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  • Articles  (8)
  • International Union of Crystallography (IUCr)  (4)
  • The American Society for Pharmacology and Experimental Therapeutics (ASPET)  (4)
  • 1
    Electronic Resource
    Electronic Resource
    Copenhagen : International Union of Crystallography (IUCr)
    Applied crystallography online 31 (1998), S. 820-822 
    ISSN: 1600-5767
    Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001
    Topics: Geosciences , Physics
    Notes: Superscrew dislocations are visible in back-reflection synchrotron white-beam X-ray topographs of basal-cut SiC wafers in striking contrast as black rings surrounding white circles, even though such topographs suffer from extensive harmonic contamination. The contributions to the synchrotron white-beam topograph of each member of its series of harmonic reflections, {\bf g}=(0006n), where n=3 to 16, were calculated. Through intensity considerations and comparison with a {\bf g}=00018 topograph taken with Cu Kα1 radiation, the {\bf g}=00024 harmonic was determined to be the most important contributor. The contrast of features lying deep beneath the crystal's surface was attributed to higher harmonics with larger penetration depths.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Copenhagen : International Union of Crystallography (IUCr)
    Applied crystallography online 34 (2001), S. 20-26 
    ISSN: 1600-5767
    Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001
    Topics: Geosciences , Physics
    Notes: Contrast is associated with micropipes in X-ray topographs of SiC crystals obtained with prismatic reflections, representing an apparent violation of the g·b = 0 invisibility criterion. This is explained as a population of basal-plane dislocations with Burgers vectors of the set b = {\textstyle{1 \over 3}}〈11{\bar{2}}0〉 that occur in a high density within a few micrometers of the micropipes, below the resolution of X-ray topography. These basal-plane dislocations could be observed under an electron microscope. The presence of the surfaces of the micropipes influences the dislocation images in the topographs taken with prismatic reflections, often resulting in a band of light contrast along the axes of the micropipes.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Copenhagen : International Union of Crystallography (IUCr)
    Acta crystallographica 55 (1999), S. 272-275 
    ISSN: 1399-0047
    Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001
    Topics: Chemistry and Pharmacology , Geosciences , Physics
    Notes: RCC1, the regulator of chromosome condensation, is the guanine nucleotide-exchange factor (GEF) of the GTP-binding protein Ran. Its GEF activity on Ran makes it a key element in nucleo-cytoplasmic transport and cell-cycle regulation. Crystals of human RCC1 suitable for X-ray analysis have been obtained using the seeding technique in hanging drops with sodium citrate as a precipitant. The crystals diffract to 1.7 Å at 100 K and belong to the space group P1, with unit-cell parameters a = 49.5, b = 84.3, c = 84.9 Å, α = 113.0, β = 103.9,γ = 103.3°. The Matthews parameter (Vm) and the self-rotation function are consistent with three molecules in the unit cell, which is confirmed by the averaged single isomorphous replacement (SIR) electron-density map.
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  • 4
    Electronic Resource
    Electronic Resource
    Copenhagen : International Union of Crystallography (IUCr)
    Applied crystallography online 32 (1999), S. 516-524 
    ISSN: 1600-5767
    Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001
    Topics: Geosciences , Physics
    Notes: A kinematic (geometrical) diffraction simulation model has been developed to provide understanding of direct dislocation images on synchrotron white-beam X-ray topographs, and has been successfully applied to illustrate the contrast formation mechanisms involved in images of micropipe-related superscrew dislocations in silicon carbide crystals. The coincidence of the simulations with the contrast features of the superscrew dislocation images, recorded using a series of synchrotron topography techniques, shows that this model is capable of revealing the detailed diffraction behavior of the highly distorted region around the dislocation core and determining the quantitative characteristics of the dislocations. The simulation technique is thus demonstrated to be a simple but efficient method for interpretation of synchrotron topographs, and may be applied to explain the topographic contrast characters of general crystal defects.
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  • 5
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    The American Society for Pharmacology and Experimental Therapeutics (ASPET)
    Publication Date: 2012-06-20
    Description: Conopeptides are a diverse group of recently evolved venom peptides used for prey capture and/or defense. Each species of cone snails produces in excess of 1000 conopeptides, with those pharmacologically characterized (~0.1%) targeting a diverse range of membrane proteins typically with high potency and specificity. The majority of conopeptides inhibit voltage- or ligand-gated ion channels, providing valuable research tools for the dissection of the role played by specific ion channels in excitable cells. It is noteworthy that many of these targets are found to be expressed in pain pathways, with several conopeptides having entered the clinic as potential treatments for pain [e.g., pyroglutamate1-MrIA (Xen2174)] and one now marketed for intrathecal treatment of severe pain [ziconotide (Prialt)]. This review discusses the diversity, pharmacology, structure-activity relationships, and therapeutic potential of cone snail venom peptide families acting at voltage-gated ion channels (-, μ-, μO-, -, -, and -conotoxins), ligand-gated ion channels (α-conotoxins, -conotoxin, ikot-ikot, and conantokins), G-protein-coupled receptors (-conopeptides, conopressins, and contulakins), and neurotransmitter transporters (-conopeptides), with expanded discussion on the clinical potential of sodium and calcium channel inhibitors and α-conotoxins. Expanding the discovery of new bioactives using proteomic/transcriptomic approaches combined with high-throughput platforms and better defining conopeptide structure-activity relationships using relevant membrane protein crystal structures are expected to grow the already significant impact conopeptides have had as both research probes and leads to new therapies.
    Print ISSN: 0031-6997
    Electronic ISSN: 1521-0081
    Topics: Chemistry and Pharmacology , Medicine
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  • 6
    Publication Date: 2015-06-21
    Description: Spider venoms are a rich source of ion channel modulators with therapeutic potential. Given the analgesic potential of subtype-selective inhibitors of voltage-gated sodium (Na V ) channels, we screened spider venoms for inhibitors of human Na V 1.7 (hNa V 1.7) using a high-throughput fluorescent assay. Here, we describe the discovery of a novel Na V 1.7 inhibitor, μ -TRTX-Tp1a (Tp1a), isolated from the venom of the Peruvian green-velvet tarantula Thrixopelma pruriens . Recombinant and synthetic forms of this 33-residue peptide preferentially inhibited hNa V 1.7 〉 hNa V 1.6 〉 hNa V 1.2 〉 hNa V 1.1 〉 hNa V 1.3 channels in fluorescent assays. Na V 1.7 inhibition was diminished (IC 50 11.5 nM) and the association rate decreased for the C-terminal acid form of Tp1a compared with the native amidated form (IC 50 2.1 nM), suggesting that the peptide C terminus contributes to its interaction with hNa V 1.7. Tp1a had no effect on human voltage-gated calcium channels or nicotinic acetylcholine receptors at 5 μ M. Unlike most spider toxins that modulate Na V channels, Tp1a inhibited hNa V 1.7 without significantly altering the voltage dependence of activation or inactivation. Tp1a proved to be analgesic by reversing spontaneous pain induced in mice by intraplantar injection in OD1, a scorpion toxin that potentiates hNa V 1.7. The structure of Tp1a as determined using NMR spectroscopy revealed a classic inhibitor cystine knot (ICK) motif. The molecular surface of Tp1a presents a hydrophobic patch surrounded by positively charged residues, with subtle differences from other ICK spider toxins that might contribute to its different pharmacological profile. Tp1a may help guide the development of more selective and potent hNa V 1.7 inhibitors for treatment of chronic pain.
    Print ISSN: 0026-895X
    Electronic ISSN: 1521-0111
    Topics: Chemistry and Pharmacology , Medicine
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  • 7
    Publication Date: 2015-05-01
    Description: The WNT/ β -catenin signaling pathway has been identified as an important endogenous regulator of hepatic cytochrome P450 (P450) expression in mouse liver. In particular, it is involved in the regulation of P450 expression in response to exposure to xenobiotic agonists of the nuclear receptors constitutive androstane receptor (CAR), aryl hydrocarbon receptor (AhR), and Nrf2. To systematically elucidate the effect of the WNT/ β -catenin pathway on the regulation and inducibility of major human P450 enzymes, HepaRG cells were treated with either the WNT/ β -catenin signaling pathway agonist, WNT3a, or with small interfering RNA directed against β -catenin, alone or in combination with a panel of activating ligands for AhR [2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD)], CAR [6-(4-chlorophenyl)imidazo[2,1- b ][1,3]thiazole-5-carbaldehyde- O -(3,4-dichlorobenzyl)oxime (CITCO)], pregnane X receptor (PXR) [rifampicin], and peroxisome proliferator–activated receptor (PPAR) α [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (WY14,643)]. Assessment of P450 gene expression and enzymatic activity after downregulation or activation of the WNT/ β -catenin pathway revealed a requirement of β -catenin in the AhR-, CAR-, and PXR-mediated induction of CYP1A, CYP2B6 and CYP3A4 (for CAR and PXR), and CYP2C8 (for PXR) gene expression. By contrast, activation of the WNT/ β -catenin pathway prevented PPAR α -mediated induction of CYP1A, CYP2C8, CYP3A4, and CYP4A11 genes, suggesting a dominant-negative role of β -catenin in PPAR α -mediated regulation of these genes. Our data indicate a significant effect of the WNT/ β -catenin pathway on the regulation of P450 enzymes in human hepatocytes and reveal a novel crosstalk between β -catenin and PPAR α signaling pathways in the regulation of P450 expression.
    Print ISSN: 0026-895X
    Electronic ISSN: 1521-0111
    Topics: Chemistry and Pharmacology , Medicine
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  • 8
    Publication Date: 2015-10-14
    Description: Enzymatic conversion of most xenobiotic compounds is accomplished by hepatocytes in the liver, which are also an important target for the manifestation of the toxic effects of foreign compounds. Most cell lines derived from hepatocytes lack important toxifying or detoxifying enzymes or are defective in signaling pathways that regulate expression and activity of these enzymes. On the other hand, the use of primary human hepatocytes is complicated by scarce availability of cells and high interdonor variability. Thus, analyses of drug metabolism and hepatotoxicity in vitro are a difficult task. The cell line HC-AFW1 was isolated from a pediatric hepatocellular carcinoma and so far has been used for tumorigenicity and chemotherapy resistance studies. Here, a comprehensive characterization of xenobiotic metabolism in HC-AFW1 cells is presented along with studies on the functionality of the most important transcriptional regulators of drug-metabolizing enzymes. Results from HC-AFW1 cells were compared with commercially available HepaRG cells and cultured primary human hepatocytes. Data show that the nuclear receptors and xenosensors AHR (aryl hydrocarbon receptor), CAR (constitutive androstane receptor), PXR (pregnane-X-receptor), NRF2 [nuclear factor (erythroid-derived 2)–like 2], and PPAR α (peroxisome proliferator–activated receptor α ) are functional in HC-AFW1 cells, comparable to HepaRG and primary cells. HC-AFW1 cells possess considerable activities of different cytochrome P450 enzymes, which, however, are lower than corresponding enzyme activities in HepaRG cells or primary hepatocytes. In summary, HC-AFW1 are a new promising tool for studying the mechanisms of the regulation of drug metabolism in human liver cells in vitro.
    Print ISSN: 0090-9556
    Electronic ISSN: 1521-009X
    Topics: Chemistry and Pharmacology , Medicine
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