A Glycine Site Associated with N-Methyl-d-Aspartic Acid Receptors: Characterization and Identification of a New Class of Antagonists

Membranes from rat telencephalon contain a single class of strychnine-insensitive glycine sites. That these sites are associated with N-methyl-D-aspartic acid (NMDA) receptors is indicated by the observations that [3H]glycine binding is selectively modulated by NMDA receptor ligands and, conversely, that several amino acids interacting with the glycine sites increase [3H]N-[1-(2-thienyl)cyclohexyl]piperidine ([3H]TCP) binding to the phencyclidine site of the NMDA receptor. The endogenous compound kynurenate and several related quinoline and quinoxaline derivatives inhibit glycine binding with affinities that are much higher than their affinities for glutamate binding sites. In contrast to glycine, kynurenate-type compounds inhibit [3H]TCP binding and thus are suggested to form a novel class of antagonists of the NMDA receptor acting through the glycine site. These results suggest the existence of a dual and opposite modulation of NMDA receptors by endogenous ligands.     

Comparison of X-ray crystal structure of the 30S subunit-antibiotic complex with NMR structure of decoding site oligonucleotide-paromomycin complex

Aminoglycoside antibiotics that bind to 16S ribosomal RNA in the aminoacyl-tRNA site (A site) cause misreading of the genetic code and inhibit translocation. Structures of an A site RNA oligonucleotide free in solution and bound to the aminoglycosides paromomycin or gentamicin C1a have been determined by NMR. Recently, the X-ray crystal structure of the entire 30S subunit has been determined, free and bound to paromomycin. Distinct differences were observed in the crystal structure, particularly at A1493. Here, the NMR structure of the oligonucleotide-paromomycin complex was determined with higher precision and is compared with the X-ray crystal structure of the 30S subunit complex. The comparison shows the validity of both structures in identifying critical interactions that affect ribosome function.     

Acetylene reduction and hydrogen metabolism by a cyanobacterial/sulfate‐reducing bacterial mat ecosystem

We report a study of nitrogenase activity (acetylene reduction) and hydrogen gas metabolism in intact smooth cyanobacterial mats from Hamelin Pool, Shark Bay, Western Australia. The predominant cyanobacterial population in these mats is Microcoleus chthonoplastes. The mats had a significant capacity for nitrogen fixation, predominantly attributable to the photosyn‐thetic component. By physical and chemical perturbation we revealed an active hydrogen metabolism within the mats. Most of the H₂ formation was attributed to fermentative processes, whereas hydrogen was consumed in light‐dependent, together with oxygen‐ and sulfate‐dependent respiratory processes. It was concluded that H₂ formed by fermentative bacteria in the dark drives a significant proportion of sulfate reduction in the mats, but there was little H₂ transfer from the cyanobacteria to the sulfate‐reducing bacteria. Thus photosynthetically produced H₂ gas is unlikely to significantly alter the previously measured carbon: sulfur ratio relating photosynthesis to sulfate reduction.     

Acceleration of cheese ripening

The characteristic aroma, flavour and texture of cheese develop during ripening of the cheese curd through the action of numerous enzymes derived from the cheese milk, the coagulant, starter and non-starter bacteria. Ripening is a slow and consequently an expensive process that is not fully predictable or controllable. Consequently, there are economic and possibly technological incentives to accelerate ripening. The principal methods by which this may be achieved are: an elevated ripening temperature, modified starters, exogenous enzymes and cheese slurries. The advantages, limitations, technical feasibility and commercial potential of these methods are discussed and compared.     

Change of Genetic Architecture in Response to Sex

A traditional view is that sexual reproduction increases the potential for phenotypic evolution by expanding the range of genetic variation upon which natural selection can act. However, when nonadditive genetic effects and genetic disequilibria underlie a genetic system, genetic slippage (a change in the mean genotypic value contrary to that promoted by selection) in response to sex may occur. Additionally, depending on whether natural selection is predominantly stabilizing or disruptive, recombination may either enhance or reduce the level of expressed genetic variance. Thus, the role of sexual reproduction in the dynamics of phenotypic evolution depends heavily upon the nature of natural selection and the genetic system of the study population. In the present study, on a permanent lake Daphnia pulicaria population, sexual reproduction resulted in significant genetic slippage and a significant increase in expressed genetic variance for several traits. These observations provide evidence for substantial genetic disequilibria and nonadditive genetic effects underlying the genetic system of the study population. From these results, the fitness function of the previous clonal selection phase is inferred to be directional and/or stabilizing. The data are also used to infer the effects of natural selection on the mean and the genetic variance of the population.     

Multicolor in situ hybridization and linkage analysis order Charcot-Marie-Tooth type I (CMTIA) gene-region markers.

This study demonstrates a clear and current role for multicolor in situ hybridization in expediting positional cloning studies of unknown disease genes. Nine polymorphic DNA cosmids have been mapped to eight ordered locations spanning the Charcot-Marie-Tooth type 1 (CMT1A) disease gene region in distal band 17p11.2, by multicolor in situ hybridization. When used with linkage analysis, these methods have generated a fine physical map and have firmly assigned the CMT1A gene to distal band 17p11.2. Linkage analysis with four CMT1A pedigrees mapped the CMT1A gene with respect to two flanking markers (8B10-5 cM[LOD 5.2]-CMT1A-3.5 cM[LOD 5.3]-10E4). Additional loci were physically mapped and ordered by in situ hybridization and analysis of phase-known recombinants in CMT1A pedigrees. The order determined by multicolor in situ hybridization was 17cen-LEW301-8B10-5H5/6A9-VAW409- 5G7-6G1-4A11-VAW412-10E4-pter. Two ordered probes, 4A11 and 6G1, reside on the same 440-kb partial SfiI restriction fragment. These data demonstrate the ability of in situ hybridization to resolve loci within 0.5 Mb on early-metaphase chromosomes. Multicolor in situ hybridization also excluded the possibility of pericentric inversions in two unrelated patients with CMT1 and neurofibromatosis type 1. When used with pulsed-field gel electrophoresis, multicolor in situ hybridization can establish physical location, order, and distance in closely spaced chromosome loci.     

Differential Survival for Men and Women with HIV/AIDS-Related Neurologic Diagnoses

Objectives

Neurologic complications of human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS) frequently lead to disability or death in affected patients. The aim of this study was to determine whether survival patterns differ between men and women with HIV/AIDS-related neurologic disease (neuro-AIDS).

Methods

Retrospective cohort data from a statewide surveillance database for HIV/AIDS were used to characterize survival following an HIV/AIDS-related neurologic diagnosis for men and women with one or more of the following conditions: cryptococcosis, toxoplasmosis, primary central nervous system lymphoma, progressive multifocal leukoencephalopathy, and HIV-associated dementia. A second, non-independent cohort was formed using university-based cases to confirm and extend the findings from the statewide data. Kaplan-Meier analysis was used to compare the survival experiences for men and women in the cohorts. Cox regression was employed to characterize survival while controlling for potential confounders in the study population.

Results

Women (n=27) had significantly poorer outcomes than men (n=198) in the statewide cohort (adjusted hazard ratio=2.31, 95% CI: 1.22 to 4.35), and a similar, non-significant trend was observed among university-based cases (n=17 women, 154 men). Secondary analyses suggested that this difference persisted over the course of the AIDS epidemic and was not attributable to differential antiretroviral therapy responses among men and women.

Conclusions

The survival disadvantage of women compared to men should be confirmed and the mechanisms underlying this disparity elucidated. If this relationship is confirmed, targeted clinical and public health efforts might be directed towards screening, treatment, and support for women affected by neuro-AIDS.