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  • 1
    Keywords: Medicine ; Toxicology ; Biochemistry ; Pharmacy ; Biomedicine ; Pharmacology/Toxicology ; Medicinal Chemistry ; Pharmacy ; Springer eBooks
    Description / Table of Contents: Chemical Probe Development Versus Drug Development -- Phosphatase High-Throughput Screening Assay Design and Selection -- Multisystemic Functions of Alkaline Phosphatases -- Robotic Implementation of Assays: Tissue-Nonspecific Alkaline Phosphatase (TNAP) Case Study -- Inhibitors of Tissue-Nonspecific Alkaline Phosphatase (TNAP): From Hits to Leads -- A Method for Direct Assessment of Tissue-Nonspecific Alkaline Phosphatase (TNAP) Inhibitors in Blood Samples -- Isolation and Characteristics of Matrix Vesicles -- The Use of Tissue-Nonspecific Alkaline Phosphatase (TNAP) and PHOSPHO1 Inhibitors to Affect Mineralization by Cultured Cells -- Modulators of Intestinal Alkaline Phosphatase -- New Activity Assays for ENPP1 with Physiological Substrates ATP and ADP -- Structure of Acid Phosphatases -- Purification of Prostatic Acid Phosphatase (PAP) for Structural and Functional Studies -- Protein Tyrosine Phosphatases: Structure, Function, and Implication in Human Disease -- High-Throughput Screening for Protein Tyrosine Phosphatase Activity Modulators -- Evaluating Effects of Tyrosine Phosphatase Inhibitors on T Cell Receptor Signaling -- Interactor-Guided Dephosphorylation by Protein Phosphatase-1 -- Structure, Regulation, and Pharmacological Modulation of PP2A Phosphatases
    Abstract: Driving further the research on mammalian alkaline phosphatase structure and function, Phosphatase Modulators collects expert contributions into one ́€œhow tó€ manual for basic scientists interested in initiating a drug discovery effort. While this book contains the traditional method chapters and some typical reviews on the structure and known functions of phosphatases, other contributions are meant to discuss approaches and alternatives useful in making ́€œgo/no-gó€ decisions in high throughput screening (HTS) and lead optimization campaigns. Many chapters focus on tissue-nonspecific alkaline phosphatase (TNAP) as well as protein phosphatases.℗ Written for the highly successful Methods in Molecular Biology series, chapters in this volume include the kind of detail and key implementation advice that promotes reproducible results. ℗ Step-by-step and practical, Phosphatase Modulators offers a path to understanding many of the facets and complexities associated with undertaking a drug discovery effort and will serve as a roadmap to initiating those efforts
    Pages: X, 315 p. 75 illus., 45 illus. in color. : online resource.
    ISBN: 9781627035620
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  • 2
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary Human placental alkaline phosphatase (PLAP) is a highly polymorphic enzyme. Several common as well as rare allelic forms of PLAP are characterized in this paper in terms of their reactivity with a murine monoclonal antibody (F11). The common type 1 (S) and 3 (I) variants, and the rare type 4 (S2) and 18 (D) variants were found to react with the F11 antibody, so as did three new electrophoretically defined variants (19, 20, and 21). In contrast, the common type 2 (F1) variant and the rare type 8 (F3) and 9 (F2) variants do not react with the F11 antibody. This selective reactivity of F11 has also allowed the identification of two molecular variants of PLAP with identical electrophoretic mobility. These results establish monoclonal antibodies as invaluable adjuncts in the study of PLAP polymorphism.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 0887-624X
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The nucleophilic substitution of the chlorine atoms of poly(vinyl chloride) with sodium thiophenate is assumed to obey an SN2 mechanism with inversion of configuration and a steric control according to which reactivities R of the triads follow the order Rmm 〉 Rmr ≫ Rrr. Such a reaction cannot be described by simple differential equations, but a Monte Carlo simulation, first generating a random Bernouillian chain and then simulating random attack of the chain by the reactant according to the triad reactivities, allows a good agreement with the experimental results of both the kinetics of a reaction carried out in cyclohexanone solution at 40°C and the evolution of the 13C and 1H NMR spectra of the tertiary carbon atoms, assuming the following parameters: Bernouillian probability for a meso placement in the initial chain: 0.431; relative reactivities of the mm, mr and rm, rr triads: 1, 0.5, and 0., respectively. The agreement is excellent until the reaction is about three-quarters complete; this shows a limiting level of about 60% substitution. Better agreement can be obtained up to the limit, if a secondary process of steric control by the substituant in a partially substituted mr triad is assumed. Other possibilities for that secondary process are discussed.
    Additional Material: 21 Ill.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 0887-624X
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Nucleophilic substitution of PVC with sodium thiophenate was carried out in cyclohexanone solution at 5, 25, 40, 60, and 70°C. The initial rate obeys an Arrhenius law from 25 to 60°C, with an activation energy of 70 kJ/mol. Conversion limits are observed which strongly depend on the temperature. The stereoselectivity of the reaction with respect to the configurational triads does not depend on the temperature: the distribution of configurations is only dependent on the conversion. Assuming an SN2 substitution mechanism governed by steric factors, the Monte Carlo simulation procedure described in a prior study is shown to give a good account for all temperatures above 40°C assuming for the mm, mr or rm, and rr triads a reactivity such as Rmm = 2 Rmr and Rrr nil at low temperature and very low at temperatures ≥ 40°C. The low conversion limits observed at 5 and 25°C cannot be explained by a limited accessibility of a part of the polymer. Finally, it is shown that the elimination reaction, which remains limited, does not interfere with the substitution process.
    Additional Material: 8 Ill.
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  • 5
    ISSN: 0887-624X
    Keywords: poly(vinyl chloride) ; interactions ; carbonyl ; local conformations ; tacticity ; stereoselective substitution ; blends ; FT infrared spectroscopy ; Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The molecular interactions of poly(vinylchloride) (PVC) with some solvents [cyclohexanone (CH), methyl ethyl ketone (MEK) and N-methylpirrolidone (MP)], esters [dioctylphthalate (DOP) and butyl stearate (BuSt)], and polyesters [poly(ethylene adipate) (PEA) and poly(ε-caprolactone) (PCL)] have been investigated by FTIR spectroscopy. In all cases the band of the carbonyl group is found to shift to lower frequencies, but significant differences between the solvent and the esters, whether polymeric or not, are evidenced. For PVC-solvent systems, the shift proves to increase linearly as PVC/solvent ratio increases, what suggests that only a definite number of polymer sites is involved. From the slopes of the straight lines this effect of composition is shown to increase in the order MP 〈 MEK 〈 CH, i.e., as the basicity of the solvent decreases. In contrast, for the PVC-esters or polyester blends, a nonlinear behavior consisting of two distinct interaction processes, is obtained. The increase of shift as PVC/ester ratio increases is faster in the first process for all PVC-ester systems and it is particularly enhanced for BuSt and, to a lesser extent, for DOP. Instead, during the second process, that increase is of little significance for BuSt relative to DOP and PCL. These results account for the saturation of the polymer structures that are capable of interacting, at different rates depending on the type of ester. Besides, the whole number of those structures appears to be lower than in the case of solvents.The results are discussed on the ground of, on one side, the mechanism of nucleophilic substitution on PVC, in the same solutions and blends, which, as found previously, is of a stereospecific nature, and, on the other, the electron-donor-acceptor concept (EDA) and the hard-soft-acid-base concept (HSAB) as applied to both the interacting agents (solvents and esters) and the isotactic GTGT and GTTG- triad conformations as well as the heterotactic GTTT. In the light of the resulting conclusions it is suggested that: (i) the linear behavior shown by the solvents obeys the solvent ability to ensure a dynamic equilibrium between the two possible conformations of -mmr- sequence, i.e., GTGTTT and GTTG-TT, through the preferential interaction with the little likely GTTG- conformation, the content of which happens so to be constant as long as there are -mmr- sequences in solution; (ii) the nonlinear behavior of PVC-ester or polyester binary systems reveals a nonequilibrium situation and so the conformational change GTGTTT ⇒ GTTG-TT, which is highly hindered, will occur occasionally depending on the ester nature. This enables one to attribute the fast and the slow interaction processes to the permanent GTTG-TT conformations derived from the polymerization and to the same conformations formed as the result of the conformational changes, respectively.Strong support for the above novel finding that PVC … O=C interaction is of a local conformational nature is given by two additional investigations. First, a similar study with a PVC sample prepared at -50°C, shows that the carbonyl band shifts of CH and PCL are appreciably lower than those of PVC prepared at 70°C. The same holds for the blendof PCL with the latter PVC sample after substitution reaction (0.6%) at -15°C in CH with sodium benzenethiolate (NaBT). Since the PVC obtained at -50°C and the 0.6% substituted polymer exhibit a lower content of both permanent GTTG-TT conformations ad -mmr- sequence, these results agree with expectatins and confirm the above suggestions. Secondly, the changes in the C—Cl stretchign frequencies of PVC with increasing amounts of solvent or ester, as extensively studied, clearly indicate the occurrence of the aforementioned conformational change, and so they are consistent with our proposals as to the actual conformational nature of PVC…O—C interactions. © 1995 John Wiley & Sons, Inc.
    Additional Material: 15 Ill.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1058-8388
    Keywords: Embryogenesis ; Neurogenesis ; Alkaline phosphatase ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The expression pattern of tissue nonspecific alkaline phosphatase (TNAP) in the developing neural tube of mouse is reported. Homogeneous AP activity in the neuroepithelium becomes prominent at E8.5. AT E9.5, distinctly AP-positive cells appear in the brain and spinal cord area. At stages E10.5 to E12.5, AP positivity is observed between the mesencephalon and the rhombencephalon, along the entire spinal cord and cranial nerves emerging from the myelencephalon. At E13.5, strongly AP positive fibers become prominent in the pons. At E14.5, AP expression in brain tissue is considerably reduced and there is a complete absence of AP activity in the nerve cells and glial cells of adult brain. The choroid plexus remains distinctly positive for AP expression until the adult stage. Northern blot analysis and reverse-transcriptase polymerase chain reaction amplification of RNA indicate that this AP activity results from the expression of the Akp-2 locus. This AP expression pattern is distinct from those reported for the expression of GD3, nestin, Hox 2.3, and Wnt-1 during brain development. We conclude that AP is a useful marker of a subpopulation of neuroectodermal cells present in the neural tube as early as E8.5, at which stages there are no other AP positive intraembryonic cells except PGCs. © 1994 Wiley-Liss, Inc.
    Additional Material: 5 Ill.
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  • 7
    ISSN: 1022-1352
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: The space charge distribution of three samples of poly(vinyl chloride) of different isotactic content has been studied by the thermal step technique, with a view to investigating the influence of some defined microstructural features on that important behaviour. It has been observed that the space charge increases substantially as the content of the local tetrad configuration, mmr, at the end of isotactic sequences increases. A first tentative interpretation is given.
    Additional Material: 4 Ill.
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  • 8
    ISSN: 1022-1352
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Notes: The space charge distribution, a basic electrical property of insulating materials, has been studied for a poly(vinyl chloride) (PVC) sample before and after nucleophilic substitution reaction up to various degrees with sodium benzenethiolate (NaBT) in cyclohexanone (CH) solution, so as to modify in a controlled way the content of the isotactic tetrad mmr and the heterotactic pentad rrmr located at the end of isotactic and syndiotactic sequences, respectively. We investigated the influence of mmr and rrmr structures on the number and type of electrical charges accumulated in the material when submitting it to an electrical field. To differentiate between the polarization charges and the trapped charges, coupling of the “thermal step” (TS) and the “thermally stimulated discharge current” (TSDC) techniques was applied. Both types of charges were proved to be related chiefly to the conformations GTTG-TT and GTGTT, having higher free volume and local mobility, characteristic of mmr structure.
    Additional Material: 7 Ill.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1058-8388
    Keywords: Feather pattern formation ; Embryonic skin cultures ; Alkaline phosphatase gene ; Life and Medical Sciences ; Cell & Developmental Biology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Alkaline phosphatase activity is present in the mesoderm of embryonic chick skin and becomes spatially restricted to the dermal condensation of the developing feather germs. Inhibitors to tissue-nonspecific (liver/bone/kidney), but not intestinal, alkaline phosphatase inhibit the establishment and growth of feather germs in cultured skins. A window of maximum sensitivity to the inhibitor was observed to be the first day of culture when early development and establishment of pattern takes place. The cDNA for the avian tissue-nonspecific alkaline phosphatase was cloned and sequenced, and Southern analysis revealed a single copy of this gene in the avian genome. Northern analysis revealed that a 2.8 kb transcript for this form of alkaline phosphatase is present in developing skin. © 1995 wiley-Liss, Inc.
    Additional Material: 7 Ill.
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  • 10
    ISSN: 1022-1336
    Keywords: Chemistry ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology , Physics
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
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