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  • 1
    Electronic Resource
    Electronic Resource
    Two domains within the first putative transmembrane domain of presenilin 1 differentially influence presenilinase and γ-secretase activity (2005)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 94 (2005), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Presenilins (PS) are thought to contain the active site for presenilinase endoproteolysis of PS and γ-secretase cleavage of substrates. The structural requirements for PS incorporation into the γ-secretase enzyme complex, complex stability and maturation, and appropriate presenilinase and γ-secretase activity are poorly understood. We used rescue assays to identify sequences in transmembrane domain one (TM1) of PS1 required to support presenilinase and γ-secretase activities. Swap mutations identified an N-terminal TM1 domain that is important for γ-secretase activity only and a C-terminal TM1 domain that is essential for both presenilinase and γ-secretase activities. Exchange of residues 95–98 of PS1 (sw95–98) completely abolishes both activities while the familial Alzheimer's disease mutation V96F significantly inhibits both activities. Reversion of residue 96 back to valine in the sw95–98 mutant rescues PS function, identifying V96 as the critical residue in this region. The TM1 mutants do not bind to an aspartyl protease transition state analog γ-secretase inhibitor, indicating a conformational change induced by the mutations that abrogates catalytic activity. TM1 mutant PS1 molecules retain the ability to interact with γ-secretase substrates and γ-secretase complex members, although Nicastrin stability is decreased by the presence of these mutants. γ-Secretase complexes that contain V96F mutant PS1 molecules display a partial loss of function for γ-secretase that alters the ratio of amyloid-β peptide species produced, leading to the amyloid-β peptide aggregation that causes familial Alzheimer's disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2005.03278.x
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  • 2
    Electronic Resource
    Electronic Resource
    A domain at the C-terminus of PS1 is required for presenilinase and γ-secretase activities (2005)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 92 (2005), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The structural requirements for presenilin (PS) to produce active presenilinase and γ-secretase enzymes are poorly understood. Here we investigate the role the cytoplasmic C-terminal region of PS1 plays in PS1 activity. Deletion or addition of residues at the PS C-terminus has been reported to inhibit presenilinase endoproteolysis of PS and alter γ-secretase activity. In this study, we use a sensitive assay in PS1/2KO MEFs to define a domain at the extreme C-terminus of PS1 that is essential for both presenilinase and γ-secretase activities. Progressive deletion of the C-terminus demonstrated that removal of nine residues produces a PS1 molecule (458ST) that lacks both presenilinase processing and γ-secretase cleavage of Notch and APP substrates. In contrast, removal of four or five residues had no effect (462ST, 463ST), while intermediate truncations partially inhibited PS1 activity. The 458ST mutant was unable to replace endogenous wtPS1 in HEK293 cells. Although 458ST was able to form a γ-secretase complex, this complex was not matured, illustrated by mutant PS1 instability, lack of endoproteolysis, and little production of mature Nicastrin. These data indicate that the C-terminal end of PS1 is essential for Nicastrin trafficking and modification as well as the replacement of endogenous PS1 by PS1 transgenes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2004.02945.x
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  • 3
    Electronic Resource
    Electronic Resource
    Metal Alkoxycarboxylate Complexes. I. Poly[aquabis(methoxyacetato)(nitrato)neodymium(III)] (1998)
    Oxford [u.a.] : International Union of Crystallography (IUCr)
    Acta crystallographica 54 (1998), S. 1588-1590 
    Details
    ISSN: 1600-5759
    Source: Crystallography Journals Online : IUCR Backfile Archive 1948-2001
    Topics: Chemistry and Pharmacology , Geosciences , Physics
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1107/S0108270198006921
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  • 4
    Electronic Resource
    Electronic Resource
    Magneto-optical observation of twisted vortices in type-II superconductors (1997)
    [s.l.] : Nature Publishing Group
    Nature 385 (1997), S. 702-705 
    Details
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] The flux structures were visualized using a magneto-optical technique. This technique was initially used to understand the basic principles of vortex line motion under the Lorentz force (j X B) due to a transport supercurrent j (ref. 11); it has been considerably developed and is now particularly ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/385702a0
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  • 5
    Electronic Resource
    Electronic Resource
    YBa2Cu3O7-δ single crystals revisited: Scanning probe data on very pure samples grown in BaZrO3 crucibles (1998)
    Springer
    Applied physics 66 (1998), S. 1219-1222 
    Details
    ISSN: 1432-0630
    Keywords: PACS: 61.16.Ch; 74.50.+r
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Notes: 2 Cu3O7-δ (YBCO) single crystals grown in BaZrO3 crucibles by scanning and friction force microscopy (SFM, FFM) as well as by scanning tunneling microscopy (STM) and angle resolved X-ray photo-electron spectroscopy (ARXPS). By STM and SFM, clean stepped terraces are observed on as-grown crystals. Friction contrast, however, implies the presence of different materials, presumably traces of flux. After oxidation of the YBCO crystals, particles of 10 to 100 nm in size appear on the surface. Their number per unit area increases with time when the crystal is stored in air. Complementary information on such aged YBCO surfaces is provided by ARXPS. These data reveal 3 nm of mainly BaCO3 and CuO on top of the YBCO matrix and suggest a very slow aging rate of the crystals, which is 20 times slower than for epitaxial thin films. The superconducting energy gap has been determined on fresh crystals by scanning tunneling spectroscopy (STS) at 4.6 K as 2Δ≈30 meV. By spatially resolved tunneling spectroscopy the vortex lattice in a magnetic field of 4 T has been imaged. The inter-vortex distance amounts to 20±2 nm.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/
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  • 6
    Electronic Resource
    Electronic Resource
    Stone algebra extensions with bounded dense sets (1997)
    Springer
    Algebra universalis 37 (1997), S. 1-23 
    Details
    ISSN: 1420-8911
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract. Stone algebras have been characterized by Chen and Grätzer in terms of triples $ (B, D, \varphi) $ , where D is a distributive lattice with 1, B is a Boolean algebra, and $ \varphi $ is a bounded lattice homomorphism from B into the lattice of filters of D. If D is bounded, the construction of these characterizing triples is much simpler, since the homomorphism $ \varphi $ can be replaced by one from B into D itself. The triple construction leads to natural embeddings of a Stone algebra into ones with bounded dense set. These embeddings correspond to a complete sublattice of the distributive lattice of lattice congruences of S. In addition, the largest embedding is a reflector to the subcategory of Stone algebras with bounded dense sets and morphisms preserving the zero of the dense set.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00000326
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  • 7
    Electronic Resource
    Electronic Resource
    In vivo apparent affinity and efficacy estimates for μ opiates in a rat tail-withdrawal assay (1998)
    Springer
    Psychopharmacology 136 (1998), S. 15-23 
    Details
    ISSN: 1432-2072
    Keywords: Key words Etonitazene ; Morphine ; Buprenorphine ; Etorphine ; GPA 1657 ; Affinity ; Efficacy ; Antinociception ; Clocinnamox
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Experiments in a rat tail-withdrawal assay tested the hypothesis that the magnitude and pattern of antagonism of μ opiate agonists by the insurmountable μ opioid antagonist clocinnamox are inversely related to agonist efficacy. In addition, these experiments examined whether this antagonism could be quantified to yield apparent affinity and efficacy estimates for the pharmacological characterization of five opiate agonists. Etonitazene, etorphine, morphine, buprenorphine, and GPA 1657 produced dose-dependent increases in tail-withdrawal latency until 100% maximum possible effect (%MPE) was obtained. Morphine required a higher dose of clocinnamox for a 50% reduction in maximal antinociceptive effect than did buprenorphine or GPA 1657. In contrast, no dose of clocinnamox tested decreased the%MPE for etonitazene or etorphine. These data suggest a rank order of relative efficacy of etonitazene ≥ etorphine 〉 morphine ≥ GPA 1657 ≥ buprenorphine. Similarly, numerical analysis of these data yielded the following apparent affinity and efficacy estimates: etonitazene (0.38 mg/kg, 128); etorphine (0.68 mg/kg, 125); morphine (50 mg/kg, 38), GPA 1657 (6.6, 39); and buprenorphine (0.042 mg/kg, 2.2). These data illustrate that in vivo affinity and efficacy estimates for a number of agonists are remarkably similar across different methods of analysis and are useful for drug classification.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050534
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  • 8
    Electronic Resource
    Electronic Resource
    Tolerance and cross-tolerance to morphine-like stimulus effects of µ opioids in rats (1997)
    Springer
    Psychopharmacology 133 (1997), S. 17-28 
    Details
    ISSN: 1432-2072
    Keywords: Key words Tolerance ; Drug discrimination ; Fentanyl ; Morphine ; Nalbuphine ; Efficacy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The purpose of these experiments was to examine the relationship of agonist relative efficacy to the pattern of tolerance and cross-tolerance to the morphine-like stimulus effects of three opioid agonists. Rats were trained to discriminate 3.2 mg/kg morphine from saline under fixed-ratio 15 schedule of food reinforcement. Morphine, nalbuphine, and fentanyl produced dose-dependent increases in morphine-like stimulus effects and decreases in response rates. Repeated treatment with 20 mg/kg per day morphine increased the ED50 for stimulus control by fentanyl, morphine, or nalbuphine two-, four-, or 40-fold, respectively. Repeated treatment with 64 mg/kg per day nalbuphine increased the ED50 for stimulus control for morphine by two-fold, but lower or higher treatment doses had no significant effect. Treatment with 100 mg/kg per day nalbuphine increased the ED50 for nalbuphine by six-fold. Repeated treatment with 0.22 mg/kg per day fentanyl increased the ED50 for stimulus control by fentanyl or morphine by approximately two-fold. Comparisons among treatment conditions suggested that magnitude of tolerance to morphine-like stimulus effects did not vary as an inverse function of the relative efficacy of the agonist used for repeated treatment. Rather repeated morphine and fentanyl treatments produced comparable tolerance, whereas repeated nalbuphine treatment did not evoke substantial tolerance. Comparisons within treatment conditions, however, suggested that magnitude of tolerance may vary inversely with relative efficacy of the agonist tested for morphine-like stimulus effects. During treatment with morphine or fentanyl, greater tolerance was observed to the morphine-like stimulus effects of the lower efficacy agonist relative to the higher efficacy agonist.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050366
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  • 9
    Electronic Resource
    Electronic Resource
    In vivo apparent pA2 analysis in rats treated with either clocinnamox or morphine (1996)
    Springer
    Psychopharmacology 125 (1996), S. 113-119 
    Details
    ISSN: 1432-2072
    Keywords: Naltrexone ; Nalbuphine ; Clocinnamox ; Morphine ; Tolerance ; Drug discrimination ; pA2 analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Experiments tested the hypothesis that loss of agonist potency or effectiveness following irreversible antagonist or chronic agonist treatment may result from affinity changes at μ opioid receptors. Apparent affinity of naltrexone or nalbuphine for μ opioid receptors was measured in vivo in rats treated with either a single dose of the irreversible antagonist clocinnamox or repeated doses of morphine. Apparent affinity of each antagonist was estimated from its potency as an antagonist of discriminative stimulus or rate-decreasing effects of morphine in rats trained to discriminate 3.2 mg/kg morphine and saline. In control rats, apparent pA2 values for naltrexone and nalbuphine were 7.5–7.6 and 5.3, respectively. In clocinnamox-treated rats, apparent pA2 values for naltrexone were 7.2–7.7, suggesting that clocinnamox treatment did not alter affinity of naltrexone for sites through which morphine exerts behavioral effects. In rats treated repeatedly with morphine, apparent pA2 values for nalbuphine were 5.1–5.3, suggesting that repeated morphine treatment did not alter affinity of nalbuphine for these sites. The observation that neither clocinnamox nor repeated morphine treatment altered in vivo affinity estimates for naltrexone or nalbuphine, respectively, suggests that the reductions in agonist potency produced by these treatments do not result from changes in affinity at μ opioid receptors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02249409
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  • 10
    Electronic Resource
    Electronic Resource
    Naltrexone and β-funaltrexamine antagonism of the antinociceptive and response rate-decreasing effects of morphine, dezocine, and d-propoxyphene (1999)
    Springer
    Psychopharmacology 144 (1999), S. 45-53 
    Details
    ISSN: 1432-2072
    Keywords: Key words Morphine ; β-Funaltrexamine ; Dezocine ; d-Propoxyphene ; Naltrexone ; Efficacy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract   Rationale: Patterns of competitive and insurmountable antagonism provide important data to guide the classification and characterization of different types of opioid agonists as well as infer the mechanism of action for agonists. Objective: Experiments with the competitive antagonist, naltrexone, and the insurmountable antagonist, β-funaltrexamine (β-FNA), were conducted to determine whether the antinociceptive and rate-decreasing effects of the opioid agonists dezocine and d-propoxyphene are 1) mediated through µ opioid receptors in rats, and 2) differ from morphine with respect to relative efficacy. Methods: The rat tail-withdrawal assay was used to measure antinociception and a fixed ratio 20 (FR20) schedule of food delivery was used to measure rate suppression. Results: Naltrexone (0.01–1.0 mg/kg) was approximately equipotent as an antagonist of the antinociceptive and rate-decreasing effects of both morphine and dezocine and as an antagonist of the antinociceptive effects of d-propoxyphene. Naltrexone failed to block the rate-decreasing effects of d-propoxyphene. β-FNA (5 and 10 mg/kg) also antagonized the antinociceptive and rate-decreasing effects of morphine and dezocine as well as the antinociceptive effects of d-propoxyphene. β-FNA failed to produce a dose-dependent antagonism of the rate-decreasing effects of d-propoxyphene. Conclusions: These data suggest that the antinociceptive effects of morphine, dezocine, and d-propoxyphene and the rate-decreasing effects of morphine and dezocine are mediated through µ opioid receptors. Overall, high doses of β-FNA produced a greater degree of antagonism of the behavioral effects of dezocine than morphine or d-propoxyphene, confirming other reports that dezocine is a lower efficacy agonist than morphine. Additionally, the degree of antagonism produced by β-FNA was greater for the antinociceptive effects of all three compounds than for the rate-decreasing effects.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050975
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