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Annemarie MM Vlaar Angela EP Bouwmans Marinus JPG van Kroonenburgh Werner H Mess Selma C Tromp Piet GWM Wuisman Alfons GH Kessels Ania Winogrodzka Wim EJ Weber 《BMC neurology》2007,7(1):28
Background
Parkinson's disease (PD) is the second most common neurodegenerative disorder. As there is no definitive diagnostic test, its diagnosis is based on clinical criteria. Recently transcranial duplex scanning (TCD) of the substantia nigra in the brainstem has been proposed as an instrument to diagnose PD. We and others have found that TCD scanning of substantia nigra duplex is a relatively accurate diagnostic instrument in patients with parkinsonian symptoms. However, all studies on TCD so far have involved well-defined, later-stage PD patients, which will obviously lead to an overestimate of the diagnostic accuracy of TCD. 相似文献4.
We compared levels of sequence divergence between fourfold synonymous coding sites and noncoding sites from the intergenic and intronic regions of the Plasmodium falciparum and Plasmodium reichenowi genomes. We observed significant differences in the level of divergence between these classes of silent sites. Fourfold synonymous coding sites exhibited the highest level of sequence divergence, followed by introns, and then intergenic sequences. This pattern of relative divergence rates has been observed in primate genomes but was unexpected in Plasmodium due to a paucity of variation at silent sites in P. falciparum and the corollary hypothesis that silent sites in this genome may be subject to atypical selective constraints. Exclusion of hypermutable CpG dinucleotides reduces the divergence level of synonymous coding sites to that of intergenic sites but does not diminish the significantly higher divergence level of introns relative to intergenic sites. A greater than expected incidence of CpG dinucleotides in intergenic regions less than 500 bp from genes may indicate selective maintenance of regulatory motifs containing CpGs. Divergence rates of different classes of silent sites in these Plasmodium genomes are determined by a combination of mutational and selective pressures. 相似文献
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Storch A Hwang YI Gearhart DA Beach JW Neafsey EJ Collins MA Schwarz J 《Journal of neurochemistry》2004,89(3):685-694
Endogenous or exogenous beta-carboline (betaC) derivatives structurally related to the selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite 1-methyl-4-phenylpyridinium (MPP(+)) may contribute to dopaminergic neurodegeneration in Parkinson's disease (PD). We addressed the importance of the dopamine transporter (DAT) for selective dopaminergic toxicity by testing the differential cytotoxicity and cellular uptake of 12 betaCs in human embryonic kidney HEK-293 cells ectopically expressing the DAT gene. Cell death was measured using [4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and trypan blue exclusion assays, and uptake by a fluorescence-based uptake assay. All betaCs and MPP(+) showed general cytotoxicity in parental HEK-293 cells after 72 h with half-maximal toxic concentrations (TC(50) values) in the upper micromolar range. Besides MPP(+), only 2[N]-methylated compounds showed enhanced cytotoxicity in DAT expressing HEK-293 cells with 1.3- to 4.5-fold reduction of TC(50) values compared with parental cell line. The rank order of selectivity was: MPP(+) > 2[N],9[N]-dimethyl-harminium > 2[N]-methyl-harminium > 2[N],9[N]-dimethyl-harmanium = 2[N]-methyl-norharmanium > 2[N]-methyl-harmanium > 2[N],9[N]-dimethyl-norharminium. Consistently, only 2[N]-methylated betaCs were transported into the cell through the DAT with up to five times greater K(m) and 12-220 times smaller V(max) values compared with dopamine and MPP(+). There was a weak relation of DAT-mediated selectivity with the affinity of betaCs at the DAT (K(m)), but not with V(max). Our data suggest that DAT-mediated cellular uptake of 2[N]-methylated betaCs represents a potential mechanism for selective toxicity towards dopaminergic neurons and may be relevant for the pathogenesis of Parkinson's disease. 相似文献
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Daniel E. Neafsey 《Molecular ecology》2013,22(2):271-272
Falling costs for genome sequencing and genotyping mean that population genomic data sets are becoming commonplace for a wide variety of species. Once these data are used for the initial tasks of investigating population structure and demographic history, however, is there reason to go back for more? In this issue of Molecular Ecology, Nkhoma et al. (2013) explore the applications of longitudinal genomic diversity data for detecting changes in the prevalence and transmission of the Plasmodium falciparum malaria parasite in South‐East Asia. While this study finds several genetic signatures indicative of reduced disease transmission, other measures, such as short‐term effective population size, geographical population structure and heterozygosity, were not informative. These results indicate the potential contribution of genomic data to the surveillance of small, dynamic populations, whether they are at risk of extinction or targeted for elimination. The interpretation of such data will require close consideration of biological context, however, at both the species and the population level. 相似文献
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The activity of -carboline-2-N-methyltransferase results in the formation of neurotoxic N-methylated -carbolinium compounds. We have hypothesized that these N-methylated -carbolinium cations may contribute to the development of idiopathic Parkinson's disease. This report describes experiments undertaken to optimize assay conditions for bovine brain -carboline-2-N-methyltransferase activity. The activity of -carboline-2-N-methyltransferase is primarily localized in the cytosol, has a pH optimum of 8.5–9, and obeys Michaelis-Menten kinetics with respect to its substrates, 9-methylnorharman (9-MeNH) and S-adenosyl-L-methionine (SAM). Kinetic constants, KM and Vmax, with respect to 9-MeNH, are 75 M and 48 pmol/h/mg protein, respectively. The KM for SAM is 81 M and the Vmax is 53 pmol/h/mg protein. In addition, enzyme activity is inhibited by S-adenosyl-L-homocysteine (SAH) or zinc, and is increased 2-fold in the presence of iron or manganese. Enzyme characterization is a prerequisite to the purification of this N-methyltransferase from bovine brain as well as comparison of its activity in human brain from control and Parkinson's disease individuals. 相似文献
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Using rat organotypic hippocampal-entorhinal cortical (HEC) slice cultures, we examined whether phospholipase A2 (PLA2) activity
is involved in binge alcohol (ethanol)-induced neurodegeneration, and whether docosahexaenoic acid (DHA; 22:6n-3), a fish
oil-enriched fatty acid that is anti-inflammatory in brain damage models, is neuroprotective. Assessed with propidium iodide
and lactate dehydrogenase (LDH) leakage, neurodamage from ethanol (6 days 100 mM ethanol with four withdrawal periods) was
prevented by the PLA2 pan-inhibitor, mepacrine. Also, ethanol-dependent neurodegeneration—particularly in the entorhinal region—was
significantly ameliorated by DHA supplementation (25 μM); however, adrenic acid, a 22:4n-6 analog, was ineffective. Consistent
with PLA2 activation, [3H] liberation was approximately fivefold greater in [3H]arachidonic acid-preloaded HEC slice cultures during ethanol withdrawal compared to controls, and DHA supplementation suppressed
[3H] release to control levels. DHA might antagonize PLA2 activity directly or suppress upstream activators (e.g., oxidative
stress); however, other DHA mechanisms could be important in subdueing ethanol-induced PLA2-dependent and independent neuroinflammatory
processes. 相似文献