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41.
The complete sequence determination of the human genome marks the start of a new era in biological science, with focus shifting from sequencing to functional mechanisms of gene products. In addition to effects on gene expression, most of the currently used therapeutic drugs either have enzymes or membrane proteins as their molecular targets of action. These membrane proteins include ion channels and transporters of small molecules, and receptors that convey signals from one side of a membrane to the other. Membrane proteins are thus involved in a variety of cellular processes and have a large potential as targets for new drug discovery. However, detailed structural information is still lacking for the majority of membrane proteins since their association with membrane constituents make NMR (nuclear magnetic resonance) spectroscopic and X-ray diffraction determinations difficult. Molecular modelling by biocomputing is a methodological alternative for structural studies of membrane proteins, but has to be based on experimental structural information in addition to computational techniques. A combination of bioinformatics and experimental techniques was used to model membrane proteins from two different classes, secondary transporters of the sodium:neurotransmitter symporter family (SNF transporters), and G-protein coupled receptors (GPCRs). The protein models were used to examine ligand-protein interactions and signalling/transport mechanisms, and to design experimental site-directed mutagenesis studies. Such studies have provided new insight into the detailed molecular mechanisms of two important classes of membrane proteins, which may be of value in the discovery and development of new pharmaceuticals. 相似文献
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Factors interfering with the cell morphology in smears 总被引:1,自引:0,他引:1
Factors interfering with the cell morphology in smears were studied. The following artifacts were observed: Lysis of cells with release of granules, cytoplasmic and nuclear proteins; fern-like structures due to detachment of protein from glass; rupture of the surface of smears; crystal formations; leakage from cells interfering with the surrounding medium; cell shrinkage, vacuolization; and aggregation of cells caused by gammaglobulins. The concentration and type of plasma protein in the medium greatly influenced the type of artifacts. The technique by which the least artifacts occurred, was cytocentrifugation of cells suspended in a cell protecting medium. 相似文献
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Franciszek Herold ukasz Izbicki Andrzej Chodkowski Maciej Dawidowski Marek Krl Jerzy Kleps Jadwiga Turo Irena Wolska Gabriel Nowak Katarzyna Stachowicz Magorzata Dybaa Agata Siwek Mateusz Nowak Elbieta Pieniek Magorzata Jaroczyk Ingebrigt Sylte Aleksander P. Mazurek 《European journal of medicinal chemistry》2009,44(11):4702-4715
Derivatives of 4-aryl-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine were synthesized. These compounds contain the 3-(4-piperidyl)-1H-indole residue or its 5-methoxy or 2-methyl derivative. In vitro binding tests were performed to determine the affinity of the compounds for the 5-HT1A receptor and serotonin transporter (SERT) proteins in the rat brain cortex. In vivo studies, particularly the inducible hypothermia test and forced swimming test, were conducted to determine agonistic/antagonistic activity with pre- and postsynaptic 5-HT1A receptors. Molecular modeling techniques were used to determine the binding modes of the selected compounds at the 5-HT1A receptor and SERT. The SAR analysis showed that the presence of the 3-(4-piperidyl)-1H-indole group or its 5-methoxy derivative, as well as a para substitution with –OCH3 or –F in the aryl ring of 4-aryl-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine, results in an increased affinity for both the 5-HT1A receptors and SERT. In contrast, the presence of the 2-methyl-3-(4-piperidyl)-1H-indole group resulted in a considerable decrease in binding affinity. 相似文献
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I Talstad 《Haemostasis》1985,15(5):304-309
Thromboplastins which were highly (Thrombotest) and slightly (Normotest) sensitive to the Pivka (protein induced by vitamin K absence) inhibitor were selected in this study. The influence of the Pivka inhibitor increased with increasing sample size and decreasing packed cell volume; however, a satisfactory correction for the Pivka inhibitor was possible. The inhibitor explained the different coagulation activities in the various assays and also interfered with the ratio method of standardization. 相似文献
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The three-dimensional structures and molecular electrostatic potentials of the cis(Z) and trans(E)-isomers of flupenthixol and clopenthixol were examined by computer graphics and molecular mechanical and quantum mechanical calculations, and their internal molecular motions were studied by molecular dynamics simulations in vacuo and in aqueous solution. The simulations demonstrated that both the side chains and the tricyclic ring systems of clopenthixol and flupenthixol are highly flexible. The angle between the two phenyl ring planes varied between 105 and 171° during the simulations in solution. The electrostatic potentials around the 2-substituent were significantly more negative in the trans(E)-isomers than in the cis(Z)-isomers. The stronger negative potentials may weaken electrostatic receptor interactions and, thereby, cause the trans(E)-isomers to be less active than cis(Z)-isomers. Differences both in three-dimensional structure and in electronic structure may cause the difference in pharmacological activity between cis(Z)- and trans(E)-thioxanthenes. 相似文献
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A Naess I Talstad C O Solberg 《International archives of allergy and applied immunology》1987,83(2):178-181
The increase of T lymphocytes in infectious mononucleosis (IM) is shown to be due to an increase of 'active' (early erythrocyte rosette-forming) T cells: 67.2 +/- 18.3% of IM lymphocytes were 'active' versus 34.7 +/- 14.9% of control lymphocytes. IM was also associated with an increase of lymphocytes demonstrating E receptors at 20 degrees C (E20-R). This phenomenon was not related to the heterophile antibody titre and could not be demonstrated with ox or rabbit erythrocytes. Patients with other lymphoproliferative diseases did not show an increase of E20-R-positive cells or of 'active' erythrocyte rosette-forming cells (E-RFC). Re-rosetting experiments indicated that E20-R and 'active' E-RFC belong to overlapping populations of cells. A double-gradient separation technique was shown to be superior to the conventional Ficoll-Isopaque method for the demonstration of 'active' and total T cells. A high proportion of T lymphocytes were also recovered in the granulocyte layer by this technique, indicating a selective loss of these cells by the conventional technique. 相似文献
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