Modulation of amyloid-beta-induced and age-associated changes in rat hippocampus by eicosapentaenoic acid

The age-related deficit in long-term potentiation (LTP) in the dentate gyrus is positively correlated with hippocampal concentration of the pro-inflammatory cytokine, interleukin-1beta (IL-1beta). Previous evidence also indicates that the inhibition of LTP induced by intracerebroventricular injection of amyloid-beta(1-40) (Abeta) is accompanied by increased hippocampal IL-1beta concentration and IL-1beta-stimulated signalling, specifically activation of the stress-activated protein kinase, c-jun N-terminal kinase (JNK). We considered that the underlying age-related neuroinflammation may render older rats more susceptible to Abeta administration and, to investigate this, young, middle-aged and aged rats were injected intracerebroventricularly with Abeta or vehicle. Hippocampal IL-1beta concentration, JNK phosphorylation, expression of the putative Abeta receptor, Receptor for advanced glycation end products (RAGE) and the microglial cell surface marker, CD40 were assessed. We report that Abeta inhibited LTP in a concentration-dependent manner in young rats and that this was accompanied by concentration-dependent increases in hippocampal IL-1beta and expression of phosphorylated JNK, RAGE and CD40. While 20 micromol/L Abeta exerted no significant effect on LTP in young rats, it inhibited LTP in middle-aged and aged rats and the increased vulnerability of aged rats was associated with increased IL-1beta concentration. Treatment of rats with eicosapentaenoic acid attenuated the inhibitory effect of 60 micromol/L Abeta on LTP in young rats and the effect of 20 micromol/L Abeta in middle-aged and aged rats. We present evidence which indicates that the effect of eicosapentaenoic acid may be linked with its ability to stimulate activation of peroxisome proliferator-activated receptor gamma.     

Glutamate Oxidation by Soybean Cotyledon and Leaf Mitochondria

Mitochondria purified from cotyledons of soybean seedlings fiveto ten days old have the capacity to rapidly oxidize glutamate(measured as glutamate dependent oxygen consumption). This capacitywas greatest at ten days after planting but was very low priorto emergence of cotyledons from the vermiculite and during senescence.Solubilized glutamate dehydrogenase activity, on the other hand,was substantial at two days after planting, peaked at sevendays, then declined and rose again during senescence. It issuggested that mitochondrial glutamate oxidation plays a rolein reserve mobilization and amino acid metabolism during seedlinggrowth. Leaf mitochondria and those from senescing cotyledonscould not sustain rapid rates of glutamate oxidation despiteready oxidation of other substrates and high solubilized glutamatedehydrogenase activity, suggesting an alternative role for theenzyme in these tissues. Possible controlling factors are discussed. ² Present address, Garvan Institute, Darlinghurst, N. S. W.,Australia. ³ Permanent address, Department de Biologia Vegetal, Facultatde Biologia, Universitat de Barcelona, Barcelona, Spain. (Received May 6, 1988; Accepted August 3, 1988)     

Inverted neurons in agyria

Summary An anatomoclinical observation of agyria is reported. The karyotype revealed a partial deletion of the short arm of chromosome 17. The etiology of agyria is reviewed in the light of this chromosomal abnormality. In addition we describe the peculiar pattern of neurons in the cortex: Golgi stain demonstrated many inverted pyramidal cells in the superficial part of the cortical layer. The mechanism of this abnormality is discussed.     

Mucosal Immunization of Lactating Female Rhesus Monkeys with a Transmitted/Founder HIV-1 Envelope Induces Strong Env-Specific IgA Antibody Responses in Breast Milk

We previously demonstrated that vaccination of lactating rhesus monkeys with a DNA prime/vector boost strategy induces strong T-cell responses but limited envelope (Env)-specific humoral responses in breast milk. To improve vaccine-elicited antibody responses in milk, hormone-induced lactating rhesus monkeys were vaccinated with a transmitted/founder (T/F) HIV Env immunogen in a prime-boost strategy modeled after the moderately protective RV144 HIV vaccine. Lactating rhesus monkeys were intramuscularly primed with either recombinant DNA (n = 4) or modified vaccinia virus Ankara (MVA) poxvirus vector (n = 4) expressing the T/F HIV Env C.1086 and then boosted twice intramuscularly with C.1086 gp120 and the adjuvant MF59. The vaccines induced Env-binding IgG and IgA as well as neutralizing and antibody-dependent cellular cytotoxicity (ADCC) responses in plasma and milk of most vaccinated animals. Importantly, plasma neutralization titers against clade C HIV variants MW965 (P = 0.03) and CAP45 (P = 0.04) were significantly higher in MVA-primed than in DNA-primed animals. The superior systemic prime-boost regimen was then compared to a mucosal-boost regimen, in which animals were boosted twice intranasally with C.1086 gp120 and the TLR 7/8 agonist R848 following the same systemic prime. While the systemic and mucosal vaccine regimens elicited comparable levels of Env-binding IgG antibodies, mucosal immunization induced significantly stronger Env-binding IgA responses in milk (P = 0.03). However, the mucosal regimen was not as potent at inducing functional IgG responses. This study shows that systemic MVA prime followed by either intranasal or systemic protein boosts can elicit strong humoral responses in breast milk and may be a useful strategy to interrupt postnatal HIV-1 transmission.     

Chromosomal inversion discovered in C3H/HeJ mice

Mice of the inbred mouse strain C3H/HeJ have been shown to be homozygous for a chromosomal inversion on Chromosome (Chr) 6. The inversion encompasses about 20% of the chromosome from approximately 73 Mb to approximately 116 Mb. The importance of this finding is that linkage crosses using C3H/HeJ will show no recombination in this region of Chr 6. The inversion has no apparent effect on the phenotype of C3H/HeJ mice and its presence should not affect biological studies; however, use of C3H/HeJ mice for genetic analysis of Chr 6 should be avoided or the results interpreted with the inversion in mind. The inversion has been named In(6)1J (inversion Chr 6, Jackson 1).     

Evidence for the mechanism of the irreversible inhibition of oestrone sulphatase (ES) by aminosulphonate based compounds

In our search for the mechanism of the enzyme oestrone sulphatase (ES) we have synthesised and evaluated a number of compounds that were predicted to possess some inhibitory activity. Some of these compounds were indeed found to be inhibitors of ES, whilst other compounds were not. From a consideration of the structure–activity relationship (SAR) of the inhibitors and non-inhibitors of this enzyme, we discovered a factor which we now believe is the main inhibitory moiety within the aminosulphonated inhibitors. We therefore report the results of our study into a series of phenyl and alkyl sulphamated compounds as inhibitors of ES. The results of the study show that the substituted phenyl sulphamates are potent inhibitors, whereas the alkyl compounds are, in general, non-inhibitors. Using the results of our SAR study, we postulate the probable mechanism for the irreversible and reversible inhibition of ES, and rationalise the role of the different physicochemical factors in the inhibition of this crucial enzyme.     

GacS sensor domains pertinent to the regulation of exoproduct formation and to the biocontrol potential of Pseudomonas fluorescens CHA0

In the root-colonizing biocontrol strain CHA0 of Pseudomonas fluorescens, cell density-dependent synthesis of extracellular, plant-beneficial secondary metabolites and enzymes is positively regulated by the GacS/GacA two-component system. Mutational analysis of the GacS sensor kinase using improved single-copy vectors showed that inactivation of each of the three conserved phosphate acceptor sites caused an exoproduct null phenotype (GacS-), whereas deletion of the periplasmic loop domain had no significant effect on the expression of exoproduct genes. Strain CHA0 is known to synthesize a solvent-extractable extracellular signal that advances and enhances the expression of exoproduct genes during the transition from exponential to stationary growth phase when maximal exoproduct formation occurs. Mutational inactivation of either GacS or its cognate response regulator GacA abolished the strain's response to added signal. Deletion of the linker domain of the GacS sensor kinase caused signal-independent, strongly elevated expression of exoproduct genes at low cell densities. In contrast to the wild-type strain CHA0, the gacS linker mutant and a gacS null mutant were unable to protect tomato plants from crown and root rot caused by Fusarium oxysporum f. sp. radicis-lycopersici in a soil-less microcosm, indicating that, at least in this plant-pathogen system, there is no advantage in using a signal-independent biocontrol strain.