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Sample records for nuclear factor-kappab ligand

  1. What are Nuclear Receptor Ligands?

    PubMed Central

    Sladek, Frances M.

    2010-01-01

    Nuclear receptors (NRs) are a family of highly conserved transcription factors that regulate transcription in response to small lipophilic compounds. They play a role in every aspect of development, physiology and disease in humans. They are also ubiquitous in and unique to the animal kingdom suggesting that they may have played an important role in their evolution. In contrast to the classical endocrine receptors that originally defined the family, recent studies suggest that the first NRs might have been sensors of their environment, binding ligands that were external to the host organism. The purpose of this review is to provide a broad perspective on NR ligands and address the issue of exactly what constitutes a NR ligand from historical, biological and evolutionary perspectives. This discussion will lay the foundation for subsequent reviews in this issue as well as pose new questions for future investigation. PMID:20615454

  2. Limited proteolysis for assaying ligand binding affinities of nuclear receptors.

    PubMed

    Benkoussa, M; Nominé, B; Mouchon, A; Lefebvre, B; Bernardon, J M; Formstecher, P; Lefebvre, P

    1997-01-01

    The binding of natural or synthetic ligands to nuclear receptors is the triggering event leading to gene transcription activation or repression. Ligand binding to the ligand binding domain of these receptors induces conformational changes that are evidenced by an increased resistance of this domain to proteases. In vitro labeled receptors were incubated with various synthetic or natural agonists or antagonists and submitted to trypsin digestion. Proteolysis products were separated by SDS-PAGE and quantified. The amount of trypsin-resistant fragments was proportional to receptor occupancy by the ligand, and allowed the determination of dissociation constants (kDa). Using the wild-type or mutated human retinoic acid receptor alpha as a model, kDa values determined by classical competition binding assays using tritiated ligands are in agreement with those measured by the proteolytic assay. This method was successfully extended to human retinoic X receptor alpha, glucocorticoid receptor, and progesterone receptor, thus providing a basis for a new, faster assay to determine simultaneously the affinity and conformation of receptors when bound to a given ligand.

  3. Constitutive and ligand-induced nuclear localization of oxytocin receptor.

    PubMed

    Kinsey, Conan G; Bussolati, Gianni; Bosco, Martino; Kimura, Tadashi; Pizzorno, Marie C; Chernin, Mitchell I; Cassoni, Paola; Novak, Josef F

    2007-01-01

    Oxytocin receptor (OTR) is a membrane protein known to mediate oxytocin (OT) effects, in both normal and neoplastic cells. We report here that human osteosarcoma (U2OS, MG63, OS15 and SaOS2), breast cancer (MCF7), and primary human fibroblastic cells (HFF) all exhibit OTR not only on the cell membrane, but also in the various nuclear compartments including the nucleolus. Both an OTR-GFP fusion protein and the native OTR appear to be localized to the nucleus as detected by transfection and/or confocal immunofluorescence, respectively. Treatment with oxytocin causes internalization of OTR and the resulting vesicles accumulate in the vicinity of the nucleus and some of the perinuclear OTR enters the nucleus. Western blots indicate that OTR in the nucleus and on the plasma membrane are likely to be the same biochemical and immunological entities. It appears that OTR is first visible in the nucleoli and subsequently disperses within the nucleus into 4-20 spots while some of the OTR diffuses throughout the nucleoplasm. The behaviour and kinetics of OTR-GFP and OTR are different, indicating interference by GFP in both OTR entrance into the nucleus and subsequent relocalization of OTR within the nucleus. There are important differences among the tested cells, such as the requirement of a ligand for transfer of OTR in nuclei. A constitutive internalization of OTR was found only in osteosarcoma cells, while the nuclear localization in all other tested cells was dependent on ligand binding. The amount of OTR-positive material within and in the vicinity of the nucleus increased following a treatment with oxytocin in both constitutive and ligand-dependent type of cells. The evidence of OTR compartmentalization at the cell nucleus (either ligand-dependent or constitutive) in different cell types suggests still unknown biological functions of this protein or its ligand and adds this G-protein-coupled receptor to other heptahelical receptors displaying this atypical and unexpected

  4. IDENTIFICATION OF VDR ANTAGONISTS AMONG NUCLEAR RECEPTOR LIGANDS USING VIRTUAL SCREENING

    PubMed Central

    Teske, Kelly; Nandhikonda, Premchendar; Bogart, Jonathan W.; Feleke, Belaynesh; Sidhu, Preetpal; Yuan, Nina; Preston, Joshua; Goy, Robin; Han, Lanlan; Silvaggi, Nicholas R; Singh, Rakesh K.; Bikle, Daniel D.; Cook, James M.; Arnold, Leggy A.

    2014-01-01

    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(OH2)D3 and 25(OH2)D3. The first virtual screen identified 32 NR ligands with a calculate 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 calculate 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. PMID:25419525

  5. Importance of the pharmacological profile of the bound ligand in enrichment on nuclear receptors: toward the use of experimentally validated decoy ligands.

    PubMed

    Lagarde, Nathalie; Zagury, Jean-François; Montes, Matthieu

    2014-10-27

    The evaluation of virtual ligand screening methods is of major importance to ensure their reliability. Taking into account the agonist/antagonist pharmacological profile should improve the quality of the benchmarking data sets since ligand binding can induce conformational changes in the nuclear receptor structure and such changes may vary according to the agonist/antagonist ligand profile. We indeed found that splitting the agonist and antagonist ligands into two separate data sets for a given nuclear receptor target significantly enhances the quality of the evaluation. The pharmacological profile of the ligand bound in the binding site of the target structure was also found to be an additional critical parameter. We also illustrate that active compound data sets for a given pharmacological activity can be used as a set of experimentally validated decoy ligands for another pharmacological activity to ensure a reliable and challenging evaluation of virtual screening methods.

  6. The Nuclear Receptor HIZR-1 Uses Zinc as a Ligand to Mediate Homeostasis in Response to High Zinc

    PubMed Central

    Warnhoff, Kurt; Roh, Hyun C.; Kocsisova, Zuzana; Tan, Chieh-Hsiang; Morrison, Andrew; Croswell, Damari; Schneider, Daniel L.; Kornfeld, Kerry

    2017-01-01

    Nuclear receptors were originally defined as endocrine sensors in humans, leading to the identification of the nuclear receptor superfamily. Despite intensive efforts, most nuclear receptors have no known ligand, suggesting new ligand classes remain to be discovered. Furthermore, nuclear receptors are encoded in the genomes of primitive organisms that lack endocrine signaling, suggesting the primordial function may have been environmental sensing. Here we describe a novel Caenorhabditis elegans nuclear receptor, HIZR-1, that is a high zinc sensor in an animal and the master regulator of high zinc homeostasis. The essential micronutrient zinc acts as a HIZR-1 ligand, and activated HIZR-1 increases transcription of genes that promote zinc efflux and storage. The results identify zinc as the first inorganic molecule to function as a physiological ligand for a nuclear receptor and direct environmental sensing as a novel function of nuclear receptors. PMID:28095401

  7. Investigation on critical structural motifs of ligands for triggering glucocorticoid receptor nuclear migration through molecular docking simulations.

    PubMed

    Liu, Ya-Lin; Jang, Soonmin; Wang, Shih-Min; Chen, Chiu-Hao; Li, Feng-Yin

    2016-06-01

    The glucocorticoid receptor (GR), a transcription factor regulating gene expression in a ligand-dependent fashion, is known for flexibility in adapting various ligands with their structures ranging from steroid to non-steroid. However, in our previous study, GR shows a stringent discrimination against a set of steroid ligands with highly similar structures for triggering its nuclear migration. In order to resolve this puzzle, we employed molecular docking simulations to investigate the origin of this structural discrimination. By analyzing the docking orientations and the related ligand-GR interaction patterns, we found that the hydrophilicity mismatch between the docking ligand and the GR ligand-binding site is the main cause combined with the steric hindrance and structural rigidness of these steroid ligands. Furthermore, we utilized this knowledge to rationalize how the structure-binding interaction of non-steroid ligands triggers GR nuclear migration with their structures available in Protein Data Bank.

  8. A photoregulated ligand for the nuclear import receptor karyopherin alpha.

    PubMed

    Park, S B; Standaert, R F

    2001-12-01

    The ability to orchestrate the transport of proteins between nucleus and cytoplasm provides cells with a powerful regulatory mechanism. Selective translocation between these compartments is often used to propagate cellular signals, and it is an intimate part of the processes that control cell division, viral replication, and other cellular events. Therefore, precise experimental control over protein localization, through the agency of light, would provide a powerful tool for the study and manipulation of these events. To this end, a prototype photoregulated nuclear localization signal (NLS) was derived from a native NLS. A library of 30 mutants of the bipartite NLS from Xenopus laevis nucleoplasmin containing a novel, photoisomerizable amino acid was prepared by parallel, solid-phase synthesis and screened in vitro for binding to the nuclear import receptor karyopherin alpha, which mediates the nuclear import of cellular proteins. A single peptide was identified in which the cis and trans photoisomers bind the receptor differentially. The strategy used to obtain this peptide is systematic and empirical; therefore, it is potentially applicable to any peptide-receptor system.

  9. Androgen receptor regulates nuclear trafficking and nuclear domain residency of corepressor HDAC7 in a ligand-dependent fashion

    SciTech Connect

    Karvonen, Ulla; Jaenne, Olli A.; Palvimo, Jorma J. . E-mail: jorma.palvimo@uku.fi

    2006-10-01

    In addition to chromosomal proteins, histone deacetylases (HDACs) target transcription factors in transcriptional repression. Here, we show that the class II HDAC family member HDAC7 is an efficient corepressor of the androgen receptor (AR). HDAC7 resided in the cytoplasm in the absence of AR or a cognate ligand, but hormone-occupancy of AR induced nuclear transfer of HDAC7. Nuclear colocalization pattern of AR and HDAC7 was dependent on the nature of the ligand. In the presence of testosterone, a portion of HDAC7 localized to pearl-like nuclear domains, whereas AR occupied with antagonistic ligands cyproterone acetate- or casodex (bicalutamide) recruited HDAC7 from these domains to colocalize with the receptor in speckles and nucleoplasm in a more complete fashion. Ectopic expression of PML-3 relieved the repressive effect of HDAC7 on AR function by sequestering HDAC7 to PML-3 domains. AR acetylation at Lys630/632/633 was not the target of HDAC7 repression, since repression of AR function was independent of these acetylation sites. Moreover, the deacetylase activity of HDAC7 was in part dispensable in the repression of AR function. In sum, our results identify HDAC7 as a novel AR corepressor whose subcellular and subnuclear compartmentalization can be regulated in an androgen-selective manner.

  10. A Nuclear Receptor Ligand-based Probe Enables Temporal Control of C. elegans Development

    PubMed Central

    Judkins, Joshua C.; Mahanti, Parag; Hoffman, Jacob; Yim, Isaiah; Antebi, Adam; Schroeder, Frank C.

    2014-01-01

    C. elegans development and lifespan are controlled by the nuclear hormone receptor DAF-12, an important model for vertebrate vitamin D and liver-X receptors. Similar to its mammalian homologs, DAF-12 function is regulated by bile acid-like steroidal ligands, the dafachronic acids; however, tools for investigating their biosynthesis and function in vivo are lacking. We report a flexible synthesis for DAF-12 ligands and masked ligand derivatives that enable precise temporal control of DAF-12 function. For ligand masking, we introduce photocleavable amides of 5-methoxy-N-methyl-2-nitroaniline (MMNA). MMNA-masked ligands are bioavailable and after incorporation into the worm can be used to trigger expression of DAF-12 target genes and initiate development from dauer larvae to adults by brief, innocuous UV-irradiation. In-vivo release of DAF-12 ligands and other small-molecule signals using MMNA-based probes will enable functional studies with precise spatial and temporal resolution. PMID:24453122

  11. Nuclear receptor ligand-binding domains: reduction of helix H12 dynamics to favour crystallization

    SciTech Connect

    Nahoum, Virginie; Lipski, Alexandra; Quillard, Fabien; Guichou, Jean-François; Boublik, Yvan; Pérez, Efrèn; Germain, Pierre; Lera, Angel R. de; Bourguet, William

    2008-07-01

    Attempts have been made to crystallize the ligand-binding domain of the human retinoid X receptor in complex with a variety of newly synthesized ligands. An inverse correlation was observed between the ‘crystallizability’ and the structural dynamics of the various receptor–ligand complexes. Crystallization trials of the human retinoid X receptor α ligand-binding domain (RXRα LBD) in complex with various ligands have been carried out. Using fluorescence anisotropy, it has been found that when compared with agonists these small-molecule effectors enhance the dynamics of the RXRα LBD C-terminal helix H12. In some cases, the mobility of this helix could be dramatically reduced by the addition of a 13-residue co-activator fragment (CoA). In keeping with these observations, crystals have been obtained of the corresponding ternary RXRα LBD–ligand–CoA complexes. In contrast, attempts to crystallize complexes with a highly mobile H12 remained unsuccessful. These experimental observations substantiate the previously recognized role of co-regulator fragments in facilitating the crystallization of nuclear receptor LBDs.

  12. Ligand-binding domains of nuclear receptors facilitate tight control of split CRISPR activity

    PubMed Central

    Nguyen, Duy P.; Miyaoka, Yuichiro; Gilbert, Luke A.; Mayerl, Steven J.; Lee, Brian H.; Weissman, Jonathan S.; Conklin, Bruce R.; Wells, James A.

    2016-01-01

    Cas9-based RNA-guided nuclease (RGN) has emerged to be a versatile method for genome editing due to the ease of construction of RGN reagents to target specific genomic sequences. The ability to control the activity of Cas9 with a high temporal resolution will facilitate tight regulation of genome editing processes for studying the dynamics of transcriptional regulation or epigenetic modifications in complex biological systems. Here we show that fusing ligand-binding domains of nuclear receptors to split Cas9 protein fragments can provide chemical control over split Cas9 activity. The method has allowed us to control Cas9 activity in a tunable manner with no significant background, which has been challenging for other inducible Cas9 constructs. We anticipate that our design will provide opportunities through the use of different ligand-binding domains to enable multiplexed genome regulation of endogenous genes in distinct loci through simultaneous chemical regulation of orthogonal Cas9 variants. PMID:27363581

  13. Proliferating cell nuclear antigen is a novel inhibitory ligand for the natural cytotoxicity receptor NKp44.

    PubMed

    Rosental, Benyamin; Brusilovsky, Michael; Hadad, Uzi; Oz, Dafna; Appel, Michael Y; Afergan, Fabian; Yossef, Rami; Rosenberg, Lior Ann; Aharoni, Amir; Cerwenka, Adelheid; Campbell, Kerry S; Braiman, Alex; Porgador, Angel

    2011-12-01

    NK cells play an important role in the early immune response to cancer. The NKp44 activating receptor is the only natural cytotoxicity receptor that is expressed exclusively by primate NK cells, yet its cellular ligands remain largely unknown. Proliferating cell nuclear Ag (PCNA) is overexpressed in cancer cells. In this study, we show that the NKp44 receptor recognizes PCNA. Their interaction inhibits NK cell function through NKp44/ITIM. The physical interaction of NKp44 and PCNA is enabled by recruitment of target cell PCNA to the NK immunological synapse. We demonstrate that PCNA promotes cancer survival by immune evasion through inhibition of NKp44-mediated NK cell attack.

  14. Alpha Radiolysis of Nuclear Solvent Extraction Ligands Used for An(III) and Ln(III) Separations

    SciTech Connect

    Mezyk, Stephen P.; Mincher, Bruce J.; Nilsson, Mikael

    2016-08-01

    This document is the final report for the Nuclear Energy Universities Program (NEUP) grant 10-910 (DE-AC07-05ID14517) “Alpha Radiolysis of Nuclear Solvent Extraction Ligands used for An(III) and Ln(III) Separations”. The goal of this work was to obtain a quantitative understanding of the impacts of both low Linear Energy Transfer (LET, gamma-rays) and high LET (alpha particles) radiation chemistry occurring in future large-scale separations processes. This quantitative understanding of the major radiation effects on diluents and ligands is essential for optimal process implementation, and could result in significant cost savings in the future.

  15. Synthesis and Activity of Dafachronic Acid Ligands for the C. elegans DAF-12 Nuclear Hormone Receptor

    PubMed Central

    Sharma, Kamalesh K.; Wang, Zhu; Motola, Daniel L.; Cummins, Carolyn L.; Mangelsdorf, David J.; Auchus, Richard J.

    2009-01-01

    The nuclear hormone receptor DAF-12 from Caenorhabditis elegans is activated by dafachronic acids, which derive from sterols upon oxidation by DAF-9, a cytochrome P450. DAF-12 activation is a critical checkpoint in C. elegans for acquisition of reproductive competence and for entry into adulthood rather than dauer diapause. Previous studies implicated the (25S)-Δ7-dafachronic acid isomer as the most potent compound, but the (25S)-Δ4-isomer was also identified as an activator of DAF-12. To explore the tolerance of DAF-12 for structural variations in the ligand and to enable further studies requiring large amounts of ligands for DAF-12 and homologs in other nematodes, we synthesized (25R)- and (25S)-isomers of five dafachronic acids differing in A/B-ring configurations. Both the (25S)- and (25R)-Δ7-dafachronic acids are potent transcriptional activators in a Gal4-transactivation assay using HEK-293 cells, with EC50 values of 23 and 33 nm, respectively, as are (25S)- and (25R)-Δ4-dafachronic acids, with EC50 values of 23 and 66 nm, respectively. The (25S)- and (25R)-Δ5-isomers were much less potent, with EC50 values approaching 1000 nm, and saturated 5α- and 5β-dafachronic acids showed mostly intermediate potencies. Rescue assays using daf- 9-null mutants confirmed the results from transactivation experiments, but this in vivo assay accentuated the greater potencies of the (25S)-epimers, particularly for the (25S)-Δ7-isomer. We conclude that DAF-12 accommodates a large range of structural variation in ligand geometry, but (25S)-Δ7-dafachronic acid is the most potent and probably biologically relevant isomer. Potency derives more from the A/B-ring configuration than from the stereochemistry at C-25. PMID:19196833

  16. Agonist ligands mediate the transcriptional response of nuclear receptor heterodimers through distinct stoichiometric assemblies with coactivators.

    PubMed

    Pavlin, Mark Remec; Brunzelle, Joseph S; Fernandez, Elias J

    2014-09-05

    The constitutive androstane (CAR) and retinoid X receptors (RXR) are ligand-mediated transcription factors of the nuclear receptor protein superfamily. Functional CAR:RXR heterodimers recruit coactivator proteins, such as the steroid receptor coactivator-1 (SRC1). Here, we show that agonist ligands can potentiate transactivation through both coactivator binding sites on CAR:RXR, which distinctly bind two SRC1 molecules. We also observe that SRC1 transitions from a structurally plastic to a compact form upon binding CAR:RXR. Using small angle x-ray scattering (SAXS) we show that the CAR(tcp):RXR(9c)·SRC1 complex can encompass two SRC1 molecules compared with the CAR(tcp):RXR·SRC1, which binds only a single SRC1. Moreover, sedimentation coefficients and molecular weights determined by analytical ultracentrifugation confirm the SAXS model. Cell-based transcription assays show that disrupting the SRC1 binding site on RXR alters the transactivation by CAR:RXR. These data suggest a broader role for RXR within heterodimers, whereas offering multiple strategies for the assembly of the transcription complex.

  17. Phosphorylated nuclear receptor CAR forms a homodimer to repress its constitutive activity for ligand activation.

    PubMed

    Shizu, Ryota; Osabe, Makoto; Perera, Lalith; Moore, Rick; Sueyoshi, Tatsuya; Negishi, Masahiko

    2017-03-06

    Nuclear receptor CAR (NR1I3) regulates hepatic drug and energy metabolism as well as cell fate. Its activation can be a critical factor in drug-induced toxicity and disease development such as diabetes and tumors. CAR inactivates its constitutive activity by phosphorylation at threonine 38. Utilizing receptor for protein kinase 1 (RACK1) as the regulatory subunit, protein phosphatase PP2A dephosphorylates threonine 38 to activate CAR. Here we have demonstrated that CAR undergoes its homodimer-monomer conversion to regulate this dephosphorylation. By co-expressing two differently-tagged CAR proteins in Huh-7 cells, mouse primary hepatocytes and mouse livers, co-immunoprecipitation and two-dimensional gel electrophoresis revealed that CAR can form a homodimer in a configuration in which the PP2A/RACK1 binding site is buried within its dimer interface. Epidermal growth factor (EGF) was found to stimulate CAR homo-dimerization, thus constraining CAR in its inactive form. The agonistic ligand CITCO binds directly to the CAR homodimer and dissociates phosphorylated CAR into its monomer, exposing the PP2A/RACK1 binding site for dephosphorylation. Phenobarbital, which is not a CAR ligand, binds the EGF receptor, reversing the EGF signal to monomerize CAR for its indirect activation. Thus, the homodimer-monomer conversion is the underlying molecular mechanism that regulates CAR activation, by placing phosphorylated threonine 38 as the common target for both direct and in direct activation of CAR.

  18. Supported Molecular Iridium Catalysts: Resolving Effects of Metal Nuclearity and Supports as Ligands

    SciTech Connect

    Lu, Jing; Serna, Pedro; Aydin, Cerem; Browning, Nigel D.; Gates, Bruce C.

    2012-02-07

    The performance of a supported catalyst is influenced by the size and structure of the metal species, the ligands bonded to the metal, and the support. Resolution of these effects has been lacking because of the lack of investigations of catalysts with uniform and systematically varied catalytic sites. We now demonstrate that the performance for ethene hydrogenation of isostructural iridium species on supports with contrasting properties as ligands (electron-donating MgO and electron-withdrawing HY zeolite) can be elucidated on the basis of molecular concepts. Spectra of the working catalysts show that the catalytic reaction rate is determined by the dissociation of H{sub 2} when the iridium, either as mono- or tetra-nuclear species, is supported on MgO and is not when the support is the zeolite. The neighboring iridium sites in clusters are crucial for activation of both H{sub 2} and C{sub 2}H{sub 4} when the support is MgO but not when it is the zeolite, because the electron-withdrawing properties of the zeolite support enable even single site-isolated Ir atoms to bond to both C{sub 2}H{sub 4} and H{sub 2} and facilitate the catalysis.

  19. Crystallographic Identification and Functional Characterization of Phospholipids as Ligands for the Orphan Nuclear Receptor Steroidogenic Factor-1

    SciTech Connect

    Li, Yong; Choi, Mihwa; Cavey, Greg; Daugherty, Jennifer; Suino, Kelly; Kovach, Amanda; Bingham, Nathan C.; Kliewer, Steven A.; Xu, H.Eric

    2010-11-10

    The orphan nuclear receptor steroidogenic factor 1 (SF-1) regulates the differentiation and function of endocrine glands. Although SF-1 is constitutively active in cell-based assays, it is not known whether this transcriptional activity is modulated by ligands. Here, we describe the 1.5 {angstrom} crystal structure of the SF-1 ligand binding domain in complex with an LXXLL motif from a coregulator protein. The structure reveals the presence of a phospholipid ligand in a surprisingly large pocket ({approx}1600 {angstrom}{sup 3}), with the receptor adopting the canonical active conformation. The bound phospholipid is readily exchanged and modulates SF-1 interactions with coactivators. Mutations designed to reduce the size of the SF-1 pocket or to disrupt hydrogen bonds with the phospholipid abolish SF-1/coactivator interactions and significantly reduce SF-1 transcriptional activity. These findings provide evidence that SF-1 is regulated by endogenous ligands and suggest an unexpected relationship between phospholipids and endocrine development and function.

  20. Radiolytic degradation of a new diglycol-diamide ligand for actinide and lanthanide co-extraction from spent nuclear fuel

    NASA Astrophysics Data System (ADS)

    Ossola, Annalisa; Macerata, Elena; Tinonin, Dario A.; Faroldi, Federica; Giola, Marco; Mariani, Mario; Casnati, Alessandro

    2016-07-01

    Within the Partitioning and Transmutation strategies, great efforts have been devoted in the last decades to the development of lipophilic ligands able to co-extract trivalent Lanthanides (Ln) and Actinides (An) from spent nuclear fuel. Because of the harsh working conditions these ligands undergo, it is important to prove their chemical and radiolytic stability during the counter-current multi-stage extraction process. In the present work the hydrolytic and radiolytic resistance of the freshly prepared and aged organic solutions containing the new ligand (2,6-bis[(N-methyl-N-dodecyl)carboxamide]-4-methoxy-tetrahydro-pyran) were investigated in order to evaluate the impact on the safety and efficiency of the process. Liquid-liquid extraction tests with spiked solutions showed that the ligand extracting performances are strongly impaired by storing the samples at room temperature and in the light. Moreover, the extracting efficiency of the irradiated samples resulted to be influenced by gamma irradiation, while selectivity remains unchanged. Preliminary mass spectrometric data showed that degradation is mainly due to the acid-catalysed reaction of the ligand carboxamide and ether groups with the 1-octanol present in the diluent.

  1. Local motifs involved in the canonical structure of the ligand-binding domain in the nuclear receptor superfamily.

    PubMed

    Tsuji, Motonori

    2014-03-01

    Structural and sequence alignment analyses have revealed the existence of class-dependent and -independent local motifs involved in the overall fold of the ligand-binding domain (LBD) in the nuclear receptor (NR) superfamily. Of these local motifs, three local motifs, i.e., AF-2 fixed motifs, were involved in the agonist conformation of the activation function-2 (AF-2) region of the LBD. Receptor-agonist interactions increased the stability of these AF-2 fixed motifs in the agonist conformation. In contrast, perturbation of the AF-2 fixed motifs by a ligand or another protein molecule led the AF-2 architecture to adopt an antagonist conformation. Knowledge of this process should provide us with novel insights into the 'agonism' and 'antagonism' of NRs.

  2. Challenges Predicting Ligand-Receptor Interactions of Promiscuous Proteins: The Nuclear Receptor PXR

    PubMed Central

    Ekins, Sean; Kortagere, Sandhya; Iyer, Manisha; Reschly, Erica J.; Lill, Markus A.; Redinbo, Matthew R.; Krasowski, Matthew D.

    2009-01-01

    Transcriptional regulation of some genes involved in xenobiotic detoxification and apoptosis is performed via the human pregnane X receptor (PXR) which in turn is activated by structurally diverse agonists including steroid hormones. Activation of PXR has the potential to initiate adverse effects, altering drug pharmacokinetics or perturbing physiological processes. Reliable computational prediction of PXR agonists would be valuable for pharmaceutical and toxicological research. There has been limited success with structure-based modeling approaches to predict human PXR activators. Slightly better success has been achieved with ligand-based modeling methods including quantitative structure-activity relationship (QSAR) analysis, pharmacophore modeling and machine learning. In this study, we present a comprehensive analysis focused on prediction of 115 steroids for ligand binding activity towards human PXR. Six crystal structures were used as templates for docking and ligand-based modeling approaches (two-, three-, four- and five-dimensional analyses). The best success at external prediction was achieved with 5D-QSAR. Bayesian models with FCFP_6 descriptors were validated after leaving a large percentage of the dataset out and using an external test set. Docking of ligands to the PXR structure co-crystallized with hyperforin had the best statistics for this method. Sulfated steroids (which are activators) were consistently predicted as non-activators while, poorly predicted steroids were docked in a reverse mode compared to 5α-androstan-3β-ol. Modeling of human PXR represents a complex challenge by virtue of the large, flexible ligand-binding cavity. This study emphasizes this aspect, illustrating modest success using the largest quantitative data set to date and multiple modeling approaches. PMID:20011107

  3. The role of ligand density and size in mediating quantum dot nuclear transport.

    PubMed

    Tang, Peter S; Sathiamoorthy, Sarmitha; Lustig, Lindsay C; Ponzielli, Romina; Inamoto, Ichiro; Penn, Linda Z; Shin, Jumi A; Chan, Warren C W

    2014-10-29

    Studying the effects of the physicochemical properties of nanomaterials on cellular uptake, toxicity, and exocytosis can provide the foundation for designing safer and more effective nanoparticles for clinical applications. However, an understanding of the effects of these properties on subcellular transport, accumulation, and distribution remains limited. The present study investigates the effects of surface density and particle size of semiconductor quantum dots on cellular uptake as well as nuclear transport kinetics, retention, and accumulation. The current work illustrates that cellular uptake and nuclear accumulation of nanoparticles depend on surface density of the nuclear localization signal (NLS) peptides with nuclear transport reaching a plateau at 20% surface NLS density in as little as 30 min. These intracellular nanoparticles have no effects on cell viability up to 72 h post treatment. These findings will set a foundation for engineering more sophisticated nanoparticle systems for imaging and manipulating genetic targets in the nucleus.

  4. Spectroscopic studies of lanthanide complexes of varying nuclearity based on a compartmentalised ligand.

    PubMed

    Olea-Román, Daniela; Bélanger-Desmarais, Nicolas; Flores-Álamo, Marcos; Bazán, Claudia; Thouin, Félix; Reber, Christian; Castillo-Blum, Silvia E

    2015-10-21

    The synthesis, characterization and solid-state luminescence spectroscopy of mononuclear (f), heterodinuclear (d-f) and heterotrinuclear (d-f-d) coordination compounds with the compartmental ligand N,N'-bis(3-hydroxyl salicylidene)benzene-1,2-diamine (H2L) are reported. The trivalent lanthanide ions Nd(III), Sm(III), Eu(III), Gd(III), Tb(III) and Dy(III) as single metal centres or in combination with either Zn(II) or Ni(II) were coordinated. Compounds are characterised by elemental analyses, IR, 1D and 2D solution (1)H and (13)C NMR spectroscopy, measurements of magnetic moments and solid state UV-Vis-NIR reflectance, luminescence and Raman spectroscopy techniques. Crystal structures of the dinuclear compounds [SmZn(O2NO)3(L)(OH2)]·EtOH and [DyZn(O2NO)2(Cl)(L)(EtOH)]·3EtOH and the trinuclear compound [TbZn2(L)2(Cl)2(OH2)](NO3)·EtOH are presented, where samarium(iii) displays a coordination number of ten, with a bicapped cubic geometry, while for the dysprosium compound a nine-coordinated environment with a tricapped trigonal prismatic geometry is shown. Their crystals belong to the triclinic system and the P1[combining macron] space group. The coordination number for terbium(iii) in the trinuclear complex is nine, with a tricapped trigonal prismatic geometry, and its crystal belongs to the monoclinic system, space group C2/c. For these three compounds, the zinc ion stabilises a penta-coordinated environment with square pyramid geometry. All mononuclear and dinuclear compounds are neutral, whereas the trinuclear complexes are ionic. The results of DFT theoretical calculations for the ligand (H2L) are used to assign the ligand singlet and triplet excited state energy levels. Luminescence studies of the neodymium compounds indicate that the ligand is a sensitizer for NIR emitters.

  5. Classical and Novel TSPO Ligands for the Mitochondrial TSPO Can Modulate Nuclear Gene Expression: Implications for Mitochondrial Retrograde Signaling.

    PubMed

    Yasin, Nasra; Veenman, Leo; Singh, Sukhdev; Azrad, Maya; Bode, Julia; Vainshtein, Alex; Caballero, Beatriz; Marek, Ilan; Gavish, Moshe

    2017-04-07

    It is known that knockdown of the mitochondrial 18 kDa translocator protein (TSPO) as well as TSPO ligands modulate various functions, including functions related to cancer. To study the ability of TSPO to regulate gene expression regarding such functions, we applied microarray analysis of gene expression to U118MG glioblastoma cells. Within 15 min, the classical TSPO ligand PK 11195 induced changes in expression of immediate early genes and transcription factors. These changes also included gene products that are part of the canonical pathway serving to modulate general gene expression. These changes are in accord with real-time, reverse transcriptase (RT) PCR. At the time points of 15, 30, 45, and 60 min, as well as 3 and 24 h of PK 11195 exposure, the functions associated with the changes in gene expression in these glioblastoma cells covered well known TSPO functions. These functions included cell viability, proliferation, differentiation, adhesion, migration, tumorigenesis, and angiogenesis. This was corroborated microscopically for cell migration, cell accumulation, adhesion, and neuronal differentiation. Changes in gene expression at 24 h of PK 11195 exposure were related to downregulation of tumorigenesis and upregulation of programmed cell death. In the vehicle treated as well as PK 11195 exposed cell cultures, our triple labeling showed intense TSPO labeling in the mitochondria but no TSPO signal in the cell nuclei. Thus, mitochondrial TSPO appears to be part of the mitochondria-to-nucleus signaling pathway for modulation of nuclear gene expression. The novel TSPO ligand 2-Cl-MGV-1 appeared to be very specific regarding modulation of gene expression of immediate early genes and transcription factors.

  6. Systematic Identification of Protein-Metabolite Interactions in Complex Metabolite Mixtures by Ligand-Detected Nuclear Magnetic Resonance Spectroscopy.

    PubMed

    Nikolaev, Yaroslav V; Kochanowski, Karl; Link, Hannes; Sauer, Uwe; Allain, Frederic H-T

    2016-05-10

    Protein-metabolite interactions play a vital role in the regulation of numerous cellular processes. Consequently, identifying such interactions is a key prerequisite for understanding cellular regulation. However, the noncovalent nature of the binding between proteins and metabolites has so far hampered the development of methods for systematically mapping protein-metabolite interactions. The few available, largely mass spectrometry-based, approaches are restricted to specific metabolite classes, such as lipids. In this study, we address this issue and show the potential of ligand-detected nuclear magnetic resonance (NMR) spectroscopy, which is routinely used in drug development, to systematically identify protein-metabolite interactions. As a proof of concept, we selected four well-characterized bacterial and mammalian proteins (AroG, Eno, PfkA, and bovine serum albumin) and identified metabolite binders in complex mixes of up to 33 metabolites. Ligand-detected NMR captured all of the reported protein-metabolite interactions, spanning a full range of physiologically relevant Kd values (low micromolar to low millimolar). We also detected a number of novel interactions, such as promiscuous binding of the negatively charged metabolites citrate, AMP, and ATP, as well as binding of aromatic amino acids to AroG protein. Using in vitro enzyme activity assays, we assessed the functional relevance of these novel interactions in the case of AroG and show that l-tryptophan, l-tyrosine, and l-histidine act as novel inhibitors of AroG activity. Thus, we conclude that ligand-detected NMR is suitable for the systematic identification of functionally relevant protein-metabolite interactions.

  7. Characterizing diamylamylphosphonate (DAAP) as an Americium Ligand for nuclear fuel cycle applications

    SciTech Connect

    Bruce J. Mincher; Nicholas C. Schmitt; Richard D. Tillotson; Gracy Elias; Byron M. White; Jack D. Law

    2014-01-01

    Successful deployment of the currently-envisioned advanced nuclear fuel cycle requires the development of a partitioning scheme to separate Am from the lanthanides. The Am/lanthanide separation is challenging since all the metals are normally trivalent and have similar ionic radii. Oxidation of Am to higher oxidation states is one option to achieve such a separation. Hexavalent Am has now been routinely prepared in our laboratory in strongly acidic solution using sodium bismuthate as the oxidant, and then extracted into diamylamylphosphonate/dodecane solution. Here, we have characterized this phosphonate-containing solvent with regard to the extraction of Am, the lanthanides, Cm, other fission product, and/or inert constituents expected in dissolved nuclear fuel. Additionally, the effects of irradiation on dispersion numbers and the phosphonate concentration were investigated.

  8. Development of radiohalogenated muscarinic ligands for the in vivo imaging of m-AChR by nuclear medicine techniques

    SciTech Connect

    McPherson, D.W.; Luo, H.; Knapp, F.F. Jr.

    1994-06-01

    Alterations in the density of acetylcholinergic muscarinic receptors (m-AChR) have been observed in various dementias. This has spurred interest in the development of radiohalogenated ligands which can be used for the non-invasive in vivo detection of m-AChR by nuclear medicine techniques. We have developed a new ligand 1-azabicyclo[2.2.2]oct-3-yl ({alpha}-hydroxy-{alpha}-(1-iodo-1-propen-3-yl)-{alpha}-phenylacetate (IQNP,12) which demonstrates high affinity for the muscarinic receptor. When labeled with radioiodine it has been shown to be selective and specific for m-ACHR. Initial studies on the separation and in vivo evaluation of the various isomers of IQNP have shown that the stereochemistry of the chiral centers and the configuration around the double bond play an important role in m-AChR subtype specificity. In vivo evaluation of these stereoisomers demonstrate that E-(R,R)-IQNP has a high affinity for the M{sub 1} muscarinic subtype while Z-(R,R)-IQNP demonstrate a high affinity for M{sub 1} and M{sub 2} receptor subtypes. These data demonstrate IQNP (12) has potential for use in the non-evasive in vivo detection of m-AChR by single photon emission computed tomography (SPECT). A brominated analogue, ``BrQNP,`` in which the iodine has been replaced by a bromine atom, has also been prepared and was shown to block the in vivo uptake of IQNP in the brain and heart and therefore has potential for positron emission tomographic (PET) studies of m-AChR.

  9. Crystal Structure of Fushi Tarazu Factor 1 Ligand Binding Domain/Fushi Tarazu Peptide Complex Identifies New Class of Nuclear Receptors*

    PubMed Central

    Yoo, Jiho; Ko, Sunggeon; Kim, Hyeyon; Sampson, Heidi; Yun, Ji-Hye; Choe, Kwang-Min; Chang, Iksoo; Arrowsmith, Cheryl H.; Krause, Henry M.; Cho, Hyun-Soo; Lee, Weontae

    2011-01-01

    The interaction between the orphan nuclear receptor FTZ-F1 (Fushi tarazu factor 1) and the segmentation gene protein FTZ is critical for specifying alternate parasegments in the Drosophila embryo. Here, we have determined the structure of the FTZ-F1 ligand-binding domain (LBD)·FTZ peptide complex using x-ray crystallography. Strikingly, the ligand-binding pocket of the FTZ-F1 LBD is completely occupied by helix 6 (H6) of the receptor, whereas the cofactor FTZ binds the co-activator cleft site of the FTZ-F1 LBD. Our findings suggest that H6 is essential for transcriptional activity of FTZ-F1; this is further supported by data from mutagenesis and activity assays. These data suggest that FTZ-F1 might belong to a novel class of ligand-independent nuclear receptors. Our findings are intriguing given that the highly homologous human steroidogenic factor-1 and liver receptor homolog-1 LBDs exhibit sizable ligand-binding pockets occupied by putative ligand molecules. PMID:21775434

  10. Crystal structure of Fushi tarazu factor 1 ligand binding domain/Fushi tarazu peptide complex identifies new class of nuclear receptors.

    PubMed

    Yoo, Jiho; Ko, Sunggeon; Kim, Hyeyon; Sampson, Heidi; Yun, Ji-Hye; Choe, Kwang-Min; Chang, Iksoo; Arrowsmith, Cheryl H; Krause, Henry M; Cho, Hyun-Soo; Lee, Weontae

    2011-09-09

    The interaction between the orphan nuclear receptor FTZ-F1 (Fushi tarazu factor 1) and the segmentation gene protein FTZ is critical for specifying alternate parasegments in the Drosophila embryo. Here, we have determined the structure of the FTZ-F1 ligand-binding domain (LBD)·FTZ peptide complex using x-ray crystallography. Strikingly, the ligand-binding pocket of the FTZ-F1 LBD is completely occupied by helix 6 (H6) of the receptor, whereas the cofactor FTZ binds the co-activator cleft site of the FTZ-F1 LBD. Our findings suggest that H6 is essential for transcriptional activity of FTZ-F1; this is further supported by data from mutagenesis and activity assays. These data suggest that FTZ-F1 might belong to a novel class of ligand-independent nuclear receptors. Our findings are intriguing given that the highly homologous human steroidogenic factor-1 and liver receptor homolog-1 LBDs exhibit sizable ligand-binding pockets occupied by putative ligand molecules.

  11. The crystal structure of the orphan nuclear receptor NR2E3/PNR ligand binding domain reveals a dimeric auto-repressed conformation.

    PubMed

    Tan, M H Eileen; Zhou, X Edward; Soon, Fen-Fen; Li, Xiaodan; Li, Jun; Yong, Eu-Leong; Melcher, Karsten; Xu, H Eric

    2013-01-01

    Photoreceptor-specific nuclear receptor (PNR, NR2E3) is a key transcriptional regulator of human photoreceptor differentiation and maintenance. Mutations in the NR2E3-encoding gene cause various retinal degenerations, including Enhanced S-cone syndrome, retinitis pigmentosa, and Goldman-Favre disease. Although physiological ligands have not been identified, it is believed that binding of small molecule agonists, receptor desumoylation, and receptor heterodimerization may switch NR2E3 from a transcriptional repressor to an activator. While these features make NR2E3 a potential therapeutic target for the treatment of retinal diseases, there has been a clear lack of structural information for the receptor. Here, we report the crystal structure of the apo NR2E3 ligand binding domain (LBD) at 2.8 Å resolution. Apo NR2E3 functions as transcriptional repressor in cells and the structure of its LBD is in a dimeric auto-repressed conformation. In this conformation, the putative ligand binding pocket is filled with bulky hydrophobic residues and the activation-function-2 (AF2) helix occupies the canonical cofactor binding site. Mutations designed to disrupt either the AF2/cofactor-binding site interface or the dimer interface compromised the transcriptional repressor activity of this receptor. Together, these results reveal several conserved structural features shared by related orphan nuclear receptors, suggest that most disease-causing mutations affect the receptor's structural integrity, and allowed us to model a putative active conformation that can accommodate small ligands in its pocket.

  12. Spectroscopic, thermal characterization and cytotoxic activity of bi-, tri- and tetra-nuclear Pd(II) and Pt(II) complexes with diSchiff base ligands

    NASA Astrophysics Data System (ADS)

    Hegazy, Wael Hussein

    2014-10-01

    In this paper; new di-, tri-, and tetra-nuclear Pd(II) and Pt(II) complexes of N,N‧-bis(3,4-dihydroxybenzylidene)ethan-1,2-diamine (EDH4), N,N‧-bis(3,4-dihydroxy-benzylidene)-benzene-1,2-diamine (PDH4) and N,N‧-bis-(3,4-dihydroxybenzylidene)-4,5-dimethyl-1,2-diamine (MPDH4) ligands were synthesized by two different methods. The first method involve the synthesis of the three ligands from condensation reaction of 3,4-dihydroxybenzaldehyde (L‧H2) with ethylenediamine (en), o-phenylenediamine (o-PD), or 4,5-dimethyl-1,2-phenylendiamine (DMPD) in a mole ratio of 2:1 followed by the reaction of the resulting Schiff bases ligands with Pd(II) or Pt(II) ions in the presence of 2,2‧-dipyridyl (L) to form the di- and tri-nuclear metal complexes. The second method involve the condensation of the Pd complex LPd(II)L‧, (L = 2,2‧-dipyridyl, L‧ = 4-formylbenzene-1,2-bis(olate)) with en, o-PD, or DMPD in a mole ratio of 2:1, respectively, followed by reaction with PdCl2 to form di-, tri-, and tetra-nuclear palladium(II) complexes, respectively. Structures of ligands and metal complexes are characterized by physical properties, FT-IR spectra and nuclear magnetic resonance. The geometries of metal complexes are suggested according to elemental analysis, electronic absorption spectra, thermal analysis, atomic absorption, magnetic susceptibility and molar conductance. Cytotoxic activity against lung large cell carcinoma (H460), prostate carcinoma (DU145), breast adenocarcinoma (MCF-7), amelanotic melanoma (M-14), colon adenocarcinoma (HT-29), and chronic myelogenous leukemia (K562) is also reported.

  13. Glucocorticoid receptor-interacting protein 1 mediates ligand-independent nuclear translocation and activation of constitutive androstane receptor in vivo.

    PubMed

    Min, Gyesik; Kemper, J Kim; Kemper, Byron

    2002-07-19

    Phenobarbital (PB) induction of CYP2B genes is mediated by translocation of the constitutively active androstane receptor (CAR) to the nucleus. Interaction of CAR with p160 coactivators and enhancement of CAR transactivation by the coactivators have been shown in cultured cells. In the present studies, the interaction of CAR with the p160 coactivator glucocorticoid receptor-interacting protein 1 (GRIP1) was examined in vitro and in vivo. Binding of GRIP1 to CAR was shown by glutathione S-transferase (GST) pull-down and affinity DNA binding. N- or C-terminal fragments of GRIP1 that contained the central receptor-interacting domain bound to GST-CAR, but the presence of ligand increased the binding to GST-CAR of only the fragments containing the C-terminal region. In gel shift analysis, binding to CAR was observed only with GRIP1 fragments containing the C-terminal region, and the binding was increased by a CAR agonist and decreased by a CAR antagonist. Expression of GRIP1 enhanced CAR-mediated transactivation in cultured hepatic-derived cells 2-3-fold. In hepatocytes transfected in vivo, expression of exogenous GRIP1 alone induced transactivation of the CYP2B1 PB-dependent enhancer 15-fold, whereas CAR expression alone resulted in only a 3-fold enhancement in untreated mice. Remarkably, CAR and GRIP1 together synergistically transactivated the enhancer about 150-fold, which is approximately equal to activation by PB treatment. In PB-treated mice, expression of exogenous CAR alone had little effect, expression of GRIP1 increased transactivation about 2-fold, and with CAR and GRIP, a 4-fold activation was observed. In untreated mice, expression of GRIP resulted in nuclear translocation of green fluorescent protein-CAR. These results strongly suggest that a p160 coactivator functions in CAR-mediated transactivation in vivo in response to PB treatment and that the synergistic activation of CAR by GRIP in untreated animals results from both nuclear translocation and

  14. Expression of receptor activator of nuclear factor-κB ligand by B cells in response to oral bacteria

    PubMed Central

    Han, X.; Lin, X.; Seliger, A. R.; Eastcott, J.; Kawai, T.; Taubman, M. A.

    2009-01-01

    Introduction We investigated receptor activator of nuclear factor-κB ligand (RANKL) expression by B lymphocytes during early and late aspects of the immune response to Aggregatibacter actinomycetemcomitans, a gram-negative, anaerobic bacterium associated with aggressive periodontal disease. Methods Expression of messenger RNA transcripts (tumor necrosis factor-α, Toll-like receptors 4 and 9, interleukins 4 and 10, and RANKL) involved in early (1-day) and late (10-day) responses in cultured rat splenocytes was examined by reverse transcription–polymerase chain reaction (RT-PCR). The immune cell distribution (T, B, and natural killer cells and macrophages) in cultured rat splenocytes and RANKL expression in B cells were determined by flow cytometric analyses. B-cell capacity for induction of osteoclast differentiation was evaluated by coculture with RAW 264.7 cells followed by a tartrate-resistant acid phosphatase (TRAP) activity assay. Results The expression levels of interleukins 4 and 10 in cultured cells were not changed in the presence of A. actinomycetemcomitans until cultured for 3 days, and peaked after 7 days. After culture for 10 days, the percentages of B and T cells, the overall RANKL messenger RNA transcripts, and the percentage of RANKL-expressing immunoglobulin G-positive cells were significantly increased in the presence of A. actinomycetemcomitans. These increases were considerably greater in cells isolated from A. actinomycetemcomitans-immunized animals than from non-immunized animals. RAW 264.7 cells demonstrated significantly increased TRAP activity when cocultured with B cells from A. actinomycetemcomitans-immunized animals. The addition of human osteoprotegerin-Fc to the culture significantly diminished such increases. Conclusion This study suggests that B-lymphocyte involvement in the immune response to A. actinomycetemcomitans through upregulation of RANKL expression potentially contribute to bone resorption in periodontal disease. PMID

  15. Structural features and ligand binding properties of tandem WW domains from YAP and TAZ, nuclear effectors of the Hippo pathway.

    PubMed

    Webb, Claire; Upadhyay, Abhishek; Giuntini, Francesca; Eggleston, Ian; Furutani-Seiki, Makoto; Ishima, Rieko; Bagby, Stefan

    2011-04-26

    The paralogous multifunctional adaptor proteins YAP and TAZ are the nuclear effectors of the Hippo pathway, a central mechanism of organ size control and stem cell self-renewal. WW domains, mediators of protein-protein interactions, are essential for YAP and TAZ function, enabling interactions with PPxY motifs of numerous partner proteins. YAP has single and double WW domain isoforms (YAP1 and YAP2) whereas only a single WW domain isoform of TAZ has been described to date. Here we identify the first example of a double WW domain isoform of TAZ. Using NMR, we have characterized conformational features and peptide binding of YAP and TAZ tandem WW domains (WW1-WW2). The solution structure of YAP WW2 confirms that it has a canonical three-stranded antiparallel β-sheet WW domain fold. While chemical shift-based analysis indicates that the WW domains in the tandem WW pairs retain the characteristic WW domain fold, 15N relaxation data show that, within the respective WW pairs, YAP WW1 and both WW1 and WW2 of TAZ undergo conformational exchange. 15N relaxation data also indicate that the linker between the WW domains is flexible in both YAP and TAZ. Within both YAP and TAZ tandem WW pairs, WW1 and WW2 bind single PPxY-containing peptide ligand concurrently and noncooperatively with sub-mM affinity. YAP and TAZ WW1-WW2 bind a dual PPxY-containing peptide with approximately 6-fold higher affinity. Our results indicate that both WW domains in YAP and TAZ are functional and capable of enhanced affinity binding to multi-PPxY partner proteins such as LATS1, ErbB4, and AMOT.

  16. Osteonecrosis of the jaw induced by receptor activator of nuclear factor-kappa B ligand (Denosumab) - Review

    PubMed Central

    Brizeno, Luiz-André-Cavalcante; de Sousa, Fabrício-Bitu; Mota, Mário-Rogério-Lima; Alves, Ana-Paula-Negreiros-Nunes

    2016-01-01

    Background Denosumab, an anti-resorptive agent, IgG2 monoclonal antibody for human Receptor activator of nuclear factor-kappa B ligand (RANKL), has been related to the occurrence of osteonecrosis of the jaws. Thus, the aim of this study was to review the literature from clinical case reports, regarding the type of patient and the therapeutic approach used for osteonecrosis of the jaws induced by chronic use of Denosumab. Material and Methods For this, a literature review was performed on PubMed, Medline and Cochrane databases, using the keywords “Denosumab” “anti-RANK ligand” and “Osteonecrosis of jaw”. To be included, articles should be a report or a serie of clinical cases, describing patients aged 18 years or over who used denosumab therapy and have received any therapy for ONJ. Results Thirteen complete articles were selected for this review, totaling 17 clinical cases. The majority of ONJ cases, patients receiving Denosumab as treatment for osteoporosis and prostate cancer therapy. In most cases, patients affected by ONJ were women aged 60 or over and posterior mandible area was the main site of involvement. Diabetes pre-treatment with bisphosphonates and exodontia were the most often risk factors related to the occurrence of this condition. It is concluded that the highest number of ONJ cases caused by the use of anti-RANKL agents occurred in female patients, aged 60 years or older, under treatment for osteoporosis and cancer metastasis, and the most affected region was the mandible posterior. Conclusions The results presented in this article are valid tool supporting the non-invasive mapping of facial vascularization. Key words:Denosumab, osteonecrosis, adverse effects, osteoporosis, antineoplastic protocols. PMID:26827069

  17. Receptor-Activator of Nuclear KappaB Ligand Expression as a New Therapeutic Target in Primary Bone Tumors

    PubMed Central

    Yamagishi, Tetsuro; Kawashima, Hiroyuki; Ogose, Akira; Ariizumi, Takashi; Sasaki, Taro; Hatano, Hiroshi; Hotta, Tetsuo; Endo, Naoto

    2016-01-01

    The receptor-activator of nuclear kappaB ligand (RANKL) signaling pathway plays an important role in the regulation of bone growth and mediates the formation and activation of osteoclasts. Osteoclasts are involved in significant bone resorption and destruction. Denosumab is a fully human monoclonal antibody against RANKL that specifically inhibits osteoclast differentiation and bone resorption. It has been approved for use for multiple myeloma and bone metastases, as well as for giant cell tumor of bone. However, there is no previous report quantitatively, comparing RANKL expression in histologically varied bone tumors. Therefore, we analyzed the mRNA level of various bone tumors and investigated the possibility of these tumors as a new therapeutic target for denosumab. We examined RANKL mRNA expression in 135 clinical specimens of primary and metastatic bone tumors using real-time PCR. The relative quantification of mRNA expression levels was performed via normalization with RPMI8226, a human multiple myeloma cell line that is recognized to express RANKL. Of 135 cases, 64 were also evaluated for RANKL expression by using immunohistochemistry. Among all of the tumors investigated, RANKL expression and the RANKL/osteoprotegerin ratio were highest in giant cell tumor of bone. High RANKL mRNA expression was observed in cases of aneurysmal bone cyst, fibrous dysplasia, osteosarcoma, chondrosarcoma, and enchondroma, as compared to cases of multiple myeloma and bone lesions from metastatic carcinoma. RANKL-positive stromal cells were detected in six cases: five cases of GCTB and one case of fibrous dysplasia. The current study findings indicate that some primary bone tumors present new therapeutic targets for denosumab, particularly those tumors expressing RANKL and those involving bone resorption by osteoclasts. PMID:27163152

  18. The role of serum osteoprotegerin and receptor-activator of nuclear factor-κB ligand in metabolic bone disease of women after obesity surgery.

    PubMed

    Balsa, José A; Lafuente, Christian; Gómez-Martín, Jesús M; Galindo, Julio; Peromingo, Roberto; García-Moreno, Francisca; Rodriguez-Velasco, Gloria; Martínez-Botas, Javier; Gómez-Coronado, Diego; Escobar-Morreale, Héctor F; Botella-Carretero, José I

    2016-11-01

    Metabolic bone disease may appear as a complication of obesity surgery. Because an imbalance in the osteoprotegerin and receptor-activator of nuclear factor-κB ligand system may underlie osteoporosis, we aimed to study this system in humans in the metabolic bone disease occurring after obesity surgery. In this study we included sixty women with a mean age of 47 ± 10 years studied 7 ± 2 years after bariatric surgery. The variables studied were bone mineral density, β-isomer of C-terminal telopeptide of type I collagen cross-links (a bone resorption marker), the bone formation markers osteocalcin and N-terminal propeptide of procollagen 1, serum osteoprotegerin and receptor-activator of nuclear factor-κB ligand. Serum osteoprotegerin inversely correlated with the bone remodeling markers osteocalcin, β-isomer of C-terminal telopeptide of type I collagen cross-links and N-terminal propeptide of procollagen 1. The osteoprotegerin and receptor-activator of nuclear factor-κB ligand ratio also correlated inversely with serum parathormone and osteocalcin. Bone mineral density at the lumbar spine was associated with age (β = -0.235, P = 0.046), percentage of weight loss (β = 0.421, P = 0.001) and osteoprotegerin and receptor-activator of nuclear factor-κB ligand ratio (β = 0.259, P = 0.029) in stepwise multivariate analysis (R (2) = 0.29, F = 7.49, P < 0.001). Bone mineral density at the hip site was associated only with percentage of weight loss (β = 0.464, P < 0.001) in stepwise multivariate regression (R (2) = 0.21, F = 15.1, P < 0.001). These data show that the osteoprotegerin and receptor-activator of nuclear factor-κB ligand system is associated with bone markers and bone mineral density at the lumbar spine after obesity surgery.

  19. Nuclear receptors Homo sapiens Rev-erbβ and Drosophila melanogaster E75 are thiolate-ligated heme proteins, which undergo redox-mediated ligand switching and bind CO and NO

    PubMed Central

    Marvin, Katherine A.; Reinking, Jeffrey L.; Lee, Andrea J.; Pardee, Keith M.; Krause, Henry M.; Burstyn, Judith N.

    2009-01-01

    Nuclear receptors E75, which regulates development in D. melanogaster, and Rev-erbβ, which regulates circadian rhythm in humans, bind heme within their ligand binding domains (LBD). The heme-bound ligand binding domains of E75 and Rev-erbβ were studied using electronic absorption, MCD, resonance Raman and EPR spectroscopies. Both proteins undergo redox-dependent ligand switching and CO- and NO-induced ligand displacement. In the Fe(III) oxidation state, the nuclear receptor hemes are low-spin and 6-coordinate with cysteine(thiolate) as one of the two axial heme ligands. The sixth ligand is a neutral donor, presumably histidine. When the heme is reduced to the Fe(II) oxidation state, the cysteine(thiolate) is replaced by a different neutral donor ligand, whose identity is not known. CO binds to the Fe(II) heme in both E75(LBD) and Rev-erbβ(LBD) opposite a sixth neutral ligand, plausibly the same histidine that served as the sixth ligand in the Fe(III) state. NO binds to the heme of both proteins; however, the NO-heme is 5-coordinate in E75 and 6-coordinate in Rev-erbβ. These nuclear receptors exhibit coordination characteristics that are similar to other known redox and gas sensors, suggesting that E75 and Rev-erbβ may function in heme-, redox- or gas-regulated control of cellular function. PMID:19405475

  20. Nuclear receptors homo sapiens Rev-erbbeta and Drosophila melanogaster E75 are thiolate-ligated heme proteins which undergo redox-mediated ligand switching and bind CO and NO.

    PubMed

    Marvin, Katherine A; Reinking, Jeffrey L; Lee, Andrea J; Pardee, Keith; Krause, Henry M; Burstyn, Judith N

    2009-07-28

    Nuclear receptors E75, which regulates development in Drosophila melanogaster, and Rev-erbbeta, which regulates circadian rhythm in humans, bind heme within their ligand binding domains (LBD). The heme-bound ligand binding domains of E75 and Rev-erbbeta were studied using electronic absorption, MCD, resonance Raman, and EPR spectroscopies. Both proteins undergo redox-dependent ligand switching and CO- and NO-induced ligand displacement. In the Fe(III) oxidation state, the nuclear receptor hemes are low spin and 6-coordinate with cysteine(thiolate) as one of the two axial heme ligands. The sixth ligand is a neutral donor, presumably histidine. When the heme is reduced to the Fe(II) oxidation state, the cysteine(thiolate) is replaced by a different neutral donor ligand, whose identity is not known. CO binds to the Fe(II) heme in both E75(LBD) and Rev-erbbeta(LBD) opposite a sixth neutral ligand, plausibly the same histidine that served as the sixth ligand in the Fe(III) state. NO binds to the heme of both proteins; however, the NO-heme is 5-coordinate in E75 and 6-coordinate in Rev-erbbeta. These nuclear receptors exhibit coordination characteristics that are similar to other known redox and gas sensors, suggesting that E75 and Rev-erbbeta may function in heme-, redox-, or gas-regulated control of cellular function.

  1. Effect of lifestyle interventions with or without metformin therapy on serum levels of osteoprotegerin and receptor activator of nuclear factor kappa B ligand in patients with prediabetes.

    PubMed

    Arslan, Muyesser Sayki; Tutal, Esra; Sahin, Mustafa; Karakose, Melia; Ucan, Bekir; Ozturk, Gulfer; Cakal, Erman; Biyikli Gencturk, Zeynep; Ozbek, Mustafa; Delibasi, Tuncay

    2017-02-01

    Osteoprotegerin has been shown to be increased in cardiovascular disorders and type 2 diabetes mellitus. Prediabetes represents a high risk condition for diabetes and diabetic complications. Therefore, we aimed to find the relationship between prediabetes and osteoprotegerin with nuclear factor-B ligand, carotid intima media thickness, and metabolic markers. A total of 54 participants with prediabetes including impaired fasting glucose (n = 21), impaired glucose tolerance (n = 8), impaired fasting glucose and impaired glucose tolerance (n = 25), and 60 healthy individuals as a control were admitted to the study. Metabolic and anthropometric parameters, insulin resistance variables, osteoprotegerin, and nuclear factor-B ligand markers, carotid intima media thickness were examined at baseline for all participants. To evaluate the effect of therapy we determined the same parameters after the end of the study. Measurements of waist circumference, body mass index, body fat percentage and levels of fasting blood glucose, fasting insulin, homeostatic model assessment of insulin resistance, triglyceride levels and hsCRP and carotid intima media thickness were significantly higher in patients with prediabetes (p < 0.05). We also found higher osteoprotegerin and lower nuclear factor-B ligand levels in patients than in controls however, the value was non-significant (p > 0.05). Patients with prediabetes were under lifestyle interventions with (group 1, n = 33) or without metformin (group 2, n = 21) therapy. Baseline anthropometric and metabolic characteristics were not found statistically different in group 1 and group 2. Mean follow up period of the patients were 7.9 ± 2.2 month (min-max: 6-12 months). After the follow up period we evaluated the same parameters and found significant differences between waist circumference, body mass index, body fat percentage, fasting insulin, homeostatic model assessment of insulin resistance, and

  2. Role of the essential yeast protein PSU1 in p6anscriptional enhancement by the ligand-dependent activation function AF-2 of nuclear receptors.

    PubMed Central

    Gaudon, C; Chambon, P; Losson, R

    1999-01-01

    Nuclear receptors (NRs) can function as ligandinducible transregulators in both mammalian and yeast cells, indicating that important features of transcriptional control have been conserved throughout evolution. We report here the isolation and characterization of an essential yeast protein of unknown function, PSU1, which exhibits properties expected for a co-activator/mediator of the ligand-dependent activation function AF-2 present in the ligand-binding domain (LBD, region E) of NRs. PSU1 interacts in a ligand-dependent manner with the LBD of several NRs, including retinoic acid (RARalpha), retinoid X (RXRalpha), thyroid hormone (TRalpha), vitamin D3 (VDR) and oestrogen (ERalpha) receptors. Importantly, both in yeast and in vitro, these interactions require the integrity of the AF-2 activating domain. When tethered to a heterologous DNA-binding domain, PSU1 can activate transcription on its own. By using yeast reporter cells that express PSU1 conditionally, we show that PSU1 is required for transactivation by the AF-2 of ERalpha. Taken together these data suggest that in yeast, PSU1 is involved in ligand-dependent transactivation by NRs. Sequence analysis revealed that in addition to a highly conserved motif found in a family of MutT-related proteins, PSU1 contains several alpha-helical leucine-rich motifs sharing the consensus sequence LLxPhiL (x, any amino acid; Phi, hydrophobic amino acid) in regions that elicit either transactivation or NR-binding activity. PMID:10205176

  3. Synthesis of new C-25 and C-26 steroidal acids as potential ligands of the nuclear receptors DAF-12, LXR and GR.

    PubMed

    Dansey, María V; Del Fueyo, María C; Veleiro, Adriana S; Di Chenna, Pablo H

    2017-05-01

    A new methodology to obtain C-25 and C-26 steroidal acids starting from pregnenolone is described. Construction of the side chain was achieved by applying the Mukaiyama aldol reaction with a non-hydrolytic work-up to isolate the trapped silyl enol ether with higher yields. Using this methodology we synthesized three new steroidal acids as potential ligands of DAF-12, Liver X and Glucocorticoid nuclear receptors and studied their activity in reporter gene assays. Our results show that replacement of the 21-CH3 by a 20-keto group in the side chains of the cholestane scaffold of DAF-12 or Liver X receptors ligands causes the loss of the activity.

  4. The Crystal Structure of the Orphan Nuclear Receptor NR2E3/PNR Ligand Binding Domain Reveals a Dimeric Auto-Repressed Conformation

    PubMed Central

    Tan, M. H. Eileen; Zhou, X. Edward; Soon, Fen-Fen; Li, Xiaodan; Li, Jun; Yong, Eu-Leong; Melcher, Karsten; Xu, H. Eric

    2013-01-01

    Photoreceptor-specific nuclear receptor (PNR, NR2E3) is a key transcriptional regulator of human photoreceptor differentiation and maintenance. Mutations in the NR2E3-encoding gene cause various retinal degenerations, including Enhanced S-cone syndrome, retinitis pigmentosa, and Goldman-Favre disease. Although physiological ligands have not been identified, it is believed that binding of small molecule agonists, receptor desumoylation, and receptor heterodimerization may switch NR2E3 from a transcriptional repressor to an activator. While these features make NR2E3 a potential therapeutic target for the treatment of retinal diseases, there has been a clear lack of structural information for the receptor. Here, we report the crystal structure of the apo NR2E3 ligand binding domain (LBD) at 2.8 Å resolution. Apo NR2E3 functions as transcriptional repressor in cells and the structure of its LBD is in a dimeric auto-repressed conformation. In this conformation, the putative ligand binding pocket is filled with bulky hydrophobic residues and the activation-function-2 (AF2) helix occupies the canonical cofactor binding site. Mutations designed to disrupt either the AF2/cofactor-binding site interface or the dimer interface compromised the transcriptional repressor activity of this receptor. Together, these results reveal several conserved structural features shared by related orphan nuclear receptors, suggest that most disease-causing mutations affect the receptor’s structural integrity, and allowed us to model a putative active conformation that can accommodate small ligands in its pocket. PMID:24069298

  5. Understanding the complexation of Eu3 + with potential ligands used for preferential separation of lanthanides and actinides in various stages of nuclear fuel cycle: A luminescence investigation

    NASA Astrophysics Data System (ADS)

    Sengupta, Arijit; Kadam, R. M.

    2017-02-01

    A systematic photoluminescence based investigation was carried out to understand the complexation of Eu3 + with different ligands (TBP: tri-n-butyl phosphate, DHOA: di-n-hexyl octanamide, Cyanex 923: tri-n-alkyl phosphine oxide and Cyanex 272: Bis (2,4,4 trimethyl) pentyl phosphinic acid) used for preferential separation of lanthanides and actinides in various stages of nuclear fuel cycle. In case of TBP and DHOA complexes, 3 ligand molecules coordinated in monodentate fashion and 3 nitrate ion in bidentate fashion to Eu3 + to satisfy the 9 coordination of Eu. In case of Cyanex 923 and Cyanex 272 complexes, 3 ligand molecules, 3 nitrate ion and 3 water molecules coordinated to Eu3 + in monodentate fashion. The Eu complexes of TBP and DHOA were found to have D3h local symmetry while that for Cyanex 923 and Cyanex 272 were C3h. Judd-Ofelt analysis of these systems revealed that the covalency of Eusbnd O bond followed the trend DHOA > TBP > Cyanex 272 > Cyanex 923. Different photophysical properties like radiative and non-radiative life time, branching ratio for different transitions, magnetic and electric dipole moment transition probabilities and quantum efficiency were also evaluated and compared for these systems. The magnetic dipole transition probability was found to be almost independent of ligand field perturbation while electric dipole transition probability for 5D0-7F2 transition was found to be hypersensitive with ligand field with a trend DHOA > TBP > Cyanex 272 > Cyanex 923. Supplementary Table 2: Determination of inner sphere water molecules from the different empirical formulae reported in the literature.

  6. Ligand modeling and design

    SciTech Connect

    Hay, B.

    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.

  7. The N-terminal part of TIF1, a putative mediator of the ligand-dependent activation function (AF-2) of nuclear receptors, is fused to B-raf in the oncogenic protein T18.

    PubMed Central

    Le Douarin, B; Zechel, C; Garnier, J M; Lutz, Y; Tora, L; Pierrat, P; Heery, D; Gronemeyer, H; Chambon, P; Losson, R

    1995-01-01

    Nuclear receptors (NRs) bound to response elements mediate the effects of cognate ligands on gene expression. Their ligand-dependent activation function, AF-2, presumably acts on the basal transcription machinery through intermediary proteins/mediators. We have isolated a mouse nuclear protein, TIF1, which enhances RXR and RAR AF-2 in yeast and interacts in a ligand-dependent manner with several NRs in yeast and mammalian cells, as well as in vitro. Remarkably, these interactions require the amino acids constituting the AF-2 activating domain conserved in all active NRs. Moreover, the oestrogen receptor (ER) AF-2 antagonist hydroxytamoxifen cannot promote ER-TIF1 interaction. We propose that TIF1, which contains several conserved domains found in transcriptional regulatory proteins, is a mediator of ligand-dependent AF-2. Interestingly, the TIF1 N-terminal moiety is fused to B-raf in the mouse oncoprotein T18. Images PMID:7744009

  8. Synthesis, spectral and magnetic studies of mono- and bi-nuclear metal complexes of a new bis(tridentate NO2) Schiff base ligand derived from 4,6-diacetylresorcinol and ethanolamine.

    PubMed

    Shebl, Magdy

    2009-07-15

    A new bis(tridentate NO2) Schiff base ligand, H(4)L, was prepared by the reaction of the bifunctional carbonyl compound; 4,6-diacetylresorcinol (DAR) with ethanolamine. The ligand reacted with iron(III), cobalt(II), nickel(II), copper(II), zinc(II), cadmium(II), cerium(III) and uranyl(VI) ions, in absence and in presence of LiOH, to yield mono- and bi-nuclear complexes with different coordinating sites. The ligand and its metal complexes were characterized by elemental analyses, IR, (1)H NMR, electronic, ESR and mass spectra, conductivity and magnetic susceptibility measurements as well as thermal analyses. In absence of LiOH, mononuclear complexes (2, 3 and 5-9) as well as binuclear complexes (1 and 4) were obtained. In mononuclear complexes, the ligand acted as a neutral, mono- and di-basic/bi- and tetra-dentate ligand while in binuclear complexes (1 and 4), the ligand acted as a bis(mono- or di-basic/tridentate) ligand. On the other hand, in presence of LiOH, only binuclear complexes (10-15) were obtained in which the ligand acted as a bis(dibasic tridentate) ligand. The metal complexes exhibited different geometrical arrangements such as octahedral, tetrahedral, square planar, square pyramidal and pentagonal bipyramidal arrangements.

  9. FUS interacts with nuclear matrix-associated protein SAFB1 as well as Matrin3 to regulate splicing and ligand-mediated transcription

    PubMed Central

    Yamaguchi, Atsushi; Takanashi, Keisuke

    2016-01-01

    FUS (Fused-in-Sarcoma) is a multifunctional DNA/RNA binding protein linked to familial amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). Since FUS is localized mainly in the nucleus with nucleo-cytoplasmic shuttling, it is critical to understand physiological functions in the nucleus to clarify pathogenesis. Here we report a yeast two-hybrid screening identified FUS interaction with nuclear matrix-associated protein SAFB1 (scaffold attachment factor B1). FUS and SAFB1, abundant in chromatin-bound fraction, interact in a DNA-dependent manner. N-terminal SAP domain of SAFB1, a DNA-binding motif, was required for its localization to chromatin-bound fraction and splicing regulation. In addition, depletion of SAFB1 reduced FUS’s localization to chromatin-bound fraction and splicing activity, suggesting SAFB1 could tether FUS to chromatin compartment thorough N-terminal DNA-binding motif. FUS and SAFB1 also interact with Androgen Receptor (AR) regulating ligand-dependent transcription. Moreover, FUS interacts with another nuclear matrix-associated protein Matrin3, which is muted in a subset of familial ALS cases and reportedly interacts with TDP-43. Interestingly, ectopic ALS-linked FUS mutant sequestered endogenous Matrin3 and SAFB1 in the cytoplasmic aggregates. These findings indicate SAFB1 could be a FUS’s functional platform in chromatin compartment to regulate RNA splicing and ligand-dependent transcription and shed light on the etiological significance of nuclear matrix-associated proteins in ALS pathogenesis. PMID:27731383

  10. Critical role of charged residues in helix 7 of the ligand binding domain in Hepatocyte Nuclear Factor 4α dimerisation and transcriptional activity

    PubMed Central

    Eeckhoute, Jérôme; Oxombre, Bénédicte; Formstecher, Pierre; Lefebvre, Philippe; Laine, Bernard

    2003-01-01

    Hepatocyte Nuclear Factor 4α (HNF4α, NR2A1) is central to hepatocyte and pancreatic β-cell functions. Along with retinoid X receptor α (RXRα), HNF4α belongs to the nuclear receptor subfamily 2 (NR2), characterised by a conserved arginyl residue and a glutamate residue insert in helix 7 (H7) of the ligand binding domain (LBD). Crystallographic studies indicate that R348 and E352 residues in RXRα H7 are involved in charge-driven interactions that improve dimerisation. Consistent with these findings, we showed that removing the charge of the corresponding residues in HNF4α H7, R258 and E262, impaired dimerisation in solution. Moreover, our results provide a new concept according to which helices of the HNF4α LBD dimerisation interface contribute differently to dimerisation required for DNA binding; unlike H9 and H10, H7 is not involved in DNA binding. Substitutions of E262 decreased the repression of HNF4α transcriptional activity by a dominant-negative HNF4α mutant, highlighting the importance of this residue for dimerisation in the cell context. The E262 insert is crucial for HNF4α function since its deletion abolished HNF4α transcriptional activity and coactivator recruitment. The glutamate residue insert and the conserved arginyl residue in H7 most probably represent a signature of the NR2 subfamily of nuclear receptors. PMID:14602925

  11. Critical role of charged residues in helix 7 of the ligand binding domain in Hepatocyte Nuclear Factor 4alpha dimerisation and transcriptional activity.

    PubMed

    Eeckhoute, Jérôme; Oxombre, Bénédicte; Formstecher, Pierre; Lefebvre, Philippe; Laine, Bernard

    2003-11-15

    Hepatocyte Nuclear Factor 4alpha (HNF4alpha, NR2A1) is central to hepatocyte and pancreatic beta-cell functions. Along with retinoid X receptor alpha (RXRalpha), HNF4alpha belongs to the nuclear receptor subfamily 2 (NR2), characterised by a conserved arginyl residue and a glutamate residue insert in helix 7 (H7) of the ligand binding domain (LBD). Crystallographic studies indicate that R348 and E352 residues in RXRalpha H7 are involved in charge-driven interactions that improve dimerisation. Consistent with these findings, we showed that removing the charge of the corresponding residues in HNF4alpha H7, R258 and E262, impaired dimerisation in solution. Moreover, our results provide a new concept according to which helices of the HNF4alpha LBD dimerisation interface contribute differently to dimerisation required for DNA binding; unlike H9 and H10, H7 is not involved in DNA binding. Substitutions of E262 decreased the repression of HNF4alpha transcriptional activity by a dominant-negative HNF4alpha mutant, highlighting the importance of this residue for dimerisation in the cell context. The E262 insert is crucial for HNF4alpha function since its deletion abolished HNF4alpha transcriptional activity and coactivator recruitment. The glutamate residue insert and the conserved arginyl residue in H7 most probably represent a signature of the NR2 subfamily of nuclear receptors.

  12. The ligand-bound thyroid hormone receptor in macrophages ameliorates kidney injury via inhibition of nuclear factor-κB activities

    PubMed Central

    Furuya, Fumihiko; Ishii, Toshihisa; Tamura, Shogo; Takahashi, Kazuya; Kobayashi, Hidetoshi; Ichijo, Masashi; Takizawa, Soichi; Kaneshige, Masahiro; Suzuki-Inoue, Katsue; Kitamura, Kenichiro

    2017-01-01

    In chronic kidney disease (CKD) patients, inflammation plays a pivotal role in the progression of renal fibrosis. Hypothyroidism is associated with an increased occurrence of atherosclerosis and inflammation, suggesting protective roles of thyroid hormones and their receptors against inflammatory processes. The contribution of thyroid hormone receptors to macrophage differentiation has not been well documented. Here, we focused on the endogenous thyroid hormone receptor α (TRα) in macrophages and examined the role of ligand-bound TRα in macrophage polarization-mediated anti-inflammatory effects. TRα-deficient irradiated chimeric mice showed exacerbated tubulointerstitial injury in a unilateral ureteral obstruction model. Compared with wild-type macrophages, macrophages isolated from the obstructed kidneys of mice lacking TRα displayed increased expression of proinflammatory cytokines that was accompanied by enhanced nuclear translocation of p65. Comparison of TRα-deficient bone marrow-derived macrophages with wild-type macrophages confirmed the propensity of the former cells to produce excessive IL-1β levels. Co-culture of these macrophages with renal epithelial cells induced more severe damage to the epithelial cells via the IL-1 receptor. Our findings indicate that ligand-bound TRα on macrophages plays a protective role in kidney inflammation through the inhibition of NF-κB pathways, possibly by affecting the pro- and anti-inflammatory balance that controls the development of CKD. PMID:28272516

  13. The ligand-bound thyroid hormone receptor in macrophages ameliorates kidney injury via inhibition of nuclear factor-κB activities.

    PubMed

    Furuya, Fumihiko; Ishii, Toshihisa; Tamura, Shogo; Takahashi, Kazuya; Kobayashi, Hidetoshi; Ichijo, Masashi; Takizawa, Soichi; Kaneshige, Masahiro; Suzuki-Inoue, Katsue; Kitamura, Kenichiro

    2017-03-08

    In chronic kidney disease (CKD) patients, inflammation plays a pivotal role in the progression of renal fibrosis. Hypothyroidism is associated with an increased occurrence of atherosclerosis and inflammation, suggesting protective roles of thyroid hormones and their receptors against inflammatory processes. The contribution of thyroid hormone receptors to macrophage differentiation has not been well documented. Here, we focused on the endogenous thyroid hormone receptor α (TRα) in macrophages and examined the role of ligand-bound TRα in macrophage polarization-mediated anti-inflammatory effects. TRα-deficient irradiated chimeric mice showed exacerbated tubulointerstitial injury in a unilateral ureteral obstruction model. Compared with wild-type macrophages, macrophages isolated from the obstructed kidneys of mice lacking TRα displayed increased expression of proinflammatory cytokines that was accompanied by enhanced nuclear translocation of p65. Comparison of TRα-deficient bone marrow-derived macrophages with wild-type macrophages confirmed the propensity of the former cells to produce excessive IL-1β levels. Co-culture of these macrophages with renal epithelial cells induced more severe damage to the epithelial cells via the IL-1 receptor. Our findings indicate that ligand-bound TRα on macrophages plays a protective role in kidney inflammation through the inhibition of NF-κB pathways, possibly by affecting the pro- and anti-inflammatory balance that controls the development of CKD.

  14. Lanthanide(III) di- and tetra-nuclear complexes supported by a chelating tripodal tris(amidate) ligand

    DOE PAGES

    Brown, Jessie L.; Jones, Matthew B.; Gaunt, Andrew J.; ...

    2015-04-06

    Syntheses, structural, and spectroscopic characterization of multinuclear tris(amidate) lanthanide complexes is described. Addition of K3[N(o-PhNC(O)tBu)3] to LnX3 (LnX3 = LaBr3, CeI3, and NdCl3) in N,N-dimethylformamide (DMF) results in the generation of dinuclear complexes, [Ln(N(o-PhNC(O)tBu)3)(DMF)]2(μ-DMF) (Ln = La (1), Ce (2), Nd(3)), in good yields. Syntheses of tetranuclear complexes, [Ln(N(o-PhNC(O)tBu)3)]4 (Ln = Ce (4), Nd(5)), resulted from protonolysis of Ln[N(SiMe3)2]3 (Ln = Ce, Nd) with N(o-PhNCH(O)tBu)3. As a result, in the solid-state, complexes 1–5 exhibit coordination modes of the tripodal tris(amidate) ligand that are unique to the 4f elements and have not been previously observed in transition metal systems.

  15. Lanthanide(III) di- and tetra-nuclear complexes supported by a chelating tripodal tris(amidate) ligand

    SciTech Connect

    Brown, Jessie L.; Jones, Matthew B.; Gaunt, Andrew J.; Scott, Brian L.; MacBeth, Cora E.; Gordon, John C.

    2015-04-06

    Syntheses, structural, and spectroscopic characterization of multinuclear tris(amidate) lanthanide complexes is described. Addition of K3[N(o-PhNC(O)tBu)3] to LnX3 (LnX3 = LaBr3, CeI3, and NdCl3) in N,N-dimethylformamide (DMF) results in the generation of dinuclear complexes, [Ln(N(o-PhNC(O)tBu)3)(DMF)]2(μ-DMF) (Ln = La (1), Ce (2), Nd(3)), in good yields. Syntheses of tetranuclear complexes, [Ln(N(o-PhNC(O)tBu)3)]4 (Ln = Ce (4), Nd(5)), resulted from protonolysis of Ln[N(SiMe3)2]3 (Ln = Ce, Nd) with N(o-PhNCH(O)tBu)3. As a result, in the solid-state, complexes 1–5 exhibit coordination modes of the tripodal tris(amidate) ligand that are unique to the 4f elements and have not been previously observed in transition metal systems.

  16. What determines catalyst functionality in molecular water oxidation? Dependence on ligands and metal nuclearity in cobalt clusters.

    PubMed

    Smith, Paul F; Kaplan, Christopher; Sheats, John E; Robinson, David M; McCool, Nicholas S; Mezle, Nicholas; Dismukes, G Charles

    2014-02-17

    The metal-oxo M4O4 "cubane" topology is of special significance to the field of water oxidation as it represents the merging of bioinspired structural principles derived from natural photosynthesis with successful artificial catalysts known to date. Herein, we directly compare the rates of water oxidation/O2 evolution catalyzed by six cobalt-oxo clusters including the Co4O4 cubanes, Co4O4(OAc)4(py)4 and [Co4O4(OAc)2(bpy)4](2+), using the common Ru(bpy)3(2+)/S2O8(2-) photo-oxidant assay. At pH 8, the first-order rate constants for these cubanes differ by 2-fold, 0.030 and 0.015 s(-1), respectively, reflecting the number of labile carboxylate sites that allow substrate water binding in a pre-equilibrium step before O2 release. Kinetic results reveal a deprotonation step occurs on this pathway and that two electrons are removed before O2 evolution occurs. The Co4O4 cubane core is shown to be the smallest catalytic unit for the intramolecular water oxidation pathway, as neither "incomplete cubane" trimers [Co3O(OH)3(OAc)2(bpy)3](2+) and [Co3O(OH)2(OAc)3(py)5](2+) nor "half cubane" dimers [Co2(OH)2(OAc)3(bpy)2](+) and [Co2(OH)2(OAc)3(py)4](+) were found capable of evolving O2, despite having the same ligand sets as their cubane counterparts. Electrochemical studies reveal that oxidation of both cubanes to formally Co4(3III,IV) (0.7 V vs Ag/AgCl) occurs readily, while neither dimers nor trimers are oxidized below 1.5 V, pointing to appreciably greater charge delocalization in the [Co4O4](5+) core. The origin of catalytic activity by Co4O4 cubanes illustrates three key features for water oxidation: (1) four one-electron redox metals, (2) efficient charge delocalization of the first oxidation step across the Co4O4 cluster, allowing for stabilization of higher oxidizing equivalents, and (3) terminal coordination site for substrate aquo/oxo formation.

  17. Differential ligand-dependent interactions between the AF-2 activating domain of nuclear receptors and the putative transcriptional intermediary factors mSUG1 and TIF1.

    PubMed Central

    vom Baur, E; Zechel, C; Heery, D; Heine, M J; Garnier, J M; Vivat, V; Le Douarin, B; Gronemeyer, H; Chambon, P; Losson, R

    1996-01-01

    Using a yeast two-hybrid system we report the isolation of a novel mouse protein, mSUG1, that interacts with retinoic acid receptor alpha (RAR alpha) both in yeast cells and in vitro in a ligand- and AF-2 activating domain (AF-2 AD)-dependent manner and show that it is a structural and functional homologue of the essential yeast protein SUG1. mSUG1 also efficiently interacts with other nuclear receptors, including oestrogen (ER), thyroid hormone (TR), Vitamin D3 (VDR) and retinoid X (RXR) receptors. By comparing the interaction properties of these receptors with mSUG1 and TIF1, we demonstrate that: (i) RXR alpha efficiently interacts with TIF1, but not with mSUG1, whereas TR alpha interacts much more efficiently with mSUG1 than with TIF1, and RAR alpha, VDR and ER efficiently interact with mSUG1 and TIF1; (ii) the amphipathic alpha-helix core of the AF-2 AD is differentially involved in interactions of RAR alpha with mSUG1 and TIF1; (iii) the AF-2 AD cores of RAR alpha and ER are similarly involved in their interaction with TIF1, but not with mSUG1. Thus, the interaction interfaces between the different receptors and either mSUG1 or TIF1 may vary depending on the nature of the receptor and the putative mediator of its AF-2 function. We discuss the possibility that mSUG1 and TIF1 may mediate the transcriptional activity of the AF-2 of nuclear receptors through different mechanisms. Images PMID:8598193

  18. Chlorogenic acid inhibits osteoclast differentiation and bone resorption by down-regulation of receptor activator of nuclear factor kappa-B ligand-induced nuclear factor of activated T cells c1 expression.

    PubMed

    Kwak, Sung Chul; Lee, Cheol; Kim, Ju-Young; Oh, Hyun Mee; So, Hong-Seob; Lee, Myeung Su; Rho, Mun Chual; Oh, Jaemin

    2013-01-01

    Excessive osteoclastic bone resorption plays a critical role in inflammation-induced bone loss such as rheumatoid arthritis and periodontal bone erosion. Therefore, identification of osteoclast targeted-agents may be a therapeutic approach to the treatment of pathological bone loss. In this study, we isolated chlorogenic acid (CGA) from fructus of Gardenia jasminoides to discover anti-bone resorptive agents. CGA is a polyphenol with anti-inflammatory and anti-oxidant activities, however, its effects on osteoclast differentiation is unknown. Thus, we investigated the effect of CGA in receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL)-induced osteoclast differentiation and RANKL signaling. CGA dose-dependently inhibited RANKL-mediated osteoclast differentiation in bone marrow macrophages (BMMs) without any evidence of cytotoxicity. CGA inhibited the phosphorylation of p38, Akt, extracellular signal-regulated kinase (ERK), and inhibitor of nuclear factor-kappa B (IκB), and IκB degradation by RANKL treatment. CGA suppressed the mRNA expression of nuclear factor of activated T cells c1 (NFATc1), TRAP and OSCAR in RANKL-treated bone marrow macrophages (BMMs). Also, overexpression of NFATc1 in BMMs blocked the inhibitory effect of CGA on RANKL-mediated osteoclast differentiation. Furthermore, to evaluate the effects of CGA in vivo, lipopolysaccharide (LPS)-induced bone erosion study was carried out. CGA remarkably attenuated LPS-induced bone loss based on micro-computed tomography and histologic analysis of femurs. Taken together, our findings suggest that CGA may be a potential treatment option for osteoclast-related diseases with inflammatory bone destruction.

  19. Arctigenin suppresses receptor activator of nuclear factor κB ligand (RANKL)-mediated osteoclast differentiation in bone marrow-derived macrophages.

    PubMed

    Kim, A-Ram; Kim, Hyuk Soon; Lee, Jeong Min; Choi, Jung Ho; Kim, Se Na; Kim, Do Kyun; Kim, Ji Hyung; Mun, Se Hwan; Kim, Jie Wan; Jeon, Hyun Soo; Kim, Young Mi; Choi, Wahn Soo

    2012-05-05

    Osteoclasts, multinucleated bone-resorbing cells, are closely associated with bone diseases such as rheumatoid arthritis and osteoporosis. Osteoclasts are derived from hematopoietic precursor cells, and their differentiation is mediated by two cytokines, including macrophage colony stimulating factor and receptor activator of nuclear factor κB ligand (RANKL). Previous studies have shown that arctigenin exhibits an anti-inflammatory effect. However, the effect of arctigenin on osteoclast differentiation is yet to be elucidated. In this study, we found that arctigenin inhibited RANKL-mediated osteoclast differentiation in bone marrow macrophages in a dose-dependent manner and suppressed RANKL-mediated bone resorption. Additionally, the expression of typical marker proteins, such as NFATc1, c-Fos, TRAF6, c-Src, and cathepsin K, were significantly inhibited. Arctigenin inhibited the phosphorylation of Erk1/2, but not p38 and JNK, in a dose-dependent manner. Arctigenin also dramatically suppressed immunoreceptor tyrosine-based activation motif-mediated costimulatory signaling molecules, including Syk and PLCγ2, and Gab2. Notably, arctigenin inhibited the activation of Syk through RANKL stimulation. Furthermore, arctigenin prevented osteoclast differentiation in the calvarial bone of mice following stimulation with lipopolysaccharide. Our results show that arctigenin inhibits osteoclast differentiation in vitro and in vivo. Therefore, arctigenin may be useful for treating rheumatoid arthritis and osteoporosis.

  20. Isoliquiritigenin Inhibits Metastatic Breast Cancer Cell-induced Receptor Activator of Nuclear Factor Kappa-B Ligand/Osteoprotegerin Ratio in Human Osteoblastic Cells

    PubMed Central

    Lee, Sun Kyoung; Park, Kwang-Kyun; Kim, Ki Rim; Kim, Hyun-Jeong; Chung, Won-Yoon

    2015-01-01

    Bone destruction induced by the metastasis of breast cancer cells is a frequent complication that is caused by the interaction between cancer cells and bone cells. Receptor activator of nuclear factor kappa-B ligand (RANKL) and the endogenous soluble RANKL inhibitor, osteoprotegerin (OPG), directly play critical roles in the differentiation, activity, and survival of osteoclasts. In patients with bone metastases, osteoclastic bone resorption promotes the majority of skeletal-related events and propagates bone metastases. Therefore, blocking osteoclast activity and differentiation via RANKL inhibition can be a promising therapeutic approach for cancer-associated bone diseases. We investigated the potential of isoliquiritigenin (ISL), which has anti-proliferative, anti-angiogenic, and anti-invasive effects, as a preventive and therapeutic agent for breast cancer cell-induced bone destruction. ISL at non-toxicity concentrations significantly inhibited the RANKL/OPG ratio by reducing the production of RANKL and restoring OPG production to control levels in hFOB1.19 cells stimulated with conditioned medium (CM) of MDA-MB-231 cells. In addition, ISL reduced the expression of cyclooxygenase-2 in hFOB1.19 cells stimulated by CM of MDA-MB-231 cells. Therefore, ISL may have inhibitory potential on breast cancer-induced bone destruction. PMID:26734591

  1. Effect of The Receptor Activator of Nuclear Factor кB and RANK Ligand on In Vitro Differentiation of Cord Blood CD133+ Hematopoietic Stem Cells to Osteoclasts

    PubMed Central

    Kalantari, Nasim; Abroun, Saeid; Soleimani, Masoud; Kaviani, Saeid; Azad, Mehdi; Eskandari, Fatemeh; Habibi, Hossein

    2016-01-01

    Objective Receptor activator of nuclear factor-kappa B ligand (RANKL) appears to be an osteoclast-activating factor, bearing an important role in the pathogenesis of multiple myeloma. Some studies demonstrated that U-266 myeloma cell line and primary myeloma cells expressed RANK and RANKL. It had been reported that the expression of myeloid and monocytoid markers was increased by co-culturing myeloma cells with hematopoietic stem cells (HSCs). This study also attempted to show the molecular mechanism of RANK and RANKL on differentiation capability of human cord blood HSC to osteoclast, as well as expression of calcitonin receptor (CTR) on cord blood HSC surface. Materials and Methods In this experimental study, CD133+ hematopoietic stem cells were isolated from umbilical cord blood and cultured in the presence of macrophage colony-stimulating factor (M-CSF) and RANKL. Osteoclast differentiation was characterized by using tartrate-resistant acid phosphatase (TRAP) staining, giemsa staining, immunophenotyping, and reverse transcription-polymerase chain reaction (RT-PCR) assay for specific genes. Results Hematopoietic stem cells expressed RANK before and after differentiation into osteoclast. Compared to control group, flow cytometric results showed an increased expression of RANK after differentiation. Expression of CTR mRNA showed TRAP reaction was positive in some differentiated cells, including osteoclast cells. Conclusion Presence of RANKL and M-CSF in bone marrow could induce HSCs differentiation into osteoclast. PMID:27602313

  2. Molecular Profiling of Giant Cell Tumor of Bone and the Osteoclastic Localization of Ligand for Receptor Activator of Nuclear Factor κB

    PubMed Central

    Morgan, Teresa; Atkins, Gerald J.; Trivett, Melanie K.; Johnson, Sandra A.; Kansara, Maya; Schlicht, Stephen L.; Slavin, John L.; Simmons, Paul; Dickinson, Ian; Powell, Gerald; Choong, Peter F.M.; Holloway, Andrew J.; Thomas, David M.

    2005-01-01

    Giant cell tumor of bone (GCT) is a generally benign, osteolytic neoplasm comprising stromal cells and osteoclast-like giant cells. The osteoclastic cells, which cause bony destruction, are thought to be recruited from normal monocytic pre-osteoclasts by stromal cell expression of the ligand for receptor activator of nuclear factor κB (RANKL). This model forms the foundation for clinical trials in GCTs of novel cancer therapeutics targeting RANKL. Using expression profiling, we identified both osteoblast and osteoclast signatures within GCTs, including key regulators of osteoclast differentiation and function such as RANKL, a C-type lectin, osteoprotegerin, and the wnt inhibitor SFRP4. After ex vivo generation of stromal- and osteoclast-enriched cultures, we unexpectedly found that RANKL mRNA and protein were more highly expressed in osteoclasts than in stromal cells, as determined by expression profiling, flow cytometry, immunohistochemistry, and reverse transcriptase-polymerase chain reaction. The expression patterns of molecules implicated in signaling between stromal cells and monocytic osteoclast precursors were analyzed in both primary and fractionated GCTs. Finally, using array-based comparative genomic hybridization, neither GCTs nor the derived stromal cells demonstrated significant genomic gains or losses. These data raise questions regarding the role of RANKL in GCTs that may be relevant to the development of molecularly targeted therapeutics for this disease. PMID:15972958

  3. Expression of the receptor activator of nuclear factor-kB ligand in peripheral blood mononuclear cells in patients with acute Charcot neuroarthropathy

    PubMed Central

    Bergamini, Alberto; Bolacchi, Francesca; Pesce, Caterina Delfina; Veneziano, Giada; Uccioli, Luigi; Girardi, Valentina; De Corato, Laura; Mondillo, Maria Teresa; Squillaci, Ettore

    2016-01-01

    Introduction. The receptor activator of nuclear factor-kB (RANK), ligand (RANK-L) and osteoprotegerin (OPG) are implicated in the pathogenesis of acute Charcot neuroarthropathy (CN). Materials and Methods. This study aimed to investigate the expression of RANK-L and OPG in peripheral blood mononuclear cells (PBMC) from patients with acute CN. Results. We found that the expression of RANK-L was lower in patients with acute CN as compared with diabetic control subjects and healthy control participants; whereas OPG expression was not detected in patients and in both control groups. RANK-L expression at the onset of disease was inversely correlated with the index of polyunsaturation (PUI), a bone marrow MRS-derived measurable index that allows evaluation of disease activity in acute CN, and recovery time. Finally, the expression of RANK-L increased at the time of healing compared with the values found during the acute phase. Conclusions. In conclusion, our preliminary data provide a first step in applying analysis of RANK-L expression in peripheral blood cells to the diagnosis of acute CN. Based on our data we also suggest that analysis of RANK-L expression could be a complementary tool that can be employed to obtain quantitative parameters that may help clinicians to monitor disease activity in patients with acute CN. PMID:28090190

  4. Effects of vitamin E on receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) in rats treated with nicotine.

    PubMed

    Norazlina, M; Maizatul-Neza, J; Azarina, A; Nazrun, A S; Norliza, M; Ima-Nirwana, S

    2010-03-01

    Vitamin E is found to reverse the effects of nicotine on bone and this study aimed to determine its mechanism. Male Sprague Dawley rats were divided into four groups and treated for 3 months: Group 1 was the control group (RC). Groups 2 (N), 3 (N+TT) and 4 (N+ATF) received nicotine 7 mg/kg throughout the treatment period. In addition, groups 3 and 4 received tocotrienol 60 mg/kg and alpha-tocopherol 60 mg/kg respectively during months 2 and 3. Parameters measured were serum osteoprotegerin (OPG), serum receptor activator of nuclear factor kappa B ligand (RANKL), femoral and lumbar bone calcium content and body weight. Nicotine did not affect OPG or RANKL levels but reduced bone calcium content suggesting the calcium loss is not due to increase osteoclastogenesis. OPG was increased in N+ATF while RANKL was slightly increased in N+TT. Both vitamin E supplements restored bone calcium loss induced by nicotine. Nicotine impaired weight gain in all treatment groups starting week 4 however, N+TT group was comparable to RC from week 6 onwards. Bone protective effects of ATF, but not TT, may be partly due to inhibition of osteoclastogenesis.

  5. Ligand modeling and design

    SciTech Connect

    Hay, B.P.

    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.

  6. Hydrothermal Crystallization of Uranyl Coordination Polymers Involving an Imidazolium Dicarboxylate Ligand: Effect of pH on the Nuclearity of Uranyl-Centered Subunits.

    PubMed

    Martin, Nicolas P; Falaise, Clément; Volkringer, Christophe; Henry, Natacha; Farger, Pierre; Falk, Camille; Delahaye, Emilie; Rabu, Pierre; Loiseau, Thierry

    2016-09-06

    Four uranyl-bearing coordination polymers (1-4) have been hydrothermally synthesized in the presence of the zwitterionic 1,3-bis(carboxymethyl)imidazolium (= imdc) anion as organic linkers after reaction at 150 °C. At low pH (0.8-3.1), the form 1 ((UO2)2(imdc)2(ox)·3H2O; ox stands for oxalate group) has been identified. Its crystal structure (XRD analysis) consists of the 8-fold-coordinated uranyl centers linked to each other through the imdc ligand together with oxalate species coming from the partial decomposition of the imdc molecule. The resulting structure is based on one-dimensional infinite ribbons intercalated by free water molecules. By adding NaOH solution, a second form 2 is observed for pH 1.9-3.9 but in a mixture with phase 1. The pure phase of 2 is obtained after a hydrothermal treatment at 120 °C. It corresponds to a double-layered network (UO2(imdc)2) composed of 7-fold-coordinated uranyl cations linked via the imdc ligands. In the same pH range, a third phase ((UO2)3O2(H2O)(imdc)·H2O, 3) is formed: it is composed of hexanuclear units of 7-fold- and 8-fold-coordinated uranyl cations, connected via the imdc molecules in a layered assembly. At higher pH, the chain-like solid (UO2)3O(OH)3(imdc)·2H2O (4) is observed and composed of the infinite edge-sharing uranyl-centered pentagonal bipyramidal polyhedra. As a function of pH, uranyl nuclearity increases from discrete 8- or 7-fold uranyl centers (1, 2) to hexanuclear bricks (3) and then infinite chains in 4 (built up from the hexameric fragments found in 3). This observation emphasized the influence of the hydrolysis reaction occurring between uranyl centers. The compounds have been further characterized by thermogravimetric analysis, infrared, and luminescence spectroscopy.

  7. Comparison the relationship between the levels of insulin resistance, hs-CRP, percentage of body fat and serum osteoprotegerin/receptor activator of nuclear factor κβ ligand in prediabetic patients.

    PubMed

    Bilgir, Oktay; Yavuz, Mehmet; Bilgir, Ferda; Akan, Ozden Y; Bayindir, Aslı G; Calan, Mehmet; Bozkaya, Giray; Yuksel, Arif

    2017-01-31

    BACKGROUND Receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPN) are soluble members of the tumor necrosis factor superfamily. Growing evidence suggest that there is link between inflammation, insulin resistance and OPG, sRANKL. We aimed to ascertain whether OPG and sRANKL levels are altered in prediabetic subjects and there is association between OPG, sRANKL and metabolic parameters.

  8. Esculetin attenuates receptor activator of nuclear factor kappa-B ligand-mediated osteoclast differentiation through c-Fos/nuclear factor of activated T-cells c1 signaling pathway

    SciTech Connect

    Baek, Jong Min; Park, Sun-Hyang; Cheon, Yoon-Hee; Ahn, Sung-Jun; Lee, Myeung Su; Oh, Jaemin; Kim, Ju-Young

    2015-05-29

    Esculetin exerts various biological effects on anti-oxidation, anti-tumors, and anti-inflammation. However, the involvement of esculetin in the bone metabolism process, particularly osteoclast differentiation has not yet been investigated. In the present study, we first confirmed the inhibitory effect of esculetin on receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast formation. We then revealed the relationship between esculetin and the expression of osteoclast-specific molecules to elucidate its underlying mechanisms. Esculetin interfered with the expression of c-Fos and nuclear factor of activated T cell c1 (NFATc1) both at the mRNA and protein level with no involvement in osteoclast-associated early signaling pathways, suppressing the expression of various transcription factors exclusively expressed in osteoclasts such as tartrate-resistant acid phosphatase (Trap), osteoclast-associated receptor (Oscar), dendritic cell-specific transmembrane protein (Dcstamp), osteoclast stimulatory transmembrane protein (Ocstamp), cathepsin K, αvβ3 integrin, and calcitonin receptor (Ctr). Additionally, esculetin inhibited the formation of filamentous actin (F-actin) ring-positive osteoclasts during osteoclast differentiation. However, the development of F-actin structures and subsequent bone resorbing activity of mature osteoclasts, which are observed in osteoclast/osteoblast co-culture systems were not affected by esculetin. Taken together, our results indicate for the first time that esculetin inhibits RANKL-mediated osteoclastogenesis via direct suppression of c-Fos and NFATc1 expression and exerts an inhibitory effect on actin ring formation during osteoclastogenesis. - Highlights: • We first investigated the effects of esculetin on osteoclast differentiation and function. • Our data demonstrate for the first time that esculetin can suppress osteoclastogenesis in vitro. • Esculetin acts as an inhibitor of c-Fos and NFATc1 activation.

  9. Receptor activator of nuclear factor-kappaB ligand-induced mouse osteoclast differentiation is associated with switching between NADPH oxidase homologues.

    PubMed

    Sasaki, Hideyuki; Yamamoto, Hironori; Tominaga, Kumiko; Masuda, Kiyoshi; Kawai, Tomoko; Teshima-Kondo, Shigetada; Matsuno, Kuniharu; Yabe-Nishimura, Chihiro; Rokutan, Kazuhito

    2009-07-15

    Reactive oxygen species (ROS) have been suggested to regulate receptor activator of nuclear factor-kappaB ligand (RANKL)-stimulated osteoclast differentiation. Stimulation of wild-type mouse bone marrow monocyte/macrophage lineage (BMM) cells by RANKL down-regulated NADPH oxidase 2 (Nox2) mRNA expression by half. RANKL reciprocally increased Nox1 mRNA levels and newly induced Nox4 transcript expression. BMM cells from Nox1 knockout (Nox1(-/-)) as well as Nox2(-/-) mice generated ROS in response to RANKL and differentiated into osteoclasts in the same way as wild-type BMM cells, which was assessed by the appearance of tartrate-resistant acid phosphatase-positive, multinucleated cells having the ability to form resorption pits and by the expression of osteoclast marker genes. A small interfering RNA (siRNA) targeting Nox1 or Nox2 failed to inhibit the RANKL-stimulated ROS generation and osteoclast formation in wild-type cells, whereas Nox1 and Nox2 siRNAs significantly suppressed the ROS generation and osteoclast formation in Nox2(-/-) and Nox1(-/-) cells, respectively. We also confirmed that Nox4 siRNA did not affect the RANKL-dependent events in Nox2(-/-) cells, whereas p22(phox) siRNA suppressed the events in both wild-type and Nox1(-/-) cells. Collectively, our results suggest that there may be a flexible compensatory mechanism between Nox1 and Nox2 for RANKL-stimulated ROS generation to facilitate osteoclast differentiation.

  10. Serum levels of osteoprotegerin and receptor activator of nuclear factor -κB ligand in children with early juvenile idiopathic arthritis: a 2-year prospective controlled study

    PubMed Central

    2010-01-01

    Background The clinical relevance of observations of serum levels of osteoprotegerin (OPG) and receptor activator of nuclear factor -κB ligand (RANKL) in juvenile idiopathic arthritis (JIA) is not clear. To elucidate the potential role of OPG and RANKL in JIA we determined serum levels of OPG and RANKL in patients with early JIA compared to healthy children, and prospectively explored changes in relation to radiographic score, bone and lean mass, severity of the disease, and treatment. Methods Ninety children with early oligoarticular or polyarticular JIA (ages 6-18 years; mean disease duration 19.4 months) and 90 healthy children individually matched for age, sex, race, and county of residence, were examined at baseline and 2-year follow-up. OPG and RANKL were quantified by enzyme-immunoassay. Data were analyzed with the use of t-tests, ANOVA, and multiple regression analyses. Results Serum OPG was significantly lower in patients than controls at baseline, and there was a trend towards higher RANKL and a lower OPG/RANKL ratio. Patients with polyarthritis had significantly higher increments in RANKL from baseline to follow-up, compared to patients with oligoarthritis. RANKL was a significant negative predictor for increments in total body lean mass. Patients who were receiving corticosteroids (CS) or disease-modifying antirheumatic drugs (DMARDs) at follow-up had higher OPG/RANKL ratio compared with patients who did not receive this medication. Conclusions The data supports that levels of OPG are lower in patients with JIA compared to healthy children, and higher levels of RANKL is associated with more serious disease. RANKL was a significant negative predictor of lean mass in patients with JIA. The OPG/RANKL ratio was higher in patients on DMARDs or CS treatment. PMID:21134287

  11. Antioxidant alpha-lipoic acid inhibits osteoclast differentiation by reducing nuclear factor-kappaB DNA binding and prevents in vivo bone resorption induced by receptor activator of nuclear factor-kappaB ligand and tumor necrosis factor-alpha.

    PubMed

    Kim, Hyon Jong; Chang, Eun-Ju; Kim, Hyun-Man; Lee, Seung Bok; Kim, Hyun-Duck; Su Kim, Ghi; Kim, Hong-Hee

    2006-05-01

    The relationship between oxidative stress and bone mineral density or osteoporosis has recently been reported. As bone loss occurring in osteoporosis and inflammatory diseases is primarily due to increases in osteoclast number, reactive oxygen species (ROS) may be relevant to osteoclast differentiation, which requires receptor activator of nuclear factor-kappaB ligand (RANKL). Tumor necrosis factor-alpha (TNF-alpha) frequently present in inflammatory conditions has a profound synergy with RANKL in osteoclastogenesis. In this study, we investigated the effects of alpha-lipoic acid (alpha-LA), a strong antioxidant clinically used for some time, on osteoclast differentiation and bone resorption. At concentrations showing no growth inhibition, alpha-LA potently suppressed osteoclastogenesis from bone marrow-derived precursor cells driven either by a high-dose RANKL alone or by a low-dose RANKL plus TNF-alpha (RANKL/TNF-alpha). alpha-LA abolished ROS elevation by RANKL or RANKL/TNF-alpha and inhibited NF-kappaB activation in osteoclast precursor cells. Specifically, alpha-LA reduced DNA binding of NF-kappaB but did not inhibit IKK activation. Furthermore, alpha-LA greatly suppressed in vivo bone loss induced by RANKL or TNF-alpha in a calvarial remodeling model. Therefore, our data provide evidence that ROS plays an important role in osteoclast differentiation through NF-kappaB regulation and the antioxidant alpha-lipoic acid has a therapeutic potential for bone erosive diseases.

  12. Multicoordinate ligands for actinide/lanthanide separations.

    PubMed

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

    2007-02-01

    In nuclear waste treatment processes there is a need for improved ligands for the separation of actinides (An(III)) and lanthanides (Ln(III)). Several research groups are involved in the design and synthesis of new An(III) ligands and in the confinement of these and existing An(III) ligands onto molecular platforms giving multicoordinate ligands. The preorganization of ligands considerably improves the An(III) extraction properties, which are largely dependent on the solubility and rigidity of the platform. This tutorial review summarizes the most important An(III) ligands with emphasis on the preorganization strategy using (macrocyclic) platforms.

  13. Role of Osteoprotegerin and Receptor Activator of Nuclear Factor-κB Ligand in Bone Loss Related to Advanced Chronic Obstructive Pulmonary Disease

    PubMed Central

    Ugay, Ludmila; Kochetkova, Evgenia; Nevzorova, Vera; Maistrovskaia, Yuliya

    2016-01-01

    Background: Osteoporosis is a common complication of chronic obstructive pulmonary disease (COPD). Recent clinical and biological researches have increasingly delineated the biomolecular pathways of bone metabolism regulation in COPD. We extended this work by examining the specific association and potential contribution of the osteoprotegerin (OPG)/receptor activator of nuclear factor-κB ligand (RANKL) axis to the pathogenesis of osteoporosis in advanced COPD. The aim of this study was to assess the relationships of serum OPG, RANKL, and tumor necrosis factor-alpha (TNF-α) with bone turnover in men with very severe COPD. Methods: Pulmonary function, T-score at the lumbar spine (LS) and femoral neck (FN), serum OPG, RANKL, soluble receptor of tumor necrosis factor-alpha-I and II (sTNFR-I, sTNFR-II), osteocalcin (OC), and β-CrossLaps (βCL) levels were measured in 45 men with very severe stage COPD and 36 male non-COPD volunteers. COPD patients and healthy controls were compared using an independent t-test and Mann–Whitney U-test. The Pearson coefficient was used to assess the relationships between variables. Results: OPG and OC were lower in male COPD patients than in control subjects whereas RANKL, serum βCL, TNF-α, and its receptors were higher. OPG directly correlated with forced expiratory volume in 1 s (FEV1) % predicted (r = 0.46, P < 0.005), OC (r = 0.34, P < 0.05), LS (r = 0.56, P < 0.001), and FN T-score (r = 0.47, P < 0.01). In contrast, serum RANKL inversely associated with LS and FN T-score (r = −0.62, P < 0.001 and r = −0.48, P < 0.001) but directly correlated with βCL (r = 0.48, P < 0.001). In addition, OPG was inversely correlated with RANKL (r = −0.39, P < 0.01), TNF-α (r = −0.56, P < 0.001), and sTNFR-I (r = −0.40, P < 0.01). Conclusion: Our results suggest that serum OPG and RANKL levels are inversely associated with bone loss in men with advanced stage COPD. PMID:27411457

  14. High-nuclearity ruthenium carbonyl cluster complexes derived from 2-amino-6-methylpyridine: synthesis of nonanuclear derivatives containing mu4- and mu5-oxo ligands.

    PubMed

    Cabeza, Javier A; del Río, Ignacio; García-Alvarez, Pablo; Miguel, Daniel

    2006-07-24

    Nonanuclear cluster complexes [Ru9(mu3-H)2(mu-H)(mu5-O)(mu4-ampy)(mu3-Hampy)(CO)21] (4) (H2ampy = 2-amino-6-methylpyridine), [Ru9(mu5-O)2(mu4-ampy)(mu3-Hampy)2(mu-CO)(CO)20] (5), [Ru9(mu5-O)2(mu4-ampy)(mu3-Hampy)2(mu-CO)2(CO)19] (6), and [Ru9(mu4-O)(mu5-O)(mu4-ampy)(mu3-Hampy)(mu-Hampy)(mu-CO)(CO)19] (7), together with the known hexanuclear [Ru6(mu3-H)2(mu5-ampy)(mu-CO)2(CO)14] (2) and the novel pentanuclear [Ru5(mu4-ampy)(2)(mu-CO)(CO)12] (3) complexes, are products of the thermolysis of [Ru3(mu-H)(mu3-Hampy)(CO)9] (1) in decane at 150 degrees C. Two different and very unusual quadruply bridging coordination modes have been observed for the ampy ligand. Compounds 4-7 also feature one (4) or two (5-7) bridging oxo ligands. With the exception of one of the oxo ligands of 7, which is in a distorted tetrahedral environment, the remaining oxo ligands of 4-7 are surrounded by five metal atoms. In carbonyl metal clusters, quadruply bridging oxo ligands are very unusual, whereas quintuply bridging oxo ligands are unprecedented. By using 18O-labeled water, we have unambiguously established that these oxo ligands arise from water.

  15. Investigation of ligand binding and protein dynamics in Bacillus subtilis chorismate mutase by transverse relaxation optimized spectroscopy-nuclear magnetic resonance.

    PubMed

    Eletsky, Alexander; Kienhöfer, Alexander; Hilvert, Donald; Pervushin, Konstantin

    2005-05-10

    The structural and dynamical consequences of ligand binding to a monofunctional chorismate mutase from Bacillus subtilis have been investigated by solution NMR spectroscopy. TROSY methods were employed to assign 98% of the backbone (1)H(N), (1)H(alpha), (15)N, (13)C', and (13)C(alpha) resonances as well as 86% of the side chain (13)C resonances of the 44 kDa trimeric enzyme at 20 degrees C. This information was used to map chemical shift perturbations and changes in intramolecular mobility caused by binding of prephenate or a transition state analogue to the X-ray structure. Model-free interpretation of backbone dynamics for the free enzyme and its complexes based on (15)N relaxation data measured at 600 and 900 MHz showed significant structural consolidation of the protein in the presence of a bound ligand. In agreement with earlier structural and biochemical studies, substantial ordering of 10 otherwise highly flexible residues at the C-terminus is particularly notable. The observed changes suggest direct contact between this protein segment and the bound ligand, providing support for the proposal that the C-terminus can serve as a lid for the active site, limiting diffusion into and out of the pocket and possibly imposing conformational control over substrate once bound. Other regions of the protein that experience substantial ligand-induced changes also border the active site or lie along the subunit interfaces, indicating that the enzyme adapts dynamically to ligands by a sort of induced fit mechanism. It is believed that the mutase-catalyzed chorismate-to-prephenate rearrangement is partially encounter controlled, and backbone motions on the millisecond time scale, as seen here, may contribute to the reaction barrier.

  16. Ligand-dependent regulation of the activity of the orphan nuclear receptor, small heterodimer partner (SHP), in the repression of bile acid biosynthetic CYP7A1 and CYP8B1 genes.

    PubMed

    Miao, Ji; Choi, Sung-E; Seok, Sun Mi; Yang, Linda; Zuercher, William J; Xu, Yong; Willson, Timothy M; Xu, H Eric; Kemper, Jongsook Kim

    2011-07-01

    Small heterodimer partner (SHP) plays important roles in diverse biological processes by directly interacting with transcription factors and inhibiting their activities. SHP has been designated an orphan nuclear receptor, but whether its activity can be modulated by ligands has been a long-standing question. Recently, retinoid-related molecules, including 4-[3-(1-adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid (3Cl-AHPC), were shown to bind to SHP and enhance apoptosis. We have examined whether 3Cl-AHPC acts as an agonist and increases SHP activity in the repression of bile acid biosynthetic CYP7A1 and CYP8B1 genes and delineated the underlying mechanisms. Contrary to this expectation, micromolar concentrations of 3Cl-AHPC increased CYP7A1 expression but indirectly via p38 kinase signaling. Nanomolar concentrations, however, repressed CYP7A1 expression and decreased bile acid levels in HepG2 cells, and little repression was observed when SHP was down-regulated by small hairpin RNA. Mechanistic studies revealed that 3Cl-AHPC bound to SHP, increased the interaction of SHP with liver receptor homologue (LRH)-1, a hepatic activator for CYP7A1 and CYP8B1 genes, and with repressive cofactors, Brahma, mammalian Sin3a, and histone deacetylase-1, and, subsequently, increased the occupancy of SHP and these cofactors at the promoters. Mutation of Leu-100, predicted to contact 3Cl-AHPC within the SHP ligand binding pocket by molecular modeling, severely impaired the increased interaction with LRH-1, and repression of LRH-1 activity mediated by 3Cl-AHPC. 3Cl-AHPC repressed SHP metabolic target genes in a gene-specific manner in human primary hepatocytes and HepG2 cells. These data suggest that SHP may act as a ligand-regulated receptor in metabolic pathways. Modulation of SHP activity by synthetic ligands may be a useful therapeutic strategy.

  17. Mapping of the C3d ligand binding site on complement receptor 2 (CR2/CD21) using nuclear magnetic resonance and chemical shift analysis.

    PubMed

    Kovacs, James M; Hannan, Jonathan P; Eisenmesser, Elan Z; Holers, V Michael

    2009-04-03

    Complement receptor 2 (CR2, CD21) is a cell membrane protein, with 15 or 16 extracellular short consensus repeats (SCRs), that promotes B lymphocyte responses and bridges innate and acquired immunity. The most distally located SCRs (SCR1-2) mediate the interaction of CR2 with its four known ligands (C3d, Epstein-Barr virus gp350, interferon-alpha, and CD23). Inhibitory monoclonal antibodies against SCR1-2 block binding of all ligands. To develop ligand-specific inhibitors that would also assist in identifying residues unique to each receptor-ligand interaction, phage were selected from randomly generated libraries by panning with recombinant SCR1-2, followed by specific ligand-driven elution. Derived peptides were tested by competition ELISA. One peptide, C3dp1 (APQHLSSQYSRT) exhibited ligand-specific inhibition at midmicromolar IC(50). C3d was titrated into (15)N-labeled SCR1-2, which revealed chemical shift changes indicative of specific intermolecular interactions. With backbone assignments made, the chemical shift changes were mapped onto the crystal structure of SCR1-2. With regard to C3d, the binding surface includes regions of SCR1, SCR2, and the inter-SCR linker, specifically residues Arg(13), Tyr(16), Arg(28), Tyr(29), Ser(32), Thr(34), Lys(48), Asp(56), Lys(57), Tyr(68), Arg(83), Gly(84), Asn(101), Asn(105), and Ser(109). SCR1 and SCR2 demonstrated distinct binding modes. The CR2 binding surface incorporating SCR1 is inconsistent with a previous x-ray CR2-C3d co-crystal analysis but consistent with mutagenesis, x-ray neutron scattering, and inhibitory monoclonal antibody epitope mapping. Titration with C3dp1 yielded chemical shift changes (Arg(13), Tyr(16), Thr(34), Lys(48), Asp(56), Lys(57), Tyr(68), Arg(83), Gly(84), Asn(105), and Ser(109)) overlapping with C3d, indicating that C3dp1 interacts at the same CR2 site as C3d.

  18. Synthesis, characterization and magnetic studies on mono-, di-, and tri-nuclear Cu(ii) complexes of a new versatile diazine ligand.

    PubMed

    Anwar, Muhammad U; Rawson, Jeremy M; Gavey, Emma L; Pilkington, Melanie; Al-Harrasi, Ahmed; Thompson, Laurence K

    2017-02-14

    The synthesis and coordination chemistry of a new open-chain diazine ligand (L4H2) containing bipyridine, oxime and hydrazone functionalities is reported. Reaction of L4H2 with CuCl2·2H2O affords the mononuclear complex [Cu(L4H2)Cl2] (1) in which the ligand acts as a neutral tridentate N,N',N'' donor, whereas treatment with a large excess of CuCl2·2H2O affords the dinuclear complex [Cu2(L4H)Cl3(CH3OH)(H2O)] (2) in which the ligand is singly-deprotonated at the diazine, offering N,N',N'' and N,N' donor sets to two Cu(ii) ions. Reaction with Cu(NO3)2·3H2O yields the trinuclear complex, [Cu3(L4H)2(CH3OH)4(NO3)4] (3) in which the ligand is again singly deprotonated, but now presents a tetradentate N,N',N'',N'''-donor set to the first Cu(ii) and behaves as an N,O-chelate to a second Cu(ii), with a conformational change from cis to trans at the diazine moiety. When the latter reaction is repeated in the presence of a mild base, a second trinuclear complex is isolated, [Cu3(L4)2(CH3CH2OH)](NO3)2 (4) in which both the diazine and oxime functionalities of the ligand are deprotonated which subsequently bridges all three Cu(ii) ions, acting as an N,N',N'' donor to the first Cu(ii), a N,N' donor to a second Cu(ii) (similar to 2) and as a terminal O-donor to a third Cu(ii) ion. The Cu(ii) ions are linked mutually cis via the two-atom diazine bridge in the case of 2 and 4 and trans in the case of 3. Magnetic studies reveal the presence of weak ferromagnetic interactions in 2 (g = 2.2, J/k = +12.8 K) and strong antiferromagnetic interactions in both 3 and 4 (g = 2.093 J/k = -140 K and g = 2.24 J/k = -300 K respectively).

  19. The nuclear corepressors NCoR and SMRT are key regulators of both ligand- and 8-bromo-cyclic AMP-dependent transcriptional activity of the human progesterone receptor.

    PubMed

    Wagner, B L; Norris, J D; Knotts, T A; Weigel, N L; McDonnell, D P

    1998-03-01

    Previously, we defined a novel class of ligands for the human progesterone receptor (PR) which function as mixed agonists. These compounds induce a conformational change upon binding the receptor that is different from those induced by agonists and antagonists. This establishes a correlation between the structure of a ligand-receptor complex and its transcriptional activity. In an attempt to define the cellular components which distinguish between different ligand-induced PR conformations, we have determined, by using a mammalian two-hybrid assay, that the nuclear receptor corepressor (NCoR) and the silencing mediator for retinoid and thyroid hormone receptor (SMRT) differentially associate with PR depending upon the class of ligand bound to the receptor. Specifically, we observed that the corepressors preferentially associate with antagonist-occupied PR and that overexpression of these corepressors suppresses the partial agonist activity of antagonist-occupied PR. Binding studies performed in vitro, however, reveal that recombinant SMRT can interact with PR in a manner which is not influenced by the nature of the bound ligand. Thus, the inability of SMRT or NCoR to interact with agonist-activated PR when assayed in vivo may relate more to the increased affinity of PR for coactivators, with a subsequent displacement of corepressors, than to an inherent low affinity for the corepressor proteins. Previous work from other groups has shown that 8-bromo-cyclic AMP (8-bromo-cAMP) can convert the PR antagonist RU486 into an agonist and, additionally, can potentiate the transcriptional activity of agonist-bound PR. In this study, we show that exogenous expression of NCoR or SMRT suppresses all 8-bromo-cAMP-mediated potentiation of PR transcriptional activity. Further analysis revealed that 8-bromo-cAMP addition decreases the association of NCoR and SMRT with PR. Thus, we propose that 8-bromo-cAMP-mediated potentiation of PR transcriptional activity is due, at least in part

  20. The Nuclear Corepressors NCoR and SMRT Are Key Regulators of Both Ligand- and 8-Bromo-Cyclic AMP-Dependent Transcriptional Activity of the Human Progesterone Receptor

    PubMed Central

    Wagner, Brandee L.; Norris, John D.; Knotts, Trina A.; Weigel, Nancy L.; McDonnell, Donald P.

    1998-01-01

    Previously, we defined a novel class of ligands for the human progesterone receptor (PR) which function as mixed agonists. These compounds induce a conformational change upon binding the receptor that is different from those induced by agonists and antagonists. This establishes a correlation between the structure of a ligand-receptor complex and its transcriptional activity. In an attempt to define the cellular components which distinguish between different ligand-induced PR conformations, we have determined, by using a mammalian two-hybrid assay, that the nuclear receptor corepressor (NCoR) and the silencing mediator for retinoid and thyroid hormone receptor (SMRT) differentially associate with PR depending upon the class of ligand bound to the receptor. Specifically, we observed that the corepressors preferentially associate with antagonist-occupied PR and that overexpression of these corepressors suppresses the partial agonist activity of antagonist-occupied PR. Binding studies performed in vitro, however, reveal that recombinant SMRT can interact with PR in a manner which is not influenced by the nature of the bound ligand. Thus, the inability of SMRT or NCoR to interact with agonist-activated PR when assayed in vivo may relate more to the increased affinity of PR for coactivators, with a subsequent displacement of corepressors, than to an inherent low affinity for the corepressor proteins. Previous work from other groups has shown that 8-bromo-cyclic AMP (8-bromo-cAMP) can convert the PR antagonist RU486 into an agonist and, additionally, can potentiate the transcriptional activity of agonist-bound PR. In this study, we show that exogenous expression of NCoR or SMRT suppresses all 8-bromo-cAMP-mediated potentiation of PR transcriptional activity. Further analysis revealed that 8-bromo-cAMP addition decreases the association of NCoR and SMRT with PR. Thus, we propose that 8-bromo-cAMP-mediated potentiation of PR transcriptional activity is due, at least in part

  1. Electronic and nuclear structural snapshots in ligand dissociation and recombination processes of iron porphyrin in solution: a combined optical/X-ray approach.

    PubMed

    Mara, Michael W; Shelby, Megan; Stickrath, Andrew; Harpham, Mike; Huang, Jier; Zhang, Xiaoyi; Hoffman, Brian M; Chen, Lin X

    2013-11-14

    The photodissociation and recombination of CO and 1-methylimidazole (Im) from iron protoporphyrin IX (FePP-ImCO) dissolved in a 30% v/v aqueous solution of Im was studied using ultrafast optical transient absorption (TA) and X-ray transient absorption (XTA) spectroscopies. FePP-ImCO was shown to lose the CO ligand upon excitation at the Q bands, with 3.8 ps vibrational cooling and 21.6 ps intersystem crossing time constants derived from optical TA experiments, followed by ligation of a second Im on the nanosecond time scale. The penta-coordinate FePP-Im intermediate which forms following CO dissociation adopts a square pyramidal geometry with a "domed" iron center that is reminiscent of that formed upon loss of CO from carbonmonoxymyoglobin (MbCO). Unlike MbCO, which typically retains its newly generated penta-coordinated geometry until CO recombination, FePP can adopt a hexa-coordinate geometry by binding an additional Im ligand (FePP-(Im)2), allowing the porphyrin to exist in the low-spin electronic state even without the CO attached. The second Im ligand remains bound until CO recombination occurs with a time constant of 283 μs. The photodissociated states of FePP-ImCO and MbCO 100 ps after photoexcitation have similar iron site geometries, implying that the protein matrix in MbCO maintains minimum potential energy in the heme center despite the large-scale reorganization in the protein secondary and tertiary structure that arises from the dynamic active site/matrix interaction.

  2. DNA-histone complexes as ligands amplify cell penetration and nuclear targeting of anti-DNA antibodies via energy-independent mechanisms.

    PubMed

    Zannikou, Markella; Bellou, Sofia; Eliades, Petros; Hatzioannou, Aikaterini; Mantzaris, Michael D; Carayanniotis, George; Avrameas, Stratis; Lymberi, Peggy

    2016-01-01

    We have generated three monoclonal cell-penetrating antibodies (CPAbs) from a non-immunized lupus-prone (NZB × NZW)F1 mouse that exhibited high anti-DNA serum titres. These CPAbs are polyreactive because they bind to DNA and other cellular components, and localize mainly in the nucleus of HeLa cells, albeit with a distinct nuclear labelling profile. Herein, we have examined whether DNA-histone complexes (DHC) binding to CPAbs, before cell entry, could modify the cell penetration of CPAbs or their nuclear staining properties. By applying confocal microscopy and image analysis, we found that extracellular binding of purified CPAbs to DHC significantly enhanced their subsequent cell-entry, both in terms of percentages of positively labelled cells and fluorescence intensity (internalized CPAb amount), whereas there was a variable effect on their nuclear staining profile. Internalization of CPAbs, either alone or bound to DHC, remained unaltered after the addition of endocytosis-specific inhibitors at 37° or assay performance at 4°, suggesting the involvement of energy-independent mechanisms in the internalization process. These findings assign to CPAbs a more complex pathogenetic role in systemic lupus erythematosus where both CPAbs and nuclear components are abundant.

  3. Does a fast nuclear magnetic resonance spectroscopy- and X-ray crystallography hybrid approach provide reliable structural information of ligand-protein complexes? A case study of metalloproteinases.

    PubMed

    Isaksson, Johan; Nyström, Susanne; Derbyshire, Dean; Wallberg, Hans; Agback, Tatiana; Kovacs, Helena; Bertini, Ivano; Giachetti, Andrea; Luchinat, Claudio

    2009-03-26

    A human matrix metalloproteinase (MMP) hydroxamic acid inhibitor (CGS27023A) was cross-docked into 15 MMP-12, MMP-13, MMP-9, and MMP-1 cocrystal structures. The aim was to validate a fast protocol for ligand binding conformation elucidation and to probe the feasibility of using inhibitor-protein NMR contacts to dock an inhibitor into related MMP crystal structures. Such an approach avoids full NMR structure elucidation, saving both spectrometer- and analysis time. We report here that for the studied MMPs, one can obtain docking results well within 1 A compared to the corresponding reference X-ray structure, using backbone amide contacts only. From the perspective of the pharmaceutical industry, these results are relevant for the binding studies of inhibitor series to a common target and have the potential advantage of obtaining information on protein-inhibitor complexes that are difficult to crystallize.

  4. The Inhibitory Effect of Angelica tenuissima Water Extract on Receptor Activator of Nuclear Factor-Kappa-B Ligand-Induced Osteoclast Differentiation and Bone Resorbing Activity of Mature Osteoclasts.

    PubMed

    Ahn, Sung-Jun; Baek, Jong Min; Cheon, Yoon-Hee; Park, Sun-Hyang; Lee, Myeung Su; Oh, Jaemin; Kim, Ju-Young

    2015-01-01

    Angelica tenuissima has been traditionally used in oriental medicine for its therapeutic effects in headache, toothache, and flu symptoms. It also exerts anti-inflammatory activity via the inhibition of the expression of cyclooxygenase-2 (COX-2). However, the effect of Angelica tenuissima on osteoclast differentiation has not been identified until recently. In this study, we first confirmed that Angelica tenuissima water extract (ATWE) significantly interrupted the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells (MNCs) in a dose-dependent manner without any cytotoxicity. Next, we clarified the underlying mechanisms linking the suppression effects of ATWE on the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. At the molecular level, ATWE induced the dephosphorylation of c-Jun N-terminal kinase (JNK) and Akt and decreased the degradation of IκB in RANKL-dependent early signaling pathways. Subsequently, ATWE caused impaired activation of the protein and mRNA levels of c-Fos and nuclear factor of activated T cell c1 (NFATc1). Moreover, the disassembly of filamentous actin (F-actin) ring and anti-resorptive activity of mature osteoclasts were triggered by ATWE treatment. Although ATWE did not enhance osteogenesis in primary osteoblasts, our results showed that ATWE is a potential candidate for anti-resorptive agent in osteoporosis, a common metabolic bone disorder.

  5. Dendrobium moniliforme Exerts Inhibitory Effects on Both Receptor Activator of Nuclear Factor Kappa-B Ligand-Mediated Osteoclast Differentiation in Vitro and Lipopolysaccharide-Induced Bone Erosion in Vivo.

    PubMed

    Baek, Jong Min; Kim, Ju-Young; Ahn, Sung-Jun; Cheon, Yoon-Hee; Yang, Miyoung; Oh, Jaemin; Choi, Min Kyu

    2016-03-01

    Dendrobium moniliforme (DM) is a well-known plant-derived extract that is widely used in Oriental medicine. DM and its chemical constituents have been reported to have a variety of pharmacological effects, including anti-oxidative, anti-inflammatory, and anti-tumor activities; however, no reports discuss the beneficial effects of DM on bone diseases such as osteoporosis. Thus, we investigated the relationship between DM and osteoclasts, cells that function in bone resorption. We found that DM significantly reduced receptor activator of nuclear factor kappa-B ligand (RANKL)-induced tartrate-resistant acid phosphatase (TRAP)-positive osteoclast formation; DM directly induced the down-regulation of c-Fos and nuclear factor of activated T cells c1 (NFATc1) without affecting other RANKL-dependent transduction pathways. In the later stages of osteoclast maturation, DM negatively regulated the organization of filamentous actin (F-actin), resulting in impaired bone-resorbing activity by the mature osteoclasts. In addition, micro-computed tomography (μ-CT) analysis of the murine model revealed that DM had a beneficial effect on lipopolysaccharide (LPS)-mediated bone erosion. Histological analysis showed that DM attenuated the degradation of trabecular bone matrix and formation of TRAP-positive osteoclasts in bone tissues. These results suggest that DM is a potential candidate for the treatment of metabolic bone disorders such as osteoporosis.

  6. Di- and octa-nuclear dysprosium clusters derived from pyridyl-triazole based ligand: {Dy2} showing single molecule magnetic behaviour.

    PubMed

    Akhtar, Muhammad Nadeem; Liao, Xiao-Fen; Chen, Yan-Cong; Liu, Jun-Liang; Tong, Ming-Liang

    2017-02-28

    Two dysprosium aggregates, formulated as [Dy2(μ-OH)2(H2bpte)2Cl2(MeOH)2]Cl2 (1), and [Dy8(μ-OH)8(bpte)8]·24H2O (2) (H2bpte = 1,2-bis(3-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl)ethane), were obtained using solvothermal reactions. Upon changing the metal salt and synthetic reaction conditions, an eight-member {Dy8} (2) ring was isolated. Complex 1 is centrosymmetric in which two {Dy2} clusters are connecting to each other through the hydrogen bonding. Complex 2 forms an eight-member Dy(III) ring with an inner diameter of 4.5 Å and is the first reported {Dy8(μ-OH)8} core in lanthanide-hydroxo clusters. The H2bpte ligand displays trans,trans- and cis,cis-coordination modes in 1 and 2, respectively. Alternating current (ac) magnetic measurements of both complexes were carried out. In 1, the out-of-phase susceptibilities (χ''M) below 9 K confirm the slow relaxation of magnetization, which is a typical characteristic of single-molecule magnets (SMMs).

  7. Antiosteoclastogenesis activity of a CO2 laser antagonizing receptor activator for nuclear factor kappaB ligand-induced osteoclast differentiation of murine macrophages

    NASA Astrophysics Data System (ADS)

    Kuo, Chun-Liang; Kao, Chia-Tze; Fang, Hsin-Yuan; Huang, Tsui-Hsien; Chen, Yi-Wen; Shie, Ming-You

    2015-03-01

    Macrophage cells are the important effector cells in the immune reaction which are indispensable for osteoclastogenesis; their heterogeneity and plasticity renders macrophages a primer target for immune system modulation. In recent years, there have been very few studies about the effects of macrophage cells on laser treatment-regulated osteoclastogenesis. In this study, RAW 264.7 macrophage cells were treated with RANKL to regulate osteoclastogenesis. We used a CO2 laser as a model biostimulation to investigate the role of osteoclastogenic. We also evaluated cell viability, cell death and cathepsin K expression. The CO2 laser inhibited a receptor activator of the NF-ĸB ligand (RANKL)-induced formation of osteoclasts during the osteoclast differentiation process. It was also found that irradiation for two times reduced RANKL-enhanced TRAP activity in a dose-dependent manner. Furthermore, CO2 laser-treatment diminished the expression and secretion of cathepsin K elevated by RANKL and was concurrent with the inhibition of TRAF6 induction and NF-ĸB activation. The current report demonstrates that CO2 laser abrogated RANKL-induced osteoclastogenesis by retarding osteoclast differentiation. The CO2 laser can modulate every cell through dose-dependent in vitro RANKL-mediated osteoclastogenesis, such as the proliferation and fusion of preosteoclasts and the maturation of osteoclasts. Therefore, the current results serve as an improved explanation of the cellular roles of macrophage cell populations in osteoclastogenesis as well as in alveolar bone remodeling by CO2 laser-treatment.

  8. Effect of gallium nitrate on the expression of osteoprotegerin and receptor activator of nuclear factor‑κB ligand in osteoblasts in vivo and in vitro.

    PubMed

    Li, Jingwu; Wang, Guang-Bin; Feng, Xue; Zhang, Jing; Fu, Qin

    2016-01-01

    Osteoporosis is characterized by the progressive loss of bone mass and the micro‑architectural deterioration of bone tissue, leading to bone fragility and an increased risk of fracture. Gallium has demonstrated efficacy in the treatment of several diverse disorders that are characterized by accelerated bone loss. Osteoblasts orchestrate bone degradation by expressing the receptor activator of NF‑κB ligand (RANKL), however they additionally protect the skeleton by secreting osteoprotegerin (OPG). Therefore, the relative concentration of RANKL and OPG in bone is a key determinant of bone mass and strength. The current study demonstrated that gallium nitrate (GaN) is able to counteract bone loss in an experimental model of established osteoporosis. Ovariectomized (OVX) rats exhibited significantly increased bone mineral density following GaN treatment for 4 and 8 weeks by 19.3 and 37.3%, respectively (P<0.05). The bone volume of the OVX + GaN group was increased by 40.9% (P<0.05) compared with the OVX group. In addition, the current study demonstrated that GaN stimulates the synthesis of OPG however has no effect on the expression of RANKL in osteoblasts, as demonstrated by RT‑qPCR, western blotting and ELISA, resulting in an increase in the OPG/RANKL ratio and a reduction in osteoclast differentiation in vivo and in vitro.

  9. Nuclear hormone receptors in podocytes

    PubMed Central

    2012-01-01

    Nuclear receptors are a family of ligand-activated, DNA sequence-specific transcription factors that regulate various aspects of animal development, cell proliferation, differentiation, and homeostasis. The physiological roles of nuclear receptors and their ligands have been intensively studied in cancer and metabolic syndrome. However, their role in kidney diseases is still evolving, despite their ligands being used clinically to treat renal diseases for decades. This review will discuss the progress of our understanding of the role of nuclear receptors and their ligands in kidney physiology with emphasis on their roles in treating glomerular disorders and podocyte injury repair responses. PMID:22995171

  10. Modulation of the ligand-field anisotropy in a series of ferric low-spin cytochrome c mutants derived from Pseudomonas aeruginosa cytochrome c-551 and Nitrosomonas europaea cytochrome c-552: a nuclear magnetic resonance and electron paramagnetic resonance study.

    PubMed

    Zoppellaro, Giorgio; Harbitz, Espen; Kaur, Ravinder; Ensign, Amy A; Bren, Kara L; Andersson, K Kristoffer

    2008-11-19

    Cytochromes of the c type with histidine-methionine (His-Met) heme axial ligation play important roles in electron-transfer reactions and in enzymes. In this work, two series of cytochrome c mutants derived from Pseudomonas aeruginosa (Pa c-551) and from the ammonia-oxidizing bacterium Nitrosomonas europaea (Ne c-552) were engineered and overexpressed. In these proteins, point mutations were induced in a key residue (Asn64) near the Met axial ligand; these mutations have a considerable impact both on heme ligand-field strength and on the Met orientation and dynamics (fluxionality), as judged by low-temperature electron paramagnetic resonance (EPR) and nuclear magnetic resonance (NMR) spectra. Ne c-552 has a ferric low-spin (S = 1/2) EPR signal characterized by large g anisotropy with g(max) resonance at 3.34; a similar large g(max) value EPR signal is found in the mitochondrial complex III cytochrome c1. In Ne c-552, deletion of Asn64 (NeN64Delta) changes the heme ligand field from more axial to rhombic (small g anisotropy and g(max) at 3.13) and furthermore hinders the Met fluxionality present in the wild-type protein. In Pa c-551 (g(max) at 3.20), replacement of Asn64 with valine (PaN64V) induces a decrease in the axial strain (g(max) at 3.05) and changes the Met configuration. Another set of mutants prepared by insertion (ins) and/or deletion (Delta) of a valine residue adjacent to Asn64, resulting in modifications in the length of the axial Met-donating loop (NeV65Delta, NeG50N/V65Delta, PaN50G/V65ins), did not result in appreciable alterations of the originally weak (Ne c-552) or very weak (Pa c-551) axial field but had an impact on Met orientation, fluxionality, and relaxation dynamics. Comparison of the electronic fingerprints in the overexpressed proteins and their mutants reveals a linear relationship between axial strain and average paramagnetic heme methyl shifts, irrespective of Met orientation or dynamics. Thus, for these His-Met axially coordinated Fe

  11. Syntheses, structures, and properties of high-nuclear 3d-4f clusters with amino acid as ligand: {Gd6Cu24}, {Tb6Cu26}, and {(Ln6Cu24)2Cu} (Ln = Sm, Gd).

    PubMed

    Zhang, Jian-Jun; Hu, Sheng-Min; Xiang, Sheng-Chang; Sheng, Tianlu; Wu, Xin-Tao; Li, Ya-Min

    2006-09-04

    Four novel high-nuclear 3d-4f heterometallic clusters were obtained through the self-assembly of Ln(III), Cu(II), and amino acid ligands (2-methylalanine (mAla), glycine (Gly), and L-proline (Pro), respectively). The metal skeleton of cluster 1, [Gd6Cu24(mu3-OH)30(mAla)16(ClO4)(H2O)22].(ClO4)17.(OH)2.(H2O)2(0), may be described as a huge {Gd6Cu12} octahedron connected with 12 additional Cu(II) ions. The structure of cluster 2, Na4[Tb6Cu26(mu3-OH)30(Gly)18(ClO4)(H2O)22].(ClO4)25.(H2O)42, may be described as a {Tb6Cu24} main structure connected with two [Cu(Gly)(H2O)2]+ groups. Compounds {[Ln6Cu24(mu3-OH)30(Pro)12(Ac)6(ClO4)(H2O)13]2Cu(Pro)2}.(ClO4)18.(OH)16.(H2O)55 (Ln= Sm (3), Gd (4)) are 61-nuclear clusters, which represent the largest known 3d-4f clusters so far, the structure can be described as two {Ln6Cu24} octahedral units connected by a trans-Cu(proline)2 bridge. The electrical conductivity measurements reveal that they are temperature-sensitive semiconductors. The magnetic susceptibility measurements display that compound 4 is ferromagnetic.

  12. Small GTPase Rho signaling is involved in {beta}1 integrin-mediated up-regulation of intercellular adhesion molecule 1 and receptor activator of nuclear factor {kappa}B ligand on osteoblasts and osteoclast maturation

    SciTech Connect

    Hirai, Fumihiko; Nakayamada, Shingo; Okada, Yosuke; Saito, Kazuyoshi; Kurose, Hitoshi; Mogami, Akira; Tanaka, Yoshiya . E-mail: tanaka@med.uoeh-u.ac.jp

    2007-04-27

    We assessed the characteristics of human osteoblasts, focusing on small GTPase Rho signaling. {beta}1 Integrin were highly expressed on osteoblasts. Engagement of {beta}1 integrins by type I collagen augmented expression of intercellular adhesion molecule 1 (ICAM-1) and receptor activator of nuclear factor {kappa}B ligand (RANKL) on osteoblasts. Rho was activated by {beta}1 stimulation in osteoblasts. {beta}1 Integrin-induced up-regulation of ICAM-1 and RANKL was inhibited by transfection with adenoviruses encoding C3 transferase or pretreated with Y-27632, specific Rho and Rho-kinase inhibitors. Engagement of {beta}1 integrin on osteoblasts induced formation of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells (MNC) in a coculture system of osteoblasts and peripheral monocytes, but this action was completely abrogated by transfection of C3 transferase. Our results indicate the direct involvement of Rho-mediated signaling in {beta}1 integrin-induced up-regulation of ICAM-1 and RANKL and RANKL-dependent osteoclast maturation. Thus, Rho-mediated signaling in osteoblasts seems to introduce major biases to bone resorption.

  13. An integrative approach combining ion mobility mass spectrometry, X-ray crystallography, and nuclear magnetic resonance spectroscopy to study the conformational dynamics of α1 -antitrypsin upon ligand binding.

    PubMed

    Nyon, Mun Peak; Prentice, Tanya; Day, Jemma; Kirkpatrick, John; Sivalingam, Ganesh N; Levy, Geraldine; Haq, Imran; Irving, James A; Lomas, David A; Christodoulou, John; Gooptu, Bibek; Thalassinos, Konstantinos

    2015-08-01

    Native mass spectrometry (MS) methods permit the study of multiple protein species within solution equilibria, whereas ion mobility (IM)-MS can report on conformational behavior of specific states. We used IM-MS to study a conformationally labile protein (α1 -antitrypsin) that undergoes pathological polymerization in the context of point mutations. The folded, native state of the Z-variant remains highly polymerogenic in physiological conditions despite only minor thermodynamic destabilization relative to the wild-type variant. Various data implicate kinetic instability (conformational lability within a native state ensemble) as the basis of Z α1 -antitrypsin polymerogenicity. We show the ability of IM-MS to track such disease-relevant conformational behavior in detail by studying the effects of peptide binding on α1 -antitrypsin conformation and dynamics. IM-MS is, therefore, an ideal platform for the screening of compounds that result in therapeutically beneficial kinetic stabilization of native α1 -antitrypsin. Our findings are confirmed with high-resolution X-ray crystallographic and nuclear magnetic resonance spectroscopic studies of the same event, which together dissect structural changes from dynamic effects caused by peptide binding at a residue-specific level. IM-MS methods, therefore, have great potential for further study of biologically relevant thermodynamic and kinetic instability of proteins and provide rapid and multidimensional characterization of ligand interactions of therapeutic interest.

  14. Receptor activator of nuclear factor kappa-B ligand (RANKL) but not sclerostin or gene polymorphisms is related to joint destruction in early rheumatoid arthritis.

    PubMed

    Boman, Antonia; Kokkonen, Heidi; Ärlestig, Lisbeth; Berglin, Ewa; Rantapää-Dahlqvist, Solbritt

    2017-02-11

    The aim of this study was to analyze relationships between receptor activator of nuclear factor kappa-B (RANKL), sclerostin and their gene polymorphisms with radiological progression in patients with early rheumatoid arthritis (RA). Patients with early RA (n = 407, symptomatic <1 year) (ARA criteria) examined radiologically at inclusion and after 24 months were consecutively included. Disease activity score and C-reactive protein were regularly recorded. Sclerostin, RANKL, and anti-CCP2 antibodies were analyzed in plasma at baseline using ELISAs. Data on gene polymorphism for sclerostin and RANKL were extracted from Immunochip analysis. Sex- and age-matched controls (n = 71) were identified from the Medical Biobank of Northern Sweden. The concentration of RANKL was significantly higher in patients compared with controls, median (IQR) 0.56 (0.9) nmol/L and 0.20 (0.25) nmol/L (p < 0.001), and in anti-CCP2-positive patients compared with sero-negative individuals. Sclerostin was significantly increased in female patients 0.59 (0.47-0.65) ng/mL compared with female controls 0.49 (0.4-0.65) ng/mL (p < 0.02). RANKL concentration was related to the Larsen score at baseline (p < 0.01), after 24 months (p < 0.001), and to radiological progression at 24 months (p < 0.001). Positivity of RANKL and anti-CCP2 yielded significant risk for progression with negativity for both as reference. No single nucleotide polymorphism encoding TNFSF11 or SOST was associated with increased concentrations of the factors. The concentration of RANKL was related to the Larsen score at baseline, at 24 months, and radiological progression at 24 months particularly in anti-CCP2-positive patients, while the concentration of sclerostin was unrelated to radiological findings.

  15. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial

    PubMed Central

    Neuschwander-Tetri, Brent A; Loomba, Rohit; Sanyal, Arun J; Lavine, Joel E; Van Natta, Mark L; Abdelmalek, Manal F; Chalasani, Naga; Dasarathy, Srinivasan; Diehl, Anna Mae; Hameed, Bilal; Kowdley, Kris V; McCullough, Arthur; Terrault, Norah; Clark, Jeanne M; Tonascia, James; Brunt, Elizabeth M; Kleiner, David E; Doo, Edward

    2015-01-01

    Summary Background The bile acid derivative 6-ethylchenodeoxycholic acid (obeticholic acid) is a potent activator of the farnesoid X nuclear receptor that reduces liver fat and fibrosis in animal models of fatty liver disease. We assessed the efficacy of obeticholic acid in adult patients with non-alcoholic steatohepatitis. Methods We did a multicentre, double-blind, placebo-controlled, parallel group, randomised clinical trial at medical centres in the USA in patients with non-cirrhotic, non-alcoholic steatohepatitis to assess treatment with obeticholic acid given orally (25 mg daily) or placebo for 72 weeks. Patients were randomly assigned 1:1 using a computer-generated, centrally administered procedure, stratified by clinical centre and diabetes status. The primary outcome measure was improvement in centrally scored liver histology defined as a decrease in non-alcoholic fatty liver disease activity score by at least 2 points without worsening of fibrosis from baseline to the end of treatment. A planned interim analysis of change in alanine aminotransferase at 24 weeks undertaken before end-of-treatment (72 weeks) biopsies supported the decision to continue the trial (relative change in alanine aminotransferase −24%, 95% CI −45 to −3). A planned interim analysis of the primary outcome showed improved efficacy of obeticholic acid (p=0·0024) and supported a decision not to do end-of-treatment biopsies and end treatment early in 64 patients, but to continue the trial to obtain the 24-week post-treatment measures. Analyses were done by intention-to-treat. This trial was registered with ClinicalTrials.gov, number NCT01265498. Findings Between March 16, 2011, and Dec 3, 2012, 141 patients were randomly assigned to receive obeticholic acid and 142 to placebo. 50 (45%) of 110 patients in the obeticholic acid group who were meant to have biopsies at baseline and 72 weeks had improved liver histology compared with 23 (21%) of 109 such patients in the placebo group

  16. All-inorganic Germanium nanocrystal films by cationic ligand exchange

    DOE PAGES

    Wheeler, Lance M.; Nichols, Asa W.; Chernomordik, Boris D.; ...

    2016-01-21

    In this study, we introduce a new paradigm for group IV nanocrystal surface chemistry based on room temperature surface activation that enables ionic ligand exchange. Germanium nanocrystals synthesized in a gas-phase plasma reactor are functionalized with labile, cationic alkylammonium ligands rather than with traditional covalently bound groups. We employ Fourier transform infrared and 1H nuclear magnetic resonance spectroscopies to demonstrate the alkylammonium ligands are freely exchanged on the germanium nanocrystal surface with a variety of cationic ligands, including short inorganic ligands such as ammonium and alkali metal cations. This ionic ligand exchange chemistry is used to demonstrate enhanced transport inmore » germanium nanocrystal films following ligand exchange as well as the first photovoltaic device based on an all-inorganic germanium nanocrystal absorber layer cast from solution. This new ligand chemistry should accelerate progress in utilizing germanium and other group IV nanocrystals for optoelectronic applications.« less

  17. All-Inorganic Germanium Nanocrystal Films by Cationic Ligand Exchange.

    PubMed

    Wheeler, Lance M; Nichols, Asa W; Chernomordik, Boris D; Anderson, Nicholas C; Beard, Matthew C; Neale, Nathan R

    2016-03-09

    We introduce a new paradigm for group IV nanocrystal surface chemistry based on room temperature surface activation that enables ionic ligand exchange. Germanium nanocrystals synthesized in a gas-phase plasma reactor are functionalized with labile, cationic alkylammonium ligands rather than with traditional covalently bound groups. We employ Fourier transform infrared and (1)H nuclear magnetic resonance spectroscopies to demonstrate the alkylammonium ligands are freely exchanged on the germanium nanocrystal surface with a variety of cationic ligands, including short inorganic ligands such as ammonium and alkali metal cations. This ionic ligand exchange chemistry is used to demonstrate enhanced transport in germanium nanocrystal films following ligand exchange as well as the first photovoltaic device based on an all-inorganic germanium nanocrystal absorber layer cast from solution. This new ligand chemistry should accelerate progress in utilizing germanium and other group IV nanocrystals for optoelectronic applications.

  18. All-inorganic Germanium nanocrystal films by cationic ligand exchange

    SciTech Connect

    Wheeler, Lance M.; Nichols, Asa W.; Chernomordik, Boris D.; Anderson, Nicholas C.; Beard, Matthew C.; Neale, Nathan R.

    2016-01-21

    In this study, we introduce a new paradigm for group IV nanocrystal surface chemistry based on room temperature surface activation that enables ionic ligand exchange. Germanium nanocrystals synthesized in a gas-phase plasma reactor are functionalized with labile, cationic alkylammonium ligands rather than with traditional covalently bound groups. We employ Fourier transform infrared and 1H nuclear magnetic resonance spectroscopies to demonstrate the alkylammonium ligands are freely exchanged on the germanium nanocrystal surface with a variety of cationic ligands, including short inorganic ligands such as ammonium and alkali metal cations. This ionic ligand exchange chemistry is used to demonstrate enhanced transport in germanium nanocrystal films following ligand exchange as well as the first photovoltaic device based on an all-inorganic germanium nanocrystal absorber layer cast from solution. This new ligand chemistry should accelerate progress in utilizing germanium and other group IV nanocrystals for optoelectronic applications.

  19. Methylation status of a single CpG locus 3 bases upstream of TATA-box of receptor activator of nuclear factor-kappaB ligand (RANKL) gene promoter modulates cell- and tissue-specific RANKL expression and osteoclastogenesis.

    PubMed

    Kitazawa, Riko; Kitazawa, Sohei

    2007-01-01

    Receptor activator of nuclear factor-kappaB ligand (RANKL) expression is tissue specific and limited to certain subsets of T-lymphocytes and stromal/osteoblastic cells. Even among osteoblasts, RANKL is expressed on about 20% of osteoblasts of the normal mouse. To clarify the mechanism of population-specific RANKL expression, we analyzed the effect of CpG methylation on its transcription, mRNA and protein expression as well as on osteoclastogenesis. Subpopulations of ST2 cells were used: P9, which expresses RANKL and supports osteoclastogenesis, and P16, which does not. By sodium bisulfite mapping, the rate of CpG methylation of the -65/+350 region, especially of CpG locus no. 1 three bases upstream of the TATA-box, was higher in P16 than in P9 ST2 cells. ChIP and gel shift assay showed that methylated CpG locus no. 1 was a target of MeCP2 binding that, in turn, blocked the binding of the TATA-box binding protein to the TATA-box. In vitro methylation by SssI of the promoter construct reduced its transcriptional activity at the steady state and its response to 1alpha,25(OH)2 vitamin D3. Conversely, treatment with DNA methylase inhibitor, 5-aza-2'-deoxycytidine, significantly restored RANKL expression and osteoclastogenesis in P16 cells. Except for primary cultured osteoblasts, CpG locus no. 1 was frequently methylated in various normal mouse tissues. We propose that the methylation status of the CpG locus three bases upstream of the TATA-box modulates the control of cell- and tissue-specific expression of RANKL gene and osteoclastogenesis. The heterogeneity of stromal/ osteoblastic cells in response to bone-resorbing stimuli may be attributed, in part, to the methylation status of the RANKL gene promoter.

  20. Modeling of the Aryl Hydrocarbon Receptor (AhR) ligand binding domain and its utility in virtual ligand screening to predict new AhR ligands

    PubMed Central

    Bisson, William; Koch, Daniel; O’Donnell, Edmond; Khalil, Sammy M.; Kerkvliet, Nancy; Tanguay, Robert; Abagyan, Ruben; Kolluri, Siva Kumar

    2012-01-01

    The Aryl Hydrocarbon Receptor (AhR) is a ligand-activated transcription factor; the AhR Per-AhR/Arnt-Sim (PAS) domain binds ligands. We developed homology models of the AhR PAS domain to characterize previously observed intra- and inter-species differences in ligand binding using Molecular Docking. In silico structure-based virtual ligand screening using our model resulted in the identification of pinocembrin and 5-hydroxy-7-methoxyflavone, which promoted nuclear translocation and transcriptional activation of AhR and AhR-dependent induction of endogenous target genes. PMID:19719119

  1. The Retinoid X Receptors and Their Ligands

    PubMed Central

    Dawson, Marcia I.; Xia, Zebin

    2014-01-01

    This chapter presents an overview of the current status of studies on the structural and molecular biology of the retinoid X receptor subtypes α, β, and γ (RXRs, NR2B1–3), their nuclear and cytoplasmic functions, post-transcriptional processing, and recently reported ligands. Points of interest are the different changes in the ligand-binding pocket induced by variously shaped agonists, the communication of the ligand–bound pocket with the coactivator binding surface and the heterodimerization interface, and recently identified ligands that are natural products, those that function as environmental toxins or drugs that had been originally designed to interact with other targets, as well as those that were deliberately designed as RXR-selective transcriptional agonists, synergists, or antagonists. Of these synthetic ligands, the general trend in design appears to be away from fully aromatic rigid structures to those containing partial elements of the flexible tetraene side chain of 9-cis-retinoic acid. PMID:22020178

  2. Serum osteoprotegerin and soluble receptor activator of nuclear factor kappaB ligand levels in patients with a history of differentiated thyroid carcinoma: a case-controlled cohort study.

    PubMed

    Giusti, Massimo; Cecoli, Francesca; Fazzuoli, Laura; De Franchis, Vincenzina; Ceresola, Enrica; Ferone, Diego; Mussap, Michele; Minuto, Francesco

    2007-05-01

    Overt hyperthyroidism is associated with changes in bone metabolism, whereas the effect of levothyroxine (L-T4) load in patients with differentiated thyroid carcinoma (DTC) is controversial. The aim of our study was to evaluate osteoprotegerin (OPG) and soluble receptor activator of nuclear factor kappaB ligand (RANK-L) in patients with DTC with suppressed endogenous thyrotropin due to L-T4 regimen. A cohort of 80 subjects with DTC (68 women and 12 men; age range, 27-81 years) was studied. A cohort of 55 subjects with a history of partial or total surgery for nonmalignant thyroid pathology served as a control group. Groups were matched for sex, age, and body mass index. Per-week dosage of L-T4 was significantly higher in patients with DTC than in controls (P < .001). More elevated free T(4) concentrations (P < .001) and more suppressed thyrotropin and thyroglobulin levels (P < .001) were found in subjects with DTC than in controls. No difference in serum or urinary parameters related to bone metabolism or dual-energy x-ray absorptiometry was noted between the groups. Overall, OPG levels were similar in both groups but were significantly (P = .03) lower in postmenopausal women with DTC than in postmenopausal control women. Only control women showed lower OPG levels in premenopausal than in postmenopausal (P = .002) conditions. Overall, RANK-L levels were significantly higher (P = .03) in subjects with DTC than in controls. In both groups, OPG and RANK-L levels were unrelated to each other. A significant positive correlation was seen between OPG levels and age in both subjects with DTC (P < .001) and controls (P < .001). Serum RANK-L correlated negatively with age in subjects with DTC (P = .05). Although there were several differences in L-T4 dosages, OPG and RANK-L levels were similar in patients with a history of DTC and those with a history of nonmalignant thyroid diseases. The correlation between circulating OPG and RANK-L levels was not significant. The increase

  3. Constitutive expression of cathepsin K in the human intervertebral disc: new insight into disc extracellular matrix remodeling via cathepsin K and receptor activator of nuclear factor-κB ligand

    PubMed Central

    2011-01-01

    Introduction Cathepsin K is a recently discovered cysteine protease which cleaves the triple helical domains of type I to II collagen. It has been shown to be up-regulated in synovial tissue from osteoarthritic and rheumatoid patients, and is a component in normal and nonarthritic cartilage, where it increases with aging. Studies on heart valve development have recently shown that receptor activator of nuclear factor-κB ligand (RANKL) acts during valve remodeling to promote cathepsin K expression. Since extracellular matrix remodeling is a critical component of disc structure and biomechanical function, we hypothesized that cathepsin K and RANKL may be present in the human intervertebral disc. Methods Studies were performed following approval of the authors' Human Subjects Institutional Review Board. Six annulus specimens from healthier Thompson grade I to II discs, and 12 specimens from more degenerate grade III to IV discs were utilized in microarray analysis of RANKL and cathepsin K gene expression. Immunohistochemistry was also performed on 15 additional disc specimens to assess the presence of RANKL and cathepsin K. Results Cathepsin K gene expression was significantly greater in more degenerated grade III to IV discs compared to healthier grade I to II discs (P = 0.001). RANKL was also identified with immunohistochemistry and molecular analyses. RANKL gene expression was also significantly greater in more degenerated discs compared to healthier ones (P = 0.0001). A significant linear positive correlation was identified between expression of cathepsin K and RANKL (r2 = 92.2; P < 0.0001). Conclusions Extracellular matrix remodeling is a key element of disc biology. Our use of an appropriate antibody and gene expression studies showed that cathepsin K is indeed present in the human intervertebral disc. Immunolocalization and molecular analyses also confirmed that RANKL is present in the human disc. Expression of RANKL was found to be significantly greater in

  4. Targeting nuclear receptors with marine natural products.

    PubMed

    Yang, Chunyan; Li, Qianrong; Li, Yong

    2014-01-27

    Nuclear receptors (NRs) are important pharmaceutical targets because they are key regulators of many metabolic and inflammatory diseases, including diabetes, dyslipidemia, cirrhosis, and fibrosis. As ligands play a pivotal role in modulating nuclear receptor activity, the discovery of novel ligands for nuclear receptors represents an interesting and promising therapeutic approach. The search for novel NR agonists and antagonists with enhanced selectivities prompted the exploration of the extraordinary chemical diversity associated with natural products. Recent studies involving nuclear receptors have disclosed a number of natural products as nuclear receptor ligands, serving to re-emphasize the translational possibilities of natural products in drug discovery. In this review, the natural ligands of nuclear receptors will be described with an emphasis on their mechanisms of action and their therapeutic potentials, as well as on strategies to determine potential marine natural products as nuclear receptor modulators.

  5. A tetra­nuclear cubane-like nickel(II) complex with a tridentate salicyl­idene­imine Schiff base ligand: tetra­kis­[μ3-4-methyl-N-(2-oxidophen­yl)salicylideneiminato]tetra­kis­[methano­lnickel(II)] methanol 0.8-solvate

    PubMed Central

    Pavlović, Gordana; Majer, Mihael; Cindrić, Marina

    2016-01-01

    The tetra­nuclear title complex, [Ni4(C14H11NO2)4(CH3OH)4]·0.8CH3OH, has a distorted cubane topology shaped by four Schiff base ligands. The cubane [Ni4(μ3-O4)] core is formed via the O atoms from the Schiff base ligands. The octa­hedrally coordinated NiII ions occupy alternating vertices of the cube. Each NiII ion is coordinated by one O,N,O′-tridentate dianionic ligand, two O atoms of oxidophenyl groups from adjacent ligands and the O atom of a coordinating methanol mol­ecule. The cubane core is stabilized via an intra­molecular O—H⋯O hydrogen bond between the hy­droxy group of the coordinating methanol mol­ecules and the phenolate O atom of the aldehyde Schiff base fragment. Additional stabilization is obtained via intra­molecular C—H⋯O hydrogen bonds involving aromatic C—H groups and the oxygen atoms of adjacent methanol mol­ecules. In the crystal, complex mol­ecules are linked into chains parallel to the c axis via weak C—H⋯O hydrogen bonds. The partial-occupancy disordered methanol solvent mol­ecule has a site occupancy of 0.8 and is linked to the tetra­nuclear unit via an inter­molecular C—H⋯O hydrogen bond involving a phenolate O atom. PMID:27980828

  6. Differences in Gene Regulation by Dual Ligands of Nuclear Receptors Constitutive Androstane Receptor (CAR) and Pregnane X Receptor (PXR) in HepG2 Cells Stably Expressing CAR/PXR.

    PubMed

    Kanno, Yuichiro; Tanuma, Nobuaki; Yazawa, Saki; Zhao, Shuai; Inaba, Miki; Nakamura, Satoshi; Nemoto, Kiyomitsu; Inouye, Yoshio

    2016-08-01

    The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) regulate various genes involved in xenobiotics and drug metabolism. In many cases, CAR/PXR share ligands termed dual ligands of CAR/PXR. It is difficult to investigate the effect of CAR/PXR dual ligands in cell lines because CAR and PXR expression is scarcely detected in cultured cell lines. Here, we established a tetracycline-inducible human CAR and stably human PXR-overexpressing HepG2 cell line (HepTR/hCAR/hPXR) to examine CAR/PXR dual ligands. In the present study, we investigated the regulation of CYP2B6, CYP2C9, CYP3A4, and UDP-glucuronosyl transferase, which are target genes of CAR/PXR, by dual ligands of CAR/PXR in two transfectants. Activation of CAR and PXR in cells treated with a high dose of CITCO [6-(4-chlorophenyl)-imidazo(2,1-b)thiazole-5-carbaldehyde] or cotreated with rifampicin and tetracycline resulted in synergistic enhancement of CYP3A4, but not CYP2B6, CYP2C9, or UGT1A1, mRNA expression in HepTR/hCAR/hPXR cells. In contrast, this synergistic effect was not observed in HepTR/hCAR cells. These observations were also demonstrated in human primary hepatocytes. Taken together, our results suggest that dual ligands of CAR/PXR show distinct gene regulation patterns by cross-talk between CAR and PXR. Furthermore, the two newly established cell lines are useful tools to investigate dual ligands of CAR/PXR.

  7. NMR-based analysis of protein-ligand interactions.

    PubMed

    Cala, Olivier; Guillière, Florence; Krimm, Isabelle

    2014-02-01

    Physiological processes are mainly controlled by intermolecular recognition mechanisms involving protein-protein and protein-ligand (low molecular weight molecules) interactions. One of the most important tools for probing these interactions is high-field solution nuclear magnetic resonance (NMR) through protein-observed and ligand-observed experiments, where the protein receptor or the organic compounds are selectively detected. NMR binding experiments rely on comparison of NMR parameters of the free and bound states of the molecules. Ligand-observed methods are not limited by the protein molecular size and therefore have great applicability for analysing protein-ligand interactions. The use of these NMR techniques has considerably expanded in recent years, both in chemical biology and in drug discovery. We review here three major ligand-observed NMR methods that depend on the nuclear Overhauser effect-transferred nuclear Overhauser effect spectroscopy, saturation transfer difference spectroscopy and water-ligand interactions observed via gradient spectroscopy experiments-with the aim of reporting recent developments and applications for the characterization of protein-ligand complexes, including affinity measurements and structural determination.

  8. Distal and proximal ligand interactions in heme proteins: correlations between C-O and Fe-C vibrational frequencies, oxygen-17 and carbon-13 nuclear magnetic resonance chemical shifts, and oxygen-17 nuclear quadrupole coupling constants in C17O- and 13CO-labeled species.

    PubMed

    Park, K D; Guo, K M; Adebodun, F; Chiu, M L; Sligar, S G; Oldfield, E

    1991-03-05

    We have obtained the oxygen-17 nuclear magnetic resonance (NMR) spectra of a variety of C17O-labeled heme proteins, including sperm whale (Physeter catodon) myoglobin, two synthetic sperm whale myoglobin mutants (His E7----Val E7; His E7----Phe E7), adult human hemoglobin, rabbit (Oryctolagus cuniculus) hemoglobin, horseradish (Cochlearia armoracia) peroxidase (E.C. 1.11.1.7) isoenzymes A and C, and Caldariomyces fumago chloroperoxidase (E.C. 1.11.1.10), in some cases as a function of pH, and have determined their isotropic 17O NMR chemical shifts, delta i, and spin-lattice relaxation times, T1. We have also obtained similar results on a picket fence prophyrin, [5,10,15,20-tetrakis(alpha, alpha, alpha, alpha, alpha-pivalamidophenyl)porphyrinato]iron(II) (1-MeIm)CO, both in solution and in the solid state. Our results show an excellent correlation between the infrared C-O vibrational frequencies, v(C-O), and delta i, between v(C-O) and the 17O nuclear quadrupole coupling constant (e2qQ/h, derived from T1), and as expected between e2qQ/h and delta i. Taken together with the work of others on the 13C NMR of 13CO-labeled proteins, where we find an excellent correlation between delta i(13C) and v(Fe-C), our results suggest that IR and NMR measurements reflect the same interaction, which is thought to be primarily the degree of pi-back-bonding from Fe d to CO pi* orbitals, as outlined previously [Li, X.-Y., & Spiro, T.G. (1988) J. Am. Chem. Soc. 110, 6024]. The modulation of this interaction by the local charge field of the distal heme residue (histidine, glutamine, arginine, and possibly lysine) in a variety of species and mutants, as reflected in the NMR and IR measurements, is discussed, as is the effect of cysteine as the proximal heme ligand.

  9. Differential Effects of TR Ligands on Hormone Dissociation Rates: Evidence for Multiple Ligand Entry/Exit Pathways

    PubMed Central

    Lima, Suzana T. Cunha; Nguyen, Ngoc-Ha; Togashi, Marie; Apriletti, James W.; Nguyen, Phuong; Polikarpov, Igor; Scanlan, Thomas S.; Baxter, John D.; Webb, Paul

    2009-01-01

    Some nuclear receptor (NR) ligands promote dissociation of radiolabeled bound hormone from the buried ligand binding cavity (LBC) more rapidly than excess unlabeled hormone itself. This result was interpreted to mean that challenger ligands bind allosteric sites on the LBD to induce hormone dissociation, and recent findings indicate that ligands bind weakly to multiple sites on the LBD surface. Here, we show that a large fraction of thyroid hormone receptor (TR) ligands promote rapid dissociation (T1/2 <2 hours) of radiolabeled T3 versus T3 (T1/2 ≈5–7 hours). We cannot discern relationships between this effect and ligand size, activity or affinity for TRβ. One ligand, GC-24, binds the TR LBC and (weakly) to the TRβ-LBD surface that mediates dimer/heterodimer interaction, but we cannot link this interaction to rapid T3 dissociation. Instead, several lines of evidence suggest that the challenger ligand must interact with the buried LBC to promote rapid T3 release. Since previous molecular dynamics simulations suggest that TR ligands leave the LBC by several routes, we propose that a subset of challenger ligands binds and stabilizes a partially unfolded intermediate state of TR that arises during T3 release and that this effect enhances hormone dissociation. PMID:19729063

  10. Selective oxoanion separation using a tripodal ligand

    DOEpatents

    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.

  11. A screening cascade to identify ERβ ligands

    PubMed Central

    Filgueira, Carly S.; Benod, Cindy; Lou, Xiaohua; Gunamalai, Prem S.; Villagomez, Rosa A.; Strom, Anders; Gustafsson, Jan-Åke; Berkenstam, Anders L.; Webb, Paul

    2014-01-01

    The establishment of effective high throughput screening cascades to identify nuclear receptor (NR) ligands that will trigger defined, therapeutically useful sets of NR activities is of considerable importance. Repositioning of existing approved drugs with known side effect profiles can provide advantages because de novo drug design suffers from high developmental failure rates and undesirable side effects which have dramatically increased costs. Ligands that target estrogen receptor β (ERβ) could be useful in a variety of diseases ranging from cancer to neurological to cardiovascular disorders. In this context, it is important to minimize cross-reactivity with ERα, which has been shown to trigger increased rates of several types of cancer. Because of high sequence similarities between the ligand binding domains of ERα and ERβ, preferentially targeting one subtype can prove challenging. Here, we describe a sequential ligand screening approach comprised of complementary in-house assays to identify small molecules that are selective for ERβ. Methods include differential scanning fluorimetry, fluorescence polarization and a GAL4 transactivation assay. We used this strategy to screen several commercially-available chemical libraries, identifying thirty ERβ binders that were examined for their selectivity for ERβ versus ERα, and tested the effects of selected ligands in a prostate cancer cell proliferation assay. We suggest that this approach could be used to rapidly identify candidates for drug repurposing. PMID:25422593

  12. Ligand binding was acquired during evolution of nuclear receptors

    PubMed Central

    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 organisms. The analysis of the NR gene duplication pattern during the evolution of metazoans shows that the present NR diversity arose from two waves of gene duplications. Strikingly, our results suggest that the ancestral NR was an orphan receptor that acquired ligand-binding ability during subsequent evolution. PMID:9192646

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

    PubMed

    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.

  14. Identification of Ligand-Receptor Interactions: Ligand Molecular Arrays, SPR and NMR Methodologies.

    PubMed

    Day, Christopher J; Hartley-Tassell, Lauren E; Korolik, Victoria

    2017-01-01

    Despite many years of research into bacterial chemotaxis, the only well characterized system to date is that of E. coli. Even for E. coli, the direct ligand binding had been fully characterized only for aspartate and serene receptors Tar and Tsr. In 30 years since, no other direct receptor-ligand interaction had been described for bacteria, until the characterization of the C. jejuni aspartate and multiligand receptors (Hartley-Tassell et al. Mol Microbiol 75:710-730, 2010). While signal transduction components of many sensory pathways have now been characterized, ligand-receptor interactions remain elusive due to paucity of high-throughput screening methods. Here, we describe the use of microarray screening we developed to identify ligands, surface plasmon resonance, and saturation transfer difference nuclear magnetic resonance (STD-NMR) we used to verify the hits and to determine the affinity constants of the interactions, allowing for more targeted verification of ligands with traditional chemotaxis and in vivo assays described in Chapter 13 .

  15. Ligand fitting with CCP4

    PubMed Central

    2017-01-01

    Crystal structures of protein–ligand complexes are often used to infer biology and inform structure-based drug discovery. Hence, it is important to build accurate, reliable models of ligands that give confidence in the interpretation of the respective protein–ligand complex. This paper discusses key stages in the ligand-fitting process, including ligand binding-site identification, ligand description and conformer generation, ligand fitting, refinement and subsequent validation. The CCP4 suite contains a number of software tools that facilitate this task: AceDRG for the creation of ligand descriptions and conformers, Lidia and JLigand for two-dimensional and three-dimensional ligand editing and visual analysis, Coot for density interpretation, ligand fitting, analysis and validation, and REFMAC5 for macromolecular refinement. In addition to recent advancements in automatic carbohydrate building in Coot (LO/Carb) and ligand-validation tools (FLEV), the release of the CCP4i2 GUI provides an integrated solution that streamlines the ligand-fitting workflow, seamlessly passing results from one program to the next. The ligand-fitting process is illustrated using instructive practical examples, including problematic cases such as post-translational modifications, highlighting the need for careful analysis and rigorous validation. PMID:28177312

  16. Catalytic dioxygen activation by Co(II) complexes employing a coordinatively versatile ligand scaffold.

    PubMed

    Sharma, Savita K; May, Philip S; Jones, Matthew B; Lense, Sheri; Hardcastle, Kenneth I; MacBeth, Cora E

    2011-02-14

    The ligand bis(2-isobutyrylamidophenyl)amine has been prepared and used to stabilize both mononuclear and dinuclear cobalt(II) complexes. The nuclearity of the cobalt product is regulated by the deprotonation state of the ligand. Both complexes catalytically oxidize triphenylphosphine to triphenylphosphine oxide in the presence of O(2).

  17. Regulation of cytochrome P450 (CYP) genes by nuclear receptors.

    PubMed Central

    Honkakoski, P; Negishi, M

    2000-01-01

    Members of the nuclear-receptor superfamily mediate crucial physiological functions by regulating the synthesis of their target genes. Nuclear receptors are usually activated by ligand binding. Cytochrome P450 (CYP) isoforms often catalyse both formation and degradation of these ligands. CYPs also metabolize many exogenous compounds, some of which may act as activators of nuclear receptors and disruptors of endocrine and cellular homoeostasis. This review summarizes recent findings that indicate that major classes of CYP genes are selectively regulated by certain ligand-activated nuclear receptors, thus creating tightly controlled networks. PMID:10749660

  18. RXR function requires binding to an endogenous terpenoid ligand

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The issue of whether the nuclear receptor RXR must bind to an endogenous, nanomolar affinity ligand in order to perform its natural function is still unsettled (1). On the basis of our previous studies establishing that the Drosophilamelanogaster ortholog of the retinoid X receptor ("ultraspiracle,"...

  19. LigandRNA: computational predictor of RNA-ligand interactions.

    PubMed

    Philips, Anna; Milanowska, Kaja; Lach, Grzegorz; Bujnicki, Janusz M

    2013-12-01

    RNA molecules have recently become attractive as potential drug targets due to the increased awareness of their importance in key biological processes. The increase of the number of experimentally determined RNA 3D structures enabled structure-based searches for small molecules that can specifically bind to defined sites in RNA molecules, thereby blocking or otherwise modulating their function. However, as of yet, computational methods for structure-based docking of small molecule ligands to RNA molecules are not as well established as analogous methods for protein-ligand docking. This motivated us to create LigandRNA, a scoring function for the prediction of RNA-small molecule interactions. Our method employs a grid-based algorithm and a knowledge-based potential derived from ligand-binding sites in the experimentally solved RNA-ligand complexes. As an input, LigandRNA takes an RNA receptor file and a file with ligand poses. As an output, it returns a ranking of the poses according to their score. The predictive power of LigandRNA favorably compares to five other publicly available methods. We found that the combination of LigandRNA and Dock6 into a "meta-predictor" leads to further improvement in the identification of near-native ligand poses. The LigandRNA program is available free of charge as a web server at http://ligandrna.genesilico.pl.

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

    DOEpatents

    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.

  1. Brain endogenous liver X receptor ligands selectively promote midbrain neurogenesis.

    PubMed

    Theofilopoulos, Spyridon; Wang, Yuqin; Kitambi, Satish Srinivas; Sacchetti, Paola; Sousa, Kyle M; Bodin, Karl; Kirk, Jayne; Saltó, Carmen; Gustafsson, Magnus; Toledo, Enrique M; Karu, Kersti; Gustafsson, Jan-Åke; Steffensen, Knut R; Ernfors, Patrik; Sjövall, Jan; Griffiths, William J; Arenas, Ernest

    2013-02-01

    Liver X receptors (Lxrα and Lxrβ) are ligand-dependent nuclear receptors critical for ventral midbrain neurogenesis in vivo. However, no endogenous midbrain Lxr ligand has so far been identified. Here we used LC/MS and functional assays to identify cholic acid as a new Lxr ligand. Moreover, 24(S),25-epoxycholesterol (24,25-EC) was found to be the most potent and abundant Lxr ligand in the developing mouse midbrain. Both Lxr ligands promoted neural development in an Lxr-dependent manner in zebrafish in vivo. Notably, each ligand selectively regulated the development of distinct midbrain neuronal populations. Whereas cholic acid increased survival and neurogenesis of Brn3a-positive red nucleus neurons, 24,25-EC promoted dopaminergic neurogenesis. These results identify an entirely new class of highly selective and cell type-specific regulators of neurogenesis and neuronal survival. Moreover, 24,25-EC promoted dopaminergic differentiation of embryonic stem cells, suggesting that Lxr ligands may thus contribute to the development of cell replacement and regenerative therapies for Parkinson's disease.

  2. Novel biosensors for the detection of estrogen receptor ligands.

    PubMed

    De, Siddhartha; Macara, Ian G; Lannigan, Deborah A

    2005-08-01

    There exists a significant need for the detection of novel estrogen receptor (ER) ligands for pharmaceutical uses, especially for treating complications associated with menopause. We have developed fluorescence resonance energy transfer (FRET)-based biosensors that permit the direct in vitro detection of ER ligands. These biosensors contain an ER ligand-binding domain (LBD) flanked by the FRET donor fluorophore, cyan fluorescent protein (CFP), and the acceptor fluorophore, yellow fluorescent protein (YFP). The ER-LBD has been modified so that Ala 430 has been changed to Asp, which increases the magnitude of the FRET signal in response to ligand-binding by more than four-fold compared to the wild-type LBD. The binding of agonists can be distinguished from that of antagonists on the basis of the distinct ligand-induced conformations in the ER-LBD. The approach to binding equilibrium occurs within 30min, and the FRET signal is stable over 24h. The biosensor demonstrates a high signal-to-noise, with a Z' value (a statistical determinant of assay quality) of 0.72. The affinity of the ER for different ligands can be determined using a modified version of the biosensor in which a truncated YFP and an enhanced CFP are used. Thus, we have developed platforms for high-throughput screens for the identification of novel estrogen receptor ligands. Moreover, we have demonstrated that this FRET technology can be applied to other nuclear receptors, such as the androgen receptor.

  3. EGF receptor ligands: recent advances

    PubMed Central

    Singh, Bhuminder; Carpenter, Graham; Coffey, Robert J.

    2016-01-01

    Seven ligands bind to and activate the mammalian epidermal growth factor (EGF) receptor (EGFR/ERBB1/HER1): EGF, transforming growth factor-alpha (TGFA), heparin-binding EGF-like growth factor (HBEGF), betacellulin (BTC), amphiregulin (AREG), epiregulin (EREG), and epigen (EPGN). Of these, EGF, TGFA, HBEGF, and BTC are thought to be high-affinity ligands, whereas AREG, EREG, and EPGN constitute low-affinity ligands. This focused review is meant to highlight recent studies related to actions of the individual EGFR ligands, the interesting biology that has been uncovered, and relevant advances related to ligand interactions with the EGFR. PMID:27635238

  4. Inhibition of Osteocyte Apoptosis Prevents the Increase in Osteocytic Receptor Activator of Nuclear Factor κB Ligand (RANKL) but Does Not Stop Bone Resorption or the Loss of Bone Induced by Unloading*

    PubMed Central

    Plotkin, Lilian I.; Gortazar, Arancha R.; Davis, Hannah M.; Condon, Keith W.; Gabilondo, Hugo; Maycas, Marta; Allen, Matthew R.; Bellido, Teresita

    2015-01-01

    Apoptosis of osteocytes and osteoblasts precedes bone resorption and bone loss with reduced mechanical stimulation, and receptor activator of NF-κB ligand (RANKL) expression is increased with unloading in mice. Because osteocytes are major RANKL producers, we hypothesized that apoptotic osteocytes signal to neighboring osteocytes to increase RANKL expression, which, in turn, increases osteoclastogenesis and bone resorption. The traditional bisphosphonate (BP) alendronate (Aln) or IG9402, a BP analog that does not inhibit resorption, prevented the increase in osteocyte apoptosis and osteocytic RANKL expression. The BPs also inhibited osteoblast apoptosis but did not prevent the increase in osteoblastic RANKL. Unloaded mice exhibited high serum levels of the bone resorption marker C-telopeptide fragments of type I collagen (CTX), elevated osteoclastogenesis, and increased osteoclasts in bone. Aln, but not IG9402, prevented all of these effects. In addition, Aln prevented the reduction in spinal and femoral bone mineral density, spinal bone volume/tissue volume, trabecular thickness, mechanical strength, and material strength induced by unloading. Although IG9402 did not prevent the loss of bone mass, it partially prevented the loss of strength, suggesting a contribution of osteocyte viability to strength independent of bone mass. These results demonstrate that osteocyte apoptosis leads to increased osteocytic RANKL. However, blockade of these events is not sufficient to restrain osteoclast formation, inhibit resorption, or stop bone loss induced by skeletal unloading. PMID:26085098

  5. Theoretical Study of the Electrostatic and Steric Effects on the Spectroscopic Characteristics of the Metal-Ligand Unit of Heme Proteins. 2. C-O Vibrational Frequencies, 17O Isotropic Chemical Shifts, and Nuclear Quadrupole Coupling Constants

    PubMed Central

    Kushkuley, Boris; Stavrov, Solomon S.

    1997-01-01

    The quantum chemical calculations, vibronic theory of activation, and London-Pople approach are used to study the dependence of the C-O vibrational frequency, 17O isotropic chemical shift, and nuclear quadrupole coupling constant on the distortion of the porphyrin ring and geometry of the CO coordination, changes in the iron-carbon and iron-imidazole distances, magnitude of the iron displacement out of the porphyrin plane, and presence of the charged groups in the heme environment. It is shown that only the electrostatic interactions can cause the variation of all these parameters experimentally observed in different heme proteins, and the heme distortions could modulate this variation. The correlations between the theoretically calculated parameters are shown to be close to the experimentally observed ones. The study of the effect of the electric field of the distal histidine shows that the presence of the four C-O vibrational bands in the infrared absorption spectra of the carbon monoxide complexes of different myoglobins and hemoglobins can be caused by the different orientations of the different tautomeric forms of the distal histidine. The dependence of the 17O isotropic chemical shift and nuclear quadrupole coupling constant on pH and the distal histidine substitution can be also explained from the same point of view. PMID:9017215

  6. Investigations into the synthesis and fluorescence properties of Tb(III) complexes of a novel bis-β-diketone-type ligand and a novel bispyrazole ligand

    NASA Astrophysics Data System (ADS)

    Xiao, Lin-Xiang; Luo, Yi-Ming; Chen, Zhe; Li, Jun; Tang, Rui-Ren

    2008-11-01

    A novel bis-β-diketone organic ligand, 1,1'-(2,6-bispyridyl)bis-3-( p-methoxyphenyl)-1,3-propanedione (L 1) and its derivatives, a novel bispyrazole ligand, 2,6-bis(5-(4-methoxyphenyl)-1H-pyrazol-3-yl)pyridine (L 2) were designed and synthesized and their complexes with Tb(III) ion were successfully prepared. The ligands and the corresponding metal complexes were characterized by elemental analysis, infrared, proton nuclear magnetic resonance spectroscopy and TG-DTA. Analysis of the IR spectra suggested that the lanthanide metal ion Tb(III) coordinated to the ligands via the nitrogen atom of the pyridine ring and the carbonyl oxygen atoms for ligand L 1 and the nitrogen atom of the pyrazole ring for ligand L 2. The fluorescence properties of the two complexes in solid state were investigated and it was discovered that the Tb(III) ions could be sensitized by both the ligand (L 1) and ligand (L 2) to some extent. In particular, the complex of ligand (L 2) is a better green luminescent material that could be used as a candidate material in organic light-emitting devices (OLEDs) since it could be much better sensitized by the ligand (L 2), and the fluorescence intensity of Tb(III) complex of L 2 are almost as twice strong as L 1's.

  7. Investigations into the synthesis and fluorescence properties of Tb(III) complexes of a novel bis-beta-diketone-type ligand and a novel bispyrazole ligand.

    PubMed

    Xiao, Lin-Xiang; Luo, Yi-Ming; Chen, Zhe; Li, Jun; Tang, Rui-Ren

    2008-11-15

    A novel bis-beta-diketone organic ligand, 1,1'-(2,6-bispyridyl)bis-3-(p-methoxyphenyl)-1,3-propanedione (L1) and its derivatives, a novel bispyrazole ligand, 2,6-bis(5-(4-methoxyphenyl)-1H-pyrazol-3-yl)pyridine (L2) were designed and synthesized and their complexes with Tb(III) ion were successfully prepared. The ligands and the corresponding metal complexes were characterized by elemental analysis, infrared, proton nuclear magnetic resonance spectroscopy and TG-DTA. Analysis of the IR spectra suggested that the lanthanide metal ion Tb(III) coordinated to the ligands via the nitrogen atom of the pyridine ring and the carbonyl oxygen atoms for ligand L1 and the nitrogen atom of the pyrazole ring for ligand L2. The fluorescence properties of the two complexes in solid state were investigated and it was discovered that the Tb(III) ions could be sensitized by both the ligand (L1) and ligand (L2) to some extent. In particular, the complex of ligand (L2) is a better green luminescent material that could be used as a candidate material in organic light-emitting devices (OLEDs) since it could be much better sensitized by the ligand (L2), and the fluorescence intensity of Tb(III) complex of L2 are almost as twice strong as L1's.

  8. Structures and regulation of non-X orphan nuclear receptors: A retinoid hypothesis.

    PubMed

    Zhi, Xiaoyong; Zhou, X Edward; Melcher, Karsten; Xu, H Eric

    2016-03-01

    Nuclear receptors are defined as a family of ligand regulated transcription factors [1-6]. While this definition reflects that ligand binding is a key property of nuclear receptors, it is still a heated subject of debate if all the nuclear receptors (48 human members) can bind ligands (ligands referred here to both physiological and synthetic ligands). Recent studies in nuclear receptor structure biology and pharmacology have undoubtedly increased our knowledge of nuclear receptor functions and their regulation. As a result, they point to new avenues for the discovery and development of nuclear receptor regulators, including nuclear receptor ligands. Here we review the recent literature on orphan nuclear receptor structural analysis and ligand identification, particularly on the orphan nuclear receptors that do not heterodimerize with retinoid X receptors, which we term as non-X orphan receptors. We also propose a speculative "retinoid hypothesis" for a subset of non-X orphan nuclear receptors, which we hope to help shed light on orphan nuclear receptor biology and drug discovery. This article is part of a Special Issue entitled 'Orphan Nuclear Receptors'.

  9. Oligo-nuclear silver thiocyanate complexes with monodentate tertiary phosphine ligands, including novel 'cubane' and 'step' tetramer forms of AgSCN : PR3 (1:1)4.

    PubMed

    Bowmaker, Graham A; Di Nicola, Corrado; Effendy; Hanna, John V; Healy, Peter C; King, Scott P; Marchetti, Fabio; Pettinari, Claudio; Robinson, Ward T; Skelton, Brian W; Sobolev, Alexandre N; Tăbăcaru, Aurel; White, Allan H

    2013-01-07

    Adducts of a number of tertiary pnicogen ligands ER(3) (triphenyl-phosphine and -arsine (PPh(3),AsPh(3)), diphenyl,2-pyridylphosphine (PPh(2)py), tris(4-fluorophenyl)phosphine (P(C(6)H(4)-4F)(3)), tris(2-tolyl)phosphine (P(o-tol)(3)), tris(cyclohexyl)phosphine (PCy(3))), with silver(I) thiocyanate, AgSCN are structurally and spectroscopically characterized. The 1:3 AgSCN : ER(3) complexes structurally defined (for PPh(3),AsPh(3) (diversely solvated)) take the form [(R(3)E)(3)AgX], the thiocyanate X = NCS being N-bound, thus [(Ph(3)E)Ag(NCS)]. A 1:2 complex with PPh(2)py, takes the binuclear form [(pyPh(2)P)(2)Ag()Ag(PPh(2)py)(2)] with an eight-membered cyclic core. 1:1 complexes are defined with PPh(2)py, P(o-tol)(3) and PCy(3); binuclear forms [(R(3)P)Ag()Ag(PR(3))] are obtained with P(o-tol)(3) (two polymorphs), while novel isomeric tetranuclear forms, which may be envisaged as dimers of dimers, are obtained with PPh(2)py, and, as further polymorphs, with PCy(3); these latter may be considered as extensions of the 'cubane' and 'step' forms previously described for [(R(3)E)AgX](4) (X = halide) complexes. Solvent-assisted mechanochemical or solvent-assisted solid-state synthesis methods were employed in some cases, where complexes could not be obtained by conventional solution methods, or where such methods yielded a mixture of polymorphs unsuitable for solid-state spectroscopy. The wavenumbers of the ν(CN) bands in the IR spectra are in broad agreement with the empirical rule that distinguishes bridging from terminal bonding, but exceptions occur for compounds that have a double SCN bridged dimeric structure, and replacement of PPh(3) with PPh(2)py apparently causes a significant decrease in ν(CN) to well below the range expected for bridging SCN in these structures. (31)P CP MAS NMR spectra yield additional parameters that allow a correlation between the structures and spectra.

  10. Role of dioxin response element and nuclear factor-kappaB motifs in 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated regulation of Fas and Fas ligand expression.

    PubMed

    Singh, Narendra P; Nagarkatti, Mitzi; Nagarkatti, Prakash S

    2007-01-01

    We have demonstrated previously that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) up-regulates Fas and FasL in immune cells, although the molecular mechanisms remain unknown. We investigated the regulation of Fas or FasL promoter by TCDD in EL4 T cells using luciferase reporter constructs. We observed 20 +/- 5- and 14 +/- 4-fold induction of promoter activity for Fas and FasL, respectively, after TCDD exposure. The induction of luciferase was significantly reduced (2 +/- 1-fold) in the presence of alpha-naphthoflavone, an aryl hydrocarbon receptor (AhR) antagonist. We noted the presence of a dioxin response element (DRE) and five nuclear factor-kappaB (NF-kappaB) motifs on Fas promoter, and no DRE but two NF-kappaB motifs on FasL promoter. When we investigated the role of DRE and NF-kappaB, we observed varying levels of luciferase induction (9 +/- 2-fold for DRE and 8 +/- 2-fold for NF-kappaBs of Fas promoter and 6 +/- 3-fold for NF-kappaBs of FasL promoter). Mutations in DRE of Fas promoter or NF-kappaBs of FasL promoter led to decreased luciferase induction, further supporting our results. Probes for DRE or NF-kappaB motifs of Fas and/or FasL promoters demonstrated mobility shift in the presence of nuclear extract from TCDD-treated EL4 cells. Furthermore, we observed supershift in mobility when DRE and NF-kappaB probes were incubated in the presence of anti-mouse AhR, and anti-NF-kappaB (RelA/p65 and p50) antibodies, respectively. Administration of TCDD into mice caused significant increase in Fas and FasL transcripts in thymus and liver. These data demonstrate that TCDD regulates Fas and FasL promoters through DRE and/or NF-kappaB motifs via AhR.

  11. Nuclear rights - nuclear wrongs

    SciTech Connect

    Paul, E.F.; Miller, F.D.; Paul, J.; Ahrens, J.

    1986-01-01

    This book contains 11 selections. The titles are: Three Ways to Kill Innocent Bystanders: Some Conundrums Concerning the Morality of War; The International Defense of Liberty; Two Concepts of Deterrence; Nuclear Deterrence and Arms Control; Ethical Issues for the 1980s; The Moral Status of Nuclear Deterrent Threats; Optimal Deterrence; Morality and Paradoxical Deterrence; Immoral Risks: A Deontological Critique of Nuclear Deterrence; No War Without Dictatorship, No Peace Without Democracy: Foreign Policy as Domestic Politics; Marxism-Leninism and its Strategic Implications for the United States; Tocqueveille War.

  12. Di- and tetra-nuclear copper(II), nickel(II), and cobalt(II) complexes of four bis-tetradentate triazole-based ligands: synthesis, structure, and magnetic properties.

    PubMed

    Olguín, Juan; Kalisz, Marguerite; Clérac, Rodolphe; Brooker, Sally

    2012-05-07

    Four bis-tetradentate N(4)-substituted-3,5-{bis[bis-N-(2-pyridinemethyl)]aminomethyl}-4H-1,2,4-triazole ligands, L(Tz1)-L(Tz4), differing only in the triazole N(4) substituent R (where R is amino, pyrrolyl, phenyl, or 4-tertbutylphenyl, respectively) have been synthesized, characterized, and reacted with M(II)(BF(4))(2)·6H(2)O (M(II) = Cu, Ni or Co) and Co(SCN)(2). Experiments using all 16 possible combinations of metal salt and L(TzR) were carried out: 14 pure complexes were obtained, 11 of which are dinuclear, while the other three are tetranuclear. The dinuclear complexes include two copper(II) complexes, [Cu(II)(2)(L(Tz2))(H(2)O)(4)](BF(4))(4) (2), [Cu(II)(2)(L(Tz4))(BF(4))(2)](BF(4))(2) (4); two nickel(II) complexes, [Ni(II)(2)(L(Tz1))(H(2)O)(3)(CH(3)CN)](BF(4))(4)·0.5(CH(3)CN) (5) and [Ni(II)(2)(L(Tz4))(H(2)O)(4)](BF(4))(4)·H(2)O (8); and seven cobalt(II) complexes, [Co(II)(2)(L(Tz1))(μ-BF(4))](BF(4))(3)·H(2)O (9), [Co(II)(2)(L(Tz2))(μ-BF(4))](BF(4))(3)·2H(2)O (10), [Co(II)(2)(L(Tz3))(H(2)O)(2)](BF(4))(4) (11), [Co(II)(2)(L(Tz4))(μ-BF(4))](BF(4))(3)·3H(2)O (12), [Co(II)(2)(L(Tz1))(SCN)(4)]·3H(2)O (13), [Co(II)(2)(L(Tz2))(SCN)(4)]·2H(2)O (14), and [Co(II)(2)(L(Tz3))(SCN)(4)]·H(2)O (15). The tetranuclear complexes are [Cu(II)(4)(L(Tz1))(2)(H(2)O)(2)(BF(4))(2)](BF(4))(6) (1), [Cu(II)(4)(L(Tz3))(2)(H(2)O)(2)(μ-F)(2)](BF(4))(6)·0.5H(2)O (3), and [Ni(II)(4)(L(Tz3))(2)(H(2)O)(4)(μ-F(2))](BF(4))(6)·6.5H(2)O (7). Single crystal X-ray structure determinations revealed different solvent content from that found by microanalysis of the bulk sample after drying under a vacuum and confirmed that 5', 8', 9', 11', 12', and 15' are dinuclear while 1' and 7' are tetranuclear. As expected, magnetic measurements showed that weak antiferromagnetic intracomplex interactions are present in 1, 2, 4, 7, and 8, stabilizing a singlet spin ground state. All seven of the dinuclear cobalt(II) complexes, 9-15, have similar magnetic behavior and remain in the [HS-HS] state

  13. Bis[2,6-bis-(1H-pyrazol-1-yl)pyridine]-deca-kis-(μ2-3-nitro-benzoato)bis-(3-nitro-benzoato)tetra-dysprosium(III): a linear tetra-nuclear dysprosium compound based on mixed N- and O-donor ligands.

    PubMed

    Hua, Rong; Wu, Xiao-Liu; Li, Jin-Ying

    2014-05-01

    The title compound, [Dy4(C7H4NO4)12(C11H9N5)2] or Dy4(L1)12(L2)2, where HL1 = 3-nitro-benzoic acid and HL2 = 2,6-bis-(1H-pyrazol-1-y1)pyridine, is a linear tetra-nuclear complex possessing inversion symmetry. The two central inversion-related Dy(III) atoms are seven-coordinate, DyO7, with a monocapped triangular-prismatic geometry. The outer two Dy(III) atoms are eight-coordinate, DyO5N3, with a bicapped triangular-prismatic geometry. The outer adjacent Dy(III) atoms are bridged by three L1(-) carboxyl-ate groups, while the inner inversion-related Dy(III) atoms are bridged by four L1(-) carboxyl-ate groups. The L2 ligands are terminally coordinated to the outer Dy(III) atoms in a tridentate manner. In the crystal, mol-ecules are linked via C-H⋯O hydrogen bonds, forming a two-dimensional network parallel to (001). Two carboxyl-ate O atoms, and N and O atoms of three nitro groups, are disordered over two positions, with a refined occupancy ratio of 0.552 (6):0.448 (6).

  14. Charge-Transfer Effects in Ligand Exchange Reactions of Au25 Monolayer-Protected Clusters.

    PubMed

    Carducci, Tessa M; Blackwell, Raymond E; Murray, Royce W

    2015-04-16

    Reported here are second-order rate constants of associative ligand exchanges of Au25L18 nanoparticles (L = phenylethanethiolate) of various charge states, measured by proton nuclear magnetic resonance at room temperature and below. Differences in second-order rate constants (M(-1) s(-1)) of ligand exchange (positive clusters ∼1.9 × 10(-5) versus negative ones ∼1.2 × 10(-4)) show that electron depletion retards ligand exchange. The ordering of rate constants between the ligands benzeneselenol > 4-bromobenzene thiol > benzenethiol reveals that exchange is accelerated by higher acidity and/or electron donation capability of the incoming ligand. Together, these observations indicate that partial charge transfer occurs between the nanoparticle and ligand during the exchange and that this is a rate-determining effect in the process.

  15. Reaction chemistry and ligand exchange at cadmium selenide nanocrystal surfaces

    SciTech Connect

    Owen, Jonathan; Park, Jungwon; Trudeau, Paul-Emile; Alivisatos, A. Paul

    2008-12-02

    Chemical modification of nanocrystal surfaces is fundamentally important to their assembly, their implementation in biology and medicine, and greatly impacts their electrical and optical properties. However, it remains a major challenge owing to a lack of analytical tools to directly determine nanoparticle surface structure. Early nuclear magnetic resonance (NMR) and X-ray photoelectron spectroscopy (XPS) studies of CdSe nanocrystals prepared in tri-n-octylphosphine oxide (1) and tri-n-octylphosphine (2), suggested these coordinating solvents are datively bound to the particle surface. However, assigning the broad NMR resonances of surface-bound ligands is complicated by significant concentrations of phosphorus-containing impurities in commercial sources of 1, and XPS provides only limited information about the nature of the phosphorus containing molecules in the sample. More recent reports have shown the surface ligands of CdSe nanocrystals prepared in technical grade 1, and in the presence of alkylphosphonic acids, include phosphonic and phosphinic acids. These studies do not, however, distinguish whether these ligands are bound datively, as neutral, L-type ligands, or by X-type interaction of an anionic phosphonate/phosphinate moiety with a surface Cd{sup 2+} ion. Answering this question would help clarify why ligand exchange with such particles does not proceed generally as expected based on a L-type ligand model. By using reagents with reactive silicon-chalcogen and silicon-chlorine bonds to cleave the ligands from the nanocrystal surface, we show that our CdSe and CdSe/ZnS core-shell nanocrystal surfaces are likely terminated by X-type binding of alkylphosphonate ligands to a layer of Cd{sup 2+}/Zn{sup 2+} ions, rather than by dative interactions. Further, we provide spectroscopic evidence that 1 and 2 are not coordinated to our purified nanocrystals.

  16. Melatonin: functions and ligands.

    PubMed

    Singh, Mahaveer; Jadhav, Hemant R

    2014-09-01

    Melatonin is a chronobiotic substance that acts as synchronizer by stabilizing bodily rhythms. Its synthesis occurs in various locations throughout the body, including the pineal gland, skin, lymphocytes and gastrointestinal tract (GIT). Its synthesis and secretion is controlled by light and dark conditions, whereby light decreases and darkness increases its production. Thus, melatonin is also known as the 'hormone of darkness'. Melatonin and analogs that bind to the melatonin receptors are important because of their role in the management of depression, insomnia, epilepsy, Alzheimer's disease (AD), diabetes, obesity, alopecia, migraine, cancer, and immune and cardiac disorders. In this review, we discuss the mechanism of action of melatonin in these disorders, which could aid in the design of novel melatonin receptor ligands.

  17. Bifunctional DTPA-type ligand

    SciTech Connect

    Gansow, O.A.; Brechbiel, M.W.

    1990-03-26

    The subject matter of the invention relates to bifunctional cyclohexyl DTPA ligands and methods of using these compounds. Specifically, such ligands are useful for radiolabeling proteins with radioactive metals, and can consequently be utilized with respect to radioimmunoimaging and/or radioimmunotherapy.

  18. Differential hydrogen/deuterium exchange mass spectrometry analysis of protein–ligand interactions

    PubMed Central

    Chalmers, Michael J; Busby, Scott A; Pascal, Bruce D; West, Graham M; Griffin, Patrick R

    2011-01-01

    Functional regulation of ligand-activated receptors is driven by alterations in the conformational dynamics of the protein upon ligand binding. Differential hydrogen/deuterium exchange (HDX) coupled with mass spectrometry has emerged as a rapid and sensitive approach for characterization of perturbations in conformational dynamics of proteins following ligand binding. While this technique is sensitive to detecting ligand interactions and alterations in receptor dynamics, it also can provide important mechanistic insights into ligand regulation. For example, HDX has been used to determine a novel mechanism of ligand activation of the nuclear receptor peroxisome proliferator activated receptor-γ, perform detailed analyses of binding modes of ligands within the ligand-binding pocket of two estrogen receptor isoforms, providing insight into selectivity, and helped classify different types of estrogen receptor-α ligands by correlating their pharmacology with the way they interact with the receptor based solely on hierarchical clustering of receptor HDX signatures. Beyond small-molecule–receptor interactions, this technique has also been applied to study protein–protein complexes, such as mapping antibody–antigen interactions. In this article, we summarize the current state of the differential HDX approaches and the future outlook. We summarize how HDX analysis of protein–ligand interactions has had an impact on biology and drug discovery. PMID:21329427

  19. Nuclear Medicine.

    ERIC Educational Resources Information Center

    Badawi, Ramsey D.

    2001-01-01

    Describes the use of nuclear medicine techniques in diagnosis and therapy. Describes instrumentation in diagnostic nuclear medicine and predicts future trends in nuclear medicine imaging technology. (Author/MM)

  20. Estrogen Receptor Ligands: A Review (2013–2015)

    PubMed Central

    Farzaneh, Shabnam; Zarghi, Afshin

    2016-01-01

    Estrogen receptors (ERs) are a group of compounds named for their importance in both menstrual and estrous reproductive cycles. They are involved in the regulation of various processes ranging from tissue growth maintenance to reproduction. Their action is mediated through ER nuclear receptors. Two subtypes of the estrogen receptor, ERα and ERβ, exist and exhibit distinct cellular and tissue distribution patterns. In humans, both receptor subtypes are expressed in many cells and tissues, and they control key physiological functions in various organ systems. Estrogens attract great attention due to their wide applications in female reproductive functions and treatment of some estrogen-dependent cancers and osteoporosis. This paper provides a general review of ER ligands published in international journals patented between 2013 and 2015. The broad physiological profile of estrogens has attracted the attention of many researchers to develop new estrogen ligands as therapeutic molecules for various clinical purposes. After the discovery of the ERβ receptor, subtype-selective ligands could be used to elicit beneficial estrogen-like activities and reduce adverse side effects, based on the different distributions and relative levels of the two ER subtypes in different estrogen target tissues. Therefore, recent literature has focused on selective estrogen ligands as highly promising agents for the treatment of some types of cancer, as well as for cardiovascular, inflammatory, and neurodegenerative diseases. Estrogen receptors are nuclear transcription factors that are involved in the regulation of many complex physiological functions in humans. Selective estrogen ligands are highly promising targets for treatment of some types of cancer, as well as for cardiovascular, inflammatory and neurodegenerative diseases. Extensive structure-activity relationship studies of ER ligands based on small molecules indicate that many different structural scaffolds may provide high

  1. Analyzing protein-ligand interactions by dynamic NMR spectroscopy.

    PubMed

    Mittermaier, Anthony; Meneses, Erick

    2013-01-01

    Nuclear magnetic resonance (NMR) spectroscopy can provide detailed information on protein-ligand interactions that is inaccessible using other biophysical techniques. This chapter focuses on NMR-based approaches for extracting affinity and rate constants for weakly binding transient protein complexes with lifetimes of less than about a second. Several pulse sequences and analytical techniques are discussed, including line-shape simulations, spin-echo relaxation dispersion methods (CPMG), and magnetization exchange (EXSY) experiments.

  2. The Orphan Nuclear Receptor TR4 Is a Vitamin A-activated Nuclear Receptor

    SciTech Connect

    Zhou, X. Edward; Suino-Powell, Kelly M.; Xu, Yong; Chan, Cee-Wah; Tanabe, Osamu; Kruse, Schoen W.; Reynolds, Ross; Engel, James Douglas; Xu, H. Eric

    2015-11-30

    Testicular receptors 2 and 4 (TR2/4) constitute a subgroup of orphan nuclear receptors that play important roles in spermatogenesis, lipid and lipoprotein regulation, and the development of the central nervous system. Currently, little is known about the structural features and the ligand regulation of these receptors. Here we report the crystal structure of the ligand-free TR4 ligand binding domain, which reveals an autorepressed conformation. The ligand binding pocket of TR4 is filled by the C-terminal half of helix 10, and the cofactor binding site is occupied by the AF-2 helix, thus preventing ligand-independent activation of the receptor. However, TR4 exhibits constitutive transcriptional activity on multiple promoters, which can be further potentiated by nuclear receptor coactivators. Mutations designed to disrupt cofactor binding, dimerization, or ligand binding substantially reduce the transcriptional activity of this receptor. Importantly, both retinol and retinoic acid are able to promote TR4 to recruit coactivators and to activate a TR4-regulated reporter. These findings demonstrate that TR4 is a ligand-regulated nuclear receptor and suggest that retinoids might have a much wider regulatory role via activation of orphan receptors such as TR4.

  3. Validity of ligand efficiency metrics.

    PubMed

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

    2014-06-12

    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 medicinal chemists.

  4. Ligand Identification Scoring Algorithm (LISA)

    PubMed Central

    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

  5. Ligand Identification Scoring Algorithm (LISA).

    PubMed

    Zheng, Zheng; Merz, Kenneth M

    2011-06-27

    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.

  6. Distal and proximal ligand interactions in heme proteins: Correlations between C-O and Fe-C vibrational frequencies, oxygen-17 and carbon-13 nuclear magnetic resonance chemical shifts, and oxygen-17 nuclear quadrupole coupling constants in C sup 17 O- and sup 13 CO-labeled species

    SciTech Connect

    Ki Deok Park; Guo, K.; Adebodun, F.; Chiu, M.L.; Sligar, S.G.; Oldfield, E. )

    1991-03-05

    The authors have obtained the oxygen-17 nuclear magnetic resonance (NMR) spectra of a variety of C{sup 17}O-labeled heme proteins, including sperm whale (Physeter catodon) myoglobin, two synthetic sperm whale myoglobin mutants (His E7 {yields} Val E7; His E7 {yields} Phe E7), adult human hemoglobin, rabbit (Oryctolagus cuniculus) hemoglobin, horseradish (Cochlearia armoracia) peroxidase isoenzymes A and C, and Caldariomyces fumago chloroperoxidase, in some cases as a function of pH, and have determined their isotropic {sup 17}O NMR chemical shifts, {delta}{sub i}, and spin-lattice relaxation times, T{sub 1}. They have also obtained similar results on a picket fence prophyrin. The results show an excellent correlation between the infrared C-O vibrational frequencies, {nu}(C-O), and {delta}{sub i}, between {nu}(C-O) and the {sup 17}O nuclear quadrupole coupling constant, and as expected between e{sup 2}qQ/h and {delta}{sub i}. The results suggest the IR and NMR measurements reflect the same interaction, which is thought to be primarily the degree of {pi}-back-bonding from Fe d to CO {pi}* orbitals, as outlined previously.

  7. Nuclear hormone receptors put immunity on sterols

    PubMed Central

    Santori, Fabio R.

    2015-01-01

    Nuclear hormone receptors (NHRs) are transcription factors regulated by small molecules. The functions of NHRs range from development of primary and secondary lymphoid organs, to regulation of differentiation and function of DCs, macrophages and T cells. The human genome has 48 classic (hormone and vitamin receptors) and non-classic (all others) NHRs; 17 non-classic receptors are orphans, meaning that the endogenous ligand is unknown. Understanding the function of orphan NHRs requires the identification of their natural ligands. The mevalonate pathway, including its sterol and non-sterol intermediates and derivatives, is a source of ligands for many classic and non-classic NHRs. For example, cholesterol biosynthetic intermediates (CBIs) are natural ligands for RORγ/γt. CBIs are universal endogenous metabolites in mammalian cells, and to study NHRs that bind CBIs requires ligand-free reporters system in sterol auxotroph cells. Furthermore, RORγ/γt shows broad specificity to sterol lipids, suggesting that RORγ/γt is either a general sterol sensor or specificity is defined by an abundant endogenous ligand. Unlike other NHRs, which regulate specific metabolic pathways, there is no connection between the genetic programs induced by RORγ/γt and ligand biosynthesis. In this review we summarize the roles of non-classic NHRs and their potential ligands in the immune system. PMID:26222181

  8. Nuclear Scans

    MedlinePlus

    Nuclear scans use radioactive substances to see structures and functions inside your body. They use a special ... images. Most scans take 20 to 45 minutes. Nuclear scans can help doctors diagnose many conditions, including ...

  9. Nuclear Winter.

    ERIC Educational Resources Information Center

    Ehrlich, Anne

    1984-01-01

    "Nuclear Winter" was recently coined to describe the climatic and biological effects of a nuclear war. These effects are discussed based on models, simulations, scenarios, and projections. Effects on human populations are also considered. (JN)

  10. Nuclear Chemistry.

    ERIC Educational Resources Information Center

    Chemical and Engineering News, 1979

    1979-01-01

    Provides a brief review of the latest developments in nuclear chemistry. Nuclear research today is directed toward increased activity in radiopharmaceuticals and formation of new isotopes by high-energy, heavy-ion collisions. (Author/BB)

  11. Rational Ligand Design for U(VI) and Pu(IV)

    SciTech Connect

    Szigethy, Geza

    2009-08-12

    Nuclear power is an attractive alternative to hydrocarbon-based energy production at a time when moving away from carbon-producing processes is widely accepted as a significant developmental need. Hence, the radioactive actinide power sources for this industry are necessarily becoming more widespread, which is accompanied by the increased risk of exposure to both biological and environmental systems. This, in turn, requires the development of technology designed to remove such radioactive threats efficiently and selectively from contaminated material, whether that be contained nuclear waste streams or the human body. Raymond and coworkers (University of California, Berkeley) have for decades investigated the interaction of biologically-inspired, hard Lewis-base ligands with high-valent, early-actinide cations. It has been established that such ligands bind strongly to the hard Lewis-acidic early actinides, and many poly-bidentate ligands have been developed and shown to be effective chelators of actinide contaminants in vivo. Work reported herein explores the effect of ligand geometry on the linear U(IV) dioxo dication (uranyl, UO2 2+). The goal is to utilize rational ligand design to develop ligands that exhibit shape selectivity towards linear dioxo cations and provides thermodynamically favorable binding interactions. The uranyl complexes with a series of tetradentate 3-hydroxy-pyridin-2-one (3,2-HOPO) ligands were studied in both the crystalline state as well as in solution. Despite significant geometric differences, the uranyl affinities of these ligands vary only slightly but are better than DTPA, the only FDA-approved chelation therapy for actinide contamination. The terepthalamide (TAM) moiety was combined into tris-beidentate ligands with 1,2- and 3,2-HOPO moieties were combined into hexadentate ligands whose structural preferences and solution thermodynamics were measured with the uranyl cation. In addition to achieving coordinative

  12. Nuclear weapons, nuclear effects, nuclear war

    SciTech Connect

    Bing, G.F.

    1991-08-20

    This paper provides a brief and mostly non-technical description of the militarily important features of nuclear weapons, of the physical phenomena associated with individual explosions, and of the expected or possible results of the use of many weapons in a nuclear war. Most emphasis is on the effects of so-called ``strategic exchanges.``

  13. Why mercury prefers soft ligands

    SciTech Connect

    Riccardi, Demian M; Guo, Hao-Bo; Gu, Baohua; Parks, Jerry M; Summers, Anne; Miller, S; Liang, Liyuan; Smith, Jeremy C

    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.

  14. Molecular Recognition and Ligand Association

    NASA Astrophysics Data System (ADS)

    Baron, Riccardo; McCammon, J. Andrew

    2013-04-01

    We review recent developments in our understanding of molecular recognition and ligand association, focusing on two major viewpoints: (a) studies that highlight new physical insight into the molecular recognition process and the driving forces determining thermodynamic signatures of binding and (b) recent methodological advances in applications to protein-ligand binding. In particular, we highlight the challenges posed by compensating enthalpic and entropic terms, competing solute and solvent contributions, and the relevance of complex configurational ensembles comprising multiple protein, ligand, and solvent intermediate states. As more complete physics is taken into account, computational approaches increase their ability to complement experimental measurements, by providing a microscopic, dynamic view of ensemble-averaged experimental observables. Physics-based approaches are increasingly expanding their power in pharmacology applications.

  15. Nuclear Fuels.

    ERIC Educational Resources Information Center

    Nash, J. Thomas

    1983-01-01

    Trends in and factors related to the nuclear industry and nuclear fuel production are discussed. Topics addressed include nuclear reactors, survival of the U.S. uranium industry, production costs, budget cuts by the Department of Energy and U.S. Geological survey for resource studies, mining, and research/development activities. (JN)

  16. Nuclear Receptors in Bone Physiology and Diseases

    PubMed Central

    Youn, Min-Young; Inoue, Kazuki; Takada, Ichiro; Kouzmenko, Alexander; Kato, Shigeaki

    2013-01-01

    During the last decade, our view on the skeleton as a mere solid physical support structure has been transformed, as bone emerged as a dynamic, constantly remodeling tissue with systemic regulatory functions including those of an endocrine organ. Reflecting this remarkable functional complexity, distinct classes of humoral and intracellular regulatory factors have been shown to control vital processes in the bone. Among these regulators, nuclear receptors (NRs) play fundamental roles in bone development, growth, and maintenance. NRs are DNA-binding transcription factors that act as intracellular transducers of the respective ligand signaling pathways through modulation of expression of specific sets of cognate target genes. Aberrant NR signaling caused by receptor or ligand deficiency may profoundly affect bone health and compromise skeletal functions. Ligand dependency of NR action underlies a major strategy of therapeutic intervention to correct aberrant NR signaling, and significant efforts have been made to design novel synthetic NR ligands with enhanced beneficial properties and reduced potential negative side effects. As an example, estrogen deficiency causes bone loss and leads to development of osteoporosis, the most prevalent skeletal disorder in postmenopausal women. Since administration of natural estrogens for the treatment of osteoporosis often associates with undesirable side effects, several synthetic estrogen receptor ligands have been developed with higher therapeutic efficacy and specificity. This review presents current progress in our understanding of the roles of various nuclear receptor-mediated signaling pathways in bone physiology and disease, and in development of advanced NR ligands for treatment of common skeletal disorders. PMID:23589826

  17. Ligand-induced Epitope Masking

    PubMed Central

    Mould, A. Paul; Askari, Janet A.; Byron, Adam; Takada, Yoshikazu; Jowitt, Thomas A.; Humphries, Martin J.

    2016-01-01

    We previously demonstrated that Arg-Gly-Asp (RGD)-containing ligand-mimetic inhibitors of integrins are unable to dissociate pre-formed integrin-fibronectin complexes (IFCs). These observations suggested that amino acid residues involved in integrin-fibronectin binding become obscured in the ligand-occupied state. Because the epitopes of some function-blocking anti-integrin monoclonal antibodies (mAbs) lie near the ligand-binding pocket, it follows that the epitopes of these mAbs may become shielded in the ligand-occupied state. Here, we tested whether function-blocking mAbs directed against α5β1 can interact with the integrin after it forms a complex with an RGD-containing fragment of fibronectin. We showed that the anti-α5 subunit mAbs JBS5, SNAKA52, 16, and P1D6 failed to disrupt IFCs and hence appeared unable to bind to the ligand-occupied state. In contrast, the allosteric anti-β1 subunit mAbs 13, 4B4, and AIIB2 could dissociate IFCs and therefore were able to interact with the ligand-bound state. However, another class of function-blocking anti-β1 mAbs, exemplified by Lia1/2, could not disrupt IFCs. This second class of mAbs was also distinguished from 13, 4B4, and AIIB2 by their ability to induce homotypic cell aggregation. Although the epitope of Lia1/2 was closely overlapping with those of 13, 4B4, and AIIB2, it appeared to lie closer to the ligand-binding pocket. A new model of the α5β1-fibronectin complex supports our hypothesis that the epitopes of mAbs that fail to bind to the ligand-occupied state lie within, or very close to, the integrin-fibronectin interface. Importantly, our findings imply that the efficacy of some therapeutic anti-integrin mAbs could be limited by epitope masking. PMID:27484800

  18. Multifunctional Ligands in Transition Metal Catalysis

    SciTech Connect

    Crabtree, Robert H

    2011-01-01

    Sophisticated ligands are now being designed that do far more than just fulfil their traditional spectator roles by binding to the metal and providing a sterically-defined binding pocket for the substrate in homogeneous transition metal catalysis. This Focus review emphasizes selected cases in which ligands carry additional functional groups that change the properties of the ligand as a result of an external stimulus or undergo catalytically-relevant ligand-based reactivity. These include proton responsive ligands capable of gaining or losing one or more protons, ligands having a hydrogen bonding function, electroresponsive ligands capable of gaining or losing one or more electrons, and photoresponsive ligands capable of undergoing a useful change of properties upon irradiation. Molecular recognition ligands and proton coupled electron transfer (PCET) are briefly discussed.

  19. A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Nuclear hormone receptors regulate diverse metabolic pathways and the orphan nuclear receptor LRH-1 (also known as NR5A2) regulates bile acid biosynthesis. Structural studies have identified phospholipids as potential LRH-1 ligands, but their functional relevance is unclear. Here we show that an unu...

  20. Pharmacophore modeling improves virtual screening for novel peroxisome proliferator-activated receptor-gamma ligands

    PubMed Central

    Lewis, Stephanie N.; Garcia, Zulma; Hontecillas, Raquel; Bassaganya-Riera, Josep; Bevan, David R.

    2015-01-01

    Peroxisome proliferator-activated receptor-gamma (PPARγ) is a nuclear hormone receptor involved in regulating various metabolic and immune processes. The PPAR family of receptors possesses a large binding cavity that imparts promiscuity of ligand binding not common to other nuclear receptors. This feature increases the challenge of using computational methods to identify PPAR ligands that will dock favorably into a structural model. Utilizing both ligand- and structure-based pharmacophore methods, we sought to improve agonist prediction by grouping ligands according to pharmacophore features, and pairing models derived from these features with receptor structures for docking. For 22 of the 33 receptor structures evaluated we observed an increase in true positive rate (TPR) when screening was restricted to compounds sharing molecular features found in rosiglitazone. A combination of structure models used for docking resulted in a higher TPR (40%) when compared to docking with a single structure model (less than 20%). Prediction was also improved when specific protein-ligand interactions between the docked ligands and structure models were given greater weight than the calculated free energy of binding. A large-scale screen of compounds using a marketed drug database verified the predictive ability of the selected structure models. This study highlights the steps necessary to improve screening for PPARγ ligands using multiple structure models, ligand-based pharmacophore data, evaluation of protein-ligand interactions, and comparison of docking datasets. The unique combination of methods presented here holds potential for more efficient screening of compounds with unknown affinity for PPARγ that could serve as candidates for therapeutic development. PMID:25616366

  1. Pharmacophore modeling improves virtual screening for novel peroxisome proliferator-activated receptor-gamma ligands

    NASA Astrophysics Data System (ADS)

    Lewis, Stephanie N.; Garcia, Zulma; Hontecillas, Raquel; Bassaganya-Riera, Josep; Bevan, David R.

    2015-05-01

    Peroxisome proliferator-activated receptor-gamma (PPARγ) is a nuclear hormone receptor involved in regulating various metabolic and immune processes. The PPAR family of receptors possesses a large binding cavity that imparts promiscuity of ligand binding not common to other nuclear receptors. This feature increases the challenge of using computational methods to identify PPAR ligands that will dock favorably into a structural model. Utilizing both ligand- and structure-based pharmacophore methods, we sought to improve agonist prediction by grouping ligands according to pharmacophore features, and pairing models derived from these features with receptor structures for docking. For 22 of the 33 receptor structures evaluated we observed an increase in true positive rate (TPR) when screening was restricted to compounds sharing molecular features found in rosiglitazone. A combination of structure models used for docking resulted in a higher TPR (40 %) when compared to docking with a single structure model (<20 %). Prediction was also improved when specific protein-ligand interactions between the docked ligands and structure models were given greater weight than the calculated free energy of binding. A large-scale screen of compounds using a marketed drug database verified the predictive ability of the selected structure models. This study highlights the steps necessary to improve screening for PPARγ ligands using multiple structure models, ligand-based pharmacophore data, evaluation of protein-ligand interactions, and comparison of docking datasets. The unique combination of methods presented here holds potential for more efficient screening of compounds with unknown affinity for PPARγ that could serve as candidates for therapeutic development.

  2. Using Nuclear Receptor Activity to Stratify Hepatocarcinogens

    EPA Science Inventory

    Nuclear receptors (NR) are a superfamily of ligand-activated transcription factors that control a range of cellular processes. Persistent stimulation of some NR is a non-genotoxic mechanism of rodent liver cancer with unclear relevance to humans. Here we report on a systematic an...

  3. Kinetics of ligand binding to nucleic acids.

    PubMed

    Arakelyan, V B; Babayan, S Y; Tairyan, V I; Arakelyan, A V; Parsadanyan, M A; Vardevanyan, P O

    2006-02-01

    Ligand binding to nucleic acids (NA) is considered as a stationary Markov process. It is shown that the probabilistic description of ligand-NA binding allows one to describe not only the kinetics of the change of number of bound ligands at arbitrary fillings but also to calculate stationary values of the number of bound ligands and its dispersion. The general analysis of absorption isotherms and kinetics of ligand binding to NA make it possible to determine of rate constants of ligand-NA complex formation and dissociation.

  4. Non-canonical modulators of nuclear receptors.

    PubMed

    Tice, Colin M; Zheng, Ya-Jun

    2016-09-01

    Like G protein-coupled receptors (GPCRs) and protein kinases, nuclear receptors (NRs) are a rich source of pharmaceutical targets. Over 80 NR-targeting drugs have been approved for 18 NRs. The focus of drug discovery in NRs has hitherto been on identifying ligands that bind to the canonical ligand binding pockets of the C-terminal ligand binding domains (LBDs). Due to the development of drug resistance and selectivity concerns, there has been considerable interest in exploring other, non-canonical ligand binding sites. Unfortunately, the potencies of compounds binding at other sites have generally not been sufficient for clinical development. However, the situation has changed dramatically over the last 3years, as compounds with sufficient potency have been reported for several NR targets. Here we review recent developments in this area from a medicinal chemistry point of view in the hope of stimulating further interest in this area of research.

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

    PubMed Central

    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

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

    PubMed

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

    2016-06-04

    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.

  7. Cancer therapy using natural ligands that target estrogen receptor beta

    PubMed Central

    Sareddy, Gangadhara R; Vadlamudi, Ratna K.

    2016-01-01

    Estrogen receptor beta (ERβ) is one of the two key receptors (ERα, ERβ) that facilitate biological actions of 17β-estradiol (E2). ERβ is widely expressed in many tissues, and its expression is reduced or lost during progression of many tumors. ERβ facilitates estrogen signaling by both genomic (classical and non-classical) and extra-nuclear signaling. Emerging evidence suggests that ERβ functions as a tissue-specific tumor suppressor with anti-proliferative actions. Recent studies have identified a number of naturally available selective ERβ agonists. Targeting ERβ using its naturally available ligands is an attractive approach for treating and preventing cancers. This review presents the beneficial actions of ERβ signaling and clinical utility of several natural ERβ ligands as potential cancer therapy. PMID:26614454

  8. On-the-Fly Integration of Data from a Spin-Diffusion-Based NMR Experiment into Protein-Ligand Docking.

    PubMed

    Onila, Ionut; ten Brink, Tim; Fredriksson, Kai; Codutti, Luca; Mazur, Adam; Griesinger, Christian; Carlomagno, Teresa; Exner, Thomas E

    2015-09-28

    INPHARMA (interligand nuclear Overhauser enhancement for pharmacophore mapping) determines the relative orientation of two competitive ligands in the protein binding pocket. It is based on the observation of interligand transferred NOEs mediated by spin diffusion through protons of the protein and is, therefore, sensitive to the specific interactions of each of the two ligands with the protein. We show how this information can be directly included into a protein-ligand docking program to guide the prediction of the complex structures. Agreement between the experimental and back-calculated spectra based on the full relaxation matrix approach is translated into a score contribution that is combined with the scoring function ChemPLP of our docking tool PLANTS. This combined score is then used to predict the poses of five weakly bound cAMP-dependent protein kinase (PKA) ligands. After optimizing the setup, which finally also included trNOE data and optimized protonation states, very good success rates were obtained for all combinations of three ligands. For one additional ligand, no conclusive results could be obtained due to the ambiguous electron density of the ligand in the X-ray structure, which does not disprove alternative ligand poses. The failures of the remaining ligand are caused by suboptimal locations of specific protein side chains. Therefore, side-chain flexibility should be included in an improved INPHARMA-PLANTS version. This will reduce the strong dependence on the used protein input structure leading to improved scores overall, not only for this last ligand.

  9. Acetylated deoxycholic (DCA) and cholic (CA) acids are potent ligands of pregnane X (PXR) receptor.

    PubMed

    Carazo, Alejandro; Hyrsova, Lucie; Dusek, Jan; Chodounska, Hana; Horvatova, Alzbeta; Berka, Karel; Bazgier, Vaclav; Gan-Schreier, Hongying; Chamulitrat, Waleé; Kudova, Eva; Pavek, Petr

    2017-01-04

    The Pregnane X (PXR), Vitamin D (VDR) and Farnesoid X (FXR) nuclear receptors have been shown to be receptors of bile acids controlling their detoxification or synthesis. Chenodeoxycholic (CDCA) and lithocholic (LCA) acids are ligands of FXR and VDR, respectively, whereas 3-keto and acetylated derivates of LCA have been described as ligands for all three receptors. In this study, we hypothesized that oxidation or acetylation at position 3, 7 and 12 of bile acids DCA (deoxycholic acid), LCA, CA (cholic acid), and CDCA by detoxification enzymes or microbiome may have an effect on the interactions with bile acid nuclear receptors. We employed reporter gene assays in HepG2 cells, the TR-FRET assay with recombinant PXR and RT-PCR to study the effects of acetylated and keto bile acids on the nuclear receptors activation and their target gene expression in differentiated hepatic HepaRG cells. We demonstrate that the DCA 3,12-diacetate and CA 3,7,12-triacetate derivatives are ligands of PXR and DCA 3,12-diacetate induces PXR target genes such as CYP3A4, CYP2B6 and ABCB1/MDR1. In conclusion, we found that acetylated DCA and CA are potent ligands of PXR. Whether the acetylated bile acid derivatives are novel endogenous ligands of PXR with detoxification or physiological functions should be further studied in ongoing experiments.

  10. DEPENDENCE OF PPAR LIGAND-INDUCED MAPK SIGNALING ON EPIDERMAL GROWTH FACTOR RECEPTOR TRANSACTIVATION HEPARIN-BINDING EGF CLEAVAGE MEDIATES ZINC-INDUCED EGF RECEPTOR PHOSPHORYLATION

    EPA Science Inventory

    Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that function as ligand-activated transcription factors regulating lipid metabolism and homeostasis. In addition to their ability to regulate PPAR-mediated gene transcription, PPARalpha and gamma li...

  11. Nuclear Receptors, RXR, and the Big Bang.

    PubMed

    Evans, Ronald M; Mangelsdorf, David J

    2014-03-27

    Isolation of genes encoding the receptors for steroids, retinoids, vitamin D, and thyroid hormone and their structural and functional analysis revealed an evolutionarily conserved template for nuclear hormone receptors. This discovery sparked identification of numerous genes encoding related proteins, termed orphan receptors. Characterization of these orphan receptors and, in particular, of the retinoid X receptor (RXR) positioned nuclear receptors at the epicenter of the "Big Bang" of molecular endocrinology. This Review provides a personal perspective on nuclear receptors and explores their integrated and coordinated signaling networks that are essential for multicellular life, highlighting the RXR heterodimer and its associated ligands and transcriptional mechanism.

  12. Nuclear Receptors, RXR & the Big Bang

    PubMed Central

    Evans, Ronald M.; Mangelsdorf, David J.

    2014-01-01

    Summary Isolation of genes encoding the receptors for steroids, retinoids, vitamin D and thyroid hormone, and their structural and functional analysis revealed an evolutionarily conserved template for nuclear hormone receptors. This discovery sparked identification of numerous genes encoding related proteins, termed orphan receptors. Characterization of these orphan receptors, and in particular of the retinoid X receptor (RXR), positioned nuclear receptors at the epicenter of the “Big Bang” of molecular endocrinology. This review provides a personal perspective on nuclear receptors and explores their integrated and coordinated signaling networks that are essential for multi-cellular life, highlighting the RXR heterodimer and its associated ligands and transcriptional mechanism. PMID:24679540

  13. Nuclear astrophysics

    SciTech Connect

    Haxton, W.C.

    1992-01-01

    The problem of core-collapse supernovae is used to illustrate the many connections between nuclear astrophysics and the problems nuclear physicists study in terrestrial laboratories. Efforts to better understand the collapse and mantle ejection are also motivated by a variety of interdisciplinary issues in nuclear, particle, and astrophysics, including galactic chemical evolution, neutrino masses and mixing, and stellar cooling by the emission of new particles. The current status of theory and observations is summarized.

  14. Nuclear astrophysics

    SciTech Connect

    Haxton, W.C.

    1992-12-31

    The problem of core-collapse supernovae is used to illustrate the many connections between nuclear astrophysics and the problems nuclear physicists study in terrestrial laboratories. Efforts to better understand the collapse and mantle ejection are also motivated by a variety of interdisciplinary issues in nuclear, particle, and astrophysics, including galactic chemical evolution, neutrino masses and mixing, and stellar cooling by the emission of new particles. The current status of theory and observations is summarized.

  15. Lack of Ligand-Selective Binding of the Aryl Hydrocarbon Receptor to Putative DNA Binding Sites Regulating Expression of Bax and Paraoxonase 1 Genes

    PubMed Central

    DeGroot, Danica E.; Hayashi, Ai; Denison, Michael S.

    2013-01-01

    The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates the biological and toxicological effects of structurally diverse chemicals through its ability to bind specific DNA recognition sites (dioxin responsive elements (DREs)), and activate transcription of adjacent genes. While the DRE has a highly conserved consensus sequence, it has been suggested that the nucleotide specificity of AhR DNA binding may be ligand-dependent. The upstream regulatory regions of the murine Bax and human paraoxonase 1 (PON1) genes reportedly contain unique DRE-like sequences that respond to AhRs activated by some ligands but not others. Given the significant implications of this observation to understanding the diversity in AhR responses and that of other ligand-dependent nuclear receptors, a combination of DNA binding, nuclear translocation and gene expression analysis was used to investigate the molecular mechanisms underlying these ligand-selective responses. Although known AhR agonists stimulated AhR nuclear translocation, DRE binding and gene expression, the ligand-selective DRE-like DNA elements identified in the Bax and PON1 upstream regulatory regions failed to bind ligand-activated AhR or confer AhR-responsiveness upon a reporter gene. These results argue against the reported ligand-selectivity of AhR DNA binding and suggest DNA binding by ligand activated AhR involves DRE-containing DNA. PMID:24200861

  16. Nuclear Fission

    NASA Astrophysics Data System (ADS)

    Denschlag, J. O.

    This chapter first gives a survey on the history of the discovery of nuclear fission. It briefly presents the liquid-drop and shell models and their application to the fission process. The most important quantities accessible to experimental determination such as mass yields, nuclear charge distribution, prompt neutron emission, kinetic energy distribution, ternary fragment yields, angular distributions, and properties of fission isomers are presented as well as the instrumentation and techniques used for their measurement. The contribution concentrates on the fundamental aspects of nuclear fission. The practical aspects of nuclear fission are discussed in http://dx.doi.org/10.1007/978-1-4419-0720-2_57 of Vol. 6.

  17. Glyconanomaterials: synthesis, characterization, and ligand presentation.

    PubMed

    Wang, Xin; Ramström, Olof; Yan, Mingdi

    2010-05-04

    Glyconanomaterials, nanomaterials carrying surface-tethered carbohydrate ligands, have emerged and demonstrated increasing potential in biomedical imaging, therapeutics, and diagnostics. These materials combine the unique properties of nanometer-scale objects with the ability to present multiple copies of carbohydrate ligands, greatly enhancing the weak affinity of individual ligands to their binding partners. Critical to the performance of glyconanomaterials is the proper display of carbohydrate ligands, taking into consideration of the coupling chemistry, the type and length of the spacer linkage, and the ligand density. This article provides an overview of the coupling chemistry for attaching carbohydrate ligands to nanomaterials, and discusses the need for thorough characterization of glyconanomaterials, especially quantitative analyses of the ligand density and binding affinities. Using glyconanoparticles synthesized by a versatile photocoupling chemistry, methods for determining the ligand density by colorimetry and the binding affinity with lectins by a fluorescence competition assay are determined. The results show that the multivalent presentation of carbohydrate ligands significantly enhances the binding affinity by several orders of magnitude in comparison to the free ligands in solution. The effect is sizeable even at low surface ligand density. The type and length of the spacer linkage also affect the binding affinity, with the longer linkage promoting the association of bound ligands with the corresponding lectins.

  18. Glyconanomaterials: Synthesis, Characterization, and Ligand Presentation

    PubMed Central

    Wang, Xin

    2010-01-01

    Glyconanomaterials, nanomaterials carrying surface-tethered carbohydrate ligands, have emerged and demonstrated increasing potential in biomedical imaging, therapeutics, and diagnostics. These materials combine the unique properties of nanometer-scale objects with the ability to present multiple copies of carbohydrate ligands, greatly enhancing the weak affinity of individual ligands to their binding partners. Critical to the performance of glyconanomaterials is the proper display of carbohydrate ligands, taking into consideration of the coupling chemistry, the type and length of the spacer linkage, and the ligand density. This article provides an overview of the coupling chemistry for attaching carbohydrate ligands to nanomaterials, and discusses the need for thorough characterization of glyconanomaterials, especially quantitative analyses of the ligand density and binding affinities. Using glyconanoparticles synthesized by a versatile photocoupling chemistry, methods for determining the ligand density by colorimetry and the binding affinity with lectins by a fluorescence competition assay are determined. The results show that the multivalent presentation of carbohydrate ligands significantly enhances the binding affinity by several orders of magnitude in comparison to the free ligands in solution. The effect is sizeable even at low surface ligand density. The type and length of the spacer linkage also affect the binding affinity, with the longer linkage promoting the association of bound ligands with the corresponding lectins. PMID:20301131

  19. Structural basis for PPAR partial or full activation revealed by a novel ligand binding mode

    NASA Astrophysics Data System (ADS)

    Capelli, Davide; Cerchia, Carmen; Montanari, Roberta; Loiodice, Fulvio; Tortorella, Paolo; Laghezza, Antonio; Cervoni, Laura; Pochetti, Giorgio; Lavecchia, Antonio

    2016-10-01

    The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors involved in the regulation of the metabolic homeostasis and therefore represent valuable therapeutic targets for the treatment of metabolic diseases. The development of more balanced drugs interacting with PPARs, devoid of the side-effects showed by the currently marketed PPARγ full agonists, is considered the major challenge for the pharmaceutical companies. Here we present a structure-based virtual screening approach that let us identify a novel PPAR pan-agonist with a very attractive activity profile and its crystal structure in the complex with PPARα and PPARγ, respectively. In PPARα this ligand occupies a new pocket whose filling is allowed by the ligand-induced switching of the F273 side chain from a closed to an open conformation. The comparison between this pocket and the corresponding cavity in PPARγ provides a rationale for the different activation of the ligand towards PPARα and PPARγ, suggesting a novel basis for ligand design.

  20. Selectivity in ligand binding to uranyl compounds: A synthetic, structural, thermodynamic and computational study

    SciTech Connect

    Arnold, John

    2015-01-21

    The uranyl cation (UO₂²⁺) is the most abundant form of uranium on the planet. It is estimated that 4.5 billion tons of uranium in this form exist in sea water. The ability to bind and extract the uranyl cation from aqueous solution while separating it from other elements would provide a limitless source of nuclear fuel. A large body of research concerns the selective recognition and extraction of uranyl. A stable molecule, the cation has a linear O=U=O geometry. The short U-O bonds (1.78 Å) arise from the combination of uranium 5f/6d and oxygen 2p orbitals. Due to the oxygen moieties being multiply bonded, these sites were not thought to be basic enough for Lewis acidic coordination to be a viable approach to sequestration. The goal of this research is thus to broaden the coordination chemistry of the uranyl ion by studying new ligand systems via synthetic, structural, thermodynamic and computational methods. It is anticipated that this fundamental science will find use beyond actinide separation technologies in areas such as nuclear waste remediation and nuclear materials. The focus of this study is to synthesize uranyl complexes incorporating amidinate and guanidinate ligands. Both synthetic and computational methods are used to investigate novel equatorial ligand coordination and how this affects the basicity of the oxo ligands. Such an understanding will later apply to designing ligands incorporating functionalities that can bind uranyl both equatorially and axially for highly selective sequestration. Efficient and durable chromatography supports for lanthanide separation will be generated by (1) identifying robust peptoid-based ligands capable of binding different lanthanides with variable affinities, and (2) developing practical synthetic methods for the attachment of these ligands to Dowex ion exchange resins.

  1. Ligand chain length conveys thermochromism.

    PubMed

    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.

  2. Presentation of Ligands on Hydroxylapatite

    NASA Technical Reports Server (NTRS)

    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.

  3. Tumor Targeting via Integrin Ligands

    PubMed Central

    Marelli, Udaya Kiran; Rechenmacher, Florian; Sobahi, Tariq Rashad Ali; Mas-Moruno, Carlos; Kessler, Horst

    2013-01-01

    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. PMID:24010121

  4. Nuclear safety

    NASA Technical Reports Server (NTRS)

    Buden, D.

    1991-01-01

    Topics dealing with nuclear safety are addressed which include the following: general safety requirements; safety design requirements; terrestrial safety; SP-100 Flight System key safety requirements; potential mission accidents and hazards; key safety features; ground operations; launch operations; flight operations; disposal; safety concerns; licensing; the nuclear engine for rocket vehicle application (NERVA) design philosophy; the NERVA flight safety program; and the NERVA safety plan.

  5. Tools for ligand validation in Coot

    PubMed Central

    Emsley, Paul

    2017-01-01

    Coot is a molecular-graphics program primarily aimed at model building using X-ray data. Recently, tools for the manipulation and representation of ligands have been introduced. Here, these new tools for ligand validation and comparison are described. Ligands in the wwPDB have been scored by density-fit, distortion and atom-clash metrics. The distributions of these scores can be used to assess the relative merits of the particular ligand in the protein–ligand complex of interest by means of ‘sliders’ akin to those now available for each accession code on the wwPDB websites. PMID:28291755

  6. Nuclear privatization

    SciTech Connect

    Jeffs, E.

    1995-11-01

    The United Kingdom government announced in May 1995 plans to privatize the country`s two nuclear generating companies, Nuclear Electric and Scottish Nuclear. Under the plan, the two companies will become operating divisions of a unified holding company, to be called British Electric, with headquarters in Scotland. Britain`s nuclear plants were left out of the initial privatization in 1989 because the government believed the financial community would be unwilling to accept the open-ended liability of decommissioning the original nine stations based on the Magnox gas-cooled reactor. Six years later, the government has found a way around this by retaining these power stations in state ownership, leaving the new nuclear company with the eight Advanced Gas-cooled Reactor (AGR) stations and the recently completed Sizewell B PWR stations. The operating Magnox stations are to be transferred to BNFL, which operates two Magnox stations of their own at Calder Hall and Chapelcross.

  7. Ligand identification using electron-density mapcorrelations

    SciTech Connect

    Terwilliger, Thomas C.; Adams, Paul D.; Moriarty, Nigel W.; Cohn,Judith D.

    2006-12-01

    A procedure for the identification of ligands bound incrystal structuresof macromolecules is described. Two characteristics ofthe density corresponding to a ligand are used in the identificationprocedure. One is the correlation of the ligand density with each of aset of test ligands after optimization of the fit of that ligand to thedensity. The other is the correlation of a fingerprint of the densitywith the fingerprint of model density for each possible ligand. Thefingerprints consist of an ordered list of correlations of each the testligands with the density. The two characteristics are scored using aZ-score approach in which the correlations are normalized to the mean andstandard deviation of correlations found for a variety of mismatchedligand-density pairs, so that the Z scores are related to the probabilityof observing a particular value of the correlation by chance. Theprocedure was tested with a set of 200 of the most commonly found ligandsin the Protein Data Bank, collectively representing 57 percent of allligands in the Protein Data Bank. Using a combination of these twocharacteristics of ligand density, ranked lists of ligand identificationswere made for representative (F-o-F-c) exp(i phi(c)) difference densityfrom entries in the Protein Data Bank. In 48 percent of the 200 cases,the correct ligand was at the top of the ranked list of ligands. Thisapproach may be useful in identification of unknown ligands in newmacromolecular structures as well as in the identification of whichligands in a mixture have bound to a macromolecule.

  8. NKG2D ligands as therapeutic targets

    PubMed Central

    Spear, Paul; Wu, Ming-Ru; Sentman, Marie-Louise; Sentman, Charles L.

    2013-01-01

    The Natural Killer Group 2D (NKG2D) receptor plays an important role in protecting the host from infections and cancer. By recognizing ligands induced on infected or tumor cells, NKG2D modulates lymphocyte activation and promotes immunity to eliminate ligand-expressing cells. Because these ligands are not widely expressed on healthy adult tissue, NKG2D ligands may present a useful target for immunotherapeutic approaches in cancer. Novel therapies targeting NKG2D ligands for the treatment of cancer have shown preclinical success and are poised to enter into clinical trials. In this review, the NKG2D receptor and its ligands are discussed in the context of cancer, infection, and autoimmunity. In addition, therapies targeting NKG2D ligands in cancer are also reviewed. PMID:23833565

  9. Nuclear stress test

    MedlinePlus

    ... Persantine stress test; Thallium stress test; Stress test - nuclear; Adenosine stress test; Regadenoson stress test; CAD - nuclear stress; Coronary artery disease - nuclear stress; Angina - nuclear ...

  10. Chemical Approaches to Nuclear Receptors in Metabolism

    PubMed Central

    Margolis, Ronald N.; Moore, David D.; Willson, Timothy M.; Guy, R. Kip

    2017-01-01

    The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) sponsored a workshop, “Chemical Approaches to Nuclear Receptors and Metabolism,” in April 2009 to explore how chemical and molecular biology and physiology can be exploited to further our understanding of nuclear receptor structure, function, and role in disease. Signaling cascades involving nuclear receptors are more complex and interrelated than once thought. Nuclear receptors continue to be attractive targets for drug discovery. The overall goal of this workshop was to identify gaps in our understanding of the complexity of ligand activities and begin to address them by (i) increasing the collaboration of investigators from different disciplines, (ii) developing a better understanding of chemical modulation of nuclear receptor action, and (iii) identifying opportunities and roadblocks in the path of translating basic research to discovery of new therapeutics. PMID:19654413

  11. Dietary modification of metabolic pathways via nuclear hormone receptors.

    PubMed

    Caiozzi, Gianella; Wong, Brian S; Ricketts, Marie-Louise

    2012-10-01

    Nuclear hormone receptors (NHRs), as ligand-dependent transcription factors, have emerged as important mediators in the control of whole body metabolism. Because of the promiscuous nature of several members of this superfamily that have been found to bind ligand with lower affinity than the classical steroid NHRs, they consequently display a broader ligand selectivity. This promiscuous nature has facilitated various bioactive dietary components being able to act as agonist ligands for certain members of the NHR superfamily. By binding to these NHRs, bioactive dietary components are able to mediate changes in various metabolic pathways, including, glucose, cholesterol and triglyceride homeostasis among others. This review will provide a general overview of the nuclear hormone receptors that have been shown to be activated by dietary components. The physiological consequences of such receptor activation by these dietary components will then be discussed in more detail.

  12. Nuclear reprogramming.

    PubMed

    Halley-Stott, Richard P; Pasque, Vincent; Gurdon, J B

    2013-06-01

    There is currently particular interest in the field of nuclear reprogramming, a process by which the identity of specialised cells may be changed, typically to an embryonic-like state. Reprogramming procedures provide insight into many mechanisms of fundamental cell biology and have several promising applications, most notably in healthcare through the development of human disease models and patient-specific tissue-replacement therapies. Here, we introduce the field of nuclear reprogramming and briefly discuss six of the procedures by which reprogramming may be experimentally performed: nuclear transfer to eggs or oocytes, cell fusion, extract treatment, direct reprogramming to pluripotency and transdifferentiation.

  13. Nuclear Speckles

    PubMed Central

    Spector, David L.; Lamond, Angus I.

    2011-01-01

    Nuclear speckles, also known as interchromatin granule clusters, are nuclear domains enriched in pre-mRNA splicing factors, located in the interchromatin regions of the nucleoplasm of mammalian cells. When observed by immunofluorescence microscopy, they usually appear as 20–50 irregularly shaped structures that vary in size. Speckles are dynamic structures, and their constituents can exchange continuously with the nucleoplasm and other nuclear locations, including active transcription sites. Studies on the composition, structure, and dynamics of speckles have provided an important paradigm for understanding the functional organization of the nucleus and the dynamics of the gene expression machinery. PMID:20926517

  14. Rifampicin-Independent Interactions between the Pregnane X Receptor Ligand Binding Domain and Peptide Fragments of Coactivator and Corepressor Proteins

    PubMed Central

    Navaratnarajah, Punya; Steele, Bridgett L.; Redinbo, Matthew R.; Thompson, Nancy L.

    2015-01-01

    The pregnane X receptor (PXR), a member of the nuclear receptor superfamily, regulates the expression of drug-metabolizing enzymes in a ligand-dependent manner. The conventional view of nuclear receptor action is that ligand binding enhances the receptor’s affinity for coactivator proteins, while decreasing its affinity for corepressors. To date, however, no known rigorous biophysical studies have been conducted to investigate the interaction among PXR, its coregulators, and ligands. In this work, steady-state total internal reflection fluorescence microscopy (TIRFM) and total internal reflection with fluorescence recovery after photobleaching were used to measure the thermodynamics and kinetics of the interaction between the PXR ligand binding domain and a peptide fragment of the steroid receptor coactivator-1 (SRC-1) in the presence and absence of the established PXR agonist, rifampicin. Equilibrium dissociation and dissociation rate constants of ~5 μM and ~2 s−1, respectively, were obtained in the presence and absence of rifampicin, indicating that the ligand does not enhance the affinity of the PXR and SRC-1 fragments. Additionally, TIRFM was used to examine the interaction between PXR and a peptide fragment of the corepressor protein, the silencing mediator for retinoid and thyroid receptors (SMRT). An equilibrium dissociation constant of ~70 μM was obtained for SMRT in the presence and absence of rifampicin. These results strongly suggest that the mechanism of ligand-dependent activation in PXR differs significantly from that seen in many other nuclear receptors. PMID:22185585

  15. Novel Ligands for a Purine Riboswitch Discovered by RNA-Ligand Docking

    PubMed Central

    Daldrop, Peter; Reyes, Francis E.; Robinson, David A.; Hammond, Colin M.; Lilley, David M.; Batey, Robert T.; Brenk, Ruth

    2011-01-01

    Summary The increasing number of RNA crystal structures enables a structure-based approach to the discovery of new RNA-binding ligands. To develop the poorly explored area of RNA-ligand docking, we have conducted a virtual screening exercise for a purine riboswitch to probe the strengths and weaknesses of RNA-ligand docking. Using a standard protein-ligand docking program with only minor modifications, four new ligands with binding affinities in the micromolar range were identified, including two compounds based on molecular scaffolds not resembling known ligands. RNA-ligand docking performed comparably to protein-ligand docking indicating that this approach is a promising option to explore the wealth of RNA structures for structure-based ligand design. PMID:21439477

  16. Quasi-epitaxial Metal-Halide Perovskite Ligand Shells on PbS Nanocrystals.

    PubMed

    Sytnyk, Mykhailo; Yakunin, Sergii; Schöfberger, Wolfgang; Lechner, Rainer T; Burian, Max; Ludescher, Lukas; Killilea, Niall A; YousefiAmin, AmirAbbas; Kriegner, Dominik; Stangl, Julian; Groiss, Heiko; Heiss, Wolfgang

    2017-02-28

    Epitaxial growth techniques enable nearly defect free heterostructures with coherent interfaces, which are of utmost importance for high performance electronic devices. While high-vacuum technology-based growth techniques are state-of-the art, here we pursue a purely solution processed approach to obtain nanocrystals with eptaxially coherent and quasi-lattice matched inorganic ligand shells. Octahedral metal-halide clusters, respectively 0-dimensional perovskites, were employed as ligands to match the coordination geometry of the PbS cubic rock-salt lattice. Different clusters (CH3NH3(+))(6-x)[M((x+))Hal6]((6-x)-) (M(x+) = Pb(II), Bi(III), Mn(II), In(III), Hal = Cl, I) were attached to the nanocrystal surfaces via a scalable phase transfer procedure. The ligand attachment and coherence of the formed PbS/ligand core/shell interface was confirmed by combining the results from transmission electron microscopy, small-angle X-ray scattering, nuclear magnetic resonance spectroscopy and powder X-ray diffraction. The lattice mismatch between ligand shell and nanocrystal core plays a key role in performance. In photoconducting devices the best performance (detectivity of 2 × 10(11) cm Hz (1/2)/W with > 110 kHz bandwidth) was obtained with (CH3NH3)3BiI6 ligands, providing the smallest relative lattice mismatch of ca. -1%. PbS nanocrystals with such ligands exhibited in millimeter sized bulk samples in the form of pressed pellets a relatively high carrier mobility for nanocrystal solids of ∼1.3 cm(2)/(V s), a carrier lifetime of ∼70 μs, and a low residual carrier concentration of 2.6 × 10(13) cm(-3). Thus, by selection of ligands with appropriate geometry and bond lengths optimized quasi-epitaxial ligand shells were formed on nanocrystals, which are beneficial for applications in optoelectronics.

  17. Synthesis and NMR characterization of ligand-capped metal and metal-oxide nanoparticles

    NASA Astrophysics Data System (ADS)

    Sharma, Ramesh

    Ligand-capped metal and metal-oxide nanoparticles (NPs) have some interesting and useful physical properties that are not present in their respective bulk materials. These properties are of research interest in many applications such as catalysis, drug delivery, biological imaging, and plasmonics. In such applications, it is critical to understand the surface structure of NPs and the roles played by the surface bound ligands. To characterize surface environment, ligand dynamics, and exchange kinetics, ligand-capped metal and metal-oxide NPs are synthesized and studied by multinuclear NMR. Phosphines and phosphonic acids are used to passivate metal (gold and silver) and metal-oxide (tin dioxide) NPs in different sizes (1-5 nm) by following published procedures or original synthesis methods. In both solution and solid state NMR, the 31P chemical shift of surface-bound ligands are distinctly different from those observed for free ligands. Additionally, NMR line widths in surface-bound ligands are highly broadened compared to those of free ligands. The lines are broadened due to both homogeneous and inhomogeneous broadening mechanisms, determined through hole burning NMR and spin-spin relaxation measurements. In small particles (< 2 nm), the main source of line broadening is inhomogeneous and originates due to structural heterogeneity and underlying chemical shift distributions. In large particles (> 2 nm), both inhomogeneous and homogeneous line broadening mechanisms are present. When the particles' sizes increase from small to large, the homogeneous broadening mechanism becomes dominant due to strong nuclear-electron interaction and reintroduction of residual dipolar coupling as shown by a combination of 1H, 13C and 31P NMR. Results from a series of ligand exchange experiments in silver and gold NPs further indicate the presence of Au(I) and Ag(I) on the particle surfaces.

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

    SciTech Connect

    Klei, Herbert E.; Moriarty, Nigel W. Echols, Nathaniel; Terwilliger, Thomas C.; Baldwin, Eric T.; Pokross, Matt; Posy, Shana; Adams, Paul D.

    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

  19. (Nuclear theory). [Research in nuclear physics

    SciTech Connect

    Haxton, W.

    1990-01-01

    This report discusses research in nuclear physics. Topics covered in this paper are: symmetry principles; nuclear astrophysics; nuclear structure; quark-gluon plasma; quantum chromodynamics; symmetry breaking; nuclear deformation; and cold fusion. (LSP)

  20. Nuclear battlefields

    SciTech Connect

    Arkin, W.M.; Fieldhouse, R.W.

    1985-01-01

    This book provides complete data on the nuclear operations and research facilities in the U.S.A., the U.S.S.R., France, China and the U.K. It describes detailed estimates on the U.S.S.R.'s nuclear stockpile for over 500 locations. It shows how non-nuclear countries cooperate with the world-wide war machine. And it maps the U.S. nuclear facilities from Little America, WY, and Charleston, SC, to the battleships patroling the world's oceans and subs stalking under the sea. The data were gathered from unclassified sources through the Freedom of Information Act, from data supplied to military installations, and from weapons source books. It provides guidance for policymakers, government and corporate officials.

  1. NUCLEAR REACTOR

    DOEpatents

    Sherman, J.; Sharbaugh, J.E.; Fauth, W.L. Jr.; Palladino, N.J.; DeHuff, P.G.

    1962-10-23

    A nuclear reactor incorporating seed and blanket assemblies is designed. Means are provided for obtaining samples of the coolant from the blanket assemblies and for varying the flow of coolant through the blanket assemblies. (AEC)

  2. Nuclear Medicine

    MedlinePlus

    ... here Home » Science Education » Science Topics » Nuclear Medicine SCIENCE EDUCATION SCIENCE EDUCATION Science Topics Resource Links for ... administered by inhalation, by oral ingestion, or by direct injection into an organ. The mode of tracer ...

  3. A Boolean Network Model of Nuclear Receptor Mediated Cell Cycle Progression

    EPA Science Inventory

    Nuclear receptors (NRs) are ligand-activated transcription factors that regulate a broad range of cellular processes. Hormones, lipids and xenobiotics have been shown to activate NRs with a range of consequences on development, metabolism, oxidative stress, apoptosis, and prolif...

  4. A Boolean Network Model of Nuclear Receptor Mediated Cell Cycle Progression (S)

    EPA Science Inventory

    Nuclear receptors (NRs) are ligand-activated transcription factors that regulate a broad range of cellular processes. Hormones, lipids and xenobiotics have been shown to activate NRs with a range of consequences on development, metabolism, oxidative stress, apoptosis, and prolif...

  5. Helix 8 of the ligand binding domain of the glucocorticoid receptor (GR) is essential for ligand binding.

    PubMed

    Deng, Qiong; Waxse, Bennett; Riquelme, Denise; Zhang, Jiabao; Aguilera, Greti

    2015-06-15

    Membrane association of estrogen receptors (ER) depends on cysteine palmitoylation and two leucines in the ligand binding domain (LBD), conserved in most steroid receptors. The role of this region, corresponding to helix 8 of the glucocorticoid receptor (GR) LBD, on membrane association of GR was studied in 4B cells, expressing endogenous GR, and Cos-7 cells transfected EGFP-GR constructs. 4B cells preloaded with radiolabeled palmitic acid showed no radioactivity incorporation into immunoprecipitated GR. Moreover, mutation C683A (corresponding to ER palmitoylation site) did not affect corticosterone-induced membrane association of GR. Mutations L687-690A, L682A, E680G and K685G prevented membrane and also nuclear localization through reduced ligand binding. L687-690A mutation decreased association of GR with heat shock protein 90 and transcriptional activity, without overt effects on receptor protein stability. The data demonstrate that palmitoylation does not mediate membrane association of GR, but that the region 680-690 (helix 8) is critical for ligand binding and receptor function.

  6. Nuclear accidents

    SciTech Connect

    Mobley, J.A.

    1982-05-01

    A nuclear accident with radioactive contamination can happen anywhere in the world. Because expert nuclear emergency teams may take several hours to arrive at the scene, local authorities must have a plan of action for the hours immediately following an accident. The site should be left untouched except to remove casualties. Treatment of victims includes decontamination and meticulous wound debridement. Acute radiation syndrome may be an overwhelming sequela.

  7. Nuclear cardiac

    SciTech Connect

    Slutsky, R.; Ashburn, W.L.

    1982-01-01

    The relationship between nuclear medicine and cardiology has continued to produce a surfeit of interesting, illuminating, and important reports involving the analysis of cardiac function, perfusion, and metabolism. To simplify the presentation, this review is broken down into three major subheadings: analysis of myocardial perfusion; imaging of the recent myocardial infarction; and the evaluation of myocardial function. There appears to be an increasingly important relationship between cardiology, particularly cardiac physiology, and nuclear imaging techniques. (KRM)

  8. Nuclear Data

    SciTech Connect

    White, Morgan C.

    2014-01-23

    PowerPoint presentation targeted for educational use. Nuclear data comes from a variety of sources and in many flavors. Understanding where the data you use comes from and what flavor it is can be essential to understand and interpret your results. This talk will discuss the nuclear data pipeline with particular emphasis on providing links to additional resources that can be used to explore the issues you will encounter.

  9. Nuclear Nonproliferation

    SciTech Connect

    Atkins-Duffin, C E

    2008-12-10

    With an explosion equivalent of about 20kT of TNT, the Trinity test was the first demonstration of a nuclear weapon. Conducted on July 16, 1945 in Alamogordo, NM this site is now a Registered National Historic Landmark. The concept and applicability of nuclear power was demonstrated on December 20, 1951 with the Experimental Breeder Reactor Number One (EBR-1) lit four light bulbs. This reactor is now a Registered National Historic Landmark, located near Arco, ID. From that moment forward it had been clearly demonstrated that nuclear energy has both peaceful and military applications and that the civilian and military fuel cycles can overlap. For the more than fifty years since the Atoms for Peace program, a key objective of nuclear policy has been to enable the wider peaceful use of nuclear energy while preventing the spread of nuclear weapons. Volumes have been written on the impact of these two actions on the world by advocates and critics; pundits and practioners; politicians and technologists. The nations of the world have woven together a delicate balance of treaties, agreements, frameworks and handshakes that are representative of the timeframe in which they were constructed and how they have evolved in time. Collectively these vehicles attempt to keep political will, nuclear materials and technology in check. This paper captures only the briefest abstract of the more significant aspects on the Nonproliferation Regime. Of particular relevance to this discussion is the special nonproliferation sensitivity associated with the uranium isotope separation and spent fuel reprocessing aspects of the nuclear fuel cycle.

  10. Looking at nuclear receptors from a new angle.

    PubMed

    Helsen, Christine; Claessens, Frank

    2014-01-25

    While the structures of the DNA- and ligand-binding domains of many nuclear receptors have been determined in great detail; the mechanisms by which these domains interact and possibly 'communicate' is still under debate. The first crystal structures of receptor dimers bound to ligand, DNA and coactivator peptides provided new insights in this matter. The observed binding modes revealed exciting new interaction surfaces between the different nuclear receptor domains. Such interfaces are proposed to be the route through which allosteric signals from the DNA are passed on to the ligand-binding domain and the activating functions of the receptor. The structural determinations of DNA-bound receptor dimers in solution, however, revealed an extended structure of the receptors. Here, we discuss these apparent contradictory structural data and their possible implications for the functioning of nuclear receptors.

  11. Nuclear telemedicine

    NASA Astrophysics Data System (ADS)

    Morrison, R. T.; Szasz, I. J.

    1990-06-01

    Diagnostic nuclear medicine patient images have been transniitted for 8 years from a regional conununity hospital to a university teaching hospital 700 kiloinetres away employing slow scan TV and telephone. Transruission and interpretation were done at the end of each working day or as circumstances required in cases of emergencies. Referring physicians received the nuclear medicine procedure report at the end of the completion day or within few minutes of completion in case of emergency procedures. To date more than 25 patient studies have been transmitted for interpretation. Blinded reinterpretation of the original hard copy data of 350 patient studies resulted in 100 agreement with the interpretation of transmitted data. This technique provides high quality diagnostic and therapeutic nuclear medicine services in remote hospitals where the services of an on-site nuclear physician is not available. 2. HISTORY Eight years ago when the nuclear medicine physician at Trail Regional Hospital left the Trail area and an other could not be recruited we examined the feasibility of image transmission by phone for interpretation since closing the department would have imposed unacceptable physical and financial hardship and medical constraints on the patient population the nearest nuclear medicine facility was at some 8 hours drive away. In hospital patients would have to be treated either based purely on physical findings or flown to Vancouver at considerable cost to the health care system (estimated cost $1500.

  12. A universal rule for organic ligand exchange.

    PubMed

    You, Hongjun; Wang, Wenjin; Yang, Shengchun

    2014-11-12

    Most synthetic routes to high-quality nanocrystals with tunable morphologies predominantly employ long hydro-carbon molecules as ligands, which are detrimental for electronic and catalytic applications. Here, a rule is found that the adsorption energy of an organic ligand is related to its carbon-chain length. Using the density functional theory method, the adsorption energies of some commonly used ligand molecules with different carbon-chain lengths are calculated, including carboxylate, hydroxyl, and amine molecules adsorbed on metal or metal oxide crystal surface. The results indicate that the adsorption energy of the ligand molecule with a long carbon chain is weaker than that of a smaller molecule with same functional group. This rule provides a theoretical support for a new kind of ligand exchange method in which large organic ligand molecules can be exchanged by small molecules with same functional group to improve the catalytic properties.

  13. Insights into an original pocket-ligand pair classification: a promising tool for ligand profile prediction.

    PubMed

    Pérot, Stéphanie; Regad, Leslie; Reynès, Christelle; Spérandio, Olivier; Miteva, Maria A; Villoutreix, Bruno O; Camproux, Anne-Claude

    2013-01-01

    Pockets are today at the cornerstones of modern drug discovery projects and at the crossroad of several research fields, from structural biology to mathematical modeling. Being able to predict if a small molecule could bind to one or more protein targets or if a protein could bind to some given ligands is very useful for drug discovery endeavors, anticipation of binding to off- and anti-targets. To date, several studies explore such questions from chemogenomic approach to reverse docking methods. Most of these studies have been performed either from the viewpoint of ligands or targets. However it seems valuable to use information from both ligands and target binding pockets. Hence, we present a multivariate approach relating ligand properties with protein pocket properties from the analysis of known ligand-protein interactions. We explored and optimized the pocket-ligand pair space by combining pocket and ligand descriptors using Principal Component Analysis and developed a classification engine on this paired space, revealing five main clusters of pocket-ligand pairs sharing specific and similar structural or physico-chemical properties. These pocket-ligand pair clusters highlight correspondences between pocket and ligand topological and physico-chemical properties and capture relevant information with respect to protein-ligand interactions. Based on these pocket-ligand correspondences, a protocol of prediction of clusters sharing similarity in terms of recognition characteristics is developed for a given pocket-ligand complex and gives high performances. It is then extended to cluster prediction for a given pocket in order to acquire knowledge about its expected ligand profile or to cluster prediction for a given ligand in order to acquire knowledge about its expected pocket profile. This prediction approach shows promising results and could contribute to predict some ligand properties critical for binding to a given pocket, and conversely, some key pocket

  14. CB receptor ligands from plants.

    PubMed

    Woelkart, Karin; Salo-Ahen, Outi M H; Bauer, Rudolf

    2008-01-01

    Advances in understanding the physiology and pharmacology of the endogenous cannabinoid system have potentiated the interest of cannabinoid receptors as potential therapeutic targets. Cannabinoids have been shown to modulate a variety of immune cell functions and have therapeutic implications on central nervous system (CNS) inflammation, chronic inflammatory conditions such as arthritis, and may be therapeutically useful in treating autoimmune conditions such as multiple sclerosis. Many of these drug effects occur through cannabinoid receptor signalling mechanisms and the modulation of cytokines and other gene products. Further, endocannabinoids have been found to have many physiological and patho-physiological functions, including mood alteration and analgesia, control of energy balance, gut motility, motor and co-ordination activities, as well as alleviation of neurological, psychiatric and eating disorders. Plants offer a wide range of chemical diversity and have been a growing domain in the search for effective cannabinoid ligands. Cannabis sativa L. with the known plant cannabinoid, Delta(9-)tetrahydrocannabinol (THC) and Echinacea species with the cannabinoid (CB) receptor-binding lipophilic alkamides are the best known herbal cannabimimetics. This review focuses on the state of the art in CB ligands from plants, as well their possible therapeutic and immunomodulatory effects.

  15. Functional interactions between polypyrimidine tract binding protein and PRI peptide ligand containing proteins.

    PubMed

    Coelho, Miguel B; Ascher, David B; Gooding, Clare; Lang, Emma; Maude, Hannah; Turner, David; Llorian, Miriam; Pires, Douglas E V; Attig, Jan; Smith, Christopher W J

    2016-08-15

    Polypyrimidine tract binding protein (PTBP1) is a heterogeneous nuclear ribonucleoprotein (hnRNP) that plays roles in most stages of the life-cycle of pre-mRNA and mRNAs in the nucleus and cytoplasm. PTBP1 has four RNA binding domains of the RNA recognition motif (RRM) family, each of which can bind to pyrimidine motifs. In addition, RRM2 can interact via its dorsal surface with proteins containing short peptide ligands known as PTB RRM2 interacting (PRI) motifs, originally found in the protein Raver1. Here we review our recent progress in understanding the interactions of PTB with RNA and with various proteins containing PRI ligands.

  16. Measurement of protein-ligand complex formation.

    PubMed

    Lowe, Peter N; Vaughan, Cara K; Daviter, Tina

    2013-01-01

    Experimental approaches to detect, measure, and quantify protein-ligand binding, along with their theoretical bases, are described. A range of methods for detection of protein-ligand interactions is summarized. Specific protocols are provided for a nonequilibrium procedure pull-down assay, for an equilibrium direct binding method and its modification into a competition-based measurement and for steady-state measurements based on the effects of ligands on enzyme catalysis.

  17. Nuclear receptors and nonalcoholic fatty liver disease.

    PubMed

    Cave, Matthew C; Clair, Heather B; Hardesty, Josiah E; Falkner, K Cameron; Feng, Wenke; Clark, Barbara J; Sidey, Jennifer; Shi, Hongxue; Aqel, Bashar A; McClain, Craig J; Prough, Russell A

    2016-09-01

    Nuclear receptors are transcription factors which sense changing environmental or hormonal signals and effect transcriptional changes to regulate core life functions including growth, development, and reproduction. To support this function, following ligand-activation by xenobiotics, members of subfamily 1 nuclear receptors (NR1s) may heterodimerize with the retinoid X receptor (RXR) to regulate transcription of genes involved in energy and xenobiotic metabolism and inflammation. Several of these receptors including the peroxisome proliferator-activated receptors (PPARs), the pregnane and xenobiotic receptor (PXR), the constitutive androstane receptor (CAR), the liver X receptor (LXR) and the farnesoid X receptor (FXR) are key regulators of the gut:liver:adipose axis and serve to coordinate metabolic responses across organ systems between the fed and fasting states. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and may progress to cirrhosis and even hepatocellular carcinoma. NAFLD is associated with inappropriate nuclear receptor function and perturbations along the gut:liver:adipose axis including obesity, increased intestinal permeability with systemic inflammation, abnormal hepatic lipid metabolism, and insulin resistance. Environmental chemicals may compound the problem by directly interacting with nuclear receptors leading to metabolic confusion and the inability to differentiate fed from fasting conditions. This review focuses on the impact of nuclear receptors in the pathogenesis and treatment of NAFLD. Clinical trials including PIVENS and FLINT demonstrate that nuclear receptor targeted therapies may lead to the paradoxical dissociation of steatosis, inflammation, fibrosis, insulin resistance, dyslipidemia and obesity. Novel strategies currently under development (including tissue-specific ligands and dual receptor agonists) may be required to separate the beneficial effects of nuclear receptor activation from unwanted metabolic

  18. Children's (Pediatric) Nuclear Medicine

    MedlinePlus Videos and Cool Tools

    ... Professions Site Index A-Z Children's (Pediatric) Nuclear Medicine Children’s (pediatric) nuclear medicine imaging uses small amounts ... Children's Nuclear Medicine? What is Children's (Pediatric) Nuclear Medicine? Nuclear medicine is a branch of medical imaging ...

  19. Affinity purification using recombinant PXR as a tool to characterize environmental ligands.

    PubMed

    Dagnino, Sonia; Bellet, Virginie; Grimaldi, Marina; Riu, Anne; Aït-Aïssa, Sélim; Cavaillès, Vincent; Fenet, Hélène; Balaguer, Patrick

    2014-02-01

    Many environmental endocrine disrupting compounds act as ligands for nuclear receptors. The human pregnane X receptor (hPXR), for instance, is activated by a variety of environmental ligands such as steroids, pharmaceutical drugs, pesticides, alkylphenols, polychlorinated biphenyls and polybromo diethylethers. Some of us have previously reported the occurrence of hPXR ligands in environmental samples but failed to identify them. The aim of this study was to test whether a PXR-affinity column, in which recombinant hPXR was immobilized on solid support, could help the purification of these chemicals. Using PXR ligands of different affinity (10 nM < EC50 < 10 μM), we demonstrated that the PXR-affinity preferentially column captured ligands with medium to high affinities (EC50 < 1 μM). Furthermore, by using the PXR-affinity column to analyze an environmental sample containing ERα, AhR, AR, and PXR activities, we show that (i) half of the PXR activity of the sample was due to compounds with medium to high affinity for PXR and (ii) PXR shared ligands with ERα, AR, and AhR. These findings demonstrate that the newly developed PXR-affinity column coupled to reporter cell lines represents a valuable tool for the characterization of the nature of PXR active compounds and should therefore guide and facilitate their further analysis.

  20. PPARγ ligand production is tightly linked to clonal expansion during initiation of adipocyte differentiation[S

    PubMed Central

    Hallenborg, Philip; Petersen, Rasmus Koefoed; Feddersen, Søren; Sundekilde, Ulrik; Hansen, Jacob B.; Blagoev, Blagoy; Madsen, Lise; Kristiansen, Karsten

    2014-01-01

    Adipocyte differentiation is orchestrated by the ligand-activated nuclear receptor PPARγ. Endogenous ligands comprise oxidized derivatives of arachidonic acid and structurally similar PUFAs. Although expression of PPARγ peaks in mature adipocytes, ligands are produced primarily at the onset of differentiation. Concomitant with agonist production, murine fibroblasts undergo two rounds of mitosis referred to as mitotic clonal expansion. Here we show that mouse embryonic fibroblasts deficient in either of two cell cycle inhibitors, the transcription factor p53 or its target gene encoding the cyclin-dependent kinase inhibitor p21, exhibit increased adipogenic potential. The antiadipogenic effect of p53 relied on its transcriptional activity and p21 expression but was circumvented by administration of an exogenous PPARγ agonist suggesting a linkage between cell cycling and PPARγ ligand production. Indeed, cell cycle inhibitory compounds decreased PPARγ ligand production in differentiating 3T3-L1 preadipocytes. Furthermore, these inhibitors abolished the release of arachidonic acid induced by the hormonal cocktail initiating adipogenesis. Collectively, our results suggest that murine fibroblasts require clonal expansion for PPARγ ligand production at the onset of adipocyte differentiation. PMID:25312885

  1. Asymmetric catalysis with chiral ferrocene ligands.

    PubMed

    Dai, Li-Xin; Tu, Tao; You, Shu-Li; Deng, Wei-Ping; Hou, Xue-Long

    2003-09-01

    Chiral ferrocene ligands have been widely used in asymmetric catalysis. The advantages of using ferrocene as a scaffold for chiral ligands are described, particularly those regarding planar chirality, rigid bulkiness, and ease of derivatization. The role of planar chirality in 1,2- and 1,1'-disubstituted ferrocene systems is discussed. By using a bulky ferrocene fragment, novel ferrocene ligands were designed, and high enantioselectivity and regioselectivity were achieved in the allylic substitution reaction of monosubstituted allyl substrates. Using the tunable electronic properties of a diphosphine-oxazoline ferrocenyl ligand, the regioselectivity of the intermolecular asymmetric Heck reaction was also examined.

  2. Integrated ligand based pharmacophore model derived from diverse FAAH covalent ligand classes.

    PubMed

    Shen, Lingling; Huang, Hongwei; Makriyannis, Alexandros; Fisher, Luke S

    2012-12-01

    3D pharmacophore modeling is an important computational methodology for ligand-enzyme binding interactions in drug discovery. More specifically, a consensus pharmacophore model derived from diverse ligands is a key determinant upon which the prediction power of computational models is based for designing novel ligands. In this work, by merging the important pharmacophore features based on four classes of covalent FAAH ligands, and then integrating the exclusion volume spheres derived from the crystal structure, we created for the first time an integrated FAAH pharmacophore model to describe the ligand-enzyme binding interactions. This new integrated FAAH pharmacophore model can correctly predict the covalent ligand binding mode, which correlates with the SAR data. The study is expected to provide insights into novel covalent ligand-FAAH binding interactions, and facilitate the design of covalent ligands against FAAH.

  3. Nuclear risk

    SciTech Connect

    Levenson, M.

    1989-01-01

    The title of our session, Nuclear Risk Versus Other Power Options, is provocative. It is also a title with different meanings to different people. To the utility chief executive officer, nuclear power is a high-risk financial undertaking because of political and economic barriers to cost recovery. To the utility dispatcher, it is a high-risk future power source since plant completion and start-up dates can be delayed for very long times due to uncertain legal and political issues. To the environmentalist, concerned about global effects such as greenhouse and acid rain, nuclear power is a relatively low risk energy source. To the financial people, nuclear power is a cash cow turned sour because of uncertainties as to what new plants will cost and whether they will even be allowed to operate. The statistics on risk are known and the results of probability risk assessment calculations of risks are known. The challenge is not to make nuclear power safer, it is already one of the safest, if not the safest, source of power currently available. The challenge is to find a way to communicate this to the public.

  4. Targeting Ligand-Dependent and Ligand-Independent Androgen Receptor Signaling in Prostate Cancer

    DTIC Science & Technology

    2013-10-01

    sub 10nM range efficacy. Our primary objective was to establish a series of compounds blocking the AR ligand-dependent and ligand-independent gene ...of AR driven genes to be more comprehensive and more in line with what is currently known about AR-driven signaling in prostate cancer. We have...developed a robust panel of genes for AR signaling that is reflective of the clinical findings in both ligand dependent and ligand-independent androgen

  5. Cis-interactions between Notch and its ligands block ligand-independent Notch activity

    PubMed Central

    Palmer, William Hunt; Jia, Dongyu; Deng, Wu-Min

    2014-01-01

    The Notch pathway is integrated into numerous developmental processes and therefore is fine-tuned on many levels, including receptor production, endocytosis, and degradation. Notch is further characterized by a twofold relationship with its Delta-Serrate (DSL) ligands, as ligands from opposing cells (trans-ligands) activate Notch, whereas ligands expressed in the same cell (cis-ligands) inhibit signaling. We show that cells without both cis- and trans-ligands can mediate Notch-dependent developmental events during Drosophila oogenesis, indicating ligand-independent Notch activity occurs when the receptor is free of cis- and trans-ligands. Furthermore, cis-ligands can reduce Notch activity in endogenous and genetically induced situations of elevated trans-ligand-independent Notch signaling. We conclude that cis-expressed ligands exert their repressive effect on Notch signaling in cases of trans-ligand-independent activation, and propose a new function of cis-inhibition which buffers cells against accidental Notch activity. DOI: http://dx.doi.org/10.7554/eLife.04415.001 PMID:25486593

  6. Nuclear waste

    SciTech Connect

    Not Available

    1988-05-01

    This paper discusses how, as part of the Department of Energy's implementation of the Nuclear Waste Policy Act of 1982, DOE is required to investigate a site at Yucca Mountain, Nevada and, if it determines that the site is suitable, recommend to the President its selection for a nuclear waste repository. The Nuclear Regulatory Commission, in considering development of the plan, issued five objections, one of which is DOE's failure to recognize the range of alternative conceptual models of the Yucca Mountain site that can be supported by the limited existing technical data. At the end of the quarter DOE directed its project offices in Washington and Texas to begin orderly phase-out of all site-specific repository activities. Costs for this phase-out are $53 million for the Deaf Smith site and $85 million for the Hanford site.

  7. Nuclear Models

    NASA Astrophysics Data System (ADS)

    Fossión, Rubén

    2010-09-01

    The atomic nucleus is a typical example of a many-body problem. On the one hand, the number of nucleons (protons and neutrons) that constitute the nucleus is too large to allow for exact calculations. On the other hand, the number of constituent particles is too small for the individual nuclear excitation states to be explained by statistical methods. Another problem, particular for the atomic nucleus, is that the nucleon-nucleon (n-n) interaction is not one of the fundamental forces of Nature, and is hard to put in a single closed equation. The nucleon-nucleon interaction also behaves differently between two free nucleons (bare interaction) and between two nucleons in the nuclear medium (dressed interaction). Because of the above reasons, specific nuclear many-body models have been devised of which each one sheds light on some selected aspects of nuclear structure. Only combining the viewpoints of different models, a global insight of the atomic nucleus can be gained. In this chapter, we revise the the Nuclear Shell Model as an example of the microscopic approach, and the Collective Model as an example of the geometric approach. Finally, we study the statistical properties of nuclear spectra, basing on symmetry principles, to find out whether there is quantum chaos in the atomic nucleus. All three major approaches have been rewarded with the Nobel Prize of Physics. In the text, we will stress how each approach introduces its own series of approximations to reduce the prohibitingly large number of degrees of freedom of the full many-body problem to a smaller manageable number of effective degrees of freedom.

  8. Ligand binding by PDZ domains.

    PubMed

    Chi, Celestine N; Bach, Anders; Strømgaard, Kristian; Gianni, Stefano; Jemth, Per

    2012-01-01

    The postsynaptic density protein-95/disks large/zonula occludens-1 (PDZ) protein domain family is one of the most common protein-protein interaction modules in mammalian cells, with paralogs present in several hundred human proteins. PDZ domains are found in most cell types, but neuronal proteins, for example, are particularly rich in these domains. The general function of PDZ domains is to bring proteins together within the appropriate cellular compartment, thereby facilitating scaffolding, signaling, and trafficking events. The many functions of PDZ domains under normal physiological as well as pathological conditions have been reviewed recently. In this review, we focus on the molecular details of how PDZ domains bind their protein ligands and their potential as drug targets in this context.

  9. Nuclear pursuits

    SciTech Connect

    Not Available

    1993-05-01

    This table lists quantities of warheads (in stockpile, peak number per year, total number built, number of known test explosions), weapon development milestones (developers of the atomic bomb and hydrogen bomb, date of first operational ICBM, first nuclear-powered naval SSN in service, first MIRVed missile deployed), and testing milestones (first fission test, type of boosted fission weapon, multistage thermonuclear test, number of months from fission bomb to multistage thermonuclear bomb, etc.), and nuclear infrastructure (assembly plants, plutonium production reactors, uranium enrichment plants, etc.). Countries included in the tally are the United States, Soviet Union, Britain, France, and China.

  10. Nuclear receptors in transgenerational epigenetic inheritance.

    PubMed

    Ozgyin, Lilla; Erdős, Edina; Bojcsuk, Dóra; Balint, Balint L

    2015-07-01

    Nuclear Receptors are ligand-activated transcription factors that translate information about the lipid environment into specific genetic programs, a property that renders them good candidates to be mediators of rapid adaptation changes of a species. Lipid-based morphogens, endocrine hormones, fatty acids and xenobiotics might act through this class of transcription factors making them regulators able to fine-tune physiological processes. Here we review the basic concepts and current knowledge on the process whereby small molecules act through nuclear receptors and contribute to transgenerational changes. Several molecules shown to cause transgenerational changes like phthalates, BPA, nicotine, tributylin bind and activate nuclear receptors like ERs, androgen receptors, glucocorticoid receptors or PPARγ. A specific subset of observations involving nuclear receptors has focused on the effects of environmental stress or maternal behaviour on the development of transgenerational traits. While these effects do not involve environmental ligands, they change the expression levels of Estrogen and glucocorticoid receptors of the second generation and consequently initiate an altered genetic program in the second generation. In this review we summarize the available literature about the role of nuclear receptors in transgenerational inheritance.

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

    PubMed Central

    Klei, Herbert E.; Moriarty, Nigel W.; Echols, Nathaniel; Terwilliger, Thomas C.; Baldwin, Eric T.; Pokross, Matt; Posy, Shana; Adams, Paul D.

    2014-01-01

    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 leverages prior knowledge from earlier structures to facilitate ligand placement in the current structure. PMID:24419386

  12. Flexible ligand docking using a genetic algorithm

    NASA Astrophysics Data System (ADS)

    Oshiro, C. M.; Kuntz, I. D.; Dixon, J. Scott

    1995-04-01

    Two computational techniques have been developed to explore the orientational and conformational space of a flexible ligand within an enzyme. Both methods use the Genetic Algorithm (GA) to generate conformationally flexible ligands in conjunction with algorithms from the DOCK suite of programs to characterize the receptor site. The methods are applied to three enzyme-ligand complexes: dihydrofolate reductase-methotrexate, thymidylate synthase-phenolpthalein and HIV protease-thioketal haloperidol. Conformations and orientations close to the crystallographically determined structures are obtained, as well as alternative structures with low energy. The potential for the GA method to screen a database of compounds is also examined. A collection of ligands is evaluated simultaneously, rather than docking the ligands individually into the enzyme.

  13. Biomimetic affinity ligands for protein purification.

    PubMed

    Sousa, Isabel T; Taipa, M Angela

    2014-01-01

    The development of sophisticated molecular modeling software and new bioinformatic tools, as well as the emergence of data banks containing detailed information about a huge number of proteins, enabled the de novo intelligent design of synthetic affinity ligands. Such synthetic compounds can be tailored to mimic natural biological recognition motifs or to interact with key surface-exposed residues on target proteins and are designated as "biomimetic ligands." A well-established methodology for generating biomimetic or synthetic affinity ligands integrates rational design with combinatorial solid-phase synthesis and screening, using the triazine scaffold and analogues of amino acids side chains to create molecular diversity.Triazine-based synthetic ligands are nontoxic, low-cost, highly stable compounds that can replace advantageously natural biological ligands in the purification of proteins by affinity-based methodologies.

  14. Nuclear orbiting

    SciTech Connect

    Shapira, D.

    1988-01-01

    Nuclear orbiting following collisions between sd and p shell nuclei is discussed. The dependence of this process on the real and imaginary parts of the nucleus-nucleus potential is discussed, as well as the evolution of the dinucleus toward a fully equilibrated fused system. 26 refs., 15 figs.

  15. Nuclear Misinformation

    ERIC Educational Resources Information Center

    Ford, Daniel F.; Kendall, Henry W.

    1975-01-01

    Many scientists feel that research into nuclear safety has been diverted or distorted, and the results of the research concealed or inaccurately reported on a large number of occasions. Of particular concern have been the emergency cooling systems which have not, as yet, been adequately tested. (Author/MA)

  16. Nuclear Terrorism.

    SciTech Connect

    Hecker, Siegfried S.

    2001-01-01

    As pointed out by several speakers, the level of violence and destruction in terrorist attacks has increased significantly during the past decade. Fortunately, few have involved weapons of mass destruction, and none have achieved mass casualties. The Aum Shinrikyo release of lethal nerve agent, sarin, in the Tokyo subway on March 20, 1995 clearly broke new ground by crossing the threshold in attempting mass casualties with chemical weapons. However, of all weapons of mass destruction, nuclear weapons still represent the most frightening threat to humankind. Nuclear weapons possess an enormous destructive force. The immediacy and scale of destruction are unmatched. In addition to destruction, terrorism also aims to create fear among the public and governments. Here also, nuclear weapons are unmatched. The public's fear of nuclear weapons or, for that matter, of all radioactivity is intense. To some extent, this fear arises from a sense of unlimited vulnerability. That is, radioactivity is seen as unbounded in three dimensions - distance, it is viewed as having unlimited reach; quantity, it is viewed as having deadly consequences in the smallest doses (the public is often told - incorrectly, of course - that one atom of plutonium will kill); and time, if it does not kill you immediately, then it will cause cancer decades hence.

  17. Nuclear medicine

    SciTech Connect

    Wagner, H.N. Jr.

    1986-10-17

    In 1985 and 1986 nuclear medicine became more and more oriented toward in vov chemistry, chiefly as a result of advances in positron emission tomography (PET). The most important trend was the extension of PET technology into the care of patients with brain tumors, epilepsy, and heart disease. A second trend was the increasing use of single-photon emission computed tomography (SPECT).

  18. NUCLEAR REACTOR

    DOEpatents

    Treshow, M.

    1961-09-01

    A boiling-water nuclear reactor is described wherein control is effected by varying the moderator-to-fuel ratio in the reactor core. This is accomplished by providing control tubes containing a liquid control moderator in the reactor core and providing means for varying the amount of control moderatcr within the control tubes.

  19. Nuclear Science.

    ERIC Educational Resources Information Center

    Pennsylvania State Dept. of Education, Harrisburg. Bureau of Curriculum Services.

    This document is a report on a course in nuclear science for the high school curriculum. The course is designed to provide a basic but comprehensive understanding of the atom in the light of modern knowledge, and to show how people attempt to harness the tremendous energy liberated through fission and fusion reactions. The course crosses what are…

  20. Nuclear energy.

    PubMed

    Wilson, Peter D

    2010-01-01

    The technical principles and practices of the civil nuclear industry are described with particular reference to fission and its products, natural and artificial radioactivity elements principally concerned and their relationships, main types of reactor, safety issues, the fuel cycle, waste management, issues related to weapon proliferation, environmental considerations and possible future developments.

  1. NMR and computational methods in the structural and dynamic characterization of ligand-receptor interactions.

    PubMed

    Ghitti, Michela; Musco, Giovanna; Spitaleri, Andrea

    2014-01-01

    The recurrent failures in drug discovery campaigns, the asymmetry between the enormous financial investments and the relatively scarce results have fostered the development of strategies based on complementary methods. In this context in recent years the rigid lock-and-key binding concept had to be revisited in favour of a dynamic model of molecular recognition accounting for conformational changes of both the ligand and the receptor. The high level of complexity required by a dynamic description of the processes underlying molecular recognition requires a multidisciplinary investigation approach. In this perspective, the combination of nuclear magnetic resonance spectroscopy with molecular docking, conformational searches along with molecular dynamics simulations has given new insights into the dynamic mechanisms governing ligand receptor interactions, thus giving an enormous contribution to the identification and design of new and effective drugs. Herein a succinct overview on the applications of both NMR and computational methods to the structural and dynamic characterization of ligand-receptor interactions will be presented.

  2. Analysis of TNF-related apoptosis-inducing ligand and receptors and implications in thymus biology and myasthenia gravis.

    PubMed

    Kanatli, Irem; Akkaya, Bahar; Uysal, Hilmi; Kahraman, Sevim; Sanlioglu, Ahter Dilsad

    2017-02-01

    Myasthenia Gravis is an autoantibody-mediated, neuromuscular junction disease, and is usually associated with thymic abnormalities presented as thymic tumors (~10%) or hyperplastic thymus (~65%). The exact role of thymus in Myasthenia Gravis development is not clear, yet many patients benefit from thymectomy. The apoptotic ligand TNF-Related Apoptosis-Inducing Ligand is thought to be involved in the regulation of thymocyte counts, although conflicting results are reported. We investigated differential expression profiles of TNF-Related Apoptosis-Inducing Ligand and its transmembrane receptors, Nuclear Factor-kB activation status, and apoptotic cell counts in healthy thymic tissue and pathological thymus from Myasthenia Gravis patients. All tissues expressed TNF-Related Apoptosis-Inducing Ligand and its receptors, with hyperplastic tissue having the highest expression levels of death receptors DR4 and DR5. No detectable Nuclear Factor-kB activation, at least via the canonical Protein Kinase A-mediated p65 Ser276 phosphorylation, was evident in any of the tissues studied. Apoptotic cell counts were higher in MG-associated tissue compared to the normal thymus. Possible use of the TNF-Related Apoptosis-Inducing Ligand within the concept of an apoptotic ligand-mediated medical thymectomy in thymoma- or thymic hyperplasia-associated Myasthenia Gravis is also discussed.

  3. Qualification of a free ligand assay in the presence of anti-ligand antibody Fab fragments.

    PubMed

    Hansen, Ryan J; Brown, Robin M; Lu, Jirong; Wroblewski, Victor J

    2013-01-01

    The aim of this work was to develop and characterize an ELISA to measure free ligand concentrations in rat serum in the presence of a Fab to the same ligand. A variety of experiments were conducted to understand optimal assay conditions and to verify that only free ligand was detected. The parameters explored included sample incubation time on plate, the initial concentrations of Fab and ligand, and the pre-incubation time required for the Fab-ligand complex concentrations to reach equilibrium. We found the optimal experimental conditions to include a 10-minute on-plate incubation of ligand-containing samples, with a 24-hour pre-incubation time for test samples of Fab and ligand to reach equilibrium. An alternative approach, involving removal of Fab-ligand complexes from the solution prior to measuring concentrations of the ligand, was also used to verify that the assay only measured free ligand. Rats were dosed subcutaneously with Fab and the assay was used to demonstrate dose-dependent suppression of endogenous free ligand levels in vivo.

  4. Chemistry of Marine Ligands and Siderophores

    NASA Astrophysics Data System (ADS)

    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 cadmium, thus defining the speciation of these metal ions in the ocean. In the case of iron, siderophores have been identified and structurally characterized. Siderophores are low molecular weight iron-binding ligands produced by marine bacteria. Although progress has been made toward the identity of in situ iron-binding ligands, few compounds have been identified that coordinate the other trace metals. Deciphering the chemical structures and production stimuli of naturally produced organic ligands and the organisms they come from is fundamental to understanding metal speciation and bioavailability. The current evidence for marine ligands, with an emphasis on siderophores, and discussion of the importance and implications of metal-binding ligands in controlling metal speciation and cycling within the world's oceans are presented.

  5. An Undecanuclear Ferrimagnetic Cu9Dy2 Single Molecule Magnet Achieved through Ligand Fine-Tuning.

    PubMed

    Kühne, Irina A; Kostakis, George E; Anson, Christopher E; Powell, Annie K

    2016-05-02

    We describe the concept of increasing the nuclearity of a previously reported high-spin Cu5Gd2 core using a "fine-tuning" ligand approach. Thus, two Cu9Ln2 coordination clusters, with Ln = Dy (1) and Gd (2), were synthesized with the Gd compound having a ground spin state of (17)/2 and the Dy analogue showing single-molecule-magnet behavior in zero field.

  6. NUCLEAR REACTOR

    DOEpatents

    Anderson, C.R.

    1962-07-24

    A fluidized bed nuclear reactor and a method of operating such a reactor are described. In the design means are provided for flowing a liquid moderator upwardly through the center of a bed of pellets of a nentron-fissionable material at such a rate as to obtain particulate fluidization while constraining the lower pontion of the bed into a conical shape. A smooth circulation of particles rising in the center and falling at the outside of the bed is thereby established. (AEC)

  7. NUCLEAR REACTORS

    DOEpatents

    Long, E.; Ashby, J.W.

    1958-09-16

    ABS>A graphite moderator structure is presented for a nuclear reactor compriscd of an assembly of similarly orientated prismatic graphite blocks arranged on spaced longitudinal axes lying in common planes wherein the planes of the walls of the blocks are positioned so as to be twisted reintive to the planes of said axes so thatthe unlmpeded dtrect paths in direction wholly across the walls of the blocks are limited to the width of the blocks plus spacing between the blocks.

  8. NUCLEAR REACTOR

    DOEpatents

    Grebe, J.J.

    1959-07-14

    High temperature reactors which are uniquely adapted to serve as the heat source for nuclear pcwered rockets are described. The reactor is comprised essentially of an outer tubular heat resistant casing which provides the main coolant passageway to and away from the reactor core within the casing and in which the working fluid is preferably hydrogen or helium gas which is permitted to vaporize from a liquid storage tank. The reactor core has a generally spherical shape formed entirely of an active material comprised of fissile material and a moderator material which serves as a diluent. The active material is fabricated as a gas permeable porous material and is interlaced in a random manner with very small inter-connecting bores or capillary tubes through which the coolant gas may flow. The entire reactor is divided into successive sections along the direction of the temperature gradient or coolant flow, each section utilizing materials of construction which are most advantageous from a nuclear standpoint and which at the same time can withstand the operating temperature of that particular zone. This design results in a nuclear reactor characterized simultaneously by a minimum critiral size and mass and by the ability to heat a working fluid to an extremely high temperature.

  9. Nuclear waste

    SciTech Connect

    Not Available

    1991-09-01

    Radioactive waste is mounting at U.S. nuclear power plants at a rate of more than 2,000 metric tons a year. Pursuant to statute and anticipating that a geologic repository would be available in 1998, the Department of Energy (DOE) entered into disposal contracts with nuclear utilities. Now, however, DOE does not expect the repository to be ready before 2010. For this reason, DOE does not want to develop a facility for monitored retrievable storage (MRS) by 1998. This book is concerned about how best to store the waste until a repository is available, congressional requesters asked GAO to review the alternatives of continued storage at utilities' reactor sites or transferring waste to an MRS facility, GAO assessed the likelihood of an MRSA facility operating by 1998, legal implications if DOE is not able to take delivery of wastes in 1998, propriety of using the Nuclear Waste Fund-from which DOE's waste program costs are paid-to pay utilities for on-site storage capacity added after 1998, ability of utilities to store their waste on-site until a repository is operating, and relative costs and safety of the two storage alternatives.

  10. Water versus acetonitrile coordination to uranyl. Effect of chloride ligands.

    PubMed

    Bühl, Michael; Sieffert, Nicolas; Chaumont, Alain; Wipff, Georges

    2012-02-06

    Optimizations at the BLYP and B3LYP levels are reported for the mixed uranyl chloro/water/acetonitrile complexes [UO(2)Cl(n)(H(2)O)(x)(MeCN)(5-n-x)](2-n) (n = 1-3) and [UO(2)Cl(n)(H(2)O)(x)(MeCN)(4-n-x)](2-n) (n = 2-4), in both the gas phase and a polarizable continuum modeling acetonitrile. Car-Parrinello molecular dynamics (CPMD) simulations have been performed for [UO(2)Cl(2)(H(2)O)(MeCN)(2)] in the gas phase and in a periodic box of liquid acetonitrile. According to population analyses and dipole moments evaluated from maximally localized Wannier function centers, uranium is less Lewis acidic in the neutral UO(2)Cl(2) than in the UO(2)(2+) moiety. In the gas phase the latter binds acetonitrile ligands more strongly than water, whereas in acetonitrile solution, the trend is reversed due to cooperative polarization effects. In the polarizable continuum the chloro complexes have a slight energetic preference for water over acetonitrile ligands, but several mixed complexes are so close in free energy ΔG that they should exist in equilibrium, in accord with previous interpretations of EXAFS data in solution. The binding strengths of the fifth neutral ligands decrease with increasing chloride content, to the extent that the trichlorides should be formulated as four-coordinate [UO(2)Cl(3)L](-) (L = H(2)O, MeCN). Limitations to their accuracy notwithstanding, density functional calculations can offer insights into the speciation of a complex uranyl system in solution, a key feature in the context of nuclear waste partitioning by complexant molecules.

  11. SPLINTS: small-molecule protein ligand interface stabilizers.

    PubMed

    Fischer, Eric S; Park, Eunyoung; Eck, Michael J; Thomä, Nicolas H

    2016-04-01

    Regulatory protein-protein interactions are ubiquitous in biology, and small molecule protein-protein interaction inhibitors are an important focus in drug discovery. Remarkably little attention has been given to the opposite strategy-stabilization of protein-protein interactions, despite the fact that several well-known therapeutics act through this mechanism. From a structural perspective, we consider representative examples of small molecules that induce or stabilize the association of protein domains to inhibit, or alter, signaling for nuclear hormone, GTPase, kinase, phosphatase, and ubiquitin ligase pathways. These SPLINTS (small-molecule protein ligand interface stabilizers) drive interactions that are in some cases physiologically relevant, and in others entirely adventitious. The diverse structural mechanisms employed suggest approaches for a broader and systematic search for such compounds in drug discovery.

  12. (S)-5-(p-Nitrobenzyl)-PCTA, a Promising Bifunctional Ligand with Advantageous Metal Ion Complexation Kinetics

    PubMed Central

    Tircsó, Gyula; Benyó, Enikő Tircsóné; Suh, Eul Hyun; Jurek, Paul; Kiefer, Garry E.; Sherry, A. Dean; Kovács, Zoltán

    2009-01-01

    A bifunctional version of PCTA (3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid) that exhibits fast complexation kinetics with the trivalent lanthanide(III) ions was synthesized in reasonable yields starting from N, N′, N″-tristosyl-(S)-2-(p-nitrobenzyl)-diethylenetriamine. pH-potentiometric studies showed that the basicities of p-nitrobenzyl-PCTA and the parent ligand PCTA were similar. The stability of M(NO2-Bn-PCTA) (M = Mg2+, Ca2+, Cu2+, Zn2+) complexes was similar to that of the corresponding PCTA complexes while the stability of Ln3+ complexes of the bifunctional ligand is somewhat lower than that of PCTA chelates. The rate of complex formation of Ln(NO2-Bn-PCTA) complexes was found to be quite similar to that of PCTA, a ligand known to exhibit the fastest formation rates among all lanthanide macrocyclic ligand complexes studied to date. The acid catalyzed decomplexation kinetic studies of the selected Ln(NO2-Bn-PCTA) complexes showed that the kinetic inertness of the complexes was comparable to that of Ln(DOTA) chelates making the bifunctional ligand NO2-Bn-PCTA suitable for labeling biological vectors with radioisotopes for nuclear medicine applications. PMID:19220012

  13. (S)-5-(p-nitrobenzyl)-PCTA, a promising bifunctional ligand with advantageous metal ion complexation kinetics.

    PubMed

    Tircsó, Gyula; Benyó, Eniko Tircsóné; Suh, Eul Hyun; Jurek, Paul; Kiefer, Garry E; Sherry, A Dean; Kovács, Zoltán

    2009-03-18

    A bifunctional version of PCTA (3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid) that exhibits fast complexation kinetics with the trivalent lanthanide(III) ions was synthesized in reasonable yields starting from N,N',N''-tristosyl-(S)-2-(p-nitrobenzyl)-diethylenetriamine. pH-potentiometric studies showed that the basicities of p-nitrobenzyl-PCTA and the parent ligand PCTA were similar. The stability of M(NO(2)-Bn-PCTA) (M = Mg(2+), Ca(2+), Cu(2+), Zn(2+)) complexes was similar to that of the corresponding PCTA complexes, while the stability of Ln(3+) complexes of the bifunctional ligand is somewhat lower than that of PCTA chelates. The rate of complex formation of Ln(NO(2)-Bn-PCTA) complexes was found to be quite similar to that of PCTA, a ligand known to exhibit the fastest formation rates among all lanthanide macrocyclic ligand complexes studied to date. The acid-catalyzed decomplexation kinetic studies of the selected Ln(NO(2)-Bn-PCTA) complexes showed that the kinetic inertness of the complexes was comparable to that of Ln(DOTA) chelates making the bifunctional ligand NO(2)-Bn-PCTA suitable for labeling biological vectors with radioisotopes for nuclear medicine applications.

  14. 01-ERD-111 - The Development of Synthetic High Affinity Ligands

    SciTech Connect

    Perkins, J; Balhorn, R; Cosman, M; Lightstone, F; Zeller, L

    2004-02-05

    The aim of this project was to develop Synthetic High-Affinity Ligands (SHALs), which bind with high affinity and specificity to proteins of interest for national security and cancer therapy applications. The aim of producing synthetic ligands for sensory devices as an alternative to antibody-based detection assays and therapeutic agents is to overcome the drawbacks associated with antibody-based in next-generation sensors and systems. The focus area of the project was the chemical synthesis of the SHALs. The project concentrated on two different protein targets. (a) The C fragment of tetanus and botulinum toxin, potential biowarfare agents. A SHAL for tetanus or botulinum toxin would be incorporated into a sensory device for the toxins. (b) HLA-DR10, a protein found in high abundance on the surface of Non-Hodgkins Lymphoma. A SHAL specific to a tumor marker, labeled with a radionuclide, would enable the targeted delivery of radiation therapy to metastatic disease. The technical approach used to develop a SHAL for each protein target will be described in more detail below. However, in general, the development of a SHAL requires a combination of computational modeling techniques, modern nuclear magnetic resonance spectroscopy (NMR) and synthetic chemistry.

  15. Nuclear photonics

    NASA Astrophysics Data System (ADS)

    Habs, D.; Günther, M. M.; Jentschel, M.; Thirolf, P. G.

    2012-07-01

    With the planned new γ-beam facilities like MEGa-ray at LLNL (USA) or ELI-NP at Bucharest (Romania) with 1013 γ/s and a band width of ΔEγ/Eγ≈10-3, a new era of γ beams with energies up to 20MeV comes into operation, compared to the present world-leading HIγS facility at Duke University (USA) with 108 γ/s and ΔEγ/Eγ≈3ṡ10-2. In the long run even a seeded quantum FEL for γ beams may become possible, with much higher brilliance and spectral flux. At the same time new exciting possibilities open up for focused γ beams. Here we describe a new experiment at the γ beam of the ILL reactor (Grenoble, France), where we observed for the first time that the index of refraction for γ beams is determined by virtual pair creation. Using a combination of refractive and reflective optics, efficient monochromators for γ beams are being developed. Thus, we have to optimize the total system: the γ-beam facility, the γ-beam optics and γ detectors. We can trade γ intensity for band width, going down to ΔEγ/Eγ≈10-6 and address individual nuclear levels. The term "nuclear photonics" stresses the importance of nuclear applications. We can address with γ-beams individual nuclear isotopes and not just elements like with X-ray beams. Compared to X rays, γ beams can penetrate much deeper into big samples like radioactive waste barrels, motors or batteries. We can perform tomography and microscopy studies by focusing down to μm resolution using Nuclear Resonance Fluorescence (NRF) for detection with eV resolution and high spatial resolution at the same time. We discuss the dominating M1 and E1 excitations like the scissors mode, two-phonon quadrupole octupole excitations, pygmy dipole excitations or giant dipole excitations under the new facet of applications. We find many new applications in biomedicine, green energy, radioactive waste management or homeland security. Also more brilliant secondary beams of neutrons and positrons can be produced.

  16. Nuclear photonics

    SciTech Connect

    Habs, D.; Guenther, M. M.; Jentschel, M.; Thirolf, P. G.

    2012-07-09

    With the planned new {gamma}-beam facilities like MEGa-ray at LLNL (USA) or ELI-NP at Bucharest (Romania) with 10{sup 13}{gamma}/s and a band width of {Delta}E{gamma}/E{gamma} Almost-Equal-To 10{sup -3}, a new era of {gamma} beams with energies up to 20MeV comes into operation, compared to the present world-leading HI{gamma}S facility at Duke University (USA) with 10{sup 8}{gamma}/s and {Delta}E{gamma}/E{gamma} Almost-Equal-To 3 Dot-Operator 10{sup -2}. In the long run even a seeded quantum FEL for {gamma} beams may become possible, with much higher brilliance and spectral flux. At the same time new exciting possibilities open up for focused {gamma} beams. Here we describe a new experiment at the {gamma} beam of the ILL reactor (Grenoble, France), where we observed for the first time that the index of refraction for {gamma} beams is determined by virtual pair creation. Using a combination of refractive and reflective optics, efficient monochromators for {gamma} beams are being developed. Thus, we have to optimize the total system: the {gamma}-beam facility, the {gamma}-beam optics and {gamma} detectors. We can trade {gamma} intensity for band width, going down to {Delta}E{gamma}/E{gamma} Almost-Equal-To 10{sup -6} and address individual nuclear levels. The term 'nuclear photonics' stresses the importance of nuclear applications. We can address with {gamma}-beams individual nuclear isotopes and not just elements like with X-ray beams. Compared to X rays, {gamma} beams can penetrate much deeper into big samples like radioactive waste barrels, motors or batteries. We can perform tomography and microscopy studies by focusing down to {mu}m resolution using Nuclear Resonance Fluorescence (NRF) for detection with eV resolution and high spatial resolution at the same time. We discuss the dominating M1 and E1 excitations like the scissors mode, two-phonon quadrupole octupole excitations, pygmy dipole excitations or giant dipole excitations under the new facet of

  17. CoMFA and docking study of novel estrogen receptor subtype selective ligands

    NASA Astrophysics Data System (ADS)

    Wolohan, Peter; Reichert, David E.

    2003-05-01

    We present the results from a Comparative Molecular Field Analysis (CoMFA) and docking study of a diverse set of 36 estrogen receptor ligands whose relative binding affinities (RBA) with respect to 17β-Estradiol were available in both isoforms of the nuclear estrogen receptors (ERα, ERβ). Initial CoMFA models exhibited a correlation between the experimental relative binding affinities and the molecular steric and electrostatic fields; ERα: r2=0.79, q2=0.44 ERβ: r2=0.93, q2=0.63. Addition of the solvation energy of the isolated ligand improved the predictive nature of the ERβ model initially; r2=0.96, q2=0.70 but upon rescrambling of the data-set and reselecting the training set at random, inclusion of the ligand solvation energy was found to have little effect on the predictive nature of the CoMFA models. The ligands were then docked inside the ligand binding domain (LBD) of both ERα and ERβ utilizing the docking program Gold, after-which the program CScore was used to rank the resulting poses. Inclusion of both the Gold and CScore scoring parameters failed to improve the predictive ability of the original CoMFA models. The subtype selectivity expressed as RBA(ERα/ERβ) of the test sets was predicted using the most predictive CoMFA models, as illustrated by the cross-validated r2. In each case the most selective ligands were ranked correctly illustrating the utility of this method as a prescreening tool in the development of novel estrogen receptor subtype selective ligands.

  18. Nuclear Receptor Activity and Liver Cancer Lesion Progression

    EPA Science Inventory

    Nuclear receptors (NRs) are ligand-activated transcription factors that control diverse cellular processes. Chronic stimulation of some NRs is a non-genotoxic mechanism of rodent liver cancer with unclear relevance to humans. We explored this question using human CAR, PXR, PPARα,...

  19. Probing vibrational anisotropy with nuclear resonance vibrational spectroscopy.

    SciTech Connect

    Pavlik, J. W.; Barabanschikov, A.; Oliver, A. G.; Alp, E. E.; Sturhahn, W.; Zhao, J.; Sage, J. T.; Scheidt, W. R.

    2010-06-14

    A NRVS single-crystal study (NRVS=nuclear resonance vibrational spectroscopy) has provided detailed information on the in-plane modes of nitrosyl iron porphyrinate [Fe(oep)(NO)] (see picture; oep=octaethylporphyrin). The axial nitrosyl ligand controls the direction of the in-plane iron motion.

  20. ProPose: steered virtual screening by simultaneous protein-ligand docking and ligand-ligand alignment.

    PubMed

    Seifert, Markus H J

    2005-01-01

    The 'model-free' screening engine ProPose implements a general method for performing simultaneous protein-ligand docking, ligand-ligand alignment, pharmacophore queries-and combinations thereof-in order to incorporate a priori information into screening protocols. In this manuscript we describe a case study on herpes simplex virus thymidine kinase, an important antiviral drug target, where we evaluate different approaches for handling a specific type of a priori information, i.e., multiple target structures. We demonstrate that a simultaneous alignment on two target structures--in conjunction with logic operations on interactions and docking constraints derived from protein structure--is an effective means of (i) improving the enrichment of chemical substructures that are compatible with the a priori known ligands, (ii) ensuring the steric fit into the target protein, and (iii) handling target flexibility. The combination of ligand- and receptor-based methods steers the virtual screening by ranking molecules according to the similarity of their interaction pattern with known ligands, thereby--to some extent--outweighing the deficiencies of simple scoring functions often used in initial virtual screening.

  1. Fatty Acid Amide Hydrolase (FAAH) Inhibition Enhances Memory Acquisition through Activation of PPAR-alpha Nuclear Receptors

    ERIC Educational Resources Information Center

    Mazzola, Carmen; Medalie, Julie; Scherma, Maria; Panlilio, Leigh V.; Solinas, Marcello; Tanda, Gianluigi; Drago, Filippo; Cadet, Jean Lud; Goldberg, Steven R.; Yasar, Sevil

    2009-01-01

    Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of anandamide (a cannabinoid CB[subscript 1]-receptor ligand) and oleoylethanolamide and palmitoylethanolamide (OEA and PEA, ligands for alpha-type peroxisome proliferator-activated nuclear receptors, PPAR-alpha) when and where they are naturally released in the brain.…

  2. Molecular systems pharmacology: isoelectric focusing signature of protein kinase Cδ provides an integrated measure of its modulation in response to ligands.

    PubMed

    Kedei, Noemi; Chen, Jin-Qiu; Herrmann, Michelle A; Telek, Andrea; Goldsmith, Paul K; Petersen, Mark E; Keck, Gary E; Blumberg, Peter M

    2014-06-26

    Protein kinase C (PKC), a validated therapeutic target for cancer chemotherapy, provides a paradigm for assessing structure-activity relations, where ligand binding has multiple consequences for a target. For PKC, ligand binding controls not only PKC activation and multiple phosphorylations but also subcellular localization, affecting subsequent signaling. Using a capillary isoelectric focusing immunoassay system, we could visualize a high resolution isoelectric focusing signature of PKCδ upon stimulation by ligands of the phorbol ester and bryostatin classes. Derivatives that possessed different physicochemical characteristics and induced different patterns of biological response generated different signatures. Consistent with different patterns of PKCδ localization as one factor linked to these different signatures, we found different signatures for activated PKCδ from the nuclear and non-nuclear fractions. We conclude that the capillary isoelectric focusing immunoassay system may provide a window into the integrated consequences of ligand binding and thus afford a powerful platform for compound development.

  3. Ligand engineering of nanoparticle solar cells

    NASA Astrophysics Data System (ADS)

    Voros, Marton

    Semiconductor nanoparticles (NP) are promising materials to build cheap and efficient solar cells. One of the key challenges in their utilization for solar energy conversion is the control of NP surfaces and ligand-NP interfaces. Recent experiments have shown that by carefully choosing the ligands terminating the NPs, one can tailor electronic and optical absorption properties of NP assemblies, along with their transport properties. By using density functional theory based methods, we investigated how the opto-electronic properties of lead chalcogenide NPs may be tuned by using diverse organic and inorganic ligands. We interpreted experiments, and we showed that an essential prerequisite to avoid detrimental trap states is to ensure charge balance at the ligand-NP interface, possibly with the help of hydrogen treatment Work supported by the Center for Advanced Solar Photophysics, an Energy Frontier Research Center funded by the US Department of Energy, Office of Science, Office of Basic Energy Sciences.

  4. Automated design of ligands to polypharmacological profiles

    PubMed Central

    Besnard, Jérémy; Ruda, Gian Filippo; Setola, Vincent; Abecassis, Keren; Rodriguiz, Ramona M.; Huang, Xi-Ping; Norval, Suzanne; Sassano, Maria F.; Shin, Antony I.; Webster, Lauren A.; Simeons, Frederick R.C.; Stojanovski, Laste; Prat, Annik; Seidah, Nabil G.; Constam, Daniel B.; Bickerton, G. Richard; Read, Kevin D.; Wetsel, William C.; Gilbert, Ian H.; Roth, Bryan L.; Hopkins, Andrew L.

    2012-01-01

    The clinical efficacy and safety of a drug is determined by its activity profile across multiple proteins in the proteome. However, designing drugs with a specific multi-target profile is both complex and difficult. Therefore methods to rationally design drugs a priori against profiles of multiple proteins would have immense value in drug discovery. We describe a new approach for the automated design of ligands against profiles of multiple drug targets. The method is demonstrated by the evolution of an approved acetylcholinesterase inhibitor drug into brain penetrable ligands with either specific polypharmacology or exquisite selectivity profiles for G-protein coupled receptors. Overall, 800 ligand-target predictions of prospectively designed ligands were tested experimentally, of which 75% were confirmed correct. We also demonstrate target engagement in vivo. The approach can be a useful source of drug leads where multi-target profiles are required to achieve either selectivity over other drug targets or a desired polypharmacology. PMID:23235874

  5. Ligand inducible assembly of a DNA tetrahedron.

    PubMed

    Dohno, Chikara; Atsumi, Hiroshi; Nakatani, Kazuhiko

    2011-03-28

    Here we show that a small synthetic ligand can be used as a key building component for DNA nanofabrication. Using naphthyridinecarbamate dimer (NCD) as a molecular glue for DNA hybridization, we demonstrate NCD-triggered formation of a DNA tetrahedron.

  6. Advanced Organic Ligands for Protecting Metal Nanoparticles

    NASA Astrophysics Data System (ADS)

    Yu, Jonathan Ka-Wing

    Organic monolayer protected metal nanoparticles have been utilized in many different fields such as catalysis, drug delivery, and sensor chemistry. However, these nanomaterials are prone to increase in size consequently losing its function at the nanoscale. The stability these nanoparticles have been a great interest of research. This thesis focuses on the synthesis of a novel cross-linkable ligand for the protection of metal nanoparticles. Chapter 1 reviews key concepts of nanoparticles, its usefulness in applications, some of the stabilizing strategies employed, and the scope of the thesis project. Chapter 2 describes the synthetic attempts and optimization of the novel cross-linkable ligand. In addition, its characterization data is also included. Section 2.8 also highlights another fully synthesized novel hydrophobic ligand. Chapter 3 contains the summary of the work and closing remarks. Future works is also included to describe the prospects of the synthesis of the novel ligand. Chapter 4 entails the experimental data and supplementary information.

  7. GW-501516 GlaxoSmithKline/Ligand.

    PubMed

    Pelton, Patricia

    2006-04-01

    GlaxoSmithKline and Ligand are developing GW-501516, a peroxisome proliferator-activator receptor-delta agonist for the potential treatment of dyslipidemia. Phase II clinical trials of this compound are ongoing.

  8. Versatility or promiscuity: the estrogen receptors, control of ligand selectivity and an update on subtype selective ligands.

    PubMed

    Ng, Hui Wen; Perkins, Roger; Tong, Weida; Hong, Huixiao

    2014-08-26

    The estrogen receptors (ERs) are a group of versatile receptors. They regulate an enormity of processes starting in early life and continuing through sexual reproduction, development, and end of life. This review provides a background and structural perspective for the ERs as part of the nuclear receptor superfamily and discusses the ER versatility and promiscuity. The wide repertoire of ER actions is mediated mostly through ligand-activated transcription factors and many DNA response elements in most tissues and organs. Their versatility, however, comes with the drawback of promiscuous interactions with structurally diverse exogenous chemicals with potential for a wide range of adverse health outcomes. Even when interacting with endogenous hormones, ER actions can have adverse effects in disease progression. Finally, how nature controls ER specificity and how the subtle differences in receptor subtypes are exploited in pharmaceutical design to achieve binding specificity and subtype selectivity for desired biological response are discussed. The intent of this review is to complement the large body of literature with emphasis on most recent developments in selective ER ligands.

  9. Affinity Electrophoresis Using Ligands Attached To Polymers

    NASA Technical Reports Server (NTRS)

    Van Alstine, James M.; Snyder, Robert S.; Harris, J. M.; Brooks, D. E.

    1990-01-01

    In new technique, reduction of electrophoretic mobilities by addition of polyethylene glycol to ligands increases electrophoretic separabilities. In immuno-affinity electrophoresis, modification of ligands extends specificity of electrophoretic separation to particles having surface electric-charge structures otherwise making them electrophoretically inseparable. Modification of antibodies by polyethylene glycol greatly reduces ability to aggregate while enhancing ability to affect electrophoretic mobilities of cells. In hydrophobic-affinity electrophoresis, addition of polyethylene glycol reduces tendency toward aggregation of cells or macromolecules.

  10. The Nuclear Power and Nuclear Weapons Connection.

    ERIC Educational Resources Information Center

    Leventhal, Paul

    1990-01-01

    Explains problems enforcing the Nuclear Non-Proliferation Treaty (NPT) of 1968. Provides factual charts and details concerning the production of nuclear energy and arms, the processing and disposal of waste products, and outlines the nuclear fuel cycle. Discusses safeguards, the risk of nuclear terrorism, and ways to deal with these problems. (NL)

  11. The Nuclear Power/Nuclear Weapons Connection.

    ERIC Educational Resources Information Center

    Totten, Sam; Totten, Martha Wescoat

    1985-01-01

    Once they have nuclear power, most countries will divert nuclear materials from commercial to military programs. In excerpts from the book "Facing the Danger" (by Totten, S. and M. W., Crossing Press, 1984), five anti-nuclear activists explain how and why they have been addressing the nuclear connection. (RM)

  12. Semiconductor Quantum Dots with Photoresponsive Ligands.

    PubMed

    Sansalone, Lorenzo; Tang, Sicheng; Zhang, Yang; Thapaliya, Ek Raj; Raymo, Françisco M; Garcia-Amorós, Jaume

    2016-10-01

    Photochromic or photocaged ligands can be anchored to the outer shell of semiconductor quantum dots in order to control the photophysical properties of these inorganic nanocrystals with optical stimulations. One of the two interconvertible states of the photoresponsive ligands can be designed to accept either an electron or energy from the excited quantum dots and quench their luminescence. Under these conditions, the reversible transformations of photochromic ligands or the irreversible cleavage of photocaged counterparts translates into the possibility to switch luminescence with external control. As an alternative to regulating the photophysics of a quantum dot via the photochemistry of its ligands, the photochemistry of the latter can be controlled by relying on the photophysics of the former. The transfer of excitation energy from a quantum dot to a photocaged ligand populates the excited state of the species adsorbed on the nanocrystal to induce a photochemical reaction. This mechanism, in conjunction with the large two-photon absorption cross section of quantum dots, can be exploited to release nitric oxide or to generate singlet oxygen under near-infrared irradiation. Thus, the combination of semiconductor quantum dots and photoresponsive ligands offers the opportunity to assemble nanostructured constructs with specific functions on the basis of electron or energy transfer processes. The photoswitchable luminescence and ability to photoinduce the release of reactive chemicals, associated with the resulting systems, can be particularly valuable in biomedical research and can, ultimately, lead to the realization of imaging probes for diagnostic applications as well as to therapeutic agents for the treatment of cancer.

  13. New bifunctional ligands for radioimmunoimaging and radioimmunotherapy

    SciTech Connect

    Brechbiel, M.W.

    1988-01-01

    The bifunctional EDTA ligand and two bifunctional DTPA ligands were synthesized by direct aminolysis of an amino acid ester followed by reduction, alkylation, and functional group modification to introduced bifunctionality. The reactive substituent chosen for protein conjugation was the isothiocyanate group. The generality of this approach was demonstrated with 9 different amino acids to produce the respective substituted diethylenetriamines. The remaining three bifunctional DTPA ligands were synthesized via classical peptide methodology producing a dipeptide amide which, after deprotection, was reduced to the triamine and alkylated to produce the ligand. Biodistribution studies of the ligands conjugated to monoclonal antibody B72.3 and labelled with In-111 revealed that superior retention of In-111 was attained and the dose to the liver was minimized when a full intact octadentate bifunctional DTPA chelate was used, e.g. DTPA > EDTA > DTTA (diethylenetritetraacetic acid from use of DTPA dianhydride (CA-DTPA)). The best scintigraphic images were obtained after 72 hours when a DTPA ligand was used to complex the In-111. Biodistribution studies using Yttrium-88 revealed that the disubstituted bifunctional DTPA was necessary to minimize the bone dose from the Yttrium while maintaining a high dose to the tumor.

  14. Nuclear energy.

    PubMed

    Grandin, Karl; Jagers, Peter; Kullander, Sven

    2010-01-01

    Nuclear energy can play a role in carbon free production of electrical energy, thus making it interesting for tomorrow's energy mix. However, several issues have to be addressed. In fission technology, the design of so-called fourth generation reactors show great promise, in particular in addressing materials efficiency and safety issues. If successfully developed, such reactors may have an important and sustainable part in future energy production. Working fusion reactors may be even more materials efficient and environmental friendly, but also need more development and research. The roadmap for development of fourth generation fission and fusion reactors, therefore, asks for attention and research in these fields must be strengthened.

  15. NUCLEAR REACTORS

    DOEpatents

    Long, E.; Ashley, J.W.

    1958-12-16

    A graphite moderator structure is described for a gas-cooled nuclear reactor having a vertical orlentation wherein the structure is physically stable with regard to dlmensional changes due to Wigner growth properties of the graphite, and leakage of coolant gas along spaces in the structure is reduced. The structure is comprised of stacks of unlform right prismatic graphite blocks positioned in layers extending in the direction of the lengths of the blocks, the adjacent end faces of the blocks being separated by pairs of tiles. The blocks and tiles have central bores which are in alignment when assembled and are provided with cooperatlng keys and keyways for physical stability.

  16. Nuclear security

    SciTech Connect

    Dingell, J.D.

    1991-02-01

    The Department of Energy's (DOE) Lawrence Livermore National Laboratory, located in Livermore, California, generates and controls large numbers of classified documents associated with the research and testing of nuclear weapons. Concern has been raised about the potential for espionage at the laboratory and the national security implications of classified documents being stolen. This paper determines the extent of missing classified documents at the laboratory and assesses the adequacy of accountability over classified documents in the laboratory's custody. Audit coverage was limited to the approximately 600,000 secret documents in the laboratory's custody. The adequacy of DOE's oversight of the laboratory's secret document control program was also assessed.

  17. Nuclear dualism.

    PubMed

    Karrer, Kathleen M

    2012-01-01

    Nuclear dualism is a characteristic feature of the ciliated protozoa. Tetrahymena have two different nuclei in each cell. The larger, polyploid, somatic macronucleus (MAC) is the site of transcriptional activity in the vegetatively growing cell. The smaller, diploid micronucleus (MIC) is transcriptionally inactive in vegetative cells, but is transcriptionally active in mating cells and responsible for the genetic continuity during sexual reproduction. Although the MICs and MACs develop from mitotic products of a common progenitor and reside in a common cytoplasm, they are different from one another in almost every respect.

  18. Interrupting autocrine ligand-receptor binding: comparison between receptor blockers and ligand decoys.

    PubMed Central

    Forsten, K E; Lauffenburger, D A

    1992-01-01

    Stimulation of cell behavioral functions by ligand/receptor binding can be accomplished in autocrine fashion, where cells secrete ligand capable of binding to receptors on their own surfaces. This proximal secretion of autocrine ligands near the surface receptors on the secreting cell suggests that control of these systems by inhibitors of receptor/ligand binding may be more difficult than for systems involving exogenous ligands. Hence, it is of interest to predict the conditions under which successful inhibition of cell receptor binding by the autocrine ligand can be expected. Previous theoretical work using a compartmentalized model for autocrine cells has elucidated the conditions under which addition of solution decoys for the autocrine ligand can interrupt cell receptor/ligand binding via competitive binding of the secreted molecules (Forsten, K. E., and D. A. Lauffenburger. 1992. Biophys. J. 61:1-12.) We now apply a similar modeling approach to examine the addition of solution blockers targeted against the cell receptor. Comparison of the two alternative inhibition strategies reveals that a significantly lower concentration of receptor blockers, compared to ligand decoys, will obtain a high degree of inhibition. The more direct interruption scheme characteristic of the receptor blockers may make them a preferred strategy when feasible. PMID:1330038

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

    PubMed Central

    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

  20. Ligand and proton exchange dynamics in recombinant human myoglobin mutants.

    PubMed

    Lambright, D G; Balasubramanian, S; Boxer, S G

    1989-05-05

    Site-specific mutants of human myoglobin have been prepared in which lysine 45 is replaced by arginine (K45R) and aspartate 60 by glutamate (D60E), in order to examine the influence of these residues and their interaction on the dynamics of the protein. These proteins were studied by a variety of methods, including one and two-dimensional proton nuclear magnetic resonance spectroscopy, exchange kinetics for the distal and proximal histidine NH protons as a function of pH in the met cyano forms, flash photolysis of the CO forms, and ligand replacement kinetics. The electronic absorption and proton nuclear magnetic resonance spectra of the CO forms of these proteins are virtually identical, indicating that the structure of the heme pocket is unaltered by these mutations. There are, however, substantial changes in the dynamics of both CO binding and proton exchange for the mutant K45R, whereas the mutant D60E exhibits behavior indistinguishable from the reference human myoglobin. K45R has a faster CO bimolecular recombination rate and slower CO off-rate relative to the reference. The kinetics for CO binding are independent of pH (6.5 to 10) as well as ionic strength (0 to 1 M-NaCl). The exchange rate for the distal histidine NH is substantially lower for K45R than the reference, whereas the proximal histidine NH exchange rate is unaltered. The exchange behavior of the human proteins is similar to that reported for a comparison of the exchange rates for myoglobins having lysine at position 45 with sperm whale myoglobin, which has arginine at this position. This indicates that the differences in exchange rates reflects largely the Lys----Arg substitution. The lack of a simple correlation for the CO kinetics with this substitution means that these are sensitive to other factors as well. Specific kinetic models, whereby substitution of arginine for lysine at position 45 can affect ligand binding dynamics, are outlined. These experiments demonstrate that a relatively

  1. Applications of nuclear physics.

    PubMed

    Hayes, A C

    2017-02-01

    Today the applications of nuclear physics span a very broad range of topics and fields. This review discusses a number of aspects of these applications, including selected topics and concepts in nuclear reactor physics, nuclear fusion, nuclear non-proliferation, nuclear-geophysics, and nuclear medicine. The review begins with a historic summary of the early years in applied nuclear physics, with an emphasis on the huge developments that took place around the time of World War II, and that underlie the physics involved in designs of nuclear explosions, controlled nuclear energy, and nuclear fusion. The review then moves to focus on modern applications of these concepts, including the basic concepts and diagnostics developed for the forensics of nuclear explosions, the nuclear diagnostics at the National Ignition Facility, nuclear reactor safeguards, and the detection of nuclear material production and trafficking. The review also summarizes recent developments in nuclear geophysics and nuclear medicine. The nuclear geophysics areas discussed include geo-chronology, nuclear logging for industry, the Oklo reactor, and geo-neutrinos. The section on nuclear medicine summarizes the critical advances in nuclear imaging, including PET and SPECT imaging, targeted radionuclide therapy, and the nuclear physics of medical isotope production. Each subfield discussed requires a review article unto itself, which is not the intention of the current review; rather, the current review is intended for readers who wish to get a broad understanding of applied nuclear physics.

  2. Applications of nuclear physics

    DOE PAGES

    Hayes-Sterbenz, Anna Catherine

    2017-01-10

    Today the applications of nuclear physics span a very broad range of topics and fields. This review discusses a number of aspects of these applications, including selected topics and concepts in nuclear reactor physics, nuclear fusion, nuclear non-proliferation, nuclear-geophysics, and nuclear medicine. The review begins with a historic summary of the early years in applied nuclear physics, with an emphasis on the huge developments that took place around the time of World War II, and that underlie the physics involved in designs of nuclear explosions, controlled nuclear energy, and nuclear fusion. The review then moves to focus on modern applicationsmore » of these concepts, including the basic concepts and diagnostics developed for the forensics of nuclear explosions, the nuclear diagnostics at the National Ignition Facility, nuclear reactor safeguards, and the detection of nuclear material production and trafficking. The review also summarizes recent developments in nuclear geophysics and nuclear medicine. The nuclear geophysics areas discussed include geo-chronology, nuclear logging for industry, the Oklo reactor, and geo-neutrinos. The section on nuclear medicine summarizes the critical advances in nuclear imaging, including PET and SPECT imaging, targeted radionuclide therapy, and the nuclear physics of medical isotope production. Lastly, each subfield discussed requires a review article unto itself, which is not the intention of the current review; rather, the current review is intended for readers who wish to get a broad understanding of applied nuclear physics.« less

  3. Applications of nuclear physics

    NASA Astrophysics Data System (ADS)

    Hayes, A. C.

    2017-02-01

    Today the applications of nuclear physics span a very broad range of topics and fields. This review discusses a number of aspects of these applications, including selected topics and concepts in nuclear reactor physics, nuclear fusion, nuclear non-proliferation, nuclear-geophysics, and nuclear medicine. The review begins with a historic summary of the early years in applied nuclear physics, with an emphasis on the huge developments that took place around the time of World War II, and that underlie the physics involved in designs of nuclear explosions, controlled nuclear energy, and nuclear fusion. The review then moves to focus on modern applications of these concepts, including the basic concepts and diagnostics developed for the forensics of nuclear explosions, the nuclear diagnostics at the National Ignition Facility, nuclear reactor safeguards, and the detection of nuclear material production and trafficking. The review also summarizes recent developments in nuclear geophysics and nuclear medicine. The nuclear geophysics areas discussed include geo-chronology, nuclear logging for industry, the Oklo reactor, and geo-neutrinos. The section on nuclear medicine summarizes the critical advances in nuclear imaging, including PET and SPECT imaging, targeted radionuclide therapy, and the nuclear physics of medical isotope production. Each subfield discussed requires a review article unto itself, which is not the intention of the current review; rather, the current review is intended for readers who wish to get a broad understanding of applied nuclear physics.

  4. Time, the Forgotten Dimension of Ligand Binding Teaching

    ERIC Educational Resources Information Center

    Corzo, Javier

    2006-01-01

    Ligand binding is generally explained in terms of the equilibrium constant K[subscript d] for the protein-ligand complex dissociation. However, both theoretical considerations and experimental data point to the life span of the protein-ligand complex as an important, but generally overlooked, aspect of ligand binding by macromolecules. Short-lived…

  5. Identification of COUP-TFII Orphan Nuclear Receptor as a Retinoic Acid–Activated Receptor

    PubMed Central

    Kruse, Schoen W; Suino-Powell, Kelly; Zhou, X. Edward; Kretschman, Jennifer E; Reynolds, Ross; Vonrhein, Clemens; Xu, Yong; Wang, Liliang; Tsai, Sophia Y; Tsai, Ming-Jer; Xu, H. Eric

    2008-01-01

    The chicken ovalbumin upstream promoter-transcription factors (COUP-TFI and II) make up the most conserved subfamily of nuclear receptors that play key roles in angiogenesis, neuronal development, organogenesis, cell fate determination, and metabolic homeostasis. Although the biological functions of COUP-TFs have been studied extensively, little is known of their structural features or aspects of ligand regulation. Here we report the ligand-free 1.48 Å crystal structure of the human COUP-TFII ligand-binding domain. The structure reveals an autorepressed conformation of the receptor, where helix α10 is bent into the ligand-binding pocket and the activation function-2 helix is folded into the cofactor binding site, thus preventing the recruitment of coactivators. In contrast, in multiple cell lines, COUP-TFII exhibits constitutive transcriptional activity, which can be further potentiated by nuclear receptor coactivators. Mutations designed to disrupt cofactor binding, dimerization, and ligand binding, substantially reduce the COUP-TFII transcriptional activity. Importantly, retinoid acids are able to promote COUP-TFII to recruit coactivators and activate a COUP-TF reporter construct. Although the concentration needed is higher than the physiological levels of retinoic acids, these findings demonstrate that COUP-TFII is a ligand-regulated nuclear receptor, in which ligands activate the receptor by releasing it from the autorepressed conformation. PMID:18798693

  6. Identification of COUP-TFII Orphan Nuclear Receptor as a Retinoic Acid-Activated Receptor

    SciTech Connect

    Kruse, Schoen W; Suino-Powell, Kelly; Zhou, X Edward; Kretschman, Jennifer E; Reynolds, Ross; Vonrhein, Clemens; Xu, Yong; Wang, Liliang; Tsai, Sophia Y; Tsai, Ming-Jer; Xu, H Eric

    2010-01-12

    The chicken ovalbumin upstream promoter-transcription factors (COUP-TFI and II) make up the most conserved subfamily of nuclear receptors that play key roles in angiogenesis, neuronal development, organogenesis, cell fate determination, and metabolic homeostasis. Although the biological functions of COUP-TFs have been studied extensively, little is known of their structural features or aspects of ligand regulation. Here we report the ligand-free 1.48 {angstrom} crystal structure of the human COUP-TFII ligand-binding domain. The structure reveals an autorepressed conformation of the receptor, where helix {alpha}10 is bent into the ligand-binding pocket and the activation function-2 helix is folded into the cofactor binding site, thus preventing the recruitment of coactivators. In contrast, in multiple cell lines, COUP-TFII exhibits constitutive transcriptional activity, which can be further potentiated by nuclear receptor coactivators. Mutations designed to disrupt cofactor binding, dimerization, and ligand binding, substantially reduce the COUP-TFII transcriptional activity. Importantly, retinoid acids are able to promote COUP-TFII to recruit coactivators and activate a COUP-TF reporter construct. Although the concentration needed is higher than the physiological levels of retinoic acids, these findings demonstrate that COUP-TFII is a ligand-regulated nuclear receptor, in which ligands activate the receptor by releasing it from the autorepressed conformation.

  7. Ligand clouds around protein clouds: a scenario of ligand binding with intrinsically disordered proteins.

    PubMed

    Jin, Fan; Yu, Chen; Lai, Luhua; Liu, Zhirong

    2013-01-01

    Intrinsically disordered proteins (IDPs) were found to be widely associated with human diseases and may serve as potential drug design targets. However, drug design targeting IDPs is still in the very early stages. Progress in drug design is usually achieved using experimental screening; however, the structural disorder of IDPs makes it difficult to characterize their interaction with ligands using experiments alone. To better understand the structure of IDPs and their interactions with small molecule ligands, we performed extensive simulations on the c-Myc₃₇₀₋₄₀₉ peptide and its binding to a reported small molecule inhibitor, ligand 10074-A4. We found that the conformational space of the apo c-Myc₃₇₀₋₄₀₉ peptide was rather dispersed and that the conformations of the peptide were stabilized mainly by charge interactions and hydrogen bonds. Under the binding of the ligand, c-Myc₃₇₀₋₄₀₉ remained disordered. The ligand was found to bind to c-Myc₃₇₀₋₄₀₉ at different sites along the chain and behaved like a 'ligand cloud'. In contrast to ligand binding to more rigid target proteins that usually results in a dominant bound structure, ligand binding to IDPs may better be described as ligand clouds around protein clouds. Nevertheless, the binding of the ligand and a non-ligand to the c-Myc₃₇₀₋₄₀₉ target could be clearly distinguished. The present study provides insights that will help improve rational drug design that targets IDPs.

  8. Novel Chemical Strategies for Labeling Small Molecule Ligands for Androgen, Progestin, and Peroxisome Proliferator-Activated Receptors for Imaging Prostate and Breast Cancer and the Heart

    SciTech Connect

    Katzenellenbogen, John, A.

    2007-04-19

    Summary of Progress The specific aims of this project can be summarized as follows: • Aim 1: Prepare and evaluate radiolabeled ligands for the peroxisome proliferator-activated receptor (PPAR), a new nuclear hormone receptor target for tumor imaging and hormone therapy. • Aim 2: Prepare steroids labeled with a cyclopentadienyl tricarbonyl technetium or rhenium unit. • Aim 3: Prepare and evaluate other organometallic systems of novel design as ligand mimics and halogenated ligands for nuclear hormone receptor-based tumor imaging. As is described in detail below, we made excellent progress on all three of these aims; the highlights of our progress are the following: • we have prepared the first fluorine-18 labeled analogs of ligands for the PPAR receptor and used these in tissue distribution studies in rats • we have developed three new methods for the synthesis of cyclopentadienyltricarbonyl rhenium and technetium (CpRe(CO)3 and CpTc(CO)3) systems and we have adapted these to the synthesis of steroids labeled with these metals, as well as ligands for other receptor systems • we have prepared a number of fluorine-18 labeled steroidal and non-steroidal androgens and measured their tissue distribution in rats • we have prepared iodine and bromine-labeled progestins with high progesterone receptor binding affinity • we have prepared inorganic metal tricarbonyl complexes and steroid receptor ligands in which the metal tricarbonyl unit is an integral part off the ligand core.

  9. Structural dynamics of liganded myoglobin

    SciTech Connect

    Frauenfelder, H.; Petsko, G.A.

    1980-10-01

    X-ray crystallography can reveal the magnitudes and principal directions of the mean-square displacements of every atom in a protein. This structural information is complementary to the temporal information obtainable by spectroscopic techniques such as nuclear magnetic resonance. Determination of the temperature dependence of the mean-square displacements makes it possible to separate large conformational motions from simple thermal vibrations. The contribution of crystal lattice disorder to the overall apparent displacement can be estimated by Moessbauer spectroscopy. This technique has been applied to high resolution x-ray diffraction data from sperm whale myoglobin in its Met iron and oxy cobalt forms. Both crystal structures display regions of large conformational motions, particularly at the chain termini and in the region of the proximal histidine. Overall, the mean-square displacement increases with increasing distance from the center of gravity of the molecule. Some regions of the heme pocket in oxy cobalt myoglobin are more rigid than the corresponding regions in Met myoglobin.

  10. Posttranslational regulation of Fas ligand function

    PubMed Central

    Voss, Matthias; Lettau, Marcus; Paulsen, Maren; Janssen, Ottmar

    2008-01-01

    The TNF superfamily member Fas ligand acts as a prototypic death factor. Due to its ability to induce apoptosis in Fas (APO-1, CD95) expressing cells, Fas ligand participates in essential effector functions of the immune system. It is involved in natural killer cell- and T cell-mediated cytotoxicity, the establishment of immune privilege, and in termination of immune responses by induction of activation-induced cell death. In addition, Fas ligand-positive tumours may evade immune surveillance by killing Fas-positive tumour-infiltrating cells. Given these strong cytotoxic capabilities of Fas ligand, it is obvious that its function has to be strictly regulated to avoid uncontrolled damage. In hematopoietic cells, the death factor is stored in secretory lysosomes and is mobilised to the immunological synapse only upon activation. The selective sorting to and the release from this specific lysosomal compartment requires interactions of the Fas ligand cytosolic moiety, which mediates binding to various adapter proteins involved in trafficking and cytoskeletal reorganisation. In addition, Fas ligand surface expression is further regulated by posttranslational ectodomain shedding and subsequent regulated intramembrane proteolysis, releasing a soluble ectodomain cytokine into the extracellular space and an N-terminal fragment with a potential role in intracellular signalling processes. Moreover, other posttranslational modifications of the cytosolic domain, including phosphorylation and ubiquitylation, have been described to affect various aspects of Fas ligand biology. Since FasL is regarded as a potential target for immunotherapy, the further characterisation of its biological regulation and function will be of great importance for the development and evaluation of future therapeutic strategies. PMID:19114018

  11. Labeling of receptor ligands and other compounds with halogen radionuclides

    SciTech Connect

    Welch, M.J. . Edward Mallinckrodt Inst. of Radiology)

    1989-08-01

    Major advances have been made in all the areas. Specifically, patient studies have been carried out. This work has shown that the uptake of fluorine-18 labeled 16{alpha}-fluoroestradiol-17{beta} correlates well with receptor levels measured in vivo and also that the uptake of the tracer is blocked in humans by the administration of the antiestrogen tamoxifen. An image from this work was designated Image of the Year by Dr. Wagner, Jr., following his summary of the 1987 Society of Nuclear Medicine Meeting. We have also evaluated the brain uptake of both estrogen and progesterone, and this work was awarded the Berson-Yalow Award from the Society of Nuclear Medicine in 1988. This publication represents a new application of radiolabeled sex hormones. Hines and coworkers have suggested that hormone levels in the brain are important for sexual differentiation of human behavior. We have shown that both 16{alpha}-(F-18)-fluoroestradiol-17{beta} and 21-(F-18)-fluoro-16{alpha}-ethyl-19-norprogesterone (FENP) accumulate in the hypothalamus and pituitary tissues of primates and humans; and in primates this uptake can be blocked by administration of nonradioactive competing ligands. This presents an opportunity for studying sex hormone receptors in mammalian brain.

  12. NUCLEAR REACTOR

    DOEpatents

    Miller, H.I.; Smith, R.C.

    1958-01-21

    This patent relates to nuclear reactors of the type which use a liquid fuel, such as a solution of uranyl sulfate in ordinary water which acts as the moderator. The reactor is comprised of a spherical vessel having a diameter of about 12 inches substantially surrounded by a reflector of beryllium oxide. Conventionnl control rods and safety rods are operated in slots in the reflector outside the vessel to control the operation of the reactor. An additional means for increasing the safety factor of the reactor by raising the ratio of delayed neutrons to prompt neutrons, is provided and consists of a soluble sulfate salt of beryllium dissolved in the liquid fuel in the proper proportion to obtain the result desired.

  13. NUCLEAR REACTOR

    DOEpatents

    Christy, R.F.

    1958-07-15

    A nuclear reactor of the homogeneous liquid fuel type is described wherein the fissionable isotope is suspended or dissolved in a liquid moderator such as water. The reactor core is comprised essentially of a spherical vessel for containing the reactive composition surrounded by a reflector, preferably of beryllium oxide. The reactive composition may be an ordinary water solution of a soluble salt of uranium, the quantity of fissionable isotope in solution being sufficient to provide a critical mass in the vessel. The liquid fuel is stored in a tank of non-crtttcal geometry below the reactor vessel and outside of the reflector and is passed from the tank to the vessel through a pipe connecting the two by air pressure means. Neutron absorbing control and safety rods are operated within slots in the reflector adjacent to the vessel.

  14. NUCLEAR REACTOR

    DOEpatents

    Grebe, J.J.

    1959-12-15

    A reactor which is particularly adapted tu serve as a heat source for a nuclear powered alrcraft or rocket is described. The core of this reactor consists of a porous refractory modera;or body which is impregnated with fissionable nuclei. The core is designed so that its surface forms tapered inlet and outlet ducts which are separated by the porous moderator body. In operation a gaseous working fluid is circulated through the inlet ducts to the surface of the moderator, enters and passes through the porous body, and is heated therein. The hot gas emerges into the outlet ducts and is available to provide thrust. The principle advantage is that tremendous quantities of gas can be quickly heated without suffering an excessive pressure drop.

  15. Nuclear reactor

    DOEpatents

    Wade, Elman E.

    1979-01-01

    A nuclear reactor including two rotatable plugs and a positive top core holddown structure. The top core holddown structure is divided into two parts: a small core cover, and a large core cover. The small core cover, and the upper internals associated therewith, are attached to the small rotating plug, and the large core cover, with its associated upper internals, is attached to the large rotating plug. By so splitting the core holddown structures, under-the-plug refueling is accomplished without the necessity of enlarging the reactor pressure vessel to provide a storage space for the core holddown structure during refueling. Additionally, the small and large rotating plugs, and their associated core covers, are arranged such that the separation of the two core covers to permit rotation is accomplished without the installation of complex lifting mechanisms.

  16. Multiple ligand simultaneous docking: orchestrated dancing of ligands in binding sites of protein.

    PubMed

    Li, Huameng; Li, Chenglong

    2010-07-30

    Present docking methodologies simulate only one single ligand at a time during docking process. In reality, the molecular recognition process always involves multiple molecular species. Typical protein-ligand interactions are, for example, substrate and cofactor in catalytic cycle; metal ion coordination together with ligand(s); and ligand binding with water molecules. To simulate the real molecular binding processes, we propose a novel multiple ligand simultaneous docking (MLSD) strategy, which can deal with all the above processes, vastly improving docking sampling and binding free energy scoring. The work also compares two search strategies: Lamarckian genetic algorithm and particle swarm optimization, which have respective advantages depending on the specific systems. The methodology proves robust through systematic testing against several diverse model systems: E. coli purine nucleoside phosphorylase (PNP) complex with two substrates, SHP2NSH2 complex with two peptides and Bcl-xL complex with ABT-737 fragments. In all cases, the final correct docking poses and relative binding free energies were obtained. In PNP case, the simulations also capture the binding intermediates and reveal the binding dynamics during the recognition processes, which are consistent with the proposed enzymatic mechanism. In the other two cases, conventional single-ligand docking fails due to energetic and dynamic coupling among ligands, whereas MLSD results in the correct binding modes. These three cases also represent potential applications in the areas of exploring enzymatic mechanism, interpreting noisy X-ray crystallographic maps, and aiding fragment-based drug design, respectively.

  17. Design of a Hole Trapping Ligand

    DOE PAGES

    La Croix, Andrew D.; O’Hara, Andrew; Reid, Kemar R.; ...

    2017-01-18

    A new ligand that covalently attaches to the surface of colloidal CdSe/ CdS nanorods and can simultaneously chelate a molecular metal center is described. The dithiocarbamate$-$bipyridine ligand system facilitates hole transfer through energetic overlap at the inorganic$-$organic interface and conjugation through the organic ligand to a chelated metal center. Density functional theory calculations show that the coordination of the free ligand to a CdS surface causes the formation of two hybridized molecular states that lie in the band gap of CdS. The further chelation of Fe(II) to the bipyridine moiety causes the presence of seven midgap states. Hole transfer frommore » the CdS valence band to the midgap states is dipole allowed and occurs at a faster rate than what is experimentally known for the CdSe/CdS band-edge radiative recombination. In the case of the ligand bound with iron, a two-step process emerges that places the hole on the iron, again at rates much faster than band gap recombination. The system was experimentally assembled and characterized via UV$-$vis absorbance spectroscopy, fluorescence spectroscopy, time-resolved photoluminescence spectroscopy, and energy dispersive X-ray spectroscopy. Lastly, theoretically predicted red shifts in absorbance were observed experimentally, as well as the expected quench in photoluminescence and lifetimes in time-resolved photoluminescence« less

  18. Chelating ligands for nanocrystals' surface functionalization.

    PubMed

    Querner, Claudia; Reiss, Peter; Bleuse, Joël; Pron, Adam

    2004-09-22

    A new family of ligands for the surface functionalization of CdSe nanocrystals is proposed, namely alkyl or aryl derivatives of carbodithioic acids (R-C(S)SH). The main advantages of these new ligands are as follows: they nearly quantitatively exchange the initial surface ligands (TOPO) in very mild conditions; they significantly improve the resistance of nanocrystals against photooxidation because of their ability of strong chelate-type binding to metal atoms; their relatively simple preparation via Grignard intermediates facilitates the development of new bifunctional ligands containing, in addition to the anchoring carbodithioate group, a second function, which enables the grafting of molecules or macromolecules of interest on the nanocrystal surface. To give an example of this approach, we report, for the first time, the grafting of an electroactive oligomer from the polyaniline family-aniline tetramer-on CdSe nanocrystals after their functionalization with 4-formyldithiobenzoic acid. The grafting proceeds via a condensation reaction between the aldehyde group of the ligand and the terminal primary amine group of the tetramer. The resulting organic/inorganic hybrid exhibits complete extinction of the fluorescence of its constituents, indicating efficient charge or energy transfer between the organic and the inorganic semiconductors.

  19. Engineering death receptor ligands for cancer therapy.

    PubMed

    Wajant, Harald; Gerspach, Jeannette; Pfizenmaier, Klaus

    2013-05-28

    CD95, TNFR1, TRAILR1 and TRAILR2 belong to a subgroup of TNF receptors which is characterized by a conserved cell death-inducing protein domain that connects these receptors to the apoptotic machinery of the cell. Activation of death receptors in malignant cells attracts increasing attention as a principle to fight cancer. Besides agonistic antibodies the major way to stimulate death receptors is the use of their naturally occurring "death ligands" CD95L, TNF and TRAIL. However, dependent from the concept followed to develop a death ligand-based therapy various limiting aspects have to be taken into consideration on the way to a "bedside" usable drug. Problems arise in particular from the cell associated transmembrane nature of the death ligands, the poor serum half life of the soluble fragments derived from the transmembrane ligands, the ubiquitous expression of the death receptors and the existence of additional non-death receptors of the death ligands. Here, we summarize strategies how these limitations can be overcome by genetic engineering.

  20. Surface Ligand Mediated Plasmon Driven Photochemical Reactions.

    PubMed

    Kafle, Bijesh; Poveda, Marisa; Habteyes, Terefe G

    2017-02-07

    Contrary to the general expectation that surface ligands reduce the reactivity of surfaces by blocking the active sites, we present experimental evidence that surface ligands can in fact increase reactivity and induce important reaction pathways in plasmon-driven surface photochemistry. The remarkable effect of surface ligands is demonstrated by comparing the photochemistry of p-aminothiophenol (PATP) on resonant plasmonic gold nanorods (AuNRs) in the presence of citrate, hexadecyltrimethylammonium bromide (CTAB), and no surface ligands under visible light irradiation. The use of AuNRs with citrate and no surface ligand results in the usual azo-coupling reaction. In contrast, CTAB coated AuNRs oxidize PATP primarily to p-nitrothiophenol (PNTP). Strong correlation has been observed between the N-O and Au-Br vibration band intensities, suggesting that CTAB influences the reaction pathway through the Br- counterions that can minimize electron-hole recombination rate by reacting with hole, and hence increasing the concentration of hot electrons that drive the oxidation reaction.

  1. Controlling Gold Nanoclusters by Diphospine Ligands

    SciTech Connect

    Chen, Jing; Zhang, Qianfan; Bonaccorso, Timary A.; Williard, Paul G.; Wang, Lai S.

    2014-01-08

    We report the synthesis and structure determination of a new Au22 nanocluster coordinated by six bidentate diphosphine ligands: 1,8-bis(diphenylphosphino) octane (L8 for short). Single crystal x-ray crystallography and electrospray ionization mass spectrometry show that the cluster assembly is neutral and can be formulated as Au22(L8)6. The Au22 core consists of two Au11 units clipped together by four L8 ligands, while the additional two ligands coordinate to each Au11 unit in a bidentate fashion. Eight gold atoms at the interface of the two Au11 units are not coordinated by any ligands. Four short gold-gold distances (2.64?2.65 Å) are observed at the interface of the two Au11 clusters as a result of the clamping force of the four clipping ligands and strong electronic interactions. The eight uncoordinated surface gold atoms in the Au22(L8)6 nanocluster are unprecedented in atom-precise gold nanoparticles and can be considered as potential in-situ active sites for catalysis.

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

    PubMed

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

    2015-09-09

    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.

  3. A General Ligand Design for Gold Catalysis allowing Ligand-Directed Anti Nucleophilic Attack of Alkynes

    PubMed Central

    Wang, Yanzhao; Wang, Zhixun; Li, Yuxue; Wu, Gongde; Cao, Zheng; Zhang, Liming

    2014-01-01

    Most homogenous gold catalyses demand ≥0.5 mol % catalyst loading. Due to the high cost of gold, these reactions are unlikely to be applicable in medium or large scale applications. Here we disclose a novel ligand design based on the privileged biphenyl-2-phosphine framework that offers a potentially general approach to dramatically lowering catalyst loading. In this design, an amide group at the 3’ position of the ligand framework directs and promotes nucleophilic attack at the ligand gold complex-activated alkyne, which is unprecedented in homogeneous gold catalysis considering the spatial challenge of using ligand to reach antiapproaching nucleophile in a linear P-Au-alkyne centroid structure. With such a ligand, the gold(I) complex becomes highly efficient in catalyzing acid addition to alkynes, with a turnover number up to 99,000. Density functional theory calculations support the role of the amide moiety in directing the attack of carboxylic acid via hydrogen bonding. PMID:24704803

  4. Doubling the Size of the Glucocorticoid Receptor Ligand Binding Pocket by Deacylcortivazol

    SciTech Connect

    Suino-Powell, Kelly; Xu, Yong; Zhang, Chenghai; Tao, Yong-guang; Tolbert, W. David; Simons, Jr., S. Stoney; Xu, H. Eric

    2010-03-08

    A common feature of nuclear receptor ligand binding domains (LBD) is a helical sandwich fold that nests a ligand binding pocket within the bottom half of the domain. Here we report that the ligand pocket of glucocorticoid receptor (GR) can be continuously extended into the top half of the LBD by binding to deacylcortivazol (DAC), an extremely potent glucocorticoid. It has been puzzling for decades why DAC, which contains a phenylpyrazole replacement at the conserved 3-ketone of steroid hormones that are normally required for activation of their cognate receptors, is a potent GR activator. The crystal structure of the GR LBD bound to DAC and the fourth LXXLL motif of steroid receptor coactivator 1 reveals that the GR ligand binding pocket is expanded to a size of 1,070 {angstrom}{sup 3}, effectively doubling the size of the GR dexamethasone-binding pocket of 540 {angstrom}{sup 3} and yet leaving the structure of the coactivator binding site intact. DAC occupies only {approx}50% of the space of the pocket but makes intricate interactions with the receptor around the phenylpyrazole group that accounts for the high-affinity binding of DAC. The dramatic expansion of the DAC-binding pocket thus highlights the conformational adaptability of GR to ligand binding. The new structure also allows docking of various nonsteroidal ligands that cannot be fitted into the previous structures, thus providing a new rational template for drug discovery of steroidal and nonsteroidal glucocorticoids that can be specifically designed to reach the unoccupied space of the expanded pocket.

  5. Modulation of Retinoic Acid Receptor-related Orphan Receptor α and γ Activity by 7-Oxygenated Sterol Ligands*

    PubMed Central

    Wang, Yongjun; Kumar, Naresh; Solt, Laura A.; Richardson, Timothy I.; Helvering, Leah M.; Crumbley, Christine; Garcia-Ordonez, Ruben D.; Stayrook, Keith R.; Zhang, Xi; Novick, Scott; Chalmers, Michael J.; Griffin, Patrick R.; Burris, Thomas P.

    2010-01-01

    The retinoic acid receptor-related orphan receptors α and γ (RORα (NR1F1) and RORγ (NR1F3)) are orphan nuclear receptors and perform critical roles in regulation of development, metabolism, and immune function. Cholesterol and cholesterol sulfate have been suggested to be RORα ligands, but the physiological significance is unclear. To date, no endogenous RORγ ligands have been described. Here, we demonstrate that 7-oxygenated sterols function as high affinity ligands for both RORα and RORγ by directly binding to their ligand-binding domains (Ki ∼20 nm), modulating coactivator binding, and suppressing the transcriptional activity of the receptors. One of the 7-oxygenated sterols, 7α-hydroxycholesterol (7α-OHC), serves as a key intermediate in bile acid metabolism, and we show that 7α-OHC modulates the expression of ROR target genes, including Glc-6-Pase and phosphoenolpyruvate carboxykinase, in an ROR-dependent manner. Furthermore, glucose output from hepatocytes is suppressed by 7α-OHC functioning as an RORα/γ ligand. Thus, RORα and RORγ are ligand-regulated members of the NR superfamily and may serve as sensors for 7-oxygenated sterols. PMID:19965867

  6. On the analysis and comparison of conformer-specific essential dynamics upon ligand binding to a protein

    SciTech Connect

    Grosso, Marcos; Kalstein, Adrian; Parisi, Gustavo; Fernandez-Alberti, Sebastian; Roitberg, Adrian E.

    2015-06-28

    The native state of a protein consists of an equilibrium of conformational states on an energy landscape rather than existing as a single static state. The co-existence of conformers with different ligand-affinities in a dynamical equilibrium is the basis for the conformational selection model for ligand binding. In this context, the development of theoretical methods that allow us to analyze not only the structural changes but also changes in the fluctuation patterns between conformers will contribute to elucidate the differential properties acquired upon ligand binding. Molecular dynamics simulations can provide the required information to explore these features. Its use in combination with subsequent essential dynamics analysis allows separating large concerted conformational rearrangements from irrelevant fluctuations. We present a novel procedure to define the size and composition of essential dynamics subspaces associated with ligand-bound and ligand-free conformations. These definitions allow us to compare essential dynamics subspaces between different conformers. Our procedure attempts to emphasize the main similarities and differences between the different essential dynamics in an unbiased way. Essential dynamics subspaces associated to conformational transitions can also be analyzed. As a test case, we study the glutaminase interacting protein (GIP), composed of a single PDZ domain. Both GIP ligand-free state and glutaminase L peptide-bound states are analyzed. Our findings concerning the relative changes in the flexibility pattern upon binding are in good agreement with experimental Nuclear Magnetic Resonance data.

  7. Cationic ruthenium alkylidene catalysts bearing phosphine ligands.

    PubMed

    Endo, Koji; Grubbs, Robert H

    2016-02-28

    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 bearing bulky phosphine ligands. Simple ligand exchange using silver(i) salts of non-coordinating or weakly coordinating anions provided either PPh3 or chelating Ph2P(CH2)nPPh2 (n = 2 or 3) ligated cationic catalysts. The structures of these newly reported catalysts feature unique geometries caused by ligation of the bulky phosphine ligands. Their activities and selectivities in standard metathesis reactions were also investigated. These cationic ruthenium alkylidene catalysts reported here showed moderate activity and very similar stereoselectivity when compared to the second generation ruthenium dichloride catalyst in ring-closing metathesis, cross metathesis, and ring-opening metathesis polymerization assays.

  8. Nuclear war: Opposing viewpoints

    SciTech Connect

    Szumski, B.

    1985-01-01

    This book presents opposing viewpoints on nuclear war. Topics discussed include: how nuclear would begin; would humanity survive; would civil defense work; will an arms agreement work; and can space weapons reduce the risk of nuclear war.

  9. Nuclear analytical chemistry

    SciTech Connect

    Brune, D.; Forkman, B.; Persson, B.

    1984-01-01

    This book covers the general theories and techniques of nuclear chemical analysis, directed at applications in analytical chemistry, nuclear medicine, radiophysics, agriculture, environmental sciences, geological exploration, industrial process control, etc. The main principles of nuclear physics and nuclear detection on which the analysis is based are briefly outlined. An attempt is made to emphasise the fundamentals of activation analysis, detection and activation methods, as well as their applications. The book provides guidance in analytical chemistry, agriculture, environmental and biomedical sciences, etc. The contents include: the nuclear periodic system; nuclear decay; nuclear reactions; nuclear radiation sources; interaction of radiation with matter; principles of radiation detectors; nuclear electronics; statistical methods and spectral analysis; methods of radiation detection; neutron activation analysis; charged particle activation analysis; photon activation analysis; sample preparation and chemical separation; nuclear chemical analysis in biological and medical research; the use of nuclear chemical analysis in the field of criminology; nuclear chemical analysis in environmental sciences, geology and mineral exploration; and radiation protection.

  10. Nuclear Quadrupole Moments and Nuclear Shell Structure

    DOE R&D Accomplishments Database

    Townes, C. H.; Foley, H. M.; Low, W.

    1950-06-23

    Describes a simple model, based on nuclear shell considerations, which leads to the proper behavior of known nuclear quadrupole moments, although predictions of the magnitudes of some quadrupole moments are seriously in error.

  11. Efficient chemoenzymatic synthesis of chiral pincer ligands.

    PubMed

    Felluga, Fulvia; Baratta, Walter; Fanfoni, Lidia; Pitacco, Giuliana; Rigo, Pierluigi; Benedetti, Fabio

    2009-05-01

    Chiral, nonracemic pincer ligands based on the 6-phenyl-2-aminomethylpyridine and 2-aminomethylbenzo[h]quinoline scaffolds were obtained by a chemoenzymatic approach starting from 2-pyridyl and 2-benzoquinolyl ethanone. In the enantiodifferentiating step, secondary alcohols of opposite absolute configuration were obtained by a baker's yeast reduction of the ketones and by lipase-mediated dynamic kinetic resolution of the racemic alcohols. Their transformation into homochiral 1-methyl-1-heteroarylethanamines occurred without loss of optical purity, giving access to pincer ligands used in enantioselective catalysis.

  12. Ligand Intermediates in Metal-Catalyzed Reactions

    SciTech Connect

    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.

  13. Assessment of automatic ligand building in ARP/wARP

    PubMed Central

    Evrard, Guillaume X.; Langer, Gerrit G.; Perrakis, Anastassis; Lamzin, Victor S.

    2007-01-01

    The efficiency of the ligand-building module of ARP/wARP version 6.1 has been assessed through extensive tests on a large variety of protein–ligand complexes from the PDB, as available from the Uppsala Electron Density Server. Ligand building in ARP/wARP involves two main steps: automatic identification of the location of the ligand and the actual construction of its atomic model. The first step is most successful for large ligands. The second step, ligand construction, is more powerful with X-ray data at high resolution and ligands of small to medium size. Both steps are successful for ligands with low to moderate atomic displacement parameters. The results highlight the strengths and weaknesses of both the method of ligand building and the large-scale validation procedure and help to identify means of further improvement. PMID:17164533

  14. Assessment of automatic ligand building in ARP/wARP.

    PubMed

    Evrard, Guillaume X; Langer, Gerrit G; Perrakis, Anastassis; Lamzin, Victor S

    2007-01-01

    The efficiency of the ligand-building module of ARP/wARP version 6.1 has been assessed through extensive tests on a large variety of protein-ligand complexes from the PDB, as available from the Uppsala Electron Density Server. Ligand building in ARP/wARP involves two main steps: automatic identification of the location of the ligand and the actual construction of its atomic model. The first step is most successful for large ligands. The second step, ligand construction, is more powerful with X-ray data at high resolution and ligands of small to medium size. Both steps are successful for ligands with low to moderate atomic displacement parameters. The results highlight the strengths and weaknesses of both the method of ligand building and the large-scale validation procedure and help to identify means of further improvement.

  15. Nuclear South Asia

    DTIC Science & Technology

    2007-11-02

    inseparable from the history of nuclear developments in both India and Pakistan. The timing of India’s tests was determined by the pronuclear stance of the...Rawalpindi, 2001), 17-18. 53 3Robert Boardman, The Politics of Fading Dreams: Britain and the Nuclear Export Business, Nuclear Exports and World Politics (New...disasters of nuclear arms race. 61 BIBLIOGRAPHY Books Boardman, Robert. The Politics of Fading Dreams: Britain and the Nuclear Export Business, Nuclear

  16. Nuclear Fuel Cycle & Vulnerabilities

    SciTech Connect

    Boyer, Brian D.

    2012-06-18

    The objective of safeguards is the timely detection of diversion of significant quantities of nuclear material from peaceful nuclear activities to the manufacture of nuclear weapons or of other nuclear explosive devices or for purposes unknown, and deterrence of such diversion by the risk of early detection. The safeguards system should be designed to provide credible assurances that there has been no diversion of declared nuclear material and no undeclared nuclear material and activities.

  17. Orphan Nuclear Receptors as Targets for Drug Development

    PubMed Central

    Mukherjee, Subhajit

    2012-01-01

    Orphan nuclear receptors regulate diverse biological processes. These important molecules are ligand-activated transcription factors that act as natural sensors for a wide range of steroid hormones and xenobiotic ligands. Because of their importance in regulating various novel signaling pathways, recent research has focused on identifying xenobiotics targeting these receptors for the treatment of multiple human diseases. In this review, we will highlight these receptors in several physiologic and pathophysiologic actions and demonstrate how their functions can be exploited for the successful development of newer drugs. PMID:20372994

  18. Synergistic induction of the Fas (CD95) ligand promoter by Max and NFkappaB in human non-small lung cancer cells.

    PubMed

    Wiener, Zoltan; Ontsouka, Edgar C; Jakob, Sabine; Torgler, Ralph; Falus, Andras; Mueller, Christoph; Brunner, Thomas

    2004-09-10

    Fas (CD95/APO-1) ligand is a member of the Tumor Necrosis Factor family and a potent inducer of apoptosis. Fas ligand is expressed in activated T cells and represents a major cytotoxic effector mechanism by which T cells kill their target cells. Activation-induced Fas ligand expression in T cells is under the stringent control of various transcription factors, including nuclear factor kappaB (NFkappaB) and c-Myc/Max. There is accumulating evidence that Fas ligand is also expressed by various non-hematopoietic tumor cells, however, little is known about Fas ligand regulation in tumor cells. In this study, we have analyzed the regulation of the Fas ligand gene promoter induction in two non-small cell lung cancer cell lines, with a major focus on the role of the c-Myc/Max transcription factor. Our results revealed that inhibition of c-Myc/Max did not substantially reduce basal levels of Fas ligand promoter activity, nor did overexpression of c-Myc significantly induce promoter activity. In contrast, we observed that overexpression of Max resulted in a marked increase in basal promoter activity and synergistically enhanced phorbolester- and doxorubicin-induced NFkappaB-mediated Fas ligand promoter activity. These results were confirmed by analyzing endogenous Fas ligand transcription. We conclude that high levels of Max and stress-induced NFkappaB activation may result in elevated expression of Fas ligand in human lung cancer cells and possibly contribute to Fas ligand-associated immune escape mechanisms.

  19. Structural basis for PPAR partial or full activation revealed by a novel ligand binding mode

    PubMed Central

    Capelli, Davide; Cerchia, Carmen; Montanari, Roberta; Loiodice, Fulvio; Tortorella, Paolo; Laghezza, Antonio; Cervoni, Laura; Pochetti, Giorgio; Lavecchia, Antonio

    2016-01-01

    The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors involved in the regulation of the metabolic homeostasis and therefore represent valuable therapeutic targets for the treatment of metabolic diseases. The development of more balanced drugs interacting with PPARs, devoid of the side-effects showed by the currently marketed PPARγ full agonists, is considered the major challenge for the pharmaceutical companies. Here we present a structure-based virtual screening approach that let us identify a novel PPAR pan-agonist with a very attractive activity profile and its crystal structure in the complex with PPARα and PPARγ, respectively. In PPARα this ligand occupies a new pocket whose filling is allowed by the ligand-induced switching of the F273 side chain from a closed to an open conformation. The comparison between this pocket and the corresponding cavity in PPARγ provides a rationale for the different activation of the ligand towards PPARα and PPARγ, suggesting a novel basis for ligand design. PMID:27708429

  20. Acetylation of pregnane X receptor protein determines selective function independent of ligand activation

    SciTech Connect

    Biswas, Arunima; Pasquel, Danielle; Tyagi, Rakesh Kumar; Mani, Sridhar

    2011-03-18

    Research highlights: {yields} Pregnane X receptor (PXR), a major regulatory protein, is modified by acetylation. {yields} PXR undergoes dynamic deacetylation upon ligand-mediated activation. {yields} SIRT1 partially mediates PXR deacetylation. {yields} PXR deacetylation per se induces lipogenesis mimicking ligand-mediated activation. -- Abstract: Pregnane X receptor (PXR), like other members of its class of nuclear receptors, undergoes post-translational modification [PTM] (e.g., phosphorylation). However, it is unknown if acetylation (a major and common form of protein PTM) is observed on PXR and, if it is, whether it is of functional consequence. PXR has recently emerged as an important regulatory protein with multiple ligand-dependent functions. In the present work we show that PXR is indeed acetylated in vivo. SIRT1 (Sirtuin 1), a NAD-dependent class III histone deacetylase and a member of the sirtuin family of proteins, partially mediates deacetylation of PXR. Most importantly, the acetylation status of PXR regulates its selective function independent of ligand activation.

  1. Hydrothermal reactions: From the synthesis of ligand to new lanthanide 3D-coordination polymers

    NASA Astrophysics Data System (ADS)

    da Silva, Fausthon Fred; de Oliveira, Carlos Alberto Fernandes; Falcão, Eduardo Henrique Lago; Gatto, Claudia Cristina; da Costa, Nivan Bezerra; Freire, Ricardo Oliveira; Chojnacki, Jarosław; Alves Júnior, Severino

    2013-11-01

    The organic ligand 2,5-piperazinedione-1,4-diacetic acid (H2PDA) was synthesized under hydrothermal conditions starting from the iminodiacetic acid and catalyzed by oxalic acid. The X-ray powder diffraction data indicates that the compound crystallizes in the P21/c monoclinic system as reported in the literature. The ligand was also characterized by elemental analysis, magnetic nuclear resonance, infrared spectroscopy and thermogravimetric analysis. Two new coordination networks based on lanthanide ions were obtained with this ligand using hydrothermal reaction. In addition to single-crystal X-ray diffraction, the compounds were characterized by infrared spectroscopy, thermogravimetric analysis, scanning electron microscopy and elemental analysis. Single-crystal XRD showed that the compounds are isostructural, crystallizing in P21/n monoclinic system with chemical formula [Ln(PDA)1.5(H2O)](H2O)3 (Ln=Gd3+(1) and Eu3+(2)).The luminescence properties of both compounds were studied. In the compound (1), a broad emission band was observed at 479 nm, redshifted by 70 nm in comparison of the free ligand. In (2), the typical f-f transition was observed with a maximum peak at 618 nm, related with the red emission of the europium ions. Computational methods were performed to simulate the crystal structure of (2). The theoretical calculations of the intensity parameters are in good agreement with the experimental values.

  2. Classical Nuclear Hormone Receptor Activity as a Mediator of Complex Concentration Response Relationships for Endocrine Active Compounds

    PubMed Central

    Cookman, Clifford J.; Belcher, Scott M.

    2014-01-01

    Nonmonotonic concentration response relationships are frequently observed for endocrine active ligands that act via nuclear receptors. The curve of best fit for nonmonotonic concentration response relationships are often inverted U-shaped with effects at intermediate concentrations that are different from effects at higher or lower concentrations. Cytotoxicity is a major mode of action responsible for inverted U-shaped concentration response relationships. However, evidence suggests that ligand selectivity, activation of multiple molecular targets, concerted regulation of multiple opposing endpoints, and multiple ligand binding sites within nuclear receptors also contribute to nonmonotonic concentration response relationships of endocrine active ligands. This review reports the current understanding of mechanisms involved in classical nuclear receptor mediated nonmonotonic concentration response relationships with a focus on studies published between 2012 and 2014. PMID:25299165

  3. Nuclear reactor

    DOEpatents

    Thomson, Wallace B.

    2004-03-16

    A nuclear reactor comprising a cylindrical pressure vessel, an elongated annular core centrally disposed within and spaced from the pressure vessel, and a plurality of ducts disposed longitudinally of the pressure vessel about the periphery thereof, said core comprising an annular active portion, an annular reflector just inside the active portion, and an annular reflector just outside the active a portion, said annular active portion comprising rectangular slab, porous fuel elements radially disposed around the inner reflector and extending the length of the active portion, wedge-shaped, porous moderator elements disposed adjacent one face of each fuel element and extending the length of the fuel element, the fuel and moderator elements being oriented so that the fuel elements face each other and the moderator elements do likewise, adjacent moderator elements being spaced to provide air inlet channels, and adjacent fuel elements being spaced to provide air outlet channels which communicate with the interior of the peripheral ducts, and means for introducing air into the air inlet channels which passes through the porous moderator elements and porous fuel elements to the outlet channel.

  4. Nuclear Proliferation: A Global Nuclear Strategy

    DTIC Science & Technology

    2007-03-30

    thinking about nuclear weapons as a “ Wild Card ” in this case. Finally, just as North Korea is using nuclear weapons as a “bargaining chip,” we...definite disadvantage for non-nuclear nations not to have a nuclear” Wild Card ”. So some misguided Japanese politicians are attracted to the “ Wild Card ” advantage

  5. Nuclear weapons modernizations

    SciTech Connect

    Kristensen, Hans M.

    2014-05-09

    This article reviews the nuclear weapons modernization programs underway in the world's nine nuclear weapons states. It concludes that despite significant reductions in overall weapons inventories since the end of the Cold War, the pace of reductions is slowing - four of the nuclear weapons states are even increasing their arsenals, and all the nuclear weapons states are busy modernizing their remaining arsenals in what appears to be a dynamic and counterproductive nuclear competition. The author questions whether perpetual modernization combined with no specific plan for the elimination of nuclear weapons is consistent with the nuclear Non-Proliferation Treaty and concludes that new limits on nuclear modernizations are needed.

  6. Nuclear weapons modernizations

    NASA Astrophysics Data System (ADS)

    Kristensen, Hans M.

    2014-05-01

    This article reviews the nuclear weapons modernization programs underway in the world's nine nuclear weapons states. It concludes that despite significant reductions in overall weapons inventories since the end of the Cold War, the pace of reductions is slowing - four of the nuclear weapons states are even increasing their arsenals, and all the nuclear weapons states are busy modernizing their remaining arsenals in what appears to be a dynamic and counterproductive nuclear competition. The author questions whether perpetual modernization combined with no specific plan for the elimination of nuclear weapons is consistent with the nuclear Non-Proliferation Treaty and concludes that new limits on nuclear modernizations are needed.

  7. Ligand expansion in ligand-based virtual screening using relevance feedback

    NASA Astrophysics Data System (ADS)

    Abdo, Ammar; Saeed, Faisal; Hamza, Hentabli; Ahmed, Ali; Salim, Naomie

    2012-03-01

    Query expansion is the process of reformulating an original query to improve retrieval performance in information retrieval systems. Relevance feedback is one of the most useful query modification techniques in information retrieval systems. In this paper, we introduce query expansion into ligand-based virtual screening (LBVS) using the relevance feedback technique. In this approach, a few high-ranking molecules of unknown activity are filtered from the outputs of a Bayesian inference network based on a single ligand molecule to form a set of ligand molecules. This set of ligand molecules is used to form a new ligand molecule. Simulated virtual screening experiments with the MDL Drug Data Report and maximum unbiased validation data sets show that the use of ligand expansion provides a very simple way of improving the LBVS, especially when the active molecules being sought have a high degree of structural heterogeneity. However, the effectiveness of the ligand expansion is slightly less when structurally-homogeneous sets of actives are being sought.

  8. CLiBE: a database of computed ligand binding energy for ligand-receptor complexes.

    PubMed

    Chen, X; Ji, Z L; Zhi, D G; Chen, Y Z

    2002-11-01

    Consideration of binding competitiveness of a drug candidate against natural ligands and other drugs that bind to the same receptor site may facilitate the rational development of a candidate into a potent drug. A strategy that can be applied to computer-aided drug design is to evaluate ligand-receptor interaction energy or other scoring functions of a designed drug with that of the relevant ligands known to bind to the same binding site. As a tool to facilitate such a strategy, a database of ligand-receptor interaction energy is developed from known ligand-receptor 3D structural entries in the Protein Databank (PDB). The Energy is computed based on a molecular mechanics force field that has been used in the prediction of therapeutic and toxicity targets of drugs. This database also contains information about ligand function and other properties and it can be accessed at http://xin.cz3.nus.edu.sg/group/CLiBE.asp. The computed energy components may facilitate the probing of the mode of action and other profiles of binding. A number of computed energies of some PDB ligand-receptor complexes in this database are studied and compared to experimental binding affinity. A certain degree of correlation between the computed energy and experimental binding affinity is found, which suggests that the computed energy may be useful in facilitating a qualitative analysis of drug binding competitiveness.

  9. Optimizing electrostatic affinity in ligand-receptor binding: Theory, computation, and ligand properties

    NASA Astrophysics Data System (ADS)

    Kangas, Erik; Tidor, Bruce

    1998-11-01

    The design of a tight-binding molecular ligand involves a tradeoff between an unfavorable electrostatic desolvation penalty incurred when the ligand binds a receptor in aqueous solution and the generally favorable intermolecular interactions made in the bound state. Using continuum electrostatic models we have developed a theoretical framework for analyzing this problem and have shown that the ligand-charge distribution can be optimized to produce the most favorable balance of these opposing free energy contributions [L.-P. Lee and B. Tidor, J. Chem. Phys. 106, 8681 (1997)]. Herein the theoretical framework is extended and calculations are performed for a wide range of model receptors. We examine methods for computing optimal ligands (including cases where there is conformational change) and the resulting properties of optimized ligands. In particular, indicators are developed to aid in the determination of the deficiencies in a specific ligand or basis. A connection is established between the optimization problem here and a generalized image problem, from which an inverse-image basis set can be defined; this basis is shown to perform very well in optimization calculations. Furthermore, the optimized ligands are shown to have favorable electrostatic binding free energies (in contrast to many natural ligands), there is a strong correlation between the receptor desolvation penalty and the optimized binding free energy for fixed geometry, and the ligand and receptor cannot generally be mutually optimal. Additionally, we introduce the display of complementary desolvation and interaction potentials and the deviation of their relationship from ideal as a useful tool for judging effective complementarity. Scripts for computing and displaying these potentials with GRASP are available at http://mit.edu/tidor.

  10. [Kinetics of ligand binding to nucleic acids at random fillings].

    PubMed

    Arakelian, V B; Babaian, S Iu; Tairian, V I; Arakelian, A V; Parsadanian, M A; Vardevanian, P O

    2006-01-01

    Ligand binding with nucleic acids is described in frames of the theory of random processes. It is shown that the probabilistic description of binding of a ligand to nucleic acid allows one to describe not only the kinetics of changes in the number of bound ligands at arbitrary fillings but also to calculate stationary values of the number of bound ligands and its dispersion. A general analysis of absorption isotherms and the kinetics of ligand binding with nucleic acids allows one to determine the rate constants of formation and decomposition of the ligand-nucleic acid complex. A comparison of the results obtained with the case of low fillings is conducted.

  11. Nuclear Power in China

    NASA Astrophysics Data System (ADS)

    Zhou, Yun

    2012-02-01

    In response to the Fukushima accident, China is strengthening its nuclear safety at reactors in operation, under construction and in preparation, including efforts to improve nuclear safety regulations and guidelines based on lessons learned from the accident. Although China is one of the major contributors in the global nuclear expansion, China's nuclear power industry is relatively young. Its nuclear safety regulators are less experienced compared to those in other major nuclear power countries. To realize China's resolute commitment to rapid growth of safe nuclear energy, detailed analyses of its nuclear safety regulatory system are required. This talk explains China's nuclear energy program and policy at first. It also explores China's governmental activities and future nuclear development after Fukushima accidents. At last, an overview of China's nuclear safety regulations and practices are provided. Issues and challenges are also identified for police makers, regulators, and industry professionals.

  12. Nuclear reactor

    DOEpatents

    Pennell, William E.; Rowan, William J.

    1977-01-01

    A nuclear reactor in which the core components, including fuel-rod assemblies, control-rod assemblies, fertile rod-assemblies, and removable shielding assemblies, are supported by a plurality of separate inlet modular units. These units are referred to as inlet module units to distinguish them from the modules of the upper internals of the reactor. The modular units are supported, each removable independently of the others, in liners in the supporting structure for the lower internals of the reactor. The core assemblies are removably supported in integral receptacles or sockets of the modular units. The liners, units, sockets and assmblies have inlet openings for entry of the fluid. The modular units are each removably mounted in the liners with fluid seals interposed between the opening in the liner and inlet module into which the fluid enters and the upper and lower portion of the liner. Each assembly is similarly mounted in a corresponding receptacle with fluid seals interposed between the openings where the fluid enters and the lower portion of the receptacle or fitting closely in these regions. As fluid flows along each core assembly a pressure drop is produced along the fluid so that the fluid which emerges from each core assembly is at a lower pressure than the fluid which enters the core assembly. However because of the seals interposed in the mountings of the units and assemblies the pressures above and below the units and assemblies are balanced and the units are held in the liners and the assemblies are held in the receptacles by their weights as they have a higher specific gravity than the fluid. The low-pressure spaces between each module and its liner and between each core assembly and its module is vented to the low-pressure regions of the vessel to assure that fluid which leaks through the seals does not accumulate and destroy the hydraulic balance.

  13. Nuclear reactor

    DOEpatents

    Yant, Howard W.; Stinebiser, Karl W.; Anzur, Gregory C.

    1977-01-01

    A nuclear reactor, particularly a liquid-metal breeder reactor, whose upper internals include outlet modules for channeling the liquid-metal coolant from selected areas of the outlet of the core vertically to the outlet plenum. The modules are composed of a highly-refractory, high corrosion-resistant alloy, for example, INCONEL-718. Each module is disposed to confine and channel generally vertically the coolant emitted from a subplurality of core-component assemblies. Each module has a grid with openings, each opening disposed to receive the coolant from an assembly of the subplurality. The grid in addition serves as a holdown for the assemblies of the corresponding subplurality preventing their excessive ejection upwardly from the core. In the region directly over the core the outlet modules are of such peripheral form that they nest forming a continuum over the core-component assemblies whose outlet coolant they confine. Each subassembly includes a chimney which confines the coolant emitted by its corresponding subassemblies to generally vertical flow between the outlet of the core and the outlet plenum. Each subplurality of assemblies whose emitted coolant is confined by an outlet module includes assemblies which emit lower-temperature coolant, for example, a control-rod assembly, or fertile assemblies, and assemblies which emit coolant of substantially higher temperature, for example, fuel-rod assemblies. The coolants of different temperatures are mixed in the chimneys reducing the effect of stripping (hot-cold temperature fluctuations) on the remainder of the upper internals which are composed typically of AISI-304 or AISI-316 stainless steel.

  14. Solar energy conversion through ligand photodissociation

    SciTech Connect

    Hoffman, B.M.; Sima, P.D.

    1983-04-06

    A new technique for photochemical conversion of solar energy based on ligand photodissociation from metal complexes is examined. The concept is illustrated with a photogalvanic cell in which voltages are generated by photodissociation of CO from carbonylferroheme and with a cell in which the illuminated electrode is coated with an iron tetraphenylporphyrin.

  15. Identification of ligands for bacterial sensor proteins.

    PubMed

    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.

  16. [Functional selectivity of opioid receptors ligands].

    PubMed

    Audet, Nicolas; Archer-Lahlou, Elodie; Richard-Lalonde, Mélissa; Piñeyro-Filpo, Graciela

    2010-01-01

    Opiates are the most effective analgesics available for the treatment of severe pain. However, their clinical use is restricted by unwanted side effects such as tolerance, physical dependence and respiratory depression. The strategy to develop new opiates with reduced side effects has mainly focused on the study and production of ligands that specifically bind to different opiate receptors subtypes. However, this strategy has not allowed the production of novel therapeutic ligands with a better side effects profile. Thus, other research strategies need to be explored. One which is receiving increasing attention is the possibility of exploiting ligand ability to stabilize different receptor conformations with distinct signalling profiles. This newly described property, termed functional selectivity, provides a potential means of directing the stimulus generated by an activated receptor towards a specific cellular response. Here we summarize evidence supporting the existence of ligand-specific active conformations for two opioid receptors subtypes (delta and mu), and analyze how functional selectivity may contribute in the production of longer lasting, better tolerated opiate analgesics. double dagger.

  17. Cooperative Ligand Binding to Linear Chain Molecules

    ERIC Educational Resources Information Center

    Applequist, Jon

    1977-01-01

    Summarizes the Ising model of ligand binding as it applies to cooperative binding to long chain molecules. Also presents some illustrations which help to visualize the connection between the interaction parameters and the shape of the binding isotherm. (Author/MR)

  18. [Central effects of ORL1 receptor ligands].

    PubMed

    Maslov, L N; Lishmanov, Iu B; Calo, G; Ma, L

    2003-01-01

    It has been discussed literature data on molecular structure of ORL1 receptor and its interaction with intracellular signal systems and neurotransmitters. Data on chemical structure of ORL1 receptor ligands and their central effects (nociception, locomotion, feeding, cognition) are presented.

  19. CXCR3 ligands in disease and therapy.

    PubMed

    Van Raemdonck, Katrien; Van den Steen, Philippe E; Liekens, Sandra; Van Damme, Jo; Struyf, Sofie

    2015-06-01

    Chemokines, binding their various G protein-coupled receptors, lead the way for leukocytes in health and inflammation. Yet chemokine receptor expression is not limited to leukocytes. Accordingly, chemokines are remarkably pleiotropic molecules involved in a range of physiological as well as pathological processes. For example, the CXCR3 chemokine receptor is expressed on activated T lymphocytes, dendritic cells and natural killer cells, but also fibroblasts and smooth muscle, epithelial and endothelial cells. In men, these cells express either CXCR3A, its splice variant CXCR3B or a balanced combination of both. The CXCR3 ligands, activating both receptor variants, include CXCL4, CXCL4L1, CXCL9, CXCL10 and CXCL11. Upon CXCR3A activation these ELR-negative CXC chemokines mediate chemotactic and proliferative responses, for example in leukocytes. In contrast, CXCR3B induces anti-proliferative and anti-migratory effects, as exemplified by angiostatic effects on endothelial cells. Taken together, the unusual and versatile characteristics of CXCR3 and its ligands form the basis for their pertinent involvement in a myriad of diseases. In this review, we discuss the presence and function of all CXCR3 ligands in various malignant, angiogenic, infectious, inflammatory and other disorders. By extension, we have also elaborated on the potential therapeutic applicability of CXCR3 ligand administration or blockade, as well as their additional value as predictive or prognostic biomarkers. This review illustrates the multifunctional, intriguing character of the various CXCR3-binding chemokines.

  20. Ligand iron catalysts for selective hydrogenation

    DOEpatents

    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. Maturing of the nuclear receptor family.

    PubMed

    Lazar, Mitchell A

    2017-04-03

    Members of the nuclear receptor (NR) superfamily of ligand-regulated transcription factors play important roles in reproduction, development, and physiology. In humans, genetic mutations in NRs are causes of rare diseases, while hormones and drugs that target NRs are in widespread therapeutic use. The present issue of the JCI includes a series of Review articles focused on specific NRs and their wide range of biological functions. Here I reflect on the past, present, and potential future highlights of research on the NR superfamily.

  2. The Notch ligand Delta-like 1 integrates inputs from TGFbeta/Activin and Wnt pathways

    SciTech Connect

    Bordonaro, Michael Tewari, Shruti Atamna, Wafa Lazarova, Darina L.

    2011-06-10

    Unlike the well-characterized nuclear function of the Notch intracellular domain, it has been difficult to identify a nuclear role for the ligands of Notch. Here we provide evidence for the nuclear function of the Notch ligand Delta-like 1 in colon cancer (CC) cells exposed to butyrate. We demonstrate that the intracellular domain of Delta-like 1 (Dll1icd) augments the activity of Wnt signaling-dependent reporters and that of the promoter of the connective tissue growth factor (CTGF) gene. Data suggest that Dll1icd upregulates CTGF promoter activity through both direct and indirect mechanisms. The direct mechanism is supported by co-immunoprecipitation of endogenous Smad2/3 proteins and Dll1 and by chromatin immunoprecipitation analyses that revealed the occupancy of Dll1icd on CTGF promoter sequences containing a Smad binding element. The indirect upregulation of CTGF expression by Dll1 is likely due to the ability of Dll1icd to increase Wnt signaling, a pathway that targets CTGF. CTGF expression is induced in butyrate-treated CC cells and results from clonal growth assays support a role for CTGF in the cell growth-suppressive role of butyrate. In conclusion, integration of the Notch, Wnt, and TGFbeta/Activin signaling pathways is in part mediated by the interactions of Dll1 with Smad2/3 and Tcf4.

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

    NASA Astrophysics Data System (ADS)

    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.

  4. Thermodynamic proton-ligand and metal-ligand stability constants of some drugs.

    PubMed

    Agrawal, Y K; Patel, D R

    1986-02-01

    The thermodynamic proton-ligand (pKa) and metal-ligand stability constants of clioquinol, clofibrate, nitrofurazone, and tetracycline with Cu2+, Zn2+, Mn2+, Mg2+, and Ca2+ have been determined at 35 degrees C in 50% ethanol-water media. An empirical pH correction for mixed-aqueous media has been applied. The metal-ligand stability constants were determined by following the Bjerrum Calvin titration technique as applied by Agrawal to mixed-aqueous solvents. The effect of the basicity of the ligand and the order of stability constants is discussed. The stability constants of the divalent metals follow the order: Cu2+ greater than Zn2+ greater than Mn2+ greater than Mg2+ greater than Ca2+ with all the drugs.

  5. Monitoring Solution Structures of Peroxisome Proliferator-Activated Receptor β/δ upon Ligand Binding

    PubMed Central

    Schwarz, Rico; Tänzler, Dirk; Ihling, Christian H.; Sinz, Andrea

    2016-01-01

    Peroxisome proliferator-activated receptors (PPARs) have been intensively studied as drug targets to treat type 2 diabetes, lipid disorders, and metabolic syndrome. This study is part of our ongoing efforts to map conformational changes in PPARs in solution by a combination of chemical cross-linking and mass spectrometry (MS). To our best knowledge, we performed the first studies addressing solution structures of full-length PPAR-β/δ. We monitored the conformations of the ligand-binding domain (LBD) as well as full-length PPAR-β/δ upon binding of two agonists. (Photo-) cross-linking relied on (i) a variety of externally introduced amine- and carboxyl-reactive linkers and (ii) the incorporation of the photo-reactive amino acid p-benzoylphenylalanine (Bpa) into PPAR-β/δ by genetic engineering. The distances derived from cross-linking experiments allowed us to monitor conformational changes in PPAR-β/δ upon ligand binding. The cross-linking/MS approach proved highly advantageous to study nuclear receptors, such as PPARs, and revealed the interplay between DBD (DNA-binding domain) and LDB in PPAR-β/δ. Our results indicate the stabilization of a specific conformation through ligand binding in PPAR-β/δ LBD as well as full-length PPAR-β/δ. Moreover, our results suggest a close distance between the N- and C-terminal regions of full-length PPAR-β/δ in the presence of GW1516. Chemical cross-linking/MS allowed us gaining detailed insights into conformational changes that are induced in PPARs when activating ligands are present. Thus, cross-linking/MS should be added to the arsenal of structural methods available for studying nuclear receptors. PMID:26992147

  6. Dissociation of Multisubunit Protein-Ligand Complexes in the Gas Phase. Evidence for Ligand Migration

    NASA Astrophysics Data System (ADS)

    Zhang, Yixuan; Deng, Lu; Kitova, Elena N.; Klassen, John S.

    2013-10-01

    The results of collision-induced dissociation (CID) experiments performed on gaseous protonated and deprotonated ions of complexes of cholera toxin B subunit homopentamer (CTB5) with the pentasaccharide (β-D-Gal p-(1→3)-β-D-Gal pNAc-(1→4)[α-D-Neu5Ac-(2→3)]-β-D-Gal p-(1→4)-β-D-Glc p (GM1)) and corresponding glycosphingolipid (β-D-Gal p-(1→3)-β-D-Gal pNAc-(1→4)[α-D-Neu5Ac-(2→3)]-β-D-Gal p-(1→4)-β-D-Glc p-Cer (GM1-Cer)) ligands, and the homotetramer streptavidin (S4) with biotin (B) and 1,2-dipalmitoyl- sn-glycero-3-phosphoethanolamine-N-(biotinyl) (Btl), are reported. The protonated (CTB5 + 5GM1)n+ ions dissociated predominantly by the loss of a single subunit, with the concomitant migration of ligand to another subunit. The simultaneous loss of ligand and subunit was observed as a minor pathway. In contrast, the deprotonated (CTB5 + 5GM1)n- ions dissociated preferentially by the loss of deprotonated ligand; the loss of ligand-bound and ligand-free subunit were minor pathways. The presence of ceramide (Cer) promoted ligand migration and the loss of subunit. The main dissociation pathway for the protonated and deprotonated (S4 + 4B)n+/- ions, as well as for deprotonated (S4 + 4Btl)n- ions, was loss of the ligand. However, subunit loss from the (S4 + 4B)n+ ions was observed as a minor pathway. The (S4 + 4Btl)n+ ions dissociated predominantly by the loss of free and ligand-bound subunit. The charge state of the complex and the collision energy were found to have little effect on the relative contribution of the different dissociation channels. Thermally-driven ligand migration between subunits was captured in the results of molecular dynamics simulations performed on protonated (CTB5 + 5GM1)15+ ions (with a range of charge configurations) at 800 K. Notably, the migration pathway was found to be highly dependent on the charge configuration of the ion. The main conclusion of this study is that the dissociation pathways of multisubunit protein-ligand

  7. The New Nuclear Nations.

    ERIC Educational Resources Information Center

    Spector, Leonard S.

    1990-01-01

    Explores the issue of nuclear proliferation, noting that the countries with nuclear capability now include Israel, South Africa, India, and Pakistan. Describes the role and problems of the United States in halting nuclearization. Supplies charts, maps, and information concerning the state of nuclear capability in each country. (NL)

  8. Nuclear air cushion vehicles

    NASA Technical Reports Server (NTRS)

    Anderson, J. L.

    1973-01-01

    The state-of-the-art of the still-conceptual nuclear air cushion vehicle, particularly the nuclear powerplant is identified. Using mission studies and cost estimates, some of the advantages of nuclear power for large air cushion vehicles are described. The technology studies on mobile nuclear powerplants and conceptual ACV systems/missions studies are summarized.

  9. Nuclear energy and security

    SciTech Connect

    BLEJWAS,THOMAS E.; SANDERS,THOMAS L.; EAGAN,ROBERT J.; BAKER,ARNOLD B.

    2000-01-01

    Nuclear power is an important and, the authors believe, essential component of a secure nuclear future. Although nuclear fuel cycles create materials that have some potential for use in nuclear weapons, with appropriate fuel cycles, nuclear power could reduce rather than increase real proliferation risk worldwide. Future fuel cycles could be designed to avoid plutonium production, generate minimal amounts of plutonium in proliferation-resistant amounts or configurations, and/or transparently and efficiently consume plutonium already created. Furthermore, a strong and viable US nuclear infrastructure, of which nuclear power is a large element, is essential if the US is to maintain a leadership or even participatory role in defining the global nuclear infrastructure and controlling the proliferation of nuclear weapons. By focusing on new fuel cycles and new reactor technologies, it is possible to advantageously burn and reduce nuclear materials that could be used for nuclear weapons rather than increase and/or dispose of these materials. Thus, the authors suggest that planners for a secure nuclear future use technology to design an ideal future. In this future, nuclear power creates large amounts of virtually atmospherically clean energy while significantly lowering the threat of proliferation through the thoughtful use, physical security, and agreed-upon transparency of nuclear materials. The authors must develop options for policy makers that bring them as close as practical to this ideal. Just as Atoms for Peace became the ideal for the first nuclear century, they see a potential nuclear future that contributes significantly to power for peace and prosperity.

  10. Terrorists and Nuclear Technology

    ERIC Educational Resources Information Center

    Krieger, David

    1975-01-01

    This essay explores the ways terrorist groups may gain possession of nuclear materials; the way in which they may use nuclear weapons and other nuclear technologies to their benefit; and various courses of action designed to minimize the possibilities of terrorists utilizing nuclear technology to their benefit and society's detriment. (BT)

  11. Frontiers of Nuclear Structure

    SciTech Connect

    Nazarewicz, Witold

    1997-12-31

    Current developments in nuclear structure at the `limits` are discussed. The studies of nuclear behavior at extreme conditions provide us with invaluable information about the nature of the nuclear interaction and nucleonic correlations at various energy-distance scales. In this talk frontiers of nuclear structure are briefly reviewed from a theoretical perspective, mainly concentrating on medium-mass and heavy nuclei.

  12. Nuclear medicine annual, 1984

    SciTech Connect

    Freeman, L.M.; Weissmann, H.S.

    1984-01-01

    The following topics are reviewed in this work: nuclear physicians role in planning for and handling radiation accidents; the role of nuclear medicine in evaluating the hypertensive patient; studies of the heart with radionuclides; role of radionuclide imaging in the patient undergoing chemotherapy; hematologic nuclear medicine; the role of nuclear medicine in sports related injuries; radionuclide evaluation of hepatic function with emphasis on cholestatis.

  13. Quantum.Ligand.Dock: protein–ligand docking with quantum entanglement refinement on a GPU system

    PubMed Central

    Kantardjiev, Alexander A.

    2012-01-01

    Quantum.Ligand.Dock (protein–ligand docking with graphic processing unit (GPU) quantum entanglement refinement on a GPU system) is an original modern method for in silico prediction of protein–ligand interactions via high-performance docking code. The main flavour of our approach is a combination of fast search with a special account for overlooked physical interactions. On the one hand, we take care of self-consistency and proton equilibria mutual effects of docking partners. On the other hand, Quantum.Ligand.Dock is the the only docking server offering such a subtle supplement to protein docking algorithms as quantum entanglement contributions. The motivation for development and proposition of the method to the community hinges upon two arguments—the fundamental importance of quantum entanglement contribution in molecular interaction and the realistic possibility to implement it by the availability of supercomputing power. The implementation of sophisticated quantum methods is made possible by parallelization at several bottlenecks on a GPU supercomputer. The high-performance implementation will be of use for large-scale virtual screening projects, structural bioinformatics, systems biology and fundamental research in understanding protein–ligand recognition. The design of the interface is focused on feasibility and ease of use. Protein and ligand molecule structures are supposed to be submitted as atomic coordinate files in PDB format. A customization section is offered for addition of user-specified charges, extra ionogenic groups with intrinsic pKa values or fixed ions. Final predicted complexes are ranked according to obtained scores and provided in PDB format as well as interactive visualization in a molecular viewer. Quantum.Ligand.Dock server can be accessed at http://87.116.85.141/LigandDock.html. PMID:22669908

  14. Quantum.Ligand.Dock: protein-ligand docking with quantum entanglement refinement on a GPU system.

    PubMed

    Kantardjiev, Alexander A

    2012-07-01

    Quantum.Ligand.Dock (protein-ligand docking with graphic processing unit (GPU) quantum entanglement refinement on a GPU system) is an original modern method for in silico prediction of protein-ligand interactions via high-performance docking code. The main flavour of our approach is a combination of fast search with a special account for overlooked physical interactions. On the one hand, we take care of self-consistency and proton equilibria mutual effects of docking partners. On the other hand, Quantum.Ligand.Dock is the the only docking server offering such a subtle supplement to protein docking algorithms as quantum entanglement contributions. The motivation for development and proposition of the method to the community hinges upon two arguments-the fundamental importance of quantum entanglement contribution in molecular interaction and the realistic possibility to implement it by the availability of supercomputing power. The implementation of sophisticated quantum methods is made possible by parallelization at several bottlenecks on a GPU supercomputer. The high-performance implementation will be of use for large-scale virtual screening projects, structural bioinformatics, systems biology and fundamental research in understanding protein-ligand recognition. The design of the interface is focused on feasibility and ease of use. Protein and ligand molecule structures are supposed to be submitted as atomic coordinate files in PDB format. A customization section is offered for addition of user-specified charges, extra ionogenic groups with intrinsic pK(a) values or fixed ions. Final predicted complexes are ranked according to obtained scores and provided in PDB format as well as interactive visualization in a molecular viewer. Quantum.Ligand.Dock server can be accessed at http://87.116.85.141/LigandDock.html.

  15. A 3D porous zinc MOF constructed from a flexible tripodal ligand: Synthesis, structure, and photoluminescence property

    SciTech Connect

    Wen Lili; Wang Dong'e; Wang Chenggang; Wang Feng; Li Dongfeng Deng Kejian

    2009-03-15

    A new metal-organic framework, [Zn{sub 5}(trencba){sub 2}(OH){sub 2}Cl{sub 2}.4H{sub 2}O] (1) [H{sub 3}trencba=N,N,N',N',N'',N''-tris[(4-carboxylate-2-yl)methyl]-tris (2-aminoethyl)amine], constructed from a flexible tripodal ligand based on C{sub 3} symmetric tris(2-aminoethyl)amine, has been synthesized hydrothermally and characterized by elemental analysis, IR, TG, XRD and single-crystal X-ray diffraction analysis. Compound 1 contains an unprecedented linear penta-nuclear zinc cluster fragment. Each ligand links four penta-nuclear fragments, and every fragment links eight ligands to generate a three-dimensional non-interpenetrated porous framework. The uncoordinated water molecules were observed trapped in the void pores. Compound 1 represents the first example of (6,8)-connected 3D bi-nodal framework based on a single kind of organic ligand. The photoluminescence measurements showed that complex 1 exhibits relatively stronger blue emissions at room temperature than that of the ligand. - Graphical abstract: The MOF [Zn{sub 5}(trencba){sub 2}(OH){sub 2}Cl{sub 2}.4H{sub 2}O] (H{sub 3}trencba=N,N,N',N',N',N'-tris[(4-carboxylate-2-yl)methyl]-tris (2-aminoethyl)amine) reveals a (6,8)-connected bi-nodal three-dimensional porous framework with unprecedented penta-nuclear fragment, which appears to be a good candidate of hybrid inorganic-organic photoactive materials.

  16. Affinity Regulates Spatial Range of EGF Receptor Autocrine Ligand Binding

    SciTech Connect

    Dewitt, Ann; Iida, Tomoko; Lam, Ho-Yan; Hill, Virginia; Wiley, H S.; Lauffenburger, Douglas A.

    2002-08-08

    Proper spatial localization of EGFR signaling activated by autocrine ligands represents a critical factor in embryonic development as well as tissue organization and function, and ligand/receptor binding affinity is among the molecular and cellular properties suggested to play a role in governing this localization. The authors employ a computational model to predict how receptor-binding affinity affects local capture of autocrine ligand vis-a-vis escape to distal regions, and provide experimental test by constructing cell lines expressing EGFR along with either wild-type EGF or a low-affinity mutant, EGF{sup L47M}. The model predicts local capture of a lower affinity autocrine ligand to be less efficient when the ligand production rate is small relative to receptor appearance rate. The experimental data confirm this prediction, demonstrating that cells can use ligand/receptor binding affinity to regulate ligand spatial distribution when autocrine ligand production is limiting for receptor signaling.

  17. Fusion of ligand-coated nanoparticles with lipid bilayers: effect of ligand flexibility.

    PubMed

    Van Lehn, Reid C; Alexander-Katz, Alfredo

    2014-08-07

    Amphiphilic, monolayer-protected gold nanoparticles (AuNPs) have recently been shown to insert into and fuse with lipid bilayers, driven by the hydrophobic effect. The inserted transmembrane state is stabilized by the "snorkeling" of charged ligand end groups out of the bilayer interior. This snorkeling process is facilitated by the backbone flexibility of the alkanethiol ligands that comprise the monolayer. In this work, we show that fusion is favorable even in the absence of backbone flexibility by modeling the ligands as rigid rods. For rigid ligands, snorkeling is still accommodated by rotations of the ligand with respect to the grafting point, but the process incurs a more significant free energy penalty than if the backbone were fully flexible. We show that the rigid rod model predicts similar trends in the free energy change for insertion as the previous flexible model when the size of the AuNPs is varied. However, the rigidity of the ligand backbone reduces the overall magnitude of the free energy change compared to that of the flexible model. These results thus generalize previous findings to systems with hindered backbone flexibility due to either structural constraints or low temperature.

  18. The nuclear freeze controversy

    SciTech Connect

    Payne, K.B.; Gray, C.S.

    1984-01-01

    This book presents papers on nuclear arms control. Topics considered include the background and rationale behind the nuclear freeze proposal, nuclear deterrence, national defense, arms races, arms buildup, warfare, the moral aspects of nuclear deterrence, treaty verification, the federal budget, the economy, a historical perspective on Soviet policy toward the freeze, the other side of the Soviet peace offensive, and making sense of the nuclear freeze debate.

  19. Crystallographic Analysis of Murine Constitutive Androstane Receptor Ligand-Binding Domain Complexed with 5[alpha]-androst-16-en-3[alpha]-ol

    SciTech Connect

    Vincent, J.; Shan, L.; Fan, M.; Brunzelle, J.S.; Forman, B.M.; Fernandez, E.J.

    2010-03-08

    The constitutive androstane receptor (CAR) is a member of the nuclear receptor superfamily. In contrast to classical nuclear receptors, which possess small-molecule ligand-inducible activity, CAR exhibits constitutive transcriptional activity in the apparent absence of ligand. CAR is among the most important transcription factors; it coordinately regulates the expression of microsomal cytochrome P450 genes and other drug-metabolizing enzymes. The murine CAR ligand-binding domain (LBD) was coexpressed with the steroid receptor coactivator protein (SRC-1) receptor-interacting domain (RID) in Escherichia coli. The mCAR LBD subunit was purified away from SRC-1 by affinity, anion-exchange and size-exclusion chromatography, crystallized with androstenol and the structure of the complex determined by molecular replacement.

  20. Exploring Flexibility of Progesterone Receptor Ligand Binding Domain Using Molecular Dynamics

    PubMed Central

    Zheng, Liangzhen; Mu, Yuguang

    2016-01-01

    Progesterone receptor (PR), a member of nuclear receptor (NR) superfamily, plays a vital role for female reproductive tissue development, differentiation and maintenance. PR ligand, such as progesterone, induces conformation changes in PR ligand binding domain (LBD), thus mediates subsequent gene regulation cascades. PR LBD may adopt different conformations upon an agonist or an antagonist binding. These different conformations would trigger distinct transcription events. Therefore, the dynamics of PR LBD would be of general interest to biologists for a deep understanding of its structure-function relationship. However, no apo-form (non-ligand bound) of PR LBD model has been proposed either by experiments or computational methods so far. In this study, we explored the structural dynamics of PR LBD using molecular dynamics simulations and advanced sampling tools in both ligand-bound and the apo-forms. Resolved by the simulation study, helix 11, helix 12 and loop 895–908 (the loop between these two helices) are quite flexible in antagonistic conformation. Several residues, such as Arg899 and Glu723, could form salt-bridging interaction between helix 11 and helix 3, and are important for the PR LBD dynamics. And we also propose that helix 12 in apo-form PR LBD, not like other NR LBDs, such as human estrogen receptor α (ERα) LBD, may not adopt a totally extended conformation. With the aid of umbrella sampling and metadynamics simulations, several stable conformations of apo-form PR LBD have been sampled, which may work as critical structural models for further large scale virtual screening study to discover novel PR ligands for therapeutic application. PMID:27824891

  1. Evolutionary diversification of retinoic acid receptor ligand-binding pocket structure by molecular tinkering

    PubMed Central

    Gutierrez-Mazariegos, Juliana; Nadendla, Eswar Kumar; Studer, Romain A.; Alvarez, Susana; de Lera, Angel R.; Kuraku, Shigehiro; Bourguet, William; Laudet, Vincent

    2016-01-01

    Whole genome duplications (WGDs) have been classically associated with the origin of evolutionary novelties and the so-called duplication–degeneration–complementation model describes the possible fates of genes after duplication. However, how sequence divergence effectively allows functional changes between gene duplicates is still unclear. In the vertebrate lineage, two rounds of WGDs took place, giving rise to paralogous gene copies observed for many gene families. For the retinoic acid receptors (RARs), for example, which are members of the nuclear hormone receptor (NR) superfamily, a unique ancestral gene has been duplicated resulting in three vertebrate paralogues: RARα, RARβ and RARγ. It has previously been shown that this single ancestral RAR was neofunctionalized to give rise to a larger substrate specificity range in the RARs of extant jawed vertebrates (also called gnathostomes). To understand RAR diversification, the members of the cyclostomes (lamprey and hagfish), jawless vertebrates representing the extant sister group of gnathostomes, provide an intermediate situation and thus allow the characterization of the evolutionary steps that shaped RAR ligand-binding properties following the WGDs. In this study, we assessed the ligand-binding specificity of cyclostome RARs and found that their ligand-binding pockets resemble those of gnathostome RARα and RARβ. In contrast, none of the cyclostome receptors studied showed any RARγ-like specificity. Together, our results suggest that cyclostome RARs cover only a portion of the specificity repertoire of the ancestral gnathostome RARs and indicate that the establishment of ligand-binding specificity was a stepwise event. This iterative process thus provides a rare example for the diversification of receptor–ligand interactions of NRs following WGDs. PMID:27069642

  2. Amino Acids in Nine Ligand-Prefer Ramachandran Regions.

    PubMed

    Cao, Chen; Wang, Lincong; Chen, Xiaoyang; Zou, Shuxue; Wang, Guishen; Xu, Shutan

    2015-01-01

    Several secondary structures, such as π-helix and left-handed helix, have been frequently identified at protein ligand-binding sites. A secondary structure is considered to be constrained to a specific region of dihedral angles. However, a comprehensive analysis of the correlation between main chain dihedral angles and ligand-binding sites has not been performed. We undertook an extensive analysis of the relationship between dihedral angles in proteins and their distance to ligand-binding sites, frequency of occurrence, molecular potential energy, amino acid composition, van der Waals contacts, and hydrogen bonds with ligands. The results showed that the values of dihedral angles have a strong preference for ligand-binding sites at certain regions in the Ramachandran plot. We discovered that amino acids preceding the ligand-prefer ϕ/ψ box residues are exposed more to solvents, whereas amino acids following ligand-prefer ϕ/ψ box residues form more hydrogen bonds and van der Waals contacts with ligands. Our method exhibited a similar performance compared with the program Ligsite-csc for both ligand-bound structures and ligand-free structures when just one ligand-binding site was predicted. These results should be useful for the prediction of protein ligand-binding sites and for analysing the relationship between structure and function.

  3. Luminescence spectroscopy of europium(III) and terbium(III) penta-, octa- and nonanuclear clusters with beta-diketonate ligands.

    PubMed

    Petit, Sarah; Baril-Robert, François; Pilet, Guillaume; Reber, Christian; Luneau, Dominique

    2009-09-14

    A series of Eu(III) and Tb(III) clusters as well as their Y(III) analogues with increasing nuclearities of 5, 8 and 9 have been synthesised using beta-diketonate ligands with decreasing steric hindrance. Their molecular structures have been established from X-ray diffraction on single crystals for most clusters and studied by luminescence and Raman spectroscopy. The Raman spectra have distinctive patterns for each nuclearity in accordance with their crystal structure. The luminescence spectra of the Eu(III) and Tb(III) clusters also show distinctive features.

  4. Formation of retinoid X receptor homodimers leads to repression of T3 response: hormonal cross talk by ligand-induced squelching.

    PubMed Central

    Lehmann, J M; Zhang, X K; Graupner, G; Lee, M O; Hermann, T; Hoffmann, B; Pfahl, M

    1993-01-01

    Thyroid hormone receptors (TRs) form heterodimers with retinoid X receptors (RXRs). Heterodimerization is required for efficient TR DNA binding to most response elements and transcriptional activation by thyroid hormone. RXRs also function as auxiliary proteins for several other receptors. In addition, RXR alpha can be induced by specific ligands to form homodimers. Here we report that RXR-specific retinoids that induce RXR homodimers are effective repressors of the T3 response. We provide evidence that this repression by RXR-specific ligands occurs by sequestering of RXR from TR-RXR heterodimers into RXR homodimers. This ligand-induced squelching may represent an important mechanism by which RXR-specific retinoids and 9-cis retinoic acid mediate hormonal cross talk among a subfamily of nuclear receptors activated by structurally unrelated ligands. Images PMID:8246986

  5. Liver X receptor ligand cytotoxicity in colon cancer cells and not in normal colon epithelial cells depends on LXRβ subcellular localization.

    PubMed

    Courtaut, Flavie; Derangère, Valentin; Chevriaux, Angélique; Ladoire, Sylvain; Cotte, Alexia K; Arnould, Laurent; Boidot, Romain; Rialland, Mickaël; Ghiringhelli, François; Rébé, Cédric

    2015-09-29

    Increasing evidence indicates that Liver X Receptors (LXRs) have some anticancer properties. We recently demonstrated that LXR ligands induce colon cancer cell pyroptosis through an LXRβ-dependent pathway. In the present study, we showed that human colon cancer cell lines presented differential cytoplasmic localizations of LXRβ. This localization correlated with caspase-1 activation and cell death induction under treatment with LXR ligand. The association of LXRβ with the truncated form of RXRα (t-RXRα) was responsible for the sequestration of LXRβ in the cytoplasm in colon cancer cells. Moreover t-RXRα was not expressed in normal colon epithelial cells. These cells presented a predominantly nuclear localization of LXRβ and were resistant to LXR ligand cytotoxicity. Our results showed that predominant cytoplasmic localization of LXRβ, which occurs in colon cancer cells but not in normal colon epithelial cells, allowed LXR ligand-induced pyroptosis. This study strengthens the hypothesis that LXRβ could be a promising target in cancer therapy.

  6. Steroid receptors and their ligands: Effects on male gamete functions

    SciTech Connect

    Aquila, Saveria; De Amicis, Francesca

    2014-11-01

    In recent years a new picture of human sperm biology is emerging. It is now widely recognized that sperm contain nuclear encoded mRNA, mitochondrial encoded RNA and different transcription factors including steroid receptors, while in the past sperm were considered incapable of transcription and translation. One of the main targets of steroid hormones and their receptors is reproductive function. Expression studies on Progesterone Receptor, estrogen receptor, androgen receptor and their specific ligands, demonstrate the presence of these systems in mature spermatozoa as surface but also as nuclear conventional receptors, suggesting that both systemic and local steroid hormones, through sperm receptors, may influence male reproduction. However, the relationship between the signaling events modulated by steroid hormones and sperm fertilization potential as well as the possible involvement of the specific receptors are still controversial issues. The main line of this review highlights the current research in human sperm biology examining new molecular systems of response to the hormones as well as specific regulatory pathways controlling sperm cell fate and biological functions. Most significant studies regarding the identification of steroid receptors are reported and the mechanistic insights relative to signaling pathways, together with the change in sperm metabolism energy influenced by steroid hormones are discussed.The reviewed evidences suggest important effects of Progesterone, Estrogen and Testosterone and their receptors on spermatozoa and implicate the involvement of both systemic and local steroid action in the regulation of male fertility potential. - Highlights: • One of the main targets of steroid hormones and their receptors is reproductive function. • Pg/PR co-work to stimulate enzymatic activities to sustain a capacitation process. • E2/ERs regulate sperm motility, capacitation and acrosome reaction and act as survival factors. • Androgens

  7. Effects of coumestrol on lipid and glucose metabolism as a farnesoid X receptor ligand

    SciTech Connect

    Takahashi, Miki; Kanayama, Tomohiko; Yashiro, Takuya; Kondo, Hidehiko; Murase, Takatoshi; Hase, Tadashi; Tokimitsu, Ichiro; Nishikawa, Jun-ichi; Sato, Ryuichiro

    2008-08-01

    In the course of an effort to identify novel agonists of the farnesoid X receptor (FXR), coumestrol was determined to be one such ligand. Reporter and in vitro coactivator interaction assays revealed that coumestrol bound and activated FXR. Treatment of Hep G2 cells with coumestrol stimulated the expression of FXR target genes, thereby regulating the expression of target genes of the liver X receptor and hepatocyte nuclear factor-4{alpha}. Through these actions, coumestrol is expected to exert beneficial effects on lipid and glucose metabolism.

  8. Nuclear receptors and pathogenesis of pancreatic cancer

    PubMed Central

    Polvani, Simone; Tarocchi, Mirko; Tempesti, Sara; Galli, Andrea

    2014-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a median overall survival time of 5 mo and the five years survival less than 5%, a rate essentially unchanged over the course of the years. A well defined progression model of accumulation of genetic alterations ranging from single point mutations to gross chromosomal abnormalities has been introduced to describe the origin of this disease. However, due to the its subtle nature and concurring events PDAC cure remains elusive. Nuclear receptors (NR) are members of a large superfamily of evolutionarily conserved ligand-regulated DNA-binding transcription factors functionally involved in important cellular functions ranging from regulation of metabolism, to growth and development. Given the nature of their ligands, NR are very tempting drug targets and their pharmacological modulation has been widely exploited for the treatment of metabolic and inflammatory diseases. There are now clear evidences that both classical ligand-activated and orphan NR are involved in the pathogenesis of PDAC from its very early stages; nonetheless many aspects of their role are not fully understood. The purpose of this review is to highlight the striking connections that link peroxisome proliferator activated receptors, retinoic acid receptors, retinoid X receptor, androgen receptor, estrogen receptors and the orphan NR Nur, chicken ovalbumin upstream promoter transcription factor II and the liver receptor homologue-1 receptor to PDAC development, connections that could lead to the identification of novel therapies for this disease. PMID:25232244

  9. Definition of a dioxin receptor mutant that is a constitutive activator of transcription: delineation of overlapping repression and ligand binding functions within the PAS domain.

    PubMed

    McGuire, J; Okamoto, K; Whitelaw, M L; Tanaka, H; Poellinger, L

    2001-11-09

    The intracellular dioxin (aryl hydrocarbon) receptor is a ligand-activated transcription factor that mediates the adaptive and toxic responses to environmental pollutants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin and structurally related congeners. Whereas the ligand-free receptor is characterized by its association with the molecular chaperone hsp90, exposure to ligand initiates a multistep activation process involving nuclear translocation, dissociation from the hsp90 complex, and dimerization with its partner protein Arnt. In this study, we have characterized a dioxin receptor deletion mutant lacking the minimal ligand-binding domain of the receptor. This mutant did not bind ligand and localized constitutively to the nucleus. However, this protein was functionally inert since it failed to dimerize with Arnt and to bind DNA. In contrast, a dioxin receptor deletion mutant lacking the minimal PAS B motif but maintaining the N-terminal half of the ligand-binding domain showed constitutive dimerization with Arnt, bound DNA, and activated transcription in a ligand-independent manner. Interestingly, this mutant showed a more potent functional activity than the dioxin-activated wild-type receptor in several different cell lines. In conclusion, the constitutively active dioxin receptor may provide an important mechanistic tool to investigate receptor-mediated regulatory pathways in closer detail.

  10. Nuclear Receptors: Small Molecule Sensors that Coordinate Growth, Metabolism and Reproduction.

    PubMed

    Pardee, Keith; Necakov, Aleksandar S; Krause, Henry

    2011-01-01

    One of the largest groups of metazoan transcription factors (TFs), the Nuclear Receptor superfamily, regulates genes required for virtually all aspects of development, reproduction and metabolism. Together, these master regulators can be thought of as a fundamental operating system for metazoan life. Their most distinguishing feature is a structurally conserved domain that acts as a switch, powered by the presence of small diffusible ligands. This ligand-responsive regulation has allowed the Nuclear Receptors to help their hosts adapt to a wide variety of physiological niches and roles, making them one of the most evolutionarily successful TF families. Originally discovered as receptors for steroid hormones, the Nuclear Receptor field has grown to encompass much more than traditional endocrinology. For example, recent work has highlighted the role of Nuclear Receptors as major regulators of metabolism and biological clocks. By monitoring endogenous metabolites and absorbed xenobiotics, these receptors also coordinate rapid, system-wide responses to changing metabolic and environmental states. While many new Nuclear Receptor ligands have been discovered in the past couple of decades, approximately half of the 48 human receptors are still orphans, with a significantly higher percentage of orphans in other organisms. The discovery of new ligands has led to the elucidation of new regulatory mechanisms, target genes, pathways and functions. This review will highlight both the common as well as newly emerging traits and functions that characterize this particularly unique and important TF family.

  11. Minireview: Pathophysiological Roles of the TR4 Nuclear Receptor: Lessons Learned From Mice Lacking TR4

    PubMed Central

    Lin, Shin-Jen; Zhang, Yanqing; Liu, Ning-Chun; Yang, Dong-Rong

    2014-01-01

    Testicular nuclear receptor 4 (TR4), also known as NR2C2, belongs to the nuclear receptor superfamily and shares high homology with the testicular nuclear receptor 2. The natural ligands of TR4 remained unclear until the recent discoveries of several energy/lipid sensors including the polyunsaturated fatty acid metabolites, 13-hydroxyoctadecadienoic acid and 15-hydroxyeicosatetraenoic acid, and their synthetic ligands, thiazolidinediones, used for treatment of diabetes. TR4 is widely expressed throughout the body and particularly concentrated in the testis, prostate, cerebellum, and hippocampus. It has been shown to play important roles in cerebellar development, forebrain myelination, folliculogenesis, gluconeogenesis, lipogenesis, muscle development, bone development, and prostate cancer progression. Here we provide a comprehensive summary of TR4 signaling including its upstream ligands/activators/suppressors, transcriptional coactivators/repressors, downstream targets, and their in vivo functions with potential impacts on TR4-related diseases. Importantly, TR4 shares similar ligands/activators with another key nuclear receptor, peroxisome proliferator-activated receptor γ, which raised several interesting questions about how these 2 nuclear receptors may collaborate with or counteract each other's function in their related diseases. Clear dissection of such molecular mechanisms and their differential roles in various diseases may help researchers to design new potential drugs with better efficacy and fewer side effects to battle TR4 and peroxisome proliferator-activated receptor γ involved diseases. PMID:24702179

  12. Enhanced Ligand Sampling for Relative Protein–Ligand Binding Free Energy Calculations

    PubMed Central

    2016-01-01

    Free energy calculations are used to study how strongly potential drug molecules interact with their target receptors. The accuracy of these calculations depends on the accuracy of the molecular dynamics (MD) force field as well as proper sampling of the major conformations of each molecule. However, proper sampling of ligand conformations can be difficult when there are large barriers separating the major ligand conformations. An example of this is for ligands with an asymmetrically substituted phenyl ring, where the presence of protein loops hinders the proper sampling of the different ring conformations. These ring conformations become more difficult to sample when the size of the functional groups attached to the ring increases. The Adaptive Integration Method (AIM) has been developed, which adaptively changes the alchemical coupling parameter λ during the MD simulation so that conformations sampled at one λ can aid sampling at the other λ values. The Accelerated Adaptive Integration Method (AcclAIM) builds on AIM by lowering potential barriers for specific degrees of freedom at intermediate λ values. However, these methods may not work when there are very large barriers separating the major ligand conformations. In this work, we describe a modification to AIM that improves sampling of the different ring conformations, even when there is a very large barrier between them. This method combines AIM with conformational Monte Carlo sampling, giving improved convergence of ring populations and the resulting free energy. This method, called AIM/MC, is applied to study the relative binding free energy for a pair of ligands that bind to thrombin and a different pair of ligands that bind to aspartyl protease β-APP cleaving enzyme 1 (BACE1). These protein–ligand binding free energy calculations illustrate the improvements in conformational sampling and the convergence of the free energy compared to both AIM and AcclAIM. PMID:25906170

  13. Protein-ligand binding affinity determination by the waterLOGSY method: An optimised approach considering ligand rebinding

    PubMed Central

    Huang, Renjie; Bonnichon, Arnaud; Claridge, Timothy D. W.; Leung, Ivanhoe K. H.

    2017-01-01

    WaterLOGSY is a popular ligand-observed NMR technique to screen for protein-ligand interactions, yet when applied to measure dissociation constants (KD) through ligand titration, the results were found to be strongly dependent on sample conditions. Herein, we show that accurate KDs can be obtained by waterLOGSY with optimised experimental setup. PMID:28256624

  14. Protein-ligand binding affinity determination by the waterLOGSY method: An optimised approach considering ligand rebinding

    NASA Astrophysics Data System (ADS)

    Huang, Renjie; Bonnichon, Arnaud; Claridge, Timothy D. W.; Leung, Ivanhoe K. H.

    2017-03-01

    WaterLOGSY is a popular ligand-observed NMR technique to screen for protein-ligand interactions, yet when applied to measure dissociation constants (KD) through ligand titration, the results were found to be strongly dependent on sample conditions. Herein, we show that accurate KDs can be obtained by waterLOGSY with optimised experimental setup.

  15. Diamine Ligands in Copper-Catalyzed Reactions

    PubMed Central

    Surry, David S.

    2012-01-01

    The utility of copper-mediated cross-coupling reactions has been significantly increased by the development of mild reaction conditions and the ability to employ catalytic amounts of copper. The use of diamine-based ligands has been important in these advances and in this review we discuss these systems, including the choice of reaction conditions and applications in the synthesis of pharmaceuticals, natural products and designed materials. PMID:22384310

  16. Container molecules based on imine type ligands.

    PubMed

    Schulze, A Carina; Oppel, Iris M

    2012-01-01

    This chapter will give a short overview about container molecules, their synthesis and possible applications. The main focus is on those which are based on imine type ligands. These containers can be used for example for guest exchange, gas separation, as chemical sensors or for the stabilisation of white phosphorus under water. The described cages have wide openings or tightly closed ones. For one cage the reversible opening and closing is also described.

  17. galectin-3 ligand — EDRN Public Portal

    Cancer.gov

    Galectin-3 is an endogenous lectin that binds glycan epitopes of cell membrane and some extracellular glycoproteins such as integrins and laminin. Galectin-3 is involved in several biological activities including regulation of cellular cycle, modulation of adhesion and tumor progression and metastasis. Serum galectin-3 ligands have been shown to modulate the immune reaction against tumors and viruses and their level increases in sera of several neoplastic diseases.

  18. The association between nuclear receptors and ocular diseases.

    PubMed

    Liu, Ke; Zou, Chang; Qin, Bo

    2017-02-07

    Nuclear hormone receptors (NRs) are one of the most abundant transcription factors in the human cells. They regulate expression of genes via interactions with corresponding ligands, co-activators, and co-repressors. These molecular pathways play important roles in the development, cell differentiation, and physiologic and metabolic processes. Increasingly, targeting nuclear receptors is becoming a promising strategy for new drug development. The aim of this review is to discuss the association between nuclear receptors and eye development, and expand their role in various ocular diseases such as keratitis, cataract, glaucoma, uveitis, retinopathy, and ophthalmic tumors. Recent studies in this area are highlighted as well as future research directions and potential clinical applications. Finally, various strategies will be elucidated to inspire more targeted therapies for ocular diseases through the use of nuclear receptors.

  19. Structure of the homodimeric androgen receptor ligand-binding domain

    PubMed Central

    Nadal, Marta; Prekovic, Stefan; Gallastegui, Nerea; Helsen, Christine; Abella, Montserrat; Zielinska, Karolina; Gay, Marina; Vilaseca, Marta; Taulès, Marta; Houtsmuller, Adriaan B.; van Royen, Martin E.; Claessens, Frank; Fuentes-Prior, Pablo; Estébanez-Perpiñá, Eva

    2017-01-01

    The androgen receptor (AR) plays a crucial role in normal physiology, development and metabolism as well as in the aetiology and treatment of diverse pathologies such as androgen insensitivity syndromes (AIS), male infertility and prostate cancer (PCa). Here we show that dimerization of AR ligand-binding domain (LBD) is induced by receptor agonists but not by antagonists. The 2.15-Å crystal structure of homodimeric, agonist- and coactivator peptide-bound AR-LBD unveils a 1,000-Å2 large dimerization surface, which harbours over 40 previously unexplained AIS- and PCa-associated point mutations. An AIS mutation in the self-association interface (P767A) disrupts dimer formation in vivo, and has a detrimental effect on the transactivating properties of full-length AR, despite retained hormone-binding capacity. The conservation of essential residues suggests that the unveiled dimerization mechanism might be shared by other nuclear receptors. Our work defines AR-LBD homodimerization as an essential step in the proper functioning of this important transcription factor. PMID:28165461

  20. PPAR-γ receptor ligands: novel therapy for pituitary adenomas

    PubMed Central

    Heaney, Anthony P.; Fernando, Manory; Melmed, Shlomo

    2003-01-01

    Pituitary tumors cause considerable morbidity due to local invasion, hypopituitarism, or hormone hypersecretion. In many cases, no suitable drug therapies are available, and surgical excision is currently the only effective treatment. We show here abundant expression of nuclear hormone receptor PPAR-γ in all of 39 human pituitary tumors. PPAR-γ activating thiazolidinediones (TZDs) rosiglitazone and troglitazone induced G0-G1 cell-cycle arrest and apoptosis in human, rat somatolactotroph, and murine gonadotroph pituitary tumor cells, and suppressed in vitro hormone secretion. In vivo development and growth of murine somatolactotroph and gonadotroph tumors, generated by subcutaneous injection of prolactin-secreting (PRL-secreting) and growth hormone–secreting (GH-secreting) GH3 cells, luteinizing hormone–secreting (LH-secreting) LβT2 cells, and α-T3 cells, was markedly suppressed in rosiglitazone-treated mice, and serum GH, PRL, and LH levels were attenuated in all treated animals (P < 0.009). These results demonstrate that PPAR-γ is an important molecular target in pituitary adenoma cells and PPAR-γ ligands inhibit tumor cell growth and GH, PRL, and LH secretion in vitro and in vivo. TZDs are proposed as novel oral medications for managing pituitary tumors. PMID:12727930

  1. Hydrothermal reactions: From the synthesis of ligand to new lanthanide 3D-coordination polymers

    SciTech Connect

    Silva, Fausthon Fred da; Fernandes de Oliveira, Carlos Alberto; Lago Falcão, Eduardo Henrique; Gatto, Claudia Cristina; Bezerra da Costa, Nivan; Oliveira Freire, Ricardo; Chojnacki, Jarosław; Alves Júnior, Severino

    2013-11-15

    The organic ligand 2,5-piperazinedione-1,4-diacetic acid (H{sub 2}PDA) was synthesized under hydrothermal conditions starting from the iminodiacetic acid and catalyzed by oxalic acid. The X-ray powder diffraction data indicates that the compound crystallizes in the P2{sub 1}/c monoclinic system as reported in the literature. The ligand was also characterized by elemental analysis, magnetic nuclear resonance, infrared spectroscopy and thermogravimetric analysis. Two new coordination networks based on lanthanide ions were obtained with this ligand using hydrothermal reaction. In addition to single-crystal X-ray diffraction, the compounds were characterized by infrared spectroscopy, thermogravimetric analysis, scanning electron microscopy and elemental analysis. Single-crystal XRD showed that the compounds are isostructural, crystallizing in P2{sub 1}/n monoclinic system with chemical formula [Ln(PDA){sub 1.5}(H{sub 2}O)](H{sub 2}O){sub 3} (Ln=Gd{sup 3+}(1) and Eu{sup 3+}(2)).The luminescence properties of both compounds were studied. In the compound (1), a broad emission band was observed at 479 nm, redshifted by 70 nm in comparison of the free ligand. In (2), the typical f–f transition was observed with a maximum peak at 618 nm, related with the red emission of the europium ions. Computational methods were performed to simulate the crystal structure of (2). The theoretical calculations of the intensity parameters are in good agreement with the experimental values. - Graphical abstract: Scheme of obtaining the ligand 2,5-piperazinedione-1,4-diacetic acid (H{sub 2}PDA) and two new isostructural 3D-coordination polymers [Ln(PDA){sub 1.5}(H{sub 2}O)](H{sub 2}O){sub 3} (Ln=Gd{sup 3+} and Eu{sup 3+}) by hydrothermal synthesis. Display Omitted - Highlights: • The ligand 2,5-piperazinedione-1,4-diacetic acid was synthetized using the hydrothermic method and characterized. • Two new 3D-coordination polymers with this ligand containing Gd{sup 3+} and Eu{sup 3+} ions

  2. Gated escaping of ligand out of protein

    NASA Astrophysics Data System (ADS)

    Sheu, Sheh-Yi; Yang, Dah-Yen

    2000-01-01

    We construct a new gating model and develop a new theory to study the escaping process of a ligand out of a spherical cavity with a puncture (or gate) on the surface. The gate undulation can be regulated by any time-dependent function and the motion of the ligand inside the spherical cavity is mapped into a two-dimensional entropy potential surface. Hence the driving force of our model is entropy only. For a static gate, the escaping process corresponds to climbing a two-dimensional entropy barrier. When the gate open angle is small, the escaping rate is proportional to the square of the opening angle. The prefactor of the escaping rate constant depends on the curvature of the entropy potential surface. For coherent gating, the survival time depends not only on the gate undulation frequency but also on how the initial state is defined. On the escaping from protein, our escaping rate shows it is qualitatively consistent with the experimental result of ligand recombination in myoglobin.

  3. RAGE and its ligands in retinal disease.

    PubMed

    Barile, Gaetano R; Schmidt, Ann M

    2007-12-01

    RAGE, the receptor for advanced glycation endproducts (AGEs), is a multiligand signal transduction receptor of the immunoglobulin superfamily of cell surface molecules that has been implicated in the pathogenesis of diabetic complications, neurodegenerative diseases, inflammatory disorders, and cancer. These diverse biologic disorders reflect the multiplicity of ligands capable of cellular interaction via RAGE that include, in addition to AGEs, amyloid-beta (Abeta) peptide, the S100/calgranulin family of proinflammatory cytokines, and amphoterin, a member of the High Mobility Group Box (HMGB) DNA-binding proteins. In the retina, RAGE expression is present in neural cells, the vasculature, and RPE cells, and it has also been detected in pathologic cellular retinal responses including epiretinal and neovascular membrane formation. Ligands for RAGE, in particular AGEs, have emerged as relevant to the pathogenesis of diabetic retinopathy and age-related macular disease. While the understanding of RAGE and its role in retinal dysfunction with aging, diabetes mellitus, and/or activation of pro-inflammatory pathways is less complete compared to other organ systems, increasing evidence indicates that RAGE can initiate and sustain significant cellular perturbations in the inner and outer retina. For these reasons, antagonism of RAGE interactions with its ligands may be a worthwhile therapeutic target in such seemingly disparate, visually threatening retinal diseases as diabetic retinopathy, age-related macular degeneration, and proliferative vitreoretinopathy.

  4. Heterodimeric interaction between retinoid X receptor alpha and orphan nuclear receptor OR1 reveals dimerization-induced activation as a novel mechanism of nuclear receptor activation.

    PubMed Central

    Wiebel, F F; Gustafsson, J A

    1997-01-01

    OR1 is a member of the steroid/thyroid hormone nuclear receptor superfamily which has been described to mediate transcriptional responses to retinoids and oxysterols. On a DR4 response element, an OR1 heterodimer with the nuclear receptor retinoid X receptor alpha (RXR alpha) has been described to convey transcriptional activation in both the absence and presence of the RXR ligand 9-cis retinoic acid, the mechanisms of which have remained unclear. Here, we dissect the effects of RXR alpha and OR1 ligand-binding domain interaction on transcriptional regulation and the role of the respective carboxy-terminal activation domains (AF-2s) in the absence and presence of the RXR ligand, employing chimeras of the nuclear receptors containing the heterologous GAL4 DNA-binding domain as well as natural receptors. The results show that the interaction of the RXR and OR1 ligand-binding domains unleashes a transcription activation potential that is mainly dependent on the AF-2 of OR1, indicating that interaction with RXR activates OR1. This defines dimerization-induced activation as a novel function of heterodimeric interaction and mechanism of receptor activation not previously described for nuclear receptors. Moreover, we present evidence that activation of OR1 occurs by a conformational change induced upon heterodimerization with RXR. PMID:9199332

  5. Nuclear Waste Disposal

    SciTech Connect

    Gee, Glendon W.; Meyer, Philip D.; Ward, Andy L.

    2005-01-12

    Nuclear wastes are by-products of nuclear weapons production and nuclear power generation, plus residuals of radioactive materials used by industry, medicine, agriculture, and academia. Their distinctive nature and potential hazard make nuclear wastes not only the most dangerous waste ever created by mankind, but also one of the most controversial and regulated with respect to disposal. Nuclear waste issues, related to uncertainties in geologic disposal and long-term protection, combined with potential misuse by terrorist groups, have created uneasiness and fear in the general public and remain stumbling blocks for further development of a nuclear industry in a world that may soon be facing a global energy crisis.

  6. Assessment of automatic ligand building in ARP/wARP

    SciTech Connect

    Evrard, Guillaume X. Langer, Gerrit G.; Lamzin, Victor S.

    2007-01-01

    The performance of the ligand-building module of the ARP/wARP software suite is assessed through a large-scale test on known protein–ligand complexes. The results provide a detailed benchmark and guidelines for future improvements. The efficiency of the ligand-building module of ARP/wARP version 6.1 has been assessed through extensive tests on a large variety of protein–ligand complexes from the PDB, as available from the Uppsala Electron Density Server. Ligand building in ARP/wARP involves two main steps: automatic identification of the location of the ligand and the actual construction of its atomic model. The first step is most successful for large ligands. The second step, ligand construction, is more powerful with X-ray data at high resolution and ligands of small to medium size. Both steps are successful for ligands with low to moderate atomic displacement parameters. The results highlight the strengths and weaknesses of both the method of ligand building and the large-scale validation procedure and help to identify means of further improvement.

  7. The Recognition of Identical Ligands by Unrelated Proteins

    PubMed Central

    Barelier, Sarah; Sterling, Teague; O'Meara, Matthew J.; Shoichet, Brian K.

    2015-01-01

    The binding of drugs and reagents to off-targets is well-known. Whereas many off-targets are related to the primary target by sequence and fold, many ligands bind to unrelated pairs of proteins, and these are harder to anticipate. If the binding site in the off-target can be related to that of the primary target, this challenge resolves into aligning the two pockets. However, other cases are possible: the ligand might interact with entirely different residues and environments in the off-target, or wholly different ligand atoms may be implicated in the two complexes. To investigate these scenarios at atomic resolution, the structures of 59 ligands in 116 complexes (62 pairs in total), where the protein pairs were unrelated by fold but bound an identical ligand, were examined. In almost half of the pairs, the ligand interacted with unrelated residues in the two proteins (29 pairs), and in 14 of the pairs wholly different ligand moieties were implicated in each complex. Even in those 19 pairs of complexes that presented similar environments to the ligand, ligand superposition rarely resulted in the overlap of related residues. There appears to be no single pattern-matching “code” for identifying binding sites in unrelated proteins that bind identical ligands, though modeling suggests that there might be a limited number of different patterns that suffice to recognize different ligand functional groups. PMID:26421501

  8. Nuclear receptors and transcription factors in the development of fatty liver disease.

    PubMed

    Vluggens, Aurore; Reddy, Janardan K

    2012-12-01

    Liver regulates certain key aspects of lipid metabolism including de novo lipogenesis, fatty acid oxidation, and lipoprotein uptake and secretion. Disturbances in these hepatic functions can contribute to the development of fatty liver disease. An understanding of the regulatory mechanisms influencing hepatic lipid homeostasis and systemic energy balance is therefore of paramount importance in gaining insights that might be useful in the management of fatty liver disease. In this regard, emerging evidence indicates that certain members of the nuclear receptor superfamily and some key transcription coactivators function as intracellular sensors to orchestrate hepatic lipid metabolism. Dysregulation of nuclear receptor-mediated transcriptional signaling and perturbations in the levels of their cognate endogenous ligands play a prominent role in the development of fatty liver disease. The potential of nuclear receptors, transcription coactivators as well as enzymes that participate in the synthesis and degradation of endogenous nuclear receptor ligands, as effective therapeutic targets for fatty liver disease needs evaluation.

  9. Nanoparticle multivalency counterbalances the ligand affinity loss upon PEGylation.

    PubMed

    Hennig, Robert; Pollinger, Klaus; Veser, Anika; Breunig, Miriam; Goepferich, Achim

    2014-11-28

    The conjugation of receptor ligands to shielded nanoparticles is a widely used strategy to precisely control nanoparticle-cell interactions. However, it is often overlooked that a ligand's affinity can be severely impaired by its attachment to the polyethylene glycol (PEG) chains that are frequently used to protect colloids from serum protein adsorption. Using the model ligand EXP3174, a small-molecule antagonist for the angiotensin II receptor type 1 (AT1R), we investigated the ligand's affinity before and after its PEGylation and when attached to PEGylated nanoparticles. The PEGylated ligand displayed a 580-fold decreased receptor affinity compared to the native ligand. Due to their multivalency, the nanoparticles regained a low nanomolar receptor affinity, which is in the range of the affinity of the native ligand. Moreover, a four orders of magnitude higher concentration of free ligand was required to displace PEGylated nanoparticles carrying EXP3174 from the receptor. On average, one nanoparticle was decorated with 11.2 ligand molecules, which led to a multivalent enhancement factor of 22.5 compared to the monovalent PEGylated ligand. The targeted nanoparticles specifically bound the AT1R and showed no interaction to receptor negative cells. Our study shows that the attachment of a small-molecule ligand to a PEG chain can severely affect its receptor affinity. Concomitantly, when the ligand is tethered to nanoparticles, the immense avidity greatly increases the ligand-receptor interaction. Based on our results, we highly recommend the affinity testing of receptor ligands before and after PEGylation to identify potent molecules for active nanoparticle targeting.

  10. Nuclear Security for Floating Nuclear Power Plants

    SciTech Connect

    Skiba, James M.; Scherer, Carolynn P.

    2015-10-13

    Recently there has been a lot of interest in small modular reactors. A specific type of these small modular reactors (SMR,) are marine based power plants called floating nuclear power plants (FNPP). These FNPPs are typically built by countries with extensive knowledge of nuclear energy, such as Russia, France, China and the US. These FNPPs are built in one country and then sent to countries in need of power and/or seawater desalination. Fifteen countries have expressed interest in acquiring such power stations. Some designs for such power stations are briefly summarized. Several different avenues for cooperation in FNPP technology are proposed, including IAEA nuclear security (i.e. safeguards), multilateral or bilateral agreements, and working with Russian design that incorporates nuclear safeguards for IAEA inspections in non-nuclear weapons states

  11. A chemogenomics view on protein-ligand spaces

    PubMed Central

    Strömbergsson, Helena; Kleywegt, Gerard J

    2009-01-01

    Background Chemogenomics is an emerging inter-disciplinary approach to drug discovery that combines traditional ligand-based approaches with biological information on drug targets and lies at the interface of chemistry, biology and informatics. The ultimate goal in chemogenomics is to understand molecular recognition between all possible ligands and all possible drug targets. Protein and ligand space have previously been studied as separate entities, but chemogenomics studies deal with large datasets that cover parts of the joint protein-ligand space. Since drug discovery has traditionally focused on ligand optimization, the chemical space has been studied extensively. The protein space has been studied to some extent, typically for the purpose of classification of proteins into functional and structural classes. Since chemogenomics deals not only with ligands but also with the macromolecules the ligands interact with, it is of interest to find means to explore, compare and visualize protein-ligand subspaces. Results Two chemogenomics protein-ligand interaction datasets were prepared for this study. The first dataset covers the known structural protein-ligand space, and includes all non-redundant protein-ligand interactions found in the worldwide Protein Data Bank (PDB). The second dataset contains all approved drugs and drug targets stored in the DrugBank database, and represents the approved drug-drug target space. To capture biological and physicochemical features of the chemogenomics datasets, sequence-based descriptors were computed for the proteins, and 0, 1 and 2 dimensional descriptors for the ligands. Principal component analysis (PCA) was used to analyze the multidimensional data and to create global models of protein-ligand space. The nearest neighbour method, computed using the principal components, was used to obtain a measure of overlap between the datasets. Conclusion In this study, we present an approach to visualize protein-ligand spaces from a

  12. Nuclear radiation actuated valve

    DOEpatents

    Christiansen, David W.; Schively, Dixon P.

    1985-01-01

    A nuclear radiation actuated valve for a nuclear reactor. The valve has a valve first part (such as a valve rod with piston) and a valve second part (such as a valve tube surrounding the valve rod, with the valve tube having side slots surrounding the piston). Both valve parts have known nuclear radiation swelling characteristics. The valve's first part is positioned to receive nuclear radiation from the nuclear reactor's fuel region. The valve's second part is positioned so that its nuclear radiation induced swelling is different from that of the valve's first part. The valve's second part also is positioned so that the valve's first and second parts create a valve orifice which changes in size due to the different nuclear radiation caused swelling of the valve's first part compared to the valve's second part. The valve may be used in a nuclear reactor's core coolant system.

  13. RBC nuclear scan

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/003835.htm RBC nuclear scan To use the sharing features on this page, please enable JavaScript. An RBC nuclear scan uses small amounts of radioactive material to ...

  14. Nuclear Thermal Propulsion (NTP)

    NASA Video Gallery

    NASA's history with nuclear thermal propulsion (NTP) technology goes back to the earliest days of the Agency. The Manned Lunar Rover Vehicle and the Nuclear Engine for Rocket Vehicle Applications p...

  15. Nuclear disarmament verification

    SciTech Connect

    DeVolpi, A.

    1993-12-31

    Arms control treaties, unilateral actions, and cooperative activities -- reflecting the defusing of East-West tensions -- are causing nuclear weapons to be disarmed and dismantled worldwide. In order to provide for future reductions and to build confidence in the permanency of this disarmament, verification procedures and technologies would play an important role. This paper outlines arms-control objectives, treaty organization, and actions that could be undertaken. For the purposes of this Workshop on Verification, nuclear disarmament has been divided into five topical subareas: Converting nuclear-weapons production complexes, Eliminating and monitoring nuclear-weapons delivery systems, Disabling and destroying nuclear warheads, Demilitarizing or non-military utilization of special nuclear materials, and Inhibiting nuclear arms in non-nuclear-weapons states. This paper concludes with an overview of potential methods for verification.

  16. Nuclear fear revisited

    NASA Astrophysics Data System (ADS)

    Crease, Robert P.

    2010-10-01

    In 1988 the science historian Spencer Weart published a groundbreaking book called Nuclear Fear: A History of Images, which examined visions of radiation damage and nuclear disaster in newspapers, television, film, literature, advertisements and popular culture.

  17. Triangle Universities Nuclear Laboratory

    SciTech Connect

    Not Available

    1991-01-01

    This report contains brief papers that discusses the following topics: Fundamental Symmetries in the Nucleus; Internucleon Interactions; Dynamics of Very Light Nuclei; Facets of the Nuclear Many-Body Problem; and Nuclear Instruments and Methods.

  18. Teaching "The Nuclear Predicament."

    ERIC Educational Resources Information Center

    Carman, Philip; Kneeshaw, Stephen

    1987-01-01

    Contends that courses on nuclear war must help students examine the political, social, religious, philosophical, economic, and moral assumptions which characterized the dilemma of nuclear armament/disarmament. Describes the upper level undergraduate course taught by the authors. (JDH)

  19. Nuclear Energy Policy

    DTIC Science & Technology

    2010-05-27

    small modular reactors and extend the lives and improve the operation of existing commercial nuclear power plants. 40 Interdisciplinary MIT Study, The Future of Nuclear Power, Massachusetts Institute of Technology, 2003, p. 79. 41 Gronlund, Lisbeth, David Lochbaum, and Edwin Lyman, Nuclear Power in a Warming World, Union of Concerned Scientists, December 2007. 42 Travis Madsen, Tony Dutzik, and Bernadette Del Chiaro, et al., Generating Failure: How Building Nuclear Power Plants

  20. JPRS Report, Nuclear Developments

    DTIC Science & Technology

    2016-03-24

    of efforts to improve the safety of nuclear reactors that were started together with the USSR. These efforts are focused in particular on...characteristics of these reactors are quite encouraging. With their improved safety and low radiation effect on environment they ensure the possi...Nuclear Power [KYODO] 3 Fukushima Nuclear Reactor Reports Leak [KYODO] 3 NORTH KOREA Nuclear Weapons Capability Discussed by ROK Paper

  1. Nuclear power browning out

    SciTech Connect

    Flavin, C.; Lenssen, N.

    1996-05-01

    When the sad history of nuclear power is written, April 26, 1986, will be recorded as the day the dream died. The explosion at the Chernobyl plant was a terrible human tragedy- and it delivered a stark verdict on the hope that nuclear power will one day replace fossil fuel-based energy systems. Nuclear advocates may soldier on, but a decade after Chernobyl it is clear that nuclear power is no longer a viable energy option for the twenty-first century.

  2. JPRS Report Nuclear Developments

    DTIC Science & Technology

    2007-11-02

    release; Distribution Unlimited | -—fb 40 Nuclear Developments JPRS-TND-88-016 CONTENTS 2 SEPTEMBER 1988 CHINA Nuclear Power Chief Seeks...Foreign Cooperation [Yuan Zhou; CHINA DAILY (BUSINESS WEEKLY) 1 Aug 88] 1 Nuclear Fusion Study Reaches Advanced Level [Xiao Longlian; Beijing...Government ’Welcomes’ Group [Beijing XINHUA 12 Aug 88] 4 No Decision on Disposal of Daya Nuclear Waste [Andy Ho; Hong Kong SOUTH CHINA MORNING POST

  3. Nuclear air cushion vehicles.

    NASA Technical Reports Server (NTRS)

    Anderson, J. L.

    1973-01-01

    This paper serves several functions. It identifies the 'state-of-the-art' of the still-conceptual nuclear air cushion vehicle, particularly the nuclear powerplant. Using mission studies and cost estimates, the report describes some of the advantages of nuclear power for large air cushion vehicles. The paper also summarizes the technology studies on mobile nuclear powerplants and conceptual ACV systems/missions studies that have been performed at NASA Lewis Research Center.

  4. Structural Conservation of Ligand Binding Reveals a Bile Acid-like Signaling Pathway in Nematodes*

    PubMed Central

    Zhi, Xiaoyong; Zhou, X. Edward; Melcher, Karsten; Motola, Daniel L.; Gelmedin, Verena; Hawdon, John; Kliewer, Steven A.; Mangelsdorf, David J.; Xu, H. Eric

    2012-01-01

    Bile acid-like molecules named dafachronic acids (DAs) control the dauer formation program in Caenorhabditis elegans through the nuclear receptor DAF-12. This mechanism is conserved in parasitic nematodes to regulate their dauer-like infective larval stage, and as such, the DAF-12 ligand binding domain has been identified as an important therapeutic target in human parasitic hookworm species that infect more than 600 million people worldwide. Here, we report two x-ray crystal structures of the hookworm Ancylostoma ceylanicum DAF-12 ligand binding domain in complex with DA and cholestenoic acid (a bile acid-like metabolite), respectively. Structure analysis and functional studies reveal key residues responsible for species-specific ligand responses of DAF-12. Furthermore, DA binds to DAF-12 mechanistically and is structurally similar to bile acids binding to the mammalian bile acid receptor farnesoid X receptor. Activation of DAF-12 by cholestenoic acid and the cholestenoic acid complex structure suggest that bile acid-like signaling pathways have been conserved in nematodes and mammals. Together, these results reveal the molecular mechanism for the interplay between parasite and host, provide a structural framework for DAF-12 as a promising target in treating nematode parasitism, and provide insight into the evolution of gut parasite hormone-signaling pathways. PMID:22170062

  5. Highly Dynamic Ligand Binding and Light Absorption Coefficient of Cesium Lead Bromide Perovskite Nanocrystals.

    PubMed

    De Roo, Jonathan; Ibáñez, Maria; Geiregat, Pieter; Nedelcu, Georgian; Walravens, Willem; Maes, Jorick; Martins, Jose C; Van Driessche, Isabel; Kovalenko, Maksym V; Hens, Zeger

    2016-02-23

    Lead halide perovskite materials have attracted significant attention in the context of photovoltaics and other optoelectronic applications, and recently, research efforts have been directed to nanostructured lead halide perovskites. Collodial nanocrystals (NCs) of cesium lead halides (CsPbX3, X = Cl, Br, I) exhibit bright photoluminescence, with emission tunable over the entire visible spectral region. However, previous studies on CsPbX3 NCs did not address key aspects of their chemistry and photophysics such as surface chemistry and quantitative light absorption. Here, we elaborate on the synthesis of CsPbBr3 NCs and their surface chemistry. In addition, the intrinsic absorption coefficient was determined experimentally by combining elemental analysis with accurate optical absorption measurements. (1)H solution nuclear magnetic resonance spectroscopy was used to characterize sample purity, elucidate the surface chemistry, and evaluate the influence of purification methods on the surface composition. We find that ligand binding to the NC surface is highly dynamic, and therefore, ligands are easily lost during the isolation and purification procedures. However, when a small amount of both oleic acid and oleylamine is added, the NCs can be purified, maintaining optical, colloidal, and material integrity. In addition, we find that a high amine content in the ligand shell increases the quantum yield due to the improved binding of the carboxylic acid.

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

    PubMed

    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.

  7. Evaluation of small ligand-protein interaction by ligation reaction with DNA-modified ligand.

    PubMed

    Sugita, Rie; Mie, Masayasu; Funabashi, Hisakage; Kobatake, Eiry

    2010-01-01

    A method for the evaluation of interactions between protein and ligand using DNA-modified ligands, including signal enhancement of the DNA ligation reactions, is described. For proof of principle, a DNA probe modified by biotin was used. Two DNA probes were prepared with complementary sticky-ends. While one DNA probe was modified at the 5'-end of the sticky-end, the other was not modified. The probes could be ligated together by T4 DNA ligase along the strand without biotin modification. However, in the presence of streptavidin or anti-biotin Fab, the ligation reaction joining the two probes could not occur on either strand.

  8. NUCLEAR REACTOR CONTROL SYSTEM

    DOEpatents

    Epler, E.P.; Hanauer, S.H.; Oakes, L.C.

    1959-11-01

    A control system is described for a nuclear reactor using enriched uranium fuel of the type of the swimming pool and other heterogeneous nuclear reactors. Circuits are included for automatically removing and inserting the control rods during the course of normal operation. Appropriate safety circuits close down the nuclear reactor in the event of emergency.

  9. Revitalizing Nuclear Safety Research.

    ERIC Educational Resources Information Center

    National Academy of Sciences - National Research Council, Washington, DC.

    This report covers the general issues involved in nuclear safety research and points out the areas needing detailed consideration. Topics included are: (1) "Principles of Nuclear Safety Research" (examining who should fund, who should conduct, and who should set the agenda for nuclear safety research); (2) "Elements of a Future…

  10. Nuclear energy technology

    NASA Technical Reports Server (NTRS)

    Buden, David

    1992-01-01

    An overview of space nuclear energy technologies is presented. The development and characteristics of radioisotope thermoelectric generators (RTG's) and space nuclear power reactors are discussed. In addition, the policy and issues related to public safety and the use of nuclear power sources in space are addressed.

  11. JPRS Report, Nuclear Developments

    DTIC Science & Technology

    2016-03-24

    a new generation of nuclear Because of the significant improvements in radiation read- reactors with an increased degree of safety are developed...With USSR [Moscow PRA VDA 14 Aug] ...................... 14 Future Nuclear Reactor Plans Detailed fIslamnahad Radio...July Stoppages /Moscow International] ........................................... 19 Suspension of Nuclear Reactor Construction Urged ITASS

  12. JPRS Report, Nuclear Developments

    DTIC Science & Technology

    2016-03-24

    extraction plant in collaboration with the Fer- Prototype Fast Breeder Reactor (PFBR). tilizers and Chemicals , Travancore (FACT) at Eloor near Cochin...Nuclear Reactor Shut Down After Malfunction [KYODO] ................................................................ 8 PHILIPPINES Proposal To Operate...Nuclear Reactor in Algeria [TELAM] .............................................................. 10 Nuclear Official Returns From Algeria [TELAM

  13. Teaching Nuclear History.

    ERIC Educational Resources Information Center

    Holl, Jack M.; Convis, Sheila C.

    1991-01-01

    Presents results of a survey of the teaching about nuclear history at U.S. colleges and universities. Reports the existence of a well-established and extensive literature, a focus on nuclear weapons or warfare, and a concentration on nuclear citizenship, therapy, or eschatology for courses outside of history departments. Discusses individual…

  14. Nuclear Medicine Imaging

    MedlinePlus

    ... necesita saber acerca de... Estudios de Imagen de Medicina Nuclear Un procedimiento de medicina nuclear se describe algunas veces como unos rayos- ... través del cuerpo del paciente. Los procedimientos de medicina nuclear utilizan pequeñas cantidades de mate- riales radiactivos, ...

  15. Nuclear fact book

    SciTech Connect

    Hill, O. F.; Platt, A. M.; Robinson, J. V.

    1983-05-01

    This reference provides significant highlights and summary facts in the following areas: general energy; nuclear energy; nuclear fuel cycle; uranium supply and enrichment; nuclear reactors; spent fuel and advanced repacking concepts; reprocessing; high-level waste; gaseous waste; transuranic waste; low-level waste; remedial action; transportation; disposal; radiation information; environment; legislation; socio-political aspects; conversion factors; and a glossary. (GHT)

  16. Effects of Nuclear Weapons.

    ERIC Educational Resources Information Center

    Sartori, Leo

    1983-01-01

    Fundamental principles governing nuclear explosions and their effects are discussed, including three components of a nuclear explosion (thermal radiation, shock wave, nuclear radiation). Describes how effects of these components depend on the weapon's yield, its height of burst, and distance of detonation point. Includes effects of three…

  17. Basic Nuclear Physics.

    ERIC Educational Resources Information Center

    Bureau of Naval Personnel, Washington, DC.

    Basic concepts of nuclear structures, radiation, nuclear reactions, and health physics are presented in this text, prepared for naval officers. Applications to the area of nuclear power are described in connection with pressurized water reactors, experimental boiling water reactors, homogeneous reactor experiments, and experimental breeder…

  18. Binuclear complexes of technetium. Evidence for bis(terdentate)bidentate coordination by the bridging ligand 2,3,5,6-tetrakis(2-pyridyl)pyrazine to technetium(V)

    SciTech Connect

    Du Preez, J.G.H.; Gerber, T.I.A.; Gibson, M.L.; Geyser, R. )

    1990-01-01

    The authors have used the potentially bis(terdentate) nitrogen aromatic heterocyclic ligand 2,3,5,6-tetrakis(2-pyridyl)pyrazine (tppz) to prepare mono- and bimetallic technetium(V) complexes bound to tppz. The stimulus for the development of the coordination chemistry of the man-made element technetium is provided by the use of complexes of this element as anatomical imaging agents in nuclear medicine. Although the chemistry of technetium(V) with nitrogen donor ligands is well understood, no complexes have been prepared using potentially terdentate neutral nitrogen donor ligands of this metal in the +5 oxidation state.

  19. Landscape of protein–small ligand binding modes

    PubMed Central

    Kinoshita, Kengo

    2016-01-01

    Abstract 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

  20. Ligand-targeted particulate nanomedicines undergoing clinical evaluation: current status.

    PubMed

    van der Meel, Roy; Vehmeijer, Laurens J C; Kok, Robbert J; Storm, Gert; van Gaal, Ethlinn V B

    2013-10-01

    Since the introduction of Doxil® on the market nearly 20years ago, a number of nanomedicines have become part of treatment regimens in the clinic. With the exception of antibody-drug conjugates, these nanomedicines are all devoid of targeting ligands and rely solely on their physicochemical properties and the (patho)physiological processes in the body for their biodistribution and targeting capability. At the same time, many preclinical studies have reported on nanomedicines exposing targeting ligands, or ligand-targeted nanomedicines, yet none of these have been approved at this moment. In the present review, we provide a concise overview of 13 ligand-targeted particulate nanomedicines (ligand-targeted PNMs) that have progressed into clinical trials. The progress of each ligand-targeted PNM is discussed based on available (pre)clinical data. Main conclusions of these analyses are that (a) ligand-targeted PNMs have proven to be safe and efficacious in preclinical models; (b) the vast majority of ligand-targeted PNMs is generated for the treatment of cancer; (c) contribution of targeting ligands to the PNM efficacy is not unambiguously proven; and (d) targeting ligands do not cause localization of the PNM within the target tissue, but rather provide benefits in terms of target cell internalization and target tissue retention once the PNM has arrived at the target site. Increased understanding of the in vivo fate and interactions of the ligand-targeted PNMs with proteins and cells in the human body is mandatory to rationally advance the clinical translation of ligand-targeted PNMs. Future perspectives for ligand-targeted PNM approaches include the delivery of drugs that are unable or inefficient in passing cellular membranes, treatment of drug resistant tumors, targeting of the tumor blood supply, the generation of targeted vaccines and nanomedicines that are able to cross the blood-brain barrier.

  1. (Ligand intermediates in metal-catalyzed reactions)

    SciTech Connect

    Not Available

    1992-01-01

    This report consists of sections on sigma bond complexes of alkenes, a new carbon-hydrogen bond activation reaction of alkene complexes, carbon-hydrogen bond migrations in alkylidene complexes, carbon- hydrogen bond migrations in alkyne complexes, synthesis, structure and reactivity of C{sub x} complexes, synthesis and reactivity of alcohol and ether complexes, new catalysts for the epimerization of secondary alcohols; carbon-hydrogen bond activation in alkoxide complexes, pi/sigma equilibria in metal/O=CXX' complexes, and other hydrocarbon ligands; miscellaneous.(WET)

  2. Transmutable nanoparticles with reconfigurable surface ligands

    NASA Astrophysics Data System (ADS)

    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.

  3. Hyperpolarized 89Y NMR spectroscopic detection of yttrium ion and DOTA macrocyclic ligand complexation: pH dependence and Y-DOTA intermediates

    NASA Astrophysics Data System (ADS)

    Ferguson, Sarah; Kiswandhi, Andhika; Niedbalski, Peter; Parish, Christopher; Kovacs, Zoltan; Lumata, Lloyd

    Dissolution dynamic nuclear polarization (DNP) is a rapidly emerging physics technique used to enhance the signal strength in nuclear magnetic resonance (NMR) and imaging (MRI) experiments for nuclear spins such as yttrium-89 by >10,000-fold. One of the most common and stable MRI contrast agents used in the clinic is Gd-DOTA. In this work, we have investigated the binding of the yttrium and DOTA ligand as a model for complexation of Gd ion and DOTA ligand. The macrocyclic ligand DOTA is special because its complexation with lanthanide ions such as Gd3+ or Y3+ is highly pH dependent. Using this physics technology, we have tracked the complexation kinetics of hyperpolarized Y-triflate and DOTA ligand in real-time and detected the Y-DOTA intermediates. Different kinds of buffers were used (lactate, acetate, citrate, oxalate) and the pseudo-first order complexation kinetic calculations will be discussed. The authors would like to acknowledge the support by US Dept of Defense Award No. W81XWH-14-1-0048 and Robert A. Welch Foundation Grant No. AT-1877.

  4. History of Nuclear India

    NASA Astrophysics Data System (ADS)

    Chaturvedi, Ram

    2000-04-01

    India emerged as a free and democratic country in 1947, and entered into the nuclear age in 1948 by establishing the Atomic Energy Commission (AEC), with Homi Bhabha as the chairman. Later on the Department of Atomic Energy (DAE) was created under the Office of the Prime Minister Jawahar Lal Nehru. Initially the AEC and DAE received international cooperation, and by 1963 India had two research reactors and four nuclear power reactors. In spite of the humiliating defeat in the border war by China in 1962 and China's nuclear testing in 1964, India continued to adhere to the peaceful uses of nuclear energy. On May 18, 1974 India performed a 15 kt Peaceful Nuclear Explosion (PNE). The western powers considered it nuclear weapons proliferation and cut off all financial and technical help, even for the production of nuclear power. However, India used existing infrastructure to build nuclear power reactors and exploded both fission and fusion devices on May 11 and 13, 1998. The international community viewed the later activity as a serious road block for the Non-Proliferation Treaty and the Comprehensive Test Ban Treaty; both deemed essential to stop the spread of nuclear weapons. India considers these treaties favoring nuclear states and is prepared to sign if genuine nuclear disarmament is included as an integral part of these treaties.

  5. Commercial nuclear power 1990

    SciTech Connect

    Not Available

    1990-09-28

    This report presents the status at the end of 1989 and the outlook for commercial nuclear capacity and generation for all countries in the world with free market economies (FME). The report provides documentation of the US nuclear capacity and generation projections through 2030. The long-term projections of US nuclear capacity and generation are provided to the US Department of Energy's (DOE) Office of Civilian Radioactive Waste Management (OCRWM) for use in estimating nuclear waste fund revenues and to aid in planning the disposal of nuclear waste. These projections also support the Energy Information Administration's annual report, Domestic Uranium Mining and Milling Industry: Viability Assessment, and are provided to the Organization for Economic Cooperation and Development. The foreign nuclear capacity projections are used by the DOE uranium enrichment program in assessing potential markets for future enrichment contracts. The two major sections of this report discuss US and foreign commercial nuclear power. The US section (Chapters 2 and 3) deals with (1) the status of nuclear power as of the end of 1989; (2) projections of nuclear capacity and generation at 5-year intervals from 1990 through 2030; and (3) a discussion of institutional and technical issues that affect nuclear power. The nuclear capacity projections are discussed in terms of two projection periods: the intermediate term through 2010 and the long term through 2030. A No New Orders case is presented for each of the projection periods, as well as Lower Reference and Upper Reference cases. 5 figs., 30 tabs.

  6. The nuclear symmetry energy

    NASA Astrophysics Data System (ADS)

    Baldo, M.; Burgio, G. F.

    2016-11-01

    The nuclear symmetry energy characterizes the variation of the binding energy as the neutron to proton ratio of a nuclear system is varied. This is one of the most important features of nuclear physics in general, since it is just related to the two component nature of the nuclear systems. As such it is one of the most relevant physical parameters that affect the physics of many phenomena and nuclear processes. This review paper presents a survey of the role and relevance of the nuclear symmetry energy in different fields of research and of the accuracy of its determination from the phenomenology and from the microscopic many-body theory. In recent years, a great interest was devoted not only to the Nuclear Matter symmetry energy at saturation density but also to its whole density dependence, which is an essential ingredient for our understanding of many phenomena. We analyze the nuclear symmetry energy in different realms of nuclear physics and astrophysics. In particular we consider the nuclear symmetry energy in relation to nuclear structure, astrophysics of Neutron Stars and supernovae, and heavy ion collision experiments, trying to elucidate the connections of these different fields on the basis of the symmetry energy peculiarities. The interplay between experimental and observational data and theoretical developments is stressed. The expected future developments and improvements are schematically addressed, together with most demanded experimental and theoretical advances for the next few years.

  7. Thermodynamics of nuclear transport

    NASA Astrophysics Data System (ADS)

    Wang, Ching-Hao; Mehta, Pankaj; Elbaum, Michael

    Molecular transport across the nuclear envelope is important for eukaryotes for gene expression and signaling. Experimental studies have revealed that nuclear transport is inherently a nonequilibrium process and actively consumes energy. In this work we present a thermodynamics theory of nuclear transport for a major class of nuclear transporters that are mediated by the small GTPase Ran. We identify the molecular elements responsible for powering nuclear transport, which we term the ``Ran battery'' and find that the efficiency of transport, measured by the cargo nuclear localization ratio, is limited by competition between cargo molecules and RanGTP to bind transport receptors, as well as the amount of NTF2 (i.e. RanGDP carrier) available to circulate the energy flow. This picture complements our current understanding of nuclear transport by providing a comprehensive thermodynamics framework to decipher the underlying biochemical machinery. Pm and CHW were supported by a Simons Investigator in the Mathematical Modeling in Living Systems grant (to PM).

  8. Tuning tetranuclear manganese-oxo core electronic properties: adamantane-shaped complexes synthesized by ligand exchange.

    PubMed

    Dubé, Christopher E; Mukhopadhyay, Sumitra; Bonitatebus, Peter J; Staples, Richard J; Armstrong, William H

    2005-07-11

    A series of adamantane-shaped [Mn4O6]4+ aggregates has been prepared. Ligand substitution reactions of [Mn4O6(bpea)4](ClO4)4 (1) with tridentate amine and iminodicarboxylate ligands in acetonitrile affords derivative clusters [Mn4O6(tacn)4](ClO4)4 (4), [Mn4O6(bpea)2(dien)2](ClO4)4)(5), [Mn4O6(Medien)4](ClO4)4 (6), [Mn4O6(tach)4](ClO4)4 (7), [Mn4O6(bpea)2(me-ida)2] (8), [Mn4O6(bpea)2(bz-ida)2] (9), [Mn4O6(bpea)2((t)bu-ida)2] (10), and [Mn4O6(bpea)2((c)pent-ida)2] (11) generally on the order of 10 min with retention of core nuclearity and oxidation state. Of these complexes, only 4 had been synthesized previously. Characterization of two members of this series by X-ray crystallography reveals that compound 7 crystallizes as [Mn4O6(tach)4](ClO4)4 x 3CH3CN x 4.5H2O in the cubic space group Fmm and compound 11 crystallizes as [Mn4O6(bpea)2((c)pent-ida)2].7MeOH in the monoclinic space group C2/c. The unique substitution chemistry of 1 with iminodicarboxylate ligands afforded asymmetrically ligated complexes 8-11, the mixed ligand nature of which is most likely unachievable using self-assembly synthetic methods. A special feature of the iminodicarboxylate ligand complexes 8-11 is the substantial site differentiation of the oxo bridges of the [Mn4O6]4+ cores. While there are four site-differentiated oxo bridges in 8, the solution structural symmetry of 8H+ reveals essentially a single protonation isomer, in contrast to the observation of two protonation isomers for 1H+, one for each of the site-differentiated oxo bridges in 1. Magnetic susceptibility measurements on 4, 7, 8, and 9 indicate that each complex is overall ferromagnetically coupled, and variable-field magnetization data for 7 and 9 are consistent with an S = 6 ground state. Electrochemical analysis demonstrates that ligand substitution of bpea affords accessibility to the Mn(V)(Mn(IV))3 oxidation state.

  9. Does the ligand-biopolymer equilibrium binding constant depend on the number of bound ligands?

    PubMed

    Beshnova, Daria A; Lantushenko, Anastasia O; Evstigneev, Maxim P

    2010-11-01

    Conventional methods, such as Scatchard or McGhee-von Hippel analyses, used to treat ligand-biopolymer interactions, indirectly make the assumption that the microscopic binding constant is independent of the number of ligands, i, already bound to the biopolymer. Recent results on the aggregation of aromatic molecules (Beshnova et al., J Chem Phys 2009, 130, 165105) indicated that the equilibrium constant of self-association depends intrinsically on the number of molecules in an aggregate due to loss of translational and rotational degrees of freedom on formation of the complex. The influence of these factors on the equilibrium binding constant for ligand-biopolymer complexation was analyzed in this work. It was shown that under the conditions of binding of "small" molecules, these factors can effectively be ignored and, hence, do not provide any hidden systematic error in such widely-used approaches, such as the Scatchard or McGhee-von Hippel methods for analyzing ligand-biopolymer complexation. © 2010 Wiley Periodicals, Inc. Biopolymers 93: 932-935, 2010.

  10. SuperLigands – a database of ligand structures derived from the Protein Data Bank

    PubMed Central

    Michalsky, Elke; Dunkel, Mathias; Goede, Andrean; Preissner, Robert

    2005-01-01

    Background Currently, the PDB contains approximately 29,000 protein structures comprising over 70,000 experimentally determined three-dimensional structures of over 5,000 different low molecular weight compounds. Information about these PDB ligands can be very helpful in the field of molecular modelling and prediction, particularly for the prediction of protein binding sites and function. Description Here we present an Internet accessible database delivering PDB ligands in the MDL Mol file format which, in contrast to the PDB format, includes information about bond types. Structural similarity of the compounds can be detected by calculation of Tanimoto coefficients and by three-dimensional superposition. Topological similarity of PDB ligands to known drugs can be assessed via Tanimoto coefficients. Conclusion SuperLigands supplements the set of existing resources of information about small molecules bound to PDB structures. Allowing for three-dimensional comparison of the compounds as a novel feature, this database represents a valuable means of analysis and prediction in the field of biological and medical research. PMID:15943884

  11. DNA-ligand interactions gained and lost: light-induced ligand redistribution in a supramolecular cascade.

    PubMed

    Berdnikova, Daria V; Aliyeu, Tseimur M; Paululat, Thomas; Fedorov, Yuri V; Fedorova, Olga A; Ihmels, Heiko

    2015-03-21

    A supramolecular five-component cascade is presented that enables light-controlled transport of an in situ modified ligand between three host systems based on the different complexation preferences of cyclodextrin, cucurbituril, and double-stranded DNA. The results point out novel approaches for the control of drug-DNA interactions in DNA-targeting therapy.

  12. Application of an in silico liver model to determine nuclear receptor mediated pathways in liver cancer

    EPA Science Inventory

    Nuclear receptors (NRs) are ligand-activated transcription factors that control diverse cellular processes. Chronic stimulation of some NRs in rodents can result in increased incidence of liver tumors. These are generally thought to develop through a non-genotoxic mechanism with...

  13. Elevated NCOR1 disrupts a network of dietary-sensing nuclear receptors in bladder cancer cells

    PubMed Central

    Abedin, S. Asad; Thorne, James L.; Battaglia, Sebastiano; Maguire, Orla; Hornung, Laura B.; Doherty, Alan P.; Mills, Ian G.; Campbell, Moray J.

    2009-01-01

    Increasingly invasive bladder cancer cells lines displayed insensitivity toward a panel of dietary-derived ligands for members of the nuclear receptor superfamily. Insensitivity was defined through altered gene regulatory actions and cell proliferation and reflected both reduced receptor expression and elevated nuclear receptor corepressor 1 (NCOR1) expression. Stable overexpression of NCOR1 in sensitive cells (RT4) resulted in a panel of clones that recapitulated the resistant phenotype in terms of gene regulatory actions and proliferative responses toward ligand. Similarly, silencing RNA approaches to NCOR1 in resistant cells (EJ28) enhanced ligand gene regulatory and proliferation responses, including those mediated by peroxisome proliferator-activated receptor (PPAR) γ and vitamin D receptor (VDR) receptors. Elevated NCOR1 levels generate an epigenetic lesion to target in resistant cells using the histone deacetylase inhibitor vorinostat, in combination with nuclear receptor ligands. Such treatments revealed strong-additive interactions toward the PPARγ, VDR and Farnesoid X-activated receptors. Genome-wide microarray and microfluidic quantitative real-time, reverse transcription–polymerase chain reaction approaches, following the targeting of NCOR1 activity and expression, revealed the selective capacity of this corepressor to govern common transcriptional events of underlying networks. Combined these findings suggest that NCOR1 is a selective regulator of nuclear receptors, notably PPARγ and VDR, and contributes to their loss of sensitivity. Combinations of epigenetic therapies that target NCOR1 may prove effective, even when receptor expression is reduced. PMID:19126649

  14. Oxysterols are agonist ligands of RORγt and drive Th17 cell differentiation

    PubMed Central

    Soroosh, Pejman; Wu, Jiejun; Xue, Xiaohua; Song, Jiao; Sutton, Steven W.; Sablad, Marciano; Yu, Jingxue; Nelen, Marina I.; Liu, Xuejun; Castro, Glenda; Luna, Rosa; Crawford, Shelby; Banie, Homayon; Dandridge, Rose A.; Deng, Xiaohu; Bittner, Anton; Kuei, Chester; Tootoonchi, Mandana; Rozenkrants, Natasha; Herman, Krystal; Gao, Jingjin; Yang, Xia V.; Sachen, Kacey; Ngo, Karen; Fung-Leung, Wai-Ping; Nguyen, Steven; de Leon-Tabaldo, Aimee; Blevitt, Jonathan; Zhang, Yan; Cummings, Maxwell D.; Rao, Tadimeti; Mani, Neelakandha S.; Liu, Changlu; McKinnon, Murray; Milla, Marcos E.; Fourie, Anne M.; Sun, Siquan

    2014-01-01

    The RAR-related orphan receptor gamma t (RORγt) is a nuclear receptor required for generating IL-17–producing CD4+ Th17 T cells, which are essential in host defense and may play key pathogenic roles in autoimmune diseases. Oxysterols elicit profound effects on immune and inflammatory responses as well as on cholesterol and lipid metabolism. Here, we describe the identification of several naturally occurring oxysterols as RORγt agonists. The most potent and selective activator for RORγt is 7β, 27-dihydroxycholesterol (7β, 27-OHC). We show that these oxysterols reverse the inhibitory effect of an RORγt antagonist, ursolic acid, in RORγ- or RORγt-dependent cell-based reporter assays. These ligands bind directly to recombinant RORγ ligand binding domain (LBD), promote recruitment of a coactivator peptide, and reduce binding of a corepressor peptide to RORγ LBD. In primary cells, 7β, 27-OHC and 7α, 27-OHC enhance the differentiation of murine and human IL-17–producing Th17 cells in an RORγt-dependent manner. Importantly, we showed that Th17, but not Th1 cells, preferentially produce these two oxysterols. In vivo, administration of 7β, 27-OHC in mice enhanced IL-17 production. Mice deficient in CYP27A1, a key enzyme in generating these oxysterols, showed significant reduction of IL-17–producing cells, including CD4+ and γδ+ T cells, similar to the deficiency observed in RORγt knockout mice. Our results reveal a previously unknown mechanism for selected oxysterols as immune modulators and a direct role for CYP27A1 in generating these RORγt agonist ligands, which we propose as RORγt endogenous ligands, driving both innate and adaptive IL-17–dependent immune responses. PMID:25092323

  15. Phenotypic spandrel: absolute discrimination and ligand antagonism

    NASA Astrophysics Data System (ADS)

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

    2016-12-01

    We consider the general problem of sensitive and specific discrimination between biochemical species. An important instance is immune discrimination between self and not-self, where it is also observed experimentally that ligands just below the discrimination threshold negatively impact response, a phenomenon called antagonism. We characterize mathematically the generic properties of such discrimination, first relating it to biochemical adaptation. Then, based on basic biochemical rules, we establish that, surprisingly, antagonism is a generic consequence of any strictly specific discrimination made independently from ligand concentration. Thus antagonism constitutes a ‘phenotypic spandrel’: a phenotype existing as a necessary by-product of another phenotype. We exhibit a simple analytic model of discrimination displaying antagonism, where antagonism strength is linear in distance from the detection threshold. This contrasts with traditional proofreading based models where antagonism vanishes far from threshold and thus displays an inverted hierarchy of antagonism compared to simpler models. The phenotypic spandrel studied here is expected to structure many decision pathways such as immune detection mediated by TCRs and FCɛRIs, as well as endocrine signalling/disruption.

  16. Molecular modulators of benzodiazepine receptor ligand binding

    SciTech Connect

    Villar, H.O.; Loew, G.H. )

    1989-01-01

    Ten derivatives of {beta}-carbolines with known affinities to the GABA{sub A}/BDZ (benzodiazepine) receptor were studied using the Am 1 and MNDO/H Semiempirical techniques to identify and characterize molecular modulators of receptor recognition. Steric, lipophilic, and electrostatic properties of these compounds were calculated and examined for their possible role in recognition. Particular attention was paid to the regions around the two most favorable proton-accepting sites, the ON and the substituent at the C{sub 3} position, already implicated in recognition, as well as to the acidic N9H group that could be a proton donating center. To probe further the role of these three ligand sites in receptor interactions, a model of the receptor using three methanol molecules was made and optimum interactions of these three sites with them characterized. The results indicate some similarity in the shape of these ligands, which could reflect a steric requirement. The receptor affinity appears to be modulated to some extent by the ratio of lipophilic to hydrophilic surface, the negative potential at the {beta}N, provided there is also one at the C{sub 3} substituent confirming the importance of two accepting sites in recognition. The acidic N9H does not appear to be a modulator of affinity or does it form a stable H-bond with methanol as acceptor. The two proton donating molecules do form such a stable complex, and both are needed for high affinity.

  17. Continuous microfluidic assortment of interactive ligands (CMAIL)

    NASA Astrophysics Data System (ADS)

    Hsiao, Yi-Hsing; Huang, Chao-Yang; Hu, Chih-Yung; Wu, Yen-Yu; Wu, Chung-Hsiun; Hsu, Chia-Hsien; Chen, Chihchen

    2016-08-01

    Finding an interactive ligand-receptor pair is crucial to many applications, including the development of monoclonal antibodies. Biopanning, a commonly used technique for affinity screening, involves a series of washing steps and is lengthy and tedious. Here we present an approach termed continuous microfluidic assortment of interactive ligands, or CMAIL, for the screening and sorting of antigen-binding single-chain variable antibody fragments (scFv) displayed on bacteriophages (phages). Phages carrying native negative charges on their coat proteins were electrophoresed through a hydrogel matrix functionalized with target antigens under two alternating orthogonal electric fields. During the weak horizontal electric field phase, phages were differentially swept laterally depending on their affinity for the antigen, and all phages were electrophoresed down to be collected during the strong vertical electric field phase. Phages of different affinity were spatially separated, allowing the continuous operation. More than 105 CFU (colony forming unit) antigen-interacting phages were isolated with ~100% specificity from a phage library containing 3 × 109 individual members within 40 minutes of sorting using CMAIL. CMAIL is rapid, sensitive, specific, and does not employ washing, elution or magnetic beads. In conclusion, we have developed an efficient and cost-effective method for isolating and sorting affinity reagents involving phage display.

  18. Continuous microfluidic assortment of interactive ligands (CMAIL)

    PubMed Central

    Hsiao, Yi-Hsing; Huang, Chao-Yang; Hu, Chih-Yung; Wu, Yen-Yu; Wu, Chung-Hsiun; Hsu, Chia-Hsien; Chen, Chihchen

    2016-01-01

    Finding an interactive ligand-receptor pair is crucial to many applications, including the development of monoclonal antibodies. Biopanning, a commonly used technique for affinity screening, involves a series of washing steps and is lengthy and tedious. Here we present an approach termed continuous microfluidic assortment of interactive ligands, or CMAIL, for the screening and sorting of antigen-binding single-chain variable antibody fragments (scFv) displayed on bacteriophages (phages). Phages carrying native negative charges on their coat proteins were electrophoresed through a hydrogel matrix functionalized with target antigens under two alternating orthogonal electric fields. During the weak horizontal electric field phase, phages were differentially swept laterally depending on their affinity for the antigen, and all phages were electrophoresed down to be collected during the strong vertical electric field phase. Phages of different affinity were spatially separated, allowing the continuous operation. More than 105 CFU (colony forming unit) antigen-interacting phages were isolated with ~100% specificity from a phage library containing 3 × 109 individual members within 40 minutes of sorting using CMAIL. CMAIL is rapid, sensitive, specific, and does not employ washing, elution or magnetic beads. In conclusion, we have developed an efficient and cost-effective method for isolating and sorting affinity reagents involving phage display. PMID:27578501

  19. NMR structure of the natural killer cell receptor 2B4 (CD244): implications for ligand recognition.

    PubMed

    Ames, James B; Vyas, Vinay; Lusin, Jacqueline D; Mariuzza, Roy

    2005-05-03

    2B4, a transmembrane receptor expressed primarily on natural killer (NK) cells and on a subset of CD8(+) T cells, plays an important role in activating NK-mediated cytotoxicity through its interaction with CD48 on target cells. We report here the atomic-resolution structure of the ligand-binding (D1) domain of 2B4 in solution determined by nuclear magnetic resonance (NMR) spectroscopy. The overall main chain structure resembles an immunoglobulin variable (V) domain fold, very similar to that seen previously for domain 1 of CD2 and CD4. The structure contains nine beta-strands assembled into two beta-sheets conventionally labeled DEB and AGFCC'C' '. The six-stranded sheet (AGFCC'C' ') contains structural features that may have implications for ligand recognition and receptor function. A noncanonical disulfide bridge between Cys2 and Cys99 stabilizes a long and parallel beta-structure between strand A (residues 3-12) and strand G (residues 100-108). A beta-bulge at residues Glu45 and Ile46 places a bend in the middle of strand C' that orients two conserved and adjacent hydrophobic residues (Ile46 and Leu47) inside the beta-sandwich as seen in other V domains. Finally, the FG-loop (implicated in ligand recognition in the CD2-CD58 complex) is dynamically disordered in 2B4 in the absence of a ligand. We propose that ligand binding to 2B4 might stabilize the structure of the FG-loop in the ligand complex.

  20. 75 FR 30078 - Entergy Nuclear Operations, Inc.; Entergy Nuclear Vermont Yankee, LLC; Vermont Yankee Nuclear...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-28

    ... Office of Nuclear Reactor Regulation (NRR). By letter dated May 20, 2010, the Director denied the... From the Federal Register Online via the Government Publishing Office ] NUCLEAR REGULATORY COMMISSION Entergy Nuclear Operations, Inc.; Entergy Nuclear Vermont Yankee, LLC; Vermont Yankee...

  1. Activating Cell Death Ligand Signaling Through Proteasome Inhibition

    DTIC Science & Technology

    2009-05-01

    Activating Cell Death Ligand Signaling Through Proteasome Inhibition PRINCIPAL INVESTIGATOR: Steven R Schwarze...SUBTITLE Activating Cell Death Ligand Signaling Through 5a. CONTRACT NUMBER Proteasome Inhibition 5b. GRANT NUMBER W81XWH-08-1-0392 5c...proteasome inhibition can act as an anti-neoplastic agent in vivo by sensitizing cancer cells to cell death ligands in the tumor microenvironment

  2. Selective high affinity polydentate ligands and methods of making such

    DOEpatents

    DeNardo, Sally; DeNardo, Gerald; Balhorn, Rodney

    2010-02-16

    This invention provides novel polydentate selective high affinity ligands (SHALs) that can be used in a variety of applications in a manner analogous to the use of antibodies. SHALs typically comprise a multiplicity of ligands that each bind different region son the target molecule. The ligands are joined directly or through a linker thereby forming a polydentate moiety that typically binds the target molecule with high selectivity and avidity.

  3. Quasielastic neutron scattering study of POSS ligand dynamics

    SciTech Connect

    Jalarvo, Niina H; Tyagi, Madhusudan; Crawford, Michael

    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.

  4. [Structure and Function of the Nuclear Receptor Constitutive Androstane Receptor].

    PubMed

    Inouye, Yoshio

    2016-01-01

    Animal defense mechanisms against both endogenous and exogenous toxic compounds function mainly through receptor-type transcription factors, including the constitutive androstane receptor (CAR). Following xenobiotic stimulation, CAR translocates into the nucleus and transactivates its target genes including oxygenic and conjugative enzymes and transporters in hepatocytes. We identified subcellular localization signals in the rat CAR: two nuclear localization signals (NLS1 and 2); two nuclear export signals (NES1 and 2); and a cytoplasmic retention region. The nuclear import of CAR is regulated by the importin-Ran system and microtubule network. Five splice variants (SV1-5) were identified in rat liver in addition to wild-type CAR. When expressed in immortalized cells, their artificial transcripts were inactive as transcription factors. A CAR mutant with three consecutive alanine residues inserted into the ligand-binding domain of CAR showed ligand-dependent activation of target genes in immortalized cells, which is in marked contrast to the constitutive transactivating nature of wild-type CAR. Using this assay system, androstenol and clotrimazole, both of which are inverse agonists of CAR, were classified as an antagonist and weak agonist, respectively. A member of the DEAD box DNA/RNA helicase family (DP97) and protein arginine methyltransferase 5 (PRMT5) were found to be gene (or promotor)-specific coactivators of CAR. The expression of the CAR gene might be under the control of clock genes mediated by the nuclear receptor Rev-erb-α.

  5. Two-dimensional (14)N HYSCORE spectroscopy of the coordination geometry of ligands in dimanganese di-μ-oxo mimics of the oxygen evolving complex of photosystem II.

    PubMed

    Chatterjee, Ruchira; Milikisiyants, Sergey; Lakshmi, K V

    2012-05-21

    We use two-dimensional hyperfine sublevel correlation (HYSCORE) spectroscopy to investigate the coordination geometry of the nitrogen ligands of biomimetic models of the oxygen-evolving complex of photosystem II. In the 2D HYSCORE spectroscopy study, [(bpy)2Mn(III)(μ-O)2Mn(IV)(bpy)2](ClO4)3 (bpy, 2,2'-bipyridine) (1) and [H2O(terpy)Mn(III)(μ-O)2Mn(IV)(terpy)OH2](NO3)3 (terpy = 2,2':6',2″-terpyridine) (2) exhibit electron-nuclear hyperfine interactions that depend on both the oxidation state of the manganese ion and the geometry of the nitrogen ligand. We observe four types of (14)N hyperfine interactions corresponding to the Mn(iii) and Mn(iv) ion of each mixed-valence complex and the equatorial and axial geometry of the ligand, respectively. The strongest and the weakest hyperfine interactions arise from the axial and equatorial ligands of the Mn(iii) ion, respectively. The hyperfine interactions of intermediate strength are due to the axial and equatorial ligands of the Mn(iv) ion. Based on the results of this study, we assign the location and ligand geometry of the Mn(iii) ion of the tetranuclear manganese-calcium-oxo cluster in the S2 state of photosystem II.

  6. Mixed Extracellular Matrix Ligands Synergistically Modulate Integrin Adhesion and Signaling

    PubMed Central

    Reyes, Catherine D.; Petrie, Timothy A.; García, Andrés J

    2008-01-01

    Cell adhesion to extracellular matrix (ECM) components through cell-surface integrin receptors is essential to the formation, maintenance and repair of numerous tissues, and therefore represents a central theme in the design of bioactive materials that successfully interface with the body. While the adhesive responses associated with a single ligand have been extensively analyzed, the effects of multiple integrin subtypes binding to multivalent ECM signals remain poorly understood. In the present study, we generated a high throughput platform of non-adhesive surfaces presenting well-defined, independent densities of two integrin-specific engineered ligands for the type I collagen (COL-I) receptor α2β1 and the fibronectin (FN) receptor α5β1 to evaluate the effects of integrin cross-talk on adhesive responses. Engineered surfaces displayed ligand density-dependent adhesive effects, and mixed ligand surfaces significantly enhanced cell adhesion strength and focal adhesion assembly compared to single FN and COL-I ligand surfaces. Moreover, surfaces presenting mixed COL-I/FN ligands synergistically enhanced FAK activation compared to the single ligand substrates. The enhanced adhesive activities of the mixed ligand surfaces also promoted elevated proliferation rates. Our results demonstrate interplay between multivalent ECM ligands in adhesive responses and downstream cellular signaling. PMID:18613064

  7. Superior serum half life of albumin tagged TNF ligands

    SciTech Connect

    Mueller, Nicole; Schneider, Britta; Pfizenmaier, Klaus; Wajant, Harald

    2010-06-11

    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.

  8. Biased ligands: pathway validation for novel GPCR therapeutics.

    PubMed

    Rominger, David H; Cowan, Conrad L; Gowen-MacDonald, William; Violin, Jonathan D

    2014-06-01

    G protein-coupled receptors (GPCRs), in recent years, have been shown to signal via multiple distinct pathways. Furthermore, biased ligands for some receptors can differentially stimulate or inhibit these pathways versus unbiased endogenous ligands or drugs. Biased ligands can be used to gain a deeper understanding of the molecular targets and cellular responses associated with a GPCR, and may be developed into therapeutics with improved efficacy, safety and/or tolerability. Here we review examples and approaches to pathway validation that establish the relevance and therapeutic potential of distinct pathways that can be selectively activated or blocked by biased ligands.

  9. ADAM Proteases: Ligand Processing and Modulation of the Notch Pathway

    PubMed Central

    Zolkiewska, Anna

    2009-01-01

    ADAM metalloproteases play important roles in development and disease. One of the key functions of ADAMs is the proteolytic processing of Notch receptors and their ligands. ADAM-mediated cleavage of Notch represents the first step of the regulated intramembrane proteolysis of the receptor, leading to activation of the Notch pathway. Recent reports indicate that the transmembrane Notch ligands also undergo ADAM-mediated processing in cultured cells and in vivo. The proteolytic processing of Notch ligands modulates the strength and duration of Notch signals, leads to generation of soluble intracellular domains of the ligands, and may support a bi-directional signaling between cells. PMID:18344021

  10. Hysteresis of ligand binding in CNGA2 ion channels

    PubMed Central

    Nache, Vasilica; Eick, Thomas; Schulz, Eckhard; Schmauder, Ralf; Benndorf, Klaus

    2013-01-01

    Tetrameric cyclic nucleotide-gated (CNG) channels mediate receptor potentials in olfaction and vision. The channels are activated by the binding of cyclic nucleotides to a binding domain embedded in the C terminus of each subunit. Here using a fluorescent cGMP derivative (fcGMP), we show for homotetrameric CNGA2 channels that ligand unbinding is ~50 times faster at saturating than at subsaturating fcGMP. Analysis with complex Markovian models reveals two pathways for ligand unbinding; the partially liganded open channel unbinds its ligands from closed states only, whereas the fully liganded channel reaches a different open state from which it unbinds all four ligands rapidly. Consequently, the transition pathways for ligand binding and activation of a fully liganded CNGA2 channel differ from that of ligand unbinding and deactivation, resulting in pronounced hysteresis of the gating mechanism. This concentration-dependent gating mechanism allows the channels to respond to changes in the cyclic nucleotide concentration with different kinetics. PMID:24287615

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

    SciTech Connect

    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.

  12. Dewetting-Controlled Binding of Ligands to Hydrophobic Pockets

    PubMed Central

    Setny, P.; Wang, Z.; Cheng, L.-T.; Li, B.; McCammon, J. A.; Dzubiella, J.

    2010-01-01

    We report on a combined atomistic molecular dynamics simulation and implicit solvent analysis of a generic hydrophobic pocket-ligand (host-guest) system. The approaching ligand induces complex wetting-dewetting transitions in the weakly solvated pocket. The transitions lead to bimodal solvent fluctuations which govern magnitude and range of the pocket-ligand attraction. A recently developed implicit water model, based on the minimization of a geometric functional, captures the sensitive aqueous interface response to the concave-convex pocket-ligand configuration semiquantitatively. PMID:19905832

  13. Design of targeting ligands in medicinal inorganic chemistry.

    PubMed

    Storr, Tim; Thompson, Katherine H; Orvig, Chris

    2006-06-01

    This tutorial review will highlight recent advances in medicinal inorganic chemistry pertaining to the use of multifunctional ligands for enhanced effect. Ligands that adequately bind metal ions and also include specific targeting features are gaining in popularity due to their ability to enhance the efficacy of less complicated metal-based agents. Moving beyond the traditional view of ligands modifying reactivity, stabilizing specific oxidation states, and contributing to substitution inertness, we will discuss recent work involving metal complexes with multifunctional ligands that target specific tissues, membrane receptors, or endogenous molecules, including enzymes.

  14. Ultrafast heme-ligand recombination in truncated hemoglobin HbO from Mycobacterium tuberculosis: A ligand cage

    NASA Astrophysics Data System (ADS)

    Jasaitis, Audrius; Ouellet, Hugues; Lambry, Jean-Christophe; Martin, Jean-Louis; Friedman, Joel M.; Guertin, Michel; Vos, Marten H.

    2012-03-01

    Truncated hemoglobin HbO from Mycobacterium tuberculosis displays very slow exchange of diatomic ligands with its environment. Using femtosecond spectroscopy, we show that upon photoexcitation, ligands rebind with unusual speed and efficiency. Only ˜1% O2 can escape from the heme pocket and less than 1% NO. Most remarkably, CO rebinding occurs for 95%, predominantly in 1.2 ns. The general CO rebinding properties are unexpectedly robust against changes in the interactions with close by aromatic residues Trp88 (G8) and Tyr36 (CD1). Molecular dynamics simulations of the CO complex suggest that interactions of the ligand with structural water molecules as well as its rotational freedom play a role in the high reactivity of the ligand and the heme. The slow exchange of ligands between heme and environment may result from a combination of hindered ligand access to the heme pocket by the network of distal aromatic residues, and low escape probability from the pocket.

  15. LibME-automatic extraction of 3D ligand-binding motifs for mechanistic analysis of protein-ligand recognition.

    PubMed

    He, Wei; Liang, Zhi; Teng, MaiKun; Niu, LiWen

    2016-12-01

    Identifying conserved binding motifs is an efficient way to study protein-ligand recognition. Most 3D binding motifs only contain information from the protein side, and so motifs that combine information from both protein and ligand sides are desired. Here, we propose an algorithm called LibME (Ligand-binding Motif Extractor), which automatically extracts 3D binding motifs composed of the target ligand and surrounding conserved residues. We show that the motifs extracted by LibME for ATP and its analogs are highly similar to well-known motifs reported by previous studies. The superiority of our method to handle flexible ligands was also demonstrated using isocitric acid as an example. Finally, we show that these motifs, together with their visual exhibition, permit better investigating and understanding of protein-ligand recognition process.

  16. British nuclear policymaking

    SciTech Connect

    Bowie, C.J.; Platt, A.

    1984-01-01

    This study analyzes the domestic political, economic, and bureaucratic factors that affect the nuclear policymaking process in Great Britain. Its major conclusion is that, although there have been changes in that process in recent years (notably the current involvement of a segment of the British public in the debate about the deployment of intermediate-range nuclear forces), future British nuclear policymaking will remain much what it has been in the past. Three ideas are central to understanding British thinking on the subject: (1) Britain's long-standing resolve to have her own national nuclear force is largely traceable to her desire to maintain first-rank standing among the nations of the world in spite of loss of empire. (2) Financial considerations have always been important--so much so that they have usually dominated issues of nuclear policy. (3) The executive branch of government dominates the nuclear policymaking process but does not always present a united front. The United States heavily influences British nuclear policy through having supplied Britain since the late 1950s with nuclear data and components of nuclear weapon systems such as Polaris and Trident. The relationship works both ways since the U.S. depends on Britain as a base for deployment of both conventional and nuclear systems.

  17. X-ray absorption fine structure (XAFS) studies of copper (II) mixed ligand complexes having tetramethylethylenediamine as one of the ligands

    NASA Astrophysics Data System (ADS)

    Sharma, Sharad; Joshi, S. K.; Shrivastava, B. D.; Hinge, V. K.; Prasad, J.; Srivastava, K.

    2014-09-01

    X-ray absorption fine structure (XAFS) has been studied at the K-edge of copper in copper(II) mixed ligand complexes, having tetramethylethylenediamine (tmen) as one of the ligands, viz., Cu(tmen)(gly)ClO4, Cu(tmen)(bipy)(ClO4)2 and Cu(tmen)(phen)(ClO4)2. The spectra have been recorded at the dispersive XAFS beamline (BL-8) at the 2.5 GeV INDUS-2 synchrotron, RRCAT, Indore, India. The data obtained has been processed and analyzed using the computer program Athena. It has been observed that K-edge has been found to split in two edges, K and K', in each of the complex. The chemical shift has been utilized to determine the oxidation state of copper in the complexes and also the effective nuclear charge (ENC). The EXAFS data has been analyzed to obtain the bond lengths in the complexes using Levy's, Lytle's and Lytle, Sayers and Stern's (LSS) methods. The first peak in the Fourier transform of the spectra gives the value of first shell phase uncorrected bond length. The results obtained from the Fourier transformation and LSS methods are in good agreement.

  18. Ligand "Brackets" for Ga-Ga Bond.

    PubMed

    Fedushkin, Igor L; Skatova, Alexandra A; Dodonov, Vladimir A; Yang, Xiao-Juan; Chudakova, Valentina A; Piskunov, Alexander V; Demeshko, Serhiy; Baranov, Evgeny V

    2016-09-06

    The reactivity of digallane (dpp-Bian)Ga-Ga(dpp-Bian) (1) (dpp-Bian = 1,2-bis[(2,6-diisopropylphenyl)imino]acenaphthene) toward acenaphthenequinone (AcQ), sulfur dioxide, and azobenzene was investigated. The reaction of 1 with AcQ in 1:1 molar ratio proceeds via two-electron reduction of AcQ to give (dpp-Bian)Ga(μ2-AcQ)Ga(dpp-Bian) (2), in which diolate [AcQ](2-) acts as "bracket" for the Ga-Ga bond. The interaction of 1 with AcQ in 1:2 molar ratio proceeds with an oxidation of the both dpp-Bian ligands as well as of the Ga-Ga bond to give (dpp-Bian)Ga(μ2-AcQ)2Ga(dpp-Bian) (3). At 330 K in toluene complex 2 decomposes to give compounds 3 and 1. The reaction of complex 2 with atmospheric oxygen results in oxidation of a Ga-Ga bond and affords (dpp-Bian)Ga(μ2-AcQ)(μ2-O)Ga(dpp-Bian) (4). The reaction of digallane 1 with SO2 produces, depending on the ratio (1:2 or 1:4), dithionites (dpp-Bian)Ga(μ2-O2S-SO2)Ga(dpp-Bian) (5) and (dpp-Bian)Ga(μ2-O2S-SO2)2Ga(dpp-Bian) (6). In compound 5 the Ga-Ga bond is preserved and supported by dithionite dianionic bracket. In compound 6 the gallium centers are bridged by two dithionite ligands. Both 5 and 6 consist of dpp-Bian radical anionic ligands. Four-electron reduction of azobenzene with 1 mol equiv of digallane 1 leads to complex (dpp-Bian)Ga(μ2-NPh)2Ga(dpp-Bian) (7). Paramagnetic compounds 2-7 were characterized by electron spin resonance spectroscopy, and their molecular structures were established by single-crystal X-ray analysis. Magnetic behavior of compounds 2, 5, and 6 was investigated by superconducting quantum interference device technique in the range of 2-295 K.

  19. Antiestrogen-binding site ligands induce autophagy in myeloma cells that proceeds through alteration of cholesterol metabolism

    PubMed Central

    Sola, Brigitte; Poirot, Marc; de Medina, Philippe; Bustany, Sophie; Marsaud, Véronique; Silvente-Poirot, Sandrine; Renoir, Jack-Michel

    2013-01-01

    Multiple myeloma (MM) is a malignancy characterized by the accumulation of clonal plasma cells in the bone marrow. Despite extensive efforts to design drugs targeting tumoral cells and their microenvironment, MM remains an incurable disease for which new therapeutic strategies are needed. We demonstrated here that antiestrogens (AEs) belonging to selective estrogen receptor modulators family induce a caspase-dependent apoptosis and trigger a protective autophagy. Autophagy was recognized by monodansylcadaverin staining, detection of autophagosomes by electronic microscopy, and detection of the cleaved form of the microtubule-associated protein light chain 3. Moreover, autophagy was inhibited by drugs such as bafilomycin A1 and 3-methyladenosine. Autophagy was mediated by the binding of AEs to a class of receptors called the antiestrogen binding site (AEBS) different from the classical estrogen nuclear receptors. The binding of specific ligands to the AEBS was accompanied by alteration of cholesterol metabolism and in particular accumulation of sterols: zymostenol or desmosterol depending on the ligand. This was due to the inhibition of the cholesterol-5,6-epoxide hydrolase activity borne by the AEBS. We further showed that the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathway mediated autophagy signaling. Moreover, AEBS ligands restored sensitivity to dexamethasone in resistant MM cells. Since we showed previously that AEs arrest MM tumor growth in xenografted mice, we propose that AEBS ligands may have a potent antimyeloma activity alone or in combination with drugs used in clinic. PMID:23978789

  20. Dialkylmethyl-2-(N,N-diisobutyl)acetamidoammonium iodide as a ruthenium selective ligand from nitric acid medium.

    PubMed

    Sharma, Shikha; Ghosh, Sunil K; Sharma, Joti N

    2015-09-15

    A new class of quaternary ammonium iodide based ligands with 2-(N,N-diisobutyl)acetamide as an alkyl appendage have been designed, synthesized and tested for their ability to extract ruthenium selectively from nitric acid medium. The 2-(N,N-diisobutyl)acetamido ammonium iodide with two propyl and a methyl substituents showed best results for the recovery of ruthenium. The optimized concentration of the solvent was found to be 0.2M in 30% isodecyl alcohol/n-dodecane. The stoichiometry of the complex was ascertained by slope analysis method and was found to be 1:1 with respect to ligand L(+)I(-) and Ru(NO)(NO3)3. Ruthenium formed an adduct of structure LRu(NO)(NO3)3 I in the extraction medium. Iodide ion played an important role in the formation of the stable and extractable complex of ruthenium. No extraction was observed when iodide was replaced by nitrate anion in the ligand. The ligand also showed good selectivity for ruthenium in the presence of other metal ions commonly found in nitric acid solutions of nuclear waste.

  1. NMR studies reveal the role of biomembranes in modulating ligand binding and release by intracellular bile acid binding proteins.

    PubMed

    Pedò, Massimo; Löhr, Frank; D'Onofrio, Mariapina; Assfalg, Michael; Dötsch, Volker; Molinari, Henriette

    2009-12-18

    Bile acid molecules are transferred vectorially between basolateral and apical membranes of hepatocytes and enterocytes in the context of the enterohepatic circulation, a process regulating whole body lipid homeostasis. This work addresses the role of the cytosolic lipid binding proteins in the intracellular transfer of bile acids between different membrane compartments. We present nuclear magnetic resonance (NMR) data describing the ternary system composed of the bile acid binding protein, bile acids, and membrane mimetic systems, such as anionic liposomes. This work provides evidence that the investigated liver bile acid binding protein undergoes association with the anionic membrane and binding-induced partial unfolding. The addition of the physiological ligand to the protein-liposome mixture is capable of modulating this interaction, shifting the equilibrium towards the free folded holo protein. An ensemble of NMR titration experiments, based on nitrogen-15 protein and ligand observation, confirm that the membrane and the ligand establish competing binding equilibria, modulating the cytoplasmic permeability of bile acids. These results support a mechanism of ligand binding and release controlled by the onset of a bile salt concentration gradient within the polarized cell. The location of a specific protein region interacting with liposomes is highlighted.

  2. Artificial ligand binding within the HIF2alpha PAS-B domain of the HIF2 transcription factor.

    PubMed

    Scheuermann, Thomas H; Tomchick, Diana R; Machius, Mischa; Guo, Yan; Bruick, Richard K; Gardner, Kevin H

    2009-01-13

    The hypoxia-inducible factor (HIF) basic helix-loop-helix Per-aryl hydrocarbon receptor nuclear translocator (ARNT)-Sim (bHLH-PAS) transcription factors are master regulators of the conserved molecular mechanism by which metazoans sense and respond to reductions in local oxygen concentrations. In humans, HIF is critically important for the sustained growth and metastasis of solid tumors. Here, we describe crystal structures of the heterodimer formed by the C-terminal PAS domains from the HIF2alpha and ARNT subunits of the HIF2 transcription factor, both in the absence and presence of an artificial ligand. Unexpectedly, the HIF2alpha PAS-B domain contains a large internal cavity that accommodates ligands identified from a small-molecule screen. Binding one of these ligands to HIF2alpha PAS-B modulates the affinity of the HIF2alpha:ARNT PAS-B heterodimer in vitro. Given the essential role of PAS domains in forming active HIF heterodimers, these results suggest a presently uncharacterized ligand-mediated mechanism for regulating HIF2 activity in endogenous and clinical settings.

  3. Artificial ligand binding within the HIF2[alpha] PAS-B domain of the HIF2 transcription factor

    SciTech Connect

    Scheuermann, Thomas H.; Tomchick, Diana R.; Machius, Mischa; Guo, Yan; Bruick, Richard K.; Gardner, Kevin H.

    2009-05-12

    The hypoxia-inducible factor (HIF) basic helix-loop-helix Per-aryl hydrocarbon receptor nuclear translocator (ARNT)-Sim (bHLH-PAS) transcription factors are master regulators of the conserved molecular mechanism by which metazoans sense and respond to reductions in local oxygen concentrations. In humans, HIF is critically important for the sustained growth and metastasis of solid tumors. Here, we describe crystal structures of the heterodimer formed by the C-terminal PAS domains from the HIF2{alpha} and ARNT subunits of the HIF2 transcription factor, both in the absence and presence of an artificial ligand. Unexpectedly, the HIF2{alpha} PAS-B domain contains a large internal cavity that accommodates ligands identified from a small-molecule screen. Binding one of these ligands to HIF2{alpha} PAS-B modulates the affinity of the HIF2{alpha}:ARNT PAS-B heterodimer in vitro. Given the essential role of PAS domains in forming active HIF heterodimers, these results suggest a presently uncharacterized ligand-mediated mechanism for regulating HIF2 activity in endogenous and clinical settings.

  4. [Effect of ligand concentration on the precision of determining the parameters of ligand-receptor interaction by serial dilution methods].

    PubMed

    Bobrovnik, S A

    2004-01-01

    Earlier we suggested the method of serial dilution, which allows one to determine the parameters of ligand-receptor interaction even if the reactants are in a mixture and their concentrations are unknown. The method is especially useful if the liability of studied receptor does not allow its separation from corresponding ligand. The important prerequisite of the method's precision is that the concentration of the ligand should be sufficiently high comparing to the concentration of the receptor. In the present paper it was demonstrated that the method allows one to obtain sufficiently good precision even in the case when the concentration of the ligand is only one tenth of the receptor concentration.

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

    PubMed

    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.

  6. Interaction between alkaline earth cations and oxo ligands: a DFT study of the affinity of Mg2+ for carbonyl ligands.

    PubMed

    Moreira da Costa, Leonardo; Stoyanov, Stanislav R; Walkimar de M Carneiro, José

    2012-09-01

    The affinities of Mg(2+) for various substituted carbonyl ligands were determined at the DFT (B3LYP/6-31+G(d)) and semi-empirical (PM6) levels of theory. Two sets of carbonyl ligands were studied: monosubstituted [aldehydes R-CHO and RPh-CHO] and homodisubstituted [ketones R(2)C=O and (RPh)(2)C=O], where R = NH(2), OCH(3), OH, CH(3), H, F, Cl, Br, CN, or NO(2)). In the (RPh)(2)CO case, the R group was bonded to the para position of a phenyl ring. The enthalpies of interaction between the ligands and a pentaaquomagnesium(II) complex were calculated to determine the affinity of each ligand for the Mg(2+) cation and to correlate with geometrical and electronic parameters. These parameters exhibited the same trends for all of the ligands studied, showing that the affinity of Mg(2+) for electron-donating ligands is higher than its affinity for electron-withdrawing ligands. In the complexes, electron-donating groups increase both the electrostatic and the covalent components of the Mg-ligand interaction. This behavior correlates with the Mg-O(carbonyl) distance and the ligand electron-donor strength.

  7. Economics of nuclear power.

    PubMed

    Rossin, A D; Rieck, T A

    1978-08-18

    With 12 percent of U.S. electricity now being supplied by nuclear power, Commonwealth Edison has found nuclear plants to be good investments relative to other base load energy sources. The country's largest user of nuclear power, Commonwealth Edison, estimates that its commitment to nuclear saved its customers about 10 percent on their electric bills in 1977, compared to the cost with the next best alternative, coal. This advantage is seen as continuing, contrary to criticisms of the economics and reliability of nuclear power and claims that it has hidden subsidies. It is concluded that there is a need for both nuclear and coal and that government policy precluding or restricting either would be unwise.

  8. Nuclear Science References Database

    SciTech Connect

    Pritychenko, B.; Běták, E.; Singh, B.; Totans, J.

    2014-06-15

    The Nuclear Science References (NSR) database together with its associated Web interface, is the world's only comprehensive source of easily accessible low- and intermediate-energy nuclear physics bibliographic information for more than 210,000 articles since the beginning of nuclear science. The weekly-updated NSR database provides essential support for nuclear data evaluation, compilation and research activities. The principles of the database and Web application development and maintenance are described. Examples of nuclear structure, reaction and decay applications are specifically included. The complete NSR database is freely available at the websites of the National Nuclear Data Center (http://www.nndc.bnl.gov/nsr) and the International Atomic Energy Agency (http://www-nds.iaea.org/nsr)

  9. Nuclear hormone receptor functions in keratinocyte and melanocyte homeostasis, epidermal carcinogenesis and melanomagenesis

    PubMed Central

    Hyter, Stephen; Indra, Arup K

    2013-01-01

    Skin homeostasis is maintained, in part, through regulation of gene expression orchestrated by type II nuclear hormone receptors in a cell and context specific manner. This group of transcriptional regulators is implicated in various cellular processes including epidermal proliferation, differentiation, permeability barrier formation, follicular cycling and inflammatory responses. Endogenous ligands for the receptors regulate actions during skin development and maintenance of tissue homeostasis. Type II nuclear receptor signaling is also important for cellular crosstalk between multiple cell types in the skin. Overall, these nuclear receptors are critical players in keratinocyte and melanocyte biology and present targets for cutaneous disease management. PMID:23395795

  10. Absolute nuclear material assay

    DOEpatents

    Prasad, Manoj K [Pleasanton, CA; Snyderman, Neal J [Berkeley, CA; Rowland, Mark S [Alamo, CA

    2012-05-15

    A method of absolute nuclear material assay of an unknown source comprising counting neutrons from the unknown source and providing an absolute nuclear material assay utilizing a model to optimally compare to the measured count distributions. In one embodiment, the step of providing an absolute nuclear material assay comprises utilizing a random sampling of analytically computed fission chain distributions to generate a continuous time-evolving sequence of event-counts by spreading the fission chain distribution in time.

  11. Absolute nuclear material assay

    DOEpatents

    Prasad, Manoj K.; Snyderman, Neal J.; Rowland, Mark S.

    2010-07-13

    A method of absolute nuclear material assay of an unknown source comprising counting neutrons from the unknown source and providing an absolute nuclear material assay utilizing a model to optimally compare to the measured count distributions. In one embodiment, the step of providing an absolute nuclear material assay comprises utilizing a random sampling of analytically computed fission chain distributions to generate a continuous time-evolving sequence of event-counts by spreading the fission chain distribution in time.

  12. Nuclear Fabrication Consortium

    SciTech Connect

    Levesque, Stephen

    2013-04-05

    This report summarizes the activities undertaken by EWI while under contract from the Department of Energy (DOE) Office of Nuclear Energy (NE) for the management and operation of the Nuclear Fabrication Consortium (NFC). The NFC was established by EWI to independently develop, evaluate, and deploy fabrication approaches and data that support the re-establishment of the U.S. nuclear industry: ensuring that the supply chain will be competitive on a global stage, enabling more cost-effective and reliable nuclear power in a carbon constrained environment. The NFC provided a forum for member original equipment manufactures (OEM), fabricators, manufacturers, and materials suppliers to effectively engage with each other and rebuild the capacity of this supply chain by : Identifying and removing impediments to the implementation of new construction and fabrication techniques and approaches for nuclear equipment, including system components and nuclear plants. Providing and facilitating detailed scientific-based studies on new approaches and technologies that will have positive impacts on the cost of building of nuclear plants. Analyzing and disseminating information about future nuclear fabrication technologies and how they could impact the North American and the International Nuclear Marketplace. Facilitating dialog and initiate alignment among fabricators, owners, trade associations, and government agencies. Supporting industry in helping to create a larger qualified nuclear supplier network. Acting as an unbiased technology resource to evaluate, develop, and demonstrate new manufacturing technologies. Creating welder and inspector training programs to help enable the necessary workforce for the upcoming construction work. Serving as a focal point for technology, policy, and politically interested parties to share ideas and concepts associated with fabrication across the nuclear industry. The report the objectives and summaries of the Nuclear Fabrication Consortium

  13. Pakistans Nuclear Weapons

    DTIC Science & Technology

    2016-02-12

    2004 revelations about a procurement network run by former Pakistani nuclear official A. Q. Khan, Islamabad has taken a number of steps to improve ...strengthened export control laws, improved personnel security, and international nuclear security cooperation programs, have improved Pakistan’s...context where these broader tensions and conflicts are present. 1 Pakistani efforts to improve the security of its nuclear weapons have been ongoing

  14. Nuclear Proliferation Challenges

    SciTech Connect

    Professor William Potter

    2005-11-28

    William C. Potter, Director of the Center for Non Proliferation Studies and the Center for Russian and Eurasian Studies at the Monterey Institute of International Studies, will present nuclear proliferation challenges following the 2005 Nuclear Non-Proliferation Treaty (NPT) Review Conference. In addition to elucidating reasons for, and implications of, the conference’s failure, Dr. Potter will discuss common ground between nuclear proliferation and terrorism issues and whether corrective action can be taken.

  15. Nuclear imaging in pediatrics

    SciTech Connect

    Siddiqui, A.R.

    1985-01-01

    The author's intent is to familiarize practicing radiologists with the technical aspects and interpretation of nuclear medicine procedures in children and to illustrate the indications for nuclear medicine procedures in pediatric problems. Pediatric doses, dosimetry, sedation, and injection techniques, organ systems, oncology and infection, testicular scanning and nuclear crystography, pediatric endocrine and skeletal systems, ventilation and perfusion imaging of both congenital and acquired pediatric disorders, cardiovascular problems, gastrointestinal, hepatobiliary, reticuloendothelial studies, and central nervous system are all topics which are included and discussed.

  16. Nuclear Politics in Iran

    DTIC Science & Technology

    2010-05-01

    system. States with prestige are recognized by other actors as having a high 21 Nuclear Politics in Iran standing either generally or with regard to...Nuclear Politics in Iran Edited by Judith S. Yaphe MIDDLE EAST STRATEGIC PERSPECTIVES 1 Center for Strategic Research Institute for National...OMB control number. 1. REPORT DATE MAY 2010 2. REPORT TYPE 3. DATES COVERED 00-00-2010 to 00-00-2010 4. TITLE AND SUBTITLE Nuclear Politics in

  17. Nonstrategic Nuclear Weapons

    DTIC Science & Technology

    2014-01-03

    William Potter , and Nikolai Sokov, Reducing and Regulating Tactical (Nonstrategic) Nuclear Weapons in Europe, The James Martin Center For...See William C. Potter and Nikolai Sokov, “Nuclear Weapons that People Forget,” International Herald Tribune, May 31, 2000. 87 Sam Nunn, Igor...their security.97 94 Kent Harris , “NATO Allies Want U.S. Nuclear Weapons out of Europe

  18. Early development of sigma-receptor ligands.

    PubMed

    Narayanan, Sanju; Bhat, Rohit; Mesangeau, Christophe; Poupaert, Jacques H; McCurdy, Christopher R

    2011-01-01

    Sigma receptors (σ-1 and σ-2) are non-opioid proteins implicated in the pathophysiology of various neurological disorders and cancer. The σ-1 subtype is a chaperon protein widely distributed in the CNS and peripheral tissues. These receptors are involved in the modulation of K(+)- and Ca(2+)-dependent signaling cascades at the endoplasmic reticulum and modulation of neurotransmitter release. σ-1 receptors are emerging targets for the treatment of neurophychiatric diseases (schizophrenia and depression) and cocaine addiction. σ-2 receptors are lipid raft proteins. They are highly expressed on many tumor cells and hence considered potential targets for anticancer drugs. σ receptors bind to a diverse class of pharmacological compounds like cocaine, methamphetamine, benzomorphans like (±)-pentazocine, (±)-SKF-10,047 and endogenous neurosteroids and sphingolipids. In this review we focus on the early development of σ receptor-specific ligands and radiolabeling agents.

  19. Phosphinothiolates as ligands for polyhydrido copper nanoclusters.

    PubMed

    Huertos, Miguel A; Cano, Israel; Bandeira, Nuno A G; Benet-Buchholz, Jordi; Bo, Carles; van Leeuwen, Piet W N M

    2014-12-01

    The reaction of [CuI(HSC6 H4 PPh2 )]2 with NaBH4 in CH2 Cl2 /EtOH led to air- and moisture-stable copper hydride nanoparticles (CuNPs) containing phosphinothiolates as new ligands, one of which was isolated by crystallization. The X-ray crystal structure of [Cu18 H7 L10 I] (L=(-) S(C6 H4 )PPh2 ) shows unprecedented features in its 28-atom framework (18 Cu and 10 S atoms). Seven hydrogen atoms, in hydride form, are needed for charge balance and were located by density functional theory methods. H2 was released from the copper hydride nanoparticles by thermolysis and visible light irradiation.

  20. Rational design of class I MHC ligands

    NASA Astrophysics Data System (ADS)

    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.

  1. Ligand interactions with galactose oxidase: mechanistic insights.

    PubMed Central

    Whittaker, M M; Whittaker, J W

    1993-01-01

    Interactions between galactose oxidase and small molecules have been explored using a combination of optical absorption, circular dichroism, and electron paramagnetic resonance (EPR) spectroscopies to detect complex formation and characterize the products. Anions bind directly to the cupric center in both active and inactive galactose oxidase, converting to complexes with optical and EPR spectra that are distinctly different from those of the starting aquo enzyme. Azide binding is coupled to stoichiometric proton uptake by the enzyme, reflecting the generation of a strong base (pKa > 9) in the active site anion adduct. At low temperature, the aquo enzyme converts to a form that exhibits the characteristic optical and EPR spectra of an anion complex, apparently reflecting deprotonation of the coordinated water. Anion binding results in a loss of the optical transition arising from coordinated tyrosine, implying displacement of the axial tyrosine ligand on forming the adduct. Nitric oxide binds to galactose oxidase, forming a specific complex exhibiting an unusual EPR spectrum with all g values below 2. The absence of Cu splitting in this spectrum and the observation that the cupric EPR signal from the active site metal ion is not significantly decreased in the complex suggest a nonmetal interaction site for NO in galactose oxidase. These results have been interpreted in terms of a mechanistic scheme where substrate binding displaces a tyrosinate ligand from the active site cupric ion, generating a base that may serve to deprotonate the coordinated hydroxyl group of the substrate, activating it for oxidation. The protein-NO interactions may probe a nonmetal O2 binding site in this enzyme. PMID:8386015

  2. Do organic ligands affect calcite dissolution rates?

    NASA Astrophysics Data System (ADS)

    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 <0.05 mol/kg of these organic anions changes calcite dissolution rates by less than a factor of 2.5 with the exception of citrate and EDTA 4-. The presence of 0.05 mol/kg citrate and EDTA 4- increases calcite dissolution rates by as much as a factor of 35 and 500, respectively, compared to rates in organic anion-free solutions. Further calcite dissolution experiments were performed in the presence of organic polymers similar to bacterial exudates, cell exopolysaccharides, and analogs of microbial cell envelopes: alginate, lichen 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.

  3. Nuclear reactor apparatus

    DOEpatents

    Wade, Elman E.

    1978-01-01

    A lifting, rotating and sealing apparatus for nuclear reactors utilizing rotating plugs above the nuclear reactor core. This apparatus permits rotation of the plugs to provide under the plug refueling of a nuclear core. It also provides a means by which positive top core holddown can be utilized. Both of these operations are accomplished by means of the apparatus lifting the top core holddown structure off the nuclear core while stationary, and maintaining this structure in its elevated position during plug rotation. During both of these operations, the interface between the rotating member and its supporting member is sealingly maintained.

  4. Comprehensive Nuclear Materials

    SciTech Connect

    Konings, Dr. Rudy J. M.; Allen, Todd R.; Stoller, Roger E; Yamanaka, Prof. Shinsuke

    2012-01-01

    This book encompasses a rich seam of current information on the vast and multidisciplinary field of nuclear materials employed in fission and prototype fusion systems. Discussion includes both historical and contemporary international research in nuclear materials, from Actinides to Zirconium alloys, from the worlds leading scientists and engineers. Synthesizes pertinent current science to support the selection, assessment, validation and engineering of materials in extreme nuclear environments. The work discusses the major classes of materials suitable for usage in nuclear fission, fusion reactors and high power accelerators, and for diverse functions in fuels, cladding, moderator and control materials, structural, functional, and waste materials.

  5. [Nuclear families in Turkey].

    PubMed

    Unalan, T

    1988-01-01

    This study examines the household or family types in Turkey in 1983, especially nuclear families. Nuclear families constitute 61.6% of all households in Turkey, and the majority of them are in the West and the Central regions. The highest % of nuclear families was found in the Mediterranean regions, and the lowest in the Black Sea region. Among all nuclear families, 87% of them consist of husband, wife and children, whereas 13% of them have only husband and wife. Nuclear families without children are common in urban areas and in the West while nuclear families with children are mostly found in rural areas and in the East and the Black Sea regions. Nuclear families with 3 or more children constitute 32% of all nuclear households in the West. On the other hand, the corresponding % is 73 for the Eastern region. As a result, it is concluded that nuclear families have significant regional and residential differentiations and households with the same formation in a developed and a less developed region should have different social, economic, and cultural characteristics.

  6. Technologists for Nuclear Medicine

    ERIC Educational Resources Information Center

    Barnett, Huey D.

    1974-01-01

    Physicians need support personnel for work with radioisotopes in diagnosing dangerous diseases. The Nuclear Medicine Technology (NMT) Program at Hillsborough Community College in Tampa, Florida, is described. (MW)

  7. Nuclear criticality safety guide

    SciTech Connect

    Pruvost, N.L.; Paxton, H.C.

    1996-09-01

    This technical reference document cites information related to nuclear criticality safety principles, experience, and practice. The document also provides general guidance for criticality safety personnel and regulators.

  8. How to Compute Labile Metal-Ligand Equilibria

    ERIC Educational Resources Information Center

    de Levie, Robert

    2007-01-01

    The different methods used for computing labile metal-ligand complexes, which are suitable for an iterative computer solution, are illustrated. The ligand function has allowed students to relegate otherwise tedious iterations to a computer, while retaining complete control over what is calculated.

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

    PubMed Central

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

    2016-01-01

    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. Regulation of ligands for the activating receptor NKG2D

    PubMed Central

    Mistry, Anita R; O'Callaghan, Chris A

    2007-01-01

    The outcome of an encounter between a cytotoxic cell and a potential target cell depends on the balance of signals from inhibitory and activating receptors. Natural Killer group 2D (NKG2D) has recently emerged as a major activating receptor on T lymphocytes and natural killer cells. In both humans and mice, multiple different genes encode ligands for NKG2D, and these ligands are non-classical major histocompatibility complex class I molecules. The NKG2D–ligand interaction triggers an activating signal in the cell expressing NKG2D and this promotes cytotoxic lysis of the cell expressing the ligand. Most normal tissues do not express ligands for NKG2D, but ligand expression has been documented in tumour and virus-infected cells, leading to lysis of these cells. Tight regulation of ligand expression is important. If there is inappropriate expression in normal tissues, this will favour autoimmune processes, whilst failure to up-regulate the ligands in pathological conditions would favour cancer development or dissemination of intracellular infection. PMID:17614877

  11. Technetium radiodiagnostic fatty acids derived from bisamide bisthiol ligands

    DOEpatents

    Jones, Alun G.; Lister-James, John; Davison, Alan

    1988-05-24

    A bisamide-bisthiol ligand containing fatty acid substituted thiol useful for producing Tc-labelled radiodiagnostic imaging agents is described. The ligand forms a complex with the radionuclide .sup.99m Tc suitable for administration as a radiopharmaceutical to obtain images of the heart for diagnosis of myocardial disfunction.

  12. Proteome-wide covalent ligand discovery in native biological systems

    PubMed Central

    Backus, Keriann M.; Correia, Bruno E.; Lum, Kenneth M.; Forli, Stefano; Horning, Benjamin D.; González-Páez, Gonzalo E.; Chatterjee, Sandip; Lanning, Bryan R.; Teijaro, John R.; Olson, Arthur J.; Wolan, Dennis W.; Cravatt, Benjamin F.

    2016-01-01

    Small molecules are powerful tools for investigating protein function and can serve as leads for new therapeutics. Most human proteins, however, lack small-molecule ligands, and entire protein classes are considered “undruggable” 1,2. Fragment-based ligand discovery (FBLD) can identify small-molecule probes for proteins that have proven difficult to target using high-throughput screening of complex compound libraries 1,3. Although reversibly binding ligands are commonly pursued, covalent fragments provide an alternative route to small-molecule probes 4–10, including those that can access regions of proteins that are difficult to access through binding affinity alone 5,10,11. In this manuscript, we report a quantitative analysis of cysteine-reactive small-molecule fragments screened against thousands of proteins. Covalent ligands were identified for >700 cysteines found in both druggable proteins and proteins deficient in chemical probes, including transcription factors, adaptor/scaffolding proteins, and uncharacterized proteins. Among the atypical ligand-protein interactions discovered were compounds that react preferentially with pro- (inactive) caspases. We used these ligands to distinguish extrinsic apoptosis pathways in human cell lines versus primary human T-cells, showing that the former is largely mediated by caspase-8 while the latter depends on both caspase-8 and −10. Fragment-based covalent ligand discovery provides a greatly expanded portrait of the ligandable proteome and furnishes compounds that can illuminate protein functions in native biological systems. PMID:27309814

  13. [Peripheral effects of ligands of ORL1 receptors].

    PubMed

    Maslov, L N; Lishmanov, Iu B; Calo, G; Ma, L; Lambert, D G

    2003-01-01

    It has been discussed literature data on the role for ORL1 (NOR) receptors in the regulation of function of gastrointestinal, respiratory, cardiovascular, immune, endocrine systems. In addition, it has been discussed a possibility of penetration of blood brain barrier for ORL1 receptor ligands and species dependence of NOR-ligands' effects.

  14. Multifunctional ligand for use as a diagnostic or therapeutic pharmaceutical

    DOEpatents

    Katti, K.V.; Volkert, W.A.; Ketring, A.R.; Singh, P.R.

    1996-05-14

    A compound and method of making a compound for use as a diagnostic or therapeutic pharmaceutical are revealed. The ligand comprises either a phosphorous or germanium core and at least two hydrazine groups forming a ligand for bonding to a metal extending from the phosphorous or germanium core.

  15. Digestive Ripening of Au Nanoparticles Using Multidentate Ligands.

    PubMed

    Sahu, Puspanjali; Shimpi, Jayesh; Lee, Han Ju; Lee, T Randall; Prasad, Bhagavatula L V

    2017-02-16

    The efficiency of multidentate ligands as digestive ripening (DR) agents for the preparation of monodisperse Au nanoparticles (NPs) was investigated. This systematic investigation was performed using ligands possessing one, two, or three thiol moieties as ligands/DR agents. Our results clearly establish that among the different ligands, monodentate ligands and the use of temperature in the range of 60-120 °C offer the best conditions for DR. In addition, when DR was carried out at lower temperatures (e.g., 60 °C), the NP size increased as the number of thiol groups per ligand increased. However, in the case of ligands possessing two and three thiol moieties, when they were heated with polydispersed particles at higher temperatures (120 or 180 °C), the etching process dominated, which affected the quality of the NPs in terms of their monodispersity. We conclude that the temperature-dependent strength of the interaction between the ligand headgroup and the NP surface plays a vital role in controlling the final particle sizes.

  16. Ligand-modified metal clusters for gas separation and purification

    DOEpatents

    Okrut, Alexander; Ouyang, Xiaoying; Runnebaum, Ron; Gates, Bruce C.; Katz, Alexander

    2017-02-21

    Provided is an organic ligand-bound metal surface that selects one gaseous species over another. The species can be closely sized molecular species having less than 1 Angstrom difference in kinetic diameter. In one embodiment, the species comprise carbon monoxide and ethylene. Such organic ligand-bound metal surfaces can be successfully used in gas phase separations or purifications, sensing, and in catalysis.

  17. Models of protein-ligand crystal structures: trust, but verify

    NASA Astrophysics Data System (ADS)

    Deller, Marc C.; Rupp, Bernhard

    2015-09-01

    X-ray crystallography provides the most accurate models of protein-ligand structures. These models serve as the foundation of many computational methods including structure prediction, molecular modelling, and structure-based drug design. The success of these computational methods ultimately depends on the quality of the underlying protein-ligand models. X-ray crystallography offers the unparalleled advantage of a clear mathematical formalism relating the experimental data to the protein-ligand model. In the case of X-ray crystallography, the primary experimental evidence is the electron density of the molecules forming the crystal. The first step in the generation of an accurate and precise crystallographic model is the interpretation of the electron density of the crystal, typically carried out by construction of an atomic model. The atomic model must then be validated for fit to the experimental electron density and also for agreement with prior expectations of stereochemistry. Stringent validation of protein-ligand models has become possible as a result of the mandatory deposition of primary diffraction data, and many computational tools are now available to aid in the validation process. Validation of protein-ligand complexes has revealed some instances of overenthusiastic interpretation of ligand density. Fundamental concepts and metrics of protein-ligand quality validation are discussed and we highlight software tools to assist in this process. It is essential that end users select high quality protein-ligand models for their computational and biological studies, and we provide an overview of how this can be achieved.

  18. Polymerization catalysts containing electron-withdrawing amide ligands

    DOEpatents

    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.

  19. An agent based model of integrin clustering: Exploring the role of ligand clustering, integrin homo-oligomerization, integrin-ligand affinity, membrane crowdedness and ligand mobility

    NASA Astrophysics Data System (ADS)

    Jamali, Yousef; Jamali, Tahereh; Mofrad, Mohammad R. K.

    2013-07-01

    Integrins are cell-surface protein heterodimers that coordinate cellular responses to mechanochemical cues from the extracellular matrix (ECM) and stimulate the assembly of small adhesion complexes, which are the initial sites of cell-ECM adhesion. Clustering of integrins is known to mediate signaling through a variety of signal transduction pathways. Yet, the molecular mechanisms of integrin clustering are poorly understood. In this paper, we develop computational models, using agent based modeling (ABM) techniques, to explore two key underlying mechanisms of integrin clustering, namely ligand organization and integrin homo-oligomerization. Our models help to shed light on the potential roles ligand clustering and integrin homo-oligomerization may play in controlling integrin clustering. A potential mechanism for the clustering of integrin is discussed and the effects of other parameters such as integrin-ligand affinity, membrane crowdedness and ligand mobility on integrin clustering are examined.

  20. Nanostructured sensors containing immobilized nuclear receptors for thyroid hormone detection.

    PubMed

    Bendo, Luana; Casanova, Monise; Figueira, Ana Carolina M; Polikarpov, Igor; Zucolotto, Valtencir

    2014-05-01

    Thyroid hormone receptors (TRs) are members of the nuclear receptors (NRs) superfamily, being encoded by two genes: TRa and TRbeta. In this paper, the ligand-binding domain (LBD) of the TRbeta1 isoform was immobilized on the surface of nanostructured electrodes for TR detection. The platforms containing TRbeta1-LBD were applied to the detection of specific ligand agonists, including the natural hormones T3 (triiodothyronine) and T4 (thyroxine), and the synthetic agonists TRIAC (3,5,3'-triiodothyroacetic acid) and GC-1 [3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl phenoxy) acetic acid]. Detection was performed via impedance spectroscopy. The biosensors were capable of distinguishing between the thyroid hormones T3 and T4, and/or the analogues TRIAC and GC-1 at concentrations as low as 50 nM. The detection and separation of thyroid hormones and analogue ligands by impedance techniques represents an innovative tool in the field of nanomedicine because it allows the design of inexpensive devices for the rapid and real-time detection of distinct ligand/receptor systems.