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101.
Carolyn Fischer-Bovenkerk Phillip E. Kish Tetsufumi Ueda 《Journal of neurochemistry》1988,51(4):1054-1059
The ATP-dependent glutamate uptake system in synaptic vesicles prepared from mouse cerebellum was characterized, and the levels of glutamate uptake were investigated in the cerebellar mutant mice, staggerer and weaver, whose main defect is the loss of cerebellar granule cells, and the nervous mutant, whose main defect is the loss of Purkinje cells. The ATP-dependent glutamate uptake is stimulated by low concentrations of chloride, is insensitive to aspartate, and is inhibited by agents known to dissipate the electrochemical proton gradient. These properties are similar to those of the glutamate uptake system observed in the highly purified synaptic vesicles prepared from bovine cortex. The ATP-dependent glutamate uptake system is reduced by 68% in the staggerer and 57-67% in the weaver mutant; these reductions parallel the substantial loss of granule cells in those mutants. In contrast, the cerebellar levels of glutamate uptake are not altered significantly in the nervous mutant, which has lost Purkinje cells, but not granule cells. In view of evidence that granule cells are glutamatergic neurons and Purkinje cells are GABAergic neurons, these observations support the notion that the ATP-dependent glutamate uptake system is present in synaptic vesicles of glutamatergic neurons. 相似文献
102.
L. Bettendorff F. Mastrogiacomo P. Wins S. J. Kish T. Grisar †M. J. Ball 《Journal of neurochemistry》1997,69(5):2005-2010
Abstract: We compared the thiamine and thiamine phosphate contents in the frontal, temporal, parietal, and occipital cortex of six patients with frontal lobe degeneration of the non-Alzheimer's type (FNAD) or frontotemporal dementia with five age-, postmortem delay-, and agonal status-matched control subjects. Our results reveal a 40–50% decrease in thiamine diphosphate (TDP) in the cortex of FNAD patients, whereas thiamine monophosphate was increased 49–119%. TDP synthesizing and hydrolyzing enzymes were unaffected. The activity of citrate synthase, a mitochondrial marker enzyme, was decreased in the frontal cortex of patients with FNAD, but no correlation with TDP content was found. These results suggest that decreased contents of TDP, which is essentially mitochondrial, is a specific feature of FNAD. As TDP is an essential cofactor for oxidative metabolism and neurotransmitter synthesis, and because low thiamine status (compared with other species) is a constant feature in humans, a nearly 50% decrease in cortical TDP content may contribute significantly to the clinical symptoms observed in FNAD. This study also provides a basis for a trial of thiamine, to improve the cognitive status of the patients. 相似文献
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106.
Although the cerebral cortical dopamine D(1) receptor is considered to play a role in normal and abnormal brain function, little information is available on its characteristics in human brain. We compared dopamine-stimulated adenylyl cyclase (AC) activity in homogenates of cerebral cortex (frontal, temporal, parietal, occipital and cingulate cortex) of autopsied brain of neurologically normal subjects to that in striatum. Cerebral cortical AC activity was modestly and dose-dependently stimulated by dopamine (maximal 20-30%) with low microM EC50s and such stimulation was inhibited by the selective dopamine D1 receptor antagonist SCH23390. The magnitude of the maximal stimulation by dopamine was similar in autopsied and biopsied cerebral cortex. The extent of maximal stimulation was similar to that in dopamine-rich striatum (caudate, putamen and nucleus accumbens), despite much lower density of dopamine D1 receptors in cerebral cortex vs. striatum. The EC50 for dopamine stimulation in cerebral cortex (approximately 1 microM) was lower than that for caudate and putamen (approximately 3 microM). No detectable dopamine stimulation was observed in cerebellar cortex, thalamus or hippocampus. Dopamine stimulation in both cerebral cortex and striatum was independent of calcium activation. We conclude that dopamine stimulated AC can be measured in cerebral cortex of human brain allowing for the possibility that this process can be examined in human brain disorders in which dopaminergic abnormalities are suspected. 相似文献
107.
Ribosomal protein S14 genes (RPS14) in eukaryotic species from protozoa to
primates exhibit dramatically different intron-exon structures yet share
homologous polypeptide-coding sequences. To recognize common features of
RPS14 gene architectures in closely related mammalian species and to
evaluate similarities in their noncoding DNA sequences, we isolated the
intron-containing S14 locus from Chinese hamster ovary (CHO) cell DNA by
using a PCR strategy and compared it with human RPS14. We found that rodent
and primate S14 genes are composed of identical protein-coding exons
interrupted by introns at four conserved DNA sites. However, the structures
of corresponding CHO and human RPS14 introns differ significantly.
Nonetheless, individual intron splice donor, splice acceptor, and upstream
flanking motifs have been conserved within mammalian S14 homologues as well
as within RPS14 gene fragments PCR amplified from other vertebrate genera
(birds and bony fish). Our data indicate that noncoding, intronic DNA
sequences within highly conserved, single-copy ribosomal protein genes are
useful molecular landmarks for phylogenetic analysis of closely related
vertebrate species.
相似文献
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Das J Moquin RV Dyckman AJ Li T Pitt S Zhang R Shen DR McIntyre KW Gillooly K Doweyko AM Newitt JA Sack JS Zhang H Kiefer SE Kish K McKinnon M Barrish JC Dodd JH Schieven GL Leftheris K 《Bioorganic & medicinal chemistry letters》2010,20(23):6886-6889
The synthesis and structure-activity relationships (SAR) of p38α MAP kinase inhibitors based on a 5-amino-pyrazole scaffold are described. These studies led to the identification of compound 2j as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound 2j was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNFα production. X-ray co-crystallography of a 5-amino-pyrazole analog 2f bound to unphosphorylated p38α is also disclosed. 相似文献
110.
Hynes J Wu H Pitt S Shen DR Zhang R Schieven GL Gillooly KM Shuster DJ Taylor TL Yang X McIntyre KW McKinnon M Zhang H Marathe PH Doweyko AM Kish K Kiefer SE Sack JS Newitt JA Barrish JC Dodd J Leftheris K 《Bioorganic & medicinal chemistry letters》2008,18(6):1762-1767
A novel structural class of p38alpha MAP kinase inhibitors has been identified via iterative SAR studies of a focused deck screen hit. Optimization of the lead series generated 6e, BMS-640994, a potent and selective p38alpha inhibitor that is orally efficacious in rodent models of acute and chronic inflammation. 相似文献