, Jan; Lissner, F.; Kaim, W.

    2010-01-01

    Roč. 363, č. 12 (2010), s. 3070-3077. ISSN 0020-1693 R&D Projects: GA MŠk OC09043 Institutional research plan: CEZ:AV0Z40400503 Keywords : arene ligand * electrochemistry * electronic structure Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 1.899, year: 2010

  20. NMR-based screening of membrane protein ligands

    NARCIS (Netherlands)

    Yanamala, Naveena; Dutta, Arpana; Beck, Barbara; Van Fleet, Bart; Hay, Kelly; Yazbak, Ahmad; Ishima, Rieko; Doemling, Alexander; Klein-Seetharaman, Judith

    2010-01-01

    Membrane proteins pose problems for the application of NMR-based ligand-screening methods because of the need to maintain the proteins in a membrane mimetic environment such as detergent micelles: they add to the molecular weight of the protein, increase the viscosity of the solution, interact with

  1. Solvent-induced desorption of alkanethiol ligands from Au nanoparticles.

    Science.gov (United States)

    Huang, Yuanyuan; Liu, Wei; Cheng, Hao; Yao, Tao; Yang, Lina; Bao, Jie; Huang, Ting; Sun, Zhihu; Jiang, Yong; Wei, Shiqiang

    2016-06-21

    Removing surfactants from a colloidal metal nanoparticle surface is necessary for their realistic applications, and how they could be stripped is a subject of active investigation. Here, we report a solvent-induced desorption of dodecanethiol ligands from the gold nanoparticle surface, and traced this desorption process using a combination of in situ X-ray absorption fine structure (XAFS) and Raman spectroscopic techniques. In situ analysis results reveal that the solvent exchange of ethanol with tetrahydrofuran (THF) can effectively remove dodecanethiol ligands while keeping the particle morphology unchanged. Upon increasing the THF/ethanol ratio from 0 : 1 to 5 : 1, the surface coverage of thiol on the Au surface is reduced from 0.47 to 0.07, suggesting the depletion of ligands first from the nanoparticle facet sites, then from the edge sites, while the ligands at the corner sites are intact. This work enriches our knowledge on surfactant removal and may pave the way towards preparing surface-clean nanoparticles for practical applications. PMID:27241025

  2. Identification of VDR Antagonists among Nuclear Receptor Ligands Using Virtual Screening

    Directory of Open Access Journals (Sweden)

    Kelly Teske

    2014-04-01

    Full Text Available Herein, we described the development of two virtual screens to identify new vitamin D receptor (VDR antagonists among nuclear receptor (NR ligands. Therefore, a database of 14330 nuclear receptor ligands and their NR affinities was assembled using the online available “Binding Database.” Two different virtual screens were carried out in conjunction with a reported VDR crystal structure applying a stringent and less stringent pharmacophore model to filter docked NR ligand conformations. The pharmacophore models were based on the spatial orientation of the hydroxyl functionalities of VDR's natural ligands 1,25(OH2D3 and 25(OH2D3. The first virtual screen identified 32 NR ligands with a calculated free energy of VDR binding of more than -6.0 kJ/mol. All but nordihydroguaiaretic acid (NDGA are VDR ligands, which inhibited the interaction between VDR and coactivator peptide SRC2-3 with an IC50 value of 15.8 μM. The second screen identified 162 NR ligands with a calculated free energy of VDR binding of more than -6.0 kJ/mol. More than half of these ligands were developed to bind VDR followed by ERα/β ligands (26%, TRα/β ligands (7%, and LxRα/β ligands (7%. The binding between VDR and ERα ligand H6036 as well as TRα/β ligand triiodothyronine and a homoserine analog thereof was confirmed by fluorescence polarization.

  3. Chronic lead intoxication; Chronische Bleiintoxikation

    Energy Technology Data Exchange (ETDEWEB)

    Wieseler, B.; Leng, G. [Duesseldorf Univ. (Germany). Inst. fuer Hygiene; Lenz, S.; Schultz, C. [Klinikum Remscheid GmbH, Remscheid (Germany); Wilhelm, M. [Bochum Univ. (Germany). Inst. fuer Hygiene, Sozial- und Umweltmedizin

    1999-02-01

    The case of a female 68 years old patient is described. Here, a chronic lead intoxication was diagnosed after a two year old medical history with increasing attacks of colic-like abdominal pain often described as life-threatening. After repeated hospitalizations and intensive search for the cause of the symptoms, porphyria and anemia was found to be a sign of a chronic lead poisoning. The blood lead concentrations were always about a level of 600 {mu}g/L. The source of exposure could not be found by now. Neither home inspection nor environmental investigations have shown a recent source of lead intake by the patient. However, a possible occupational source of lead exposure at a blast furnace was established by anamnesis for 1952 to 1962. Thus, osteoporosis induced lead mobilisation was suspected. Noticeable are the results of the six abdominal survey radiographies taken during hospitalization within one year; three radiographies were taken following clinical admission and three before discharge of the patient. In comparison, the course shows a chronic relapsing alimentary supply from metallic particles of unknown genesis. The patient was treated with the sodium salt of 2,3-dimercapto-1-propansulfonic acid (DMPS, Dimaval{sup TM}). She was free of complain afterwards. Following therapy, the blood lead concentrations fell under a level of 400 {mu}m/L, but after several weeks the lead level raised up to the original level of 600 {mu}g/L. (orig.) [Deutsch] Es wird eine 68jaehrige Patientin vorgestellt, bei der nach fast zweijaehriger Krankengeschichte, die gekennzeichnet war durch rezidivierende, teils als lebensbedrohlich geschilderte Bauchkoliken, eine chronische Bleiintoxikation diagnostiziert wurde. Erst nach wiederholten stationaeren Krankenhausaufenthalten mit intensiver Suche nach der Krankheitsursache wurden das Krankheitsbild und die Laborwerte durch Zusatzuntersuchungen ergaenzt, so dass sich in der festgestellten Porphyrie und Anaemie die Diagnose der

  4. OPAL 96 Blocks Lead Glass

    CERN Multimedia

    This array of 96 lead glass bricks formed part of the OPAL electromagnetic calorimeter. One half of the complete calorimeter is shown in the picture above. There were 9440 lead glass counters in the OPAL electromagnetic calorimeter. These are made of Schott type SF57 glass and each block weighs about 25 kg and consists of 76% PbO by weight. Each block has a Hamamatsu R2238 photomultiplier glued on to it. The complete detector was in the form of a cylinder 7m long and 6m in diameter. It was used to measure the energy of electrons and photons produced in LEP interactions.

  5. Magnesium incorporation in calcite in the presence of organic ligands

    Science.gov (United States)

    Mavromatis, Vasileios; Baldermann, Andre; Purgstaller, Bettina; Dietzel, Martin

    2015-04-01

    The formation of authigenic Mg-calcites in marine early diagenetic environments is commonly driven by a bio-induced process, the anaerobic oxidation of methane (AOM), which provides inorganic carbon required for the precipitation of such authigenic carbonates. In such settings the availability of major and/or trace divalent metal cations (Me2+) incorporated in calcite and their aqueous speciation are controlled by the presence of aqueous organic molecules that are produced either as (by-)products of biological activity (i.e. exopolymeric substances) or during degradation of allochthonous organic matter in the sediments. Despite the fact that the presence of aqueous organic ligands strongly affects the growth rates and the mineralogy of precipitating CaCO3 polymorphs, till now no study addresses the role of Me2+-ligand aqueous complexes on the extent of Mg and/or other trace element content of Mg-calcites. In order to shed light on this process, relevant to authigenic calcite formation in organic-rich marine sediments and continental soils, we precipitated calcite in the presence of aqueous Mg and a variety of low molecular weight carboxylic- and aminoacids. Our experimental data indicate that the presence of organic ligands augments significantly the saturation state of calcite in the parent fluid during its precipitation. Moreover, they suggest that the higher the ligand concentration, the higher the obtained distribution coefficient of Mg in calcite. The latter is directly proportional to the ratio of Mg2+/Ca2+ aqueous ions for all ligands used. Hydrogeochemical modelling of the aqueous fluids indicate that the observed correlation can be explained by the stronger complexation of Ca2+ with organic ligands compared to Mg2+, which results in higher availability of Mg2+ vs. Ca2+ aqueous ions. Overall the obtained results suggest that the higher the organic ligand aqueous concentration the higher the Mg content of calcite forming from this fluid. These findings are

  6. Ligand influences on properties of uranium coordination complexes. Structure, reactivity, and spectroscopy

    International Nuclear Information System (INIS)

    In this thesis several different aspects of uranium chemistry are presented. It was shown that terminal uranium(V) oxo and imido complexes [((RArO)3tacn)UV(O)] and [((RArO)3tacn)UV(NSiMe3)] (R = t Bu, Ad) can be oxidized by silver(I) hexafluoro-antimonate to the uranium(VI) oxo and imido complexes [((RArO)3tacn)UVI(O)]SbF6 and [((RArO)3tacn)UVI(NSiMe3)]SbF6. While for the t Bu-derivative of the oxo complex an equatorial coordination is observed due to stabilization by the inverse trans-influence, normal axial coordination is observed for the Ad-derivative and both imido complexes. The inverse trans-influence was thus proven to be a key factor for the coordination mode of a terminal ligand on high valent uranium complexes. LIII XANES was shown to be a great tool for the determination of oxidation states of uranium complexes. Therefore, a series of uranium complexes in all stable oxidation states for uranium, +III to +VI was prepared, and their spectra analyzed. All compounds bear only O-donor ligands in addition to the chlating trisaryloxide-tacn-ligand. A separation of 1.5 to 3 eV in the white line energy is observed between the different oxidation states. This series can be used as reference for compounds, where oxidation state assignment is not obvious, such as a ketyl radical complex [((t-BuAr)O3tacn)U(O-C(t-BuPh)2.-)]. For this complex, the oxidation state of +IV could be assigned. Moreover, a series of isostructural uranium(IV) complexes was prepared. The influence of different ligands according to the spectrochemical series on the electronic and magnetic properties could be shown using UV/vis/NIR spectroscopy and variable temperature SQUID measurements. Calculations of uranium LIII XANES spectra show a variation in the shape of the spectra and thus high resolution PFY-XANES would be a great tool to determine the electronic influence of these different axial ligands. Using the single N-anchored ligand system, the first example of a uranium(IV)

  7. Ligand influences on properties of uranium coordination complexes. Structure, reactivity, and spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Kosog, Boris

    2012-11-02

    influence of these different axial ligands. Using the single N-anchored ligand system, the first example of a uranium(IV) μ-trithiocarbonate was synthesized and characterized. Reaction of the μ-sulfide complex [{(("A"dArO)_3N)U"I"V}{sub 2}(μ-S)], which is obtained by reaction of the uranium(III) complex with triphenylphosphine sulfide, with CS{sub 2} leads to the formation of the [{(("A"dArO)_3N)U"I"V}{sub 2}(μ-κ{sup 2}:κ{sup 2}-CS{sub 3})]. The coordination mode of the trithicarbonate differes from that of the respective carbonate, obtained previously from a similar reaction of the μ-oxo complex with CO{sub 2}. With the help of detailed DFT calculations, the different reactivity of uranium(III) towards CO{sub 2} and CS{sub 2} is rationalized. Finally, a series of the first uranium vinyl complexes is presented. These are obtained through inter- and intramolecular C-C-coupling reactions of terminal mono- or bisalkynes on a uranium(III) complex. Detailed mechanistic DFT calculations show that a bimetallic mechanism is energetically most likely. This mechanism can be transferred to the catalytic alkyne coupling using both uranium(III), as reported by Eisen in the late 90's, and also transition metal catalyzed C-C-coupling, where a bimetallic mechanism should be taken into account.

  8. Specific uranyl binding by macrocyclic ligands attached to resins

    International Nuclear Information System (INIS)

    Macrocyclic polydentates have attracted enormous attention from chemists because of their unique and significant characteristics of the strong and selective binding of a variety of metal ions. The metal binding is governed mostly by the size of the macroring and the nature of heteroatoms involved. The most important role of the macrocyclic structure is, in general, the so-called macrocyclic effect - to increase (making less negative) a large negative entropy change involved in the polydentate chelation. Basic strategy of uranium binding, is to design a ligand of very strong metal binding to take advantage of this macrocyclic effect, where number of chelating heteroatoms and their spatial arrangement is designed to be most appropriate for uranyl (UO22+) binding, since in natural sea water uranium is dissolved mostly in a form of uranyl carbonate. The following macrocylic ligands, hexamine, hexaketone, hexacarboxylic acid, were prepared and tested. The macrocyclic hexacarboxylic ligand was the most promising. The addition of hexacarboxylic acid to a uranyl tricarbonate solution gave a change of visible absorption due to the competitive formation of the uranyl complex. From this competitive binding, a relative formation constant was estimated to be 10-5, giving a log K/sub f/ value of 16.4 at 250C for the uranyl complex. This value is the largest among the hosts ever reported to bind uranyl ion.The selectivity of the macrocyclic hexacarboxylic ligand was also ascertained by testing with other metal cations. Results indicate that uranyl ions can be extracted efficiently from sea water using the hexacarboxylic acid ligands which are attached to a polymer insoluble in water

  9. Highly selective hydrogenation of halonitroaromatics to aromatic haloamines by ligand modified Ni-based catalysts

    Institute of Scientific and Technical Information of China (English)

    Chun Shan Lu; Jing Hui Lv; Lei Ma; Qun Feng Zhang; Feng Feng; Xiao Nian Li

    2012-01-01

    Ligand modification of Ni-based catalysts by coordination of dicyandiamide to Ni metal leads to enhanced selectivity for the selective hydrogenation of halonitroaromatics.The selectivity of above 99.9% to aromatic haloamines can be achieved at the conversion of 100%.The results of H2-TPD and FT-IR experiments show that Ni-H+ species possessing the properties of Lewis acid site on the surface of Raney Ni could be responsible for the hydrodehalogenation.When Raney Ni was treated by dicyandiamide,Ni-H+ species interacted with N atom from the dicyandiamide.This interaction was stable even at reaction temperature,which reduced the possibility to form the intermediate state of Ar-Cl …H+Ni-.And then C-Cl bond could not be polarized and activated.The hydrodechlorination process was suppressed effectively.

  10. Another Piece in the Fibrotic Puzzle: TSLP as a Novel Ligand for Fibrocyte Activation.

    Science.gov (United States)

    Christmann, Romy Beatriz

    2016-02-01

    Thymic stromal lymphopoietin (TSLP) has emerged as an important cytokine in the pathogenesis of nonallergic diseases, especially in diseases that include fibrosis. It has been shown to be upregulated in both cutaneous and lung fibrotic conditions. Shin et al. report that TSLP may also play a role in the pathogenesis of keloids. The main mechanism of TSLP profibrotic effects is not as yet fully understood, although the data suggest that it involves collagen production through transforming growth factor-β, at least in the case of dermal fibroblasts. The authors also report that TSLP is able to activate fibrocytes, probably by inducing stromal cell-derived factor-1 (also termed CXCL12), one of its main ligands. These findings support the concept that TSLP plays a role in the development of fibrosis, and they should lead to mechanistic studies on TSLP profibrotic signaling. PMID:26802232

  11. Ionotropic excitatory amino acid receptor ligands. Synthesis and pharmacology of a new amino acid AMPA antagonist

    DEFF Research Database (Denmark)

    Madsen, U; Sløk, F A; Stensbøl, T B;

    2000-01-01

    We have previously described the potent and selective (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor agonist, (RS)-2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA), and the AMPA receptor antagonist (RS)-2-amino-3-[3-(carboxymethoxy)-5-methyl-4...... excitatory amino acid (EAA) receptors using receptor binding and electrophysiological techniques, and for activity at metabotropic EAA receptors using second messenger assays. Compounds 1 and 4 were essentially inactive. (RS)-2-Amino-3-[3-(2-carboxyethyl)-5-methyl-4-isoxazolyl]propionic acid (ACMP, 2), on......-isoxazolyl]propionic acid (AMOA). Using these AMPA receptor ligands as leads, a series of compounds have been developed as tools for further elucidation of the structural requirements for activation and blockade of AMPA receptors. The synthesized compounds have been tested for activity at ionotropic...

  12. Synthesis, crystal structures and spectroscopic properties of cobalt(II) complexes with chelating sulfonylamidophosphate ligands

    Science.gov (United States)

    Znovjyak, Kateryna O.; Seredyuk, Maksym; Kusz, Joachim; Nowak, Maria; Moroz, Olesia V.; Sliva, Tetiana Yu; Amirkhanov, Vladimir M.

    2015-11-01

    Two new cobalt(II) complexes with general formula Co(L1)2Phen (1) and Co(L2)2Phen (2), in which HL1 = dimethyl phenylsulfonylphosphoramidate and HL2 = dimethyl tosylphosphoramidate, were prepared in one-step synthesis and characterized by IR, UV-VIS spectroscopy, TGA-DTA and elemental analysis. Moreover, the single crystal structures of 1 and 2 were determined by single crystal X-ray diffractometry. Complexes consist of mononuclear units comprising two L1-(or L2-) and phenanthroline ligands bidentatly linked to metal ion. The UV-VIS spectra of complexes in the solid state show broad asymmetric band at 530 nm attributed to the d-d transition of the metal ion. Comparing of these spectra with the absorption spectra in acetone, octahedral environment of the cobalt(II) ion in solution were considered. The structural similarity of 1 and 2 leads to a similar thermal decomposition profile.

  13. Spectroscopic properties of highly Nd-doped lead phosphate glass

    International Nuclear Information System (INIS)

    The spectroscopic characteristics of highly Nd3+-doped lead phosphate glasses (xNd:Pb3(PO4)2) have been investigated. The X-ray spectra show that the matrices are glassy up to 25 wt% of Nd3+ doping. From the Judd–Ofelt analysis we observe that while the Ω(2) parameter remains constant indicating that the 4fN and 4fN−15 d1 configurations are not affected by the Nd3+ doping, the behavior of both Ω(4) and Ω(6) changes for 15 wt% of Nd3+ doping. The reduction of the Ω(6) parameter is related to the increase of the covalence bonding between the ligands and the Nd3+ ions. At this particular concentration, the radiative lifetime has a four-fold enhancement. Such behaviors are likely to be related to a modification in the glass structure for high Nd3+ concentrations. - Graphical abstract: Highly doped lead-phosphate glass matrix, with nominal concentration of up to 25 wt%, maintain the spectroscopic properties without deterioration. The analysis concerning the point of view of Nd3+ ions showed that high concentrations only affects the rare earth electronic charge density distribution. - Highlights: • Spectroscopic characterization of Nd2O3 highly doped lead phosphate glasses. • Phosphate glass doped with Nd3+ for applications in photonic devices. • Judd–Ofelt analysis in phosphate glasses doped with Neodymium

  14. Blood Lead and Reading Readiness

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2013-08-01

    Full Text Available Investigators at the University of Maryland School of Nursing, Johns Hopkins School of Public Health, and Department of Health, Providence, Rhode Island, evaluated the relationship between reading readiness test scores for children attending public kindergarten in Providence, RI, and state health department records of blood lead levels (BLLs.

  15. All Roads Lead To Rome

    DEFF Research Database (Denmark)

    Ottosen, Thorsten Jørgen; Vomlel, Jiri

    2010-01-01

    treewidth criterion for optimality of a triangulation. However, this criterion may lead to a somewhat harder inference problem than the total table size criterion. We therefore investigate new methods for depth-first search and best-first search for finding optimal total table size triangulations. The...

  16. How to lead complex situations

    DEFF Research Database (Denmark)

    Hansen, Michael Pingel

    2013-01-01

    The military leader is experiencing increasingly more complex situations, whether it is as leader in a foreign combat environment or in the home-based public administration. Complex situations like these call for a special set of managerial responses and a special way of leading organisations. The...

  17. All roads lead to Rome

    DEFF Research Database (Denmark)

    Ottosen, Thorsten Jørgen; Vomlel, Jiri

    2012-01-01

    for existing methods to use the treewidth criterion for optimality of a triangulation. However, this criterion may lead to a somewhat harder inference problem than the total table size criterion. We therefore investigate new methods for depth-first search and best-first search for finding optimal...

  18. NA49: lead ion collision

    CERN Multimedia

    1995-01-01

    This is an image of an actual lead ion collision taken from tracking detectors on the NA49 experiment, part of the heavy ion project at CERN. These collisions produce a very complicated array of hadrons as the heavy ions break up. It is hoped that one of these collisions will eventually create a new state of matter known as quark-gluon plasma.

  19. NA49: lead ion collision

    CERN Multimedia

    1995-01-01

    This is an image of an actual lead ion collision taken from the NA49 experiment, part of the heavy ion project at CERN. These collisions produce a very complicated array of hadrons as the heavy ions break up. It is hoped that one of these collisions will eventually create a new state of matter known as the quark-gluon plasma.

  20. Leading in a Technological Age

    Science.gov (United States)

    Yadgir, Sheri A.

    2011-01-01

    Technology is advancing more rapidly than at any time in history since the beginning of the Industrial Revolution. In fact, experts say that the world is leaving the Industrial Age of the 20th century and entering an Information Age that will lead into the future. These advances mean that important changes are being made in all areas of life--and…