Proceedings of the National Academy of Sciences of the United States of America
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Proc. Natl. Acad. Sci. U.S.A. · Mar 1987
Protracted treatment with diazepam increases the turnover of putative endogenous ligands for the benzodiazepine/beta-carboline recognition site.
DBI (diazepam-binding inhibitor) is a putative neuromodulatory peptide isolated from rat brain that acts on gamma-aminobutyric acid-benzodiazepine-Cl- ionophore receptor complex inducing beta-carboline-like effects. We used a cDNA probe complementary to DBI mRNA and a specific antibody for rat DBI to study in rat brain how the dynamic state of DBI can be affected after protracted (three times a day for 10 days) treatment with diazepam and chlordiazepoxide by oral gavage. Both the content of DBI and DBI mRNA increased in the cerebellum and cerebral cortex but failed to change in the hippocampus and striatum of rats receiving this protracted benzodiazepine treatment. ⋯ An antibody was raised against a biologically active octadecaneuropeptide (Gln-Ala-Thr-Val-Gly-Asp-Val-Asn-Thr-Asp-Arg-Pro-Gly-Leu-Leu-Asp-Leu-Lys ) derived from the tryptic digestion of DBI. The combined HPLC/RIA analysis of rat cerebellar extracts carried out with this antibody showed that multiple molecular forms of the octadecaneuropeptide-like reactivity are present and all of them are increased in rats receiving repeated daily injections of diazepam. It is inferred that tolerance to benzodiazepines is associated with an increase in the turnover rate of DBI, which may be responsible for the gamma-aminobutyric acid receptor desensitization that occurs after protracted benzodiazepine administration.
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Proc. Natl. Acad. Sci. U.S.A. · May 1986
High-affinity antibodies to the 1,4-dihydropyridine Ca2+-channel blockers.
Antibodies with high affinity and specificity for the 1,4-dihydropyridine Ca2+-channel blockers have been produced in rabbits by immunization with dihydropyridine-protein conjugates. Anti-dihydropyridine antibodies were found to specifically bind [3H]nitrendipine, [3H]-nimodipine, [3H]nisoldipine, and [3H]PN 200-110 (all 1,4-dihydropyridine Ca2+-channel blockers) with high affinity, while [3H]verapamil, [3H]diltiazem, and [3H]trifluoperazine were not recognized. The average dissociation constant of the [3H]nitrendipine-antibody complex was 0.06 (+/- 0.02) X 10(-9) M for an antiserum studied in detail and ranged from 0.01 to 0.24 X 10(-9) M for all antisera. ⋯ Structurally unrelated Ca2+-channel blockers, calmodulin antagonists, inactive metabolites of nitrendipine, and UV-inactivated nisoldipine did not modify [3H]nitrendipine binding to the anti-dihydropyridine antibodies. Dihydropyridines without a bulky substituent in the 4-position of the heterocycle were able to displace [3H]nitrendipine binding, but the concentrations required for half-maximal inhibition were greater than 800 nM. In summary, anti-dihydropyridine antibodies have been shown to have high affinity and specificity for the 1,4-dihydropyridine Ca2+-channel blockers and to exhibit dihydropyridine binding properties similar to the membrane receptor for the 1,4-dihydropyridine Ca2+-channel blockers.
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Proc. Natl. Acad. Sci. U.S.A. · Feb 1985
Comparative StudyInfluence of solvent accessibility and intermolecular contacts on atomic mobilities in hemerythrins.
Thermal factor parameters (B values) have been compared from the refined crystal structures of the myohemerythrin from Themiste zostericola and of the octameric hemerythrin from Themiste dyscrita. These B values, which are directly related to atomic mobilities, were found to correlate rather closely with the solvent accessible areas within the respective crystals. ⋯ The differences correspond to lattice and oligomer contacts. An adjustment of the B values based on the fraction of accessible area occluded by contacts yields values that correlate well between the independent subunits and that should pertain more closely to those for the protomer free in solution.
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Proc. Natl. Acad. Sci. U.S.A. · Jul 1983
A quantitative genetic model of reciprocal altruism: a condition for kin or group selection to prevail.
A condition is derived for reciprocal altruism to evolve by kin or group selection. It is assumed that many additively acting genes of small effect and the environment determine the probability that an individual is a reciprocal altruist, as opposed to being unconditionally selfish. The particular form of reciprocal altruism considered is TIT FOR TAT, a strategy that involves being altruistic on the first encounter with another individual and doing whatever the other did on the previous encounter in subsequent encounters with the same individual. ⋯ Here, C, Vb, and Tb are the population mean, between-group variance, and between-group third central moment of the trait value and r is the correlation between the additive genotypic values of interacting kin or of individuals within the same breeding group. The right-hand side of the above inequality is monotone decreasing in C if we hold Tb/Vb constant, and kin and group selection become superfluous beyond a certain threshold value of C. The effect of finite group size is also considered in a kin-selection model.
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Proc. Natl. Acad. Sci. U.S.A. · Jun 1983
Topographical arrangement of basement membrane proteins in lactating rat mammary gland: comparison of the distribution of type IV collagen, laminin, fibronectin, and Thy-1 at the ultrastructural level.
The topographical distribution of type IV collagen, laminin, fibronectin, and the thymocyte differentiation antigen Thy-1 in the basement membrane of the lactating rat mammary gland was investigated. Small cubes of tissue, which had not been subjected to prior fixation or freezing, were incubated with monospecific or monoclonal antibodies to these proteins, and the antibodies were located by an indirect immunoperoxidase staining technique and observed in the electron microscope. The lamina densa stained uniformly with antibodies to type IV collagen and laminin. ⋯ These maxima occurred in regions adjacent to Thy-1-bearing stromal cells. Thus, the topographical distribution of proteins within a basement membrane varies in a nonrandom manner, and local factors can modify this distribution. We suggest that this topographical variability may play a role in cell recognition and signalling processes that occur across the basement membrane.