Hypothesis: A nicotine-dopamine interaction linking smoking with Parkinson's disease and tardive dyskinesia

1. Nicotine, an important pharmacological component of cigarette smoke, is known to have significant effects on central nervous system (CNS) dopaminergic function. Although acute doses of nicotine have been shown to facilitate dopamine release, recent data indicate that chronic nicotine treatment may actually decrease CNS dopamine turnover in the striatum. 2. A number of epidemiological investigations have demonstrated that individuals who are or who have been smokers are less likely to develop idiopathic Parkinson's disease (a disorder involving a deficit in nigrostriatal dopaminergic neurotransmission). In addition, there is preliminary evidence that individuals with tardive dyskinesia (a hyperkinetic movement disorder observed in some cases of chronic neuroleptic treatment and thought by some to be associated with striatal dopamine receptor supersensitivity) are more likely to be smokers. 3. A unitary hypothesis is presented, proposing that smoking in early adult life may decrease CNS catecholamine turnover, thereby protecting against free radical formation from catecholamine oxidation that in turn damages striatal neurons. These individuals are thereby "protected" from the later development of Parkinson's disease. In this hypothetical scheme, individuals who are given neuroleptics and who also are smokers may develop a greater degree of dopamine receptor supersensitivity due to combined receptor blockade by neuroleptics and a decrease in CNS dopamine turnover caused by nicotine, resulting in an increased prevalence of tardive dyskinesia in this group.     

A reevaluation of the amino acid sequence of human follitropin beta-subunit

A collaborative study from two laboratories has been undertaken to re-evaluate the human follitropin -subunit sequence (hFSH), since areas of uncertainty remain in the wake of two earlier reports. The first report was by Shome and Parlow (1974). The second, by Saxena and Rathnam (1976), proposed revisions for sequence not definitively placed in the first study, as well as some differences in other placements. We have re-examined the sequence of the hFSH with more recent methodology. This has led to revision of certain areas of the sequence and resolution of differences between the two earlier proposals. Specifically, an-Ile-Ser- is established at 21–22, Asp at 41, Arg at 44, Lys at 46, and Glu at 111. These were areas of disagreement in the earlier proposals. A definitive placement of the residues around tryptophan-27 has now been obtained by three laboratories. C-terminal heterogeneity was observed with subunits ending at residue 107, 109, or 111. N-terminal heterogeneity has been observed in all preparations examined to date. A significant population of molecules with a proteolytic nick between residues 38–39 is noted. This is very likely an artifact of the collection and processing. The preparations examined in the present studies showed no evidence of residues 112–118 proposed by Saxena and Rathnam.     

The replicative origin of the E. coli chromosome binds to cell membranes only when hemimethylated

DNA from the E. coli replicative origin binds with high affinity to outer membrane preparations. Specific binding regions are contained within a 463 bp stretch of origin DNA between positions -46 and +417 on the oriC map. This region of DNA contains an unusually high number of GATC sites, the recognition sequence for the E. coli DNA adenine methylase. We show here that oriC DNA binds to membrane only when it is hemimethylated. The E. coli chromosomal origin is hemimethylated for 8-10 min after initiation of replication, and origin DNA binds to membranes only during this time period. Based on these results, we propose a speculative model for chromosome segregation in E. coli.     

Class II genes of miniature swine

Class II genes of miniature swine have been characterized by restriction fragment length polymorphism (RFLP) analysis and by analysis of a series of clones isolated from a lymphocyte genomic library. For RFLP analysis, DNA samples from three independent major histocompatibility complex homozygous lines and three intra-MHC recombinant lines were digested with a variety of restriction enzymes and analyzed in Southern blots using human cDNA probes for DP, DQ, DR, and DZ alpha genes, and DP, DQ, DR, and DO beta genes. One, or at most two, unique fragments were detected by hybridization with each of the human probes tested. In contrast, multiple bands (five to six for most enzymes examined) were detected by each of the human probes tested, the majority of which were found to cross-react with at least three of these probes under conditions of moderate stringency. Genomic DNA from the SLA ^c haplotype was cloned into an EMBL-3 bacteriophage vector, and the corresponding genomic library was screened with each of these human cDNA probes. The class II genes thereby isolated from this library showed characteristics consistent with those anticipated from the RFLP analysis. Thus, unique genes were obtained which showed no evidence of cross-hybridization, while genes showed extensive cross-hybridization and were frequently detected in the library by more than one human gene probe. These data are consistent with early evolutionary divergence of a genes, prior to mammalian speciation, and with continuing evolution of genes, with possible shared usage of these genes by different a loci. The data also imply that genes can readily be assigned to loci homologous to their human counterparts, but that genes will require further mapping and/or sequence analysis to confirm assignments.     

The effect of food consumption on sodium and water balance in the predaceous diving beetle,Dytiscus verticalis

Summary Sodium and water balance ofDytiscus verticalis in fresh water were investigated under three feeding regimes: unfed, and fed a diet either low or high in sodium chloride. Unfed sodium influx was 0.13 and sodium efflux was 0.74 moles/100 gwm·h. These values are low in comparison with most freshwater animals. The electrical potential difference across the integument in artificial soft water (ASW) was about 150 mV smaller than the potential necessary to maintain sodium balance in the absence of active transport. However, sodium influx did not show saturation kinetics over an external concentration range of 91 to 1725 M. Unfed beetles failed to arrest net sodium loss to baths that were initially distilled water or ASW, even when bath sodium concentrations reached 75–298 M. The long-term rate of net sodium loss ranged from 0.61 to 4.4 moles/100 gwm·h for four sets of animals. Beetles decreased sodium efflux during a period of fasting. During subsequent feeding, beetles fed a high sodium diet (HSD) increased sodium efflux while beetles fed a low sodium diet (LSD) maintained low rates of sodium efflux. HSD fed beetles increased body sodium and hemolymph sodium concentration, and expanded extracellular fluid, relative to LSD fed beetles. Thus beetles cannot achieve sodium balance in fresh water without dietary sodium input, although they are able to regulate sodium loss.Abbreviations gwm grams wet mass - ASW artificial soft water - DW distilled water - HSD high sodium diet - LSD low sodium diet - ECF extracellular fluid volume     

Behavioral,physiological, and morphological components of dominance and mate attraction in male green iguanas

This study investigated the morphological, physiological, and behavioral components of social dominance important for mate attraction in male green iguanas (Iguana iguana). A group of 9 male and 11 female adult green iguanas was studied in a large semi-natural enclosure during one reproductive season (October–January). Four of the nine males never initiated aggressive encounters; the other five were observed to display aggressively toward each other and were ranked in a linear dominance hierarchy. Head size was the most important factor influencing fighting success. Head size and display frequency were positively correlated with plasma testosterone levels. Dominance rank directly influenced ability to monopolize areas containing resources used by females. The quality of a male's home range, measured as his access to a large basking rock in the enclosure, was related to the proportion of potential mates found within his home range. One male greatly surpassed the others in his ability to defend a home range of high quality and attract potential mates. These data suggest that physiological and morphological factors, through their influence on social behavior, may ultimately affect male reproductive fitness. © 1992 Wiley-Liss, Inc.     

The malmö polymorphism of coagulation factor IX, an immunologic polymorphism due to dimorphism of residue 148 that is in linkage disequilibrium with two other F.IX polymorphisms

A mouse monoclonal antibody (MAB 9.9) to coagulation factor IX (F.IX) detects a polymorphism in the plasma of normal people. Its epitope has been narrowed down to <6 amino acids in the activation peptide of the X-linked F.IX protein. The activation peptide contains a dimorphism—Thr:Ala—at position 148 of the protein. Using synthetic oligonucleotides, we have demonstrated that (1) the F.IX which reacts with 9.9 has Thr at position 148 and (2) that which does not has Ala. Positive reactors (148^thr) are designated Malmö A, and negative reactors (148^ala) are designated Malmö B. The plasma levels of AA women are indistinguishable from those of A men, and both B men and BB women are null against MAB 9.9. The plasma level of Malmö A in AB women is approximately half that of AA women, and “lyonization” is clearly operating in the heterozygotes. The dimorphism is in strong linkage disequilibrium with two other intragenic RFLPs, TaqI and XmnI. Furthermore, intragenic crossing-over—including double crossing-over—appears to have occurred between the three sites. Seven of the eight possible haplotypes have been identified, five in men and two others in women. The immunoassay that identifies ～50% of the AB women in the pool of Malmö A females with 95% confidence identifies men unambiguously as A or B. The assay would be very useful for population-genetic studies of the Malmö epitope if the studies were limited to men.     

Localization of phosphorylation sites with respect to the functional domains of the mouse L cell glucocorticoid receptor

Digestion of the rat liver glucocorticoid receptor with chymotrypsin results in the generation of a 42-kDa fragment which contains the steroid-binding and DNA-binding domains and the antigenic site for the BuGR anti-glucocorticoid receptor monoclonal antibody, while digestion with trypsin generates a 15-kDa receptor fragment containing only the DNA-binding function and the BuGR epitope (Eisen, L.P., Reichman, M.E., Thompson, E.B., Gametchu, B., Harrison, R. W., and Eisen, H.J. (1985) J. Biol. Chem. 260, 11805-11810). In this paper, glucocorticoid receptor of mouse L cells that were grown in the presence of [32P]orthophosphate was digested with trypsin or chymotrypsin (either before or after immune purification with BuGR antibody) and analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, autoradiography, and Western blotting. The receptor is endogenously phosphorylated only on serine residues. Chymotrypsin digestion results in a 32P-labeled 42-kDa receptor fragment which contains steroid-binding, DNA-binding, and BuGR-reactive sites. Trypsin digestion generates a 27-kDa steroid-bound fragment (meroreceptor) which is not labeled with 32P and a 32P-labeled 15-kDa fragment which contains both the DNA-binding domain and the BuGR epitope. We have calculated that there are 4 times as many phosphate residues in the intact receptor than in the 42-kDa chymotrypsin fragment. From examination of 32P-labeled receptor fragments, we have deduced that one phosphate is located between amino acids 398 and 447, a region containing the BuGR epitope and about one-third of the DNA-binding domain, and the remaining three phosphates appear to be clustered just to the amino-terminal side of the BuGR epitope in a region defined by amino acids 313 to 369. Treatment of intact 32P-labeled receptor in cytosol with alkaline phosphatase removes these three phosphates, but it does not remove the phosphate from the DNA-binding-BuGR-reactive fragment and it does not affect the ability of the transformed receptor to bind to DNA-cellulose.     

Mechanism of inhibition of RTEM-2 beta-lactamase by cephamycins: relative importance of the 7 alpha-methoxy group and the 3' leaving group

Cefoxitin is a poor substrate of many beta-lactamases, including the RTEM-2 enzyme. Fisher and co-workers [Fisher, J., Belasco, J. G., Khosla, S., & Knowles, J. R. (1980) Biochemistry 19, 2895-2901] showed that the reaction between cefoxitin and RTEM-2 beta-lactamase yielded a moderately stable acyl-enzyme whose hydrolysis was rate-determining to turnover at saturation. The present work shows first that the covalently bound substrate in this acyl-enzyme has a 5-exo-methylene-1,3-thiazine structure, i.e., that the good (carbamoyloxy) 3' leaving group of cefoxitin has been eliminated in formation of the acyl-enzyme. Such an elimination has recently been shown in another case to yield an acyl-beta-lactamase inert to hydrolysis [Faraci, W. S., & Pratt, R. F. (1985) Biochemistry 24, 903-910]. Thus the cefoxitin molecule has two potential sources of beta-lactamase resistance, the 7 alpha-methoxy group and the good 3' leaving group. That the latter is important in the present example is shown by the fact that with analogous substrates where no elimination occurs at the enzyme active site, such as 3'-de(carbamoyloxy)cefoxitin and 3'-decarbamoylcefoxitin, no inert acyl-enzyme accumulates. An analysis of the relevant rate constants shows that the 7 alpha-methoxy group weakens noncovalent binding and slows down both acylation and deacylation rates, but with major effect in the acylation rate, while elimination of the 3' leaving group affects deacylation only.(ABSTRACT TRUNCATED AT 250 WORDS)     

Maternal influence on activity rhythms and reproductive development in Djungarian hamster pups

Photoperiodism and entrainment of the circadian rhythm of locomotor activity were investigated in juvenile Djungarian hamsters. Animals were housed in simulated burrows. Activity was measured as the animal's emergence from a dark nest chamber into an outer box exposed to the room illumination. This burrow emergence activity exhibited marked circadian rhythmicity. Interactions between mother hamsters and their offspring were examined in the simulated burrow system. Male reproductive responses were determined by measuring testicular weights at the time of weaning. It was shown that photoperiodic information received between Days 1 and 15 of life failed to alter the rate of testicular development, but that after Day 15 testicular growth was photoperiod-dependent. The mother, when entrained to a long photoperiod, did not influence the photoperiodic responses of her pups when they were confined to a dark nest box. In contrast, the mother did influence the circadian entrainment patterns of her pups. Pups exhibited a well-developed circadian activity rhythm at weaning with a phase angle roughly similar to that of the mother's activity rhythm. When the maternal rhythms were discrepant with photoperiod information received by the pups directly from the environment, the pups' activity rhythms were synchronized with the light/dark cycle rather than with the rhythm of their mother. Thus, it appears that although pups may first become entrained by maternal cues, they rapidly adjust to the environmental light cycle after leaving the nest.